Side Effects of Drugs Annual 33

HONORARY EDITOR

Prof. M.N.G. Dukes, Oslo, Norway

ADVISORY EDITORIAL BOARD

Prof. F. Bochner, Adelaide, Australia

Prof. I.R. Edwards, Uppsala, Sweden
Prof. G.P. Velo, Verona, Italy
Elsevier
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 Contributors

M.C. ALLWOOD, BPHARM, PHD

Pharmacy Academic Practice Unit, School of Biological, Forensic and
Pharmaceutical Sciences, University of Derby, Mickleover, Derby, UK.
E-mail: M.C.Allwood@derby.ac.uk.

LUIS H. MARTN ARIAS, MD, PHD

Instituto de Farmacoepidemiologa, Facultad de Medicina, 47005 Valladolid, Spain.
E-mail: lmartin@ife.uva.es.

J.K. ARONSON, MA, MBCHB, DPHIL, FRCP, FBPHARMACOLS, FFPM(HON)

University of Oxford Department of Primary Health Care, 2338 Hythe Bridge Street,
Oxford OX1 2ET. E-mail: jeffrey.aronson@clinpharm.ox.ac.uk.

V.V. BANU REKHA

Tuberculosis Research Centre, Mayor VR Ramanathan Road, Chetpet, Chennai 600031,
India. E-mail: banu24@yahoo.com.

ANDREAS J. BIRCHER
Allergy Unit, Department of Dermatology, University Hospital Basel, Petersgraben 4,
4031 Basel, Switzerland. E-mail: andreas.bircher@unibas.ch.

CORRADO BLANDIZZI, MD, PHD

Division of Pharmacology & Chemotherapy, Department of Internal Medicine,
University of Pisa, Via Roma 55, 56126 Pisa, Italy. E-mail: c.blandizzi@gmail.com.

KRISTIEN BOELAERT, MD, PHD, MRCP

School of Clinical and Experimental Medicine, College of Medical and Dental Sciences,
IBR Building 2nd oor, University of Birmingham, Birmingham B15 2TT, UK.
E-mail: k.boelaert@bham.ac.uk.

ALFONSO CARVAJAL, MD, PHD,

Instituto de Farmacoepidemiologa, Facultad de Medicina, 47005 Valladolid, Spain.
E-mail: carvajal@ife.uva.es.

K. CHAN PHD, DSC, FIBIOL, FCP, FRPHARMS, FRSM

Faculty of Pharmacy, The University of Sydney and Centre for Complementary
Medicine Research, University of Western Sydney, Locked Bag 1797, Penrith South DC
NSW 2751, Australia. E-mail: JCTCM@uws.edu.au.

N.H. CHOULIS, MD, PHD

LAVIPHARM Research Laboratories, Agias Marinas Street, 19002 Peania, Attika,
Greece. E-mail: nicoly@otenet.gr.

v
vi Contributors

JAMIE J. COLEMAN, MBCHB, MA (MED ED), MD, MRCP(UK)

Department of Clinical Pharmacology, College of Medical and Dental Sciences,
University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
E-mail: j.j.coleman@bham.ac.uk.

NATASCIA CORTI, MD
University Hospital Zurich, Department of Medicine, Division of Infectious Diseases
and Hospital Epidemiology, Rmistrasse 100, CH-8091 Zrich, Switzerland.
E-mail: natascia.corti@usz.ch.

J. COSTA, MD
Clinical Pharmacology Department, Hospital Universitari Germans Trias i Pujol,
Universitat Autnoma de Barcelona, Ctra. de Canyet s/n, 08916 Badalona, Spain.
E-mail: jcosta.germanstrias@gencat.cat.

NICHOLAS J. COWLEY, MBCHB, MRCP(UK), FRCA

School of Clinical and Experimental Medicine, College of Medical and Dental Sciences,
University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
Email: n.j.cowley@bham.ac.uk.

ANTHONY R. COX, PHD

Pharmacy Practice Group, School of Pharmacy, Aston University, Birmingham, B4 7ET,
UK. Email: a.r.cox@aston.ac.uk.

STEPHEN CURRAN, BSC, MBCHB, MMEDSC, MRCPSYCH, PHD

Fieldhead Hospital, South West Yorkshire Mental Health NHS Trust, Ouchthorpe
Lane, Wakeeld, WF1 3SP, UK. E-mail: steve.curran@hud.ac.uk.

GWYNETH A. DAVIES, MD, MRCP

Senior Clinical Lecturer, Asthma & Allergy, School of Medicine, Swansea University,
Swansea, Wales, UK. E-mail: gwyneth.davies@swansea.ac.uk.

S. DITTMANN, MD, DSCMED

19 Hatzenporter Weg, 12681 Berlin, Germany.
E-mail: sd.internat.immun.consult@t-online.de.

IDA DUARTE
Santa Casa de So Paulo Medical School, So Paulo, Brazil.
E-mail: idaduarte@terra.com.br.

M.N.G. DUKES, MD, MA, LLM

Trosterudveien 19, 0778 Oslo, Norway. E-mail: mngdukes@online.no.

RIF S. EL-MALLAKH, MD
Mood Disorders Research Program, Department of Psychiatry and Behavioral Sciences,
University of Louisville School of Medicine, MedCenter One, 501 E Broadway, Suite
340, Louisville, Kentucky 40202, USA. E-mail: rselma01@louisville.edu.

M. FARR, MD
Human Pharmacology and Neurosciences, Institut de Recerca Hospital del Mar
(IMIM) Parc de Salut Mar, Universitat Autnoma de Barcelona, Doctor Aiguader 88,
08003 Barcelona, Spain. E-mail: mfarre@imim.es.
Contributors vii

A. FINZI, MD
Istituto di Ricerche Farmacologiche M. Negri,via G La Masa 19, 20156 Milan, Italy.
E-mail: andrea.nzi@marionegri.it.

M.G. FRANZOSI, PHD

Department of Cardiovascular Research, Istituto di Ricerche Farmacologiche
Mario Negri, Via Eritrea 62, 20157 Milan, Italy. E-mail: franzosi@marionegri.it.

S. GALEA, MD, MRCPSYCH, MSC (ADDICTIVE BEHAVIOUR), DIP (FORENSIC

MENTAL HEALTH)
Auckland Community Alcohol & Drugs Services, 50 Pitman House, Carrington Road,
Point Chevalier, Auckland, New Zealand, & Centre for Addiction Studies, St George's
Hospital Medical School, 6th Floor, Hunter Wing, Cranmer Terrace, London SW17
0RE, UK. E-mail: susanna.galea@waitematadhb.govt.nz.

YONGLIN GAO, MD
Mood Disorders Research Program, Department of Psychiatry and Behavioral Sciences,
University of Louisville School of Medicine, MedCenter One, 501 E Broadway,
Suite 340, Louisville, Kentucky 40202, USA. E-mail: ylgao001@gwise.louisville.edu.

A.H. GHODSE, MD, PHD, DSC, FFPH, FRCP, FRCPE, FRCPSYCH

International Centre for Drug Policy, St George's University of London, 6th Floor,
Hunter Wing, Cranmer Terrace, London SW17 0RE, UK.
E-mail: h.ghodse@sghms.ac.uk.

ANDREAS H. GROLL, MD
Infectious Disease Research Program, Center for Bone Marrow Transplantation and
Department of Hematology/Oncology, University Children's Hospital, Albert-
Schweitzer-Strasse 33, 48129 Muenster, Germany. E-mail: grollan@ukmuenster.de.

AVINASH GUPTA, MBBS, BSC, MRCP

University of Oxford, Department of Medical Oncology, Churchill Hospital, Oxford
OX3 7LJ, UK. E-mail: Avinash.Gupta@orh.nhs.uk.

ALISON HALL, BSC, MBCHB, FRCA

School of Clinical Science, University of Liverpool, The Duncan Building, Daulby
Street, Liverpool, L69 3GA, UK. E-mail: alih101@yahoo.com.

ALEXANDER IMHOF, MD
University Hospital Zurich, Department of Medicine, Division of Infectious Diseases
and Hospital Epidemiology, Rmistrasse 100, CH-8091 Zrich, Switzerland.
E-mail: alexander.imhof@sro.ch.

M.S. JAWAHAR, MD, MSC, DLSHTM

Tuberculosis Research Centre, Chennai 600031, India.
E-mail: shaheedjawahar@hotmail.com.

NATALIA JIMENO, MD, PHD

Instituto de Farmacoepidemiologa, Facultad de Medicina, 47005 Valladolid, Spain.
E-mail: najimeno@med.uva.es.
viii Contributors

CLARICE KOBATA
Santa Casa de So Paulo Medical School, So Paulo, Brazil.
E-mail: clakobata@yahoo.com.

SARAH LANGENFELD, MD
University of Massachusetts Medical School, Department of Psychiatry, 361 Plantation
Street, Worcester, MA 01605, USA. E-mail: sarah.langenfeld@umassmemorial.org.

M. LARTEY, MBCHB, MSC, FWACP

Department of Medicine & Therapeutics, University of Ghana Medical School,
PO Box 4236, Accra, Ghana. E-mail: mlartey@ug.edu.gh.

R. LATINI, MD
Department of Cardiovascular Research, Istituto di Ricerche Farmacologiche Mario
Negri, Via Eritrea 62, 20157 Milan, Italy. E-mail roberto.latini@marionegri.it.

ROSANA LAZZARINI
Santa Casa de So Paulo Medical School, So Paulo, Brazil.
E-mail: lazzarini@fototerapia.com.br.

M. LEUWER, MD
School of Clinical Science, University of Liverpool, The Duncan Building, Daulby
Street, Liverpool, L69 3GA, UK. E-mail: mleuwer@liv.ac.uk.

Z.X. LIN, BSC, PHD

School of Chinese Medicine, Faculty of Science, 1/F Sino Building, The Chinese
University of Hong Kong, Shatin NT, Hong Kong SAR, PR China. E-mail: linzx@cuhk.
edu.hk.

PAM MAGEE, BSC, MSC, MRPHARMS

Fillongley, Coventry, UK. Email: pam.magee@macace.net.

R.H.B. MEYBOOM, MD, PHD

Department of Pharmacoepidemiology and Pharmacotherapy, Faculty of Pharmacy,
Utrecht University, PO Box 80082, 3508 TB Utrecht, The Netherlands.
E-mail: r.meyboom@who-umc.org.

MARK MIDDLETON, PHD, FRCP

University of Oxford, Department of Medical Oncology, Churchill Hospital, Oxford
OX3 7LJ, UK. E-mail: mark.middleton@medonc.ox.ac.uk.

TORE MIDTVEDT, MD, PHD

Department of Microbiology, Tumor and Cell Biology (MTC), Von Eulers v. 5,
Karolinska Institutet, Box 60 400, S-171 77 Stockholm, Sweden.
E-mail: tore.midtvedt@cmb.ki.se.

PHILIP B. MITCHELL, AM, MBBS, MD, FRANZCP, FRCPSYCH

University of New South Wales School of Psychiatry, Prince of Wales Hospital,
Randwick, NSW 2031, Australia. E-mail: phil.mitchell@unsw.edu.au.
Contributors ix

SHABIR MUSA, MBCHB, MRCPSYCH

Fieldhead Hospital, South West Yorkshire Mental Health NHS Trust, Ouchthorpe
Lane, Wakeeld, WF1 3SP, UK. E-mail: shabir.musa@swyt.nhs.uk.

PAUL NESTEL, MD, FRACP

Baker Heart & Diabetes Institute, PO Box 6492, St Kilda Road Central, Melbourne,
Victoria 8008, Australia. E-mail: paul.nestel@bakeridi.edu.au.

JULIE OLLIFF, MBCHB, MRCP, FRCR

Imaging Department, Queen Elizabeth Hospital Birmingham, Mindelsohn Way,
Edgbaston, Birmingham, B15 2WB, UK. E-mail: Julie.Olliff@uhb.nhs.uk.

R.C.L. PAGE, MD, FRCP, MA(ED)

Endocrine Unit, Dundee House, City Hospital, Hucknall Road, Nottingham NG5 1PB,
UK. Email: renee.page@nuh.nhs.uk; rpage@ncht.trent.nhs.uk.

JAYENDRA K. PATEL, MD
University of Massachusetts Medical School, Department of Psychiatry, 361 Plantation
Street, Worcester, MA 01605, and Lake Area Psychiatry, 333 Dr. Michael DeBakey
Drive, Lake Charles, LA 70601, USA. E-mail: jkprjs@gmail.com.

MIKE PYNN, MRCP

Clinical Lecturer, School of Medicine, Swansea University, Swansea, Wales, UK.
E-mail: m.c.pynn@swansea.ac.uk.

ALEXANDER RAYMANN, MD, DESA (DEAA)

Department of Anaesthesiology, Intensive Care and Pain Medicine, Klinikum Region
Hannover Nordstadt, Hannover, Germany. E-mail: AlexanderRaymann@aol.com.

PETER RILEY, MBCHB, MRCP, FRCR

Imaging Department, Queen Elizabeth Hospital Birmingham, Mindelsohn Way,
Edgbaston, Birmingham, B15 2WB, UK. E-mail: Riley.Riley@uhb.nhs.uk.

ANITA ROTTER
Clinic of Dermatology, Santa Casa de So Paulo, So Paulo, Brazil.
E-mail: arotter@terra.com.br.

CARMELO SCARPIGNATO, MD, DSC, PHARMD, FRCP, FCP, FACG

Laboratory of Clinical Pharmacology, School of Medicine & Dentistry, University of
Parma, Via Volturno, 3943125 Parma, Italy. E-mail: scarpi@tin.it.

MICHAEL SCHACHTER, MD
Department of Clinical Pharmacology, National Heart and Lung Institute, Imperial
College, St Mary's Hospital, London W2 1NY, UK. E-mail: m.schachter@imperial.ac.uk.

J.S.A.G. SCHOUTEN, MD
Department of Ophthalmology, Maastricht University Hospital, PO Box 5800, 6202 AZ
Maastricht, The Netherlands. E-mail: J.Schouten@MUMC.nl.
x Contributors

DOMINIK SCHREY, MD
Infectious Disease Research Program, Center for Bone Marrow Transplantation and
Department of Hematology/Oncology, University Children's Hospital,
Albert-Schweitzer-Strasse 33, 48129 Muenster, Germany.
E-mail: Dominik.Schrey@ukmuenster.de.

STEPHAN A. SCHUG, MD, FANZCA, FFPMANZCA

Level 2, MRF Building G Block, Royal Perth Hospital, GPO Box X2213, Perth, WA
6847, Australia. E-mail: stephan.schug@uwa.edu.au.

REGINALD P. SEQUEIRA, PHD, FCP

Department of Pharmacology & Therapeutics, College of Medicine & Medical Sciences,
Arabian Gulf University, PO Box 22979, Manama, Bahrain.
E-mail: Sequeira@agu.edu.bh.

OSCAR OZMUND SIMOOYA, BSC, MBCHB, MSC

The Copper belt University, Health Services Division, PO Box 21692, Kitwe, Zambia,
Central Africa. E-mail: oscar.simooya@cbu.ac.zm.

REBECCA SPENCER
Fieldhead Hospital, South West Yorkshire Mental Health NHS Trust, Ouchthorpe
Lane, Wakeeld, WF1 3SP, UK. E-mail: Rebecca.Spencer@swyt.nhs.uk.

D. SPOERL
Allergy Unit, Department of Dermatology, University Hospital Basel, Petersgraben 4,
4031 Basel, Switzerland. E-mail: spoerld@uhbs.ch.

SEBASTIAN STRAUBE, BMBCH, MA, DPHIL

Department of Occupational, Social and Environmental Medicine, University Medical
Center Gttingen, Waldweg 37 B, D-37073 Gttingen, Germany. E-mail: sebastian.
straube@googlemail.com.

P.F.W. STRENGERS, MD
Sanquin Blood Supply Foundation, Plesmanlaan 125, 1066 CX Amsterdam,
The Netherlands. E-mail: p.strengers@sanquin.nl.

ANNE TAEGTMEYER, MD
University Hospital Zurich, Department of Medicine, Division of Infectious Diseases
and Hospital Epidemiology, Rmistrasse 100, CH-8091 Zrich, Switzerland.
E-mail: AnneBarbara.taegtmyer@usz.ch.

K. TORPEY, MD, PHD, MPH

Family Health International, 4401 Wilson Boulevard, Suite 700, Arlington, VA 22203,
USA. E-mail: ktorpey@fhi.org.

LUCIANA TRAMACERE
U.O. Neurologia, Ospedale S Giovanni di Dio, Via Torregalli 3, 50143 Firenze, Italy.
E-mail: luciana.tramacere@asf.toscana.it.

GIJSBERT B. VAN DER VOET, PHD, ERT

Health Council of The Netherlands, Parnassusplein 5 (C709)2511 VX The Hague, The
Netherlands. E-mail: b.v.d.voet@gr.nl.
Contributors xi

P.J.J. VAN GENDEREN, MD, PHD

Department of Internal Medicine, Harbour Hospital and Institute of Tropical
Diseases, Haringvliet 2, 3011 TD Rotterdam, The Netherlands.
E-mail: p.van.genderen@havenziekenhuis.nl.

K.J. VELTHOVE, PHARMD, PHD

Sanquin Blood Supply Foundation, Plesmanlaan 125, 1066 CX Amsterdam,
The Netherlands. E-mail: k.velthove@sanquin.nl.

P. VERHAMME, MD
Vascular Medicine and Haemostasis, University of Leuven, Herestraat, 49, 3000 Leuven,
Belgium. E-mail: Peter.Verhamme@uzleuven.be.

GARRY M. WALSH, MSC, PHD

School of Medicine, Institute of Medical Sciences Building, University of Aberdeen,
Foresterhill, Aberdeen AB25 2ZD, UK. E-mail: g.m.walsh@abdn.ac.uk.

THOMAS J. WALSH, MD
Transplantation-Oncology Infectious Diseases Program, Division of Infectious Diseases,
Weill Cornell Medical College of Cornell University, New York, New York, USA.
E-mail: thw2003@med.cornell.edu.

MANUEL WENK, MD
Department of Anaesthesia and Pain Medicine, Royal Perth Hospital, Perth, Australia
& Department of Anesthesiology and Intensive Care, University Hospital Muenster,
Albert-Schweitzer-Str. 33, 48149 Muenster, Germany.
E-mail: manuelwenk@uni-muenster.de.

C. WILLIAMS, BSC, MBCHB, FRCA

Department of Anaesthesia, 12th Floor, Royal Liverpool University Hospital, Prescot
Street, Liverpool, L7 8XP, UK. E-mail: colinwilliams99@yahoo.com.

EILEEN WONG, MD
Harvard Medical School, Massachusetts Mental Health Center, Department of
Psychiatry, Jamaica Plain, MA 02130, USA. E-mail: ewong88@juno.com.

GAETANO ZACCARA, MD
U.O. Neurologia, Ospedale S Giovanni di Dio, Via Torregalli, 50100 Firenze, Italy.
E-mail: gaetano.zaccara@asf.toscana.it.

H.W. ZHANG, BSC, MPHIL, PHD

School of Chinese Medicine, Faculty of Science, 1/F Sino Building, The Chinese
University of Hong Kong, Shatin NT, Hong Kong SAR, PR China.
E-mail: zhanghw@cuhk.edu.hk.
 Special reviews

SSRIs and emergent suicidal ideation 26

Antidepressants in pregnancy 27
The uses of lithium 39
Adulteration of street drugs with clenbuterol 53
Flumazenil 79
Typical versus atypical antipsychotic drugs 89
Weight gain and diabetes mellitus due to antipsychotic drugs 94
Suicidality and antiepileptic drugs 127
Lacosamide 139
Visual impairment and vigabatrin 178
An update on adverse events in patients taking COX-2 selective and non-selective 241
NSAIDs
Urinary tract dysfunction after recreational use of ketamine 268
Cartilage toxicity from local anesthetics 281
Tetrabenazine 305
Stress cardiomyopathy and catecholamines 313
Inhaled glucocorticoids and the risk of pneumonia 353
Inhaled glucocorticoids and skeletal adverse effects 355
Long-term safety of long-acting beta2-adrenoceptor agonists (LABAs)an update 357
Cardiovascular risks of inhaled anticholinergic drugs 364
More about amiodarone-induced thyrotoxicosis and its management 382
Dronedarone 386
Nervous system adverse effects of triptans 408
Antihypertensive drugs and their adverse effects in the perioperative period 413
Thimerosal and neurodevelopment in infants 453
Titanium allergy 456
Pro-oxidant effects of deferiprone 468
Disinfectants and bacterial resistance 479
Triphenylmethane dyes 481
Carbapenems and seizures 491
Tetracyclines and the environment 497
Drug-drug interactions with antifungal azoles 545
Adverse metabolic effects of antiretroviral drugs 582
Amantadine and corneal edema 602
Multidrug-resistant tuberculosis and extensively drug-resistant tuberculosis 623
Antituberculosis drug treatment in transplant recipients 627
Problems in interpreting interaction studies with protease inhibitors in patients 628
co-infected with tuberculosis and AIDS
Dapsone-induced hematological abnormalities and their management 630
Pandemic inuenza H1N1 vaccines 659
Autism and vaccines 661
The risks of infections from transfusions 669
Vitamin A supplementation in infants at times of immunization 691
Aprotinin and renal function 724

xvi
Special reviews xvii

Cross-reactivity between thiopurines 824

Attitudes to the use of hormone replacement therapy 853
Can HRT activate latent breast cancer? 856
Intrauterine administration of levonorgestrel 865
Abuse of anabolic steroids and the justication of control measures 869
Is there an increased risk of cancer in patients using insulin? 890
Taxanes and other microtubule stabilizing agents 935
Use of carboxypeptidase in the treatment of methotrexate toxicity 950
Cardiotoxicity of mad honey 996
 Cumulative indexes of special
reviews, Annuals 1132
1. Index of drugs
Note: the format 32.609 refers to SEDA-32,
p. 609.
Abetimus, drug development, 29.460
ACE inhibitors
acetylsalicylic acid, interaction, 28.124
angioedema, 22.225, 29.207, 31.352, 32.380
cough, 19.211
indications, 24.233
Acetaminophen, see Paracetamol
Acetylsalicylic acid, 21.100
ACE inhibitors, interaction, 28.124
antithrombotic effectiveness, 12.74
benet to harm balance in preventing strokes
and heart attacks, 27.109
co-medication, 26.423
gastrointestinal effects, 17.95, 18.90
Reye's syndrome, 11.79, 15.85
rhinosinusitis/asthma, 17.94
respiratory disease, 31.193
sensitivity, 12.75
Acupuncture
incidence of adverse effects, 29.589
traumatic effects, 29.590
Adenosine, dyspnea and bronchospasm, 32.337
Adrenaline, myocardial infarction and
vasospasm, 31.259
Aerosols, delivery, 27.172
Albumin, human, anaphylaxis, 14.296
Alcohol, 31.757
vitamin A, beta-carotene, interaction, 24.442
Aldosterone antagonists, in heart failure, 24.246
Alkylating drugs, 31.721
Aluminium
in albumin solutions, 23.359
toxicity in children, 12.185
tumorigenicity, 31.383
Aminoglycoside antibiotics, 17.304
contact dermatitis, 13.225
dosage regimens, 20.234, 21.265, 23.264
nephrotoxicity, 15.268, 17.305
ototoxicity, 14.222, 18.268
xviii
and ribostamycin, 15.270
Amiodarone, dysrhythmias, 25.211
eryptosis, 32.339
respiratory toxicity, 15.168
thyroid disease, 27.192, 31.327
Amphetamines, 29.3
Amphotericin, liposomal, 17.319
nephrotoxicity, 13. 231, 14.229, 27.276
Anabolic steroids
abuse, 29.508, 32.751
Analgesics
agranulocytosis and aplastic anemia, 11.87
choice of drug and dose, 12.63
headache, 21.95
headaches in children, 23.114
nephropathy, 21.98
Androgens, in women, 24.477
Anesthesia, dental, safety of, 16.122
Anesthetics
halogenated, renal damage, 20.106
local, and lipid emulsion, 32.261
local, combinations, 20.121
local, lipid rescue, 31.231
local, neurotoxicity, 21.129, 25.152
ocular, 17.542
Angiotensin II receptor antagonists, angioedema
30.238
Anisoylated plasminogen-streptokinase
activator complex (APSAC), 12.313
Anorectic drugs
cardiac valvulopathy 22.3, 23.2, 24.4, 25.5
primary pulmonary hypertension, 18.7, 21.2,
23.2, 25.5
Anthracyclines, 25.533
Antiallergic drugs, ocular treatment, 11.420
Antibacterial drugs, resistance, 31.413, 32.445
intrapartum, 32.446
Anticancer antimetabolites, 29.531
Anticholinergic drugs, 22.507, 31.273
cardiovascular risks, 32.318
Anticoagulants, oral, skin necrosis, 29.358
Cumulative indexes of special reviews, Annuals 1132 xix

Anticonvulsants, see Antiepileptic drugs seizures, 18.261

Antidepressants, see also individual agents side chains, 16.264
during and after pregnancy, 21.17 Antioxidant vitamins, 20.363
and emergent suicidality, 32.29 Antiprotozoal drugs
mania, 29.18 African trypanosomiasis, 18.293
overdose, 28.14 toxoplasmosis, 20.262
pregnancy, 32.31 Antipsychotic drugs
relative risks, 11.16 comparisons of different
Antidysrhythmic drugs types 25.53, 27.50
in atrial brillation, 24.197 deaths, 32.89
prodysrhythmic effects, 17.218, 23.196 diabetes mellitus, 28.60
Antiepileptic drugs use in conditions other than schizophrenia,
bone loss, 27.74 27.49
comparison, 25.78 use in elderly patients, 30.59
death, 23.83 weight gain, 26.56
overdosage, 22.84 Antiretroviral drugs, metabolic complications,
psychiatric effects, 22.82, 27.72 28.329
Antiestrogens, genotoxicity and tumorigenicity, Antischistosomal drugs, 12.261
27.429 Antithyroid drugs, pregnancy, 13.377
Antifungal drugs Antituberculosis drugs, 16.341, 31.500
drug interactions (azoles), 24.318, 28.299, children, 32.557
29.282, 30.320, 31.459, 32.497 genetic susceptibility, 28.342
Pneumocystis jiroveci (carinii) pneumonia, hepatotoxicity, 25.363, 26.339, 31.495, 32.555
18.289 Mycobacterium aviumcomplex infection,
Antihelminthic drugs 20.278
Mazzotti reaction, 31.507 transplant recipients, 32.559
pharmacovigilance in developing countries, Appetite suppressants
32.571 cardiac valvulopathies, 22.3, 23.2, 24.4, 25.5
Antihistamines primary pulmonary hypertension, 18.7, 21.2,
cardiovascular adverse effects, 17.196, 22.176, 23.2, 25.5
25.183, 26.180 Aprotinin, market withdrawal, 32.642
drowsiness/sedation, 21.170, 23.171, 26.182 Aripiprazole, 31.70
Antihypertensive drugs, 19.209 Arylpropionic acids, stereoisomers 32.229
in diabetes mellitus, 28.226 Aspirin, see Acetylsalicylic acid
xed-dose combinations, 22.224 Asthma medications, exacerbation of asthma,
individualizing therapy, 17.246 20.165
quality of life, 32.375 Atovaquone, 19.266
Antimalarial drugs, 14.237, 17.325, 20.257 Avoparcin
adjunctive treatments, 24.330 lessons from, 27.242
prophylaxis, 13.239, 23.304 resistance, 29.244
Antimicrobial drugs, see also different types Azathioprine, see Thiopurines
allergic reactions, 23.251 Azoles, see Antifungal drugs
coagulation disorders, 18.258
colitis, 12.216, 17.303 Baclofen, withdrawal syndrome, 26.152
intestinal motility, 13.220 Bambuterol, cardiac failure, 23.181
male fertility, 16.262 Benzodiazepines
new, 13.210 brain damage, 14.36
new, with adjuvants, 17.296 dependence, 12.41
the pill and pregnancy, 24, 274 depression, 17.43
policies and politics, 16.273 medicolegal aspects, 13.33
pregnancy, 11.231 Beta2-adrenoceptor agonists, 18.159
prescribing, 15.254 asthma, 19.178, 21.179
preterm infants, 21.258 asthma deaths, 17.164
prudent use, 25.279 , 27.242, 28. 265 long-acting, respiratory adverse effects,
resistance, 12.206, 13.210, 19.237, 20.228, 30.198, 31.309
21.257, 22.265, 23.250, 24.273, 29.244, long-acting, genetic susceptibility factors,
31.413 30.199, 31.310
xx
Beta-adrenoceptor antagonists
arthralgia, 11.164
sexual function, 15.188
Beta-carotene, see also Vitamin A
alcohol, vitamin A, interaction, 24.442
tumorigenicity, 25.454
Beta-lactam antibiotics
effects on eukaryotic cells, 13.212
immediate hypersensitivity reactions, 14.211
pregnancy, 25.280
Blood, see Transfusions
Botulinum toxin A, use in primary axillary
hyperhidrosis, 27.161
Budesonide, children, susceptibility factors,
30.194
Calcium antagonists, long-term safety, 20.185,
21.208, 22.214
Carbamazepine, skin reactions, 32.129
Carnitine, 13.269
Carotenoids, tumorigenicity, 25.454
Ceftriaxone, 15.258
nephrolithiasis, 29.246
Cephalosporins
immunological reactions, 28.267
hypersensitivity reactions, cross-reactivity with
penicillins, 30.280
and vitamin K, 12.210
Charcoal, activated, in digitalis overdose, 24.201
Chinese medicines, injectable formulations,
32.880
Chloramphenicol, children, 15.267
Chloroquine, 15.286
Chondroprotective agents, 14.439
Chymopapain, 11.279, 14.264
Ciclesonide, 30.196
Ciclosporin, urinary system, 19.348
Clozapine, 15.50
agranulocytosis, 22.1359
Cocaine
cardiovascular reactions, 18.5
fetotoxicity, 29.41, 30.35
prenatal exposure and perinatal effects, 27.1
second-generation effects, 20.24
Cocamidopropylbetaine, allergy, 19.151
Codeine, breast feeding, 31.154
Complementary and alternative therapies,
indirect risks, 27.521
esophagus, adverse effects on, 14.442
Contrast media
adverse reactions, 13.431, 24.525
anaphylactoid and allergic reactions, 20.422
delayed reactions, 26.513
in magnetic resonance imaging, 20.419
nephrotoxicity, 27.500, 28.556, 29.575, 31.731,
31.735, 32. 846
sialadenitis, 32.845
Cumulative indexes of special reviews, Annuals 1132
systemic brosis, 32.852
Corticosteroids, see Glucocorticoids
Cosmetics
adverse reactions, 13/117
contact allergy, 11.142, 16.150, 19.151
ingredient labeling 22.159
Co-trimoxazole, hypersensitivity reactions,
20.264
COX-2 inhibitors, 24.115, 25.126, 26.116
cardiovascular disease, 29.116, 32.225
gastrointestinal adverse reactions, 32.225
Danaparoid sodium, 32.631
Daptomycin, muscle damage, 30.309
Deferiprone, cardiac siderosis, 29.235
Deferoxamine, 16.247
bone dysplasia, 23.241
cardiac siderosis, 29.235
bone dysplasia, 23.241
cardiac siderosis, 29.235
yersiniosis, 11.215
Diamorphine, progressive spongiform
leukoencephalopathy, 24.40
Diclofenac, liver damage, 20.91
Diethylstilbestrol, transgenerational effects,
31.657
Digitalis, in atrial brillation, 24.197
Digoxin, compared with other drugs in heart
failure in sinus rhythm, 14.141
compared with other drugs in chronic
uncomplicated atrial brillation, 14.144
in atrial brillation, 32.333
in heart failure in sinus rhythm, 18.196
Dimethylfumarate, 32.295
Dipeptidyl peptidase IV inhibitors, 30.498
Diuretics
diabetes mellitus, electrolyte abnormalities,
and the ALLHAT trial, 27.219
hyponatremia, 29.219
interactions with NSAIDs, 12.80
renal cell carcinoma, 23.225
renal insufciency, 25.250
thiamine deciency, 32. 401
DNA alkylating drugs, 31.721
Dofetilide, 26.208
Dopamine receptor agonists
pathological gambling, 30.174
sleep disorders, 26.160, 27.149
Doxylamine, overdose and rhabdomyolysis,
31.298
Drotrecogin alfa (activated), 32.591
Ecstasy, see MDMA
EDTA, pseudothrombocytopenia, 21.250
Endothelin receptor antagonists, in
hypertension, 26.233
Enzyme inhibitors, 15.337
Cumulative indexes of special reviews, Annuals 1132
Epinephrine, see Adrenaline
Erythromycin, versus the new macrolides, 21.269
Erythropoietin, pure red cell aplasia, 27.348
status and safety, 16.400
Ethambutol, optic neuropathy, 30.358
Ethylene oxide, dialyser hypersensitivity,
11.219
Etomidate, adrenal suppression, 32.249
Etoposide, 27.477
Etretinate, ossication, 12.127
Euxyl K 400, contact allergy, 16.150
Fat emulsions, priapism, 11.313
Felbamate
aplastic anemia, 19.68, 22.86
risk/benet ratio, 23.86
Fenuramine
cardiac valvulopathies, 22.3, 23.2, 24.4, 25.5
primary pulmonary hypertension, 18.7, 21.2,
23.2, 25.5
Fenoterol, safety in severe asthma, 23.182
Fentanyl, buccal and transdermal
administration, 20.77
Fertility drugs
malignant melanoma, 26.434
ovarian cancer, 24.474
Finasteride, 30.480
Fish oil, 13.460
Flecainide, in supraventricular dysrhythmias,
21.200
Fluoroquinolones, 12.250, 18.271
Fluorouracil, adverse reactions, 23.476
Folic acid, dietary supplementation, 19.369
safety aspects, 27.407
Formoterol, tolerance, 24.187
Fragrances, contact allergy, 20.149
Gadolinium salts, nephrotoxicity, 28.561, 31.735,
32.852
General anesthetics, see Anesthetics
Germanium, 16.545
Glucocorticoids
bone, 16.447, 22.182, 25.195
contact allergy, 15.139, 21.158
effective dose and therapeutic ratio, 23.175
and eyes, 29.481
and growth, 14.335
inhaled, children, risks in, 27.174
inhaled, effects on mouth and
throat, 29.168
inhaled, effects on skin, 29.169
inhaled, fracture risk, 31.307
inhaled, growth inhibition, 26.186
inhaled, hypothalamicpituitaryadrenal
gland function, 31.305
inhaled, pneumonia risk, 32.311
inhaled, systemic availability, 24.185, 26.187
xxi
musculoskeletal adverse reactions, 21.417,
32.312
osteoporosis and osteonecrosis, 16.447,
19.377, 20.374, 21.417, 22.182, 28.473
preterm infants, 17.445
Glucose solutions, hypophosphatemia, 11.312
Grapefruit juice, drug interactions 23.519
Growth hormone
adults, 16.501
CreutzfeldtJakob disease, 11.371
insulin resistance, 24.504
malignancy, 23.468
Heparin
low-molecular-weight, 12.311
thrombocytopenia, 30.404, 32.626
Hepatitis B vaccine, demyelinating diseases,
21.331, 22.346, 24.374
Herbal medicines, warfarin, interactions,
30.400
Heroin, see Diamorphine
Histamine (H2) receptor antagonists, 13.330,
15.393
HIV-protease inhibitors
insulin resistance, 22.317
lipodystrophy, 22.317
HMG Co-A reductase inhibitors, interactions,
25.530, 30.517
Hormone replacement therapy
cardiovascular reactions, 31.659
ovarian cancer, 32.740
Hormones, sex
breast cancer 11.346
tumors, 22.465
HRT, see Hormone replacement therapy
5-HT, see Serotonin
Hydrochlorothiazide, non-cardiogenic
pulmonary edema, 31.373
Hypnotics, 20.30
avoiding adverse reactions, 21.37
Hypoglycemic drugs, combinations of, 27.458,
28.521
Immunization
adverse reactions, 24.364
and autoimmune disease, 27.336
bioterrorism, 25.378, 26.354
multiple, 27.334
surveillance after, 15.340, 22.333, 23.335,
24.364, 25.376, 26.353, 27.334
Immunotherapy, in leishmaniasis, 15.299
Incretin mimetics, 29.528
Indacaterol, 32.317
Indometacin, fetal and neonatal complications,
18.102
Inuenza vaccine, 29.332
Inhalations, 11.151
xxii
Insulin
edema, 11.364
human, and hypoglycemia, 15.452
inhalation, 30.495
modes of administration, 26.464
resistance, and growth hormone, 24.504
synthetic analogues, 24.489
Interferon ribavirin, 30.344
Interferons, psychological and psychiatric
reactions, 29.384
Interleukin-2, 14.325
Ipecacuanha, myopathy, 11.422
Irinotecan, 27.477
Iodine, radioactive, 11.358
Iron chelators, combinations, 31.399
Isoniazid
genetic susceptibility factors, 12.257
prophylactic, toxicity, 24.352
Kathon CG, 31.134
Kava kava
liver damage, 27.518
adverse reactions, 28.579
Ketoconazole, hepatotoxicity, 12.229
Ketorolac, risk of adverse reactions, 17.110
Khat, 30.43
Lamotrigine, skin rashes, 20.62, 24.88
Latex, allergy, 31.761
Laxatives, abuse, 13.336
Leunomide, 29.435
Leukotriene receptor antagonists,
ChurgStrauss syndrome, 24.183, 27.177,
29.174
Levacetylmethadol, 32.193
Levodopa, and malignant melanoma, 31.267
Lipid-lowering drugs, 13.402, 15.479
Lithium
adverse reactions, prevention and treatment,
13.17, 17.28
benecial uses other than in bipolar disorder,
27.19
efcacy, comparisons with other
agents, 30.23
interactions, 16.13, 18.30
intoxication, prevention and
treatment, 17.29
monitoring therapy, 11.24, 18.25
mortality, 19.14
neuroprotection, 32.41
urinary system, 14.18, 19.16
thyroid, 12.26
Local anesthetics, see Anesthetics
Loop diuretics, see Diuretics
Lorenzo's oil, 27.475
Lyme disease vaccine, autoimmune disease,
24.366
Cumulative indexes of special reviews, Annuals 1132
Macrolides, drug interactions, 14.220
intestinal motility, 18.269
Malaria vaccines, 22.306
Mannitol, 28.236
MAO inhibitors, see Monoamine oxidase
inhibitors
MDMA (ecstasy)
cognitive reactions, 26.32, 32.63
deaths, 24.32
epidemiology of use, 30.37
Measles immunization, see also MMR
autism, 23.350
Crohn's disease, 23.350
neurological adverse reactions, 23.348
subacute sclerosing panencephalitis, 29.335
Mebendazole, hypersensitivity reactions, 12.263
Melatonin, 25.523
Mercaptopurine, see Thiopurines
Metamfetamine, 29.3
Metformin
contraindications, 28.515
lactic acidosis, 23.459, 29.526
Methyldibromoglutaronitrile, contact allergy,
16.150, 19.151
Methylphenidate, effects at different ages, 31.6
Methylthiotetrazole, 11.226
Mibefradil, drug interactions, 23.210
Midazolam, 15.112
Midodrine, 26.159
Milrinone, intravenous, acute heart failure,
21.196
MMR immunization
autism, 23.350, 25.387, 28.363
Crohn's disease, 23.350, 25.387
Mometasone furoate, 30.197
Monoamine oxidase inhibitors, 12.8, 13.6, 17.361
Monofunctional alkylating agents, 32.827
Morphine, managing adverse reactions, 26.98
Muscle relaxants
emergency medicine, 20.133
eyes, 21.145
hypersensitivity reactions, 27.138
intensive care, 19.140
Neuromuscular blocking agents, anaphylaxis,
29.145
non-depolarizing neuromuscular blockers,
15.127
recovery in intensive care, 12.114
residual paralysis, 27.139
Niacin, extended-release, 16.440
N-Lost derivatives, 31.721
Nomifensine, 11.15
NSAIDs, see also COX-2 inhibitors
acute renal insufciency, 28.122
blood pressure, 19.92, 27.102
cardiovascular adverse reactions, 32.225
Cumulative indexes of special reviews, Annuals 1132
children, 19.96
current controversies, 17.102
COX-2 inhibitors, 24.115, 25.126, 26.116
dyspepsia, 28.120
gastrointestinal adverse reactions, 14.79,
17.95, 18.90, 18.99, 20.86, 21.96, 22.108,
23.114, 32.225
gastrointestinal damage, role of Helicobacter
pylori, 27.105
gastrointestinal damage, reducing,
30.125
gastrointestinal toxicity, prevention, 19.93
inammatory bowel disease, 25.131
inhibiting cardioprotective effects of
acetylsalicylic acid, 28.118
interactions with diuretics, 12.80
intracerebral hemorrhage, 28.119
necrotizing fasciitis, 28.121
nephrotoxicity, 11.82, 18.100, 20.89, 24.120,
26.111
osteoarthritis, 11.87
skin reactions, 13.72
topical, 18.163
Ocular drugs
allergic reactions, 21.486
geriatric patients, 16.542
risk factors for adverse reactions, 22.507
Omeprazole, tumors, 16.423
Opioids
abuse, 29. 44
adverse reactions, frequency, 32.183
adverse reactions, prevention, 24.100
death, 25.37
obstetric use, 24.102
routes of administration, 30.106
tolerance in neonates, 23.97
Oral contraceptives
antimicrobial drugs, and pregnancy, 24.274
and breast cancer, 15.426
formulations, 24.472
third-generation, 25.484, 26.442
venous thromboembolism, 23.442
Orlistat, 30.429
Oxymorphone, 32.203
Paclitaxel, adverse reactions, 21.463
Pancreatic enzyme supplements, brosing
colonopathy, 20.322
Paracetamol
asthma, 30.129
hepatotoxicity in alcoholism, 12.76
liver damage, 17.98, 18.94
overdose, 13.68, 23.117
Parenteral nutrition
bone reactions, 22.378
cholestasis, 22.376
xxiii
infections 22.379
Penicillins
acute desensitization, 23.252
hypersensitivity reactions, cross-reactivity with
cephalosporins, 30.280
immunological reactions, 28.267
Peritoneal dialysis uids, effects on peritoneum,
22.381
Peroxisome proliferator-activated receptors, see
also Thiazolidinediones
dual agonists, 32.782
Pertussis vaccine, 11.284, 11.285
Phentermine, cardiac valvulopathies, 24.4
Pholcodine, 32.206
Photodynamic therapy, cancers 32.832
Phytoestrogens, in foodstuffs, 31.655
Pilsicainide, 32.348
Piroxicam
gastrointestinal reactions, 11.97, 12.91
Pivalic acid, and carnitine, 12.209
Platinum compounds, 26.490
Polio vaccine, AIDS, 23.352
Polyaspartic acid, protective against
nephrotoxicity, 17.305
Polyethylene glycol, electrolyte, mineral, metal,
and uid balance, 29.376
Polystyrene sulfonates, 25.271
Polyvinylpyrrolidone, storage disease, 22.522
PPAR, see Peroxisome proliferator-activated
receptors
Pregabalin, 30.86
Propofol
infusion syndrome, 26.135
prevention of pain, 30.143
Propolis, allergy, 17.181
Proton pump inhibitors, tumors, 23.383
Psilocybin, 31.49
PUVA, malignant melanoma, 22.166
Pyrazinamide, in latent pulmonary tuberculosis,
27.323
Pyrimethamine sulfadoxine, prevention of
malaria, 32.523
Quinidine, versus quinine, 15.295
Quinine, versus quinidine, 15.295
Rasagiline, 31.270
Rasburicase, 31.203
Renin inhibitors, 30.242
Rhesus anti-D, prophylaxis, 13.297
Ribavirin interferon, 30.344
Ribostamycin, and aminoglycosides, 15.270
Rocuronium, allergic reactions, 26.150
and pholcodine, 31.249
Rotashield, intussusception, 23.354
Rotavirus vaccine, Kawasaki disease, 31.522
Rubella vaccine, joints, 11.295
xxiv Cumulative indexes of special reviews, Annuals 1132

Salbutamol, adrenoceptor genotypes, 29.173 Topiramate, cognitive reactions, 26.81

Salmeterol, tolerance, 24.187 Topoisomerase inhibitors, 27.477
Sapropterin, 32.609 Topotecan, 27.477
Sedatives, 29.128 Trocetrapib, 32.816
Sex hormones, tumors, 22.465 Transfusions
Serotonin AIDS, 12.298
receptor antagonists, 15.391 complications, 12.300
selective serotonin reuptake inhibitors, drug Tretinoin, topical, teratogenicity, 18.164
interactions, 22.13 Triazolam, 16.33
selective serotonin reuptake inhibitors, Tricyclic antidepressants
gastrointestinal bleeding, 32.33 endocrine reactions, 11.12
selective serotonin reuptake inhibitors, mania, 13.8
suicidal behavior, 29.19, 31.18 L-tryptophan, eosinophiliamyalgia syndrome,
Smallpox vaccination, 27.339 15.514
Somatostatin, 15.468 Tumor necrosis factor antagonists, infection risk,
Spinal manipulation, adverse reactions, 29.591 29.395, 31.594
SSRIs, see Serotonin Tyrosine kinase inhibitors, 30.520
Statins, see HMG Co-A reductase inhibitors
Steroids, see Glucocorticoids Vaccines, see also individual agents
Stimulants, in ADHD, 31.4 adjuvants, 32.577
Sugammadex, 32.275 autism, 31.516
Sulfonamide derivatives, hypersensitivity combinations, 29.327, 30.369
reactions, 30.252 GuillainBarr syndrome, 31.515
Sumatriptan, 17.171 HIV-infected individuals, 12.269
Suprofen, nephrotoxicity, 12.88 Kawasaki disease, 31.522
Suramin, patients with prostate cancer, 20.283 national compensation systems, 12.271
Surgam, gastric reactions, 12.89 poliomyelitis, 22.352
Suxamethonium, postoperative myalgia, thiomersal in, 28.357
28.155 Valproate, overdose, 32.157
polycystic ovary syndrome, 26.81
Tamoxifen, versus aromatase Vancomycin
inhibitors, 30.475 lessons from, 27.242
Teniposide, 27.477 resistance, 29.244
Tetracyclines Vigabatrin
adverse reactions, 12.212, 26.268 psychosis and abnormal behavior, 18.71
chemically modied, 31.419 visual eld defects, 21.78, 24.95,
comparative toxicity, 22.268 25.98, 26.82
and metalloproteinases, 26.266 Vinca alkaloids, 28.538
non-antimicrobial properties, 30.288 Vitamin A, 17.436
in pregnancy, 25.280 alcohol, beta-carotene, interaction, 24.442
in rheumatology, 23.255 hypervitaminosis, 15.411
therapeutic effects, 24.278 in pregnancy, 21.405
Tetrahydrobiopterin, 32.609 and prostate cancer, 13.346
TGN 1412, 32.642 Vitamin B6, debate, 23.420
Theophylline, asthma, 17.2, 18.1, 18.2 Vitamin E, co-medication, 26.423
Thiazides, see Diuretics Vitamin K
Thiazolidinediones cancer, 23.424
cardiovascular reactions, 31.697 skin reactions, 25.461
musculoskeletal reactions, 32.779 Vitamins, in old age, 22.431
peripheral edema, 29.531
Thiomersal, in vaccines, 28.357 Warfarin, herbal medicines, interactions,
Thiopurines, genetic susceptibility, 31.634 30.400
Thyroid hormones, 29.464
Thyroxine, drug interactions, 24.484 Ximelagatran, hepatotoxicity, 30.411
Tiaprofenic acid, cystitis, 18.106
TNF, see tumor necrosis factor Zidovudine, 13.246
Tolcapone, 32.289 Zileuton, 32.322
Cumulative indexes of special reviews, Annuals 1132
2. Index of adverse reactions
Cardiovascular
anticholinergic drugs, 32.318
atrial brillation, antidysrhythmic drugs,
24.197
atrial brillation, digitalis, 24.197
cardiac failure, aldosterone antagonists,
24.246
cardiac failure, bambuterol, 23.181
cardiac siderosis, deferoxamine/deferiprone,
29.235
cardiotoxicity, antihistamines, 17.196, 25.183,
26.180
cardiotoxicity, calcium antagonists, 20.185
cardiotoxicity, cocaine, 18.5
cardiotoxicity, coxibs, 29.116
cardiotoxicity, hormone replacement therapy,
31.659
cardiotoxicity, propofol, 26.135
cardiotoxicity, thiazolidinediones, 31.697
dysrhythmias, antihistamines, 22.176
dysrhythmias, amiodarone, 25.211
hypertension, NSAIDs, 19.92, 27.102
myocardial infarction, acetylsalicylic acid,
27.109
myocardial infarction, adrenaline, 31.259
NSAIDs, 32.225
prodysrhythmic reactions, antidysrhythmic
drugs, 17.218, 23.196
QT interval prolongation, 24.54
valvulopathies, fenuramine, 22.3, 23.2, 24.4,
25.5
valvulopathies, phentermine, 24.4, 25.5
vasospasm, adrenaline, 31.259
venous thromboembolism, oral
contraceptives, 23.442
Respiratory
amiodarone, 15.168
asthma, acetylsalicylic acid, 17.94, 31.193
asthma, fenoterol, 23.182
asthma, paracetamol, 30.129
asthma, in pregnancy, 28.186
asthma deaths, beta2-adrenoceptor agonists,
17.164
asthma exacerbation, asthma medications,
20.165
beta2-adrenoceptor agonists, long-acting,
30.198
bronchoconstriction, paradoxical, nebulizer
solutions, 13.134
bronchospasm, adenosine, 32.337
ChurgStrauss syndrome, leukotriene
receptor antagonists, 24.183, 27.177,
29.174
cough, ACE inhibitors, 19.211
xxv
dyspnea, adenosine, 32.337
long-acting beta2-adrenoeceptor agonists,
31.309
pneumonia, glucocorticoids, 32.311
primary pulmonary hypertension, appetite
suppressants, 18.7, 21.2, 23.2, 25.5
pulmonary edema, non-cardiogenic,
hydrochlorothiazide, 31.373
rhinosinusitis, acetylsalicylic acid, 17.94
Ear, nose, throat
glucocorticoids, inhaled, 29.168
Nervous system
anticholinergic effects, 31.273
brain damage, benzodiazepines, 14.36
CreutzfeldtJakob disease, growth hormone,
11.371
demyelinating diseases, hepatitis B vaccine,
21.331, 22.346, 24.374
drowsiness/sedation, antihistamines, 21.170,
23.171, 26.182
GuillainBarr syndrome, vaccines 31.515
headache, analgesics, 21.95, 23.114
intracerebral hemorrhage, NSAIDs, 28.119
neuroleptic malignant syndrome, 11.47, 20.41
neurotoxicity, anesthetics, local, 21.129
neurotoxicity, measles immunization, 23.348
overdosage, antiepileptic drugs, 22.84
pain, propofol, 30.143
poliomyelitis, vaccines, 22.352
progressive spongiform leukoencephalopathy,
diamorphine, 24.40
seizures, antimicrobial drugs, 18.261
sleep disorders, dopamine receptor agonists,
26.160, 27.149
strokes, acetylsalicylic acid, 27.109
strokes, risperidone, 28.76
subacute sclerosing panencephalitis, measles
vaccine, 29.335
tardive dyskinesia, 14.47, 20.38
tardive syndromes, 17.54
transient symptoms, intrathecal anesthetics,
25.152
Neuromuscular
residual paralysis, neuromuscular blocking
drugs, 27.139
Sensory systems
eye reactions, drug abuse, 12.33
eye reactions, glucocorticoids, 29. 481
eye reactions, muscle relaxants, 21.145
optic neuropathy, ethambutol, 30.358
ototoxicity, aminoglycosides, 14.222, 18.268
visual eld defects, vigabatrin, 21.78, 24.95,
25.98, 26.82
Psychological
cognitive reactions, MDMA, 26.32, 32.63
cognitive reactions, metamfetamine, 29.3
cognitive reactions, topiramate, 26.78
xxvi
Psychological (cont)
gambling, dopamine receptor agonists, 30.174
interferons, 29.384
Psychiatric
antiepileptic drugs, 22.82, 27.72
autism, MMR/measles immunization, 23.350,
25.387, 28.363, 31.516
depression, benzodiazepines, 17.43
mania, antidepressants, 13.8, 29.18
interferons, 29.384
psychosis and abnormal behavior, vigabatrin,
18.71
suicidal behavior, antidepressants, 32. 29
suicidal behavior, SSRIs, 29.19, 31.18
Endocrine
Adrenal suppression, etomidate, 32.249
diabetes mellitus, antihypertensive drugs,
28.226
diabetes mellitus, antipsychotic drugs, 28.60
diabetes mellitus, diuretics, 27.219
hypothalamicpituitaryadrenal gland
function, inhaled glucocorticoids, 31.305
insulin resistance, growth hormone, 24.504
insulin resistance, HIV-protease inhibitors,
22.317
ovarian hyperstimulation syndrome,
valproate, 26.477
polycystic ovary syndrome, valproate, 26.81
thyroid disease, amiodarone, 27.192, 31.310
thyroid disease, lithium, 12.26
tricyclic antidepressants, 11.12
Metabolism
antiretroviral drugs, 28.329
hyperlactatemia, 29.302
hypoglycemia, insulin, 15.452
lactic acidosis, metformin, 23.459, 29.526
lipoatrophy, 29.302
lipodystrophy, HIV-protease inhibitors,
22.317
metabolic acidosis, propofol, 26.135
mitochondrial toxicity, 29.302
polyvinylpyrrolidone storage disease, 22.522
weight gain, antipsychotic drugs, 26.56
Nutrition
thiamine deciency, diuretics, 32.401
Electroyte balance
electrolyte abnormalities, diuretics, 27.219,
29.219
polyethylene glycol, 29.376
Mineral balance
hypophosphatemia, glucose solutions, 11.312
polyethylene glycol, 29.376
Metal balance
polyethylene glycol, 29.376
Fluid balance
edema, insulin, 11.364
edema, thiazolidinediones, 29.531
Cumulative indexes of special reviews, Annuals 1132
polyethylene glycol, 29.376
Hematologic
agranulocytosis, analegsics, 11.89
agranulocytosis, clozapine, 22.59
aplastic anemia, analegsics, 11.89
aplastic anemia, felbamate, 19.68, 22.86
coagulation disorders, beta-lactam antibiotics,
18.258
eosinophiliamyalgia syndrome, tryptophan,
15.514
hemolytic disease of the newborn, anti-D
prophylaxis, 12.293
hemostasis, cephalosporins, 12.210
pseudothrombocytopenia, EDTA, 21.250
pure red cell aplasia, erythropoietin, 27.348
thrombocytopenia, heparin, 30.404, 32.626
Mouth
Glucocoricoids, inhaled, 29.168
Salivary glands
sialadenitis, iodinated contrast media, 32.845
Gastrointestinal
bleeding, acetylsalicylic acid, 17.95, 18.90
cholestasis, total parenteral nutrition, 22.376
colitis, antimicrobial drugs, 12.216, 17.303
Crohn's disease, MMR/measles immunization,
23.350, 25.387
dyspepsia, NSAIDs, 28.120
brosing colonopathy, pancreatic enzyme
supplements, 20.322
inammatory bowel disease, NSAIDs, 25.131
intestinal motility, antimicrobial drugs, 13.220
intestinal motility, macrolides, 18.269
intussusception, Rotashield, 23.354
NSAIDs, 32.225
piroxicam, 12.91
SSRIs, 32.33
Surgam, 12.89
ulceration, bleeding and perforation,
NSAIDs, 11.97, 14.79, 16.103, 17.95,
18.90, 18.99, 19.93, 20.86, 21.96, 22.108,
23.114, 27.105, 30.125
Liver
hepatotoxicity, alcohol/vitamin A/beta-
carotene, 24.442
hepatotoxicity, antituberculosis drugs, 25.363,
26.339, 31.495, 32.555
hepatotoxicity, diclofenac, 20.91
hepatotoxicity, kava kava, 27.518
hepatotoxicity, ketoconazole, 12.229
hepatotoxicity, paracetamol, 12.76, 17.98,
18.94
hepatotoxicity, ximelagatran, 30.411
Reye's syndrome, acetylsalicylic acid, 11.79,
15.85
Urinary tract
acute renal insufciency, NSAIDs, 28.122
cystitis, tiaprofenic acid, 18.106
Cumulative indexes of special reviews, Annuals 1132
nephrolithiasis, ceftriaxone, 29.246
nephrotoxicity, aminoglycosides, 15.268,
17.305
nephrotoxicity, amphotericin, 13.231, 14.229,
27.276
nephrotoxicity, analgesics, 21.98
nephrotoxicity, anesthetics, halogenated,
20.106
nephrotoxicity, ciclosporin, 19.348
nephrotoxicity, contrast media, 27.500, 28.556,
29.575, 31.731, 31.735, 32.846
nephrotoxicity, gadolinium salts, 28.561
nephrotoxicity, lithium, 14.18, 19.16
nephrotoxicity, NSAIDs, 11.82, 18.100, 20.89,
24.120, 26.111
nephrotoxicity, suprofen, 12.88
renal cell carcinoma, diuretics, 23.225
renal insufciency, diuretics, 25.250
Skin
contact allergy, 23.160
contact allergy, glucocorticoids, 15.139
contact dermatitis, aminoglycosides, 13.225
cutaneous reactions, NSAIDs, 13.72
glucocorticoids, inhaled, 29.169
necrosis, oral anticoagulation, 29.358
rashes, lamotrigine, 20.62, 24.88
serious reactions, carbamazepine, 32.129
systemic brosis, contrast media, 32.852
vitamin K1, 25.461
Serosae
peritoneum, peritoneal dialysis, 22.381
pleurodesis, 25.189
Musculoskeletal
arthralgia, beta-adrenoceptor antagonists,
11.164
arthralgia, rubella vaccination, 11.295
bone, total parenteral nutrition, 22.378
bone dysplasia, deferoxamine, 23.241
bone loss, antiepileptic drugs, 27.74
bone mineral density, glucocorticoids, 25.195
eosinophiliamyalgia syndrome, tryptophan,
15.514
fractures, inhaled glucocorticoids, 31.307,
32.312
fractures, thiazolidinediones, 32.779
growth in children, inhaled glucocorticoids,
26.186
growth in children, oral glucocorticoids,
14.335
growth in children, stimulants, 31.4
muscle damage, daptomycin, 30.309
myopathy, ipecacuanha, 11.422
ossication, etretinate, 12.127
osteoarthritis, NSAIDs, 1187
osteoporosis and osteonecrosis,
glucocorticoids, 16.447, 19.377, 20.374,
21.417, 22.182, 28.473
xxvii
rhabdomyolysis, doxylamine overdose, 31.298
rhabdomyolysis, propofol, 26.135
postoperative myalgia, suxamethonium,
28.155
Sexual function
beta-adrenoceptor antagonists, 15.188
priapism, fat emulsions, 11.313
Immunologic
allergic reactions, antimicrobial drugs, 23.251
allergic reactions, contact allergy, cosmetics,
11.142
allergic reactions, contact allergy, Kathon
CG, 11.134
allergic reactions, latex, 31.761
allergic reactions, rocuronium, 26.150
allergy testing, chymopapain, 11.279
anaphylaxis, human albumin, 14.296
anaphylaxis, neuromuscular blocking agents,
29.145
angioedema, ACE inhibitors, 22.225, 29.207
aspirin sensitivity, 12.75
autoimmune disease, immunizations, 27.336
autoimmune disease, Lyme disease vaccine,
24.366
cocamidopropylbetaine, 19.151
contrast agents, 20.422
cosmetics, 16.150, 19.151
co-trimoxazole, 20.264
desensitization, penicillin, 23.252
Euxyl K 400, 16.150
fragrances, 20.149
glucocorticoids, 21.158
hypersensitivity reactions, beta-lactam
antibiotics, 14.211, 30.280
hypersensitivity reactions, ethylene oxide,
11.219
hypersensitivity reactions, muscle relaxants,
27.138
hypersensitivity reactions, mebendazole,
12.263
hypersensitivity reactions, rocuronium,
31.249
hypersensitivity reactions, sulfonamide
derivatives, 30.252
immune reconstitution disease, 29.315
Kawasaki disease, rotavirus vaccine, 31.522
Mazzotti reaction, antihelminthic drugs,
31.507
methyldibromoglutaronitrile, 16.150, 19.151
ocular drugs, 21.486
propolis, 17.181
red man syndrome, 17.312
Autacoids
angioedema, angiotensin converting enzyme
inhibitors, 31.352, 32. 380
angioedema, angiotensin II receptor
antagonists, 30.238
xxviii Cumulative indexes of special reviews, Annuals 1132

Infection risk asthma, 28.186

AIDS, polio vaccine, 23.352 beta-lactams, 25.280
AIDS, transfusions, 12.298 cocaine, 27.1
necrotizing fasciitis, NSAIDs, 28.121 opioids, 24.102
total parenteral nutrition, 22.379 tetracyclines, 25.280
tumor necrosis factor antagonists, 29.395, vitamin A, 21.405
31.594 Teratogenicity
yersiniosis, deferoxamine, 11.215 antibiotics, 11.231
Body temperature tretinoin, topical, 18.164
malignant hyperthermia, 18.112 Fetotoxicity
Trauma cocaine, 20.24, 27.1, 29.41, 30.35
acupuncture, 29.590 diethylstilbestrol, transgenerational reactions,
Death 31.657
antiepileptic drugs, 23.83 indometacin, 18.102
antipsychotic drugs, 32.89 Lactation
calcium antagonists, 22.214 cocaine, 31.154
digoxin, 32.333 Susceptibility factors
ecstasy, 24.32 age, methylphenidate, 31.6
lithium, 19.14 children, aluminium, 12.185
opiates, 25.37, 29.44 children, antituberculosis drugs, 32.557
Drug abuse children, budesonide, 30.194
anabolic steroids, 29.508, 32.751 children, inhaled glucocorticoids 27.174
Drug tolerance children, NSAIDs, 19.96
antimicrobial drug resistance, 11.223, 12.208, elderly patients, antipsychotic drugs, 30.59
19.237, 20.228, 21.257, 22.265, 23.250, genetic susceptibility, antituberculosis drugs,
24.273, 25.279, 29.244, 31.413, 32.445 28.342
opioids in neonates, 23.97 genetic susceptibility, beta-adrenoceptor
Drug dependence agonists, 29.173, 30.199, 31.310
benzodiazepines, 12.41 genetic susceptibility, isoniazid, 12.257
Drug withdrawal genetic susceptibility, thiopurine toxicity,
baclofen, 26.152 31.634
Genotoxicity HIV infection, immunization, 12.269
antiestrogens, 27.429 intensive care, muscle relaxants, 19.140
Tumorigenicity neonatal complications, indometacin, 18.102
alcohol/vitamin A/beta-carotene, 24.442 ocular drugs, 22.507
aluminium, 31.383 old age, vitamins, 22.431
antiestrogens, 27.429 preterm infants, beta-lactam antibiotics,
beta-carotene, 25.454 21.258
carotenoids, 25.454 transplant recipients, antituberculosis drugs,
fertility drugs, 24.474, 26.434 32.559
growth hormone, 23.468 Drug administration
hormone replacement therapy, 32.740 delivery of aerosols, 27.172
levodopa, 31.267 dosage regimens, aminoglycosides, 23.264
omeprazole, 16.423 errors, 28.587, 29.596
oral contraceptives, 11.346, 15.426 formulations, oral contraceptives, 24.472
proton pump inhibitors, 23.383 inhaled glucocorticoids, systemic availability,
PUVA, malignant melanoma, 22.166 24.185
sex hormones, 22.465 inhaled insulin, 30.495
vitamin K, 23.424 intravitreal and parabulbar injection,
Fertility 29.581
fertility, male, antimicrobial drugs, 16.262 labeling problems, cosmetics, 22.159
Pregnancy opioids, 30.106
affective disorders in, 21.17 Drug overdose
antibiotics, 11.231, 32.446 antidepressants, 28.14
antidepressants, 32.31 digitalis, charcoal, 24.201
antimicrobial drugs and the pill, 24.274 paracetamol, 23.117
antithyroid drugs, 13.377 valproate, 32.157
Cumulative indexes of special reviews, Annuals 1132
Drug formulations
enantiomers and racemates, 13.442
Drugdrug interactions
acetylsalicylic acid/ACE inhibitor, 28.124
acetylsalicylic acid/NSAIDs, 28.118
alcohol/vitamin A/beta-carotene, 24.442
antimicrobial drugs/the pill, 24.274
antifungal azoles, 24.318, 28.299, 29.282,
30.320, 31.459, 32.497
diuretics/NSAIDs, 12.80
grapefruit juice, 23.519
herbal medicines/warfarin, 30.400
HMG Co-A reductase inhibitors, 25.530,
30.517
lithium, 16.13
lithium/selective serotonin reuptake
inhibitors, 18.30
macrolides, 14.220
mibefradil, 23.210
xxix
monoamine oxidase inhibitors/foods, 13.6
NSAIDs/ACE inhibitors, 28.122
paracetamol, 13.68
selective serotonin reuptake inhibitors, 22.13
thyroxine, 24.484
Management of adverse drug reactions
local anesthetics, lipid emulsion, 32.261
Methods
ethnopharmacology, 14.429
eukaryotic cells, effects of beta-lactams,
13.212
hemolytic disease of the newborn,
prophylaxis, 13.297
lithium, monitoring, 11.24
local anesthetic toxicity, lipid rescue, 31.231
onchocerciasis, treatment, 14.261
post-marketing surveillance, 14.210, 15.266,
24.274
 Table of Essays, Annuals 132
SEDA Author Country Title

1 M.N.G. Dukes The Netherlands The moments of truth

2 K.H. Kimbel Germany Drug monitoring: why care?
3 L. Lasagna USA Wanted and unwanted
drug effects: the need for perspective
4 M.N.G. Dukes The Netherlands The van der Kroef syndrome
5 J.P. Grifn, P.F. D'Arcy UK Adverse reactions to drugsthe information lag
6 I. Bayer Hungary Science vs practice and/or practice vs science
7 E. Napke Canada Adverse reactions: some pitfalls and postulates
8 M.N.G. Dukes Denmark The seven pillars of foolishness
9 W.H.W. Inman UK Let's get our act together
10 S. Van Hauen Denmark Integrated medicine, safer medicine and AIDS
11 M.N.G. Dukes Denmark Hark, hark, the ctitious dogs do bark
12 M.C. Cone Switzerland Both sides of the fence
13 C. Medawar UK On our side of the fence
14 M.N.G. Dukes, E. Helsing Denmark The great cholesterol carousel
15 P. Tyrer UK The nocebo effectpoorly known but getting
stronger
16 M.N.G. Dukes Denmark Good enough for Iganga?
17 M.N.G. Dukes Denmark The mists of tomorrow
18 R.D. Mann UK Databases, privacy, and condentialitythe effect
of proposed legislation on pharmacoepidemiology
and drug safety monitoring
19 A. Herxheimer UK Side effects: freedom of information and the
communication of doubt
20 E. Ernst UK Complementary/alternative medicine: what should
we do about it?
21 H. Jick USA Thirty years of the Boston Collaborative Drug
Surveillance Program in relation to principles
and methods of drug safety research
22 J.K. Aronson, RE Ferner UK Errors in prescribing, preparing, and giving
medicines: denition, classication, and prevention
23 K.Y. Hartigan-Go, Philippines Inclusion of therapeutic failures as adverse drug
J.Q. Wong reactions
24 I. Palmlund UK Secrecy hiding harm: case histories from the past
that inform the future
25 L. Marks UK The pill: untangling the adverse effects of a drug
26 D.J. Finney UK From thalidomide to pharmacovigilance:
a personal account
26 L.L. Iversen UK How safe is cannabis?
27 J.K. Aronson UK Louis LewinMeyler's predecessor
27 H. Jick USA The General Practice Research Database
28 J.K. Aronson UK Classifying adverse drug reactions in the 21st century
29 M. Hauben, A. Bate USA/Sweden Data mining in drug safety
30 J.K. Aronson UK Drug withdrawals because of adverse effects
31 J. Harrison, P. Mozzicato USA MedDRA: the Tale of a Terminology
32 K. Chan Australia Regulating complementary and alternative medicines

xxx
 Mechanistic and clinical
descriptions of
adverse drug reactions
Adverse drug reactions are described in the Side Effects of Drugs Annuals using two com-
plementary systems, EIDOS and DoTS [13]. These two systems are illustrated in Figures 1
and 2. Examples of their use have been discussed elsewhere [48].

1. EIDOS
The EIDOS mechanistic description of adverse drug reactions [3] has ve elements:

the Extrinsic species that initiates the reaction (Table 1);

the Intrinsic species that it affects;
the Distribution of these species in the body;
the (physiological or pathological) Outcome (Table 2), which is the adverse effect;
the Sequela, which is the adverse reaction.

Extrinsic species This can be the parent compound, an excipient, a contaminant or adulter-
ant, a degradation product, or a derivative of any of these (e.g. a metabolite) (for examples
see Table 1).
Intrinsic species This is usually the endogenous molecule with which the extrinsic species
interacts; this can be a nucleic acid, an enzyme, a receptor, an ion channel or transporter,
or some other protein.
Distribution A drug will not produce an adverse effect if it is not distributed to the same
site as the target species that mediates the adverse effect. Thus, the pharmacokinetics of
the extrinsic species can affect the occurrence of adverse reactions.
Outcome Interactions between extrinsic and intrinsic species in the production of an
adverse effect can result in physiological or pathological changes (for examples see
Table 2). Physiological changes can involve either increased actions (e.g. clotting due to
tranexamic acid) or decreased actions (e.g. bradycardia due to beta-adrenoceptor antago-
nists). Pathological changes can involve cellular adaptations (atrophy, hypertrophy, hyper-
plasia, metaplasia, and neoplasia), altered cell function (e.g. mast cell degranulation in
IgE-mediated anaphylactic reactions), or cell damage (e.g. cell lysis, necrosis, or apoptosis).
Sequela The sequela of the changes induced by a drug describes the clinically recognizable
adverse drug reaction, of which there may be more than one. Sequelae can be classied
using the DoTS system.

xxxi
xxxii Mechanistic and clinical descriptions of adverse drug reactions

1. EIDOS: a mechanistic description 2. DoTS: a clinical description

Drug Dose-relatedness

Drug
Extrinsic
on
u ti
trib
Dis

Intrinsic Outcome Patient Adverse reaction

Patient Adverse reaction Susceptibility factors Time course

Figure 1. The EIDOS and DoTS systems of describing adverse drug reactions.

Dose-relation
(benefit:harm)

Drug

Extrinsic
on
uti
trib

Outcome
Dis

Intrinsic Sequela
Patient Adverse reaction
Susceptibility Time course

Figure 2. How the EIDOS and DoTS systems relate to each other.
Mechanistic and clinical descriptions of adverse drug reactions xxxiii

Table 1 The EIDOS mechanistic description of adverse drug effects and reactions

Feature Varieties Examples

E. Extrinsic species 1. The parent compound Insulin

2. An excipient Polyoxyl 35 castor oil
3. A contaminant 1,1-Ethylidenebis
[L-tryptophan]
4. An adulterant Lead in herbal medicines
5. A degradation product formed Outdated tetracycline
before the drug enters the
body
6. A derivative of any of these Acrolein (from
(e.g. a metabolite) cyclophosphamide)
I. The intrinsic species and the
nature of its interaction with
the extrinsic species
(a) Molecular 1. Nucleic acids

DNA Melphalan

RNA Mitoxantrone
2. Enzymes

Reversible effect Edrophonium

Irreversible effect Malathion
3. Receptors

Reversible effect Prazosin

Irreversible effect Phenoxybenzamine
4. Ion channels/transporters Calcium channel blockers;
digoxin and Na/K-ATPase
5. Other proteins

Immunological proteins Penicilloyl residue hapten

Tissue proteins N-acetyl-p-benzoquinone-
imine (paracetamol
[acetaminophen])
(b) Extracellular 1. Water Dextrose 5%
2. Hydrogen ions (pH) Sodium bicarbonate
3. Other ions Sodium ticarcillin
(c) Physical or 1. Direct tissue damage Intrathecal vincristine
physicochemical 2. Altered physicochemical Sulindac precipitation
nature of the extrinsic species

D. Distribution 1. Where in the body the extrinsic Antihistamines cause

and intrinsic species occur drowsiness only if they affect
(affected by pharmacokinetics) histamine H1 receptors in the
brain
O. Outcome (physiological or The adverse effect (see Table 2)
pathological change)
S. Sequela The adverse reaction (use the
Dose, Time, Susceptibility
[DoTS] descriptive system)
xxxiv Mechanistic and clinical descriptions of adverse drug reactions

Table 2 Examples of physiological and pathological changes in adverse drug effects (some categories can be
broken down further)

Type of change Examples

1. Physiological changes
(a) Increased actions Hypertension (monoamine oxidase inhibitors); clotting (tranexamic acid)
(b) Decreased actions Bradycardia (beta-adrenoceptor antagonists); QT interval prolongation
(antiarrhythmic drugs)
2. Cellular adaptations
(a) Atrophy Lipoatrophy (subcutaneous insulin); glucocorticosteroid-induced myopathy
(b) Hypertrophy Gynecomastia (spironolactone)
(c) Hyperplasia Pulmonary brosis (busulfan); retroperitoneal brosis (methysergide)
(d) Metaplasia Lacrimal canalicular squamous metaplasia (uorouracil)
(e) Neoplasia

Benign Hepatoma (anabolic steroids)

Malignant
j Hormonal Vaginal adenocarcinoma (diethylstilbestrol)
j Genotoxic Transitional cell carcinoma of bladder (cyclophosphamide)
j Immune Lymphoproliferative tumors (ciclosporin)
suppression
3. Altered cell function IgE-mediated mast cell degranulation (class I immunological reactions)
4. Cell damage
(a) Acute reversible
damage

Chemical damage Periodontitis (local application of methylenedioxymetamfetamine [MDMA,
ecstasy])

Immunological Class III immunological reactions
reactions
(b) Irreversible injury

Cell lysis Class II immunological reactions

Necrosis Class IV immunological reactions; hepatotoxicity (paracetamol, after
apoptosis)

Apoptosis Liver damage (troglitazone)
5. Intracellular
accumulations
(a) Calcication Milk-alkali syndrome
(b) Drug deposition Crystal-storing histiocytosis (clofazimine)
Skin pigmentation (amiodarone)

2. DOTS
In the DoTS system (SEDA-28, xxviixxxiii; 1,2) adverse drug reactions are described
according to the Dose at which they usually occur, the Time course over which they occur,
and the Susceptibility factors that make them more likely, as follows:

Relation to dose

Toxic reactions (reactions that occur at supratherapeutic doses)

Collateral reactions (reactions that occur at standard therapeutic doses)

Hypersusceptibility reactions (reactions that occur at subtherapeutic doses in suscep-
tible individuals)
Mechanistic and clinical descriptions of adverse drug reactions xxxv

Time course

Time-independent reactions (reactions that occur at any time)

Time-dependent reactions
j Immediate or rapid reactions (reactions that occur only when a drug is administered

too rapidly)
j First-dose reactions (reactions that occur after the rst dose of a course of treatment

and not necessarily thereafter)

j Early reactions (reactions that occur early in treatment and then either abate with

continuing treatment, owing to tolerance, early tolerant, or persist, early persistent)

j Intermediate reactions (reactions that occur after some delay but with less risk

during longer term therapy, owing to the healthy survivor effect)

j Late reactions (reactions the risk of which increases with continued or repeated

exposure)
j Withdrawal reactions (reactions that occur when, after prolonged treatment, a drug

is withdrawn or its effective dose is reduced)

j Delayed reactions (reactions that occur at some time after exposure, even if the

drug is withdrawn before the reaction appears)

Susceptibility factors

Genetic

Age

Sex

Physiological variation (e.g. weight, pregnancy)

Exogenous factors (for example, the effects of other drugs, devices, surgical
procedures, food, smoking)

Diseases

The following reactions are described in SEDA-33 using the EIDOS and DoTS systems:

ACE inhibitors: angioedema 417

Adrenaline: ischemic tissue damage 315
Angiotensin II receptor antagonists: angioedema 418
Antipsychotic drugs: weight gain and diabetes mellitus 94
Benzocaine: methemoglobinemia 289
Bisphosphonates: osteonecrosis of the jaw 1009
Catecholamines: takotsubo cardiomyopathy 313
Cocaine: ischemic cardiac events 58
Contrast media: nephrotoxicity 965
Dapsone: hemolytic anemia and/or methemoglobinemia 630
Diuretics, loop and thiazide: hyponatremia and hypokalemia 439
Dopamine receptor agonists: pathological gambling 322
Dopamine receptor agonists: sleep attacks 322
Ephedrine: ischemic heart disease 317
Ergot-derived dopamine receptor agonists: brotic reactions 321
Ethambutol: optic neuropathy 634
Gadolinium salts: systemic brosis 969
Glucocorticoids: osteoporosis 843
Glucocorticoids, inhaled in COPD: pneumonia 353
Heparin: type II thrombocytopenia 714
Incretin mimetics: nausea and vomiting 896
Iodides: sialadenitis 965
Nitrofurantoin: lung disease 524
Statins: myopathy, myalgia, and rhabdomyolysis 925
Thiazolidinediones: reduced bone density and increased risk of fractures 899
Thionamides: agranulocytosis 884
Vigabatrin: visual eld loss 178
xxxvi Mechanistic and clinical descriptions of adverse drug reactions

The following reactions have also been described in previous editions of SEDA using the
DoTS system:

Adrenaline: hypertension 30.170

Anticoagulants, oral: skin necrosis 29.358
Antituberculosis drugs: hepatotoxicity 31.495
Pseudoephedrine: toxic epidermal necrolysis 30.172
SSRIs: suicidal behavior 29.19
Statins: acute pancreatitis 31.715
Ximelagatran: liver damage 30.411

References
1. Aronson JK, Ferner RE. Joining the DoTS. New approach to classifying adverse drug reactions.
BMJ 2003; 327: 12225.
2. Aronson JK, Ferner RE. Clarication of terminology in drug safety. Drug Saf 2005; 28(10):
85170.
3. Ferner RE, Aronson JK. EIDOS: A mechanistic classication of adverse drug effects. Drug Saf
2010; 33(1): 1323.
4. Callrus T. Use of the dose, time, susceptibility (DoTS) classication scheme for adverse drug
reactions in pharmacovigilance planning. Drug Saf 2006; 29(7): 55766.
5. Aronson JK, Price D, Ferner RE. A strategy for regulatory action when new adverse effects of a
licensed product emerge. Drug Saf 2009; 32(2): 918.
6. Caldern-Ospina C, Bustamante-Rojas C. The DoTS classication is a useful way to classify
adverse drug reactions: a preliminary study in hospitalized patients. Int J Pharm Pract 2010;
18(4): 2305.
7. Ferner RE, Aronson JK. Preventability of drug-related harms. Part 1: A systematic review. Drug
Saf 2010; 33(11): 98594.
8. Aronson JK, Ferner RE. Preventability of drug-related harms. Part 2: Proposed criteria, based on
frameworks that classify adverse drug reactions. Drug Saf 2010; 33(11): 9951002.
 How to use this book
THE SCOPE OF THE SIDE EFFECTS OF DRUGS ANNUALS

Volumes in the Side Effects of Drugs Annual (SEDA) series have been published since
1977. The series is designed to provide a critical account of new information relating to
adverse drug reactions and interactions. It complements the standard encyclopedic work
in this eld, Meyler's Side Effects of Drugs: The International Encyclopedia of Adverse
Drug Reactions and Interactions, the 15th edition of which was published in 2006.

PERIOD COVERED

The present Annual reviews all reports that presented signicant new information on
adverse reactions to drugs during the second half of 2008 and the whole of 2009; the next
volume (SEDA-34) will cover 2010. During the production of this Annual, some more
recent papers have also been included; older literature has also been cited when it is rele-
vant. Special reviews (see below) often cover a much wider range of literature.

SELECTION OF MATERIAL

In compiling the Side Effects of Drugs Annual particular attention is devoted to publica-
tions that provide essentially new information or throw a new light on problems already
recognized. Some conrmatory reports are also described. In addition, some authoritative
new reviews are listed. Publications that do not meet these criteria are omitted. Readers
anxious to trace all references on a particular topic, including those that duplicate earlier
work, or to cross-check an electronic search, are advised to consult Adverse Reactions
Titles, a monthly bibliography of titles from about 3400 biomedical journals published
throughout the world, compiled by the Excerpta Medica International Abstracting Service.

Special reviews
The special reviews deal in more detail with selected topics, often interpreting conicting evi-
dence, providing the reader with clear guidance. They are not restricted to literature pub-
lished in the period covered by the volume and are identied by the traditional
prescription symbol and are printed in italics. This volume includes a Cumulative Index of
the Special Reviews that were published in SEDA-11 to SEDA-32 and a list of the Special
Reviews that appear in the current Annual.

CLASSIFICATION OF DRUGS

Drugs are classied according to their main eld of use or the properties for which they
are most generally recognized. In some cases a drug is included in more than one chapter
(for example, lidocaine is mentioned in Chapter 11 as a local anesthetic and in Chapter 17
as an antidysrhythmic drug). Fixed combinations of drugs are dealt with according to their
most characteristic component or as a combination product.
xxxvii
xxxviii How to use this book

NAMES OF DRUGS AND CHEMICALS

Drugs are usually called by their recommended or proposed International Non-proprietary

Names (rINN or pINN); when these are not available, chemical names have been used. If a
xed combination has a generic combination British Approved Name (e.g. co-trimoxa-
zole for trimethoprim sulfamethoxazole) that name has been used; in some cases brand
names have been used instead. When the plus symbol () is used to link drug names (for
example, lopinavir ritonavir), it implies that the two drugs are administered either in
one formulation or in conjunction with one another; otherwise the word plus is used.
Chemicals are named according to the rules of the International Union of Pure and
Applied Chemistry (IUPAC; http://www.iupac.org); for example, we use aluminium,
not aluminum.

SYSTEM OF TAGGING REFERENCES

References in the text are tagged using the following system, which was introduced in
SEDA-24:

M A meta-analysis or other form of systematic review.

A An anecdote or set of anecdotes (i.e. case histories).
R A major review, including non-systematic statistical analyses of published studies.
r A brief commentary (e.g. in an editorial or a letter).
C A major randomized controlled trial or observational study.
c A minor randomized controlled trial or observational study or a non-randomized study.
H A hypothesis article.
E An experimental study (animal or in vitro).
S A statement from an ofcial body (e.g. Governments, WHO), a manufacturer, or a guidelines
group, or a statement about a forthcoming clinical trial.

The various editions of Meyler's Side Effects of Drugs are cited in the text as SED-l4,
SED-15, etc; the Side Effects of Drugs Annuals 132 are cited as SEDA-1, SEDA-2, etc.
References are cited in the bibliography to each chapter using the Vancouver method.
Titles of articles in [square brackets] are English translations of original titles.

INDEXES

Index of drugs: this index provides a complete listing of all references to a drug for which
adverse reactions and/or drug interactions are described.
Index of adverse reactions: this index is necessarily selective, since a particular adverse
reaction may be caused by very large numbers of compounds; the index is therefore mainly
directed to adverse reactions that are particularly serious or frequent, or are discussed in
special detail.
For indexing purposes American spelling has, with a few exceptions, been used, e.g.
anemia and estrogen rather than anaemia and oestrogen.
 Abbreviations

The following abbreviations are used throughout the book:

ADP adenosine diphosphate

APACHE acute physiology and chronic health evaluation [score]
ASA American Society of Anesthesiologists
AUC the area under the concentration versus time curve from zero
to innity
AUC0!x the area under the concentration versus time curve from zero to
time x
AUCt the area under the concentration versus time curve during a dosage
interval
bd twice a day (bis in die)
BMI body mass index
CAPD continuous ambulatory peritoneal dialysis
CD [4, 8, etc] cluster of differentiation (describing various glycoproteins that are
expressed on the surfaces of T cells, B cells, and other cells, with
varying functions)
CI condence interval
Cmax maximum (peak) concentration after a dose
Cmin minimum (trough) concentration after a dose
COX-1 and COX-2 cyclo-oxygenase enzyme isoforms 1 and 2
CT computed tomography
CYP [e.g. CYP2D6, cytochrome P450 isoenzymes
CYP3A4]
eGFR estimated glomerular ltration rate
ESR erythrocyte sedimentation rate
FDA [US] Food and Drug Administration
FEV1 forced expiratory volume in 1 second
G6PD glucose-6-phosphate dehydrogenase
HbA1c hemoglobin A1c
HDL, LDL, VLDL high-density lipoprotein, low-density lipoprotein, and very low
density lipoprotein [cholesterol]
HR hazard ratio
IGF insulin-like growth factor
INR international normalized ratio
IQ [range] interquartile [range]
MAC minimum alveolar concentration
MIC minimum inhibitory concentration
MIM Mendelian Inheritance in Man (see http://www.ncbi.nlm.nih.gov/
omim/607686)
MRI magnetic resonance imaging
NNT, NNTB, number needed to treat [for benet, for harm]
NNTH
NSAIDs non-steroidal anti-inammatory drugs
xxxix
xl Abbreviations

od once a day (omne die)

OR odds ratio
PCR polymerase chain reaction
PPAR peroxisome proliferator-activated receptor
RR risk ratio or relative risk
SNP single nucleotide polymorphism
tds three times a day (ter die summendum)
tmax the time at which Cmax is reached
Vmax maximum velocity [of a reaction]

SIDE EFFECTS OF DRUGS ESSAY
Third-generation
oral contraceptives:
time to look again?
It is difcult to say what an essay is . . ..
Remembering its French origin in essai,
perhaps one may call the essay simply
an attempt to open out a subject.
Chambers and King [1]
The history of the oral contraceptives
and their association with thromboembolic
complications has been repeatedly
reviewed in these volumes, and with good
reason. No apology is needed for consider-
ing the issue anew, since concerns persist,
and it seems that there is remarkably little
solid evidenceperhaps none at allto
allay them. That, surely, is sufcient reason
to broach the subject once more in an
essay, in the hope that others will now take
a much closer look and succeed in penetrat-
ing to the truth of the matter.
THREE GENERATIONS
The rst generation of the oral contracep-
tive products, introduced in around 1960,
*Professor M. N. G. Dukes is a physician and inter-
national lawyer who has worked in pharmaceutical
research management, public health, and develop-
ment aid. He edited Meyler's Side Effects of Drugs
from 1975 to 2000 and the Side Effects of Drugs
Annuals from 1977 to 1992. He is currently
External Professor of Drug Policy Studies at the
University of Oslo, Norway.
Graham Dukes*
was widely and properly welcomed as con-
stituting a breakthrough in family planning.
The method was simpler and considerably
more reliable than anything that had pre-
ceded it. However, within a few years it
became unhappily evident that these prod-
uctstypically comprising up to 5 mg of a
progestogen (such as norethinodrel, nor-
ethisterone, levonorgestrel, or lynestrenol)
and 150 micrograms of the estrogen mestra-
nolwere associated with a signicant inci-
dence of thromboembolic complications.
The response to the problem took time,
but it ultimately became clear that consid-
erable reductions in the doses of both com-
ponents were both feasible and necessary.
The dose of progestogen was lowered to
2.5 mg and thereafter typically to 1 mg or
less; mestranol was replaced by the more
potent ethinylestradiol, and the dose of
the latter was reduced markedly, in some
cases to a mere 30 micrograms. These
changes proved to be possible without any
loss of contraceptive effect. The resulting
products were not all of identical composi-
tion, but the risk of thromboembolic
complications had clearly been contained,
or at least reduced to a tolerable level. As
a group, the reformulated products became
known as the second generation of oral
contraceptives.
So it was in the 1980s, and so it might
well have remained, but for one element:
the expiry of patents. The estrogen mestra-
nol enjoyed no patent protection, but
xli
xlii
norethinodrel had been patented in the
USA as early as 1954, norethisterone in
1956, and lynestrenol in 1958, while
levonorgestrel was patented in Britain in
1961 [2]. Two decades further on such pro-
tection would expire, and manufacturers of
generic products would then be at liberty to
use these substances freely, marketing
unbranded products at substantially lower
costs. By all accounts, therefore, research-
based rms with interests in the eld set
about searching for new progestogenic
molecules that would replace their older
congeners and earn patents of later date,
enjoying protection for a further period.
In due course, several such newly synthe-
sized substances, eligible to play this role,
emerged. Desogestrel had been developed
by the Organon company, and patent appli-
cations that were lodged in Germany in
1973 [3] and in the Netherlands in 1974 [4]
were duly granted. It was introduced in
Britain as Marvelon (containing 150
micrograms of desogestrel with 30 micro-
grams of ethinylestradiol) and Mercilon
(with a lower dose of the estrogen). Simi-
larly, the Schering company developed the
progestogen gestodene: it introduced it as
a component of Femodene (Femovan),
which contained 75 micrograms of the pro-
gestogen and 30 micrograms of ethinyl-
estradiol. Other combinations that included
gestodene were marketed under licence by
the Wyeth company. As a group these refor-
mulated products became known as the
third generation of oral contraceptives.
Even more recently, a further series of
progestogens (such as drospirenone) have
emerged, which some workers have
regarded as comprising a fourth generation
[5, 6], a matter to which we shall return
shortly.
RENEWED CONCERN
During the years that followed the market-
ing of the third generation of products, a
series of publications appeared in the
Third-generation oral contraceptives: time to look again?
medical literature, voicing the fear that with
their appearance the risk of thrombo-
embolic complications had once more
increased. In October 1995 the UK regula-
tory authorities informed all physicians
and pharmacists of three new (and at the
time still unpublished) epidemiological
studies that suggested that combined oral
contraceptives of the third generation
caused an approximately twofold increase
in the risk of venous thromboembolism; a
series of precautions with regard to the
use of these products was set out and the
data sheets were revised accordingly [7].
Although the regulatory authorities of the
European Union did not follow the British
lead, considering that further evidence was
still needed, matters in Britain came to a
head in court. Civil actions were brought
against the companies owned in the United
Kingdom by Schering, Organon, and
Wyeth on behalf of a series of women or
their families who claimed to have suffered
the ill effects of the third generation of
products in the form of serious (and in
some instances fatal) episodes of venous
thromboembolism.
The litigation, before Mr. Justice Mackay
in the High Court in London, was consid-
ered in detail in SED-15 (pp. 16512). As
anyone who was present in court can attest,
the hearings were marked by a series of
direct and sharp conicts between medical
statisticians giving evidence for the plain-
tiffs or the defendants. Having considered
the evidence, the learned judge issued on
29 July 2002 an extensive judgement on a
series of lead cases [8]. Following a critical
consideration of the facts, the contradic-
tions, and the uncertainties, and the some-
times defective quality of the evidence, he
came to the conclusion that the products
of the third generation did indeed carry a
greater risk of complications than those of
the second generation. As he put it, The
most likely gure to represent the relative
risk is around 1.7.
Since the parties had agreed in advance
that the plaintiffs cases should be allowed
only if the risk was at least doubled, the
claims for damages failed. Not surprisingly,
Third-generation oral contraceptives: time to look again?
the subsequent press releases by defen-
dants to the media stressed the failure of
the claims, rather than the judge's nding
that with the introduction of the third-gen-
eration products the risk had indeed been
increased, apparently by some 70%. Here
one must pause for a moment to reect on
what this means. If the learned judge was
right in his assessment, then among the mil-
lions of women using the pill the propor-
tion of users likely to suffer clinically
manifest (and sometimes fatal) thrombo-
embolic events must have risen by some
two-thirds once they started to take the
third-generation products rather than those
of the second generation. One must also
realize that no clear added benet
appeared to have been demonstrated with
the new products, such as might have out-
weighed the added risk. In theory they
might have a benecial effect on the lipid
prole, but even in large casecontrol stud-
ies one has seen no reduced incidence of
stroke or myocardial infarction [9, 10].
It would seem that the move to the third
generation was a matter of patents, prices,
and prots, no more than that.
PROFILING THE RISK
In the continuing debate about the third
generation of oral contraceptives one rele-
vant consideration sometimes appears to
have received too little attention. That is
the possibilityand even the extreme like-
lihoodthat the thromboembolic risks of
the oral contraceptives are particularly pro-
nounced in a subgroup of users who are
identiable in advance and can thus be
excluded from exposure to products that
carry a relatively high risk. In the mid-
1990s, a team at Leiden University in The
Netherlands advanced evidence that such
a well-dened subpopulation of individuals
at particular risk did indeed exist; it com-
prised carriers of the thrombogenic factor
V Leiden mutation [11]. When 126 women
of fertile age who had had episodes of deep
xliii
vein thrombosis were compared with 259
control subjects, the highest age-adjusted
relative risk for thrombosis (with a mean of
8.7) was associated with a third-generation
product based on desogestrel; lower relative
risks (ranging from 2.2 to 3.8) were found
for all other types of oral contraceptive.
However, the most striking nding was that
among carriers of the factor V Leiden muta-
tion the risk of deep vein thrombosis with
desogestrel-based products was almost
50 times higher than in non-carriers who were
not using an oral contraceptive. The risk of
using desogestrel products was also higher,
as one might have expected, in women with
a family history of deep vein thrombosis.
The numbers of women in the study popula-
tion using other third-generation products
were too small to draw conclusions.
Two years later complementary evidence
was provided by a group working else-
where in the Netherlands on thrombin for-
mation [12]. Their ndings were at the
time concisely summarized under three
headings in a commentary by Vanden-
broucke and Rosendaal in The Lancet
[13]. To quote them literally,
One, third-generation oral contracep-
tives induce a resistance to the blood's nat-
ural anticoagulation system (APC-
resistance) of almost the same magnitude
as the resistance induced by a mutation in
coagulation factor V (factor V Leiden);
two, second-generation contraceptives
show only part of this effectin that users
of second-generation pills can be clearly
demarcated both from women not on oral
contraceptives and from women on third-
generation pills; three, in women hetero-
zygous for the factor V Leiden mutation
who take oral contraceptives, APC-resis-
tance is as high as that among homozygotes
for the mutation.
To put it simply, this work further delin-
eated the nature of the thromboembolic
risk associated with oral contraceptives as
a whole, dened more clearly the suscepti-
ble groups, and also underlined the particu-
lar problem attached to products of the
third generation.
xliv
A FOURTH GENERATION?
Of the progestogens that have emerged still
more recently from the laboratory (the so-
called fourth generation), drospirenone
has been the most prominent, having been
developed for contraceptive purposes in a
series of combinations with an estrogen.
One of these, which contains 3 mg of dro-
spirenone plus 30 micrograms of ethinyl-
estradiol, has been marketed under the
name Yasmin, with a variant known as
Yaz. These products have given rise to
various controversies of their own [14],
but again thromboembolism has come to
the fore. In 2003 the suspicion was voiced
that drosperidone-based contraceptives
might be just as likely to cause thrombo-
embolism as products of the third genera-
tion [15]; 1 year later, an inter-university
study group in The Netherlands showed that
the combination did indeed increase APC-
resistance, just as the products of the third
generation had done. Not unexpectedly, a
subsequent casecontrol study in that same
country showed that the thrombotic risk was
at least as high with drospirenone combina-
tions as with the third generation, and
perhaps rather higher [16]. Almost simulta-
neously, a national follow-up study in
Denmark independently conrmed these
ndings [17], and as we shall see, there was
more to come. One might add that, in both
of these studies and others, similar ndings
were reported for another product in which
the progestogen used was cyproterone.
THE DEFENDERS
However concerned one may be, it is only
fair to examine whatever arguments have
been advanced by those who continue to
champion either the products of the third
generation or those that have emerged still
later. When, at a drug policy meeting orga-
nized by Healthy Skepticism in Amsterdam
in October 2010, a speaker pointed to per-
sisting concerns about thromboembolism,
a medical spokesman for a pharmaceutical
Third-generation oral contraceptives: time to look again?
company stood up to assure the audience
that the industry was now aware of substan-
tial evidence for the safety of the third-gen-
eration products. To date, unfortunately,
it remains unclear where satisfactory evi-
dence to this effect is to be found. The most
widely cited sources for such a view appear
to be two papersfrom 2007 and 2010
respectivelycommissioned or nanced by
Bayer Schering Pharma and published
from Berlin. The rst of these reported a
European Active Surveillance study on
Oral Contraceptives, commissioned by
the manufacturer of drospirenone. It was pri-
marily concerned with that drug, although it
also involved a series of others and extended
to issues beyond thromboembolism. Summa-
rizing 142 475 women-years of observations
[18] its authors concluded in so many
words that . . . Risks of adverse cardiovascu-
lar and other serious events in users of a
drospirenone-containing oral contraceptive
are similar to those associated with the use
of other oral contraceptives.
At rst sight the discrepancy between
this comfortable conclusion and the solidly
incriminating ndings of the drospirenone
studies in the Netherlands and Denmark
seem puzzling, but a closer look provides
a series of explanations. First, the work
related to a whole series of adverse events,
of which venous thromboembolism was
only one; secondly, although a comparison
with levonorgestrel-based products of the
second generation was properly included,
the formulations in use varied, the estrogen
content being either less than 30 micro-
grams or more than 30 micrograms in half
the subjects involved, while a sixth of this
group were using a sequential rather than
a monophasic formulation; thirdly, the reas-
suring general conclusion related to a com-
parison of drospirenone formulations with
all others, the latter even including third-
generation products.
Similarly, one experiences certain doubts
regarding the second of the industry-spon-
sored Berlin studies, which centred on
gestodene and was published in 2010 [19].
To their credit, the authors themselves
expressed a series of reservations, because
of the constraints under which their work,
Third-generation oral contraceptives: time to look again?
in Austria, had been performed. Neverthe-
less, to quote their cautious conclusion, this
casecontrol study does not suggest that
there is an increased risk of venous throm-
boembolism for users of oral contraceptives
containing gestodene compared with users
of second-generation oral contraceptives.
Findings in earlier studies may indeed, as
these investigators argued, have been inu-
enced to some extent by the time factor;
users of second-generation products had
commonly taken them for 8 years or more
at a time when their experiences were com-
pared with those of women taking third-
generation contraceptives, who tended to
be in an earlier phase of treatment. Since,
in the view of the Berlin group, the risk of
thromboembolic complications may be
higher during the early months of use, this
could have adversely affected the adverse
effects data in the third-generation group.
Arguments such as these merit consider-
ation, although the question remains
whether they could possibly attenuate
the impressive and incriminating evidence
derived from earlier laboratory and
casecontrol studies.
THE VIEW TODAY
Two decades have elapsed since the earliest
expressions of concern that the oral contra-
ceptives of the third generation might be
less safe than their predecessors. Many
more grounds for worry have appeared in
print as the years have gone by. Authorita-
tive recent studies only seem to have con-
rmed that the risks are at least as great
as was estimated in the 1990s; independent
reviews appear to have underlined that
conclusion [20, 21]. Defence of these prod-
ucts has at times been vigorous but (per-
haps inevitably) awed, with every shot
from the ramparts promptly challenged by
new assaults. At the moment of writing that
is most clearly the case where the drospire-
none-based products are concerned. The
Berlin studies in their defence have been
xlv
followed by the appearance of two large
nested casecontrol studies from Susan
Jick's group, which have further empha-
sized the degree of risk attached to the
drospirenone products, contrasted with sec-
ond-generation levonorgestrel combina-
tions that contain 30 micrograms of
estrogen. The rst study [22], built around
186 American cases of thromboembolism,
points to a mean relative risk of no less
than 2.8 (2.13.8). The second study [23],
based on 61 British cases plus controls, sim-
ilarly showed a relative risk of 2.7 (1.54.7),
contrasted with the levonorgestrel product.
Differences between the treatment and
control groups, including age, duration of
contraceptive use, or pre-existing suscepti-
bility factors, were examined, but none suf-
ced to explain the striking differences in
the risks associated with the two products.
In retrospect, one is bound to wonder
whether the originators of drospirenone
tested in the early stages its effect in the
APC-resistance test; that would have pro-
vided in good time a pointer to its apparent
potential for thrombogenesis.
CONCLUSIONS
The battle around drospirenone is not the
rst to be fought in the eld of oral contra-
ception, and it seems unlikely to be the last.
However, over a longer period one sees
that such dramatic skirmishes have alter-
nated with an uneasy calm, during which
the regulators and experts step aside to
deal with other conundrums; at some
moments one senses a vague belief and
hope that, given time, the thromboembo-
lism problem will simply go away. Regula-
tors have been heard justifying their
inaction in the matter, on the grounds that
society has a duty to demand absolute
proof of a problem before taking restrictive
action; but if that were true, would we not
still be hopefully treating dyspepsia with
Mother Seigel's Syrup, which consisted pri-
marily of hydrochloric acid and treacle [24]
xlvi
and consuming a range of quack medicines
contained conventional treatments (such as
opium and ipecacuanha in Dover's pow-
der), poisons (such as hemlock), or nothing
of value whatsoever [25]? And here and
there a faintly protesting voice still argues
that the pill is no more risky than preg-
nancy. Is that true? And if it is indeed so,
is that a sufcient reason to tolerate the
imposition of risks on healthy women,
when they can be avoided or reduced?
It is surely time for patients and pre-
scribers, regulators and lawyers to demand
greater clarity in these matters. Issues of
public health are rarely black and white,
but that is no reason to ignore shades of
grey. One cannot leave vital questions
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[1] Chambers R, King C. A book of essays.
Preface. Toronto: Macmillan of Canada;
1963.
[2] Patent data are as cited by Kleemann A,
Engel J. Sostanze Farmmaceutiche: Sintesi,
Brevetti, Applicazioni Milano: OEMF;
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[3] Deutsches Bundespatent. DBP 2.361.120.
[4] Netherlands Patent 7.411.607.
[5] Sitruk-Ware R. New progestagens: a review
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[6] Anonymous. Progestin. Wikipedia. Last
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[7] Rawlins MD. Dear Doctor/Pharmacist let-
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[8] High Court: XYZ (Claimants) and others
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Holzmann I, Bruppacher R. Casecontrol
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unanswered and important business unn-
ished. This is an area in which we have
much reason to believe that unnecessary
harm has been done and may continue to
be done unless proper action is taken.
If we are wrong in that belief, so be it. At
the very least, society should now try to
penetrate to the truth and accept whatever
consequences that truth may bring with it.
Acknowledgements
The author would like to express his
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of the University of Leiden, who critically
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1 Central nervous system
stimulants and drugs that
suppress appetite
AMPHETAMINES [SED-15, 180;
SEDA-30, 1; SEDA-31, 1; SEDA-32, 1]
Note on spelling In International Non-
proprietary Names (INNs) the digraph -ph-
is usually replaced by -f-, although usage is
not consistent, and -ph- is used at the begin-
nings of some drug names (for example, com-
pare fenuramine and phentermine) or when
a name that begins with a ph- is modied by
a prex (for example, chlorphentermine).
For the amphetamines the spellings that
are used in SEDA are as follows: amfetamine,
benzfetamine,dexamfetamine,metamfetamine
(methylamphetamine), and methylenedioxy-
metamfetamine (ecstasy); however, for the
general term for the group of drugs the more
common spelling amphetamines is used.
Amfetamine and dexamfetamine
[SEDA-30, 1; SEDA-32, 1]
Systematic reviews A search of 2187 articles
and 9 grey literature sources identied 72
studies of amfetamine-related mortality,
seven of which provided data from cohort
studies of users. The estimated crude mortal-
ity rates ranged from 0 in Australia to 2.95
Side Effects of Drugs, Annual 33
J.K. Aronson (Editor)
ISSN: 0378-6080
DOI: 10.1016/B978-0-444-53741-6.00001-5
# 2011 Elsevier B.V. All rights reserved.
Reginald P. Sequeira
(CI 1.45, 4.59) in Thailand. The Czech
cohort reported only the standardized mor-
tality rate, which was 6.22 overall [1C]. This
variation in death rate suggests that mortal-
ity among amfetamine users varies geo-
graphically in important ways. The low
mortality rate in the Czech cohort may have
been explained by the absence of AIDS-
related deaths [2c]. The high death rates in
the Dutch cohort were not consistent with
data that suggest that access to both harm
reduction (needle and syringe programs)
and treatment services for general health
care were high during the period of study
[3C]. There is evidence that injection of
amphetamines was associated with a higher
mortality than other primary routes of
administration [4C]. This is consistent with
the well-documented increased risks in
intravenous users of HIV and hepatitis C
infections, both of which cause substantial
morbidity and mortality [5c]. There was evi-
dence that length of amfetamine use was
associated with a high mortality rate in those
who had been users for 5 years or more. It is
unclear how mortality among amfetamine
users varies with age.
Cardiovascular There is no evidence at
present to support the use of amfetamine
to enhance recovery after stroke. Despite
a trend to improved motor function, doubts
remain over its safety and it has signicant
hemodynamic adverse effects, the conse-
quences of which are unknown. Further-
more, there are insufcient data from which
to draw conclusions regarding the effects of
1
2 Chapter 1
amfetamine on mood or communication or
quality of life [6M]. Both raised blood pres-
sure and raised heart rate are associated with
poor outcomes after stroke [7C], as is
impaired baroreceptor sensitivity with
increased cardiac events and dysrhythmias
[8C]. Despite concerns regarding increasing
heart rate and blood pressure, up to a fth
of patients with acute strokes have low blood
pressure, and hypotension is associated with
a poor outcome [9M].
Cardiomyopathy due to a toxic effect of
Adderall, intermediate in onset, with
uncertain susceptibility factors such as pre-
existing coronary artery disease and
possibly drugdrug interactions, has been
reported [10A].
A 33-year-old man treated with Adderall
(dexamfetamine amfetamine) for ADHD.
Adderall was started initially at 20 mg daily
and two months later increased to 40 mg,
and uoxetine 20 mg/day was added as a
mood stabilizer. Seven months later the daily
dosage of both drugs doubled, and a month
later Adderall was again increased to 80 mg
bd. On the higher dose of Adderall, the
patient experienced increased hyperactivity
and irritability. Two months later, he devel-
oped symptoms of abdominal pain, vomiting,
and cough that lasted a month. He was diag-
nosed as having a cardiomyopathy and
underwent a successful cardiac transplant.
Microscopic examination of heart tissue
revealed (a) focally severe coronary athero-
sclerosis of the proximal right coronary artery;
(b) cardiomyopathy, mild cardiomegaly, with
biventricular myocyte hypertrophy; (c) mild
focal nonspecic interstitial myocarditis sug-
gestive of hypersensitivity; and (d) fatty inl-
tration on the right ventricular myocardium.
The contribution of coronary artery athero-
sclerosis to the development of cardiomyopa-
thy was uncertain.
There have been eight previously reported
cases of cardiomyopathy associated with
Adderall. Whether an interaction between
Adderall and uoxetine would have contrib-
uted to the cardiomyopathy in this patient is
uncertain.
Death In a matched casecontrol study,
mortality data from 1985 to 1996 were used
to identify 564 cases of sudden death at
ages 719 years across the USA, and a
Reginald P. Sequeira
matched group of 564 young people who
died as passengers in motor vehicle trafc
accidents [11C]. There was a signicant
association of stimulant use with sudden
unexplained death. The primary exposure
measure was the presence of amfetamine,
dexamfetamine, metamfetamine, or methyl-
phenidate, according to informant reports
or as noted in medical examiner records,
toxicology results, or death certicates. In
10 of the sudden unexplained deaths
(1.8%) the youths had taken stimulants,
specically methylphenidate; in contrast,
only two subjects in the motor vehicle acci-
dent comparison group (0.4%) had used
stimulants, and only one case involved
methylphenidate. As a result of this study,
the US Food and Drug Administration
issued a safety communication, stating
that given the limitation of this study, it
was unable to conclude that these data
affect the overall benet to harm prole
of stimulant medications used to treat
ADHD in children [12S]. The FDA advised
health-care professionals to follow the
current prescribing information, including
taking a medical history for cardiovascular
disease and performing a physical exam-
ination focusing on the cardiovascular
system.
Susceptibility factors Genetic Further evi-
dence that genetic variants in the SLC6A2
gene are involved in acute responses to
amfetamine, which may progress to
amfetamine abuse, has been reported [13C].
In a three-session, double-blind, crossover
study, 162 healthy Caucasians (90 men),
aged 1835 years took either a placebo or
oral dexamfetamine (10 or 20 mg). The
associations between the degrees of self-
reported elation and vigor after amfetamine
and single nucleotide polymorphisms
(SNPs) and SNP haplotypes in SLC6A2
were determined. SNPs rs36017 and
rs1861647 were associated with signicantly
higher ratings of elation and vigor after
amfetamine 20 mg. Ratings of vigor after
amfetamine 20 mg were also associated with
a two-SNP haplotype formed with rs1861647
and rs5569 and a three haplotype formed
Central nervous system stimulants and drugs that suppress appetite
with rs36017, rs10521329, and rs3785155.
The authors postulated that people with
genotype C/C at rs36017 or with genotype
A/A at rs1861647 would experience more
profound increases in feelings of vigor and
elation after taking amfetamine and would
therefore be more inclined to use
amfetamine again. It is unclear whether the
highly linked polymorphisms are in linkage
dysequilibrium with a functional variant that
has not been identied yet or whether these
polymorphisms directly inuence mRNA
processing, stability, or splicing. Neverthe-
less, these ndings add to a growing litera-
ture on the genetic determinants of
responses to amphetamines. Such studies
are important because acute differences in
responses to a drug may contribute to vari-
ability in the risk of abuse and drug
dependence.
Drug overdose Outcomes after accidental
amfetamine ingestion in children under 7
years have been evaluated in a retrospec-
tive chart review over 4 years (January
2003 to December 2007) in 118 patients,
average age 3.1 years (range 8 months to
7 years), of whom 90 (76%) were nave
to the medication and accidentally
ingested amfetamine prescribed for sib-
lings [14c]. In all, 28 took a double dose
of their normally prescribed medication,
of whom 25 were observed at home and
developed no or minimal symptoms; three
were referred to an emergency depart-
ment with headache or mild agitation but
were subsequently discharged. In all, 76
developed symptoms and were evaluated
at a health-care facility; 15 received ben-
zodiazepines for agitation and 16 were
observed for more than 12 hours. All
the patients had favorable outcomes.
Although toxic exposure in this study
resulted in mild to moderate symptoms,
amfetamine exposure has the potential
to cause severe adverse effects. Therefore,
toxic exposure should be evaluated and
treated individually based on the symp-
toms each patient has.
Chapter 1 3
Ecstasy (3,4-
methylenedioxymetamfetamine,
MDMA)
See Chapter 4.
Metamfetamine [SEDA-30, 2;
SEDA-31, 1; SEDA-32, 3]
Cardiovascular It is generally presumed that
in patients who develop chest pain after using
amfetamine the risk of acute myocardial
infarction is increased [15c]. However, in a
systematic review, although there was a high
incidence of acute coronary syndrome in
patients with chest pain after metamfetamine
ingestion, there was no evidence that the inci-
dence of acute myocardial infarction was
increased [16R]. Evolving diagnostic criteria
[17C] were used: acute coronary syndrome
diagnosis was based on measurement of myo-
cardial creatine kinase (CK-MB) and also
included unstable angina, which is diagnosed
in patients with angina and a normal CK-
MB relative index and evidence of myocar-
dial ischemia on non-invasive cardiac stress
testing or signicant coronary artery disease
by coronary angiography.
The prevalence of self-reported illicit use
of cocaine and/or metamfetamine in
patients with acute decompensated heart
failure has been studied, using a multi-
center observational registry, in 11 258
patients, of whom 594 (5%) had previously
used cocaine (96%) and/or metamfetamine
(5%) [18C]. Users had a median age of 50
years compared with 76 years in non-users.
As there were disproportionately more
young AfricanAmerican men with hyper-
tension, left ventricular systolic dysfunction,
and markedly raised B-type natriuretic pep-
tide concentrations, the authors speculated
that the severity of cardiac dysfunction in
these young patients would probably result
in higher morbidity, mortality, and health
costs. Although these patients had a greater
degree of left ventricular dysfunction (ejec-
tion fraction <40%), they did not have a
greater risk-adjusted mortality.
4 Chapter 1
In a casecontrol chart review, 107
metamfetamine users and 114 controls
were identied [19C]. The two groups had
similar sex distribution, length of hospital
stay, prevalence of coronary artery disease,
diabetes mellitus, hypertension, cigarette
smoking, and alcohol, marijuana, and cocaine
abuse. The cases were older than the controls
(mean age 38 versus 35 years), had higher
values of BMI (37 versus 30 kg/m2), and had
a higher prevalence of renal insufciency
(13% versus 4.4%). Metamfetamine users
had a 3.7-fold higher odds ratio for
cardiomyopathy, after adjusting for age,
BMI, and renal insufciency. LVEF was
signicantly lower in cardiomyopathy
patients with metamfetamine use.
Nervous system Use of metamfetamine is
associated with ischemic stroke, intracereb-
roventricular hemorrhage, and subarachnoid
hemorrhage, especially among young indi-
viduals. All cases of subarachnoid hemor-
rhage were aneurysmal, and most were
located in the anterior circulation, as were
most of the strokes. Although in many cases
imaging conrmed arterial stenosis in the
vascular distribution of the stroke, there
was no evidence that the ischemic stroke
associated with the use of metamfetamine
was due to an inammatory cause rather than
a process of accelerated atherosclerosis [20C].
These conclusions were based on a retrospec-
tive chart review of admissions to a tertiary
care neurovascular service from January
2003 to July 2007; there were 30 cases out of
1574 patients who had used metamfetamine,
documented by history or urine toxicology
screening. There was an apparent selection
bias in this study: neither the duration nor
the severity of substance use was estimated.
Nevertheless, metamfetamine is a susceptibil-
ity factor for stroke in young adults, consis-
tent with previous reports [21c, 22c]. It is
likely that various stroke subtypes are related
to metamfetamine-induced hypertension-
related vascular pathology rather than vascu-
litis, as has been suggested before [23R, 24c].
In 20 adults with a conrmed history of
metamfetamine use and dependence, curr-
ently engaged in rehabilitation and conrmed
to have been abstinent for an average of
Reginald P. Sequeira
6 months, there was memory impairment
compared with 20 metamfetamine-naive par-
ticipants [25c]. These memory decits did not
vary as a function of specic memory task
demands. Of all the cognitive measures, cog-
nitive inhibition shared greatest variance with
group effects on the prospective memory
measure.
Periventricular leukomalacia has been
reported after prenatal metamfetamine
exposure [26A].
A 23-year-old woman gave birth to a male
infant weighing 1080 g at 30 weeks of gestation.
She reported using metamfetamine and mari-
juana once 3 days before delivery and denied
any other drug use during pregnancy. After
cesarean section the infant's Apgar scores were
6 at 1 minute and 7 at 5 minutes. The initial cap-
illary pH was 7.27, with a PaCO2 of 6.9 kPa and
a base decit of 4 mmol/l. A drug screen of
meconium was positive for metamfetamine
(850 ng/g) and tetrahydrocannabinol (54 ng/
g). Cranial ultrasound at 1 week was
unremarkable, but at 6 weeks it was highly
abnormal, with multiple small cysts bilaterally
in the subependymal white matter anterior
to the lateral ventricle consistent with
periventricular leukomalacia. Ophthalmology
was normal. At 24 months he had severe devel-
opmental delay, with spastic quadriplegic cere-
bral palsy.
The authors thought that this patient had no
risk factors for periventricular leukomalacia,
except for prematurity. They also thought
that the cranial ultrasound results at weeks
1 and 6 were consistent with a history of
metamfetamine exposure at 3 days before
birth. They postulated that metamfetamine
had caused cerebral ischemia and subse-
quent destruction of white matter and cyst
formation 6 weeks later. However, they
acknowledged that other factors could have
contributed to the pathophysiology, includ-
ing contamination of metamfetamine.
Gastrointestinal Occult metamfetamine
abuse should be considered when young
patients present with signs and symptoms
suggestive of ischemic colitis.
A 44-year-old man developed ischemic colitis
after abusing crystalline metamfetamine
[27A]. Although a direct causal relation was
not established, the temporality in this case,
Central nervous system stimulants and drugs that suppress appetite
with the absence of classic susceptibility fac-
tors, made metamfetamine the presumptive
etiology.
Drug abuse In the York Region in Toronto,
Canada, a new strategy has been developed
to curb metamfetamine use, modeling on
Vancouver's four-pillar drug strategy (pre-
vention, treatment, harm reduction, and
enforcement) [28S]. However, more than
70% of Vancouver's street-involved
youth have used metamfetamine and
metamfetamine use increased signicantly
in intravenous drug users, from 2% to 15%
in 8 years, despite Vancouver's four-pillar
strategy [29r]. It may therefore be
unjustiably optimistic to anticipating that
the supply of metamfetamine can be
suppressed, as, unlike other drugs,
metamfetamine can be inexpensively pro-
duced locally, and the likelihood that law
enforcement can successfully curbing the
growth in the supply of metamfetamine is
exceedingly small. There is also pessimism
about the benets of antidrug media cam-
paigns and Drug Abuse Resistance Educa-
tion (DARE) programs.
It has been suggested that D-
metamfetamine hydrochloride, or crystal
meth, is more likely to cause dependency
than other forms of metamfetamine [30r].
When smoked or injected it causes an
almost immediate rush, compared with
20 minutes after oral ingestion. It is used
rectally as well as snorted. The authors also
stated that when compared with cocaine,
crystal meth . . . can keep the user up
for 12 hours. A user binging in crystal meth
(on a run) may stay awake for 10 days.
Prolonged use can lead to tweaking or
psychosis with extreme paranoia and result
in body scabs from picking at imaginary
bugs crawling on or under the skin. About
25 million people worldwide may have used
amphetamine and metamfetamine in 12
months, making it the most widely used
illicit drug after cannabis. Although the
authors appreciated the reported decline
in the use of amphetamines among school
students, they did not believe that it is
enough. The reasons for using crystal meth
among women may include a desire to lose
Chapter 1 5
weight; in men it often improved sex per-
formance. Self-identied gay/bisexual stu-
dents were 26 times more likely to have
used crystal meth in the previous year.
Street youth reportedly used crystal meth
as a coping strategy against negative emo-
tions and circumstances. The authors
acknowledged that pharmacological treat-
ment is challenging, as there is no effective
medication for amphetamine abuse; non-
pharmacological treatments, although
effective, may not have enduring effects.
Bellemare reacted to this article by raising
unique child protection concerns that are
associated with the use and production of
crystal meth, which are not relevant to
other drugs [31r]. The specic concerns
were about children who live in places
where metamfetamine is produced. Besides
neglect of child care by those who are
actively engaged in metamfetamine produc-
tion, these laboratories can explode, expose
children to strangers and drug users, and
expose them to drug seeking behaviors,
including hypersexuality and sexual abuse.
The author strongly urged clinicians to
exercise their legal and moral duty to pro-
tect these children by calling the child wel-
fare authorities as appropriate.
Teratogenicity In 29 children, aged 34
years, who had been exposed to
metamfetamine in utero, and 37 unexposed
children, fractional anisotropy and appar-
ent diffusion coefcients were determined
in various parts of the brain [32c]. There
were alterations in white matter maturation,
involving more compact axons or greater
dendritic density. The ndings of this study
were confounded by incomplete drug histo-
ries from some subjects, which could have
minimized or exaggerated the effects of
metamfetamine. In addition, genetic and
environmental inuences cannot be ruled
out as a source of lower white matter diffu-
sion. It is also not known whether the diffu-
sion changes observed in metamfetamine-
exposed children remain low, normalize,
or become higher with age.
The molecular mechanisms that might be
responsible for metamfetamine neurotoxicity
include oxidative stress, activation of
6 Chapter 1
transcription factors, DNA damage,
excitotoxicity, bloodbrain barrier break-
down, and various apoptotic pathways [33ER].
Congenital cataract with triangular mor-
phology has been reported in association
with prenatal metamfetamine exposure
[34A]. Although this association was proba-
bly coincidental, the morphology of the cata-
ract and the specic timing of prenatal
exposure (67 weeks of gestation) suggested
that further studies would be worthwhile.
Maternal depressive symptoms are associ-
ated with neurodevelopmental patterns of
reduced arousal and increased stress. Among
13 808 screened subjects from Honolulu,
1632 were eligible and 176 mothers were
enrolled; prenatal metamfetamine exposure
combined with maternal depression was not
associated with any additional neurodeve-
lopmental differences [35C]. When adjusted
for co-variates, metamfetamine exposure
was associated with lower arousal and higher
lethargy scores. Only 136 biological mothers
with child custody (50 of whom had used
metamfetamine) had the Addiction Severity
Index (ASI) administered at 1 month. The
NICU Network Neurobehavioral Scale
(NNNS) was administered to the neonate
within the rst 5 days of life by an examiner
blinded to metamfetamine exposure. There
were several limitations to this study. The
severity of depression in the mothers was
assessed not at the neonatal visit but after 1
month. Since only the biological mothers
were included in the study, the sample size
was limited, because several infants who had
been exposed to metamfetamine were placed
in foster care or the care of relatives, so that
data from their biological mothers was not
assessed.
Fenuramines [SED-15, 1333;
SEDA-30, 7; SEDA-32, 7]
Cardiovascular A wide range of drugs,
including those used for migraine prophy-
laxis (ergotamine, methysergide), appetite
suppressants (fenuramine and dexfen-
uramine), dopamine receptor agonists
(pergolide and cabergoline), and ecstasy
Reginald P. Sequeira
(methylenedioxymetamfetamine, MDMA)
[36A] have been implicated in drug-induced
brotic valvular disease [37R]. 5HT2B receptor
activity through activation of protein kinase
and potentiation of the effect of transforming
growth factor b is thought to result in
mitogenesis of cardiac valves [38r, 39r]. Inves-
tigations into individual susceptibility need to
establish which clinical and demographic fac-
tors predict patients at greatest risk of drug-
induced valvular heart disease, and the role
of genetic polymorphisms. It is also important
that new drugs that interact with the serotonin
pathways and 5HT2B receptors should be
assessed at the clinical trials stage, in order
to establish the risk of valvular heart disease
before they are used in clinical practice.
Hematologic In a cross-sectional study,
platelet counts in 47 patients with pulmonary
arterial hypertension (PAH) receiving intra-
venous epoprostenol were compared with
platelet counts in 44 patients who were taking
oral agents [40C]. Idiopathic PAH accounted
for 69% of cases; the rest were associated
with fenuramine (18%), connective tissue
disease (10%), or congenital heart disease
(2%). There was thrombocytopenia in 34%
of the patients who were treated with
epoprostenol compared with 15% of those
who took oral therapy (OR 2.9). Higher
doses of epoprostenol were associated with
lower platelet counts than lower doses. The
effects of hemodynamics and epoprostenol
were independent and additive, with
the highest rates of thrombocytopenia seen
among patients with both severe hemo-
dynamic abnormalities and use of epo-
prostenol. Treatment options for
thrombocytopenia in PAH are limited, owing
to incomplete understanding of its patho-
physiology; withdrawal of epoprostenol is
rarely recommended.
Atomoxetine
Observational studies In an open study of
the use of atomoxetine for over 4 years in
384 adults with ADHD, the adverse events
Central nervous system stimulants and drugs that suppress appetite
were mainly related to the expected nor-
adrenergic effects of the drug [41c].
Systematic reviews In a systematic review
of data from 13 double-blind, placebo-
controlled trials and three open extension
studies in 714 children and adolescents with
ADHD treated with atomoxetine for at
least 3 years, under 6% had aggressive/hos-
tile behavior and under 1.6% reported sui-
cidal ideation/behavior; there were no
clinically signicant effects on growth rate,
vital signs, or electrocardiography [42M].
Cardiovascular In children, adolescents,
and adults there was a small but signicant
prolongation of the QT interval in electro-
cardiogram when Bazett's correction was
used but not when the Fridericia formula
was used [43c]. The effects of atomoxetine
on hERG potassium channels have been
studied in human embryonic kidney cells
[44E]. Atomoxetine inhibited hERG cur-
rent with an IC50 of 6.3 mmol/l. The effect
occurred quickly and was washed out
quickly. Channel activation and inactiva-
tion were not affected. Inhibition was
state-dependent, suggesting open channel
blockade. Use dependence was not
observed.
Nervous system In a cohort study of 21 606
patients with ADHD treated with
atomoxetine and 21 606 treated with other
medications, the rate ratios were 1.38
(95% CI 0.42, 4.54) for the risk of stroke
and 0.31 (95% CI 0.04, 2.63) for the risk
of a transient ischemic attack (TIA) [45C].
There was an increased risk of TIA when
those with ADHD treated with any medi-
cations were compared with the general
population (HR 3.44; 95% CI 1.13,
11), but no increased risk of stroke.
Sensory systems Mydriasis has been
reported in a 15-year-old girl who took
atomoxetine for ADHD [46A].
Psychiatric A report of aggression in a boy
taking atomoxetine has again raised the
question of whether this is an adverse effect
of the drug [47AM].
Chapter 1 7
A 13-year-old boy with ADHD was given
atomoxetine and 5 weeks later developed
changed behavior, disorientation, irrelevant
speech, and self-harming behavior. He was
very aggressive and hostile towards other chil-
dren and adults. No organic cause was found.
The boy improved after withdrawal of
atomoxetine.
In an extensive review of the literature
the authors found no evidence of other
reports of such an effect. However, in one
unpublished study four subjects stopped
taking the drug because of irritability or
aggression [48S]. This could be a rare
adverse effect that has not been noticed in
trials, although a previous meta-analysis
was negative (SEDA-32, 8).
Acute agitation and suicidal ideation
occurred in an 11-year-old boy after he
started to take atomoxetine [49A]. How-
ever, a previous meta-analysis was negative
(SEDA-32, 8).
Teeth Nocturnal bruxism worsened in a
12-year-old boy with ADHD when he was
given atomoxetine, improved after with-
drawal, and recurred after rechallenge; it
responded to the addition of buspirone
[50A].
Drugdrug interactions Methylphenidate
In an open study in children aged 617
years the addition of OROS methylpheni-
date increased the rates of insomnia, irrita-
bility, and loss of appetite compared with
atomoxetine alone [51c].
Susceptibility factors Alcohol abuse and
dependence increase the risk of
atomoxetine-related adverse events [52C].
Methylphenidate [SED-15, 2307;
SEDA-30, 4; SEDA-3, 3; SEDA-32, 10]
Observational studies Treatment with rela-
tively high doses (up to 1.5 mg/kg/day) of
OROS methylphenidate in 114 adolescents
with ADHD was associated with small but
statistically signicant mean increases in
8 Chapter 1
blood pressure and heart rate, primarily dur-
ing the rst 6 weeks of treatment, without
clinically important ECG changes [53C].
Only 57 subjects had completed 6 months
of treatment and 19 dropped out because
of non-cardiovascular adverse events:
reduced appetite/weight loss (n 6),
reduced appetite/weight loss and irritability
(n 3), mood changes (n 3), stomach ache
(n 1), headache (n 1), light-headedness
(n 1), and excessive sweating (n 1).
One subject discontinued medication
because of recurrent bouts of palpitation
during the rst 6 weeks of treatment. Being
an open study, there was no comparison of
the cardiovascular end-points with a placebo
or active comparator. Also, since most of the
visits occurred at 710 hours after the morn-
ing dose of medication, the timing of blood
pressure measurement may not have
coincided with the peak action of the
medication.
Comparative studies Exposure to methyl-
phenidate and amfetamine salts carried sim-
ilar risks for cardiac emergency department
visits in a retrospective cohort study of
claims data from the Florida Medical data
on 2 131 953 children and adolescents,
between 1994 and 2004, with a diagnosis of
ADHD [54C]. However, emergency depart-
ment visits may reect parent concern rather
than acute cardiac adverse events. The drug
dosages were not considered, because treat-
ment recommendations included dosage
titration according to patient response and
the occurrence of adverse effects.
In a study based on the UK General
Practice Research Database (GPRD) in
patients with ADHD, aged 221 years,
from 1993 to 2006 with prescriptions
for methylphenidate, dexamfetamine, or
atomoxetine, there was no increase in the
risk of sudden death but there was an
increased risk of suicide [55C]. Seven
patients died in a cohort of 18 637 patient-
years, and cause of death was obtained in
six; none was deemed to be a case of sud-
den death (incident rate ratio 1.63; 95%
CI 0.04, 9.71). The standardized mortal-
ity ratios for suicide were 162 (95% CI
20, 585) in patients aged 1114 years and
Reginald P. Sequeira
1.84 (95% CI 0.05, 10) in patients aged
1521 years. Although the medications
may have contributed to the increased risk
of suicide, other factors that can also pre-
dispose to suicide, such as depression and
antisocial behavior, frequently co-exist with
ADHD [56c, 57R].
Placebo-controlled trials In a randomized,
double-blind, placebo-controlled crossover
trial of methylphenidate in 13 patients with
apathetic Alzheimer's disease stabilized on a
cholinesterase inhibitor, methylphenidate
produced signicant benet [58c]. There was
a positive relation between the acute effects
of dexamfetamine and the response to meth-
ylphenidate, implicating a role for dopami-
nergic dysfunction in the development and
treatment of apathy in Alzheimer's disease.
A signicantly higher proportion of patients
had at least one adverse event with methyl-
phenidate compared with placebo; two had
serious adverse events while taking methyl-
phenidate, consisting of delusions, agitation,
anger, irritability, and insomnia, which
resolved on withdrawal of methylphenidate.
Systematic reviews In 26 placebo-con-
trolled trials in 811 adults with ADHD,
methylphenidate was well tolerated in the
short-term and produced no serious
adverse effects [59M]. However, there is lit-
tle information on the long-term safety of
methylphenidate in adults, although the
number of serious adverse effects reported
has so far been low. Methylphenidate is
associated with modest increases in blood
pressure and heart rate. Surveys of the use
of stimulants in US universities have shown
that misuse of prescribed medications, for
recreation or to enhance the ability to
study, is fairly common, although the mag-
nitude of harm that arises from such prac-
tices is unclear.
Warnings from the FDA and scientic
debate surrounding the potential of
psychostimulants to exacerbate tics have
created clinical uncertainty for practitioners
treating ADHD in children with comorbid
tics. A meta-analysis of nine studies
involving 477 subjects has suggested that
among six medications used in ADHD
Central nervous system stimulants and drugs that suppress appetite
(the alpha-adrenoceptor agonists clonidine
and guanfacine, atomoxetine, desipramine,
dexamfetamine, methylphenidate, and
selegiline), methylphenidate seems to offer
the greatest and most immediate improve-
ment in the symptoms of ADHD and does
not seem to worsen tics [60M]. Alpha ago-
nists offer the best combined improvement
in both tics and symptoms of ADHD.
Atomoxetine and desipramine offer addi-
tional evidence-based treatments for
ADHD in children with comorbid tics;
supratherapeutic doses of dexamfetamine
should be avoided. However, it is important
to note that effect size of medications in tri-
als is inuenced by many factors besides
the efcacy of the medication, including dif-
ferences in the precision of rating scales.
This difference may have been particularly
inuential in measures of efcacy in
treating ADHD and the inattention and
hyperactivity/impulsive symptom subtypes,
because multiple rating scales and raters
were used. The trials in this meta-analysis
included primarily male subjects and it is
not known how well the results would
apply to girls with ADHD and comorbid
tics. For several outcomes, there was signif-
icant heterogeneity between studies,
suggesting that differences in trial design
may have inuenced effect sizes. Such dif-
ferences in trial design include the type of
rating scale and dose and duration of treat-
ment. With a relatively smaller number of
studies contributing to this meta-analysis,
it is not possible to determine which of
these hypothesized factors contributed to
heterogeneity.
Methylphenidate is considered safe for
children who are seizure free. However,
a few reports of seizure aggravation in
methylphenidate-treated children with
uncontrolled epilepsy have raised concerns
about its use in this group [61R].
Psychiatric Psychosis is an important but
unpredictable adverse effect of stimulant
medications and can mimic the symptoms
of ADHD. Four cases of stimulant-induced
psychosis (three with methylphenidate and
one with Concerta XL) resolved sponta-
neously on withdrawal of medication and
Chapter 1 9
recurred on rechallenge [62A]. It is impor-
tant to screen and identify psychotic symp-
toms during stimulant drug treatment,
because they could be mistaken for deterio-
ration in the symptoms of ADHD and
result in dosage titration upwards, with seri-
ous implications.
Urinary tract A possible association of
methylphenidate and enuresis has been
reported [63A].
An 11-year-old boy with ADHD was given
methylphenidate and after the daily dosage
had been titrated to 20 mg enuresis started
to occur. After 2 months, the medication was
withdrawn and the enuresis stopped immedi-
ately. About 1 month later, methylphenidate
was restarted and the enuresis reoccurred
when the dose reached 20 mg/day. It contin-
ued for about 3 months but immediately
stopped when the medication was withdrawn.
Another rechallenge after 2 months, followed
by withdrawal of methylphenidate, replicated
the response. Other causes of enuresis were
excluded and the patient never had daytime
urinary incontinence.
In previous reports methylphenidate was
reportedly effective in controlling giggle
incontinence [64A, 65A].
Skin The potential for vasculopathy in
patients with ADHD taking stimulants has
been reported in four patients, two of whom
were taking methylphenidate and two
dexamfetamine [66A]. They developed acral
cyanosis, livedo reticularis, or Raynaud's
syndrome. Two (one each taking methyl-
phenidate and dexamfetamine) had positive
antinuclear antibody titers and one (taking
dexamfetamine) had histological evidence
of stratum malpigian necrosis with
perivascular lymphocytic inltration on skin
biopsy. Both of the patients who were taking
methylphenidate had antihistone antibodies.
One patient improved after withdrawal of
dexamfetamine and her medication for
ADHD was changed to bupropion; others
had worsening of their symptoms on higher
doses of medication.
Genotoxicity Recent studies have added to
the accumulating evidence that therapeutic
10
concentrations of methylphenidate do not
cause cytogenetic damage in humans [67C].
In 109 children with ADHD taking methyl-
phenidate (starting dose 10 mg/day to a
maximum of 60 mg/day) for a total duration
of 84 days, cytogenetic anomalies were
investigated, including chromosomal aber-
rations, micronuclei, and sister chromatid
exchanges in peripheral blood lymphocytes
in culture. None was signicantly affected
by methylphenidate. Since dosage titration
was used in the study design, both the daily
dose administered and the total cumulative
dose over the course of this study differed
according to the needs of the patients.
These results are in marked contrast to pre-
vious ndings of signicant increases in all
three end-points with a similar study design
but with a smaller sample size and a behav-
ior therapy only control group [68c]. Other
mutational end-points are consistent with
the human and animal cytogenetic data on
methylphenidate [69ER]. Taken together,
these ndings show a high degree of consis-
tency and conrm that methylphenidate
does not induce chromosomal aberrations
or other type of genetic damage in children
with ADHD [70C]. It is important to note
that an epidemiological study of the risk
of cancer among 35 400 methylphenidate-
treated patients with ADHD, who take this
medication before age 20, showed no mod-
erate or strong association [71c].
Susceptibility factors Genetic There has
been considerable interest in the evaluation
of genetic determinants of the response to
methylphenidate in ADHD. Preliminary
studies have suggested that dopaminergic
genes [72C] and noradrenergic and possibly
glutaminergic genes [73C] may be involved.
Juvenile Huntington disease with acute
onset of motor symptoms coincident with
initiation of treatment with methylphenidate
has been reported [74A].
An 8-year-old boy, otherwise healthy, with
symptoms of ADHD was given methylpheni-
date and within 4 weeks had a rapid decline
in ne motor skills, with dysarthria, intention
tremor, motor impersistence, and diffusely
increased tone. His symptoms persisted
Chapter 1 Reginald P. Sequeira
despite withdrawal of methylphenidate. There
was a paternal history of Huntington disease
and a molecular analysis suggested juvenile
Huntington disease.
This report suggests the possibility that
methylphenidate (a dopamine receptor ago-
nist) in patients with a family history of Hun-
tington disease may lead to clinical
exacerbation of motor symptoms and/or an
unwitting diagnosis in an unprepared family.
Many children who develop the juvenile
form of Huntington disease are initially
misdiagnosed as having ADHD [75A],
and one-quarter of those with juvenile Hun-
tington disease have attention decits [76A].
Thus, a child with an unrecognized family his-
tory of Huntington disease presenting with
isolated cognitive symptoms may be treated
with stimulants, and this association may
therefore have been coincidental.
Drugdrug interactions Fluoxetine Tactile
and visual hallucinations with the combina-
tion of methylphenidate and uoxetine
have been reported [77A].
A 10-year-old boy with ADHD, oppositional
deant disorder, and generalized and separa-
tion anxiety disorders started taking OROS
methylphenidate 18 mg/day and uoxetine 10
mg/day. Four days later, he had an acute epi-
sode of intense hallucinations 3 hours after
taking the medications. His mother reported
that the visual hallucinations lasted about 1
hour and the tactile hallucinations more than
2 hours. Two days later he had a similar epi-
sode. His mother withdrew the medications
for 10 days, during which time he was symp-
tom free. When OROS methylphenidate 18
mg/day monotherapy was restarted he did
not report any hallucinations. Mirtazapine 15
mg/day was added for symptoms of anxiety
and sleep disturbances. During the next 2
months his condition improved and he had
no further hallucinations.
There has been a previous report of
treatment-related hallucinations with the
combination of methylphenidate and uox-
etine in a 14-year-old girl with ADHD
depressive disorder [78A]. The mechanism
whereby methylphenidate uoxetine
might cause hallucinations is unclear.
Central nervous system stimulants and drugs that suppress appetite
Modanil [SED-15, 2369; SEDA-30, 6;
SEDA-31, 7; SEDA-32, 6]
Observational studies Armodanil, the
R-isomer of modanil, produces consis-
tently higher plasma concentrations late in
the day than modanil, when compared
milligram for milligram. In two multiple-
dose pharmacokinetic studies in healthy
men aged 1850 years adverse events were
studied in subjects who completed 7 days
of once-daily armodanil (n 34) or
modanil (n 18) [79c]. The most common
adverse events were headache, palpitation,
nausea, and dizziness with armodanil,
and headache, palpitation, insomnia, and
anxiety with modanil. With both drugs,
adverse events were mild or moderate in
intensity. While the adverse events were
similar at lower doses, they were more fre-
quent with higher doses, requiring with-
drawal of the 400 mg dose of armodanil
and the 800 mg dose of modanil after 7
and 3 days respectively. Two subjects who
took armodanil 400 mg/day had events
that led to withdrawal, one with multiple
events (headache, abdominal pain, pharyn-
gitis, hypertonia, vasodilatation, nausea,
insomnia, anorexia, conjunctivitis, anxiety,
emotional liability, confusion, and weak-
ness) and one with mild nausea and moder-
ate amblyopia. There were clinically
signicant cardiovascular changes, includ-
ing sustained hypertension in one subject,
in those who took modanil 800 mg/day.
There were no serious adverse events with
armodanil, while two adverse events were
reported after administration of modanil.
Both of the subjects with serious adverse
event required hospitalization for monitor-
ing and evaluation. There were electro-
cardiographic abnormalities in one subject
taking 400 mg/day and anxiety/tachycardia
in one taking 800 mg/day.
In patients with primary biliary cirrhosis
the dosage of modanil was limited to 200
mg/day because of the possibility of
reduced drug metabolism in this population
[80c]. Despite the low dosage, some
patients had adverse effects, including nau-
sea, insomnia, headache, and nervousness.
Chapter 1 11
Other adverse effects reported at higher
doses, such as diarrhea and dyspepsia, were
not seen.
Placebo-controlled studies There was redu-
ced appetite in patients with ADHD treated
with modanil [81c].
Gastrointestinal adverse events, such as
nausea and dry mouth, were more common
compared with placebo in cocaine depen-
dent subjects who took modanil 200 mg/
day, and one of 70 subjects had an abnor-
mal electrocardiogram, hypertension, chest
discomfort, a bitter taste sensation, irritabil-
ity, agitation, anxiety, and tension, and there
were two instances of insomnia, one
instance of sweaty palms, and one case of
upper lip swelling in those who took 400
mg/day [82c].
There was exacerbation of psychosis in
ve of 83 patients with schizophrenia who
took modanil compared with two of 70
who took placebo [83R].
Psychiatric Long-term modanil treatment
can rarely cause psychotic symptoms [84A].
A 25-year-old woman with a history of narco-
lepsy took modanil, titrated up to 300 mg/
day, and had dry mouth and tachycardia.
After 5 days, she continued to take 300 mg/
day without any apparent adverse effects.
About 6 months later she had visual and audi-
tory hallucinations and delusions of reference.
Modanil was withdrawn and her psychotic
symptoms resolved. After restarting modanil
on alternate days occasional hallucinations
recurred.
There have been other reports of
modanil-associated psychosis in patients
with narcolepsy [85A, 86A, 87A].
METHYLXANTHINES
Caffeine [SED-15, 588; SEDA-30, 5;
SEDA-31, 8; SEDA-32, 14]
Teratogenicity Adenosine receptors are
among the rst receptors to be expressed
in the embryonic brain, and modulation
12
potentially affects axon formation [88E].
Intrauterine exposure to 10 or more cups
of coffee per day was associated with a
threefold increased risk of hyperkinetic dis-
order and ADHD [89C]. After adjustment
for a number of confounding factors, such
as smoking, alcohol intake, sex of the child,
maternal age, a family history of psycho-
pathology and parental socio-economic fac-
tors, the risk fell and became statistically
insignicant (RR 2.3; 95% CI 0.9, suggested that both phenylephrine and lido-
5.9). This study was based on Aarhus Birth
Cohort data in Denmark and included
24 068 singletons delivered between 1990
and 1998. Linkage was performed with
three Danish longitudinal registers: the Psy-
chiatric Central Register, the Integrated
Database for Labor Market Research, and
the Danish Civil Registration System.
Information about coffee consumption dur-
ing pregnancy was obtained at 16 weeks of
gestation from a self-administered ques-
tionnaire. A methodological strength of this
study was the community-based sample and
disentangling of confounding effects using
Cox regression analysis. It is important to
pursue a synergistic effect of intrauterine
exposure to caffeine and cigarette smoke
on the risk of hyperkinetic disorder and
ADHD. A randomized, controlled trial
has shown that the effect of caffeine on
fetal growth was found only among
smokers [90C]. Moreover, the implications
of reduced maternal metabolism of caffeine
during the third trimester [91c] need to be
considered.
In the National Birth Defects Prevention
Study in the USA, a population-based,
casecontrol study of major birth defects,
excluding infants with single-gene disorders
and chromosomal abnormalities, there was
no association between maternal dietary
caffeine intake and orofacial clefts [92C].
This analysis included 1531 infants with
cleft lip with or without cleft palate, 813
infants with cleft palate only, and 5711
infants with no major birth defects as con-
trols. Maternal caffeine intake was self-
reported. Dietary caffeine intake may have
changed during pregnancy, making expo-
sure assessment during the critical period
for orofacial development difcult.
Chapter 1 Reginald P. Sequeira
Drug overdose Hemodynamic instability
and hypotension after massive caffeine
overdose improved with loading doses
followed by continuous infusions of both
phenylephrine and lidocaine [93A]. Hypo-
tension in caffeine overdose is multifactorial:
b2-adrenoceptor agonism causes peripheral
vasodilatation and b1-adrenoceptor stimula-
tion leads to profound tachycardia with
incomplete diastolic lling. The authors
caine should be considered in the treatment
of cardiovascular collapse secondary to
methylxanthine poisoning.
Lactic acidosis has been reported in caf-
feine poisoning [94A].
A 17-year-old woman was admitted to the
emergency department 30 minutes after tak-
ing 12 g of caffeine (266 mg/kg) in a suicide
attempt. She had constant nausea with
repeated vomiting, tremor, anxiety, and
hyperventilation, hypokalemia of 2.4 mmol/l,
and a blood lactate concentration of 3.1
mmol/l. The lactate concentration rose to 7.0
mmol/l at 9 hours after ingestion, and no other
cause besides caffeine poisoning was identi-
ed. She was given ondansetron and
midazolam intravenously for nausea and anxi-
ety, and the hypokalemia was cautiously
corrected. She was also given propranolol.
Excessive sympathetic stimulation with
increased glycogenolysis and lipolysis and
a secondary rise in pyruvate could explain
lactic acidosis in caffeine poisoning.
Theophylline [SED-15, 3361; SEDA-30,
5; SEDA-31, 8; SEDA-32, 15]
Nervous system Status epilepticus has been
attributed to theophylline in two cases.
A 5-year-old boy with no history of convul-
sions had a generalized tonicclonic seizure
after taking oral theophylline for 2 days
followed by non-convulsive status epilepticus
[95A]. The serum theophylline concentration
was 19.7 mg/l. An intravenous bolus dose
of midazolam 0.26 mg/kg largely restricted
seizure activity to the right hemisphere and
another 0.24 mg/kg followed by a continuous
infusion of 0.20 mg/kg/hour completely
abolished the electrical status.
Central nervous system stimulants and drugs that suppress appetite
An 8-month-old boy who had been given oral
modied-release theophylline and additional
aminophylline suppositories developed con-
vulsive status epilepticus [96A]. A combination
of diazepam, lidocaine, and thiopental was
required to stop the convulsion. A pharmaco-
kinetic study showed that the use of the mod-
ied-release formula would have given a
plasma concentration of no more than 15 mg/
l, but that the addition of aminophylline would
have increased it to over 20 mg/l.
Drug overdose Acute pancreatitis has been
reported after severe theophylline overdose
[97A].
DRUGS THAT SUPPRESS
APPETITE [SEDA-30, 7; SEDA-31,
9; SEDA-32, 16]
The need for studies of the long-term safety
and efcacy of antiobesity drugs [98R] and
the regulatory challenges for new drugs to
treat obesity with comorbid metabolic dis-
orders [99R, 100R, 101C] have been
reviewed. New central targets for the treat-
ment of obesity are being explored [102R].
Phentermine [SED-15, 2804; SEDA-31,
9; SEDA-32, 17]
Cardiovascular Ventricular tachycardia/
brillation in an otherwise healthy 48-year-
old woman who was taking no medications
other than phentermine was attributed to
sympathetic activation [103A]. The cardiac
safety concern of phentermine suggested by
these authors has been debated [104r].
Sibutramine [SED-15, 3131; SEDA-30,
7; SEDA-31, 9; SEDA-32, 17]
Cardiovascular Acute myocardial infarc-
tion in a 24-year-old man with a low risk
of atherosclerosis, possibly associated with
sibutramine, has been reported [105A].
Other causes were ruled out, including
Chapter 1 13
cocaine abuse, viral myocarditis, aortic
dissection, hypercoagulable states, and
autoimmune vasculitis.
Susceptibility factors Genetic Patient selec-
tion based on candidate genes may enhance
the response to sibutramine in obesity
[106C].
Rimonabant [SEDA-32, 19]
Rimonabant has been withdrawn because
of psychiatric adverse effects [107r, 108r,
109r], including, in one case, a major
depressive episode with melancholic fea-
tures that resolved after withdrawal of
rimonabant [110A]. In a placebo-controlled
trial in obesity there was an excess risk of
psychiatric reactions (43% versus 28%)
[111C].
Systematic reviews In a systematic review
of 28 randomized placebo-controlled trials
lasting 1224 months in adults using
licensed doses of orlistat (16 trials),
sibutramine (7 trials), and rimonabant (5
trials), the risk ratios (RRs) for withdrawal
because of adverse events were signicantly
increased for rimonabant (2.00; CI 1.66,
2.41) and orlistat (1.59; 1.21, 2.08), but not
sibutramine (0.98; 0.68, 1.41) [112M]. Com-
pared with placebo, the risk difference for
rimonabant was 7% (NNTH 14) and for
orlistat 3% (NNTH 39). The most common
adverse events that led to withdrawal were
gastrointestinal with orlistat (40%) and psy-
chiatric with rimonabant (47%).
In another systematic review of nine
published randomized placebo-controlled
trials of rimonabant in 9635 adults,
rimonabant 20 mg/day was associated with
increased risks of adverse events (RR
1.35; 95% CI 1.17, 1.56), withdrawal
(RR 1.79; 95% CI 1.35, 2.38), psychiat-
ric adverse events (RR 2.35; 95% CI
1.66, 3.34), and nervous system adverse
events (RR 2.35; 95% CI 1.49, 3.70);
the NNTH for psychiatric adverse events
was 30 [113M].
14
Cardiovascular Atrial brillation has been
attributed to rimonabant in two cases [114A].
A man who took rimonabant for 5 weeks
developed palpitation, fatigue, and exertional
dyspnea. He had atrial brillation with a ven-
tricular rate of 98135/minute. No other cause
of atrial brillation was found and rimonabant
was withdrawn. After 2 weeks his rhythm had
reverted to sinus rhythm. The patient refused
re-challenge and 9 months later was still in
sinus rhythm.
After taking rimonabant for 3 weeks a man
developed dizziness, palpitation, and exer-
tional dyspnea. He had atrial brillation, for
which no other causes were found.
Rimonabant was withdrawn and 10 days later
the rhythm had reverted to sinus rhythm with
rst-degree atrioventricular block.
Nervous system Rimonabant has been
reported to cause partial seizures in a
patient with a history of generalized epi-
lepsy [115A]
A 52-year-old obese man with hypertension,
diabetes mellitus, and a history of absences
and two generalized tonicclonic seizures at
ages 415 years, but who had been seizure
free for over 20 years took rimonabant 20
mg/day and 2 months later started to have
nocturnal partial seizures consisting of a
stereotypical feeling of falling into a deep
hole, often followed by right leg jerks lasting
3 minutes on average. These seizures were
totally different from the generalized seizures
he had had in his youth. After withdrawal of
rimonabant the seizures disappeared. A few
weeks later he restarted rimonabant and 3 days
later his partial seizures returned. Routine
and sleep-deprivation electroencephalography
showed frequent epileptiform paroxysms,
consisting of generalized irregular slow waves
intermingled with frontal and temporal spikes
and focal epileptiform abnormalities in the left
temporal lobe, as in previous recordings over
20 years before. The seizures again resolved
immediately after rimonabant withdrawal, and
3 months later sleep-deprived electroencepha-
lography showed mainly focal (left > right)
temporal epileptiform discharges and gene-
ralized irregular slow-wave paroxysms.
A proconvulsant effect of rimonabant is not
unexpected, since cannabinoids have anti-
convulsant properties in animals.
Psychological In a double-blind, placebo-
controlled study in 30 healthy adults, a sin-
gle dose of rimonabant 20 mg did not alter
Chapter 1 Reginald P. Sequeira
subjective mood but did reduce incidental
recall of positive self-relevant adjectives,
an effect opposite to that seen with antide-
pressants [116c]. Rimonabant did not affect
other measures of emotional processing.
Drugdrug interactions Ciclosporin The
interaction of rimonabant with ciclosporin
(n 10) and tacrolimus (n 8) has been
assessed in stable renal transplant recipi-
ents [117c]. Rimonabant increased the
AUC0!12 of ciclosporin by 20%. The
authors concluded that this effect was prob-
ably of marginal clinical relevance since
trough concentrations were unaltered.
Tacrolimus pharmacokinetics were unaf-
fected by rimonabant.
Tesofensine
Tesofensine is an inhibitor of neuronal
reuptake of dopamine, noradrenaline, and
serotonin. There has been considerable
interest in this investigational drug for
weight reduction as an adjunct to energy
restriction.
Placebo-controlled studies In a phase II
clinical trial of tesofensine in Denmark there
was a signicant reduction in body weight
compared with placebo [118C]. The common
adverse events were dry mouth, nausea, con-
stipation, diarrhea, and insomnia. After 24
weeks, tesofensine 0.25 and 0.5 mg/day had
no signicant effect on systolic and diastolic
blood pressures compared with placebo,
but heart rate increased by 7.4/minute. How-
ever, there is a reduction in blood pressure of
35 mmHg systolic and 23 mmHg diastolic
with weight losses of 45 kg, and increases
of 1 mmHg in systolic pressure and 23
mmHg in diastolic pressure among partici-
pants taking tesofensine 0.5 mg compared
with controls seem to suggest that
tesofensine can increase blood pressure
[119r]. Drug development in the eld of
weight reduction has regularly faced
pharmacovigilance hurdles, because anorexi-
genic drugs affect various neurotransmitter
systems and can lead to serious adverse
Central nervous system stimulants and drugs that suppress appetite
effects. It has been suggested that the bar
should be set high when new drugs are intro-
duced for obesity, in order to avoid repetition
of drug scandals related to antiobesity drugs
[120r].
DRUGS USED IN
ALZHEIMER'S DISEASE
[SEDA-30, 8; SEDA-31, 10;
SEDA-32, 19]
Observational study In an open study in
patients with ADHD rivastigmine produced
sustained inhibition of acetylcholinesterase
and butyrylcholinesterase, whereas don-
epezil and galantamine did not inhibit
butyrylcholinesterase and were associated
with increases in CSF acetylcholinesterase
[121c]. The clinical implications of these
ndings require evaluation.
Smell identication function could be use-
ful as a clinical measure for assessing treat-
ment response in Alzheimer's disease [122c].
Improved olfaction with donepezil correlated
strongly with improvement in Clinician Inter-
view Based Impression of Change plus Care-
giver Input (CIBIC-plus), and predicted
global improvement better than other mea-
sures, such as cognition. These ndings are
biologically plausible, because olfaction
depends on brain regions that are primarily
affected by Alzheimer's disease.
Donepezil [SED-15, 1179; SEDA-30, 8;
SEDA-31, 10; SEDA-32, 19]
Observational studies Donepezil improved
cognitive dysfunction in patients with
Alzheimer's disease, but also ameliorated
behavioral and psychological symptoms of
dementia (BPSD), including hallucinations/
delusions, wandering, and aggression
[123c]. Donepezil also alleviated the burden
on care-givers for about 60% of patients.
There were 30 reports of adverse drug
Chapter 1 15
reactions from 23 of 289 patients, an inci-
dence rate of 8%. The major adverse reac-
tions were ve cases of upper abdominal
discomfort (1.73%) and two each of anemia,
insomnia, delusions, dizziness, and gait dis-
order (0.69%). Serious reactions were one
case each of anemia, anorexia, dizziness,
upper abdominal discomfort, and gait
disorder.
In a study of the effect of donepezil 10 mg/
day the progression of cognitive dysfunction
was slowed [124c]. The incidence of adverse
events was 11.5% lower than the rate of
40% or higher recorded during previous
clinical trials. The incidence of adverse
events was 12%, lower than the rate of
40% or higher that has been recorded during
previous trials in Japan. Seven of the 61
patients enrolled in this study were forced
to withdraw because of adverse events that
occurred within 1 month of treatment with
donepezil 10 mg/day. If longer-term
donepezil treatment is planned, it is appro-
priate to start with a dose of 5 mg/day and
then increase to 10 mg/day to minimize the
adverse effects, particularly those that occur
at the start of treatment
Placebo-controlled studies In a 6-month,
randomized, double-blind, placebo-con-
trolled study of 189 Japanese patients, 68
were given placebo, 69 were given
donepezil 5 mg/day, and 52 were given
donepezil 10 mg/day [125c]. Those who
took donepezil 10 mg/day with little or no
interruption achieved the best long-term
outcome. Overall, 177 patients (93.7%)
had at least one adverse event. There were
severe adverse events in 15 patients (7.9%)
and serious adverse events in 33 (17.5%).
Since altered expression of central mus-
carinic and nicotinic acetylcholine receptors
in hippocampal and cortical regions might
contribute to cognitive impairment in
patients with schizophrenia, increasing cho-
linergic activity might help improve cogni-
tion in these patients. With this in mind,
donepezil, a cholinesterase inhibitor,
has been examined in a 12-week, multi-
center, placebo-controlled, double-blind,
parallel-group study in 250 patients with
schizophrenia or schizoaffective disorder
16
who were clinically stabilized on
aripiprazole, olanzapine, quetiapine, risper-
idone, or ziprasidone, alone or in combina-
tion [126C]. They were randomized to co-
treatment with donepezil (5 mg/day for 6
weeks and then 10 mg/day for 6 weeks;
mean age 41 years; n 121) or with pla-
cebo (mean age 40 years; n 124). Adjunc-
tive donepezil therapy did not signicantly
improve cognitive impairment in moder-
ately ill patients with schizophrenia or
schizoaffective disorder maintained on anti-
psychotic drugs. Treatment-emergent
adverse events were reported by 55% of
those who took donepezil and 61% of those
who took placebo; the frequency of severe
adverse events was similar in the two
groups (8.3% and 8.9% respectively) as
were serious adverse events (5.8% and
5.6%). There were no differences in the
frequency of dosage reduction or tempo-
rary study drug withdrawal because of
adverse events (donepezil, n 3; placebo
n 2) or in the frequency of adverse
event-related withdrawal (donepezil n
10; placebo, n 13). The most common
adverse events were headache and those
affecting the digestive and nervous systems;
treatment groups were comparable with
regard to changes in vital signs and labora-
tory analyses throughout the study.
Huperzine
Huperzine, an alkaloid from the plant
Huperzia serrata, is a potent and highly selec-
tive, reversible acetylcholinesterase inhibitor.
Systematic reviews In a meta-analysis of the
efcacy and safety of huperzine-A 300500
micrograms/day in Alzheimer's disease, the
estimated effect size on the Mini-Mental
State Examination (MMSE) and Activity of
Daily Living (ADL) increased over the treat-
ment time. Most of the adverse effects were
cholinergic and there were no serious adverse
events [127M]. The meta-analysis included
four double-blind, randomized, placebo-con-
trolled trials, with more than 20 participants
Chapter 1 Reginald P. Sequeira
in each arm. All were carried out in China.
In all, 474 patients were included, 235 in the
huperzine group and 237 in the control group.
The trial durations ranged from 8 to 24 weeks;
the longer duration resulted in better efcacy
on MMSE scores. Adverse symptoms
included tachycardia, low energy, dry mouth,
and hypertension at multiple-dose ranges;
bradycardia, headache, and intense dreams
at a dose of 400 micrograms bd; muscle
cramps at 400 micrograms bd; arthralgia at
300400 micrograms bd; and nausea, drowsi-
ness, and diarrhea.
A meta-analysis has shown that most
clinical studies of huperzine showed prom-
ising results in Alzheimer's disease; how-
ever, most of the studies were found to
have methodological shortcomings [128M],
further conrmed recently [129R].
Memantine [SED-15, 2250;
SEDA-32, 20]
The efcacy and adverse effects of
memantine have been reviewed [130R].
The following adverse effects occur in more
than 2% of patients: fatigue, pain, hyperten-
sion, dizziness, headache, constipation,
vomiting, back pain, confusion, somnolence,
hallucinations, coughing, dyspnea, agitation,
falls, injuries, urinary incontinence, diarrhea,
bronchitis, insomnia, urinary tract infection,
inuenza-like symptoms, abnormal gait,
depression, upper respiratory tract infections,
anxiety, peripheral edema, nausea, anorexia,
and arthralgia. Memantine undergoes both
hepatic and renal elimination. In patients
with severe liver or kidney impairment
lower dosages are required, but in patients
with mild to moderate renal impairment, no
adjustment is necessary.
Rivastigmine [SED-15, 3072; SEDA-30,
10; SEDA-31, 11; SEDA-32, 20]
Observational studies In a multicenter
study of a transdermal rivastigmine patch
Central nervous system stimulants and drugs that suppress appetite
(9.5 mg/day) for up to 1 year, 870 of 1195
patients completed the double-blind phase
and entered the open extension [131c].
Nausea and vomiting (16% and 14%
respectively) were the most frequent
adverse effects. Skin tolerability at the site
of application was generally good, with no,
slight, or mild irritation as the most com-
mon application site reaction. Erythema
(7.7%) and pruritus (5.6%) were moderate
or severe reactions to rivastigmine, and
3.7% withdrew owing to reactions at the
site of application. There was also a trend
towards an increase in adverse skin reac-
tions over time. Rivastigmine was with-
drawn in 73 patients (8.4%) during the
extension phase because of reactions at
the site of application (3.6%) or gastro-
intestinal disorders (2.9%).
In a prospective, non-interventional, post-
marketing observational study in Taiwan,
rivastigmine 36 mg/day was well tolerated
by patients with Alzheimer's disease [132C].
In 261 patients, the mean duration of
rivastigmine exposure was 151 days. Of 253
patients, 155 (61%) reported at least one
adverse event, the most frequent of which
were psychiatric (9.1%) and gastrointestinal
(8.3%). The most common adverse events
were mild dizziness (5.5%), insomnia
(5.1%), anorexia (4.0%), constipation (4%),
vomiting (4%), and nausea (3.6%). In all, 12
patients (4.7%) reported 16 serious adverse
events, including two deaths, one case of syn-
cope with head trauma, one peptic ulcer, and
six other hospitalizations. None was reported
to be related to rivastigmine. The authors
stressed the importance of starting with a
low dose of rivastigmine and gradually
increasing the dosage.
Systematic reviews There is evidence that
a lower dose small transdermal patch is
associated with fewer adverse effects than
capsules or a higher dose larger patch, with
efcacy comparable to both [133M].
Liver Hepatotoxicity associated with trans-
dermal rivastigmine use has been reported
[134A].
Chapter 1 17
Two months after starting to use a rivastigmine
transdermal patch (4.6 mg/day, increased to 9.5
mg/day 1 month later), an 84-year-old woman
developed fatigue, weakness, abdominal
bloating, yellowish eyes, dark urine, and a tran-
sient rash. Her other medications included aspi-
rin, ramipril, and valproic acid. She had a raised
total bilirubin concentration with a conjugated
fraction of 36 mmol/l, raised aminotransferases,
alkaline phosphatase, and gamma-glutamyl
transpeptidase activities, and an eosinophilia.
Tests for hepatic virus markers and autoanti-
bodies were negative. Ultrasonography
showed a normal echogenic liver and no bile
duct or gall bladder abnormalities.
Rivastigmine was withdrawn, and the signs
and symptoms of hepatitis gradually improved.
She continued taking other medications, and 5
weeks after withdrawal of rivastigmine her liver
function tests were normal.
The explanation of liver toxicity in this
patient is uncertain, but a hypersensitivity
reaction was possible.
Drug overdose An 80-year-old woman with
Alzheimer's disease had an overdose when
she used nine 5 cm2 transdermal patches of
rivastigmine [135A]. She had fasciculation
of her gastrocnemius and quadriceps mus-
cles bilaterally. The patches were removed
and the underlying skin was cleansed with
soap and water. Although the working diag-
nosis was rivastigmine overdose, due to min-
imal pulmonary muscarinic ndings,
atropine was not used. She was instead given
pralidoxime 1 g intravenously. Within 30
minutes of the end of the infusion her sweat-
ing and miosis had improved and her fascic-
ulation had resolved.
Although the use of pralidoxime is
debated, a clinical trial has conrmed a signif-
icant advantage for oxime therapy in organo-
phosphate poisoning [136C]. In poisoning
with carbamates (such as rivastigmine), the
clinical course tends to be mild and self-limit-
ing, because carbamate-induced cholinester-
ase inhibition tends to be mild and
spontaneously reversible. This case of appar-
ently safe and effective pralidoxime adminis-
tration without the use of atropine in a
patient with transdermal rivastigmine toxicity
reinforces recent data demonstrating the
potential safety of pralidoxime in carbamate
poisoning.
18
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2 Antidepressant drugs
GENERAL
Comparative rates of adverse effects with
different antidepressants One limitation of
meta-analyses is that they depend on the
particular head-to-head comparisons chosen
by the researchers, be they industry-based
or academic-based. Multiple-treatments
meta-analysis is a statistical technique that
was developed to extract data from multi-
ple randomized controlled trials to test for
comparative efcacy and tolerability of
agents that were not compared in individ-
ual reports. The relative efcacy and
tolerability of 12 different antidepressants
have been studied in a multiple-treatments
meta-analysis, which showed that
escitalopram, sertraline, bupropion, and
citalopram were better tolerated than the
other antidepressants studied [1M]. The
cumulative probabilities of being among
the most acceptable four treatments were:
escitalopram (28%), sertraline (27%),
bupropion (19%), citalopram (19%),
milnacipram (7%), mirtazapine (4%), u-
oxetine (3%), venlafaxine (1%), duloxetine
(1%), uvoxamine (0.4%), paroxetine
(0.2%), and reboxetine (0.1%).
Susceptibility factors Cardiac disease In a
comprehensive review of all (old and new)
antidepressant medications and cardiovas-
cular disease, it was concluded that tricyclic
Side Effects of Drugs, Annual 33
J.K. Aronson (Editor)
ISSN: 0378-6080
DOI: 10.1016/B978-0-444-53741-6.00002-7
# 2011 Elsevier B.V. All rights reserved.
Philip B. Mitchell
antidepressants should be avoided in
those with or at risk of cardiovascular dis-
ease; that reboxetine, duloxetine, and
venlafaxine increase the blood pressure;
and that there is a dearth or absence of
data about the use of many antidepressants
in patients with cardiac disease [2R].
MONOAMINE OXIDASE
INHIBITORS [SED-15, 2371;
SEDA-32, 32]
Moclobemide
Drugdrug interactions Carbamazepine
and valproate The mood stabilizers carba-
mazepine and valproate are often used in
combination with antidepressants in patients
with unipolar or bipolar affective disorder.
The effects of valproate and carbamazepine
on the steady-state pharmacokinetics of
moclobemide and two metabolites have been
studied in a non-randomized crossover study
in 21 patients with unipolar depression [3c].
Valproate had no effect, but carbamazepine
was associated with a 35% reduction in
moclobemide AUC, a 28% reduction in Cmax,
and a 41% reduction in clearance after
4 weeks of co-administration. These changes
were interpreted as being due to induction
carbamazepine of the metabolism of
moclobemide and its main metabolite. How-
ever, there was no concurrent loss of efcacy,
throwing into doubt the clinical signicance of
these signicant kinetic effects.
25
26
SELECTIVE SEROTONIN
RE-UPTAKE INHIBITORS
(SSRIS) [SED-15, 3109; SEDA-30, 16;
SEDA-31, 18; SEDA-32, 33]
Cardiovascular Carotidynia, a focal cervi-
cal pain that involves the anatomical terri-
tory of the affected carotid artery and
often radiates to the ipsilateral side of the
face or ear, has been attributed to uoxe-
tine and citalopram [4A].
After taking uoxetine 20 mg for 5 months, a
43-year-old man developed left intercostal
pain, which became bilateral, steadier, episodic,
and stabbing on deep breathing and movement
of the trunk. Two weeks later, he noted a tender
swollen mass at the level of the right carotid
bifurcation, accompanied by a severe pulsating
pain, which radiated to the ipsilateral jaw
on contralateral head movement. Cervical
magnetic resonance and angiomagnetic reso-
nance studies showed abnormal soft tissue
thickening of the right common carotid and its
bifurcation. Fluoxetine was withdrawn and the
carotidynia and intercostal pain resolved
completely. Fluoxetine was restarted on two
further occasions, and the pain recurred within
4 weeks and resolved on withdrawal. The
same symptoms recurred after challenge with
citalopram on two occasions.
SSRIs and emergent suicidal
ideation
Further data have claried the highly contro-
versial relation between SSRI antidepressants
and emergent suicidality. Prior studies have
suggested that this adverse effect may be more
likely to occur in children, adolescents, and
young people than in older adults (SEDA-
31, 18; SEDA-32, 29). The ndings of three
prospective trials of depressed or anxious
children and adolescents have thrown new
light on this question.
Results have been reported from the
Treatment of Adolescents with Depression
Study (TADS) [5C, 6C], in which 439 ado-
lescents were randomly allocated to 12 weeks
of uoxetine, cognitive behavioral therapy,
the combination of these, or clinical
Chapter 2 Philip B. Mitchell
management with placebo. Those allocated
initially to placebo received open active
treatment as clinically indicated after
12 weeks, and all subjects were followed
for 36 weeks. There were no differences
between the groups in the rates of suicidal
events (suicide attempts, preparation for sui-
cidal behavior, or suicidal ideation) during
either the initial 12-week double-blind phase
or the 36-week open treatment phase. There
were no suicides in either group.
In the Treatment of SSRI-Resistant
Depression in Adolescents (TORDIA) study
[7C], 334 depressed adolescents, who had
not responded to a previous trial with an
SSRI antidepressant, were randomized to
either another SSRI or venlafaxine, with or
without cognitive behavioral therapy. There
were no signicant differences between the
groups in the rates of suicidal and non-sui-
cidal self-injury, although the signicance
of this was limited by the lack of a placebo
comparison group [8r].
In 488 children and adolescents (aged
717 years) with an anxiety disorder who
were randomized to 12 weeks of sertraline
up to 200 mg/day, cognitive behavioral ther-
apy, the combination of these, or placebo,
suicidal and homicidal ideation were no
more common with sertraline than placebo;
no child attempted suicide [9C].
Combining the ndings of these child-
hood and adolescent studies, the two large
placebo-controlled trials [5C, 9C] were con-
sistent in not demonstrating an increased
rate of suicidal thoughts or behavior with
SSRI antidepressants compared with pla-
cebo, while Brent et al. [7C] found no differ-
ence between an SSRI and venlafaxine.
Interpreting these controlled studies conser-
vatively, the data suggest either that these
agents do not increase the risk of suicidal
thoughts or behavior in depressed or anx-
ious children and adolescents, or that such
outcomes are uncommon.
With respect to the adult literature, a
pooled analysis, by Pzer-employed staff,
of sertraline placebo-controlled trials, using
the FDA-dened search method, showed
no evidence of an increase in the risk of
suicidality compared with placebo in those
who took sertraline. In the open citalopram
Antidepressant drugs Chapter 2
phase of the STAR*D depression trial [10C]
74% of the 1909 subjects with baseline sui-
cidal ideation (i.e. before they started to take
citalopram) improved by the nal visit,
while 4% worsened [11M]. Of 1721 without
baseline suicidal ideation, 7% experienced
emergence of such thoughts by the rst
post-baseline visit, but 63% of these had no
suicidal ideation at their nal visit.
Finally, the effect of the warning issued by
the UK Medicines and Healthcare products
Regulatory Authority (MHRA) in Decem-
ber 2003, not to prescribe SSRI antidepres-
sants, except uoxetine, for those younger
than 18 years, has been examined [12C].
Prescriptions fell signicantly (by 51%) dur-
ing 20002006. However, there were no
changes in the rates of non-fatal self-harm
or self-poisoning.
Skin SSRI-induced photosensitivity is
uncommon. Three cases have been reported,
in association with sertraline [13A] and
with uvoxamine and paroxetine [14A].
Sexual function SSRIs can cause sexual
dysfunction, particularly reduced libido,
impaired orgasm in women, and inhibition
of ejaculation or erectile difculties in men.
There have been two reports of unusual
male sexual dysfunction. In two cases of
spermatorrhea (excessive emission of
semen without orgasm or erection) in men
taking uvoxamine, the problem resolved
on drug withdrawal [15A]. Spontaneous
ejaculations occurred daily in a 27-year-
old man after he had taken citalopram for
2 weeks [16A]. They were unrelated to
sexual fantasies, arousal, erection, or any
sensation of orgasm and resolved on drug
withdrawal. They did not recur when he
took paroxetine.
There have been two reports of the man-
agement of SSRI-induced sexual adverse
effects. First, in an 8-week prospective
double-blind placebo-controlled trial of sil-
denal 50100 mg/day in 98 previously sex-
ually functioning premenopausal women
whose major depression had remitted on
SSRIs, but who were also experiencing sex-
ual dysfunction, sildenal was associated
27
with a signicant reduction in adverse sex-
ual effects [17C]. Secondly, in an 8-week
open study, mirtazapine produced signi-
cant reductions in SSRI-induced sexual dys-
function in 49 outpatients (men and
women) [18c].
Antidepressants in pregnancy
[SEDA-30, 16; SEDA-31, 19; SEDA-32, 31]
Intense interest in the potential for SSRI
antidepressants to have teratogenic and
adverse pregnancy outcomes continues, and
four further major data-based reports have
appeared [19C, 20C, 21C, 22C], as well as a
report on the management of depression in
pregnancy from two leading US professional
bodies [23S] and three leading editorials or
commentaries [24r, 25r, 26r].
Previous reports had suggested that SSRIs
can cause cardiovascular abnormalities, and
the strongest evidence related to paroxetine.
However, the relative contributions of these
medications and the effect of depressive
illness have remained uncertain.
In a prospective study of pregnant women
who had contacted teratology information
services in Israel, Italy, and Germany
because of rst-trimester exposure to uoxe-
tine (n 346) or paroxetine (n 463),
compared with a control group (n 1467)
who had contacted these services regarding
exposure to non-teratogenic agents during
the same time period, miscarriage rates were
higher after exposure to uoxetine, but this
was not signicantly different from controls
after accounting for other factors such
as smoking rates and maternal age [19C].
After exclusion of genetic and cytogenetic
anomalies, there were higher rates of major
anomalies after exposure to uoxetine
(4.7%) and paroxetine (5.2%) than in con-
trols (2.5%), and most of this was related
to cardiovascular anomalies (uoxetine
2.8%; paroxetine 2.0%; controls 0.6%).
After accounting for relevant confounders,
uoxetine remained signicantly associated
with higher rates of cardiovascular anoma-
lies (OR 4.47; 95% CI 1.31, 15).
28
In a prospective observational study the
separate effects of SSRI antidepressants and
depression in 238 women were assessed at
20, 30, and 36 weeks of gestation, and neo-
natal outcomes were determined on blinded
review of delivery records and infant exami-
nations [20C]. The women were categorized
into three exposure groups: (i) no SSRIs,
no depression (n 131); (ii) SSRI expo-
sure, either continuous (n 48) or partial
(i.e. at some point during the pregnancy; n
23); and (iii) no SSRI exposure, but
depression that was either continuous
(n 14) or partial (i.e. at some point during
the pregnancy; n 22). Infants who were
exposed to either SSRIs (RR 3.56; 95%
CI 1.40, 9.01) or continuous depression
(RR 4.25; 95% CI 1.06, 15) through-
out the pregnancy were more likely to be born
before term than infants with no exposure to
SSRIs or depression. However, after control-
ling for maternal age and race, only continu-
ous SSRI exposure remained signicantly
related to the risk of preterm delivery (RR
5.43; 95% CI 1.98, 15). Neither expo-
sure to an SSRI nor depression increased the
risk of minor physical abnormalities.
In a study of a Danish population-based
cohort of 493 113 children, in which four
nationwide registers were linked (births;
medicinal products; fertility; and hospital
diagnoses), redemptions for SSRIs during
early pregnancy (dened as up to 112 days
of gestation) were not associated with major
anomalies overall, but were associated with
a greater risk of septal heart defects (OR
1.99; 95% CI 1.13, 3.53) [21C]. This
was signicant for sertraline (OR 3.25;
95% CI 1.21, 8.75) and citalopram (OR
2.52; 95% CI 1.04, 6.10), but not for
paroxetine or uoxetine. Rates were also
higher when there had been redemptions
for more than one type of SSRI (OR 4.70;
95% CI 1.74, 13). However, absolute
increases in rates of septal heart defects were
low: 0.5% in unexposed children; 0.9% in
those whose mothers redeemed one SSRI;
and 2.1% in those whose mothers redeemed
more than one type of SSRI.
In a second Danish study, this time focus-
ing on outcomes in women who were receiv-
ing prenatal care at Aarhus University
Chapter 2 Philip B. Mitchell
Hospital, the relation between in utero
exposure to SSRIs (at any stage during the
pregnancy) and pregnancy outcome was
examined [22C]. The researchers compared
outcomes in 329 women exposed to SSRIs,
4902 with a history of psychiatric illness
but no SSRIs during pregnancy, and
51 770 women with no history of psychiatric
illness or SSRI exposure during pregnancy.
There was a greater likelihood of preterm
birth in those exposed to SSRIs compared
with women with no history of psychiatric
illness (OR 2.0; 95% CI 1.3, 3.2). Neo-
nates who had been exposed to SSRIs were
also more likely than those with no psychiat-
ric history to be admitted to a neonatal inten-
sive care unit (OR 2.4; 95% CI 1.7,
3.4) and to have a low Apgar score (<8)
(OR 4.4; 95% CI 2.6, 7.6). There were
similar differences in the exposed group
compared with those with a psychiatric his-
tory but who had not been exposed to these
medications.
What conclusions can be drawn from
these four studies? First, the reports of
Diav-Citrin et al [19C] and Pedersen et al
[21C] conrm prior reports of increased
rates of cardiovascular anomalies with
SSRIs, suggesting that this is a class effect
rather than specic to paroxetine, as some
previous studies had suggested. The report
of Diav-Citrin highlights the importance of
accounting for other potential confounders,
such as smoking and maternal age, while
that of Pedersen et al suggests that the main
anomaly is that of septal heart defects and
that the use of multiple SSRIs may further
increase risk.
Second, the studies of Wisner et al [20C]
and Lund et al [22C] are consistent in dem-
onstrating higher rates of preterm deliveries
in neonates exposed to SSRIs. Wisner et al
examined for the effect of depression, but
found no convincing statistical evidence for
an additional effect of depression indepen-
dent of SSRI exposure. Lund et al extended
the ndings of higher rates of premature
delivery, demonstrating the greater rates of
poor physical health in exposed neonates,
who had higher rates of low Apgar scores
and neonatal intensive care admissions.
While they could not examine the effect of
Antidepressant drugs Chapter 2
depression during pregnancy, Lund et al
found no evidence of an effect of pre-existing
psychiatric diagnosis.
In a report from the American Psychiatric
Association and the American College of
Obstetricians and Gynecologists, based on a
comprehensive review of the literature before
the publication of the above four studies, the
authors concluded that while there had been
reports linking antidepressants to both fetal
anomalies and neonatal dysfunction, the
effect of confounding factors such as depres-
sive symptoms during pregnancy had not
been adequately investigated [23S]. The
recent studies of Wisner et al and Lund et al
suggest that the effect of SSRI antidepressants
is unrelated to current depression or pre-
existing psychiatric illness.
Susceptibility factors Genetic There has
been a growing number of reports of attempts
to identify genetic predictors of the adverse
effects of SSRIs, largely arising out of two
large effectiveness trials, the US STAR*D
[27R, 28R] and the European GENDEP pro-
ject. Using the STAR*D dataset, Perlis et al
looked for genetic predictors of sexual dys-
function in depressed patients taking
citalopram, and found an association with
the glutamatergic genes GR1A1, GR1A3,
GR1K2, and GR1N3A [29C]. Perroud et al.
from the GENDEP project, looked for
genetic predictors of treatment-emergent sui-
cidal ideation during treatment with
escitalopram or nortriptyline [30C]. Polymor-
phisms in BDNF (the gene for brain-derived
neurotrophic factor) were signicantly associ-
ated with an increase in suicidal ideation.
While they are of substantial interest, both
of these reports should be regarded as prelim-
inary, in the absence of replication in inde-
pendent datasets.
Citalopram and escitalopram
Cardiovascular Long QT syndrome is asso-
ciated with an increased risk of life-threaten-
ing cardiac dysrhythmias. Torsade de pointes
has been attributed to citalopram [31A].
29
An 81-year-old man with hypertension, diabe-
tes, end-stage renal disease, and depression,
became dizzy and had an episode of torsade
de pointes, with a prolonged QT interval of
572 ms (QTc 695 ms). An ECG recorded
1 month before he started to take citalopram
had shown a normal QT interval.
The citalopram was withdrawn and the QT
interval normalized.
Infection risk In two cases Herpes zoster
infection occurred within 6 weeks of treat-
ment with citalopram [32A]. There have
been no previous reports of such an associ-
ation with any SSRI, and there is no de-
nite effect of these agents on immune
function. The association should therefore
be regarded as provisional.
Drug overdose Seizures are a recognized,
albeit uncommon, complication of overdose
with a number of SSRI antidepressants, but
the susceptibility factors have not been elu-
cidated. Of 241 patients who presented with
overdose of citalopram, 7.5% had general-
ized seizures [33C]. Co-ingested venlafaxine
or tricyclic antidepressants increased the
risk substantially (OR 15). In the
absence of co-ingested drugs, the minimum
citalopram dose associated with seizures
was 400 mg, with an increase in the odds
ratio for seizures of 1.1 for every 100 mg
increment in citalopram dose.
Drugdrug interactions Propafenone A
possible interaction of citalopram and the
class 1C antidysrhythmic drug propafenone
(which is metabolized by CYP2D6) has
been reported [34A].
An 80-year-old white woman took
propafenone 900 mg/day for more than
10 years for paroxysmal atrial brillation with-
out adverse effects. She then took citalopram
20 mg/day for 3 months for anxiety attacks
and began to have episodes of chest tightness
and dizziness, which became more frequent
during the following months, causing several
falls and requiring visits to the emergency
department. However, no coronary event
was diagnosed. The dose of propafenone was
then halved while the citalopram was contin-
ued. She recovered and had no further symp-
toms 1 year later.
30
Paroxetine
Psychological There has been continuing
debate within professional circles and the
public about the effect of the newer antide-
pressants on personality, though there have
been few data to throw light on this conten-
tious issue. In one of the few controlled
studies, personality (as measured by neu-
roticism and extraversion on the NEO
Five-factor inventory) was examined in a
placebo-controlled study of paroxetine for
depression [35C], in which 120 subjects
were randomized to paroxetine, 60 to
placebo, and 60 to cognitive therapy.
There was normalization of personality
measures, i.e. reduced neuroticism and
increased extraversion, with paroxetine
compared with placebo (after statistically
accounting for changes in degrees of
depression). These ndings suggest that
SSRIs may have a pharmacological effect
on personality distinct from their antide-
pressant action. There was no evidence of
any pathological effect on personality.
Susceptibility factors Genetic Impaired
platelet function due to SSRIs has been
well-documented, and is associated with
clinical evidence of an increased bleeding
tendency. The mechanism is related to the
effect of SSRIs on the serotonin transporter
(5-HTTLPR) in the platelet membrane,
which leads to reduced platelet serotonin
concentrations; however, there have been
no studies of the relation of genetic poly-
morphisms of 5-HTTLPR to this pharma-
cological action. In a prospective prepost
trial of paroxetine, the effect of paroxetine
was most pronounced in patients with no
LA alleles or only a single allele, and was
most marked in those with the S/S genotype
[36C].
Drugdrug interactions Flecainide Fleca-
inide, a class 1C antidysrhythmic agent, is
metabolized by CYP2D6. In a study of the
interaction of the CYP2D6*10 allele and
paroxetine in an open crossover study in
healthy Korean subjects, paroxetine signi-
cantly increased the AUC of ecainide and
Chapter 2 Philip B. Mitchell
reduced its clearance in heterozygotes but
had no effects in homozygotes [37C]. The
CYP2D6*10 allele is one of the most com-
mon intermediate metabolism alleles in East
Asians.
Delirium occurred in a 69-year-old
woman who had been taking paroxetine
regularly for 5 years after she took
ecainide for atrial brillation for 2 weeks;
her serum ecainide concentration was
markedly raised and the delirium resolved
3 days after ecainide withdrawal [38A].
Sertraline
Musculoskeletal Rhabdomyolysis has again
been attributed to sertraline [39A].
A 71-year-old woman took sertraline 50 mg/day
for depression and 2 months later was found
to have markedly increased creatine kinase,
lactate dehydrogenase, and aspartate amino-
transferase activities and serum myoglobin
concentration. These abnormalities resolved
within 1 week of sertraline withdrawal, but
recurred dramatically 2 weeks after re-introduc-
tion of sertraline. Once again, everything
resolved after withdrawal of sertraline. She was
successfully treated with escitalopram without
recurrence of the biochemical disturbances.
Liver Hepatotoxicity has again been attrib-
uted to sertraline (SEDA-30, 16) [40A]. In
this case report, it presented within 6 months
of treatment in a 17-year-old boy with no
other demonstrable explanation.
SEROTONIN AND
NORADRENALINE
RE-UPTAKE INHIBITORS
(SNRIS)
Psychiatric Mania and hypomania due to
SNRIs have been reviewed in the light of
a case of duloxetine-induced hypomania in
a non-bipolar patient [41Ar]. The data
suggest that SNRIs, especially venlafaxine,
Antidepressant drugs Chapter 2
can induce mood switching in patients
with bipolar depression and in certain
patients with unipolar depression, and that
duloxetine and milnacipran can also cause
manic or hypomanic symptoms. The authors
suggested starting treatment with a low dose
and titrating upwards as required.
Duloxetine [SEDA-32, 34]
Placebo-controlled studies In a placebo-
controlled study of 1491 patients nausea
was more frequent in those who took
duloxetine (30% versus 7.1%) and weight
loss was signicantly greater; all of those
who withdrew because of an adverse event
were taking duloxetine (22%) [42C].
Systematic reviews In a systematic review
of 36 experimental and observational stud-
ies duloxetine caused nausea, vomiting,
and dry mouth more often than comparator
drugs, but these differences did not lead to
higher withdrawal rates than in patients
taking SSRIs [43M].
Cardiovascular Symptomatic tachycardia
has been attributed to duloxetine 20 mg/day
in a 26-year-old man; it resolved on with-
drawal and recurred after rechallenge; it
responded to treatment with propranolol
while the duloxetine was continued [44A].
An apical cardiomyopathy has also been
attributed to duloxetine [45A].
Nervous system Shock-like sensations in
the head (encephalastrapy [46r]) have
occasionally been reported in association
with antidepressants, and particularly after
withdrawal of venlafaxine [47Ar]. Another
report has now implicated withdrawal of
duloxetine [48A].
Serotonin syndrome has been attributed
to duloxetine [49A, 50A].
Psychiatric Binge eating has been attrib-
uted to duloxetine 90 mg/day in a 37-year-
old woman; the behavior resolved when
the dosage was reduced to 60 mg/day
31
[51A]. Such behavior might be related to
altered serotonin function.
Electrolyte balance Hyponatremia has
been attributed to duloxetine [52A].
An 85-year-old woman with major depression
was given duloxetine 30 mg/day and
within 6 days developed an unstable gait and
reduced vigilance. Her serum sodium concen-
tration was 110 mmol/l, the serum osmolality
234 mOsm/kg, and urine osmolality (310
mOsm/kg), suggesting the syndrome of inap-
propriate antidiuretic hormone secretion
(SIADH). She recovered after withdrawal of
duloxetine.
Sexual function Increased sexual desire
has been attributed to duloxetine [53A].
A 36 year-old man who had had a right parie-
tal lobe stroke took duloxetine 30 mg/day
for 1 week and developed mild nausea and
sedation were mentioned. The dose was
increased to 60 mg/day and he started to have
increased sexual desires and masturbated 34
times a day, even in front of his children
or wife. There were no other hypomanic,
manic, or obsessivecompulsive symptoms.
Drug overdose Overdose with duloxetine
has been described in a 38-year-old man
who had become suicidal within 4 days
after having switched from escitalopram
20 mg/day to duloxetine 30 mg/day [54A].
He was unconscious and severely hypoten-
sive but recovered after treatment in inten-
sive care. The authors discussed the
possibility that duloxetine had made him
feel suicidal, although such an effect has
not emerged in clinical trials.
A 30-year-old woman with major depres-
sion and multiple sclerosis took duloxetine
1680 mg, pipamperone 380 mg, amitripty-
line 250 mg and became unconscious,
had a seizure, and became delirious with
agitation and hallucinations; her plasma
duloxetine concentration was >2000 ng/ml
and the CSF concentration was 15 ng/ml
[55A]. Despite the very high plasma
concentration, she survived. The authors
suggested that active transporters (the
bloodbrain barrier) had protected
the brain.
32
Pregnancy and lactation A 29-year-old
woman took duloxetine for depression
during the second half of an otherwise
uncomplicated pregnancy, gave birth at
term to a healthy girl, and breastfed her
without incident while continuing to take
duloxetine [56A].
Drugdrug interactions Warfarin In 15
healthy subjects taking warfarin 29 mg/
day with a stable international normalized
ratio (INR) of 1.52.0, duloxetine 60 mg
for 14 days or 60 mg for 4 days then
120 mg for 10 days had no clinically or
statistically signicant effect on the steady-
state pharmacodynamics or pharmacokinet-
ics of warfarin [57C].
Venlafaxine and desvenlafaxine
[SED-15, 3614; SEDA-30, 19; SEDA-31,
22; SEDA-32, 35]
Desvenlafaxine, the major active metabo-
lite of venlafaxine, has been relatively
recently introduced as an antidepressant
[58R]. It has been approved for marketing
in the USA but not Europe.
Placebo-controlled studies In an 8-week
placebo-controlled exible-dose (200400
mg/day) study in 235 subjects with major
depressive disorder treatment-emergent
adverse effects were reported by 96% of
those taking desvenlafaxine and 86% of those
taking placebo; 12% of those taking
desvenlafaxine withdrew because of adverse
effects, nausea being the most common
[59C]. Adverse effects reported by at least
5% and at a frequency of at least twice that
of the placebo control group were: nausea
(36%), dry mouth (31%), hyperhidrosis
(20%), insomnia (16%), somnolence (15%),
reduced appetite (15%), tremor (11%),
blurred vision (10%), yawning (9%), sedation
(9%), vomiting (9%), mydriasis (9%), middle
insomnia (8%), initial insomnia (6%), erectile
dysfunction (6%), constipation (6%), feeling
jittery (5%), and dyspepsia (5%).
In an 8-week, randomized, placebo-
controlled comparison of desvenlafaxine
(50 or 100 mg/day) and duloxetine in 638
Chapter 2 Philip B. Mitchell
subjects with major depressive disorder,
7% of those taking desvenlafaxine 100 mg/
day withdrew because of adverse events
[60C]. The most frequent adverse effects
were: nausea (23%), insomnia (14%), som-
nolence (11%), fatigue (10%), reduced appe-
tite (9%), constipation (7%), hyperhidrosis
(6%), blurred vision (5%), vomiting (4%),
abnormal dreams (2%), and yawning (1%).
On withdrawal by tapering at the end of the
study, 27% described withdrawal symptoms,
the most common being dizziness (10%),
headache (5%), and nausea (5%).
Liver Fulminant hepatic failure has been
attributed to a combination of venlafaxine
and trazodone [61A].
A 48-year-old woman with normal liver func-
tion took venlafaxine 75 mg/day and trazo-
done 200 mg/day for depression and
4 months later developed increasing jaundice
and encephalopathy. She had markedly raised
transaminases and bilirubin. There were no
other explanations for her hepatic failure,
and she received an urgent liver transplanta-
tion. The pathology showed severe acute hep-
atitis compatible with toxic acute liver failure.
She recovered fully, and had normal liver
function tests 1 year later.
Drug overdose There has been growing
awareness of the cardiac adverse effects
of venlafaxine (SEDA-32, 35). A 51-year-
old woman with no known risk factors
for coronary artery disease had an episode
of non-ST-elevation myocardial infarction
in association with an overdose of
venlafaxine [62A].
However, in a case series of 273 patients
who took an overdose of venlafaxine,
overdose caused only minor abnormalities
in the QT and QRS intervals, and was
unlikely to be associated with major dys-
rhythmias, except possibly with large doses
(> 8 g) [63C]. The commonest cardiovas-
cular effects were tachycardia (54% of
patients) and mild hypertension (40%).
Drugdrug interactions Desvenlafaxine has
been reported to have minimal effect on
CYP2D6 in a comparison with duloxetine, a
moderate inhibitor of CYP2D6, in a random-
ized, open, crossover study in healthy
Antidepressant drugs Chapter 2
subjects, in which desvenlafaxine had a mini-
mal effect on desipramine pharmacokinetics
[64C].
OTHER
ANTIDEPRESSANTS
Agomelatine
Agomelatine is an agonist at melatonin
(MT1/MT2) receptors and an antagonist at
5-HT2C receptors; it shares the latter action
with other antidepressants, such as
mirtazapine [65R, 66R].
Comparative studies In a 12-week ran-
domized controlled trial in 276 depressed
patients allocated to agomelatine 50 mg/
day or venlafaxine (titrated to a target dose
of 150 mg/day), of those randomized to
agomelatine 20% reported treatment-emer-
gent adverse effects, the most common
being nausea (12%), headache (10%), and
upper respiratory tract infections (7%); 2%
withdrew because of adverse effects [67C].
The rate of treatment-emergent sexual
dysfunction (reduced libido in males and
impaired orgasm in females) was lower than
in those who took venlafaxine.
Placebo-controlled studies In a 24-week
placebo-controlled study in 339 patients with
major depressive disorder there was a with-
drawal rate of 2%; most of the adverse
events were of mild to moderate intensity
[68C]. The most common adverse effects of
agomelatine, which occurred more fre-
quently than with placebo, were headache
(8%), back pain (6%), neck pain (2%), con-
stipation (2%), dyspepsia (2%), and initial
insomnia (2%). There were no symptoms
associated with abrupt withdrawal.
Bupropion (amfebutamone)
[SED-15, 108; SEDA-30, 20; SEDA-31, 22;
SEDA-32, 35]
Observational studies In a study of 698 000
individuals using the French Pharma-
covigilance Database 20012004, the use of
33
bupropion during the rst 3 years of its mar-
keting in France was associated with 475 seri-
ous adverse reactions (SARs), including 21
deaths [69C]. The most common SARs were
cutaneous or allergic reactions (31%
of SARs), including angioedema and serum
sickness-like reactions. Serious neurological
reactions were frequent (23% of SARs),
mostly comprising seizures.
Drug overdose The incidence and nature
of seizures after overdoses of bupropion
XL have been reported in a study of 117
patients who presented to ve poison cen-
ters in the USA [70C]. Seizures occurred
in 32%, and the median dose of those
who had a seizure was 4350 mg, compared
with 2400 mg in those who did not. One-
third had delayed initial convulsions,
dened as occurring more than 8 hours
after the overdose. This suggests the need
for a minimum observation period of
24 hours after overdosage with bupropion.
Drugdrug interactions The inhibitory
effect of bupropion on CYP2D6 metabo-
lism has been previously demonstrated
in vivo, for example by inhibition of dextro-
methorphan metabolism (SEDA-30, 20).
An in vitro study using desipramine as sub-
strate has suggested that this effect is due
to the metabolites erythrohydrobupropion
and threohydrobupropion, which were
much more potent inhibitors of CYP2D6
than hydroxybupropion or bupropion
itself [71E].
Mirtazapine [SED-15, 2356;
SEDA-32, 36]
Nervous system There have been two
reports of movement disorders induced by
mirtazapine. Most of a case series of 14
patients with restless legs syndrome
presented within a few days of starting
treatment, and the symptom occurred more
often in those who also took tramadol or
dopamine receptor antagonists, such as
antiemetics [72c]. In one case, severe
akathisia developed within 4 hours of a rst
34
dose of mirtazapine and required treatment
with intravenous diazepam [73A].
Somnambulism [74A] and severe night-
mares [75A] have been attributed to
mirtazapine.
Electrolyte balance Mirtazapine can cause
hyponatremia (SEDA-32, 37) and many
reports of antidepressant-induced hypo-
natremia have been in elderly patients. A
76-year-old man developed delayed onset
of hyponatremia, and developed worsening
lethargy and confusion after taking
mirtazapine for 2 months [76A].
Skin StevensJohnson syndrome has been
attributed to mirtazapine [77A].
A 29-year-old man developed a disseminated
pruritic eruption with conuent red macules
and bullous lesions after taking mirtazapine
15 mg/day for 3 weeks. The lesions involved
1015% of his body and there were severe oral
and genital erosions. He became generally
unwell and lost 5 kg. The lesions improved after
withdrawal of mirtazapine and treatment with
topical glucocorticoids for 1 week.
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Chapter 2 Philip B. Mitchell
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Declaration of potential conicts of interest
Philip Mitchell has received remuneration
for lectures or advisory board membership
from AstraZeneca, Eli Lilly & Co,
Janssen-Cilag, and Lundbeck in the last
5 years. He has not been a member of an
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38
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 Rif S. El-Mallakh and Yonglin Gao
3 Lithium
The uses of lithium
Acute mania In a review of 60 years of data
examining lithium use in bipolar disorder,
Grof and Muller-Oerlinghausen noted that
despite being the psychotropic drug with the
best demonstrated efcacy, lithium is also
the most contested [1R]. Many studies con-
tinue to demonstrate its efcacy and superior-
ity or equivalence to alternative agents. In a
12-month retrospective clinical audit of two
adult psychiatric units in Auckland, New
Zealand, lithium was the drug of choice in
33% of acutely manic patients [2C].
In clinical practice in the treatment of bi-
polar disorder, many agents are used. Com-
parative or adjunctive efcacy are important
considerations. In an open 12-week, random-
ized assignment study valproate was com-
pared with lithium in 300 patients with acute
mania [3C]. Overall the two drugs reduced
manic symptoms equally well, but valproate
was superior to lithium in the number of sub-
jects who achieved remission (72% versus
66%, dened as a Young Mania Rating Scale
score of less than 12). Both drugs were associ-
ated with a 44% adverse effect rate.
Similarly, the authors of a review of
published randomized comparisons of lith-
ium and carbamazepine concluded that the
two drugs are equivalent in both acute and
prophylactic efcacy [4M]. Carbamazepine
was associated with fewer withdrawals due
to adverse effects in acute mania, while with
lithium there were fewer discontinuations
during maintenance treatment.
Side Effects of Drugs, Annual 33
J.K. Aronson (Editor)
ISSN: 0378-6080
DOI: 10.1016/B978-0-444-53741-6.00003-9
# 2011 Elsevier B.V. All rights reserved.
Antipsychotic drugs are more often used
in the treatment of bipolar illness. Lithium
was equivalent to aripiprazole, and both
were superior to placebo, in a 3-week, dou-
ble-blind, randomized, placebo-controlled
study of acutely manic patients [5C]. The
improvement was maintained for an addi-
tional 9 weeks (a total of 12 weeks), with a
12.7 point drop in Young Mania Rating
Scale score for lithium and a 14.5 point drop
for aripiprazole. The most common adverse
events with aripiprazole were headache,
nausea, akathisia, sedation, and constipation
and with lithium nausea, headache, consti-
pation, and tremor.
In a 4-week randomized, double-blind
study of 50 patients with acute mania, lith-
ium and verapamil produced equivalent
signicant improvement in mania versus
baseline [6c].
Combined treatment approaches are
becoming the standard of care, but these
approaches are only now being examined.
In a 6-month augmentation study, lithium
alone was equivalent to lithium divalproex
in the prevention of mood recurrence in rap-
idly cycling patients with type I and II bipolar
affective disorder with co-morbid substance
abuse [7C]. Of 149 patients, most withdrew
early (79%: poor adherence 42%, non-
response 26%; adverse effects 10%). Of the
31 who remained in the study 55% relapsed
into an abnormal mood state.
A more novel approach has been exam-
ined in a 4-week double-blind, randomized,
placebo-controlled study of lithium alone
(n 60) or lithium allopurinol (n 60)
[8C]. Lithium reduced manic symptoms,
but the combination was more effective.
The improvement in allopurinol-treated
patients correlated positively with a reduc-
tion in plasma uric acid concentrations.
39
40 Chapter 3 Rif S. El-Mallakh and Yonglin Gao

Animal models of mania help explain Table 1 Patients reporting adverse reactions in
the mechanisms of lithium action. Positron cases in which there were signicant between group
emission tomography (PET) was used differences (% of 45 patients in each group) [13C]
to study glucose utilization (using
18
F-uorodeoxyglucose) in the ouabain Adverse reaction Lithium Lamotrigine
animal model of mania [9E]. Motor hyper-
activity induced by intracerebroventricularly Dry mouth 53 20
Thirst 49 7.3
administered ouabain was associated with
Nausea/vomiting 47 24
reduced cerebral glucose utilization. Lithium Upset stomach 43 20
administration normalized glucose uptake. In Tremor 41 9.8
the D-amphetamine model of mania, hyper- Increased urinary 33 2.4
activity is associated with lipid peroxidation frequency
and DNA damage. Treatment with either lith- Dizziness/ 31 7.3
ium or valproate ameliorated both the lipid lightheadedness
peroxidation and DNA damage [10E]. Drowsiness/panic 31 9.8
Increased appetite 29 4.9
Cognitive slowing 27 7.3
Bipolar depression The acute efcacy of Word nding 25 4.9
lithium has been compared with that of other Increased weight 23 4.9
agents in three studies in bipolar depression. Impaired memory 20 0
In a 12-week, open study of 83 depressed Feeling dull 18 2.4
patients with type II illness who were random- Reduced sexual 16 2.4
interest
ized to either venlafaxine (n 43) or lithium
Ringing in ears 12 0
(n 40), improvement in depressive symp-
toms was signicantly greater with
venlafaxine [11C]. The rate of mood switches Unipolar depression In an open ran-
was not different between treatments in either domized study in 46 subjects with unipolar
rapid cycling or non-rapid cycling patients.
depression examined over 3 weeks lithium
Therapy was prematurely discontinued in 26
augmented mirtazapine successfully (n 13),
patients, 11 because of lack of efcacy, 13 but carbamazepine was ineffective when
because of adverse events, two because of added to mirtazapine (n 10) compared with
non-compliance; another seven were lost to
mirtazapine alone (n 23) [14C]. Lithium
follow-up. There was one serious adverse augmentation in treatment-resistant depres-
event, an increase in suicidal ideation, during sion remains among the best studied successful
lithium therapy, judged to be unrelated to the
interventions [15C].
drug. Polydipsia, polyuria, and tremor were
the most common adverse events during
lithium therapy. Prevention of recurrence of affective disor-
In a double-blind, placebo-controlled, der Insight into how best to use lithium to
multicenter trial of type I and II depressed reduce the recurrence of new mood episodes
patients treated with either lithium alone continues to accrue. In long-term prospec-
(plus placebo) or lithium plus lamotrigine, tive study in ve centers, the International
improvement was greater with combination Group for the Study of Lithium-Treated
treatment [12C]. Patients examined the relative stability of
In a randomized, blind-rater 16-week patients with predominantly atypical features
comparison in 90 patients, lithium and (n 100; e.g. mixed states or rapid cycling)
lamotrigine were associated with similar sig- or more typical bipolar features (n 142)
nicant improvements over baseline, but the over a mean of 10 years [16C]. There were
early drop-out rate was high at 42% [13C]. no differences in the overall measures of
Adverse events were more common in those morbidity in the two groups.
taking lithium than in those taking This was not consistent with the results of
lamotrigine (Table 1). another study in which 100 patients were
Lithium Chapter 3
studied retrospectively over 3 years of use of
life charting [17C]. Atypical features, such as
mixed episodes and rapid cycling, were less
likely to be associated with remission and
more predictive of greater severity of dura-
tion of episodes.
In a 2-year randomized double-blind
study of the comparative efcacy of a mood
stabilizer alone (lithium or valproate plus
placebo) or a mood stabilizer added to
quetiapine in 628 bipolar subjects, combina-
tion treatment resulted in fewer mood epi-
sodes (20%) versus a mood stabilizer alone
(52%), and mania and depression were
prevented to an equal degree [18C].
Serum lithium concentrations may be
related to the polarity of recurrence. In an
18-month maintenance trial, relapses or
recurrences of depressive episodes were pre-
ceded by serum concentrations above the
mean, both when evaluated individually or
across the entire study population [19C].
The authors concluded that lower concentra-
tions were adequate for preventing depres-
sion, and that higher concentrations
prevented episodes of mania and hypo-
mania. However, the data can also be
interpreted in the opposite mannerthat
higher lithium concentrations are required
to prevent depression.
Dementia Lithium has neuroprotective
properties in vivo. In human endothelial cell
and rat cortical astrocyte cultures, lithium
0.2 mmol/l increased phosphorylation of
GSK-3b (inactivation of GSK-3b) and pro-
moted secretion of vascular endothelial
growth factor (VEGF) [20E]. The effect on
GSK-3b may be more general, since lithium
also reduced GSK-3b concentrations in pri-
mary cultures of rat cortical and hippocam-
pal cells [21E] and in neural precursor cells
[22E]. This effect on GSK-3b expression
and activity is probably related to the obser-
vation that lithium treatment of primary cul-
ture cortical cells reduces both tau protein
concentrations and tau phosphorylation
(tau is phosphorylated by GSK-3b) [23E].
Similarly, in PC12 cells, lithium 1.2 mmol/l
reduced morphine-induced apoptosis by
down-regulating the BAX, which is pro-
41
apoptotic and up-regulating BCL-2, which
is protective [24E].
At the organ level, lithium has been asso-
ciated with an increase in cortical
grey matter as examined using structural
magnetic resonance imaging (MRI) [25R]
and an increase in N-acetyl-aspartate,
a derivative of aspartic acid, which is a
marker of neuronal health, measured by
magnetic resonance spectroscopy [26C].
These neuroprotective characteristics of
lithium may reduce the risk of dementia.
In an observational cohort study using
national medical databases in Denmark,
patients who had received a prescription
for lithium at least once (n 16 238) had
a higher rate of subsequent dementia than
those who had never used lithium (n 1
487 177) (RR 1.47; 95% CI 1.22,
1.76), but long-term use of lithium was asso-
ciated with a dramatic reduction in the likeli-
hood of eventual dementia [27C]. By
contrast, the use of anticonvulsants was
associated with a signicantly increased risk
of dementia and the risk increased with
long-term use.
For all these reasons, it is not surprising
that lithium has independently been pro-
posed in Alzheimer's disease as a potential
agent for prevention [28R] and treatment
[29R]. The effects of lithium have been stud-
ied for up to 1 year in 22 patients with
Alzheimer's disease, of whom 14 stopped
the study early, in three cases because of
adverse effects [30R]. The Mini-Mental State
Exam (MMSE) score did not change in
those who took lithium compared with the
controls. In a 10-week, randomized, pla-
cebo-controlled study of lithium in 71 sub-
jects with mild dementia (MMSE 2126; 38
placebo, 33 lithium) there was no change in
cognition, mood, GSK-3b activity in lym-
phocytes, or phosphorylated tau concentra-
tions in the cerebrospinal uid [31C].
Amyotrophic lateral sclerosis The neuro-
protective effects of lithium suggest that it
might be useful in other neurodegenera-
tive or neurodestructive conditions. Amy-
otrophic lateral sclerosis (ALS), a disease
of wasting of the motor neurons of the spinal
cord, is of particular interest. In a mouse Au1
42
model of ALS, the combination of lithium
and valproate was more effective in delaying
disease onset and reducing neurological def-
icits than either lithium or valproate alone
[32E].
HIV infection Imaging was used in an open
study for 10 weeks in 15 subjects with
human immunodeciency virus (HIV) and
evidence of cognitive decline; there was no
evidence of improvement in either cognition
or mood [33C].
Multiple sclerosis Lithium was effective in a
mouse model of experimental autoimmune
encephalomyelitis (a model of multiple scle-
rosis). It reduced neurological symptoms if
administered both before and after induction
of the illness and the animals rapidly
relapsed if lithium was withdrawn [34E].
Cerebral ischemia Lithium was efcacious
in a rat model of cerebral ischemia; given
alone or in combination with prostaglandin
E1 it reduced infarct size and cerebral
edema [35E].
Use in children The Collaborative Lithium
Trials (CoLT) is a large multicenter study
that has been initiated at seven sites to exam-
ine the best practices in using lithium in chil-
dren with mania [36r]. Data are currently
being gathered and analysed.
The rst randomized, double-blind, pla-
cebo-controlled trial of severe mood
dysregulation (SMD) in youths has been
performed. SMD is a proposed disorder that
distinguishes children who have persistent
severe irritability and hyperarousal and
who do not t the criteria for current disor-
ders [37R]. Children aged 717 years were
assigned to lithium (n 14) or placebo
(n 11) after a 2-week single-blind placebo
run-in phase and were followed for 6 weeks
[38C]. Nearly half (45%) of the children
improved during the 2-week placebo period
and were not randomized. Among the
remaining 25 subjects, lithium was not dif-
ferent from placebo in reducing the patients
mood or behavior symptoms.
In a retrospective study of the effective-
ness of lithium in 60 youths with a similar
Chapter 3 Rif S. El-Mallakh and Yonglin Gao
symptom complexconduct disorderwho
were followed for an average of 8.4 months,
29 had at least a 50% reduction in the Mod-
ied Overt Aggression Scale score or were
rated as much improved or very much
improved on the Clinical Global Impres-
sion scale [39C]. Ten took lithium alone
and 19 took a concomitant atypical antipsy-
chotic drug. Less severely affected children
generally did better.
Cardiovascular Lithium generally does not
have signicant cardiac effects. However,
lithium toxicity has been associated with
transient electrocardiographic changes.
In a 46-year-old man who had had confusion
and ataxia for 2 days the serum lithium con-
centration was 4.69 mmol/l [40A]. The electro-
cardiogram was normal but there was ST
segment elevation in the anterior leads and
biphasic T waves. Although these changes
suggested ischemia, the cardiac enzymes were
normal as was echocardiography. The patient
was hemodialysed and the electrocardio-
graphic normalized over several days.
In a 39-year-old woman with signs of lithium
toxicity, the serum lithium concentration was
2.96 mmol/l and the potassium 2.72 mmol/l
[41A]. Her electrocardiographic showed ST
segment depression in leads V2 and V3, wide-
spread T wave inversion, and prolongation of
the P wave (180 msec), QRS complex
(120 msec), QT interval (640 msec), and PR
interval (320 msec). She improved rapidly
and the electrocardiographic with normalized
after hemodialysis reduced her serum lithium
concentration to 0.57 mmol/l and normalized
the potassium.
While lithium may have played a role in
the second case, the signicant hypo-
kalemia may have been responsible.
Lithium can also be associated with
changes in cardiac conduction [42A].
A 57-year-old woman developed acute mental
status changes. Her serum lithium concentra-
tion was 2.2 mmol/l and the creatinine
187 mmol/l. She was hypotensive (70/
45 mmHg) and bradycardic (37/minute).
An electrocardiogram showed complete atrio-
ventricular block. Her hemodynamic status
normalized when she cleared the lithium.
While the AV block in this case may seem
to have been related to lithium toxicity,
Lithium Chapter 3
the presentation was more consistent with a
rise in the serum lithium concentration due
to reduced renal clearance after the onset
of heart block.
Nervous system In 16 patients with acute
lithium intoxication treated on a toxicologi-
cal unit, intensity was mild in 25%, moder-
ate in 50%, and severe in 25% [43C].
Over one-third required hemodialysis.
Mean length of hospitalization was 16 days,
of which 4.8 were spent in acute care and
11.2 in recovery. There was long-lasting
ataxia in two subjects.
Severe lithium toxicity is associated with
seizures. In two cases, seizures were associ-
ated with high lithium concentrations
(4.86 mmol/l in a 25-year-old woman and
2.5 mmol/l in a 48-year-old man) [44A]. A
third case occurred in a 20-year-old man
whose lithium concentration was only
0.8 mmol/l [45A]. Status epilepticus that
lasted 45 minutes occurred in a middle-
aged woman undergoing electroconvulsive
therapy (ECT) while she had therapeutic
serum concentrations of lithium and was
also taking agents that reduce the seizure
threshold (clomipramine and quetiapine)
[46A]. It has been previously proposed that
ECT can cause the intracellular concentra-
tion of lithium to rise without a concomi-
tant rise in serum concentration [47H].
In three cases lithium was associated
with nervous system toxicity.
A 24-year-old woman who was 24 weeks preg-
nant and had pregnancy-related hyponatremia
and mood symptoms was given lithium and
developed diabetes insipidus, which rapidly
corrected her hyponatremia and caused cen-
tral pontine and extrapontine myelinolysis
[48A].
An 11-year-old boy who had taken lithium for
6 months developed pseudotumor cerebri with
secondary visual eld loss [49A].
A 42-year-old woman developed dementia in
the setting of atrophy and multiple diffuse
areas of brain calcication when she took lith-
ium for antidepressant drug-associated mania
[50A]. She became semi-comatose, with dysar-
thria and right-sided dystonia. Her serum lith-
ium concentration was only 0.57 mmol/l, but
her neurological signs resolved when lithium
was discontinued.
43
A complicated case of thyroiditis and
Hashimoto's encephalopathy has been asso-
ciated with lithium [51A].
A 61-year-old woman with type II bipolar ill-
ness, who was taking levothyroxine for thy-
roiditis, developed an encephalopathy within
40 days of starting to take lithium. Her serum
antithyroid antibodies were raised and anti-
thyroid antibodies were detectable in the cere-
brospinal uid. She improved with a course of
methylprednisolone.
The authors suggested that lithium-induced
antibodies can have a shared target in both
the thyroid and the brain, although how an
ion can induce such antibodies is not clear.
Lithium can affect peripheral nerves, but
deleterious consequences are rare.
A 73-year-old man taking lithium for bipolar
II disorder (serum concentration 0.8 mmol/l)
developed confusion, dysarthria, gait distur-
bance, muscle stiffness, and twitching [52A].
A brain CT scan was consistent with vascular
encephalopathy. Peripheral electromyography
(EMG) showed many intermittent spontane-
ous motor unit discharges in doublets, triplets,
and multiplets, consistent with peripheral
nerve hyperexcitability. The EMG normalized
after withdrawal of lithium.
Severe lithium toxicity can have perma-
nent or long-lived sequelae. This has been
called the syndrome of irreversible lithium-
effectuated neurotoxicity (SILENT) [53A].
A 44-year-old woman continued to have
dyscoordination 1 year after an overdose of
lithium 6 g (lithium concentration not stated).
In another case a maximum lithium concentra-
tion 1.9 mmol/l was associated with dysmetria
and unsteady gait, which persisted for 3 years
after the episode of toxicity, and 2 years later
a brain MRI scan showed prominent cerebel-
lar atrophy [54A].
Psychological The effect of lithium on cog-
nition remains unclear. Most studies have
found minimal drug-related cognitive de-
cits. When 40 euthymic bipolar I patients
were compared with 40 healthy controls,
the only neuropsychological abnormalities
were in patients who were taking antipsy-
chotic drugs; they had reduced semantic u-
ency, verbal learning, recognition memory,
44
and planning abilities [55C]. Patients who
were taking only mood stabilizers (includ-
ing lithium, n 14) were not affected. Sim-
ilarly, in 44 patients with bipolar I disorder,
22 of whom were drug free, all the cogni-
tive symptoms that were noted (delayed
verbal recall and perseverations during the
ve-point test) became insignicant after
control of residual depressive symptoms
[56C]. Finally, in 33 patients with bipolar
depression taking lithium or valproate, 32
taking no medication, and 52 controls,
those taking the medications had greater
response latency and made more errors in
tasks of sustained attention [57C].
In a meta-analysis of 12 studies (539 sub-
jects, of whom 276 took lithium for an aver-
age of 3.9 years), in which patients were
comparable for medication, mood state,
educational level, cognitive abilities, and
medications, lithium was associated with
reduced immediate verbal learning,
reduced verbal memory, and reduced crea-
tivity [58M]. Longer duration of lithium
treatment was associated with reduced psy-
chomotor performance. Many aspects were
unaffected, including delayed verbal mem-
ory, visual memory, attention, executive
function, and processing speed.
Endocrine Thyroid A woman with thyroid
carcinoma who was taking lithium for bipolar
disorder discontinued her thyroid hormone
replacement in preparation for radioactive
iodine (131I) treatment [59A]. Within 3 weeks
she developed severe lithium toxicity, which
the authors attributed to renal insufciency
associated with hypothyroidism [60R]. Lith-
ium was not withdrawn in this patient, because
of an earlier suggestion that lithium can be
used as an adjunct in 131I treatment [61R].
In an in vitro study using follicular thyroid
carcinoma cell lines, lithium 1020 mmol/l
induced expression of NR4A1 and FOSB,
genes whose underexpression is associated
with malignancy [62E].
Parathyroid In some individuals lithium
can increase serum calcium and parathy-
roid hormone concentrations [63M]. In a
Chapter 3 Rif S. El-Mallakh and Yonglin Gao
retrospective study of patients who had
taken lithium for at least 1 year, laboratory
personnel monitored the frequency of serum
calcium determinations [64C]. Of 100
patients, 43 had had at least one serum cal-
cium concentration measurement. Of these,
ve had raised calcium concentrations.
However, lithium also increases bone
density [65C] and reduces the risk of bone
fracture [66C] (see Musculoskeletal).
In six cases of lithium-associated hyper-
parathyroidism, four had parathyroid ade-
nomas [67A, 68A]. The authors suggested
that lithium can help uncover pre-existing
parathyroid disease, although there does
appear to be an increased incidence of
multiglandular or multiadenomatous dis-
ease in patients taking lithium. Surgical
treatment is often curative when adenomas
are discovered. When hypercalcemia per-
sists, cinacalcet, a calcimimetic can be used
effectively.
Diabetes insipidus In a retrospective chart
review of 116 subjects taking lithium, in
whom 24-hour urine collections had been
performed, 46 had polyuria; 12 of these were
also taking serotonergic antidepressants,
compared with only 10 of the 70 subjects
who did not have polyuria, a signicant
difference (OR 2.86; 95% CI 1.00,
8.21) [69C].
When diabetes insipidus occurs, amiloride
can be an effective treatment. In 87 subjects
(45 taking lithium and 42 taking other psy-
chotropic drugs) there was impaired urinary
concentrating ability and reduced urinary
excretion of aquaporin 2 and cyclic AMP;
11 were given amiloride 10 mg/day for
6 weeks in a double-blind, crossover design,
and when they were then given 40 micro-
grams of desmopressin (dDAVP), amiloride
was associated with an increase in urinary
osmolality and aquaporin 2 excretion [70C].
The authors concluded that this effect was
mediated by increased responsiveness to
the ability of desmopressin to increase
translocation of aquaporin 2 to the apical
membrane in principal cells of the collecting
duct.
Lithium Chapter 3
Hematologic Lithium increases bone mar-
row neutrophil production, protects bone
marrow hemopoietic stem cells after expo-
sure to anticancer drugs or radiation, and
increases platelet count [71R]. These effects
suggest several potential uses in medicine,
such as concomitant use in patients who
have clozapine-induced neutropenia.
A 26-year-old AfricanBrazilian man with
paranoid schizophrenia improved with cloza-
pine 400 mg/day, but his absolute neutrophil
count fell to 600  106/l; coadministration of
lithium (serum concentration 0.6 mmol/l)
allowed clozapine to be used in a dose of
600 mg/day while maintaining an absolute
neutrophil count of 2.53.0  109/l [72A].
Gastrointestinal In the acetic acid-induced
colitis rat model for inammatory bowel
disease, lithium 20 mg/kg given 1 hour
before the acetic acid ameliorated the mac-
roscopic and microscopic gut abnormalities,
including reduced neutrophil inltration,
reduced myeloperoxidase activity, and
reduced lipid peroxidation [73E].
Urinary tract The association of lithium
with renal dysfunction has again been con-
rmed in a retrospective record review of
59 out-patients [74C]. There was a positive
association between duration of lithium
treatment and serum creatinine concentra-
tion, but the duration of treatment was also
greater in older patients (14.2 years for
those over 65 years of age and 6.9 years
for those under 65 years of age).
Lithium was associated with an increased
incidence of kidney microcysts (12 mm
diameter) in patients taking lithium, in both
the cortex and medulla of the kidneys
and more prevalent in areas of atrophy or
brosis [75r].
Skin Lithium is associated with an
increased risk of psoriasis [76R, 77R]. In a
10-year database study using the UK-based
General Practice Research Database
(GPRD) 36 702 subjects with psoriasis
were compared with an equivalent matched
group without psoriasis; long-term use of
lithium (ve or more prescriptions) was
45
associated with an increased risk of psoria-
sis (OR 1.68; 95% CI 1.18, 2.39) [78C].
Musculoskeletal Lithium is associated with
increased bone density. In 75 patients with
mood disorders taking lithium and 75 with-
out mood disorders and no lithium expo-
sure, mean bone density was an average
of 4.57.5% higher in those taking lithium
[66C]. Furthermore, in a 10-year adminis-
trative database study in which subjects
older than 50 years in Manitoba 15 792 sub-
jects with bone fractures were compared
with a matched sample of 47 289 without
fractures, there was a signicantly reduced
risk of fractures in those taking lithium
(OR 0.63; 95% CI 0.43, 0.93). By con-
trast, antidepressant drug treatment
increased the risk (OR 1.15; 95% CI
1.07, 1.24; serotonin reuptake inhibitors
had the highest risk: OR 1.45; 95%
CI 1.32, 1.59) as did benzodiazepines
(OR 1.10; 95% CI 1.04, 1.16).
Drug withdrawal Lithium withdrawal can
cause neurological adverse effects. Recur-
rent night-time headaches are frequently
referred to as alarm clock headaches or
hypnic headaches, and this has now been
reported after lithium withdrawal [79A].
A 54-year-old woman with bipolar disorder
who had taken lithium for 6 years
(600900 mg/day with serum, concentrations
of 0.81.5 mmol/l) stopped taking lithium
because of renal dysfunction. About 1 month
after withdrawal she began to have nocturnal
headaches about 4 hours after going to sleep.
They were of mild to moderate intensity,
lasted for 34 hours, and resolved spontane-
ously. The headaches persisted for 1 month
and then ended without treatment.
Sudden lithium withdrawal also causes
mood disorders to recur. A retrospective
review of 310 charts yielded 53 cases of
withdrawal [80C]. Recurrence of a mood
episode after lithium withdrawal was
highest at 86% within 3 months. With-
drawal of antipsychotic drugs (64%) and
antidepressants (58%) were associated with
lower rates of recurrence. More than half of
these episodes required hospitalization.
46
Teratogenicity In a review of all English
language literature published between
1969 and 2005, a total of 24 pregnancies in
women taking lithium were reported, but
only eight included women who took only
lithium. The most common ndings were
larger infant size, transient lithium toxicity
with concentrations in the infants higher
than in their mothers, and two cases of con-
genital heart abnormalities (Ebstein's
anomaly and patent ductus arteriosus)
[81R]. Similarly, registry data (n 225)
had also reported an increased risk of car-
diovascular defects (8%, n 18) among
the 25 (11%) with any congenital defect,
an increased risk of prematurity (36%),
and increased size for gestational age
(37%). However, prospective studies that
do not pick reporting due to outcome (as
is the case for published reports and regis-
try data) have generally shown no change
in the risk of malformations compared with
controls (2.7% in lithium-treated mothers,
n 377, versus 3.2% in controls). Lithium
is not benign in pregnancy, but the risk of
teratogenicity may have been exaggerated.
Drug overdose Treatment of lithium over-
dose must be individualized to the clinical
condition. Three case reports have
highlighted the number of options that are
available to clinicians.
A 47-year-old woman with somnolence and a
serum lithium concentration of 3.5 mmol/l
was treated with an infusion of isotonic saline
200 ml/hour [82A]. Over the next 25 hours
her concentration fell to 0.9 mmol/l and her
mental status normalized; intravenous uids
were withdrawn. After 48 hours her lithium
concentration had fallen to 0.3 mmol/l.
A 47-year-old woman took an overdose of
lithium [83A]. Her initial serum lithium con-
centration was 1.62 mmol/l, but it rose to
2.77 mmol/l 8 hours later, despite intravenous
uids, and she was lethargic and nauseated.
She was given sustained low-efciency hemo-
dialysis for 8 hours. The lithium concentration
fell quickly and remained at under 1.0 mmol/l
for the duration of her course.
An 80-year-old woman became obtunded
after slowly deteriorating over the previous
week. Her serum lithium concentration was
3.4 mmol/l and her creatinine was 125 mmol/l
[84A]. Because of poor diuresis (10 ml/hour)
she was hemodialysed for 4 hours until her
Chapter 3 Rif S. El-Mallakh and Yonglin Gao
lithium concentration had fallen to
0.84 mmol/l. This was followed by continuous
veno-venous hemoltration, which prevented
rebound, and the lithium concentration con-
tinued to fall over the next 14 hours to
0.3 mmol/l. Some of her neurological symp-
toms improved quickly, but her lethargy did
not clear for a further 3 weeks.
In the rst case, a young, otherwise
healthy woman, with normal renal function,
conservative treatment was adequate. In
the second case, with rapidly rising concen-
trations hemodialysis produced recovery
within 4 hours, since lithium had not had
an opportunity to accumulate in the intra-
cellular compartment. The third patient
required aggressive treatment because of
her age and the slow onset of toxicity, which
conspired to slow her recovery.
Drugdrug interactions Angiotensin
converting enzyme (ACE) inhibitors ACE
inhibitors can increase lithium concen-
trations, and in one case this combination
caused dyspnea and bradycardia [85A]. In
another case the addition of a loop diuretic
and an ACE inhibitor precipitated lithium
toxicity within 3 days [86A].
Non-steroidal anti-inammatory drugs
Non-steroidal anti-inammatory drugs can
reduce lithium renal clearance and increase
lithium concentrations.
A 76-year-old woman took lithium 1000 mg/
day and several over-the-counter pain medica-
tions [87A]. Diclofenac 75 mg bd was added,
and after 1 week, she developed a confusional
state, a raised serum creatinine, and a serum
lithium concentration of 2.43 mmol/l. She
recovered completely 4 days after withdrawal
of lithium and diclofenac and then tolerated
reintroduction of lithium at a lower dosage
(400 mg/day).
Management of adverse drug reactions
Guidelines, 19 in all from seven countries,
for treating toxicity have been evaluated
using the Appraisal of Guidelines Research
and Evaluation (AGREE) instrument;
there were deciencies in nearly every sin-
gle guideline [88M]. Many had missing
information. For example, none highlighted
Lithium Chapter 3
the importance of taking a psychiatric his-
tory and only one suggested psychiatric
evaluation. Only two provided information
regarding monitoring during hemodialysis
and only ve provided information about
discharge. In more general terms, 60% pro-
vided information regarding supportive
care, 53% regarding diagnosis, 76% regard-
ing appropriate treatment, and 20% regard-
ing discharge and follow-up. The authors
recommended frequent updating of treat-
ment guidelines to improve their utility.
Monitoring therapy One of the predictors of
lithium clearance, and consequently lithium
toxicity, is creatinine clearance [89c], and lith-
ium concentrations are closely associated
with its adverse effects. In a study of 186
patients who were followed between 1973
and 2000 (an average of 5.7 years/patient) in
which nine specic adverse effects were
recorded monthly in a standardized manner
(diarrhea, nausea, vomiting, stomach ache,
tiredness, concentration decits, tremor,
polyuria, and polydipsia), the frequency of
adverse effects increased as a function of lith-
ium concentration as did their intensity
[90C]. The mean number of adverse effects
increased from 3.3 at a concentration of
0.6 mmol/l to 3.8 in patients with a concentra-
tion of 1.2 mmol/l. However, there was also a
relation between mood state and adverse
effects. Patients with manic symptoms had
fewer adverse effects (an average of 2.0),
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 Jayendra K. Patel, Sarah Langenfeld, and
4 Drugs of abuse
Adulteration of street drugs
with clenbuterol
Street drugs are often modied by substitution,
dilution, contamination, or adulteration [1rc].
Substitution involves complete replacement of
one drug by another one.
Dilution involves the addition of pharmacolog-
ically inert or dissimilar compounds to reduce
the content of active drug in the product. Typi-
cal diluents used are sugars, starches, talc, and
quinine.
Contamination involves unintentional inclusion
of a foreign substance, often a by-product of
the process of synthesis.
Adulteration involves the intentional addition
of a pharmacologically active substance in an
attempt to use less of the intended product with-
out making the user aware.
These changes may go unnoticed or can on
occasion cause morbidity and/or mortality.
From 28 January to 2 February 2005, nine
cases of atypical reactions to heroin were
reported from a county in New Jersey, USA.
The patients had nausea, chest pain, palpita-
tion, agitation, anxiety, tachycardia, hypoten-
sion, hyperglycemia, hypokalemia, and
metabolic acidosis with increased lactate con-
centrations. Cyanide poisoning was suspected,
but cyanide was not found and specic treat-
ment was ineffective. However, clenbuterol
was identied as an adulterant in a sample of
heroin obtained by the police. A public health
alert was issued using the USA Centers for Dis-
ease Control and Prevention's EPI-X system
Side Effects of Drugs, Annual 33
J.K. Aronson (Editor)
ISSN: 0378-6080
DOI: 10.1016/B978-0-444-53741-6.00004-0
# 2011 Elsevier B.V. All rights reserved.
Eileen Wong
which included a request to report all poten-
tially exposed cases to regional poison centers.
There were 34 patients from ve centers in
USA that met the case denitions or proba-
ble clenbuterol poisoning over a period of
6 months. Thirteen cases met criteria for con-
rmed exposure. The initial nine cases or the
index cases were listed with the 21 probable
exposures, even though they tested positive
for clenbuterol, as the test was done by the
law ofcers. The mean age of the patients was
34 years, and 31 were men. The results of a
urine drug screen were reported in 27 of the
34 cases, and eight were positive for cocaine.
All the patients survived and were discharged.
Clenbuterol is a potent, long-acting b2-
adrenoceptor agonist with unique b3-
adrenoceptor agonist effects. It is often used
illegally by ranchers to increase the lean mass
of cattle and by body builders for its anabolic
effects. The authors suggested that as
clenbuterol causes excessive stimulation of b-
adrenoceptors, it can cause hypokalemia and
hyperglycemia. As this was often observed in
these cases, the authors suggested a possible
diagnostic value to these observations. Cardiac
markers were documented in 14 of 34 patients;
six had evidence of myocardial injury, as
evidenced by increased troponin concentra-
tions. Two of these also had metabolites of
cocaine in the urine. The authors cited previous
reports of clenbuterol-associated myocardial
infarction. The clinicians used b-adrenoceptor
antagonists to treat 10 patients before
clenbuterol was identied or suspected in these
cases; no adverse events were reported.
Thus, adulteration of heroin by clenbuterol
was associated with sympathomimetic effects,
metabolic acidosis, and myocardial injury.
However, collaborative efforts among the
53
54 Chapter 4
poison control centers using the CDC Epi-X
system rapidly led to identication of the dis-
ease outbreak. In another paper, with some
of the same authors involved in the report
mentioned above, a small epidemic of an
atypical neuromuscular syndrome in ve
individuals who had used clenbuterol-tainted
heroin has been described [2cr].
A 47-year-old man injected heroin and devel-
oped diffuse muscle cramping that progressed
over 16 hours. He had severe pain, agitation,
sweating, and opisthotonos. His mental status
was clear with no focal motor decits. Limited
physical examination was unremarkable. His
potassium was 3.3 mmol/l, glucose 7.2 mmol/l,
creatine kinase 5539 U/l; troponin concentra-
tions and the cerebrospinal uid were normal.
To achieve adequate sedation, he required
endotracheal intubation, and after sedation
had intermittent spasms of his legs, hyper-
reexia, and clonus. Strychnine poisoning and
tetanus were suspected. He was intubated for
8 days and recovered completely. However,
his urine and blood were negative
for strychnine. Subsequent testing revealed
clenbuterol in urine, blood, and CSF.
A 40-year-old opioid-dependent man currently
taking methadone maintenance treatment
developed nausea, vomiting, and bilateral spas-
modic leg pain. He had insufated heroin
3 days before admission and reported symptoms
within 2 hours of drug use followed by diffuse
crampy muscle aches and right ank pain. He
reported that friends who had used the same her-
oin had had similar symptoms. He was in mod-
erate distress, with akathisia, muscular spasm
of both hamstrings, hyper-reexia throughout,
and clonus in the knees and ankles. The creatine
kinase activity was 9734 U/l. He was treated with
midazolam, ketorolac, lorazepam, and
ondansetron and subsequently admitted to
intensive care. His condition improved 24 hours
later and the creatine kinase fell to 2398 U/l. He
was discharged 36 hours after admission and
later his urine was found to be negative for
strychnine but positive for clenbuterol. Heroin
metabolites were absent.
A 35-year-old woman with a history of mild
asthma and substance abuse insufated heroin
and rapidly developed diffuse muscular pain
and spasms involving the face, neck, arms, and
chest. She reported that other friends had had
similar experiences. She had mild physical dis-
tress, was anxious, and had hyper-reexia with-
out clonus. Her creatine kinase activity was
395 U/l. She received 1 liter of isotonic saline
and intravenous lorazepam and improved
symptomatically. She was discharged. Her urine
was negative for strychnine but positive for
clenbuterol, morphine, 6-MAM, and codeine.
Jayendra K. Patel, Sarah Langenfeld, and Eileen Wong
A 33-year-old man who both sold and was
known to have used the same heroin as patients
2 and 3 above reported palpitation, shaking,
and muscle tightness involving the face, neck,
and shoulders within minutes of insufating
heroin. He had mild resting tremor in the arms
and hyper-reexia without clonus. He refused
serum laboratory studies but agreed to a urine
drug test. He was given lorazepam and left.
His urine was negative for strychnine but posi-
tive for morphine, 6-MAM, and clenbuterol.
A 45-year-old man developed nausea,
vomiting, and leg shaking within 5 minutes of
insufating heroin. He had mild distress, anxi-
ety, hyper-reexia, and ankle clonus. His potas-
sium was 5.8 mmol/l and creatine kinase
activity 296 U/ml. Urine testing was negative
for strychnine but positive for clenbuterol, mor-
phine, 6-MAM, and codeine.
The authors reported that these patients
had an unusual neuromuscular syndrome
(which has not previously been described),
characterized by muscle spasms and hyper-
reexia that lasted between 2 and 8 days.
They reported that though clenbuterol toxicity
has been reported to cause muscle tremors
and myalgia, previous patients did not have
tetany, muscle spasms, or hyper-reexia.
None of the drug screens detected strychnine,
which is a common contaminant of heroin.
They concluded that this novel neuromuscu-
lar syndrome was probably due to
clenbuterol-adulterated heroin, but acknowl-
edged that there could be other possible expla-
nations/contaminations that were not
detected.
Benzylpiperazine and related
compounds [SEDA-32, 55]
Placebo-controlled studies In a random-
ized, double-blind, placebo-controlled
study in 27 healthy, right-handed, non-
smoking women, mean age 22 years,
benzylpiperazine increased blood pressure
and heart rate, euphoria, and dysphoria,
and sociability and drug liking [3c].
Nervous system In 178 individuals who
were reviewed in hospital after having
Drugs of abuse Chapter 4
taken benzylpiperazine, 69% had also taken
other substances, most commonly ethanol
[4c]. In those who took benzylpiperazine
alone, increased plasma benzylpiperazine
concentrations were associated with
increased seizure frequency. Ethanol co-
ingestion reduced the incidence of seizures,
but signicantly increased the likelihood of
confusion and agitation.
Drugdrug interactions Benzylpiperazine
and its analogue 3-triuoromethylphenyl-
piperazine are often used in combination
[5c], mimicking the effects of ecstasy. The
combination can cause dissociative-type
symptoms, nausea, and signs consistent with
sympathomimetic toxicity [6A]. Both com-
pounds inhibit CYP2D6, CYP1A2, and
CYP3A4 [7E, 8E], and mutual inhibition of
metabolism occurred when the two com-
pounds were co-administered in seven
healthy volunteers, with reduced production
of their metabolites, 3-hydroxybenzylpiper-
azine and hydroxytriuoromethylphenyl-
piperazine [9c].
CANNABINOIDS [SED-15, 614;
SEDA-30, 31; SEDA-31, 33;
SEDA-32, 55]
Systematic reviews Serious and non-seri-
ous adverse events associated with medical
cannabinoids in 321 reports, as reported
during the last 40 years, have been system-
atically reviewed [10M]. Those that focused
on recreational cannabis were excluded, and
23 randomized controlled studies and eight
observational studies, describing 4779
adverse events, were included. Serious
events were dened as those that were life-
threatening or resulted in death, or required
admission to a hospital or prolonged a cur-
rent admission, or resulted in persistent or
signicant disability or incapacity, or were
congenital malformations. Of the adverse
events, 4615 (96%) were not serious. Of the
55
164 serious events, 21 (13%) were relapses
of multiple sclerosis, 16 (9.8%) were
vomiting, and 15 (9.1%) were urinary tract
infections. The rate of non-serious adverse
events was higher among those randomized
to cannabinoids versus controls (RR 1.86;
95% CI 1.57, 2.21); there was no differ-
ence in serious adverse events between the
two groups. The most common non-serious
adverse event (714 events, 15.5%) was dizzi-
ness. The median exposure time was 2 weeks
(range 8 hours to 12 months). The authors
concluded that while the short-term use of
medical cannabinoids increases the risk of
non-serious adverse events, it does not seem
to increase the risk of serious events. They
found little information about long-term
risks of exposure. Others have commented
that these ndings support the use of canna-
binoids to treat acute medical conditions
such as pain, but for longer term use more
data is needed [11r]. They also noted that
none of the trials involved smoked cannabis,
which may have its own set of adverse
effects. They also drew attention to the need
to examine the risks as they apply to older
adults, for example, risks of cardiovascular
disease, cancer, and any differences in the
risk of dependence.
In another systematic review of the evi-
dence for using cannabinoids in the manage-
ment of chemotherapy-induced nausea and
vomiting in patients with cancer, nabilone,
dronabinol, and levonantradol was superior
to placebo and neuroleptic drugs [12M].
However, the cannabinoids caused adverse
effects in some patients, even when they
were given orally and their use was limited
to 24 hours. Some untoward reactions
occurred almost exclusively in patients who
were exposed to them: paranoid delusions
(5%), hallucinations (6%), and dysphoria
and/or depression (13%). Although the
patients had more adverse effects and
greater intensity of symptoms during treat-
ment with cannabinoids, most of the drop-
outs, which were responsible for almost
30% of the nearly 400 dropouts in all the
studies included in the systematic review,
were probably not due to cannabinoid
toxicity.
56 Chapter 4
Cardiovascular Preliminary results from a
cohort study in adults recruited after hospi-
talization for myocardial infarction have
suggested that cannabis use may increase
the risk of death among people with coro-
nary heart disease [13R]. Of 1913 patients,
52 reported cannabis use during the previ-
ous year. During the mean follow-up time
of 3.8 years, 317 died. Compared with those
who did not report cannabis use, those who
had used it at least weekly had a hazard
ratio of 4.2 (95% CI 1.2, 14). The age-
and sex-adjusted risk for any use was
greater for both cardiovascular mortality
(HR 1.9; 95% CI 0.6, 6.3) and mortal-
ity from non-cardiovascular causes (HR
4.9; 95% CI 1.6, 15). The authors
suggested that the effects of cannabis that
may affect the cardiovascular risk include:
increased heart rate and blood pressure,
reduced oxygen uptake (due to carbon
monoxide exposure) at a time when
increased heart rate increases oxygen
demand. However, they also noted
the increased risk of mortality from non-
cardiac causes. They cautioned that these
results should be viewed as preliminary,
given, for example, the small proportion
of cannabis users in the study and the wide
condence intervals; additionally, although
they controlled for important clinical char-
acteristics, such as alcohol and nicotine
use, there may have been more complex
confounders from lifestyle or other factors.
Nervous system Both cannabis use and
schizophrenia have been linked to progres-
sive loss of gray matter and cannabis use
has also been associated with poorer clini-
cal outcomes in people with schizophrenia.
From the results of a longitudinal MRI
study in 51 patients with recent-onset
schizophrenia and 31 sex- and age-matched
healthy subjects, the authors hypothesized
that loss of gray matter volume in people
with schizophrenia who use cannabis may
be greater than in non-users [14Cr]. Of the
51 subjects with schizophrenia, 19 used can-
nabis over the 5-year study period and 32
did not. Cannabis use was assessed using
the Composite Diagnostic Interview
(CIDI) and random urine toxicology
Jayendra K. Patel, Sarah Langenfeld, and Eileen Wong
screens throughout the study. The Positive
and Negative Symptom Scale (PANSS)
was used to assess symptoms. The canna-
bis-using patients had a larger gray matter
volume loss than the healthy controls and
non-cannabis-using patients. Non-canna-
bis-using patients also experienced some,
but less, volume loss than the healthy con-
trols. The cannabis-using patients also had
more marked enlargement of both the third
ventricle and the lateral ventricles than the
controls and the non-cannabis-using
patients. There was no difference in overall
positive and negative symptoms between
those who did or did not use cannabis, nor
any difference in the overall cumulative
length of hospitalization, but those who
did not use cannabis had a slightly greater
improvement in their positive and negative
symptoms. Increased ventricular size corre-
lated with a greater need for help with daily
functioning and with a lower GAF score;
however, there was no apparent direct cor-
relation with cannabis use. The authors
provided several potential explanatory
mechanisms, not directly demonstrated in
this study: cannabis might augment vulner-
ability to the gray matter changes that are
associated with schizophrenia by direct
effects, by heightening psychotic symptoms
(which in turn might facilitate loss of gray
matter volume), or by reducing adherence
to medications that would otherwise atten-
uate the brain changes. Limitations of this
study included the relatively small number
of patients, the lack of a cannabis-using
otherwise healthy control group, and dif-
culty in quantifying the amount of cannabis
exposure (since amounts were based on
patient and family recall and since there
are differences in the amount of tetra-
hydrocannabinol in cannabis preparations).
Psychological The cerebellum contains
the highest density of cannabinoid recep-
tors in the brain, but little is known about
the effects of cannabis on cerebellar-depen-
dent learning. The long-term effects of can-
nabinoids on the cerebellum have been
assessed based on Eyeblink conditioning,
an associated motor learning task that
pairs a conditioned stimulus (tone) to an
Drugs of abuse Chapter 4
unconditioned stimulus (a puff of air), lead-
ing to a conditioned eye blink; the cerebel-
lum is critically involved in this process.
Current cannabis users (n 14) and
healthy drug-naive controls (n 10) were
evaluated [15C]. The cannabis users had
used cannabis at least once a week in the
past month, had a positive urine toxicology
screen, and had used no other illicit drugs
in the past 6 months. The cannabis users
had fewer conditioned responses and their
conditioned responses were poorly timed;
however, they had normal unconditioned
responses, and the problem seems specic
to acquisition of the conditioned response.
Limitations of this study included the small
sample size and the lack of information
about whether or not a period of absti-
nence could improve these effects.
Cannabis use may worsen cognitive func-
tion among patients with multiple sclerosis
and may affect emotional functioning.
Cognitive impairment, most commonly
impaired attention and slower processing,
is an important predictor of quality of life
for both patients and families. Of 140 con-
secutive community patients with multiple
sclerosis, 10 (7.7%) were current cannabis
users (using at least once a month) and
had a slower mean processing time [16c].
While the cannabis users were younger,
there were no signicant differences
between the users and non-users in sex,
education, disease course or duration, or
physical disability (as measured by the
Expanded Disability Status Scale). Because
age could affect cognitive status indepen-
dent of cannabis use, the 10 cannabis users
were each age-matched to four subjects
who did not use cannabis. Using the Struc-
tured Clinical Interview IV, there were no
differences in the percentages of patients
who met current criteria for any diagnosis,
although the cannabis users had a higher
rate of lifetime psychiatric diagnoses. The
subjects were assessed using the Neuropsy-
chological Battery for multiple sclerosis
(NPBMS), which includes the Selective
Reminding Test, the 7/24 Spatial Learning
Test, the Paced Auditory Serial Addition
Task, and the Controlled Oral Word
Association Test. The NPBMS was
57
supplemented with a computerized version
of the Symbol Digit Modalities Test, which
tests processing speed and working mem-
ory. Among cognitive variables, the canna-
bis users performed less well in the
measure of performance time for visual
working memory. The authors noted that
direction of causality could not be deter-
mined and pointed out that differences
may not be direct differences due to canna-
bis use, if, for example, cannabis use is a
marker for some other risk factor. The lim-
itations of the study included the small sam-
ple size, self-reporting of cannabis use, and
lack of urine toxicology conrmations, but
it has provided information about an area
not previously examined.
Teeth An association between cannabis use
and periodontal disease has been reported
from a prospective cohort study of 903 indi-
viduals born in Dunedin, New Zealand,
between 1972 and 1973 [17c]. Cannabis use
data were collected at ages 18, 21, 26, and
32 and dental examinations were done at
ages 26 and 32. After controlling for tobacco
smoking, sex, irregular use of dental ser-
vices, and dental plaque, the cannabis users
had a higher relative risk of periodontal
combined attachment loss: 1.6 (95% CI
1.2, 2.2) for having one site or more with
4 mm or greater combined attachment loss;
3.1 (95% CI 1.5, 6.4) for having one site
or more with 5 mm or greater combined
attachment loss; and 2.2 (95% CI 1.2,
3.9) for having incident attachment loss
(compared with those who had never smoked
cannabis). There was a doseresponse
relation.
Liver Daily cannabis use may be a suscep-
tibility factor for steatosis in chronic hepat-
itis C, an important consideration, since
steatosis has been reported to increase
brosis and reduce the rate of viral eradica-
tion. In 315 consecutive patients with
chronic hepatitis C undergoing liver biopsy
collected, the patients were categorized as
non-users (64%), occasional users (12%),
and daily users (24%) [18c]. After alcohol
intake and viral genotype were controlled
for, marked steatosis (at least 30% of
58 Chapter 4
hepatocytes with cytoplasmic fat vacuoles)
was more frequent in daily cannabis users
than in non-users (OR 2.1; 95% CI
1.01, 4.50).
Infection risk A 56-year-old woman with
underlying COPD, a past cigarette smoker
and current cannabis smoker, had multiple
pulmonary nodules seen in a routine chest
X-ray [19A]. Biopsy of the nodules showed
cavitary lesions and invasive pulmonary
aspergillosis. Aspergillus can be found in sam-
ples of marijuana and chronic cannabis use
probably predisposed her, perhaps owing to
impairment in mucociliary activity and alveo-
lar macrophages function. While prior reports
of invasive pulmonary aspergillosis have been
documented in immunocompromised indi-
viduals who use cannabis, she was not
immunocompromised.
COCAINE [SED-15, 848; SEDA-30,
31; SEDA-31, 37; SEDA-32, 58]
Cardiovascular
Ischemic cardiac events due to cocaine
EIDOS classication:
Extrinsic moiety: Cocaine
Intrinsic moiety: Alpha-adrenoceptors
Distribution: Myocardium and platelets
Outcome: Vasospasm and increased
platelet aggregability
Sequela: Ischemic cardiac events due to
cocaine
DoTS classication:
Dose-relation: Toxic
Time-course: Time independent
Susceptibility factors: Not known
In the USA, cocaine is the illicit recrea-
tional drug that leads to the most emer-
gency room visits and chest pain is the
most common complaint. The American
Heart Association has reviewed the current
Jayendra K. Patel, Sarah Langenfeld, and Eileen Wong
literature on cocaine-associated chest pain
and myocardial infarction and has provided
guidance on diagnosis and clinical manage-
ment [20R].
Cardiovascular toxicity due to cocaine
abuse forms a spectrum of adverse medical
conditions. The pathophysiology of cardio-
vascular events has been reviewed [21R].
Ischemia and vasospasm are adrenergically
mediated and there is a prothrombotic effect
due to increased platelet aggregability. In
the setting of hypoxia, intracoronary throm-
bosis can occur.
In the acute setting of cocaine-induced
chest pain, assessment includes the possible
diagnosis of acute myocardial infarction.
However, cocaine may independently affect
cardiac biomarkers [22r]. Recent cocaine use
may alter the specicity of measurement of
serum creatine kinase and its MB fraction.
Among cocaine users, increased serum crea-
tine kinase activities and increased mean
myoglobin concentrations are common.
Increased skeletal muscle activity and rhab-
domyolysis are often present, possibly
because of cocaine-induced hyperthermia.
Troponin I concentrations are more reliable
cardiac biomarkers for detecting cocaine-
induced myocardial infarction and are asso-
ciated with a poor prognosis.
Aortic dissection is an uncommon cardio-
vascular complication of cocaine use. In a
retrospective chart review of 164 patients
with acute aortic dissection [23c] 16 (9.8%)
had used cocaine or crack cocaine within
24 hours before the onset of symptoms and
148 (90%) had no history of cocaine use. In
the cocaine group, 11 had inhaled intrana-
sally and ve had smoked crack cocaine.
The length of time between cocaine use
and the onset of aortic dissection was 424
(mean 13) hours. The cocaine users were
younger, were more often men, and had
more co-morbid polysubstance abuse. In
those who had surgery there was a higher
rate of pulmonary complications in the
cocaine users. The authors suggested that
this may have been due to lung impairment
caused by smoking cocaine; many cocaine
users were also cigarette smokers.
Painless aortic dissection has been attrib-
uted to cocaine use [24A].
Drugs of abuse Chapter 4
A 48-year-old man had sudden paralysis of his
legs with loss of bowel control. His medical his-
tory included hypertension, post-traumatic
stress disorder, depression, and cigarette
smoking. His blood pressure was 60/40 mmHg
and his pulse 56/minute. His muscle strength
was 0/5, and there was areexia in the legs.
From the umbilicus down there was loss of sen-
sation to touch. Rectal tone was absent. The
serum creatinine was 186 mmol/l, lactic acid
9.5 mmol/l, and serum alcohol 78 mmol/l, and
a urine screen was positive for cocaine. The
electrocardiogram showed sinus bradycardia
at 60/minute. A chest X-ray showed a widened
mediastinum. There was a moderate pericardial
effusion with right ventricular collapse, severe
aortic regurgitation, and extensive aortic dissec-
tion starting from the aortic valve. After cardiac
surgery he developed spinal cord damage.
Severe gangrene of all four limbs due to
cocaine-associated peripheral vasospasm
has been reported [25A].
A 43-year-old woman developed reduced
mental responsiveness after using crack
cocaine the previous night and repeatedly in
previous weeks. Her hands and legs were cya-
notic. She developed bilateral hand compart-
ment syndrome and required emergency
fasciotomy and carpal tunnel release. Despite
anticoagulant and antithrombotic therapy her
condition deteriorated and she developed dry
gangrene of eight digits and the legs below
the knees, requiring digital and above-knee
amputations. There was no evidence of auto-
immune disorders or vasculitis.
The authors suggested that cocaine-induced
peripheral vasospasm with associated
delayed and persistent vasospasm was a
probable mechanism for this outcome. The
vasospastic action of cocaine peaks at 1 hour
after use and correlates with an increased
serum concentration of cocaine
(benzoylmethylecgonine). Delayed and per-
sistent vasospasm can occur, as the major
metabolites of cocaine, benzyolecgonine
and ecgonine methyl ester, can also report-
edly cause vasospasm [26r].
Respiratory Cocaine use is associated with
various pulmonary complications. Pneumo-
thorax, lung cavitation, and pleural empy-
ema have been reported [27A].
A 32-year-old chronic cocaine user developed
a cough, shortness of breath, fever, and
59
left-sided chest pain. The white blood cell
count was 14.7 109/l, a chest X-ray showed
a left-sided pneumothorax, and a CT scan
showed ve cavities in the right lower lung
lobe, the largest being 5 cm in diameter. Gram
stain of the sputum showed Staphylococcus
aureus. The diseased lobe was excised and his-
tology showed diffuse alveolar damage, pneu-
monic inltration, thrombosis in subsegmental
arteries, areas of pulmonary infarction, and
brinopurulent material in the pleura.
Cocaine powder has a direct effect on the
lungs and there is an indirect effect via
vasoconstriction. Barotrauma was the most
likely cause for the pneumothorax and
pneumomediastinum in this case.
An uncommon pulmonary inltrate called
exogenous lipoid pneumonia occurs second-
ary to aspiration or inhalation of fat-like sub-
stances, such as oil-based laxatives.
Exogenous lipoid pneumonia has been
attributed to inhalation of crack cocaine
mixed with petroleum jelly [28A].
A 42-year-old AfricanAmerican man with
paranoid schizophrenia who smoked crack
cocaine mixed with petroleum jelly and ciga-
rettes developed progressive shortness of
breath. His medications included uticasone,
ipratropium, and salbutamol inhalers, haloperi-
dol, quetiapine, trihexyphenidyl, and celecoxib.
His oxygen saturation fell from 93% on room
air to 88% after 1 minute of walking. There were
ne inspiratory crackles in both lung bases. A
chest X-ray showed diffuse reticular inltrates.
Pulmonary function tests showed a combined
restrictive and obstructive ventilatory defect
with a reduced diffusion capacity. A course of
high-dose glucocorticoids was ineffective. A
wedge biopsy showed exogenous lipoid pneu-
monia, with lipid vacuoles surrounded by inam-
matory inltrates.
The prevalence of self-reported illicit use
of cocaine and/or metamfetamine in
patients with acute decompensated heart
failure has been studied, using a multi-
center observational registry, in 11 258
patients, of whom 594 (5%) had previously
used cocaine (96%) and/or metamfetamine
(5%) [29C]. Users had a median age of
50 years compared with 76 years in non-
users. As there were disproportionately
more young AfricanAmerican men with
hypertension, left ventricular systolic dys-
function, and markedly raised B-type
60 Chapter 4
natriuretic peptide concentrations, the
authors speculated that the severity of car-
diac dysfunction in these young patients
would probably result in higher morbidity,
mortality, and health costs. Although these
patients had a greater degree of left ventric-
ular dysfunction (ejection fraction < 40%),
they did not have a greater risk-adjusted
mortality.
Musculoskeletal Osteonecrosis of the calca-
neus following cocaine injection in the foot
has been reported [30A].
A 49-year-old man developed pain, redness,
and swelling in his left foot 3 days after having
injected cocaine into veins on the top of his
left foot. He had a fever of 39.4 C, edema,
and erythema of the lower third of the left
leg, with supercial blisters and skin excoria-
tion. The white blood cell count was
24  109/l and an X-ray and MRI scan showed
sclerosis of the navicular bone, suggestive of
osteonecrosis, soft tissue swelling around the
ankle, consistent with cellulitis, and osteo-
arthritis of the talonavicular joint, with a
subchondral cyst at the head of the talus.
The fever and ankle swelling persisted despite
intravenous antibiotics, and aspiration of
the ankle joint yielded a purulent uid. As
blood cultures were positive for meticillin
resistant Staphylococcus aureus (MRSA), he
was given intravenous vancomycin. The
wound and ankle joint were debrided and irri-
gated several times. Bone histology showed
focal areas of necrotic bone with calcication
surrounded by vascularized brous tissue in
the bone marrow, consistent with healing of
infarcted bone.
The calcaneus has a rich vascular supply
and is an uncommon site of infarction.
Endocrine Panhypopituitarism with posi-
tive autoimmune serology secondary to
cocaine use has been reported [31A].
A 41-year-old man who habitually inhaled
cocaine developed severe fatigue, cold intoler-
ance, anorexia, and weight loss of 20 kg over
6 months. He had low serum concentrations
of TSH, free thyroxine, and free triiodothyro-
nine, FSH, LH, ACTH, cortisol, prolactin, and
testosterone. MRI and CT scans showed a
normal sized pituitary gland within a dense,
edematous, contrast-enhancing mass. The
nasal septum was destroyed, and there were
no conchae and severely eroded sinus walls.
Jayendra K. Patel, Sarah Langenfeld, and Eileen Wong
A transnasal biopsy showed a non-specic,
non-granulomatous inammation and coloniza-
tion with Staphylococcus aureus. There was a
strongly positive C-ANCA titer (320 U/l) with
specicity for human neutrophil elastase-specic
anti-neutrophil cytoplasmic antibodies (HNE-
ANCA); PR3-ANCA was negative. These
results ruled out Wegener's granulomatosis
and a diagnosis of cocaine-induced HNE-
ANCA associated panhypopituitarism was
made. He stopped using cocaine and 2 years
later the ANCA titers were repeatedly negative.
Skin The adverse effects of cocaine on the
skin include vasculitides, purpura, urticar-
ial, and non-specic eruptions. The delu-
sion of parasitosis or formication, the false
belief that insects are crawling underneath
the skin, has also been described. Two
other reactions have been described in a
review [32Ar].
A 37-year-old woman developed numerous
discrete papular erythematous excoriations
with overlying crusts on the lower legs, thighs,
and forearms. She also had worsened
dental caries and unexplained weight loss of
18 kg. A urine test was positive for
benzoylecgonine.
A 39-year-old man had itchy skin and weight
loss of 1418 kg over 3 months and described
a whitish, hairy substance that protruded from
burning skin lesions. He had erythematous,
excoriated papules on the arms, legs, the front
of the trunk, and buttocks. A urine test was
positive for cocaine.
The authors recommended that when a
patient presents with chronic skin lesions,
a vague medical history, negative ndings
during previous examinations, labile affect,
and delusional behavior, a drug screen
should be obtained to check for cocaine use.
Fetotoxicity Cocaine exposure in utero may
have a direct effect on autonomic nervous
system regulation, cardiac control mecha-
nisms, and cardiovascular functioning in
neonates [33C]. In 21 prenatally cocaine-
exposed infants and 23 non-exposed con-
trols, studied within 120 hours of birth, there
was a positive interaction between prenatal
cocaine exposure and orthostatic stress.
Whereas both exposed and non-exposed
infants had increased heart rates and heart
rate variability, the responses of the exposed
Drugs of abuse Chapter 4
infants to orthostatic stress were both
delayed and prolonged. The responses of
the non-exposed infants were immediate
but transient. The authors suggested that
cocaine exposure in utero may alter develop-
ment of the sympathetic and parasympa-
thetic systems and thus lead to altered
neonatal cardiovascular function.
Cocaine exposure in utero and its possi-
ble effect on language development has
been studied in a prospective, longitudinal
study in 398 children (209 cocaine-exposed
and 189 non-exposed), who were evaluated
at birth, 1, 2, 4, and 6 years of age [34C].
Cocaine exposure had a negative effect on
all language domains during the rst 6 years
of life. Over time, the cocaine-exposed
group showed stable language growth but
did not catch up in the areas of linguistic
decits. The authors also mentioned that
the cumulative risk of language decits is
also based on other variables, such as other
toxic exposures and environmental, genetic,
and social factors.
The effect of cocaine exposure in utero
on subsequent growth has been studied by
enrolling mothers from a prenatal clinic
and interviewing them at the end of each
trimester about their use of cocaine and
other substances; follow-up assessments of
the offspring were done at 1, 3, 7, and
10 years [35C]. This study was the rst to
conduct longitudinal growth-curve analysis
using four time-points and to extend into
childhood. The offspring who were exposed
to cocaine during the rst trimester
grew at a slower rate than non-exposed
controls. At 7 and 10 years, but not at 1
or 3 years, children with prenatal cocaine
exposure were smaller on all growth
parameters than the children who had not
been exposed.
There have been two radiological studies
of the effect of in utero cocaine exposure
on neurocognitive development in older
offspring. In the rst study, 24 cocaine-
exposed adolescents and 25 matched non-
cocaine-exposed controls underwent struc-
tural and perfusion functional MRI during
resting states [36C]. The cocaine-exposed
adolescents had signicantly reduced global
cerebral blood ow. The affected areas
61
were mainly in the posterior and inferior
brain regions, including the occipital cortex
and thalamus. In addition, the cocaine-
exposed group had increased relative cere-
bral blood ow in the anterior and superior
brain regions, such as the prefrontal, cingu-
late, insular, amygdala, and superior parie-
tal cortex. These ndings suggest that
there may be compensatory mechanisms
for reduced global cerebral blood ow due
to a prenatal cocaine effect during neural
ontogeny.
In the second study volumetric MRI data
of brains were collected in 35 children,
mean age 12 years, with intrauterine expo-
sure to cocaine, alcohol, tobacco, and mari-
juana (14 cocaine-exposed and 21 non-
cocaine-exposed) [37c]. The children with
cocaine exposure had lower mean cortical
gray matter, total parenchymal volumes,
and smaller mean head circumference. As
the number of exposures to prenatal sub-
stances grew, these specic measured areas
showed further reductions in size. Even
though the sample size was small, this study
has provided relevant information on the
adverse effect of prenatal drug exposure
among older children.
Fibromuscular dysplasia has been reported
in a child with in utero cocaine exposure
[38A].
A 21-month-old boy began vomiting daily. He
had been exposed to cocaine in utero. His
symptoms improved initially and then deterio-
rated, with loss of consciousness. He devel-
oped pneumonia, a dilated cardiomyopathy,
and presumptive myocarditis, had a respira-
tory arrest and renal failure and died. Post-
mortem ndings were consistent with dilated
cardiomyopathy and the major coronary arter-
ies had moderate luminal narrowing by inti-
mal broplasia. Histology showed changes of
intimal broplasia diffusely present in the
intramyocardial coronary artery branches,
consistent with intimal broplasia, a rare vari-
ant of bromuscular dysplasia. There was no
evidence of myocarditis.
Fibromuscular dysplasia is an idiopathic
disease of small and medium sized arteries.
The authors postulated that cocaine had
altered transforming growth factor beta,
which had caused intimal broplasia.
62 Chapter 4
Ecstasy (3,4-methylene-
dioxymetamfetamine, MDMA)
[SED-15, 180; SEDA-30, 37; SEDA-31, 41;
SEDA-32, 61; for other amphetamines see
Chapter 1]
Cardiovascular Based on reports that
in vitro MDMA can cause proliferation of
cardiac valvular interstitial cells, the authors
of a study recruited 29 subjects who were
using or had used MDMA, mean age 24 years,
and 29 sex- and age-matched controls to
evaluate the occurrence of cardiac valvular
disease in Belgium from December 2004 to
February 2006 [39c]. Subjects who had used
drugs that could cause valvulopathy and sub-
jects with any current or past cardiac disease
were excluded. Eight users had abnormal
echocardiograms using the US FDA criteria
for appetite suppressant-induced valvular
heart disease, compared with none in the con-
trol group. Users with valvular regurgitation
of  2/4 for mitral and tricuspid valves or any
aortic regurgitation had used on average
higher cumulative doses of MDMA than
those with lower grades of regurgitation. Six
had mitral regurgitation of 1/4 and four of
2/4, compared with none in the control
group. Tricuspid regurgitation of  2/4 was
present in 13 MDMA users and absent in
the controls. Four MDMA users had mild
aortic regurgitation. There were valvular
strands, dened as thin, mobile, lamentous
projections attached to the valvular leaets,
in six MDMA users and none in the controls.
The authors described these strands as wit-
nesses of an abnormal underlying valvular
structure. They observed that this was the rst
time valvulopathy in young adults using
MDMA has been reported. They speculated
that the possible mechanism may be activa-
tion of serotonin 5HT2B receptors and
induction of mitogenic responses in human
valvular interstitial cells. They proposed that
this might explain the fact that intermittent
use in these young patients could give rise
to cardiac valvulopathy. They were also
concerned that valvular strands are associated
with ischemic stroke in young individuals.
Jayendra K. Patel, Sarah Langenfeld, and Eileen Wong
Sensory systems Vision Acute bilateral
angle closure and transient myopia has
been attributed to MDMA [40A].
A previously emmetropic 39-year-old healthy
man developed bilateral angle closure and
transient myopia after using MDMA for
2 weeks. He had painless progressive reduc-
tion in vision in both eyes over 2 days, bilat-
eral myopic refraction, and an intraocular
pressure of 4041 mmHg in both eyes, with
bilateral ciliochoroidal effusions. Bilateral
neodymium-doped yttrium aluminium garnet
peripheral iridotomy was performed, but the
intraocular pressures remained high. His
vision improved following treatment with
brimonidine 0.2% and timolol maleate 0.5%
topically and then oral acetazolamide for
4 days.
The authors suggested that uid movement in
choroidal effusion could have been related to
drug-induced membrane potential changes or
a possible idiosyncratic reaction. The acute
myopia was probably due to forward displace-
ment of the lens caused by superciliary effu-
sion, although ciliary body swelling and lens
thickening could also have played a role. They
also postulated that the ciliary effusion in this
case could have been due to the serotonergic
effects of MDMA.
Psychological The effects of four different
single intranasal doses of metamfetamine (0,
12, 25, and 50 mg/70 kg) on a broad range of
behavioral and physiological measures have
been studied in 11 non-treatment seeking
metamfetamine abusers in a double-blind
study [41c]. Metamfetamine concentrations
rose progressively for 4 hours after adminis-
tration. The cardiovascular and subjective
effects increased and peaked about
515 minutes after administration. Cognitive
performance and less complicated tasks
improved on all active doses, whereas perfor-
mance in more complicated tasks was
improved only by the intermediate doses.
The authors proposed that the rapid action
on subjective well-being probably contributes
to increased abuse liability, as may the perfor-
mance enhancing effect. However, they were
puzzled by the rapidity of the subjective
Drugs of abuse Chapter 4
effects and the effects on performance, which
occurred before the plasma concentrations
had peaked. They quoted previous data that
suggest that metamfetamine is commonly
abused in multiple dose cycles, with an inter-
dose interval of 0.53 hours and may continue
for several days, suggesting that binging may
result in for very high, potentially toxic,
plasma concentrations of amphetamines.
They further contrasted the effects of cocaine
and metamfetamine: the cardiovascular
effects of cocaine last 3050 minutes while
those of metamfetamine last more than
240 minutes, making metamfetamine poten-
tially more toxic.
Prospective memory, which involves
remembering future intentions, has been
reported to be negatively affected by
MDMA in a double-blind, placebo-con-
trolled, two-way crossover study of a single
dose of MDMA 75 mg in 12 recreational
MDMA users [42C]. A single dose of
MDMA increased the number of prospec-
tive memory failures, which correlated with
plasma MDMA concentration. Functional
imaging showed that MDMA decreased
BOLD activation in the left thalamus, left
putamen, left precuneus, and the bilateral
inferior parietal lobules. The authors con-
cluded that loss of deactivation in the inferior
parietal lobules may account for increments
in memory failures observed during MDMA
intoxication. The effect of MDMA on mem-
ory was small. The detrimental effect of
MDMA did not correlate with lifetime use.
There was a threefold intersubject variability
in plasma concentrations of MDMA, imply-
ing that pharmacokinetic variables may play
an important part in these effects. The
authors speculated that MDMA suppresses
brain processes that are normally involved
in prospective memory.
Prospective memory has been assessed in
20 adults with amfetamine abuse/depen-
dence who were abstinent for an average
period of 6 months and 20
metamfetamine-naive participants using
Virtual Week, a laboratory measure that
closely approximates the type of prospec-
tive memory tasks that actually occur in
everyday life [43c]. Metamfetamine users
were signicantly impaired, and the decits
63
did not vary as a function of specic pro-
spective memory task demands. The
authors suggested that these decits were
not secondary to the effects of other illicit
drug use. They found prospective memory
impairment in those who had used
metamfetamine but had been abstinent on
average for 6 months, suggesting that the
neurocognitive decits were not transient.
The authors made the case that failure to
respond was the most common type of
error made by both groups, but across all
tasks. The metamfetamine users had signif-
icant impairment of retrospective memory
and executive functioning. However, the
cross-sectional design, small sample size,
and other factors limited their conclusions.
In a comparison of 29 current MDMA
users, 10 previous users, and 46 non-users,
using tests of working memory MDMA users
performed worse than non-MDMA users in a
letter comparison task, although the overall
difference was not signicant [44c]. Current
MDMA users made signicantly more errors
in pattern recognition task than the other
groups. When the results were combined, cur-
rent MDMA users made signicantly more
errors than non-users. Working memory de-
cits were signicantly greater in both MDMA
groups compared with the controls. Although
MDMA users made more errors in informa-
tion processing speed and in letter compari-
son tasks at all levels of complexity
compared with non-MDMA users, the differ-
ences were not statistically signicant. The
authors suggested that age-related impair-
ment of information processing is more global
in nature and is characterized by more global
slowing, compared with the MDMA-related
impairment, which appears to be more spe-
cic and localized, perhaps reecting some
kind of attentional decit among current
users. They acknowledged that MDMA users
had used a range of other drugs, making it dif-
cult to attribute the results unambiguously to
MDMA alone.
MDMA has been suggested to alter cogni-
tive function and impulsivity, but the data
have often been tainted by the concurrent
use of other drugs of abuse. Decision-making,
self-reported impulsivity, and drug use have
been studied in 22 abstinent MDMA users,
64 Chapter 4
30 other drug users, and 29 healthy non-drug
controls [45c]. Users of MDMA and other
drugs had comparable patterns of decision-
making and impulsivity. However, both drug
groups had poorer decision-making and
impulsivity than controls. Poorer decision-
making was related to heavier drug use in
the past year, heavier weekly alcohol use,
and lifetime substance use disorder, while
increased impulsivity was associated with
heavier drug use, heavier weekly alcohol
use, more lifetime substance use disorders,
and more self-reported depression. MDMA
users had heavier patterns of drug use in gen-
eral, making a specic role of MDMA use in
reward-related decision-making and impul-
sivity questionable. No particular drug class
emerged as being most strongly associated
with decision-making decits.
Immunologic Death from a possible ana-
phylactic reaction to MDMA has been
reported [46A].
A healthy 13-year-old girl took MDMA and
had swelling of her lips. A few weeks later
she took 1 tablets of MDMA and soon after
complained of nausea and took an antiemetic
containing zingerone, without much effect.
After about 4 hours she became apneic, coma-
tose, hypothermic (33 C), hypotensive, and
tachycardic. She died 30 hours after ingestion.
Autopsy showed massive brain edema with
tonsillor and transtentorial herniations and
anoxic/ischemic encephalopathy. Her lungs
were congested and she had laryngeal edema.
There was zingerone in the urine and MDMA
blood concentrations were too low to explain
death by acute intoxication alone. Concomi-
tant intoxication from alcohol and other drugs
was excluded. There was no evidence of dis-
seminated intravascular coagulopathy, rhab-
domyolysis, hyponatremia, acute renal or
liver failure, or water intoxication. A friend
had taken a similar formulation of MDMA
and had had no reaction.
The authors concluded that this was most
probably a case of anaphylactic reaction to
MDMA or an adulterant or contaminant
and did not nd any other similar published
reports.
Susceptibility factors Sex Sex differences
associated with the effects of MDMA as
reported in 28 studies have been reviewed
Jayendra K. Patel, Sarah Langenfeld, and Eileen Wong
[47M]. The preclinical and clinical data sug-
gest that adult women are more susceptible
than men to the acute and subacute psycho-
logical and physical adverse effects of
MDMA. However, men appear to be more
sensitive to the physiological effects of
MDMA. The authors suggested that these
data are consistent with what has been
reported with amphetamines and cocaine.
They also commented on the relevance of
these data to the preponderance of mood dis-
orders, especially depression, in women.
Specically, they raised concerns that
women who use MDMA and have a history
of depression may be at greater risk of future
psychological difculties, such as relapse of
depression. As MDMA consumption occurs
at dance parties, and can be associated with
unprotected sexual activity, they expressed
the concern that users are at increased risk
of accidental gestation, since gestational
exposure to MDMA can increase the risk of
abnormal neurodevelopment. They
acknowledged that there is much that is not
known about why there are sex differences
in responses to MDMA. They postulated
that the reasons for these differences are:
(1) regulation by MDMA of gonadal hor-
mone responses in women by altered seroto-
nin and dopamine neurotransmission or by
regulation of gene expression; (2) sex-based
pharmacokinetic variables affecting the
systemic availability and distribution of
MDMA; (3) sex differences in brain
structures, which may afford different
vulnerability.
Gamma-hydroxybutyric acid
(sodium oxybate) and analogues
[SED-30, 1479; SEDA-32, 68]
Systematic reviews The tolerability and
abuse liability of gamma-hydroxybutyric
acid (GHB) have been reviewed [48M].
GHB is abused by a small percentage of
people (<1%) as a club drug and is com-
monly associated with enhanced sexual
experiences (65%), euphoria (41%), somno-
lence (71%), and confusion (24%).
Drugs of abuse Chapter 4
Although it can be associated with serious
coma, there have been few reported deaths.
Formal studies of its abuse liability do not
suggest that it has a high abuse propensity,
mainly because oversedation and dizziness
at high doses are unpleasant. Years of clin-
ical use in narcolepsy do not support the
development of tolerance or withdrawal
symptoms in the absence of substance
dependence.
Nervous system Fixed, dilated, asymmetric
pupils developed in two patients during
continuous intravenous therapy with
gamma-hydroxybutyrate, in the absence of
cerebral herniation [49A].
Drug abuse The incidence of craving for
and abuse of gamma-hydroxybutyric acid
has been studied in four groups of patients:
pure alcoholics, alcoholics with a sustained
full remission from cocaine dependence,
alcoholics with a sustained full remission
from heroin dependence, and alcoholics in
a methadone maintenance treatment pro-
gram [50c]. All were given oral gamma-
hydroxybutyric acid 50 mg/kg tds for
3 months. There was signicantly more
craving for gamma-hydroxybutyric acid in
those in remission from cocaine depen-
dence than in the pure alcoholics and in
those in remission from heroin dependence
than in those taking methadone. The
authors recommended that gamma-
hydroxybutyric acid should not be used in
alcoholics with sustained full remission
from heroin or cocaine dependence.
Drug overdose Two deaths and one non-
fatal intoxication following ingestion of
gamma-butyrolactone, a precursor of
gamma-hydroxybutyric acid, have been
reported; in another case a 36-year-old
woman obtained gamma-butyrolactone
from nail polish remover pads [51A].
A 25-year-old drug addict died from an
overdose of gamma-butyrolactone after mis-
taking it for water in preparing a dilution
[52A].
65
Khat [SEDA-30, 43; SEDA-31, 48;
SEDA-32, 69]
The experimental and clinical pharmacol-
ogy of khat, models of addiction, and its
adverse effects have been thoroughly
reviewed [53R]. In a special edition of the
journal Substance Use and Misuse the
moral, political, cultural, and economic
inuences of khat in Kenyan society have
been reviewed, dealing with the complex
question of whether khat should be consid-
ered an illicit drug [54c]. Other articles
included a review of the impact of khat on
women's economic independence and
moral standing in East Africa [55A], a case
study of a London neighborhood's
response to the use of khat [56c], and an
analysis of the public discourse regarding
the role of khat in Ethiopia [57c].
Cardiovascular Perioperative considera-
tions specic to habitual khat chewers have
been reviewed [58c]. Given the sympathomi-
metic effects of khat and its potential for car-
diac toxicity, the author recommended
vigilant monitoring of perioperative cardio-
vascular function and the selection of anes-
thetics with fewer sympathomimetic or
cardiovascular effects. Acute use of khat
(within 4 hours before surgery) can lead to
increased anesthetic requirements, whereas
chronic users, if their catecholamines are
depleted, may need less anesthesia and are
at risk of perioperative hypotension.
Psychiatric Susceptibility factors, including
use of khat, associated with violent expres-
sion have been studied among 1294 male
college students in Ethiopia [59c]. A self-
administered survey asked for numbers of
violent acts, dened as an intentional act
of physical force or power, threatened or
actual, against another, with a high likeli-
hood of resultant physical or psychological
harm. The authors collected socio-
demographic information and asked about
hypothesized susceptibility factors, includ-
ing the style of anger expression (measured
by the Spielberger Anger-Out Expression
66 Chapter 4
Scale), negative life events, and substance
use (whether or not the person labelled
themselves as a user of khat, alcohol, and/
or tobacco). They found that 54% of the
students surveyed had committed at least
one violent act in the past academic year.
While alcohol and cigarette use did not
increase the risk of violence, the use of khat
increased the risk signicantly (OR 1.46;
95% CI 1.02, 2.08). Having a moderate
or high level of anger expression and hav-
ing more than four negative life events in
the past year was more highly associated
with violent acts. This study was limited
by the lack of details about any immediate
temporal relation between violence and
the use of khat, the amount or frequency
used, and the use of any substances other
than khat, alcohol, or tobacco. The authors
suggested that schools should implement
screening for violence and prevention
programs that target the susceptibility fac-
tors of stress, anger management, and sub-
stance use.
Pregnancy In an analysis of data from the
1997 Yemen Demographic and Maternal
Health Survey (7343 women who had at least
one live birth in past 5 years), 41% of the
women surveyed answered yes when
asked if they had smoked khat while preg-
nant [60c]. There were associations between
khat smoking during pregnancy and lack of
education, poverty, and living in a rural area.
The authors did not comment on how this
pattern may have changed over the years
since that 1997 survey.
Drug overdose Hagigat, which contains
200 mg of cathinone (one of the compo-
nents of khat leaves), approximately equiv-
alent to 555 g of khat, are marketed in
Israel in capsules as a natural stimulant.
Reports to Israel's poison control center
of exposure to hagigat have been analysed
[61c]. During the 10-month data collection
period, there were 34 reports about
patients aged 1654 (median 25) years, 24
men and 10 women. In two cases the drug
was inhaled. Myocardial ischemia was
Jayendra K. Patel, Sarah Langenfeld, and Eileen Wong
reported in three cases, pulmonary edema in
two, and intracerebral hemorrhage in one.
Common adverse effects were headache,
nausea, vomiting, hypertension, tachycardia,
chest pain, and myalgia. There was no associ-
ation between the number of capsules
ingested and the intensity of the poisoning;
however, this might have been due to the
small number of cases. The authors estimated
that a typical khat session involves 100200 g
of leaves (about 3672 mg of cathinone);
this difference in amount ingested, as well as
the faster absorption of hagigat, probably
modies the clinical effects.
OPIOID ANALGESICS
See Chapter 8, in which both therapeutic
and abuse aspects of the opioids are
covered.
Psilocybin [SEDA-31, 49; SEDA-32, 69]
Drug overdose A 28-year-old man with a
history of drug and alcohol abuse came to
hospital on several occasions during
2 months with a variety of symptoms,
including altered mental status, vomiting,
sweating, and mydriasis, which resolved
spontaneously on each occasion; each time
he required a high level of care [62A]. He
later admitted using mushrooms.
Of 742 patients with acute intentional
exposures to mushrooms, 59 (7.9%) were
admitted to hospital, 17 of whom required
admission to a critical care unit and four
required in-patient psychiatric admission
[63c]. Their average age was 21 years and
there was a male-to-female predominance
of 3.3:1. The actual mushroom was identi-
ed in 11 cases, 10 of which involved psilo-
cybin. The most common symptoms were
vomiting (n 34), nausea (n 19), altered
mental status (n 17), abdominal pain
(n 13), and diarrhea (n 10).
Drugs of abuse Chapter 4
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 Rebecca Spencer, Stephen Curran, and Shabir Musa
5 Hypnosedatives and
Comparative studies Experience and
perceptions of using Z drugs (zaleplon,
zolpidem, and zopiclone) and benzodiaze-
pine hypnotics in the community have been
studied in a cross-sectional survey of general
practice patients [1c]. Patients who had
received at least one prescription for a Z drug
or a benzodiazepine in the previous 6 months
were sent a postal questionnaire. Of 1600 sur-
veys posted, 935 responses (58%) were
received, of which 705 (75%) were from
patients taking drugs for insomnia. Of those
705 patients, 88% rst received a prescription
for a hypnotic from their GP, and 95% had
taken a sleeping tablet for 4 weeks or more.
At least one adverse effect was reported in
42%; 19% wanted to stop taking the hypnotic;
and 49% had tried to stop. Compared with
those taking benzodiazepines patients who
were taking Z drugs were more likely to
express a wish to stop (23% versus 12%; OR
1.67; 95% CI 1.13, 2.49), or to have
attempted to stop (52% versus 41%; OR
1.54; 95% CI 1.12, 2.12). The two groups
did not differ signicantly in respect of bene-
ts or adverse effects. There were no signi-
cant differences in patients perceptions of
efcacy or adverse effects. Adverse effects
were commonly reported, which may have
contributed to a high proportion of
responders, particularly patients taking Z
drugs who wanted to stop or who had previ-
ously tried to stop taking the medication.
Side Effects of Drugs, Annual 33
J.K. Aronson (Editor)
ISSN: 0378-6080
DOI: 10.1016/B978-0-444-53741-6.00005-2
# 2011 Elsevier B.V. All rights reserved.
anxiolytics
Reported prescribing practices were often at
variance with the licence for short-term use.
AZASPIRONES [SEDA-28, 52;
SEDA-32, 75]
Buspirone [SED-15, 575; SEDA-32, 75]
Placebo-controlled studies In a placebo-
controlled study of the use of buspirone
(maximum 60 mg/day for 12 weeks) and
motivational interviewing in 50 subjects with
marijuana dependence, all the adverse events
were mild to moderate in intensity [2C]. Most
of those who took buspirone (96%) had at
least one adverse event compared with 78%
of those who took placebo. Dizziness was
more common with buspirone (RR 3.52;
95% CI 1.08, 11). Dry mouth (RR 2.35),
ushing/sweating (RR 2.93), and cold-like
symptoms (RR 2.35) were also more
common with buspirone than placebo, but
not signicantly so.
BENZODIAZEPINES [SED-15,
429; SEDA-30, 49; SEDA-31, 57;
SEDA-32, 75]
Nervous system In a study of the relation
between the blood concentration of benzo-
diazepines and their effects on performance
71
72 Chapter 5
in eld sobriety tests, a retrospective case
le evaluation was conducted to select 171
drivers who had been tested positive for
benzodiazepines only in the period from
January 1999 to December 2004 [3c].
Drivers were grouped into those with
subtherapeutic, therapeutic, or high con-
centrations. The outcomes of the tests
(walking, walking after turning, nystagmus,
Romberg's test, behavior, pupils, and orien-
tation) were binomial. Observations of
behavior (n 137), walking (n 109),
walking after turning (n 89), and
Romberg's test (n 88) were signicantly
related to the benzodiazepine concentra-
tion. There was no signicant relation
between benzodiazepine concentration
and pupil size, nystagmus, or orientation.
These results suggest a relation between
the concentration of benzodiazepines and
the results of some performance tests. The
authors concluded that more effort is
needed to standardize the tests and to
determine their sensitivity and specicity.
Psychiatric In a prospective study of the
use of benzodiazepines or opioids in rela-
tion to the incidence and duration of delir-
ium in 304 admissions to an intensive care
unit, 72% of patients had delirium on their
rst day of admission and lasting a median
of 3 days [4c]. After controlling for baseline
dementia, use of haloperidol, and health
status, the use of either a benzodiazepine
or an opioid within 48 hours was associated
with the duration of delirium and in those
without pre-existing dementia, there was a
142% increase in the rate of delirium.
Teratogenicity The incidence of congenital
anomalies after prenatal exposure to selec-
tive serotonin reuptake inhibitor antide-
pressants (SSRIs) used alone and in
combination with benzodiazepines has
been studied [5C] by linking population
health data, maternal health, and prenatal
prescription records to neonatal records,
representing all live births (British Colum-
bia, Canada, n 119 547) during 39 months
(19982001). The incidence and risk differ-
ences (RD) for major congenital anomalies
and congenital heart disease, including
Rebecca Spencer, Stephen Curran, and Shabir Musa
ventricular and atrial septal defects, were
recorded in the infants of mothers who
had used an SSRI alone, a benzodiazepine
alone, or the combination, and were com-
pared with outcomes after no exposure.
The risk of a major congenital anomaly or
congenital heart disease increased after
combined SSRI benzodiazepine expo-
sure compared with no exposure. However,
using a weighted regression model, control-
ling for maternal illness characteristics,
combination therapy risk was signicantly
associated only with congenital heart dis-
ease. The risk of an atrial septal defect
was higher after SSRI monotherapy com-
pared with no exposure, after adjustment
for maternal covariates. Daily dose was
not associated with an increased risk.
Infants who had been exposed to prenatal
SSRIs in combination with benzodiazepines
had a higher incidence of congenital heart
disease compared with no exposure, even
after controlling for maternal illness charac-
teristics. SSRI monotherapy was not associ-
ated with an increased risk of major
congenital anomalies, but was associated
with an increased incidence of atrial septal
defect.
Clobazam [SED-15, 806]
Skin StevensJohnson syndrome has been
reported in a patient taking a combination of
clobazam, lamotrigine, and valproic acid [6A].
Clonazepam [SED-15, 815]
Psychological The relation between clo-
nazepam plasma concentrations after a sin-
gle oral dose of 4 mg and impairment of
psychomotor performance has been studied
in 23 healthy volunteers [7c]. Clonazepam
reduced psychomotor performance by up
to 72% at 1.54 hours after administration
and there was time-dependent tolerance.
However, there was too much
interindividual variation to allow individual
prediction of these effects.
Hypnosedatives and anxiolytics Chapter 5
Hair Hair loss has been reported in associ-
ation with clonazepam [8A].
Drug withdrawal Withdrawal of benzodia-
zepines is associated with a risk of features
such as rebound insomnia, anxiety, percep-
tual changes, convulsions, or delirium [9A].
Malignant catatonia has also rarely been
reported, as another case illustrates.
A 60-year-old man developed acute confusion,
grimacing, stereotypy, refusal of food and
water, muscle rigidity, mutism, and extreme
negativism after abruptly discontinuing all
psychotropic medications. He was given loraz-
epam and then clonazepam was re-started. His
catatonic symptoms and autonomic instability
resolved completely.
The mechanism by which catatonia is pre-
cipitated by benzodiazepine withdrawal is
not known; the authors speculated that it
may involve a rapid reduction in GABA
transmission.
Drug abuse Clonazepam is often used as a
drug of abuse and to treat drug addicts. In
cases referred to the Section of Forensic
Chemistry at the University of Copenhagen
in 20022007 clonazepam and its metabolite
7-aminoclonazepam were detected in 297
cases after trafc accidents (median
0.067 mg/kg), in 92 perpetrators or victims of
a crime (median 0.071 mg/kg), and in 140
postmortem cases (median 0.115 mg/kg)
[10c]. In 27 of the postmortem cases with high
concentrations other drugs had been taken,
but clonazepam was thought to have been
the primary cause of death in ve (concentra-
tions 0.260.54 mg/kg).
The extent of abuse of clonazepam has
been assessed in a French study, in which
deliveries of clonazepam to individuals who
had had a prescription reimbursed were mon-
itored for 9 months [11c]. There was an
increase of 82% in participants who had a
delivery of clonazepam between 2001 and
2006, and some deviant participants were
identied; they included a higher proportion
of men, benzodiazepine users, and
buprenorphine users. The proportion of devi-
ant participants increased between 2001 and
2006 from 0.86% to 1.38%.
73
Diazepam [SED-15, 1103; SEDA-30, 50;
SEDA-31, 57; SEDA-32, 75]
Drug resistance P glycoprotein can confer
drug resistance on cells by allowing them to
export drugs. In a study of the binding of
some benzodiazepines (bromazepam, chlor-
diazepoxide, diazepam, and urazepam) to
P glycoprotein in proteoliposomes and their
effects on its transport function and ATPase
activity in the human cancer cell line, KB-
V1, the toxicity of the benzodiazepines
towards the KB-V1 cells was rst evaluated
and the non-toxic drug concentrations were
used to assess drug efux and ATPase activity
[12E]. Using ow cytometry, accumulation
and efux of daunorubicin were studied by
measuring the daunorubicin-associated geo-
metric mean uorescence intensity. Vana-
date was used as a comparative inhibitor.
Flurazepam inhibited daunorubicin efux
in 80%. ATPase activity showed that
urazepam inhibits P glycoprotein-linked
enzyme activity, indicating coupling between
drug transport and ATP hydrolysis. Brom-
azepam, chlordiazepoxide, and diazepam
activated P glycoprotein-linked ATPase
activity, suggesting a role as transported sub-
strates, but they did not interfere with dauno-
rubicin transport.
Drug administration route Intranasal and
intravenous diazepam have been compared
[13A]. The tmax and half-life were similar after
5 and 10 mg intranasally and the systemic
availability was 75%. There were no adverse
events, although many subjects reported
swallowing much of the preparation. All
reported transient pain and watery eyes.
Flunitrazepam [SED-15, 1394;
SEDA-31, 58]
Cardiovascular Accidental injection of
unitrazepam tablets dissolved in tap water
into the left femoral artery by a 22-year-old
drug abuser caused acute ischemia of the
leg with severe rhabdomyolysis within
5 hours [14A]. There was acute occlusion
74 Chapter 5
of the posterior tibial artery, which resolved
with intra-arterial urokinase and prostaglan-
dins and intravenous anticoagulation.
Nervous system The risk of road trafc
accidents in individuals who have lled a
prescription for unitrazepam, nitrazepam,
zolpidem, or zopiclone has been studied
[15c]. All Norwegians aged 1869 years
(3.1 million) were followed from January
2004 until the end of September 2006.
Information on prescriptions, road trafc
accidents, and emigration/death was
obtained from three Norwegian popula-
tion-based registries. The rst week after
the hypnotics had been dispensed was con-
sidered to be the exposure period. Stan-
dardized incidence ratios (SIRs) were
calculated by comparing the incidence of
accidents in the exposed person-time to
the incidence of accidents in the unexposed
person-time. During exposure, 129 acci-
dents were registered for zopiclone, 21 for
zolpidem, 27 for nitrazepam, and 18 for
unitrazepam. The SIRs were: Z hypnotics
(zopiclone zolpidem) 2.3; nitrazepam
2.7; and unitrazepam 4.0. The highest
SIRs were found among the youngest users
for all hypnotics. Thus, users of hypnotics
had a clearly increased risk of road trafc
accidents, and the risk for unitrazepam
was particularly high.
Flurazepam
Nervous system The residual effects of
gaboxadol 10 mg and urazepam 30 mg
on the day after bedtime administration
have been compared in a crossover, dou-
ble-blind, randomized, placebo-controlled
study in 25 healthy elderly subjects [16c].
Flurazepam signicantly impaired choice
reaction time, the threshold for critical
icker fusion, digit symbol substitution,
and speed of compensatory tracking, but
did not alter immediate or delayed word
recall or the eyes-closed endpoint of the
body sway test. Gaboxadol had no deleteri-
ous effects.
Rebecca Spencer, Stephen Curran, and Shabir Musa
Lorazepam [SED-15, 2163; SEDA-30,
51; SEDA-31, 58; SEDA-32, 76]
Sexual function Greatly enhanced sexual
desire has been attributed to lorazepam
[17A].
A 62-year-old married woman with carcinoma
of the breast was given lorazepam 1 mg at
bedtime for insomnia. At her next follow-up
appointment, she reported with some embar-
rassment how she felt after taking the rst
dose. Over the next hour, she had developed
a strangely intense sexual desire, an over-
whelming pleasant sensation climbing over
her inner thighs, progressing to the genitalia,
followed by the sensation of having sexual
intercourse, which she repressed before get-
ting an orgasm. She said that for the rst time
in some years she had seriously thought about
waking up her husband to initiate intercourse.
I had not felt like this in years. It was like
having sexual intercourse without wanting it.
I could not help myself feeling an intense but
unwanted pleasure. The sensations faded
gradually over the next few hours. The symp-
toms were repeated when she took a dose on
the next evening.
The authors suggested that this could have
been explained by inhibition of the action
of serotonin in the septal and amygdaline
nuclei.
Drug formulations Propylene glycol is used
as a solvent for many liquid formulations of
drugs, including lorazepam. There is a high
risk of propylene glycol toxicity during the
administration of large doses of lorazepam
intravenously, as has been reported in criti-
cally ill adults [18c]. This has been studied
in 35 adults who received any dose of par-
enteral lorazepam and in 14 patients who
received lorazepam in doses of 1 mg/kg/
day or more [19c]. The osmolar gap (mea-
sured serum osmolality minus calculated
osmolarity) was used as a measure of toxic-
ity. The serum propylene glycol concentra-
tion was measured when the osmolar gap
exceeded 10. In phase 1, 35 patients were
monitored for 186 patient-days; 10 devel-
oped an osmolar gap greater than 10, but
only one had a propylene glycol concentra-
tion over 180 mg/l. In phase 2, 14 patients
received lorazepam in a median dose of
Hypnosedatives and anxiolytics Chapter 5
631 mg (interquartile range 437972 mg)
over a median of 5.5 days. Nine patients
had propylene glycol concentrations over
180 mg/l and six of them developed tran-
sient acute kidney injury, metabolic acido-
sis, or both. There was a correlation
between the osmolar gap and the propyl-
ene glycol concentration. An osmolar gap
of 10 or greater had a likelihood ratio of
4.4 to predict a propylene glycol concentra-
tion over 180 mg/l; an osmolar gap of 12 or
greater had a likelihood ratio of 2.7 to pre-
dict the development of propylene glycol
toxicity. The authors concluded that the
osmolar gap may be helpful in screening
for propylene glycol toxicity in patients
who are receiving intravenous lorazepam
in doses of 1 mg/kg/day or more.
Drugherb interactions The dangers of
herbal medicines have been highlighted by
the case of a man who self-medicated with
Valeriana ofcinalis and Passiora incarnata
while he was also taking lorazepam and
developed shaking hands, dizziness, throb-
bing, and muscle fatigue [20A]. The authors
suggested that the active principles in vale-
rian and passionower might increase the
inhibitory effects of benzodiazepines.
Lormetazepam [SED-15, 2167;
SEDA-32, 77]
Drug overdose Although benzodiazepine
overdose is rarely fatal, a very large over-
dose can be [21A].
A 34-year-old woman was found dead in her
bed with evident traces of vomit and feces.
No medicinal products or drugs of abuse were
found around the body and there was no evi-
dence of injury or trauma. At the autopsy,
3 days later, external examination was
unremarkable and there were no signs of
chronic drug abuse. Internal examination
showed pulmonary edema and severe vascular
congestion in all internal organs. Toxicological
analysis of blood, urine, and bile samples
showed the presence of lormetazepam and its
metabolite lorazepam in traces. This, together
with the absence of other drugs or alcohol,
strongly suggested that death was due to acute
overdose of lormetazepam only.
75
Midazolam [SED-15, 2337; SEDA-30,
51; SEDA-31, 59; SEDA-32, 77]
Observational studies In a prospective
study of 516 children undergoing CT scans,
who received midazolam 0.212 mg/kg, there
was adequate sedation in 5.9 minutes and
only a few patients required additional
boluses [22c]. There were adverse effects
in 9.1% of patients, including desaturation
in 6.9%, all of whom were treated success-
fully with oxygen, hiccups in 1.4%, and agi-
tation in 0.79%. All the adverse effects
were self-limiting.
In 41 adults undergoing transesophageal
echocardiography, who received
midazolam either alone (2.5 mg bolus plus
1 mg increments as required) or in combi-
nation with remifentanil (midazolam 0.5 mg
remifentanil 0.08 micrograms/kg/
minute), the median time to an acceptable
Aldrete score (a measurement of readiness
for discharge) was much slower after
midazolam than remifentanil midazolam
(30 versus 5 minutes) [23c]. There were sig-
nicant reductions in blood pressure but not
heart rate in both groups and there were no
adverse respiratory events.
In a study of sedation during local anes-
thesia for bone marrow aspiration, 46 adults
were randomized to midazolam 2 mg every
2 minutes (n 21) until conscious sedation
was achieved or Entonox (n 25) delivered
by the patient [24c]. Amnesia was induced by
midazolam in 55% compared to 4% with
Entonox. There was greater pain and dizzi-
ness with Entonox, but midazolam caused
desaturation in 19% of patients. Midazolam
reversal was required in 10 patients for
either desaturation or prolonged sedation
(after a mean dose of 0.08 mg/kg).
Respiratory The effect of oral midazolam
0.3 mg/kg on respiratory function has been
studied in 18 children (median age
78 months) without cardiorespiratory dis-
ease undergoing elective surgery [25c].
There was a reduction in tidal and minute
volume but not respiratory rate or expiratory
times. There was a 6.5% reduction in func-
tional residual capacity and corresponding
76 Chapter 5
increases in LCI, respiratory resistance, and
elastance (7.8%, 7.4%, and 9.2% respec-
tively) 20 minutes after pre-medication.
There were no episodes of desaturation.
Nervous system Extrapyramidal adverse
effects have been attributed to midazolam
[26A] and hypothesized to have been due
to inhibition of ring in the substantia nigra
secondary to an effect on a3-containing
GABAA receptors [27r].
Acidbase balance A severe
hyperchloremic metabolic acidosis with a
normal anion gap occurred in a 9-year-old
girl who was given a high-dose continuous
intravenous infusion of midazolam for
refractory status epilepticus and resolved
within 5 hours of withdrawal [28A]. The
authors suggested that it was due to the
use of hydrochloric acid in the parenteral
formulation.
Drug administration route Intranasal
midazolam is used widely and successfully
as pre-medication, particularly in children,
avoiding rst-pass metabolism and increas-
ing systemic availability [29A].
In a double-blind, crossover, randomized
trial in 10 healthy volunteers midazolam
0.2 mg/kg was given by nebulizer and liquid
instillation nasally 5 days apart [30c].
Plasma concentrations were greater after
intranasal midazolam. Nasal instillation
caused increased sedation but no difference
in the time to sedation. There were no
respiratory adverse events. Blood pressure
and oxygen saturation fell in both groups
(peak reduction at 15 minutes) but none
required extra oxygen. Mean heart rate
and diastolic pressure were increased. The
incidence of unpleasant adverse effects
was greater after intranasal midazolam,
and nasal stinging, eye irritation, hiccups,
and excessive secretions were common.
One patient with asthma became wheezy
after intranasal administration.
Intranasal midazolam 2.5 and 5 mg have
been compared with intravenous
midazolam 2.5 mg in a crossover study in
18 healthy volunteers [31c]. The tmax was
Rebecca Spencer, Stephen Curran, and Shabir Musa
10 minutes at both intranasal doses and
the systemic availability was 60%. The
maximum concentration was dose-depen-
dent but half-life was not affected by dose
or route of administration. The most com-
mon adverse events were pharyngitis
(n 11), rhinitis (14), and taste distur-
bances (11), but all were transient and
lasted only 214 minutes. There were no
serious adverse events or changes in endo-
scopic nasal examination.
Drugdrug interactions Antifungal azoles
Posaconazole inhibits CYP3A4, by which
midazolam is metabolized. The effects of
oral posaconazole 200 mg bd for 7 days
and ketoconazole 400 mg od for 7 days on
the pharmacokinetics of oral and intrave-
nous midazolam have been studied in 12
healthy volunteers [32c]. Both azoles
reduced the clearance and prolonged the
half-life of midazolam, ketoconazole more
so than posaconazole. Seven subjects
reported at least one adverse event during
the study (ve with posaconazole alone
and four with posaconazole midazolam).
The most common adverse events were
diarrhea (n 3 with posaconazole alone,
two with ketoconazole alone, and one with
posaconazole midazolam) and atulence
(one with posaconazole alone and one with
midazolam alone).
Opioids Drugdrug interactions with
midazolam have been studied in 7431
patients in a Brazilian hospital (28% of all
the patients who had been admitted to the
hospital) [33c]. Flumazenil was given to 26
patients within 24 hours after midazolam
and there were clinically signicant
drugdrug interactions resulting from pre-
scriptions of drugs preceding the use of
umazenil in 23 cases. The most common
interactions were related to central nervous
system depressants (22 cases), mainly
opioid agonists.
Protease inhibitors The effects of multiple
doses of ritonavir-boosted saquinavir
(100 mg 1000 mg bd for 2 weeks) on
the pharmacokinetics of a single oral dose
Hypnosedatives and anxiolytics Chapter 5
of midazolam 7.5 mg have been studied in
18 healthy volunteers [34c]. Saquinavir
ritonavir increased the Cmax of midazolam
4.3-fold and the AUC 12.4-fold; the half-life
was prolonged from 4.7 to 15 hours. The
Cmax and AUC of 10 -hydroxymidazolam
were reduced by about sevenfold and two-
fold respectively. The combination resulted
in prolonged sedation.
Drug overdose Between November 2004
and November 2008, UK health-care staff
reported 498 dosing errors for midazolam
to the National Patient Safety Agency
(NPSA); there were three deaths [35S].
The following problems were reported:
drawing up part content of a high-strength
injection ampoule (10 mg in 2 ml or 10 mg in
5 ml) or giving the whole ampoule by mistake;
failing to titrate the dose to the needs of the
individual patient;
not understanding the risks of combining
midazolam with other drugs, such as opioids;
widespread use of, and possible over-reliance
on, the reversing agent, umazenil.
The Agency made the following
recommendations:
remove high-strength midazolam from all but
dened clinical areas (such as general anesthe-
sia, intensive care, and palliative care) and
replace with low-strength alternatives;
review training needs;
identify a lead (usually an anesthetist) for
sedation policy and auditing the use of
umazenil locally;
routinely use the safer 1 mg/ml strength
(in 2 ml or 5 ml ampoules) rather than high-
strength midazolam in general areasfor
example, where outpatient diagnostic proce-
dures are performed;
do not use part-ampoules or part-phials of
high-strength midazolam;
do not rely on umazenil to reverse
oversedation by midazolam, but aim to pre-
vent oversedation in the rst place; however,
if you need to use umazenil, audit its use;
continue to use high-strength midazolam for
general anesthesia and intensive care seda-
tion, and for palliative care when syringe
drivers are used; in the latter case undertake
a formal risk assessment, especially when dif-
ferent strengths of midazolam are stocked for
different indications in a single clinical area.
77
Drugherb interactions Interactions of
midazolam with herbal medicines have
been reviewed [36R].
Temazepam [SED-15, 3312;
SEDA-30, 52]
Susceptibility factors Age Temazepam
15 mg and diphenhydramine 50 mg for 14
nights have been compared in elderly indi-
viduals with insomnia (mean age 74, range
7089 years) in a randomized, placebo-con-
trolled, crossover study [37c]. Primary out-
come measures were subjective assessments
of sleep recorded on sleep diaries. Secondary
measures were the morning-after psychomo-
tor impairment, using the digital symbol sub-
stitution task and the manual tracking task,
and the morning-after memory impairment,
using a free-recall procedure. Temazepam
improved sleep quality, total sleep time,
number of awakenings, and sleep-onset
latency compared with placebo. Diphenhy-
dramine improved the number of awaken-
ings only. The numbers of adverse events
were similar after all treatments, although
there was one fall during temazepam treat-
ment. This suggests that temazepam is more
effective than diphenhydramine, although
this advantage is mitigated by the risk of falls.
The choice of agent to use in elderly people
must consider these relative benets and
harms.
Triazolam [SED-15, 3486; SEDA-31, 60;
SEDA-32, 79]
Nervous system The effects of triazolam
0.375 mg, and zolpidem 10 mg, two
GABAA allosteric activators, on sleep-
dependent motor skill memory consolida-
tion have been studied in a placebo-con-
trolled study in 12 healthy men [38C].
Triazolam was associated with longer total
sleep time and increased stage 2 sleep. Both
zolpidem and triazolam were associated
with an increased latency to rapid eye
78 Chapter 5
movement (REM) sleep. Overnight motor
learning correlated with total sleep time
after placebo but not after triazolam or
zolpidem. Motor performance was signi-
cantly impaired overnight by triazolam only.
Drug overdose A 76-year-old woman died
after taking a combination of triazolam and
promazine in overdose [39A]. Post-mortem
triazolam and promazine concentrations
were respectively: blood 1100 and 3450 ng/ml;
gastric contents 1300 and 5800 ng/ml.
BENZODIAZEPINE-LIKE
DRUGS
Zaleplon [SED-15, 3710; SEDA-29, 57]
Psychiatric Perceptual disturbances have
been attributed to zaleplon [40A].
A 20-year-old Caucasian woman with DSM-
IV diagnoses of major depressive disorder
and borderline personality disorder reported
insomnia characterized by difculty falling
asleep, but no difculty maintaining sleep, for
6 months. She was given zaleplon 10 mg cap-
sules and advised to take one at bedtime as
needed. She was also taking uoxetine 60 mg
od, ziprasidone 40 mg/day, and the oral con-
traceptive Alesse. When her insomnia
persisted the dose of zaleplon was increased
to 20 mg and she took it about six times during
the next month. On three of those occasions
she had had some unusual perceptual experi-
ences, including seeing tree branches moving
closer to her, seeing movements of water and
re in a painting on a wall, and seeing people
moving and talking to her on another picture.
After each episode, she had fallen asleep and
wakened the next morning with no unwanted
after-effects.
Tumorigenicity Data from controlled trials
have been analysed to determine whether
hypnotics can cause cancer [41M]. The US
Food and Drug Administration (FDA)
Approval History and Documents were
accessed for zaleplon, eszopiclone,
zolpidem, and ramelteon. Incident cancers
that occurred during randomized adminis-
tration or placebo administration were
Rebecca Spencer, Stephen Curran, and Shabir Musa
tabulated. Combining controlled trials for
the four drugs, there were 6190 participants
who had taken hypnotics and 2535 who had
taken placebo in parallel. There were eight
mentions of incident non-melanoma skin
cancers among participants who took hyp-
notics but no comparable mentions of can-
cers among those receiving placebo. There
were also four mentions of incident tumors
of uncertain malignancy among those who
took hypnotics but none among those who
took placebo. FDA les showed that all four
of the new hypnotics were associated with
cancers in rodents. Three had been shown
to be clastogenic. Together with epidemio-
logical data and laboratory studies, the avail-
able evidence suggests that new hypnotics
may increase the risk of cancers.
Drug overdose A case of zaleplon over-
dose has been described [42A].
A 24-year-old woman took 28 or so tablets of
zaleplon. The time of ingestion was
undetermined but it was probably more than
4 hours earlier. She was confused and sleepy.
She looked pale and her mouth and lips were
stained blue-green. Soon after arrival she
vomited dark blue-green stomach contents.
Although a complete neurological examination
was difcult to perform, there were no major
abnormalities. Her blood pressure was low but
responded to 20 ml/kg of isotonic saline. The
electrocardiogram showed sinus tachycardia. A
urine sample was strongly blue-green in color
and a urine drug screen for opioids, benzodiaze-
pines, cocaine, amphetamines, barbiturates,
methadone, and cannabinoids was negative.
She subsequently became restless, was confused,
and had visual hallucinations and intermittent
myoclonus. The next day she was alert and co-
operative and a complete examination was
normal.
The authors concluded that the blue-green-
ish discoloration of the vomit and urine could
be an important sign of zaleplon overdose.
Zolpidem [SED-15, 3723; SEDA-30, 53;
SEDA-31, 61; SEDA-32, 80]
Nervous system Sleep walking has been
attributed to zolpidem [43r].
Hypnosedatives and anxiolytics Chapter 5
A 51-year-old, white, married woman experi-
enced two episodes of somnambulism with
amnesia while taking zolpidem 10 mg at bed-
time. During these episodes, she walked down
the steps from her second-storey bedroom to
the kitchen and ate normal amounts of food.
She stopped taking zolpidem and had no
further problems.
Cases of sleep driving associated with the
use of non-benzodiazepine hypnotics
reported to the US Food and Drug Admin-
istration (FDA) Adverse Events Reporting
System have been summarized [44c]. On 1
March 2006, the FDA Adverse Events
Reporting System was searched for
postmarketing reports of sleep driving asso-
ciated with zolpidem, zaleplon, and
eszopiclone. Each identied case was evalu-
ated to ensure that it met the general
requirements for sleep driving. There were
14 cases, 13 of which involved zolpidem.
Of these 13, eight involved concomitant
use of a psychotropic drug (benzodiaze-
pine, alcohol, or a narcotic). Zolpidem was
the most commonly implicated drug in
sleep driving, but it is unclear whether this
is attributable to a greater risk of sleep
driving with zolpidem, more widespread
use of the drug, or other factors. Concomi-
tant use of other psychotropic drugs could
have potentiated the effect of zolpidem.
Zopiclone [SED-15, 3710; SEDA-31, 62]
Nervous system The residual effects at
1011 hours after evening doses of
temazepam 20 mg and zopiclone 7.5 mg on
driving performance in a standardized high-
way driving test have been evaluated in 18
healthy elderly drivers in a double-blind,
three-way, placebo-controlled crossover
study [45C]. Driving performance did not dif-
fer between temazepam and placebo but was
signicantly impaired after zopiclone. The
magnitude of the impairment was compara-
ble with that found before in younger
volunteers.
79
BENZODIAZEPINE
ANTAGONISTS
Flumazenil
Flumazenil is a benzodiazepine antagonist
used to reverse the effects of benzodiaze-
pines in the treatment of poisoning or in
anesthesia [46c, 47R, 48R, 49A]. It reduces
the risks of complications from drug over-
dose, obviating the need for invasive inter-
ventions such as mechanical ventilation and
invasive hemodynamic monitoring [50c].
However, it is not effective in reversing the
amnesic effects of midazolam [51A]. It has
also been used to reverse the effects of
zaleplon [52A], zolpidem [53A, 54A, 55C],
zopiclone [56A, 57A], antihistamines such
as promethazine [58A, 59A], baclofen
[60A], cannabis [61A], carisoprodol [62A],
chloral hydrate [63A], chlorzoxazone
[64A], carbamazepine [65A], gabapentin
[66A], paclitaxel [67A], propofol [68C], and
thiopental [69C]. Guidelines for its use have
been summarized [70R].
The problems in using umazenil are
those of dose adjustment, the risks of panic
anxiety, seizures, or other signs of exces-
sively rapid benzodiazepine withdrawal. Its
use is also commonly associated with
vomiting and headache, and rarely with psy-
chosis or sudden cardiac death [71A], espe-
cially in mixed overdoses. It can
occasionally cause a benzodiazepine with-
drawal reaction [72C].
In 17 patients who were given umazenil to
reverse the effect of midazolam after upper
gastrointestinal endoscopy, it reversed the sed-
ative effects in under 2 minutes but did not
affect the ventilatory effects [73c]. However,
in a randomized, double-blind, placebo-con-
trolled crossover study in 12 healthy volunteers
intravenous umazenil 1.0 mg restored respi-
ratory function within 3 minutes [74C].
Since umazenil has a short half-life (about
1 hour) compared with the longer half-lives of
most benzodiazepines, its benecial effects
can wear off before the effects of the benzodi-
azepines [75R]. Re-sedation occurs in about
80 Chapter 5
65% of patients, usually within 0.53 hours
after the rst dose, the shorter interval being
associated with poisoning with combinations
of drugs; repeated doses of umazenil, some-
times followed by continuous infusion are
effective [76M]. In 50 patients who were given
intravenous placebo or umazenil 15 minutes
after injection of unitrazepam 0.03 mg/kg in
a randomized, double-blind study,
umazenil promptly reversed sedation for
30 minutes, hypotonia for 45 minutes, and
anterograde amnesia for 60 minutes, and
improved orientation and collaboration for
60 minutes; however, anterograde amnesia
recurred after 60 minutes and sedation after
90 minutes [77C]. In a placebo-controlled
study in 30 patients who had received
midazolam followed by intravenous
umazenil, subcutaneous umazenil did not
prevent the rebound sedation that occurred
after 90 min; adverse effects included nausea
and vomiting [78C]. However, a continuous
infusion of umazenil 0.5 mg/hour can pre-
vent re-sedation [79C].
Paradoxical adverse effects of benzo-
diazepines, such as aggressive behavior, can
occur [80r] and can be reversed by umazenil
[81A, 82A, 83A, 84A, 85A]. In 58 patients under-
going surgery under spinal or epidural anes-
thesia, umazenil 0.1 mg over 10 seconds
abolished the agitation without reversing seda-
tion (total dose range 0.10.5 mg) [86cr]. In 30
patients who had been given midazolam,
umazenil 0.150.5 mg resulted in cessation
of the agitation without reversal of sedation
[87A]. Adverse effects of umazenil were not
reported in these studies.
Flumazenil has been used as a non-specic
treatment in patients with hepatic encephalopa-
thy [88c, 89R]. However, it was effective in only
some subjects in a double-blind, placebo-con-
trolled, crossover study in 527 patients with cir-
rhosis and hepatic encephalopathy grade III
and IVa, of whom 265 received umazenil
and 262 received placebo [90C]. There was
improvement of the neurological score in 18%
of the patients with grade III encephalopathy
and in 15% of those with grade IVa compared
with 3.8% and 2.7% respectively of those
who received placebo; electroencephalography
improved in 28% and 22% compared with
Rebecca Spencer, Stephen Curran, and Shabir Musa
5% and 3.3%. Similar results were obtained in
a study of 236 patients with grade IVa hepatic
encephalopathy [91C].
In a single-dose, crossover, double-blind,
placebo-controlled study of umazenil and
placebo in 16 subjects with Parkinson's dis-
ease, scores on the Unied Parkinson's Dis-
ease Rating Scale tended to improve, but the
effect was not signicant; the most common
adverse events were light-headedness or diz-
ziness [92C].
Flumazenil is not anxiolytic after alcohol
withdrawal [93C].
It is not generally helpful to measure ben-
zodiazepine plasma concentrations, but they
can assist in the diagnosis of overdose and
thus guide the use of antagonists [94c].
Placebo-controlled studies In a double-
blind, randomized, placebo-controlled study
in 105 unconscious adults with suspected
drug overdose, 73 of whom had taken ben-
zodiazepines, umazenil caused adverse
effects in nine cases: agitation (n 3), a
depressive mood (n 3), nausea and
vomiting (n 1), shivering (n 1), and
one severe adverse reactiona sudden fall
in blood pressure in a 28-year-old woman
in deep coma after combined poisoning with
benzodiazepines and maprotiline [95C].
In a multicenter, double-blind, placebo-
controlled study of the effects of intravenous
umazenil 0.7 mg in reversing the effects of
midazolam, 82% of 131 umazenil-treated
patients had complete reversal of sedation,
compared with 15% of 65 placebo-treated
patients. However, umazenil reversed
midazolam-induced amnesia in only 60%
of patients. Dizziness (10%) and nausea
(9%) were the most common adverse effects
[96C]. Similar results were obtained in a
double-blind, placebo-controlled study in
patients who had been given midazolam
plus an opioid (fentanyl, pethidine, or mor-
phine) [97C], intravenous diazepam [98C],
or diazepam plus an opioid [99C].
Cardiovascular Multifocal ventricular extra
beats with short runs of ventricular tachycar-
dia occurred within seconds after the admin-
istration of umazenil to reverse oxazepam
Hypnosedatives and anxiolytics Chapter 5
toxicity in a 30-year-old woman [100A]. She
had also taken chloral hydrate, which may
have sensitized the heart. Ventricular brilla-
tion has also been reported in a 60-year-old
man [101A].
In another case co-administration of a tri-
cyclic antidepressant may also have
increased the risk of dysrhythmias [102A].
A 57-year-old woman took an overdose of loraz-
epam and amitriptyline and became deeply
unconscious. She had a nodal rhythm and fre-
quent multifocal ventricular extra beats, ventric-
ular couplets and triplets, and salvos of
ventricular tachycardia. She was given intra-
venous umazenil in divided doses to a total of
500 micrograms. Her respiratory rate increased
to 20/minute and after 5 minutes she had general-
ized tonicclonic convulsions, followed in 15 sec-
onds by ventricular tachycardia, with no cardiac
output, which reverted to sinus rhythm with
direct current cardioversion. The convulsion
ended spontaneously after 30 seconds but
recurred within 2 minutes, again followed by
sustained ventricular tachycardia. This pattern
of events recurred and nine cardioversions were
required. The convulsions eventually resolved
with intravenous diazepam and thiopental.
Complete heart block occurred when
umazenil was given to a woman who had
taken an overdose of paracetamol and
temazepam [103A].
Nervous system Seizures have been attri-
buted to umazenil [104A, 105A, 106A, 107A,
108A, 109A, 110A, 111R], including status
epilepticus [112A, 113A], which can be fatal.
However, it has been suggested that seizures
are not a toxic effect of umazenil, but are in
many cases instead due to unmasking of the
anticonvulsant effect of the benzodiazepine
or to a severe benzodiazepine-withdrawal syn-
drome; furthermore, in some cases they may be
due to other drugs taken at the same time, such
as tricyclic antidepressants [114c]. Thus, it has
been recommended that umazenil should
not be given to patients who have used benzo-
diazepines for seizure disorders or to patients
who have taken other drugs that increase the
risk of seizures (e.g. bupropion, ciclosporin,
cocaine, cyclic antidepressants, isoniazid, lith-
ium, methylxanthines, monoamine oxidase
inhibitors, and propoxyphene).
81
Opisthotonos after umazenil has been
reported [115A].
A healthy 17-year-old man received an
interscalene brachial plexus block using
mepivacaine 600 mg and bupivacaine 150 mg.
He became disorientated and showed signs of
local anesthetic toxicity, for which he was given
midazolam 5 mg. Flumazenil 0.5 mg was given
23 minutes after the end of the procedure, causing
opisthotonos.
Ballismus has also been reported [116A].
Psychiatric Oral umazenil was used in a
woman who had had several episodes of
hepatic encephalopathy, in an attempt to pre-
vent deterioration into coma, but after 2 days
she had an acute psychosis; the symptoms
resolving rapidly when umazenil was with-
drawn [117c].
Endocrine The effects of umazenil and
midazolam on adrenocorticotrophic hor-
mone and cortisol responses to a cortico-
trophin-releasing hormone challenge have
been assessed in eight healthy men [118c].
Flumazenil signicantly caused reduced adre-
nocorticotrophic responses compared with
midazolam or placebo, but had no effects on
cortisol secretion. The authors suggested that
this agonist effect of umazenil on the pitui-
tary-adrenal axis might account for the anxio-
lytic activity of umazenil, which has been
observed during simulated stress.
Susceptibility factors Age The usefulness
and relative safety of midazolam in children
have been reviewed [119R]. Myoclonic-like
movements associated with midazolam in
three full-term newborns were reversed by
umazenil [120A].
The pharmacokinetics of umazenil are
not altered in elderly people [121c].
Drug withdrawal In individuals who have
taken long-term benzodiazepines, umazenil
can provoke acute withdrawal reactions
[122C, 123C] and extreme anxiety [124A].
Duration of exposure to the benzodiazepine
does not affect the intensity of withdrawal
beyond the rst week of exposure [125C].
82 Chapter 5
In a placebo-controlled study in 34
chronic users of diazepam 520 mg/day for
528 years, a single-dose of umazenil
caused anxiety reactions; in nine of 15 sub-
jects with a history of panic attacks, panic
attacks were precipitated [126C].
Drug administration route In six patients
undergoing elective surgery during general
anesthesia endotracheal umazenil 1.0 mg
in 10 ml of saline therapeutic blood concen-
trations were rapidly achieved [127c].
In 11 patients aged 26 years undergoing
general anesthesia for dental surgery intra-
nasal drops of umazenil resulted in plasma
concentrations similar to those reported after
intravenous administration [128c].
OTHER HYPNOSEDATIVES
Chloral hydrate [SED-15, 705; SEDA-
30, 52; SEDA-31, 60; SEDA-32, 79]
Nervous system Paradoxical reactions to
hypnosedatives occur occasionally and can
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 Alfonso Carvajal, Luis H. Martn Arias, and
6 Antipsychotic drugs
GENERAL [SED-15, 2438;
SEDA-32, 83]
Typical versus atypical
antipsychotic drugs
Data from two major government-funded
studies of comparative antipsychotic drug
effectiveness in schizophrenia contradict the
widely prevalent belief that the newer sec-
ond-generation medications are vastly supe-
rior to the older rst-generation drugs
[SEDA-30, 56; SEDA-31, 65]. The World
Psychiatry Association Section on
Pharmacopsychiatry has reviewed the litera-
ture on the comparative effectiveness of dif-
ferent antipsychotic drug treatments for
schizophrenia and has issued a statement
[1R]. They reported that antipsychotic drugs
are very heterogeneous, with substantial dif-
ferences in adverse effects proles from drug
to drug. Second-generation antipsychotic
drugs were also found to be inconsistently
more effective than rst-generation agents
in alleviating negative, cognitive, and depres-
sive symptoms, and were less likely to cause
tardive dyskinesia; these modest benets
were principally driven by the ability of sec-
ond-generation antipsychotics to provide
equivalent improvement in positive symp-
toms along with a lower risk of causing
extrapyramidal adverse effects. Clozapine
was shown to be more efcacious than other
agents in treatment-refractory schizophrenia.
Side Effects of Drugs, Annual 33
J.K. Aronson (Editor)
ISSN: 0378-6080
DOI: 10.1016/B978-0-444-53741-6.00006-4
# 2011 Elsevier B.V. All rights reserved.
Natalia Jimeno
Dosage was a key variable in optimizing
effectiveness of both rst- and second-genera-
tion antipsychotic drugs. In contrast to their
relatively similar efcacy in treating positive
symptoms, there were substantial differences
between rst- and second-generation antipsy-
chotic agents with regard to their propensity
to cause extrapyramidal, metabolic, and other
adverse effects: second-generation agents are
less likely to cause acute extrapyramidal
symptoms and tardive dyskinesia but have a
tendency to cause greater metabolic adverse
effects than rst-generation agents.
Observational studies Psychiatrists attit-
udes to and actual practices in using typical
and atypical antipsychotic drugs in elderly
people have been audited in 321 patients
(mean age 76 years) in 18 old-age psychiatry
units across Australia, in which the attitudes
of a sample of 57 prescribing doctors (mean
age 46 years) were assessed [2c]. Over 96%
of the doctors reported that adverse events
were obstacles to prescribing typical anti-
psychotic drugs; the most common concerns
with typical drugs were related to acute
extrapyramidal symptoms (86%), tardive
dyskinesia (80%), sedation (35%),
hyperprolactinemia (18%), and weight gain
(18%). With regard to atypical drugs, 33%
of the doctors reported that weight gain
was an obstacle to prescribing, and they
were concerned about olanzapine (91%),
clozapine (60%), oral risperidone (32%),
and quetiapine (25%). Despite these con-
cerns, psychiatrists used the full repertoire
of antipsychotic drugs for a range of mental
illness in elderly people, including more than
20% of off-label indications. Antipsychotic
89
90 Chapter 6 Alfonso Carvajal, Luis H. Martn Arias, and Natalia Jimeno
drugs are currently used off-label in demen-
tia [SEDA-31, 65].
Antipsychotic drug-induced short-term
serious events have been assessed in a retro-
spective cohort study in older adults with
dementia [3C]. A serious event was a com-
posite outcome dened as an event serious
enough to lead to an acute care hospital
admission or death within 30 days of starting
therapy. Older adults with dementia, some
living in the community (n 20 682) and
others living in a nursing home (n 20 559)
were identied. Propensity-based matching
was used to balance differences between
the drug exposure groups in each setting.
Among 6894 community-dwelling older
adults taking atypical antipsychotic drugs,
960 (14%) were classied as having had
any serious event; of those, 186 (2.7%)
died. Relative to community-dwelling older
adults with dementia who did not receive a pre-
scription for antipsychotic drugs (n 6894),
similar older adults who did receive atypical
antipsychotic drugs (n 6894) were 3
times more likely (adjusted OR 3.2; 95%
CI 2.8, 3.7), and those who received a con-
ventional antipsychotic drug (n 6894) 3.8
times more likely, to have a serious adverse
event within 30 days of starting therapy
(adjusted OR 3.8; 95% CI 3.3, 4.4). The
pattern of serious events was similar but less
pronounced among older adults living in a
nursing home. In a survey, only two of six
published randomized controlled trials of anti-
psychotic drug therapy for dementia gave data
on any adverse event [4c]; in two of these trials
there was no information about deaths. The
risk of death in elderly users of antipsychotic
drugs has previously been reviewed [5C].
The incidence rates for six categories of
adverse events of antipsychotic drug use
have been compared in a retrospective
cohort study of 4140 children and adoles-
cents (mean age 10 years) and 4500 children
(mean age 7.2 years) with similar service
encounters but not treated with psychotropic
drugs [6c]. Six atypical and two conven-
tional antipsychotic drugs were studied.
The overall incidence/prevalence rates in
the control and treated groups differed dra-
matically in obesity/weight gain (8.6% ver-
sus 20%), type 2 diabetes (1.9% versus
5.2%), dyslipidemia (11% versus 4.2%),
cardiovascular conditions (3.4% versus
14.2%), neurological/sensory symptoms
(14% versus 65%), and digestive/urogenital
problems (71% versus 93%); the odds of
obesity/excessive weight gain, type 2 diabetes
and dyslipidemia, digestive/urogenital prob-
lems, and neurological/sensory symptoms
were higher in girls and those for whom
multiple antipsychotic drugs had been pre-
scribed. Multiple antipsychotic drugs were
prescribed in 42% of the treated cohort, in
whom the adjusted OR was 2.6 (95% CI
1.5, 4.7) for metabolic adverse events
and 1.7 (95% CI 1.12.7) for cardio-
vascular conditions.
Metabolic and cardiovascular adverse
events were further studied by the same
authors in the same sample of children
and adolescents [7C]. Compared with the
controls, the treated cohort had a higher
prevalence of obesity (OR 2.1), type 2
diabetes mellitus (OR 3.2), cardiovascu-
lar conditions (OR 2.7), and orthostatic
hypotension (OR 1.6). In the treated
cohort, those who had been exposed to mul-
tiple antipsychotic drugs had a signicantly
higher risk of incident obesity/weight gain
(OR 2.3), type 2 diabetes mellitus (OR
2.4), and dyslipidemia (OR 5.3). Incident
cardiovascular events were more likely with
the use of conventional antipsychotic drugs
(OR 4.3) and mood stabilizers (OR
1.3). Incident orthostatic hypotension was
more prevalent in those co-prescribed selec-
tive serotonin reuptake inhibitors (OR
1.8) and mood stabilizers (OR 1.3).
People with schizophrenia have substan-
tially increased rates of mortality than the
general population because of chronic ill-
ness, particularly cardiovascular disease
[8M]. In an 11-year follow-up study of mor-
tality in patients with schizophrenia (n 66
881), the gap in life expectancy between
patients with schizophrenia and the general
population in Finland did not widen
between 1996 (25 years) and 2006 (23 years)
[9C, 10r]. During that time, the proportion of
use of second-generation antipsychotic drugs
rose from 13% to 64%. Compared with cur-
rent use of perphenazine, the highest risk of
overall mortality was recorded for
Antipsychotic drugs Chapter 6
quetiapine (adjusted HR 1.4; 95% CI
1.1, 1.8) followed by haloperidol (HR 1.4;
95% CI 1.1, 1.7) and risperidone (HR
1.3; 1.1, 1.6), and the lowest risk for cloza-
pine (HR 0.7; 95% CI 0.6, 0.9).
Long-term cumulative exposure (711 years)
to any antipsychotic drug was associated
with a lower mortality than with no drug
use (HR 0.8; 95% CI 0.77, 0.84). It is
said that the difference in mortality between
clozapine and other antipsychotic drugs
might be attributable to more intensive mon-
itoring during clozapine treatment, the
greater effectiveness of clozapine, the poor
safety of other drugs, or all these causes.
According to the authors, current results
raise the question of whether clozapine
should be used as a rst-line treatment,
because it seems to be the safest antipsy-
chotic drug in terms of mortality and is also
the most effective.
Comparative studies First- and second-
generation antipsychotic drugs have been
compared in 119 children and adolescents
(aged 819 years) with early-onset schizo-
phrenia and schizoaffective disorder [11C],
who were randomized to olanzapine
2.520 mg/day, risperidone 0.56 mg/day,
or molindone 10140 mg/day, plus
benzatropine 1 mg/day for 8 weeks; some
subjects were excluded because of a previous
history of non-response to a study drug.
There were no signicant differences among
the treatment groups in response rates,
which were low in all three groups
(molindone: 50%, n 40; olanzapine:
34%, n 35; risperidone: 46%, n 41) or
in the magnitude of symptom reduction.
Olanzapine and risperidone were associated
with signicantly greater weight gain.
Olanzapine had the greatest risk of weight
gain (average 6.1 kg) and signicant
increases in fasting cholesterol, low density
lipoprotein, insulin, and liver transaminases.
Akathisia led to treatment discontinuation in
two participants taking molindone and in
one taking risperidone.
In an open randomized study in patients
with schizophrenia, supported by the mar-
keting authorization holders of some of the
antipsychotic drugs studied, AstraZeneca,
91
Pzer, and Sano-Aventis, there were no
differences between atypical antipsychotic
drugs and haloperidol after 1 year [12c].
More of those who took haloperidol had
signs of parkinsonism than those who took
an atypical antipsychotic drug; in contrast,
the proportion of patients who were over-
weight was higher with olanzapine than with
haloperidol. With haloperidol 72% of
patients discontinued treatment for any cause
within the 12 months (dose range 14 mg/day;
n 103), with amisulpride 40% (dose range
200800 mg/day; n 104), with olanzapine
22% (520 mg/day; n 105), with quetiapine
53% (200750 mg/day; n 104), and with
ziprasidone 45% (40160 mg/day; n 82).
Rates of admission to hospital were 723%
and did not differ signicantly between treat-
ments. Since the study was open, the psychia-
trists expectations could have led to
haloperidol being withdrawn more often.
The authors stated that it cannot be concluded
that second-generation antipsychotic drugs
are more efcacious than haloperidol in the
treatment of these patients.
Placebo-controlled studies In a study of the
effect of long-term treatment with neuro-
leptic drugs on global cognitive decline and
neuropsychiatric symptoms in patients with
Alzheimer's disease, 64 patients were
randomized to continue treatment with
thioridazine, chlorpromazine, haloperidol,
triuoperazine, or risperidone and 64 to pla-
cebo [13c]. There was no signicant differ-
ence in global cognitive functioning or
neuropsychiatric symptoms between the
groups after 6 months. There was a higher
risk of parkinsonism in the treated patients,
but the differences were not signicant.
Systematic reviews First-generation and
second-generation antipsychotic drugs in
patients with schizophrenia have been com-
pared in a meta-analysis [14M] (for an in-
depth review, see SEDA-27, 50). The study
included 150 double-blind, mostly short-
term, randomized clinical trials with 21 533
participants. Four second-generation anti-
psychotic drugs (amisulpride, clozapine,
olanzapine, and risperidone) were better
than rst-generation ones for overall
92 Chapter 6 Alfonso Carvajal, Luis H. Martn Arias, and Natalia Jimeno
efcacy, with small to medium effect sizes,
which is similar to the results of a previous
meta-analysis [15M]. The overall results are
not consistent with the view that second-gen-
eration drugs improve negative symptoms,
depression, and quality of life. Second-gen-
eration antipsychotic drugs caused fewer
extrapyramidal adverse effects than haloper-
idol (even at low doses), but only clozapine,
olanzapine, and risperidone caused fewer
extrapyramidal adverse effects than low-
potency rst-generation antipsychotic drugs.
With the exception of aripiprazole and
ziprasidone, second-generation antipsych-
otic drugs produced more weight gain, in
various degrees, than haloperidol but not
than low-potency rst-generation drugs.
The authors concluded that second-genera-
tion antipsychotic drugs differ in many
properties and are not a homogeneous class.
They also suggested that public institutions
could save costs by funding studies to dene
selected old compounds accurately, because
they were not rigorously studied at the time
they were introduced. This meta-analysis
merited an editorial, in which some points
were further emphasized [16r]; thus, the
name second-generation antipsychotic
drugs would be inaccurate, as this group
of drugs is in fact a heterogeneous mixture
of compounds, some being superior to
others. Accordingly, the spurious invention
of the atypical drugs can be regarded as an
invention, cleverly manipulated by drug
companies for marketing purposes. The
authors mentioned that using an inadequate
comparator (haloperidol) favors the atypical
drugs.
Different second-generation antipsychotic
drugs have been compared in another
meta-analysis [17M]. The primary outcome
measure was the change in total score on
the Positive and Negative Syndrome Scale
(PANSS); secondary outcome measures
were subscores for positive and negative
symptoms and rates of dropout because of
inefcacy. The analysis included 78 random-
ized studies, at least single-blind, with 167
relevant arms and 13 558 participants; 49
studies were mainly sponsored by pharma-
ceutical companies, 22 were publicly funded,
and in seven funding was uncertain.
Olanzapine was superior to aripiprazole,
quetiapine, risperidone, and ziprasidone,
and its efcacy was similar to that of
amisulpride and clozapine; risperidone was
more efcacious than quetiapine and
ziprasidone. Clozapine and olanzapine,
followed by quetiapine and then risperidone,
were the most likely to cause weight gain
and glucose and lipid abnormalities.
Amisulpride and risperidone carried a risk
of extrapyramidal symptoms and substantial
increases in prolactin concentrations. The
effect sizes ranged between 1.9 (olanzapine
versus risperidone) and 8.3 (olanzapine ver-
sus ziprasidone) PANSS points, and the
clinical relevance of the difference between
olanzapine and risperidone (1.9 PANSS
points) based on a large sample size
(n 2404) is particularly doubtful. For per-
spective, the average difference between
second-generation antipsychotic drugs and
placebo in another meta-analysis was only
10 PANSS points [18M]. A sensitivity analy-
sis was also performed with sponsor, dose,
study quality, treatment resistance, study ori-
gin, and trial duration as moderators, and
there were only a few differences; excluding
studies sponsored by pharmaceutical com-
panies did not change the result. This is sim-
ilar to the result of another meta-analysis of
the effects of several potentially biasing fac-
tors (e.g. industry support, extrapyramidal
adverse effects) on drug efcacy in compar-
ison of second-generation and rst-genera-
tion antipsychotic drugs [19M].
The effectiveness of second-generation
antipsychotic drugs has been addressed in
a systematic review of 16 randomized
head-to-head comparisons of second-gener-
ation antipsychotic drugs [20M]. The trials
were categorized as effectiveness studies if
there was a statement from the authors that
a naturalistic, pragmatic, practical, or real-
life study design was used, or if the methods
section was presented in corresponding
terms. There were differences in sample
sizes, inclusion criteria, follow-up periods,
and sources of funding. In acute episodes
and rst episodes there were no differences
between the second-generation antipsychotic
drugs in relief of symptoms; during long-
term treatment those who used olanzapine
Antipsychotic drugs Chapter 6
had longer times to discontinuation of treat-
ment and better treatment adherence com-
pared with those who used other atypical
drugs. Olanzapine was associated with
more metabolic adverse effects than other
second-generation antipsychotic drugs.
Cardiovascular Extensive data link the
typical antipsychotic drugs with an
increased risk of sudden cardiac death
[SEDA-24, 54; SEDA-30, 56]. The adjusted
incidence of sudden cardiac death among
current users of single antipsychotic drugs
has been estimated in a retrospective
cohort of Tennessee Medicaid enrolees
[21C]. Current users of both typical drugs
(n 44 218) and atypical drugs (n
46 089) had greater rates of sudden cardiac
death than non-users (n 186 600), with
adjusted incidence-rate ratios for use of
2.0 (95% CI 1.7, 2.3) and 2.3 (1.9, 2.7)
respectively. For typical antipsychotic drugs
the risk increased from 1.3 (1.0, 1.8) for low
doses to 2.4 (1.9, 3.1) for high doses; for
atypical agents the risk increased from 1.6
(1.0, 2.5) for low doses to 2.9 (2.2, 3.6) for
high doses. The incidence-rate ratios for
atypical versus typical antipsychotic drugs
was 1.1 (0.3, 1.4). The authors suggested
that antipsychotic drugs increase the risk
of serious ventricular dysrhythmias, proba-
bly through blockade of potassium
channels and prolongation of cardiac
repolarization.
Changes in the 10-year risk of coronary
heart disease have been compared between
treatment groups in 1125 patients followed
for 18 months or until treatment discontinu-
ation in the Clinical Antipsychotic Trials
of Intervention Effectiveness (CATIE)
in schizophrenia [22C]. The mean change
in 10-year coronary heart disease risk dif-
fered signicantly between treatments.
Olanzapine was associated with a 0.5%
increase and quetiapine with a 0.3%
increase, while the risk fell in patients who
used perphenazine (0.5%), risperidone
( 0.6%), and ziprasidone (0.6%). The
difference in 10-year coronary heart disease
risk between olanzapine and risperidone
was statistically signicant.
93
Nervous system A re-analysis of the
CATIE study (n 1443) has been
performed in order to compare the incidence
of treatment-emergent extrapyramidal
effects between second-generation anti-
psychotic drugs and perphenazine in people
with schizophrenia [23R]. There were no sig-
nicant differences in the incidence of par-
kinsonism, dystonia, akathisia, or tardive
dyskinesia. The probabilities of tardive
dyskinesia event within 1 year in people
with no tardive dyskinesia at baseline, with
adjustment for baseline co-variates, were:
olanzapine 0.01 (95% CI 0.002, 0.03); per-
phenazine 0.03 (95% CI 0.01, 0.07);
quetiapine 0.02 (95% CI 0.001, 0.06);
and risperidone 0.01 (95% CI 0.004,
0.04). There were greater rates of concomi-
tant antiparkinsonian medication among
individuals taking risperidone and lower
rates among individuals taking quetiapine;
there were lower rates of withdrawal
because of parkinsonism among people tak-
ing quetiapine or ziprasidone. There was a
trend to a greater likelihood of concomitant
medications for akathisia among individuals
taking risperidone and perphenazine. The
authors suggested that previous reports of a
relatively lower incidence of extrapyramidal
symptoms with second-generation anti-
psychotic drugs were likely to be related to
the use of higher dosages of the high-
potency rst-generation antipsychotic drug,
haloperidol. One of the limitations pointed
out in the study was the relatively short dura-
tion of exposure.
Neurological adverse events associated
with antipsychotic drug use in children and
adolescents have been studied retrospec-
tively using medical and pharmacy claims
from one state's Medicaid program [24C].
The incidence rates for these events in
4140 children who were taking anti-
psychotic drugs (mean age 10 years) and
an untreated sample of 4500 children
(mean age 7.2 years) were compared. The
treated cohort had a higher prevalence of
involuntary movements (OR 6.2; 95%
CI 4.5, 8.3), sedation (OR 1.8; 95%
CI 1.2, 2.3), and seizures (OR 6.2;
95% CI 5.3, 7.7). The odds of incident
involuntary movements were signicantly
94 Chapter 6 Alfonso Carvajal, Luis H. Martn Arias, and Natalia Jimeno
higher in those taking aripiprazole, risperi-
done, haloperidol, and multiple antipsy-
chotic drugs; the odds of incident seizures
were greater for those taking risperidone
and multiple antipsychotic drugs; the odds
of incident sedation were greater for those
taking ziprasidone, risperidone, quetiapine,
and multiple antipsychotic drugs. Exposure
to risperidone and multiple antipsychotic
drugs consistently confers a higher risk
of a range of neurological adverse events
in young patients, especially those with
pre-existing central nervous system or car-
diovascular disorders or mental retardation.
Levetiracetam, the levorotary stereo-
isomer of an ethylated congener of pirace-
tam, was effective in the treatment of
tardive dyskinesia in a randomized, double-
blind, placebo-controlled study [25c]. The
levetiracetam/placebo difference reached a
trend level by week 4 and was statistically sig-
nicant at weeks 6, 9, and 12; at week 12 the
AIMS total score model-estimated marginal
mean in the levetiracetam group dropped
44% from baseline, and the placebo group
estimated mean fell 19%. Overall adverse
effects were similar in the two groups; since
there have been reports of leukopenia,
neutropenia, pancytopenia, and thrombo-
cytopenia in patients taking levetiracetam,
particular attention was given to these reac-
tions: in no patient did the white blood cell
count fall below 2.8  109/l, the neutrophil
count below 1.0  109/l, or the platelet count
below 75  109/l.
Sensory systems Typical antipsychotic
drugs, mainly phenothiazines, have been
associated with cataract formation [SEDA-
24, 57]. There were lenticular opacities in
21 of 52 patients who used typical anti-
psychotic drugs and in 5 of 28 patients
who used atypical antipsychotic drugs
[26c]. Patients who used typical antipsy-
chotic drugs had earlier mental illness
onset, had used antipsychotic drugs for lon-
ger periods, had used higher doses, and
were older. No pigment deposition was
found, neither in the cornea nor in the ret-
ina of these patients.
Weight gain and diabetes mellitus
due to antipsychotic drugs
EIDOS classication:
Extrinsic moiety Antipsychotic drugs
Intrinsic moiety [?]H1, M3, and 5-HT2C
receptors
Distribution Adipocytes and other cells
Outcome Altered physiology (leptin
secretion, insulin resistance,
impaired glucose tolerance)
Sequela Weight gain and diabetes
mellitus due to antipsychotic drugs
DoTS classication:
Dose-relation Collateral reaction
Time-course Intermediate
Susceptibility factors Genetic
(AfricanAmerican origin; the
102T allele of HTR2A, the 825T
allele of GNB3, the 23Cys allele of
HTR2C, and the 64Arg/Arg
genotype of ADRB3; see Table 1);
sex (male)
The potential interactions between atypi-
cal antipsychotic drugs and several hor-
mones that affect appetite regulation and
carbohydrate metabolism have been
reviewed [27r]. The effects of atypical anti-
psychotic drugs on carbohydrate intolerance
and the development of diabetes show that
they produce abnormalities in glucose toler-
ance by altering appetite regulation, insulin
secretion and action, and the release of insu-
lin counter-regulatory hormones, in particu-
lar leptin and ghrelin; high concentrations of
those hormones have been observed in
patients taking atypical antipsychotic drugs.
Receptor-binding proles of different anti-
psychotic drugs may also help explain the
occurrence of some metabolic adverse effects
associated with each drug [28r]. Thus, drug
afnity at histamine H1 receptors is linked
to weight gain; this is consistent with data
demonstrating that histamine H1 receptor
antagonism promotes feeding in rodents
and that H1 knockout mice are susceptible
to weight gain. It has also been observed that
atypical orexigenic antipsychotic drugs
Antipsychotic drugs Chapter 6
reverse the actions of leptin, an anorexigenic
hormone. Drug afnity for H1, M3, and
5-HT2C receptors correlates with an
increased risk of diabetes. The receptor-
binding proles that correlate with antipsy-
chotic drug-associated dyslipemia are not
well understood; however, it has been
suggested that peroxisome proliferator-acti-
vated receptor (PPAR) agonists may convey
therapeutic benet.
Metabolic syndrome The metabolic syn-
drome is highly prevalent among patients
with schizophrenia, due in part to medica-
tions. The metabolic syndrome is a cluster
of metabolic abnormalities (glucose intoler-
ance, hypertension, obesity) in a single
subject. These abnormalities dene a contin-
uum of risk, and those who have more fea-
tures of this syndrome appear to be more
predisposed to type 2 diabetes mellitus and
cardiovascular disease. The nding of differ-
ential metabolic proles for atypical anti-
psychotic drugs has been conrmed in
numerous prospective studies [29R]; accord-
ingly, the parameters that are most
inuenced by treatment with metabolically
offending medications are weight, serum tri-
glycerides, and measures of glycemic con-
trol, with substantially less effect on serum
HDL cholesterol or blood pressure.
The change in the proportion of subjects
with the metabolic syndrome and individual
criteria has been compared between anti-
psychotic drugs, along with mean changes
for individual criteria in phase 1 of the
CATIE schizophrenia study [30C]. Among
all subjects whose metabolic syndrome sta-
tus could be determined at 3 months (n
660), the prevalence of the metabolic syn-
drome increased for olanzapine (from 35%
to 44%), but decreased for ziprasidone
(from 38% to 30%). Although effect sizes
varied across subgroups, at 3 months
olanzapine and quetiapine had the largest
mean increases in waist circumference (0.7
inches for both) followed by risperidone
(0.4 inches), compared with no change for
ziprasidone and a reduction in waist
circumference for perphenazine (0.4
inches). Olanzapine also had signicant
effects on fasting triglycerides at 3 months
95
( 0.25 mmol/l) compared with ziprasidone
( 0.35 mmol/l).
Consistent results were found in a study
carried out in India, in which all consecutive
drug-nave patients with a rst episode of
schizophrenia (n 99) were recruited into
a randomized, double-blind, controlled
study; the prevalence of metabolic syndrome
after 6 months (10% and 18% as assessed
by ATPIA and International Diabetes Fed-
eration criteria respectively) was ve times
as high compared with the matched healthy
control group [31c]. Olanzapine had a max-
imum prevalence of metabolic syndrome at
2025% (n 35), followed by risperidone
at 924% (n 33) and haloperidol at
03% (n 31).
In a prospective study, fasting serum and
anthropometric measures were obtained
from 45 patients with rst-episode psychosis
and 41 healthy adults of similar age, ethnic-
ity, and sex [32c]. At baseline, the distribu-
tions of cardiovascular risk markers were
similar and the percentages of young
patients with rst-episode psychosis and
healthy controls who were overweight/obese,
dyslipidemic, hyperglycemic, and
hyperinsulinemic did not differ. At 24 weeks,
compared with baseline, 16 of the patients
with psychosis who continued to take the
same antipsychotic medication had statisti-
cally signicant increases in BMI, glucose,
insulin, cholesterol, leptin, and E-selectin,
and a reduction in adiponectin.
Patients with bipolar disorder and schizo-
phrenia who are treated with second-genera-
tion antipsychotic drugs had similar high
rates of the metabolic syndrome in a retro-
spective comparison of different metabolic
parameters [33c]. The prevalence of meta-
bolic syndrome in a matched and randomly
selected sample was 43% in bipolar disorder
(n 74) and 46% in schizophrenia
(n 111).
Diabetes mellitus [SEDA 28, 60; SEDA-30,
58; SEDA-31, 67; SEDA-32, 87] The preva-
lence of detected diabetes in the general pop-
ulation is around 34%; type 2 diabetes
accounts for 8590% of all cases and results
from a combination of insulin resistance and
96 Chapter 6 Alfonso Carvajal, Luis H. Martn Arias, and Natalia Jimeno
relative insulin deciency. The prevalence of
type 2 diabetes in patients with schizophre-
nia has been estimated at 9% [34C]. Atypical
antipsychotic drugs have been linked to a
higher risk of glucose intolerance, and con-
sequently development of type 2 diabetes
mellitus. The acute effects of oral administra-
tion of olanzapine and ziprasidone on whole-
body insulin sensitivity in healthy subjects
have been investigated [35c] using the stan-
dardized hyperinsulinemic euglycemic clamp
technique in 29 healthy male volunteers who
took either olanzapine 10 mg/day (n 14)
or ziprasidone 80 mg/day (n 15) for
10 days. Olanzapine caused a signicant
reduction in mean whole-body insulin sensi-
tivity from 5.7 ml/hour/kg at baseline to
4.7 ml/hour/kg; ziprasidone had no effect
(5.2 ml/hour/kg versus 5.1 ml/hour/kg).
In another study, medication-nave
patients with schizophrenia were ran-
domized to olanzapine (n 35), risperi-
done (n 33), or haloperidol (n 31)
[36c]. After 6 weeks, there were signicant
increases in weight, fasting blood sugar,
and 2-hour postprandial blood sugar
between the matched healthy control group
(n 51; mean age, 28 years) and the treat-
ment group as a whole (n 99; mean age
26 years). There was also a signicant
increase in the incidence of diabetes mellitus
at end-point by the WHO criteria (10%;
olanzapine, n 3; risperidone, n 3; halo-
peridol, n 3).
The risks of diabetes with different anti-
psychotic drugs have been compared in a
meta-analysis of 11 studies in people with
schizophrenia or related disorders, including
cross-sectional studies, casecontrol studies,
cohort studies, and controlled trials [37M].
The relative risk of diabetes in patients with
schizophrenia taking one of the second-gen-
eration versus rst-generation antipsychotic
drugs was 1.3 (95% CI 1.1, 1.5).
According to the authors, there were meth-
odological limitations in most of the studies,
leading to heterogeneity and difculty in
interpreting the data; they pointed out that
one residual confounder not reported in
any of the studies was whether an increased
amount of screening occurred in those
taking second-generation antipsychotic
drugs, owing to greater clinical awareness.
Triglycerides Atypical antipsychotic drugs
have been linked to hyperlipidemia [SEDA-
30, 58]. Taking advantage of the data gath-
ered in the CATIE study [SEDA-30, 56],
the effects of antipsychotic drugs on triglycer-
ides have been explored [38R]. In 246 subjects
there were signicant treatment differences in
the 3-month change from baseline; the
greatest increases in median and adjusted
mean non-fasting triglycerides concentrations
were seen among those randomized to
quetiapine (mean 0.62 mmol/l) and
olanzapine (mean 0.26 mmol/l).
Ziprasidone had no effect. There were reduc-
tions with risperidone (mean 0.21 mmol/l)
and perphenazine (mean 0.1 mmol/l).
Raised triglycerides due to olanzapine
usually involve weight gain accompanied
by insulin resistance. However, serum tri-
glyceride concentrations can rise without
weight gain or abnormal glucose metabo-
lism [39A, 40A].
Weight gain [SEDA-32, 87] In the CATIE
study (see SEDA-30, 56), there was weight
gain of 7% or more in 30% of patients with
schizophrenia taking olanzapine 7.530 mg/
day; the amount of weight gain induced by
olanzapine was much greater than that
induced by quetiapine, risperidone, or
ziprasidone. There were statistically signi-
cant differences in weight gain at 3 months
with olanzapine, risperidone, and haloperi-
dol in a randomized study of drug-nave
patients [41C]. At 3 months there were
increases of 3.8 kg for haloperidol (n 46),
5.9 kg for risperidone (n 52), and 8.4 kg
for olanzapine (n 49); after 1 year, the
difference in weight gain had disappeared:
9.7 kg for haloperidol (n 24), 8.9 kg for
risperidone (n 35), and 10.9 kg for
olanzapine (n 36). The ndings, contrary
to those reported in other studies, were
explained by the authors as being due to
differences in follow-up periods.
The effects of antipsychotic drugs (halo-
peridol, olanzapine, and risperidone) on
peptides involved in energy balance (insulin,
Antipsychotic drugs Chapter 6
ghrelin, leptin, adiponectin, visfatin, and
resistin) have been studied in 70 drug-nave
patients with a rst episode of psychosis
[42C]. There were signicant increases in
weight (10.2 kg), body mass index (3.56 kg/
m2), and fasting plasma insulin (3.93 mU/
ml), leptin (6.76 ng/ml), and ghrelin (15.47
fmol/ml) concentrations. The increments in
insulin and leptin concentrations correlated
with the increments in weight and body mass
index and seem to have been a consequence
of higher fat stores; the three antipsychotic
drugs had similar effects on all the parameters
evaluated. The authors suggested that the
unexpected increase in ghrelin concentrations
might have been causally related to weight
gain from antipsychotic drugs.
Prescription of second-generation anti-
psychotic drugs has increased dramatically
in recent years in children [SEDA-31, 66],
in whom metabolic effects, and weight gain
in particular, are supposed to be greater than
in adults. The metabolic and hormonal
adverse effects in children and adolescents
(mean age 15 years) after 6 months of treat-
ment have been evaluated [43c]. After
6 months, BMI increased signicantly in
those taking olanzapine (baseline 22.7 kg;
change 3.7 kg; n 20) and risperidone
(baseline 21.8 kg; change 1.4 kg; n 22),
but not in those taking quetiapine (baseline
21.5 kg; change 0.9 kg; n 24). Mean total
cholesterol concentrations increased signi-
cantly in patients receiving olanzapine
(baseline 4.1 mmol/l; change 0.27) and
quetiapine (baseline 4.2; change, 0.38).
Susceptibility factors Genetic factors associ-
ated with olanzapine-induced weight have
been studied in Japan [44C]. Patients with
schizophrenia (n 164) took olanzapine
(mean dose 15.5 mg/day) for 824 weeks.
BMI rose by a mean of 4.3%. Olanzapine-
induced weight gain correlated negatively
with baseline BMI and positively with clini-
cal global improvement and the length of
olanzapine treatment, but did not correlate
with the daily dose of olanzapine, concomi-
tant antipsychotic drugs, sex, age, or
smoking. Among 21 polymorphisms exam-
ined, four genetic variants, the 102T allele
of HTR2A, the 825T allele of GNB3, the
97
23Cys allele of HTR2C, and the 64Arg/Arg
genotype of ADRB3, were signicantly
associated with olanzapine-induced weight
gain. Stepwise regression analysis showed
that the baseline BMI predicted 13% of the
weight gain, and the two latter genetic factors
added 6.8%. The patients with double and
triple genetic risk factors had 5.1% and
8.8% increases in BMI respectively; the
patients with a single or no risk factor had
about a 1% increase.
In a review of the use of pharmacogenetic
testing to predict the likelihood of some
adverse drug reactions the authors empha-
sized that the mechanisms of olanzapine-
induced weight gain may involve the gene
for 5-HT2C receptors; other candidate genes
that may be associated with olanzapine-
induced weight gain include CYP2D6, the
synaptosomal-associated protein of 25 kDa
(SNAP25), G-protein beta 3 subunit gene
(GNB3), the alpha2a-adrenergic receptor
(ADRA2A), leptin (LEP), and the leptin
receptor (LEPR) [45R]. For a summary of
other genetic factors that have been investi-
gated in relation to antipsychotic drug-
induced metabolic reactions, see Table 1.
Management The effects of lifestyle inter-
vention and metformin, alone and in combi-
nation, for antipsychotic-induced weight
gain and abnormalities in insulin sensitivity,
have been evaluated in a randomized con-
trolled trial in adult Chinese patients with
schizophrenia [53c]. Those who gained
more than 10% of their predrug weight
within the rst year of treatment with cloza-
pine, olanzapine, risperidone, or sulpiride
were assigned to one of four groups, in
which patients continued their antipsychotic
drug treatment and were randomly assigned
for 12 weeks to placebo (n 32), 750 mg/
day of metformin alone (n 32), 750 mg/
day of metformin and lifestyle intervention
(n 32), or lifestyle intervention only
(n 32). All patients with rst-episode
schizophrenia maintained relatively stable
psychiatric improvement. The lifestyle-plus-
metformin group had a mean reduction in
BMI of 1.8 (95% CI 1.3, 2.3), the metfor-
min-alone group had a mean reduction in
BMI of 1.2 (95% CI 0.9, 1.5), and the
 Table 1 Genetic factors and antipsychotic drug-induced metabolic reactions

Antipsychotic
drug/reaction Genetic factor No. Comments Ref.

Several antipsychotic 5-HT2C receptors 123 Conicting results SEDA-27, 53

drugs/weight gain
Olanzapine/weight gain CYP2D6 11 Association SEDA-27, 61
Olanzapine/weight gain 5-HT2C receptors (759C/T) 42 Possible protective effect of the T allele SEDA-30, 66
Clozapine/weight gain ADRA2A (1291C/G) 91 GG associated with a higher risk SEDA-30, 63
Olanzapine/weight gain ADRA2A (1291C/G) 62 G allele associated with a higher risk SEDA-31, 85
Olanzapine/weight gain Apolipoproteins E and A4 and scavenger 67 Weight proles signicantly associated SEDA-32, 103
receptor class B, member 1
Olanzapine/weight gain L/S promoter (SERTPR) and l/s intron 2 (SERTin2) 94 S SERTPR allelic variant and SS genotype was SEDA-32, 103
genetic variants of serotonin transporter (SERT) associated with signicantly higher weight gain
polymorphisms
Olanzapine/weight gain 102T allele of HTR2; 825T allele of GNB3, the 23Cys 164 Association [44c]
allele of HTR2C; 64Arg/Arg genotype of ADRB3
Olanzapine/weight gain Leptin gene (LEP) (AG 2548) 74 Weight gain was signicantly higher for patients with [46c]
the AG genotype than for those with the AA genotype
(Korean patients)
Olanzapine/weight gain LEP- and LEPR 200 LEPR Q223R polymorphism may be associated with [47c]
obesity in women with a psychotic disorder treated
with atypical antipsychotic drugs
Atypical drugs/metabolic 5-HT2C receptors (759C/T) and leptin 134 Higher risk in those carrying the leptin 2548A/G [48c]
disturbances (2548A/G) allele within the high risk group carrying the
5-HT2C receptor gene 759C/CC
Several atypical drugs/ Acetyl-coenzyme A carboxylase alpha SNP 357 These genes may be promising candidates for studies [49c]
hyperlipidemia, direct (rs4072032); neuropeptide Y (rs1468271); of the direct effects of some antipsychotic drugs on
effects ACCbeta (rs2241220) hyperlipidemia
Atypical drugs/metabolic MTHFR 677C/T and 1298A/C genotype 58 MTHFR 677C/T variant may predispose patients to [50c]
syndrome metabolic complications
Clozapine/weight gain Genes involved in the SREBP activation of fatty 160 Strong association between three markers localized [51c]
acids and cholesterol production (SREBF1, within or near the INSIG2 gene (rs17587100,
SREBF2, SCAP, INSIG1, and INSIG2) rs10490624, and rs17047764) and antipsychotic drug-
related weight gain
Several antipsychotic Alpha1A-adrenoceptor gene (563C/T, 4155G/C, 427 The results do not support a major role of alpha1A- [52c]
drugs/obesity and 4884A/G) adrenoceptor genetic variants in obesity
Antipsychotic drugs Chapter 6
lifestyle-plus-placebo group had a mean
reduction in BMI of 0.5 (95% CI 0.3,
0.8); however, the placebo group had a
mean increase in BMI of 1.2 (95% CI
0.9, 1.5). There were no signicant differ-
ences in the frequencies and types of adverse
effects among the groups.
The benecial effect of metformin alone
had already been seen in a previous dou-
ble-blind study by the same authors [54c],
in which 40 in-patients with schizophrenia
were randomized for 12 weeks to
olanzapine 15 mg/day plus metformin
750 mg/day (n 20) or olanzapine 15 mg/
day plus placebo (n 20). Of the 40
patients, 37 completed treatment; all had a
restricted diet. Metformin attenuated the
increases in weight (0.5 kg versus 5.4 kg),
BMI (0.1 versus 1.8), waist circumference
(0.3 cm versus 1.2 cm), and waist-to-hip
ratios (0.003 versus 0.184).
In a meta-analysis of randomized controlled
trials adjunctive non-pharmacological inter-
ventions, either individual or group interven-
tions or cognitive-behavioral therapy, and
nutritional counselling were similarly effective
in reducing or attenuating antipsychotic drug-
induced weight gain and treatment effects were
maintained during follow-up [55M].
Urinary tract Drug-induced urinary reten-
tion has been reviewed, emphasizing the
anticholinergic activity of some anti-
psychotic drugs [56r].
Sexual dysfunction Ischemic priapism, pain-
ful and persistent penile erection unrelated
to sexual desire or stimulation, has been
described in association with antipsychotic
drugs [SEDA-24, 59; SEDA-28, 64]. Four
men aged 2555 years developed priapism
while taking antipsychotic drugs
(amisulpride, clozapine, levomepromazine,
olanzapine, pipotiazine, risperidone, or
zuclopenthixol) [57A]; they were treated
with aspiration and irrigation of the corpora
cavernosa with sympathomimetic drugs,
followed in one case by a surgical distal
cavernoglandular shunt; all cases resolved.
99
INDIVIDUAL DRUGS
Amisulpride [SED-15, 173; SEDA-31,
69; SEDA-32, 92]
Observational studies In an open study, 29
patients were treated with a wide range of
doses of amisulpride (501200 mg/day) [58c].
After 2 weeks, brain single photon emission
tomography scans were performed 2 hours
after intravenous injection of 185 MBq of
(123I)IBZM iodobenzamide. D2 receptor
blockade correlated with doses and plasma
concentrations of amisulpride; there was no
correlation between the clinical response
and striatal D2 occupancy. There were extra-
pyramidal adverse effects, which had to be
treated with biperiden, in 31% of the patients.
Aripiprazole [SEDA-30, 61; SEDA-31,
70; SEDA-32, 93]
Placebo-controlled studies In a 6-week
multicenter, double-blind, randomized,
placebo-controlled study, patients aged
1317 years with schizophrenia were
assigned to aripiprazole (10 mg/day,
n 100; 30 mg/day, n 102) or placebo
(n 100) [59C]. At the end of the study,
both doses of aripiprazole signicantly
reduced PANSS total scores. Adverse
events that occurred in more than 5% of
subjects in either aripiprazole group and
with a combined incidence at least twice
the rate for placebo were extrapyramidal
disorders, somnolence, and tremor. Mean
changes in prolactin concentrations were
8.5, 12, and 15 ng/ml for placebo and
for 10 and 30 mg of aripiprazole respec-
tively. Mean body weight changes were
0.8, 0.0, and 0.2 kg for placebo and for
10 and 30 mg of aripiprazole respectively.
Aripiprazole has been previously com-
pared with placebo in patients with bipolar
I disorder [SEDA-31, 74]. Now the results
of several studies in such patients have
emerged. In a 100-week, double-blind, pla-
cebo-controlled study in 28 patients with
100 Chapter 6 Alfonso Carvajal, Luis H. Martn Arias, and Natalia Jimeno
rapid-cycling bipolar disorder the most
common adverse reactions to aripiprazole
( 10% incidence and twice the placebo
rate) were anxiety (n 4), sinusitis (n 4),
depression (n 3), and upper respiratory
infection (n 3) [60C]. One patient with-
drew because of akathisia. There were no
signicant between-group differences in
mean changes in weight or metabolic
parameters. However, the results of this
study were seriously limited by the fact that
only 12 patients completed the initial 26-
week treatment period and only three com-
pleted the 100-week double-blind period.
Re-analyses of the results of two random-
ized, 3-week, exible-dose, double-blind,
placebo-controlled trials in subpopulations
of patients with acute mania or mixed epi-
sodes of bipolar I disorder have been
performed [61C]. Aripiprazole signicantly
reduced mean Young Mania Rating Scale
(YMRS) total scores at end-point compared
with placebo and in three subgroups
stratied by baseline severity of depressive
symptoms using the Montgomery-Asberg
Depression Rating Scale (MADRS). In the
overall population, the most common
adverse reactions to aripiprazole (n 263),
which occurred in  5% of patients and were
at least twice the rate of the placebo group (n
260) were somnolence (aripiprazole 21%
versus placebo 8%), dyspepsia (19% versus
9), akathisia (14% versus 5%), and acciden-
tal injury (9% versus 2%).
In a multicenter study, out-patients were
randomly assigned to adjunctive
aripiprazole (15 or 30 mg/day; n 253)
or placebo (n 131) for 6 weeks [62C].
They had had a manic or mixed episode
(with or without psychotic features) with
partial non-response to lithium/valproate
monotherapy and with target serum con-
centrations of lithium (0.61.0 mmol/l)
or valproate (50125 mg/l). Improvement
was signicantly greater with aripiprazole
than with placebo. Withdrawal rates due
to adverse reactions were higher with
aripiprazole than with placebo (9% versus
5% respectively). Akathisia was the most fre-
quently reported extrapyramidal symptom-
related adverse reaction, and it occurred
signicantly more frequently among those
taking aripiprazole (19%) than among those
taking placebo (5.4%). There were no signi-
cant differences between treatments in weight
changes.
The efcacy and safety of adjunctive
aripiprazole added to standard antidepres-
sant therapy in 736 patients with major
depressive disorder with anxious/atypical
features at baseline have been evaluated
[63C]. Data from two identical 14-week
studies (an 8-week prospective antidepres-
sant treatment phase and a 6-week random-
ized, double-blind phase) were used.
Patients who took aripiprazole had signi-
cantly greater improvement in Montgom-
ery-Asberg Depression Rating Scale
(MADRS) total scores than patients taking
placebo. Treatment-emergent adverse
effects that occurred in 5% of patients
were akathisia (25% aripiprazole; 4% pla-
cebo), restlessness (12% versus 2%), fatigue
(8% versus 4%), insomnia (8% versus 2%),
and blurred vision (6% versus 1%). An
analysis of weight change over the course
of double-blind treatment showed that the
increase was greater with aripiprazole
(1.611.83 kg) than placebo (0.220.48 kg).
In a 12-week, multicenter, randomized,
double-blind, placebo-controlled trial of
aripiprazole in the treatment of alcoholism
in 295 subjects, aripiprazole produced more
positive subjective effects and less overall
severity of alcohol dependence than pla-
cebo, although there was no difference
between aripiprazole and placebo on the pri-
mary end-point, possibly because of dose-
related attrition (treatment was started at
2 mg/day and titrated to a maximum
of 30 mg/day at day 28). Withdrawals
(40% versus 27%) and treatment-related
adverse effects (83% versus 64%) were
more common with aripiprazole. The most
common treatment-related adverse events
that differed signicantly between
aripiprazole and placebo were: fatigue,
insomnia, restlessness, somnolence, anxiety,
and altered attention; serious adverse reac-
tions attributed to aripiprazole were chest
pain, cellulitis, migraine, and thrombosis;
extrapyramidal adverse reactions attributed
Antipsychotic drugs Chapter 6
to aripiprazole were akathisia (6%), tremor
(3.4%), and dyskinesias (1.4%).
Observational studies In a 6-week, pro-
spective, unrandomized, open study in 20
patients with acute bipolar depression,
aripiprazole up to a maximum of 30 mg/
day improved Montgomery-Asberg
Depression Rating Scale (MADRS) and
Mania Rating Scale (MRS) scores signi-
cantly [64c]. The most frequent adverse
reactions were nausea and akathisia; two
patients withdrew because of akathisia.
In an open 16-week study of the efcacy
and tolerability of aripiprazole in 85
patients with bipolar disorder and acute
depression inadequately responsive to a
mood stabilizer there were signicant
reductions in mean MADRS and Clinical
Global Impression-Severity (CGI-S) scales
[65c]. Three patients withdrew because of
adverse reactions, the most common of
which was akathisia, which occurred in
21% of subjects; there was also a statisti-
cally non-signicant weight gain (0.9 kg).
The effectiveness and cognitive effects of
aripiprazole (mean dose 6.7 mg/day) have
been assessed in a 6-week, open study in
23 children with attention-decit/hyper-
activity disorder [66c]. There was overall
signicant improvement from baseline on
attention-decit/hyperactivity disorder and
functional outcome measures. The most
common adverse events were sedation
(n 18), headache (n 11), nausea (n
7), increased appetite (n 6), musculoskele-
tal pain (n 6), stomach ache (n 5), hic-
cups (n 4), and u-like symptoms (n
4). There was a signicant increase in
weight, with an increase from a mean of
37.6 kg at baseline to a mean of 39.6 kg at
end of the study.
Nervous system Aripiprazole has been pre-
viously associated with neuroleptic malig-
nant syndrome but with doubts about the
validity of the diagnoses. However,
postmarketing pharmacovigilance schemes
in Australia have collected a higher propor-
tion of cases of neuroleptic malignant syn-
drome with aripiprazole compared with
the total number of reports received for
101
other antipsychotic drugs [SEDA-31, 76].
In a new case, neuroleptic malignant syn-
drome occurred when aripiprazole was
added to olanzapine [67A].
In a 33-year-old man taking olanzapine 10 mg/
day aripiprazole and benzatropine were
added; after 2 weeks the dose of aripiprazole
was increased from 5 to 10 mg/day and shortly
afterwards the patient developed sweating, a
raised temperature, tachycardia, and muscle
rigidity, with raised alanine aminotransferase,
aspartate aminotransferase, and creatine
phosphokinase (peak 3210 U/l).
Reduced choreiform movements have been
reported when a 47-year-old man with
Huntington's disease was given aripiprazole
20 mg/day for 2 weeks; his gait became sta-
ble, enabling him to walk smoothly without
assistance [68A].
Endocrine Aripiprazole is said to stabilize
the dopaminergic system and thus amelio-
rate schizophrenic symptoms without
increasing serum prolactin [SEDA-31, 76].
Prolactin concentrations and sexual func-
tion in schizophrenic patients have been
evaluated in an open, 26-week, multicenter
study, in which 555 patients were random-
ized to aripiprazole (n 284) or standard
care (olanzapine, quetiapine, or risperi-
done; n 271) [69C]. At 8 weeks, those
who took aripiprazole reported signicantly
greater improvement in sexual function.
Baseline mean serum prolactin concentra-
tions were similar in the two groups (434
and 423 mg/l respectively); however, at
week 26, the mean fall in serum prolactin
was 342 mg/l with aripiprazole compared
with 133 mg/l with the other treatments.
Susceptibility factors Hepatic or renal
impairment Two open, single-dose studies
have been conducted to investigate whether
the pharmacokinetics of aripiprazole are
altered in individuals with hepatic or renal
impairment [70c]. In study 1, six subjects with
normal hepatic function and 19 with hepatic
impairment (mild, n 8; moderate, n 8;
severe, n 3) received a single dose of
aripiprazole 15 mg. The same dose was used
in study 2, in seven patients with normal
102 Chapter 6 Alfonso Carvajal, Luis H. Martn Arias, and Natalia Jimeno
renal function and six with severe renal
impairment. There were no differences in
aripiprazole pharmacokinetics in either
study.
Drugdrug interactions
Cocaine Six cocaine-dependent subjects
were given aripiprazole 15 mg/day and pla-
cebo for 10 days in counterbalanced order
before assessment of the physiological and
subject-rated effects of intranasal cocaine
[71c]. Intranasal cocaine produced proto-
typical stimulant-like effects (for example,
increased blood pressure and heart rate,
increased subject ratings of Like Drug and
Stimulated) and aripiprazole enhanced
these effects. The authors concluded that
although these results suggest that
aripiprazole is safe and tolerable when
combined with cocaine, enhancement of
the effects of cocaine during maintenance
is not desirable.
Metamfetamine The results of a double-
blind study of potential interactions of
intravenous metamfetamine (15 and
30 mg) with oral aripiprazole (15 mg) have
been published [72C]. The effects of
aripiprazole on abstinence-related craving
and cue-induced craving were also evalu-
ated. Participants included non-treatment-
seeking metamfetamine-dependent patients
who took aripiprazole (n 8) or placebo
(n 8) for 2 weeks. Aripiprazole had no
effect on cue-induced metamfetamine crav-
ing, but was associated with increased crav-
ing independent of metamfetamine dose,
euphoria, and amphetamine-like effects
after metamfetamine. Aripiprazole reduced
the increase in systolic blood pressure
after metamfetamine, but it had no other
effects on cardiovascular responses to
metamfetamine. Aripiprazole did not alter
the pharmacokinetics of metamfetamine.
The adverse events tended to be equally dis-
tributed between the two groups, except for
tremor (n 4) and restlessness (n 3),
which were more common in those who took
aripiprazole.
Clozapine [SED-15, 823; SEDA-30, 61;
SEDA-31, 78; SEDA-32, 94]
Comparative studies Clozapine and
olanzapine The efcacy and safety of cloza-
pine (300 mg/day; n 18) and olanzapine
(up to 30 mg/day; n 21) have been evalu-
ated in a 12-week double-blind study of
treatment-refractory children and adoles-
cents with schizophrenia aged 1018 years
[73C]. Signicantly more clozapine-treated
adolescents met response criteria (66%)
compared with the olanzapine-treated sub-
jects (33%); clozapine was also superior to
olanzapine in terms of reductions in the psy-
chosis cluster scores and negative symptoms
from baseline to end-point. Signicant weight
gain and metabolic abnormalities were major
problems associated with both treatments.
Five of 39 subjects (three taking clozapine
and two taking olanzapine) gained more than
7% of their baseline body weight, and nine
(four taking clozapine and ve taking
olanzapine) had newly emergent fasting tri-
glyceride concentrations over 1.24 mmol/l.
Furthermore, ve patients, all taking cloza-
pine, had serious adverse events and/or
discontinued treatment because of adverse
reactions neutropenia, upper bowel obstruc-
tion, increased thirst and polyuria, weight
gain (3.2 kg), and drug-induced diabetes (glu-
cose 8.0 mmol/l). Subsequently, 33 patients
(14 taking clozapine and 19 taking
olanzapine) were available for a 12-week
open extension study [74c]. The incidence of
hypertriglyceridemia, dened as fasting tri-
glycerides over 1.41 mmol/l (10/14), and the
incidence of prediabetes, dened as a fasting
blood glucose of 5.5 mmol/l or more (4/
14 29%), at week 24 in the clozapine-
treated subjects were high. However, 7 of 10
young patients with schizophrenia who failed
treatment with olanzapine responded in a 12-
week, open trial of clozapine.
Clozapine, olanzapine, and haloperidol In
a randomized, double-blind, parallel-group,
12 week study, 100 physically aggressive
in-patients with schizophrenia were given
clozapine (n 33), olanzapine, (n 34),
Antipsychotic drugs Chapter 6
or haloperidol (n 33) [75C]. Olanzapine
was associated with better cognitive func-
tion relative to haloperidol and clozapine,
and this improvement was associated with
a reduction in aggressive behavior. There
were no differences among the groups in
adverse effects, including sedation and
extrapyramidal effects; however, those
who took haloperidol were also given
benzatropine.
Cardiovascular Clozapine has been associ-
ated with venous thromboembolism. The
mortality rate associated with pulmonary
embolism has been estimated to be about
28 times higher than in the general popula-
tion of similar age and sex; it is not clear
whether pulmonary embolism can be attrib-
uted to clozapine or some characteristic of
its users [SEDA-28, 65]. A new case of pul-
monary embolism has been reported [76A].
A 45-year-old man became acutely confused
after taking an overdose of clozapine, which
he had previously been taking for 6 months.
He had acute dyspnea due to bilateral pulmo-
nary emboli. He was not overweight, but was
a heavy smoker; plasma concentrations of clo-
zapine are lower in smokers than in non-
smokers [SEDA-31, 81].
Hematologic Agranulocytosis, leukopenia,
and neutropenia associated with clozapine
have been extensively studied and
discussed [SED-15, 829; SEDA-32, 97].
A 55-year-old man developed neutropenia
after taking clozapine 750800 mg/day for
12 years [77A]. Valproic acid 1500 mg/day
had been added 2 years before. When
donepezil was added his white blood cell and
neutrophil counts fell.
Of 26 Korean children and adolescents
with refractory early-onset schizophrenia
(mean age 14 years) nine developed neutro-
penia; there was no agranulocytosis [78c].
Drugdrug interactions Benzodiazepines
In 152 patients who concomitantly took clo-
zapine and benzodiazepines from 2001 to
2006 there were no reports of deaths [79c].
103
Iloperidone
Iloperidone is a novel antipsychotic drug
which is a mixed dopamine D2/serotonin
5-HT2A receptor antagonist. In 2008, the
US Food and Drug Administration
required Vanda Pharmaceuticals, the man-
ufacturers, to carry out a comparison of
iloperidone with placebo and an active
comparator such as olanzapine or risperi-
done [80S]. It was nally approved in the
USA in May 2009.
Comparative studies Iloperidone has been
compared with haloperidol in patients with
schizophrenia using data from three
prospective multicenter studies, each with
a 6-week stabilization period followed by
a 46-week, double-blind, maintenance
phase [81M]. In all, 1644 patients were ran-
domized to iloperidone 416 mg/day or hal-
operidol 520 mg/day; of the 1326 patients
who completed the 6-week phase and who
improved, only 473 (iloperidone, n 359;
haloperidol, n 114) were included in the
long-term efcacy analysis; mean doses at
end-point were 12.5 mg/day in both groups.
Mean time to relapse was 90 (median 50)
days with iloperidone and 102 (median 78)
days with haloperidol; relapse rates were
slightly higher with iloperidone than with
haloperidol (44% and 41% respectively).
The adjusted mean change from baseline
to end-point in PANSS-T score (last obser-
vation carried forward) was  16.1 for
iloperidone and 17.4 for haloperidol. For
the safety analysis, a total of 489 patients
(iloperidone, n 371, mean age 35 years,
64.4% men; haloperidol, n 118, mean
age, 35 years, 60.2% men) were included.
In the maintenance phase, serious adverse
events were reported by 18% of patients
who took iloperidone and by 16% of those
who took haloperidol; exacerbation of psy-
chotic symptoms was the most frequent
adverse event (iloperidone, 11%; haloperi-
dol, 5.9%). Of all the patients who were eval-
uated, 224 (18%) of those who took
iloperidone were hospitalized, and there were
four deaths (0.3%); two other patients treated
with iloperidone died in the rst month after
104 Chapter 6 Alfonso Carvajal, Luis H. Martn Arias, and Natalia Jimeno
the study ended. Of those who took haloperi-
dol, 56 (14%) were hospitalized; there was
one death (0.2%). The most common adverse
events in the maintenance phase were insom-
nia (18%), anxiety (11%), and aggravated
schizophrenia (8.9%) with iloperidone; and
insomnia (17%), akathisia (14%), tremor
(13%), and muscle rigidity (13%) with halo-
peridol. Mean changes in Fridericia's QTc
interval at end-point were 10.3 ms for
iloperidone and 9.4 ms for haloperidol; meta-
bolic changes were minimal in both groups.
Placebo-controlled studies In a randomized,
placebo-controlled, multicenter study, with a
1-week titration period and a 3-week dou-
ble-blind maintenance period, 593 patients
with acute exacerbations of schizophrenia
were randomized to iloperidone 24 mg/day,
ziprasidone 160 mg/day as an active control,
or placebo [82C]. Like ziprasidone,
iloperidone produced signicant improve-
ment compared with placebo. Iloperidone
was associated with higher rates of weight
gain, tachycardia, orthostatic hypotension, diz-
ziness, and nasal congestion. There was
similar QT interval prolongation with both
active treatments, although no patient had
a treatment-emergent corrected QT in-
terval of 500 ms or greater. The incidence
of clinically relevant changes in labora-
tory parameters was comparable between
iloperidone and ziprasidone. Iloperidone
was associated with a low incidence of extra-
pyramidal symptoms.
Olanzapine [SED-15, 2598; SEDA-30,
64; SEDA-31, 81; SEDA-32, 99]
Observational studies The use of anti-
psychotic drugs in children and adolescents
is of particular concern. In a 24-week, mul-
ticenter, open study supported by Eli-Lilly,
the marketing authorization holder, 96 ado-
lescents with schizophrenic disorder (mean
age 16 years; 68% boys) were given
olanzapine 10 mg/day [83c]. BPRS scores
fell from baseline to week 6 by a mean of
17. The most common adverse events were
weight gain and increased prolactin. Weight
gain was observed in 29 patients; mean
weight gain from baseline to week 6 was
5.1 kg (n 76) and from baseline to
24 weeks 11.7 kg (n 32); the mean BMI
rose from 21.2 at baseline to 22.8 at week
6 and to 25.0 at week 24; 24 patients had
a 7% or greater weight gain. There were
higher-than-normal prolactin concentrations
(boys 16 mg/l; girls 29 mg/l) in 28% at baseline,
82% at week 2, and 59% at week 6; there was
a similar pattern of prolactin concentrations,
with a peak of 27 mg/l at week 4 in the boys
(n 58) and 45 mg/l in the girls (n 26).
One patient discontinued treatment because
of weight gain and one girl because of
galactorrhea.
In a prospective open trial in 40 boys with
autism (mean age 12 years) who took
olanzapine (mean dose 7.5, range 510 mg/
day) for 13 weeks, there were signicant
improvements in scores on the Aberrant
Behavior Checklist scale [84c]. Extrapyrami-
dal symptoms and dyskinetic symptoms did
not change from baseline to end-point.
There were no signicant increases in
hepatic enzymes or any serum chemistry.
There were transient mild adverse reactions
such as drowsiness and sedation, when treat-
ment was begun (13% of patients). Mean
body weight was 52.5 kg before treatment
and 52.8 kg after treatment.
In an open 6-week trial mean weight
increased by 4.1 kg (range 1.17.7 kg) in 12
children and adolescents with Tourette's syn-
drome (age range 714 years; 11 boys) [85c].
Of 278 adults (mean age 36 years, 180
men) with acute psychosis and agitation,
148 took oral olanzapine monotherapy
(mean dose 12 mg/day); only mild adverse
events were observed, including brady-
cardia, dry mouth, sedation, hypertension,
hypotension, and orthostatic hypertension
(one case each) [86c].
Comparative studies Olanzapine and clo-
zapine The efcacy and safety of clozapine
(300 mg/day; n 18) and olanzapine (up to
30 mg/day; n 21) have been evaluated in
a 12-week double-blind study of treatment-
refractory children and adolescents with
schizophrenia aged 1018 years [73C].
Antipsychotic drugs Chapter 6
Signicantly more clozapine-treated adoles-
cents met response criteria (66%) compared
with the olanzapine-treated subjects (33%);
clozapine was also superior to olanzapine in
terms of reductions in the psychosis cluster
scores and negative symptoms from baseline
to end-point. Signicant weight gain and
metabolic abnormalities were major prob-
lems associated with both treatments. Five
of 39 subjects (three taking clozapine and
two taking olanzapine) gained more than
7% of their baseline body weight, and nine
(four taking clozapine and ve taking
olanzapine) had newly emergent fasting tri-
glyceride concentrations over 1.24 mmol/l.
Furthermore, ve patients, all taking cloza-
pine, had serious adverse events and/or
discontinued treatment because of adverse
effects: neutropenia, upper bowel obstruc-
tion, increased thirst and polyuria, weight
gain (3.2 kg), and drug-induced diabetes
(glucose 8.0 mmol/l). Subsequently, 33
patients (14 taking clozapine and 19 taking
olanzapine) were available for a 12-week
open extension study [87C]. The incidence
of hypertriglyceridemia, dened as fasting
triglycerides over 1.41 mmol/l (10/14), and
the incidence of prediabetes, dened as a
fasting blood glucose of 5.5 mmol/l or more
(4/14 29%), at week 24 in the clozapine-
treated subjects were high. However, 7 of
10 young patients with schizophrenia who
failed treatment with olanzapine responded
in a 12-week, open trial of clozapine.
Olanzapine and clozapine were effective
in a 6-month, double-blind study in treat-
ment-resistant schizophrenia patients [88c]
who were randomized to olanzapine mean
dose 34 mg/day (n 19) or clozapine mean
dose 564 mg/day (n 21). Mean weight
gain was 1.6 kg in patients taking clozapine
and 7.2 kg in those on olanzapine; there
was no signicant relationship between
olanzapine dose and change in weight.
Olanzapine and droperidol In a ran-
domized non-blinded clinical trial, patients
attending an emergency department for pri-
mary headache were given either intramus-
cular droperidol 5 mg (n 42) or off-label
olanzapine 10 mg (n 45). There were no
signicant differences between the groups
105
in measures of efcacy, nausea, or akathisia
[89c].
Olanzapine and lithium Chinese patients
with bipolar manic or mixed episodes were
randomized to olanzapine (mean daily dose
18 mg/day; mean age 31 years; n 69) or
lithium carbonate (mean daily dose
1110 mg/day; mean age 34 years; n 71)
for 4 weeks in a multicenter, double-blind,
controlled study [90c]. Patients in both
groups improved in different psychopatho-
logical assessments. Treatment-emergent
adverse events during the study occurred
in 55% with olanzapine and 42.3% with
lithium; the most common events with
olanzapine were constipation (13%), nau-
sea (7.2%), and somnolence (7.2%); with
lithium they were nausea (13%) and
nasopharyngitis (5.6%). More of those
who took olanzapine reported adverse
events relating to the following MedDRA
system organ classes: metabolism and nutri-
tion disorders (olanzapine 5.8%; lithium
1.4%), nervous system disorders
(olanzapine 13%; lithium 5.6%), and psy-
chiatric disorders (olanzapine 5.8%; lithium
0.0%). There were no serious adverse
events or deaths during this study; one
patient taking lithium withdrew because of
abnormal hepatic function. Mean weight
increased during the 4-week study in both
groups but was signicantly higher with
olanzapine (1.85 kg versus 0.73 kg). In
addition, signicantly more of those who
took olanzapine had a clinically signicant
weight increase (7% of baseline weight)
compared with lithium (16% versus 2.9%).
The blood glucose concentration increased
in one patient taking olanzapine (baseline:
5.6 mmol/l; end-point: 10.8 mmol/l) and
total cholesterol increased in four patients
(three taking olanzapine and one taking
lithium).
Olanzapine, quetiapine, and risperidone In
two studies olanzapine, quetiapine, and ris-
peridone had similar efcacies in patients
with psychoses but differed in adverse
effects.
In a comparative study, 75 in-patients
with schizophrenia were randomized to
106 Chapter 6 Alfonso Carvajal, Luis H. Martn Arias, and Natalia Jimeno
olanzapine (mean dose at end-point 15 mg/
day; mean age 35 years; n 25),
quetiapine (mean dose at end-point
590 mg/day; mean age 39 years; n 25),
or risperidone (mean dose at study end-
point 5.1 mg/day; mean age 43 years;
n 25) [91c]. After 8 weeks, there were
signicant clinical improvements in all
treatment arms, with no signicant differ-
ences. There were 14 withdrawals: ve on
olanzapine, four on quetiapine, and ve
on risperidone. At the nal visit there was
a 7% increase in baseline body weight
in 8%, 8%, and 29% with quetiapine, ris-
peridone, and olanzapine respectively.
Extrapyramidal symptoms were signi-
cantly worse with risperidone than both
olanzapine and quetiapine at week 3 and
compared with quetiapine thereafter.
In the Child and Adolescent First-Epi-
sode Psychosis Study (CAFEPS), a longitu-
dinal multicenter study, 110 patients aged
917 years were treated for a rst psychotic
episode [92c]. Only patients who received
one antipsychotic drug from baseline to
6 months of follow-up were included in
the safety analysis (risperidone, n 50;
quetiapine, n 18; olanzapine, n 16).
Using the baseline score as a co-variate,
there were no signicant differences in the
reductions in any of the four clinical scales
in patients who took risperidone, quetiapine,
or olanzapine for 6 months. As expected,
olanzapine caused signicantly greater gains
in weight and BMI than the other two drugs
(mean body weight gain 12 kg for olanzapine
versus 6.0 kg for quetiapine and 6.1 kg for
risperidone; mean BMI increase 3.9 for
olanzapine versus 1.4 for quetiapine and 1.9
for risperidone), even after controlling
for initial weight or BMI. The percentage
of patients with hypokinesia/akinesia was
signicantly higher with risperidone than
with olanzapine or quetiapine (50% versus
15% and 13%); there was dystonia in one
patient taking risperidone.
Olanzapine and risperidone Atypical anti-
psychotic drugs are occasionally used
off-label for obsessive symptoms. From an
initial sample of 96 Italian patients with
obsessivecompulsive disorder who
underwent a 16-week rst phase of treat-
ment with SSRIs, 50 were judged to be
resistant and were randomized to addi-
tional risperidone (mean age 36 years;
mean daily dose 2.1 mg; n 25) or
olanzapine (mean age 34 years; mean daily
dose 5.3 mg; n 25) in an 8-week, single-
blind, second phase [93c]. Adverse experi-
ences were reported by 52% of those who
took additional risperidone and 64% of
those who took olanzapine; adverse events
motivated withdrawal in two patients tak-
ing olanzapine (reduced sexual desire and
weight gain).
Placebo-controlled studies Subjects with
borderline personality disorder (n 314)
have been treated off-label with olanzapine
(modal dose 7.1 mg/day) in a 12-week ran-
domized, double-blind, placebo-controlled
trial [94C]. Olanzapine and placebo pro-
duced similar signicant improvements,
but time to response was signicantly
shorter with olanzapine. Withdrawal rates
because of adverse events were 11% for
both olanzapine and placebo. Increased
appetite and weight gain were signicantly
greater with olanzapine (mean weight gain
2.8 kg versus  0.4 kg); olanzapine also pro-
duced signicantly larger increases in
fasting total cholesterol, fasting LDL choles-
terol, total and direct bilirubin, hepatic
enzymes, and prolactin. There were serious
adverse events in 15 patients: six taking
olanzapine (suicidal ideation, n 4;
aggression, agitation, alcoholism, drug mis-
use, impulsive behavior, self-mutilation,
and self-injurious ideation, n 1 each)
and nine taking placebo (suicidal ideation,
n 4; aggression, anxiety, exacerbation of
borderline personality disorder symptoms,
n 2 each; and depressed mood, fatigue,
and weight reduction, n 1 each).
Increased appetite and signicantly more
weight gain (2.7 kg versus 0.1 kg) were also
found in 42 patients with pathological gam-
bling who were randomized in a 12-week
study to olanzapine (mean dose 8.9 mg/
day) or placebo [95c].
Antipsychotic drugs Chapter 6
In a double-blind, placebo-controlled
study, 34 patients with anorexia nervosa
were randomly assigned to either
olanzapine plus day-hospital treatment
(n 16) or placebo plus day-hospital treat-
ment (n 18) [96c]. At 10 weeks, body
weight had increased in both groups,
although the achievement of target body
mass index was greater and earlier in those
who took olanzapine.
Cardiovascular Clozapine, which is close
related to olanzapine, has been implicated
as an independent susceptibility factor for
pulmonary embolism [SEDA-28, 65]. A
possible association between olanzapine
and pulmonary thromboembolism has also
been described [SEDA-32, 102]. New cases
have been reported [97A, 98A].
A 47-year-old woman with schizophrenia was
found dead in her apartment. She had been
taking lithium and olanzapine. Autopsy
showed an acute pulmonary embolus in the
left main pulmonary artery, with extension
into the lobar branches and an adherent
thrombus in the left popliteal vein. There
was no evidence of other pathology. Post-
mortem toxicology conrmed the presence of
olanzapine and showed no other substances.
There were no other risk factors, such as obe-
sity, a sedentary lifestyle, a history of smoking,
recent trauma or immobilization, use of estro-
gens, or a family history of thrombotic events;
factor V Leiden and prothrombin mutations
were negative.
In previous cases, identied by specic
searching, one subject had two known risk
factors for pulmonary embolism (obesity
and a recent ankle fracture), one had one
risk factor (obesity), and three had none.
A 23-year-old man, not overweight, a smoker of
1 pack/day, with an early-onset schizoaffective
disorder was given olanzapine 20 mg/day, par-
oxetine 20 mg/day, and valproate 2000 mg/
day. After 12 weeks, he suddenly developed
back pain radiating to the left anterosuperior
part of the thorax; over the next few hours he
became dyspneic and had an episode of hemop-
tysis. Arterial blood gases were normal. Bilat-
eral pulmonary embolism was conrmed by a
CT scan. Olanzapine was withdrawn and oral
anticoagulation was given for 6 months. As his
psychotic symptoms recurred 12 weeks
later, he was given risperidone 3 mg/day and
107
3 weeks later had a second episode of pulmo-
nary embolism, which was attributed to non-
adherence to the anticoagulant treatment.
However, 16 weeks later he had a third episode;
following exhaustive investigations, anti-
psychotic drugs (olanzapine and risperidone)
remained the most probable causal factor.
He improved with anticoagulation and
amisulpride 400 mg/day. Paroxetine 20 mg/day
and valproate 2 g/day were maintained
throughout these episodes.
Nervous system Abnormality of P300
waveforms of event-related potentials has
been suggested to represent an aspect of
the pathophysiology of schizophrenia; low
resolution electromagnetic tomography
analysis (LORETA) has been used to
obtain current density images of P300 in 16
patients with schizophrenia taking
olanzapine and 16 healthy controls [99c].
The patients had signicantly smaller
LORETA values in several brain regions
on the left side, particularly in the superior
temporal gyrus, middle frontal gyrus, and
precentral gyrus, than control subjects. After
treatment for 6 months with olanzapine the
P300 source density increased signicantly
only in the left superior temporal gyrus,
suggesting positive changes in cortical activ-
ity; however, the small sample size pre-
cluded rm conclusions.
Drug withdrawal Switching patients from
one antipsychotic drug to another is a com-
mon practice; three strategies for changing
olanzapine to risperidone have been
assessed in a 6-week, randomized, open
study in 123 patients with schizophrenia or
schizoaffective disorder: (i) an abrupt strat-
egy, in which olanzapine was withdrawn
when risperidone was started; (ii) a gradual
strategy, in which olanzapine was given at
50% entry dose for 1 week after risperi-
done was started and then discontinued;
and (iii) a very gradual strategy, in which
olanzapine was given at 100% entry dose
for 1 week, then at 50% in the second
week, and then withdrawn [100c]. All-cause
treatment withdrawal was lowest (12%) in
those with the slowest olanzapine dosage
reduction; adverse events accounted for
withdrawal in 5% of patients on the abrupt
108 Chapter 6 Alfonso Carvajal, Luis H. Martn Arias, and Natalia Jimeno
and very gradual strategies, and in 15% of
those on the gradual strategy.
Management of adverse drug reactions In
a second phase of the previous study, 71
patients with a BMI over 26 kg/m2 were
enrolled in a weight-loss program while
taking risperidone and randomly assigned
to 14 weeks of a behavioral treatment pro-
gram for weight reduction (n 34) or
usual care (risperidone modal dose
4.5 mg/day; n 37), there was signicant
weight loss in both treatment groups after
14 weeks: mean changes were 2.0 kg in
the subjects enrolled in the behavioral pro-
gram and 1.1 kg in the control group
[100c]. The authors concluded that specic
weight-loss behavioral programs might pre-
vent weight gain associated to olanzapine.
Paliperidone
Paliperidone, or 9-hydroxyrisperidone, is
the major active metabolite of risperidone.
It binds to both dopamine D2 and serotonin
5-HT2A receptors, and antagonism at these
receptors is thought to account for its ther-
apeutic activity in schizophrenia. It was
approved by the US Food and Drug
Administration in 2007 for acute and main-
tenance treatment of schizophrenia; it is
available in modied-release tablets. The
available literature on the pharmaco-
dynamics, pharmacokinetics, clinical ef-
cacy, and tolerability of paliperidone has
been extensively reviewed [101R].
Placebo-controlled studies Paliperidone
modied-release, quetiapine, and placebo
have been compared in patients with
recently exacerbated schizophrenia requir-
ing hospitalization in a 6-week double-blind
study [102C]. In-patients were randomly
assigned to paliperidone modied-release
(n 160), quetiapine (n 159), or pla-
cebo (n 80). A 2-week monotherapy
phase was followed by a 4-week additive-
therapy phase; target doses were at the
upper end of the recommended ranges:
paliperidone modied-release, 9 or 12 mg/
day, and quetiapine, 600 or 800 mg/day.
Six-week completion rates were 78% with
paliperidone modied-release, 67% with
quetiapine, and 64% with placebo.
Improvement in mean PANSS total change
score was greater with paliperidone
modied-release than with quetiapine from
day 5 (11 versus 8.2) to the mono-
therapy phase end-point (23.4 versus
17.1). At the 6-week end-point, there
was signicantly greater improvement with
paliperidone than quetiapine or placebo,
despite similar use of additive therapy (pre-
dominantly other antipsychotic drugs).
Over the entire study period, serious
adverse events were reported by 13
(8.2%) patients taking paliperidone, 7
(4.4%) taking quetiapine, and 2 (2.5%) tak-
ing placebo; the most common adverse
event was schizophrenia (3.8%, 1.9%, and
0.0% respectively). There were signicantly
higher values for changes in prolactin with
paliperidone; the values at end-point were
32, 6.7, and 4.5 ng/ml respectively.
Elderly patients with schizophrenia
(mean age 70 years; n 114) who took
paliperidone in a 6-week double-blind, pla-
cebo-controlled study followed by a 24-
week open extension with paliperidone
(mean doses 7.4 and 8.5 mg/day respec-
tively) treatment-emergent adverse events
were similar (71% with placebo and 67%
with paliperidone), as were withdrawal
rates because of adverse events (8% and
7% respectively) [103c]. There were serious
adverse events in three patients taking pla-
cebo and in two taking paliperidone (acute
coronary syndrome and mania, n 1
each); there was also an age-related
increase in the incidence of somnolence.
There was a higher incidence of tachycardia
with paliperidone in both phases, increases
being more pronounced in patients aged
7075 years compared with those aged
6469. There was prolongation of the QTc
interval to over 500 ms in the rst phase,
leading to discontinuation (n 2), and in
the second phase (n 1); these three
patients had histories of QT interval
Antipsychotic drugs Chapter 6
prolongation. In the double-blind phase,
there were raised prolactin concentrations
in 45% of the men and 49% of the women
taking paliperidone, but they returned to
normal at the end of the study; prolactin
concentrations also rose in patients taking
paliperidone who had previously taken pla-
cebo. The incidence of extrapyramidal
symptoms was low throughout the study;
during the second phase, medication for
treatment of this effect was used in 27%
and 22% respectively.
In a re-analysis of different short-term
studies, the efcacy and tolerability of modi-
ed-release paliperidone have been assessed
in patients with acute schizophrenia [104M].
Patients were randomly allocated to
paliperidone 3 mg/day (n 123), 6 mg/day
(n 234), 9 mg/day (n 245), 12 mg/day
(n 240), 15 mg/day (n 113), or placebo
(n 351); mean ages were 3639 years. All
doses of paliperidone were signicantly bet-
ter than placebo. There were treatment-
emergent adverse events in 6677% in those
who took paliperidone and in 6% of those
who took placebo; serious adverse events
occurred in 56% of patients in all groups,
the most common being exacerbation of psy-
chotic symptoms. Orthostatic hypotension
occurred from 1% at 6 mg/day to 4% at
12 mg/day. A higher proportion of patients
assigned to paliperidone above 6 mg/day
had extrapyramidal symptoms; one patient
with a previous history of tardive dyskinesia
with clozapine had an episode after taking
paliperidone for 4 days. Glucose-related
adverse events were reported in both groups
(paliperidone, 1%; placebo, 1%). Mean
body weight increased by 0.6 kg with
paliperidone 3 mg/day and 1.9 kg with
15 mg/day, and fell by 0.4 kg with placebo.
Median prolactin concentration increases
were larger among women (81 ng/ml)
than men (24 ng/ml) when all paliperidone
groups were combined; the magnitude
of this effect increased with increasing
drug doses and there were prolactin-related
adverse events in 12% of patients taking
paliperidone 312 mg and 4% of those tak-
ing 15 mg. There were no deaths, cases of
109
neuroleptic malignant syndrome, or other
severe symptoms.
Cardiovascular Paliperidone has been
associated with seizures and atrial brilla-
tion [105A].
A 46-year old man with bipolar disorder, dia-
betes mellitus, hypertension, hyperlipidemia,
and tobacco use took metformin hydrochlo-
ride 2 g/day, insulin glargine 64 units/day,
insulin lispro 44 units/day, simvastatin 20 mg/
day, enalapril maleate 5 mg/day, escitalopram
30 mg/day, lamotrigine 200 mg/day, and
clonazepam 2 mg as needed. Owing to stress
at work, he was given paliperidone 3 mg
orally on day 1 and 6 mg/day thereafter.
After 4 days he had a possible tonicclonic sei-
zure, a headache, palpitation, and mild dys-
pnea. An electrocardiogram showed atrial
brillation, a ventricular rate of 151/minute, a
QTc interval of 461 ms, and no signicant
changes in the ST segment or T wave. Sinus
rhythm recurred after the administration of
single oral doses of potassium chloride
20 mmol and diltiazem 10 mg. The heart rate
and QTc interval normalized to 68/minute
and 392 ms.
In this case pharmacogenetic testing revealed
CYP2D6 alleles *4 and *10 and CYP3A4
alleles *16B and *1F, which are associated
with poor-to-intermediate CYP2D6 activity
and reduced CYP3A4 activity in vitro.
Drugdrug interactions In September 2008,
the FDA Center for Drug Evaluation and
Research changed the information in the
section included in the safety labelling of
paliperidone [106S], as follows:
Potential for Invega (paliperidone) to affect
other drugs Paliperidone is a weak inhibitor
of P-glycoprotein at high concentrations. No
in vivo data are available and the clinical rele-
vance is unknown.
Potential for other drugs to affect Invega
In vitro studies have shown that paliperidone
is a P-glycoprotein substrate.
Co-administration of Invega 6 mg once
daily with carbamazepine 200 mg twice
daily caused a decrease of approximately
37% in the mean steady-state Cmax and
AUC of paliperidone.
110 Chapter 6 Alfonso Carvajal, Luis H. Martn Arias, and Natalia Jimeno
Quetiapine [SED-15, 2995; SEDA-30,
67; SEDA-31, 87; SEDA-32, 104]
Quetiapine has been approved in the USA
for the treatment of schizophrenia in ado-
lescents aged 1317 years, bipolar mania
in children and adolescents aged
1017 years, and as adjunctive therapy for
treatment of major depressive disorder
[107S].
Observational studies In 477 patients with
schizophrenia (mean age 38 years), who
were switched from their medication to
quetiapine (mean median dose 575 mg/
day) because of insufcient efcacy (66%)
or insufcient tolerability (34%) in a 12-
week, multicenter, open-label study
supported by AstraZeneca, the marketing
authorization holder of quetiapine common
adverse events included somnolence
(18%), sedation (15%), and dizziness and
dry mouth (14% each), and extrapyramidal
symptoms (8.0%) [108C]. There were
higher glucose concentrations both at base-
line (n 8) and end-point (n 12). The
mean body weight change was 1.0 kg.
In a 12-week, open, exible-dose study
of quetiapine in 40 out-patients with gener-
alized anxiety disorder who had not
achieved remission after at least 8 weeks
of adequate doses of standard therapy, the
most common adverse reactions were seda-
tion (n 29), dry mouth (n 12), and sex-
ual dysfunction (n 10) [109c]. Mean total
weight gain from pre-treatment to week 12
was about 0.5 kg and 14% of patients had
a 7% weight gain. Seven patients withdrew
because of adverse events: sedation
(n 5), panic attacks (n 1), and bilateral
iritis (n 1).
Adverse reactions to quetiapine have
been studied in 13 children aged
1012 years, 14 adolescents aged
1317 years, and 29 adults, mean age
37 years, with a psychotic disorder, in a
study that was supported by AstraZeneca,
the marketing authorization holder;
quetiapine was titrated up to 400 mg/day
over 12 days [110c]. None of the children
withdrew because of adverse events, two
had dyskinesias, dizziness, and somnolence
and required dosage reduction. The most
common adverse events were somnolence
(26%), orthostatic hypotension (22%), diz-
ziness (15%), and sedation (7.4%); the
heart rate increased by more than 145/
minute in four patients. One of the adults
withdrew because of agitation, and there
were treatment-related adverse events in
19, including orthostatic hypotension (about
50%), dizziness (45%), anxiety (24%), leth-
argy (21%), and dry mouth and insomnia
(both 17%); the heart rate increased by
more than 120/minute in 17 patients; all
hematological tests were within the refer-
ence ranges.
Quetiapine has been used in very small
numbers of patients for off-label indications:
prevention of migraine (75 mg/day; mean
age 39 years; n 34) [111c] and cocaine
dependence (mean dose 429 mg/day; mean
age 47 years; n 22) [112c]. In the rst study
the most common adverse events, which
occurred in nine patients, were worsening
headache, drowsiness, somnolence, increased
appetite, weight gain, and nausea. In the
second study, all the subjects had seda-
tion at some time during treatment, and
several dropped out because of it; weight
increased signicantly and other reactions
were dry mouth, orthostatic faintness, and
constipation.
Comparative studies Quetiapine and lith-
ium In a 4-week, multicenter, double-blind
study, Chinese patients with bipolar mania
were randomized to quetiapine (mean
dose, 648 mg/day; mean age, 33 years; n
77) or lithium (mean serum concentration
0.80 mmol/l; mean age 34 years; n 77)
[113c]. The proportion of patients with at
least one adverse event during the study
was higher with quetiapine (78%) than lith-
ium (69%). The most common (5%)
adverse events with quetiapine were consti-
pation (35%), dizziness (15%), diarrhea
(10%), increased alanine aminotransferase
(9.0%), bouts of palpitation (9.0%), in-
creased aspartate aminotransferase (7.7%),
pharyngolaryngeal pain (6.4%), upper respi-
ratory tract infections (6.4%), and dry mouth
Antipsychotic drugs Chapter 6
(5.1%). In those who took lithium the most
common adverse events were nausea (17%),
constipation (13%), vomiting (13%),
nasopharyngitis (12%), dizziness (6.5%),
diarrhea (6.5%), and upper respiratory tract
infections (6.5%); one patient had bone mar-
row depression and three had adverse events
(pruritus, vomiting, and depressed level of
consciousness and dizziness) that led to with-
drawal. Tachycardia, bradycardia, and minor
conduction block occurred in both groups.
There were transient increases in hepatic
enzyme activities in ve patients taking
quetiapine and in two taking lithium. There
were high blood glucose concentrations in
three patients in each group. Mean weight
gain was 1.5 kg with quetiapine and 0.3 kg
with lithium. Extrapyramidal symptoms (dys-
tonia, akathisia, tremor, and extrapyramidal
disorder) were similar with quetiapine
(5.1%) and lithium (6.5%).
Quetiapine and risperidone In a 12-month
multicenter, non-randomized study in
patients with acute schizophrenia who were
given quetiapine (mean age 37 years; mean
dose 719 mg/day; n 367) or risperidone
(mean age 36 years; mean dose 7.0 mg/
day; n 125), serious adverse events with
quetiapine (n 3) were death by suicide,
tachycardia, and dystonia; and with risperi-
done (n 3), severe rigidity/dysphagia,
sedation, and acute dystonia [114C]. Ortho-
static hypotension was more frequent with
quetiapine than with risperidone (14% ver-
sus 6.7%); male sexual dysfunction (loss of
libido 22% versus 11%; erectile dysfunction
21% versus 9.4%; and impaired ejaculation
18% versus 6.9%) were more common with
risperidone. Extrapyramidal symptoms
(including rigidity and hypokinesia)
occurred in 33% and there were no signi-
cant differences between the two groups
in female sexual dysfunction, somnolence,
constipation, reduced salivation, headache,
dyspepsia, tachycardia, or weight gain.
Quetiapine and valproate In a 12-month
comparison of quetiapine (mean dose
465 mg/day; n 22) and valproate (mean
dose 720 mg/day; n 16) in patients with
rapid-cycling bipolar disorder, orthostatic
111
dysregulation (59% versus 19%) and seda-
tion (50% versus 6%) were the most fre-
quent adverse events [115c]. Other effects
were dry mouth (27% versus 13%) and
headache (23% versus 19%). Adverse
events were the most frequent reason for
discontinuation only in the quetiapine
group. Adverse events leading to with-
drawal in patients taking quetiapine
included abnormal electroencephalo-
graphic signs of arousal, suicide attempt,
and lymphedema (one each), and body
weight changes (mean 4.5 kg in patients
taking quetiapine and 2.7 kg in those taking
valproate).
Drug abuse [SEDA-30, 68; SEDA-32,
107] Quetiapine abuse has again been
described [116A].
A 29-year-old man reported that the local
police were disturbing his sleep by electroni-
cally monitoring his testicles; he also said he
had schizophrenia and was being treated with
quetiapine 600 mg nightly. He received his
usual dose and slept soundly. The next
morning he was still somnolent without
thought or mood disturbance. His urine toxi-
cology screen was negative. A pharmacy
review revealed that he had received different
and excessive amounts of quetiapine from sev-
eral sources during the past few months. On
confrontation, he admitted both excessive use
and sale of quetiapine.
Risperidone [SED-15, 3052; SEDA-30,
69; SEDA-31, 90; SEDA-32, 107]
In a review of the use of risperidone in
autistic disorder in children and adolescents
it was stressed that somnolence, increased
appetite, increased prolactin concentrations,
and fatigue were the most common adverse
events [117R].
Observational studies In an open study,
232 children and adolescents (mean age
11 years) with disruptive behavioral disor-
ders were followed during 1 year in an
extension period with risperidone, having
been previously randomized to risperidone
112 Chapter 6 Alfonso Carvajal, Luis H. Martn Arias, and Natalia Jimeno
or placebo in a double-blind, 6-month with-
drawal study [118C]. Weight gain and extra-
pyramidal symptoms (most frequently
dystonia, n 7) were each reported by 10
subjects. Prolactin concentration increased
with risperidone; median prolactin concen-
trations at baseline were 237 mU/l in
women and 175 mU/l in men; at end-point
the values were 356 and 238 mU/l respec-
tively. There was gynecomastia in two men
and transient dysmenorrhea in one woman.
Twenty had serious adverse events, includ-
ing psychiatric aggravation in 10.
In a retrospective study of male delin-
quents, mean age 16 years, with childhood
onset and persistent conduct disorder
treated either with psychosocial treatment
and risperidone (mean dose 2.5 mg/day; n
60) or cognitive-behavioral treatment
alone (n 69), the most common adverse
events in the patients taking risperidone
were somnolence (26%), weight gain
(18%), increased appetite (17%), and con-
stipation (14%); mean body weight
increased by 6.8 kg during a mean time of
9 months [119c].
Comparative studies Risperidone and
divalproex In a retrospective study of 28
patients aged 514 years with bipolar disor-
der who had been treated with risperidone
(n 16) or divalproex (n 12), risperi-
done was associated with faster clinical
improvement and signicantly more weight
gain than divalproex (mean changes 2.46 kg
versus 0.43 kg); however, the small sample
size precluded denitive conclusions [120c].
Risperidone and haloperidol In a 24-week
study (12-week double-blind and 12-week
open), 28 children and adolescents with
autistic disorder were treated either with
risperidone (mean age 10 years; n 13)
or haloperidol (mean age 11 years; n 15),
both in doses of 0.010.08 mg/kg/day [121c].
There were signicant mean weight gains
from baseline to end-point (4.2 kg with ris-
peridone and 6.3 kg with haloperidol).
However, there were no signicant differ-
ences in weight and prolactin concentra-
tions between the two groups at end-point.
Other common events were constipation
(risperidone 29%; haloperidol 23.1%) and
nocturnal enuresis (20% and 23%
respectively).
There were greater increases in prolactin
concentrations with risperidone in a 12-
week, double-blind study, in which children
and adolescents with autistic disorder were
assigned to either risperidone (mean age
10 years; n 15) or haloperidol (mean
age 11 years; n 15); the mean doses were
2.6 mg/day for both drugs [122c].
Combination studies Herbal preparations
are occasionally used as adjunctive treat-
ments to antipsychotic drugs. In an 8-week,
randomized, double-blind, placebo-con-
trolled study of warm-supplementing kid-
ney yang capsule 2.7 g/day added to
risperidone in 200 patients with schizophre-
nia [123c]. Performance on the Wisconsin
Card Sorting Test was signicantly higher
in the group of patients taking the combina-
tion than in those taking placebo; there
were no signicant differences in adverse
events; tremor, akathisia, weight gain, and
insomnia occurred in more than 10% of
patients in both groups.
Placebo-controlled studies In 86 non-
psychotic patients who presented with
aggressive challenging behavior from 10
centers in England and Wales and one in
Queensland, Australia, who were randomly
assigned to haloperidol (n 28), risperi-
done (n 29), or placebo (n 29), aggres-
sion was substantially reduced by all three
treatments after 4 weeks; the placebo group
showed the greatest change (a median
reduction in the modied overt aggression
scale score) after 4 weeks of 9 for placebo
(79% from baseline); 7 for risperidone
(58% from baseline); and 6.5 for haloperi-
dol (65% from baseline) [124c]. There were
no important differences between the treat-
ments, including adverse effects; patients
who took placebo had no evidence at any
time of a worse response than patients
who had been assigned to either of the anti-
psychotic drugs. The authors suggested that
antipsychotic drugs should no longer be
regarded as acceptable in the routine
Antipsychotic drugs Chapter 6
treatment for aggressive challenging behav-
ior in people with intellectual disabilities.
The authors of an accompanying editorial
pointed out that the sample size in this
study was impressive, in view of the practi-
cal, legal, and cultural problems associated
with recruitment for such research [125r].
Off-label uses of risperidone have been
assessed in two studies. In a double-blind
study, elderly patients with depression
resistant to citalopram, who had previously
responded to adjunctive therapy with
risperidone, where randomly allocated to
continue with adjunctive therapy with ris-
peridone (modal dose 0.8 mg/day; n 32)
or to receive placebo (n 31) [126c]. Three
patients taking risperidone reported
headache.
In a 12-week, double-blind study,
cocaine-dependent men were randomized
to risperidone (n 16) or placebo (n
15); mean weight changes were 2.9 kg
and 0.2 kg respectively, one patient tak-
ing risperidone withdrew because of tardive
dyskinesia [127c].
Nervous system Impaired sensorimotor
function was observed in 33 antipsychotic
drug-nave patients with schizophrenia
after they were given risperidone (n 29)
or olanzapine (n 4); mean doses at 6
and 26 weeks were 3.9 and 3.2 mg/day for
risperidone and 11.3 and 15 mg/day for
olanzapine [128c].
Drug formulations Long-acting injectable
risperidone is commonly used in patients
with psychoses. There have been two stud-
ies sponsored by Janssen Cilag, the risperi-
done marketing authorization holder. In
the rst, an observational study in 842 indi-
viduals (mean age 41 years), 27% had with-
drawn after 6 months because of adverse
events (mean dose at end-point 36 mg)
[129c].
In the second study, which lasted 2 years,
long-acting injectable risperidone (n 50)
was compared with oral risperidone
(n 47) and haloperidol (n 47) [130c].
Prolactin-related adverse events occurred
in four of those who received injectable ris-
peridone (galactorrhea in one; amenorrhea
113
and galactorrhea in two; amenorrhea
and delayed menses in one); there was one
case of menorrhagia with haloperidol and
one case of gynecomastia with oral risperi-
done. The percentage of dropouts for any
reason was 20% for injectable risperidone
compared with 49% for the oral
medications.
In 529 patients (mean age 39 years)
treated with long-lasting injectable risperi-
done (modal dose 25 mg), the median
time to discontinuation was 16 months
[131C]. A total of 13% (n 69) withdrew
because of an adverse event, including
disease exacerbation and delirium
(n 4 each); mean body weight increased
by 1.0 kg from baseline to end-point; glu-
cose-related events were reported by four
patients. The most common treatment
adverse events were anxiety (24%), insom-
nia (19%), weight increase (14%), depression
(11%), exacerbation of disease (10%), head-
ache (7.7%), relapse (7.4%), tremor (6.0%),
and weight reduction (5.5%); 94 patients
gained >7% of their body weight and six
reported pain or injection-site reactions.
In 50 patients with newly diagnosed
schizophrenia (mean age 25 years) who
were treated with injectable risperidone
2550 mg every 2 weeks for 2 years [132c],
prolactin concentrations increased in 18
patients, four of whom reported possible
prolactin-related adverse events (amenorrhea
in one; galactorrhea in one; amenorrhea and
galactorrhea in one; amenorrhea and
delayed menses in one). Mean increase in
body mass index was 4.8 kg/m2; 10 subjects
required anticholinergic medication, and
one developed persistent dyskinesia.
Management of adverse reactions The
herbal preparation Peony-Glycyrrhiza
Decoction 45 g/day for 4 weeks increased the
efcacy of bromocriptine 5 mg/day in reducing
risperidone-induced hyperprolactinemia in 20
women with hyperprolactinemia (serum pro-
lactin concentration >50 mg/l), who were
currently experiencing oligomenorrhea or
amenorrhea; one patient withdrew after
taking bromocriptine for 5 days because of
worsening of facial acne [133c].
114 Chapter 6 Alfonso Carvajal, Luis H. Martn Arias, and Natalia Jimeno
Sertindole [SED-15, 3120; SEDA-30, 72;
SEDA-32, 110]
Cardiovascular Sertindole has been associ-
ated with prolongation of the QT interval
in clinical trials; it was withdrawn from the
market because of an excessive relative
reporting rate of sudden deaths in 1998
and then re-introduced in 2001 in Europe
under certain restrictions [SEDA-26, 66].
Some re-analyses, sponsored by H
Lundbeck A/S, the marketing authorization
holder, have been published [134c, 135c];
they have not added any substantial infor-
mation to that already published from the
European Sertindole Safety and Exposure
Survey [SEDA-32, 110].
Ziprasidone [SED-15, 3721; SEDA-30,
72; SEDA-31, 94; SEDA-32, 111]
Observational studies Numerous open stud-
ies of ziprasidone promoted by Pzer, the
marketing authorization holder, have previ-
ously been published [SEDA-32, 111] and
further studies, similarly promoted, have
emerged. Of 185 subjects who were switched
from olanzapine or risperidone to
ziprasidone, 72 completed a 1-year extension
study [136c]. The most common adverse
effects were insomnia (23%) and somnolence
(11%); no patient had a corrected QT inter-
val over 500 ms at any time during the study.
In 63 subjects aged 1017 years in an
open study of oral ziprasidone, consisting
of a 3-week xed-dose period and a subse-
quent 24-week exible-dose period,
adverse effects occurred mostly during dose
titration and in the high-dose (160 mg/day)
group [137c]. The most common adverse
effects during the rst period were sedation
(32%), somnolence (30%), and nausea
(25%), and during the exible-dose period
sedation (30%), somnolence (30%), and
headache (25%). The incidences of move-
ment disorders were 22% and 16% during
the rst and second periods. Adverse
effects caused withdrawal in 6%
during the xed-dose period and in 20%
in the exible-dose period. One-third
gained 7% of their baseline weight.
There were no changes in Fridericia-
corrected QT intervals by more than
60 ms from baseline.
In 70 patients with schizophrenia and per-
sistent symptoms or troublesome adverse
effects who were assigned to a exible dos-
age (40160 mg/day) in a 12-month open
trial of ziprasidone looking for cognitive
improvement, there were signicant
improvements in executive functions, atten-
tion, and information processing domains,
but the effect sizes were moderate [138c].
Cardiovascular It is unknown to what
extent QT interval prolongation due to
ziprasidone increases cardiovascular risk;
particular attention has been devoted to
sudden death [SEDA-31, 95]. In an open,
randomized, postmarketing study
(the Ziprasidone Observational Study of
Cardiac OutcomesZODIAC), whose pri-
mary outcome measure was the rate of mor-
tality, 18 094 patients with schizophrenia
were randomly assigned to either
ziprasidone or olanzapine [139c]. Baseline
data suggested that this population had a
substantial prevalence of cardiovascular risk
factors, and concomitant medications were
often used, but no other data were released.
Zotepine
Sexual function Spontaneous ejaculation
related to zotepine therapy has been
reported, supposedly for the rst time
[140c].
A 38-year-old man with schizophrenia was
given a combination of zotepine 100 mg/day
and haloperidol ester 100 mg every 2 weeks
and complained of spontaneous ejaculation,
which became more severe when the dosage
of zotepine was increased to 150 mg/day.
Zotepine was discontinued and the spontane-
ous ejaculation no longer occurred with halo-
peridol monotherapy. A combination of
haloperidol 100 mg every 2 weeks and
quetiapine was then used, and spontaneous
ejaculation did not recur.
Antipsychotic drugs Chapter 6
Zuclopenthixol [SED-15, 3722;
SEDA-32, 112]
Placebo-controlled studies The effects of
zuclopenthixol on aggressive behavior in
patients with intellectual disabilities have
previously been investigated [SEDA-32,
112], and a secondary parameter analysis
of the results of this study has been
published [141R]. After open treatment with
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 Gaetano Zaccara and Luciana Tramacere
7 Antiepileptic drugs
GENERAL
Clinicians have only recently realized that
chronic adverse effects of antiepileptic
drugs, mainly those involving central ner-
vous system, may be more disabling to the
patient than the seizures themselves. Up
to a few years ago, the historical belief that
seizure frequency is the major determinant
of health-related quality of life and that
adverse reactions are merely a secondary
end-point was the prevalent opinion. It
has been shown that changes in seizure rate
among patients with drug-resistant epilepsy
are only modestly correlated with quality of
life, while adverse reactions and depression
are critical determinants of subjective
health status [1C].
Observational studies In an attempt to
dene specic patterns of adverse reactions
and their clinical relevance to subjective
health status, 200 subjects with epilepsy
completed validated self-report health
assessments, including the Adverse Event
Prole and Quality of Life in Epilepsy
Inventory (QOLIE)-89 [sic] [2C]. The mean
number of adverse reactions per subject
was 6.5. Factor analysis segregated all
adverse reactions into ve classes:
cognition/coordination;
mood/emotion;
sleep;
weight/cephalalgia;
tegument/mucosa.
Side Effects of Drugs, Annual 33
J.K. Aronson (Editor)
ISSN: 0378-6080
DOI: 10.1016/B978-0-444-53741-6.00007-6
# 2011 Elsevier B.V. All rights reserved.
Higher scores in each adverse reaction
class were associated with lower QOLIE-89
scores, and Cognition/Coordination scores
were the strongest predictor. A subgroup of
62 subjects met criteria for a prospective ran-
domized trial on the value of using the
Adverse Event Prole score in clinical man-
agement. They were randomly assigned to a
group in which treating physicians had
access to adverse events prole scores at
each visit or to another group in which
these data were not made available.
Improvements in Cognition/Coordination,
Mood/Emotion, and Tegument/Mucosa
scores were associated with improvements
in QOLIE-89 scores and improved Cogni-
tion/Coordination was the only predictor of
improved QOLIE-89.
Using a questionnaire to assess com-
plaints of adverse reactions to antiepileptic
drugs, an active intervention policy has
been studied in a randomized controlled
study in 111 adults with epilepsy who had
had moderate to severe complaints [3C].
Drug therapy was either continued
unchanged (n 58) or adjusted by reduc-
ing the dose or switching to other anti-
epileptic drug (n 53). After 7 months,
the relative chance of improvement in qual-
ity of life was 1.80 (1.043.12) for the inter-
vention group compared with the controls
and the relative chance of a reduction in
the number of complaints was 1.34 (0.88
2.05).
Different strategies for detecting adverse
effects have been compared in a cross-sec-
tional epidemiological study in standard
clinical practice in 579 patients: spontane-
ous reporting by the patient and a checklist
of possible treatment-related adverse reac-
tions completed by the patient34%
reported adverse reactions spontaneously
125
126
and 65% did so through the checklist [4C].
Signicant adverse reactions were an
important reason for modifying treatment
in patients who reported higher degrees of
discomfort.
In an open, long-term, observational
study, retention in the study, the percent-
age of patients who withdrew because of
adverse events, and the percentage of
patients who achieved seizure freedom
were assessed in 1066 epileptic patients tak-
ing lamotrigine (n 336), levetiracetam
(n 301), or topiramate (n 429) in a sin-
gle epilepsy center [5C]. Two-year retention
rates were 69%, 46%, and 38% respectively.
Seizure freedom rates were lowest for lamo-
trigine and highest for levetiracetam. The
numbers of patients who withdrew because
of adverse events were 154/429 (36%) with
topiramate, 52/336 (15%) with lamotrigine,
and 68/301 (23%) with levetiracetam.
The technique of event symmetry analysis
has been used to identify adverse reactions
from a population of 479 000 subjects [6C].
All prescription data from the Odense Uni-
versity Pharmacoepidemiological Database
for the period August 1990 to December
2006 and diagnoses from the County Hospi-
tal register for the period 1994 to 2006
were used. The method assesses the distribu-
tion of disease entities and prescription of
other drugs, before and after antiepileptic
treatment, as asymmetry in these distribu-
tions may indicate adverse reactions
to antiepileptic drugs. All incident anti-
epileptic drug users during the study period
(n 24 882) were identied. Known adverse
events (for example, constipation, nausea,
hyponatremia, and osteoporosis) were
detected. Unanticipated signals from analy-
sis without any preselection of drugs and
diagnoses were the association of topiramate
with dopaminergic agents, of gabapentin
with glaucoma, and of valproic acid with
hypothyroidism.
Studies of the contribution of specic
adverse reactions to impaired health-related
quality of life have been reviewed [7R].
Cardiovascular Major atherogenic risk
factors among epileptic children, including
altered metabolism of homocysteine,
Chapter 7 Gaetano Zaccara and Luciana Tramacere
disordered lipid proles, and increased
lipoprotein(a) serum concentrations, as
well as thyroid hormone deciency, with
particular emphasis on the clinical implica-
tions, have been reviewed [8R].
Measurement of intima media thickness
at the wall of the common carotid artery by
B mode ultrasonography has been per-
formed in 195 patients taking long-term anti-
epileptic drugs and 195 healthy age- and
sex-matched control subjects [9C]. The
intima media thickness was signicantly
increased in patients with epilepsy, more in
men than in women. Furthermore, whereas
body mass index, homocysteine, C-reactive
protein, and thiobarbituric acid reactive
substances were signicantly raised,
folic acid and thiols were signicantly
reduced in the patients with epilepsy. In
addition, the log-transformed common
carotid artery intima media thickness
increased linearly with duration of anti-
epileptic drug therapy after adjustments
for age, sex, and thiobarbituric acid reactive
substance concentration.
Total plasma homocysteine concentrations
and other cardiovascular risk factors
have been evaluated in 60 children taking
long-term carbamazepine or valproate [10c].
Plasma total homocysteine, urine methyl-
malonic acid, and lipoprotein(a) were signi-
cantly higher in children taking these drugs
than in controls. Lower serum vitamin B12,
serum folate, and ApoB were also found in
children taking antiepileptic drugs. High
homocysteine concentrations were signi-
cantly associated with urine methylmalonic
acid.
Psychological Children with new-onset,
idiopathic epilepsy have been evaluated at
baseline and at 6 months (n 45) and 12
months (n 31) after starting antiepileptic
drug therapy [11c]. Cognitive functioning
after 12 months of treatment was signi-
cantly improved. However, there was a
transient drop in performance of children
with generalized seizures after the 6
months, which may have been caused by
persistent seizures or by the drug used
(mainly ethosuximide). There was also
worsening of reaction time and reaction
Antiepileptic drugs Chapter 7
time variability in those with focal seizures
at 12 months, which was attributed to the
medications used, mainly carbamazepine.
The clinical aspects of the cognitive adverse
effects of antiepileptic drugs have been
reviewed [12R]. In an overview of studies that
highlighted cognitive evaluation in adults and
children with epilepsy, it emerged that
although aspects of cognitive dysfunction, risk
factors, and consequences have been investi-
gated in many studies, the mechanisms of
contribution of epilepsy-related variables,
including antiepileptic drugs, to patients cog-
nition have largely been unexplored [13R].
The differential effect of antiepileptic drugs
on mature and immature brains and the
mechanisms that underlie epilepsy and the
adverse effects of antiepileptic drugs on cog-
nition are discussed.
Suicidality and antiepileptic
drugs
Up to a few years ago, the association
between the risk of suicidal ideation and
behavior and the use of antiepileptic drugs
had been explored in very few studies. In
an observational study of 517 consecutive
patients taking levetiracetam, four (0.7%)
reported suicidal ideation [14C]. The inci-
dence of suicidal ideation and behavior
resulting from antiepileptic drug exposure
in clinical trials is unknown, because most
published data group all psychiatric adverse
events together rather than reporting suicid-
ality by itself [15R, 16R, 17R].
In 2005, in a sponsor's report of a double-
blind study, there was a slightly higher risk
of suicidality in the antiepileptic drug-treated
patients compared with those taking placebo
and there were also reports of suicidality
related to the branded formulation of gaba-
pentin [18r].
These data prompted the US Food and
Drug Administration (FDA) to reanalyse
all data on the risk of suicide in controlled
studies of antiepileptic drugs.
127
In January 2008, the FDA issued an alert
that a meta-analysis had shown a signi-
cantly increased risk of suicidality associated
with all antiepileptic drugs. Suicidality
occurred in 4.3 per 1000 patients taking anti-
epileptic drugs in the active arm compared
with 2.2 per 1000 patients in the comparison
arm [19S]. This represents a risk difference
of 2.1 per 1000 (95% CI 0.7, 4.2). This
analysis had grouped data from 199 ran-
domized clinical trials, including 43 892
patients with epilepsy, psychiatric disorders
and other disorders, predominantly pain.
Eleven drugs had been evaluated: carba-
mazepine, felbamate, gabapentin, lamotri-
gine, levetiracetam, oxcarbazepine,
pregabalin, tiagabine, topiramate, valproate,
and zonisamide.
For many clinicians, the FDA alert was
particularly surprising, because antiepileptic
drugs were considered to be a class (dened
as all drugs that share the ability to reduce
the frequency of seizures) despite their dif-
ferent mechanisms of action, and conse-
quently all of them were considered to be
associated with this risk. This procedure
has been criticized. In fact, analyses for sin-
gle antiepileptic drugs were also done and
showed a signicant protective effect on sui-
cidality for carbamazepine and divalproex
while all other antiepileptic drugs had odds
ratios greater than 1, indicating an
increased risk, although the increase
reached statistical signicance only with
lamotrigine (OR 2.08; 95% CI 1.03,
4.40) and topiramate (OR 2.53; 95% CI
1.21, 5.85). Other methodological prob-
lems should be considered. For example,
the FDA included only 33% of these trials
in the main analysis, because trials without
reports of suicidality were excluded.
It has also been considered that although
the question of suicidality with these drugs is
controversial, the adverse effects of failing to
control epilepsy are not. If antiepileptic drugs
are less frequently prescribed or taken, sei-
zure control may worsen, with associated
increases in accidents and mortality, or sud-
den unexplained death from seizures [20R].
In a large study of people with epilepsy it
has been reported that 21% had an accident
128
during the study, of which 24% were seizure-
related [21C]. Sudden unexpected death in
epilepsy (SUDEP) occurs in 0.352.7 per
1000 people with epilepsy in population-
based studies [22R] and is more common in
people with uncontrolled seizures [23R].
Even if the FDA analysis is correct, the risk
of suicidality, predominantly suicidal idea-
tion, is only 3.4/1000 in people with epilepsy
taking the 11 antiepileptic drugs.
The rate of completed suicides in the gen-
eral population is 12.0/100 000 [24C], with
a marked predominance in men [25C],
while the lifetime prevalence of suicide
attempts is 0.64.9% overall [26C], with a
preponderance in women. Epilepsy is co-
morbid with suicidality [27C] and with
major depression [28C]. After a diagnosis
of epilepsy, the risk of completed suicide
increases: the overall standardized mortality
ratio ranges from 3.5 to 5.0 and is higher in
the presence of a known psychiatric diagno-
sis [29C]. In addition, suicidal ideation and
behavior have been identied as psychiatric
phenomena in patients with drug-resistant
epilepsy [30C].
After the FDA alert, several reviews ana-
lysed data on the association between suicidal-
ity and psychiatric compliance in patients with
epilepsy, and hypotheses have been proposed.
For example, it has been suggested that forced
normalization, although rare, may be an epi-
lepsy-related process that could result in
increased suicidality [31C]. It consists of the
development of depressive or psychotic epi-
sodes in patients who become seizure-free after
having suffered chronic drug-resistant epilepsy
[32C].
This alert can be expected to cause con-
cern among patients and family members.
Accordingly, clinicians should provide a
comprehensive explanation of the alert,
describing this drug-related suicidality risk
in the context of the complexity of suicidality
in this disease [33R, 34r, 35r].
It is likely that in the future a prospective
investigation of suicidality in every regula-
tory trial will be required, and it is also pos-
sible that patients will need to be screened
for suicidality, depression, and anxiety
before randomization [36R].
Chapter 7 Gaetano Zaccara and Luciana Tramacere
The reaction of neurologists to the FDA
alert concerning suicidal ideation or behav-
ior and antiepileptic drugs has been
explored in a study of 175 of 780 partici-
pants who answered a questionnaire via e-
mail on the approach to suicidality and
depression in patients with epilepsy [37c].
Although 98% warned about behavioral
adverse effects when starting antiepileptic
drugs, only 44% warned specically about
suicidal ideation or behavior. More than
half were not aware of patients who
attempted to commit suicide or who had
committed suicide.
In 47 918 patients with bipolar disorder
suicide attempt rates were studied before
and after treatment with antiepileptic drugs
and the results were compared with a medi-
cation-free control group [38C]. There was
no signicant difference in suicide attempt
rates in patients taking an antiepileptic drug
(13 per 1000 person-years) compared with
patients not taking an antiepileptic drug or
lithium (13 per 1000 person-years). In anti-
epileptic drug-treated subjects, the rate of
suicide attempts was signicantly higher
before treatment (72 per 1000 person-years)
than after treatment (13 per 1000 person-
years). In patients taking no concomitant
treatment with an antidepressant or an anti-
psychotic drug, antiepileptic drugs were sig-
nicantly protective relative to no drug
treatment (3 per 1000 versus 15 per 1000 per-
son-years). The authors concluded that in this
population of patients, the use of antiepileptic
drugs reduces suicide attempt rates.
There has been a longitudinal, retrospec-
tive cohort study of all individuals who
obtained anticonvulsants (valproic acid, car-
bamazepine, oxcarbazepine, or lamotrigine;
n 9952) or lithium (n 6693) from 1995
to 2001, and who also obtained anti-
psychotic drugs at least once [39C]. Among
the patients who obtained an antipsychotic
drug at least once during the study period,
more consistent purchasing of anticonvul-
sants (at least 6 prescriptions) was associated
with a substantial reduction in the risk of
suicide compared with individuals who
received only a single anticonvulsant
prescription.
Antiepileptic drugs Chapter 7
Metabolism The relation between weight
gain and the homeostatic hormones leptin
and insulin has been explored in 70 treated
and 20 untreated patients with epilepsy
[40C]. Body mass index, serum leptin, and
serum insulin were signicantly raised in
patients taking valproate compared with
untreated patients and those taking carba-
mazepine or lamotrigine. In those taking
valproate, serum insulin correlated with
body mass index, leptin, treatment dura-
tion, and drug dosage, and serum leptin
correlated with age, body mass index,
serum insulin, treatment duration, and drug
and valproate dosage.
Liver The pathogenesis and clinical charac-
teristics of drug-induced liver injury associ-
ated with antiepileptic drugs has been
reviewed [41R]. Reactive metabolites can,
in some cases, lead to direct cytotoxicity
and liver cell necrosis, whereas in other
cases they can cause neoantigen formation,
inducing immunoallergic mechanisms. In
fact, hypersensitivity features are found in
more than 70% of patients with pheny-
toin-induced liver injury, whereas this is
only observed in 30% of carbamazepine-
associated hepatotoxicity and very rarely
with valproate-induced liver injury. No spe-
cic therapy is of proven value in these
cases. However, carnitine, which is an
important co-factor in mitochondrial beta-
oxidation of fatty acids, is recommended
in valproate-associated liver injury, and N-
acetylcysteine is an appropriate treatment
in patients with liver injury due to pheny-
toin and carbamazepine. Liver transplanta-
tion may be required for patients with the
most severe liver reactions.
Skin The clinical and laboratory ndings of
anticonvulsant hypersensitivity syndrome
have been retrospectively evaluated using
the medical records of 31 patients over a 12-
year period [42C]. The syndrome was related
to carbamazepine in 48% of all cases, phe-
nytoin in 35%, and lamotrigine in 9.6%,
and in co-treatment with lamotrigine and
valproic acid in 6.5% of cases. Symptoms
appeared at 286 (mean: 36) days after the
start of treatment. The rashes were
129
maculopapular and/or erythrodermic in
77% of patients, bullous in 19%, and erythe-
matopustular in 3.2%. Fever and peripheral
lymphadenopathy were detected in 61%
and 55% of cases respectively. Hepatic
enzymes were raised in 71% and there was
a leukocytosis in 43% and a peripheral eosin-
ophilia in 64%.
Musculoskeletal Hip bone mineral density
was measured in 4222 older community-
dwelling men at baseline and at an average
of 4.6 years later, of whom 62 were
taking enzyme-inducing antiepileptic drugs,
100 were taking non-enzyme-inducing anti-
epileptic drugs, and 4060 were taking no
antiepileptic drugs [43C]. The average rate
of change in total hip bone mineral density
was  0.35%/year among non-users com-
pared with  0.53%/year among users of
non-enzyme-inducing antiepileptic drugs
and 0.46%/year among users of enzyme-
inducing antiepileptic drugs. In these old
people, the use of non-enzyme-inducing
antiepileptic drugs was independently asso-
ciated with increased rates of hip bone loss.
Bone mineral density has been assessed
in 96 children with epilepsy taking anti-
epileptic drugs and in 63 healthy children
and adolescents [44c]. There was abnormal
bone mineral density in 56, with values doc-
umenting osteopenia in 42 and osteoporosis
in 14. There was a signicant difference
between patients with epilepsy and con-
trols. Lack of autonomous gait, severe men-
tal retardation, a long duration of
antiepileptic drug treatment, topiramate
adjunctive therapy, and less physical activ-
ity correlated signicantly with abnormal
bone mineral density.
In a casecontrol study using data from a
hip fracture register of a US county with a
population of almost 500 000 inhabitants,
7557 patients were admitted to county hospi-
tals with a hip fracture [45C]. Controls (n
27 575) were frequency matched by age
and sex. Fracture risk was increased with
ever use of any antiepileptic drug. The risk
was also increased in those who used only
enzyme-inducing drugs, and not in those
who used non-inducing antiepileptic drugs.
130
Fracture risk was higher with recent use and
high daily dosages.
The adverse effects on bone caused by
chronic anticonvulsant drug therapy have
been reviewed [46R].
Bone mineral density at the left femoral
neck and spine has been measured in 130
Thai patients with epilepsy who had been
taking long-term antiepileptic drugs, either
as monotherapy (n 79) or polytherapy
(n 51) [47c]. Bone mineral density at the
femoral neck had a mean Z-score of
0.15 and at the lumbar spine 0.56.
There was osteopenia in the spine in 31
patients and in the femoral neck in 30.
Three patients had osteoporosis of the
spine and one had osteoporosis of the fem-
oral neck.
In a cross-sectional observational study of
the effects of antiepileptic drug treatment on
vitamin D status and markers of bone turn-
over in 38 children with epilepsy, the results
were compared with those obtained in 44
healthy controls [48c]. More than 75% of
the patients were vitamin D decient and
21% had insufcient vitamin D. Serum con-
centrations of osteocalcin and bone alkaline
phosphatase were signicantly raised, but
the concentrations of C terminal telopeptide
of type I collagen were signicantly reduced.
There were signicantly lower concentra-
tions of vitamin D and C terminal telopep-
tide of type I collagen and higher activities
of bone alkaline phosphatase in those taking
polytherapy.
Sexual function The effects of oxcarbaz-
epine monotherapy on sexual function have
been studied in 673 men with partial epi-
lepsy [49C]. In 181 (79%) of 228 patients
with pre-existing impairment, sexual func-
tion improved; 23 had no impairment at
the nal visit. The improvements were most
marked in patients who stopped taking
enzyme-inducing antiepileptic drugs after
starting to take oxcarbazepine. The authors
suggested that enzyme induction has nega-
tive effects on sexual function and that sub-
stitution with less inducing drugs may be
benecial.
Chapter 7 Gaetano Zaccara and Luciana Tramacere
Teratogenicity The mental and motor
developmental quotients of 395 infants of
mothers with epilepsy have been prospec-
tively evaluated [50C]. Infants not exposed
to antiepileptic drugs (n 32) had a higher
mental developmental quotient (mean 92;
95% CI 81, 103) and motor developmen-
tal quotient (mean 95; 95% CI 85, 105)
than those who had been exposed to anti-
epileptic drugs (mean 89; 95% CI 86, 92
and mean 90; 95% CI 87, 93 respec-
tively). Those exposed to polytherapy had
signicantly lower developmental quotients
than those exposed to monotherapy. On
multiple regression analysis, polytherapy
was a stronger predictor of lower develop-
mental quotients than dosage. Valproate
monotherapy was associated with signi-
cantly lower mental and motor develop-
mental quotients.
All births delivered in Norway from 1999
to 2005 (n 372 128) have been analysed,
and 2805 pregnancies in women with a cur-
rent or past history of epilepsy (0.8%) and
362 302 pregnancies in women without a
history of epilepsy were selected [51C].
Women with epilepsy had an increased risk
of mild pre-eclampsia and delivery before
week 34. Antiepileptic drugs were used in
233 of the pregnant women with epilepsy
(94%). These patients had an increased risk
of mild pre-eclampsia, gestational hyper-
tension, vaginal bleeding late in pregnancy,
and delivery before 34 weeks of gestation.
There was no signicant increase in the risk
of these complications in women with epi-
lepsy who were not using antiepileptic
drugs.
All 2861 deliveries by women with epilepsy
recorded in Norway in a certain period were
compared to all 369 267 non-epilepsy deliver-
ies observed in the same period [52C]. Most of
those with epilepsy (n 1900) did not use
antiepileptic drugs during pregnancy, while
in 961 pregnancies there was exposure. Com-
pared with non-epilepsy controls, antiepilep-
tic drug-exposed infants were signicantly
more often preterm and more often had low
birth weights (<2500 g), low head circum-
ferences (< 2.5 percentile), and low Apgar
scores. The frequency of major congenital
malformations was 2.8% (n 81) in the
Antiepileptic drugs Chapter 7
epilepsy group versus 2.5% in the controls.
An increased risk of major malformations
could be demonstrated only for exposure to
valproate (5.6%) and polytherapy (6.1%).
Cesarean section was performed more
often in maternal epilepsy, regardless of drug
exposure.
The use of antiepileptic drugs in 4798
pregnancies in women with epilepsy has
been prospectively studied using data from
38 countries. Exposure to second-genera-
tion antiepileptic drugs ranged from 3.5%
in India and 7.3% in Italy to 75% in Den-
mark. The use of second-generation drugs
has increased over time (for lamotrigine,
from 9.9% of all pregnancies before 2001
to 30% after 2003) [53C].
In an interim analysis of cognitive out-
comes at 3 years of age in 309 children whose
mothers who took a single antiepileptic
agent (carbamazepine, lamotrigine, pheny-
toin, or valproate) during pregnancy in the
USA and the UK, children who had been
exposed to valproate had signicantly lower
IQ scores than those who had been exposed
to other antiepileptic drugs [54C]. After
adjustment for maternal IQ, maternal age,
antiepileptic drug dosage, gestational age at
birth, and maternal preconception use of
folate, the mean IQ was 101 in children
exposed to lamotrigine, 99 in those exposed
to phenytoin, 98 in those exposed to
carbamazepine, and 92 in those exposed
to valproate. The association between
valproate use and IQ was dose-related. This
nding supports a recommendation that
valproate should not be used as a rst-choice
drug in women of childbearing potential.
The consequences of exposing fetuses to
antiepileptic drugs during pregnancy have
been discussed in several reviews and cor-
respondences [55R, 56r, 57R, 58R, 59R, 60R].
All new information on the teratogenic
effects of the most frequently used anti-
epileptic drugs has been reviewed [61R].
The prevalence of major congenital malfor-
mations associated with exposure to carba-
mazepine or lamotrigine was only
marginally increased from expected, while
malformation rates with valproate have been
reported to be 24 times higher. This adverse
outcome appears to be dose-related.
131
Furthermore, exposure to valproate in utero
seems to be associated with poorer postnatal
cognitive development.
The available evidence on the manage-
ment of women with epilepsy during preg-
nancy, including the risk of pregnancy-
associated complications or other medical
problems, have been discussed by a commit-
tee of the American Academy of Neurology
[62S, 63S]. For women with epilepsy taking
antiepileptic drugs, there is probably no sub-
stantially increased risk of cesarean delivery
or late pregnancy bleeding, and probably
no moderately increased risk of premature
contractions or premature labor and deliv-
ery. However, smoking may increase the
risk. Seizure freedom for at least 9 months
before pregnancy is probably associated with
a high likelihood (8492%) of remaining
seizure-free during pregnancy. Preconcep-
tional folic acid supplementation was possi-
bly effective in preventing major congenital
malformations in the children of women with
epilepsy taking antiepileptic drugs [64S, 65S].
Supplementation with vitamin K was not
considered useful, because there is no evi-
dence of an increased risk of hemorrhagic
complications.
Lactation Concerning transfer of anti-
epileptic into breast milk, it was judged that
primidone and levetiracetam transfer into
breast milk in clinically important amounts,
and that valproate, phenobarbital, pheny-
toin, and carbamazepine probably are not
transferred in clinically important amounts
[64S, 65S]. During pregnancy, there is an
increase in the clearance of lamotrigine,
phenytoin, and to a lesser extent carbamaz-
epine, and possibly reduced concentrations
of levetiracetam and of the active metabo-
lite of oxcarbazepine. Supplementing with
at least 0.4 mg of folic acid before preg-
nancy and monitoring lamotrigine, carba-
mazepine, and phenytoin concentrations
and probably also levetiracetam and the
monohydroxy derivative of oxcarbazepine
is recommended.
Susceptibility factors Genetic Genetic pre-
dictors of susceptibility to adverse reactions
132
to antiepileptic drugs and their molecular
mechanisms have been reviewed [66R].
Drug overdose Of 16 796 toxic exposures
to antiepileptic drugs (phenytoin, valproic
acid, and carbamazepine) in the USA in
2006, 12 resulted in death, as reported by
the US Toxic Surveillance System [67c].
Some specic problems determined by over-
dose of some old and new antiepileptic
drugs have been briey reviewed. For exam-
ple, topiramate can cause a signicant meta-
bolic acidosis, lamotrigine StevensJohnson
syndrome, oxcarbazepine hyponatremia,
and levetiracetam psychosis. Possible adop-
tion of guidelines for critical care manage-
ment of overdose are discussed.
Drugdrug interactions In a pharmaco-
epidemiological study, the likelihood of rel-
evant drug interactions of antiepileptic
drugs with other drugs has been analysed
through inspection of a medical and phar-
maceutical claims database. All the data of
adults with epilepsy and taking any anti-
epileptic drug during the period from 1 July
2001 to 31 December 2004 were extracted
and analysed for concomitant non-anti-
epileptic drugs used after the start of
antiepileptic drug therapy. Concomitant
medications were used in every age group
and use increased with age in both men
and women. Polypharmacy with non-anti-
epileptic drug medications was common in
both men and women and was not unique
to elderly patients with epilepsy. These
ndings suggest that clinicians must be
mindful of potential interactions of anti-
epileptic and non-antiepileptic drugs in
patients of all age groups [68C].
Interactions of antiepileptic drugs with
drugs that are usually prescribed in the
postsurgical care of transplant recipients
have been reviewed [69R].
The possible adverse consequences of
CYP isoenzyme induction have been
reviewed and the authors suggested that
new treatment for epilepsy be started with
non-inducing antiepileptic drugs unless
there is a clear indication for one of the
inducing drugs [70R].
Chapter 7 Gaetano Zaccara and Luciana Tramacere
Management of adverse drug reactions
The clinical characteristics and treatment
of the anticonvulsant hypersensitivity syn-
drome have been reviewed. Treatment with
N-acetylcysteine and intravenous immuno-
globulin is suggested. The rationale for this
relies on the scavenging properties of N-
acetylcysteine and on modulation of the
over-reactive immune system by immuno-
globulin [71R].
Carbamazepine [SED-15, 627; SEDA-
30, 78; SEDA-31, 107; SEDA-32, 126]
Observational studies In a long-term,
open, observational study, the long-term
retention rate and adverse effects of carba-
mazepine (n 105) were evaluated and
compared with topiramate (n 41) in
infants and toddlers with epilepsy [72c].
After 6 months, 73% of those who had
been treated with topiramate and 63% of
those who had been treated with carbamaz-
epine were improved. Topiramate was
withdrawn because of adverse effects in
only one case (2.4%), whereas carbamaze-
pine was withdrawn because of adverse
effects in 6.7% of patients.
Comparative studies Carbamazepine and
oxcarbazepine as adjunctive therapy in 52
patients with bipolar I and bipolar II affec-
tive disorder taking lithium maintenance
treatment have been compared in an 8-
week, double-blind, randomized, parallel-
group, single-center study [73c]. Several
adverse events were signicantly more fre-
quent with carbamazepine: sedation (n
16), increased appetite (n 13), weight gain
(n 11), tremor (n 5), constipation (n
3), nausea/vomiting (n 3), dry mouth (n
2), and insomnia (n 2). Hyponatremia,
hypertension, tachycardia, diplopia, rush,
and electrocardiographic abnormalities
were not observed.
Systematic reviews A systematic analysis
of seven randomized controlled trials
assessing the comparative efcacy of
Antiepileptic drugs Chapter 7
carbamazepine and lithium in the treatment
of acute mania and in the maintenance
phase of bipolar disorder has been per-
formed [74M]. In three acute studies with-
drawals due to adverse effects and the
numbers of subjects with at least one
adverse effect were not different between
carbamazepine and lithium. In four studies
of maintenance treatment the number of
withdrawals because of adverse effects was
signicantly higher with carbamazepine.
Cardiovascular A retrospective electrocar-
diographic study in elderly patients (>65
year old) with newly diagnosed epilepsy
and randomized to sustained-release carba-
mazepine or lamotrigine in 108 patients
who had been previously included in an
international randomized double-blind, 40-
week trial, excluding patients with signi-
cant unpaced atrioventricular conduction
defects, there were no signicant changes
in QRS duration or QT intervals between
baseline and treatment visit, but heart rate
fell and PQ intervals increased slightly with
both treatments. There were no differences
between the groups in changes from base-
line to treatment visit and no relations
between individual electrocardiographic
changes and serum drug concentrations,
except for QTc intervals, which shortened
slightly with increasing carbamazepine
concentrations.
Respiratory Acute interstitial pneumonitis
with atypical features has been attributed
to carbamazepine in a patient with post-
herpetic neuralgia [75A].
Nervous system Drug-resistant hyperten-
sion with leukoencephalopathy might have
been due to carbamazepine [76A].
A 21-year-old man who took carbamazepine
for idiopathic trigeminal neuralgia for several
days developed arterial hypertension (from
110/60 to 170/126 mmHg) followed by distur-
bance of consciousness. An MRI scan showed
transient hyperintense lesions in the bilateral
fronto-parieto-occipital subcortical white mat-
ter, suggesting the presence of vasogenic
edema caused by hypertension. Despite the
administration of various antihypertensive
133
drugs, the blood pressure improved only after
withdrawal of carbamazepine.
A lesion in the splenium of the corpus cal-
losum occurred 10 days after sudden carba-
mazepine withdrawal and resolved 2
months later; this could have been coinci-
dental [77A].
Endocrine The effects of long-term carba-
mazepine (n 18) and valproate (n 14)
on thyroid function in newly diagnosed
children with epilepsy have been evaluated
in a prospective open comparison with 32
sex- and age-matched controls [78c]. At
baseline evaluation, thyroid function was
normal. At the 3rd, 6th, and 12th month
evaluations, patients taking carbamazepine
had serum thyroxine (T4) and free thyrox-
ine (fT4) concentrations signicantly lower
than baseline and control subjects; valpro-
ate had no such effect.
In a prospective, randomized study of
thyroid function in 160 men and women
with epilepsy both before and after dou-
ble-blind withdrawal of antiepileptic drug
monotherapy, serum samples were
obtained from 130 [79C]. After drug with-
drawal, there were signicant increases in
free thyroxine serum concentrations in
those who had taken carbamazepine.
Metabolism A role of carbamazepine in
the pathogenesis of hyperammonemia was
suspected in a 26-year-old man with bipolar
disorder [80A].
A 26-year-old man with bipolar disorder, sei-
zures, and mild mental retardation, who had
started taking carbamazepine for aggression
and seizure control 3 weeks before, developed
severe agitation and aggressive behavior.
Other medications, which had been stable for
at least 6 months, included topiramate, olanza-
pine, quetiapine, guanfacine, and desmopres-
sin acetate. All laboratory examinations and
vital signs were normal. The serum carbamaz-
epine concentration was 3.9 mg/l and serum
ammonia 127 (reference range 1960) mg/l.
Carbamazepine was withdrawn and he was
given oral lactulose. His serum ammonia con-
centration returned to normal after 4 days.
This patient had previously a raised serum
ammonia concentrations while taking valproic
acid.
134
Serum leptin and insulin concentrations
have been measured in 56 epileptic patients
who had been on monotherapy with carba-
mazepine for at least 6 months and in 42
control healthy subjects [81c]. Body mass
index and leptin and insulin concentrations
were not different in those taking carba-
mazepine compared with controls.
Hematologic It has been suggested that
carbamazepine may have caused a fatal
case of anaplastic large cell lymphoma in a
73-year-old man with diabetic neuropathy
and rapidly progressive erythematous skin
lesions [82A].
Skin Drug reactions with eosinophilia and
systemic symptoms (DRESS) in patients
taking carbamazepine have been reported
[83A]. Involvement of internal organs was
often characterized by liver injury [84A,
85Ar].
In four cases drug hypersensitivity syn-
drome was triggered by carbamazepine in
the presence of concomitant active human
herpesvirus (HHV-6), demonstrated by
positive PCR for viral DNA and an
increased anti-HHV-6 IgG titer. In one of
these patients, drug-specic lymphocytes
were detected by a lymphocyte transforma-
tion test when the virus was active. Further-
more, two genetic factors previously
associated with intolerance to carbamaze-
pine were detected: the allele HLA-A*3101
(a genetic variant of human leukocyte anti-
gen) and a homozygous variant allele of
SNP rs1051740 of the peroxide hydrolase
gene [86c]. One patient with carbamazepine
hypersensitivity syndrome had a strongly
positive prick and patch skin tests 6
weeks after complete recovery. The useful-
ness of skin tests in diagnosing carbamaze-
pine-induced DRESS has been emphasized
[87A].
A 34-year-old man with epilepsy who was tak-
ing valproic acid and phenobarbital was also
given carbamazepine and 34 days later devel-
oped hyperthermia and cervical lymph-
adenopathy and subsequently a generalized
cutaneous eruption (exfoliative conuent mac-
ules and papules) [88A]. The white cell count
Chapter 7 Gaetano Zaccara and Luciana Tramacere
was raised, with an eosinophilia, and there
was liver dysfunction. On day 21 after the start
of symptoms anti-HHV6 IgM was detected.
About 1 month later, the skin eruption, fever,
lymphadenopathy, liver dysfunction, and
eosinophilia progressively disappeared.
A patient who had had carbamazepine-
induced DRESS presented with the same
clinical picture after taking lamotrigine for
52 days. The authors discussed cross-reac-
tivity between carbamazepine and lamotri-
gine, which are aromatic and non-aromatic
anticonvulsants [89A].
HLA allele B*1502 is a marker for an
increased risk of carbamazepine-induced
StevensJohnson syndrome and toxic epi-
dermal necrolysis in Han Chinese. The
FDA has therefore changed the carbamaz-
epine label, recommending genotyping in
all Asians [90S].
Carbamazepine-induced toxic epidermal
necrolysis has been reported in a child
[91A].
The possible association between HLA-
B*1502 and carbamazepine- or phenytoin-
induced StevensJohnson syndrome or
maculopapular eruptions has been explored
in 31 Thai subjects who had these antiepi-
leptic drug-induced complications between
1994 and 2007 and in 50 antiepileptic
drug-tolerant controls [92c]. There was a
strong association between HLA-B*1502
and phenytoin- and carbamazepine-
induced StevensJohnson syndrome. How-
ever, some patients with HLA-B*1502 had
had carbamazepine-induced StevensJohn-
son syndrome and were tolerant of pheny-
toin and vice versa, which suggests that
other factors contribute to this adverse
reaction.
The association between HLA-B*1502
and carbamazepine-induced Stevens John-
son syndrome and toxic epidermal necroly-
sis has been investigated in eight Indian
patients, of whom six had the HLA-
B*1502 allele, conrming the association
in Indian patients [93c].
The risk of erythema multiforme, Stevens
Johnson syndrome, or toxic epidermal necro-
lysis in 72 patients with bipolar disorder tak-
ing carbamazepine, valproate, or other
medications has been analysed using a large
Antiepileptic drugs Chapter 7
database [94C]. Both carbamazepine (OR
3.7; 95% CI 2.0, 6.8) and valproate (OR
2.2; 95% CI 1.2, 4.2) were associated.
In a young patient with carbamazepine-
induced toxic epidermal necrolysis, blister
uid was analysed for protein, chemical,
and mineral contents [95A]. There was a
threefold increase in albumin and protein
compared with burns blisters.
Musculoskeletal In a young patient a ten-
don sheath abscess was considered a possi-
ble complication of severe carbamazepine
hypersensitivity [96A].
Sexual function Sexual function has been
investigated in patients with epilepsy (aged
1845 years) taking carbamazepine (63
men/30 women), lamotrigine (37 men/40
women), or levetiracetam (30 men/26
women) monotherapy and in healthy con-
trols (36 men/44 women) [97c]. In women
using carbamazepine, steroid hormone-
binding globulin concentrations were
higher and progesterone concentrations
lower. Arizona Sexual Experience Scale
scores suggested that women taking lamo-
trigine and levetiracetam have better sexual
function than those taking carbamazepine
and controls. In men, carbamazepine was
associated with lower free androgen indices
and dehydroepiandrosterone sulfate con-
centrations and higher concentrations of
steroid hormone-binding globulin, follicle-
stimulating hormone, and luteinizing hor-
mone. Arizona Sexual Experience Scale
scores for men were similar in all groups.
Susceptibility factors Genetic Polymorphic
variants in various genes involved in the
pharmacokinetics and pharmacodynamics
of carbamazepine have been investigated
in 70 patients with epilepsy who had
beneted from carbamazepine monother-
apy [98C]. Known variants in drug-metabo-
lizing enzyme genes and a sodium channel
polymorphism in SCN2A were screened
using polymerase chain reaction-restriction
fragment length polymorphism or direct
sequencing. No single genetic variable was
of sufcient power to inuence carbamaze-
pine dosing requirements independently.
135
However, a multivariate model, incorporat-
ing age and specic genotypes of the
EPHX1 gene encoding microsomal epoxide
hydrolase, showed a signicant association
with the maintenance dose of
carbamazepine.
Drug formulations In a 3-month, random-
ized, blinded study in patients with type I
or type II bipolar affective disorder, who
were already taking carbamazepine or
who were starting to take it, immediate-
release or extended-release carbamazepine
capsules were substituted. Autonomic and
gastrointestinal adverse events were signi-
cantly less common in those who took the
extended-release formulation [99C].
Drug overdose In 115 of 130 poisoned
patients aged 1459 years plasma carba-
mazepine concentrations were above the
usual target range [100C]. There was acute
pulmonary failure in three cases. There
was a positive correlation between plasma
carbamazepine concentrations and both
systolic blood pressure and heart rate.
Drugdrug interactions Aripiprazole The
pharmacokinetic interaction of carbamaze-
pine with aripiprazole has been studied in
18 in-patients with schizophrenia [101c].
One week after co-administration of carba-
mazepine 400 mg/day plasma concentra-
tions of aripiprazole and its metabolite
dehydroaripiprazole fell by 64% and 68%
respectively.
Paracetamol A pharmacokinetic inter-
action was suspected in a 34-year-old man
taking carbamazepine for complex partial
seizures, who developed acute liver and
renal failure after taking less than 2.5 g a
day of paracetamol [102A].
Tacrolimus The metabolism of tacrolimus
is largely via CYP3A4, and all agents that
induce or inhibit this enzyme can change
its blood concentration. The interaction of
tacrolimus with carbamazepine has been
studied in a patient who underwent heart
transplantation [103A]. The dose-corrected
AUC0!12h of tacrolimus 11 days after
136
carbamazepine treatment was about 50%
of the value before carbamazepine, and
about 70% after 3 months.
Ethosuximide
Immunologic Systemic lupus erythematosus
with an increase in anti-double-strand
DNA antibodies has been attributed to
ethosuximide [104A].
A woman with refractory absence epilepsy at
age 8 years developed arthritis with an
increase in anti-double-strand DNA anti-
bodies while taking ethosuximide and carba-
mazepine. Both drugs were withdrawn and
the symptoms were ascribed to carbamaze-
pine. At age 24, because of numerous absence
seizures, ethosuximide 1000 mg/day was again
prescribed and 1 month later she had arthral-
gia and fever and the antinuclear antibody
concentration was were 80 UI/ml. Etho-
suximide was continued and 3 weeks later
the antinuclear antibodies were 640 UI/ml
and the anti-double-strand DNA antibodies
were 33 IU/ml. Ethosuximide was withdrawn
and the antibodies normalized and the arthral-
gia and fever abated.
This case was unusual, since drug-induced
lupus is usually associated with antibodies
to single-stranded, not double-stranded,
DNA.
Felbamate [SED-15, 1328]
Observational studies In a retrospective
chart review study of felbamate in 53 chil-
dren under 4 years, 16 reported at least
one adverse event while taking felbamate
and none required drug withdrawal [105c].
The events were somnolence (n 7), loss
of appetite (n 6), sleep disturbance (n
5), behavioral changes (n 4), and vomit-
ing (n 1). There were no serious adverse
effects during the study and no signicant
laboratory changes in liver or renal func-
tion or hematology.
Chapter 7 Gaetano Zaccara and Luciana Tramacere
Gabapentin [SED-15, 1465; SEDA-30,
80; SEDA-31, 110; SEDA-32, 131]
Observational studies In an open study in
75 patients with chemotherapy-induced
neuropathic pain, gabapentin monotherapy
800 mg/day caused mild somnolence in
about 25%, but none stopped taking the
drug [106c].
Comparative studies In a 6-week, double-
blind, double-dummy, crossover trial in 56
patients with diabetic polyneuropathy or
post-herpetic neuralgia, daily oral gaba-
pentin, nortriptyline, and their combination
were compared and drug doses were
titrated to the maximum tolerated dose
[107C]. There was less pain with combina-
tion treatment than with gabapentin or nor-
triptyline alone. During dose titration,
moderate or severe dry mouth was signi-
cantly more frequent with nortriptyline or
combination treatment than with gaba-
pentin, whereas an inability to concentrate
was signicantly more frequent with gaba-
pentin. At the maximum tolerated dose,
moderate or severe dry mouth was signi-
cantly more frequent with nortriptyline or
combination treatment than with gabapen-
tin. There were no serious adverse events.
Gabapentin and lorazepam have been
compared in the treatment of alcohol with-
drawal symptoms in a double-blind study in
100 patients, who were randomized to two
doses of gabapentin (900 mg/day tapering
to 600 mg/day or 1200 mg/day tapering to
800 mg/day) or lorazepam (6 mg/day taper-
ing to 4 mg/day) for 4 days [108C]. There
was a tendency for lorazepam to cause
more sedation and for gabapentin more
pruritus. One patient who used gabapentin
was withdrawn because of urticaria. Two
participants who stopped taking gabapentin
600 mg had probable withdrawal seizures
and one had a syncopal event. No patients
had delirium tremens.
In a double-blind, 4-week, placebo-con-
trolled trial, 214 men with hot ushes, on
a stable androgen deprivation therapy pro-
gram for prostate cancer, were randomized
to placebo or gabapentin at target doses of
Antiepileptic drugs Chapter 7
300, 600, or 900 mg/day, without benet
[109C]. The only adverse effects that were
signicantly different between the com-
bined gabapentin arms and the placebo
arm were loss of appetite and constipation,
which were more common with placebo.
Gabapentin and controlled-release oxy-
codone have been used for acute pain in
87 patients with herpes zoster in a 28-day,
double-blind, placebo-controlled trial, start-
ing within 6 days from the onset of the rash,
with only modest benet from gabapentin
during the rst week [110C]. There were
signicantly more withdrawals among those
taking oxycodone. Four of those who took
gabapentin did not complete the study
because of adverse effects or serious
adverse effects (two with imbalance and
dizziness, one with tremulousness and dizzi-
ness, and one with fever). The NNTH for
withdrawal because of adverse effects or
serious adverse effects was 5.8 for con-
trolled-release oxycodone and 9.7 for
gabapentin.
Systematic reviews In a systematic review
of four randomized placebo-controlled
studies of gabapentin in women with hot
ushes after natural or tamoxifen-induced
menopause, dropouts due to adverse events
were more frequent in those who took
gabapentin, particularly two adverse
effects, dizziness/unsteadiness and fatigue/
somnolence [111M].
Nervous system Bilateral ballismus has
been observed in a woman with Parkinson's
disease after the administration of gabapen-
tin; it resolved fully after drug withdrawal
[112A].
An 83-year-old woman with Parkinson's dis-
ease was given gabapentin for neuropathic
pain and after 5 days developed generalized
dyskinetic movements involving all four limbs,
which were so severe that they prevented her
from standing. Her mental function was nor-
mal and she had no other neurological signs.
A CT scan of the brain and laboratory tests
were normal. Gabapentin was withdrawn and
within 4 weeks the involuntary movements
resolved completely.
137
Gabapentin-induced myoclonus occurred
in an elderly patient with no other medical
conditions that could have caused it [113A].
A patient with end-stage renal disease
developed an encephalopathy a few days
after taking gabapentin in usual adult
doses. Gabapentin is excreted unchanged
in the urine and its half-life, normally 59
hours, increases to up to 132 hours in
anuria [114A].
Chorea in an elderly patient with anxiety
resolved completely after gabapentin was
withdrawn [115A].
A 75-year-old man with anxiety disorder
developed choreiform movements involving
the neck, trunk, upper and lower limbs, and
tongue after taking gabapentin 300 mg three
times a day (tds) for 1 month. He had no fam-
ily history of Huntington's disease or other
conditions that might have caused chorea.
The symptoms resolved within 2 days of gaba-
pentin withdrawal.
In a retrospective study in 162 patients
with epilepsy taking gabapentin, pre-existing
myoclonus was worsened in two cases within
2 weeks of starting gabapentin; in another
case it occurred de novo [116c]. Withdrawal
of gabapentin or clonazepam add-on treat-
ment resulted in resolution of myoclonus
with no serious sequelae in all three cases.
Sensory systems Hearing loss was attributed
to high concentrations of gabapentin in a
patient with renal insufciency [117A].
A 46-year-old woman with a 6-year history of
diabetes mellitus and previously normal renal
function developed anuria, hearing loss, myoclo-
nus, and confusion with hallucinations. She was
taking lisinopril, hydrochlorothiazide, furose-
mide, atorvastatin, omeprazole, salmeterol/uti-
casone and salbutamol by inhalation,
metformin, insulin, oxycodone, alprazolam, ven-
lafaxine, and gabapentin 300 mg tds. The gaba-
pentin blood concentration was 17.6 mg/l. All
her symptoms improved after one session of
hemodialysis and had resolved at the time of dis-
charge 4 days later.
Skin A xed drug eruption has been associ-
ated with gabapentin [118A].
A 44-year-old man with post-herpetic neural-
gia was given amitriptyline and gabapentin
138
300 mg tds. After 2 days he developed a
mildly itchy and painful bullous eruption in
the mouth; it soon ruptured leaving an ero-
sion. Gabapentin was withdrawn. The lesion
healed slowly in 810 days. He was subse-
quently treated with pregabalin which was
well tolerated. Repeated patch testing was
always negative. However, oral provocation
with gabapentin 300 mg produced the same
bullous lesion at the same site after 4 hours.
An urticarial rash has been attributed to
gabapentin [119A].
Hair Acute alopecia developed in a patient
who took gabapentin for neuropathic pain
[120A].
A 28-year-old woman took gabapentin 1800
mg/day for a continuous sharp pain and a
burning sensation with allodynia and hyper-
algesia in her right shoulder blade. After 1
week she noticed signicant hair loss with pat-
chy areas of alopecia among areas of normal
hair growth. Hematological tests, plasma elec-
trolytes, blood iron and ferritin concentra-
tions, thyroid hormones, cortisol, and
adrenocorticotropic hormone were all within
normal limits. Pregnancy, fever, malnutrition,
dermatological problems, and autoimmune
disorders such as systemic lupus erythemato-
sus were excluded. Gabapentin was with-
drawn, and hair shedding stopped 2 months
later, followed by gradual regrowth.
Psychiatric A 38-year-old male physician
developed delirium and gabapentin depen-
dence after high self-administered doses
[121A].
Musculoskeletal Gabapentin can rarely
cause a myopathy and rhabdomyolysis.
Myoglobinuria, causing acute renal insuf-
ciency, has been described in a patient with
painful diabetic neuropathy [122A].
A 63-year-old woman took gabapentin for
painful diabetic neuropathy and after 3 weeks
developed fatigue, gait instability, diffuse mus-
cle pain, muscle weakness in her legs, and
reduced urine output with a reddish color.
She was taking insulin, irbesartan, and gaba-
pentin 900 mg/day. She had proximal muscle
tenderness and weakness. The ankle reexes
were both absent and vibration sensation was
reduced in both feet. There was acute renal
insufciency (creatinine concentration 700
mmol/l). Creatine kinase activity was 75 680
U/l (26167 U/l), lactate dehydrogenase activity
Chapter 7 Gaetano Zaccara and Luciana Tramacere
1847 U/l (240480 U/l), and the serum potas-
sium concentration was 6.3 mmol/l (3.55.5
mmol/l). There was myoglobin in the urine.
Electromyography conrmed a myopathy.
She underwent emergency hemodialysis. A
muscle biopsy showed changes of myopathy.
Gabapentin was withheld. She was given par-
enteral uids and furosemide and gradually
improved.
Susceptibility factors Renal disease Un-
recognized gabapentin toxicity, mainly
characterized by a signicant deterioration
in consciousness, occurred in a patient with
acute renal impairment [123A]. During epi-
sodes of acute renal insufciency the dose
of gabapentin should be reduced.
Drug formulations Gabapentin has a short
half-life and a saturable mechanism of
absorption, with consequent lack of propor-
tionality between doses and concentrations.
New formulations have therefore been
developed. An extended-release formula-
tion may overcome the problems of satura-
ble absorption and short half-life. When
administered with a meal, this formulation
gradually expands and releases the drug to
the upper gastrointestinal tract over an
extended period of time. This enables it to
be taken once or twice a day compared
with three times a day or more for immedi-
ate-release gabapentin.
In a double-blind, placebo-controlled
study of extended-release gabapentin in
147 patients with painful diabetic neuropa-
thy, the patients were randomized to pla-
cebo or gabapentin 3000 mg, either as a
single evening daily dose or as two divided
doses (1200 mg in the morning and 1800
mg in the evening) for 4 weeks. The inci-
dence of adverse events was low: dizziness
in 17%, 12%, and 0% and somnolence in
13%, 4.1%, and 0% of patients in the gaba-
pentin extended single-dose, divided-dose,
and placebo groups respectively [124C].
Gabapentin enacarbil is another attempt
to overcome the problem of gabapentin sat-
urable absorption. It is a prodrug that is
actively transported and provides predict-
able dose-proportional gabapentin expo-
sure and oral availability of about 70%.
Antiepileptic drugs Chapter 7
In a randomized, double-blind, placebo-
controlled, crossover study, extended-
release gabapentin enacarbil 600 mg tablets
were given as single oral doses of 2400,
3600, 4800, or 6000 mg to 32 healthy volun-
teers. Gabapentin exposure in blood was
proportional to the dose of gabapentin ena-
carbil over the range 24006000 mg (equiva-
lent to 12503125 mg of gabapentin).
Blood concentrations of intact gabapentin
enacarbil were low and transient. The
most commonly reported adverse effects,
mild to moderate in intensity, were
dizziness and nausea (50% and 25% of sub-
jects respectively). Two subjects had treat-
ment-emergent adverse effects rated as
severe: psychomotor retardation, vertigo,
and sedation (after a dose of 4800 mg) and
somnolence (after 6000 mg). There were
no clinically signicant changes in laboratory
parameters, vital signs, or electrocardiogra-
phy; QTc intervals did not exceed 480 ms or
change from baseline by more than 30 ms
at any dose of gabapentin enacarbil [125C].
In a 14-day, double-blind, controlled
trial, 96 subjects with restless legs syndrome
were randomized to the prodrug gabapen-
tin enacarbil 1200 or 600 mg/day or pla-
cebo, with benet by day 14 [126C]. The
most common treatment-emergent adverse
events were somnolence (gabapentin ena-
carbil: 1200 mg, 36% and 600 mg, 14%; pla-
cebo, 15%) and dizziness (18%, 14%, 3%),
most of which were rated mild or moderate
in intensity.
Drug overdose Patients with impaired
driving who were positive for gabapentin
and were submitted to a Toxicology Labo-
ratory between 2003 and 2007 have been
reviewed [127c]. The concentrations of
gabapentin in blood in 137 cases ranged
from <2.0 to 24.7 mg/l, with a mean of 8.4
mg/l. In four cases gabapentin was the only
drug detected as a possible cause of driving
impairment. The subjects had characteristic
clinical symptoms (horizontal gaze nystag-
mus, poor performance on standardized
eld sobriety tests, dilated pupils, low body
temperature, and increased heart rate and
blood pressure).
139
Lacosamide
The antiepileptic drug lacosamide, a functio-
nalized amino acid, has a novel mechanism
of actionselective enhancement of slow
inactivation of voltage-gated sodium chan-
nels, resulting in stabilization of hyperexcita-
ble neuronal membranes [128R].
In August 2008, lacosamide was granted
market authorization by the European
Commission as an adjunctive therapy for
partial-onset seizures with or without sec-
ondary generalization. It was approved by
the FDA as an adjunctive therapy for par-
tial-onset seizures in October 2008 [129r].
It is also effective against neuropathic pain
attributed to distal diabetic neuropathy
[130R]. It is available as oral or intravenous
formulations.
The apparent lack of sedative effects
makes lacosamide attractive for patients
who are likely to develop somnolence with
other antiepileptic drugs. Reports of poten-
tial electrocardiographic changes with laco-
samide suggest that caution is needed
before using it in patients with pre-existing
cardiac disease and in those taking class I
antidysrhythmic drugs or drugs that cause
PR interval prolongation. When used as
short-term replacement for oral lacosamide,
intravenous lacosamide is well tolerated
when administered as a 15-, 30-, or 60-
minute infusion.
Observational studies In a 6-month, open
study, lacosamide was given to 25 patients
with drug-resistant focal epilepsy [131c].
One patient became seizure-free for 5
months and two for 1 and 4 months. Eight
patients reported a greater than 50% reduc-
tion in seizure frequency. Thirteen patients
reported adverse effects during the titration
period. In ve patients the adverse effects
disappeared during the maintenance phase
and/or with dosage reduction. Most fre-
quently observed were fatigue (n 6), dou-
ble vision (n 5), depression (n 5),
dizziness (n 4), nausea (n 3), irritability
(n 2), word-nding difculties (n 2),
tremor (n 2), and coordination problems
140
(n 2). Two patients lost more than 10% of
their body weight.
In an open study of lacosamide in 69
patients with painful diabetic neuropathy
the initial dose was followed by escalation
by 100 mg/day up to a maximum of 400
mg/day [132c]. Patients then entered a 20-
week maintenance period after which they
could opt to continue for up to about 2.5
years. The most commonly reported adverse
events that were considered possibly related
to the trial medication were headache
(7%), dizziness (7%), tremor (4%), fatigue
(6%), and diarrhea and nausea (4%). The
adverse events occurred most often during
the titration period. Seven patients withdrew
because of adverse effectselectrocardio-
graphic changes (n 2), dizziness and nau-
sea (n 1), chest pain and nausea (n 1),
dizziness, fatigue, and tinnitus (n 1), pos-
sible stroke and convulsion (n 1, this was
considered a serious adverse event), acciden-
tal overdose (n 1).
Placebo-controlled studies Lacosamide 200,
400, or 600 mg/day has been studied in three
randomized, placebo-controlled trials with a
12-week maintenance period, in which
about 1300 patients with partial-onset seizures
were included [133M]. There was a statistically
signicant reduction in 28-day seizure fre-
quency compared with placebo. Lacosamide
was generally well tolerated in adult patients
with partial-onset seizures, and most treat-
ment-emergent adverse events were of mild or
moderate intensity. Dizziness was the most
common treatment-related adverse event
[134R].
In a double-blind, randomized, placebo-
controlled trial, oral lacosamide (200, 400,
and 600 mg/day) was given to 654 patients
with painful diabetic neuropathy for 12
weeks after a 6-week dose titration period
[135C]. The proportions of patients with
treatment-emergent adverse effects that were
considered to be at least possibly related to
the trial medication were 31% for placebo,
39% for lacosamide 200 mg/day, 53% at
400 mg/day, and 68% at 600 mg/day. The
most common included dizziness (n 3, 8,
27, and 39 in those treated with placebo,
lacosamide 200, 400, and 600 mg/day
Chapter 7 Gaetano Zaccara and Luciana Tramacere
respectively) nausea (n 4, 14, 9, and 25),
and headache (n 8, 14, 10, and 18). Ver-
tigo was reported in eight patients and
blurred vision in seven of those taking 600
mg/day. Other neurological adverse events,
such as somnolence and behavioral or cog-
nitive effects, were relatively uncommon.
Nine subjects in the placebo group (n
65), 17 in the lacosamide 200 mg/day group
(n 141), 30 in the 400 mg/day group (n
125), and 58 in the 600 mg/day group (n
137) withdrew because of an adverse event,
the most common of which were dizziness
and nausea. One patient in the lacosamide
600 mg group died in cardiac arrest. How-
ever, this was considered unlikely to have
been related to the trial medication rather
than pre-existing cardiac disease. There were
changes in laboratory measurements, weight
gain, and peripheral edema in very few sub-
jects. Lacosamide had no effect on the QT
interval, but there was a small prolongation
in the mean PR interval (mean change 5.1
milliseconds in the lacosamide 200 mg/day
group, 13 milliseconds in the 400 mg/day
group, and 12 milliseconds in the 600 mg/
day group, compared with 2.3 millisec-
onds in the placebo group). There was a
slight prolongation in mean QRS duration
in patients taking lacosamide. First-degree
atrioventricular block (PR interval > 200
ms) was reported in under 2% of patients
in any treatment group. There was one case
of second-degree atrioventricular block in a
patient with a normal baseline PR interval
in the lacosamide 600 mg/day group 5 days
after the last dose.
In a multicenter, randomized, placebo-
controlled, double-blind trial in 495 patients
with painful diabetic neuropathy who took
lacosamide 200, 400, or 600 mg/day for 12
weeks after a 6-week titration phase, the
lacosamide 400 mg/day group had signi-
cant improvement in the primary efcacy
measure [136C]. The most common treat-
ment-emergent adverse events included diz-
ziness, nausea, fatigue, headache, and
tremor and all appeared to be dose-related.
For example, the incidence of dizziness was
5% at 400 mg/day and 22% at 600 mg/day.
There was nausea in 5% of patients taking
400 mg/day and 12% of those taking
Antiepileptic drugs Chapter 7
600 mg/day. Fatigue was present in 2%
and 7% of patients respectively, and tremor
in 2% and 6%. Other central nervous system
adverse effects, specically somnolence and
behavioral or cognitive effects, were relatively
uncommon. For example, somnolence
occurred in 3% and memory impairment in
2%. There were 8, 8, 21, and 37 withdrawals
in patients treated with placebo, 200, 400, or
600 mg lacosamide respectively, and most
occurred early in the study. Dizziness, nau-
sea, and disordered balance were the most
common adverse events that led to drug with-
drawal. The incidence of edema was low (3%
with lacosamide, 4% with placebo). There
were no effects on laboratory measurements
attributable to the experimental drug. There
were no effects on heart rate or QT interval;
the placebo-subtracted mean maximum
change from baseline in PR interval was 6.1
milliseconds with lacosamide 200 mg/day,
8.3 milliseconds with 400 mg/day, and 9.8 mil-
liseconds with 600 mg/day. The incidence
of rst degree atrioventricular block was
similar in all the groups and there were no
reports of second-degree atrioventricular
block.
Lacosamide 200 and 400 mg/day as add-
on therapy in 485 patients with uncontrolled
partial-onset seizures has been studied in a
multicenter, double-blind, placebo-con-
trolled trial, which consisted of an 8-week
baseline, a 4-week titration period, and a
12-week maintenance period [137C]. The
median percentage reduction in seizure fre-
quency was 21% for placebo, 35% for laco-
samide 200 mg/day, and 36% for 400 mg/
day. The most clearly dose-related treat-
ment-emergent adverse events included diz-
ziness (17 and 25 patients randomized to
200 or 400 mg of lacosamide respectively),
nausea (9 and 13 patients), and vomiting (5
and 9 patients). Diplopia (13 and 16
patients) did not appear to be dose-related.
The incidence of somnolence was low
(4.3%, 3.8%, and 3.7% in patients random-
ized to lacosamide 200 mg, 400 mg, and pla-
cebo respectively). The experimental drug
was withdrawn in 42 patients because of
adverse effects; eight had been randomized
to placebo, 10 to lacosamide 200 mg/day,
and 24 to 400 mg/day. The adverse effects
141
that most often led to withdrawal were diplo-
pia (2.2%), vertigo (1.6%), and vomiting
(1.2%). There were no effects on QT inter-
val or QRS duration. Lacosamide was asso-
ciated with a dose-related increase in mean
PR interval (4.6 msec at the end of mainte-
nance with 400 mg/day). Laboratory ana-
lyses were not affected and body weight did
not change.
Lamotrigine [SED-15, 1990; SEDA-30,
80; SEDA-31, 113; SEDA-32, 134]
Observational studies Lamotrigine has
been evaluated in a study that included an
open, 1-week screening phase, a 20-week
escalation phase, and a 12-week mainte-
nance phase in 54 children aged under 13
years who had newly diagnosed absence
epilepsy and had not previously been trea-
ted with antiepileptic drugs [138c]. Rash
was reported in six patients (11%), urticaria
in one patient (2%), and pruritus in two
patients (4%). None of these events was
serious or resulted in premature with-
drawal. Three patients had adverse events
that led to premature withdrawal: increased
seizure activity in one, tremor in one, and
vomiting and dizziness in one patient.
In a retrospective study of lamotrigine
monotherapy for seizure control in 72 chil-
dren and adolescents with epilepsy, the
mean follow-up period was 33 months
[139c]. In six patients lamotrigine was with-
drawn because of adverse events (rash 4,
low white cell count 1, severe sleepiness 1).
Rashes occurred 23 weeks after the start
of therapy in four patients.
In 204 infants (aged 124 months) with
partial seizures who had been previously
given lamotrigine in a randomized, dou-
ble-blind, placebo-controlled study and
who were followed in a long-term study
for at least 24 weeks, the only adverse
event that was thought to be attributable
to the drug was irritability (n 10) [140c].
There were no cases of serious rash.
Lamotrigine has been assessed in 196
patients with bipolar disorder for a mean
142
duration of 434 days and a mean nal dos-
age of 236 mg/day without valproate and
169 mg/day with valproate [141c]. Lamotri-
gine was withdrawn in about one-quarter
of cases after a mean of 255 days, most
often because of inefcacy and seldom
because of adverse effects. In only 3.5%
of cases (7/200) was lamotrigine withdrawn
because of rashes. Ratings for central
nervous system adverse effects (tremor,
sedation, headache, memory problems,
akathisia, and other extra pyramidal symp-
toms) and gastrointestinal adverse effects
(nausea, vomiting, diarrhea, and constipa-
tion), dry mouth, sexual dysfunction, and
increased appetite did not change signi-
cantly between baseline and the last visit.
Some patients had reduced weight, which
correlated with impaired appetite.
The pharmacodynamic interaction
between lamotrigine and valproic acid has
been evaluated retrospectively in 35
patients with drug-resistant epilepsy [142c].
Median follow-up was 42 months. With
lamotrigine valproate, 18 patients
became seizure-free, 4 improved, and 13
did not improve. Of the 22 patients who
improved, 11 had previously failed lamotri-
gine and valproate monotherapy. Of the 13
patients who did not respond, 5 stopped
taking the combination, primarily because
of adverse effectstremor (n 4), weight
gain (n 3), dizziness (n 2), and insomnia
(n 2). Of the 22 patients who improved
with the combination, 16 had some adverse
effect, which resolved after the dosage of
either lamotrigine or valproate was reduced.
Comparative studies Lamotrigine versus
divalproex sodium In a 12-week, double-
blind, randomized, placebo-controlled com-
parison of lamotrigine and divalproex
sodium in 25 patients with schizophrenia
or schizoaffective disorders stabilized on
an antipsychotic drug, there were no differ-
ences in any outcome measure [143C]. Very
few patients reported adverse effects. Two
patients randomized to divalproex sodium
and placebo reported depression and sui-
cidal thought or tremors respectively. Two
patients (one taking lamotrigine and one
Chapter 7 Gaetano Zaccara and Luciana Tramacere
taking divalproex sodium) reported small
weight gains.
Lamotrigine versus levetiracetam Adjunc-
tive lamotrigine (n 132) and adjunctive
levetiracetam (n 136) have been com-
pared in an 8-week, randomized, double-
blind, parallel-group escalation phase and
a 12-week maintenance phase adults with
partial seizures [144C]. Adverse events that
led to withdrawal were reported in 11% of
those who took lamotrigine and 18% of
those who took levetiracetam. Non-serious
rashes were reported as adverse events in
eight of those who took lamotrigine and
nine of those who took levetiracetam. The
most common adverse events with lamotri-
gine were headache (n 42), dizziness
(n 17), nausea (n 14), fatigue (n 10),
and somnolence (n 7).
Lamotrigine versus lithium Lamotrigine
(up to 200 mg/day) and lithium (up to 900
mg/day) have been compared in a 16-week,
open, randomized study in 98 patients with
bipolar II disorders [145c]. The mean num-
ber of adverse effects in those taking lamo-
trigine was 4.2 and the mean number of
adverse effects in those taking lithium was
9.2. The most common adverse effects in
those taking lamotrigine were nausea/
vomiting (24%), upset stomach (20%), dry
mouth (20%), tremor (9.8%), and drowsi-
ness/panic (9.8%).
Placebo-controlled studies In a 16-week,
double-blind, placebo-controlled, exible-
dose study of lamotrigine in binge-eating
disorder associated with obesity, 51 out-
patients were randomized to either lamotri-
gine (n 26) or placebo (n 25) [146c].
Four patients withdrew because of adverse
events (lamotrigine, n 3; placebo, n
1), the most common of which were head-
ache (35% versus 28%), insomnia (35%
versus 20%), somnolence (27% versus
8%), rash (15% versus 12%), and dry
mouth (15% versus 0%).
Systematic reviews In a systematic review
of ve randomized, placebo-controlled
Antiepileptic drugs Chapter 7
studies in 161 patients, in which lamotrigine
or placebo had been administered to
patients with psychoses who were already
taking clozapine, the dropout rate did not
differ between lamotrigine and placebo.
[147M]. Three patients had severe adverse
events from lamotrigine (psychiatric symp-
toms in three, facial pain and gingival infec-
tion in one), and two among those who
took placebo (psychiatric symptoms).
Rashes were reported in four patients dur-
ing lamotrigine therapy and in two during
placebo.
Cardiovascular In a subcohort (n 108) of
a 40-week, randomized, double-blind com-
parison of lamotrigine and sustained-
release carbamazepine in patients aged 65
and over with newly diagnosed epilepsy,
target drug maintenance doses were 400
mg/day for carbamazepine and 100 mg/day
for lamotrigine, with adjustments based on
clinical response [148C]. Resting 12-lead
electrocardiograms were recorded under
standardized conditions at baseline and at
40 weeks. Of the 108 patients randomized,
60 (carbamazepine n 29; lamotrigine
n 30) were evaluated. There were no sig-
nicant changes recorded between baseline
and nal visit in QRS duration and QT
intervals, but heart rate fell and the PQ
interval was slightly prolonged by both
treatments. However, there were no differ-
ences between the groups in the changes
from baseline to nal visit and no signi-
cant relations between individual electro-
cardiographic changes and serum drug
concentrations.
Nervous system Two cases of lamotrigine-
associated aseptic meningitis recurred after
rechallenge [149A, 150A].
A 25-year-old woman developed meningism,
vomiting, conjunctivitis, and myalgia 8 days
after starting lamotrigine 25 mg/day. She had
generalized epilepsy, peptic ulcer disease,
and celiac disease, and her medications were
phenytoin, rabeprazole, and levonorgestrel/
ethinylestradiol. Cerebrospinal uid values
were protein 1.14 g/l, glucose 3.4 mmol/l,
erythrocytes 22  106/l, leukocytes 112  106/l
(67% neutrophils, 32% mononuclear cells).
Cerebrospinal uid and blood cultures for
143
bacteria, mycobacteria, fungi, and viruses were
negative and a CT scan was normal. Lamotri-
gine was withdrawn and she was discharged on
day 4 with a diagnosis of presumed viral menin-
gitis. She took lamotrigine again and 15 days
later she developed a severe headache, photo-
phobia, neck stiffness, vomiting, dysesthesia,
and fever. All tests were again negative and an
MRI scan was normal. Lamotrigine was again
withdrawn and her fever and meningism rapidly
resolved.
Psychiatric Psychiatric problems that can
occur in patients using lamotrigine for men-
tal disorders (mainly bipolar disorder) or
epilepsy have been reviewed [151R]. The
main features of these psychiatric adverse
effects are affective switches, full acute psy-
chotic episodes, and hallucinations.
Obsessive symptoms occurred in a
patient taking lamotrigine 100 mg/day and
improved after dosage reduction and then
withdrawal [152A].
Lamotrigine-induced mania has been
reported in a child with autism spectrum
disorder and epilepsy [153A].
A 10-year-old boy suddenly developed behav-
ioral changes (frequent laughing without any
reason, increased hyperactivity, a reduced
need for sleep, increased irritability, and
aggressive behavior). He was hyperactive and
distractible but had no psychotic symptoms.
His mother had noted this behavior when
lamotrigine, which had been substituted for
carbamazepine for epilepsy, had reached a
dosage of 100 mg/day. Lamotrigine was gradu-
ally withdrawn and his manic symptoms grad-
ually subsided.
Endocrine Polycystic ovary syndrome,
hyperandrogenism, or ovulatory dysfunc-
tion in women with epilepsy after starting
to take valproate or lamotrigine have been
prospectively studied in patients with epi-
lepsy, who were randomized to valproate
(n 225) or lamotrigine (n 222) for 12
months [154C]. More of those who took
valproate group developed ovulatory dys-
function or polycystic ovary syndrome.
Hyperandrogenism was more frequent with
valproate among those who started treat-
ment at ages under 26 years but was similar
if treatment was started at age 26 years or
over. Similar percentages of patients had
adverse effects between those randomized
144
to lamotrigine or valproate. Tremor, vomit-
ing, nausea, alopecia, and weight gain were
reported more often with valproate. Rashes
caused withdrawal in ve patients taking
lamotrigine and none taking valproate.
The proportion of participants who with-
drew because of an adverse event was sim-
ilar between the groups (4%).
Salivary glands Sjgren's syndrome has
been attributed to lamotrigine [155A].
Liver Three cases of anticonvulsant hyper-
sensitivity syndrome or drug-related rash
with eosinophilia and systemic symptoms
(DRESS) have been described in conjunc-
tion with lamotrigine-associated hepatitis;
two recovered after withdrawal of lamotri-
gine [156A, 157A], but the third required
liver transplantation [158A].
A 43-year-old woman taking oxcarbazepine
for depression was given lamotrigine and after
2 weeks developed nausea, a generalized mac-
ular rash, and abnormal liver function tests
(AsT 6079 IU/l; AlT 6900 IU/l; total bilirubin
67 mmol/l; alkaline phosphatase 149 IU/l).
There were no intraoral lesions, lymphade-
nopathy, or hepatosplenomegaly and no signs
of encephalopathy. All drugs were withdrawn
and management included intravenous hydra-
tion and supportive care. After 3 days her
liver enzymes improved substantially and 1
month later were in the reference range.
Skin StevensJohnson syndrome [159A]
and anticonvulsant hypersensitivity syn-
drome [160A] have been described in
patients taking lamotrigine.
Possible cross-reactivity between carba-
mazepine and lamotrigine, which are aro-
matic and nonaromatic anticonvulsants,
has been illustrated [89A].
A 14-year-boy developed erythroderma,
fever, and interstitial pneumonitis after taking
carbamazepine for 44 days and had a positive
patch test to carbamazepine 6 weeks after
recovery. He developed a similar clinical and
biological picture after taking lamotrigine for
52 days.
Cutaneous adverse drug reactions to psy-
chotropic drugs have been studied using a
database of 208 401 psychiatric in-patients
Chapter 7 Gaetano Zaccara and Luciana Tramacere
monitored in a multicenter drug safety sur-
veillance project [161C]. There were 214 cases
of clinically relevant cutaneous drug reac-
tions, of which seven were life-threatening.
Substances with the highest and statistically
signicant risk were antiepileptic drugs, par-
ticularly lamotrigine and carbamazepine.
In a prospective study, the incidence of
rash was calculated in 237 patients who
were taking lamotrigine for bipolar I disor-
der in Korea, of whom 30 developed a rash
at a median time of onset of 16 days [162c].
In two cases the rash was serious, but none
developed StevensJohnson syndrome or
toxic epidermal necrolysis.
Lamotrigine-induced rash and rechal-
lenge have been systematically reviewed,
44 papers being retrieved [163M]. In 39
cases, rechallenge was attempted and rash
recurred in only ve cases. Thus, many
patients who develop benign rashes from
lamotrigine can be rechallenged without
adverse consequences. However, very slow
titration of lamotrigine is of crucial impor-
tance for reducing the rate of recurrence.
Sexual function Reproductive and sexual
function have been investigated in patients
with epilepsy aged 1845 taking lamotrigine
(37 men/40 women), levetiracetam (30 men/
26 women), or carbamazepine (63 men/30
women) monotherapy and in healthy con-
trols (36 men/44 women) [97c]. Dehydroepi-
androsterone sulfate concentrations were
higher and androstenedione concentrations
lower in lamotrigine-treated women. In
women, Arizona Sexual Experience Scale
scores were signicantly lower in those using
lamotrigine or levetiracetam, suggesting that
they have better sexual function than carba-
mazepine users and controls. Men in all
treatment groups had lower androstenedione
and free testosterone concentrations. Ari-
zona Sexual Experience Scale scores for
men were similar in all groups.
Drug withdrawal The potential for with-
drawal symptoms during treatment with
lamotrigine has been investigated retrospec-
tively [164c]. Six patients with epilepsy were
identied who reported transient psychologi-
cal symptoms during stable, chronic
Antiepileptic drugs Chapter 7
lamotrigine monotherapy. These consisted
largely of irritability, in addition to complaints
of anxiety, difculty in thinking, and weak-
ness, and they occurred in the 12 hours
before the patients were due to take their next
dose of medication. However, some patients
were also taking other psychoactive medica-
tions, including benzodiazepines, and the
hypothesis that these are an end-of-dose
phenomenon should be further explored.
Pregnancy In 20 women with epilepsy who
took lamotrigine during pregnancy [165c]
all the pregnancies and births were normal,
but three gave birth to healthy twins, two
had vanished twin syndromes, and one had
a miscarriage. The authors suggested that
lamotrigine might induce twin pregnancy.
Teratogenicity Data from the North Amer-
ican antiepileptic drug Pregnancy Registry
have shown an unexpectedly high preva-
lence of isolated orofacial clefts in infants
exposed to lamotrigine monotherapy dur-
ing the rst trimester of pregnancy, with a
rate of 8.9 per 1000 [166C]. To verify this,
a population-based casecontrol study with
malformed controls based on EUROCAT
congenital anomaly registers (which covers
3.9 million births) has been performed
[167C]. The odd ratios for lamotrigine
monotherapy versus no antiepileptic drug
use were 0.67 (95% CI 0.10, 2.34) for
orofacial clefts relative to other malforma-
tions, 0.80 (95% CI 0.11, 2.85) for iso-
lated orofacial clefts, 0.79 (95% CI 0.03,
4.35) for cleft palate, and 1.01 (95% CI
0.03, 5.57) for isolated cleft palate. There
was no evidence of a specic increased risk
of isolated orofacial clefts relative to other
malformations due to lamotrigine
monotherapy.
However, the nding of an increased risk
of oral clefts in offspring exposed to lamotri-
gine during pregnancy has been questioned
by other workers [168r]. Data from the UK
Epilepsy & Pregnancy Register, another
independent prospective registration and
follow-up study (a total of 1229 pregnancies
exposed to lamotrigine monotherapy
resulting in 1151 live births), have not con-
rmed the nding. Suggested possible
145
explanations for these different results are
an improbable difference for oral clefts
between the populations studied in the
USA and the UK or some bias associated
with the design of the studies.
A literature search for congenital malfor-
mations after the use of lamotrigine during
pregnancy yielded 10 studies and birth reg-
isters; the risk of a major congenital malfor-
mation due to lamotrigine was 14%
[169M].
A female infant was born with micro-
gnathia, low-set ears, facial dysmorphism,
and unilateral radius aplasia to a mother
who used lamotrigine 100 mg/day and
oxcarbazepine 1200 mg/day during preg-
nancy for seizures [170A].
Fetotoxicity A 3-day-old full-term new-
born had from series of tonic-clonic and
myoclonic seizures [171A]. The authors
speculated that these seizures were caused
by the drop in lamotrigine concentrations
in his blood after delivery.
Susceptibility factors Genetic High-resolu-
tion HLA genotyping has also been per-
formed in 65 patients of European
ancestry taking lamotrigine (22 cases with
lamotrigine-induced severe cutaneous drug
reactions and 43 controls taking lamotrigine
without such symptoms) and the associa-
tion of HLA genetic variants with these
adverse reactions was evaluated by con-
trasting allele frequencies between the
cases and the controls for each of 112
HLA four-digit alleles [172C]. Five alleles
were found with higher frequencies in the
cases compared with the treated controls,
although none of the associations identied
was statistically signicant; they included
B*580, previously reported to be associated
with allopurinol-induced serious cutaneous
adverse reactions. Marginal association evi-
dence was also observed for alleles
Cw*0718 and DQB1*0609, both of which
were strongly correlated with B*5801.
Other alleles identied were A*6801and
DRB1*1301. None of the cases carried
B*1502. Thus, there is suggestive evidence
for some associations, but no single major
HLA-related genetic factor has been
146
identied for lamotrigine-induced severe
cutaneous drug reactions in patients of
European origin.
Drug overdose Lamotrigine overdose with
life-threatening consequences has been
reported [173A].
A 23-year-old woman took an intentional
overdose of lamotrigine 9.2 g, chlorphenamine
56 mg, and citalopram 220 mg while intoxi-
cated with alcohol. Her heart rate was 107/
minute, blood pressure 140/73 mmHg, and
respiratory rate 36/minute with an oxygen sat-
uration of 97%. Her temperature was 38.5  C
and she had a partially compensated
metabolic acidosis. She was agitated with a
reduced conscious level, tremor, and bilateral
horizontal nystagmus. Electrocardiography
showed sinus tachycardia, a widened QRS
complex (>120 msec), and a prolonged QTc
interval (>470 msec). She was intubated and
ventilated and given intravenous magnesium
and sodium bicarbonate. The next morning
the electrocardiographic changes had
resolved.
Drugdrug interactions Lamotrigine Poly-
pharmacy with enzyme inducers is an
important susceptibility factor for valproate
encephalopathy. Valproic acid-induced
hyperammonemic encephalopathy devel-
oped exclusively during concomitant treat-
ment with lamotrigine valproate in a
psychiatric setting [174A].
A 72-year-old woman with bipolar I disorder,
who was taking a combination of valproic acid
and clozapine, was admitted with acute mania
and psychosis following 2 months of poor drug
compliance. Lamotrigine was added initially in
a dosage of 12.5 mg/day and increased by 12.5
mg every 3 days up to nal dose of 75 mg/day
after 2 weeks. She developed weakness, hand
tremor, lethargy, and asterixis after 3 weeks
and electroencephalography showed typical
triphasic waves. The ammonia concentration
rose to 59 mmol/l (reference range 930
mmol/l), the valproate concentration was 86
mg/l, and liver enzymes were in the reference
range. Valproate was withdrawn and the
hyperammonemia and symptoms resolved
during the next week.
Oral contraceptives Serum antiepileptic
drug concentrations of lamotrigine and
valproate were measured at two times dur-
ing a single menstrual cycle in four groups
Chapter 7 Gaetano Zaccara and Luciana Tramacere
of 12 women with epilepsy [175C]. Both
valproate and lamotrigine concentrations
were signicantly reduced by the oral con-
traceptive (median reductions of 23%
for valproate and 33% for lamotrigine).
Serum lamotrigine concentrations fell
non-signicantly by 31% during the mid-
luteal phase compared with the early-mid
follicular phase in the absence of oral
contraception.
Raltegravir In 12 healthy volunteers, the
AUC, Cmax, and the mean ratio of the
AUCs of lamotrigine-2N-glucuronide to
lamotrigine have been measured after a sin-
gle dose of lamotrigine 100 mg during treat-
ment with raltegravir 400 mg twice a day
(bd) and after a washout period [176c].
There were no signicant effects.
Management of adverse reactions
Intravenous immunoglobulin was success-
fully given to a patient with epilepsy and
toxic epidermal necrolysis, which appeared
after 2 weeks of treatment with lamotrigine
and valproate [177A].
Levetiracetam [SED-15, 2035; SEDA-
30, 82; SEDA-31, 116; SEDA-32, 137]
Observational studies Levetiracetam
monotherapy has been investigated in 35
patients with late-onset post-stroke seizures
in a prospective open study [178c]. At a
mean follow-up period of 18 months, 27
patients had achieved seizure freedom.
Four of 35 patients stopped taking levetira-
cetam because of severe adverse events:
drowsiness with gait disturbance and aggres-
sive behavior in two cases, and severe psy-
chomotor agitation with aggressive
behavior in the other two patients.
The use, safety, and efcacy of leve-
tiracetam in 51 patients in intensive care
unit have been retrospectively analysed
[179c]. Nineteen patients rst received
levetiracetam intravenously formulation
before receiving it orally, 18 received the
Antiepileptic drugs Chapter 7
intravenous formulation only, and the other
14 the oral doses only. The most common
maintenance dose was 500 mg bd and the
average duration of therapy was 13 days.
There were no cases of adverse hemo-
dynamic events or cardiac dysrhythmias.
In a prospective multicenter, open, add-
on study, 33 children aged 416 years with
refractory epilepsy were given levetira-
cetam in addition to their previous treat-
ment regimen [180c]. The retention rate
was 70% after 26 weeks, with a median
levetiracetam dosage of 22 mg/kg/day. Most
reported adverse effects were hyperactivity
(49%), somnolence (36%), irritability
(33%), and aggressive behavior (27%).
Comparative studies Levetiracetam versus
phenytoin Levetiracetam monotherapy has
been compared with phenytoin for post-
operative control of glioma-related seizures
in a randomized pilot study [181c]. Over 13
months, 29 patients were randomized in a
2:1 ratio to start levetiracetam within 24
hours of surgery or to continue phenytoin
therapy. Similar percentages of patients
were seizure-free after 6 months of treat-
ment. Reported adverse effects at 6 months
were: dizziness (0% levetiracetam, 14%
phenytoin), difculty with coordination
(0% versus 29%), depression (7% versus
14%), lack of energy or strength (20% ver-
sus 43%), insomnia (40% versus 43%),
and mood instability (7% versus 0%). No
adverse effect resulted in hospitalization
or withdrawal from the study.
Levetiracetam and phenytoin have been
retrospectively compared in the prophylaxis
of early and late postoperative seizures
in 315 patients [182c]. Levetiracetam
(n 105) was at least as effective as pheny-
toin (n 210) and signicantly better toler-
ated. Adverse effects that prompted a
change in antiepileptic drug therapy
occurred in one patient taking levetira-
cetam, who had visual hallucinations, com-
pared with 38 patients taking phenytoin
(18%). In patients who were followed for at
least 1 year and developed epilepsy, levetira-
cetam also had a higher retention rate.
147
Placebo-controlled studies The effect of
levetiracetam as adjunctive therapy in Chi-
nese patients with refractory partial sei-
zures has been evaluated in a 4-week
titration and 12-week maintenance period,
randomized, placebo-controlled trial in 56
patients [183c]. There were adverse events
in 23 patients taking levetiracetam and 22
taking placebo. These were generally mod-
erate and no patient withdrew. Levetirace-
tam was associated with somnolence,
dizziness, and agitation in more than 10%
of patients. There were no treatment-emer-
gent serious adverse events.
Levetiracetam has been evaluated as
add-on therapy in Chinese patients with
refractory partial-onset seizures in a multi-
center, 4 week titration and 12-week main-
tenance, double-blind, placebo-controlled
trial, in which 206 patients aged 1670
years were randomized to levetiracetam
(n 103) or placebo (n 103) [184C].
Levetiracetam signicantly reduced the
weekly partial-onset seizure frequency over
placebo by 27%. Adverse events, which
were of mild-to-moderate intensity, were
reported by 65 patients taking levetiracetam
and 62 taking placebo. The most common
were somnolence (18% levetiracetam and
placebo), reduced platelet counts (9.7% ver-
sus 9.7%), dizziness (7.8% versus 14%),
and headache (3.9% versus 8.7%).
Cardiovascular Maintaining adequate cere-
bral perfusion pressure is key in the man-
agement of patients with acute cerebral
symptoms. For this reason, data from 148
consecutive patients with acute cerebral
symptoms who received intravenous infu-
sions of a single dose of 750 mg or more
of either fosphenytoin (n 78) or levetira-
cetam (n 71) and had blood pressures
documented in the 2 hours before and the
2 hours after their intravenous infusion
have been retrospectively analysed [185c].
Following the infusion, there was a more
than a 10 mmHg fall in systolic, diastolic,
and mean blood pressures in those who
were given fosphenytoin, while there were
only very slight changes in these values in
patients who received levetiracetam. This
148
difference was statistically signicant after
adjusting for age and clinical presentation.
Nervous system In a retrospective analysis
of 207 patients treated with levetiracetam,
there was a paradoxical increase in seizure
frequency or more severe seizures, includ-
ing generalized tonic-clonic seizures, in
14% of patients [186c]. Of the 30 patients
in the paradoxical effect group, 15 were
mentally retarded compared with a much
lower percentage of mentally retarded
patients in the rest of the group (16/177
9%).
A metabolic encephalopathy with tripha-
sic waves and myoclonus has been associ-
ated with levetiracetam intoxication in a
patient with chronic renal insufciency
[187A].
An 80-year-old woman developed status myo-
clonicus combined with a moderate confu-
sional state. Electroencephalography showed
diffuse theta-delta slowing with prominent
multifocal triphasic waves. She was taking
levetiracetam 2000 mg/day for post-stroke
symptomatic seizures, in addition to verapa-
mil, propranolol, metformin, oxazepam,
escitalopram and co-beneldopa. Standard lab-
oratory tests showed stable renal insufciency.
The serum levetiracetam concentration was
184 mmol/l and the dose was reduced to 500
mg/day. Three days later, the myoclonic jerks
had disappeared, cognitive function was nor-
mal, and electroencephalography showed nor-
mal background activity.
Psychological In a prospective, open, non-
interventional study, objective and subjec-
tive cognitive measures were evaluated in
401 patients with epilepsy before and 3
and 6 months after introducing levetira-
cetam [188c]. Very good tolerance was
reported by 68% and cognitive improve-
ment by 58%. Objective improvement was
signicant in one-quarter of the patients,
while 56% deteriorated. Adverse events
were reported in 28 patients. Psychotropic
effects were reported by 1.5%, tiredness by
0.7%, vegetative symptoms by 1.7%, and
increased seizure frequency by 0.7% of
patients.
In a double-blind, placebo-controlled,
non-inferiority study, 99 children with
Chapter 7 Gaetano Zaccara and Luciana Tramacere
inadequately controlled partial-onset sei-
zures were randomized (2:1) to adjunctive
levetiracetam or placebo for 12 weeks
[189c]. Adverse events were reported by
89% of those who took levetiracetam and
85% of those who took placebo. Those
reported more often with levetiracetam
were headache (27%), nasopharyngitis
(17%), fatigue (14%), vomiting (14%),
somnolence (14%), and aggression (13%).
Psychiatric When 288 consecutive patients
with epilepsy who had taken levetiracetam
(90% polytherapy, mean dose 2689 mg)
and 135 of their relatives were asked
whether levetiracetam had caused positive
or negative behavioral changes, 59%
reported a behavioral change that they
explicitly attributed to the drug, which was
very negative (12%), negative (25%), posi-
tive (16%), or very positive (6%), com-
pared with only 9% of 43 control patients
who took other antiepileptic drugs [190C].
Negative ratings were due to loss of self-
control, restlessness, sleeping problems, and
aggression. Positive ratings were due to
increased energy, vigilance, and activation.
These changes were not related to the type
of epilepsy, co-therapy, dose, drug load, or
psychiatric history, even though the nega-
tive effects were associated with poorer sei-
zure control and mental retardation.
Depression has been described in both
elderly epileptic patients [191A] and a child
with epilepsy [192A], probably caused by
levetiracetam.
A 73-year-old black man with stage 4 kidney
disease was given levetiracetam 500 mg bd
for treatment of partial seizures. After 5
months he developed new-onset depression,
with low mood, weight loss, and fatigue. Leve-
tiracetam was withdrawn and 4 weeks later
the depressive symptoms had nearly
completely resolved.
Negative behavioral effects of levetira-
cetam have been reported to have been
mitigated by pyridoxine [193A].
In a randomized, double-blind, parallel-
group study in adults with partial seizures,
including an 8-week escalation phase and
a 12-week double-blind maintenance phase,
Antiepileptic drugs Chapter 7
lamotrigine adjunctive therapy (n 132)
and levetiracetam adjunctive therapy (n
136) have been compared [144C]. Lamotri-
gine was more efcacious than levetirace-
tam in relieving symptoms of anger and
hostility, depression and dejection, fatigue,
and confusion and bewilderment.
Hematologic Thrombocytopenia has been
reported in a child [194A] and an adult with
epilepsy [195A] during treatment with leve-
tiracetam, in one case requiring blood
transfusion. The adverse effect occurred
within days or weeks and quickly resolved
after withdrawal.
Altered platelet function probably caused
by levetiracetam has been reported in a
75-year-old man with focal epilepsy
[196A]. Platelet aggregation prole normal-
ized 3 weeks after drug discontinuation.
Pancytopenia has been described in two
elderly patients who took levetiracetam
for seizures [197A, 198A].
A 76-year-old woman with seizures secondary
to ischemic stroke developed status epilepticus
despite treatment with clonazepam. She was
given intravenous levetiracetam 1000 mg/day
and 2 days later developed pancytopenia, with
a hemoglobin concentration of 9.8 g/dl, a
platelet count of 83  109/l, and a white blood
cell count of 5.7  106/l. These changes wors-
ened during the next 4 days and she required
blood transfusion. Levetiracetam was with-
drawn and 2 days later the blood cell count
improved. When rechallenge with oral levetir-
acetam 0.5 g/day 1 year later pancytopenia
rapidly recurred.
Liver Fulminant liver failure has been
reported, with rapid recurrence after
rechallenge [199A].
A 21-year-old man took levetiracetam for par-
tial seizures for 1 month, and had a general-
ized seizure preceded by a 6-day history of
pale stools, dark urine, and jaundice. The
serum bilirubin was 591 mmol/l, alanine ami-
notransferase 1610 U/l, alkaline phosphatase
246 U/l, and the international normalized ratio
(INR) 3.6. A liver biopsy showed massive con-
uent hepatocyte necrosis with no evidence of
pre-existing liver disease. Levetiracetam was
withdrawn but the liver failure continued to
deteriorate and he subsequently required liver
transplantation. Postoperatively levetiracetam
149
was restarted, but his liver function tests rapid
deteriorated during the next few days. After 4
days levetiracetam was again withdrawn, with
immediate improvement. A liver biopsy per-
formed 2 days later showed a limited acute
resolving insult.
Urinary tract A 17-year-old patient with
epilepsy and normal renal function devel-
oped interstitial nephritis and renal failure
while taking levetiracetam [200A].
A 17-year-old girl took levetiracetam 250 mg
bd for generalized tonic-clonic seizures and
10 days later developed intermittent vomiting,
abdominal pain, and loose stools. She had a
high serum creatinine concentration (290
mmol/l) and the urine was positive for protein
and blood. A renal biopsy conrmed subacute
allergic interstitial nephritis with multifocal
tubular degeneration, interstitial edema, early
brosis, and inltration with lymphocytes and
eosinophils. There were no interstitial granu-
lomas, vasculitis, or glomerulopathy, and glo-
merular and tubular immunoglobulins and
complement were not identied. Viral parti-
cles were not seen at electron microscopy.
The serum creatinine rose further to 680
mmol/l. Levetiracetam was withdrawn and oral
glucocorticoids were administered. He made a
complete and rapid recovery.
Pregnancy Levetiracetam clearance in-
creases in pregnancy. Levetiracetam
plasma concentrations have been prospec-
tively monitored in ve women during
pregnancy and 2 and 12 months after deliv-
ery [201c]. Without change in the dosage of
levetiracetam, the mean levetiracetam con-
centrations during the third trimester were
62% of the 12-month postpartum concen-
trations, but only 47% of the 2-month post-
partum concentrations. The authors
concluded that if the 2-month postpartum
concentrations are considered as baseline,
as is usually the case in prospective studies
on antiepileptic drug pharmacokinetics
during pregnancy, the gestational fall in
levetiracetam concentration throughout
pregnancy would be overestimated. In
three other patients who took lamotrigine,
baseline late postpartum levetiracetam
clearance was 63%, as in the second trimes-
ter. In these patients, the number of sei-
zures was not changed once the dosage of
lamotrigine was increased and none of the
150
women had adverse effects during the puer-
perium. The mean umbilical cord/maternal
levetiracetam plasma concentration ratio
was 1.21 and none of the neonates had mal-
formations; they were normal for their ges-
tational age.
A woman developed status epilepticus
during the rst trimester of pregnancy,
which might have been caused by a fall in
her levetiracetam blood concentrations
[202A]. The clearance of levetiracetam
increases during pregnancy, particularly
during the third trimester, probably due to
increased renal blood ow.
Teratogenicity Of 147 patients 2% had
children with a major congenital malforma-
tion and 4.8% had a minor anomaly; in all
these patients, levetiracetam was associated
with the use of other antiepileptic drugs
[203M].
Drug formulations Extended-release leve-
tiracetam Once-daily extended-release
levetiracetam as add-on therapy in refractory
partial-onset seizures has been evaluated in
a 12 week, double-blind, randomized, pla-
cebo-controlled trial in 158 patients [204C].
There were adverse events in 41 (53%)
of those who used extended-release leve-tira-
cetam and in 43 (54%) of those who used pla-
cebo; the most common were somnolence,
inuenza, irritability, nasopharyngitis, dizzi-
ness, and nausea.
Once-daily adjunctive extended-release
levetiracetam 1000 mg/day (n 70) and
adjunctive immediate-release levetiracetam
500 mg bd (n 204) have been compared
in a meta-analysis of three randomized, pla-
cebo-controlled, phase III trials in 555
patients aged over 16 years with partial-
onset seizures [205M]. After adjustment for
placebo-associated adverse events, immedi-
ate-release levetiracetam was associated
with statistically more treatment-emergent
adverse effects than extended-release
levetiracetam across nervous system disor-
ders (risk difference 18%), psychiatric dis-
orders (risk difference 11%), and
Chapter 7 Gaetano Zaccara and Luciana Tramacere
disorders of metabolism and nutrition (risk
difference 3%).
Intravenous levetiracetam The safety of
rapid intravenous loading doses (20, 40,
and 60 mg/kg; corresponding to maximum
doses of 1000, 2000, and 3000 mg) of leve-
tiracetam has been prospectively evaluated
in healthy subjects and patients with epi-
lepsy [206C]. There were no signicant
effects on blood pressure or electrocardiog-
raphy and no local infusion site reactions.
In a retrospective analysis of 118 intra-
venous infusions of levetiracetam in 15 chil-
dren with epilepsy, most of whom were
aged under 4 years, the following adverse
effects were noted during the post-infusion
period: lethargy (n 2), agitation (1), irrita-
bility (1), mild tremors (1), and ataxia (1);
no adverse effects required drug
withdrawal [207c]. Three patients had
reductions in white blood cell counts within
the rst 4 days after administration of the
rst dose of levetiracetam.
In 12 adults with status epilepticus, intra-
venous levetiracetam 2500 mg was added as
soon as possible to a standardized regimen
of intravenous clonazepam and/or rectal
diazepam as needed followed by phenytoin
or valproic acid; no serious adverse effects
could be related directly to the administra-
tion of levetiracetam [208c].
In a retrospective analysis of 36 patients
who received intravenous levetiracetam
for refractory status epilepticus [209c] a
median dose of 3000 mg/day (range 1000
9000) was used as a loading bolus or by
continuous pump infusion. Status epilepti-
cus was terminated in 69% of patients.
None had cardiac dysrhythmias or signi-
cantly reduced blood pressure, or required
an increase in the dose of catecholamines.
Two patients had nausea and vomiting dur-
ing levetiracetam loading, leading to aspira-
tion pneumonia in one.
In a retrospective study of 32 patients
who had been given intravenous levetirace-
tam for status epilepticus, there was arterial
hypotension after intravenous levetirace-
tam in four patients during co administra-
tion of propofol and during rapid infusion
of phenytoin in one patient [210c]. There
Antiepileptic drugs Chapter 7
were no cardiac dysrhythmias and no
impairment of respiration or oxygenation.
There was sedation after drug administra-
tion in six patients, but only in those who
had previously received benzodiazepines.
Nausea and vomiting occurred in one
patient and another had raised liver
enzymes. There were no signs of local irri-
tation at injection sites.
In a retrospective study in 43 patients with
various forms of status epilepticus after inef-
fective treatment with benzodiazepines,
intravenous levetiracetam was given as a
short infusion of 1000 or 2000 mg [211c]. Sta-
tus epilepticus was terminated in 19. There
were no severe adverse reactions. Among
patients aged over 80, somnolence was
reported, which could have been due to
benzodiazepines, and/or post-seizure
twilight state. There were no metabolic
disturbances or interactions.
In a retrospective chart study of 34 patients
with status epilepticus who were given intra-
venous levetiracetam, the median loading
dose of levetiracetam was 1000 mg and the
maintenance dosage was 5001500 mg/12
hours (median 1000 mg/12 hours) [212c]. Sta-
tus epilepticus stopped in a clear temporal
relation to drug infusion in 71% of patients
and there were no serious adverse events.
Management of adverse drug reactions
The possible benet of pyridoxine (vitamin
B6) in the treatment of levetiracetam-
induced behavioral adverse effects has
been explored in a questionnaire study in
90 children with epilepsy, 22 of whom
started taking pyridoxine after having been
taking levetiracetam [213c]. There was
behavioral improvement in nine, no effect
in eight, deterioration in four, and an
uncertain effect in one.
Oxcarbazepine [SED-15, 2646; SEDA-
30, 83; SEDA-31, 118; SEDA-32, 141]
Observational studies In a prospective
open study in 147 patients with newly diag-
nosed epilepsy, followed for a median of
151
18 months, 92 became seizure-free [214c].
Overall, 13 (8.8%) stopped taking oxcarba-
zepine because of intolerable adverse
effects: nausea, and vomiting with low
serum sodium concentrations (5); Stevens
Johnson syndrome (n 2); fatigue and
drowsiness (2); dizziness, nausea, and
vomiting (2); and severe headache, dizzi-
ness, and raised serum gamma-glutamyl
transferase activity (1 each). Only one
elderly patient had hyponatremia with mild
symptoms, which responded to uid restric-
tion and did not require drug withdrawal.
In 36 children with newly diagnosed par-
tial epilepsy who were given oxcarbazepine
monotherapy (average dose 22, range 10
35 mg/kg) and were followed for 36
months, 18% had adverse effects (fatigue,
headache, sedation, memory decit, agita-
tion) after 1 year, but during the second
year only one patient still had an adverse
effect (headache) and during the third one
had reduced vigilance [215c]. There were
no cases of hyponatremia or hepatic dys-
functions. Oxcarbazepine was withdrawn
because of sedation in one patient.
Comparative studies Oxcarbazepine has
been compared with traditional anti-
epileptic drugs in 35 patients with brain
tumor-related epilepsy in a retrospective
observational study [216c]. Oxcarbazepine
and traditional antiepileptic drugs had sim-
ilar efcacy but different patterns of
adverse effects. Signicantly fewer of those
who took oxcarbazepine dropped out and
in relation to serious adverse effects, only
three of those who took oxcarbazepine
compared with 13 of those who took other
drugs had to stop treatment. As regards
the total incidence of adverse effects, four
patients had adverse effects during oxcar-
bazepine treatment compared with 15 of
those who took other drugs.
In a retrospective study of the medical
records of 26 children and adolescents with
epilepsy who had been rapidly switched
from carbamazepine to oxcarbazepine
(dose conversion ratios 1.01.5), the transi-
tion was well tolerated; three patients had
adverse events (rashes) [217c].
152
Oxcarbazepine and carbamazepine have
been compared for 8 weeks in 52 patients
with bipolar disorders already taking lith-
ium [73c]. Both drugs reduced bipolar
scores; 14 patients taking oxcarbazepine
and 15 taking carbamazepine reported at
least one adverse event.
Oxcarbazepine (10002400 mg/day) and
divalproex sodium (7502000 mg/day) have
been compared in a 12 week, randomized,
double-blind pilot study in 60 patients with
acute mania [218c]. The median time to
symptomatic remission of and the relapse
rate did not differ. There were 22 adverse
events in those who took oxcarbazepine
group compared with 56 in those who took
divalproex. The most common adverse
events with oxcarbazepine were nausea
(n 5), dizziness (3), vomiting (4), sedation
(3), and dyspepsia (3).
Systematic reviews Oxcarbazepine is claim-
ed to be better tolerated than carbamazepine.
In a meta-analysis of blinded and unblinded
randomized controlled trials (723 partici-
pants) of carbamazepine versus oxcarbaze-
pine monotherapy for partial-onset seizures,
the most common adverse events were
allergic rash, dizziness or vertigo, and head-
ache; there were no signicant differences
between the two drugs [219M]. There was a
trend towards a clinical advantage of oxcarba-
zepine in the occurrence of fatigue/drowsi-
ness/sedation, and there were signicantly
more episodes of nausea, vomiting, or both
among those who used oxcarbazepine.
Nervous system Parkinsonism has been
attributed to oxcarbazepine [220A].
A 38-year-old woman with trigeminal neural-
gia was given oxcarbazepine 900 mg/day and
after 1 week developed slowing of body move-
ments, monotonous speech, gait abnormality,
and tremor in her hands. There was facial
hypomimia, bilateral bradykinesia, cogwheel
rigidity, postural instability and a slight inter-
mittent rest tremor in the hands. Cranial
MRI, MR angiography, and laboratory exam-
inations were normal. Oxcarbazepine was
Chapter 7 Gaetano Zaccara and Luciana Tramacere
withdrawn and 2 weeks later all the extrapyra-
midal symptoms had resolved.
Neuroleptic malignant syndrome without
fever occurred when oxcarbazepine was
given in addition to long-term administra-
tion of amisulpride [221A].
A 31-year-old man who was already taking
amisulpride 400 mg bd for chronic schizophre-
nia took oxcarbazepine up to a maintenance
dose of 1200 mg/day. After a few days he
developed altered consciousness, tremor,
rigidity, slow movements, a wooden appear-
ance, sweating, a high blood pressure (165/95
mmHg), and a uctuating pulse rate. His tem-
perature was 37  C. He had a mild leukocyto-
sis, raised serum AST and ALT activities, and
markedly raised creatine kinase and lactate
dehydrogenase activities (3038 and 727 U/l
respectively). Other laboratory results were
normal. A brain CT scan was normal and
there was no evidence of infection or thyroid
disease. A diagnosis of neuroleptic malignant
syndrome was made. Amisulpride was with-
drawn and the dose of oxcarbazepine was
reduced to 600 mg/day. Amantadine and levo-
dopa were added and the serum creatine
kinase, which peaked (4019 U/L) on the sec-
ond day, fell thereafter and become normal
after 10 days. The syndrome resolved
completely after 7 days.
The association between oxcarbazepine was
not clear in this case.
Hematologic Reversible leukopenia and
hyponatremia have been attributed to
high-dose oxcarbazepine [222A].
A 38-year-old man with partial epilepsy taking
a stable regimen of levetiracetam (3000 mg/
day), clonazepam (4 mg/day), and oxcarbaze-
pine (1800 mg/day) increased the dosage of
oxcarbazepine to 2400 mg/day because of par-
tial seizures with secondary generalization. He
developed hyponatremia (125 mmol/l) and
leukopenia (total white cell count 2.8  109/l;
50% neutrophils). The dosage of oxcarbaze-
pine was reduced to 1800 mg/day and a few
days later the white cell count was 3.8  109/l
with a parallel increase in sodium concentra-
tion to 132 mmol/l. The dosage of oxcarbaze-
pine was again increased to 2400 mg/day, and
after 2 more days both the white cell count
and serum sodium fell (to 3.2  109/l and 125
mmol/l respectively). Oxcarbazepine was with-
drawn and replaced by topiramate; 2 days
Antiepileptic drugs Chapter 7
later the white cell count was 4.8  109/l and
the serum sodium concentration was normal.
Skin Oxcarbazepine is considered to be
much less likely than carbamazepine to cause
skin reactions, owing to its different meta-
bolic pathway. Oxcarbazepine-associated
StevensJohnson syndrome has been
described in two Chinese patients with epi-
lepsy, one of whom was positive for HLA-
B*1502 [223A, 224A].
A 53-year-old man, who was taking enalapril
maleate, amlodipine besylate, and aspirin,
had several seizures and was given rst pheno-
barbital, then valproic acid, and then oxcarba-
zepine. After 20 days he developed a
generalized skin rash and oral ulceration fol-
lowed by a high fever. He had widespread
conuent erythematous macules and papules
and numerous at atypical target lesions with
central dusky discoloration on the face, neck,
trunk, and proximal arms. Genotyping showed
the presence of an HLA-B*1502 allele.
A 13-year-old boy developed a severe
rash and systemic symptoms after starting
to take oxcarbazepine [225A].
Musculoskeletal The effect of oxcarbaze-
pine on bone metabolism has been inve-
stigated in two studies, with slightly different
results.
In a cross-sectional study in 28 adults with
epilepsy who took oxcarbazepine monother-
apy for 1 year and 28 healthy volunteers,
[226c] although alkaline phosphatase and
vitamin D3 concentrations were signicantly
different, calcium, phosphate, alkaline phos-
phatase, and bone densitometry were not dif-
ferent from baseline after 1 year.
In a second study, the effect of oxcarbaze-
pine monotherapy for 18 months on bone
turnover was longitudinally explored in 34
newly diagnosed prepubertal and pubertal
children [227c]. The serum concentrations of
25-hydroxycolecalciferol were signicantly
reduced by oxcarbazepine, while osteocalcin
and gamma-glutamyl transferase activity
were signicantly increased compared with
baseline values. Phosphorus, parathyroid
hormone, and calcitonin concentrations and
alkaline phosphatase activity increased non-
signicantly. In three patients who had
153
T scores of bone mineral density worse than
1.5 before treatment, there was osteopenia
after oxcarbazepine treatment (T scores
worse than 2.0).
Immunologic A lupus-like syndrome occur-
red in a young boy who took oxcarbazepine
and valproic acid [228A].
A 7-year-old boy with epilepsy, who was taking
oxcarbazepine, developed a fever, anorexia,
diffuse arthralgias, myalgias, weight loss, and
swelling of the nger and toe joints. He had a
raised erythrocyte sedimentation rate and C-
reactive protein and antinuclear antibodies
were positive (1/160). Since he was having
recurrent seizures, valproic acid and levetirace-
tam were added and the dosage of oxcarbaze-
pine was reduced. After 45 days he was still
symptomatic. He had generalized lymphade-
nopathy, hepatosplenomegaly, and arthritis in
the proximal interphalangeal joints of the
hands, wrists, and ankles. The main laboratory
ndings were strongly positive Coombs test
and antinuclear antibody (1/1000) and positive
anti-histone and anti-nucleosome antibodies.
Oxcarbazepine and valproic acid were with-
drawn and glucocorticoid treatment was
started. The syndrome resolved after 2 days
and the laboratory tests gradually normalized.
Teratogenicity A female infant was born
with micrognathia, low-set ears, facial dys-
morphism, and unilateral radius aplasia to
a mother who had used lamotrigine 100
mg/day and oxcarbazepine 1200 mg/day
during pregnancy for seizures [170A].
Drug formulations Extended-release oxcar-
bazepine should cause fewer adverse effects
because of the less marked peak serum oxcar-
bazepine concentration before metabolism to
its active monohydroxy derivate. In an open
study, 27 patients with difcult-to-treat locali-
zation-related epilepsies who had been taking
immediate-release oxcarbazepine were
abruptly switched to extended-release oxcar-
bazepine in identical dosages and the concen-
trations of oxcarbazepine and its active
metabolite were measured before and after
the switch [229c]. The new formulation was
associated with signicantly fewer adverse
effects and better quality of life, and this was
explained by lower peak oxcarbazepine
concentrations.
154
Drug overdose Oxcarbazepine overdose
has been described in a child [230A].
A 13-year-old boy with autism spectrum disor-
der taking risperidone accidentally ingested
oxcarbazepine suspension 15 g after it was
added in a dosage of 300 mg bd to treat persis-
tent aggression. He had normal vital signs and
was somnolent but rousable to painful stimuli.
Neurological examination, electrocardiogra-
phy, and laboratory tests were normal. He was
given activated charcoal by nasogastric tube
and remained hemodynamically stable and did
not need ventilatory support. His somnolence
progressively improved over the next 12 hours.
Phenobarbital and primidone
[SED-15, 2798; SEDA-30, 85;
SEDA-32, 145]
Observational studies When patients with
partial epilepsy who were taking carbamaz-
epine were randomized to either valproate
(n 68) or primidone (n 68) in an open
study, signicantly more of those who took
valproate achieved a greater than 50% sei-
zure reduction [231c]. Of those taking pri-
midone, three withdrew because of
dizziness, three because of drowsiness, and
one because of gastrointestinal complaints.
Nervous system An infant with drug-
resistant epilepsy associated with bilateral
SturgeWeber syndrome became comatose
after taking high-dose phenobarbital for a
few months and regained consciousness as
the serum phenobarbital concentration fell
to below 40 mg/ml. The authors suggested
that patients with severe cerebrovascular
diseases are more susceptible to the seda-
tive effects of phenobarbital [232A].
A 13-year-old girl with acute intermittent
porphyria had several attacks of the disease
and developed an acute severe axonal motor
neuropathy after taking porphyrinogenic
medications, including phenobarbital, for 3
weeks [233A].
Skin Seven children aged 211 years devel-
oped severe skin reactions (erythema
Chapter 7 Gaetano Zaccara and Luciana Tramacere
multiforme, StevensJohnson syndrome,
and toxic epidermal necrolysis) while taking
barbiturates [234A] and another case of
toxic epidermal necrolysis has been
described [235A].
A 3-year-old boy who had had an anti-
convulsant hypersensitivity syndrome
developed alopecia areata universalis while
convalescent [236A]. Skin histology showed
perifollicular, peribulbar, and suprabulbar
lymphocyte inltration.
Recurrent plantar bromatosis, also
known as Ledderhose syndrome, occurred
in a patient who had taken phenobarbital
for a long time [237A].
Teratogenicity The teratogenic potential of
high doses of phenobarbital has been studied,
in a comparison of the number of congenital
anomalies observed in exposed children born
to pregnant patients who attempted suicide
with phenobarbital during pregnancy with
the number observed in unexposed children
born to the same patients [238c]. Of 1044
self-poisoned pregnant women, 88 took phe-
nobarbital 4003000 mg in a suicide attempt
and delivered live babies; 12 (14%) of the 88
exposed children and 8 (10%) of their 78 sib-
lings had congenital abnormalities; 34 of the
88 exposed children were born to mothers
who attempted suicide with phenobarbital
between the 3rd and 12th post-conceptional
weeks, the critical period for most congenital
abnormalities. The authors concluded that
the use of phenobarbital once but in
extremely large doses in non-epileptic preg-
nant women does not seem to be associated
with an increased risk of congenital
abnormalities.
Drug withdrawal Seizures have been re-
ported after withdrawal of phenobarbital,
despite very slow tapering [239A].
A 51-year-old woman, who had been seizure-
free for 3 years after the removal of a cavernous
angioma in her right anterolateral temporal
lobe, and who had taken phenobarbital 150
mg/day for 11 years, started reducing the dose
and replacing it with lamotrigine. When the
dose of phenobarbital reached 60 mg/day
(blood concentration 7 mg/ml) with lamotrigine
25 mg bd, complex partial seizures occurred.
Antiepileptic drugs Chapter 7
Her dose of phenobarbital was increased to 90
mg/day and she again became seizure-free.
Lamotrigine had to be withdrawn because of a
rash. Levetiracetam was started and at a dose
of 500 mg bd the dose of phenobarbital was
tapered again at a slower rate. However, she
had complex partial seizures again when she
was taking phenobarbital 30 mg/day and leve-
tiracetam 750 mg bd. The dose of levetiracetam
was increased to 1000 mg bd, but complex par-
tial seizures continued while the dose of pheno-
barbital was being tapered and for 3 weeks after
withdrawal. No further seizures occurred dur-
ing the next 24 months.
The authors suggested that molecular
changes in the GABA system probably
accounted for many of the effects of pheno-
barbital withdrawal.
Drug overdose A man who was dependent
on phenobarbital committed suicide by tak-
ing twenty 60-mg tablets [240A].
Phenytoin and fosphenytoin
[SED-15, 2813; SEDA-30, 85;
SEDA-31, 120; SEDA-32, 145]
Comparative studies Phenytoin and leve-
tiracetam Phenytoin has been compared
retrospectively with levetiracetam for pro-
phylaxis of early and late postoperative sei-
zures in 315 patients [182c]. Adverse effects
prompting a change in antiepileptic drug
therapy in only one patient taking levetira-
cetam, who had visual hallucinations, but in
38 (18%) of those who took phenytoin. In
patients who were followed for at least 1
year and developed epilepsy, levetiracetam
had also a higher retention rate.
Phenytoin and valproate Phenytoin (n 25)
by infusion and intravenous valproate (n 49)
have been compared in status epilepticus
or acute repetitive seizures in 74 patients
[241c]. There were no adverse effects with
valproate but three patients who received
phenytoin had adverse effects (cardiac
dysrhythmias, vertigo, and hyponatremia).
155
Cardiovascular Life-threatening junctional
bradycardia occurred in a patient with a
high serum phenytoin concentration (91
mg/l, 23 mmol/l). The authors suggested that
in this case severe cardiotoxicity had been
caused by the high concentration of pheny-
toin and the presence of predisposing fac-
tors that enhanced drug toxicity [242A].
Fulminant myopericarditis occurred in a
patient with drug-induced lupus from
chronic use of phenytoin [243A].
Respiratory Pneumonitis has been attri-
buted to phenytoin [244A].
A 48-year-old woman who had taken pheny-
toin for 30 years developed a dry cough and
a low-grade fever and was given various anti-
biotics for 1.5 years, without effect. A chest
X-ray and a CT scan showed diffuse reticular
ground glass opacities in both lung elds. A
drug lymphocyte stimulation test for pheny-
toin was positive. A lung biopsy showed pre-
dominant lymphocytic inltration of the lung
parenchyma, compatible with drug-induced
pneumonitis. Phenytoin was withdrawn and
oral prednisolone was given. The symptoms
and X-ray improved.
Neuromuscular function Phenytoin toxicity
masquerading as motor neuron disease has
been described [245A].
A middle-aged lady who was taking phenytoin
600 mg/day, sodium valproate 1000 mg/day,
and clonazepam 1 mg/day developed progres-
sive difculty in walking, dysarthria, dyspha-
gia, and weight loss. She had diplopia and
motor weakness greater on the right, with
hyper-reexia and fasciculation. Electromyog-
raphy and nerve conduction studies showed
chronic denervation with signs of re-innerva-
tion. She was hypoalbuminemic and had a
high serum phenytoin concentration (237
mmol/l). Phenytoin was withdrawn and when
the concentration fell, her motor power, respi-
ratory function, and bulbar weakness became
normal.
Endocrine A 48-year-old woman with epi-
lepsy and hypothyroidism had an episode
of phenytoin intoxication and was found
to be profoundly hypothyroid, despite ade-
quate thyroid replacement therapy; normal-
ization of the phenytoin concentration was
associated with reversion to euthyroidism
[246A].
156
Metabolism Of 30 patients with epilepsy
who were taking long-term phenytoin, 10
had osteoporosis and 17 had osteopenia,
affecting predominantly the femur, without
any signicant reduction in bone mineral
density in the lumbar spine [247cE]. There
were small changes calcium and phosphate
metabolism with trends towards hypocalce-
mia and secondary hyperparathyroidism,
which were not due to vitamin D de-
ciency, as the serum vitamin concentrations
were normal.
Hematologic Agranulocytosis has been
observed as an unexpected progression
from a phenytoin-associated antiepileptic
drug hypersensitivity syndrome [248A].
A 5-year-old boy with a drug-resistant form of
epilepsy received intravenous phenytoin
because of very frequent focal and generalized
seizures. His seizure frequency improved.
Phenytoin was continued orally, and 12 days
later he suddenly developed a high fever, a
diffuse erythematous maculopapular rash
involving the face and trunk, bilateral cervical
lymphadenopathy, and increased serum trans-
aminase activities, consistent with drug hyper-
sensitivity syndrome. Phenytoin was
immediately withdrawn and high-dose intra-
venous methylprednisolone pulse therapy
was introduced. The fever abated within 2
days, the skin rash gradually resolved, and
the transaminases normalized. However, on
the 8th day after defervescence, the high fever
reappeared without any other symptoms or
localized signs. On the same day, he had neu-
trophil were barely detected in a peripheral
blood lm. He was given granulocyte colony-
stimulating factor, cefepime, and intravenous
immunoglobulin and recovered completely
within 1 week.
Urinary tract Fibrillary glomerulonephritis,
a rare form of glomerulopathy with immu-
noglobulin deposition, has been associated
with phenytoin in a patient with epilepsy
[249A].
Granulomatous interstitial nephritis has
been reported in a 25-year-old man who
had been taking phenytoin 300 mg/day
[250A].
Urolithiasis due to phenytoin has been
reported [251A].
Chapter 7 Gaetano Zaccara and Luciana Tramacere
A 79-year-old woman, who had been taking
phenytoin for 10 years, developed a fever
and seizures and was found to have a right
pelvic kidney with hydronephrosis and multi-
ple large calcications. Urinary stones were
removed by percutaneous nephrolithotomy
and contained the phenytoin metabolite
5-(para-hydroxyphenyl)-5-phenylhydantoin
(35%) and proteinaceous material (65%).
This was a between-the-eyes adverse reaction
of type 1a [252H]. In this patient, the average
total serum phenytoin concentration in the
previous year was in the usual target range.
The authors concluded that a metabolite of
phenytoin can cause urolithiasis.
Skin A woman developed localized skin
necrosis after intravenous administration of
phenytoin for generalized convulsive status
epilepticus. The authors consequently made
some recommendations for the intravenous
administration of phenytoin: a dedicated
intravenous cannula should be inserted in a
large peripheral vein; the rate of administra-
tion should not exceed 50 mg/minute; the can-
nula should be periodically ushed with saline
after each bolus; continuous monitoring
for signs of extravasation, hypotension, and
bradycardia should be performed [253A].
Phenytoin has been implicated in two
cases of drug rash with eosinophilia and sys-
temic symptoms (DRESS) in children
[254A].
Susceptibility factors Genetic Phenytoin is
metabolized principally by CYP2C9 and less
so by CYP2C19. There is conicting evi-
dence about the potential role of P glycopro-
tein (coded by the adenosine triphosphate-
binding cassette subfamily B member 1;
ABCB1) in transporting phenytoin out of
the central nervous system. The association
between common genetic variants in the
exons of the genes for cytochrome CYP2C9,
CYP2C19, and ABCB1 and the risk of acute
nervous system toxicity has been retrospec-
tively explored in 14 patients with epilepsy
receiving phenytoin, who had acute pheny-
toin intoxication [255c]. The adjusted OR
for the CYP2C9*1/*3 genotype was 8.91
(95% CI 0.79, 100). The adjusted OR
for the CYP2C9*2/*2 genotype was 9.48
Antiepileptic drugs Chapter 7
(95% CI 0.79, 115). The adjusted OR for
the CYP2C19*1/*3 genotype was 4.21 (95%
CI 0.58, 31). All of the other odds ratios
were close to unity. However, these data
were not statistically signicant, and it is
not clear whether these putative genetic
associations are important in determining
the adverse effects of phenytoin.
The possible association between HLA-
B*1502 and carbamazepine- or phenytoin-
induced StevensJohnson syndrome or macu-
lopapular eruptions has been explored in 31
Thai subjects who had these antiepileptic
drug-induced complications between 1994
and 2007 and in 50 subjects who had no such
reactions [92c]. There was a strong association
between HLA-B*1502 and phenytoin- and
carbamazepine-induced StevensJohnson
syndrome. However, some patients with the
allelic variant HLA-B*1502 had Stevens
Johnson syndrome while taking carbamaze-
pine but not while taking phenytoin and vice
versa, which suggests that other factors con-
tribute to this adverse reaction.
A 53-year-old Asian woman took pheny-
toin for 4 days and became lethargic, with a
high unbound concentration 4.4 mg/l. She
was a CYP2C9 poor metabolizer [256A].
Gastrointestinal disease A patient with
epilepsy taking phenytoin had intes-
tinal obstruction and developed status epi-
lepticus as a result of phenytoin
intoxication, which was caused by altered
absorption due to paralytic ileus [257A].
A19-year-old woman with cerebral palsy and
epilepsy had her convulsions well controlled
by phenytoin, phenobarbital, and nitrazepam.
She developed a diagnosis of paralytic ileus
related to acute gastroenteritis, and was given
intravenous infusions in lieu of eating and
drinking. The antiepileptic drugs were given
orally as before. After 7 days she developed
status epilepticus. Diazepam failed to control
the convulsions, and she was intubated and
pentobarbital was given; the convulsions
stopped. The serum phenytoin concentration
3 days later was 69 mg/l (17 mmol/l).
Prolonged stasis of phenytoin in the
obstructed intestinal tract was believed
to have delayed drug absorption and
nally increased the serum concentration,
157
causing phenytoin intoxication and status
epilepticus.
Drugdrug interactions Clozapine Pheny-
toin intoxication occurred after the intra-
venous administration of a loading dose of
phenytoin in a patient with clozapine-
related seizures; phenytoin intoxication
was supposed to have been due to inhibi-
tion of CYP2C9 by clozapine [258A].
TS-1 A patient who took phenytoin and
TS-1, a combination formulation of tegafur,
gimeracil, and oteracil potassium, for 1
month became lightheaded and had re-
peated falls associated with a serum
phenytoin concentration of 34 mg/l
(8.6 mmol/l). The authors suggested that
the time between the start of combined
treatment and the onset of the adverse
symptoms suggested an indirect mecha-
nism, rather than direct inhibition of
phenytoin-metabolizing enzymes by TS-1
[259A].
Management of adverse drug reactions
Several methods have been proposed to
enhance the elimination of phenytoin after
overdose, and the effectiveness of hemo-
perfusion is debated. A woman with severe
iatrogenic phenytoin overdosage, with a
peak plasma concentration of 117 mg/l (29
mmol/l) beneted substantially from three
sessions of a 4-hour long combination of
activated charcoal hemoperfusion and
high-ux hemodialysis; these procedures
considerably shortened the half-life of
phenytoin from 40100 hours to 713 hours
[260A].
Pregabalin [SEDA-30, 86;
SEDA-32, 146]
Observational studies In 15 patients with
familial dysautonomia, pregabalin up to a
dose of 6 mg/kg/day gave good results in
the treatment of nausea and dysautonomic
crises [261c]. Adverse effects included
peripheral edema in one patient who
158
stopped taking pregabalin, weight gain in
four, and worsened balance in seven.
In a prospective open pilot study, 16
patients with multiple sclerosis and painful
paroxysmal symptoms were treated with
pregabalin 75300 mg/day for at least 3
months [262c]. Three dropped out of the
study because of adverse effects: one with
dizziness, two with difculty in concentra-
tion and general malaise.
In an open study, 30 children, who had
been treated for solid tumors and leukemia
and had developed a painful peripheral
neuropathy, were given pregabalin 150
300 mg/day for 8 weeks [263c]. There was
signicant long-lasting pain relief in 25
them. There were mild or moderate
adverse effects (nausea and drowsiness in
the titration phase) in four patients; drug
withdrawal was not required.
Long-term persistence with pregabalin
treatment has been retrospectively evalu-
ated in 402 patients with epilepsy, of whom
15 stopped taking it within 1 week (all
reported either adverse effects or worsen-
ing of seizures) [264C]. At last follow-up,
168 patients (42%) continued to take pre-
gabalin. Adverse effects were reported by
220 patients, of whom 162 withdrew. The
most frequent adverse effects were nervous
system-related, including lethargy, tiredness,
headaches, blurred vision, double vision,
unsteadiness, and ataxia, which were
reported by 141 patients. Weight gain was
reported by 48 patients (30 withdrew). Psy-
chiatric adverse effects were observed in 26
patients (12 reported depression, low
mood, or mood swings, and 24 withdrew).
Woman were more likely to report adverse
effects than men, but not more likely to
report weight gain.
Comparative studies Pregabalin and 5%
lidocaine in a medicated plaster have been
compared in a randomized, open, multicen-
ter, non-inferiority study in 96 patients with
post-herpetic neuralgia and 204 with pain-
ful diabetic polyneuropathy [265C]. Overall,
66% of those who used the lidocaine plas-
ter and 62% of those who used pregabalin
were considered to have responded. There
Chapter 7 Gaetano Zaccara and Luciana Tramacere
were fewer adverse effects from lidocaine
than pregabalin (5.8% versus 41%).
In an open study 409 patients with neu-
ropathic pain were given pregabalin con-
trolled-release oxycodone (n 169) or
monotherapy with either oxycodone (n
106) or pregabalin (n 134) [266C]. The
combination of controlled-release oxy-
codone pregabalin and controlled-release
oxycodone monotherapy were both more
effective in alleviating neuropathic pain
than pregabalin monotherapy. Combina-
tion therapy had a better safety prole than
monotherapy with either drug, with a drop-
out rate due to adverse events of 5.9%
compared with 10% and 19% respectively.
The most frequently reported adverse
events with pregabalin were somnolence
and peripheral edema. Combination ther-
apy was most often associated with consti-
pation. Overall, the combination of
controlled-release oxycodone and pregaba-
lin resulted in an improved adverse events
prole compared with pregabalin
monotherapy.
Pregabalin and celecoxib, alone and in
combination, have been evaluated in the
treatment of chronic low-back pain in 36
patients in a 12-week, randomized, cross-
over study [267c]. The combination was
more effective than either monotherapy.
Adverse effects were recorded in 16
patients and four patients withdrew as a
result. Five patients reported nausea or diz-
ziness during treatment with pregabalin and
seven had similar symptoms during treat-
ment with celecoxib pregabalin.
Placebo-controlled studies Pregabalin has
been compared with amitriptyline in allevi-
ating pain associated with diabetic periph-
eral neuropathy in a randomized, double-
blind, crossover, active-control, 5-week
maintenance trial with variable dose titra-
tion in 51 [268c] subjects, who were ran-
domized to pregabalin (starting at 75 mg/
day and increasing to 150 and 300 mg bd
after 1 and 2 weeks) or amitriptyline (start-
ing at 10 mg/day and increasing to 25 and
50 mg at night-time). There was no signi-
cant difference between the treatments.
There were 34 treatment-emergent adverse
Antiepileptic drugs Chapter 7
events with amitriptyline and 18 with pre-
gabalin. Amongst pregabalin users, three
patients developed daytime somnolence,
three developed dizziness, three had consti-
pation, two developed peripheral edema,
and one developed u-like symptoms.
Six patients withdrew as a result of
adverse events (three with somnolence,
two with peripheral edema, and one with
constipation).
Of 20 patients with essential tremor who
were randomized to pregabalin 150600
mg/day or placebo in a double-blind, cross-
over study four withdrew during pregabalin
treatment because of postural instability,
nausea, and dizziness (two cases) [269c].
Other adverse effects were mild to moder-
ate in intensity. More common during preg-
abalin versus placebo were drowsiness
(pregabalin 5 versus placebo 3), dizziness
(4 versus 1), and fatigue (3 versus 0).
Systematic reviews A systematic review
and meta-analysis of randomized, double-
blind studies of the analgesic effect of pre-
gabalin in acute and chronic neuropathic
pain conditions showed no clear evidence
of benecial effects in acute postoperative
pain [270M]. Pregabalin 300, 450, and 600
mg/day was effective in patients with post-
herpetic neuralgia, painful diabetic neuropa-
thy, central neuropathic pain, and bromyal-
gia. The number of patients with a serious
adverse event during pregabalin treatment
was the same as in those who took placebo.
Treatment was withdrawn because of
adverse events in 1828% of subjects. Day-
time somnolence typically occurred in 15
25% and dizziness occurred in 2746% at a
pregabalin dose of 600 mg/day.
Nervous system Pregabalin-associated my-
oclonus and confusion has been de-
scribed in a patient with chronic renal
insufciency [271A].
A 47-year-old man with chronic renal insuf-
ciency (baseline urea and creatinine concentra-
tions of 22 mmol/l and 359 mmol/l respectively)
secondary to insulin-dependent diabetes melli-
tus and self-administered peritoneal dialysis
started to take pregabalin 75 mg bd for distal
neuropathic pain and 2 days later became
159
confused and drowsy, had visual hallucinations,
and developed large-amplitude myoclonic jerks
that prevented ambulation. Noises provoked
startle responses. Pregabalin was withdrawn,
and 90 hours later (16 dialysates), the myoclo-
nus and other symptoms had resolved.
This patient previously had similar revers-
ible confusion and myoclonus while taking
gabapentin 300 mg tds.
Parkinsonism has been associated with
pregabalin [272A].
A 64-year-old woman with a diabetic sensori-
motor polyneuropathy for which she was tak-
ing gabapentin 300 mg/day amitriptyline 25
mg/day was given pregabalin 75 mg bd in
addition to her usual medications, and 3
months later developed a resting chin tremor
that resolved with speech, impaired writing
with micrographia, general slowness, and dif-
culty in executing certain activities of daily liv-
ing. The diagnosis was parkinsonism, with
axial symptoms, bilateral symmetrical postural
tremor, bradykinesia, and rigidity. Pregabalin
was withdrawn and 6 months later she had
almost completely recovered.
Two patients with multiple sclerosis, who
were taking pregabalin for pain, developed
acute delirium and delusions [273A].
A 65-year-old woman with multiple sclerosis,
spastic paraparesis, and chronic pain, who
had previously taken gabapentin, lamotrigine,
and amitriptyline, with partial pain relief, was
given pregabalin 75 mg/day; after 3 days she
developed slurred speech, delusions, and
insomnia. Pregabalin was withdrawn, and she
recovered her normal cognitive function.
Demyelinating lesions throughout the CNS
may have facilitated this unusual effect of
pregabalin.
Electrolyte balance Severe clinical confu-
sion secondary to hyponatremia has been
associated with pregabalin and attributed
to pregabalin-induced sodium wasting
nephropathy [274A].
A 74-year-old man with type II diabetes melli-
tus and an ischemic cardiomyopathy with con-
gestive heart failure had a below-knee
amputation because of chronic osteomyelitis
and was given pregabalin for neuropathic
pain. After several weeks he became weak
and confused. There were no signs of
160
peripheral edema or pulmonary congestion.
The serum sodium was 110 mmol/l, potassium
4.40 mmol/l, and osmolarity 232 mOsm/kg.
Pregabalin was withdrawn, followed by uid
restriction and isotonic saline. The sodium
concentration rose to 125 mmol/l and the con-
fusion resolved. On day 4 the sodium concen-
tration had risen to 130 mmol/l.
Urinary tract Pregabalin toxicity in a
hemodialysis patient has been successfully
treated with hemodialysis [275A].
Runamide
Runamide is a novel anticonvulsant that
prolongs the inactivated state of voltage-
gated sodium channels. It was approved for
use in Europe in January 2007 and by the
Food and Drug Administration in the USA
in January 2009 as add-on therapy for sei-
zures in patients aged 4 years and older with
LennoxGastaut syndrome. Somnolence
and vomiting are common adverse effects,
as are headache, dizziness, fatigue, nausea,
diplopia, and tremor. Electrocardiography
shows that runamide shortens the QT inter-
val, which seems to be free of risk, but it
should be avoided in patients with familial
short QT syndrome, and caution must be
exercised when using it with other medica-
tions that can shorten the QT interval [276S].
Observational studies Non-blinded studies
have suggested benecial effects in patient
with myoclonic and absence seizures [277c].
Runamide has been studied in 409 chil-
dren with epilepsy in the double-blind pla-
cebo-controlled studies and in 391 patients
receiving runamide in double-blind and/
or open extensions. Somnolence, vomiting,
and headache were the most common
adverse events. There was no change in
hematology or body weight [278C].
In a retrospective analysis of all data
from patients taking runamide in Ger-
many and Austria, 45 children and 15
adults were identied with various severe
and inadequately controlled epilepsy syn-
dromes. The response rate (at least a 50%
Chapter 7 Gaetano Zaccara and Luciana Tramacere
seizure reduction) was 47% (28 of 60
patients); 35 (58%) had at least one adverse
event during runamide treatment. The
most common adverse events were fatigue
in 11 patients, vomiting in eight, loss of appe-
tite in six, and behavioral disturbances in ve.
Tremor, sleep disturbances, exhaustion,
unstable gait, and dizziness were reported
in three patients, and headache, depression,
and increased appetite in two. Four patients
withdrew because of adverse events, depres-
sion, fatigue, and vomiting.
Placebo-controlled studies The efcacy of
runamide in LennoxGastaut syndrome
has been demonstrated in a randomized
double-blind clinical trial in 138 patients
with highly refractory epilepsy [279C].
Runamide 3200 mg/day as adjunctive
therapy was also more effective than pla-
cebo in a multicenter trial of refractory par-
tial seizures [280C].
Stiripentol [SED-15, 3182]
Stiripentol inhibits GABA reuptake and
produces barbiturate-like positive allosteric
modulation of GABAA receptors [281E].
It has non-linear pharmacokinetics, with a
marked reduction in clearance with
increased dosages [282c, 283c]. Stiripentol
is highly (>99%) protein bound, which
probably limits its clearance by dialysis.
Stiripentol was given marketing authori-
zation in the European Union on 4 January
2007 for use in conjunction with clobazam
and valproate as adjunctive therapy of
refractory generalized tonicclonic seizures
in patients with severe myoclonic epilepsy
in infancy (Dravet's syndrome) whose sei-
zures are not adequately controlled with
clobazam and valproate [284R].
Observational studies In an open study in
25 young patients with severe myoclonic
epilepsy (Dravet's syndrome) who were
already taking at least one conventional
antiepileptic drug and who had more than
four tonicclonic seizures per month, 14
Antiepileptic drugs Chapter 7
had a more than 50% reduction in seizures
[285c]. During titration, the most common
adverse effects were loss of appetite
(n 8), sleep disturbance (2), hyperactivity
or irritability (6), and ataxia (5). These
effects required dosage modication of
stiripentol or other antiepileptic drugs.
One patient stopped taking stiripentol in
the later phase of the study because of loss
of appetite.
Drugdrug interactions Care must be
taken in using stiripentol as add-on therapy
with carbamazepine, clobazam, pheno-
barbital, phenytoin, and valproate, because
stiripentol inhibits the metabolism of these
drugs and/or their metabolites [286c].
Tiagabine [SED-15, 3419; SEDA-30, 89;
SEDA-31, 123; SEDA-32, 148]
The efcacy and tolerability of tiagabine
have been reviewed [287R].
Observational studies Almost 2000 pati-
ents have been recruited in an open pro-
spective study in which tiagabine was
added to a previous unsatisfactory anti-
epileptic treatment in patients with partial
seizures [288c]. At the second month of
treatment, adverse effects were reported
by 13% of patients and after 4 months by
8.6%. The most frequent were somno-
lence/fatigue, headache/nausea, and anxiety/
mood disorders. No serious adverse events
were reported.
Patients who withdrew because of
adverse effects in three trials of tiagabine
for the treatment of generalized anxiety
disorder have been briey described
[289r]. Patients taking tiagabine were signif-
icantly more likely than placebo-treated
patients to discontinue the experimental
dug during exible-dose trials. In one
xed-dose trial, there was a trend for a
higher adverse event dropout rate among
those who took 8 or 12 mg/day relative to
placebo; in those who took 4 mg/day, there
was no such trend.
161
Drugdrug interactions Gembrozil An
interaction between gembrozil and tia-
gabine has been described [290A].
A 39-year-old man who was taking oral tia-
gabine 16 mg tds and oral carbamazepine
500 mg bd for complex partial seizures sec-
ondary to mesial temporal sclerosis and had
type IV hypertriglyceridemia was given gem-
brozil, soon after a single 600 mg dose of
which he reported severe confusion and
altered consciousness. A further single dose
of gembrozil 300 mg resulted in lightheaded-
ness and led to 59% and 75% increases in
total serum tiagabine concentrations at 2 and
5 hours respectively, without signicant
changes in carbamazepine concentrations.
Monitoring therapy The evidence for tia-
gabine drug concentration monitoring has
been reviewed. There are large intra- and
inter-individual variations in serum concen-
trations and hepatic insufciency requires
dosage adaptation. In patients taking thera-
peutic doses, target serum concentrations
are 20100 mg/l (50250 nmol/l) and the
importance of this for drug monitoring has
yet to be assessed [291R].
Topiramate [SED-15, 3447; SEDA-30,
89; SEDA-31, 124; SEDA-32, 148]
Observational studies Topiramate has
been retrospectively evaluated in 227
patients with symptomatic epilepsy, of
whom 12 withdrew because of adverse
effects [292c]. The incidence of adverse
effects was 36% and the most common
were weight loss, memory impairment, par-
esthesia, headache, and dizziness; most were
mild to moderate in intensity and transient.
In a multicenter, open, single-arm, non-
interventional study in 147 patients aged
12 years and over with epilepsy, in whom
valproate was poorly tolerated or was not
effective, topiramate was added at a start-
ing dose of 25 mg/day and titrated up
at 25 mg/day increments every 12 weeks
to a nal maintenance dose of 50200
162
mg/day. Average duration of follow-up was
20 weeks and the overall discontinuation
rate was 16%, mainly because of adverse
effects (in 8.2% of 147 patients). The most
frequent adverse effects were weight loss
(4.8%), paresthesia and fatigue (4.1% each),
and speech disorders and headaches (2.7%
each).
Topiramate monotherapy has been stud-
ied in a 24-week, multicenter, open trial in
244 patients with epilepsy [293c]. The mean
stabilized daily dose of topiramate over the
last 28 days of treatment was signicantly
lower in patients who reported 13 seizures
(n 147) than in those who reported more
than three seizures (n 66) during a
3-month retrospective baseline period (191
versus 239 mg/day). The incidences of
drug-related treatment-emergent adverse
effects were similar in the two groups, but
there was a lower frequency of serious
adverse effects in in the low-seizure-fre-
quency group (12/259, 4.6%) than in those
in the high-seizure-frequency group (8/131,
6.1%). In addition, more patients in the
high-seizure-frequency group withdrew
because of adverse effects and the inci-
dence of cognitive effects was higher (26%
versus 24%). The other most common
adverse effects were paresthesia (25%),
fatigue (12%), anorexia (11%), dizziness
(11%), somnolence (10%), headache
(9.7%), and hypesthesia (9.7%).
In a prospective open study in 21 intel-
lectually disabled patients who were given
topiramate for epilepsy there were 57 treat-
ment-emergent adverse events, 23 of
which (40%) were at least possibly related
to treatment; during topiramate therapy,
there were two sudden, unexpected deaths
[294c].
Comparative studies In a 26-week, multi-
center, randomized, double-blind, double-
dummy, parallel-group non-inferiority com-
parison of topiramate and amitriptyline in
the prophylaxis of episodic migraine in
331 subjects (172 topiramate, 159 amitripty-
line) there were no signicant differences
between the groups in any of the outcome
measures [295C]. There were treatment-
Chapter 7 Gaetano Zaccara and Luciana Tramacere
emergent adverse effects in 152 (86%) of
the 177 who took topiramate and 150
(89%) of the 169 who took amitriptyline.
The most common effects of topiramate
were paresthesia (30%), fatigue (17%),
somnolence (12%), hypesthesia (11%), and
nausea (10%) and the most frequent
adverse effects leading to study withdrawal
were fatigue (3.4%), dizziness (1.7%),
hypesthesia (1. 7%), anxiety (1.7%), and
confusion (1.7%).
In a single-center, 8-week titration and
4-week maintenance period, double-blind,
randomized study of topiramate or amitrip-
tyline, alone or in combination, in 73
patients with migraine with or without aura
all the treatments resulted in signicant
improvements in all efcacy measures
[296c]. Discontinuation rates due to adverse
events were 8.3%, 14%, and 4.3% with
topiramate, amitriptyline, and the combina-
tion respectively. The most common
adverse effects in the topiramate group
were paresthesia (35% at 8 weeks and
40% at 12 weeks), weight loss (25% and
35% respectively), and memory impairment
(10% and 15%, respectively).
Two dosages of topiramate have been
compared in 38 elderly patients (aged over
60 years) with non-controlled partial-onset
seizures in a pilot, 24-week, double-blind,
randomized, parallel-group study [297c].
They were randomized to topiramate 50 or
200 mg/day, either as monotherapy or added
to previous monotherapy. The overall inci-
dence of adverse events was similar for the
two dosages (66% with 50 mg/day and 62%
with 200 mg/day). The most common
adverse events were somnolence (13%
with 50 mg/day and 8% with 200 mg/day),
dizziness (13% versus 8%), and headache
(13% versus 5%). There were adverse
cognitive effects in six patients taking 50
mg/day and in four taking 200 mg/day. A
total of 14 patients (seven in each group)
stopped taking topiramate because of
adverse events.
In 62 patients who were randomized to
low-dose topiramate or propranolol for
migraine prophylaxis in a randomized,
8-week, double-blind trial both drugs signif-
icantly reduced the frequency, intensity,
Antiepileptic drugs Chapter 7
and duration of attacks [298c]. The most
common adverse effects of topiramate were
paresthesia (n 7), weight loss (5), somno-
lence (4), and dizziness (3); all were of mild
to moderate intensity.
In a double-blind, randomized, placebo-
controlled study, in which 103 adolescents
with at least a 6-month history of migraine
were assigned to daily topiramate (50 or
100 mg/day) or placebo for 16 weeks [299c].
29 of the 35 who took topiramate 50 mg/
day, 30 of the 35 who took topiramate 100
mg/day, and 26 of the 33 who took placebo
completed double-blind treatment. Topi-
ramate 100 mg/day, but not 50 mg/day,
resulted in a statistically signicant reduction
in the monthly migraine attack rate. Six sub-
jects had treatment-emergent adverse events
that led to withdrawal from the study. Of
those who took topiramate 50 mg/day, three
withdrew because of fatigue (n 1), nervous-
ness (1), and headache/emotional lability/
depression (1). Of those who took topira-
mate 100 mg/day, two withdrew because of
treatment-emergent fatigue (n 1), renal
calculus (1) or epistaxis (1). There was dose-
related weight loss of at least 10% from base-
line in 22% of the placebo group, 28% in the
50 mg/day topiramate group, and 48% in the
100 mg/day topiramate group.
Systematic reviews A meta-analysis of the
efcacy and safety of topiramate when used
as add-on treatment in drug-resistant partial
epilepsy has been updated [300M]. Ten trials
that included 1312 randomized participants
were analysed. The risk ratios of the common-
est adverse effects were: ataxia 1.95 (99% CI
1.04, 3.65); dizziness 1.55 (99% CI 1.08,
2.22); fatigue 2.19 (99% CI 1.43, 3.35); nau-
sea 2.35 (99% CI 1.28, 4.29); somnolence
2.18 (99% CI 1.47, 3.21) and thinking
abnormally 5.77 (99% CI 2.50, 13.35).
The risk ratio for withdrawal for any reason
was 2.26 (95% CI 1.55, 3.31).
A comparison of adverse drug reactions to
topiramate in different diseases has been sys-
tematically reviewed [301M]. All published
randomized controlled trials that compared
topiramate monotherapy with other drugs in
epilepsy and migraine were analysed. Four
163
randomized clinical trials in patients with epi-
lepsy (n 1179 treated with topiramate) and
six randomized trials in patients with
migraine (n 1723 treated with topiramate)
were included. The risk ratios for paresthesia
in migraine versus epilepsy trials were 2.5
(99% CI 1.66, 3.77) for 50 mg/day, 2.7
(99% CI 1.80, 3.97) for 100 mg/day, and
3.0 (99% CI 1.95, 4.56) for 200 mg/day.
For dropouts related to adverse effects in
migraine versus epilepsy trials, the risk ratio
was 2.5 (95% CI 2.03, 2.98) for 50 mg but
there were no differences for the other doses.
Behavioral adverse drug reactions and head-
ache were found only in the case of epilepsy,
whereas cognitive complaints and altered
taste were found only in the case of migraine.
The authors concluded that at equal doses of
topiramate, migraineurs have a different pat-
tern of adverse effects than patients with epi-
lepsy and are more likely to drop out because
of adverse effects.
All the available evidence for the use of
topiramate as monotherapy in patients with
newly or recently diagnosed epilepsy has
been examined in a systematic review of
three randomized, double-blind, controlled
trials which recruited more than 1000
patients [302M]. The most common adverse
events associated with topiramate 50500
mg/day generally occurred early in the
course of treatment and were nervous sys-
tem-related effects: headache (1525%),
dizziness (1219%), fatigue (1123%), som-
nolence (1017%), anorexia (810%),
insomnia (710%), and hyperesthesia (5
10%). Adverse events that were likely to
have been related to the carbonic-anhy-
drase activity of topiramate (e.g. paresthe-
sia, changes in serum bicarbonate) were
frequent (1335%) but were not usually
considered clinically relevant. Renal calculi
occurred infrequently (1%). The most fre-
quent adverse events during maintenance
therapy were headache (20%), reduced
appetite (11%), and weight loss (11%).
Nervous system A woman with familial
hemiplegic migraine experienced worsen-
ing of her symptoms after repeated doses
of topiramate [303A].
164
A 33-year-old woman with familial hemiplegic
migraine was given topiramate 25 mg/day for
monthly attacks of migraine. She had never
had status migrainosus. After a week she
developed dysphasia, disorientation, and pro-
longed severe right-sided weakness complicat-
ing a migraine attack and lasting about 4 days.
She had right-sided weakness involving the
arm and leg and cortical sensory loss. All
blood tests were normal and a brain MRI scan
was unremarkable. Topiramate was with-
drawn and her symptoms resolved within 48
hours. Six months later she took topiramate
again and after 5 days had a new severe
attack. Topiramate was immediately tapered
off, with prompt resolution of the symptoms.
A 42-year-old woman developed tremor
and myoclonus after topiramate 50 mg/day
was added to uvoxamine 300 mg/day as
an antimigraine agent [304A].
Two cases of restless legs syndrome have
been attributed to topiramate [305A].
Sensory systems There have been several
cases of angle-closure glaucoma and/or
acute myopia associated with topiramate
[306A, 307A, 308A].
One patient who developed impaired
vision while taking topiramate for symptom-
atic epilepsy had signs of a maculopathy
[309A]. The topiramate was withdrawn, but
vision failed to improve signicantly over 6
months of follow-up. The authors speculated
that topiramate, like vigabatrin, may cause
persistent visual impairment through direct
retinal toxicity.
A 3-year-old boy with idiopathic general-
ized epilepsy lost his ability to detect and
recognize taste and smell during treatment
with topiramate, and improved after drug
withdrawal [310A].
Psychological The cognitive effects of
topiramate have been explored in two small
studies.
In an open, prospective study of 35
patients with migraine aged over 18 years
topiramate was started at 25 mg/day and
increased by 25 mg/day each week, until
the maximum dose of 50 mg bd was
reached in the fourth week [311c]. Only
22 patients completed the 3-month study.
Although 41% complained of cognitive
Chapter 7 Gaetano Zaccara and Luciana Tramacere
effects, neuropsychological evaluation, which
was performed using the Wechsler mem-
ory scale, showed signicant changes only
in the visual memory section. There was a
non-signicant increase in the latency of
P300, especially in the frontal and central
areas, while P300 amplitude did not change
signicantly.
The cognitive effects of levetiracetam
and topiramate have also been evaluated
in a blinded but non-randomized study in
79 patients with intractable epilepsy [312c].
Assessments were done at baseline and
after 1 year of treatment using the Cogni-
tive Abilities Screening Instrument. There
were no relevant differences between the
two drugs.
Psychiatric A patient with migraine devel-
oped reversible, dose-related, auditory hal-
lucinations during topiramate therapy
[313A].
A 27-year-old woman took topiramate 25 mg/
day for migraine prophylaxis, and the dose
was gradually increased to 100 mg/day,
at which point she reported frightening
auditory hallucinations. Psychiatric examina-
tion was normal. Laboratory ndings, electro-
encephalography, brain-stem auditory-evoked
potentials, audiometry, and a cranial MRI
scan were normal. The auditory hallucinations
disappeared after the dosage of topiramate
was gradually reduced to 50 mg/day.
Metabolism Valproate reduces free and
total carnitine concentrations in children.
In a cross-sectional study in 91 children,
the effects of some new antiepileptic drugs
(vigabatrin, n 24; lamotrigine, n 28;
and topiramate) on serum carnitine concen-
trations have been studied; 18 children tak-
ing valproate served as positive controls
[314c]. Carnitine concentrations were unaf-
fected by the new drugs.
Uric acid, cholesterol, and lipoprotein
serum concentrations have been measured
in 53 patients with migraine taking topira-
mate and 44 age- and sex-matched controls.
Topiramate signicantly increased uric acid
concentrations [315c].
Valproic acid-induced hyperammonemic
encephalopathy is characterized by confu-
sion and possible exacerbation of an
Antiepileptic drugs Chapter 7
underlying psychiatric disorder; it can be
difcult to diagnose. In one case co-admin-
istration of topiramate with valproate may
have triggered this complication. The
authors speculated that this synergistic
effect of topiramate may relate to its ability
to inhibit carbonic anhydrase, with conse-
quent alteration of some enzymes in the
urea cycle whose rst step uses HCO in
the synthesis of carbamoylphosphate
[316A].
Nutrition Vitamin B12 deciency has been
attributed to topiramate [317A].
Acidbase balance In some patients topir-
amate can cause metabolic acidosis, whose
susceptibility factors, underlying mech-
anisms, and clinical effects have been
reviewed [318R]. Topiramate impairs both
the normal reabsorption of ltered HCO
by the proximal renal tubule and the excre-
tion of H by the distal renal tubule. This
combination of defects is termed mixed
renal tubular acidosis. The mechanism
involves inhibition of carbonic anhydrase.
This mechanism can make patients acutely
ill, and chronically can lead to nephrolithia-
sis, osteoporosis, and in children growth
retardation. The usefulness of monitoring
HCO concentrations has not been proven
and is not routine. Hence, there is no
proven method for predicting or preventing
the effect of topiramate on acidbase bal-
ance. However, patients with a history of
renal calculi or known mixed renal tubular
acidosis should not receive topiramate.
Another case of topiramate-induced
metabolic acidosis has been discussed
[319A].
Hematologic A patient who took topira-
mate 100 mg/day for migraine had epistaxis,
without a history of nosebleeds; laboratory
parameters were within the reference
ranges [320A]. The epistaxis resolved within
12 hours of drug withdrawal. The authors
discussed the possible antiplatelet activity
of topiramate.
165
Urinary tract The susceptibility factors for
topiramate-induced renal stones have been
studied in six subjects [321c]. After 5 days
treatment there was a 31% reduction in
mean calcium and a 40% reduction in mean
citrate urinary concentrations. Dose escala-
tion was associated with a further reduction
in citrate concentration. The authors con-
cluded that topiramate causes a profound
reduction in urinary citrate concentrations,
equivalent to the changes seen in distal
renal tubular acidosis.
In a retrospective study of non-ambula-
tory and neurologically impaired individ-
uals in a long-term care facility, 13 of 24
who were taking topiramate monotherapy
or polytherapy developed clinical evidence
of urolithiasis after a mean treatment dura-
tion of 36 months [322c].
Sweat glands The pathogenesis of hypo-
hidrosis, a rare and reversible adverse
effect of topiramate that is often associated
with hyperthermia, has been studied in two
children [323A]. Sympathetic skin responses
were recorded during topiramate treatment
and after withdrawal. Electrophysiology
showed normal function of both beta and
delta sensory bers and absent sympathetic
skin responses, which recovered to normal
after topiramate withdrawal. The authors
concluded that topiramate may cause tran-
sient specic inhibition of carbonic anhy-
drase in sweat glands, without involvement
of peripheral nervous system.
Topiramate-associated blue pseudo-
chromhidrosis has been described [324A].
Chromhidrosis is a rare skin disorder, in
which the apocrine glands excrete sweat that
contains lipofuscin pigments. Pseudo-
chromhidrosis is a term used when the eccrine
sweat is colored on the surface of the skin as a
result of the deposit of extrinsic dyes or
paints. Since some carbonic anhydrase iso-
enzymes are expressed in the sudoral eccrine
glands, the hypothesized mechanism of this
adverse effect was inhibition of this enzyme
by topiramate.
Sexual function Sexual dysfunction in
response to new antiepileptic drugs has
rarely been described. Reversible erectile
166
dysfunction has been described in a man tak-
ing topiramate, in which other possible path-
ogenic mechanisms were excluded [325A].
Body temperature Several post-marketing
reports have suggested that topiramate can
be associated with hypothermia, which is
dened as a fall in body core temperature to
less than 35 C. The US Food and Drug
Administration's Adverse Events Reporting
System database has been searched for
reports of hypothermia in association with
the use of topiramate [326c]. Attention was
focused on the possible association between
the concomitant use of topiramate and val-
proic acid and the induction of hypothermia.
There were 22 unduplicated reports of hypo-
thermia in patients exposed to topiramate.
More than one antiepileptic drug had been
used in most reports; valproic acid was men-
tioned in seven and topiramate in four, which
was seven times more often in the database
as a cause of hypothermia than would be sta-
tistically expected when considering all other
drugs. Hypothermia has also been found in
association with concomitant administration
of topiramate and valproic acid in patients
who tolerated either drug alone.
Teratogenicity The UK Epilepsy and Preg-
nancy Register is a prospective pregnancy
register set up to determine the relative
safety of all antiepileptic drugs taken in
pregnancy. Suitable cases of women with
epilepsy who become pregnant while taking
topiramate either singly or together with
other antiepileptic drugs have been ana-
lysed [327c]. Full outcome data were avail-
able on 203 pregnancies. Of these, 178
resulted in live births; 16 (9.0%) had a
major congenital malformation, four of
which were oral clefts and four of which
were cases of hypospadias. Three of these
complications (4.8%) were observed in 70
monotherapy exposures and 13 (11%) in
cases exposed to topiramate as part of a
polytherapy regimen. The authors asserted
that the rate of oral clefts observed was 11
times the background rate. Although these
data should be interpreted with caution,
they raise some concerns about the poten-
tial teratogenic effects of topiramate.
Chapter 7 Gaetano Zaccara and Luciana Tramacere
Experimental data in support of a terato-
genic effect of topiramate have been briey
reviewed [328r]. Topiramate inhibits his-
tone deacetylases and may cause low birth
weight and teratogenic effects.
Susceptibility factors Genetic Three single
nucleotide polymorphisms of the glutamate
receptor GluR5 gene (GRIK1) have been
studied as possible predictors of topira-
mate-induced adverse effects in 51 heavy
drinkers who completed a 5-week dose esca-
lation schedule to a target dose of either 200
or 300 mg/day or matched placebo [329c]. A
SNP in intron 9 of the GRIK1 gene
(rs2832407) was associated with the intensity
of topiramate-induced adverse effects and
with serum concentrations of topiramate.
Drug dosage regimens Several studies
have shown that high starting doses and/or
fast titration inuence the tolerability of
topiramate.
In a retrospective study of fast titration
in 423 epileptic patients taking topiramate,
42 developed depression [330c]. Rapid titra-
tion was associated with a vefold
increased risk of depression. This risk fur-
ther increased in the presence of other risk
factors (13-fold when rapid titration was
associated with febrile seizures, 23-fold
when associated with a previous history of
depression, and 7.6-fold in the presence of
hippocampal sclerosis).
In one case serious adverse effects, such
as seizures and polymyoclonus, were proba-
bly caused by a high initial dose and the
fast rate of increase in dosage [331A].
A 26-month-old girl, who was given topiramate
6 mg/kg/day for 2 weeks developed seizures and
myoclonus. Topiramate had been started in a
dosage of 1 mg/kg/day and increased to 6 mg/
kg/day by increments at 3-day intervals. The
advised topiramate initial dose is 13 mg/kg/
day, which is normally increased at 1- or 2-week
intervals by increments of 13 mg/kg/day. The
drug was withdrawn and after 3 days her myo-
clonus had resolved.
In a prospective, observational study of
rapid oral initiation of topiramate in 19 mul-
tiply handicapped children with resistant epi-
lepsy who were given a mean initial dose of
Antiepileptic drugs Chapter 7
topiramate of 1.1 (range 0.662.67) mg/kg/
day following rapid titration, the mean nal
dose was 3.3 mg/kg/day [332c]. Six patients
withdrew because of adverse events (behav-
ioral disturbances in three, fatigue in one,
vomiting in one, and hyperkinesias in one).
There was at least one adverse event in 17
patients; the most common was fatigue, fol-
lowed by reduced appetite and unspecied
psychiatric disorders.
Drug overdose Seven cases of acute topira-
mate toxicity observed in two clinical units
of poison centers have been described
[333A]. The doses of topiramate were 11
218 mg/kg. Somnolence was characteristic
and vertigo, agitation, and mydriasis were
less common. There was a metabolic acidosis
in four cases. One patient who had not
previously taken topiramate and who had
taken 31 mg/kg had three secondarily gener-
alized tonicclonic seizures. All recovered
without sequelae and were discharged after
48 days.
Drugdrug interactions Glucocorticoids
Topiramate is a weak inducer of CYP3A4,
which is involved in steroid metabolism. In
one case a modest dose of topiramate accel-
erated the metabolic clearance of dexa-
methasone and udrocortisone and caused
hypoadrenalism [334A]. According to the
authors, this effect of topiramate can occur
in any patient who is taking a xed-dose
of a glucocorticoid.
A 35-year-old woman who was taking dexa-
methasone and udrocortisone replacement for
congenital adrenal hyperplasia and with bio-
chemical evidence of good control started to
take topiramate 100 mg/day for atypical sei-
zures. Within a few weeks she complained of
tiredness, nausea, weight loss, and muscle aches.
A diagnosis of hypoadrenalism was supported
by raised plasma 17-hydroxyprogesterone, adre-
nocorticotrophin, and plasma renin activity.
Posaconazole Posaconazole inhibits
CYP3A4, which can increase topiramate
concentrations [335A].
A 48-year-old man with long-standing epilepsy,
stabilized with valproate 700 mg bd and
167
topiramate 100 mg bd, underwent partial pneu-
monectomy for invasive aspergillosis and was
given posaconazole. After 2 weeks he devel-
oped progressive stupor, daytime somnolence,
anorexia, and weight loss. Topiramate toxicity,
secondary to a drug interaction with posacona-
zole, was suspected. Posaconazole was replaced
with intravenous amphotericin, and topiramate
was continued. His stupor and appetite gradu-
ally improved over 10 days. The topiramate
plasma concentration was 27 mmol/l on admis-
sion and 12 mmol/l 11 days after withdrawal of
posaconazole.
Management of adverse drug reactions
Five patients with topiramate associated
bilateral acute angle-closure glaucoma unre-
sponsive to ocular hypotensive therapy and
drug discontinuation were effectively trea-
ted with argon laser peripheral iridoplasty
[336A, 337A].
Valproate sodium and
semisodium (divalproex) [SED-15,
3579; SEDA-30, 92; SEDA-31, 126; SEDA-
32, 153]
Observational studies In a phase III, open,
multicenter study, 169 children with partial
seizures were treated with divalproex
sodium sprinkle capsules as monotherapy
or add-on treatment [338c]. The most com-
mon treatment-emergent adverse events
were vomiting (14%), tremor (9%), somno-
lence (8%), and diarrhea (8%). Patients
had similar overall adverse event incidence
rates whether they received polytherapy at
any time during the study or monotherapy
(83% and 80% respectively). However,
patients taking polytherapy were more
likely to have gastrointestinal disorders
(36% versus 21%), diarrhea (11% versus
5%), vomiting (17% versus 10%), and
increased weight (4% versus 2%). Nine
patients (5.3%) prematurely withdrew
because of an adverse event. Ammonia
concentrations were increased in 31
patients and there was a mean increase in
uric acid concentrations and fall in
168
platelets, although these changes were
asymptomatic in most cases.
Divalproex sodium extended-release has
been evaluated in a 12-month, open exten-
sion of a 3-month, double-blind, placebo-
controlled, multicenter study in 112 adoles-
cents with migraine [339C]. The most com-
mon symptomatic adverse events were
weight gain (15%), nausea (14%), somno-
lence (12%), upper respiratory tract infec-
tion (11%), and sinusitis (8%). Five
subjects had serious adverse events, and
15 prematurely withdrew because of an
adverse event. Plasma ammonia concentra-
tions were increased in 8% but there were
no other clinically signicant changes in
laboratory values, vital signs, or
electrocardiography.
In a 6-month open study of divalproex
sodium extended-release (15 mg/kg/day on
day 1 with increases allowed to a maximum
of 35 mg/kg) in 226 children and adoles-
cents with acute mania associated with
bipolar I disorder the most common
adverse events were weight gain (16%),
nausea (9%), and increased appetite (8%);
raised plasma ammonia concentrations
were non-symptomatic in all cases [340c].
Comparative studies In an open prospec-
tive comparison of valproate and primidone
in 136 patients with partial epilepsy un-
responsive to carbamazepine signicantly
more of those who took valproate (51%)
achieved a greater than 50% seizure reduc-
tion than those who took primidone (34%)
[231c]. One patient withdrew from valpro-
ate because of dizziness and three because
of nausea. Of those who took primidone,
three withdrew because of dizziness, three
patients because of drowsiness, and one
because of gastrointestinal complaints.
Adverse effects in other patients were mild
and gradually disappeared during
treatment.
Long-term valproate (starting dose 20
mg/kg/day) and lithium (starting dose 400
mg/day) have been compared in 300
patients with bipolar I disorder presenting
with acute mania in a 12-week open study
[341c]. Remission rates were 66% for those
who took lithium and 72% for those who
Chapter 7 Gaetano Zaccara and Luciana Tramacere
took valproate. The most frequently
reported treatment-related adverse events
were nausea (14 treated with lithium versus
16 treated with valproate), tremor (25 ver-
sus 2), weight gain (6 versus 13), and
fatigue (2 versus 9). Tremor was signi-
cantly more common with lithium and
fatigue with valproate. Treatment was dis-
continued because of an adverse event in
14 patients who took lithium and in ve
who took valproate.
Placebo-controlled studies Valproic acid is
a histone deacetylase inhibitor which has
antioxidative and antiapoptotic properties
and reduced glutamate toxicity in preclini-
cal studies. It has therefore been evaluated
in a double-blind, placebo-controlled study
in 163 patients with amyotrophic lateral
sclerosis, who were randomized to valpro-
ate 1500 mg/day or placebo [342C]. Valpro-
ate did not affect survival or the rate of
decline of functional status. The most fre-
quent adverse events were diarrhea (n
16 versus 14 with placebo), nausea (15 ver-
sus 12), vomiting (0 versus 3), abdominal
pain (14 versus 15), increased appetite (19
versus 17), reduced appetite (17 versus 20),
weight gain (20 versus 19), and tremor (39
versus 40). One patient taking valproate
withdrew because of severe cognitive
impairment.
In a 3-week double-blind study patients
with mild to moderate mania were random-
ized to divalproex (n 201; 5002500 mg/
day), olanzapine (n 205; 520 mg/day),
or placebo (n 105) [343C]. Those who
completed the rst part of the study contin-
ued with a 9-week double-blind extension.
Olanzapine was signicantly more efca-
cious than placebo at 3 weeks and signi-
cantly more efcacious than divalproex at
12 weeks. Adverse effects caused with-
drawal from the study in 13% (28/215) of
those who took olanzapine and 9.5% (19/
201) of those who took divalproex. Signi-
cantly more of those who took olanzapine
reported weight increase and somnolence
compared with divalproex or placebo. Sig-
nicantly more of those who took dival-
proex reported nausea and insomnia
compared with olanzapine. Those who took
Antiepileptic drugs Chapter 7
olanzapine also had signicantly greater
increases in concentrations of glucose, cho-
lesterol, triglycerides, uric acid, and prolac-
tin than those who took divalproex.
In a 28-day, double-blind, placebo-con-
trolled study, followed by a 6-month open
extension study of divalproex extended-
release in 150 children and adolescents with
bipolar disorders, there were no signicant
differences in efcacy [344C]. Four of those
who took divalproex extended-release and
three of those who took placebo withdrew
because of adverse effects. Mean plasma
ammonia concentrations increased with
divalproex extended-release, but only one
patient was symptomatic. In the 6-month
open extension study, the most common
adverse events were headache and
vomiting.
Systematic reviews In an updated system-
atic review of all randomized, placebo-con-
trolled trials of the use of valproate to
control agitation in patients with dementia,
valproate did not produce improvement
[345M]. There were more adverse events
(falls, infection, gastrointestinal disorders)
among those who took valproate.
Cardiovascular Carotid artery intima media
thickness and serum lipids have been mea-
sured in 44 children with epilepsy taking
valproic acid and 40 healthy children.
Although there was no difference in serum
lipid proles, the intima media of the com-
mon carotid artery was signicantly thicker
in those who took valproic acid [346c]. This
nding has uncertain signicance and may
be due to epilepsy and not to the drug.
Hyperhomocysteinemia occurred in a 23-
year-old patient with the 677C/T polymor-
phism in the MTHFR gene taking valpro-
ate who had an ischemic stroke in the left
temporo-parieto-occipital region [347A].
Respiratory Eosinophilic pleural effusion
(dened as more than 10% eosinophils),
which can sometimes be caused by drugs,
was suspected to have been due to valpro-
ate in two cases [348A, 349A].
169
Nervous system Encephalopathy There
have been several further reports of valpro-
ate-induced hyperammonemic encephalop-
athy [350A, 351A, 352A, 353A]. In one case
it was associated with central pontine mye-
linolysis and coma in a patient with Sjg-
ren's syndrome who had taken long-term
valproic acid for a psychotic disorder
[354A].
Encephalopathy has been studied in 63
adults who had taken valproate for a mini-
mum of at least 2 years in a retrospective
analysis [355c]. Long duration of valproate
treatment did not correlate with the risk
of encephalopathy. In seven cases, tempo-
rary administration of lactulose alone was
effective and valproate was not withdrawn.
The authors also concluded that this com-
plication is relatively common.
In one patient there was a possible syner-
gistic interaction of valproic acid and topir-
amate with respect to the emergence of
hyperammonemic encephalopathy [316A].
The authors speculated that inhibition of
carbonic anhydrase by topiramate might
be the basis of this, since HCO is used in
the synthesis of carbamoylphosphate in
the urea cycle.
In a young child valproate-induced
stupor was unusually associated with
an electroencephalographic pattern of in-
creased fast activity [356A]. The authors
speculated that this effect of valproate was
related to an interaction of valproate with
GABA metabolism and GABA neuronal
networks.
Parkinsonism Parkinsonism has been
attributed to valproate [357A], in one case
associated with cognitive impairment
[358A].
One patient with Huntington's disease
developed both parkinsonism and Pisa syn-
drome secondary to valproic acid [359A].
Pisa syndrome is an uncommon type of
truncal dystonia manifested by persistent
lateral exion of the trunk.
A 67-year-old man with Huntington's disease
(CAG expanded repeat of 41 triplets) and
clear symptoms of the disease (hypotonia, dys-
arthria, generalized chorea, facial grimacing,
170
slow saccadic eye movements, and impaired
cognitive functions) was initially given olanza-
pine 10 mg/day, sertraline 50 mg/day, and clo-
nazepam 1 mg/day, followed by valproic acid
500 mg bd because of progression of the cog-
nitive impairment and psychiatric symptoms.
Some days later, he developed worsening of
gait impairment and a resting tremor in both
arms, mild bilateral rigidity, marked bradykine-
sia, and anterior and right exion of the trunk.
Valproic acid was withdrawn and 1 week later
his trunk posture improved dramatically, the
right exion disappeared, and he was able to
walk without aid. His parkinsonian symptoms
improved slightly and completely resolved
within 2 months.
A 45-year-old man with a 10-year history
of post-traumatic stress disorder and alco-
holism started stuttering after taking dival-
proex sodium 600 mg/day for 4 days [360A].
Psychological The effects of lithium and
valproate on the risk of being involved in
trafc accidents have been studied using
three population-based registries [361C].
Exposure consisted of receiving prescrip-
tions for either lithium or valproate. Stan-
dardized incidence ratios were calculated
by comparing the incidence of motor vehi-
cle accidents during time exposed with the
incidence during the time not exposed.
During the study period, more than 20 000
road accidents occurred, including 36 dur-
ing exposure to lithium and 31 during expo-
sure to valproate. The overall risk of an
accident was not increased, with the excep-
tion of a three-fold increase in risk among
younger female drivers taking lithium.
Psychiatric Confusion, delirium, and
dementia Using the French Pharma-
covigilance database, 272 cases (153 women
and 119 men) of confusion associated with
valproic acid were selected [362c]. This
adverse reaction mostly occurred in
patients aged 6180 years and in 40% was
observed during the rst 2 weeks of val-
proic acid exposure. It was labeled as seri-
ous in almost 63% and its outcome was
favorable in 82%.
Worsening of cognitive symptoms
and delirium has been reported after
Chapter 7 Gaetano Zaccara and Luciana Tramacere
the use of valproate in a patient with
dementia [363A].
A 75-year-old woman with Alzheimer's
dementia developed moderate cognitive
impairment associated with aggression, agita-
tion, and severe insomnia. She had been tak-
ing galantamine, promazine, acetylsalicylic
acid, and pantoprazole. Valproate 500 mg/
day for the rst week and then twice a day
was prescribed. After 16 days she suddenly
developed hyperactive delirium characterized
by worsening of insomnia and agitation,
severe confusion, delusions, and visual halluci-
nations. She also became ataxic and
completely dependent in activities of daily liv-
ing. Organic and metabolic abnormalities
were excluded. Valproate was withdrawn and
haloperidol 5 mg and intravenous saline were
given. She recovered after 1 week.
Dementia has been attributed to valproic
acid after 1 year in an elderly fragile patient
who had had a convulsive crisis after an
ischemic stroke [364A].
Endocrine In a prospective, randomized
study of thyroid function in 160 men and
women with epilepsy, both before and after
double-blind withdrawal of antiepileptic
drug monotherapy, serum samples were
obtained from 130 patients [79C]. Following
antiepileptic drug withdrawal, there were
signicant increases in free thyroxine serum
concentrations in those who were taking
carbamazepine while in women taking
valproate serum concentrations of free tri-
iodothyronine (T3) fell signicantly com-
pared with the non-withdrawal group. The
effect was reversed by withdrawal.
However, in another comparison of car-
bamazepine (n 18) and valproate (n
14) on thyroid function in newly diagnosed
children with epilepsy, valproate had no
effect on serum thyroxine (T4) and free
thyroxine (fT4) concentrations [78c].
Metabolism Ammonia Asymptomatic
hyperammonemia occurred after an intra-
venous loading dose of valproate in 30 of
40 participants at 1 hour after infusion of
valproate (20 or 30 mg/kg at a rate of 6 or
10 mg/kg/minute) and usually fell over the
following 24 hours [365c]. Multivariable
Antiepileptic drugs Chapter 7
repeated-measures analysis suggested that
age, time since dosing, and co-therapy with
enzyme-inducing antiepileptic drugs were
signicant predictors of changes in ammo-
nia concentrations. Valproate dose, concen-
trations, infusion rate, and sex made no
contribution.
Carnitine In 60 children with primary epi-
lepsy free of neurological or nutritional
problems who took valproate for at least 1
year, mean total carnitine and free carnitine
concentrations were signicantly lower
compared with pre-treatment and control
concentrations, while ammonia, acyl-
carnitine, and the acylcarnitine/free carni-
tine ratio were signicantly higher [366c].
Total carnitine and free carnitine were neg-
atively associated with ammonia concentra-
tion. These results conrm previous
ndings of an interaction between the
metabolism of valproate and carnitine.
Weight The effect of valproate on body
weight and hormones has been studied in
52 healthy adults who were randomized to
valproate or placebo in a double-blind pro-
tocol [367C]. Weight increased signicantly
with valproate but not placebo. Those who
took valproate also had increased cravings
for fast food and reduced glucose concen-
trations compared with placebo. Physical
activity, hunger, binge eating, depression,
and GLP-1 were increased by valproate.
The authors concluded that valproate-asso-
ciated weight gain is probably due to
reduced glucose concentrations and an
increased motivation to eat.
Insulin resistance, components of the
metabolic syndrome, and adiponectin con-
centrations in 60 overweight bipolar
patients taking sodium valproate have been
compared with those observed in 60 non-
psychiatric overweight control subjects
[368c]. There was a high frequency of the
metabolic syndrome in the two groups
(50% and 32% respectively) and similar
frequencies of insulin resistance, abdominal
obesity, hypertriglyceridemia, hyperten-
sion, and fasting hyperglycemia were found
in both groups. High-density lipoprotein
cholesterol concentrations were lower,
171
while adiponectin was unexpectedly higher
in patients taking valproate.
Weight gain in children has been speci-
cally investigated in three studies. In a
retrospective study weight gain associated
with valproic acid (n 31) or carbamaze-
pine (n 49) monotherapy was studied in
children with epilepsy, aged over 12 years
[369c]. With valproic acid there was no gain
in body mass index over time, but there was
a signicant gain with carbamazepine.
Of 94 children taking valproate, 23 had a
greater than 0.25 SD/year weight gain and
12 had a greater than 0.5 SD/year gain
[370c]. There was a negative correlation
between duration of treatment and weight
gain. The results of these two studies sug-
gest that children are less likely than adults
to gain weight when taking valproate.
The relationships between valproate-
induced obesity in children and concomi-
tant metabolic changes, such as hyper-
insulinemia and insulin resistance,
hyperleptinemia and leptin resistance, and
an increase in the availability of long-chain
free fatty acids, have been reviewed
[371R]. The authors concluded that,
although mechanisms of hyperinsulinemia
in valproate-induced weight gain are
unclear, it is likely that obesity is the cause
of hyperinsulinemia and all related meta-
bolic changes.
Hematologic In a prospective study in
24 children with newly diagnosed epilepsy,
valproate caused an early reduction in plate-
let counts and concentrations of factor VII,
factor VIII, protein C, and brinogen,
and increased lipoprotein (a) concentrations
[372c].
In a prospective study of 23 children sev-
eral coagulation disorders were associated
with valproate: thrombocytopenia (n 2),
acquired von Willebrand's disease (6), a sig-
nicant fall in brinogen concentrations
(12), and a reduction in factor XIII (4)
[373c]. Thrombelastography showed altered
platelet function in 11 and prothrombin
time was signicantly prolonged, with many
other coagulation defects.
Susceptibility factors for thrombophilia
have been investigated in 21 children with
172
newly diagnosed epilepsy taking valproic
acid monotherapy [374c]. After 912
months there was a statistically signicant
increase in lipoprotein(a) concentrations
and a reduction in brinogen.
In 50 children taking valproate there
were signicant changes in brinogen,
platelet count, and von Willebrand factor,
but no patient developed the laboratory
changes that are typical of von Willebrand's
syndrome [375c].
Neutropenia occurred in a patient who
had taken stable therapy with delayed-
release divalproex sodium for almost
8 years; despite the delay, a causal relation
was considered probable [376A].
The incidences of leukopenia and neutro-
penia have been evaluated retrospectively
in 131 children and adolescents taking
valproate, quetiapine, or the combination
[377c]. The combined incidences of neutro-
penia and/or leukopenia were 44%, 26%,
and 6% with the combination, valproate
monotherapy, and quetiapine monotherapy
respectively. There were statistically signi-
cant differences in the incidences of neutro-
penia and/or leukopenia between
quetiapine and valproate and between que-
tiapine alone and the combination. Leuko-
penia and neutropenia induced by
valproate and quetiapine co administration
are not rare and patients taking a combina-
tion of these drugs should be monitored.
Liver Reversible non-alcoholic fatty liver
disease occurred in a child who developed
obesity while taking valproate [378A].
Acute cholestatic hepatitis with hepatic
failure occurred in 48-year-old patient with
a glioblastoma taking long-term valproate
when temozolomide and the integrin inhib-
itor cilengitide were added [379A]. Valpro-
ate was withdrawn and the liver tests
normalized.
Pancreas Acute pancreatitis has been
described in a 7-year-old girl who took
valproate 15 mg/kg/day for generalized epi-
lepsy [380A].
Skin A severe psoriasiform eruption has
been reported in a 14-year-old boy patient
Chapter 7 Gaetano Zaccara and Luciana Tramacere
taking sodium valproate [381A]. Histology
of the skin showed hyperkeratosis, paraker-
atosis, loss of the granular layer, irregular
acanthosis in the epidermis, and a perivas-
cular inltrate (mononuclear cells in the
upper dermis). Valproate was withdrawn
and the eruption completely disappeared
in 4 months.
Onychomadesis, complete separation
and subsequent shedding of the nail plate,
beginning at the proximal nail fold (unlike
onycholysis, which begins distally), has
been attributed to valproate [382A].
Onychomadesis of both the thumbnails
and two toenails developed after 4 years
of treatment and gradually resolved after
valproate withdrawal.
In a large database study, treatment with
valproic acid was signicantly associated
with erythema multiforme, StevensJohnson
syndrome, or toxic epidermal necrolysis
among patients with bipolar disorder [94C]
(see Carbamazepine for details).
Hair In 32 children, hair and serum zinc
concentrations and serum biotinidase activ-
ity were measured before valproate and
after 3 and 6 months. Mean serum and hair
zinc concentrations were reduced at 3 and 6
months, and the mean serum biotinidase
activity was lower than the pre-treatment
values at 3 months but returned to initial
values by 6 months. The authors suggested
that hair loss in patients taking valproate
can be attributed to zinc and biotinidase
depletion, but the differences were not sta-
tistically signicant and so the conclusion is
unwarranted [383c].
Musculoskeletal Myopathy has been asso-
ciated with valproate in an elderly patient
with a schizoaffective disorder [384A].
An 85-year-old woman with a schizoaffective
disorder was given valproate 600 mg/day and
after 4 days complained of muscle pain and
weakness. Other medications were quetiapine
200 mg/day, nifedipine 10 mg/day, torsemide
10 mg/day, levothyroxine 75 micrograms/day,
and acetylsalicylic acid 100 mg/day. There
was a vefold increase in myoglobin concen-
tration (292 mg/l), a sixfold increase in creatine
kinase activity (14 mmol/l), and slightly
increased liver enzyme activities. The serum
Antiepileptic drugs Chapter 7
concentration of valproate was 46 (target
range 30100) mg/l. Valproate and quetiapine
were withdrawn and torsemide was replaced
by furosemide 10 mg/day. After 15 days the
myoglobin concentration and creatine kinase
activity returned to normal. Reintroduction
of quetiapine caused no deterioration in mus-
cle symptoms and laboratory measures.
Reproductive system Polycystic ovary syn-
drome, hyperandrogenism, or ovulatory
dysfunction in women with epilepsy taking
valproate or lamotrigine have been pro-
spectively studied in patients with epilepsy,
who were randomized for 12 months to
valproate (n 225) or lamotrigine (n
222) [154C]. More women taking valproate
developed ovulatory dysfunction or poly-
cystic ovary syndrome. Hyperandrogenism
was more frequent with valproate than
lamotrigine among those who were youn-
ger than 26 years at the start of treatment
but similar in older women. Tremor, vomit-
ing, nausea, alopecia, and weight gain were
more common with valproate. Rashes
caused withdrawal from the study in ve
patients taking lamotrigine and none taking
valproate. The proportion of participants
who withdrew because of an adverse event
was 4% in each group.
Polycystic ovarian syndrome and men-
strual irregularities were more prevalent in
those taking valproate within a population
of 71 women with epilepsy who had taken
antiepileptic drugs for a minimum of 2
years [385c]. There was no correlation
between dose and duration of treatment
and the probabilities of such complications.
The increased prevalence of polycystic
ovary syndrome associated with valproate
has been reviewed [386R]. The risk seems
to be higher in women with epilepsy
than in women with bipolar disorders, and
this might be due to underlying neuroendo-
crine dysfunction related to the seizure
disorder.
Immunologic Rowell's syndrome is the
association of a lupus-like syndrome (sys-
temic, subacute cutaneous, or discoid)
together with erythema multiforme (includ-
ing toxic epidermal necrolysis) and evi-
dence of antinuclear antibodies and other
173
immunological markers. Exposure to some
medications can cause this syndrome, which
has been reported with valproate [387A].
A 51-year-old woman, who had taken valpro-
ate, sertraline, and olanzapine for severe
depression over 5 months, developed ery-
thematous erosive skin lesions affecting large
areas of skin, associated with a sensation of
burning in the skin, arthralgia, general fatigue,
and subclinical fever. There were many ery-
thematous lesions on the face, neck, arms,
and trunk and elsewhere generalized erythro-
derma-like skin inammation, with involve-
ment of the oral mucosa. There were also
leukopenia, anemia, and thrombocytopenia,
with increased erythrocyte sedimentation rate,
serum aminotransferases, and creatine kinase,
hypergammaglobulinemia and a positive rheu-
matoid factor. Echocardiography showed peri-
carditis. Serum immunouorescence showed a
speckled pattern of antinuclear antibodies.
Immunoenzymatic assay showed titers of
1:5000 for SS-A, SS-B, and Ro-52. Direct
immunouorescence of skin samples showed
granular deposits of IgG and IgA at the epi-
dermodermal junction. Histopathology
showed features consistent with lupus erythe-
matosus. Valproate was withdrawn and pred-
nisolone was started; 2 weeks later the titer
of antinuclear antibodies had fallen to 1:
3200. After 4 months of clinical remission,
sodium valproate was again introduced and
the symptoms recurred.
A lupus-like syndrome occurred in a small
boy taking oxcarbazepine and valproic acid
[228A] (see Oxcarbazepine).
Body temperature In an analysis per-
formed using the US Food and
Drug Administration's Adverse Events
Reporting System database, hypothermia
was associated with concomitant adminis-
tration of topiramate and valproic acid in
patients who tolerated either drug alone
(see also Topiramate) [326c].
Teratogenicity In an analysis of the medi-
cal records of 284 valproate-exposed preg-
nancies in the North American
Antiepileptic Drug Pregnancy Registry 30
(11.0%) were associated with malforma-
tions [388c]. There were 15/126 (12%) mal-
formations in patients with idiopathic
generalized epilepsy, 4/28 (14%) in patients
with partial epilepsy, 9/105 (9%) in those
174
with non-classiable epilepsy, and 2/25
(8%) in non-epileptic patients. This con-
rms that valproate, and not the underlying
syndrome, is associated with an increased
risk of malformations in drug-exposed
fetuses. There was a trend toward an
increased risk of malformations at higher
doses of valproate.
A newborn girl had right bular aplasia
and an absent fth toe [389A].
Exposure of fetuses to valproate uncom-
monly results in pulmonary anomalies, as in
a newborn boy with unilateral lung agenesis
[390A].
A newborn girl who was exposed in
utero to antiepileptic drugs, especially
valproate, had craniosynostosis, trigono-
cephaly, right radius aplasia, a hypoplastic
thumb, and cardiac and renal malforma-
tions; her brother, who was similarly
exposed had BallerGerold syndrome phe-
notype, trigonocephaly, polymastia, and
hypospadias [391A].
Four cases of fetal valproate syndrome,
characterized by major and minor malfor-
mations in association with developmental
delay, have been reported [392A]. The
mothers were screened for the 677C-T
mutation but only one was heterozygous
for this mutation.
Further cases of fetal valproate syn-
drome with unusual characteristics have
been described [393A, 394A].
A review of the evidence has suggested
that there is a longer-term risk of impaired
cognitive and behavioral development of
children who have been exposed in utero to
sodium valproate [59R]. The effects of fetal
exposure to carbamazepine, lamotrigine,
and valproate on cognitive uency and exi-
bility have been investigated prospectively
in 54 children; uency and originality
were signicantly worse after exposure to
valproate than after lamotrigine and carba-
mazepine [395c].
Drug formulations In seven healthy men
who took an oral dose of conventional
and slow-release formulations of valproate
800 mg on two separate days, blood sam-
ples were taken for determination of
Chapter 7 Gaetano Zaccara and Luciana Tramacere
valproate and its monounsaturated (2-en,
3-en, and 4-en) and hydroxylated (3-OH,
4-OH, and 5-OH) metabolites [396c]. After
the slow-release formulation there was a
reduced Cmax, a prolonged tmax, and a
reduced AUC of the metabolites that are
produced by microsomal oxidation (4-en,
4-OH, and 5-OH). In contrast, the kinetics
of the beta-oxidative metabolites (2-en, 3-
en, and 3-OH) were unchanged irrespective
of formulation. The slow-release formula-
tion may be safer, because of reduced
formation of 4-en valproate, the most toxic
metabolite, together with reduced peak
concentrations of the parent compound.
The pharmacokinetics of valproate have
been studied in 27 patients with focal or
generalized epilepsy taking a single daily
dose of prolonged-release valproate given
in the evening [397c]. In about 60% of the
patients the serum concentration measured
at 0900 h corresponded to the peak value.
In another 33% the peak concentration
was reached at either 2400 h or at 0300 h.
The pharmacokinetics of single oral
doses of magnesium valproate solution, sus-
pension, and enteric-coated tablets have
been studied in 24 healthy volunteers; the
three formulations met the regulatory cri-
teria for bioequivalence [398c].
In a prospective evaluation of 41 consec-
utive adult out-patients who were followed
for 6 months after switching overnight from
immediate-release to extended-release
divalproex sodium, seizure frequency and
the adverse effects prole did not change
signicantly after switching drug formula-
tions, but there was a signicant subjective
improvement in tremor with the extended-
release formulation [399c].
Overnight versus gradual switching to
extended-release divalproex sodium have
been compared in adults with intellectual
and developmental disabilities taking dival-
proex sodium for epilepsy (n 9) or for co-
morbid bipolar disorder (n 7) [400c].
There were no major differences. One sub-
ject in the overnight group had sedation,
seizures, worsening of tremor, or gastro-
intestinal adverse events and one had acute
diarrhea and vomiting, followed by a very
brief tonic leg seizure 6 days later.
Antiepileptic drugs Chapter 7
The effect of intravenous valproate when
given for the treatment of status epilepticus
has been studied in small retrospective case
series.
In 32 patients who received intravenous
valproate for status epilepticus as rst or
second line therapy there were no serious
cardiovascular complications; the only
adverse events reported were initial leuko-
cytosis and hypotension [401c].
In a prospective study of 48 patients with
status epilepticus refractory to benzo-
diazepines, intravenous valproate (30 mg/
kg, 6 mg/kg per hour was not associated
with systemic or local adverse effects [402c].
In a comparison of intravenous valproate
(n 49) and phenytoin infusion (n 25) in
74 patients with status epilepticus or acute
repetitive seizures, the two drugs were
equally effective but there were adverse
effects in none of those given valproate
and in three of those who were given phe-
nytoin (cardiac dysrhythmia, vertigo, and
hyponatremia) [241c].
Drug overdose Valproate overdose can
mimic brain death [403A].
A 19-year-old man developed severe confu-
sion and rapidly became deeply comatose.
All brain-stem reexes were absent, including
missing pupillary responses to light. The
serum valproic acid concentration was 12 430
mmol/L (usual target range 350700) and there
was severe hyperammonemia (500 mmol/l;
normal <30). Brain edema was ruled out by
CT scan. He was given L-carnitine and contin-
uous venovenous hemodialtration and made
a full clinical recovery.
A patient with schizophrenia developed
a confusional state and was initially treated
for non-convulsive seizures until the serum
valproic acid concentration test showed
acute intoxication [404A].
Guidelines have been published on the
conditions for emergency department refer-
ral and prehospital care for patients who
have ingested toxic amounts of valproate
immediate-release or extended-release dos-
age forms [405S].
Drugdrug interactions Aspirin A 59-year-
old white woman with moderate mental
175
retardation and a schizoaffective disorder
developed confusion, dizziness, lethargy, and
tremor of the hands after starting low-dose
valproate treatment [406A]. The valproate
unbound fraction was increased, which may
have been due to displacement by aspirin
and other drugs.
Carbapenems An old Chinese man with
epilepsy had seizures when meropenem
was added to treatment with valproate
[407A]. In a retrospective study of six criti-
cally ill patients taking valproate who con-
currently received meropenem (n 4),
imipenem (n 1), or ertapenem (n 1)
mean plasma valproate trough concentra-
tions fell by 58% and estimated mean
valproate clearance increased by 191%
compared with values obtained while they
were not receiving a carbapenem; ve
patients had generalized seizures during
concurrent valproate carbapenem treat-
ment, including two with no prior history
of seizures [408A]. Meropenem is an
enzyme inducer. Because of this pharmaco-
kinetic interaction, concurrent use of these
medications should be avoided.
Chitosan Two cases of a probable inter-
action of valproate with chitosan, a sub-
stance available to help weight loss, have
been reported; chitosan may reduce the
absorption of valproate [409A].
A 35-year-old woman taking valproate 500 mg
bd and phenobarbital 75 mg/day for idiopathic
generalized epilepsy who had been seizure-
free for 3 years had a recurrence of myoclonic
jerks, absences, and a tonic-clonic seizure a
few days after taking a dietary supplementa-
tion that contained chitosan 500 mg bd for
weight loss. The seizures remitted after chito-
san was stopped. Three months later she
restarted chitosan and within 5 days once
more had seizures. Serum valproate was
undetectable. Chitosan was withdrawn, the sei-
zures remitted, and the valproate concentration
returned to baseline (50 mg/l) within 4 days.
Oral contraceptives Serum concentrations
of lamotrigine and valproate were mea-
sured twice during a single menstrual cycle
in four groups of 12 women with epilepsy
[175C]. Both valproate and lamotrigine
176
concentrations were signicantly reduced
by the oral contraceptive (median reduc-
tions of 23% for valproate and 33% for
lamotrigine). Serum lamotrigine concentra-
tions fell non-signicantly by 31% during
the mid-luteal phase compared with the
early-mid follicular phase in the absence
of oral contraception.
Oxcarbazepine An interaction of oxcarba-
zepine with valproate resulted in an
increase in both total valproate and a dis-
proportionately larger increase in the
unbound fraction, which may have been
due to both inhibition of valproate metabo-
lism and displacement from protein binding
sites; the authors also hypothesized that
oxcarbazepine had inhibited protein-medi-
ated valproate transport into the site of
metabolism in hepatocytes [410A].
Quetiapine One patient taking long-term
valproate developed edema in both legs 7
days after the addition of quetiapine, which
promptly resolved after drug withdrawal
[411A]. Valproate inhibits quetiapine
metabolism and increases its plasma con-
centration by about 77%.
Management of adverse drug reactions
Two identical cases of life-threatening
valproate overdose which were treated with
two different approaches have been
described [412A]. One patient was treated
with supportive therapy alone until cerebral
edema and seizures developed; the other
was treated with immediate extended
hemodialysis followed by high-volume
hemodialtration. The rst patient
remained critically ill with high valproate
and ammonia concentrations, seizures, and
life-threatening cerebral edema. The sec-
ond patient's valproate and ammonia con-
centrations rapidly fell with hemodialysis
and hemodialtration and he improved
rapidly.
In another patient severe valproate over-
dose associated with a serum valproate con-
centration of 1320 mg/l resulted in coma
Chapter 7 Gaetano Zaccara and Luciana Tramacere
but consciousness was regained after three
sessions of hemodialysis [413A].
The advantages of using carnitine in
patients with valproate overdose or valpro-
ate-induced hepatotoxicity and hyper-
ammonemic encephalopathy have been
discussed [414R]. Carnitine supplementa-
tion may increase the beta-oxidation of
valproate, thereby limiting cytosolic
omega-oxidation and the production of
toxic metabolites that are involved in liver
toxicity and ammonia accumulation.
In a systematic literature search, 31
reports have been identied of the use of
extracorporeal elimination in acute valpro-
ate poisoning [415M]. Even though there
have been no controlled comparisons of
the clinical outcomes with or without extra-
corporeal elimination in valproate poison-
ing, extracorporeal methods of elimination
should be considered in patients with fea-
tures of severe valproate poisoning (coma
or hemodynamic compromise) and plasma
valproate concentrations over 850 mg/l,
particularly if severe hyperammonemia
and electrolyte and acidbase disturbances
are present. Hemodialysis appears to be
the extracorporeal method of choice to
enhance valproate elimination in acute poi-
soning, and several case reports have con-
sistently shown that during hemodialysis
the half-life of valproate can be reduced to
around 2 hours and that enhanced clear-
ance is often associated with clinical
improvement.
Vigabatrin [SED-15, 3623; SEDA-30,
98; SEDA-31, 136; SEDA-32, 160]
The pharmacokinetics, mechanism of
action, and toxicology of vigabatrin have
been reviewed [416R]. Another review
focused on clinical problems [417R].
Observational studies In a retrospective
review of 84 children who were taking
Antiepileptic drugs Chapter 7
vigabatrin for infantile spasms and partial
epilepsies related to tuberous sclerosis com-
plex and other etiologies, control of infan-
tile spasms was achieved in 73% of those
with tuberous sclerosis complex and 27%
of those with other etiologies [418c]. Partial
onset seizures were controlled in 34% of all
the children; there were adverse events in
13%. Electroretinography and/or behav-
ioral visual eld testing was done in 52%
and the drug was withdrawn in one case
because of an abnormal result.
Placebo-controlled studies Vigabatrin has
been evaluated in cocaine-dependent indi-
viduals, who were randomly assigned to
vigabatrin (n 50) or placebo (n 53) in
a 9-week double-blind trial and a 4-week
follow-up assessment [419C]. Twelve of
those who took vigabatrin and two of those
who took placebo maintained abstinence
through the follow-up period. The reten-
tion rate was 62% with vigabatrin arm ver-
sus 42% with placebo. The rates of adverse
events were the same in the two groups.
Early somnolence was the most common
complaint among those taking vigabatrin
(n 12) and those taking placebo
(n 8). There was transient hypertension
in two subjects taking placebo and four tak-
ing vigabatrin. There were visual abnormal-
ities in three patients taking vigabatrin and
in one taking placebo.
Systematic reviews The use of vigabatrin in
partial epilepsy has been evaluated in a sys-
tematic review and meta-analysis of 11
short-term, randomized, placebo-controlled
trials, testing doses of 10006000 mg,
[420M]. There were 982 observations in
the primary intention-to-treat analysis of
efcacy. Patients who took vigabatrin were
signicantly more likely to obtain a 50%
or greater reduction in seizure frequency
than those who took placebo (RR 2.58;
95% CI 1.87, 3.57). Those who took vig-
abatrin were also signicantly more likely
to have treatment withdrawn (RR 2.49;
95% CI 1.05, 5.88), and more likely to
177
experience a number of adverse effects, sig-
nicantly so for fatigue or drowsiness.
Nervous system There was white matter
vacuolation and intramyelinic edema in the
brain of a child with quadriparetic cerebral
palsy secondary to hypoxic brain injury fol-
lowing premature birth, who died 3 weeks
after the start of a course of vigabatrin
[421A]. This increases concerns about the
use of vigabatrin in individuals with pre-
existing abnormalities of myelin.
In 8 of 23 patients there were MRI abnor-
malities attributable to vigabatrin and char-
acterized by new-onset and reversible T2-
weighted hyperintensities and restricted dif-
fusion in thalami, globus pallidus, dentate
nuclei, brainstem, or corpus callosum [422c].
Diffusion-weighted imaging was positive,
and apparent diffusion coefcient maps
demonstrated restricted diffusion. Young
age and relatively high doses were suscepti-
bility factors. All the ndings reversed after
drug withdrawal.
The frequency of transient MRI abnormal-
ities in children taking vigabatrin has been
retrospectively reviewed in 205 infants with
infantile spasms (332 cranial images) and
668 children and adults with partial epilepsies
(2074 images) [423c]. Among infants with
infantile spasms, the prevalence of prespeci-
ed MRI abnormalities was signicantly
higher among vigabatrin-treated versus viga-
batrin-naive subjects (22% versus 4%). Of
nine subjects in the prevalent population with
at least one subsequent MRI scan, there was
resolution of abnormalities in six. Among
adults and children who took vigabatrin for
partial seizures, there was no statistically sig-
nicant difference in the incidence or preva-
lence of prespecied MRI abnormalities
between vigabatrin-exposed and vigabatrin-
naive subjects. The authors concluded that
vigabatrin is associated with transient, asymp-
tomatic magnetic resonance imaging abnor-
malities in infants treated for infantile
spasms and that most of these abnormalities
resolve, even in subjects who continue to take
the drug.
178
Visual impairment and vigabatrin
EIDOS classication:
Extrinsic moiety Vigabatrin
Intrinsic moiety Not known
Distribution Nerve bers in the retina
Outcome Atrophy
Sequela Visual eld loss from vigabatrin
DoTS classication:
Dose-relation Collateral reaction
Time-course Late
Susceptibility factors Age (more
common in adults)
Vigabatrin-induced ocular adverse effects
have been reviewed [424R].
In 734 patients with refractory partial epi-
lepsy, divided into three groups and strati-
ed by age (812 years; >12 years) and
exposure to vigabatrin, the frequencies of
visual eld loss differed across the groups
[425c]. The three groups were: patients who
had taken vigabatrin for at least 6 months
(current users); patients who had previously
taken vigabatrin for at least 6 months but
who had not taken it for at least 6 months
(prior users); patients who had never taken
vigabatrin (never users). The results are
shown in Table 1.
Since the probability of vigabatrin-associ-
ated visual eld loss is positively associated
with treatment duration, careful assessment
of the balance of benet to harm in continu-
ing treatment with vigabatrin is recom-
mended in patients who are currently
taking it. In those who continue to take it,
visual eld examination at least every 6
months is recommended.
In 204 patients with epilepsy, grouped on
the basis of antiepileptic drug therapy (cur-
rent, previous, or no exposure to vigaba-
trin), there was bilateral visual eld
constriction in 59% of current users, 43%
of prior users, and 24% of never users
[426c]. Assessment of retinal function
showed abnormal responses in 48% of cur-
rent users and 22% of prior users, but in
none of the never users.
Chapter 7 Gaetano Zaccara and Luciana Tramacere
In eight patients with visual eld constric-
tion, who were examined 46 years after
they had stopped taking vigabatrin visual
eld constriction was unchanged [427c].
The amplitude of the 30 Hz icker response
was still reduced. The authors concluded
that vigabatrin causes permanent retinal
damage.
Persistence of visual loss after vigabatrin
therapy has also been studied in 16 school-
age children who had taken vigabatrin in
infancy for infantile spasms, and who were
examined by Goldmann kinetic perimetry
at age 612 years [428c]. Vigabatrin had
been started at a mean age of 7.6 (range
3.220) months and the mean duration of
therapy was 21 (9.330 months) with a
cumulative dose of 655 (2091109) g. Fifteen
children had normal visual elds. There was
mild visual eld loss in one child who had
taken vigabatrin for 19 months to a cumula-
tive dose of 572 g. The authors concluded
that the risk of visual loss may be lower in
children who are given vigabatrin in infancy.
In a retrospective study of charts from 47
children with infantile spasms who were
given vigabatrin as a rst-line drug and
charts from 15 children at the age of at least
6 years without neurological or cognitive
decits, who had taken vigabatrin for at least
6 months during infancy, only one patient
had visual eld defects after at least two
examinations [429c]. These results conrm
that this adverse effect plays a minor role
in young children and that treatment of
infantile spasms for 36 months with vigaba-
trin seems to carry minimal risk.
Table 1 Frequencies of visual loss in different
groups of patients taking vigabatrin
Frequency
Age 812 Age
Group years >12 years
Current 10/38 (26%) 65/150 (43%)
users
Prior users 7/47 (15%) 37/151 (25%)
Never users 1/186
Antiepileptic drugs Chapter 7
In 42 children with infantile spasms, all of
whom had been exposed to vigabatrin for a
minimum of 1 month, and in whom contrast
sensitivity and grating acuity were measured
using sweep visual evoked potential testing,
grating acuity was signicantly reduced in chil-
dren with evidence of retinal toxicity based on
30-Hz icker amplitude reductions on full-
eld electroretinography [430c]. There were
no differences in contrast sensitivity between
children with and without retinal toxicity.
In 28 of 31 young children with epilepsy who
were taking vigabatrin binocular white sphere
kinetic perimetry was used to test peripheral
visual elds; their median visual eld extents
were smaller than in controls [431c]. In eight
of these subjects, binocular eld extents were
smaller than the minimum in the controls.
Monocular white sphere kinetic perimetry did
not differ between the two groups. In nine
patients who were tested with both this new
technique and Goldmann kinetic perimetry,
visual eld extents did not differ between tests.
Screening procedures that have been recom-
mended before and during treatment with vig-
abatrin have been reviewed [432R]. As a rule, a
complete ophthalmological examination,
including perimetry and retinal electrophysiol-
ogy, should be performed every 6 months.
However, it may be necessary to rely on retinal
electrophysiology, since some patients may not
be able to undergo perimetry.
Until now, the incidence of vigabatrin-asso-
ciated retinal toxicity in Asian populations
has not been studied. In 18 Chinese patients,
8 men and 10 women, who had taken vigaba-
trin for 13 months to 5 years, mean dosage
1581 mg/day, there were signicant bilateral
visual eld defects in 20 eyes, and 80%
showed a concentric pattern, compared with
none in the control group [433c].
Impairment of visual processing due to vig-
abatrin (not simply visual eld loss) has been
studied using a spatial attention task [434c].
Performance was tested at eccentricities vary-
ing from 30 degrees to 60 degrees on a pano-
ramic screen covering 180 degrees.
Participants were patients with epilepsy tak-
ing vigabatrin, patients taking other antiepi-
leptic drugs, and healthy controls. Nine
patients in the vigabatrin group had mild
visual eld constriction. In those taking
179
vigabatrin there was a general slowing down
of response times, which could only be
explained by an alteration in the photorecep-
tors not yet detected by perimetry. The slow-
ing down of visual processing at large
eccentricity for ashed stimuli suggested that
patients taking vigabatrin might have
impaired ability to detect moving objects in
the periphery before visual eld restriction.
Four children who had been exposed to
vigabatrin in utero all had normal visual
elds and retinal nerve ber layer thick-
nesses, suggesting that vigabatrin does not
cause visual toxicity in children exposed to
vigabatrin prenatally [435c].
Metabolism The effects of vigabatrin
(n 24), topiramate (n 21), and lamotri-
gine (n 28) on serum carnitine concentra-
tions have been investigated in 91 children
and compared with those obtained from 18
children taking valproate [314c]. The new
drugs did not alter carnitine concentrations.
Drugdrug interactions Metamfetamine
Treatment of metamfetamine dependence
with vigabatrin has been suggested. Possible
cardiovascular adverse effects induced by
the co-administration of these substances
and the possible interaction between vigaba-
trin and metamfetamine have been evaluated
in a double-blind, placebo-controlled, paral-
lel-group study in healthy volunteers [436c].
Vigabatrin did not alter metamfetamine or
amfetamine plasma concentrations or toxic-
ity. There were no serious adverse events
and the total number of adverse effects was
similar in the two groups. There were no sig-
nicant differences in systolic or diastolic
blood pressures or heart rate.
Zonisamide [SED-15, 3728; SEDA-30,
99; SEDA-31, 137; SEDA-32, 161]
Observational studies In an open prospec-
tive study in 13 patients with idiopathic
generalized epilepsies who were taking
zonisamide mean dosage 319 mg/day, 12
continued to take zonisamide at month 6
180
and 11 at month 12 [437c]. Seven patients
were seizure-free and four had adverse
eventsloss of appetite and weight loss in
three and headache, somnolence, and irri-
tability in the other. Two patients withdrew
because of adverse events.
In a retrospective study of 74 patients
with epilepsy taking zonisamide mean dos-
age 368 mg/day, of whom 34 continued to
take zonisamide for 12 months after the
start of therapy, 11 had at least a 50%
reduction in seizure frequency [438c]. There
were adverse effects in 45, which led to
drug withdrawal in 24.
In a prospective, add-on, open study in 82
patients, aged 334 years, with partial
(n 47) or generalized (n 35) refractory
epilepsy, zonisamide was started in a dosage
of 1 mg/kg/day and increased by 2 mg/kg
every 12 weeks over a period of 3 months
up to a maximum dose of 12 mg/kg/day
[439c]. After 12 months the mean dosage
was 5.7 mg/kg/day and nine patients were sei-
zure-free. There were adverse effects in 22
patients. The most common treatment-
emergent adverse effects were nervous sys-
tem irritability (n 9), weakness (n 5),
reduced appetite (n 3), drowsiness (n 2),
and insomnia (n 2). One patient developed
a rash 10 days after starting zonisamide,
which required drug withdrawal; when zoni-
samide was tried again, the rash recurred.
In 317 patients with refractory partial
epilepsy who had completed a xed-dose,
randomized, double-blind, add-on trial with
zonisamide, and were recruited into an
open extension study, retention rates at 1,
2, and 3 years were 65%, 45%, and 29%
respectively [440c]. Adverse effects were
reported by 89% of patients, the most com-
monly reported being dizziness (12%),
somnolence (12%), and weight loss (11%).
Serious adverse effects were reported in
52 patients (16%) and convulsions were
the most common. The overall withdrawal
rate due to adverse effects was 22%.
In 17 children with infantile spasms who
were given zonisamide at a starting dose
of 28 mg/kg/day, the dose was increased
by 25 mg/kg/day every 34 days until the
seizures disappeared or the dose reached
30 mg/kg/day [441c]. Adverse reactions
Chapter 7 Gaetano Zaccara and Luciana Tramacere
included irritability in four patients and
reduced appetite in two.
Of 109 children with epilepsy prospectively
treated with zonisamide at a starting dose of 1
mg/kg/day, and increased by 2 mg/kg/day
every 12 weeks to an initial maximum dose
of 12 mg/kg/day, 52 completed 15 months of
treatment [442c]. The most common treat-
ment-related adverse effects were somno-
lence (n 22), reduced appetite (n 20),
hostility (n 9), nervousness (n 9), reduced
sweating (n 8), emotional lability (n 6),
weakness (n 5), abnormal thoughts (n
5), and dizziness (n 4). Seven patients with-
drew from the study because of adverse
effects; these included increases in drug-
metabolizing enzymes (n 3), hostility (n
2), and rash, pancreatitis, and nervousness (1
each). Analysis of adverse events according
to use of concomitant enzyme-inducing drugs
showed no signicant differences between the
groups. The patient who withdrew because of
severe pancreatitis was taking zonisamide 6.1
mg/kg and was also taking valproate.
Zonisamide has been evaluated as add-
on therapy in six patients with epilepsy
due to brain tumors [443c]. Two patients
had adverse effects: one had sexual dys-
function and one had drowsiness.
Zonisamide has been assessed in 63
patients with migraine refractory to topira-
mate [444c]. The initial dosage was 50 mg/
day, with gradual titration to 400 mg/day.
After 2 and 6 months there was a statistically
signicant improvement in the number of
migraine attacks, headache severity, and
reduced use of acute medication. There were
adverse effects in 15 patients. The most com-
mon were difculty in concentrating (n 9),
fatigue (n 7), and paresthesia (n 6). Four
patients stopped taking zonisamide because
of adverse effects (three because of difculty
in concentrating and one because of restless
legs syndrome).
In 12 subjects with isolated head tremor
who were given either zonisamide or pro-
pranolol in a randomized, crossover pilot
study, zonisamide was more effective than
propranolol [445c]. There were adverse
effects in eight, mild sedative effects in ve
and gastrointestinal problems, such as diar-
rhea and abdominal discomfort, in three.
Antiepileptic drugs Chapter 7
Metabolism Possible zonisamide-induced
hyperammonemia occurred in a child with
citrullinemia [446A]. Inhibition of carbonic
anhydrase by zonisamide, which in turn
reduces the availability of bicarbonate ions
for carbamylphosphate synthesis, was the
suggested mechanism.
Immunologic Patients who develop an anti-
convulsant hypersensitivity syndrome after
taking an aromatic antiepileptic drug are
more likely to develop a similar complication
after taking other aromatic antiepileptic
drugs. Cross-reactivity between zonisamide
and other anticonvulsants and/or sulfo-
namides and prediction using the lymphocyte
toxicity assay have been studied in 40 adults
who had had clinical hypersensitivity syn-
drome reactions to sulfamethoxazole (n
20) or anticonvulsant drugs (n 20) [447c].
Patients with sulfamethoxazole-related but
not anticonvulsant drug-related hypersensi-
tivity syndrome reactions showed cross-
reactivity to zonisamide. The lymphocyte tox-
icity assay predicted a possible reaction to
zonisamide only in those who were sensitive
to sulfamethoxazole.
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Antiepileptic drugs Chapter 7
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8 Opioid analgesics and
narcotic antagonists
Note on receptor nomenclature: Opioid
receptors, originally called d, k, and m
receptors, are also referred to as OP1, OP2,
and OP3 receptors, or DOR, KOR, and
MOR receptors respectively.
GENERAL
Observational studies Tincture of opium is
a preparation of powdered opium, which
contains morphine, codeine, papaverine,
and alcohol. It is used as an antidiarrheal
agent, to treat neonatal abstinence syn-
drome, in the management of pain, and tra-
ditionally for the management of opioid
dependency in some Asian countries. In
an open study, opium-dependent subjects
were allocated to three different doses of
tincture of opium twice a day: 10 ml
(6.66 mg morphine equivalents; n 13),
20 ml (13.3 mg morphine equivalents;
n 8), and 30 ml (20 mg morphine equiva-
lents; n 11) [1c]. In all the subjects tinc-
ture of opium effectively suppressed
withdrawal symptoms without causing sig-
nicant adverse effects.
Nervous system Opioid-related sleep disor-
ders are increasingly being recognized as a
Side Effects of Drugs, Annual 33
J.K. Aronson (Editor)
ISSN: 0378-6080
DOI: 10.1016/B978-0-444-53741-6.00008-8
# 2011 Elsevier B.V. All rights reserved.
A.H. Ghodse and S. Galea
common cause for concern. Of 98
patients with chronic pain, long-term
opioid therapy was associated with obstruc-
tive, central, and combined sleep apnea in
83 [2c].
Of six patients with central sleep apnea,
who were receiving opioids (morphine
equivalent doses of 120420 mg/day) for
chronic pain, four achieved symptomatic
improvement when treated with bi-level
ventilation, correcting nocturnal hypoxemia
and reducing sleep fragmentation [3A].
Three cases of central sleep apnea
induced by acute ingestion of opioids have
been described [4A]. In the rst case, inges-
tion of unknown quantities of oxycodone
was associated with an increase in the
apneahypopnea index from 3.3 to 93 and
an increase in the central apnea index from
0 to 76. In the second case, oxycodone
15 mg was associated with an increase in
the apneahypopnea index from 0.6 to 28
and an increase in the central apnea index
from 0 to 28. In the third case, extended-
release morphine 120 mg was associated
with an increase in the apneahypopnea
index from 38 to 120 and an increase in the
central apnea index from 2.1 to 76.
Respiratory Practice guidelines have been
proposed to reduce the incidence and
severity of neuraxial opioid-related respira-
tory depression, improving the quality of
anesthetic care and patient safety [5R].
The authors suggested guidelines for the
identication of patients at increased risk,
the prevention of respiratory depression
after administration, the detection of respi-
ratory depression, and management.
205
206
Psychological The cognitive effects of
long-term opioid treatment for manage-
ment of cancer pain has been reviewed,
highlighting the paucity of studies and the
fact that existing studies only showed minor
cognitive decits, such as reaction time,
attention, balance, and memory. Cognitive
impairment was also associated with dosage
increases and short-acting opioid supple-
mentation [6R].
The cognitive effects of fentanyl given by
intravenous patient-controlled analgesia
and patient-controlled epidural analgesia
have been compared in patients who were
randomized to intravenous administration
(n 30), epidural administration (n 30),
or no treatment (n 20) [7C]. The intra-
venous group had impairment of attention,
sustained attention, attention span and
memory, and processing speed ability. The
epidural group had only impaired proces-
sing speed ability, which is regarded as a
very sensitive measure, even after minor
neurological insults.
Opioids are associated with a longer
duration of a rst episode of delirium,
which was associated with opioids, includ-
ing morphine and fentanyl, often combined
with benzodiazepines in an older popula-
tion of 304 patients admitted for intensive
care treatment [8C].
Endocrine Reduced cortisol concentrations
were reported in 44 newly admitted critical
care patients. Cortisol concentrations were
lower after parenteral opioid administra-
tion in opioid-nave patients (n 33) but
not in patients with a recent history of
long-term opioid use [9c].
Gastrointestinal Narcotic bowel syndrome,
dened as chronic and/or frequent recur-
ring abdominal pain aggravated by use of
narcotics, has been investigated in a ran-
dom cohort of 4898 people in the commu-
nity. Narcotic bowel syndrome was rare
(n 5), but those who used narcotics
reported more gastrointestinal symptoms
and tended to use more laxatives [10C].
The effects of long-term treatment with
oral sustained-release hydromorphone,
transdermal fentanyl, and transdermal
Chapter 8 A.H. Ghodse and S. Galea
buprenorphine on nausea, vomiting, and
constipation, have been prospectively
explored in 174 patients with cancer pain
[11C]. There was constipation in 15% and
nausea and vomiting in 21%. There was a
higher incidence of 72 hours stool-free
periods among those who used transdermal
opioids, suggesting that transdermal opioids
do not offer much benet with gastrointes-
tinal adverse effects.
Sexual function Sexual behavior and sex-
ual dysfunction have been explored in 60
patients taking buprenorphine (n 30) or
methadone maintenance treatment
(n 30). Those who took methadone had
more problems with sexual excitation
(33% versus 3.3%) and difculty in reach-
ing orgasm (40% versus 10%) than those
who took buprenorphine. Sexual satisfac-
tion was also signicantly greater in those
who used buprenorphine (90% versus
63%) [12r].
There was sexual dysfunction in 47
women who used sustained-action oral or
transdermal opioids for non-malignant pain
[13c]. Concentrations of testosterone, estra-
diol, and dehydroepiandrosterone were
4857% lower than concentrations in the
control group (n 68). Luteinizing
hormone and follicle-stimulating hormone
concentrations were also lower in both pre-
menopausal and postmenopausal women.
Oophorectomized women also had 39%
lower concentrations of free testosterone.
These ndings suggested hypogonadotrophic
hypogonadism and reduced adrenal andro-
gen production.
Similar ndings have been found in both
men and women in a systematic review
[14M]. The authors recommended routine
screening of patients taking long-term opi-
oids and management of opioid-induced
hypogonadism by opioid rotation, non-opi-
oid pain management, or sex hormone
supplementation.
Death Lack of consensus and disparities in
clinical practice are seen as common con-
tributors to deaths related to prescription
opioids [15r]. The main sources of diverted
prescription opioids are patients for whom
Opioid analgesics and narcotic antagonists
opiates are prescribed for pain, elderly
patients, doctor shoppers, and pill bro-
kers. Education of physicians and patients
could address these concerns [16r, 17c].
Drug abuse In body packing, multiple
packets of substances are packed generally
in the bowel. A 45-year-old man developed
miosis and respiratory depression; he had
multiple packets in the bowel, seen on
abdominal radiography [18A].
Safety concerns related to medication
adherence have been explored in 91 metha-
done-maintained patients attending com-
munity pharmacies [19C]. There was non-
adherence to prescribing recommendations
in 42% of cases. Non-adherent behaviors
included splitting of the dose, storage of
the dosage form, missed pick up, formula-
tion given away, sold, or exchanged,
and formulation stolen or lost. The authors
suggested that medication adherence should
be regularly reviewed.
Oxycodone, hydrocodone, and hydro-
morphone have been compared with regards
to abuse liability. They did not differ sub-
stantially from one another, suggesting that
analgesic potencies did not reect relative
differences in abuse liability [20c].
In an epidemiological study of pain and
attendant psychopathology in opioid anal-
gesic abusers, 6070% of all those started
on a legitimate prescription of opioids for
pain later misused opioids [21C].
In an exploratory qualitative study of 25
street drug users in Toronto, Canada, 14
had a history of fentanyl use in at least the
past 3 months [22c]. Abuse practices
included extracting fentanyl from its matrix
patch with vinegar and water; sharing the
extracted fentanyl with other users by load-
ing syringes from one container, hence
increasing the risk of infection with blood-
borne viruses; and overdosing because of
difculty in gauging the concentration of
fentanyl in the extract. Hence, fentanyl
patches on the street pose a signicant pub-
lic health risk.
The abuse potential of opioids is evident
through the experience of withdrawal
symptoms. In a prospective study, 79 chil-
dren receiving midazolam and/or opioids
Chapter 8 207
for more than 5 days, and were followed
up for withdrawal symptoms [23c]. Most of
them (73 out of 79) received both medica-
tions and withdrawal symptoms were attrib-
utable to both. Agitation, anxiety, muscle
tension, sleep difculties, diarrhea, fever,
sweating, and tachypnea were the most
common symptoms.
In a cross-sectional study of abuse and
dependence of drugs used for self-medica-
tion over 2 months, among those who had
used codeine in the previous month
(n 53), there was misuse by 15%, abuse
by 7.5%, and lack of control and depen-
dence in 7.5% [24C].
In a randomized study, the abuse potential
of ALO-01 extended-release capsules con-
taining morphine sulfate and naltrexone was
studied with regards to pharmacodynamic
effects, including drug-liking and euphoria
[25C]. Participants were randomized to either
two 60-mg capsules, two 60-mg capsules
crushed, morphine sulfate 120 mg, or
placebo. There was reduced desirability asso-
ciated with ALO-01, whether whole or
crushed.
Fetotoxicity Exposure to opioids in utero
can lead to the development of the neonatal
abstinence syndrome, especially in infants
born to mothers who have misused these
drugs. Neonatal abstinence syndrome in neo-
nates born to mothers taking treatment has
been investigated in 68 neonates. Pre-deliv-
ery higher doses of maternal methadone were
associated with an increased incidence of
treatment for withdrawal and with longer epi-
sodes of neonatal abstinence syndrome.
There was a doseresponse relationship
for every 1 mg increase in last maternal meth-
adone dosage before delivery, an extra
0.18 days of infant treatment for neonatal
abstinence syndrome were required; further-
more, breastfeeding reduced the duration of
neonatal abstinence syndrome by 7.76 days
[26c].
In a similar study, involving 450 singleton
pregnancies in drug misusing women taking
methadone, 46% of the neonates devel-
oped the neonatal abstinence syndrome
[27C]. Breastfeeding was associated with
amelioration of symptoms. Admissions to
208
the neonatal unit were necessary in 48%,
40% being due to neonatal abstinence syn-
drome. Infants born to poly-drug misusing
women, compared with those only taking
prescribed methadone, were more vulnera-
ble, and required longer hospital stays (11
versus 8 days), and used more health-care
resources. Infants born to mothers who
had misused drugs accounted for 2.9% of
all births but disproportionately used 18%
of neonatal unit days.
In a prospective study, the neonatal
abstinence syndrome has also been
described in 58 infants who had been
exposed to buprenorphine in utero. There
was neonatal abstinence syndrome in 38
infants, most of whom had been hospital-
ized for around 28 days. There was a
positive correlation between urinary norbu-
prenorphine concentrations over the rst
3 days of life and the duration of morphine
treatment and length of hospital stay. The
authors also studied social problems, which
were evident in all infants and contributed
to the length of hospital stay [28c].
Sublingual buprenorphine has been pro-
posed as an effective and well-tolerated
treatment for neonatal abstinence syn-
drome. In a randomized trial, infants with
neonatal abstinence syndrome, who had
been born to mothers taking maintenance
methadone, were randomized to either sub-
lingual buprenorphine 1339 micrograms/
kg per day (n 13) or standard-of-care
oral neonatal opium solution (n 13)
[29C]. Buprenorphine administration was
associated with a 31% reduction in length
of treatment and a 29% reduction in the
length of hospital stay. One infant had
seizures after buprenorphine, but it was
not clear whether buprenorphine was
causal.
Susceptibility factors Age Susceptibility to
adverse effects in patients with chronic
non-malignant pain has been reviewed
[30R]. Opioid prescribing in the elderly is
indicated for severe pain that has not
responded to non-opioid drugs. Slow titra-
tion of the dose until adequate benet is
achieved. Opioids to be avoided in such
patients include pethidine, because of the
Chapter 8 A.H. Ghodse and S. Galea
risk of seizures; pentazocine, because of
associated neuropsychiatric toxicity; dextro-
propoxyphene, because of neural and car-
diac toxicity; and methadone, because of
its long half-life. Combinations of drugs
should also be avoided.
Critically ill patients Management of pain
in critically ill patients has been reviewed
[31R]. Opioids remain the mainstay of
treatment in intensive care units. The
benetharm balance of opioid analgesics
requires continued assessment. The choice
of opioid and dosage regimen should take
into account the evidence base, as well as
the physicochemical, pharmacokinetic, and
pharmacodynamic characteristics of the
drugs. The potential and actual develop-
ment of adverse effects needs to be moni-
tored and doses titrated accordingly. Lean
rather than total body weight should be
used when calculating weight-based dosing
regimens. The determination of effective
equianalgesic alternative doses or routes
of administration is complex, and factors
such as age, comorbidities, and tolerance
need to be considered. Opioid adjuncts
need to be considered case by case.
The authors also supported the use of
non-pharmacological interventions, such as
music and relaxation techniques.
Adjunct techniques can provide opioid-
sparing effects, reducing the incidence of
opioid-related adverse effects. According
to the results of a meta-analysis, adjunctive
acupuncture reduced the consumption of
opioid-related adverse effects such as nau-
sea, dizziness, sedation, pruritus, and uri-
nary retention [32M].
Of 2169 patients who received palliative
care in 95 general practices in the Nether-
lands during the 3 months before their
death, a signicant proportion (16%) were
given strong opioids before a trial of weak
opioids; in 48% of all patients who were
given opioids, laxatives were not prescribed
and antiemetics were prescribed in 29%
[33C].
Pharmacological tolerance of analgesic
effects, symptoms of withdrawal, opioid-
induced hyperalgesia, and psychological
factors have been reported as contributing
Opioid analgesics and narcotic antagonists
to analgesic failure, giving rise to contro-
versy around the efcacy of long-term opi-
oids. The increased risk of abuse and
diversion necessitates monitoring, taking
into consideration reliable predictors, such
as a history of prior substance use, younger
age, depression, and anxiety. Opioid-
induced hyperalgesia presents another chal-
lenge, which, if recognized, could affect the
efcacy of opioids in the management of
pain [34r, 35R, 36R, 37R].
Management of adverse drug reactions
The translation of knowledge about drug
safety into clinical practice has been studied
through the creation of a Patient-orien-
tated Prescription for Analgesia, which
contained evidence-based medical knowl-
edge at the point of prescribing [38C]. Such
a method of prescribing was shown to
reduce the occurrence of opioid-associated
severe/fatal adverse events.
OPIOID RECEPTOR
AGONISTS
Alfentanil [SED-15, 72; SEDA-31, 153;
SEDA-32, 187]
Observational studies In a study involving
50 patients with osteoporotic vertebral frac-
tures, scheduled for percutaneous vertebro-
plasty, an infusion of alfentanil 1.05 mg/hour
was effective for intraoperative pain relief;
transient apnea of less than 10 seconds
occurred in only two patients and nausea
and vomiting in three [39c].
Nervous system Emergence agitation has
again been described in a randomized pla-
cebo-controlled study in 105 children hav-
ing adenotonsillectomy, who were given
alfentanil 10 or 20 micrograms/kg after loss
of the eyelash reex. Induction and main-
tenance was with sevourane 1.52.5%
[40C]. Emergence delirium was measured
using Aono's scale and the pediatric anes-
thesia emergence delirium (PAED) scale.
Chapter 8 209
The incidence of severe agitation postoper-
atively was signicantly lower with alfenta-
nil than placebo, but there were no
differences between the two doses of alfen-
tanil. Adverse events were rare, but signi-
cantly more children given 20 micrograms/
kg of alfentanil became hypotensive on
induction. There was no difference in respi-
ratory adverse effects or recovery times.
Higher doses of alfentanil can cause respi-
ratory adverse effects, and therefore a dose
of 10 micrograms/kg should have the most
benet in reducing emergence delirium
and fewer adverse effects.
Codeine [SED-15, 880; SEDA-31, 156;
SEDA-32, 187]
Lactation Breastfeeding by mothers taking
codeine may be ill-advised, particularly if
they are ultrarapid metabolizers of codeine,
in whom morphine is formed in large
amounts, because of the risk of adverse
effects on the baby [SEDA-31, 154].
Reports of this association continue to
appear. For example, a baby died after its
breastfeeding mother took codeine and
paracetamol, although the death could not
be directly linked to codeine [41A].
It is important to consider interindividual
variations in drug response, such as geno-
types linked with increased opioid concentra-
tions, the doseresponse relation to drug
toxicity, and the susceptibility of the very
young or premature infant whose drug-excre-
tory mechanisms are underdeveloped [42r].
In a casecontrol study, neonatal CNS
depression was reported in 24% of breastfed
infants whose mothers used codeine [43C].
The mothers of these infants had consumed
59% more codeine than mothers whose
infants did not experience toxicity. Toxicity
also occurred in some babies whose mothers
had taken low doses (mean 0.63 mg/kg/day),
highlighting increased sensitivity of infants
to the CNS depressant effects of opioids.
Susceptibility factors Genetic The use of
codeine as an antitussive in children can
be associated with severe and even fatal
210
adverse effects. When 3-year-old twins
were given 10 drops of codeine per day
for 6 days for an upper respiratory tract
infection, one was found lying in vomit
and apneic, and required mechanical ventila-
tion and the other died following aspiration of
gastric contents [44A]. Blood codeine concen-
trations were high (total codeine 489 ng/ml
and 645 ng/ml). Both were extensive metabo-
lizers by CYP2D6. These cases also highlight
the danger posed by inaccurate dosing when
giving codeine by drops [45R].
A healthy 2-year-old boy with a history of
sleep apnea was given 1012.5 mg codeine
orally every 46 hours after elective adenoton-
sillectomy [46A]. After 2 days, he developed
fever and wheezing due to bronchopneumonia
and the next day had absent vital signs. The
blood concentration of codeine was 0.70 mg/l
and of morphine 32 ng/ml. He was an ultra-
rapid metabolizer.
Dextromethorphan [SED-15, 1088;
SEDA-30, 109; SEDA-31, 158; SEDA-32,
187]
Comparative studies In 90 children under-
going adenotonsillectomy who were ran-
domized to placebo, dextromethorphan
cough syrup (1 mg/kg), or tramadol syrup
pre-operatively plus intravenous tramadol
1 mg/kg during induction of anesthesia,
the incidence of nausea and vomiting was
highest in the tramadol group (10% com-
pared to 5.5% with dextromethorphan
group and 6.6% with placebo); however,
signicantly fewer patients (6.6% versus
40%) who received tramadol required sup-
plementary pethidine [47c].
Psychiatric A 60-year-old lady developed
agitation, paranoia, and psychosis after tak-
ing dextromethorphan, propoxyphene, and
hydrocodone [48A]. She had no history of
previous mental illness. She had taken pro-
poxyphene and hydrocodone paraceta-
mol for pain and dextromethorphan for
cough in higher than recommended doses
associated with a respiratory tract infection.
Chapter 8 A.H. Ghodse and S. Galea
Dextropropoxyphene [SED-15, 1092;
SEDA-30, 109; SEDA-31, 156]
Death Co-proxamol, a combination of
dextropropoxyphene and paracetamol, was
gradually withdrawn from the UK market
following a change in legislation in 2005.
In a retrospective observational study of
mortality data in Scotland over the period
20002006, the change in legislation was
associated with a reduction in co-proxa-
mol-related deaths, without a compensa-
tory rise in mortality from other analgesics
[49C].
Diamorphine (heroin) [SED-15,
1096; SEDA-30, 110; SEDA-31, 158;
SEDA-32, 188]
Comparative studies In a randomized com-
parison of injectable diamorphine (mean
dose 392 mg/day; n 115), oral methadone
(mean dose 96 mg/day; n 111), and
injectable hydromorphone (n 25) in
patients with opioid dependence refractory
to treatment, those who received diamor-
phine had more adverse events (51 events)
than those who received methadone (18
events) or hydromorphone (10 events)
[50C]. The most serious events were seizures
(seven events with diamorphine in six
patients) and overdose (11 events with dia-
morphine and two with hydromorphone).
However, outcome measures were more
favorable with diamorphine. The authors
suggested that although diamorphine was
benecial it should be delivered in settings
where prompt medical intervention could
be provided.
Cardiovascular In 21 diamorphine-related
deaths, myocarditis was found at autopsy
[51c]. There was a vefold increase in
inammatory cells in the myocardial inter-
stitium. The effect of potential contami-
nants was unclear.
A 29-year-old with a history of substance
abuse presented with cardiac arrest and coma
[52A]. Toxicology showed that he had used
Opioid analgesics and narcotic antagonists Chapter 8
benzodiazepines and opiates. He received
therapeutic hypothermia, maintaining his core
temperature at 3234 C. He eventually recov-
ered fully.
Nervous system Heroin-associated spongi-
form leukoencephalopathy has been
described in a 36-year-old heroin abuser
who had a 3-day history of lethargy and
increasing unresponsiveness [53A]. A CT
scan showed scattered small foci of hemor-
rhage and an MRI scan showed injury in
the bilateral subcortical white matter con-
sistent with restricted diffusion and T2
hyperintense lesions 3 months later.
Psychiatric Hallucinations occurred in a
patient who had received diamorphine by
subcutaneous infusion for several months;
they resolved when he switched to oxy-
codone [54Ar].
Musculoskeletal A 21-year-old man who
had recently used heroin and cocaine devel-
oped atraumatic rhabdomyolysis, with
extensive swelling of his left leg, drowsiness,
and agitation [55A]. He had a high creatine
kinase activity and myoglobinuria, and
methadone, heroin, and benzodiazepines
were found in his urine. The rhabdomyolysis
was attributed to the coma, rather than a
direct effect of the drugs.
Drug dependence The prescribing of dia-
morphine for the management of depen-
dence has been reviewed [56R]. In one
survey, adverse reactions to diamorphine
included pruritus, sweating, reddening of
the skin, dry mouth, nausea, vomiting, con-
stipation, dizziness, impaired vision, head-
ache, muscle twitching, fatigue, impaired
concentration and memory, and impaired
sex drive [57C]. However, these were not
necessarily solely related to diamorphine,
since most of the patients were using other
substances or medications. More severe
adverse reactions included death, seizures,
and respiratory depression. The authors
mentioned the importance of ensuring ade-
quately supervised treatment models to
reduce the potential risk of diversion.
211
Drug overdose The prevalence, character-
istics, and outcomes of non-fatal diamor-
phine overdoses presenting to a large
hospital in Western Australia over 12 months
have been studied prospectively [58C]. Of all
emergency department presentations, 249
(0.5%) were for non-fatal diamorphine over-
dose. Individuals had a mean age of 19 years
and 61% were men. The highest proportion
of overdoses occurred on Wednesdays, and
most had used the heroin in the presence of
others. There was a trend to an increasing fre-
quency in teenage girls and repeat overdosing
was common. Other substances were com-
monly used: benzodiazepines 27%, alcohol
16%, cannabis 11%, amphetamines 5.8%,
hallucinogens 1.3%, and other drugs 4%.
In a community hospital in the USA,
there was a signicant increase in diamor-
phine overdoses over a 1-month period
(JuneJuly 2006) [59r]. There were 30 over-
doses in this period and nine of these
reported having used blue bag heroin,
diamorphine laced with fentanyl. During a
similar period in the previous year, only
six overdoses had been due to diamor-
phine. The authors suggest that fentanyl-
laced heroin may have contributed to the
increased increase.
Dihydrocodeine [SED-15, 1125;
SEDA-32, 190]
Nervous system Generalized convulsions
and a mixed acidosis have been attributed
to intoxication with an over-the-counter anti-
tussive medication containing dihydrocodeine
and chlorphenamine (SS Bron); however, the
effects were attributed to the chlorphenamine
[60A].
Fentanyl [SED-15, 1346; SEDA-30, 110;
SEDA-31, 159; SEDA-32, 191]
Comparative studies In a comparison of
fentanyl 0.5 micrograms/kg and remifentanil
0.5 micrograms/kg in patients undergoing
gastroscopy, those who received intravenous
212
fentanyl (n 99) took signicantly longer to
recover (8.7 minutes) compared with those
who received remifentanil (n 100;
7.6 minutes). The latter required less propo-
fol, which contributed to the faster recovery
time [61C].
In a randomized blind comparison,
patients undergoing sedation for emer-
gency procedures received either ketamine
0.3 mg/kg or fentanyl 1.5 micrograms/kg
followed by intravenous propofol 0.4 mg/
kg bolus [62c]. All ve severe events were
in those who received fentanyl and fentanyl
caused more mild (OR 5.9), moderate
(OR 3.8), and severe (OR 12.3)
adverse events. Desaturation was the main
contributor to this difference. Fentanyl
was 5.1 times more likely to cause sedation
than ketamine, and this persisted after
adjustment for age, weight, procedure type,
and pre-procedure pain (OR 4.6).
Cardiovascular In patients undergoing
orthopedic reduction or abscess drainage
who were randomized to ketamine 0.3 mg/
kg (n 32) or fentanyl 1.5 micrograms/kg
(n 31) intravenously, the latter had sig-
nicantly more cardiorespiratory events
(5.1 times the odds for serious events); only
16% did not experience any cardiorespira-
tory events, compared with 53% of those
who received ketamine [63c]. Of those
who received fentanyl, 32% reported mild
cardiorespiratory events, 36% moderate,
and 16% severe. In those who received
ketamine, the incidences were 25%, 22%,
and 0% respectively.
Fentanyl enhances vagal tone and can
cause bradycardia. In 27 children undergoing
catheter ablation under propofol anesthesia,
which has minimal effect on the sinus node,
electrophysiological stimulation was per-
formed before and after a bolus dose of
fentanyl 2 micrograms/kg and a subsequent
infusion of 0.075 micrograms/kg/minute
[64c]. There was an increase in calculated
sinus node recovery time but no change in
sinoatrial conduction time after fentanyl, sug-
gesting that fentanyl propofol impairs
sinus node recovery and therefore
Chapter 8 A.H. Ghodse and S. Galea
reduces automaticity without affecting con-
duction time.
Respiratory The incidence of fentanyl-
induced cough has been investigated and
correlated with the speed and dose of injec-
tion in 476 non-smoking patients free from
respiratory tract infections and bronchial
hyper-reactivity undergoing elective sur-
gery [65C]. They received fentanyl 1.5
micrograms/kg over 2 seconds (n 120),
over 5 seconds (n 118), or over 10 sec-
onds (n 119); 119 received placebo. The
incidences of cough within 5 minutes after
injection were similar in all the groups,
at 36%.
Upper respiratory tract events and post-
operative hypoxemia were more common
in 18 children undergoing elective orchido-
pexy who received intravenous fentanyl
than in 18 who received caudal analgesia
in a randomized comparison (seven versus
one) [66c].
Nervous system In a 58-year-old man with a
history of Parkinson's disease, fentanyl as an
anesthetic and for postoperative analgesia
was associated with severe bradykinesia and
rigidity [67A]. The mechanism was unclear
but probably resulted from an effect on the
dopaminergic nigrostriatal system.
Endocrine Secondary adrenal insufciency
was reported in a 64-year-old man with a
history of diffuse large B cell lymphoma
after he was given transdermal fentanyl
75 micrograms/hour for multifactorial pain
[68A]. Adrenal insufciency recurred when
he was re-started on fentanyl by his general
practitioner.
Musculoskeletal Muscle rigidity resulting in
reduced thoracic wall compliance occurred
intraoperatively in a 2-year-old child soon
after fentanyl administration, although the
dose was low (1 microgram/kg) [69A].
Immunologic A 46-year-old woman devel-
oped generalized erythema, bronchospasm,
and hypotension 4 hours after exposure to
Opioid analgesics and narcotic antagonists
transdermal fentanyl [70A]. She had had a
previous allergic reaction to fentanyl.
The delayed onset was thought to have been
due to the cutaneous route of administration.
Susceptibility factors Age In a comparison
of 30 elderly patients (>75 years) under-
going cardiac surgery and 20 younger ones
(< 60 years), the former had higher fenta-
nyl plasma concentrations (mean 5.7 versus
3.8 ng/ml) 2 hours postoperatively [71C].
Concentrations of oxycodone were similar,
but the elderly patients had less pain, with
longer intervals between dose require-
ments, and were more sedated.
Drug administration route Transdermal
The efcacy and safety of a fentanyl ionto-
phoretic transdermal system have been
explored in a meta-analysis of six trials
[72M]. In comparisons of the fentanyl trans-
dermal system and morphine in patient-
controlled analgesia, fewer of those who
received fentanyl withdrew because of
adverse effects, fewer had nausea and pru-
ritus, and none had respiratory depression;
however, more had headaches.
Nebulizer Nebulized fentanyl has been stud-
ied in children with suspected limb fractures
who were randomized to nebulized fentanyl
4 micrograms/kg (n 36) or intravenous
morphine 0.1 mg/kg (n 37) [73c]. There
were no reported adverse effects in those
who received nebulized fentanyl, but one
patient was withdrawn from the study
because of inadequate analgesia.
Drugdrug interactions Paroxetine Sero-
tonin syndrome in a 49-year-old woman
after cardiac surgery was linked to an inter-
action of paroxetine 40 mg/day with periop-
erative fentanyl 5 micrograms/kg [74A].
Ropivacaine In 108 children who were
given epidural fentanyl (0.2 micrograms/
kg/hour) in combination with ropivacaine
(1.25 or 1.5 mg/ml) for postoperative anal-
gesia after hypospadias repair, adverse
effects were more common in those who
Chapter 8 213
received the combination than in those
who received ropivacaine alone [75c].
Management of adverse drug reactions
5HT3 receptor antagonists The addition of
ondansetron and ketorolac to fentanyl was
associated with less nausea and vomiting
and dizziness in 135 patients undergoing
thyroid surgery [76c].
In a prospective, randomized, double-
blind comparison of ramosetron or ondan-
setron in the management of opioid-
induced postoperative nausea and vomit-
ing, 94 patients received fentanyl 25 micro-
grams/kg in a total volume of 100 ml at a
rate of 2 ml/hour and 0.5 ml per demand
with a 15-minute lockout period [77c].
Ramosetron was superior to ondansetron
in preventing vomiting and reducing the
severity of nausea.
Ketamine In 202 adults, low-dose ketamine
(1 mg/kg 42 and 83 micrograms/kg/hour
for 24 hours) improved the analgesic effects
of fentanyl (0.5 micrograms/kg basal and
0.5 micrograms/kg on demand with 6 minutes
lockout for 48 hours) and was associated with
lower incidence of postoperative nausea and
vomiting [78C]. In contrast, in women who
underwent abdominal hysterectomy, the use
of ketamine and fentanyl (infusion of keta-
mine 15 micrograms/kg/min three boluses
of fentanyl 1 microgram/kg) was associated
with hallucinations (in seven out of 15
patients) during and after surgery [79c].
Those who received ketamine alone also
had hallucinations (in nine out of 15 cases).
Propofol In a randomized study in 60 chil-
dren who underwent interventional radiology
and were allocated to propofol 0.5 mg/kg
fentanyl 1 microgram/kg ketamine 0.5
mg/kg (n 30) or propofol 0.5 mg/kg fen-
tanyl 1 microgram/kg saline 0.9% (n 30)
intravenously, there was oxygen desaturation
in three of those who received ketamine and
nine of those who did not [80c]. Those who
received ketamine also had agitation (n 2)
and tachycardia (n 1), which did not
occur in the other group. Nystagmus was also
a common adverse reaction (19 cases versus
214
one). The addition of low-dose ketamine
reduced the risk of desaturation.
Hydromorphone [SED-15, 1703;
SEDA-31, 162; SEDA-32, 193]
Observational studies In 223 patients who
were given intravenous hydromorphone
1 mg followed by an optional 1 mg
15 minutes later, there was oxygen desat-
uration in 5%, bradycardia in 10%, nausea
in 13%, vomiting in 7%, and pruritus in
5%; no serious adverse events were
reported [81c].
Comparative studies A xed dose of intra-
venous hydromorphone 1 mg followed by
an optional 1 mg 15 minutes later (n 112)
has been compared with analgesia provided
at the discretion of the clinician (n 112) in
patients who presented to an emergency
department [82C]. There was adequate anal-
gesia in both groups and the adverse effects
proles were similar. Adverse events in those
who received hydromorphone included oxy-
gen desaturation (5%), nausea (17%), vomit-
ing (4.7%), and pruritus (6.5%).
In a randomized controlled comparison of
hydromorphone and morphine in patient-
controlled analgesia, 50 patients were ran-
domized to either hydromorphone 0.2 mg/
ml or morphine 1 mg /ml; there was no differ-
ence in the adverse reactions prole
between the two regimens [83c].
Levacetylmethadol (levo-a-
acetylmethadol, LAAM) [SEDA-32,
193]
Cardiovascular The effects of levacetyl-
methadol (n 31) on the QT interval have
been studied in a randomized controlled com-
parison with racemic methadone (n 22)
[84C]. After 24 weeks, levacetylmethadol
caused signicant prolongation of the QTc
interval (0.409 versus 0.418 seconds), while
methadone had no effect. There was no statis-
tically signicant change in QT dispersion in
either group. There were more patients with
Chapter 8 A.H. Ghodse and S. Galea
borderline prolonged and prolonged QTc
intervals among those who received
levacetylmethadol (seven versus one).
The authors recommended careful electro-
cardiographic monitoring in patients receiv-
ing levacetylmethadol.
Methadone [SED-15, 2270; SEDA-30,
112; SEDA-31, 163; SEDA-32, 196]
Observational studies The adverse effects
prole of methadone has been compared
with that of morphine [95c]. Methadone
was associated with fewer adverse events,
because it is more lipophilic and has no
active metabolites. Symptoms due to meth-
adone overdose generally occur within
9 hours of ingestion with a mean onset of
symptoms at 3.2 hours.
In an open study in 21 opioid-tolerant
patients with severe cancer pain who were
switched to methadone, the switch was gen-
erally well tolerated; only one patient
required treatment withdrawal, because of
respiratory depression [85c]. Drowsiness
was one of the most frequent adverse
effects (in six patients) but it was of moder-
ate intensity and responded to dosage
reduction. Constipation was problematic in
six. Other effects included nausea and
vomiting (n 2), sweating (n 2), and
confusion (n 1).
Cardiovascular A 56-year-old man was
successfully switched from methadone
100 mg/day to buprenorphine after metha-
done-induced torsade de pointes [86A].
Morphine was used to counteract with-
drawal symptoms. The QT interval normal-
ized over the 3 days and remained normal
even 12 months later.
The factors that predispose to metha-
done-induced QT interval prolongation
have been reviewed [87R]. It was associated
with female sex, hypokalemia, high-dose
methadone, drug interactions (for example,
with medications that inhibit the metabo-
lism of methadone or with protein-bound
drugs), underlying cardiac problems or con-
genital unrecognized QT prolongation, and
Opioid analgesics and narcotic antagonists Chapter 8
DNA polymorphisms. The authors sug-
gested that despite the risk of mortality
associated with methadone-induced QT
prolongation, the high mortality in
untreated drug users tips the balance in
favor of methadone.
In 10 of 109 patients receiving metha-
done maintenance treatment in whom the
QTc interval was prolonged (>400 ms),
the susceptibility factors were older age,
higher methadone dose, and the use of anti-
depressants (trazodone and mirtazapine)
[88C].
Sensory systems Acute bilateral sensori-
neural hearing loss followed methadone
overdose (75 mg) in an opioid-nave indi-
vidual; there was gradual improvement in
hearing over 10 days [89A].
Skin Necrolytic migratory erythema has
been attributed to methadone [90A].
An 18-year-old woman presented with severe
symptoms of thick scales, pustules, and hair
loss suggestive of seborrheic dermatitis in the
scalp area. Descaling measures, antifungal
agents, potent topical steroids, and systematic
antibiotics produced limited benet. Over the
next 12 months she developed an erythema-
tous, scaly, weepy rash in the axillae and toe
webs, which waxed and waned. Skin scrapings
were repeatedly negative for fungi. She was
then lost to follow up for 2 years. When she
returned, her seborrheic dermatitis had
become much worse, having spread to the
groin and perianal area. She admitted to using
heroin, underwent detoxication, and was
enrolled into a methadone maintenance pro-
gram. Her symptoms were difcult to control
after 6 months of additional treatment and
she was admitted with septicemia secondary
to cutaneous herpes simplex and staphylo-
coccal infection of the groin. Recurrent viral
and bacterial infections of the groin area
remained a problem. Immunodeciency was
ruled out. Some symptom control was
achieved with prophylactic systemic antiviral
drugs, antibiotics, systemic and topical ste-
roids, antifungal drugs, and antibiotics. Gluca-
gonoma syndrome and zinc deciency were
ruled out. A biopsy from the groin area
showed a combination of parakeratosis and
keratinocyte vacuolar changes, supporting a
diagnosis of necrolytic migratory erythema.
This was considered to be secondary to
215
opiates. After patient was off methadone for
4 months, the rash cleared and the hair
completely regrew. The rash returned when
she restarted methadone.
Necrolytic migratory erythema is usually
part of the glucagonoma syndrome, which
is characterized by an alpha cell tumor of
the pancreas, leading to adult onset diabetes
mellitus, weight loss, and glossitis. It is often
mistaken for intertrigo or seborrheic derma-
titis. Its pathogenesis is not well understood.
The role of opiates in this case was not clear,
but it was not due to poor nutrition or poor
absorption of nutrients. The authors specu-
lated that opiates had had a direct effect on
epidermal metabolism.
Death Mortality from a naltrexone implant
(n 376) and methadone (n 658) have
been compared in opioid-dependent indi-
viduals [91C]. Methadone was associated
with increased mortality during the induc-
tion period.
Fetotoxicity Visual evoked potentials, indi-
cators of the integrity and maturity of the
visual pathway, were recorded within 4 days
from birth of 21 full-term infants of mothers
who had taken methadone [92c]. The drug-
exposed infants had small-amplitude or
non-detectable immature waveforms
compared with 20 controls. This suggests
that maternal methadone and other illicit
drugs altered on visual development in
infants.
Pregnancy Preterm births were reported as
being more prevalent in 258 opiate-
addicted pregnant women who were taking
methadone in a retrospective cohort study
[93C]. The preterm rate was 29% (almost
3 times the national average of 11%). The
higher rate was not affected by medical or
infectious co-morbidity, but there was a
correlation between preterm birth and the
use of more than one substance.
Susceptibility factors HIV infection A 36-
year-old woman with advanced HIV infec-
tion and taking methadone 70 mg/day and
diazepam 20 mg/day had recurrent attacks
216
of syncope due to prolongation of the QT
interval (QTc 540 ms) and torsade de
pointes [94A]. The authors postulated that
she had acquired HIV-induced long QT
syndrome.
Drugdrug interactions The use of metha-
done in treating cancer pain is limited by
its potential for interactions and its
adverse effects prole [95R]. Some drugs
(for example, antifungal azoles, quinolones,
macrolides, selective serotonin reuptake
inhibitors) can inhibit the metabolism of
methadone, increasing the risk of QT inter-
val prolongation, respiratory depression,
or other adverse effects; others (such as
anticonvulsants, antituberculosis drugs,
antiretroviral drugs, high doses of glucocor-
ticoids, risperidone, St John's wort, fusidic
acid, spironolactone, alcohol consumption,
and cigarette smoking) increase the speed
of methadone metabolism, potentiating
withdrawal effects. Conversely, methadone
can reportedly inhibit the metabolism of
other drugs (for example, tricyclic anti-
depressants), increasing the risk of QT
interval prolongation, NSAIDs (affecting
analgesia), or benzodiazepines (causing
nervous system toxicity). Of the selective
serotonin re-uptake inhibitors, uvoxamine,
uoxetine, and paroxetine signicantly
inhibit methadone metabolism, whereas
with sertraline and citalopram the effect is
minimal; the interaction with venlafaxine
is unclear.
Antiretroviral drugs In 12 healthy HIV-
negative volunteers, nelnavir reduced
plasma methadone concentrations by
4050%, increased its renal clearance, and
increased hepatic metabolism, extraction,
and clearance [96c].
Nevirapine and efavirenz increase the
R/S enantiomer concentration ratio, hence
increasing the therapeutic effects of metha-
done, which are almost exclusively medi-
ated by the R enantiomer, as has been
shown in ve patients taking nevirapine
and nine taking efavirenz [97c]. These inter-
actions are thought to be mediated by
induction of CYP2B.
Chapter 8 A.H. Ghodse and S. Galea
Cannabis The combination of cannabis
with methadone has been studied in 77
Australian and 74 Swiss methadone main-
tenance patients [98c]. There were lower
24-hour dose-corrected trough plasma con-
centrations of both (R)-methadone and
(S)-methadone; there was no effect of sex,
alcohol, tobacco smoking, or duration of
methadone treatment.
Nicotine In 40 patients taking methadone
maintenance treatment, nicotine enhanced
opioid withdrawal suppression and metha-
done attenuated nicotine withdrawal [99C].
The interaction of nicotine with methadone
increased ratings of euphoria and drug
liking and reduced restlessness, irritability,
and depression. Non-pharmacological
effects were also reported, with experiences
of positive effects and reduced negative
effects. These ndings could explain the
high prevalence of smoking among patients
who take methadone.
Morphine [SED-15, 2386; SEDA-30,
113; SEDA-31, 164; SEDA-32, 199]
Comparative studies An evaluation of the
use of postoperative intravenous patient-
controlled analgesia across a decade
highlighted that this method of administra-
tion has become more popular and is asso-
ciated with reduction in morphine
consumption and respiratory depression;
however, there are signicant risks of nau-
sea (47%) and vomiting (19%) [100C].
In the emergency treatment of acute
severe pain, intravenous morphine titration
(median 0.16 mg/kg with three boluses) was
associated with adverse effects in 11% of
patients (67 events) [101c]. Nausea and
vomiting were the most common events,
followed by dizziness, urinary retention,
respiratory depression (not severe), pruri-
tus, and allergy.
Intrathecal morphine (400 micrograms)
combined with intravenous patient-con-
trolled analgesia using fentanyl has been
compared with intravenous patient-
controlled analgesia alone in 40 patients
Opioid analgesics and narcotic antagonists
undergoing liver surgery [102c]. The inci-
dences of adverse effects were comparable
except for pruritus, which was signicantly
more common in those who received intra-
thecal morphine.
Epidural morphine 4 mg has been com-
pared with epidural morphine 5 mg as
patient-controlled analgesia for postopera-
tive analgesia in women after cesarean sec-
tion; the latter had more nausea and
vomiting (16% versus 72%) and more pru-
ritus (29% versus 82%) [103c].
In a comparison of oral sustained-release
morphine (mean 94 mg/day) and hydromor-
phone (138 or 206 mg/day) with regard to
nausea, vomiting, and constipation, in
patients receiving opioids for cancer pain,
morphine provided better pain relief at lower
doses (after accounting for dose conversion)
but was associated with more nausea, consti-
pation, and higher consumption of antiemetic
and gastroprotective drugs [104C].
Morphine (mean dose 112 mg) and mex-
iletine (mean dose 933 mg) have been com-
pared in the management of post-
amputation pain in a double-blind, random-
ized, placebo-controlled, crossover study in
60 patients [105c]. Morphine was associated
with a higher rate of adverse effects, mainly
constipation (17 versus two), drowsiness
(nine versus four), and nausea (four versus
zero).
Systematic reviews In a meta-analysis of
the benets and harms associated with
intrathecal morphine without local anes-
thetic in patients undergoing major surgery,
morphine was associated with respiratory
depression; the NNTH was 84 [106M]. The
authors also reported that the NNTH was
worse (15) when only the data from three
studies that specically reported respiratory
depression were used. The NNTH for pruri-
tus was 6. The incidence of urinary retention
was 12% (compared with 8.5% in controls).
There was no difference in the incidence of
nausea and vomiting.
Respiratory The safety of intravenous
morphine 0.050.1 mg/kg has been
explored in 43 non-intubated neonates
undergoing central line placement. Five
Chapter 8 217
had respiratory depression compared with
none of the 43 controls; however, these
infants had underlying respiratory insuf-
ciency and two of them were given an over-
dose of morphine [107c]. Morphine should
be used with caution in this population.
A 38-year-old woman undergoing laparotomy
with removal of intra-abdominal abscess fol-
lowing a duodenectomy developed acute lung
injury after switching from sufentanil to mor-
phine 0.1 mg/kg/hour; her symptoms devel-
oped within 34 hours and resolved after
withdrawal of morphine [108A].
Nervous system A 74-year-old man devel-
oped downbeat nystagmus after receiving
epidural morphine 3 mg every 12 hours for
postoperative pain (total dose 12 mg over
48 hours) [109A]. The nystagmus resolved
36 hours after morphine withdrawal.
A 50-year-old woman who was given intra-
thecal morphine 0.5 mg in conjunction with
general anesthesia for lung surgery did not
regain consciousness postoperatively [110A].
A brain scan showed cortical and subcortical
increased uid-attenuated inversion recovery
intensities in the occipitoparietal and upper
frontal regions, effacement of sulci, and corti-
cal and leptomeningeal enhancement. She
gradually recovered over the next few days.
This presentation suggested posterior revers-
ible encephalopathy syndrome, which the
authors suggested might have been caused
by intrathecal morphine.
Gastrointestinal Postoperative nausea due
to morphine is associated with genetic vari-
ation at position 118 of the m opioid recep-
tor. In 270 women who received
intrathecal morphine 0.1 mg as postopera-
tive analgesia, those who were homozygous
for the A118G polymorphism had a higher
incidence of nausea and vomiting [111C].
Musculoskeletal Muscle rigidity, laryngo-
spasm, and respiratory compromise
occurred twice in a 2-day-old full-term neo-
nate, rst after a bolus dose of morphine
100 micrograms/kg and then after a contin-
uous infusion of 4.4 micrograms/kg/hour
[112A].
218
Drug administration route The effects of
intravenous morphine 10 mg given to 38
patients with moderate pain after surgery
have been compared with those of intra-
muscular morphine 10 mg [113c]. There
was quicker analgesia with intravenous
morphine, without serious respiratory
depression. The level of sedation was
greater after intravenous morphine, but this
lasted for only 5 minutes.
Intranasal morphine 7.5 mg (n 45) or
15 mg (n 45) has been compared with
intravenous morphine 7.5 mg (n 45) and
oral morphine 60 mg (n 45) in a pla-
cebo-controlled study in 225 patients with
moderate to severe pain after third molar
extraction [114C]. Intranasal morphine
15 mg had similar efcacy to intravenous
morphine and caused typical systemic
opioid effects. The highest incidence of
adverse events was experienced by those
who received oral morphine. Nasal irrita-
tion was most common in those who
received intranasal morphine 15 mg (11%).
Drugdrug interactions Itraconazole Itra-
conazole 200 mg/day for 4 days increased
the absorption and plasma concentrations
of oral morphine by 2030% in 12 healthy
volunteers; the pharmacodynamic effects
of morphine were not enhanced [115c].
Oprelvekin An interaction of oprelvekin
(50 micrograms/kg/day) with morphine
(120 mg orally bd) was suggested as the
probable cause of respiratory depression
and sedation in a 20-year-old woman with
thrombocytopenia associated with chemo-
therapy [116A]. Oprelvekin was thought to
have reduced the renal excretion of mor-
phine metabolites.
Management of adverse drug reactions
Dexmedetomidine Combining dexmedeto-
midine 5 micrograms/ml and morphine
1 mg/ml in intravenous patient-controlled
analgesia resulted in better analgesia,
reduced morphine consumption, and a
reduced incidence of nausea and vomiting
Chapter 8 A.H. Ghodse and S. Galea
in a double-blind randomized study in 100
women undergoing hysterectomy [117c].
In a similar study, 64 patients undergoing
laminectomy received morphine 0.15 mg/kg
and were later randomized to receive
morphine alone (0.02 mg/kg intravenous
with 15 minutes lockout time) or morphine
and dexmedetomidine (0.02 mg/kg
intravenous morphine 0.1 microgram/kg
dexmedetomidine, lock out interval
15 minutes); the combination treatment
produced higher sedation scores but a
lower incidence of nausea [118c].
5HT receptor antagonists In a systematic
review of nine randomized controlled stud-
ies, serotonin receptor antagonists signi-
cantly reduced the severity of pruritus and
the need for treatment, but did not affect
its incidence; the incidence of postoperative
nausea and vomiting was reduced [119M].
Gabapentin Preoperative gabapentin 1200
mg reduced the incidence and severity of
morphine-induced pruritus and delayed its
time of onset compared with placebo
(48% versus 78%) in 86 patients who
received preservative-free morphine
0.2 mg intrathecally [120c].
Ketamine In 81 patients undergoing abdomi-
nal surgery, who were randomized to intra-
operative and postoperative ketamine
(0.5 mg/kg bolus 2 micrograms/kg/minute
for 48 hours), intraoperative ketamine only
(0.5 mg/kg bolus 2 micrograms/kg/
minute), or placebo, ketamine signicantly
reduced morphine requirements and the fre-
quency of nausea [121c].
The addition of ketamine as an opiate
sparer, 1.5 or 5 mg per bolus morphine
dose, has been studied in 58 patients under-
going transthoracic heart and lung surgery,
a procedure that is associated with severe
pain [122c]. Those who took ketamine used
50% less morphine and required less rescue
diclofenac for pain control. Pain scores were
consistently lower with ketamine, despite
reduced amounts of morphine administered.
Respiratory parameters were much better
with ketamine: none compared with seven
patients requiring oxygen for hypoxia. The
Opioid analgesics and narcotic antagonists
morphine group had increased postopera-
tive nausea and vomiting, but the difference
did not reach signicance and there were no
psychotomimetic adverse effects with keta-
mine. Although small in numbers this well-
powered study suggests a signicant mor-
phine-sparing effect of ketamine, accompa-
nied by fewer adverse effects.
In another study, postoperative ketamine
as an adjuvant to morphine (1 mg
morphine 5 mg ketamine with a 7-
minute lock out time) was associated with
fewer adverse effects; one patient who
received the combination regimen reported
lightheadedness, which resolved spontane-
ously [123c].
In 75 patients who were randomly assigned
to placebo, ketamine, or nefopam, those in
the two treatment groups consistently
required less morphine at all times compared
with placebo (59, 39, and 39 mg in the pla-
cebo, nefopam, and ketamine groups respec-
tively) and had a longer time to rst
analgesia during recovery [124c]. There were
no differences in the two treatment groups
with regard to morphine consumption at any
time. There was signicantly more postopera-
tive nausea and vomiting after placebo, but
there were no other differences in the inci-
dence of adverse effects.
Mirtazapine In a placebo-controlled study,
110 patients undergoing lower limb surgery,
who received morphine 0.2 mg as spinal
anesthesia, were randomized to preopera-
tive placebo or mirtazapine 30 mg [125C].
The incidence of pruritus was signicantly
reduced by mirtazapine (52% versus 75%)
and the period of onset was longer (7.2 ver-
sus 3.2 hours).
Nalbuphine The combination of morphine
nalbuphine reduced the incidence of
morphine-induced pruritus [126C]. Patients
undergoing gynecological operations were
randomly allocated to ve groups, each of
which received varying ratios of the combi-
nation regimen:
1. morphine 1 mg/ml (n 65)ratio 1:0;
2. morphine 0.75 mg/ml nalbuphine 0.25 mg/
ml (n 65)ratio 1:3;
Chapter 8 219
3. morphine 0.5 mg/ml and nalbuphine 0.5 mg/
ml (n 59)ratio 1:1;
4. morphine 0.25 mg/ml and nalbuphine
0.75 mg/ml (n 63)ratio 3:1;
5. nalbuphine 1 mg/ml (n 59)ratio 0:1.
The incidence of pruritus gradually fell
from group 1 to 5 showing that the benecial
effect of nalbuphine was ratio-dependent.
Naloxone Co-infusion of morphine (median
dose 1.14 mg/kg on day 1; 1.50 mg/kg on day
2) with low-dose naloxone (0.25 micrograms/
kg/hour) and high-dose naloxone (1 micro-
grams/kg/hour) for amelioration of pruritus
has been studied in 18 children with sickle cell
pain crises [127c]. Pruritus was rated as less
severe in the high-dose group. The combina-
tion treatment was feasible and acceptable.
However, one patient was withdrawn from
the trial because of excessive somnolence;
nausea and vomiting were also reported.
In 15 male volunteers, naloxone-3-glucu-
ronide 0.16 mg/kg reversed constipation
due to morphine without altering its anal-
gesic effects; colonic transit time was
delayed with the addition of naloxone-3-
glucuronide [128c].
In infants treated with continuous mor-
phine infusion (0.04 mg/ml), those who
were also given oral naloxone hydrochlo-
ride (3 micrograms/kg qds) had improved
mean stool frequency and mean total food
intake [129c].
Ondansetron In a randomized, double-blind
study in 150 patients undergoing abdominal
surgery with patient-controlled analgesia
using morphine 1.5 mg, the combination of
ondansetron 30 mg and prochlorperazine
20 mg reduced postoperative nausea and
vomiting in the rst 24 hours after surgery
but not during the next 24 hours [130c].
Oxycodone [SED-15, 2651; SEDA-30,
115; SEDA-31, 167; SEDA-32, 202]
The use of oxycodone has been reviewed,
highlighting the importance of hepatic and
renal dysfunction [131R]. In severe hepatic
impairment the clearance of oxycodone
falls by 75% and the volume of distribution
220
increases by 50%; renal impairment also
reduces clearance. Rifampicin increases
the clearance of oxycodone, reducing expo-
sure by 85%, and hence providing inade-
quate analgesia.
Observational studies In patients with
moderate to severe cancer pain taking
OxyContin (controlled-release oxycodone
hydrochloride), adverse reactions occurred
in 25% in the rst week and the incidence
gradually fell with time, to 12% in the 8th
week [132C]. The most common adverse
effects reported in the rst week were con-
stipation (26%), nausea (13%), vomiting
(6.2%), dizziness (5%), and lethargy
(3.7%). Other effects included dysuria,
fatigue, headache, pruritus, and thirst.
There was a similar pattern at 8 weeks. Five
patients had delusions after dosage reduc-
tion or withdrawal, and another had delir-
ium on days 2 and 3. The authors
suggested that the adverse effects of Oxy-
Contin could be reduced with preventive
medication.
In 236 patients taking OxyContin for
moderate to severe postherpetic neuralgia
adverse effects abated with time on treat-
ment; they included nausea (18%), consti-
pation (10%), dizziness (10%), and
somnolence (5.1%) [133C].
In 67 patients with malignant or non-
malignant neuropathic pain, dizziness and
nausea were reported under 5%; respira-
tory depression and excessive sedation
were not reported [134c].
Comparative studies In 14 patients using
controlled-release oxycodone for postoper-
ative pain and nine using patient-controlled
morphine, there was a lower incidence of
postoperative nausea and vomiting with
oxycodone (14% versus 20%) [135c]. There
was no somnolence, respiratory depression,
confusion, or pruritus in either group.
In a comparison of controlled-release
oxycodone 20 mg and controlled-release
tramadol 200 mg in the management of
postoperative pain after surgery for breast
cancer in 54 patients, there were no signi-
cant differences in adverse events [136c].
Chapter 8 A.H. Ghodse and S. Galea
The effects of oxycodone, methadone,
morphine, and tramadol on the QT interval
and HERG channels involved have been
studied in 100 patients taking opioids for
chronic non-malignant pain [137C]. Oxy-
codone and methadone caused prolonga-
tion of the QT interval, while morphine
and tramadol did not; oxycodone blocked
HERG channels in vitro. An increase in
oxycodone dose of 100 mg was associated
with a 10 msec increase in QTc interval.
Gastrointestinal In a randomized study, 87
patients with pain due to herpes zoster infec-
tion taking famciclovir were allocated to
controlled-release oxycodone, gabapentin,
or placebo; eight patients withdrew, in four
cases because of constipation, and of the
others, 15 also had constipation [138c, 139r].
Drugdrug interactions Rifampicin Rifam-
picin reduced the therapeutic effect of oxy-
codone by inducting CYP3A in 12 healthy
volunteers [140c].
Voriconazole Voriconazole markedly
caused a 3.6-fold increase in plasma oxy-
codone concentrations after oral oxycodone
in 12 healthy subjects, by inhibiting CYP3A-
mediated N-demethylation of oxycodone
[141c]. Eight subjects reported adverse
events, but none was severe.
Management of adverse drug reactions
Naloxone The combination of rectal oxy-
codone 40, 60, or 80 mg/day and rectal nal-
oxone 10, 20, or 40 mg/day has been
studied in a randomized, placebo-con-
trolled 202 patients with chronic pain
[142c]. The addition of naloxone reduced
opioid-induced constipation.
The combination of prolonged-release
oxycodone 40, 60, or 80 mg/day and pro-
longed-release naloxone has been studied
in 202 patients with chronic pain [143C,
144r]. Naloxone 20 and 40 mg signicantly
improved bowel function. A 2:1 oxycodone:
naloxone combination ratio was identied
as most suitable and there were no unex-
pected adverse events. With the higher doses
Opioid analgesics and narcotic antagonists
of naloxone there was a tendency to an
increased incidence of diarrhea.
Pregabalin The combination of controlled-
release oxycodone with pregabalin reduced
the incidence of somnolence associated
with oxycodone in 169 patients compared
with 106 on oxycodone alone [145c].
Oxymorphone [SED-15, 2270;
SEDA-32, 203]
Systematic reviews In a review of nine tri-
als of oxymorphone alone or compared
with placebo or other active agents, concen-
trating on its use in elderly patients, there
were few adverse events [146M].
The authors suggested that oxymorphone
should be considered appropriate for use
in elderly, particularly those in whom there
is concern about interactions with drugs
that are metabolized by CYP isoenzymes,
which oxymorphone does not inhibit.
Death Two opiate abusers using oxymor-
phone by inhalation died; the post-mortem
blood concentrations were 50 and 120 mg/l
[147A].
Papaverine [SED-15, 2678; SEDA- 30,
115; SEDA-31, 168; SEDA-32, 205]
Nervous system In a 67-year-old woman
who had had a subarachnoid hemorrhage,
intra-arterial papaverine was associated with
development of a lesion in the left mesen-
cephalon without a signicant mass effect
[148A]. The authors postulated that the
papaverine had disrupted the bloodbrain
barrier, causing extravasation of blood and
radiographic contrast agents, possibly facili-
tated by secondary hyperperfusion.
Sensory systems Ears Topical papaverine
for the treatment of vasospasm in neurosur-
gery was associated with transient distur-
bance for neurophysiological function of
the ascending auditory pathway [149c].
Chapter 8 221
There was a temporal relation between
papaverine and changes in brainstem audi-
tory evoked potentials, leading to wave-
form loss. Other cases have been reported,
as have patients with focal seizures [150r].
Sexual function In penile smooth muscle
cells, endothelial cells, and broblasts intra-
cavernosal injection of papaverine causes
dose-dependent cytotoxicity and muscle
hypertrophy and brosis [151r]. However,
these effects tend to be limited to minor struc-
tural changes at the injection site and no
signicant effects on penile architecture. The
incidence of brotic changes was low.
Drug administration route Intracavernosal
papaverine has been studied in 60 patients
with normal Doppler studies of the penis.
Injecting on one side of the penis affected
the sinusoids and cavernosal artery on that
side more than on the other side; ve patients
had priapism [152c]. The authors suggested
dividing the dose and injecting both sides.
Pentazocine [SED-15, 2777; SEDA-30,
115; SEDA-31, 168; SEDA-32, 205]
Skin A 54-year-old man developed deep
punched-out ulcers with yellowish exudates
and hyperpigmented and sclerotic surround-
ing skin on both thighs after using subcutane-
ous and intramuscular pentazocine for
paraplegia and chronic back pain [153A]. A
few months before the appearance of the
ulcers he had increased the dosage to 30 mg
up to 20 times a day. The lesions improved
with a local antibiotic cream under occlusion.
Pethidine (meperidine) [SED-15,
2791; SEDA-30, 115; SEDA-31, 168;
SEDA-32, 206]
Systematic reviews Pethidine has been
compared with dihydroergotamine, anti-
emetics, and ketorolac in acute migraine
[154M]. Pethidine caused more dizziness
and sedation and was less efcacious than
the antiemetics, although they were associ-
ated with akathisia. There were no
222
differences in efcacy or adverse effects
between pethidine and ketorolac.
Nervous system Pethidine is not recom-
mended in the management of chronic pain
because its active metabolite, norpethidine
(normeperidine), is excitatory and can
cause seizures [155R].
A 27-year-old pregnant woman underwent
cesarean section under epidural anesthesia
and was given patient-controlled epidural
analgesia, resulting in a total dose of 180 mg
of pethidine over 9 hours; she had a
tonicclonic seizure, thought to be secondary
to a high CSF concentration of norpethidine
[156A].
Piritramide
Respiratory When piritramide (mean dose
64 micrograms/kg) was given to 39 neo-
nates and infants for postoperative analge-
sia, respiratory depression occurred in one
case [157c].
Pholcodine [SEDA-32, 206]
Immunologic Anaphylactic reactions have
been attributed to the use of a cough syrup
containing pholcodine, explaining the differ-
ence in risk between Norway and Sweden,
and leading to the withdrawal of pholcodine
from the Norwegian market and to examina-
tion of the role of pholcodine-containing
products in other countries [158R].
In a multinational study of the effect of
pholcodine-containing cough mixtures on
the prevalence of IgE antibodies to various
drugs, using the United Nations International
Narcotics Control Board (INCB) database,
there was a signicant positive association
between pholcodine consumption and the
prevalence of IgE sensitization to pholcodine
and morphine, but not to suxamethonium
and p-aminophenyl-phosphoryl choline
[159C]. This could be associated with an
increased risk of allergic reactions.
Chapter 8 A.H. Ghodse and S. Galea
Remifentanil [SED-15, 3030; SEDA-30,
116; SEDA-31, 168; SEDA-32, 207]
Observational studies When remifentanil
was given by intravenous infusion pump at
a rate of 0.10.15 micrograms/kg/minute to
186 patients undergoing percutaneous
transhepatic biliary drainage (mean total
dose 116 micrograms), 10% had transient
bradycardia and 2% had respiratory depres-
sion [160C].
Comparative studies In a randomized
study, 30 ASA I and II patients undergoing
hysteroscopy were given propofol, mean
dosage 90 micrograms/kg/minute) and
either fentanyl 1 microgram/kg followed
by boluses of 0.5 micrograms/kg if there
were signs of insufcient analgesia or remi-
fentanil 0.5 micrograms/kg followed by an
infusion of 0.05 micrograms/kg/minute
[161c]. Remifentanil was associated with a
signicantly lower mean arterial pressure
after 1 minute but other adverse events
(hypotension, respiratory depression) were
similar between the two groups and all were
successfully remedied by improving airway
patency and reducing the dose.
When intravenous remifentanil 2 micro-
grams/kg was compared with fentanyl 2
micrograms/kg and sufentanil 0.2 micro-
grams/kg in 315 patients undergoing elective
abdominal surgery, there was a higher inci-
dence of cough with remifentanil (54%
versus 33% with fentanyl and 31%
with sufentanil); the severity of cough was
also greater with remifentanil [162C].
Cardiovascular In 132 patients undergoing
elective craniotomy, remifentanil was in 12
different doses (0.100.21 micrograms/kg/
minute) was associated with hypotension at
a median dose of 0.13 micrograms/kg/minute
and bradycardia at 0.17 micrograms/kg/
minute [163c].
Respiratory In a comparison of remi-
fentanil 1 microgram/kg and alfentanil
10 micrograms/kg in preventing withdrawal
movements after rocuronium injection in
115 adults undergoing elective surgery,
Opioid analgesics and narcotic antagonists Chapter 8
remifentanil was associated with a higher
frequency of cough (24% versus 2%); one
patient who received remifentanil devel-
oped apnea [164c].
Bolus remifentanil can be associated with
thoracic muscle rigidity and consequent dif-
culty in mask or pressure-controlled venti-
lation [166R].
Drug tolerance Tolerance to remifentanil
has been studied after short-term adminis-
tration of remifentanil to 36 healthy volun-
teers [165C]. After a 3-hour infusion its
analgesic potency fell by 524%, the risk of
respiratory depression fell by 2048%, and
the risk of sedative effects fell by 32%. The
authors concluded that short-term clinically
useful doses of remifentanil were not associ-
ated with signicant tolerance.
Drug withdrawal A withdrawal syndrome
has been described after the use of remifenta-
nil by infusion in intensive care units [166R].
Within 10 minutes of withdrawal, patients
experienced tachycardia, hypertension,
sweating, mydriasis, and myoclonus. These
symptoms persisted despite the use of mor-
phine and clonidine and only resolved on re-
administration of remifentanil. Gradual
tapering of remifentanil reduces the inci-
dence of withdrawal symptoms.
Susceptibility factors Intensive care The
use of remifentanil in intensive care has
been reviewed [167R]. Remifentanil is
metabolized by unspecic blood and tissue
esterases and its clearance is independent
of organ insufciency. The most commonly
reported adverse events in mechanically
ventilated critically ill patients include
hypotension, bradycardia, and nausea. Tho-
racic and muscle rigidity and shivering have
been reported with higher doses. Other
reported concerns include tolerance and
withdrawal pain.
Drug administration route Remifentanil by
manually controlled continuous infusion
(0.125 micrograms/kg/minute for 2 minutes
a continuous infusion of 0.05 micrograms/
kg/minute) has been compared with
223
target-controlled infusion [168c]. In target-
controlled infusion, the amount of medica-
tion received is the amount required to
achieve the target. When 57 patients were
given manually controlled continuous
infusion remifentanil, target-controlled infu-
sion remifentanil, or placebo, fewer of those
who received the target-controlled infusion
had bradypnea (ve versus eight), apnea
(two versus eight), or drowsiness (two
versus ve) compared with those who
received manually controlled continuous
infusion.
Drugdrug interactions Morphine In a ran-
domized double-blind study in 40 children
undergoing surgical correction of idiopathic
scoliosis, pre-treatment with morphine
150 micrograms/kg did not attenuate remi-
fentanil-induced hyperalgesia, and there
were trends to the use of more opioid after
surgery and an increase in opioid-related
adverse effects [169c].
Sufentanil [SED-15, 3210; SEDA-31,
169; SEDA-32, 208]
Comparative studies In a comparison of
epidural sufentanil 0.015 micrograms/kg
and fentanyl 0.1 micrograms/kg in children
undergoing urological surgery, the former
was associated with a higher incidence of
pruritus (in six out of 32 compared with
none) [170c].
Drugdrug interactions Midazolam A com-
bination of midazolam (5 mg initially followed
by 2.5 mg) and sufentanil 15 micrograms was
given to a 3-year-old 14-kg girl as sedation for
a dental procedure [171A]. She developed
laryngospasm, airway obstruction, and deep
sedation. She was given positive pressure
ventilation, 0.4 mg naloxone intranasally, and
two doses of umazenil 100 micrograms
intranasally. She recovered rapidly.
Tilidine
Tilidine is a low to medium potency analge-
sic. It undergoes rapid rst-pass metabolism
224
to its active metabolites, nortilidine and bis-
nortilidine. Its analgesic activity is largely
exerted through nortilidine which is a
potent agonist at m opioid receptors.
Drugdrug interactions Voriconazole In 16
volunteers, there was an interaction of tili-
dine with voriconazole, resulting in a 20-
fold increase in tilidine exposure [172c].
Voriconazole inhibits the metabolism of
tilidine, resulting in increased exposure to
the active metabolite nortilidine. This inter-
action was associated with an increased inci-
dence of adverse drug reactions (from 40 to
79). The adverse reactions included dizziness
(94%), nausea (75%), headache (56%),
visual disturbances/photophobia (50%),
vomiting (38%), and pruritus (31%).
Tramadol [SED-15, 3469; SEDA-30,
117; SEDA-31, 170; SEDA-32, 208]
Comparative studies In 90 children under-
going adenotonsillectomy who were ran-
domized to placebo, dextromethorphan
cough syrup 1 mg/kg, or tramadol syrup
pre-operatively plus intravenous tramadol
1 mg/kg during induction of anesthesia,
the incidence of nausea and vomiting was
highest in the tramadol group (10% com-
pared to 5.5% with dextromethorphan
group and 6.6% with placebo); however,
signicantly fewer patients (6.6% versus
40%) who received tramadol required sup-
plementary pethidine [47c].
Tramadol 100 mg/day has been com-
pared with ibuprofen and pregabalin in 20
healthy volunteers [173c]. Tramadol was
associated with mild adverse effects, mainly
fatigue/drowsiness (eight episodes), nausea/
vomiting (seven), dizziness/headache/dif-
culty in concentrating (seven). The NNTH
for tramadol was 1.6.
Placebo-controlled studies In a placebo-
controlled study of the use of tramadol
50 mg tds in 35 patients with neuropathic
pain due to spinal cord injuries adverse
effects were substantial and resulted in
withdrawal in 43% of patients compared
Chapter 8 A.H. Ghodse and S. Galea
with 17% of those on placebo [174c].
Adverse events were experienced by 91%;
the common events included tiredness
(74%), dry mouth (52%), dizziness (52%),
sweating (39%), nausea (39%), and consti-
pation (35%).
Respiratory Respiratory depression is rare
after the use of tramadol. A 66-year-old
man developed respiratory depression after
being given tramadol for postoperative
pain [175A]. He responded to assisted mask
ventilation and intravenous naloxone
0.4 mg. He had renal impairment and was
an ultrarapid CYP2D6 metabolizer of tra-
madol, which has an active metabolite O-
desmethyltramadol.
Nervous system A 74-year-old man with
Parkinson's disease was given tramadol
100 mg qds and his tremor worsened after
2 weeks, causing signicant functional impair-
ment [176A]. There was rapid improvement
within 2 weeks of tramadol withdrawal. The
authors speculated that the mechanism of this
adverse effect might be related to effects on
serotonergic pathways.
Gastrointestinal In a randomized prospec-
tive comparison of lornoxicam 16 mg and
tramadol 1 mg/kg every 6 hours for 24 hours
for postoperative pain after inguinal hernia
repair, tramadol caused nausea in 10%
[177C].
Multiorgan failure Acute respiratory dis-
tress and multiple organ dysfunction
occurred in a 19-year-old with a 6-month
history of tramadol abuse; the blood trama-
dol concentration was 9.5 mg/l, which is
well above the lethal blood concentration
of 2 mg/l [178A].
Drug withdrawal A withdrawal syndrome
has been described in a neonate born to a
mother who was taking tramadol 400 mg/
day for chronic low back pain [179A]. Dur-
ing the last weeks of pregnancy, the dose
was reduced to 200 mg/day. At 35 hours
of age, the neonate had signs of severe
withdrawal. The symptoms occurred earlier
Opioid analgesics and narcotic antagonists
and lasted for a shorter time than symp-
toms after withdrawal of methadone or
buprenorphine. The authors suggested
that the shorter course was related to the
half-life of the tramadol metabolite,
O-demethyl-tramadol hydrochloride.
Drug overdose Tramadol intoxication was
responsible for 4.9% of admissions to an Ira-
nian poisoning ward over a 2-month period
(114 patients) [180c]. Most were men and
the most common age group was
2130 years. The most common adverse
effects of tramadol toxicity were nausea,
vomiting, nervous system depression, tachy-
cardia, and seizures. Most of the toxic effects
resolved within 24 hours. Patients who did
not survive were reported to have taken high
doses, ranging from 5000 to 8200 mg.
Drugdrug interactions Paracetamol The
synergistic effects and associated adverse
effects of tramadol and paracetamol have
been compared with those of codeine
paracetamol (co-codamol) and dextro-
propoxyphene paracetamol (co-proxamol)
[181C]. The combination of tramadol para-
cetamol was associated with the highest
reporting rate and seriousness of adverse
events. The most common adverse events
were gastrointestinal, vascular, neurological,
psychiatric, and cutaneous. There were fewer
hepatobiliary events.
PARTIAL OPIOID
RECEPTOR AGONISTS
Buprenorphine [SED-15, 571; SEDA-
30, 118; SEDA-31, 171; SEDA-32, 209]
The safety of transdermal buprenorphine
has been reviewed [182R]. Buprenorphine
can be effectively and safely combined with
full m receptor agonists, and switching
between buprenorphine and other opioids
at equianalgesic doses is not associated with
inadequate analgesic efcacy. The risk of
Chapter 8 225
respiratory depression with buprenorphine
is lower than with other opioids and it is
not associated with immunosuppression.
Older age and severe impairment of renal
function do not alter buprenorphine phar-
macokinetics. There is a relatively low inci-
dence of adverse effects, such as nervous
system effects and constipation with trans-
dermal buprenorphine, making it suitable
for administration to at-risk patients, such
as those requiring hemodialysis.
Observational studies The role of bup-
renorphine in the treatment of non-psy-
chotic major depression has been explored
in six treatment-resistant patients with
severe non-psychotic depression [183c].
They received buprenorphine 0.82 mg/day
and their depressive symptoms improved
within 1 week. In the initial days, they had
adverse effects such as nausea, constipation,
sedation, dizziness, and sweating.
Respiratory Buprenorphine-induced respi-
ratory depression has been studied in 24 sub-
jects who received buprenorphine 0.2 mg
and increasing doses of naloxone [184c].
Reversal of buprenorphine-induced respira-
tory depression required high doses of nal-
oxone (over 2 mg) and further increases in
naloxone dose (to over 4 mg) resulted in
recurrent respiratory depression.
Liver Therapeutic doses of buprenorphine
have been linked to acute hepatitis and
renal failure [185A].
A 33-year-old man with a history of heroin
addiction, alcohol abuse, and hepatitis C infec-
tion, developed hepatic and renal failure after
switching from methadone to buprenorphine
20 mg/day. Investigations excluded the possi-
bility of hepatitis reactivation.
The authors highlighted the need for liver
function monitoring in the rst few weeks
of buprenorphine treatment in susceptible
patients, such as those with hepatitis, alco-
hol abuse, or concomitant use of drugs that
cause mitochondrial toxicity.
Two patients developed acute hepatitis
that occurred after abuse of buprenorphine
intravenously [186A]. Both were taking
226
sublingual buprenorphine 8 mg/day and
were hepatitis C virus carriers. The authors
stressed that buprenorphine had been the
probable cause of the acute hepatitis and
that the main mechanism was mitochon-
drial toxicity, exacerbated by other factors,
such as concomitant use of alcohol. In both
cases, acute hepatitis was followed by dis-
appearance of hepatitis C RNA, suggesting
clearance of the virus.
Death The susceptibility factors that are
associated with mortality among opioid-
dependent people taking buprenorphine
or methadone treatment have been
explored in an epidemiological study
[187C]. Drug overdose and trauma were
the major contributors to increased mortal-
ity. Periods of higher risk included the
induction period on to methadone (but
not on to buprenorphine) and at times of
treatment withdrawal, which tend to be
associated with a risk of relapse and an
increased risk of suicide. Buprenorphine
and methadone have similar standardized
mortality ratios. The authors postulated
that although buprenorphine induction
was not associated with an increased risk,
treatment with buprenorphine was linked
to shorter periods of treatment, balancing
the increased mortality rate. During the
study period (19852006), the treatment
program reduced mortality by 29%.
Drug dependence Buprenorphine is suit-
able for treating opioid withdrawal. In a
systematic review, buprenorphine was asso-
ciated with low rates of full abstinence from
drugs after opioid detoxication, and
although detoxication with buprenorphine
occurred over a shorter period, this was not
associated with shifts in abstinence rates
[188M].
Drug withdrawal Withdrawal symptoms
have been described in a 2-year-old girl,
who had been given regular buprenorphine
tablets by her mother [189A]. She devel-
oped irritability, agitation, crying, yawning,
piloerection, dilated pupils, a high pulse
Chapter 8 A.H. Ghodse and S. Galea
rate, and a blood pressure of 89/43 mmHg.
Her symptoms resolved over 5 weeks after
administration of morphine and then
methadone.
Pregnancy The roles of buprenorphine and
methadone in the clinical management of
opioid dependence during pregnancy and
breast feeding have been reviewed [190R].
The dosages must be tailored to the needs
of each opioid-dependent pregnant woman.
Drug formulations A novel implant of
buprenorphine (Probuphine) with sus-
tained-release technology has been evalu-
ated in 12 subjects with opioid
dependence maintained on sublingual
buprenorphine [191c]. Most of them (92%)
had at least one adverse event and 58%
had events related to the insertion or
removal of the implant. Other adverse
events were experienced by 42% and
included dizziness, constipation, abdominal
pain, implant site reactions, ushing, and
pallor. There were no serious events.
Drug administration route Transdermal
buprenorphine has been studied in children
with cancer pain in three case studies. An
adverse event occurred in only one case
erythema and pruritus at the patch site
[192A].
In 30 elderly patients over the age of 65
adverse events were comparable to those
experienced by younger patients; however,
23% of elderly patients withdrew prematurely
from the study owing to adverse events [193c].
In 30 adults, transdermal buprenorphine
35 micrograms/hour produced adequate
pain relief, but there was a high incidence
of adverse events: patients developed consti-
pation (n 3), hypotension (3), urinary
retention (2), or paradoxical hyperalgia (1);
nine discontinued treatment mostly because
of nausea and daytime sleepiness [194c].
Drug overdose During November 2002 to
December 2005 there were 96 reports of
unintentional buprenorphine overdose in
children under 6 years of age from US
Opioid analgesics and narcotic antagonists
poison centers to the Research Abuse,
Diversion & Addiction-Related Surveil-
lance System; 10 patients were excluded
because they did not meet the inclusion cri-
teriaseven were lost to follow-up and
three had taken multiple substances [195c].
Of the others, 32 had no symptoms after
overdose, 48 had minor reactions, and six
had severe reactions. The mean time of
onset of the adverse reactions was
64 minutes and they lasted 28 hours in most
cases. There was signicant central nervous
system and respiratory depression in 7%.
The clinical implications of this are that gener-
ally buprenorphine overdose is well tolerated,
but any child under 2 years of age and any
child who has taken more than 2 mg would
require observation for a minimum of 6 hours.
Butorphanol [SED-15, 582; SEDA-31,
172; SEDA-32, 210]
Comparative studies When patients with
suspected biliary colic were randomized to
intravenous ketorolac 30 mg (n 21) or
intravenous butorphanol 1 mg (n 25),
the former had more nausea (24% versus
4%) and vomiting (5% versus none); the
latter had more sedation (36% versus
5%), dizziness (28% versus none), and
rashes (4% versus none) [196c].
When butorphanol 4 micrograms/kg/hour
was compared with fentanyl 0.4 micrograms/
kg/hour as intravenous patient-controlled
analgesia for postoperative pain after abdom-
inal hysterectomy in 100 patients, there were
few adverse reactions [197c]. Respiratory rate
was reduced by butorphanol 1 hour after the
start of treatment.
Drug withdrawal A 58-year-old man, who
took midazolam 1.2 mg and butorphanol
0.12 mg/hour for 12 hours for insomnia
over 2 weeks, had an acute withdrawal
syndrome during tracheotomy; accumula-
tion of butorphanol triggered withdrawal
when remifentanil was used during the
operation [198A].
Chapter 8 227
OPIOID RECEPTOR
ANTAGONISTS
Methylnaltrexone [SED-15, 2307;
SEDA-32, 211]
Methylnaltrexone has been widely used to
manage opioid induced constipation and
acts by blocking the entry of opioids into
cells [199r]. The common adverse effects
include abdominal pain, gas, nausea, dizzi-
ness, and diarrhea. The FDA has recom-
mended that patients should stop taking
methylnaltrexone if it causes severe diar-
rhea, vomiting, nausea, or abdominal pain.
Placebo-controlled studies In a double-
blind, randomized, placebo-controlled trial
in 154 patients with advanced illness and
opioid induced constipation a single sub-
cutaneous injection of methylnaltrexone
0.15 or 0.3 mg/kg was compared with pla-
cebo [200C]. The most common adverse
events were abdominal pain and atulence,
and three patients had serious adverse
events attributed to methylnaltrexone.
Nalmefene [SED-15, 2420; SEDA-30,
119; SEDA-32, 211]
Placebo-controlled studies The effect of
nalmefene on gambling symptoms and
urges has been investigated using three
doses of nalmefene (25, 50, and 100 mg)
[201R]. Those who took 25 mg improved
overall; those who took 50 and 100 mg did
not, perhaps because of the frequency of
adverse effects.
Naloxone [SED-15, 2421; SEDA-30,
119; SEDA-31, 172]
Cardiovascular Cardiac arrest occurred in a
preterm neonate (gestation 27 weeks) after
a bolus of naloxone (100 micrograms/kg)
for the treatment of a 10-fold morphine
228
overdose [202A]. Profound bradycardia and
asystole occurred immediately after nalox-
one administration, the immediacy suggest-
ing a causal relationship.
Biliary tract Pruritus due to cholestasis in a
73-year-old man was treated with naloxone
2 nanograms/kg/minute, doubled every
12 hours up to 200 nanograms/kg/minute
[203A]. The pruritus improved after 2 days
but on the third day he had pain from metas-
tases. The authors suggested caution in using
opioid antagonists for pruritus, because of
the possibility of unmasking pain.
Naltrexone [SED-15, 2423; SEDA-30,
120; SEDA-31, 172; SEDA-32, 211]
The adverse reactions associated with the
use of naltrexone in patients with alcohol
dependence tend to be mild gastrointestinal
reactions (nausea, vomiting, and abdominal
pain or discomfort) and they occur early in
treatment [204R]. Hepatotoxicity has been
reported with high doses (100300 mg/
day) and especially in obese individuals.
Naltrexone can also precipitate opioid with-
drawal and may not be suitable for those
requiring future opioids, such as those
requiring surgery.
In 12 subjects with kleptomania the most
common adverse reaction to naltrexone
50150 mg/day was nausea (in ve subjects,
one of whom withdrew as a result) [205c].
Other events included dry mouth and
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9 Anti-inammatory and
antipyretic analgesics and
drugs used in gout
An update on adverse events in
patients taking COX-2 selective
and non-selective NSAIDs
Cyclo-oxygenase-2 (COX-2) selective inhib-
itors (coxibs) were developed because of
reduced gastrointestinal adverse reactions
compared with traditional non-selective
NSAIDs, but later evidence suggested an
increased cardiovascular risk [1R, 2R]. More
information has recently been published
about adverse events in patients taking
COX-2 selective and non-selective NSAIDs.
1. Gastrointestinal adverse events
A lower gastrointestinal risk with coxibs was
conrmed in a retrospective casecontrol
study of the incidence of peptic ulcer bleed-
ing and perforation in users of COX-2 selec-
tive and non-selective NSAIDs [3C]. The
study was based on 2.2 million adults taking
celecoxib, diclofenac, ibuprofen, naproxen,
rofecoxib, or valdecoxib. Adjusted odds
ratios (OR) compared with naproxen were:
ibuprofen 0.86 (95% CI 0.68, 1.09),
rofecoxib 0.79 (0.62, 1.02), diclofenac 0.66
(0.47, 0.94), valdecoxib 0.50 (0.26, 0.97),
and celecoxib 0.45 (0.35, 0.58). The overall
Side Effects of Drugs, Annual 33
J.K. Aronson (Editor)
ISSN: 0378-6080
DOI: 10.1016/B978-0-444-53741-6.00009-X
# 2011 Elsevier B.V. All rights reserved.
Sebastian Straube
OR for peptic ulcer bleeding and perforation
of non-selective NSAIDs compared with
coxibs was 1.51 (95% CI 1.26, 1.98).
A meta-analysis of 21 randomized con-
trolled trials of celecoxib and non-selective
NSAIDs included 7797 patients taking
celecoxib 200 mg/day, 6653 taking celecoxib
400 mg/day, 2953 taking naproxen, 499 tak-
ing ibuprofen, and 5643 taking diclofenac
[4M]. Gastrointestinal adverse events were
reported by fewer patients taking celecoxib
(16%) than patients taking naproxen (24%),
ibuprofen (24%), or diclofenac (20%).
In a review of coxibs for osteoarthritis
based on 17 studies with over 10 000
patients the relative risk (RR) of gastro-
duodenal ulcers while taking a coxib com-
pared with taking a non-selective NSAID
was 0.26 (95% CI 0.23, 0.30) [5M].
A study in 23 504 patients with osteo-
arthritis or rheumatoid arthritis, the
MEDAL (Multinational Etoricoxib and
Diclofenac Arthritis Long-term) study, con-
rmed lower gastrointestinal/liver adverse
event discontinuation rates for etoricoxib
versus diclofenac; the hazard ratios (HR)
were 0.46 (95% CI 0.39, 0.54), 0.52
(0.42, 0.63), and 0.49 (0.39, 0.62) for
etoricoxib 60 mg/day versus diclofenac
150 mg/day in osteoarthritis, etoricoxib
90 mg/day versus diclofenac 150 mg/day in
osteoarthritis, and etoricoxib 90 mg/day ver-
sus diclofenac 150 mg/day in rheumatoid
arthritis respectively [6C].
While lower rates of upper gastrointestinal
events with coxibs versus non-selective
NSAIDs are now well established, there
241
242
seems to be little difference with regard to
lower gastrointestinal adverse events, at least
when etoricoxib and diclofenac are com-
pared. In an analysis of 34 701 patients with
osteoarthritis or rheumatoid arthritis ran-
domized to etoricoxib (60 or 90 mg/day) or
diclofenac (150 mg/day) from the MEDAL
study, the EDGE (Etoricoxib versus
Diclofenac Sodium Gastrointestinal Tolera-
bility and Effectiveness) study, and the
EDGE II study, there was no reduction in
lower gastrointestinal clinical events (includ-
ing perforation, obstruction requiring hospi-
talization, and bleeding) with etoricoxib
compared with diclofenac [7C]. Rates of
lower gastrointestinal clinical events were
0.32 and 0.38 per 100 patient-years for
etoricoxib and diclofenac respectively (HR
0.84; 95% CI 0.63, 1.13).
2. Cardiovascular adverse events
Several studies have suggested that regular
use of coxibs increases the risk of myocar-
dial infarction. New analyses have con-
rmed this view. In a retrospective cohort
study (n 38 258 patients; 26 376 patient-
years), the odds of acute myocardial infarc-
tion during exposure to etodolac, naproxen,
celecoxib, or rofecoxib were reported. Com-
pared with naproxen, there was no signi-
cantly increased risk with etodolac, whereas
with celecoxib (OR 2.18; 95% CI 1.09,
4.35) and rofecoxib (OR 2.16; 95% CI
1.04, 4.46) there was an increased risk [8C].
However, some non-selective NSAIDs
other than naproxen may also increase car-
diovascular risk. Coxibs cause more cardio-
vascular adverse events than naproxen but
do not seem to increase cardiovascular risk
compared with some other non-selective
NSAIDs [5M, 9M]. For example, data from
the MEDAL study (n 23 504 patients,
see above) showed that the thrombotic car-
diovascular risk hazard ratio of etoricoxib
versus diclofenac was 0.96 (95% CI 0.81,
1.15), suggesting that etoricoxib was not
more dangerous than diclofenac [6C].
A meta-analysis has shown that after non-
cardiac surgery, valdecoxib and its prodrug
parecoxib did not increase the risk of
Chapter 9 Sebastian Straube
cardiovascular adverse events [10M]. This
contrasts with coronary artery bypass graft
surgery, after which an increased incidence
of cardiovascular adverse events has been
reported [11C].
Recent analyses have allowed a more pre-
cise estimation of the increased cardiovascu-
lar risk associated with regular use of coxibs
or non-selective NSAIDs. The 5-year efcacy
and safety analysis of the Adenoma Preven-
tion with Celecoxib Trial (2035 patients
receiving placebo, celecoxib 200 mg bd, or
celecoxib 400 mg bd) showed that for cardio-
vascular and thrombotic adverse events, the
RR compared with placebo was 1.6 (95% CI
1.0, 2.5) for patients taking celecoxib
200 mg bd and 1.9 (95% CI 1.2, 3.1) for
patients taking celecoxib 400 mg bd [12C].
The nal analysis of the Adenomatous
Polyp Prevention on Vioxx (APPROVe)
study (n 2587 patients; rofecoxib 25 mg,
n 1287; and placebo, n 1300) included
the combined incidence of non-fatal myocar-
dial infarction, non-fatal stroke, and death
from cardiovascular, hemorrhagic, and
unknown causes (Antiplatelet Trialists' Col-
laboration, APTC, combined end-point)
and found that 59 individuals had an
APTC combined end-point in the rofecoxib
25 mg group versus 34 in the placebo group
(HR 1.79; 95% CI 1.17, 2.73) [13C].
In a casecontrol study using drug-dispens-
ing and hospitalization data from more than 2
million residents in The Netherlands, subjects
with a rst hospitalization for acute myocar-
dial infarction, cardiovascular and gastrointes-
tinal events were identied [14C]. Use of coxibs
and non-selective NSAIDs was classied into
remote, recent, and current use. Compared
with remote use, the risk of acute myocardial
infarction was increased in current users of
all coxibs (adjusted OR 1.73; 95% CI
1.37, 2.19) and all non-selective NSAIDs
(adjusted OR 1.41; 95% CI 1.23, 1.61).
Analysis by separate agents showed that the
risk of acute myocardial infarction was
increased with celecoxib (OR 2.53; 95%
CI 1.53, 4.18), rofecoxib (OR 1.60; 95%
CI 1.22, 2.10), ibuprofen (OR 1.56;
95% CI 1.19, 2.05), and diclofenac (OR
1.51; 95% CI 1.22, 1.87), but not with
naproxen (OR 1.21; 95% CI 0.87, 1.68).
Anti-inammatory and antipyretic analgesics and drugs used in gout
The cardiovascular risk with coxibs and
non-selective NSAIDs seems to depend not
only on which drug is used, but also on
patient characteristics and past medical his-
tory. In a cohort study of beneciaries of
US Medicare and a drug benet program
(Pharmaceutical Assistance Contract for
the Elderly in Pennsylvania), 76 082 new
users of coxibs, 53 014 new users of
nonselective NSAIDs, and 46 558 non-users
were identied [15C]. Compared with non-
users, the adjusted RR of cardiovascular dis-
ease events for new users of coxibs and non-
selective NSAIDs varied between agents; for
example it was increased for rofecoxib (1.22;
95% CI 1.14, 1.30), not signicantly
different for ibuprofen (0.96; 95% CI
0.83, 1.10), and reduced for celecoxib
(0.89; 95% CI 0.83, 0.94) and naproxen
(0.79; 95% CI 0.67, 0.93). The authors
went on to determine the cardiovascular dis-
ease event rates for different NSAIDs in var-
ious patient subgroups and observed
increased event rates with certain agents in
certain patients. For example, among those
aged 80 years or over, patients taking
rofecoxib had 4.8 more cardiovascular dis-
ease events per 100 person-years and
patients taking ibuprofen had 3.4 more
events compared with non-users. For
patients with a prior myocardial infarction,
those taking rofecoxib had 9.4 more cardio-
vascular disease events and those taking
ibuprofen had 11.4 more events per 100
person-years than non-users.
In a retrospective cohort study patients
with osteoarthritis (6580 patients chronically
exposed to celecoxib, 9800 to rofecoxib,
2907 to naproxen, and 51 539 non-chroni-
cally exposed controls, either non-chronic
users or non-users) were investigated. Com-
paring the risk of hospitalization for acute
myocardial infarction or ischemic stroke
with the non-chronic users as the reference
group, there was an increased risk with
rofecoxib (adjusted HR 1.25; 95% CI
1.04, 1.50) but no signicantly increased
risk with celecoxib or naproxen. Further-
more, the risk of hospitalization for acute
myocardial infarction or ischemic stroke
varied considerably with patient characteris-
tics: the excess risk attributable to rofecoxib
Chapter 9 243
(comparison with non-chronic NSAID
users) varied from three per 1000 person-
years in those under 65 years old with no pre-
vious ischemic stroke to 19 per 1000 person-
years for patients aged 65 or over and with a
history of ischemic stroke [16C]. In patients
with chronic heart failure, coxibs and
non-selective NSAIDs, including naproxen,
were associated with increased mortality and
cardiovascular morbidity.
In a Danish study of 107 092 patients who
survived their rst hospitalization because of
heart failure between 1995 and 2004 and their
subsequent use of NSAIDs, the hazard ratios
for death associated with rofecoxib, celecoxib,
ibuprofen, diclofenac, naproxen, and other
NSAIDs were 1.70 (95% CI 1.58, 1.82),
1.75 (95% CI 1.63, 1.88), 1.31 (95% CI
1.25, 1.37), 2.08 (95% CI 1.95, 2.21),
1.22 (95% CI 1.07, 1.39), and 1.28 (95% CI
1.21, 1.35) respectively [17C].
3. Gastrointestinal
The question of whether coxibs can exacer-
bate inammatory bowel disease has been
addressed in a systematic review, which
found only two randomized placebo-con-
trolled trials including 363 patients [18M].
There was no signicant difference in the
relapse rate between coxibs and placebo.
The authors concluded that there were insuf-
cient data to determine the effect of coxibs
on exacerbations of inammatory bowel
disease.
4. Urinary tract
The association between COX-2 selective
and non-selective NSAIDs and acute kidney
injury has been investigated in 183 446
Medicare beneciaries [19C]. There was
acute kidney injury in 870 (0.47%) users of
non-selective NSAIDs or coxibs. Compared
with celecoxib there was a signicantly
higher risk with indometacin (RR 2.23;
95% CI 1.70, 2.93), ibuprofen (RR
1.73; 95% CI 1.36, 2.19), and
244
rofecoxib (RR 1.52; 95% CI 1.26,
1.83). Overall, acute kidney injury requiring
hospitalization was a relatively rare adverse
event in users of non-selective NSAIDs or
coxibs.
5. Liver
In a pooled analysis of 41 randomized trials
of the hepatic safety of celecoxib and non-
selective NSAIDs there were fewer
hepatobiliary adverse events with celecoxib
(1.1%) than diclofenac (4.2%). For ibupro-
fen (1.5%) and placebo (0.89%) the inci-
dence of adverse events was comparable to
that with celecoxib. The incidence of serious
hepatic adverse events was low: 0.05%
among 24 933 celecoxib-treated patients,
and 0.21% among 7639 diclofenac-treated
patients [20M]. However, rare cases of
celecoxib-induced liver failure requiring
transplantation have been reported [21A].
6. Respiratory
While the use of coxibs as an alternative to
other NSAIDs has been suggested for
patients with aspirin-induced asthma, there
have been case reports of asthmatic reactions
to coxibs in patients with aspirin-sensitive
asthma [22A, 23A]; so caution is necessary.
Conclusions
Recent evidence has conrmed the lower risk
of upper (but not lower) gastrointestinal
adverse events with coxibs compared with tra-
ditional NSAIDs and also the increased car-
diovascular risk with regular use of coxibs
compared with placebo. However, the evi-
dence now suggests that there may also be
an increased cardiovascular risk for some
(non-naproxen) non-selective NSAIDs.
Postoperative use of coxibs after non-car-
diac surgery seems not to be associated with
an increased cardiac risk, in contrast to
coronary artery bypass graft surgery.
Chapter 9 Sebastian Straube
The magnitude of the cardiovascular risk
with COX-2 selective and non-selective
NSAIDs depends on patient characteristics
and past medical (especially cardiovascular)
history. The choice of the best NSAID
should take account of individual patient
characteristics.
AMIDOPYRINE AND
RELATED COMPOUNDS
Metamizole (dipyrone)
[SED-15, 2268]
Nervous system A series of 28 cases of
post-injection injuries after intragluteal
injections recorded over 8 years in an
electroneuromyography laboratory has
been reported [24c]. A complete history
was available in 26 cases. They all had sud-
den pain and subsequent radiation of pain
and numbness in the distribution of the sci-
atic nerve. In 23 cases the injected drug was
known; it was metamizole (dipyrone) in 11.
ANILINE DERIVATIVES
[SED-15, 2679; SEDA-30, 129]
Paracetamol (acetaminophen)
Respiratory More evidence has been
published about the possible association
between paracetamol and asthma. In a
multicenter casecontrol study of 521
patients with asthma and 507 controls,
weekly use of paracetamol, compared with
less frequent use, was associated with
asthma [25C]. A study of 19 349 adult twins
enrolled in the nationwide Danish Twin
Registry showed a higher prevalence of
asthma in subjects with frequent intake of
paracetamol (OR 2.16; 95% CI 1.03,
4.53) after adjusting for confounders [26C].
Furthermore, a study of 205 487 children
aged 67 years showed that paracetamol
use for fever in the rst year of life was
associated with a higher risk of asthma
Anti-inammatory and antipyretic analgesics and drugs used in gout
symptoms at age 67 (OR 1.46; 95% CI
1.36, 1.56) [27C]. Current use of paracet-
amol was also associated with a higher
risk of asthma symptoms. Moreover,
paracetamol use, both in infancy and at
age 67 years, was associated with
rhinoconjunctivitis and eczema.
Skin A vulval xed drug eruption has been
attributed to paracetamol [28A].
Immunologic Two cases of paracetamol-
associated anaphylaxis and angioedema
have been reported [29A, 30A].
ANTHRANILIC ACID
DERIVATIVES
Etofenamate
Skin A series of 14 cases of allergic and
photoallergic contact dermatitis induced by
etofenamate has been reported [31c].
According to the authors, about 20 previ-
ous cases have been described in the
English language literature.
Mefenamic acid [SED-15, 2230]
Sensory systems A 30-year-old man devel-
oped bilateral transient myopia, secondary
angle closure glaucoma, and choroidal detach-
ment while taking mefenamic acid [32A].
He was successfully managed by stopping
the medication and symptomatic treatment.
ARYLALKANOIC ACID
DERIVATIVES [SED-15, 2555;
SEDA-31, 186; SEDA-32, 229]
Bufexamac
Skin Pigmented purpuric dermatosis has
been attributed to bufexamac [33A].
Four days after using a bufexamac-containing
cream for hemorrhoids a 56-year-old man
Chapter 9 245
developed mostly non-palpable purpura
beginning on the trunk and generalizing
within a few days. There was moderate itch,
especially perianally. Pervious patch testing
had shown sensitization to bufexamac. The
clinical and histological picture was of a
pigmented purpuric eruption.
Acute generalized exanthematous
pustulosis has been attributed to bufexamac
[34A].
A 3-year-old girl used topical bufexamac twice
a day for mild eczema of the cheeks and after
2 days developed erythematous and pustular
lesions, at rst on the face and then rapidly
spreading to the rest of the body, associated
with a fever. Acute generalized exanthema-
tous pustulosis was conrmed by skin biopsy.
Diclofenac
Cardiovascular Kounis syndrome (acute
myocardial infarction occurring during the
course of an allergic reaction) has been
attributed to diclofenac [35A].
Gastrointestinal In a retrospective case
control study of 75 patients undergoing lap-
aroscopic colorectal resection with primary
anastomosis, there was a higher rate of
anastomotic leakages in patients who took
oral diclofenac for postoperative analgesia
(seven of 33 patients) compared with
patients who received opioid analgesia
(one of 42 patients) [36c].
Liver In 17 289 patients who had used
diclofenac for a mean of 18 months there
were rises in aminotransferases to more
than three times the upper limit of normal
in 527 cases (3.1%) and to more than
10 times the upper limit of normal in 86
(0.5%); there were liver-related hospitaliza-
tions in four (0.023%) [37C].
Skin Allergic contact dermatitis [38A] and
photoallergic contact dermatitis [39A] have
been attributed to topical diclofenac. In
the two cases with photoallergic contact
dermatitis, there was cross-reactivity with
aceclofenac.
246
Musculoskeletal Bleeding outside the
gastrointestinal tract due to diclofenac, a
rare event, has been reported [40A].
A 60-year-old woman developed a spontane-
ous thigh hematoma after taking diclofenac
100 mg/day for osteoarthritis for 9 days. On
the ninth day a severe sharp pain developed
in her right thigh and was followed 2 days
later by extensive bruising of her right leg.
Flurbiprofen
Skin A xed drug eruption in association
with a drug-induced myocarditis has been
attributed to urbiprofen [41A].
23-year-old man with chest pain noted skin
eruptions on his hands, lips, mouth, and penis
2436 hours after he had taken urbiprofen
(dose not stated). The electrocardiogram showed
widespread ST elevation and cardiac markers
(troponin I, creatine kinase) were raised.
Ibuprofen
Gastrointestinal Esophageal perforation
has been attributed to ibuprofen [42A].
An 18-year-old man developed sudden onset,
severe, retrosternal pain, dysphagia, and
odynophagia after taking ibuprofen capsules.
An X-ray and CT scan showed esophageal
perforation.
Liver Ibuprofen has been linked with
hyperbilirubinemia in preterm neonates. In
a retrospective comparison of 418 preterm
infants receiving ibuprofen prophylaxis of
patent ductus arteriosus and 288 infants
who were not treated with ibuprofen those
who received ibuprofen had a higher
peak serum bilirubin concentration, needed
more phototherapy, and had a longer
duration of phototherapy [43C].
Skin A 64-year-old woman who had taken
ibuprofen 400 mg for toothache developed
multiple pustular lesions and underlying ery-
thema of the cheeks and chin due to acute
localized exanthematous pustulosis [44A].
Chapter 9 Sebastian Straube
Ketoprofen
Skin Erythema multiforme induced by
photocontact dermatitis occurred in a
patient taking ketoprofen [45A].
A 74-year-old man developed erythema
multiforme on his left elbow where a
ketoprofen-containing tape had been applied
and exposed to sunlight. The eruption
subsequently spread to the limbs and trunk.
Lymphocyte stimulation tests showed lympho-
cytes reactive with a photohaptenic moiety of
ketoprofen.
Ketorolac
Respiratory Acute asthma with a fatal out-
come has been attributed to ketorolac in a
woman with a history of asthma [46A].
A 45-year-old woman with a history of asthma
collapsed and died within a few minutes after
an intramuscular injection of ketorolac
tromethamine. Autopsy conrmed a recent
asthma attack. Based on the timing of the col-
lapse after ketorolac tromethamine injection,
her death was attributed to an adverse reac-
tion to ketorolac tromethamine, resulting in
acute bronchospasm and cardiac arrest.
Loxoprofen
Liver A 36-year-old woman developed
progressive intrahepatic cholestasis after a
5-day course of loxoprofen 180 mg/day for
menstrual pain [47A].
COX-2 SELECTIVE
INHIBITORS [SEDA-30, 130;
SEDA-31, 190; SEDA-32, 232]
Celecoxib [SED-15, 685; SEDA-31, 190;
SEDA-32, 233]
Immunologic Celecoxib-associated ana-
phylaxis has been described in a patient
who had previously tolerated it [48A].
Drug overdose In 177 cases of pediatric
celecoxib ingestion reported to Texas poison
control centers during 20002007, the dose
Anti-inammatory and antipyretic analgesics and drugs used in gout
was reported in 92; the mean dose was 306 mg
(range 102300 mg) [49C]. Specic effects
were rash, abdominal pain, vomiting, agita-
tion/irritability, and drowsiness (reported in
one case each). None of the ingestions
resulted in more than minor effects.
Drugdrug interactions Docetaxel Cele-
coxib may enhance the marrow toxicity of
docetaxel [50c]. In patients (24 enrolled, 20
treated) with non-small cell lung cancers
celecoxib 400 mg orally bd was started 7 days
before the rst cycle of docetaxel and contin-
ued without interruption. Docetaxel 75 mg/
m2 was administered intravenously on a 21-
day cycle. Frequent neutropenia (14 patients,
58%) and neutropenic fever (5 patients,
21%) resulted in early closure of the trial.
Rofecoxib [SED-15, 3076; SEDA-31,
191; SEDA-32, 233]
Observational studies In postmarketing
surveillance of serious adverse events asso-
ciated with the use of rofecoxib from 1999
to 2002 there were 31 024 reports of serious
adverse events, and the drug was consid-
ered the primary suspect in 97.8% of
reports [51C]. There were 3915, 3677,
1653, 1917, and 233 reports of hemorrhage,
edema, death, thrombosis, and embolism
respectively. The authors argued that, in
addition to the risk of myocardial infarction
and stroke, rofecoxib use might be associ-
ated with an increased risk of hemorrhage.
A limitation of this analysis was that the
data may have contained multiple reports
from the same individual.
INDOLEACETIC ACIDS
[SEDA-25, 134]
Indometacin [SED-15, 1739]
Observational studies In 105 preterm
infants randomized to receive an extended
3-day course of either low-dose
indometacin (0.1 mg/kg/day) or higher-dose
indometacin (0.2 or 0.5 mg/kg/day) for per-
sistent patent ductus arteriosus, increasing
Chapter 9 247
indometacin concentrations above those
achieved with a conventional dosing regi-
men was associated with higher rates of
moderate or severe retinopathy of prematu-
rity and raised serum creatinine [52c].
OXICAMS [SEDA-15, 2555;
SEDA-28, 128; SEDA-30, 132;
SEDA-32, 233]
Meloxicam [SEDA-15, 2248;
SEDA-31, 192]
Drugdrug interactions Antifungal azoles
In a crossover study in 12 healthy volunteers
who took meloxicam 15 mg without
pretreatment (controls), after pretreatment
with voriconazole (an inhibitor of CYP2C9
and CYP3A4), and after pretreatment with
itraconazole (an inhibitor of CYP3A4),
voriconazole increased the AUC0!72h of
meloxicam by 47% and itraconazole reduced
it by 37% [53c]. The lower plasma meloxicam
concentrations during the itraconazole phase
were associated with a reduced effect of
meloxicam, as demonstrated by weaker inhi-
bition of thromboxane B2 synthesis.
Piroxicam [SED-15, 2843; SEDA-31, 192]
Skin A xed drug eruption with mucosal
involvement has been attributed to
piroxicam; the authors referred to 11 previ-
ous similar reports, two of which had muco-
sal involvement [54A].
PYRAZOLONE
DERIVATIVES
(PHENYLBUTAZONE AND
RELATED COMPOUNDS)
[SEDA-27, 111]
Phenylbutazone [SEDA-15, 2805]
Skin Drug rash with eosinophilia and
systemic symptoms (DRESS) has been
attributed to phenylbutazone [55A].
248
A 57-year-old woman developed a drug rash
with eosinophilia and systemic symptoms after
taking phenylbutazone for 15 days. She had a
skin eruption, hypereosinophilia, and liver
involvement and made a full recovery after
drug withdrawal.
Another case was reported of Sweet's
syndrome with sialadenitis induced by
phenylbutazone [56A].
Interference with diagnostic tests Facti-
tious rises in serum testosterone (DPC
RIA, Los Angeles, CA, USA) in ve
patients taking phenylbutazone have previ-
ously been described [57A] and six further
cases using other assays (DSL RIA, Web-
ster, TX, USA; and BRAHMS TRACE
on KRYPTOR, Berlin, Germany) have
been reported [58A].
SALICYLATES [SED-15, 15;
SEDA-30, 128]
Acetylsalicylic acid (aspirin)
Respiratory More genetic determinants of
aspirin-intolerant asthma have been identi-
ed. Interleukin-10 (IL-10), transforming
growth factor b-1 (TGF-b1) [59C], angioten-
sin I-converting enzyme (ACE) [60C], and
high-afnity IgE receptor (FceR1) promoter
polymorphisms [61C] have been associated
with aspirin-intolerant asthma, as have poly-
morphisms in the genes for indoleamine-
pyrrole 2,3 dioxygenase (INDO) and the
interleukin 1 receptor, type II (IL1R2) [62C].
Nervous system A spontaneous spinal epi-
dural hematoma in a 62-year-old man tak-
ing aspirin 100 mg/day caused low back
pain, progressive bilateral lower limb weak-
ness and numbness, and urinary retention
[63A]. He subsequently developed para-
plegia with a sensory level at L1, lax anal
tone, and reduced perianal sensation.
Emergency decompression laminectomy
was followed by recovery.
Chapter 9 Sebastian Straube
Gastrointestinal Hypertriglyceridemia may
be a susceptibility factor for peptic ulcera-
tion caused by aspirin. In 137 patients
newly diagnosed with gastroduodenal
ulcers and 274 controls, high serum triglyc-
erides were associated with aspirin-related
peptic ulceration [64C]. In patients with
high serum triglycerides not taking aspirin
the risk of peptic ulceration was not
increased.
Skin Genetic determinants of aspirin-
induced urticaria and aspirin-intolerant
chronic urticaria have been identied.
Two tumor necrosis factor a (TNF-a) pro-
moter polymorphisms and a leukotriene
C4 synthase promoter polymorphism are
associated with aspirin-induced urticaria
[65C, 66C]. A transforming growth factor
b-1 (TGFb1) promoter polymorphism is
associated with aspirin-intolerant chronic
urticaria [67C].
Drug rash with eosinophilia and systemic
symptoms (DRESS) occurred in a 2-year-
old boy with Kawasaki disease taking
aspirin 80 mg/kg/day [68A].
Reproductive system Recurrent hemato-
spermia has been attributed to aspirin (dose
not stated) [69A].
Death In a registry-based study of 58 465
Swedish patients with diabetes aspirin sig-
nicantly increased the risk of death in
those without cardiovascular disease (previ-
ous or acute myocardial infarction, angina
pectoris, ischemic stroke, transient ischemic
attack, intermittent claudication, previous
coronary artery bypass graft surgery, or
percutaneous coronary intervention) by
17% (95% CI 1, 36) at age 50 years
and by 29% (95% CI 16, 43) at age
85 years [70C]. In elderly patients with dia-
betes with cardiovascular disease who used
aspirin there was a non-signicant trend
towards reduced mortality, by 11% at age
85 years. The risk of serious bleeding was
also increased by aspirin in those without
cardiovascular disease and reduced by aspi-
rin in those with cardiovascular disease.
Anti-inammatory and antipyretic analgesics and drugs used in gout
Drug overdose A report of salicylate intox-
ication has shown that salicylate absorption
and metabolism after a large overdose can
be unpredictable and that there is a risk of
delayed toxicity [71A].
A 53-year-old man attempted suicide by tak-
ing about 200 aspirin tablets (325 mg each).
The serum salicylate concentration 7 hours
after admission was 0.96 mmol/l and after
17 hours 3.5 mmol/l, when he was sweating,
tachypneic, and unresponsive to questioning.
He died 20 hours after the initial admission
despite intensive treatment.
MISCELLANEOUS DRUGS
Benzydamine (benzindamine)
[SEDA-15, 443]
Drug abuse Benzydamine is used as a hal-
lucinogen in Brazil. Of 2807 street youths
aged 1018 years 78 reported lifetime rec-
reational benzydamine use in a survey
[72c]. Unwanted effects were reported by
21 of 30 recent users, including nausea and
vomiting in six.
Drug overdose In a retrospective study of
ingestions of benzydamine-containing vagi-
nal irrigation products reported to the Span-
ish Poison Control Centre (19912003) there
were 724 reports [73c]. When present, signs
and symptoms were largely gastrointestinal
(48% of symptomatic patients), neurological
(31%), or both (21%). The most frequent
symptoms were nausea (33% of symptomatic
patients), vomiting (28%), dizziness (20%),
hallucinations (15%), abdominal pain
(13%), esophageal irritation (11%), and agita-
tion (11%). Six of 68 children had hallucina-
tions and a 4-year-old developed convulsions.
Diacerein (diacetylrhein)
[SEDA-15, 1094]
Placebo-controlled studies In a placebo-
controlled trial of diacerein in osteoarthritis
(n 64) there were signicantly more
Chapter 9 249
adverse events in the diacerein arm, most
commonly yellow discoloration of the urine
and soft stools [74c].
Flupirtine [SEDA-15, 1425]
Nervous system Abuse of upirtine can
cause nervous system symptoms [75A].
A 17-year-old girl developed a headache,
blurred vision, confusion, ataxia, and syncope.
A urine sample was green in color and
contained a high concentration of upirtine
(which had caused the green coloration). Her
symptoms resolved in 24 hours. Because she
did not admit to having taken upirtine, the
ingested dose was unclear.
Nimesulide [SED-15, 2524]
Liver Nimesulide-induced hepatotoxicity
can occur, with serious and potentially fatal
outcomes. Three cases of liver failure related
to nimesulide have been reported [76A, 77A,
78A]. In a retrospective analysis from the
Irish national liver transplant unit all recipi-
ents of a liver transplant for fulminant hepatic
failure of unknown cause (19942007)
were evaluated [79c]. There were 32 patients
with seronegative, non-paracetamol-induced
liver failure. Nimesulide had been started
within 6 months in six patients and was
assessed as probably associated with liver
injury in all of these cases.
Skin Two cases of xed drug eruptions
associated with nimesulide have been
reported [80A, 81A].
Fetotoxicity The use of cyclo-oxygenase
inhibitors in pregnancy is associated with a
risk of premature closure of the ductus
arteriosus, as occurred after maternal self-
medication with nimesulide for low back
pain at 39 weeks of gestation [82A].
Phenazopyridine [SED-15, 2795]
Hematologic Two new cases of cyanosis
(acrocyanosis and purple hands) associated
250
with sulfhemoglobinemia and methemoglo-
binemia after phenazopyridine have been
reported [83A, 84A].
DRUGS USED IN THE
TREATMENT OF GOUT
Allopurinol [SEDA-15, 80; SEDA-31, 201]
Skin Allopurinol has commonly been
implicated in StevensJohnson syndrome
and toxic epidermal necrolysis [85C]. This
association has been conrmed by an anal-
ysis from Singapore. Of 85 cases of
StevensJohnson syndrome and toxic epi-
dermal necrolysis managed in Singapore
from 2003 to 2007, allopurinol was impli-
cated in 13 cases [86c]. The HLA-B*5801
allele is associated with severe cutaneous
adverse reactions caused by allopurinol in
the Han Chinese population [87c]. The
association between allopurinol-related
StevensJohnson syndrome and toxic epi-
dermal necrolysis and HLA-B*5801 has
also been conrmed in Thai and Japanese
patients [88c, 89c].
Two more cases of drug rash with eosino-
philia and systemic symptoms (DRESS)
associated with allopurinol have been
reported [90A, 91A].
Oral ulceration has been attributed to
allopurinol; the authors found a total of
six reported cases of allopurinol-induced
oral mucosal ulcers including the new case
[92A].
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Chapter 9 Sebastian Straube
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10 General anesthetics and
therapeutic gases
ANESTHETIC VAPORS
[SEDA-30, 137; SEDA-31, 217;
SEDA-32, 243]
HALOGENATED VAPORS
Chloroform [SED-15, 721]
Chloroform is a halogenated hydrocarbon
used previously as an anesthetic agent and
a general industrial solvent. Short-term
exposure has adverse health effects, such
as hepatitis, dysrhythmias, and carbon mon-
oxide poisoning [1A].
A 23-year-old man attempted suicide by
ingesting 100 ml chloroform and dichloro-
methane. His Glasgow Coma Score was 9/15
and his pupils were mildly dilated but respon-
sive. Initial hemodynamic variables and blood
and radiology investigations were normal. The
carbon monoxide concentration was 8.9%
(reference range 01.9%) and he was treated
with activated charcoal. On day 3 he devel-
oped nausea, vomiting, abdominal pain, and
jaundice and on days 4 and 5 aminotransferase
activities peaked (AsT 1617 IU/l and AlT 2677
IU/l). A CT scan showed severe fatty inltra-
tion of the liver parenchyma. Four weeks later
the liver enzymes returned to normal and
ultrasonography of the liver was normal 6
months after the event.
The mechanism of hepatic injury in
this case had two potential mechanisms:
oxidative metabolism, producing phosgene
(a hepatotoxin), hydrochloric acid, and
Side Effects of Drugs, Annual 33
J.K. Aronson (Editor)
ISSN: 0378-6080
DOI: 10.1016/B978-0-444-53741-6.00010-6
# 2011 Elsevier B.V. All rights reserved.
Alison Hall and M. Leuwer
carbon monoxide; and metabolism via the
glutathione pathway, yielding carbon diox-
ide and a glutathione conjugate, similar to
paracetamol overdose.
Halothane [SED-15, 1581]
Liver Halothane hepatitis has again been
described [2A]. Susceptibility factors are
increasing age, female sex, obesity, auto-
immune disease, and previous exposure to
hepatotoxic drugs such as isoniazid or
rifampicin.
A 4-year-old obese (36-kg) Hispanic girl
underwent adenotonsillectomy using halo-
thane general anesthesia, during which there
were no perioperative adverse events. She
was discharged on the same day. She had been
treated with isoniazid and rifampicin 4 years
previously, because of a positive Mantoux test.
On day 10 she developed a fever, vomiting,
and malaise and had raised liver enzymes.
On day 12 she was lethargic with an all-over
body rash, hepatomegaly (AsT 7876 IU/l,
AlT 6090 IU/l), and a raised white cell count
(14
109/l). She had renal insufciency (blood
urea nitrogen 23 mmol/l and creatinine 274
mmol/l) and a coagulopathy. Hepatitis serol-
ogy and an autoimmune screen were normal
and EpsteinBarr virus serology showed pre-
vious but not current infection. She was trea-
ted with uids, clotting products, antibiotics,
and N-acetylcysteine. She did not require ven-
tilator or inotropic support and on day 21 was
discharged home. One month later, her liver
and renal function and coagulation were nor-
mal. Subsequent analysis showed IgG autoan-
tibodies to a 58 kDa endoplasmic reticulum
protein, ERp58, and CYP2E1 and triuoroa-
cetylated IgG4 antibodies.
257
258
This child developed halothane hepatitis
after her rst vapor anesthetic but she had
susceptibility factors of obesity, female sex,
and previous exposure to isoniazid and
rifampicin, albeit 4 years before. Isoniazid
induces CYP2E1 and therefore increases
the metabolism of halothane, perhaps plac-
ing her at increased risk. Although there is
no dened diagnostic test for halothane hep-
atitis, most experts feel that the presence of
hepatitis, eosinophilia, CYP2E1 or ERp58
autoantibodies, or triuoroacetyl chloride
specic IgG antibodies after the exclusion
of infection increases the probability.
Isourane [SED-15, 1921; SEDA-30,
138; SEDA-31, 218; SEDA-32, 244]
Psychological Isourane can be used for
sedation in intensive care units (ICUs). In a
retrospective chart review, 335 patients who
received isourane for more than 12 hours
were investigated for psychomotor dysfunc-
tion [3c]. In 12 cases, there was generalized
tremor, facial tremor, generalized chorea, or
hallucinations. There were no signicant dif-
ferences in MAC-hours or the use of adjuncts
to isourane (midazolam, morphine, fenta-
nyl, glucocorticoids, or aminophylline)
between patients with and without psycho-
motor dysfunction. Regression analysis
showed that age under 4 years and duration
of isourane (but not MAC-hours) correlated
with the occurrence of psychomotor dysfunc-
tion. Psychomotor dysfunction was signi-
cantly less if duration of isourane
inhalation was less than 24 hours (0% versus
7.1%). Inhalation for more than 24 hours
made no further difference. The limitations
of this study were that the conclusions were
drawn from 10 patients who developed symp-
toms; when they were further divided into
groups according to age and duration of
exposure, there were fewer than four patients
per group. Also, as some of the described
symptoms were very mild and short lived, it
is possible that some were missed. There
was no mention of whether the study was con-
ducted retrospectively or prospectively,
Chapter 10 Alison Hall and M. Leuwer
which will almost certainly have affected the
quantity of missing data.
Methoxyurane [SED-15, 2290;
SEDA-32, 244]
Systematic reviews A review of all articles
concerning the use of methoxyurane in
the emergency and pre-hospital setting
yielded 48 relevant articles; all except one
were from case series [4M]. Six articles
investigated the analgesic efcacy of
methoxyurane, using doses of less than
0.5%. Most described an absolute pain
reduction of 14 points on a 10-point scale
with variable patient satisfaction. One pro-
spective observational study described a
lack of success with methoxyurane in
patients who were unable to achieve a suf-
cient degree of analgesia before a painful
stimulus; the authors hypothesized that
pre-empting the painful stimulus may
increase the success of procedural manage-
ment. In pre-hospital use, two large case
series (105 children and 83 adults) describe
no serious adverse effects. Minor adverse
effects of hallucinations, vomiting, dizzi-
ness, cough, and headache have been
described. Comparative data with other
agents are minimal.
Urinary tract Methoxyurane can cause
dose-dependent renal toxicity in anesthetic
doses. There have been no cases of renal
toxicity using the current analgesic dosage
recommendations (one 3 ml cartridge used
to deliver up to 0.7% using a penthrox
inhaler). However, there have been reports
of renal and hepatic dysfunction when
methoxyurane has been used as a drug
of abuse and in obstetric practice, although
the doses used were not described.
Sevourane [SED-15, 3123; SEDA-30,
138; SEDA-31, 218; SEDA-32, 245]
Comparative studies In a prospective sin-
gle-blind trial in 125 randomized patients
General anesthetics and therapeutic gases Chapter 10
who received a standardized general anes-
thetic and then either propofol (2 mg/kg/
hour) or sevourane (0.51%), all other
postoperative management was standard-
ized [5c]. The duration of postoperative
sedation was comparable in the two groups.
Although length of stay in the Intensive
Care Unit (ICU) did not differ, ventilated
time and length of stay in the hospital were
signicantly shorter with sevourane. Post-
operative adverse effects (nausea and vomit-
ing, agitation and delirium) were similar in
the two groups. Inorganic uoride ions were
signicantly increased by sevourane. Con-
centrations of alpha-glutathione-S-transfer-
ase (alpha-GST, a cytosolic protein highly
specic to cells in the proximal tubules, used
for predicting toxicity) were signicantly
raised in both groups at 24 and 48 hours from
baseline with no differences between the
groups. There was no correlation between
inorganic uoride concentrations and
alpha-GST or serum creatinine concentra-
tions. The activity of N-acetyl-glucosamini-
dase (NAG, a lysosymal enzyme released
into the urine in tubular injury) was
unchanged in both study arms. This study
suggests that short-term sedation with sevo-
urane does not affect renal integrity, even
in the presence of increased inorganic uo-
ride concentrations.
The effects of desurane or sevourane
on immediate recovery and return to nor-
mal function have been studied in 130
patients who were randomized to sevour-
ane or desurane (approximately 0.8
MAC) as maintenance anesthesia for
supercial, non-cavitational surgery [6c].
Early recovery end-points (eye opening,
obeying commands, and orientation) were
signicantly shorter with desurane but
there were no differences in the times to sit-
ting, tolerating uids, or length of stay in
the post-anesthesia care unit. Normal activ-
ities of daily living were resumed on the
rst postoperative day by 60% of those
who had received desurane and 48% of
those who had received sevourane, a
non-signicant difference. Over 95% of
both groups were satised with their overall
experience. The incidences of coughing
were similar in the two groups during
259
induction, maintenance, and emergence,
but in the overall period those who
received desurane had a higher incidence
of coughing, although all the episodes were
short lasting and none resulted in laryngos-
pasm. There were no differences in the inci-
dences of postoperative sore throat, pain,
or nausea and vomiting between the two
groups. Composite end-points were used
to achieve statistical signicance in the inci-
dence of coughing, but as none resulted in a
clinically signicant airway event, the clini-
cal relevance is debatable. The anesthetist
was not blinded but was instructed to main-
tain a minimally acceptable level of anes-
thesia, to prevent movement and achieve
rapid wake up, which may have biased
the results.
In a double-blind randomized study, 179
children undergoing day-case dental surgery
received either sevourane (2%) or propofol
(250 micrograms/kg/minute with additional
boluses of 1 mg/kg as required). Rescue
analgesia was provided using boluses of fen-
tanyl and emergence delirium was measured
using the pediatric anesthesia emergence
delirium (PAED) score [7C]. There were no
differences in premedication, duration of
procedure, or dose of intraoperative fentanyl
between the groups. There were no signi-
cant differences in the PAED scores.
Patients who required more postoperative
rescue analgesia had a higher PAED score,
perhaps suggesting confusion between pain
and delirium. The incidence of postoperative
nausea and vomiting was higher with sevo-
urane (odds ratio, OR 5.3) and more
nursing interventions were also required in
the recovery room. It may be that patients
with postoperative pain in this study were
dened as having emergence delirium, and
this may have inuenced the outcome of
the study. Also, patients in the propofol
group received sevourane for induction.
Although this is a common anesthetic tech-
nique in children, it may have affected the
results.
Systematic reviews In a meta-analysis of 23
prospective randomized studies of the inci-
dence of emergence delirium in children
under 12 years of age anesthetized with
260
sevourane (n 1252) or halothane (n
1111) the pooled OR of the incidence of
emergence delirium with sevourane was
2.21 [8M]. In all subgroup analyses (better
quality-rated studies, children under 7
years, inguinal or minor urological surgery,
and myringotomy surgery), the higher OR
for sevourane-induced emergence delir-
ium remained signicant. There is no
widely used denition of emergence delir-
ium, which made these studies heteroge-
neous, but tests for heterogeneity in this
study showed no differences. No study used
a validated tool for emergence delirium,
such as the PAED score, and blinding was
variable. Emergence delirium is difcult to
dene and often, especially in younger chil-
dren, difcult to distinguish from pain. The
authors of this study claimed to show that
sevourane still has a greater incidence of
emergence delirium if a pain strategy is
provided, but there were no comparisons
of pain scores to assess the adequacy of
the analgesic strategies used.
Cardiovascular Sevourane is a drug with
minimal cardiovascular adverse effects,
although cardiac rhythm disturbances have
been recorded [9A].
A 4-year-old boy underwent repair of a gastro-
cutaneous stula. After inhalational induction,
anesthesia was maintained at 2% sevourane
with 66% N2O and 30 minutes later he devel-
oped third-degree heart block. Sevourane was
withdrawn and replaced with propofol; 5
minutes later he reverted spontaneously to sinus
rhythm. A postoperative 12-lead electrocardio-
gram was normal with borderline prolongation
of the QTc interval to 466 ms.
Sevourane prolongs cardiac conduction
and the QTc interval by inhibiting voltage-
gated sodium and L-type calcium channels.
Body temperature Sevourane has once
again been linked to malignant hyperthermia,
in a 37-year-old man in whom the genetic link
was found in the ryanodine receptor [10A].
The current recommendations of the Euro-
pean Malignant Hyperthermia Group are to
perform open muscle biopsy followed by an
in vitro contracture test and molecular
Chapter 10 Alison Hall and M. Leuwer
testing for families known to carry causative
mutations.
OTHER VAPORS
Nitric oxide [SED-15, 2538]
Observational studies In 11 patients with
severe pulmonary hypertension, six due to
primary pulmonary arterial hypertension
and four due to chronic thromboembolic
disease, inhaled nitric oxide was used either
alone or combined with a phosphodiester-
ase type 5 inhibitor [11c]. After 6 months
of treatment, seven patients had clinical
deterioration that was reversed on adding
a phosphodiesterase type 5 inhibitor. One
died after 8 months and another underwent
pulmonary transplantation after 9 months.
Nitrous oxide [SED-15, 2550; SEDA-
30, 140; SEDA-31, 221; SEDA-32, 247]
Observational studies In a prospective
observational study of the analgesic efcacy
of N2O for procedural sedation, children
aged 117 years underwent predominantly
orthopedic procedures and laceration
repairs under 5070% N2O, delivered
either by a demand valve or a continuous-
ow device; 94% of the patients had mild
to moderate sedation and only two patients,
who had both received 70% N2O, were
deeply sedated [12c]. Parental satisfaction
scores were generally very high (over
92%). No patients had a serious adverse
event. Pre-procedural and peri-procedural
pain scores were very different, depending
on the presenting condition, and ranged
from 2 to 10 cm on a 10-cm visual analogue
scale. Only 124 of the initial 220 children
enrolled had complete data sets, which
may have biased the results.
In a prospective study of the effects of
different concentrations of N2O (50% and
70%) on sedation and incidence of adverse
General anesthetics and therapeutic gases Chapter 10
events in 762 children, there was a signi-
cant increase in the degree of sedation with
70% N2O [13c]. There were adverse events
in 8.3% (vomiting 5.7%, agitation 1.3%,
and nausea 0.9%, with individual cases of
other minor adverse effects), although
there were no differences between the two
groups. Two patients had serious adverse
events, both of whom received 70% N2O:
one developed chest pain associated with
normal vital signs, which was resolved with
oral antacids, and one developed repeated
episodes of hypoxia, which resolved with
oxygen. There were no episodes of aspira-
tion or laryngospasm. Documentation of
adverse events in this study relied on accu-
rate charts, and there may be a tendency to
under-report minor adverse effects.
Comparative studies In a study of the role
of either EMLA cream or N2O to alleviate
pain induced by intramuscular palivizumab
injections in children aged under 24 months
in a crossover study, 55 children were ran-
domized to EMLA plus air inhalation or
N2O (50/50) plus placebo cream, or both at
each of three injections over a course of 3
months [14c]. Baseline behavioral and pain
scores were similar with the three interven-
tions. The EMLA N2O combination had
signicantly reduced behavioral and pain
scores than EMLA or N2O alone. There
was no effect of gestational age, sex, or birth
weight. Parental pain assessment mirrored
this and was assessed as being signicantly
lower in the combination group. All the
adverse effects were minor and self-limiting
(one episode of vomiting in the combination
group) and there were no cases of drowsi-
ness. There were no differences in the inci-
dences of skin reactions (78% in each
group, including placebo cream). A com-
plete placebo group, although acknowl-
edged to have been omitted, was
considered unethical, as EMLA cream has
already been shown to be efcacious.
Placebo-controlled studies In a double-
blind, randomized, placebo-controlled study
of the efcacy of N2O enteral midazolam
for botulinum toxin injections, children with
cerebral palsy received midazolam 0.350.5
261
mg/kg either orally or rectally or nitrous
oxide 070% in oxygen delivered using a
continuous-ow device [15c]. Children who
were randomized to midazolam received
100% oxygen via the continuous-ow device
and those who were randomized to N2O
received the same volume of isotonic saline
enterally. There were no differences in the
maximal levels of sedation achieved, but
sedation scores at discharge were higher in
the midazolam group. Pain scores in the chil-
dren who received N2O were signicantly
lower. Nine children had adverse events,
one in the midazolam group (hypoxia
resolved with extra oxygen) and eight in
the N2O group (one each of nausea and
headache, two with brief hypoxia resolved
with extra oxygen, and four with vomiting).
There were no episodes of airway obstruc-
tion or apnea. The small numbers made it
difcult to draw conclusions concerning
adverse events, because although N2O
appears to have increased the numbers of
adverse events when combined, individual
types of event are rare. In this group of chil-
dren, who often have problems with secre-
tions and gastroesophageal reux disease, it
is hard to draw rm conclusions.
Nervous system N2O can interfere with
methionine synthesis by inactivating
methylcobalamin. This can result in demye-
lination of the nervous system and cause a
polyneuropathy [16A].
A 19-year-old girl with a history of recreational
N2O use developed progressive weakness of
the legs and a gait disturbance and was unable
to walk without assistance. Nerve conduction
studies showed a demyelinating polyneuropathy,
and somatosensory evoked potentials suggested
a central pathway lesion. A magnetic resonance
imaging (MRI) scan showed high-intensity sig-
nals involving the posterior columns of the cervi-
cal and thoracic spinal cord. N2O-induced
subacute degeneration of the cord was
diagnosed, and she was given vitamin B12. After
1 week, there was improvement, and after 2
months neurological function was normal.
Medsafe in New Zealand has reminded
prescribers that prolonged use of nitrous
oxide has been associated with neurological
and hematological adverse effects such as
262
megaloblastic anemia and myelopathy, due
to inactivation of vitamin B12 [17S]. Neuro-
logical symptoms can occur without any
other hematological changes. Prescribers
are also advised to check vitamin B12 con-
centrations in those with risk factors for
vitamin B12 deciency before using N2O
and to seek specialist advice, if necessary.
N2O should not be used continuously for
more than 24 hours or more often than
every 4 days without clinical supervision
and hematological monitoring.
Gastrointestinal N2O causes postoperative
nausea and vomiting by several mecha-
nisms, such as increased middle ear pres-
sure, bowel distension, and activation of
the dopaminergic system in the chemo-
receptor trigger zone. In 147 patients
undergoing gynecological laparoscopic sur-
gery, who were randomized to 30% O2 in
air, 50% O2 50% N2O, or 70% N2O
30% O2 after a standardized general anes-
thetic with no prophylaxis of nausea and
vomiting, there was a signicant difference
at 24 hours between 70% N2O and 0%
N2O with respect to postoperative nausea
and vomiting (62% versus 33%) and nau-
sea (56% versus 26%) [18c]. There were
no differences between 0% and 50% N2O
and 50% and 70% N2O. Severe vomiting
rates (more than two episodes within 30
minutes or more than three in 24 hours)
were similar between the groups. There
were no differences in opiate or rescue
antiemetic drug use.
In a large prospective, multicenter ran-
domized trial the incidence of severe post-
operative nausea and vomiting was
investigated in 2050 patients undergoing
general anesthesia expected to exceed 2
hours, who received either 70% N2O with
O2 or 80% O2 with air after airway instru-
mentation until completion of surgery
[19C]. Overall 17% had nausea and vomit-
ing in the rst 24 hours after surgery. Age
over 55 years, female sex, abdominal sur-
gery, N2O administration, absence of bis-
pectral index (BIS) monitoring, and longer
duration of anesthesia were predictors of
severe nausea and vomiting. The presence
or absence of BIS monitoring is an
Chapter 10 Alison Hall and M. Leuwer
interesting predictor in this study and is
consistent with other studies, probably
mediated via a reduction in the amount of
anesthesia required. The investigators did
not record a past history of postoperative
nausea and vomiting, motion sickness, or
postoperative opioids, which may have sig-
nicantly affected these results. This iden-
ties a potential problem with post hoc
data analysis of other than primary end-
points.
Genotoxicity DNA damage by N2O has
been studied in 84 medical staff who had
had occupational exposure to N2O and halo-
genated hydrocarbons for at least 5 years
[20c]. The control group consisted of 83 staff
members working outside the theatre envi-
ronment. DNA damage in peripheral blood
leukocytes was measured, and the exposed
subjects had a signicantly higher DNA
damage score. N2O and vapor concentra-
tions were measured in the operating the-
atres and were consistently higher than the
recommended national guidelines. Further,
single regression analysis showed a signi-
cant correlation between N2O exposure
and DNA damage. After adjusting for age,
sex, smoking, and hospital location, DNA
damage score was still signicantly associ-
ated with N2O concentrations. In contrast,
there was no signicant correlation between
DNA damage score and concentrations of
halogenated hydrocarbons.
INTRAVENOUS AGENTS:
NON-BARBITURATE
ANESTHETICS
Etomidate [SED-15, 1302; SEDA-30,
140; SEDA-31, 221; SEDA-32, 248]
Comparative studies In a randomized con-
trolled multicenter trial of the effect of eto-
midate versus ketamine in emergency
intubation, 655 patients were randomized
to either etomidate 0.3 mg/kg or ketamine 2
mg/kg [21C]. Maximum SOFA (Sequential
General anesthetics and therapeutic gases Chapter 10
Organ Failure Assessment) scores and its
components did not differ between the
groups during the rst 3 days of admission.
Basal cortisol concentrations were signi-
cantly lower in those who received etomi-
date (441 versus 690 nmol/l) as was the
percentage of non-responders to a standard
ACTH stimulation test (93% versus 49%).
This resulted in a higher incidence of adrenal
insufciency in those who received etomi-
date (OR 6.7). There were no differences
in mortality between either the ketamine/
etomidate groups or responders and non-
responders to ACTH stimulation. There
were no differences in the duration of cate-
cholamine use, duration of weaning from
respiratory support or length of stay in the
ICU. There were no serious adverse events
in either group.
Endocrine Etomidate can cause adrenal
suppression, which has been linked to
increased mortality in critically ill patients
requiring anesthesia for ventilation after
injury or illness. This retrospective data-
base review was undertaken to assess any
association between the use of etomidate
and outcomes after trauma that resulted in
hypotension in 97 patients [22c]. Stepwise
multivariate regression analysis, adjusted
for confounding variables (hypertonic
saline and blood transfusion, APACHE II
score and Injury Severity Score, ISS)
showed that those who received etomidate
there was a trend in towards a signicant
increase in adult respiratory distress syn-
drome (ARDS; 40% versus 20%) and mul-
tiple-organ dysfunction syndrome (MODS;
46% versus 25%). This corresponded to a
signicant increase in the number of venti-
lated days and length of stay in the ICU
in those who received etomidate. As these
data were not collected primarily to look
at this outcome, it is difcult to assess for
missing data and the effect of both differ-
ences in practice between anesthetists and
the use of etomidate in sicker patients,
owing to its inherent lack of cardiovascular
adverse effects. Despite this, there was
good homogeneity between the two groups
with respect to physiological and injury
263
severity scores and the comparison may
therefore be valid.
Ketamine [SEDA-32, 250]
Observational studies In a small retrospec-
tive review of 65 children and adolescents
who received intravenous ketamine for
elective percutaneous solid organ biopsies
under radiological guidance the patients
received 2 mg/kg followed by an infusion
of up to 150 micrograms/kg/minute (median
70 micrograms/kg/minute) [23c]. Median
recovery time was 60 minutes. There were
two adverse effects during sedation: agita-
tion and hypertension in a patient with
poorly controlled pre-operative hyperten-
sion. In the recovery period, there were
eight adverse events, most of which were
nausea and vomiting. Patient and parent
satisfaction was high (92%). This small trial
has added to the evidence that ketamine
can maintain cardiovascular stability and is
suitable for procedural sedation in selected
groups of patients.
There is some prior evidence that the use
of ketamine during emergency care corre-
lates with sustained post-traumatic stress
disorder symptoms in trauma victims. In a
prospective non-randomized study in 50
adults who had had mild to moderate
trauma without loss of consciousness 13,
24, and 13 received ketamine, opioids, and
non-opioid analgesics in weight-related
doses [24c]. On the third day after admis-
sion, questionnaires were completed inves-
tigating dissociation, re-experiencing,
avoidance, and hyperarousal. Previous
traumatic experiences were also investi-
gated using the traumatic life event ques-
tionnaire. Patients who were given
ketamine had consistently higher scores
than the other two groups, with specically
higher incidences of re-experiencing, avoid-
ance, and hyperarousal. Doses were not
reported and the numbers were small, but
this study has shown a strong and consistent
increase in symptoms of post-traumatic
stress disorder in patients treated with race-
mic ketamine.
264
In 82 children undergoing tonsillectomy
who were randomized to morphine 0.1
mg/kg alone or in combination with keta-
mine 0.25 mg/kg after sevourane induc-
tion, there were no differences in the
duration of anesthesia, surgery, or recovery
between the two groups [25c]. There were
no differences in pain scores or total mor-
phine consumption, but the ketamine group
required less rescue morphine during
recovery. There were no episodes of hallu-
cinations after ketamine. However, the inci-
dence of vomiting was 7.5% with morphine
and 2.3% with ketamine.
Ketamine has also been studied as an
adjuvant to lidocaine intravenous regional
anesthesia for hand surgery in 40 patients
who received ketamine 0.1 mg/kg either as
an adjuvant to the lidocaine or as an intra-
venous injection [26c]. There were no sig-
nicant differences in tourniquet pain or
opiate requirements, either intraoperatively
or during the recovery period. There were
no difference in the incidence of psychoto-
mimetic effects and satisfaction was high
in both groups. The authors felt that it
would be unethical to include a control
group, as ketamine has already been shown
to be superior to placebo. However, this
makes the conclusions hard to interpret.
In a prospective analysis of 92 adults who
underwent procedural sedation using intra-
venous ketamine (mean dose 0.7 mg/kg) for
almost exclusively orthopedic procedures,
91 achieved adequate sedation as dened
by their physician, but heart rate and blood
pressure increased by 21% and 18% respec-
tively [27c]. There were adverse events in
21%, including recovery agitation (13%),
vomiting (4%), and clonic movements
(4%). Seven of 12 patients with recovery
agitation required intravenous midazolam.
There were no episodes of laryngospasm.
There were no standard criteria for the
diagnosis of recovery agitation or clonic
movements in this study.
In a retrospective database review of 1030
adults, 1.6% received pre-hospital ketamine
for induction of anesthesia and the rest for
sedation (dose 0.51.0 mg/kg) [28c]. In no
case was an airway manoeuvre required
and no patient required intubation. About
Chapter 10 Alison Hall and M. Leuwer
90% of the patients had midazolam co-
administered, usually in a dose of 12 mg.
In some cases there were emergence
phenomena, but missing data cannot be
accounted for.
In a prospective observational study of
the effectiveness of ketamine 10 mg and
midazolam 0.5 mg delivered as a bolus by
patient-controlled administration as analge-
sia for changing burns dressings, 44 patients
underwent 95 treatments, each requiring
an average of 9.4 ml (94 mg ketamine and
4.7 mg midazolam) over a mean of 78
minutes [29c]. Average effectiveness scores
were 8.5 out of 10 for both staff and
patients. There were 23 adverse events in
15 patients, the most common being hallu-
cinations (11/23) and desaturation <95%
(5/23). There was no difference in total
drug dose in those with and without
adverse events. Many of the patients
received preprocedure opioids (morphine
and oxycodone) in varying amounts, which
may have affected pain scores, depending
on the dose and timing of the adjunctive
analgesia.
Comparative studies Sevourane and keta-
mine have been prospectively compared in
induction of anesthesia in 50 children with
congenital heart disease [30c]. After pre-
medication, they were given either intra-
muscular ketamine 5 mg/kg with high-ow
oxygen or incremental doses of sevourane
(up to 8%) via a face mask. Following
intravenous cannulation, all the children
received a standardized anesthetic induc-
tion, and there were no differences
between the groups with regard to loss of
eyelash reex, time to intravenous access
or intubation, and heart rate or oxygen sat-
uration (SpO2). Systolic blood pressure was
signicantly lower after sevourane at all
times but only transiently, and no vasopres-
sors were required. There were 17 respira-
tory events: breath holding (n 13),
coughing (3), and hiccups (1) after sevour-
ane, and none resulted in a serious adverse
event, such as laryngospasm. There was
excessive salivation in 16% after ketamine.
These data imply that ketamine is a safe
and hemodynamically stable alternative to
General anesthetics and therapeutic gases
inhalational induction for children with
congenital heart disease.
In a prospective analysis, 210 patients
who required emergency procedural seda-
tion and who were given midazolam
(51%), ketamine (40%), and propofol
(9%) were used as primary agents; median
doses were 5, 65, and 100 mg respectively,
and 64% also received opioid analgesia
[31c]. The time to full orientation was lon-
ger after midazolam and ketamine than
propofol (30 and 25 versus 10 minutes). Sig-
nicantly more of those who were given
midazolam had recall of the procedure.
There was also a signicant association
between the administration of ketamine
and re-emergence phenomena, although
there was no standardized description of
these symptoms and those affected were
much younger, both factors that could have
biased this result. Overall, 16% had an
adverse event and there was no signicant
association between an agent and adverse
events. However, there was apnea or
hypoxia (desaturation <94%) in 17% and
12% after propofol and midazolam respec-
tively compared with 1% after ketamine.
The highest incidence of adverse events
occurred when patients were sedated to a
no response level, although the authors
did not elaborate on which type of adverse
events. When patients were oversedated
with midazolam, there was a signicant
increase in adverse reactions, which was
not seen at the same level of sedation with
ketamine. There was no mention of the
use of adjunctive opioids or adverse events
that may have contributed to respiratory
episodes. This study gives further evidence
of the safety and perhaps superiority of
ketamine over midazolam in emergency
procedures. The number of patients in this
study who received propofol was very
small, and it is therefore difcult to draw
conclusions.
In a prospective non-randomized obser-
vational study of behavioral changes and
vomiting after discharge in 554 children
who had undergone procedural sedation
with ketamine alone (66%), ketamine
midazolam (19%), or midazolam fenta-
nyl (15%) questionnaires were collected
Chapter 10 265
from parents [32c]. Those who received fen-
tanyl midazolam had a signicantly
higher risk of maladaptive behavior than
those who received ketamine midazolam.
Post Hospital Behavior Questionnaire
(PHBQ) scores increased by 0.4 per
increase in fentanyl dose by 1 microgram/
kg and by 0.6 per 1 mg/kg increase in keta-
mine dose. There was vomiting during the
procedure in 5.9%, 11%, and 3.7% after
ketamine, ketamine midazolam, and
fentanyl midazolam respectively. Vomit-
ing after discharge occurred in 20% and
14% of those that had received ketamine
and fentanyl midazolam. After controlling
for age, sex, fasting status, duration and type
of procedure, and the presence of a parent,
the choice of sedation agent did not affect
the odds of vomiting after discharge. Not
all eligible children were enrolled in this
study and a signicant number of missed
cases may have biased the results. Non-
blinding of the parents and reliance on
parental questioning without face-to-face
interviews may have introduce further bias.
Combination studies The addition of keta-
mine to fentanyl has also been studied in
a randomized placebo-controlled study in
200 patients undergoing cervical spine sur-
gery [33c]. All received non-steroidal anti-
inammatory drugs (NSAIDs) at the end
of surgery and for rescue analgesia. After
cervical surgery, visual analogue scores
were signicantly lower in the high-dose
ketamine group for 48 hours and in the
low-dose ketamine for 24 hours. Fentanyl
and NSAID requirements were signi-
cantly lower after high-dose ketamine.
Low-dose ketamine provided improved
pain scores at rest but not on movement.
Postoperative nausea and vomiting was sig-
nicantly less common in the high-dose
ketamine group, presumably because of
the lower doses of opiate required.
Placebo-controlled studies In a double-
blind randomized study of propofol (0.5
mg/kg) fentanyl (1 microgram/kg) with
or without the addition of ketamine 0.5
mg/kg in 60 children undergoing interven-
tional radiological procedures, the addition
266
of ketamine provided superior sedation,
and signicantly fewer children required
extra doses of propofol [34c]. There were
fewer respiratory complications with keta-
mine (10% versus 30%) but no patient
required intubation. There were no other
differences with respect to adverse events
(agitation and tachycardia) between the
two groups, with the exception of a signi-
cant increase in nystagmus with ketamine.
This study provides further evidence that
ketamine is suitable for out-patient radiol-
ogy procedures in children.
Regional anesthesia causes shivering by
effects on the thermoregulatory system,
causing hypothermia. Patients who were
having a spinal anesthetic with bupivacaine
15 mg were randomized in a double-blind
study to saline, midazolam 75 micrograms/
kg, ketamine 0.5 mg, or midazolam 0.25 mg
ketamine 37.5 micrograms/kg [35c]. At 15
minutes, the incidences of shivering were
60, 50, 23, and 3.3% in the four groups
respectively. There were signicantly more
patients with a higher shivering score among
the controls compared with the others.
Axillary body temperature increased signi-
cantly in all the groups compared with con-
trols. There were no signicant differences
in the incidences of hypotension, nausea
and vomiting, or hallucinations between the
groups. Although there was a relatively high
incidence of hypotension, all responded to
ephedrine and all were hemodynamically
stable by 30 minutes after spinal anesthesia.
The authors concluded that combinations
of very low doses of midazolam and keta-
mine are most effective in shivering induced
by regional anesthesia. The postulated
mechanisms are that ketamine induces non-
shivering thermogenesis by an action on the
hypothalamus or that an effect of noradren-
aline and midazolam reduces core body
temperature by inhibiting tonic thermoregu-
latory vasoconstriction.
Ketamine has been investigated in the
prevention of chronic pain after thoracot-
omy in 86 patients who were randomized
to ketamine or placebo after a standardized
general anesthetic using propofol or etomi-
date [36c]. The treatment group received
Chapter 10 Alison Hall and M. Leuwer
ketamine 1 mg/kg at induction, 1 mg/kg/
hour perioperatively, and 1 mg/kg infused
over the rst 24 hours postoperatively in
addition to a 1 mg/bolus of morphine. Sig-
nicantly, more patients had a pain score
of more than 3/10 in the rst 24 hours in
the placebo groups, and there was a trend
towards reduced morphine consumption
after ketamine (37 versus 41 mg). There
were no differences in adverse events (bra-
dycardia, hypotension, hypoxia, bradypnea,
vomiting, dizziness, or oversedation) attrib-
utable to either drug, and naloxone was
not required. At 6 weeks and 4 months,
there were no differences in the incidences
of chronic pain between the groups. More
than 50% of all patients had symptoms of
neuropathic pain at 4 months.
The role of ketamine in the treatment of
chronic pain has been studied in 60 patients
who were randomized to S-ketamine or
placebo over 4.2 days starting at 1.2 micro-
grams/kg/minute and increasing if pain con-
trol was insufcient to a maximum of 7.2
micrograms/kg/minute or placebo [37c].
The two groups differed signicantly in
depression and anxiety scores, but below
the threshold for psychopathology. Baseline
pain scores were 7.2 and 6.8 out of 10 for
ketamine and placebo respectively. Keta-
mine improved pain scores over the 11-week
follow-up period but lost signicance at
week 12. Univariate analysis showed that
baseline pain scores predicted pain at week
1. Most patient had adverse effects during
the treatment period: those who were given
ketamine had higher incidences of nausea
(63% versus 17%), vomiting (47% versus
10%), and psychotomimetic effects (drug
high and hallucinations) (93% versus 17%);
headache was present in about one-third of
both groups. Although powered to show a
reduction in pain scores, the differences in
depression and anxiety scoring may have
biased the results.
Systematic reviews The authors of a review
of all published studies of low-dose keta-
mine for procedural sedation concluded
that the drug confers a high degree of
safety with minimal cardiovascular adverse
General anesthetics and therapeutic gases
effects [38M]. They also commented that
ketamine is a respiratory stimulant and that
patients retain their pharyngeal reexes;
however, reports of apnea are not uncom-
mon, and those who administer ketamine
should have airway skills. Reports of psy-
chiatric adverse effects on emergence were
variable, with variable end-points. For keta-
mine monotherapy they quoted an inci-
dence of 1020%, but this is difcult to
interpret because of the variable and surro-
gate outcomes used. There was vomiting in
515% of cases.
Nervous system In a double-blind, ran-
domized placebo-controlled trial the inci-
dence of unpleasant dreams after
subanesthetic doses of ketamine was inves-
tigated in 30 healthy volunteers using home
nightmare frequency [39c]. They received
either low-dose ketamine (plasma concen-
tration 115 ng/ml), high-dose ketamine
(plasma concentration 219 ng/ml), or pla-
cebo. There were no signicant differences
between high-dose and low-dose ketamine,
and the groups were therefore combined to
increase the sample size. Ketamine resulted
in the same number of unpleasant dreams
as placebo, but the dreams were signi-
cantly more unpleasant. This was due to a
lack of positive dream emotions rather than
an increase in negativity. A possible expla-
nation may be that the effect of ketamine
on the electroencephalogram was similar
to that of sleep deprivation, with increases
in non-rapid eye movement (non-REM)
sleep followed by a rebound increase in
REM sleep over the 12 hours after keta-
mine, suggested to cause intensication of
dream imagery.
Psychological The incidences of different
types of emergence phenomena after intra-
venous ketamine, mean dose 1.15 mg/kg,
for procedural sedation have been investi-
gated in children [40c]. Of 745 patients, 93
(13%) cried on awakening from sedation,
of whom 84 were consoled by their parents.
The rest were dened as having emergence
delirium. Another seven children were
Chapter 10 267
recorded as having emergence delirium, but
there was no standard denition of this.
Emergence delirium was not associated with
age or sex. At least one nightmare occurred
in 3.4% in the weeks after sedation. There
were pleasant visual hallucinations in 47%,
facial distortion and double vision being the
most common. It is difcult to assess very
young patients; with no standard denition,
what might perhaps have been disorienta-
tion on waking may have been interpreted
as emergence delirium. It would be interest-
ing to dene these events and to distinguish
between emergence phenomena, some of
which may be pleasant experiences, and
emergence delirium and other unpleasant
psychological experiences.
Salivary glands Ketamine has traditionally
been co-administered with atropine to
counteract increased salivation and oropha-
ryngeal secretions. In a prospective obser-
vational study in 1090 children, excessive
salivation was assessed on a 10-cm visual
analogue scale [41c]. The mean total dose
of ketamine was 2.1 mg/kg and only 0.5%
received adjunctive atropine; 92% were
assigned as having salivation rates of zero
and only 1.3% of cases had scores over 50
mm. There was one brief episode of desa-
turation attributed to laryngospasm from
excessive salivation, which was treated with
brief assisted ventilation. There was vomit-
ing during sedation or recovery in 7.5%,
and agitation, crying, and hallucination
scores were all low, with under 1.5%
patients scoring over 5 cm on the 10-cm
scale in each group. Although this was an
unblinded observational study, with subjec-
tive end-points, the numbers were large
and this suggests that excessive salivation
may not be a problem with this dose of
ketamine for procedural sedation.
Biliary tract In three ketamine abusers
with recurrent epigastric pain the common
bile ducts were dilated, mimicking choledo-
chal cysts on imaging [42A].
268
Urinary tract dysfunction after
recreational use of ketamine
Urinary tract dysfunction has been associ-
ated with recreational use of ketamine
[43R]. It was rst described in a series of
nine patients, all of whom were daily keta-
mine users, who presented with severe dys-
uria, frequency, urgency, and gross
hematuria [44c]. The urine cultures were
sterile in all cases. CT scans showed marked
thickening of the bladder wall, a small
capacity, and perivesicular stranding, consis-
tent with severe inammation. All had severe
ulcerative cystitis. Biopsies in four patients
showed epithelial denudation and inamma-
tion with a mild eosinophilic inltrate.
Withdrawal of ketamine, and treatment with
pentosan polysulfate, gave symptomatic
relief.
In a retrospective chart review of 233
abusers of ketamine aged 1360 (median
22) years, there were lower urinary tract
symptoms in 12% [45c].
The cause of this complication is not
known. One postulated mechanism is direct
damage to the urinary tract mucosa from
metabolites of ketamine causing submucosal
inammation and eventually edema and
brosis; microvascular changes may com-
promise the intrinsic microcirculation, caus-
ing neovascularization. The preponderance
of abnormalities in the lower urinary tract
may be due to increased time spent in con-
tact with ketamine metabolites.
The clinical features could be secondary
to bladder ischemia and an autoimmune
reaction to the bladder urothelium and
submucosa triggered by the drug and
metabolites.
Case reports There have been several indi-
vidual case reports [46A, 47A, 48A, 49A,
50A, 51r], including the following.
A 26-year-old man, a known ketamine user,
collapsed. He had previously had severe uri-
nary tract dysfunction treated with antibiotics
[52A]. A CT scan of the abdomen showed
bilateral hydronephrosis and cystoscopy
showed a signicantly reduced bladder capacity
without ureteric obstruction. He was hypoten-
sive, acidotic, and in acute renal failure and
Chapter 10 Alison Hall and M. Leuwer
required invasive respiratory support, hemol-
tration, and inotropic support. Bilateral
nephrostomies released gelatinous debris from
the left pelvicalyceal system, which contained
ketamine, cannabinoid, and lidocaine metabo-
lites. His urine output returned and although
he required intermittent renal support for 24
days, his renal function began to recover and
follow-up ultrasonography showed resolution
of the hydronephroses.
The presence of ketamine in the renal pelvis in
this case suggests a between-the-eyes adverse
reaction of type 1a [53H]. However, ketamine
does not usually precipitate in the renal pelvis
and therefore the added presence of the can-
nabinoid metabolites may have been crucial
to the presentation in this case.
A 27-year-old man, a regular ketamine user,
developed severe suprapubic pain, increased
urinary frequency, and hematuria [54A]. All
investigations, including renal function, urinal-
ysis, and culture, were normal. Cystoscopy
showed a small erythematous bladder. Biopsies
showed ulcerative hemorrhagic cystitis. His
symptoms did not respond to drug withdrawal,
opioids, antispasmodics, and anticholinergic
drugs. He underwent cystoprostatectomy with
new bladder formation and recovered.
A 26-year-old man developed increased uri-
nary frequency, nocturia, dysuria, and hematu-
ria which lasted for 7 months after he started to
use recreational ketamine weekly [55A]. Antibi-
otics and anticholinergic drugs were ineffective.
Urinalysis and culture were normal. Ultraso-
nography showed a thickened bladder wall
with a small capacity, and cystoscopy showed
mild inammatory changes. Bladder biopsies
were negative, although they were not taken at
a time an active episode of cystitis.
The last patient may have mild disease, as he
had used ketamine only weekly rather than
daily. He benetted symptomatically from
drug withdrawal.
A 16-year-old girl who took oral ketamine
8 mg/kg/day for 9 days for neuropathic pain
developed dysuria, increased frequency,
urgency, and incontinence [56A]. Urinalysis
was normal and urine culture was negative.
The symptoms abated when the dose of keta-
mine was reduced to 6 mg/kg/day and
completely disappeared at 2 mg/kg/day. When
ketamine was reintroduced the urinary symp-
toms reappeared at a dose of 5 mg/kg/day.
This case shows that ketamine-associated
cystitis may not be limited to drug abusers.
General anesthetics and therapeutic gases Chapter 10
A 19-year-old woman who had abused keta-
mine daily for 3 years developed severe lower
urinary tract symptoms [57A]. Her symptoms
resolved after she took duloxetine 60 mg/day
for 2 weeks.
Case series Seven men and three women,
aged 2030 (mean 25) years, who had all
abused ketamine for 14 years, developed
dysuria, increased frequency (having to void
once every 15 minutes), urgency, urge incon-
tinence, and painful hematuria [58c]. None
had positive urine cultures. Functional blad-
der capacities were 30100 ml. Urodynamic
tests showed detrusor overactivity, with uri-
nary leakage when the bladder was lled to
a capacity of 3050 ml. There was bilateral
reux in one case and unilateral reux in
two; seven had bilateral hydronephrosis.
[The title of this paper is confusing, since
street ketamine is a term that is used to
refer to phencyclidine; however, in the paper
the authors refer to ketamine.]
In 11 patients with severe urinary tract
symptoms after recreational use of ketamine,
renal function was normal in all cases and
urinalysis showed non-bacterial pyuria neg-
ative for tuberculosis [59c]. Urodynamic
studies in patients who tolerated the proce-
dure showed a small bladder capacity and
detrusor overactivity. Five patients under-
went bladder wall biopsy, which showed
eosinophilia and mast cells in high concen-
trations. Their symptoms slightly improved
after drug withdrawal, but six patients were
given intravesical instillations of hyaluro-
nan, a heparin-like substance used to
increase the growth of the glycosaminogly-
can layer of the damaged urothelium.
In 17 patients with ketamine-associated
cystitis, who underwent urinary tract biop-
sies, the characteristic histopathological fea-
tures were ulceration, eosinophilia, and
atypical urothelium [60c]. Urine cytology in
four patients showed hypercellularity and
cellular atypia. Immunohistochemistry in
10 patients showed a high expression of
p53 (9/10) and Ki67 (6/10) and no expres-
sion of CK20. Two had metaplastic changes.
These markers are expressed in most cases
of bladder carcinoma in situ, which
269
ketamine-induced urinary tract destruction
may therefore mimic.
A syndrome of cystitis and contracted
bladder has been described in a retrospective
analysis of 59 ketamine abusers in Hong
Kong, all had moderate to severe lower
urinary tract symptoms, with increased fre-
quency, urgency, dysuria, urge incontinence,
and occasionally painful hematuria [61c].
Average micturition frequency was 20200
ml every 1590 minutes. At cystoscopy in
42 patients there were various degrees of epi-
thelial inammation similar to that seen in
chronic interstitial cystitis. All of 12 bladder
biopsies had histological features resembling
interstitial cystitis. Urodynamically, there
was detrusor overactivity or reduced bladder
compliance with or without vesicoureteric
reux in 47 patients who were studied. There
was unilateral or bilateral hydronephrosis
on renal ultrasonography in 30 patients,
and four had features suggestive of papillary
necrosis on radiological imaging. Eight
patients had a raised serum creatinine
concentration.
The radiological ndings of this adverse
reaction have been described in 23 patients,
all with a history of ketamine abuse, who had
severe lower urinary tract symptoms [62c].
Ultrasonography showed a small bladder
volume and wall thickening. CT scans showed
marked generalized bladder wall thickening,
mucosal enhancement, and perivesical inam-
mation; ureteric wall thickening and enhance-
ment were also observed. In advanced cases,
CT scans and urography showed ureteric nar-
rowing and strictures.
Drug administration route Ketamine can
be associated with long recovery periods
and potential psychiatric adverse events.
All patients who had received ketamine
for out-patient emergency procedural seda-
tion at a tertiary children's hospital were
entered into a sedation registry and retro-
spectively identied [63c]. Of 229 patients
48% received ketamine intramuscularly
and 52% intravenously. The mean doses
were higher in the former (3.7 versus 1.5
mg). Adverse events occurred in 35% of
270
the former and 20% of the latter; the most
common were excess salivation (11% versus
1.7%) and emesis. There were ve episodes
of desaturation in each group all treated
with simple airway manoeuvres and oxy-
gen. No patient required intubation or
admission. Those who received intramuscu-
lar ketamine had a signicantly longer
length of stay in hospital after sedation
(2.9 versus 2.2 hours). This was a small sin-
gle-center retrospective study, and missing
data cannot be accounted for. In addition,
the attending physicians may have unknow-
ingly biased the results depending on per-
sonal preference of administration and the
individual patient.
Management of adverse drug reactions
The use of ketamine and dexmedetomidine
sedation combined with caudal anesthesia
for incarcerated inguinal hernia repair has
been described in three high-risk infants with
bronchiolitis [64A]. All had congenital heart
disease with associated acute viral bronchiol-
itis, making them at high risk for general
anesthesia. Although the documented
adverse effects of dexmedetomidine include
bradycardia, hypotension, tachycardia, fever,
and nausea, in this case series the authors
reported no effect on respiratory rate, end-
tidal CO2, or cardiovascular function. The
addition of ketamine may have prevented
the bradycardia and hypotension associated
with dexmedetomidine and vice versa for
the hypertension, tachycardia, and emer-
gence phenomena associated with ketamine.
Propofol [SED-15, 2945; SEDA-30, 142;
SEDA-31, 222; SEDA-32, 252]
Observational studies In a study of reloca-
tion of hip prostheses, 98 adults received
intravenous morphine titrated to relieve
pain and then a bolus of propofol 1 mg/kg
60 seconds before the procedure [65c].
Fracture reduction was successful in 94
patients, but 41 required additional doses
of propofol because of inadequate sedation
or a prolonged reduction time. Eight had
Chapter 10 Alison Hall and M. Leuwer
desaturation, which responded to either air-
way repositioning or brief supplementary
ventilation. Four had hypotension, and all
responded to a-adrenoceptor agonists. The
doses of propofol that were associated with
adverse events were not mentioned.
In 500 infants undergoing MRI scans,
sedation was induced using intravenous
nalbuphine 0.1 mg/kg and propofol 1 mg/
kg mixed with lidocaine 0.25 mg/ml [66c].
Extra doses of propofol 0.5 mg/kg were
given as required, followed by a mainten-
ance dose of 5 mg/kg/hour. Induction time
and recovery were longest in infants,
although the duration of the procedure
was similar at all ages. Sedation was ade-
quate in all but nine children, who required
one extra dose of propofol and an increase
in the rate of infusion to 6 mg/kg/hour.
There was hypoxia (SpO2 <92%) in ve
cases. Three had partial airway obstruction,
which resolved after repositioning, and two
required brief additional ventilation. There
were no cardiovascular adverse events and
all recovered uneventfully.
In a pediatric sedation database (PSRC)
from 37 centers, 88 672 records were retro-
spectively reviewed, of which 49 836
involved propofol as the sole or primary
sedative for a selection of procedures, most
of which were radiological [67C]. Desatura-
tion (716/10 000), airway obstruction (432/
10 000), cough interrupting the procedure
(356/10 000), and secretions requiring suc-
tion (341/10 000) were the most common
respiratory adverse events. There were
changes in hemodynamic variables of
>30% in 282/10 000. Other adverse events
were rare. There were two cases of cardiac
arrest requiring resuscitation, in a child with
a tracheoesophageal stula who developed
laryngospasm, hypoxia, bradycardia, and
asystole, which resolved with adrenaline,
and in a healthy 16-year-old who received
a large dose of propofol (195 mg) and
became apneic and hypotensive, resulting
in asystole for about 30 seconds. There
were four episodes of aspiration after
vomiting, followed by deterioration in
respiratory function; all had signicant
desaturation but all resolved with positive
pressure ventilation. Susceptibility factors
General anesthetics and therapeutic gases
for adverse pulmonary events included
higher ASA status, age over 6 months,
inadequate nutrition, and use of adjunctive
opiates.
Comparative studies Propofol and pento-
barbital have been compared for radiologi-
cal imaging in two studies in children. In a
retrospective study using the PSRC data-
base, 7079 cases were identied, 5072
involving propofol and 2007 pentobarbital
[68c]. Signicantly more children received
adjunctive midazolam after pentobarbital
than propofol (73% versus 24%). Compli-
cation rates in the two groups were 6.83%
and 4.99% with propofol and pentobarbital
respectively, but individual complication
rates were below 1%. Multivariate analysis,
controlling for age, sex, weight, and ASA
grading, showed an association between
pentobarbital and increased adverse events,
specically inadequate sedation, prolonged
recovery, allergic complications, and vomit-
ing; however, controlling for adjunctive
midazolam only inadequate sedation and
vomiting remained statistically signicant.
There were no signicant differences in
respiratory or airway events and there were
no episodes of aspiration.
In another study, in which parents chose
propofol or pentobarbital for their child's
sedation during CT scanning, there were
conicting results [69c]. Pentobarbital 12
mg/kg as a bolus dose was followed by
further boluses as required to a maximum
of 6 mg/kg. Propofol 12 mg/kg as a bolus
dose was followed by further 1 mg/kg
boluses to achieve adequate sedation, fol-
lowed by an infusion of 150200 micro-
grams/kg/minute. Although overall
adverse events in the two groups were
similar (12% versus 4% for propofol and
pentobarbital respectively), there were
higher incidences of airway events (23%
versus 0%) and respiratory events (12%
versus 0%) with propofol. Study times were
signicantly longer with propofol, perhaps
due to the increased incidence of airway
and respiratory events, whereas recovery
times were signicantly longer with pento-
barbital (100 versus 34 minutes). Parent
Chapter 10 271
choice may have signicantly biased the
results.
Sedation rather than general anesthesia
is required for some forms of middle ear
surgery in which it is desirable to test hear-
ing. In a prospective study, 70 patients aged
1670 years were randomized to propofol
11.5 mg/kg followed by an infusion of
12 mg/kg/hour or midazolam 0.020.05
mg/kg, and a maintenance dose of
0.010.02 mg/kg titrated to a bispectral
index (BIS) score of 7080 [70c]. Surgery
and sedation times and recovery times were
signicantly longer after midazolam. Pain
and sedation scores were similar, but BIS
scores were lower after propofol at the start
of sedation (71 versus 80). Patient and sur-
geon satisfaction was greater with propofol.
There were few adverse events (three after
propofol and none after midazolam
groups), but the study was not powered to
look at adverse events, and it is difcult to
draw any useful conclusions from this.
Placebo-controlled studies Sedation for
lumbar puncture on 44 occasions in 22 chil-
dren has been investigated in a double-
blind, crossover, randomized trial [71c].
They received propofol 12 mg/kg/minute
with or without fentanyl 1 microgram/kg 5
minutes before. The mean total doses of
propofol were 3 and 5 mg/kg when given
with and without fentanyl. Adverse events
occurred in 18% and 50% of patients with
and without fentanyl. Hypotension was the
most common adverse event, but it
occurred in the two groups equally. There
were no episodes of airway obstruction in
the propofol fentanyl group, but there
were three episodes in those who received
propofol alone. In this small study the anes-
thetizing physician was not blinded, and
along with the low incidence of adverse
events this makes it difcult to draw any
signicant conclusions from the composite
end-point of all adverse events.
In another similar double-blind, cross-
over, randomized, placebo-controlled study
of 22 children with acute leukemia, mean
age 6.4 years, on 44 occasions, there were
adverse events in 11 patients after propofol
272
and four after propofol fentanyl [72c].
Average recovery times were 37 versus 26
minutes. Most of the families preferred pro-
pofol fentanyl.
Propofol infusion syndrome Propofol infu-
sion syndrome has been reported in chil-
dren and adults after short-term high-dose
propofol. It presents with variations of
severe metabolic acidosis, rhabdomyolysis,
myoglobinuria, cardiac failure, and death.
The pathophysiology is unknown, but
genetic predisposition, mitochondrial
inhibition, and increases in serum free fatty
acids are believed to play a role. Catechol-
amines and corticosteroids may act as
triggering agents.
A 67-year-old man underwent anesthesia
for coronary artery bypass grafts induced
with midazolam, thiopental, fentanyl, and
vecuronium [73A]. He had a mild lactic acido-
sis before general anesthesia. Anesthesia was
maintained using isourane and propofol 0.8
mg/kg/hour, increasing to 5.2 mg/kg/hour dur-
ing cardiopulmonary bypass (total 79
minutes). During the operation, there was a
worsening metabolic acidosis, and he required
intravenous adrenaline postoperatively. Pro-
pofol was stopped on wound closure but the
acidosis continued to worsen, with a peak
serum lactate of 13 mmol/l. His urine became
weakly positive for myoglobin and hemoglo-
bin but was negative for ketones. The serum
creatine kinase activity was increased (260
mmol/l) with predominantly CK-MM, but
liver function tests and troponin were normal.
Propofol was withdrawn and the metabolic
parameters recovered within 6 hours.
In an analysis of 1139 patients with sus-
pected propofol infusion syndrome in
adults (mean age 52 years) and children
(mean age 9 years), the presenting symp-
toms included cardiac (43%), hypotension
(34%), rhabdomyolysis (27%), hepatic
(24%), renal (24%), metabolic acidosis
(20%), hypoxia (18%), and hyperthermia
(12%) [74M]. Propofol infusion ranges
exceeded 5 mg/kg/hour in 129 cases in
which the dose was reported. Regrettably,
two important variables with respect to
the propofol infusion syndrome, dosage
and timing of propofol infusion, were not
recorded in about 90% of papers. Multivar-
iate logistic regression analysis identied
Chapter 10 Alison Hall and M. Leuwer
age over 18 years, male sex, propofol
administration for over 48 hours, and con-
comitant treatment with catecholamines as
independent susceptibility factors for death.
Cardiac failure was independently associ-
ated with death. Rhabdomyolysis, renal
failure, and hypotension were cumulative
susceptibility factors.
In a retrospective review of patients
admitted with head trauma who were given
propofol by infusion for sedation, propofol
infusion syndrome was dened by unex-
plained acidosis, a raised creatine kinase
activity unrelated to trauma, and electrocar-
diographic changes [75cA]. Of 50 patients, 30
had received concomitant vasopressors; only
three developed propofol infusion syn-
drome. The dose of propofol used in these
cases was higher than the recommended
5 mg/kg/hour (83 micrograms/kg/minute)
and it was given for longer than the recom-
mended time (48 hours). The authors con-
cluded that concomitant use of
vasopressors confers an odds ratio of 29 for
propofol infusion syndrome, although the
sample size was too small for this to be calcu-
lated accurately.
Two cases of propofol infusion syndrome
in children undergoing cardiac surgery have
been reported after short infusions of average
doses of propofol. The diagnosis was based
on the absence of other causes and abrupt
resolution on drug withdrawal. A possible
cause in this case was the combination of pro-
pofol with an inadequate carbohydrate intake
to suppress fat metabolism [76A].
Respiratory In a non-blinded prospective
study in adults undergoing sedation for
emergency procedures 146 patients were
randomized to propofol 1 mg/kg followed
by 0.5 mg/kg every 3 minutes, with or with-
out alfentanil 10 micrograms/kg; all
received intravenous morphine before
sedation [77c]. There was a high incidence
of adverse respiratory effects in both
groups, as judged by the need for extra oxy-
gen (propofol 34%, alfentanil 44%) and
either airway adjuncts (9.5% and 17%) or
repositioning (18% and 28%); these differ-
ences were not signicant, but signicantly
more of those who received alfentanil
General anesthetics and therapeutic gases Chapter 10
required stimulation to induce breathing
(28% versus 15%) and had an absent trace
detected on the end-tidal CO2 monitor. The
addition of morphine did not improve pain
relief but did increase the incidence of
respiratory depression.
Nervous system Although propofol has
anticonvulsant action it can rarely cause sei-
zures [78A].
A 50-year-old man with no previous history of
seizures was anesthetized with fentanyl 100
micrograms and propofol 100 mg. Within 30
seconds of receiving the propofol, he devel-
oped tonic-clonic seizures over the trunk and
lower body. Despite thiopental 125 mg the sei-
zures recurred and required further boluses of
thiopental and midazolam. Surgery continued
uneventfully and postoperative recovery was
unremarkable. A CT scan of the brain was
normal.
Propofol has previously been associated
with tonic-clonic seizures and jerky move-
ments, many of which go unreported. The
pathophysiology is unknown, but spontane-
ous movements induced by propofol are
probably not related to cortical activity
but potentially to subcortical activity. In
high doses, propofol depresses both the
cortex and subcortex, thus acting as an anti-
convulsant. In low doses, it may inhibit the
subcortex only, resulting in cortical
hyperactivity.
Propofol-induced hiccups have been
reported [79A].
A 3-year-old girl was repeatedly sedated
with propofol for radiotherapy, and during
the rst and fth episodes developed hiccups
rapidly after propofol induction. The rst epi-
sode passed uneventfully, but the second was
complicated by laryngospasm. This was man-
aged by bag and mask ventilation and recov-
ery was uneventful. She had two further
similar episodes, both of which were treated
with lidocaine.
The reported incidence of hiccups after
propofol is under 1%. Propofol is often
given with lidocaine to prevent pain during
injection, which may mask the hiccups;
thus, the incidence may have been underes-
timated. In this case lidocaine was not used,
as there was a tunnelled Hickman line in
273
situ. The dose of propofol was not
mentioned.
Functional magnetic resonance imaging
(fMRI) scanning to visualize brain activity
relies primarily on the blood oxygen level
dependent (BOLD) signal, an indirect mea-
surement of cerebral blood ow associated
with neuronal activity. In a prospective
study of fMRI, 14 children were random-
ized to propofol 1 mg/kg by bolus injection
followed either by propofol 4 mg/kg/hour
or by midazolam 0.6 mg/kg/hour [80c].
There were no differences in MRI time,
and all studies were completed without
movement or adverse events. The children
in both groups required further boluses of
sedation, and there were no differences in
recovery time. Midazolam temporally
affected neuronal activity and vascular
response leading to a delay in functional
response whereas propofol produced a sim-
ilar activation pattern to non-sedated
adults.
Pain Propofol can reportedly cause hypo-
tension and pain on injection. In 156
patients who were randomized to lidocaine
1%, ephedrine 15 mg, or ephedrine 30 mg
per 20 ml of propofol, there was no signi-
cant difference in the distribution of pain
on injection [81c]. However, six of 51
patients who were given lidocaine required
rescue medication for hypotension com-
pared with no patients in either ephedrine
group. The authors suggested that ephed-
rine is therefore as good as lidocaine in pre-
venting pain on injection. However, in the
absence of control group these results must
be interpreted with caution.
Pain on injection with propofol is
thought to be more common and more dif-
cult to avoid in children. An emulsion
containing medium-chain and long-chain
triglycerides (mct/lct) has been introduced
as a solvent that is suggested to cause less
pain on injection than standard long-chain
triglyceride propofol. In a double-blind,
randomized, placebo-controlled trial study
in 160 preschool children comparing both
propofol emulsions with and without added
lidocaine, there were signicant reductions
274
in pain scores in those who received
the new solvent plus lidocaine [82C]. There
was no correlation of pain with the size and
site of the cannula.
In a prospective double-blind study in
120 children who were randomized to
alfentanil 15 micrograms/kg 90 seconds
before propofol 3 mg/kg or to propofol 3
mg/kg mixed with 0.1% lidocaine, or both,
the incidence of injection pain was
signicantly lower in the combined group
(2.6%) than either of the other two groups
(38% and 30% respectively).
Endocrine Transient diabetes insipidus has
been attributed to propofol [83A].
A 13-year-old boy with hyperparathyroidism
and multiple endocrine neoplasia type I was
due to have elective parathyroidectomy. He
was known to be susceptible to malignant
hyperthermia and so general anesthesia was
performed with propofol 100200 micrograms/
kg/minute and remifentanil 0.050.15 micro-
grams/kg/minute. After 1 hour his urine output
was 1000 ml despite only 400 ml input. Urine
specic gravity was low, with high plasma
osmolality and serum sodium. Desmopressin
postoperatively restored normal urine output.
Either remifentanil or propofol could
have been responsible in this case. Remi-
fentanil is a pure m opioid receptor agonist,
which inhibits vasopressin release from the
posterior pituitary; however, this patient
had previously had a hypophysectomy. Pro-
pofol reversibly inhibits the action of anti-
diuretic hormone in rat hypothalamus, and
this could have formed the basis of tran-
sient diabetes insipidus.
Acid-base balance The incidence of meta-
bolic acidosis has been studied in patients
undergoing elective intracranial surgery
using either propofol by target-controlled
infusion (23.5 micrograms/ml) or sevour-
ane 12.5% remifentanil 0.10.5 micro-
grams/kg/minute [84c]. There were no
signicant differences between the two
groups with respect to duration of anesthe-
sia, dose of remifentanil, or amount of
intravenous uid resuscitation. The pH
values were similar, but the anion gap was
signicantly higher in those who received
Chapter 10 Alison Hall and M. Leuwer
propofol. There was a metabolic acidosis
in seven of the patients who were given
propofol compared with one of those who
were given sevourane. The lowest base
excess measured correlated with the lactate
concentration, the total dose of propofol,
and the length of the procedure. There
were high lactate concentrations in those
who were given sevourane, but they did
not correlate with acidosis. Interventions
to treat hypotension and tachycardia were
signicantly more common in those who
received propofol (13 versus 1) but hypo-
tension and bradycardia were more com-
mon with sevourane (22 versus 12). The
mild to moderate metabolic acidosis associ-
ated with increases in lactate concentration
may have been evidence of early propofol
infusion syndrome. Mannitol may have
contributed, as there was a trend towards
greater use of mannitol in those who
received propofol.
Liver In a prospective study of the effects of
propofol infusion on hepatic and pancreatic
enzymes in 30 children undergoing elective
craniotomy who had taken phenytoin for at
least 1 week the total dose of propofol was
2200 mg (about 75 mg/kg) for a mean
duration of 4.9 hours [85c]. Serum amino-
tranferases, alkaline phosphate, and
gamma-glutamyl transferase rose and
peaked on the rst postoperative day and
returned to baseline within 37 days. Serum
amylase activity and triglyceride concentra-
tions were signicantly higher for 5 days,
but no child had symptoms of pancreatitis.
There was no correlation between total pro-
pofol dose and peak enzyme activities on
day 1. Although the changes were statisti-
cally signicant, all the values remained
within the reference ranges and may be of
little clinical signicance.
Pancreas Propofol can reportedly cause
pancreatitis, perhaps because of alterations
in lipid metabolism, leading to hypertrigly-
ceridemia, release of free fatty acids, and
chylomicron plugging of pancreatic capil-
laries. In a retrospective case note review
of 479 children with acute leukemia who
underwent general anesthesia for a
General anesthetics and therapeutic gases Chapter 10
diagnostic procedure, ve developed acute
pancreatitis [86c]. However, none of the
cases occurred within 24 hours of adminis-
tration of propofol, and all occurred sooner
after the administration of other drugs,
including cytosine arabinoside, mercapto-
purine, and L-asparaginase, any one of
which could have been responsible.
Urinary tract There have been two reports
of propofol-associated green urine [87A,
88A].
A 53-year-old man with liver cirrhosis had a
large upper gastrointestinal hemorrhage and
was given propofol 100 mg for induction of
anesthesia; 1 hour later he was noted to have
green urine. No other medications or recent
food could have caused this.
A 40-year-old man who was given a propofol
infusion after trauma developed green urine
after 4 days; his urine returned to normal
within 24 hours of propofol withdrawal.
Green discoloration of the urine due to
propofol probably occurs from the produc-
tion of a phenolic green chromophore
which is conjugated in the liver and
excreted in the urine. Other causes include
ingestion of methylthioninium chloride
(methylene blue) or food coloring, pigment
from Pseudomonas urine infection, or
biliverdin.
Immunologic Anaphylaxis with pulmonary
edema has been described after the use of
propofol at cesarean section [89A].
A 35-year-old woman, scheduled for an emer-
gency cesarean section, was anesthetized with
propofol 2 mg/kg and rocuronium 0.9 mg/kg
and maintained with sevourane. About 15
minutes before the end of the operation she
became tachycardic, difcult to ventilate, and
hypoxic despite 70% oxygen. After a second
dose of propofol for reintubation, she again
became hypotensive and profoundly hypoxic
and required inotropic support. Pulmonary
edema was diagnosed. Afterwards, a skin test
showed a strong weal and are reaction to
propofol.
Anaphylactic reactions usually occur sec-
onds to minutes after antigen administra-
tion, but late onset anaphylaxis can also
occur, as in this case.
275
INTRAVENOUS AGENTS:
BARBITURATE
ANESTHETICS
Thiopental sodium [SED-15, 3395;
SEDA-30, 146; SEDA-31, 226; SEDA-32,
255]
Comparative studies In a randomized con-
trolled trial of thiopental and pentobarbital
in the control of refractory intracranial
hypertension in 44 patients with severe
traumatic brain injuries the former was
more efcacious in reducing refractory
intracranial pressure (OR 5.1) [90c].
There were no differences in adverse
effects with respect to infections or the
SOFA score before or maximum score
attained between the two groups; almost
all of the patients had hypotension on at
least one occasion.
Gastrointestinal There have been two
reports of bowel ischemia after barbiturate
coma treatment for refractory status epilep-
ticus [91A].
A 72-year-old man was given thiopental 303
mg/kg over 48 hours and 36 hours later devel-
oped abdominal tenderness, peritonism, and
hyperlactatemia (11 mmol/l). At emergency
laparotomy there was extensive fresh necrosis
of the terminal ileum extending to the retro-
sigmoid junction. Histology showed no vascu-
lar or inammatory changes. He developed
septic shock and died 12 hours
postoperatively.
A 21-year-old woman with complex partial
seizures followed by secondary generalized
status epilepticus, refractory to burst suppres-
sion with various agents, including propofol,
ketamine, and thiopental for more than 2
months, was then given thiopental 840 mg/kg
over 150 hours combined with hypothermia
(34 C). On day 6, while normothermic, she
developed ileus and hyperlactatemia (5.6
mmol/l). At laparotomy she had megacolon
with focal cecal necrosis. Histology showed
no signs of vascular or inammatory change.
The postulated mechanism in these cases
was ileus, a known rare complication of
high-dose barbiturates, possibly compli-
cated by hypothermia in the second case.
276
Electrolyte balance Disturbances of potas-
sium homeostasis rarely complicate thera-
peutic barbiturate coma [92A].
A 14-year-old girl with a severe traumatic
brain injury developed a raised intracranial
pressure, which was treated with 2900 mg of
thiopental over 42 hours. Before the infusion
she had hypokalemia (2.5 mmol/l), which was
corrected, but it persisted despite potassium
replacement of 200 mmol. She suddenly devel-
oped tachycardia, anterior ST segment
changes, and atrial brillation 7 hours after
the end of the infusion. Her serum potassium
peaked at 7.0 mmol/l and hyperkalemia per-
sisted for 36 hours.
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 Stephan A. Schug, Alexander Raymann, and
11 Local anesthetics
GENERAL
Nervous system Horner's syndrome, the
triad of miosis, ptosis, and enophthalmos,
is a common complication of regional
blockade of the brachial plexus, following
disruption of sympathetic nerve input from
the cervical sympathetic ganglia [1A]. In
rare cases it has been witnessed after inter-
costal regional anesthesia. It has also been
reported in connection with thoracic epi-
dural anesthesia [2A, 3A] and extrapleural
regional anesthesia [4A]. Although it can
be disconcerting for the awake patient,
Horner's syndrome is generally well toler-
ated. Permanent lesions have been
reported, but in the vast majority of cases
the symptoms disappear after discontinua-
tion of the regional anesthesia. It is advis-
able to inform patients having the above
procedures of the possibility of Horner's
syndrome and its generally benign course,
in order to avoid distress and subsequent
refusal of regional anesthesia.
In a retrospective analysis of 334 patients
with a history of seizure disorder undergoing
411 regional blocks, local anesthesia was
implicated in seizure activity in only ve of
24 seizures, judging by the time-course of
the events [5R]. There was no proof that the
local anesthetic had caused the seizure.
Depending on the classication of these ve
cases, the authors estimated the incidence of
Side Effects of Drugs, Annual 33
J.K. Aronson (Editor)
ISSN: 0378-6080
DOI: 10.1016/B978-0-444-53741-6.00011-8
# 2011 Elsevier B.V. All rights reserved.
Manuel Wenk
seizures after regional blockade in patients
with a history of seizure disorder at 0120
per 10 000 (95% CI 0280 per 10 000). They
concluded that a pre-existing seizure disor-
der does not contraindicate the use of
regional anesthesia, but should always trig-
ger precautions for potential perioperative
seizures.
Cartilage toxicity from local
anesthetics
Intra-articular injection of local anesthetics for
pain relief after surgical procedures is an off-
label use of these compounds, but is com-
monly practised and widely published.
Although its effectiveness is questionable and
inferior to other modes of pain relief, such as
peripheral regional blockade [6C, 7c], intra-
articular injection is still widely used in various
settings, possibly because of ease of
administration.
However, a growing body of evidence
from laboratory data, animals, and case
series in humans has emerged, raising con-
cerns about the safety of intra-articular injec-
tion of local anesthetics. The direct toxic
effects of local anesthetics on cartilage have
been widely discussed.
Animal studies After injection of saline,
bupivacaine, or neostigmine into 45 knee joints
in rabbits, there were no histopathological
changes with saline, but signicant changes
with bupivacaine and neostigmine [8E].
In a study of the long-term effects of contin-
uous intra-articular infusion of bupivacaine
0.25%, 36 rabbits were randomized into three
281
282 Chapter 11 Stephan A. Schug, Alexander Raymann, and Manuel Wenk
groups and given an infusion of saline,
bupivacaine, or bupivacaine adrenaline
over 48 hours into the glenohumeral joint
[9E]. Histopathological examination after
3 months showed no permanent impairment
of cartilage function, suggesting that cartilage
can recover from exposure to bupivacaine.
Whether these results can be extrapolated to
human chondrocytes is unclear.
In vitro studies A direct toxic effect of 0.5%
bupivacaine solution on bovine articular
chondrocytes in vitro has been reported [10E].
Even a short exposure of 1530 minutes was
associated with up to 42% dead chondrocytes,
and the rate was even higher (72%) when the
articular surface was removed.
Similar results were obtained in a study in
which bovine articular chondrocytes were
exposed to lidocaine 1% or 2% solution
[11E]. There was a dose-dependent cytotoxic
effect on chondrocytes that was less promi-
nent than with bupivacaine, but still signi-
cant, suggesting that local anesthetics as a
class (rather than a specic compound)
may adversely affect cartilage metabolism.
The effects of the common practice of
injecting local anesthetics in combination with
methylprednisolone have been investigated
in vitro [12E]. Chondrocyte viability fell signif-
icantly with increasing doses and time of expo-
sure to clinically relevant doses.
The rst studies involving human articu-
lar chondrocytes were published in 2008. In
a study of the effect of bupivacaine in differ-
ent concentrations for various exposure
times on human and bovine chondrocytes
longer exposure resulted in higher
chondrotoxicity [13E].
The chondrotoxic effects of bupivacaine
0.5% and ropivacaine 0.5% have been stud-
ied in an in vitro model using human articular
cartilage [14E]. Ropivacaine was signicantly
less toxic than bupivacaine, and the effects of
ropivacaine on chondrocytes were compara-
ble to those of saline.
Chondrocytes isolated from human artic-
ular cartilage harvested during total knee
replacement have been cultured for 24, 48,
and 72 hours in articial synovial uid and
continuously perfused with differing concen-
trations of lidocaine and bupivacaine in
combination with or without adrenaline
[15E]. Bupivacaine 0.25% and 0.5% caused
only minimal chondrocyte necrosis within
the rst 48 hours, but bupivacaine 0.5%
caused signicant chondrotoxic effects after
72 hours. All combinations of local anes-
thetics with adrenaline caused signicant
chondrotoxicity.
Human reports As of now, only case
reports have been published, no controlled
studies.
Having retrospectively reviewed 12 cases
of postoperative chondrolysis, all of which
involved the use of a high-ow intra-articu-
lar infusion of bupivacaine 0.25% with
adrenaline, the authors recommended that
intra-articular infusions of local anesthetics
combined with adrenaline should not be
used until more data are available [16c].
Of 23 patients with post-arthroscopic
glenohumeral chondrolysis, all of whom
had received a 20 ml intra-articular bolus
injection of bupivacaine 0.25% with adrena-
line, 14 occurred in patients after labral
repair using a bioabsorbable device and
seven had involved a thermal probe; four
occurred in shoulders in which xation
anchors, pain pumps, and thermal probes
had not been used [17A]. The authors stated
that they had not seen any cases of
chondrolysis before they started to inltrate
local anesthetics into the glenohumeral joint.
Mechanism of action The mechanisms of
chondrotoxicity due to local anesthetics are
not well understood and remain speculative.
One mechanism could be related to the
pro-inammatory effects of bupivacaine and
lidocaine. Bupivacaine potentiates nitric
oxide synthase-2 (NOS2) activity in rat glial
cells, stimulating inammation through the
production of nitric oxide [18E] and lidocaine
selectively upregulates pro-inammatory
proteins [19E]. This might not be a class effect
of local anesthetics, as newer local anesthetics,
such as ropivacaine, do not promote inam-
matory processes [20E, 21E, 22E].
Clinical implications In view of the mounting
evidence of the chondrotoxicity of local anes-
thetics in general, or at least some
Local anesthetics Chapter 11
local anesthetics, several authors have
recommended that until better data become
available, only newer local anesthetics, such
as ropivacaine, should be used intra-articularly
[23r] or that injection of local anesthetics into
joints should be completely avoided [24r].
These recommendations are in line with a
warning by the FDA against the intra-articu-
lar infusion of local anesthetics after
reviewing 35 reports of chondrolysis given
continuous intra-articular infusions of local
anesthetics with elastomeric infusion devices
to control post-surgical pain [25S].
Chondrolysis was diagnosed within a
median of 8.5 months after the infusion.
Almost all of the reported cases occurred
after shoulder surgery. Joint pain, stiffness,
and loss of motion occurred as early as the
second month after infusion. In more than
half of these reports, the patients required
additional surgery, including arthroscopy
or arthroplasty. The FDA noted that
chondrolysis in these cases was multifacto-
rial and could have been related to the local
anesthetics, the device materials, and/or
other sources, and that single intra-articular
injections of local anesthetics in orthopedic
procedures have been used for many years
without any reports of chondrolysis. Based
on these reports, the FDA has required drug
manufacturers to update their product labels
to warn health-care professionals about this
potential serious adverse effect and has
required the manufacturers of pumps that
may be used to infuse local anesthetics,
including elastomeric infusion devices, to
include similar warnings with their products.
EFFECTS RELATED TO
MODES OF USE [SED-15, 2121;
SEDA-30, 152; SEDA-31, 233;
SEDA-32, 262]
Brachial plexus anesthesia
Nervous system Horner's syndrome occur-
red in a patient who received a sagittal
infraclavicular block with levobupivacaine
283
100 mg and lidocaine 400 mg [1A]. It
occurred 30 minutes after the block and
resolved after 2 hours. There was no respira-
tory compromise and surgery was completed
without further complications.
Delayed quadriparesis occurred after an
interscalene brachial plexus block with
Winnie's technique [26A].
A 71-year-old woman scheduled for arthro-
scopic rotator cuff repair of the right shoulder
received an interscalene brachial plexus block
with ropivacaine 75 mg and mepivacaine
150 mg. After 15 minutes she had complete
motor blockade of the right arm. She was
anesthetized and the operation was
performed, taking 80 minutes. She was trans-
ferred to the recovery room, and 2 hours later
she noted weakness in both legs when she
tried to walk. The right arm had complete sen-
sory and motor block and the left arm had
motor weakness (III/V) and reduced thermo-
analgesic sensitivity. She had bilateral ptosis.
Electromyography of the arms and legs and
craniocervical T12 MRI showed no pathol-
ogy. The symptoms resolved without treat-
ment 72 hours after brachial plexus blockade.
She was hemodynamically stable through the
entire episode, and required no ventilatory
assistance.
The onset and duration of the symptoms in
this case could not be satisfactorily
explained by a local anesthetic effect;
whether the interscalene blockade caused
the quadriparesis was not proven but could
not be ruled out.
CAUDAL, EPIDURAL, AND
SPINAL ANESTHESIA
Epidural anesthesia
Nervous system Three cases of Horner's syn-
drome have been reported with the use of tho-
racic epidural catheters. This adverse effect is
considered to be due to either high epidural or
inadvertent subdural catheter placement.
A 13-year-old boy had a thoracic epidural at
T7/8 plus general anesthesia for left thoracot-
omy using levobupivacaine 0.125% [2A]. After
72 hours of continuous infusion at a rate of
284 Chapter 11 Stephan A. Schug, Alexander Raymann, and Manuel Wenk
68 ml/hour he developed miosis and ptosis on
the right side and 4 hours after the end of the
epidural infusion the symptoms resolved.
Two patients developed unilateral Horner's
syndrome 20 minutes after a test dose of 3 ml
of 1.5% lidocaine with adrenaline 1:200 000 in
an epidural catheter at level T4/5 and T5/6
respectively [3A]. In both cases epidural position-
ing of the catheter was demonstrated by CT
epidurography. The symptoms resolved after
90 minutes and did not return after using the epi-
dural catheter in theatre and postoperatively with
bupivacaine 0.125% plus fentanyl 3 micrograms/
ml at an infusion rate of 69 ml/hour.
The authors argued that an anatomical
change might have occurred between the
injection and the infusion; the different
pressure applied when injecting the local
anesthetic during testing and then infusing
it may have led to the reported effect.
Prolonged leg pain after insertion of an
epidural catheter into the thoracic sub-
arachnoid space has been reported [27A].
In a 31-year-old woman scheduled for laparo-
scopic myomectomy a thoracic epidural cathe-
ter was placed at T12/L1 and elicited pain in
the leg. The catheter was drawn back 3 cm.
The pain subsided, no blood or CSF was aspi-
rated, and a test dose of 2 ml of lidocaine 2%
was injected. Within minutes she developed
symptoms of spinal analgesia and a second
aspiration proved that the catheter was in the
intrathecal position. Therefore, only 20 micro-
grams of fentanyl in 2 ml of saline were given,
and the catheter was removed afterwards.
After an uncomplicated perioperative period,
she developed severe pain extending from
the left buttock to the tips of the toes in a
radicular distribution from L2 to L5. It was
treated with a lumbar epidural infusion for
the rst 13 days and afterwards with carba-
mazepine and amitriptyline for 12 more days.
The pain and allodynia abated by 25 days
after insertion of the catheter. An MRI scan
showed a small area of high intensity in the
ipsilateral dorsal column.
The authors assumed that a small spinal
cord lesion had caused this transient epi-
sode of neuropathic pain.
Acute transient hiccups after epidural
injection of levobupivacaine have been
described [28A].
A 30-year-old primigravida with a twin preg-
nancy received an epidural catheter at L3/4
for pain relief. Within minutes of a loading dose
of 5 ml of levobupivacaine 0.125% she devel-
oped hiccups. Epidural analgesia was contin-
ued with levobupivacaine 0.1% plus alfentanil
40 micrograms/ml at a rate of 10 ml/hour. The
hiccups continued for 1 hour and then resolved
spontaneously. Minutes after a second bolus to
treat breakthrough pain the hiccups returned
for 2 hours before resolving again.
Hiccups have been associated with
administration of glucocorticoids into the
epidural space [29A, 30A]. Their cause is
not understood. They are usually transient
and self-limiting, and reassurance is often
the only treatment needed.
Spinal (intrathecal) anesthesia
Cardiovascular Hypotension during sur-
gery for femoral neck fracture in elderly
patients is common. In a retrospective com-
parison of the incidence of hypotension
between general anesthesia, single injection
spinal anesthesia, and continuous spinal
anesthesia, with bolus injections of either
2.5 or 5 mg as needed in 333 patients hypo-
tension was rare in those who received con-
tinuous spinal anesthesia with 2.5 mg (4%),
compared with 83%, 68%, and 34% in the
other groups [31C].
In a prospective study in 32 elderly
patients, ASA grades 13, who received spi-
nal anesthesia with bupivacaine 1017.5 mg,
baseline blood pressure variability and near-
infrared spectroscopy reduction predicted
hypotension with high sensitivity (0.73 and
0.90 respectively) and specicity (0.78 and
0.64, respectively) [32C]. However, heart
rate, systemic vascular resistance index,
baroreceptor sensitivity, and heart rate vari-
ability were of limited predictive value.
Respiratory The risk of postoperative
spells of apnea in preterm infants has pro-
moted the use of spinal anesthesia, because
of improved safety. However, high spinal
anesthesia has been associated with respira-
tory failure in a preterm infant [33A].
The authors concluded that the cephalad
spread of spinal anesthesia is less
Local anesthetics Chapter 11
predictable in preterm infants and that cau-
tion is warranted. Since high spinal anesthe-
sia after using an adequate weight-adjusted
dose of local anesthetic is very rare it is still
a safe alternative to general anesthesia in
preterm infants.
Nervous system A Cochrane review of 16
trials has compared the risk of transient
neurological symptoms after spinal anesthe-
sia with lidocaine versus other local anes-
thetics [34R]. There were 1467 patients, of
whom 125 developed transient neurological
symptoms, i.e. slight to severe pain in the
buttocks and legs after full recovery from
the spinal anesthesia. The symptoms usu-
ally develop 224 hours after intrathecal
injection and last 12 days. There is no evi-
dence that this painful condition is associ-
ated with nervous system damage. The
symptoms disappeared spontaneously by
the fth postoperative day in all patients.
The relative risk of transient neurological
symptoms after spinal anesthesia with lido-
caine compared with other local anesthetics
(bupivacaine, levobupivacaine, prilocaine,
procaine, ropivacaine, or 2-chloroprocaine)
was 7.3 (95% CI 4.2, 13). Mepivacaine
gave similar results to lidocaine. The
authors concluded that since the risk of
transient neurological symptoms is signi-
cantly higher when lidocaine or
mepivacaine are used for spinal anesthesia,
alternative local anesthetics should be used.
Microradiculopathy after spinal anesthe-
sia with bupivacaine has been reported
[35A].
A 48-year-old man underwent uneventful spi-
nal anesthesia at L3/4 with 3 ml of 0.5%
hyperbaric bupivacaine solution for varicose
vein surgery of the lower limb. Postopera-
tively, the left leg recovered adequately but
the right leg had persistent lower limb motor
decits and absent patellar and Achilles
reexes but a normal plantar reex and a sen-
sory hypesthesia below T10. A thoracolumbar
MRI scan was unremarkable, but electro-
myography showed normal sensory action
potentials and acute motor denervation in
right L4S5 (severe) and left L5S1 (moder-
ate), indicative of multiradiculopathy.
The motor and sensory decits remained
unchanged during 2 years of follow-up.
285
The asymmetrical presentation in this case
differs from previous reports [36A], but in
the absence of any other reasonable expla-
nation this injury was attributed to
bupivacaine.
Persistent cauda equina syndrome has
been reported after spinal anesthesia with
procaine [37A].
A 52-year-old woman underwent uneventful
spinal anesthesia at L3/4 with 1.5 ml procaine
10% for elective knee arthroscopy. Postopera-
tively, her sensory levels decreased adequately
and she was discharged. However, she became
unable to urinate, was intermittently inconti-
nent of urine, and noticed pelvic numbness
from the right perineum to the perianal
region. Later, she developed parasacral burn-
ing and throbbing with an intermittent shoot-
ing right thigh pain. She was unable to
defecate for a week until she was given laxa-
tives. MRI scans were normal. Detailed neu-
rological examinations were consistent with
cauda equina syndrome. After 1 year the neu-
rological ndings were essentially unchanged.
This is the rst report of cauda equina syn-
drome induced by procaine. The relative
risk compared with other local anesthetics
needs to be established.
Spinal anesthesia with intrathecal bupi-
vacaine has been associated with spinal
myoclonus [38A].
A 52-year-old woman developed spinal myo-
clonus 60 minutes after receiving 60 mg of
hyperbaric prilocaine 5%. She had involun-
tary, asymmetrical, brief movements of the
legs at a frequency of 1020/minute. Treat-
ment with intravenous diazepam 5 mg blunted
the symptoms but did not abolish them; they
resolved completely 60 minutes after full
recovery from spinal anesthesia. There were
no residual signs of neurological impairment.
Spinal myoclonus is postulated to be caused
by reduced activity of inhibitory pathways
at the level of motor neurons or interneu-
rons. It is a rare self-limiting adverse event
and has so far been evoked by bupivacaine
and prilocaine. Diazepam has been
reported to be effective in the past, but
did not convince in this case.
Spinal anesthesia with intrathecal
bupivacaine has also been associated with
286 Chapter 11
propriospinal myoclonus [39A], a rare
involuntary rhythmic movement of muscles
of one myelomere, spreading to rostral and
caudal myotomes. It originates in the spinal
cord with no pathological ndings in
the electroencephalogram corresponding
to abnormal movement. It is elicited by
tumors, trauma, neurodegenerative
disease, spinal compression, and drugs.
Propriospinal myoclonus has previously
been described after intrathecal application
of bupivacaine (plain and hyperbaric). In
the case described here the myoclonus
started after 24 hours and lasted for 3 days,
although valproate and clonazepam were
started early on. In previous reports the
symptoms often began within 3 hours of
spinal administration and the myoclonus
ceased after the effect of the local anes-
thetic ended. It remains unclear if this case
was an unusual example of delayed myo-
clonus evoked by spinal administration of
bupivacaine or propriospinal myoclonus of
unknown cause.
A subdural hematoma occurred after
spinal anesthesia for cesarean section [40A].
Spinal anesthesia was performed with a 25-
gauge Quincke needle in a 31-year-old woman
who had no hemostatic susceptibility factors
or bleeding disorders. Her symptoms started
48 hours after surgery, with right retro-orbital
pain and persistent, moderate right headache.
After 2 hours she became drowsy, her Glas-
gow Coma Scale score fell to 8, she had
anisocoric pupils (right > left) and marked
right hemiparesis, and a CT scan showed a
right temporoparietal subdural hematoma
with midline displacement.
The authors explained the ipsilateral hemi-
paresis by invoking the KernohanWoltman
notch phenomenon, in which intracranial
mass lesions compress the cerebral peduncle
on the opposite side against the tentorial
notch, interrupting the bers of the cerebro-
spinal tract. The subdural hematoma was
aspirated and she was discharged with mini-
mal weakness of the right leg.
Chemical meningitis has been reported in
four patients undergoing spinal anesthesia
for different procedures [41A]. All devel-
oped meningitis on the rst postoperative
day. In each case cerebrospinal uid
Stephan A. Schug, Alexander Raymann, and Manuel Wenk
analysis suggested bacterial meningitis, but
all blood cultures taken before antibiotic
treatment were negative. Their symptoms
improved with antibiotics and dexametha-
sone within 24 hours. Further investigations
showed that all patients had received the
local anesthetic bupivacaine chloral hydrate
in a generic formulation called TradinolTM
(lot 001), produced by a local pharma-
ceutical company in Brazil. The national
health surveillance agency was notied
and published a resolution to suspend the
distribution and sale of the product, men-
tioning another eight similar cases in other
Brazilian states.
Death Fatal cardiac arrest following blad-
der catheterization for urinary retention
after spinal anesthesia has been reported
[42A].
A 16-year-old girl underwent appendectomy
with spinal anesthesia and 6 hours after sur-
gery developed abdominal pain due to a
distended bladder. When she was
catheterized, she went into cardiopulmonary
arrest. Despite immediate resuscitation, she
died.
The proposed reason for cardiovascular
arrest in this case was urinary syncope,
which can follow rapid loss of tension in
the bladder. Care has to be taken to avoid
rapid emptying of a distended bladder,
although the fatal outcome is difcult to
understand.
Inltration anesthesia
Nervous system Pain on injection is a very
common adverse reaction to local anes-
thetics when used for inltration. A review
of the efcacy of bicarbonate in reducing
pain on intradermal injection of local anes-
thetic agents showed a signicant advan-
tage of the buffered solution [43R]. When
bicarbonate was added to the local anes-
thetic pain scores on a visual analogue scale
were reduced by 12% (95% CI 6.7, 17).
Local anesthetics Chapter 11
Dental anesthesia
Nervous system Mandibular nerve block
with articaine has been associated with pos-
sible precipitation of multiple sclerosis
[44A].
A 30-year-old man developed an isolated left
abducens nerve palsy 1 day after removal of the
mandibular right second and third molars under
mandibular nerve block with 1.8 ml of articaine
with 1:100 000 adrenaline. Multiple sclerosis
was diagnosed because of the sudden onset of
the symptom and the presence of typical MRI
abnormalities. The symptoms subsided 20 days
after starting glucocorticoid therapy.
However, the association of the mandibular
block or the agent articaine with the onset
of multiple sclerosis was not proven and
does not seem likely.
Extrapleural anesthesia
Nervous system Horner's syndrome has
been reported after extrapleural infusion
of bupivacaine.
After extrapleural infusion of bupivacaine
0.5% (3 ml/hour) via a catheter with multiple
side holes, ipsilateral Horner's syndrome was
diagnosed on the rst postoperative day [4A].
After discontinuing the infusion the symptoms
resolved without further complications.
Horner's syndrome due to extrapleural
infusions is a rare complication, thought to
indicate local anesthetic spread from the tho-
racic paravertebral to the cervical region [45r].
Intravenous regional anesthesia
In a review of the literature on adverse
events associated with intravenous regional
anesthesia the author concluded that Bier's
block is safe when anesthetic doses are kept
low [46R]. Seizures have been reported at
doses as low as 1.4 mg/kg of lidocaine,
4 mg/kg of prilocaine, and 1.6 mg/kg of
bupivacaine. Serious cardiac events have
only been reported with lidocaine and
bupivacaine.
287
Ocular anesthesia
Cardiovascular Three cases of central reti-
nal artery occlusion after surgery with
peribulbar anesthesia have been reported
[47A]. In two cases ropivacaine 0.75% (17
and 13 ml) was used; in the third case the
block was done with 14 ml of 2%
mepivacaine. The authors suggested that
these cases might be related to raised intra-
ocular pressure due to the block or vaso-
constriction caused by the local anesthetics.
Sensory systems Eyes Photorefractive kera-
tectomy is a widely performed procedure for
improving visual acuity. There are various
regimens of medication for postoperative
pain management, including the use of oral
medications, topical non-steroidal anti-
inammatory drugs, and local anesthetic solu-
tions. The risk associated with long-term use
of topical local anesthetic solutions has been
highlighted [48A].
A 51-year-old woman underwent photo-
refractive keratectomy and 7 days later devel-
oped epithelial basement membrane dystrophy
in both corneas. After repeat keratectomy and
antibiotic treatment she returned on day 3 with
impaired vision, large epithelial defects, and cor-
neal inltrates in both eyes. Cultures were nega-
tive. She had continued to instill non-prescribed
comfort drops made up of a 0.05% tetracaine
solution every 30 minutes in both eyes from the
initial surgery. She was asked to stop using the
drops, and 2 weeks later the eyes had fully re-
epithelialized, the inltrates had begun to clear,
and vision improved.
While pain after photorefractive keratec-
tomy needs to be treated effectively, the
non-prescribed long-term misuse of local
anesthetics can lead to impaired wound
healing. Postulated mechanisms include
inhibition of corneal epithelial migration
and adhesion and toxic effects on stromal
keratocytes [49E, 50E].
Peripheral nerve block
Nervous system In an analysis of closed
claims by the American Society of
Anesthesiologists concerning complications
288 Chapter 11 Stephan A. Schug, Alexander Raymann, and Manuel Wenk
associated with eye blocks and peripheral
nerve blocks 6894 claims led in the years
19802000 were identied [51R]. Only 159
claims were associated with peripheral nerve
blocks. Most of these were due to temporary
injuries (56%), while 36% related to perma-
nent injuries and 8% were due to death or
brain damage. Permanent injuries were
mainly at the level of the brachial plexus
and were associated with axillary and
interscalene brachial blocks. However,
median nerve and ulnar nerve injuries were
also common. Unintentional intravascular
injection of local anesthetic with systemic
local anesthetic toxicity was the cause in 7
of 19 cases that resulted in death or brain
damage. Of the total, 97 were associated with
eye blocks. An anesthetist provided the
block in 59 cases and in 38 the anesthetist
only provided monitored anesthesia care.
Claims with eye blocks had a signicantly
higher rate of payments to the plaintiff
mainly because of permanent nerve damage
due to needle trauma.
Topical anesthesia
Observational studies Topical anesthetic
exposure in children younger than 6 years
old has been reviewed, including 8576 cases
of exposure to topical anesthetics reported
to the American Association of Poison
Control Centers from 1983 to 2003 [52R].
There were seven deaths due to local anes-
thetic toxicity, mainly because of aspiration
or ingestion of topical anesthetics. These
rare serious events are alarming, because
many topical anesthetics are available
over-the-counter.
Placebo-controlled studies In a randomized,
double-blind, placebo-controlled study of
the effect of 4 mg/kg of nebulized lidocaine
2% before insertion of a nasogastric tube in
children no adverse events were reported
[53c]. Although pain scores were signicantly
lower in the treatment arm in the period after
insertion of the nasogastric tube, the inter-
vention did not seem to be useful because
the nebulization itself was very distressing.
Cardiovascular Ingested lidocaine meant
for gargling before direct laryngoscopy led
to cardiac arrest [54A].
A 50-year-old woman received 20 ml of lido-
caine 5% as a gargling solution before direct
laryngoscopy and accidently swallowed the
solution; 20 minutes later she had a cardiac
arrest and was successfully resuscitated.
Plasma lidocaine concentrations were not
measured.
Lidocaine has a systemic availability of
3035% after ingestion and the use of such
a high oral dose (1000 mg, 20 mg/kg) is
dangerous.
A 48-year-old man sprayed an unknown
amount of lidocaine on to his penis before
sexual activity and developed chest tightness
and bradycardia for 2 days [55A]. Cardiac
enzymes were normal and an electrocardio-
gram showed sinus bradycardia without
ST segment changes. The symptoms resolved
after several hours of observation without
any treatment.
The authors proposed that the chest tight-
ness might have been caused by systemic
intoxication by the local anesthetic. Unfor-
tunately the amount of lidocaine used, the
exact timing between use and onset of
symptoms, and serum lidocaine concentra-
tion were not reported. A history of con-
comitant use of other medications was also
missing. The duration of the symptoms
(2 days) was rather long for an effect of
lidocaine, although its toxic metabolites
have quite long half-lives.
Nervous system A patient who used lido-
caine 5% and phenylephrine 0.5% as a
nasal decongestant for left sinus surgery
developed an ipsilateral xed dilated pupil
[56A]. The consensual pupillary light reex
in the right eye was normal, suggesting that
the optic nerve was not damaged. The eye
returned to normal after 4 hours, sugg-
esting that the dilated pupil was a drug
effect of either lidocaine interacting with
the short ciliary nerve or direct stimulation
of the sympathetic bers of the eye by
phenylephrine. Since papillary status is
used to nd out early about intraocular
Local anesthetics Chapter 11
complications in sinus surgery, care should
be taken to avoid spillage of decongestant
agents into the eyes.
Immunologic Allergic reactions to lido-
caine for beroptic bronchoscopy have
been reviewed [57R]. The authors con-
cluded that lidocaine is safe in bronchos-
copy, provided that care is taken to limit
the dose. In suspected local anesthetic
allergy they suggested patch testing before
the use of any topical anesthesia.
The combination of lidocaine 7% tet-
racaine 7% (LT peel) is a novel topical
anesthetic cream formulation mainly used
in dermatological procedures, such as laser
treatment [58R]. An allergic reaction has
been reported [59A].
A 26-year-old woman with no history of atopy
developed erythema and edema of the face
and angioedema of the lips 15 minutes after
applying LT peel to her entire face before
laser surgery. She reported mild pruritus,
burning, and tingling of the face. The cream
was removed, she was given a single oral dose
of diphenhydramine 50 mg, and the symptoms
resolved within 30 minutes.
Whether the allergic reaction was directly
due to one of the local anesthetic compo-
nents of the cream or an immunogenic
metabolite (such as p-aminobenzoic acid)
was not further investigated.
INDIVIDUAL COMPOUNDS
Benzocaine [SED-15, 427; SEDA-30,
158; SEDA-31, 239; SEDA-32, 266]
Hematologic Methemoglobinema
EIDOS classication:
Extrinsic moiety Benzocaine
Intrinsic moiety Hemoglobin
Distribution Erythrocytes
Outcome Oxidation of iron in
hemoglobin
289
Sequela Methemoglobinemia due to
benzocaine
DoTS classication:
Dose-relation Hypersusceptibility
Time-course Immediate
Susceptibility factors Sepsis, anemia
Methemoglobinemia related to local anes-
thetics has been reviewed [60R]. Benzocaine
has reportedly caused methemoglobinemia
after as little as a single spray, and rebound
symptoms have occurred 18 hours after treat-
ment of benzocaine-induced methemoglobin-
emia with methylthioninium chloride
(methylene blue). The author concluded that
benzocaine should not be used anymore. An
accompanying editorial underlined the
importance of avoiding benzocaine, because
of an inability to predict potentially fatal
events relating to the use of this drug [61r].
This statement has been supported by
the continuing ow of case reports on
hematological adverse effects of benzo-
caine. For example, a 3-year-old child
developed marked cyanosis after ingesting
benzocaine 330 mg in a falsely mixed
magic mouth wash [62A].
Several cases of methemoglobinemia have
followed the use of marketed formulations
of benzocaine, such as Baby OrajelTM (which
contains benzocaine 7.5%) and CetacaineTM
(14% benzocaine 2% tetracaine).
A 6-year-old boy was treated with an unknown
amount of a benzocaine gel for toothache and
developed cyanosis, vomiting, and lethargy
3 hours later [63A]. Methemoglobinemia (70%,
a potentially fatal concentration) was immedi-
ately treated with methylthioninium chloride
1 mg/kg. The symptoms resolved within the next
hour.
A 15-month-old 6.8 kg girl had general anesthe-
sia for rigid bronchoscopy to rule out a recurrent
tracheoesophageal stula after tracheo-
esophageal stula repair, fundoplication, and
gastrostomy in the past [64A]. Because she had
residual tracheomalacia and recurrent aspiration
she was brought to ICU postoperatively for
weaning and extubation. Extubation was
uneventful, but her mother attributed crying to
teething pain and used Baby OrajelTM for pain
relief. Shortly afterwards the baby desaturated,
which was attributed to atelectasis; it responded
290 Chapter 11 Stephan A. Schug, Alexander Raymann, and Manuel Wenk
after several hours to oxygen. This sequence
was repeated three times. After the fourth
application of a pea-sized drop of benzocaine
7.5% the baby developed profound cyanosis
and tachycardia, and an arterial blood gas
showed methemoglobinemia of 43%. She was
treated with methylthioninium chloride 1 mg/
kg and her symptoms improved promptly. The
methemoglobin concentration was 0.9% 2 hours
later.
A 69-year-old woman had CetacaineTM
(14% benzocaine 2% tetracaine) sprayed
into the oropharynx before awake beroptic
intubation [65A]. The exact amount of spray
was not reported. After an hour her SaO2
fell to 85% and her skin appeared dusky. Met-
hemoglobinemia was diagnosed and she was
given methylthioninium chloride 2 mg/kg, after
which the symptoms resolved within 1 hour.
These cases stress the importance of
keeping methemoglobinemia in mind when
desaturation occurs after the use of local
anesthetics.
Skin Contact dermatitis has occurred after
the use of benzocaine 5% in a condom [66A].
A 22-year-old man developed recurrent
erythematousedematous dermatitis of the
shaft of the penis a few hours after sexual
intercourse using condoms. Tests for latex
protein hypersensitivity were negative. A
patch test established the diagnosis of contact
allergy to benzocaine.
Bupivacaine [SED-15, 568; SEDA-30,
159; SEDA-31, 239; SEDA-32, 267]
Cardiovascular A bupivacaine infusion
caused a signicant dysrhythmia in an
elderly patient [67A].
A 78-year-old woman received a femoral
nerve block with 30 ml of bupivacaine 0.5%
for total knee replacement. After surgery an
infusion of bupivacaine 0.25% (8 ml/hour)
was given via a femoral nerve catheter. She
developed complete heart block 9 hours later.
A preoperative electrocardiogram had shown
sinus rhythm and electrolytes were normal.
Sinus rhythm resumed 6 hours after the end
of the infusion. There was no other cardiac
pathology, and the authors assumed that
bupivacaine had caused the dysrhythmia.
Cardiac arrest has been reported after
femoral nerve block [68A].
A 17-year-old patient had seizures directly
after receiving 20 ml of bupivacaine 0.5% over
23 minutes for femoral nerve blockade; aspi-
ration tests every 5 ml were negative. He was
bag-ventilated and given 3 mg of midazolam
intravenously, followed by Intralipid 20%;
12 minutes later he went into cardiac arrest
with ventricular brillation. He was success-
fully resuscitated.
It is not clear that it was the bupivacaine
that was responsible in this case.
Dibucaine
Drug overdose Dibucaine has been with-
drawn from the market as an injectable spi-
nal anesthetic, because of its adverse
reactions prole, but it remains available as
an over-the-counter topical formulation.
Ingestion of a potentially lethal dose of
dibucaine in a child has been reported [69A].
An 18-month-old girl weighing 15 kg ingested
an estimated 150 mg (12.5 mg/kg) of dibucaine
from a tube of sunburn medication that
contained 1% dibucaine. Within 30 minutes
she became unresponsive and cyanotic and
had intermittent generalized tonicclonic sei-
zures for about 10 minutes. She was given
diazepam 5 mg rectally and was intubated.
The electrocardiogram showed a wide-com-
plex bradycardia with frequent paroxysmal
ventricular extra beats and later atrioventricu-
lar nodal block with a QRS complex duration
of 200 ms, a QT interval of 513 ms, and fre-
quent transient episodes of ventricular tachy-
cardia. She was given sodium bicarbonate,
magnesium sulfate, and intermittent intra-
venous diazepam. She remained in sinus
rhythm with subsequent narrowing of the
QRS complex, was extubated 12 hours after
presentation, and recovered without sequelae.
Lidocaine [SED-15, 2051; SEDA-30,
160; SEDA-31, 240; SEDA-32, 267]
Cardiovascular The ECG manifestations of
Brugada syndrome are often concealed but
can be unmasked by sodium channel
Local anesthetics Chapter 11
blockers with slow dissociation kinetics.
Lidocaine has rapid dissociation kinetics
and thus has little or no effect on the ST
segment in patients with Brugada syn-
drome. However, a novel mutation of the
sodium channel has been described in a
patient in whom lidocaine precipitated the
Brugada syndrome [70A].
A 45-year-old man with no history of
cardiac disease had a seizure. His electrocar-
diogram was normal. He then suddenly
developed a monomorphic wide-complex ven-
tricular tachycardia for which he was given
lidocaine 70 mg followed by a continuous infu-
sion of 1 mg/minute. This led to ST segment
elevation in leads V13, which persisted even
1 year later. There was no evidence of myo-
cardial infarction and he had no chest pain.
He was genotyped and the sodium channel
mutation was discovered.
Nervous system Possible central nervous
system toxicity after low-dose lidocaine
has been reported [71A].
A 26-year-old woman weighing 50 kg had a
subdural hematoma and was scheduled for
elective percutaneous dilatational trache-
ostomy. While the skin above the trachea
was being inltrated with 1 ml of lidocaine
2% she developed generalized convulsions.
Aspiration conrmed intravascular placement
and the convulsions stopped after intravenous
thiopental 100 mg. An MRI scan showed an
aberrant carotid artery overlying the trachea.
The authors assumed that injection of as lit-
tle as 20 mg of lidocaine into the carotid
artery had caused the convulsions. Although
this possibility cannot be excluded, it should
be noted that early postoperative convul-
sions after brain surgery for epidural and
subdural hematomas are common, and these
convulsions may have been independent of
the lidocaine.
Respiratory Intravenous lidocaine is com-
monly used as part of anesthetic induction,
especially in children, to prevent reex
bronchoconstriction caused by endo-
tracheal intubation. Intravenous lidocaine
signicantly improves intubating conditions
when it is used as part of inhalational
induction. However, intravenous lidocaine
can cause reduced airway diameter in
291
asthmatics, as has been illustrated in a child
with asthma [72A].
A 17-month-old girl weighing 9 kg underwent
anesthesia for elective upper gastrointestinal
endoscopy. She had a history of seasonal aller-
gies and intermittent mild episodes of asthma.
Induction of anesthesia with a volatile anes-
thetic was initially uneventful. After venous
access had been established she was given
intravenous lidocaine 1.5 mg/kg and immedi-
ately developed bilateral expiratory wheezes
and a marked increase in inspiratory peak
pressure. There were no rashes and no other
signs of an allergic reaction. The wheezing
resolved over 5 minutes without any further
interventions and the trachea was later
intubated without any problems. There were
no further respiratory symptoms during the
operation or postoperatively.
The mechanism of action in this case was
not fully understood. A central mechanism
of action of lidocaine may have reduced
activity of the noradrenergic non-choliner-
gic bronchodilatory system [73c].
Immunologic Type IV allergic reactions to
lidocaine are rare. However, cross-reactiv-
ity to the amide local anesthetics has been
described [74A].
A 54-year-old woman, who had used lidocaine
cream intermittently for over 1 year for hem-
orrhoids, suddenly developed a severe
perianal bullous eczematous type IV reaction
a few days after applying the cream again.
Subsequent patch testing with a local anes-
thetic series showed cross-reactivity to the
amide local anesthetics lidocaine, bupivacaine,
mepivacaine, and prilocaine. There was no
cross-reactivity with an ester-type anesthetic.
Prilocaine and EMLA
(prilocaine lidocaine) [SED-15,
2916; SEDA-31, 240; SEDA-32, 268]
Hematologic Methemoglobinemia related
to local anesthetics has been reviewed
[60R]. Plain prilocaine can cause methemo-
globinemia in the following doses:
patients taking other oxidizing drugsdoses
over 1.3 mg/kg;
292 Chapter 11 Stephan A. Schug, Alexander Raymann, and Manuel Wenk
children under 6 months of agedoses over
2.5 mg/kg;
renal insufciencydoses over 3.2 mg/kg;
healthy adultsdoses over 5 mg/kg.
Several case reports have substantiated
the opinions in this review.
An otherwise healthy 32-year-old woman
received prilocaine 60 mg for removal of a glu-
teal abscess and developed symptoms of
suspected methemoglobinemia, with dizziness,
fever, and headache 1 hour after surgery and
peripheral cyanosis and tachycardia 3 hours later
[75A]. She was given 5 ml of methylthioninium
chloride 1% and her symptoms resolved within
30 minutes. Erythrocyte glucose-6-phosphate-
dehydrogenase activity was normal.
The weight of this patient was not reported;
however, the dose that she was given was
very low for the development of methemo-
globinemia in an otherwise healthy patient.
So far only benzocaine had been reported
to cause cyanosis in very low doses.
A 42-day-old boy received prilocaine 40 mg
during circumcision [76A]. The route of adminis-
tration was not reported. He developed cyanosis
1 hour later. The methemoglobin concentration
was 45%. Because methylthioninium chloride
was unavailable, he was given intravenous
ascorbic acid 300 mg/kg and his symptoms
abated after 30 minutes and disappeared after
2 hours.
The authors suggested that high-dose
ascorbic acid can be used as an alternative
in methemoglobinemia if methylthioninium
chloride cannot be used.
A 19-month-old boy received EMLA cream
60 g for analgesia on 250 cm of skin with sec-
ond-degree burns [77A] and 5 hours later
became cyanosed during induction of
general anesthesia for wound debridement.
The methemoglobin concentration was 16%.
After surgery he had a seizure while recovering
from anesthesia and was given intravenous
midazolam 2 mg. Plasma concentrations of
prilocaine and lidocaine were 4.4 and 12.5 mg/l
respectively. He was given no specic treat-
ment, and after 9 hours the methemoglobin
concentration was normal.
The maximum dose of EMLA cream for chil-
dren aged 15 years is 10 g on 100 cm of intact
skin. This was therefore a case of overdose
with the additional problem of unpredictable
absorption of the agent through
compromised skin. Neurological sequelae
are expected at plasma prilocaine and lido-
caine concentrations of 50100 mg/l, but the
two agents may have had additive or synergis-
tic neurological toxicity or the seizure may not
have been due to the local anesthetics.
Immunologic Tumescent local anesthesia is
widely used for liposuction as well as
phlebectomy procedures and can cause
severe adverse effects including fatal com-
plications [78A]. An allergic reaction to
prilocaine has been reported.
A 55-year-old woman underwent varicose sur-
gery on her right leg using tumescent local
anesthesia with 883 ml of prilocaine 0.065%
adrenaline 1:1 000 000. Surgery was unevent-
ful, but 1 week later she developed erythema
and swelling in the groin spreading to the dis-
tal injection sites. When initial broad spectrum
antibiotics failed and papulovesicles devel-
oped, an allergic reaction was suspected and
conrmed by patch testing, which was positive
with prilocaine and lidocaine. Oral predniso-
lone 20 mg/day led to rapid improvement.
An immediate allergic reaction to
prilocaine has been reported [79A].
A 60-year-old women underwent intravenous
regional anesthesia with 3 mg/kg of prilocaine
0.5% diluted with saline to a total of 40 ml for
surgical treatment of carpal tunnel syndrome
and 3 minutes after injection developed severe
erythema and edema in the limb below the
tourniquet. Intravenous hydrocortisone was
started and the tourniquet was released after
20 minutes. All the skin signs disappeared
within 1 hour and there were no systemic reac-
tions after release of the tourniquet. A skin
prick test later conrmed allergy to prilocaine.
Another report has stressed the rare atopic
potential of amide local anesthetics [80A].
An 80-year-old woman with persistent left-
thoracic pain after an episode of herpes zoster
used EMLA daily for pain relief and after
10 days developed erythema and inammation
at the site of administration. There were no sys-
temic effects and the lesions resolved with local
glucocorticoids. Patch tests conrmed hyper-
sensitivity to both lidocaine and prilocaine.
A rare adverse effect of EMLA on blood
vessels has been reported [81A].
Local anesthetics Chapter 11
A 3-year-old boy with molluscum contagiosum
was scheduled for curettage and EMLA
cream was applied 60 minutes before the pro-
cedure and covered with plastic lm. When
the plastic lm was removed, petechial and
purpuric macules were seen. Surgery
proceeded. There was no excessive bleeding
and a platelet count was normal. After 1 week
the purpuric lesions disappeared.
Patch testing was not performed. The path-
ogenesis in this case was not known. The
authors discussed the possible association
between atopic dermatitis and purpura
after the application of EMLA, although
the patient did not have a family or
personal history of atopic dermatitis.
Propitocaine
Skin A xed drug eruption after
propitocaine has been reported [82A].
A 50-year-old Japanese man received
propitocaine hydrochloride and felypressin
for dental treatment and 1 day later developed
slate-colored, well-circumscribed, round ery-
thematous lesions on the face and upper arms
and on the oral and genital mucosae. He had
had macular erythema after a nerve block
1 year earlier using mepivacaine and after
dental treatment involving lidocaine. The
symptoms resolved after treatment for 9 days
with oral prednisolone. Patch tests showed
reactions to the amide local anesthetics, lido-
caine, propitocaine, and mepivacaine.
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293
Ropivacaine [SED-15, 3078; SEDA-30,
161; SEDA-31, 240; SEDA-32, 269]
Nervous system High doses of ropivacaine
can lead to seizures [83A].
An 18-year-old man with a history of childhood
febrile convulsions received a combined axil-
lary/interscalene brachial plexus block with
two doses of ropivacaine 150 mg 15 minutes
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The authors hypothesized that the history of
febrile convulsions in this patient might have
been a susceptibility factor for seizures pro-
voked by local anesthetics. However, this is
contradicted by the study quoted above,
which showed that a history of seizure disor-
der is only a minor susceptibility factor for
postoperative seizures after regional block-
ade, even if there was recent seizure activity
[5R]. Since the febrile convulsions were very
long ago in the case reported here, the sei-
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Jude N, Delaitre B, Ozier Y. Persistent
cauda equina syndrome with no identiable
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[37] Johnson ME, Swanson JW. Procaine spinal
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[40] Ramos-Aparici R, Segura-Pastor D, Edo-
Cebollada L, Vila-Snchez M. Acute subdural
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ric patient. J Clin Anesth 2008; 20(5): 3768.
[41] Santos MC, de Albuquerque BC,
Monte RL, Filho GG, Alecrim MG. Out-
break of chemical meningitis following spi-
nal anesthesia caused by chemically
related bupivacaine. Infect Control Hosp
Epidemiol 2009; 30(9): 9224.
[42] Mandal K, Ranjan P, Mathur S. Urinary
syncope following spinal anesthesia leading
to cardio respiratory arrest and death. Acta
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Lesley M, Lissauer J, Richman JM,
Wu CL. Efcacy of bicarbonate in decreas-
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[44] Kocer B, Ergan S, Nazliel B. Isolated
abducens nerve palsy following mandibular
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[45] Aniteye EA, Edwin F, Tettey MM,
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act Cardiovasc Thorac Surg 2009; 9(2): 310.
[46] Guay J. Adverse events associated with
intravenous regional anesthesia (Bier block):
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to central retinal artery occlusion. J Clin
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[50] Moreira LB, Kasetsuwan N, Sanchez D,
Shah SS, LaBree L, McDonnell PJ. Toxicity
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5623.

12 Neuromuscular blocking
agents and skeletal muscle
relaxants
DEPOLARIZING
NEUROMUSCULAR
BLOCKING AGENTS
Suxamethonium [SED-15, 2489;
SEDA-31, 247; SEDA-32, 273]
Systematic reviews The place of suxa-
methonium in pediatric practice has been
reviewed [1r]. It has signicant adverse
effects, some of which can be life-threaten-
ing. This is particularly relevant in pediatric
anesthesia, because the spectrum of child-
hood diseases may expose susceptible indi-
viduals to an increased chance of adverse
events compared with adults. The authors
suggested that the rapidity of onset and off-
set of suxamethonium encourages its use by
practitioners with only occasional experi-
ence of pediatric anesthesia. Rocuronium
has a similar onset of action at a dose of
1.2 mg/kg, but sugammadex (a reversal
agent specic to rocuronium) does not have
a product licence for immediate reversal of
neuromuscular blockade in children.
Cardiovascular Tako-Tsubo syndrome is
transient left ventricular apical ballooning,
very similar to acute myocardial infarction,
Side Effects of Drugs, Annual 33
J.K. Aronson (Editor)
ISSN: 0378-6080
DOI: 10.1016/B978-0-444-53741-6.00012-X
# 2011 Elsevier B.V. All rights reserved.
C. Williams and M. Leuwer
but with an excellent short-term prognosis,
has been reported after physical or emo-
tional stress. It has also been reported after
anaphylaxis caused by suxamethonium [2A].
Musculoskeletal Spontaneous subluxation
of the temporomandibular joint has been
reported in a 39-year-old woman with pri-
mary hyperparathyroidism and a normal
airway after induction of anesthesia and
the administration of suxamethonium [3A].
Her mouth could not be opened, and direct
laryngoscopy was not possible. Her trachea
was intubated with a TrachlightTM device
and the temporomandibular joint was
reduced after surgery.
Thiopental can reduce muscle fascicula-
tion associated with suxamethonium. In
300 ASA I and II patients, who were ran-
domized to suxamethonium immediately
after thiopental or 30 seconds later the
onset of fasciculation was earlier in the for-
mer and the duration of fasciculation was
shorter [4c]. In addition, there was moder-
ate to severe fasciculation in the latter.
The relation between fasciculations and
postoperative myalgia has not been well
dened. The authors did not comment on
the incidence and severity of myalgia after
surgery, which has greater clinical
relevance.
Immunologic Refractory shock from ana-
phylaxis can occur after induction of gen-
eral anesthesia [5A].
299
300
A 74-year-old woman with acute appendicitis
was scheduled for emergency surgery. She
had no history of atopy or pre-existing allergy.
Anesthesia was induced with propofol 2 mg/kg
and suxamethonium 1 mg/kg and 4 minutes
later she developed severe bronchospasm with
high airway pressure, a reduced end-tidal CO2
from 32 to 15 mmHg, undetectable oxygen
saturation, hypotension (40/28 mm Hg),
and bradycardia (40/minute). Despite the
absence of any cutaneous signs, anaphylactic
shock was immediately suspected and cardio-
pulmonary resuscitation was started without
delay. After 60 minutes of unsuccessful resus-
citation, she was given two boluses of terli-
pressin 1 mg at 5-minute intervals without
benet. She died after 90 minutes. After
70 minutes the serum tryptase concentration
was more than 200 mg/l (threshold 13.5 mg/l)
and a specic IgE for suxamethonium con-
rming the diagnosis of anaphylactic shock.
The allergic reaction was conrmed by quater-
nary ammonium xation of 4.44% (> 3% con-
rms an allergic reaction) and inhibition by
suxamethonium of 92% (> 20% conrms an
allergic reaction).
A 49-year-old man, scheduled for emergency
appendectomy, had general anesthesia
induced with propofol 2 mg/kg and suxa-
methonium 1 mg/kg. He immediately devel-
oped a low end-tidal CO2 (25 mm Hg) and
extensive erythema with piloerection. After
15 min of CPR, including cardioversion and
IV amiodarone 300 mg, two boluses of 1 mg
terlipressin at 5-min intervals were adminis-
tered. Emergency circulatory support was
instituted after 75 min of cardiopulmonary
resuscitation; using extracorporeal membrane
oxygenation his systolic blood pressure
remained low at 60 mm Hg and he died
12 hours later from refractory shock and mul-
tiple organ failure. Blood tests 50 minutes
after the onset of the reaction showed a serum
tryptase concentration over 200 mg/l and spe-
cic IgE against suxamethonium conrming
the diagnosis of anaphylactic shock.
Raised serum tryptase concentrations and
immunoglobin E to suxamethonium con-
rmed anaphylaxis to suxamethonium in
these two patients. Hypotension was refrac-
tory to terlipressin in both cases and to extra-
corporeal membrane oxygenation in one.
However, both interventions were instituted
after a prolonged period of resuscitation.
Methythioninium chloride, glucagon, and
a1-adrenoceptor agonists have been pro-
posed as alternative therapeutic options in
Chapter 12 C. Williams and M. Leuwer
adrenaline-resistant anaphylactic shock.
Direct myocardial injury has been suggested
in anaphylaxis with early cardiac arrest.
Myocardial injury could be related to a high
degree of myocardial mast cell inltration
in these patients. In these two patients
the degree of cardiac mast cell inltration
could not be investigated because autopsies
were refused.
Body temperature Malignant hyperthermia
occurred 3 hours after the start of an opera-
tion for esophageal resection in an 82-year-
old man after anesthesia induced with pro-
pofol and suxamethonium and maintained
with sevourane [6A]. Masseter spasm was
not a feature. End-tidal CO2 rose to
55 mmHg and body temperature exceeded
39.0
C. The patient responded promptly to
dantrolene. Reports of malignant hyperther-
mia in patients over the age of 80 years are
unusual. Both suxamethonium and sevour-
ane are potent triggers.
Susceptibility factors Bariatric surgery A
34-year-old obese woman who received suxa-
methonium while undergoing laparoscopic
Roux-en-Y gastric bypass later developed
suxamethonium myalgia leading to a pro-
longed stay in hospital and subsequent pneu-
monia [7A]. The authors concluded that in the
presence of suitable alternative paralytic
agents, suxamethonium should be avoided
in patients undergoing bariatric surgery.
However obese patients are at greater risk
of aspiration pneumonia, and rapid-sequence
induction of anesthesia with suxamethonium
is standard practice. Pneumoperitoneum is
also associated with atelectasis and postoper-
ative pneumonia.
Drugdrug interactions Carbamate An 18-
year-old woman took an intentional over-
dose of N-methyl carbamate, an insecticide
[8A]. She was uneventfully intubated using
propofol and extubated after 10 days, but
required emergency re-intubation due to
respiratory failure. Propofol 150 mg and
suxamethonium were used to facilitate
intubation. Masseter muscle spasm led to
difculty in intubation and ventilation.
Neuromuscular blocking agents and skeletal muscle relaxants
Hypoxic cardiac arrest occurred before her
airway was secured and she died of hypoxic
brain injury 3 days later. The authors pro-
posed that masseter muscle spasm may be
associated with suxamethonium even late
in the setting of carbamate poisoning. How-
ever masseter muscle spasm commonly
occurs after suxamethonium and is occa-
sionally life-threatening [9A].
Distigmine A patient taking the anticholin-
esterase distigmine bromide for urinary
retention underwent ECT facilitated by
suxamethonium 1 mg/kg [10A]. Paralysis
after administration of suxamethonium
lasted 30 minutes and plasma cholinester-
ase activity was below the reference range.
Reduced plasma cholinesterase activity
leads to reduced clearance of suxametho-
nium and prolonged action, a predictable
interaction.
NON-DEPOLARIZING
NEUROMUSCULAR
BLOCKING AGENTS [SED-15,
2489; SEDA-31, 248; SEDA-32, 274]
Rocuronium [SED-15, 3073; SEDA-31,
248; SEDA-32, 274]
Systematic reviews Because of its fast onset
of action, rocuronium is a potential alterna-
tive to suxamethonium for rapid-sequence
intubation in patients with an increased
risk of aspiration. Four relevant studies
considering the use of suxamethonium and
rocuronium in emergency departments were
selected from an evidence search and a
structured review performed [11r]. For the
outcomes of clinically acceptable intubation
conditions and time to onset, the two
agents were not statistically signicantly
different. Suxamethonium seems to produce
conditions that have higher satisfaction
scores. The authors concluded that suxa-
methonium remains the drug of choice for
emergency department rapid-sequence
induction, unless there is a contraindication.
Chapter 12 301
This is a slightly different conclusion from
that reached in a Cochrane review of rocuro-
nium versus suxamethonium for rapid-
sequence intubation, which was that suxa-
methonium creates excellent intubation con-
ditions more reliably than rocuronium [12R].
However, the ability of sugammadex to
reverse deep neuromuscular blockade under
rocuronium may alter the benet to harm
balance in comparison with suxamethonium.
Sugammadex [SEDA-32, 275]
There have been many reviews of the phar-
macology and uses of sugammadex [13R,
14R, 15R, 16R, 17R, 18R, 19R, 20R, 21R].
Observational studies In an open, random-
ized doseresponse study of sugammadex
for reversal of deep neuromuscular blockade
induced by rocuronium or vecuronium dur-
ing anesthesia with propofol followed by
sevourane, in 102 patients aged 2065 years,
a single bolus dose of sugammadex 0.5, 1.0,
2.0, 4.0, or 8.0 mg/kg was given for reversal
of neuromuscular blockade [22C]. There
was a dose-related effect on the mean time
to recovery of the T4/T1 ratio to 0.9 with
increasing doses of sugammadex. There was
recurrent neuromuscular blockade in ve
patients, all of whom had received rocuro-
nium (two given sugammadex 0.5 mg/kg
and three given 1.0 mg/kg), but there were
no accompanying clinical events.
Comparative studies In a multicenter, ran-
domized, controlled comparison, sugamma-
dex was associated with signicantly faster
reversal of vecuronium-induced neuro-
muscular blockade than neostigmine; there
were no serious or unexpected adverse
events [23C].
Placebo-controlled studies In a randomized,
assessor-blinded, placebo-controlled study of
sugammadex 2 or 4 mg/kg in 116 patients with
underlying cardiovascular disease (New York
Heart Association class IIIII) undergoing
non-cardiac surgery, sugammadex had no
302
overall adverse effects on the QTc (Fridericia)
interval [24C]. There were three serious
adverse events, one in each treatment group.
Blood pressure and heart rate fell after the
start of anesthesia, but blood pressure was sig-
nicantly higher after both doses of sugamma-
dex at 30 minutes. The fall in heart rate from
baseline was signicantly greater with sugam-
madex 2 mg/kg and at both doses the increase
at 30 minutes was greater than with placebo.
Both doses of sugammadex resulted in a con-
siderably shorter time to recovery of the T4/
T1 ratio to 0.9.
In a multicenter, double-blind, random-
ized study in 20 ASA 13 patients aged
1869 years and scheduled for elective sur-
gery lasting at least 120 minutes, anesthesia
was induced with remifentanil and rocuro-
nium and maintained with sevourane or
propofol; remifentanil was used for analge-
sia and rocuronium to maintain a block of
greater than 90% [25C]. After surgery,
sugammadex was used for reversal of
neuromuscular blockade. There were no
signs of recurarization or associated
adverse effects. The authors concluded that
interaction of neuromuscular blocking
agents with sevourane appears not to
affect the reversal time after sugammadex.
Systematic reviews In a systematic review of
18 randomized controlled trials in which
sugammadex was compared with placebo or
other medications or in which different doses
of sugammadex were compared with each
other in a total of 1321 adults, sugammadex
reversed rocuronium-induced neuromuscu-
lar blockade, regardless of the depth of the
block, more rapidly than placebo or neostig-
mine [26C]. There were serious adverse
events in under 1% of patients and no signif-
icant difference between sugammadex and
either placebo or neostigmine.
Cardiovascular In 176 adults who were
randomized to sugammadex (2, 4, 8, 12, or
16 mg/kg) or placebo at 3 or 15 minutes
after high-dose rocuronium (1.0 or 1.2 mg/
kg) during propofol anesthesia, there was
no evidence of recurrent neuromuscular
Chapter 12 C. Williams and M. Leuwer
blockade or residual neuromuscular block-
ade [27C]. There was prolongation of the
corrected QT interval, which was possibly
related to sugammadex, in one patient and
another two had markedly abnormal arte-
rial blood pressure lasting about 15 minutes
after sugammadex.
Susceptibility factors Age In a placebo-con-
trolled comparison of infants (28 days to
23 months; n 8), children (211 years;
n 22), adolescents (1217 years; n
28), and adults (1865 years; n 26),
sugammadex satisfactorily reversed neuro-
muscular blockade dose-relatedly [28C].
There was no evidence of recurrence of
blockade, inadequate reversal, signicant
QT prolongation, or other abnormalities.
Renal disease Sugammadex is primarily
cleared by the kidneys. In 15 adults with
end-stage renal failure and 15 controls,
anesthesia was induced and maintained
using intravenous opiates and propofol
[29C]. There was no signicant difference
in the time from administration of sugamma-
dex to recovery, no evidence of recurrence of
neuromuscular blockade, and no sugamma-
dex-related serious adverse events.
SKELETAL MUSCLE
RELAXANTS
Baclofen [SED-15, 408; SEDA-30, 164;
SEDA-31, 250; SEDA-32, 276]
Systematic reviews The use of baclofen has
been reviewed [30r] and specically in
adults with cerebral palsy [31r].
Observational studies In a multicenter
study of baclofen 60 mg/day for abstinence
initiation in severe cocaine-dependent indi-
viduals there was no effect on cocaine use
after 8 weeks [32c].
In a retrospective questionnaire study of
overall satisfaction among caregivers with
intrathecal baclofen in six children and
Neuromuscular blocking agents and skeletal muscle relaxants
adolescents with progressive neurological
disorders causing spasticity, most were
overall satised with the effects of treatment
[33c]. Reported adverse reactions were
increased drooling, increased swallowing
difculties, reduced head balance, abdomi-
nal discomfort, constipation, back pain due
to worsening scoliosis, and increased toler-
ance of baclofen, requiring frequent pump
adjustments.
In a prospective study of the efcacy at
12 months and safety up to 24 months of
intrathecal baclofen in 17 children with
spastic cerebral palsy, there were 80
adverse events; eight of which were serious
but not life-threatening [34c].
In a prospective multicenter study of
long-term outcomes in 115 adults who were
given a continuous infusion of intrathecal
baclofen over 12 months, 66 had no adverse
events. The reported adverse events were
wound complications (22%), catheter prob-
lems (36%), cerebrospinal uid leakage
(25%), and other complications (17%)
[35C].
In a single-blind, placebo-run-in, dose-
escalation study in 36 patients with complex
regional pain syndrome, followed for
12 months, there were substantial improve-
ments in patient and assessor-rated dysto-
nia scores, pain, disability, and quality-of-
life [36C]. There were 89 adverse events in
26 patients; they were related to baclofen
(n 19) or pump/catheter system defects
(n 52) or could not be specied (n 18).
Placebo-controlled studies In a double-
blind, placebo-controlled smoking
reduction study in 60 smokers titrated
upwards to baclofen 20 mg qds, the most
common adverse effect during baclofen
treatment was transient drowsiness; how-
ever, there were no differences between
the groups in mild, moderate, or severe
sedation [37c].
Nervous system In a study of the useful-
ness of intrathecal baclofen in severe spas-
tic hemiparesis following stroke in eight
patients, six had functional deterioration
and weakening of their paretic side, with
walking disability [38c].
Chapter 12 303
Psychiatric In a retrospective study based
on a review of the clinical histories of all
patients with an intrathecal baclofen infu-
sion system in a neurorehabilitation hospi-
tal, 12 (9.5%) of 126 patients developed
delirium related to baclofen [39c]. Eight
cases were due to intoxication and four to
withdrawal. There were no deaths.
Gastrointestinal Intrathecal baclofen can
affect peristalsis, and constipation is a com-
monly reported adverse effect. In severe
cases paralytic ileus can result [40A].
A 62-year-old woman with myelitis and trea-
ted with intrathecal baclofen developed vomit-
ing, epigastric pain, and absent peristalsis
7 months after implantation of the intrathecal
device. Her last bowel evacuation had
occurred 24 days before. She died from com-
plications after surgery.
Infection risk Infection of an intrathecal
baclofen delivery device with Mycobacte-
rium fortuitum with associated meningitis
was successfully treated by removing the
device and giving prolonged antibiotic ther-
apy [41A].
Pregnancy In a review of neonatal in-
patient medical records from four pregnan-
cies in three women receiving intrathecal
baclofen for spasticity two of the infants
were born preterm, one by urgent cesarean
delivery for maternal pre-eclampsia and the
other a spontaneous vaginal delivery [42A].
Both preterm infants were of appropriate
size and weight for preterm gestational
age; the two full-term infants were small
and large for gestational age. The authors
concluded that it was not possible to draw
conclusions about pregnancy outcomes in
patients with intrathecal baclofen from
these few cases.
Drug tolerance In a retrospective study in
37 patients treated with intrathecal baclo-
fen, the dose increased in the rst 18 months
after implantation and then stabilized
around a mean dose of 350 micrograms/
day [43c]. Eight patients developed toler-
ance, dened as a dose increase of over
304
100 micrograms/year. No predictive factors
for the development of tolerance could
be determined. Pulsatile bolus infusion
(n 1) and a drug holiday (n 2) were
both effective in reducing the daily dose of
baclofen. Patients who needed surgical
revision of the pump system because of
mechanical failures (n 11) had a signi-
cant dose reduction during the rst month
after revision.
Drug administration route An obstructed
catheter connection pin discovered during
intrathecal baclofen pump exchange caused
increased intrathecal drug dosage require-
ments and eventual oral baclofen was
required [44A].
In a retrospective clinical and radio-
graphic review of complications related to
intrathecal baclofen and posterior spine
fusion in patients with cerebral palsy, the
dosage of baclofen did not increase despite
the operation [45c].
Drugdrug interactions Alcohol An acute
interaction of baclofen in combination with
intoxicating doses of alcohol in 18 heavy
social drinkers was well tolerated [46c].
Botulinum toxins [SED-15, 551;
SEDA-30, 165; SEDA-31, 252; SEDA-32,
276]
Nomenclature Although botulinum toxin is
commonly known as botox, that name is
in fact only one of the brand names of formu-
lations in which botulinum toxins are avail-
able. For example, in the UK, the following
branded formulations are available:
botulinum toxin type A: Bocouture (50-unit
vials), Vistabel (50-unit vials), Xeomin (100-
unit vials);
botulinum toxin type Ahemagglutinin com-
plex: Azzalure (125-unit vials), Botox (50-unit
vials), Dysport (500-unit vials);
botulinum toxin type B: Neurobloc
(5000 units/ml in vials containing 0.5, 1, or 2 ml).
This can cause considerable confusion.
In July 2009 the US Food and Drug
Administration approved the following
Chapter 12 C. Williams and M. Leuwer
revisions to the prescribing information of
botulinum toxin products (Botox, Botox
Cosmetic, and Myobloc) [47S]:
a boxed warning highlighting the possibility of
experiencing potentially life-threatening dis-
tant spread of toxin effect from the injection
site after local injection.
the issue of a medication guide to help
patients understand the risks and benets of
botulinum toxin products.
The established drug names have also
been changed, in order to reinforce individ-
ual potencies and prevent medication
errors. The new name to replace botuli-
num toxin type A is OnabotulinumtoxinA
(marketed as Botox and Botox Cosmetic).
The name that replaces to botulinum toxin
type B is RimabotulinumtoxinB (mar-
keted as Myobloc). The FDA has also
approved another botulinum toxin product
in this class, AbobotulinumtoxinA (mar-
keted as Dysport), and this product also
includes boxed warnings.
Uses The uses of botulinum toxin in Par-
kinson's disease [48r], anal ssure [49r],
and women with chronic pain [50r] have
been reviewed.
Comparative studies In a randomized
blinded comparison of botulinum toxin
with isosorbide dinitrate in the treatment
of chronic anal ssure, adverse effects were
similar in the two groups [51c].
Neuromuscular function Long-term data
on the use of botulinum toxin type A in
the treatment of hyperhidrosis are required
in order for the implications to be fully
appreciated. Muscle weakness has been
reported during long-term therapy [52A].
A 14-year-old girl with excessive sweating of
the hands, feet, and axillae was given a trial
course of botulinum toxin type A (Dysport,
Speywood, UK). The dose was no greater
than 500 IU to each palm, which is well within
recommended guidelines. She reported suc-
cessful symptom control, and injections were
continued every 9 month to a total of ve
treatments. However, 2 years after the rst
course of injections, she complained of
Neuromuscular blocking agents and skeletal muscle relaxants
functionally debilitating weakness in both
hands, with increasing difculty in performing
manoeuvres such as buttoning clothing and
opening packaged foods. There was mild atro-
phy of the muscles of the thenar eminence
bilaterally. There was no weakness in the feet,
which had also been treated. Nerve conduction
studies showed reduced responses in the hands.
After starting a rehabilitation program the
amplitude in all the nerves studied improved,
as did the atrophy, although there was residual
weakness in the thenar and hypothenar emi-
nences and in the interossei.
Maximum bite force has been measured
in 30 subjects who had an injection of botu-
linum toxin to treat masseter muscle hyper-
trophy, followed by a booster injection in
14 patients after 18 weeks [53c]. Mean max-
imum bite force was about 20% lower at
2 weeks than before the injection, gradually
recovered after 4 weeks, and returned to
the pre-injection level at 12 weeks.
Cyclobenzaprine [SED-15, 1023]
Neuromuscular function Torticollis, respon-
sive to intravenous biperiden, presented
as an extrapyramidal adverse effect of cyclo-
benzaprine in a patient with liver impair-
ment [54A].
Drug dosage regimens In a double-blind,
randomized, two-period crossover study
in 16 healthy volunteers single oral doses
of cyclobenzaprine extended-release 15
and 30 mg were compared [55C]. Cycloben-
zaprine 15 mg was associated with adverse
events in ve subjects: headache, dizziness,
musculoskeletal pain, dermatitis, and glosso-
dynia; cyclobenzaprine 30 mg was associated
with adverse events in two subjects: somno-
lence and dysmenorrhea. All the adverse
events were mild in intensity.
In a randomized, open, two-period
crossover comparison of once-daily cycloben-
zaprine extended-release 30 mg versus cyclo-
benzaprine immediate release 10 mg tds in 18
healthy young adults all adverse events were
mild in intensity; the most common was som-
nolence [56C].
Chapter 12 305
Drugdrug interactions Escitalopram A
27-year-old woman taking the selective sero-
tonin reuptake inhibitor escitalopram took
an intentional overdose of cyclobenzaprine
and developed the serotonin syndrome,
which was successfully treated with support-
ive measures and cyproheptadine [57A].
This case was complicated by a positive
opiate screen, as opiates can precipitate the
serotonin syndrome.
Dantrolene sodium [SED-15, 1048]
Skin A severe acneiform eruption exacer-
bated by dantrolene sodium has been
reported [58A].
Tetrabenazine [SEDA-32, 277]
Tetrabenazine, a benzoquinolizine deriva-
tive, inhibits vesicular monoamine trans-
porter 2, leading to depletion of dopamine
and other monoamines in the central ner-
vous system. It was licensed in 2008 by the
US Food and Drug Administration for use
in the treatment of chorea associated with
Huntingdon's disease. It is also used in the
treatment of hemiballismus, tardive dyskine-
sia, and Tourette syndrome.
Tetrabenazine was synthesized in the
1950s as part of research into compounds
with reserpine-like activity and was initially
used in the treatment of schizophrenia. Its
common reversible adverse effects include
drowsiness/sedation, weakness, parkinson-
ism, depression, and acute akathisia.
The pharmacology of tetrabenazine has
been reviewed [59R, 60R, 61R].
Observational studies In a randomized pla-
cebo-controlled study in 84 ambulatory
patients with Huntington's disease who took
tetrabenazine (n 54) or placebo (n 30)
for 12 weeks, there were ve serious adverse
events in four subjects who took tetrabena-
zine (suicide by drowning, a complicated
fall, restlessness/suicidal ideation, and breast
306
cancer) compared with one withdrawal and
no serious adverse events with placebo
[62C].
The same group has reported an open
extension study in 75 participants, designed
to assess the long-term safety and effective-
ness of tetrabenazine for chorea in Hunting-
ton's disease for up to 80 week [63c]. Three
participants withdrew because of adverse
events, including depression, delusions with
associated previous suicidal behavior, and
vocal tics. When mild and unrelated adverse
events were excluded, the most commonly
reported adverse events were sedation/som-
nolence (n 18), depressed mood (17), anx-
iety (13), insomnia (10), and akathisia (9).
Parkinsonism and dysphagia scores were sig-
nicantly increased at week 80 compared
with baseline.
In 68 patients with Huntington's disease
treated with tetrabenazine for a mean period
of 34 (range 3104) months, there were two
withdrawals because of adverse effects; 34
patients reported at least one adverse effect
[64c].
In a prospective evaluation of 19 patients
(12 women), mean age 56 (range 3776) years,
with Huntington's disease [65c] 18 patients
completed the study and were rated after an
average of 5.9 (range 211) months at a nal
mean tetrabenazine dose of 63 (range
25150) mg/day. Adverse events included
akathisia, insomnia, constipation, depression,
drooling, and subjective weakness.
In a retrospective chart review of 448
patients who had used tetrabenazine between
1997 and 2004 (mean age at onset of the move-
ment disorder, 43 years; 42% men) for a vari-
ety of hyperkinesias, including tardive
dyskinesia (n 149), dystonia (n 132),
chorea (n 98), tics (n 92), and myoclo-
nus (n 19), treatment lasted for a mean of
2.3 years and efcacy was sustained in most
cases [66c]. Common adverse effects included
drowsiness (25%), parkinsonism (15%),
depression (7.6%), and akathisia (7.6%).
Comparative studies In six patients with
Huntington's disease, in whom aripiprazole
and tetrabenazine were compared, aripipra-
zole caused less sedation and sleepiness [67c].
Chapter 12 C. Williams and M. Leuwer
Nervous system Tetrabenazine inhibits
vesicular monoamine transporter 2, leading
to depletion of dopamine and other mono-
amines in the central nervous system. In a
retrospective chart review, 448 patients who
had used tetrabenazine between 1997 and
2004 (mean age at onset of the movement
disorder, 43 years; 42% men) were treated
for a variety of hyperkinesias, including
tardive dyskinesia (n 149), dystonia
(n 132), chorea (n 98), tics (n 92),
and myoclonus (n 19) [68c]. They took
treatment for a mean of 2.3 years and ef-
cacy was sustained in most cases. Common
adverse effects included drowsiness (25%),
parkinsonism (15%), depression (7.6%),
and akathisia (7.6%). Although it has
repeatedly been observed that tetrabenazine
alleviates hyperkinetic movements, it can
worsen parkinsonism [69R].
Psychiatric In a retrospective review of the
charts of 518 patients treated with tetrabena-
zine, 246 had no history of depression, of
whom 28 (11%) developed depression [70c].
Of 272 patients with a documented history of
depression had a signicantly higher rate of
worsening in 50 cases (18%).
Metabolism Weight gain over time has been
compared in 32 boys with tics taking tetra-
benazine (mean age 13 years) and an age-
matched group of 41 patients (33 boys) with
tics taking only antipsychotic drugs (mean
age 12 years) [71c]. Weight gain with tetrabe-
nazine was 0.36 kg/month (mean follow-up
duration 25 months) and with antipsychotic
drugs 0.75 kg/month (mean follow-up dura-
tion 19 months).
Body temperature Neuroleptic malignant
syndrome has been attributed to tetrabena-
zine [72A, 73A].
In a patient with Huntington's disease neuro-
leptic malignant syndrome followed abrupt
introduction of tetrabenazine and discontinua-
tion of haloperidol, which may have contrib-
uted [74A]. Recovery was uneventful, and
rechallenge with tetrabenazine in conventional
doses and slow upward titration was not fol-
lowed by recurrence.
Neuromuscular blocking agents and skeletal muscle relaxants
A 45-year-old patient developed severe hyper-
thermia (rectal temperature above 41
C), with
intense rhabdomyolysis and liver cytolysis dur-
ing tetrabenazine therapy for neuroleptic tardive
dyskinesia [75A]. There was a good response to
parenteral sodium dantrolene and oral bromo-
criptine. In addition to tetrabenazine, this patient
took lorazepam and two antidepressant drugs:
clomipramine and mianserin.
Susceptibility factors Age In a review of tet-
rabenazine therapy in 31 children with hyper-
kinetic movement disorders refractory to
other medications, adverse effects were simi-
lar to those in adults; however, the children
had a lower incidence of drug-induced par-
kinsonism [76c].
Tizanidine [SED-15, 3436; SEDA-28,
157; SEDA-32, 278]
Comparative studies Oral baclofen has
been compared retrospectively with tizani-
dine as adjuvant therapy to botulinum toxin
type A in the management of spasticity in
children [77c]. In 30 children with gastroc-
nemius spasticity, of whom 17 were treated
with adjuvant oral baclofen and 13 received
tizanidine, the mean Gross Motor Func-
tional Measurement scores (77 versus 68)
and caregiver questionnaire scores (70 ver-
sus 67) were higher with tizanidine than
baclofen. The authors suggested that the
combination of botulinum toxin type A
with tizanidine is more effective and causes
fewer adverse reactions than the combina-
tion of botulinum toxin type A and oral
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Chapter 12 307
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13 Drugs that affect autonomic
functions or the
extrapyramidal system
DRUGS THAT STIMULATE
BOTH ALPHA- AND BETA-
ADRENOCEPTORS [SEDA-30,
170; SEDA-31, 259; SEDA-32, 281]
Stress cardiomyopathy and
catecholamines
Stress cardiomyopathy (takotsubo cardio-
myopathy, broken heart syndrome, or
gebrochenes Herz Syndrom) was rst
described in Japan in the early 1990s [1c]
and has been reviewed [2M]. Tako tsubo
means octopus trap in Japanese.
EIDOS classication:
Extrinsic moiety Catecholamines
Intrinsic moiety? Adrenoceptors
Distribution Myocardium
Outcome Takotsubo cardiomyopathy
Sequela Takotsubo cardiomyopathy due
to catecholamines
DoTS classication:
Dose-relation Toxic
Time-course Time-independent
Susceptibility factors Sex
(postmenopausal women); diseases
(pre-existing ischemia)
Side Effects of Drugs, Annual 33
J.K. Aronson (Editor)
ISSN: 0378-6080
DOI: 10.1016/B978-0-444-53741-6.00013-1
# 2011 Elsevier B.V. All rights reserved.
Michael Schachter
Mechanism In various observational studies
of this type of cardiomyopathy there was
an association with raised catecholamine
concentrations [3A, 4c, 5M]. There have also
been several reports following severe emo-
tional stress [6A, 7A], in patients with pheo-
chromocytomas, both adrenal [8A, 9A, 10c,
11A] and extra-adrenal [12A, 13A, 14A], and
in patients who have been given catechol-
amines [15c, 16A, 17A, 18A, 19A, 20A]. In ve
consecutive patients with takotsubo-like left
ventricular dysfunction there was local release
of noradrenaline from the heart as measured
in blood taken from the aortic root and coro-
nary sinus [21c].
Indirect effects of drugs on catecholamines
have also resulted in takotsubo syndrome. In
one case there was transient typical balloon-
ing of the left ventricular apex during systole
following the use of cocaine, thought to have
been due to inhibition of catecholamine re-
uptake [22A]. A 43-year-old woman who took
an overdose of venlafaxine, an inhibitor of
serotonin and noradrenaline reuptake, devel-
oped a takotsubo cardiomyopathy and there
was an increase in urinary normetadrenaline
(normetanephrine) concentration [23A].
Irukandji syndrome, which follows a sting
from the jellysh called Carukia barnesi,
found in Far North Queensland, Australia,
presents with sympathetic overdrive, with
direct pressor effects and tachycardia sec-
ondary to sudden release of endogenous
noradrenaline and adrenaline; it can include
stress cardiomyopathy [24A].
Cases of takotsubo cardiomyopathy
reported after anaphylaxis [25A, 26A, 27A]
313
314
may in fact have been, at least in part, due to cat-
echolamines given as part of treatment [28A].
Catecholamines do not improve function in
the apical ballooning syndrome and may make
it worse. In 11 patients an infusion of low-dose
dobutamine did not improve the akinetic wall
motion, despite the hypercontractile basal left
ventricular wall, and despite the fact that the
syndrome is reversible [29c]. In other cases,
takotsubo syndrome was worsened by infu-
sion of catecholamines (in one case adrenaline,
dobutamine, and noradrenaline and in
another dopamine) and improved when the
catecholamines were withdrawn [30A, 31A];
beta-blockade was benecial.
The mechanism is presumed to be mediated
by adrenoceptors, since in animals the reaction
is signicantly attenuated by pretreatment with
alpha- and beta-adrenoceptor antagonists.
It has been hypothesized that high concentra-
tions of circulating adrenaline, by an action
on beta2-adrenoceptors, trigger a switch in
intracellular signal trafcking in ventricular
cardiomyocytes, from G(s) protein to G(i)
protein signalling [32H]. Although G(i)
protein signalling protects against the apopto-
tic effects of intense activation of beta1-adreno-
ceptors, it is also negatively inotropic. This
effect is greatest in the apical myocardium, in
which the beta-adrenoceptor density is greatest.
It is not known what role vasospasm plays.
Most cases occur in postmenopausal women,
for reasons that are not understood. However,
there have also been reports in younger
patients [33A, 34c], particularly after catechol-
amine overdose [35A, 36A, 37A].
Diagnosis The diagnosis depends on four
criteria [38M]:
1. ST segment changes or T wave inversion.
2. Transient wall motion abnormalities that are
often inconsistent with coronary anatomy.
3. Absence of obstructive coronary artery disease
or evidence of acute plaque rupture.
4. Absence of signicant head trauma, intracra-
nial hemorrhage, pheochromocytoma, or other
causes of myocardial dysfunction.
Myocardial edema with consequent
regional wall thickening has been seen using
magnetic resonance imaging [39A].
Chapter 13 Michael Schachter
Varieties There are three main types: left
ventricular apical ballooning (classical
takotsubo cardiomyopathy), an inverted or
reverse variant (basal akinesis with a hyper-
dynamic apex, also called the artichoke
heart), and a midventricular variant.
Reports Stress cardiomyopathy has been
described in six patients after infusion of
adrenaline and in three patients after infu-
sion of dobutamine [40c]. No obstructive
coronary artery disease was demonstrated
in any patient and follow-up was uneventful,
with return to normal hemodynamics and
echocardiography. A 27-year-old man also
developed transient left ventricular dysfunc-
tion resembling takotsubo syndrome after
self-injection of adrenaline [41A] and a 41-
year-old woman developed takotsubo syn-
drome after receiving two doses of intra-
venous adrenaline 500 micrograms for an
anaphylactic reaction to a bee sting [42A].
Takotsubo cardiomyopathy was also
reported in a 62-year-old man with non-
topic severe persistent asthma and chronic
obstructive disease, who received repeated
subcutaneous injections of adrenaline (300
micrograms 8 times in 4 hours) for severe
asthma [43A].
Reverse takotsubo cardiomyopathy has
also been attributed to adrenaline in a 24-
year-old woman with no previous history
of cardiac disease [44Ar].
Reversible severe left ventricular systolic
dysfunction with apical ballooning has also
been reported during dobutamine stress echo-
cardiography [45A, 46A, 47A, 48A, 49A, 50A,
51A, 52A, 53A, 54A] and also in one case after
recovery from stress echocardiography
[55A]. In one case it occurred in a patient with
previous orthotopic heart transplantation
[56A]. In another case it occurred in a patient
who had had a subarachnoid haemorrhage
[57A], in which sympathetic nervous system
activity is increased and in which acute myo-
cardial infarction can also occur.
Almost all cases after exposure to cate-
cholamines have occurred acutely. However,
in one case a dilated cardiomyopathy was
attributed to chronic overexposure to
inhaled adrenaline [58A].
Drugs that affect autonomic functions or the extrapyramidal system
A 44-year-old man, who had had asthma since
childhood, and who was taking Franol (ephed-
rine hydrochloride 11 mg phenobarbital
8 mg theophylline 120 mg) three times a day
and using a Brovon inhalant spray (0.5% adren-
aline 0.14% atropine methonitrate 0.88%
papaverine hydrochloride) as required, devel-
oped a dilated cardiomyopathy. He had been
using the inhaler up to 40 times a day and had
done so for 20 years. The inhaler and
tablets were withdrawn and he improved with
conventional management of asthma and heart
failure.
Adrenaline (epinephrine) [SED-15,
41; SEDA-30, 170; SEDA-31, 259; SEDA-
32, 281]
Cardiovascular The incidences of intra-
operative critical dysrhythmias related to
adrenaline in patients who have received
inhalational anesthesia with halogenated
agents have been analysed in a retrospec-
tive questionnaire study of Japanese Anes-
thesiologists in 583 institutions; critical
dysrhythmias were recorded in 1.2 case
per 100 000 cases [59c].
Isolated atrial brillation, which resolved
spontaneously, has been attributed to local
anesthesia with adrenaline during a dental
procedure in an anxious patient [60A].
Often one of the earliest therapeutic
principles a medical student learns is that
adrenaline is key in the treatment of ana-
phylaxis. A very unusual case from Glas-
gow suggests that this life-saving use of
the drug can produce late thrombosis in a
drug-eluting coronary stent [61A].
A 78-year-old man developed anaphylaxis
after exposure to peanuts and was given intra-
muscular adrenaline 0.5 mg with very good
response. However, very shortly afterwards
he became sweaty and nauseated, without
chest pain, but with a tachycardia of 107/
minute and ST segment elevation in the ante-
rior chest leads of the electrocardiogram. He
had has a stent inserted for established coro-
nary artery disease in the left anterior des-
cending artery 4 years earlier. Cardiac
catheterization showed occlusion of the same
artery, without apparent restenosis.
Chapter 13 315
The authors concluded that this complication
had occurred because of platelet activation by
the exogenous adrenaline. If so, it would be
the rst such case, causing very late stent
thrombosis (more than 1 year after interven-
tion), which seems unlikely; other cases have
been described, mostly associated with the
withdrawal of antiplatelet drug therapy.
Vasoconstriction Reports of acute myocar-
dial infarction attributed to adrenaline con-
tinue to appear, as in the cases occurred in
two elderly women with pre-existing coronary
artery disease after the use of intramuscular
adrenaline 0.5 mg to treat acute anaphylaxis
[62A].
EIDOS classication:
Extrinsic moiety Adrenaline
Intrinsic moiety Alpha-adrenoceptors
Distribution Blood vessels (for example
myocardial)
Outcome Vasoconstriction
Sequela Ischemic tissue damage disease
due to adrenaline
DoTS classication:
Dose-relation Toxic
Time-course Time-independent
Susceptibility factors Diseases
(pre-existing ischemia)
In a 61-year-old man topical endobronchial
administration of adrenaline (3 ml of a
1:10 000 solution) resulted in chest pain, ST
segment elevation, and ventricular extra
beats; the chest pain with sublingual glyceryl
trinitrate resolved, as did the ST segment
abnormalities [63A]. Cardiac catheterization
showed that he had mild coronary artery
disease.
Myocardial damage can also occur in
patients who do not have pre-existing coro-
nary artery disease, particularly if large
doses are used.
A 37-year-old woman with an acute anaphylac-
tic reaction to amoxicillin was given two intra-
venous bolus doses of adrenaline 500
micrograms (diluted 1:10 000) 5 minutes apart;
her blood pressure remained low and she
was given another intravenous dose of 1 mg,
316
which was accidentally infused undiluted
(1:1000). The blood pressure rose but immedi-
ately afterwards she developed chest tightness
and ST segment depression. The symptoms dis-
appeared spontaneously after 20 minutes.
Serum troponin T and creatine kinase MB frac-
tion rose during the next 24 hours.
Although this reaction could have been due to
adrenaline toxicity, the authors also discussed
the possibility that it was part of the so-called
Kounis syndrome or allergic angina, which
is the occurrence of chest pain after an allergic
reaction, accompanied by clinical and labora-
tory ndings of classic angina pectoris or acute
myocardial infarction, caused by inamma-
tory mediators [64Ar]. In another case of pos-
sible Kounis syndrome, anaphylaxis and
adrenaline treatment were accompanied by
transient left ventricular dysfunction, similar
to the takotsubo syndrome [65A].
Splenic infarction and abscess has been
reported in a 68-year-old woman who had
received two injections of a solution of hyper-
tonic saline plus adrenaline 1 day apart during
endoscopy on separate occasions for a bleed-
ing gastric ulcer [66A]. The authors recom-
mended the use of adhesive agents, small
amounts of sclerosants, and a slow injection
speed for endoscopic injection therapy.
The vasoconstrictor effect of adrenaline
should cause hypertension. However, para-
doxical hypotension has been reported in
three patients with massive quetiapine over-
dose, in whom the blood pressure fell dramat-
ically after infusion of adrenaline;
hemodynamic stability was restored when
noradrenaline was substituted for adrenaline
[67A].
Sensory systems Vision Acute macular
neuroretinopathy has been attributed to
adrenaline [68A].
A 21-year-old woman was given adrenaline, in
an unspecied dose, for a severe generalized
urticarial reaction of unknown cause. Very
soon after she developed blurred vision in
both eyes and 6 days later developed persis-
tent visual impairment, like looking through
black spots. The visual acuity was 20/40 in
the right eye and 20/30 in the left. Slit lamp
examination of the eyes was normal, but there
were bilateral central visual eld defects and
reddish-brown petal-shaped lesions in both
Chapter 13 Michael Schachter
maculae. Electroretinography was consistent
with bilateral maculopathy, which was con-
rmed by optical coherence tomography,
which was abnormal in the outer retina. After
a year she had recovered normal visual acuity.
Acute macular neuroretinopathy, a condi-
tion of uncertain cause and variable progno-
sis, occurs mostly in young women. Viral,
autoimmune, and ischemic causes have been
proposed, and the last might be the mecha-
nism in the cases that have been ascribed to
adrenaline. No treatment is available.
A 66-year-old Chinese man developed
corneal endothelial decompensation after
intraocular lens repositioning using intra-
cameral adrenaline, attributed to prolonged,
direct exposure of the corneal endothelium
to relatively high concentrations of adrena-
line [69A]. The authors recommended that
intracameral epinephrine should not be used
for intraoperative mydriasis in procedures in
which high concentrations of adrenaline are
likely to result.
Nervous system Cervical cord injuries effec-
tively inactivate most of the sympathetic ner-
vous system, leading to denervation
hypersensitivity to exogenous catecholamines.
The potential consequences of this have been
demonstrated in two cases [70A].
A 63-year-old man with paralysis below C4
developed chest pain but had no positive evi-
dence of myocardial infarction. His pulse rate
suddenly fell to 24/minute and he collapsed. He
was given intravenous adrenaline 1 mg and atro-
pine 0.4 mg, after which he developed a supra-
ventricular tachycardia at 156/minute followed
very soon after by ventricular tachycardia and
then brillation. Resuscitation was unsuccessful.
A 60-year-old man with an injury at C6 had a
cardiac arrest while being prepared for sur-
gery; the rhythm was not mentioned. He
responded to intravenous adrenaline in a dose
of only 0.1 mg and recovered fully.
The authors pointed out the difference in
outcomes in these two cases and suggested
that the standard dose of adrenaline given
to the rst patient was in effect excessive,
because of denervation hypersensitivity,
while the low dose given in the second case
was effective and safe.
Drugs that affect autonomic functions or the extrapyramidal system
Drug administration route Intracavernous
instillation of adrenaline for acute priapism
does not usually cause systemic effects. How-
ever, a 39-year-old man, who was given three
injections of adrenaline 100 micrograms
lidocaine 9 mg 20 minutes apart, developed
hypertension (blood pressure 221/124 mmHg)
and a sinus tachycardia (heart rate 108/minute
without extra beats) [71A]. He recovered after
being given oral aspirin 325 mg, sublingual
glyceryl trinitrate 0.4 mg, and intravenous
labetalol 10 mg. There was no evidence of
myocardial damage.
The risks of unintentional injection of
adrenaline in autoinjectors used in the rst
aid treatment of anaphylaxis have been the
subject of a systematic review of 26 reports
detailing 69 cases (58% women); 42% were
injured in the home and 91% sustained
injury to a nger or thumb; 45 were evalu-
ated in an emergency department and nine
were not treated or were only observed
[72M]. The injured part was warmed in
25% of cases, glyceryl trinitrate paste was
used in 9%, local injections of phentolamine
and/or lidocaine in 22%, and other treat-
ments in 20%. There were no permanent
sequelae. The authors concluded that peo-
ple who are at risk of anaphylaxis need reg-
ular coaching in how to use adrenaline
autoinjectors correctly and safely and that
improved autoinjector design would address
the problems that they had identied.
Ephedra and ephedrine [SED-15,
1221; SEDA-30, 171; SEDA-31, 262;
SEDA-32, 282]
Cardiovascular Myocardial infarction
EIDOS classication:
Extrinsic moiety Ephedrine
Intrinsic moiety Alpha-adrenoceptors
Distribution Myocardial blood vessels
Outcome Vasospasm
Sequela Ischemic heart disease due to
ephedrine
DoTS classication:
Dose-relation Toxic
Chapter 13 317
Time-course Time-independent
Susceptibility factors Diseases (pre-
existing ischemic heart disease)
Another case of acute myocardial infarc-
tion has been attributed to ephedrine abuse
in a young athlete in whom an intracoronary
thrombus was found in the left anterior des-
cending coronary artery at urgent angiogra-
phy and was successfully removed; there was
an underlying non-obstructive atherosclerotic
plaque but no evidence of plaquerupture; the
authors suggested that this event had been
precipitated by vasoconstriction [73A].
In another case, a 29-year-old man, who
had at various times used Ma Huang, Xena-
drine RFX, and Hydroxycut, had an acute
myocardial infarction secondary to coro-
nary artery aneurysms and thrombosis; with
the analogy of cocaine, the authors sug-
gested that chronic use of ephedrine may
have led to coronary artery aneurysms, per-
haps due to recurrent vasospasm [74A].
A 31-year-old woman with no risk fac-
tors for cardiac disease had a perioperative
myocardial infarction during spinal anes-
thesia, attributed to coronary artery vaso-
spasm secondary to ephedrine and/or
metaraminol [75AR].
Teratogenicity An association between peri-
conceptional use of weight loss products and
certain birth defects has been reported [76C].
Mothers of infants with birth defects (case
infants) and a random selection of live births
(control infants) born during the period
19982003 in the USA participated in the
National Birth Defects Prevention Study.
Mothers of control infants (2.4%) and 2.6%
of mothers of case infants reported using
ephedrine-containing weight loss products.
The use of any weight loss product
was associated with anencephaly (adjusted
OR 2.6; 95% CI 1.3, 5.3), transposition
of the great arteries (adjusted OR 2.1; 95%
CI 1.1, 4.3), and aortic stenosis (adjusted
OR 3.4; 95% CI1.5, 7.9). The use of prod-
ucts containing ephedra was associated with
an increased risk of anencephaly (adjusted
OR 2.8; 95% CI 1.0, 7.3) while other
318
weight loss products were associated with
transposition of the great arteries (adjusted
OR 1.8; 95% CI 1.2, 2.7) and aortic steno-
sis (adjusted OR 2.1; 95% CI 1.3, 3.5).
This study had several strengths: consistent
case denition (both the specic period of
use and the product used), detailed informa-
tion on potential confounders from the mater-
nal interview, and a large sample size. The
limitations were that there was no specic
question on dieting, and a more general ques-
tion on herbal products that included use of
weight loss products; because this was a
hypothesis generating, rather than a hypothe-
sis testing, study, no corrections were made for
multiple testing, resulting in an increased
probability of false-positive associations.
Notwithstanding these caveats, the American
College of Obstetrics and Gynecology has
recommended that women refrain from
attempting to lose weight during pregnancy,
unless they are advised to do so by their physi-
cians [77S].
Drug overdose Of children aged under 2
years who presented to the pediatric emer-
gency department of a large, urban, tertiary-
care children's hospital with signs and symp-
toms of an apparent life-threatening event, a
substantial number had a positive toxicology
screen [78c]. In particular, several had been
given an over-the-counter (OTC) cold medi-
cation. Of 596 children, 274 (46%) had a tox-
icology screen performed, of which 50 were
considered true positives (18%) and 23 posi-
tive results were considered clinically signi-
cant (8.4%); 13 were positive for an OTC
formulation (4.7%), mostly ephedrine and
pseudoephedrine, antihistamines, and anti-
tussives. No parents or caregivers admitted
to having given their child an OTC cold med-
ication. The authors speculated that infants
could have received these medications either
inadvertently, through breastfeeding, or
deliberately, in a misguided attempt to treat
the symptoms of a cold and congestion. A pre-
vious report from the Centers for Disease
Control and Prevention suggested that OTC
cold medications are more widely used in
infants than suspected [79CS].
Chapter 13 Michael Schachter
Pseudoephedrine [SED-15, 1221;
SEDA-30, 171; SEDA-31, 263; SEDA-32,
282]
Cardiovascular A 45-year-old man had
signs of an inferior myocardial infarction
after taking pseudoephedrine; metoprolol
reversed the signs and symptoms and coro-
nary angiography showed normal coronary
arteries [80A]. A similar case was reported
in a 33-year-old man [81A].
Skin A 30-year-old woman took Actifed
(pseudoephedrine triprolidine) for 5 days
and developed a generalized, maculopapu-
lar, pruriginous dermatitis with facial
edema, malaise, and fever [82A]. Patch tests
with Actifed and pseudoephedrine alone
were both positive; tests with ephedrine
and phenylephrine were negative; triproli-
dine was not tested.
Drug overdose A 16-year-old girl took 25
tablets of Sudafed, each containing pseudo-
ephedrine 60 mg [83A]. She complained of
nausea and headache and had a ne tremor
of the ngers and a tachycardia of 140/
minute. The serum creatine kinase activity
and myoglobin were increased. In another
case accidental overdose of a modied-
release formulation of pseudoephedrine
was associated with a hypertensive crisis
and a non-ST-elevation myocardial infarc-
tion [84A].
DRUGS THAT
PREDOMINANTLY
STIMULATE ALPHA 1 -
ADRENOCEPTORS [SEDA-27,
147; SEDA-30, 172; SEDA-31, 264;
SEDA-32, 283]
Phenylephrine [SED-15, 2808; SEDA-
30, 172; SEDA-31, 264; SEDA-32, 283]
Cardiovascular Although phenylephrine
might be expected to produce an increased
Drugs that affect autonomic functions or the extrapyramidal system
blood pressure, reports of such an effect are
very rare, certainly with oral formulations.
A report from Spain appears to be the rst
to describe hypertension in a child attribut-
able to phenylephrine [85A].
A 5-year-old girl was found by chance to have
a blood pressure of 135/80 mmHg, conrmed
by ambulatory monitoring. She had taken a
cold remedy containing phenylephrine (total
dose 7.5 mg in 24 hours) for 4 days before
the blood pressure measurement. No other
cause for the raised blood pressure was found
and the readings returned to normal (109/66
mmHg) 1 week after withdrawal.
This effect was attributed to phenyleph-
rine; the other components of the remedy
did not have the potential to increase the
blood pressure.
DRUGS THAT STIMULATE
BETA 1 -ADRENOCEPTORS
[SEDA-30, 173; SEDA-31, 265; SEDA-32,
284]
Dobutamine [SED-15, 1169; SEDA-30,
173; SEDA-31, 265; SEDA-32, 285]
Cardiovascular Dobutamine may cause
coronary artery spasm. Cardiologists from
France and Tunisia reviewed over 6000
patients who underwent dobutamine stress
echocardiography over a 4-year period
[86C]. Of these, nearly 600 had an abnormal
result and 471 underwent coronary angiogra-
phy; 20 had apparently structurally normal
coronary arteries, but two of those had spon-
taneous vasospasm. The rest had vasospasm
in response to intracoronary methylergo-
metrine 0.2 mg. The vessels involved corre-
sponded to the territories with abnormal
wall movements during stress echocardiogra-
phy, and the authors concluded that in this
small proportion of cases dobutamine actu-
ally caused vasospasm, as of course did the
methylergometrine. The authors considered
the possibility of false negatives, in whom
Chapter 13 319
dobutamine did not cause spasm and who
were therefore not given the provocation test.
A case of acute myocardial infarction has
been reported during dobutamine stress echo-
cardiography [87A].As the pain did not resolve
with intravenous nitrates, thrombolysis was
given. A subsequent coronary angiography
showed only mild atheroma and no stenoses.
In another case, there was 10-mm ST
segment elevation during dobutamine stress
echocardiographyin a patient in whom there
was no signicant coronary stenosis [88A].
This effect was attributed to dobutamine-
induced coronary artery spasm.
Complete heart block is also a potential
risk of dobutamine, although it is
uncommon.
A 50-year-old woman with chest pain under-
went stress testing with dobutamine sestamibi
20 micrograms/kg/minute [89A]. Shortly after-
wards she felt faint, her pulse rate fell to 50/
minute, and she became hypotensive. Shortly
thereafter she developed third-degree heart
block and the dobutamine was withheld. After
being placed in the Trendelenburg position
her systolic blood pressure rose to 220 mmHg,
but it fell to 180 mmHg after sublingual glyc-
eryl trinitrate. She recovered rapidly, and a
subsequent electrocardiogram and serum tro-
ponin measurements were normal.
The authors thought that this was the
rst recorded case of complete heart block
associated with dobutamine, although there
have been a few case reports of bradycardia
with second-degree heart block.
A more widely recognized complication
of diagnostic dobutamine administration is
the so-called empty ventricle syndrome, char-
acterized by outow or midcavity obstruction
and symptomatic hypotension. The possibility
that this could be avoided or mitigated by con-
current infusion of isotonic saline based on
some positive animal experiments has been
investigated in 100 patients, mean age 66
years, who were randomized to dobutamine
1050 micrograms/kg/minute with atropine
0.61 mg if the target heart rate was not
achieved, with or without saline 800 ml/hour
during the test [90C]. The patients were asked
to rate their symptoms on a scale from 1 to 10
and echocardiography was performed to doc-
ument end-systolic volume and to delineate
320
the left ventricular outow tract before the
procedure and at the peak dose. There were
no signicant differences in symptom scores
(3.5 with saline vs. 3.0), end-systolic volume
at peak (18 vs. 16), maximal left ventricular
outow tract gradient (16 mmHg vs. 14
mmHg), or change in systolic blood pressure
(0.7 mmHg vs. 0.9 mmHg). The authors
concluded that this approach is not worth
pursuing.
Death due to rupture of a splenic artery
aneurysm occurred during dobutamine
atropine stress echocardiography in a 55-
year-old man [91A].
Stress cardiomyopathysee under
Adrenaline.
Nervous system A 68-year-old woman who
underwent routine stress echocardiography
with dobutamine atropine, which was neg-
ative as regards coronary disease, immedi-
ately developed transient global amnesia,
which recovered in about 5 hours [92A]. CT
and MRI scans and electroencephalography
were normal. The mechanism was not clear,
although atropine may have had a greater
role than dobutamine, given the effects of
anticholinergic drugs on memory.
Piloerection, which occurred in 92 (42%)
of 218 consecutive patients who under-
went dobutamine stress echocardiography,
correlated with the age of the patients and
was present in 73% of patients aged 50
years or younger [93c]. Piloerection is a fre-
quent adverse effect of dobutamine infu-
sion, particularly in patients aged 50 years
or less, and it occurs most often at a dose
of 10 micrograms/kg/minute. It usually pre-
cedes the increase in heart rate caused by
dobutamine, and is therefore an early and
clear indication that the intravenous infu-
sion is working properly.
Levodopa [SED-15, 2039; SEDA-28, 162;
SEDA-30, 174; SEDA-31, 266; SEDA-32,
285]
Nervous system Severe hiccups have been
attributed to levodopa [94A].
Chapter 13 Michael Schachter
An 81-year-old man with probable Parkinson's
disease was given increasing doses of levodopa
combined with benserazide. When the dose
reached a total of 500 mg/day of levodopa he
developed hiccups, which lasted for 3 days. He
took no further levodopa and the hiccups
stopped. On restarting at a dose of 100 mg the
hiccups returned, though only for 1 hour. How-
ever, this was enough for the patient to refuse all
follow-up and treatment.
The authors thought that this was only the
second report of levodopa-induced hiccups,
but they noted that dopamine receptor
antagonists have been used to treat hiccups
due to other causes.
Ever since the introduction of levodopa
there have been concerns that it may be neu-
rotoxic, particularly towards neurons in the
substantia nigra, which are in any case
depleted in Parkinson's disease. There is a
plausible mechanism for this, through gener-
ation of free radicals. The evidence from cell
culture studies, animal studies, and clinical
data has been reviewed, and the authors con-
cluded that the culture experiments are con-
founded by lack of ascorbate in the medium,
which would act as an important protective
agent, as it appears to do in vivo in animals,
notably in primates [95R]. The clinical data
have failed to support the idea that levodopa
accelerates striatal neuronal loss. However,
the evidence is contradictory, and it seems
unlikely that even after 50 years we shall
get a denitive answer.
Mouth A rare and rather bizarre adverse
effect of levodopa is so-called serpentine
tongue [96A].
A 60-year-old man with early Parkinson's dis-
ease who was given co-careldopa 200/20 mg
daily developed involuntary but not wholly
uncontrollable movements of his tongue,
which greatly interfered with his speech. He
had repetitive twisting and turning movements
of the tongue, which ceased on protrusion.
The levodopa was replaced by ropinirole, with
resolution of the abnormal movements.
The authors drew attention to the occur-
rence of levodopa-associated involuntary
movements even in early Parkinson's dis-
ease, and to the possibility that these may
take very atypical forms.
Drugs that affect autonomic functions or the extrapyramidal system
Dopamine receptor agonists
Cardiovascular Syncope due to cardiac
pauses on four occasions has been
described in a 51-year-old woman taking
ropinirole 0.5 mg/daily for restless legs
[97A]. During 24-hour electrocardiography
she had two further episodes without warn-
ing, and the recording showed 15-second
pauses. An adverse reaction to ropinirole
was suspected and the drug was withdrawn.
There were no subsequent episodes and
repeat electrocardiography was normal.
Although a possible association between
ropinirole and syncope has been suggested,
this appears to be the rst detailed case
report.
Fibrotic reactions The literature on dopa-
mine agonists and brotic heart valve dis-
ease continues to grow.
EIDOS classication:
Extrinsic moiety Dopamine receptor
agonists (especially pergolide and
cabergoline)
Intrinsic moiety 5HT2B receptors
Distribution Serosae, cardiac valves
Outcome Hyperplasia (brosis)
Sequela Fibrotic reactions due to some
ergot-derived dopamine receptor
agonists
DoTS classication:
Dose-relation Collateral
Time-course Late
Susceptibility factors Unknown
Of 33 patients (mean age 62 years, 26
men) who had taken pergolide (mean dos-
age 2.8 mg/day) for a median duration of
5.1 years [98c]. Seven had detectable struc-
tural changes, of whom two had valvular
regurgitation, which was considered to be
not clinically signicant. The authors noted
that according to some reports similar rates
of non-signicant valvular anomalies are
seen in control populations, and that total
abandonment of pergolide may be unwar-
ranted, as the non-ergot dopamine agonists
appear to have less efcacy.
Chapter 13 321
Bromocriptine has received less attention
than pergolide in this controversy, but is the
subject of a paper from Singapore [99c]. In
patients with Parkinson's disease, of whom
72 were taking bromocriptine, 21 were taking
pergolide, and 47 were taking neither of these
drugs, the odds ratio (OR) for valvular regur-
gitation was 3.32 with bromocriptine and 3.66
with pergolide, compared with the patients
who had not been exposed to dopamine recep-
tor agonists. In the patients taking bromocrip-
tine the risk of valve lesions was related to the
cumulative dose. The severity of the lesions
was greater in general among the pergolide-
treated patients. The three groups were not
ideally comparable: the mean ages were simi-
lar (5961 years), but the control group con-
tained fewer women, had shorter durations
of illness, and had less motor disability. How-
ever, it is not clear that these differences had
any effect on the results. The authors specu-
lated that Asian patients may be particularly
susceptible to this type of adverse reaction, as
the dose of bromocriptine was modest com-
pared with those used in clinical trials: 19 mg/
day rather than 2452 mg/day.
It is clearly important to consider who
might be at particular risk of this adverse
reaction. In 223 patients (mean age 70 years,
132 women) the incidences of aortic, mitral,
and tricuspid regurgitation were 27%, 16%,
and 25% respectively [100c]. The details of
drug usage are difcult to summarize, as
there was a great deal of switching between
drugs, but at the time of analysis the num-
bers taking cabergoline, pergolide, and bro-
mocriptine were respectively 90, 57, and 38.
Bromocriptine was not associated with val-
vular lesions, although the other two ergot-
derived drugs were. For these drugs, age
70 years and over and hypertension were
associated with a striking increase in the risk
of aortic and mitral regurgitation, with an
odds ratio of 95 compared with normoten-
sive younger patients. The authors also con-
cluded that low doses of both agents
(cabergoline 0.9 mg/day, pergolide 1.1 mg/
day) were still associated with an increased
risk, raising the question of differential eth-
nic susceptibility compared with Caucasians,
in whom the risk is generally associated with
considerably higher doses.
322
A 49-year-old woman who took low-dose per-
golide (0.625 mg/day) daily for 5 years for
restless legs syndrome developed chronic and
then acute heart failure and had moderate to
severe aortic and mitral regurgitation, requir-
ing replacement of both valves [101A].
This is very unusual at such a low dose of
pergolide.
Cabergoline, rather than pergolide, is the
dopamine receptor agonist that is most often
used in patients with prolactinoma. There
have been several studies, in the UK, Italy,
and Belgium, of whether the lower doses of
drug used in this condition, as opposed to
those used in Parkinson's disease, are associ-
ated with valve abnormalities [102c, 103c,
104c, 105c]. Nearly 400 patients have been
described, with treatment durations of 113
years and cumulative doses of 300400 mg,
although in a few cases this was greatly
exceeded. All four groups of investigators
concluded that in these circumstances caber-
goline is not implicated as a cause of clinically
signicant valvelesions, though in one report
[102c] there was an increased incidence of
clinically non-signicant right-sided valvular
regurgitation.
The Dutch authors of a report on
patients with prolactinoma arrived at a
broadly similar conclusion [106c]. Of 78
patients, 47 were treated for up to 8 years
(mean 5.2 years) with a mean cumulative
dose of 363 mg. There was mild tricuspid
regurgitation in 41% of cabergoline treated
subjects (vs. 26% of controls), and aortic
calcication in 40% (vs. 18%). However,
none of these abnormalities was regarded
as clinically relevant. One can therefore be
reasonably condent of the safety of low-
dose cabergoline in endocrine disease, but
not with any complacency.
Nervous system Sleep attacks Sleep attacks
attributable to dopamine receptor agonists
continue to be reported.
EIDOS classication:
Extrinsic moiety Dopamine receptor
agonists, particularly ergot-related
compounds
Chapter 13 Michael Schachter
Intrinsic moiety Dopamine (?D2)
receptors
Distribution Brain
Outcome Altered cell function (nature
unknown)
Sequela Sleep attacks due to dopamine
receptor agonists
DoTS classication:
Dose-relation Collateral
Time-course Time-independent
Susceptibility factors Not known
An 86-year-old woman with restless legs took
cabergoline 0.5 mg/day for 6 weeks and had
ve episodes of sleep attacks associated with
amnesia [107A]. Cabergoline was withdrawn
and the sleep attacks ceased within 72 hours.
She later took ropinirole 0.25 mg at night for
4 weeks increasing to 0.5 mg at night and
had no sleep attacks.
Psychiatric Panic attacks have occasionally
been attributed to levodopa therapy and
to pramipexole, and ropinirole may also
be implicated [108A].
A 73-year-old woman, with a 9-year history of
Parkinson's disease, developed attacks of
acute anxiety, crying, tachypnea, and hyper-
tension after each of three daily doses of ropi-
nirole 1 mg. These episodes lasted up to 2
hours. Rotigotine was substituted, at an even-
tual dose of 8 mg/day, and the attacks ceased:
it had earlier been shown that ropinirole with-
drawal also led to cessation of the attacks.
Compulsive behaviors Disorders of impulse
control, including compulsive gambling, can
occur with all dopamine receptor agonists.
EIDOS classication:
Extrinsic moiety Dopamine receptor
agonists
Intrinsic moiety Dopamine (?D1/D3)
receptors
Distribution Brain
Outcome Altered cell function (nature
unknown)
Drugs that affect autonomic functions or the extrapyramidal system
Sequela Pathological gambling due to
dopamine receptor agonists
(particularly pramipexole) and
other compulsive behaviors
DoTS classication:
Dose-relation Collateral
Time-course Intermediate
Susceptibility factors Genetic
(dopamine D1 receptor gene allele
DRD1-800 T/C), age (younger age
of onset of Parkinson's disease), sex
(male), drugs (combined therapy
with levodopa)
Hypersexuality and compulsive gambling
have been reported with the relatively new
drug rotigotine, which is delivered by trans-
dermal patch, in three patients with Parkin-
son's disease, all of whom were also taking
levodopa [109A].
A 44-year-old man took rotigotine 18 mg/day
and developed symptoms of hypersexuality,
which persisted for several months but
resolved when the drug was withdrawn.
A 58-year-old woman started to gamble com-
pulsively while taking rotigotine 22.5 mg/day;
she had gambled for many years but never to
the same extent. This behavior ceased when
the dosage was reduced to 9 mg/day.
A 48-year-old man developed hypersexuality
and compulsive gambling, in the process losing
over $100 000. He also had punding behavior,
including daily mowing the lawn. Normal behav-
ior resumed after he stopped taking rotigotine.
Although the authors did not mention it, it
is striking that all three affected patients
were young in terms of the general popula-
tion with Parkinson's disease.
A 64-year-old woman had compulsive behaviors
due to pramipexole, which were greatly improved
by replacement with rotigotine [110A]. While tak-
ing pramipexole 4.5 mg/day she developed sev-
eral compulsions, including constant snacking,
gambling, and playing computer games. The lat-
ter in particular greatly interfered with her daily
life. After changing to rotigotine 6 mg/day all
the compulsive behaviors ceased.
Clearly there is still a great deal to be
learned about the mechanisms of these
extraordinary effects. A functional MRI study
Chapter 13 323
in 12 women has supported the hypothesis that
chronic ventral striatal activation is a key part
of the process, although the practical implica-
tions of this are not clear at the moment [111c].
DRUGS THAT STIMULATE
BETA 2 -ADRENOCEPTORS
For inhaled beta2-adrenoceptor agonists
see Chapter 16.
Clenbuterol
Drug adulteration Adulteration of heroin
with clenbuterol is frequently reported
[112A]. In 13 conrmed cases of exposure to
clenbuterol in this way, clenbuterol was identi-
ed in the blood and or urine of 12 [113c].
Symptoms included nausea, chest pain, palpi-
tation, dyspnea, and tremor. The physical nd-
ings included signicant tachycardia and
hypotension, and there was laboratory evi-
dence of hyperglycemia, hypokalemia, and
increased lactate concentrations; six patients
had biochemical evidence of myocardial
injury. Ten were given beta-adrenoceptor
antagonists without adverse effects.
Clenbuterol was detected in 12 of 106 post-
mortem cases in the USA in which the cause
of death was attributed to illicit drug use
[114c]. In each case heroin use was either con-
rmed by the presence of 6-acetylmorphine
or strongly suspected by the presence of mor-
phine with a history of heroin abuse. The
authors suggested that one should test for
clenbuterol when treating a suspected heroin
user with an atypical presentation.
A novel neuromuscular syndrome, charac-
terized by muscle spasm, tremor, hyper-
reexia, and raised serum creatine kinase activ-
ity, has been described in ve heroin users and
attributed to clenbuterol adulteration [115c].
Ritodrine
Musculoskeletal Rhabdomyolysis with
severe generalized weakness and muscle pain
occurred when a pregnant woman without
a history was given ritodrine hydrochloride;
324
the creatine kinase was raised and there was
myoglobinuria [116A]. Electromyography
showed a typical myogenic pattern and
diffuse denervation activity. Muscular biopsy
ruled out inammatory and metabolic
myopathies.
OTHER DRUGS THAT
INCREASE DOPAMINE
ACTIVITY
Catechol-O-methyl transferase
inhibitors [SED-15, 1219;
SEDA-32, 289]
Tolcapone
Monitoring therapy Monitoring for abnor-
mal liver function tests is mandatory in
patients taking tolcapone. However, [117c]
of 21 patients only ve fully complied with
the monitoring regimen in the rst 6 months
after starting therapy and this fell further in
the next half-year. The authors noted that
post-marketing surveillance may be very
different in reality from that intended by
regulatory bodies and manufacturers. In this
case no problems arose during the period of
observation.
DRUGS THAT AFFECT THE
CHOLINERGIC SYSTEM
[SEDA-30, 177; SEDA-31, 272;
SEDA-32, 290]
Anticholinergic drugs [SED-15, 264;
SEDA-30, 153; SEDA-31, 273;
SEDA-32, 290]
Nervous system In 54 patients (39 women),
with a history of migraine, intramuscular
hyoscine butylbromide 20 mg/kg, used as
premedication for gastroduodenal imaging,
caused severe migrainous headaches
Chapter 13 Michael Schachter
accompanied by nausea and vomiting
[118c]. There was no preceding aura, and
the headache started 2030 minutes after
the injection and lasted 618 hours. In con-
trast, of 1865 non-migraineurs only one
experienced a mild headache. The authors
cited a report that suggested that the
cholinesterase inhibitor donepezil appeared
to be effective in migraine prophylaxis,
more so than propranolol, although this
appears to have been published in abstract
form only [119r].
Psychological Most anticholinergic drug
use today is intended to have a peripheral
autonomic effect, especially on the bladder.
Drugs designed for this purpose have poor
central nervous system penetration, in
order to minimize cognitive and behavioral
effects. However, as authors from the US
FDA have noted, this is not always success-
ful, especially in children [120c]. They iden-
tied 27 children and 143 adults in whom
central anticholinergic effects were
reported during treatment with oxybutynin.
The median age of the children was 6 years,
and the most common indication was
enuresis, followed by neurogenic bladder.
About 30% of the children were aged
under 5 years, Hallucinations, sedation,
and confusion were the commonest events
(each 2122% of the total), followed by agi-
tation, anxiety, and insomnia (78% each).
The authors stated that the incidence of
central nervous system adverse effects in
proportion to all reports is considerably
higher in children than adults, although
from the way the data were presented it
was difcult to quantify this. Certainly,
stimulant adverse effects are much more
common in children, as opposed to more
frequent sedation in adults.
However, it has long been known that
anticholinergic drugs have marked cogni-
tive effects at the other end of the age
range. In a cross-sectional study of 750 sub-
jects aged 65 years or over (median age 74
years, 61% women) exposed to anticholin-
ergic drugs, cognitive and functional perfor-
mance was assessed by the Mini-Mental
State Examination and the Global
Drugs that affect autonomic functions or the extrapyramidal system
Deterioration Scale [121C]. The authors
concluded that those taking anticholinergic
drugs (about 20% of the total) were signif-
icantly more likely to have cognitive
impairment than the other (OR 2.3, after
adjustment for possible confounding vari-
ables). Although this was not surprising,
the range of drugs they classied as anti-
cholinergic was surprisingly wide, including
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Chapter 13 331
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 Ida Duarte, Rosana Lazzarini, Anita Rotter, and
14 Dermatological drugs,
topical agents, and cosmetics
Editor's note: The adverse effects of many
drugs that are used to treat some skin dis-
eases are covered in other chapters; for
example, monoclonal antibodies in Chapter
37 and non-topical corticosteroids in
Chapter 39. Vitamin A carotenoids are cov-
ered in Chapter 34. Many adverse effects of
other drugs on the skin are covered in their
relevant chapters.
Contact dermatitis
Further reviews of systemic contact dermati-
tis have appeared, including descriptions of
common allergens and some insights into
the possible mechanisms of action [1r]. It is
a cutaneous eruption that occurs in response
to systemic exposure to allergens. The exact
pathological mechanism is uncertain. The
broad spectrum of presentations, which are
often non-specic, can make it difcult for
clinicians to suspect the diagnosis, but it is
an important diagnosis to consider in the
case of recalcitrant, widespread, or recurrent
dermatitis, in which patch testing often
reveals allergies. Diagnosis and appropriate
management can be life-altering for affected
patients.
Systemic contact dermatitis can occur
after many routes of exposure, such as
Side Effects of Drugs, Annual 33
J.K. Aronson (Editor)
ISSN: 0378-6080
DOI: 10.1016/B978-0-444-53741-6.00014-3
# 2011 Elsevier B.V.
Clarice Kobata
transdermal, subcutaneous, intravenous,
intramuscular, inhalation, and oral ingestion
[2r]. However, the most important factor to
consider is the time-course of exposure to
possible allergens and the development of
symptoms, because contact dermatitis can
have a latency period of a few hours to a
few days after systemic exposure [3r].
Allergic contact dermatitis is commonly
dened by two phases: a sensitization
phase, in which the patient remains asymp-
tomatic, and an elicitation phase, in which
cutaneous inammation occurs mediated
by the immune system [4r].
Various metals, medicaments, foods,
botanicals, and chemicals have been impli-
cated as causative agents. For example,
nickel allergy is one of the most common
causes of allergic contact dermatitis and its
incidence is thought to be increasing; other
common metal allergens include cobalt,
gold, mercury, and copper. A broad range
of drugs has also been implicated, including
allopurinol, ampicillin, benzocaine, erythro-
mycin, methylsalicylate, naproxen, neo-
mycin, and streptomycin.
Camphor [SED-15, 612]
Nervous system Isolated cases of camphor-
induced seizures have been reported in
young children after gastrointestinal, der-
mal, and inhalational exposure. In 1982,
after a series of unintentional ingestions of
camphor products, the US Food and Drug
333
334 Chapter 14 Ida Duarte, Rosana Lazzarini, Anita Rotter, and Clarice Kobata
Administration restricted the camphor con-
tent to less than 11% in some products
intended for medicinal use, and in May
2010 warned consumers not to purchase or
use various products that contained methyl
salicylate and camphor [5S].
Three cases of seizures have been associ-
ated with imported, illegally sold camphor in
children aged 1536 months who presented
to a large, urban children's hospital during a
2-week period [6c]. Two had ingested cam-
phor, and one had been exposed
through repetitive rubbing of camphor on
her skin. All three required pharmacological
interventions to terminate the seizures.
One required bag-valve-mask ventilation
for transient respiratory depression. All
three patients had leukocytosis and two
patients had hyperglycemia. Exposure oc-
curred as a result of using camphor for spiri-
tual purposes, as a cold remedy, or for pest
control.
Coal tar
Lactation Ointments that contain coal tar
contain genotoxic polycyclic aromatic
hydrocarbons [7A].
A woman with atopic dermatitis used oint-
ments containing coal tar. Over a period of
50 days the accumulated dose of different such
ointments corresponded to 993 mg of pyrene
and 464 mg of benz[a]pyrene. During this
time, she gave breast milk to her 3-month-
old daughter. Analysis of urine samples
from the breast-fed child showed high
concentrations of a metabolite of pyrene
(1-hydroxypyrene, 1-OHP), in the same range
as urinary concentrations of this metabolite in
the mother's urine.
As no pyrene was observed in the breast
milk at a limit of detection of 0.0035 mmol/
l, transfer of pyrene from mother to child
via breast milk was not likely. Furthermore,
the concentration of 1-hydroxypyrene
observed in the mother's milk was too low
to not account for the observed urinary
excretion in the child. The authors there-
fore assumed that pyrene was transferred
from mother to child via another route,
presumably direct skin-to-skin or skin-to-
mouth contact.
COSMETICS
Acetaldehyde mouthwashes
Tumorigenicity Increasing evidence suggests
that acetaldehyde, the rst metabolite of etha-
nol, mediates the carcinogenicity of alcoholic
beverages. Ethanol is also found in a number
of mouthwashes at a typical concentration of
527% (v/v). It has been suggested that there
may be an increased risk of oral cancer in users
of such mouthwashes, but the epidemiological
evidence has been inconclusive. Acetalde-
hyde concentrations in saliva have been mea-
sured after the use of 13 alcohol-containing
mouthwashes, which were rinsed in the mouth
by four healthy, non-smoking volunteers (n
4) as directed by the manufacturers (20 ml
for 30 seconds) [8C]. Saliva was collected at
0.5, 2, 5, and 10 minutes afterwards and ana-
lysed using headspace gas chromatography.
The concentrations were signicantly above
endogenous concentrations and correspond-
ing to concentrations normally found after
consumption of alcoholic beverages. Using
alcohol-containing mouthwashes twice a day
leads to systemic acetaldehyde exposure of
0.26 micrograms/kg/day on average, which
corresponds to a lifetime cancer risk of
3  106, a low public health concern. How-
ever, the acetaldehyde concentrations in the
saliva are those that are associated with
DNA adduct formation and sister chromatid
exchange in vitro, raising concerns about local
carcinogenic effects in the oral cavity.
Mascara
Sensory systems Eyes Mascara is associated
with eye pathology, such as blepharitis,
madarosis, and contact dermatitis. Its ocular
adverse effects include secondary allergic
Dermatological drugs, topical agents, and cosmetics
conjunctivitis, Pseudomonas-induced corneal
ulcers, and a conjunctival mass (a mascar-
oma). Three cases of eye problems second-
ary to long-term mascara use have been
reported [9cr]. Two patients had multiple pig-
mented conjunctival lesions. One had a history
of melanoma of the hand. Conjunctival
biopsy showed non-melanocytic pigment
granules in conjunctival stroma cells in both
cases. The other patient had a history of dry
eyes, and also had pigment clumping around
a punctal plug. The third patient had canalic-
ular obstruction from a mascara-laden
dacryolith (a dacryomascaralith).
DERMAL FILLERS
Hydroxyethylmethacrylate and
ethylmethacrylate
Skin Dermalive is a mixture of 60% of a
biodegradable uid-cross-linked hyaluronic
acid, which is obtained through bacterial
fermentation, and 40% non-biodegradable
soft hydroxyethylmethacrylate and ethyl-
methacrylate particles. This has been used
as an injectable ller for nearly a decade.
Data from the Berlin registry for adverse
reactions to injectable llers have been ana-
lysed [10C]. Of 118 registered patients, 34
had been treated with this ller. Of 95 trea-
ted areas, 87 had responded with a reac-
tion. The most common adverse events
were nodules (n 85) in 87 affected
areas, discoloration (n 39), erythema
or inammation (n 32), and swelling
(n 24). Most of the nodular reactions
were rated as severe. The mean latency
period for these mostly severe reactions
was nearly 2 years. Adverse reactions to
injectable llers may be due to the material
itself (e.g. the irregularly shaped surface),
the patient, or the technique used by the
physician. Based on the frequency and
severity of these reactions, the use of this
ller is not advisable.
Chapter 14 335
Non-animal stabilized hyaluronic
acid (NASHA)
Skin Non-permanent biodegradable dermal
llers, including non-animal stabilized hya-
luronic acid (NASHA), have been consid-
ered to be non-toxic and non-immunogenic,
although recent evidence shows that these
statements can no longer be supported. Stud-
ies of localized and generalized hypersensi-
tivity reactions, formation of immune-
mediated granulomas, and sarcoidosis-like
disease have been published.
The ability of hyaluronic acid analogues to
cause immune-mediated reactions is a matter
of discussion. Theoretically, hyaluronic acid
obtained biosynthetically by bacterial fermen-
tation (NASHA) has the advantage of being
free from the risk of transmitting diseases
between species or of eliciting allergic reac-
tions in patients who are sensitive to foods
such as beef, chicken, and eggs. Although
more than 99% of NASHA is protein-free, it
may contain small amounts of hyaluronin-
associated proteins, and there is therefore a
theoretical risk of adverse reactions. The pro-
tein load in Restylane is about 120170 ng/l.
On the other hand, NASHA uses cross-link-
ing compounds, mainly butanediol diglicidil-
eter, which is not NASHA specic. This
cross-linker could play a role in the adverse
effects related to these compounds.
Vasculitis has been reported [11A].
A 45-year-old woman developed acute urti-
caria and purpura about 3 weeks after Rest-
ylane (Q-Med, Uppsala, Sweden) had been
injected to correct facial wrinkles. Vasculitis
was later conrmed histologically. A second
bout of vasculitis occurred, supposedly related
to new exposure to hyaluronic acid.
The authors analysed the possible relation
between vasculitis and the use of hyaluro-
nic acid and NASHA (Restylane) com-
pounds. Although hyaluronic acid is a
universal polysaccharide in living organisms
and is considered inert, glycosaminoglycans
can be immunogenic and may provoke
humoral and cellular responses.
The prevalence of delayed adverse reac-
tions related to hyaluronic acid is not
336 Chapter 14 Ida Duarte, Rosana Lazzarini, Anita Rotter, and Clarice Kobata
known, because doctors tend not to com-
municate negative events. According to
published data in Europe, the prevalence
ranges from 0.06% to 8.2% [12c, 13C, 14C].
Dimethylfumarate [SEDA-32, 295]
Skin More cases of contact dermatitis attrib-
uted to dimethylfumarate in armchairs have
been reported [15A, 16A], and other cases
affecting the feet have been reported, owing
to its use in shoes [17A, 18A, 19A].
DYESTUFFS [SEDA-15, 1573;
SEDA-30, 182; SEDA-31, 288;
SEDA-32, 296]
Henna [SEDA-32, 296]
Skin Temporary henna tattoos have become
increasingly popular. The active dyestuff in
henna is 2-hydroxy-1,4-naphthoquinone
(Lawsone). Contact allergy and immediate
hypersensitivity reactions to henna are rare
events, as traditionally henna is used as a pure
dye prepared from the stems and the leaves of
the plant, with the addition of coffee or tea for
enhancing the color. The growing practice of
mixing in various chemical dyes, such as para-
phenylenediamine (PPD; a chemical sensi-
tizer), to enhance the properties of henna has
resulted in an increase in the number of
adverse allergic reactions caused by these
tattoos.
Contact leukoderma has been attributed
to henna [20A].
An 8-year-old Indian girl developed an
area of depigmentation over the site of
a henna tattoo which had been applied
3 days before. Leukoderma caused by the
paraphenylenediamine in the henna paste
was considered the most probable cause.
Allergic contact dermatitis to black henna
has rarely been reported in children. Con-
tact leukoderma has been described after
the use of agents such as monobenzyl ether
of hydroquinone, phenol, and catechol
derivatives. The short time interval in this
case suggested a direct toxic effect of para-
phenylenediamine or some other chemical
ingredient of the henna paste in these tat-
toos. Contact leukoderma can persist for
up to 2 years.
Three patients used paint-on henna tat-
toos and about 1 week later developed
localized hypertrichosis over the same area
as the tattoo, which resolved spontaneously
within 34 months [21A].
Hair dyes [SEDA-32, 296]
Tumorigenicity Previous studies have sug-
gested an association between the use of hair
dyes and some cancers [SEDA-15, 1573;
SEDA-30, 182, SEDA-31, 288]. Hair dyes
are among the chemicals most extensively
used and they contain aromatic amine deri-
vates, many of which are mutagenic, and
which are associated with a risk of basal cell
carcinoma. In a cohort study of hairdressers,
there was an increased risk of in situ skin can-
cers. In this casecontrol study, patients with
basal cell carcinomas on the head and neck
were matched with controls to assess the rela-
tion with the use of hair dyes [22C]. Patients
without a history of known susceptibility fac-
tors for basal cell carcinoma were asked about
the details of their use of hair dyes. Of 100
women with basal cell carcinomas, 64 had
used hair dyes, compared with 54 of 117 con-
trols. The patients with basal cell carcinomas
also tended to use darker hair dyes and used
dyes more frequently than those without
basal cell carcinomas.
FRAGRANCES
Geraniol
Skin Fragrance chemicals included in topi-
cal medications have been implicated as
offending agents in leg ulcers, especially in
Dermatological drugs, topical agents, and cosmetics
patients of advanced age, through allergic
contact dermatitis. Geraniol is usually found
in cosmetics and household products. How-
ever, it is one of the less potent contact
allergens of the eight compounds compris-
ing the fragrance mix [23A].
A man developed an allergic contact dermati-
tis on his leg with secondary spread after using
a topical medication containing geraniol and lav-
ender essence for 3 weeks. He was patch-tested
with the Spanish standard series, fragrance
series (Chemotechnique, Malmo, Sweden),
Blastoestimulina cream, and Betadine. There
were positive results with Blastoestimulina
(), fragrance mix (), potassium dichro-
mate (), cobalt chloride (), nickel (/
), geraniol (), Bulgarian rose oil (),
geranium oil bourbon (), and geranium
essence (). The ingredients of Blastoestimu-
lina were patch-tested, yielding positive reac-
tions to geraniol (), lavender essence (/
), and neomycin sulfate (/).
There have been very few cases of sensiti-
zation to geraniol and lavender in relation
to excipients of topical medications. The
authors emphasized the importance of reg-
ulating the presence of potent fragrance
allergens contained in topical drugs to
reduce the frequency of this problem.
Lyral (hydroxyisohexyl
3-cyclohexene carboxaldehyde)
Skin Lyral was created and introduced in
1960 by the International Flavors and Fra-
grances Company. It is an aromatic chemi-
cal that is formed through the reaction of
myrcenol with acrolein and it is found with
high frequency in fragrances and deodor-
ants. Repeated exposure may be required
for eventual sensitization. It is estimated
to have a reactivity rate of 2.7% in the gen-
eral population. Contact dermatitis has been
reported in a 65-year-old man with recur-
rent axillary dermatitis, who had a
reaction to Lyral 5% in petrolatum; Lyral
was found in his deodorant, Brut Deodor-
ant Spray (by Helen of Troy LP, Idelle
Labs, EI Paso, Texas) [24A].
Chapter 14 337
Fumaric acid esters [SED-15, 1453]
Tumorigenicity Fumaric acid esters have
been used in the treatment of psoriasis
since 1959, after Schweckendiek's descrip-
tion. They induce a shift from the T-helper
1 (Th-1) cytokine response to a Th-2 cyto-
kine response and subsequent lymphopenia
with low CD3 and CD4 counts. Low CD4
counts reect the degree of immunosup-
pression and, in organ transplant recipients
increase the risk of skin cancers, such as
squamous cell carcinoma [25A].
A 49-year-old man with psoriasis, who had
been treated with PUVA, sun exposure,
methotrexate, and ciclosporin for extensive
disease covering 90% of his body surface area,
and had actinic damage to his face, with multi-
ple actinic keratoses, was given a fumaric acid
ester (Fumaderm); after 6 weeks the psoria-
sis was well controlled. However, he devel-
oped two tender 1-cm erythematous nodules
on his right calf and left thigh, which were
squamous cell carcinomas. A month later, a
third, rapidly growing nodule was excised and
was found to be an inltrating squamous cell
carcinoma. The total lymphocyte count during
this period was low (290  106/l) and he had
low CD4, CD8, and CD19 counts, the CD4
count being signicantly reduced (104  106/l).
This patient had had high UV exposure
over his lifetime, including both PUVA
and sunlight, which would have put him at
high risk of skin cancer. In addition, he
had lymphopenia and a reduction in CD
subsets after taking a fumaric acid ester,
resulting in profound immunosuppression.
Immunomodulators, topical
[SEDA-32, 297]
Pimecrolimus and tacrolimus
Skin Pimecrolimus and tacrolimus can be
used for prolonged periods, avoiding the
adverse effects that are related to long-term
use of topical glucocorticoids. Although
atrophy, telangiectasia, and tachyphylaxis
have not been described, topical tacrolimus
338 Chapter 14 Ida Duarte, Rosana Lazzarini, Anita Rotter, and Clarice Kobata
and pimecrolimus can cause transient adverse
reactions, generally of mild to moderate
intensity, such as burning, a feeling of warmth,
smarting, pain, soreness, and rosaceiform der-
matitis at the site of application.
Drugdrug interactions Alcohol Several
cases of an asymptomatic red ushing of
the face after moderate alcohol ingestion
in tacrolimus-treated patients have been
described. Erythematous ushing of the
face occurred after ingestion of a small
amount of alcohol in seven patients during
treatment of their facial vitiligo with topical
calcineurin inhibitors [26A]. When 25
patients with chronic stable localized viti-
ligo were instructed to apply the calcineurin
inhibitors to lesions on the face twice daily
for 24 weeks, a facial ush occurred in two
of 13 who had used pimecrolimus 1%
cream and in ve of 12 who had used tacro-
limus 0.1% ointment after they drank small
quantities of beer or wine. They reported
sudden onset of an itchingburning sensa-
tion quickly followed by ushing. The facial
reaction occurred within 510 minutes after
alcohol ingestion and at 24 weeks after the
start of treatment. The facial ushing disap-
peared after 2030 minutes. After the end
of the treatment, the ushing reaction did
not recur, even after alcohol intake.
The association between ushing of the
face and alcohol consumption occurs in
67% of patients who use topical tacrolimus.
The pathophysiological mechanism is not
known, but there are four hypotheses.
1. Both ethanol and calcineurin inhibitors can
release neuropeptides, leading to extreme
vasodilatation.
2. Calcineurin inhibitors inhibit aldehyde-
dehydrogenase in the areas to which they
are applied, and subsequent accumulation of
acetaldehyde could lead to vasodilatation
after alcohol consumption, as in patients
who take disulram.
3. There may be an interaction of the two drugs
on the calcineurincalmodulincalcium com-
plex, on which both alcohol and tacrolimus/
pimecrolimus are known to act.
4. Demodex mites has been observed in abun-
dance in patients with ares of rosacea
during topical treatment with tacrolimus and
pimecrolimus; it is possible that treatment
with calcineurin inhibitors leads to incipient
rosacea with ares after alcohol consumption.
Facial ushing should be recognized as
an adverse effect of topical calcineurin in-
hibitors, both pimecrolimus and tacrolimus,
independently from the skin disease.
Minoxidil [SEDA-32, 2997]
See Chapter 20.
PHOTOTHERAPY AND
PHOTOCHEMOTHERAPY
[SED-15, 2823; SEDA-32, 297]
Aminolevulinic acid [SEDA-32, 297]
Nervous system Pain during photodynamic
therapy with topical aminolevulinic acid
limits its use. In a systematic review of trials
(20002008) in which aminolevulinic acid
or methylaminolevulinic acid were used in
at least 10 patients per trial, and in which
a semiquantitative pain scale was used, 43
articles were identied [27M]. Pain intensity
was associated with lesion size and location
and was severe in some diagnoses, such as
plaque-type psoriasis. There were results
inconsistent for correlations of pain with
the light source, the wavelength of light, u-
ence rate, and the total light dose. GABA
receptors, cold/menthol receptors (transient
receptor potential cation channel, subfamily
M, member 8), and vanilloid/capsaicin recep-
tors (transient receptor potential cation chan-
nel, subfamily V, member 1) may be involved
in pain perception during photodynamic ther-
apy with aminolevulinic acid and are there-
fore worth further investigation.
Skin Erosive pustular dermatosis of the
scalp is a rare inammatory disease of
unknown cause that usually occurs in
elderly people. It is characterized by sterile
pustules, chronic crusted erosions, cicatri-
cial alopecia, and skin atrophy [28A].
Dermatological drugs, topical agents, and cosmetics
A 93-year-old woman with long standing
female-type androgenetic alopecia had actinic
keratoses on the scalp that were treated with
two sessions of topical methylaminolevulinate
photodynamic therapy, with improvement.
However, 28 days after the rst treatment, she
developed burning erosions, which extended
slowly but progressively, and areas of scarring
alopecia. The clinical and histopathological fea-
tures were consistent with a diagnosis of erosive
pustular dermatosis. She was treated with oral
methylprednisolone (16 mg/day with progres-
sive tapering) in combination with topical gen-
tamicin betamethasone cream, resulting in
marked improvement of the lesions and
partial resolution of the cutaneous atrophy
after 3 months, but with residual scarring
alopecia.
Severe phototoxic reactions occurred
in four patients undergoing methylaminole-
vulinate photodynamic therapy for histolog-
ically conrmed basal cell carcinomas or
actinic keratosis on the nose [29c]. All com-
plained of severe discomfort, burning, and a
stinging sensation during irradiation. They
also developed severe phototoxic reactions,
with erythema, edema, and crust formation,
which spread widely outside the clinically
affected areas. After topical mupirocin there
was complete healing within 7 days with
excellent cosmetic results.
PUVA (psorsalens UVA light)
Tumorigenicity Exposure to cutaneous car-
cinogens in young people results in a greater
risk of basal cell carcinoma than comparable
exposure in older people. A prospective
cohort study of the incidence of basal cell
carcinomas in a subtropical Australian pop-
ulation [30C] provided a population with
which North American patients treated with
PUVA could be compared [31c]. During a
10-year period 1380 patients were enrolled
and 692 were followed for the entire decade.
Of the rest, 254 had died and 88 were lost to
follow-up. Complete data (up to death)
were available for 92%. Those who had
received PUVA were older, a higher pro-
portion were men (64%), and fewer patients
were fair-skinned (30% of skin types 1 and
2). Although they were older, those who
Chapter 14 339
had received PUVA had a lower percentage
of patients with a history of basal cell carci-
noma before the decade in which they were
studied. Those who had started PUVA
treatment by the age of 25 years and were
40 years old in the 1990s had a signicantly
higher risk. When each tumor was counted,
the incidence of tumors was far higher after
PUVA. The incidence of basal cell carcino-
mas was signicantly higher in patients with
more than 200 PUVA treatments than those
with fewer treatments. The greatest increase
in risk was among those who started PUVA
before the age of 25 years. The average
number of tumors per patient who devel-
oped at least one basal cell carcinoma was
about three times higher in those who
received PUVA patients than in the Austra-
lian cohort.
VITAMIN A (RETINOIDS)
[SED-15, 3653; SEDA-30, 185;
SEDA-32, 298; for vitamin a
carotenoids see chapter 34]
Acitretin [SEDA-32, 298]
Hair A 70-year-old woman with psoriasis
developed darkening of her previously
white hair, which also became curly after
taking acitretin for 6 months [32A].
Pregnancy Pregnancy outcomes have been
assessed in nine women who inadvertently
received transfusions of potentially acitre-
tin-contaminated blood products in South
Korea, matched with 18 women by age,
gravidity, and singleton- or twin-pregnancy,
and who had received transfusions that
were not so contaminated [33c]. There were
no differences between cases and controls
in gestational age at delivery, birth weight,
rate of pre-term deliveries, or rate of low
birth weight. There were no cases of mal-
formations or neurological abnormalities
in either group. Inadvertent exposure to
acitretin-contaminated blood products was
not associated with adverse pregnancy
340 Chapter 14 Ida Duarte, Rosana Lazzarini, Anita Rotter, and Clarice Kobata
outcomes, perhaps because acitretin and
etretinate were removed during the
manufacturing process.
Drug overdose Fulminant hepatic failure
occurred after an intentional overdose of
acitretin 600 mg [34A]. The patient fullled
the King's College Hospital poor prognos-
tic criteria by 66 hours after overdose, but
rapidly improved thereafter and did not
require liver transplantation.
Isotretinoin [SEDA-32, 298]
Cardiovascular A 17-year-old boy with
minimal pre-existing risk for thromboses
had a central retinal vein occlusion in one
eye while taking isotretinoin for acne
[35A]. DNA testing showed that he was a
heterozygous carrier of the G20210A muta-
tion of the prothrombin gene. Despite the
fact that this mutation is thought to repre-
sent only a minor susceptibility factor for
thrombosis, it is possible that isotretinoin
greatly increased the risk of a vaso-occlu-
sive incident in this patient.
Gastrointestinal A systematic search for
case reports, case series, and clinical studies
of the association between isotretinoin and
inammatory bowel disease yielded 12 case
reports and one case series of such an asso-
ciation, to which the Bradford Hill guide-
lines to evaluate causality [36H] were
applied [37c]. The cases occurred in seven
countries over 23 years and differed with
respect to isotretinoin dose, duration of
treatment before development of the dis-
ease, whether the disease developed on or
off medication, and the clinical presenta-
tion. There have been no prospective or
retrospective studies. An estimated 59 coin-
cident cases of inammatory bowel disease
would be expected in isotretinoin users
each year, assuming no increased risk. The
current evidence is insufcient to conrm
or refute a causal association.
Panenteritis has been attributed to iso-
tretinoin [38A].
A 22-year-old man who had taken isotretinoin
20 mg bd for 5 days for nodular acne devel-
oped melena. Upper gastrointestinal endos-
copy showed edema and hyperemia of the
gastric mucosa of the body and antrum. Flexi-
ble sigmoidoscopy showed edema and hyper-
emia of the mucosa of the rectum and
sigmoid colon, with numerous erosions. To
exclude the possibility of small bowel involve-
ment, he underwent video capsule endoscopy,
which showed diffuse and extensive intestinal
inammation with aphthae and multiple lin-
ear, irregular-shaped jejunal ulcers. Isotreti-
noin was withdrawn and he had a complete
resolution.
Metabolism In a prospective controlled
study in 74 patients taking isotretinoin for
cystic acne, blood concentrations of homo-
cysteine, vitamin B12, and folate were
assessed before and after 45 days of isotret-
inoin therapy [39C]. The control group con-
sisted of 80 individuals. Homocysteine
concentrations were signicantly higher in
those who took isotretinoin. The vitamins
were unaffected, but serum lipids and liver
enzymes increased signicantly. These
effects may have been due to inhibition of
cystathionine-beta-synthase, an enzyme
required for the metabolism of homocyste-
ine by either the drug or liver dysfunction.
Daily supplementation with vitamin B12
and folate can lower plasma concentrations
of homocysteine, and the authors therefore
recommended the use of these vitamins in
patients taking isotretinoin.
Sensory systems Eyes Conjunctival epithe-
lial cells, basal tear secretion, and tear qual-
ity were markedly affected in patients
during treatment with isotretinoin 0.8 mg/
kg [40c]. Ocular adverse effects of isotreti-
noin are generally not serious and resolve
after withdrawal.
Corneal steepening occurred in a patient
after systemic treatment with isotretinoin
for 7 weeks [41A]. There was signicant
impairment of visual acuity, which could
not be explained by the change in refractive
error. All the signs and symptoms resolved
within 7 weeks after withdrawal.
Skin In a retrospective study, ve patients
who took isotretinoin developed, during
Dermatological drugs, topical agents, and cosmetics
or after treatment, a peculiar facial erup-
tion resembling seborrheic dermatitis [42c].
The pathogenesis of this effect probably
involves a minimal toxic retinoid effect on
epidermal differentiation, with overgrowth
of commensal micro-organisms in suscepti-
ble individuals.
Tretinoin (all-trans retinoic acid,
ATRA) [SEDA-30, 186; SEDA-32, 301]
Skin Of four prospective, randomized,
controlled trials in healthy volunteers at
two independent research facilities, two
examined phototoxicity after 24 hours of
drug exposure under occlusion (combined n
51), and two examined photoallergenicity
after a 3-week, six-dose induction phase
(combined n 72) followed by challenge
[43M]. There were no phototoxic or photo-
allergic reactions with tretinoin 0.05% in a
new gel formulation. These ndings are
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consistent with previous studies of tretinoin
in various formulations, and support the con-
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VITAMIN D ANALOGUES,
TOPICAL [SED-15, 594; SEDA-31,
293; SEDA-32, 301; for oral vitamin d
analogues see chapter 34]
Tacalcitol [SEDA-32, 301]
Placebo-controlled studies In a double-
blind, randomized, vehicle-controlled study
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[9] Ciolino JB, Mills DM, Meyer DR. Ocular
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[10] Rossner M, Rossner F, Bachmann F, Wiest L,
Rzany B. Risk of severe adverse reactions to
an injectable ller based on a xed combina-
tion of hydroxyethylmethacrylate and ethyl-
methacrylate with hyaluronic acid. Dermatol
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[11] Alijotas-Reig J. Recurrent urticarial vascu-
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skin ller injection. Dermatol Surg 2009;
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[12] Duranti F, Salti G, Bovani B, Calandra M,
Rosati ML. Injectable hyaluronic acid gel
for soft tissue augmentation. Dermatol Surg
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[13] Friedman PM, Mafong EA, Kauvar ANB.
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lized hyaluronic acid gel for soft tissue aug-
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4914.
[14] Andr P. Evaluation of the safety of a non-
animal stabilized hyaluronic acid (NASHA)
in European countries: a retrospective
study from 1997 to 2001. J Eur Acad Der-
matol Venereol 2004; 18(4): 4228.
[15] Mercader P, Serra-Baldrich E, Alomar A.
Contact dermatitis to dimethylfumarate in
armchairs. Allergy 2009; 64(5): 8189.
[16] Guillet G, Coindre M, Levillain P,
Guillet GH. Dermite lichnode par hyper-
sensibilit au dimthylfumarate: prsenta- [27]
tion atypique du syndrome du fauteuil
chinois. [Lichenoid dermatitis resulting
from sensitization to dimethylfumarate:
atypical presentation of Chinese sofa der-
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136(3): 27981.
[17] Vigan M, Biver C, Bourrain JL, Pelletier F,
Girardin P, Aubin F, Humbert P. Eczema
aigu d'un pied au dimethylfumarate. [Acute
dimethylfumarate-induced eczema on the
foot.]. Ann Dermatol Venereol 2009; 136
(3): 2813.
[18] Mata Cubillo AC, Emilio Huertes
Garca JJ, De Juana Izquierdo FJ. Dermati-
tis alergica de contacto por calzado con dime-
tilfumarato. [Allergic contact dermatitis due
to shoes with dimethylfumarate.] Med Clin
(Barc) 2010; 135(3): 1389.
[19] Santiago F, Andrade P, Gonalo M,
Mascarenhas R, Figueiredo A. Allergic
contact dermatitis to shoes induced by
dimethylfumarate: a new allergen imported
from China. Dermatol Online J 2010; 16(3): 3.
[20] Mendiratta V. Acquired leucoderma after
henna tattoo in an Indian girl. J Eur Acad
Dermatol Venereol 2009; 23(5): 5823.
[21] Kartal Durmazlar SP, Tatlican S, Eskioglu F.
Localized hypertrichosis due to temporary
henna tattoos: report of three cases. J Der-
matolog Treat 2009; 20(6): 3713.
[22] Feizy V, Toosi S. Relation of basal cell car-
cinoma to hair dye use. J Am Acad Derma-
tol 2009; 61(3): 5323.
[23] Juarez A, Goiriz R, Sanchez-Perez J, Gar-
cia-Diez A. Disseminated allergic contact
dermatitis after exposure to a topical medi-
cation containing geraniol. Dermatitis 2008;
19(3): 163.
[24] Jacob SE. Allergic contact dermatitis from
Lyral in an aerosol deodorant. Dermatitis
2008; 19(4): 2167.
[25] Jennings L, Murphy GM. Squamous cell
carcinoma as a complication of fumaric acid
ester immunosuppression. J Eur Acad Der-
matol Venereol 2009; 23(12): 144569.
[26] Stinco G, Piccirillo F, Sallustio M,
Patrone P. Facial ush reaction after alco-
hol ingestion during topical pimecrolimus
and tacrolimus treatment. Dermatology
2009; 218(1): 712.
Warren CB, Karai LJ, Vidimos A,
Maytin EV. Pain associated with aminolevuli-
nic acid-photodynamic therapy of skin dis-
ease. J Am Acad Dermatol 2009; 61(6):
103343.
[28] Guarneri C, Vaccaro M. Erosive pustular der-
matosis of the scalp following topical methyl-
aminolaevulinate photodynamic therapy.
J Am Acad Dermatol 2009; 60(3): 5212.
[29] Toll A, Parera ME, Vlez M, Pujol RM.
Photodynamic therapy with methyl amino-
levulinate induces phototoxic reactions on
areas of the nose adjacent to basal cell car-
cinomas and actinic keratoses. Dermatol
Surg 2008; 34(8): 11457.
[30] Richmond-Sinclair NM, Pandeya N,
Ware RS, Neale RE, Williams GM, van der
Pols JC, Green AC. Incidence of basal cell
carcinoma multiplicity and detailed ana-
tomic distribution: longitudinal study of an
Australian population. J Invest Dermatol
2009; 129(2): 3238.
Dermatological drugs, topical agents, and cosmetics
[31] Stern RS. Putting iatrogenic risk in perspec-
tive: basal cell cancer in PUVA patients
and Australians. J Invest Dermatol 2009;
129: 23156.
[32] Seckin D, Yildiz A. Repigmentation and
curling of hair after acitretin therapy. Aus-
tralas J Dermatol 2009; 50(3): 2146.
[33] Han JY, Choi JS, Chun JM, Park HD,
Lee SY, Kim CH, Park Q, Nava-
Ocampo AA, Koren G. Pregnancy
outcome of women transfused during preg-
nancy with blood products inadvertently
obtained from donors treated with acitretin.
J Obstet Gynaecol 2009; 29(8): 6947.
[34] Leithead JA, Simpson KJ, MacGilchrist AJ.
Fulminant hepatic failure following overdose
of the vitamin A metabolite acitretin. Eur J
Gastroenterol Hepatol 2009; 21(2): 2302.
[35] Labiris G, Katsanos A, Karapetsa M,
Mpanaka I, Chatzoulis D. Association
between isotretinoin use and central retinal
vein occlusion in an adolescent with minor
predisposition for thrombotic incidents: a case
report. J Med Case Reports 2009; 3: 58.
[36] Howick J, Glasziou P, Aronson JK. The
evolution of evidence hierarchies: what
can Bradford Hill's guidelines for causa-
tion contribute? J R Soc Med 2009; 102:
18694.
[37] Crockett SD, Gulati A, Sandler RS,
Kappelman MD. A causal association
between isotretinoin and inammatory
bowel disease has yet to be established.
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[38] Spada C, Riccioni ME, Marchese M,
Familiari P, Costamagna G. Isotretinoin-
Chapter 14 343
associated panenteritis. J Clin Gastroenterol
2008; 42(8): 9235.
[39] Polat M, Lenk N, Bingl S, Ozta P,
Ilhan MN, Artz F, Alli N. Plasma homo-
cysteine level is elevated in patients on iso-
tretinoin therapy for cystic acne: a
prospective controlled study. J Dermatolog
Treat 2008; 19(4): 22932.
[40] Karalezli A, Borazan M, Altinors DD,
Dursun R, Kiyici H, Akova YA. Conjuncti-
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tear-lm changes in patients treated with
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4650.
[41] Santodomingo-Rubido J, Barrado-
Navascues E, Rubido-Crespo M-J. Drug-
induced ocular side-effects with isotretinoin.
Ophthalmic Physiol Opt 2008; 28(5): 497501.
[42] Barzila A, David M, Trau H, Hodak E.
Seborrheic dermatitis-like eruption in
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[43] Slade HB, Shroot B, Feldman SR,
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[44] Rodrguez-Martn M, Garca Bustnduy M,
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160(2): 40914.

15 Antihistamines
(H1 receptor antagonists)
Antihistamines, or H1 receptor antagonists,
have an established and valued place in the
symptomatic treatment of the manifestations
of allergic disease and can be administered
orally, nasally, or as eye drops. The H1
histamine receptor is a heptahelical trans-
membrane molecule that transduces extra-
cellular signals to intracellular second
messenger systems via G proteins. H1 anti-
histamines act as inverse agonists that com-
bine with the H1 receptor, stabilizing it in
the inactive form and shifting the equilibrium
toward the inactive state [1R].
Cetirizine [SED-15, 702; SEDA-30, 189;
SEDA-31, 297; SEDA-32, 305]
Nervous system Acute dystonia has been
attributed to cetirizine [2A].
A 6-year-old boy developed an involuntary
deviation of his jaw to the left and an inability
to swallow after taking cetirizine 5 mg/day for
3 days for allergic rhinitis. The acute dystonic
reaction responded to intramuscular biperiden
5 mg within 1 hour.
Dystonic movements are thought to be due
to imbalances in cholinergic stimulation.
Cetirizine is a piperazine derivative and the
authors postulated that the dystonia may
have been due to its dopamine receptor
blocking properties.
Side Effects of Drugs, Annual 33
J.K. Aronson (Editor)
ISSN: 0378-6080
DOI: 10.1016/B978-0-444-53741-6.00015-5
# 2011 Elsevier B.V. All rights reserved.
Garry M. Walsh
Immunologic Anaphylactic shock has been
attributed to cetirizine.
A 30-year-old woman with chronic idiopathic
urticaria took a single oral dose of cetirizine
10 mg and about 15 minutes later developed
widespread severe pruritus and urticarial erup-
tions, severe breathlessness, and an inability to
speak. She became restless and disoriented and
lost consciousness. Her respiration was very
shallow and her pulse and blood pressure were
unrecordable.
This was her rst exposure to cetirizine or
any other piperazine derivative, and on
recovery she reported no previous history
of allergic drug reactions or concomitant
use of any other medication or alcohol [3A].
Although xed drug eruptions have been
previously reported with both cetirizine
and levocetirizine [SEDA-31, 30] anaphy-
laxis caused by systemic antihistamines is
very rare, particularly in the absence of
known previous exposure. The authors
speculated that the potential antigenic
nature of the piperazine ring may have been
a factor [4A].
Teratogenicity In a prospective cohort
study in 196 pregnant women who had
taken cetirizine during the rst trimester
and 1686 controls who had not been
exposed to potential teratogens there was
no evidence of teratogenicity [5C].
Chlorphenamine
Nervous system A generalized convulsion
has been attributed to acute intoxication
with chlorphenamine [6C].
345
346
A 35-year-old man developed generalized con-
vulsions and a mixed acidosis attributed to
abuse of SS Bron tablets, an over-the-counter
antitussive medication sold in Japan that con-
tains chlorphenamine. He was confused, with
bilateral pinpoint pupils. The blood pressure
was 143/94 mmHg, the heart rate 113/minute,
and the respiratory rate 16/minute. There was
a metabolic acidosis and the blood lactate con-
centration was 300 mg/l. He had generalized
convulsions that were treated with diazepam
20 mg. Midazolam was continuously admin-
istered intravenously for sedation and 12 hours
later he recovered consciousness and became
alert with no further convulsions. The serum
concentration of chlorphenamine on admission
was 0.43 mg/l, i.e. more than 20 times greater
than the mean peak concentration after a single
dose (417 mg/l).
Others later speculated that the toxicity of
chlorphenamine had been due to inhibition
of serotonin reuptake and postsynaptic
5HT1A receptor agonism [7r].
Immunologic Contact dermatitis has been
attributed to chlorphenamine in combina-
tion with other compounds [8A].
An 89-year-old man who had used over-the-
counter topical antiseptics developed pruritic
lesions over his left knee after using a topical
medication containing benzalkonium chloride,
dibucaine hydrochloride, chlorphenamine
maleate, naphazoline hydrochloride, and a
mixture of fragrance ingredients. There were
pruritic erythematous papules and vesicles
over the knee, and linear extensions down
the lower leg appeared the next day. The der-
matitis was successfully treated with topical
glucocorticoids. Subsequent patch testing of
the over-the-counter antiseptic was positive.
The authors diagnosed allergic contact der-
matitis to dibucaine hydrochloride, chlor-
phenamine maleate, and naphazoline
hydrochloride, although none of these was
patch tested in isolation. They speculated
that sensitization to these three agents had
occurred sequentially during previous
exposures to the topical antiseptic.
Desloratadine [SED-15, 1074; SEDA-
30, 189; SEDA-31, 298; SEDA-32, 306]
Observational studies In a post-marketing
study using prescription event monitoring
Chapter 15 Garry M. Walsh
in general practice in England desloratadine
was well tolerated [9C].
Mouth Oral ulceration occurred when a
tablet of desloratadine was allowed to
dissolve under the tongue [10A]
A 53-year-old woman with a history of hyper-
tension, mild psoriasis, and allergic rhinitis
developed acute, painful, irregular, non-indu-
rated yellow-based ulcers on the oor of the
mouth with more supercial but
more extensive ulceration on the inner side of
the tongue. There was no prior history of
chronic oral aphthosis and no lesions
present anywhere else. She had taken one tab-
let of desloratadine about 30 minutes
before the ulceration occurred. However,
rather than swallowing the tablet with water,
she had kept it under the tongue, as she
had previously done for homeopathic treat-
ments, and after 30 minutes felt pain and
inammation at the application site; the painful
oral ulcers were present the next morning. She
had taken desloratadine before for allergic rhi-
nitis without any cutaneous or systemic adverse
effects, ruling out hypersensitivity.
This was a between-the-eyes adverse reac-
tion of type 2 [11H].
Skin A xed drug eruption has been attrib-
uted to desloratadine [12A].
A 22-year-old man with a history of xed drug
eruptions, seasonal rhinitis, and mild atopic der-
matitis took one tablet of desloratadine and on
the next day developed generalized eczema.
Patch tests performed 2 months later were
strongly positive and were followed during the
next 24 hours by a relapse of the pruriginous
eczematous lesions spreading on the trunk.
The authors further investigated the inci-
dence of false-positive xed drug eruptions
in healthy volunteers and concluded that
these can be avoided by using 1% deslora-
tadine diluted with petrolatum.
Diphenhydramine [SED-15, 1134;
SEDA-30, 189; SEDA-31, 298; SEDA-32,
307]
Skin Allergic contact dermatitis has been
attributed to diphenhydramine [13A].
Antihistamines (H1 receptor antagonists) Chapter 15
A 45-year-old woman developed an acute,
itchy, vesicular, erythematous eruption around
the mouth associated with treatment of a previ-
ous rosacea with an anti-allergic cream
composed of chlorophyll, kamillosan, erythro-
mycin, metronidazole, and diphenhydramine
(concentrations not recorded). Within 10 days
of discontinuing the cream and applying a topi-
cal corticosteroid the lesions cleared. Subse-
quent patch testing with the anti-allergic cream
was positive, and patch tests with the individual
ingredients were positive for diphenhydramine
and metronidazole. Ultraviolet A irradiation
before patch testing with diphenhydramine
was positive, while patch tests in 12 healthy
patients were negative.
The authors concluded that the patient had
had allergic contact dermatitis due to both
metronidazole and diphenhydramine.
Drug overdose Misuse of diphenhydramine
appears to be associated with elevated
mood, increased energy, and in some cases
hallucinogenic effects [14A]. Diphenhydra-
mine overdose is therefore relatively com-
mon, but although it is considered to be
relatively non-toxic, serious adverse effects
and even death have been reported in
adults [15A].
A 39-year-old man with no signicant previ-
ous medical history was found in a lethargic
state after taking an over-the-counter anti-
emetic that contained diphenhydramine salic-
ylate 40 mg per tablet. The number of tablets
and time of ingestion were not stated, and he
denied taking any other medication. He
became unresponsive and developed dry skin
and increased muscle tone in the limbs. His
pupils were 4.5 mm in diameter and sluggishly
reactive to light. The blood pressure was 83/
40 mmHg, heart rate 150/minute, and respira-
tory rate 30/minute. Circulatory collapse with
severe dehydration and metabolic acidosis
induced by diphenhydramine toxicity was
diagnosed. Repeated intravenous administra-
tion of sodium bicarbonate was necessary to
maintain the pH above 7.20. He then developed
status epilepticus and was given intravenous
diazepam 10 mg followed by a continuous infu-
sion of midazolam 38 mg/hour. The systolic
blood pressure fell below 60 mmHg, and he
was intubated and given mechanical ventilatory
assistance, intravenous catecholamines, and
volume resuscitation. Despite intravenous dopa-
mine (20 micrograms/kg/minute) and noradren-
aline (1 microgram/kg/minute), his systolic
blood pressure fell further, to less than
40 mmHg. He gradually became edematous,
347
and foamy sputum began to appear. A chest X-
ray showed a diffuse inltrate. The metabolic
acidosis worsened and continuous hemodialysis
was initiated for renal support and maintenance
of acidbase balance. He developed severe
pulmonary edema and died. Ingestion of
diphenhydramine was conrmed by toxicologi-
cal analysis.
The authors reported that the clinical man-
ifestations of coma, status epilepticus, car-
diogenic shock, metabolic acidosis, and
pulmonary edema were compatible with
previously reported fatal cases of acute
diphenhydramine poisoning.
Opsoclonus and rhabdomyolysis have
been reported after diphenhydramine
overdose [16A].
A 22-year-old man took 3.3 g of diphenhydra-
mine in a suicide attempt was found uncon-
scious in bed and soon afterwards had a
generalized seizure. He was unresponsive to
painful stimuli. His pupils were dilated and
sluggishly reactive to direct light. He had rapid
conjugate oscillations of the eyes in the hori-
zontal, vertical, and rotatory planes, inter-
preted as opsoclonus. The white blood cell
count was 22.9
109/l, pH 6.84, anion gap
33 mmol/l, serum creatinine 1.32 mg/dl, and
creatine kinase 292 IU/l. Several hours later
his serum creatine kinase rose to 72 312 IU/l
and he developed oliguric acute renal failure.
The serum diphenhydramine concentration
was 26 mg/l 10 hours after ingestion. There
were no benzodiazepines or tricyclic antide-
pressants or their metabolites in the urine.
Electroencephalography showed diffuse beta
waves without epileptiform activity. A brain
MRI scan and lumbar puncture were normal.
In healthy subjects, the mean Cmax after
oral diphenhydramine 50 mg was 0.66 mg/l
[17C]. Opsoclonus is most usually associ-
ated with viral or paraneoplastic encephali-
tis. The authors speculated that the
anticholinergic activity of diphenhydramine
had been responsible in this patient.
Hydroxyzine [SED-15, 1705]
Cardiovascular Like some other antihist-
amines, hydroxyzine can cause prolonga-
tion of the QT interval [18A].
348
A 34-year-old woman took hydroxyzine 75 mg/
day for chronic prurigo and 3 days later had
repetitive syncope. An electrocardiogram
showed marked QT interval prolongation
(640 ms, QTc 630 ms). She reported no prior
family history, but she had had a presyncopal
attack of unknown origin several years before.
Hydroxyzine was withdrawn immediately and
she had no more attacks of syncope. The QT
interval gradually shortened to 460 ms
(QTc 464 ms) 3 weeks after the episode.
The authors concluded that hydroxyzine
had caused extreme prolongation of the
QT interval. However, because the QT
interval remained slightly prolonged after
withdrawal of hydroxyzine, they conducted
genetic testing and identied a hetero-
zygous missense HERG mutation, A614V,
causing a substitution of alanine at codon
614 to valine that resulted in a dominant
negative effect on HERG expression.
Promethazine [SED-15, 2938]
Cardiovascular In a double-blind study of the
effect of promethazine on ventricular repolar-
ization (QT interval and transmural disper-
sion of repolarization) in patients undergoing
elective surgical procedures who had no car-
diovascular disorders, promethazine caused
signicant prolongation of the QTc interval.
However, the authors also concluded that the
lack of simultaneous changes in transmural
dispersion of repolarization reduced the risk
of ventricular dysrhythmias [19C].
There have been two reports of intra-
arterial promethazine injection that led to
digital necrosis; both eventually led to
amputations [20A].
A 43-year-old woman was given accidently an
injection of promethazine into the brachial
artery of the left arm. Immediately after the
injection, she had burning pain from the left
antecubital fossa to the hand. Vasospasm
occurred in the left hand, which subsequently
became erythematous. She was discharged,
but 5 days later returned complaining of pain
and discoloration of the left index and ring n-
gers and purple discoloration of the thumb
and little nger. The radial pulse was intact
and she was given an analgesic, but 5 days
Chapter 15 Garry M. Walsh
later the thumb and digits of her left hand
were cyanotic distal to the proximal segments,
with a palpable radial pulse. Angiography
showed an occluded ulnar artery from its ori-
gin, with occlusion of multiple distal digital
arteries. After treatment with intra-arterial
lidocaine, papaverine, and alteplase for
24 hours angiography showed a patent radial
artery, an occluded ulnar artery with some col-
lateral ow, a patent arch, and occlusion of the
distal digital arteries to the thumb and ngers.
She subsequently developed necrosis of the
left hand and required amputations of all ve
digits 6 weeks after the initial event. Histo-
pathology showed coagulation necrosis.
A 26-year-old woman was accidentally given
intra-arterial injections of isotonic saline, pethi-
dine 50 mg, and promethazine 12.5 mg through
a catheter in the anatomical snuffbox in the left
wrist. She reported pain, swelling, and discolor-
ation of her left hand, which was grossly edema-
tous with second digit cyanosis distal to the
proximal interphalangeal joint. Stellate ganglion
block was performed in an effort to relieve vaso-
spasm and anticoagulation with heparin and
later coumadin was started. However, 2 weeks
later, there was demarcation of the terminal seg-
ment of the left index nger. The left thumb was
involved, with focal ischemia and cyanosis along
the ventral aspect of the terminal pulp. There
was also cephalic vein thrombosis extending
from the left mid-forearm to the level of the rst
carpometocarpal joint. Arteriography showed
normal blood ow to the level of the left wrist,
but occlusion of the radial artery in the anatomi-
cal snuffbox, with segmental occlusion of multi-
ple distal digital arteries. The left index nger
was amputated 3 weeks after the initial injury,
with no further progression in the left thumb.
Microscopy of the amputated digit showed inti-
mal hyperplasia with occlusion of the small ves-
sel muscular arteries.
The authors pointed out that inadvertent
intra-arterial administration of promethazine
leads to ischemia and tissue necrosis. They
further suggested that hand surgeons must
be aware of this complication and consider
the diagnosis of intra-arterial promethazine
administration when evaluating patients with
digital and hand ischemia who have recently
had intravenous injection of medications.
Pregnancy Self-poisoning with large doses
of promethazine during pregnancy does
not appear to result in teratogenic, feto-
toxic, or neurotoxic effects in the children
born to these mothers [21C].
Antihistamines (H1 receptor antagonists) Chapter 15
Drug overdose Promethazine is a pheno-
thiazine derivative rst-generation H1 recep-
tor antagonist but is also an antagonist at
muscarinic (M1) and dopamine (D2) recep-
tors. Adverse effects associated with thera-
peutic use of promethazine include dystonic
reactions, psychosis in the absence of other
anticholinergic symptoms or signs, and neuro-
leptic malignant syndrome. The principal
effects of promethazine overdose are central
nervous system depression and anticholiner-
gic effects, including delirium, agitation, and
hallucinations. In an analysis of a series of
cases of promethazine overdose in a prospec-
tive database of poisoning admissions to an
Australian regional toxicology service, the
main feature of promethazine toxicity was
delirium, the probability of which was related
to dose [22C]. Administration of activated
charcoal reduced the probability of delirium.
Rupatadine [SEDA-32, 308]
Rupatadine is both an H1 receptor antagonist
and a potent antagonist of the pro-inamma-
tory lipid mediator, platelet activating factor
(PAF); it has been used to treat allergic
rhinitis [23C, 24R].
Cardiovascular Rupatadine can cause pro-
longation of the QT interval [25A].
A 73-year-old man with diabetes, dyslipidemia,
intermittent claudication, and adenocarcinoma
of the prostate took rupatadine 10 mg/day for
1 week for cold symptoms and had presyncopal
episodes accompanied by sweating and dizzi-
ness and one syncopal episode that resolved
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 Gwyneth A. Davies and Mike Pynn
16 Drugs that act on the
respiratory tract
INHALED
GLUCOCORTICOIDS
[SEDA-30, 193; SEDA-31, 305;
SEDA-32, 311]
Inhaled glucocorticoids and
the risk of pneumonia
EIDOS classication:
Extrinsic species Glucocorticoids
Intrinsic species Not known
Distribution Lungs
Outcome Not known
Sequela Pneumonia from inhaled
glucocorticoids in COPD
DoTS classication:
Dose-relation Collateral reaction
Time-course Early
Susceptibility factors Age (over
55 years); physiological changes
(low body mass index); diseases
(severe COPD)
The association between the use of inhaled
glucocorticoids and pneumonia in patients
with chronic obstructive pulmonary disease
(COPD) was reviewed in SEDA-32
(p. 311). More data have appeared. A
meta-analysis of 11 randomized controlled
trials that lasted at least 6 months, involving
Side Effects of Drugs, Annual 33
J.K. Aronson (Editor)
ISSN: 0378-6080
DOI: 10.1016/B978-0-444-53741-6.00016-7
# 2011 Elsevier B.V. All rights reserved.
14 426 patients with COPD compared dif-
ferent inhaled glucocorticoid subclasses
without and without long-acting beta-
adrenoceptor agonists (LABAs) versus
bronchodilators or placebo [1M]. Seven of
the trials (10 776 patients) examined pneu-
monia as one of their outcomes, and a
pooled analysis showed a higher risk in
those who used inhaled glucocorticoids
(RR 1.34; CI 1.03, 1.75). Subgroup
analysis showed that the risk of pneumonia
increased with the dose of inhaled glucocor-
ticoid, the severity of COPD, and concomi-
tant use of a LABA.
In a meta-analysis of 18 randomized con-
trolled trials involving 16 996 patients with
COPD who were followed up for
24156 weeks inhaled glucocorticoids with
or without a LABA were compared with
either placebo or a LABA alone [2M]. Most
of the studies included high-dose inhaled
glucocorticoids (2 mg beclometasone equiv-
alents). Inhaled glucocorticoids were associ-
ated with an increased incidence of
pneumonia (RR 1.60; CI 1.33, 1.92),
including serious pneumonia (life-threaten-
ing, requiring hospitalization, or leading to
death or disability) (RR 1.71; CI 1.46,
1.99). However, this was not associated with
an increased risk of pneumonia-related mor-
tality. The number needed to harm (NNTH)
was 47.
In a systematic review of 18 randomized
controlled trials the combination of inhaled
glucocorticoids a LABA was compared
with a LABA alone in 12 446 patients with
COPD; the studies lasted 12156 weeks
[3M]. There was a signicantly increased
risk of pneumonia (RR 1.63; CI 1.35,
353
354
1.98) with an NNTH of 40 for those who
used inhaled glucocorticoids a LABA.
In a post-hoc analysis of data from the
TORCH study the risk of pneumonia was
examined in patients with moderate to severe
COPD using inhaled glucocorticoids [4c]. In
the original study, 6184 patients were random-
ized to one of four treatment arms (uticasone,
salmeterol, uticasone salmeterol, or pla-
cebo). Inhaled glucocorticoids were associated
with a signicantly increased incidence of
pneumonia, 84 and 88/1000 patient-years for
uticasone and uticasone salmeterol
respectively versus 52/1000 patient-years for
salmeterol or placebo. For pneumonia as a
serious adverse event there was a similar trend,
with an NNTH of 47. Death due to pneumonia
occurred in under 1% of participants, and
therefore the numbers of events were too small
to detect any difference between the groups.
Susceptibility factors for pneumonia in this
group were increasing age (over 65 years), a
low FEV1 (under 30%), COPD exacerbations
within the last year, a high MRC dyspnea score
(categories 4 and 5), and a low BMI.
The meta-analyses highlighted so far have
involved trials with any subclass of inhaled
glucocorticoids. In a meta-analysis of
data on 7042 patients from seven studies of
budesonide (dosage range 3201280 micro-
grams/day) with or without formoterol versus
control treatment (placebo or formoterol), in
which the authors also adjusted for baseline
characteristics, there was no signicant differ-
ence in the incidence of pneumonia in those
who used inhaled glucocorticoids (OR
1.05; CI 0.81, 1.37) [5M]. Proposed expla-
nations for this contradictory nding
included different pharmacokinetics of
budesonide and uticasone (faster clearance
from the lungs) and different pharmaco-
dynamics (reduced potency).
An updated meta-analysis of 24 random-
ized controlled trials in 23 096 patients with
COPD showed that inhaled glucocorticoids
were associated with a risk of pneumonia
(RR 1.57; CI 1.41, 1.75) [6M]. How-
ever, subgroup analysis showed that
although inhaled uticasone and
mometasone were signicantly associated
with pneumonia, the data on budesonide
Chapter 16 Gwyneth A. Davies and Mike Pynn
showed only a non-signicant trend towards
an increased risk.
Conclusions Overall, most of the published
data suggest an increased risk of pneumonia
in patients with COPD who use inhaled glu-
cocorticoids, but without an increased risk
of related mortality. However, all the meta-
analyses have weaknesses, which limit their
interpretation. Pneumonia was not a primary
outcome in any of the included studies and the
criteria used to make a diagnosis were not
stringent, with no requirement for radiologi-
cal conrmation. Furthermore, it has been
argued [7r] that many of the analyses did not
have access to adequate baseline patient data,
leading to difculties in excluding potential
confounders. Whether there are differences
in the risk of pneumonia between various
subclasses of inhaled glucocorticoids remains
to be determined. Large long-term studies
with stringent criteria for the diagnosis
of pneumonia and measurement of the risk
of pneumonia as a primary outcome are
required, including analyses of potential dif-
ferences between inhaled glucocorticoids.
Ear, nose, throat In a study of the risk of
pharyngitis in 55 patients who used inhaled
glucocorticoids (controls and asthmatics),
inhaled glucocorticoids were associated
with throat irritation, sore throat, weakness
of voice/hoarseness, and clinical pharyngitis.
However, the clinical appearances of phar-
yngitis in these individuals did not correlate
with cellular markers of inammation.
A post-marketing study of 158 patients
using inhaled steroids and LABAs for
asthma or COPD showed that throat symp-
toms were the most common adverse
effects related to glucocorticoid therapy,
including sore throat (54%), dry throat
(52%), and oral thrush (11%); there was
skin bruising in 35% [8c].
In a systematic review there was an
increased risk of oropharyngeal candidiasis
in 12 446 patients (RR 1.59; CI 1.07,
2.37; NNTH 22) [3M].
Drugs that act on the respiratory tract Chapter 16
Sensory systems Vision In a systematic
review of four casecontrol studies in
nearly 200 000 patients, there was a signi-
cant relation between cataracts and the
dose of inhaled glucocorticoid; the ran-
dom-effects pooled odds ratio for the risk
of cataracts per 1000 micrograms increase
in daily beclomethasone dipropionate dose
was 1.25 [9M].
Endocrine The effects of inhaled gluco-
corticoids on the hypothalamicpituitary
adrenal axis in adults and children were
reviewed in SEDA-31 (p. 305). In sum-
mary, at low doses inhaled glucocorticoids
have little effect, but at high doses
(2000 micrograms beclometasone equiva-
lents) adrenal suppression can occur. In
a French survey of 11 783 hospital special-
ists combined with a pharmacovigilance
database, there were 46 cases of adrenal
insufciency attributable to inhaled cortico-
steroids at doses of over 500 micrograms
beclometasone equivalents in children and
over 1000 micrograms beclometasone
equivalents in adults; 12 cases were associ-
ated with concomitant use of enzyme inhib-
itors [10C].
In a cohort study in 50 patients with bron-
chiectasis, basal cortisol and a short
Synacthen test were used to study adrenal
gland function [11c]. There was adrenal sup-
pression in 24% of these patients not using
glucocorticoids, but it was signicantly
more likely in those who used inhaled gluco-
corticoids (49%). This was associated with
symptoms of adrenal suppression and worse
quality of life. The effect was not related to
the dose of inhaled glucocorticoids, the use
of other topical glucocorticoids, or the use of
oral glucocorticoids in the preceding year.
In contrast, in a randomized controlled
trial in 645 patients with moderate asthma
uncontrolled by regular inhaled gluco-
corticoids compared with combined
beclometasone diproprionate and formoterol,
there was no evidence of adrenal suppression
[12C]. This may suggest that the doses of
glucocorticoids were too low.
In 41 patients aged 818 years
with asthma, using uticasone 200300
micrograms/day (400660 micrograms
355
beclometasone equivalents) there was no
evidence of adrenal suppression or differ-
ences between dosage regimens during fol-
low-up for 10 weeks [13c].
In a review of the literature published to
date in this area the authors concluded that
at higher than recommended doses inhaled
glucocorticoids can precipitate adrenal cri-
ses in children and adults [14R]. They cited
observational data that suggest a more
prominent effect of uticasone propionate,
but acknowledged that study designs are
open to bias. Furthermore, the authors of
a previous Cochrane review of uticasone
versus beclomethasone and budesonide
concluded that although there were con-
cerns about the risk of adrenal suppression
in children using uticasone (in doses over
400 micrograms) the randomized controlled
trials analysed did not provide sufcient
data to address this question [15M].
Musculoskeletal A link between high-dose
inhaled corticosteroids and Achilles tendon-
itis, an adverse effect seen with oral
steroids, has been suggested [16A].
Inhaled glucocorticoids and
skeletal adverse effects
Children Several randomized controlled tri-
als have shown an association between the
use of inhaled corticosteroids and reduced
growth velocity in the rst year of treatment
in pre-pubertal children, although in trials
in which these individuals have been
followed for longer (up to 10 years) this
effect appears to diminish (SEDA-32, 312).
More recently the effects of inhaled
budesonide (200 micrograms bd),
nedocromil, and placebo have been studied
in the Childhood Asthma Management
Programme (CAMP), in children with mild
to moderate asthma, conducted over
4.3 years [17C]. At the end of the trial the
children who had used budesonide were a
mean of 1.1 cm shorter than those in the
other treatment arms. In a follow-up study
of the long-term benets and harms 4.8 years
356
after the end of the study, in the 941 children
from the original cohort, growth suppres-
sion, while less during follow-up, neverthe-
less persisted (0.9 cm in the treatment
group versus placebo) [18C]. The effect
was more pronounced in girls (1.7 cm) than
in boys (0.3 cm), which differs from previ-
ous ndings of a greater effect in boys
[19C]. It should be noted that 54% of the
boys and 25% of the girls had not reached
their full adult height at the end of the study.
Bone mineral density was also examined in
this cohort [20C]. In the 531 boys and 346 girls
followed for a median of 7 years there was an
association between reduced bone mineral
accretion with oral glucocorticoid use, which
was dose-related, but only in boys. With
regards to the use of inhaled glucocorticoids,
this was associated with a statistically signi-
cant reduction in bone mineral accretion in
boys but not in girls. The effect did not appear
to be dose-related. Inhaled glucocorticoids,
unlike their oral counterparts, did not increase
the risk of osteopenia or fractures. The
authors argued that inhaled glucocorticoids
appeared to be much safer in terms of effects
on bone mineral density than bursts of oral
glucocorticoids and that therefore the ability
of regular inhaled glucocorticoids to reduce
the need for oral glucocorticoids outweighed
the small risks.
In 2978 children with cystic brosis inhaled
glucocorticoids caused a small but signicant
reduction in height for age and increased use
of oral hypoglycemic drugs [21C].
The authors of two reviews have con-
cluded that overall treatment with inhaled
glucocorticoids can cause slowing of growth
velocity in the early stages of treatment,
although previous long-term studies have
shown that the children will eventually reach
their anticipated adult heights [22R].
Adults Previous observational data have
suggested that inhaled glucocorticoids reduce
bone mineral density and increase the risk of
fractures (SEDA-31, 307; SEDA-32, 313).
An analysis of a subset of 685 patients using
inhaled glucocorticoids in the TORCH study,
and excluding patients taking oral
Chapter 16 Gwyneth A. Davies and Mike Pynn
glucocorticoids, showed no changes in bone
mineral density from a baseline in which
30% of women had osteoporosis and 41%
osteopenia (overall prevalence 65%) density
[23C]. There was a low incidence of fractures
(5.16.3%). While recognizing the limitations
of this study, including the short follow-up
time and high drop-out rate, the authors
suggested that the frequencies of osteopenia
and osteoporosis in patients with COPD are
high, but that there is no evidence to suggest
a signicant link between inhaled glucocorti-
coids and low bone mineral density.
In a meta-analysis of 13 observational
and randomized controlled trials there was
no overall increased risk of fractures associ-
ated with inhaled glucocorticoids (RR
1.02; CI 0.96, 1.08) even when the analy-
sis was restricted to the four randomized
controlled trials [24M]. However when strat-
ied by the dose of inhaled glucocorticoid
there was a small increased risk of fractures
amongst those taking high doses (RR
1.30; CI 1.07, 1.58).
In contrast, another meta-analysis of
three double-blind randomized controlled
trials, including TORCH, in a total of 8131
patients, showed no increased risk of fractures
(OR 1.09; CI 0.89, 1.33) despite the
use of high-dose inhaled glucocorticoids
(beclomethasone 800 micrograms, uticasone
1000 micrograms) [1M].
In a more recent review of the literature,
including trial and observational data, the
authors concluded that inhaled glucocorti-
coids may produce a modest reduction in
bone mineral density and a small associated
increase in the risk of fracture, which appears
to be dose-related [22R]. However, it has been
argued that most of this evidence comes from
observational data, with risks of bias (recall
and confounding) and that adequately
powered randomized controlled trials are
needed to clarify this risk and quantify it accu-
rately [25R]. In the meantime, physicians need
to be aware of this potential adverse effect,
and, certainly in the case of asthma, try to
maintain patients on the lowest dose of
inhaled glucocorticoids required to control
their disease.
Drugs that act on the respiratory tract Chapter 16
BETA 2 -ADRENOCEPTOR
AGONISTS [SEDA-30, 198;
SEDA-31, 308; SEDA-32, 314]
For non-respiratory uses of b2-adrenoceptor
agonists, see Chapter 13.
Long-term safety of long-acting
beta2-adrenoceptor agonists
(LABAs)an update
Concerns have been raised about the long-
term safety of LABAs; the overall and respi-
ratory adverse effects were reviewed in
SEDA-30 (p. 198) and SEDA-31 (p. 309).
Meta-analysis, using data from 33 826
patients with asthma, has shown that LABAs
are associated with an increased risk of exac-
erbations requiring hospitalization (OR
2.6; 95% CI 1.6, 4.3), life-threatening exac-
erbations (OR 1.8; 95% CI 1.1, 3.9),
and death from asthma (OR 3.5; 95% CI
1.3, 9.3) in a small subgroup of patients
[26M, 27M]. Potential publication bias was a
limitation of the meta-analysis; furthermore,
the Salmeterol Multicenter Asthma Research
Trial (SMART) provided 80% of the data
and accounted for most of the asthma-related
deaths [28r].
The authors of a Cochrane review (n
42 333) concluded that there were poten-
tial safety problems associated with LABAs,
particularly in patients who are not taking
inhaled glucocorticoids [29M].
In December 2008, the US Food and
Drug Administration (FDA) concluded that
the benets of single-agent LABAs did not
outweigh the risks and removed the asthma
indication for single-agent salmeterol and
formoterol [30r]. The revised label was
informed mainly by data from the Serevent
Nationwide Surveillance (SNS) study and
the SMART study, and a 2008 meta-analysis
conducted by the FDA.
In a systematic review comparing LABAs
and placebo and LABAs inhaled glucocor-
ticoids and inhaled glucocorticoids alone for at
least 12 weeks (n 36 588), LABAs were
associated with an increase in catastrophic
357
events (asthma-related intubations and deaths)
(OR 2.10; 95% CI 1.37, 3.22) [31M].
This was signicant for LABAs variable
doses of glucocorticoids versus placebo (OR
1.83; 95% CI, 1.142.95) and for a LABA
an inhaled glucocorticoid versus an inhaled
glucocorticoid alone (OR 3.65; 95% CI
1.39, 9.55). There were similar increases in risk
for variable and concomitant inhaled gluco-
corticoids, salmeterol and formoterol, and in
children and adults. In the analysis of patients
using concomitant inhaled glucocorticoids,
there remained an association with increased
numbers of catastrophic events compared with
inhaled glucocorticoids alone (OR 8.19;
95% CI 1.10, 61), but studies without
catastrophic events were excluded.
Cochrane reviewers have sought to address
serious adverse events associated with the use
of regular LABAs combined with inhaled
glucocorticoids for asthma. In one review (n
15 155; 1155 children, 14 000 adults) the
combination of a LABA an inhaled gluco-
corticoid was compared with higher doses of
inhaled glucocorticoids [32M]. In adolescents
and adults, a LABA an inhaled glucocor-
ticoid was modestly more effective at reducing
exacerbations. LABAs led to an increased
frequency of tremor (RR 1.84; CI 1.20,
2.82) and less oral candidiasis, but adverse
effects associated with long-term inhaled glu-
cocorticoids were rarely monitored. In chil-
dren, combination therapy was associated
with a non-signicant trend towards an
increased risk of oral glucocorticoid-treated
exacerbations and hospital admissions. The
authors therefore raised concerns about the
safety of combination therapy, in view of the
modest improvement in children under the
age of 12 years.
However, a larger Cochrane review in chil-
dren, in which the addition of a LABA to an
inhaled glucocorticoid was compared with
the same or an increased dose of inhaled glu-
cocorticoid (n 5572), showed no difference
in the risk of overall adverse effects. While
there was no difference in the number of exac-
erbations requiring systemic glucocorticoids,
LABAs were associated with improved lung
function and short-term growth [33M].
In another Cochrane review (n 21 248;
4625 children, 16 623 adults) the addition of
358
a LABA to the same dose of an inhaled glu-
cocorticoid was studied [34M]. There was no
signicant difference in serious adverse
events with the LABAs (RR 1.06; CI
0.87, 1.30), but the condence intervals were
wide. In adults, add-on LABA therapy
reduced the rate of exacerbations requiring
oral glucocorticoids, improved lung function
and symptoms, and modestly reduced the
use of SABAs.
In a meta-analysis of about 96 000
patients, the combination of a LABA an
inhaled glucocorticoid reduced asthma-
related hospitalizations and/or emergency
visits compared with inhaled glucocorticoids
alone (OR 0.82; CI 0.72, 0.94) [35M].
In a meta-analysis of the effect of at least
12 weeks of treatment with a LABA on
asthma-related and total morbidity and mor-
tality in patients who were concomitantly
using inhaled glucocorticoids (n 29 401
patients; over 8200 patient-years) there were
14 deaths in those using a LABA and eight
in controls; there were three asthma-related
deaths and two asthma-related non-fatal intu-
bations, all in those using a LABA (n 15
710) [36M]. The OR for total mortality was
1.26 (CI 0.58, 2.74). Asthma-related deaths
and intubations were few and there was insuf-
cient power to draw conclusions about the
effect of LABAs on these outcomes.
In a Cochrane review the combination of
a LABA an inhaled glucocorticoid was
compared with the glucocorticoid alone in
8050 glucocorticoid-naive adults and chil-
dren with asthma [37M]. There was no sig-
nicant difference in the risk of serious
adverse events or any adverse events. While
the addition of a LABA signicantly
improved lung function, reduced symptoms,
and marginally reduced the need for rescue
SABAs, a higher dose of inhaled glucocorti-
coids was more effective in reducing the risk
of exacerbations that required rescue sys-
temic corticosteroids, and the risk of with-
drawals, than combination therapy. Small
numbers of children precluded rm conclu-
sions in that group.
In a systematic review the addition of a
LABA to inhaled glucocorticoids signi-
cantly reduced the risk of exacerbations
compared with a similar dose of inhaled
Chapter 16 Gwyneth A. Davies and Mike Pynn
glucocorticoids [38M]. There was signi-
cantly more tremor with the LABA
inhaled glucocorticoid combination (NNTH
21) and compared with higher doses of
inhaled glucocorticoids (NNTH 74). The
authors concluded that benet to harm balance
favors the addition of a LABA to an inhaled
glucocorticoid in adults with symptomatic
asthma.
In a large observational study (n 507 966)
patients who had recently started asthma
medication (SABA, LABA, inhaled gluco-
corticoids) were at an initial increased risk
of myocardial infarction, particularly in the
rst 3 months, which then fell; there was no
signicant difference in the risk between treat-
ments (RRs: SABA 2.4, LABA 1.5,
inhaled glucocorticoids 1.5) [39C]. Heavy
long-term use (more than 13 prescriptions in
1 year) of an inhaled glucocorticoid and a
SABA was also associated with an increased
risk of myocardial infarction. Limitations of
this study included potential confounders
and the possibility that inhalers are sometimes
incorrectly given for cardiac asthma
(i.e. pulmonary edema).
Comparative studies Adrenoceptor ago-
nists versus glucocorticoids Add-on LABA
therapy (n 17 418) has been compared
with high-dose inhaled glucocorticoids
(n 46 930) in a 12-month observational
study in patients with asthma [40C]. The
use of rescue bronchodilators was lower in
those taking LABAs, but higher usage of
inhaled glucocorticoids was associated with
a lower risk of severe exacerbations and
hospitalizations. However, a post-hoc analy-
sis (with its inherent limitations) of the
Formoterol and Corticosteroid Establishing
Therapy study (n 852 treated) showed
that add-on formoterol increased the dura-
tion of well-controlled asthma, compared
with a fourfold increase in budesonide [41C].
In a 3-year comparison of salmeterol,
uticasone, and salmeterol uticasone,
the frequencies of adverse events were sim-
ilar across the groups [42C]. Hoarseness/
dysphonia was the most common adverse
event that the investigator considered to
be drug-related; it occurred in 15% of
Drugs that act on the respiratory tract Chapter 16
patients using salmeterol, in 5% of those
using uticasone, and 9% of those using
salmeterol uticasone.
In children with persistent asthma in the
VIAPAED study, adding salmeterol to
uticasone in a single inhaler was more
effective than doubling the dose of inhaled
glucocorticoids [43C].
In a similar study in adults with COPD,
salmeterol uticasone was associated
with a higher incidence of pneumonia [44C].
Formoterol versus salmeterol In a random-
ized controlled trial in patients with COPD,
formoterol had a faster onset of action with
no signicant difference in treatment-asso-
ciated adverse events (5.8% versus 1.5%
with salmeterol) [45C]. Headache was the
most common adverse event with
formoterol (3.6%); bronchitis and upper
respiratory tract infections were the most
common adverse events with salmeterol
(2.3% each).
Levosalbutamol versus racemic salbutamol
In 49 patients, mean heart rate and plasma
(R)-salbutamol concentrations were
higher with racemic salbutamol than
levosalbutamol, with similar improvements
in FEV1 [46c].
Combination studies Asthma guidelines
recommend adding long-acting beta2-
adrenoceptor agonists (LABAs) to inhaled
glucocorticoids at step 3 in adults and ado-
lescents, before increasing the dose of
beclometasone or other glucocorticoids
above 400 microgram equivalents and cer-
tainly before increasing above 800 micro-
grams [47S, 48S]. LABAs and combination
therapy are licensed for children over
5 years, but have not yet been adequately
evaluated in younger children. LABAs
should not be used as monotherapy in
asthma but as add-on therapy to inhaled
glucocorticoids [49S].
Cardiovascular In a randomized placebo-
controlled study of nebulized arformoterol
15/25 micrograms bd or 50 micrograms/
359
day or salmeterol 42 micrograms bd in
1429 patients with COPD the risk of atrial
tachycardia was increased by 25% [50C].
More serious dysrhythmias (atrial brilla-
tion/utter, non-sustained/sustained ven-
tricular tachycardia) were uncommon and
were not increased by LABAs. LABAs
did not increase the mean heart rate.
Musculoskeletal In an observational study
in 158 patients minor adverse reactions were
common in association with LABAs (studied
in combination with inhaled glucocorticoids)
and the reactions were dose-related [51c].
Of those taking LABAs, 72% reported
potential adverse reactions, the commonest
being muscle cramps (62%) and muscle
twisting (39%).
Teratogenicity Beta2-adrenoceptor agonists
can cause functional and behavioral terato-
genic effects and have been associated with
increases in autism spectrum disorders, psy-
chiatric disorders, poor cognitive and motor
function, poor school performance, and
changes in blood pressure in the offspring
[52R]. It should be emphasized that risks of
untreated disease to the mother and fetus
are greater than the risk of using a beta2-
adrenoceptor agonist but that the drugs
should only be used when clearly indicated.
In a comparison of 502 infants with car-
diac anomalies (Congenital Malformations
Registry) with matched controls, the off-
spring of women with asthma who had used
bronchodilators were at increased risk of
any heart defect (OR 2.20; 95%
CI 1.05, 4.61) and specically obstructive
defects (OR 4.49; CI 2.03, 9.94),
which remained signicant when looking
at only salbutamol (OR 4.62; CI 1.66,
12.85) [53C]. Unfortunately, there was no
information on frequency or dosing of med-
ications, and multiple medications were
also associated with a risk of cardiac
defects. The authors suggested that both
maternal asthma status (control; severity)
and use of asthma medications, particularly
bronchodilators, may play a role in cardiac
malformations in their offspring.
360
In 24 children with major congenital
malformations, there was no increased risk
of malformations with gestational expo-
sures to short- or long-acting beta-
adrenoceptor agonists [54C].
Susceptibility factors Genetic The LARGE
study showed a signicant B16 genotype-
specic difference in methacholine respon-
siveness but no difference in salmeterol
response between Arg/Arg (n 42) or
Gly/Gly (n 45) in individuals with
asthma [55c]. Post-hoc subgroup analyses
in AfricanAmericans showed signicant
changes in peak expiratory ow (PEF) in
the eight Gly/Gly subjects but not in the
nine Arg/Arg subjects, but the numbers
were small. Minor adverse events were
mainly nasopharyngitis/pharyngitis.
Formoterol [SED-15, 1443;
SEDA-32, 316]
Combination studies Formoterol versus/
plus tiotropium See under Tiotropium.
Formoterol added to an inhaled glucocor-
ticoid In a review of the use of formoterol
in adults and adolescents (n 8028) and
children (n 2788) there were four adult
deaths among 6594 people randomized to
inhaled glucocorticoids formoterol and
none in those who used inhaled glucocorti-
coids alone; one death was reported to be
asthma-related but the difference was not
statistically signicant [56M]. There were no
signicant differences in non-fatal serious
adverse events from any cause in adults,
and a non-signicant increase in events in
children who used formoterol was not statis-
tically signicant. Asthma-related serious
adverse events in adults using formoterol
were less common (OR 0.53; CI 0.28,
1.00), with a non-signicant higher trend in
children. In children, the number of events
was too small to assess whether the increase
in all-cause non-fatal serious adverse events
found in a previous meta-analysis of regular
formoterol alone was abolished by the addi-
tional use of inhaled glucocorticoids. The
Chapter 16 Gwyneth A. Davies and Mike Pynn
review was inconclusive regarding denite
evidence of harm/no harm relating to the
use of formoterol inhaled glucocorticoids.
Only one asthma-related death was reported
with formoterol over 3000 patient-years.
In a systematic review of asthma-related
mortality in patients using formoterol com-
pared with those not using formoterol,
including all AstraZeneca parallel-group ran-
domized controlled trials lasting 312 months,
there were eight asthma-related deaths (0.34
per 1000 person-years) in 49 906 patients
using formoterol (92% also using inhaled glu-
cocorticoids), and two (0.22 per 1000 person-
years) in 18 098 patients (83% also using
inhaled glucocorticoids) not randomized to
formoterol; this was a non-signicant differ-
ence [57M]. Asthma-related serious adverse
events (over 90% of which were associated
with hospitalization) were signicantly fewer
in those who used formoterol (0.75% versus
1.10%). Increased daily doses of formoterol
caused no increase in asthma-related serious
adverse events. There was no signicant dif-
ference in cardiac mortality, non-cardiac
non-asthma-related mortality, nor all-cause
mortality in those who used formoterol.
Among those who were given an inhaled glu-
cocorticoid at baseline, there were seven
asthma-related deaths (0.32 per 1000 per-
son-years) in 46 003 patients randomized to
formoterol and one (0.14 per 1000 person-
years) in 13 905 patients not randomized to
formoterol; this was also non-signicant.
There were few asthma-related or cardiac-
related deaths among patients randomized
to formoterol, and all the differences were
non-signicant. However, despite over
68 000 patients, there was insufcient power
to conclude that there was no increased mor-
tality with formoterol. Cardiac-related seri-
ous adverse events were not increased, and
asthma-related serious adverse events were
signicantly reduced in those who used
formoterol.
Formoterol budesonide as maintenance
and reliever therapy Budesonide
formoterol (Symbicort) for maintenance
and reliever therapy (Symbicort SMART)
has been evaluated in a Cochrane review
of ve trials (n 5378) compared with
Drugs that act on the respiratory tract Chapter 16
inhaled glucocorticoids for maintenance
a separate reliever inhaler [58M]. There
was no signicant difference in fatal/non-
fatal serious adverse events. Single inhaler
therapy was associated with a reduced
mean total daily dose of inhaled glucocorti-
coids (mean reduction from 107 to
267 micrograms/day; results not combined
owing to heterogeneity) and reduced
asthma exacerbations requiring oral gluco-
corticoids, with no signicant reduction in
hospitalization. In 224 children, single
inhaler therapy was associated with a
reduced need for inhaled glucocorticoids
and oral corticosteroids, and the annual
height gain was 1 cm greater in this group
(CI 0.3, 1.7 cm). Single inhaler therapy
is not currently licensed for children under
18 years of age in the UK.
In a meta-analysis of eight trials the
SMART approach reduced the risk of
severe exacerbations and severe exacerba-
tions requiring hospitalization or emer-
gency treatment, with no increase in
adverse events [59M]. However, there was
heterogeneity among these trials.
Data relating to budesonide formoterol
therapy from six randomized controlled trials
of at least 6 months (n 14 346) have been
analysed [60M]. SMART therapy was well
tolerated compared with xed-dose alterna-
tives, and there was no increased risk of death
or cardiac-related serious adverse events or
withdrawals because of adverse events;
asthma-related serious adverse events and
withdrawals were signicantly reduced. Limi-
tations of the randomized controlled trials
were noted, particularly exclusion of patients
with co-morbidities, necessitating continuing
surveillance.
A pooled analysis of six 6-month, ran-
domized, open studies showed that serious
adverse events were uncommon, with com-
parable incidences in the two treatment
groups [61M].
Higher eosinophil counts were associated
with maintenance and reliever therapy
compared with xed-dose combination
treatment containing a fourfold higher
maintenance dose of budesonide, but these
remained within the range associated with
stable control [62C]. There were no
361
signicant differences in adverse events,
exacerbation rates, or lung function.
A 12-month open study in primary care
showed no clinically important differences
in adverse events between exible and
xed dosing of budesonide formoterol.
Maintenance and reliever therapy was asso-
ciated with a signicantly lower daily dose
of budesonide and direct cost savings, with
at least equivalent efcacy [63C]; there were
similar ndings in other studies [64C].
Route of administration Nebulized versus
inhaled formoterol Dose-ranging and PK/
PD studies have shown that 20 micrograms
of a nebulized formoterol fumarate inhala-
tion solution was comparable to 12 micro-
grams of formoterol fumarate dry powder
in patients with COPD [65c]. The former
transiently reduced the mean serum potas-
sium concentration and increased the mean
serum glucose in a dose-related manner.
There were no clinically signicant electro-
cardiographic changes, but mean heart rate
increased by up to 6/minute after a total
dose of nebulized formoterol of
244 micrograms.
In a 12-month open study of the long-term
safety of nebulized formoterol [66C] there
was no signicant difference between twice-
daily nebulized formoterol 20 micrograms
bd compared with formoterol fumarate dry
powder 12 micrograms. There were exacer-
bations of COPD in 16% and 18% respec-
tively. Deaths, serious adverse events, and
withdrawals because of adverse events
occurred in 1.3%, 16%, and 5.4% with nebu-
lized formoterol compared with 1.9%, 18%,
and 7.5% with inhaled formoterol. There
were no clinically important changes in serum
potassium or glucose, and no treatment-
related increases in cardiac dysrhythmias,
heart rate, or QTc interval.
Indacaterol [SEDA-32, 317]
Comparative studies Indacaterol versus
formoterol In a comparison of once-daily
indacaterol and twice-daily formoterol in
patients with COPD, indacaterol had a
362
greater effect on inspiratory capacity [67c].
Cough was the commonest adverse event;
it occurred most frequently with
indacaterol (20%) compared with placebo
(3.3%) and formoterol (none).
Salmeterol [SED-15, 3099; SEDA-30,
202]
Combination studies Salmeterol an
inhaled glucocorticoid In a meta-analysis
of asthma-related deaths in patients taking
salmeterol compared with those taking non-
LABA comparators, there were 35 deaths in
106 575 subjects [68M]. Two studies
(SMART and SNS) contributed 30 of these
deaths and therefore dominated the meta-
analysis. The odds ratio for asthma mortality
with salmeterol was 2.7 (CI 1.4, 5.3). The
relative risk of death from asthma in patients
who had not used inhaled glucocorticoids was
7.3 (CI 1.8, 29.4). In patients who had used
inhaled glucocorticoids, the relative risk of
death was 2.1 (CI 0.6, 7.9). In 63 studies
in which patients were randomized to
salmeterol uticasone or inhaled glucocor-
ticoids, there were no asthma deaths in
22 600 patients. The authors concluded that
salmeterol monotherapy in asthma increases
the risk of asthma mortality and that the risk
is reduced by concomitant use of an inhaled
glucocorticoid. There is no evidence that
salmeterol uticasone is associated with
increased asthma mortality, although the sta-
tistical power of available studies was low.
In a Cochrane review of salmeterol for at
least 12 weeks added to inhaled glucocorti-
coids versus inhaled glucocorticoids alone
in 10 873 adults and 1173 children, there
were no signicant differences in fatal or
non-fatal serious adverse events in those
who used salmeterol an inhaled gluco-
corticoid and there were no asthma-related
deaths [69M]. The number of adverse
events was too small to assess whether the
increase in all-cause non-fatal serious
adverse events found in previous meta-
analysis of regular salmeterol alone is
abolished by additional use of inhaled
Chapter 16 Gwyneth A. Davies and Mike Pynn
glucocorticoids. The GSK website, compar-
ing salmeterol with placebo in 14 studies
(n 14 983), has reported deaths in only
two adult studies [28C, 70C]. There were 44
deaths with salmeterol compared with 33
with placebo. The pooled OR was not statis-
tically signicant (1.33; CI 0.85, 2.10).
The results of a systematic review (n
74 092) have reinforced the view that
LABAs cannot be prescribed as
monotherapy: although serious exacerba-
tions were reduced, there was a contrasting
increase in asthma-related deaths (RR
3.83; CI 1.21, 12) [71M]. A LABA an
inhaled glucocorticoid reduced exacerba-
tions and hospitalizations and was equiva-
lent to inhaled glucocorticoids in terms of
life-threatening episodes and asthma-
related deaths. However, despite the pro-
tective effect of inhaled glucocorticoids,
children and those who used salmeterol
had an increased risk of non-fatal serious
adverse events.
In a meta-analysis of trials lasting over
12 weeks (n 20 966) there was no evidence
of increased serious adverse events with
salmeterol [72M]. There was a reduced risk
of severe exacerbations and no increased risk
of asthma-related hospitalization. Asthma-
related deaths and intubations were too few
(one of each in those taking a LABA alone)
to draw conclusions.
In 18 patients with mild allergic asthma,
salmeterol increased serum and platelet con-
centrations of neurotrophin brain-derived
neurotrophic factor (BDNF), which may
underlie the adverse effects of monotherapy
on airway responsiveness in asthma [73c].
In summary, salmeterol monotherapy in
asthma increases the risk of asthma mortal-
ity, and this risk is reduced by concomitant
use of an inhaled glucocorticoid. There is
no evidence that combination salmeterol
uticasone in adults is associated with
increased risks of serious adverse events
or asthma mortality, although the latter
conclusion is limited by low statistical
power in the available studies. There may
be an increased risk of non-fatal serious
adverse events in children using salmeterol.
Drugs that act on the respiratory tract Chapter 16
A lack of large, well-designed, prospective,
controlled studies of the asthma-related risks
associated with LABAs makes it difcult to
reach a consensus regarding their best use in
asthma [74R]. Further data are needed in
relation to fatal or near-fatal events. Clinical
judgement is needed to weigh the symptom-
atic benets of add-on LABAs to inhaled glu-
cocorticoids in the context of persistent
uncertainty regarding potential adverse
effects. Combination of a LABA an
inhaled glucocorticoid remains a mainstay of
asthma treatment (step 3); LABA
monotherapy is contraindicated.
ANTICHOLINERGIC
DRUGS [SEDA-30, 203; SEDA-31,
311; SEDA-32, 318]
Tiotropium bromide [SED-15, 3433;
SEDA-30, 203, SEDA-31, 311; SEDA-32,
319]
Combination studies In a randomized
study in 225 patients who were given
tiotropium, formoterol, or the combination
over 12 weeks, there was no difference in
adverse events with the addition of a
LABA [75c]. There were no signicant dif-
ferences in the numbers of adverse events,
including cardiovascular events, between
the groups.
In a comparison of tiotropium
formoterol versus salmeterol uticasone
in 605 long-term smokers with chronic
obstructive pulmonary disease (COPD) aged
over 40 years, adverse events were not signif-
icantly different between the groups [76C].
Placebo-controlled studies In a random-
ized placebo-controlled study of
tiotropium, formoterol, or the combination
for 6 months in 847 patients with COPD
aged over 40 years, adverse events were
no different between the groups; combina-
tion therapy did not appear to confer any
additional risk [77C].
In a placebo-controlled comparison of
tiotropium administered by two different
363
devices (Handihaler and Respimat) in 207
patients with COPD over 30 weeks, there
were more withdrawals because of adverse
events with placebo (8.2% versus
1.62.1%); adverse reactions were compa-
rable between the inhaler devices [78C].
Systematic reviews Inhaled tiotropium has
gained widespread acceptance in the treat-
ment of COPD and is now recommended
by the UK National Institute for Health
and Clinical Excellence (NICE) as a thera-
peutic option for those who are still symp-
tomatic despite the use of short-acting
bronchodilators. In 2009 a large meta-
analysis of 20 phase III and IV placebo-
controlled studies of the tiotropium
Handihaler in 17 041 patients updated the
evidence in this area [79M]. Inclusion
criteria were duration of treatment over
4 weeks, patients aged over 40 years with
more than a 10 pack-year smoking history,
and a diagnosis of COPD evidenced by air-
way obstruction on spirometry. Other
respiratory medications were permitted.
Overall there was a lower incidence of
adverse events in the active treatment
group versus placebo, expressed as a rate
difference (RD) per 100 patient-years at
risk and 95% condence intervals (17;
22,  12) with a non-signicant reduction
in serious adverse events (1.41;  2.8,
0.0) and a signicant reduction in fatal
events (0.63;  1.14, 0.12). This
included a lower risk of respiratory events
( 14;  17,  12) and major adverse cardio-
vascular events (0.45; 0.85, 0.05). Typi-
cal anticholinergic drug effects were
highlighted and included increased risks of
dry mouth (1.68; 1.28, 2.03), constipation
(0.34; 0.04, 0.64), gastrointestinal obstruc-
tion (0.15; 0.01, 0.28), and pharyngitis
(0.73; 0.06, 1.4). Urinary symptoms were
also more likely in those taking tiotropium,
including dysuria (0.016; 0.05, 0.27). How-
ever, unlike in previous studies, although
there was a trend towards an increased risk
of urinary retention it was not statistically
signicant.
In a meta-analysis of 11 randomized con-
trolled trials in a total of 1006 Chinese
364
patients with COPD who had taken treat-
ment for at least 4 weeks compared with
either placebo or ipratropium, the most
common adverse effects were anticholiner-
gic, including dry mouth and urinary reten-
tion [80M]. Although there was a trend to
an overall increased risk of adverse events
with tiotropium, it did not reach signi-
cance (RR 1.16; 0.76, 1.77).
Cardiovascular risks of inhaled
anticholinergic drugs
The risk of adverse cardiovascular events
during the use of inhaled anticholinergic
drugs was reviewed in SEDA-32 (p. 318).
Further information has come to light in this
controversial area.
Ipratropium bromide The Lung Health
Study was the rst randomized controlled
trial to suggest an increased risk of adverse
cardiovascular outcomes with anticholiner-
gic drugs [81C]. Conducted over 5 years, it
examined the benets of ipratropium bro-
mide and smoking cessation versus placebo
and noted a higher risk of supraventricular
tachycardia and cardiovascular morbidity
and mortality in smokers randomized to
the anticholinergic drug. However, it has
been argued that the cardiovascular mortal-
ity outcomes were not adjusted for multiple
end-points. Nor was a doseresponse rela-
tion established. Furthermore, post-hoc
analysis of adherence to inhaler therapy
showed that although the risk of supraven-
tricular tachycardia and subsequent hospi-
talization was strongest in those who were
most compliant with therapy, overall cardio-
vascular morbidity and mortality appeared
to be centred on patients who were non-
compliant [82r].
In a casecontrol study of 2242 patients
discharged from hospital with asthma, treat-
ment with ipratropium bromide at discharge
was associated with an increased risk of
death, specically related to cardiovascular
events [83C].
Chapter 16 Gwyneth A. Davies and Mike Pynn
In a nested casecontrol study in US Vet-
erans with COPD identied by the National
Veterans Affairs database who were
followed up between 1999 and 2004, the
relation between the use of various respira-
tory medications and cause of death was
examined [84C]. There was an association
between all-cause mortality and ipratropium
bromide and more specically cardiovascu-
lar deaths (OR 1.34; CI 1.22, 1.47);
however, the study lacked critical baseline
data, including lung function and smoking
status. Later, a subset of the same cohort
was examined to look at the effects of
ipratropium on all cardiovascular events
[85C]. The primary end-point was the time
to rst hospitalization because of a cardiac
dysrhythmia, heart failure, or acute coro-
nary syndrome. Of 82 717 veterans with
COPD, 6234 had a cardiovascular event
during the follow-up period, and this was
signicantly higher in those who had used
ipratropium in the previous 6 months (HR
1.40; CI 1.30, 151). In those who had
used ipratropium more than 6 months
before there was no difference. This study
had several limitations, including a lack of
baseline data on other cardiovascular risk
factors and data on COPD disease severity,
including spirometry.
Tiotropium A potential association with
cardiovascular risk has been suggested for
long-acting anticholinergic drugs. In a 2-
year randomized controlled study of the
benets of tiotropium versus uticasone
and salmeterol in 1323 patients with severe
COPD, tiotropium was associated with sig-
nicantly increased mortality (3% versus
6%), with an increase in cardiac events
[86C]. However, in a case series that speci-
cally studied stroke in relation to tiotropium,
there was no association [87c].
In a large meta-analysis in 2008, in which
data from 17 randomized controlled trials of
either ipratropium bromide or tiotropium in
13 654 patients were pooled, further concerns
arose [88M]. Placebo-controlled and alterna-
tive treatment studies were included and
patients were followed up for 6 weeks to
5 years. The primary end-point was combined
Drugs that act on the respiratory tract Chapter 16
cardiovascular deaths, myocardial infarctions,
and stroke. It was higher in those who had
used anticholinergic drugs: 1.9% versus 1.2%
on control therapy (RR 1.60; CI 1.22,
2.10). This appeared to be due to a signi-
cantly increased incidence of cardiovascular
death or myocardial infarction, without a sig-
nicantly increased risk of stroke. Most of the
data on increased cardiovascular events came
from the Lung Health Study (weight 51%),
with the problems already highlighted above.
It has been suggested that the contradiction
between this study and that of subsequent
meta-analyses could be explained rst by the
inclusion of ipratropium bromide trials [89r]
and secondly by the inclusion of trials that
compared tiotropium with inhaled glucocorti-
coids, which may reduce cardiovascular events
[90C]. Some have argued that the study did not
take into account differential drop-out rates:
patients tended to drop out earlier from the
placebo group and were therefore followed
up for different periods of time, during which
adverse events could have been reported.
Methodological problems were also
highlighted, including the double inclusion of
1000 patients (from the original study and a
subsequent meta-analysis) [91r].
In a large randomized, placebo-controlled
trial of tiotropium in 5994 subjects over
4 years, Understanding Potential Long Term
Impacts on Function and Tiotropium
(UPLIFT) [92C], a post-hoc analysis [93C]
examined mortality and observed 792 deaths;
there was a lower risk with tiotropium than
with placebo (HR 0.84; CI 0.73, 0.97).
In contrast to the previous meta-analysis, this
included a reduction in cardiac mortality
(HR 0.86; CI 0.75, 0.99).
The meta-analysis of Chinese patients
mentioned above found no increased risk
of cardiovascular events in this population,
but it included relatively small numbers
and follow-up for only 6 months [80M].
In another meta-analysis of the cardiovas-
cular effects of tiotropium, 19 randomized
controlled trials in 18 111 participants were
pooled to look at the primary end-point of
major adverse cardiovascular events, cardio-
vascular deaths, non-fatal myocardial
infarctions, or strokes [94M]. All the studies
included tiotropium in one treatment arm,
365
15 compared with placebo, two with combi-
nation therapy of salmeterol and uticasone,
and two with salmeterol. All the studies
involved adults with COPD of varying
degrees of severity who had used treatment
for more than 4 weeks and for up to 4 years.
Overall there was no difference in cardiovas-
cular end-points (0.96; CI 0.82, 1.12).
However, the authors noted an apparent
modication of this risk with increasing
smoking history, with a trend towards
increased cardiovascular risk in patients
with a greater than 55 pack-year history.
They concluded that overall tiotropium does
not appear to increase the risk of cardiovas-
cular events or related mortality but that the
potential interaction with other risk factors
should be noted and caution exercised.
In a meta-analysis of 30 placebo-controlled
trials of duration 4 weeks to 4 years, the analy-
sis involved 19 545 individuals who were ran-
domized to tiotropium (n 10 846) as a dry
powder inhaler (Handihaler) or a soft mist
generating inhaler (Respimat) [95M]. There
was lower all-cause mortality in the tiotropium
group (RR 0.88; CI 0.77, 1.0). The main
cardiovascular end-point was combined car-
diovascular deaths, non-fatal myocardial
infarctions, non-fatal strokes, and deaths (sud-
den death, sudden cardiac death, or cardiac
death). The incidence of cardiovascular events
was 2.15 per 100 patient-years in the treatment
group versus 2.67 in the placebo group. The
apparent reduction in events with tiotropium
was signicant (RR 0.83; CI 0.71, 0.98).
The risk of myocardial infarction, cardiac fail-
ure, or stroke showed a trend towards reduc-
tion with tiotropium.
There are conicting data on the risk of
adverse cardiovascular reactions to inhaled
anticholinergic drugs. Some have argued
that adverse reactions are seen more consis-
tently in studies of short-acting drugs.
Certainly, the more recent data on the long-
acting counterparts seems more reassuring.
Adequately powered randomized control
trials with cardiovascular safety as their
primary end-point are needed.
Urinary tract In 25 patients with COPD
and co-existing benign prostatic
366
hyperplasia, tiotropium had no adverse
effects on lower urinary tract function [96c].
LEUKOTRIENE MODIFIERS
[SEDA-30, 203; SEDA-31, 312;
SEDA-32, 319]
Montelukast [SED-15, 2384; SEDA-32,
319]
Comparative studies Montelukast versus
uticasone and/or uticasone salmeterol
In a randomized controlled trial in preschool
children with asthma-like symptoms
uticasone had a benecial effect on symp-
toms and montelukast on blood eosinophils
compared with placebo [97c]. There were
more upper respiratory tract infections in both
active treatment groups compared with pla-
cebo, and concomitant medication, such as
antibiotics, was also more common in the
active treatment groups.
Placebo-controlled studies In a randomized
placebo-controlled study of montelukast 4 or
8 mg in infants aged 324 months with symp-
toms of post-respiratory syncytial virus bron-
chiolitis over 20 months there was no benet
and no signicant differences in clinical or
laboratory adverse events compared with pla-
cebo [98C].
There were no signicant differences in
adverse events or suspected adverse reactions
between montelukast 5 or 10 mg and placebo
in Japanese patients with seasonal allergic
rhinitis [99C]. Similar ndings were reported
in children with allergic rhinitis [100c].
Systematic reviews Montelukast has been
examined in seven randomized controlled
trials and their open extensions in 2751 chil-
dren [101M]. Montelukast had a clinical and
laboratory safety prole similar to placebo
or active control/usual care therapies,
which did not change with long-term use.
Clinical/laboratory adverse events were
generally mild and transient. The
commonest adverse events included upper
Chapter 16 Gwyneth A. Davies and Mike Pynn
respiratory infections, worsening asthma,
pharyngitis, and fever in all groups.
Respiratory ChurgStrauss syndrome
There has been controversy regarding the
association between leukotriene receptor
antagonists and ChurgStrauss syndrome,
and it has been unclear whether the associ-
ation is causal or a result of unmasking as
glucocorticoid therapy is withdrawn.
ChurgStrauss syndrome was reported in a
woman with a background of asthma and
eczema, not on oral glucocorticoids, 5 weeks
after starting montelukast therapy [102A].
Cutaneous leukocytoclastic vasculitis and
eosinophilia completely resolved within
4 weeks of withdrawal.
The relation between montelukast and
the onset of ChurgStrauss syndrome has
been examined in a retrospective case-
crossover study in 78 patients. The odds
ratios for ChurgStrauss syndrome were
4.5 (CI 1.5, 14) for montelukast, 3.0
(CI 0.8, 11) for LABAs, 1.7 (CI 0.5,
5.4) for inhaled glucocorticoids, and 4.0
(CI 1.3, 12.5) for oral glucocorticoids.
However, positive estimates associated with
asthma medications suggested potential
confounding by a general escalation of
asthma therapy before the onset of
ChurgStrauss syndrome. The apparent
association between montelukast and
ChurgStrauss syndrome could also have
been explained by the increasing use of this
medication over time [103c].
In a systematic review 62 patients with
ChurgStrauss syndrome were distinguished
in terms of glucocorticoid use (nil/
unchanged/reduced) [104M]. Most of the
patients in each group showed a clear tempo-
ral relationship between the start
of leukotriene antagonist drug therapy
and the onset of ChurgStrauss syndrome,
with no evidence of pre-existing disease,
suggesting that the association may be causal.
Psychiatric The US FDA has stated that
post-marketing cases of neuropsychiatric
events have been reported for montelukast
and zarlukast [105S]. The events included
agitation, aggression, anxiousness, dream
abnormalities, hallucinations, depression,
Drugs that act on the respiratory tract Chapter 16
insomnia, irritability, restlessness, suicidal
thinking and behavior, and tremor. The
FDA recommended that patients should
be informed of the potential for these
events and requested a review of reports
of suicidality in clinical trials of
montelukast amidst their examination of
several drug classes in this regard. The
reviewers found no reports of completed
suicide, and reports of possibly suicidality-
related adverse events (PSRAEs) were rare
on montelukast and similar to controls
[106M]. As reported under conicts of inter-
est, employees of Merck and Co Inc were
authors of this study, and a further retro-
spective analysis of Merck data in 11 673
adults and children taking montelukast
showed that behavior-related adverse expe-
riences (BRAEs) were infrequent in clini-
cal trials of montelukast. The frequencies
of patients with one or more behavior-
related adverse experience were 2.73%
and 2.27% in the montelukast and placebo
groups respectively. The odds ratio for
montelukast versus placebo was 1.12 (CI
0.93, 1.36). Serious events, including
those that led to withdrawal, were rare.
A further review of three randomized con-
trolled trials showed no evidence of a nega-
tive effect of montelukast on emotional well-
being, using quality of life rather than indices
of depression [107R]. However, the studies
that were included in these reviews were not
originally designed to assess suicidality or
behavior-related adverse events. The authors
also pointed out that sufferers of asthma and
atopy have a higher than usual incidence of
psychological morbidity, and that such
reports are not unexpected.
Autacoids Possible montelukast-induced
angioedema has been reported in a woman
who had four such episodes over a month,
with onset 5 days after starting montelukast
[108A]. Given the history of severe allergies
in this case, causality was uncertain.
Pregnancy Outcomes in infants born to
women who took montelukast during preg-
nancy have been compared with outcomes
in the infants of disease-matched controls
who used inhalers for a similar indication
367
and women who did not have asthma and
had not been exposed to any known terato-
gens in a prospective multicenter study
[109C]. Of 180 montelukast-exposed preg-
nancies, there were 160 live births, 20 sponta-
neous abortions, and one major
malformation. Birth weight was lower
(304 g) in the babies of women who had taken
montelukast, which was attributed to the
severity of maternal asthma. Montelukast
did not appear to increase the baseline rate
of major malformations.
Pranlukast [SED-15, 2908]
Comparative studies Pranlukast versus
fexofenadine No clinically important adverse
effects were seen in a comparison of
pranlukast 60 mg bd and fexofenadine
120 mg bd ( mequitazine in both groups)
in non-asthmatic patients with Japanese cedar
pollinosis, but the numbers were small [110c].
Pranlukast appeared to inhibit airway hyper-
responsiveness whereas fexofenadine did not.
Pranlukast versus montelukast There was
no signicant difference in adverse events
between pranlukast 450 mg and montelukast
5 or 10 mg in a double-blind non-inferiority
study in seasonal allergic rhinitis [111C]. Diar-
rhea, thirst, and somnolence were suspected
adverse reactions that occurred in over 1%
in any of the three groups. One patient in
each montelukast group withdrew because
of diarrhea, which was considered a serious
adverse event and which resolved on
withdrawal.
PHOSPHODIESTERASE
TYPE IV INHIBITORS [SEDA-
29, 174; SEDA-30, 203; SEDA-31, 313;
SEDA-32, 321]
Cilomilast [SEDA-30, 203; SEDA-31,
313; SEDA-32, 321]
Placebo-controlled studies In ve phase III
double-blind, randomized, placebo-controlled,
368
parallel-group studies in patients with
resistant asthma who were randomized to
oral cilomilast 15 mg (n 2088) or placebo
(n 1408) twice daily for 24 weeks, the mean
change from baseline in FEV1 in those who
took cilomilast was greater than that with
placebo in all the studies (range 2444 ml)
[112R]. The effect on exacerbations of COPD
was variable. And there were no signicant
changes in the primary end-points of the
anti-inammatory studies, although some
anti-inammatory activity was detected,
including a reduction in tissue CD8 T lym-
phocytes and CD68 macrophages in airway
biopsies. There was no consistent effect of
cilomilast on hyperination. In all studies,
gastrointestinal adverse events were
reported more often in those who took
cilomilast and they mostly occurred in the
rst 2 weeks. There were no serious adverse
reactions. However, subsequent phase III
studies failed to conrm the earlier results,
and the development of cilomilast was
terminated.
Roumilast [SEDA-30, 203; SEDA-31,
313; SEDA-32, 321]
Roumilast has received approval from the
European Medicines Agency (EMA) for
use as maintenance treatment in severe
COPD associated with chronic bronchitis
with frequent exacerbations, as an add-on
to bronchodilator therapy.
In a pooled analysis of two identical multi-
center randomized placebo-controlled trials,
roumilast (n 1537) and placebo
(n 1534) were compared in patients with
severe COPD with a chronic bronchitis
phenotype and at least one exacerbation
requiring glucocorticoids treatment in
the previous year [113C]. Inhaled glucocorti-
coids, tiotropium, and theophylline were not
allowed. Treatment with roumilast
increased the pre-bronchodilator FEV1 and
reduced the rate of exacerbations. However,
adverse events were more common in the
intervention group (67% versus 62%), and
withdrawal secondary to these effects;
including headaches, nausea, and diarrhea,
Chapter 16 Gwyneth A. Davies and Mike Pynn
was more likely (14% versus 11%). The
probability of withdrawal was higher during
the rst 12 weeks. There was weight loss in
those who took roumilast (mean 2.1 kg),
whereas placebo treatment was associated
with slight weight gain (0.08 kg). Weight
reduction occurred in the rst 6 months and
was more marked in those who reported
gastrointestinal adverse reactions or head-
ache or in obese individuals.
In two randomized controlled trials
published simultaneously the benets of
roumilast, in addition to the long-acting
bronchodilators tiotropium (HELIOS trial,
n 934) [114C] and salmeterol (EOS trial,
n 744), were compared with placebo.
The patients had moderate to severe
COPD and did not require a history of
recent exacerbation for inclusion. The addi-
tion of roumilast to long-acting broncho-
dilators improved FEV1. In both studies
roumilast was associated with higher with-
drawal rates and this was statistically signif-
icant in the EOS trial. The incidence of
adverse events thought to be drug-related
was also highest in the roumilast treat-
ment arms (18% and 12% when it was
combined with salmeterol and tiotropium
respectively versus 3% and 2% in the two
placebo arms.) The main adverse reactions
were diarrhea, nausea, and weight loss,
2 kg in the EOS trial and 1.8 kg in the
HELIOS trial after 24 weeks. In contrast
to the previous study, weight loss was not
inuenced by baseline BMI but was more
common in those with adverse gastrointes-
tinal effects.
The trials to date suggest a NNT of 5 to
prevent one exacerbation; however, such
benets have to be weighed against the sig-
nicant adverse effects, although it has
been argued that the adverse events that
have led to withdrawal were transient and
occurred early on in treatment. Weight loss
in the 6-month trial was of similar magni-
tude to that in the 1-year trial suggesting
that this is an early phenomenon. However,
this adverse effect is of concern, especially
in COPD, in which a low BMI is associated
with a worse prognosis. On the other hand,
this adverse effect has been suggested to be
of some benet and has been associated
Drugs that act on the respiratory tract Chapter 16
with a possible reduction in both blood glu-
cose and glycosylated haemoglobin [115c].
Whether roumilast is more efcacious
than inhaled glucocorticoids in preventing
exacerbations has yet to be determined,
but currently clinicians have to weigh the
adverse effects prole against the increased
apparent risk of pneumonia with inhaled
glucocorticoids [116r].
LIPOXYGENASE
INHIBITORS
Zileuton [SEDA-15, 3717; SEDA-32, 322]
Psychiatric The US FDA has stated that
post-marketing cases of neuropsychiatric
events have been reported in patients taking
zileuton [105S]. However, to date neuropsy-
chiatric events in patients taking zileuton
have not been specically studied. It should
be noted that patients with asthma have
more psychological co-morbidity.
Combination studies Add-on zileuton
600 mg qds has been evaluated in
patients with asthma using uticasone 250
micrograms salmeterol 50 micrograms in
a pilot non-randomized, non-placebo, sin-
gle-blind study [117c]. Three of 22 patients
stopped taking zileuton because of headache
and/or nausea. There were small increases in
lung function with zileuton but no changes in
symptoms or nitric oxide.
MUCOLYTICS [SEDA-32, 325]
Systematic reviews In a Cochrane review
of 28 trials in 7042 patients with COPD,
oral mucolytic treatment was not associated
with an increase in adverse events com-
pared with placebo [118M]. In fact, the
meta-analysis showed a signicant effect in
favor of the mucolytic drugs (OR 0.81;
369
CI 0.70, 0.94) but this did not include
data from several large studies, and the
authors concluded that there is probably
no difference from placebo.
In a meta-analysis of 15 randomized con-
trolled studies of erdosteine with various
comparators, including placebo and other
mucolytic drugs, in 1046 patients, 54 patients
(10%) reported adverse events with
erdosteine compared with 57 (11%) in the
reference groups [119M]. Some of the trials
were not double-blind. The most common
adverse events were gastrointestinal com-
plaints, namely nausea, epigastric pain or
heartburn, and diarrhea. One patient
reported taste loss with erdosteine. Equal
numbers experienced allergic reactions
(three in each group).
Non-prescription cough and cold
medicines [SEDA-31, 314; SEDA-32, 326]
Death All 90 unexpected infant deaths that
occurred in Arizona in 2006 have been
reviewed by the Arizona Child Fatality
Program, in order to determine whether
there was an association of death with
over-the-counter cough and cold medica-
tions [120R]. There were 10 unexpected
infant deaths associated with use of cold
medications. The infants were aged 17 days
to 10 months. Post-mortem toxicology
found evidence of recent administration of
pseudoephedrine, antihistamines, dextro-
methorphan, and/or other ingredients
of cold medications. The families who
had used these medications had
sociodemographic risk factors, and 50% of
them had limited English prociency. Only
four of the infants had received medical
care for their current illness before death,
and only one had had the over-the-counter
medication prescribed by a clinician. This
study has raised concerns regarding the role
of the over-the-counter cough and cold
medications in deaths and supports the rec-
ommendation that such medications should
not be given to infants, and certainly not
without consulting a clinician.
370
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Chapter 16 Gwyneth A. Davies and Mike Pynn
acting bronchodilators: two randomised
clinical trials. Lancet 2009; 374(9691):
685704.
[115] Wouters EFM, Teichmann P, Brose M,
Gke B, Rabe KF, Fabbri LM. Effects of
roumilast, a phosphodiesterase 4 inhibi-
tor, on glucose homeostasis in patients
with treatment-nave diabetes. Am J
Respir Crit Care Med 2010; 181: A4471.
[116] O'Byrne PM, Gauvreau G. Phosphodies-
terase-4 inhibition in COPD. Lancet
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[117] Gelb AF, Taylor CF, Simmons M,
Shinar C. Role of add-on zileuton on total
exhaled, large airway, and small airway/
alveolar nitric oxide in moderate-severe
persistent adult asthmatics on uticasone
250 microg/salmeterol 50 microg. Pulm
Pharmacol Ther 2009; 22(6): 51621.
[118] Poole P, Black PN. Mucolytic agents for
chronic bronchitis or chronic obstructive
pulmonary disease. Cochrane Database
Syst Rev 2010;(2): CD001287.
[119] Cazzola M, Floriani I, Page CP. The ther-
apeutic efcacy of erdosteine in the treat-
ment of chronic obstructive bronchitis: a
meta-analysis of individual patient data.
Pulm Pharmacol Ther 2010; 23(2): 13544.
[120] Rimsza ME, Newberry S. Unexpected
infant deaths associated with use of cough
and cold medications. Pediatrics 2008; 122
(2): e31822.

17 Positive inotropic drugs and
drugs used in dysrhythmias
CARDIAC GLYCOSIDES
[SED-15, 648; SEDA-30, 209;
SEDA-31, 321; SEDA-32, 333]
Placebo-controlled trials A new post-hoc
analysis of the Digoxin Investigation Group
(DIG) study has examined the effect of
digoxin on mortality and hospitalization
during the rst year of follow-up in patients
with chronic heart failure randomized to
digoxin or placebo (3889 and 3899 respec-
tively) [1C]. The rationale was that the
median dose of digoxin (0.25 mg/day) and
the target serum digoxin concentration
(0.82.5 ng/ml) were higher than currently
recommended, which in part may explain
the lack of long-term mortality benet of
digoxin in the DIG trial. At 1 year all-cause
mortality was 392 and 448 patients with
digoxin and placebo respectively (HR in
favour of digoxin 0.87; 95% CI 0.76,
0.995). Respective hazard ratios for cardio-
vascular and heart failure deaths were 0.87
(95% CI 0.76, 1.01) and 0.66 (95%
CI 0.52, 0.85). All-cause hospitalization
occurred in 1411 and 1529 patients taking
digoxin and placebo respectively (HR
0.89; 95% CI 0.83, 0.96). Hospitaliza-
tions included a larger number of suspected
cases of digoxin toxicity in those taking
digoxin compared with those taking placebo
(120 versus 36) and of atrioventricular block
Side Effects of Drugs, Annual 33
J.K. Aronson (Editor)
ISSN: 0378-6080
DOI: 10.1016/B978-0-444-53741-6.00017-9
# 2011 Elsevier B.V. All rights reserved.
A. Finzi
or bradydysrhythmias (30 versus 5). Respec-
tive hazard ratios for cardiovascular and
heart failure hospitalizations were 0.82
(95% CI 0.75, 0.89) and 0.59 (95%
CI 0.52, 0.66). Thus, digoxin reduced
1-year mortality and hospitalization in
patients with chronic heart failure taking
angiotensin-converting enzyme inhibitors
and diuretics. The authors hypothesis was
not conrmed, as the serum digoxin con-
centration was not a strong predictor of
adverse outcomes. However, the conclu-
sions of this study were limited by the fact
that the patients were relatively young and
in sinus rhythm.
Drugdrug interactions Eslicarbazepine In
a double-blind, placebo-controlled, cross-
over trial in healthy volunteers, co-adminis-
tration of eslicarbazepine, a blocker of
voltage-gated sodium channels, which has
been used in the treatment of epilepsy,
had no clinically relevant effect on systemic
exposure to digoxin; there was no signi-
cant effect on digoxin Cmax or steady-state
plasma concentrations [2c].
Etoricoxib In a double-blind, randomized,
placebo-controlled trial of the effects of
etoricoxib 120 mg/day on the steady-state
pharmacokinetics of digoxin 0.25 mg/day,
etoricoxib increased digoxin Cmax by 33%,
but did not affect steady-state digoxin con-
centration [3c]. There were no serious
adverse effects. However, this study was
carried out in 14 healthy volunteers aged
2135, who are not representative of the
real-world users of these drugs.
377
378
Macrolides The interaction of digoxin with
macrolide antibiotics in patients with digi-
talis toxicity has been investigated in two
recent studies. The association between
hospitalization for digoxin toxicity and
recent exposure to individual macrolide
antibiotics has been investigated in a 15-
year, population-based, nested casecontrol
study [4c]. Clarithromycin was associated
with the highest risk of digoxin toxicity
(OR 15; 95% CI 7.9, 28), whereas
erythromycin and azithromycin were asso-
ciated with much lower risks.
In another retrospective population-
based case-control study, data from the
National Health Insurance Research
Database were scrutinized in a search for
patients with heart failure newly treated
with digoxin between January 2001 and
December 2004 who were hospitalized
for digitalis toxicity; they were compared with
the matched controls for use of clarithromycin
[5c]. Prescription of clarithromycin before the
index date was associated with increased risk
of hospitalization for digoxin intoxication;
the relative risks were 4.36 at 7 days (95% CI
1.28, 15), 5.07 at 14 days (95% CI 2.36,
11), and 2.98 at 30 days (95% CI 1.59,
5.63). The effect was dose related.
Varenicline The effects of varenicline on
the multiple-dose pharmacokinetics of
digoxin have been investigated in 18 smokers
who were randomized to digoxin 0.2 mg with
varenicline 1 mg bd or placebo for 14 days
[6c]. There were no adverse effects, and the
authors suggested that digoxin can be safely
administered with varenicline without the
need for dosage adjustment.
Management of adverse drug reactions As
there are no evidence-based guidelines for
treating patients with digoxin toxicity, differ-
ences among specialists in the use of digoxin-
specic antibody fragments and the decision
to admit these patients have been evaluated
by asking cardiologists, emergency physi-
cians, and medical toxicologists about their
practices [7c]. There were signicant differ-
ences among clinicians in various specialties
regarding the treatment of chronic digoxin
Chapter 17 A. Finzi
toxicity, which may reect diverse perspec-
tives or knowledge gaps and may translate
into excess costs or less than ideal care.
The efcacy and safety of a step-by-step
xed dose protocol for digoxin-specic Fab
fragments in the management of digoxin tox-
icity has been investigated in an open un-
controlled prospective study in 20 elderly
patients with acute or chronic digoxin intoxi-
cation [8c]. Two vials of specic antidigoxin
antibody Fab fragments were administered
on admission and repeated if after 1 hour
the electrocardiographic signs of toxicity
had not resolved. As 70% of patients needed
only the rst dose, the authors suggested that
this protocol is as effective as an equimolar
dose of Fab fragments, with signicant cost
reduction.
Although hyperkalemia is often treated
with intravenous calcium, this is tradition-
ally contraindicated in digoxin toxicity,
although this dogma has been questioned
(SEDA-32, 335). In a retrospective analysis
of the records of patients who were given
intravenous calcium while suffering from
digoxin toxicity, there were no life-threat-
ening dysrhythmias within 1 hour of cal-
cium administration and mortality was
similar among those who did not receive
calcium (27/136, 20%) and those who did
(5/23, 22%) [9c]. This conrms that in acute
digoxin intoxication intravenous calcium
does not seem to cause malignant dysrhyth-
mias or increase mortality.
OTHER POSITIVE
INOTROPIC DRUGS [SED-15,
2822; SEDA-30, 212; SEDA-31, 323;
SEDA-32, 336]
Milrinone [SED-15, 2346; SEDA-30,
212; SEDA-31, 323; SEDA-32, 336]
Cardiovascular Atrial brillation Post-
operative atrial brillation is a frequent com-
plication after cardiac surgery. Inotropic
drugs are commonly used perioperatively
Positive inotropic drugs and drugs used in dysrhythmias
to support ventricular function. In a retro-
spective analysis of 232 patients who under-
went cardiac surgery, the use of milrinone
was associated with a signicantly increased
risk of postoperative atrial brillation (58%
versus 26% in non-users) [10C]. Older age
(63 versus 57 years), hypertension, a lower
preoperative ejection fraction, mitral valve
surgery, right ventricular dysfunction, and a
higher mean pulmonary artery pressure (27
versus 22 mmHg) were also associated with
postoperative atrial brillation. A multivari-
able logistic regression analysis showed that
age, ejection fraction, and use of milrinone
(OR 4.86; 95% CI 2.31, 10) indepen-
dently predicted postoperative atrial
brillation.
Ventricular dysrhythmias and hypotension
In a retrospective study of 60 patients listed
for cardiac transplantation, pre-treatment
at home with intravenous milrinone was
an effective strategy as a bridge to trans-
plant if the waiting time was short (mean
60, range 9257 days) [11C]. There were
adverse effects potentially due to milrinone
in two cases: syncopal episodes and dis-
charge of an automated implantable cardio-
verter debrillator.
ANTIDYSRHYTHMIC
DRUGS
ADENOSINE AND ANALOGUES
[SED-15, 36; SEDA-30, 212; SEDA-31,
323; SEDA-32, 337]
Cardiovascular
Atrial brillation is an infrequent complica-
tion of adenosine treatment of supraven-
tricular dysrhythmias, but is rare when it is
used for diagnostic purposes. In a series of
adenosine stress tests, atrial brillation
occurred in 8 (0.41%) of 1948 patients and
lasted from 15 seconds to 6 hours; there
was spontaneously reversion to sinus
rhythm in all cases [12c].
Ventricular extra beats and/or ventricu-
lar tachycardia are prodysrhythmic effects
Chapter 17 379
of adenosine in terminating supraventricular
tachycardia. In 46 patients ventricular
tachycardia occurred in 8 (17%); it was
always polymorphic, short-lived, and self-
terminating [13c].
Respiratory
The safety of adenosine in myocardial perfu-
sion testing as an alternative to dipyridamole,
which is contraindicated in patients with
obstructive airways disease, has been exam-
ined in 46 consecutive patients who received
intravenous adenosine 140 mg/kg/minute for
4 minutes; only 14 complained of chest dis-
comfort and nine had dyspnea; none required
intravenous aminophylline or resuscitation
[14c].
Gastrointestinal
Adenosine can cause reduced esophageal
distensibility and visceral hyperalgesia, pro-
ducing symptoms similar to those described
in patients with functional esophageal non-
cardiac chest pain. In 14 healthy volunteers
who were studied by stepwise graded esoph-
ageal balloon distension with impedance pla-
nimetry before and after receiving placebo-
matched intravenous adenosine 100 mg/kg/
minute, adenosine signicantly lowered the
thresholds for rst perception, discomfort,
and pain; the cross-sectional area of the
esophagus increased and the esophageal wall
became stiffer after adenosine [15c].
Adenosine receptor agonists
[SEDA-30, 213; SEDA-31, 324; SEDA-32,
337]
Binodenoson
Placebo-controlled studies In a dose-
escalating, double-blind, placebo-controlled
study, young adults with mild intermittent
380
asthma were randomly assigned to either
binodenoson 1.5 micrograms/kg (n 41) or
placebo (n 22) [16C]. Binodenoson caused
no clinically signicant bronchoconstriction
or alterations in pulmonary function and tran-
siently increased heart rate and systolic blood
pressure. The most common treatment-emer-
gent adverse events were tachycardia, dizzi-
ness, and ushing.
Regadenoson
Observational studies The effects of age,
sex, body mass index, and diabetes on the
effects of regadenoson stress myocardial per-
fusion imaging have been studied on an analy-
sis of a database of 2015 patients [17c].
Compared with adenosine, regadenoson had
a lower combined symptom score and less
chest pain, ushing, and throat, neck, or jaw
pain, but more headache and gastrointestinal
discomfort.
Cardiovascular Patients who required myo-
cardial perfusion imaging were randomized
double-blind to low-level exercise with bolus
intravenous injection of regadenoson (n
39) or placebo (n 21); there were
adverse events in 77% and 33% respectively
[18C]. Peak heart rate was 13/minute higher
after exercise with regadenoson. There were
no differences in changes in blood pressure,
and no cases of second-degree or higher AV
block.
Respiratory In a double-blind, randomized,
placebo-controlled, crossover study of rega-
denoson in 38 patients with moderate
chronic obstructive pulmonary disease
(COPD) and 11 with severe COPD, 18 of
whom had dyspnea during activities of daily
living, there were no differences between
regadenoson and placebo on lung function;
there was new-onset wheezing in 6% and
12% respectively, but none of the patients
required acute treatment with broncho-
dilators or oxygen [19C].
The effects of regadenoson on airway resis-
tance have been investigated in a double-
blind, randomized, placebo-controlled,
Chapter 17 A. Finzi
crossover trial in patients with asthma and a
positive adenosine monophosphate challenge
test [20C]. The mean ratio of the FEV1 at each
time tested relative to the baseline FEV1 was
signicantly higher after treatment with rega-
denoson than with placebo from 10 to
60 minutes after treatment. One patient had
a 36% asymptomatic reduction in FEV1 after
regadenoson, with spontaneous reversion.
The most common adverse events with rega-
denoson were tachycardia (66%), dizziness
(53%), headache (45%), and dyspnea
(34%); mean heart rate increased signi-
cantly, up to a maximum of 10/minute.
Amiodarone [SED-15, 148; SEDA-30,
213; SEDA-31, 324; SEDA-32, 339]
Observational studies In a 10-year pro-
spective study of the effects of the timing
of the introduction of amiodarone after cor-
rective surgery for congenital heart defects,
71 of 2651 patients (2885 procedures,
2106 cardiopulmonary bypass procedures)
received amiodarone for newly detected
postoperative atrial tachydysrhythmias
(n 70) or ventricular tachydysrhythmias
(n 7) as early treatment (i.e. within
60 minutes from detection; n 29) or late
treatment (i.e. after 60 minutes from
detection; n 42) [21C]. There were signif-
icant benets of early treatment for time to
rate and rhythm control, reduction in the
dose needed to obtain rate control, and
reduction of pediatric cardiac intensive care
stay. No adverse events in either group
required additional catecholamine therapy,
additional uids, or resuscitation.
In a randomized study of treatment with
amiodarone for 6 days after pulmonary
resection in 65 patients and 65 controls who
received no amiodarone, there was a signi-
cant reduction in the frequency of atrial
brillation in treated patients (14% versus
32%); there were no signicant differences
in the incidences of pulmonary complica-
tions or amiodarone-related adverse effects
between treated and control patients (brady-
cardia in 4 versus 1 and QTc interval prolon-
gation in 1 versus 0 respectively) [22c].
Positive inotropic drugs and drugs used in dysrhythmias
Systematic reviews In a systematic review of
15 randomized studies in 8422 patients, amio-
darone reduced the risk of sudden cardiac
death (7.1% versus 9.7%) and cardiovascular
death (14% versus 16%) [23M]. Amiodarone
increased the risk of pulmonary toxicity
(2.9% versus 1.5%; OR 1.97) and thyroid
toxicity (3.6% versus 0.4%; OR 5.68).
Cardiovascular Amiodarone-induced tor-
sade de pointes has been reported in a
patient with WolffParkinsonWhite syn-
drome who had been given intravenous
amiodarone for a wide-complex tachycar-
dia [24A]. Aas sinus rhythm was restored,
QT interval prolongation and T wave alter-
nans occurred, followed by symptomatic
torsade de pointes. The dysrhythmia sponta-
neously terminated after discontinuation of
intravenous amiodarone.
Amiodarone-induced torsade de pointes
occurred in a woman with decompensated
liver cirrhosis, ischemic heart disease, and
prolongation of the QT interval, who devel-
oped atrial brillation. After DC cardiover-
sion and restoration of sinus rhythm, a new
episode of atrial brillation was successfully
treated with intravenous metoprolol, and
the QT interval normalized [25A].
In a retrospective study of the potential for
major adverse cardiovascular events in 57
patients with amiodarone-induced thyrotox-
icosis compared with 224 euthyroid patients
for a mean of 49 months, the patients with
thyrotoxicosis had a higher rate of events
(32% versus 11%), mostly driven by a higher
rate of ventricular tachydysrhythmias requir-
ing admission (7.0% versus 1.3%); overall,
there was a 2.7 times increased risk [26c].
Thyrotoxicosis (HR 2.68) and a left ven-
tricular ejection fraction below 45% (HR
2.52) were independent predictors of
major adverse cardiovascular events.
Acute cardiogenic shock with profound
hypotension has been reported in a neonate
who was given intravenous amiodarone for
paroxysmal supraventricular tachycardia
[27A].
A 4-day-old neonate was given an intravenous
loading dose of amiodarone erroneously pre-
scribed at the oral dose (1200 mg/m2 47 mg/kg).
Chapter 17 381
During the rst 24 hours he developed acute car-
diogenic shock, profound hypotension, myocar-
dial ischemia, a severe encephalopathy, and
multiple organ failure, with acute hepatic and
renal insufciency, which recovered within a
few days.
The hypothesis that the two excipients, benzyl
alcohol and polysorbate 80, precipitated car-
diogenic shock seems plausible, particularly
because the plasma concentrations
of amiodarone and desethylamiodarone
never reached toxic concentrations.
Respiratory Amiodarone pulmonary toxic-
ity has been described after lung transplan-
tation [28A].
A 61-year-old man with idiopathic pulmonary
brosis underwent lung transplantation and
received intravenous and oral amiodarone for
recurrent postoperative atrial brillation. After
2 months he developed a bilateral pleural effu-
sions and lung consolidation. There was high
attenuation of the liver parenchyma, compati-
ble with amiodarone deposition. Because of
possible acute allograft rejection, he was given
glucocorticoids. Bronchoscopy and broncho-
alveolar lavage showed a white blood cell count
of 36  106/l, with 52% neutrophils, 39% lym-
phocytes, 8% monocytes and no eosinophils.
Blood cultures were negative. Transbronchial
biopsies showed no evidence of rejection but
there were intra-alveolar foamy macrophages.
Right thoracentesis conrmed the presence of
a sterile exudative pleural effusion. Withdrawal
of amiodarone led to complete resolution of the
pleural effusions and lung consolidation within
8 weeks.
In another case a post-mortem lung mass
was found to be due to lymphoplasmacytic
inltrates in the alveolar walls and intra-
alveolar accumulation of foamy macro-
phages containing myelinoid bodies, suggest-
ing that it was due to amiodarone [29A].
Amiodarone lung toxicity, exceedingly
rare in children, has been described in a
child with supraventricular tachycardia
after repair of a transposition of the great
vessels, who developed acute amiodarone-
induced pulmonary toxicity [30A]. Recent
cardiac surgery, a high concentration of
inspired oxygen during mechanical ventila-
tion, and chest trauma were considered
associated susceptibility factors.
382
As interferon gamma (IFN-g: Th1 cyto-
kine) inhibits pulmonary broblast prolifer-
ation, whereas interleukin-4 (IL-4:
Th2 cytokine) augments broblast growth
and collagen production, it has been
hypothesized that amiodarone-induced lung
toxicity is related to the balance of Th1/Th2.
In 26 Japanese patients, six with and 20
without radiological signs of amiodarone
lung toxicity, the Th1/Th2 balance was
investigated by measuring the ratio of IFN-
g and IL-4 produced by activated peripheral
CD4 T cells [31cH]. The Th1/Th2 balance
was signicantly different and was the most
powerful indicator of amiodarone-induced
subclinical lung toxicity.
Nervous system In a retrospective study of
the medical records of 707 patients treated
with amiodarone over 151 months, there
was a cumulative incidence of probable
amiodarone-induced neurotoxic effects in
2.8%, 1.6% being referred to a neurology
department. The neurological problems
included tremor, gait ataxia, peripheral neu-
ropathy, and cognitive impairment. The pri-
mary susceptibility factor for amiodarone-
related toxicity was duration of treatment,
not age, dose, sex, or indication. However,
the higher incidence of neurotoxic effects
that was observed when amiodarone was
rst introduced may have been related to
a much higher daily dose [32C].
Amiodarone-associated neurotoxicity has
been reported [33A].
A 76-year-old man developed ataxia after tak-
ing amiodarone hydrochloride 400 mg orally
tds for more than 2 months, intended as a
loading dosage. The ataxia lessened over the
rst 2 weeks after the amiodarone was with-
drawn and resolved completely within
5 months.
This case emphasizes the need for strict
monitoring of patient adherence to the
scheduled loading dose period.
Sensory systems Cornea verticillata has
been studied in 22 patients with Fabry dis-
ease and in 11 patients taking amiodarone,
comparing the corneal microstructure in
both types [34c]. Confocal laser-scanning
Chapter 17 A. Finzi
microscopy showed the same pattern of
hyper-reective deposits in the basal cell
layer of corneal epithelium in both sets of
patients. Microdot changes in the anterior
stroma were more prevalent in those who
were taking amiodarone.
More about amiodarone-induced
thyrotoxicosis and its management
Diagnosis Amiodarone-induced thyrotoxi-
cosis occurred in a patient with an autono-
mously functioning nodular goiter [35A].
A 64-year-old woman with atrial brillation
and a nodular goiter developed overt thyrotox-
icosis after taking amiodarone 200 mg/day for
less than 12 weeks. A thyroid scan showed a
hyperfunctioning nodule in the left lobe, and
the thyroid-stimulating hormone (TSH) recep-
tor antibody titer was transiently raised. Amio-
darone was withdrawn and she was given
propylthiouracil 100 mg tds, but developed a
severe generalized rash, a fever, and leukocyto-
sis after 4 weeks. Thyroidectomy was per-
formed, and histopathology was compatible
with type 1 amiodarone-induced thyrotoxicosis.
Differentiating between the two types of
thyrotoxicosis is difcult but important for
implementation of the correct therapeutic
strategy. Amiodarone should be avoided in
patients with toxic nodular goiters and sub-
total thyroidectomy may be the treatment of
choice.
A patient taking amiodarone for atrial
brillation developed hyperthyroxinemia,
which led to a diagnosis of thyroid hormone
resistance syndrome [36A]. Although
thyroid hormone resistance is not a compli-
cation of amiodarone treatment, hyper-
production of hormone, accompanied by
high concentrations of thyroid hormone
without TSH suppression, is a rare genetic
disorder that is worth being aware of.
Presentation Atrial brillation can be
induced by amiodarone-induced thyrotoxi-
cosis even some time after drug withdrawal,
as has been described in a patient who had
taken oral amiodarone for 2.5 years for ven-
tricular dysrhythmias, in whom it had been
withdrawn 6 months before [37A].
Positive inotropic drugs and drugs used in dysrhythmias
Pathophysiology Concentrations of amio-
darone and desethylamiodarone were mea-
sured simultaneously in plasma and fat in
30 patients who had taken amiodarone for
3 months to 12 years [38c]. Amiodarone
concentrations in fat were 4226 (mean 55)
times higher than in plasma, and correlated
with plasma concentrations (r 0.68). Nine
of 12 patients who had taken amiodarone
for at least 2 years developed clinically
important adverse reactions, predominantly
hypothyroidism (n 6), compared with
two of 18 patients who had taken it for less
time (RR 6.75; 95% CI 1.8, 26). The
risk of adverse reactions did not correlate
with amiodarone concentrations in plasma
or fat.
Management Glucocorticoids are the rst-
line treatment in type 2 amiodarone-induced
thyrotoxicosis, and thionamides play no
role. In a matched retrospective cohort com-
parison of the efcacy of a thionamide
(methimazole) or a glucocorticoid (pred-
nisone) for 40 days in type 2 amiodarone-
induced thyrotoxicosis, in 42 patients, 23%
of those who took prednisone were still
thyrotoxic, compared with 86% of those
who took methimazole [39C]. When those
who had taken methimazole were then given
prednisone, 94% achieved euthyroidism
within another 40 days.
The American Thyroid Association has
investigated how North American thyroid-
ologists assess and treat amiodarone-induced
thyrotoxicosis and has compared the results
with those of a survey using the same ques-
tionnaire previously carried out among Euro-
pean thyroidologists [40C]. Most of the
respondents (91% versus 68% in Europe)
see under 10 new cases of amiodarone-
induced thyrotoxicosis per year, which seems
to be less common than amiodarone-induced
hypothyroidism in North America (34% and
66% of amiodarone-induced thyroid dys-
function respectively, compared with 75%
and 25% in Europe). When thyrotoxicosis is
suspected in North America hormonal assess-
ment is mostly based on measurements of
serum-free T4 and TSH, while serum-free
T3 determination is requested less often than
Chapter 17 383
in Europe; thyroid autoimmunity is included
in the initial assessment less than in Europe.
Withdrawal of amiodarone is more often
considered unnecessary by North American
thyroidologists in type 1 amiodarone-
induced thyrotoxicosis (which occurs in
patients with latent disease, due to the iodine
contained in amiodarone) than in type 2
amiodarone-induced thyrotoxicosis (which
is due to destructive thyroiditis in a previ-
ously normal gland): 21% versus 10% in
Europe in type 1; 34% versus 20% in type
2. In type 1 thyrotoxicosis thionamides rep-
resent the treatment of choice in North
America and Europe, but as monotherapy
in 65% compared with 51%; European
thyroidologists more often consider potas-
sium perchlorate as a useful addition (31%
versus 15%). Glucocorticoids are the
selected treatment for type 2 thyrotoxicosis,
either alone (62% vs. 46% in Europe) or
in association with thionamides (16% versus
25%). After restoration of euthyroidism,
thyroid ablation in the absence of recurrent
thyrotoxicosis is recommended in type 1 less
often in North America. If amiodarone
needs to be restarted, prophylactic thyroid
ablation is advised by 76% in type 1 thyro-
toxicosis, while a wait-and-see strategy is
adopted by 61% in type 2, as in Europe.
This survey shows differences in therapeutic
attitudes, which reect the frequent uncer-
tainty of the underlying mechanism that
leads to amiodarone-induced thyrotoxicosis.
Liver In a Bayesian approach, linking
information from clinical trials with hepato-
toxicity from published case reports,
the maximum number of expected cases
of hepatotoxicity in patients taking amio-
darone or placebo was calculated using a
Poisson distribution [41H]. The calculated
odds ratio was used as a prior for the subse-
quent quantication of the likelihood of
amiodarone-induced hepatotoxicity in indi-
viduals. The prior odds of amiodarone-
induced hepatotoxicity was 0.48. The
Bayesian model combined information
about the latency period and the period of
remission, together with analytical parame-
ters that properly dened the toxicity
384
prole reported in a series of 39 cases. The
analytical pattern dened by this model was
different from that expected if liver injury
in published cases had been due to other
causes. This method deserves further evalu-
ation using a larger database.
Amiodarone has been associated with
steatohepatitis with advanced brosis, pre-
senting with hepatic decompensation and
portal hypertension, with ascites and recur-
rent hemorrhage from esophageal varices
[42A]. There was marked histological simi-
larity between amiodarone-induced liver
disease and alcoholic and non-alcoholic
steatohepatitis.
Immunologic Amiodarone is contraindi-
cated in patients with hypersensitivity to
intravenous contrast media. Three patients
with previous reactions to contrast media
had no adverse reactions during prolonged
amiodarone treatment 100200 mg/day
[43A]. Poor absorption of oral amiodarone
and reactions to other components of con-
trast media besides iodine, causing hista-
mine release, could explain this lack of
cross-reactivity.
Drug dosage regimens In a randomized
study of the major events that occurred in
209 patients who received episodic or con-
tinuous amiodarone for prevention of atrial
brillation after electrical cardioversion fol-
lowing amiodarone loading, with a median
follow-up of 2.1 years, only 48% of the
patients who took episodic treatment were
in sinus rhythm, compared with 64% of
those on continuous treatment [44C]. The
causes of amiodarone withdrawal were not
signicantly different (20/106 during epi-
sodic treatment and 25/103 during continu-
ous treatment). Hyperthyroidism and
hypothyroidism were the most frequent
adverse effects (in 11 and 10 patients
respectively). Thus, episodic treatment with
amiodarone appears to be less effective in
the prevention of atrial brillation recur-
rences without any advantage in terms of
adverse effects.
Drugdrug interactions Enalapril In a
study of the combined use of amiodarone
Chapter 17 A. Finzi
100200 mg/day with enalapril 5 mg/day in
58 patients with paroxysmal atrial brillation,
adverse reactions to amiodarone that
required drug withdrawal included only inter-
stitial pneumonia in two subjects (3.4%) and a
rash in one (1.7%) [45c].
Haloperidol In a series of 381 patients
there was a small, potentially signicant
prolongation of the QTc interval in 49 of
them who were taking amiodarone and
haloperidol, but there were no tachydys-
rhythmias; in 138 other patients who were
taking at least one other drug that prolongs
the QT interval, there was no apparent
effect [46c].
Monitoring therapy In a retrospective chart
review of antidysrhythmic drug therapy in
patients taking class I or class III antidys-
rhythmic drugs, adherence to monitoring pro-
tocols was assessed, and the type and
frequency of pharmacist-identied events
and interventions were determined [47c]. In
all, 134 patients were studied, including 58
taking amiodarone, 40 taking sotalol, 28 tak-
ing dofetilide, and 8 taking propafenone.
Amiodarone was associated with the highest
rate of adverse events (23% of patient visits).
A change in the antiarrhythmic medication
regimen was recommended for nine patients
and resulted in drug withdrawal in three.
Bepridil [SED-15, 445; SEDA-31, 329]
Respiratory Three cases of interstitial pneu-
monia have been described in Japanese
patients during treatment with bepridil. In
one case, exertional dyspnea developed over
8 months and transbronchial lung biopsy
specimens showed moderate lymphocytic
inltration; glucocorticoid therapy led
to resolution in 3 weeks [48A]. The
other two patients developed pneumonia
after 20 and 60 days; one required
glucocorticoid treatment and the other was
discharged having improved after bepridil
withdrawal [49A].
Positive inotropic drugs and drugs used in dysrhythmias
Cibenzoline [SED-15, 740; SEDA-30,
217; SEDA-31, 330; SEDA-32, 347]
Nervous system Acute myasthenia has
been reported in a Japanese patient with
chronic renal dysfunction [50A].
A woman in her late 60s with chronic kidney
disease was given cibenzoline 300 mg/day for
atrial brillation. After 3 days, she developed
blepharoptosis. Anti-acetylcholine receptor
antibodies were not found and an edropho-
nium test was negative. She developed pneu-
monia with a pleural effusion and diarrhea,
and her renal function worsened. At the same
time, her blepharoptosis worsened and she
developed a dull headache, weakness, and dif-
culty in chewing. Dyspnea was accompanied
by hypercapnia. Cibenzoline was withdrawn.
Her condition improved and she was taken
off the respirator on day 35. Repetitive stimu-
lation of 5 Hz was applied to her right facial
nerve along with evoked electromyography
on days 2 and 11 after withdrawal of cibenzo-
line. On day 2, electromyography showed a
waning phenomenon, whereas no such phe-
nomenon was seen on day 11. The blood con-
centration of cibenzoline immediately after
withdrawal was extremely high (2448 ng/ml).
Disopyramide [SED-15, 1145;
SEDA-30, 217; SEDA-32, 347]
Musculoskeletal Myasthenia gravis, in a
patient with pre-existing disease, was exacer-
bated after the use of disopyramide for atrial
brillation, followed by a takotsubo-shaped
cardiomyopathy, QT interval prolongation,
and torsade de pointes [51A].
Drugdrug interactions Sulfonylureas Severe
hypoglycemia occurred in a 62-year-old
woman with type 2 diabetes taking low-
dose glimepiride after disopyramide was
introduced; she had no further episodes
occurred after withdrawal of disopyramide
[52AE]. Current recordings of KATP chan-
nels expressed in Xenopus oocytes showed
that at concentrations that are associated
with clinical benet, disopyramide and gli-
mepiride both inhibited KATP channels by
Chapter 17 385
5060%. However, when both drugs were
applied together, the KATP channels were
almost completely closed. Dramatic inhibi-
tion of KATP channels is sufcient to cause
membrane depolarization in the pancreatic
beta cells and stimulate insulin secretion.
Monitoring therapy The relation between
the anticholinergic effects of disopyramide
and serum concentrations of disopyramide
or its metabolite mono-N-dealkyldisopyra-
mide have been studied in 141 in-patients
[53c]. There was no correlation of creatinine
clearance and the ratio of the serum concen-
tration to the dose of disopyramide, but a
signicant inverse correlation between cre-
atinine clearance and the concentration to
dose ratio of the metabolite. There was no
signicant difference in disopyramide con-
centration between patients with and with-
out anticholinergic adverse effects, but
there were signicant differences in the
metabolite concentration, creatinine clear-
ance, and the ratio of metabolite to parent.
The authors recommended that when the
serum concentration of the metabolite is
over 1 mg/l, disopyramide should be discon-
tinued or the dose reduced.
Dofetilide [SED-15, 1173; SEDA-30,
217; SEDA-32, 347]
Cardiovascular One case of torsade de
pointes was observed in a series of 160
patients taking dofetilide, mean dose
428 mg/dose, for chemical cardioversion of
atrial brillation or utter, 50 of whom
were also taking magnesium sulfate in an
attempt to improve the chance of success
[54c]. The addition of magnesium sulfate
resulted in a 107% increase in success rate.
However, the patient with the dysrhythmia
did not receive magnesium sulfate.
In another efcacy study in 36 patients
accepted for ablation of atrial brillation
who started taking dofetilide before the
procedure and 91 who were given dofeti-
lide after ablation, six stopped taking it
386
because of QT interval prolongation with-
out dysrhythmias [55c].
Dronedarone
Many amiodarone congeners have been devel-
oped over a long period in the hope of over-
coming its frequent, often severe, multiorgan
adverse effects. Among them, dronedarone
has been the most promising. It is a
non-iodinated benzofuran derivative, charac-
terized, in comparison with amiodarone, by
deletion of the two atoms of iodine and the addi-
tion of a methylsulfonyl group [56R]. Drone-
darone shares most of its electrophysiological
and pharmacological properties with amiodar-
one, prolonging the action potential duration by
blocking Na and Ca2 channels. It has a non-
specic sympatholytic effect and slows the sinus
rate by inhibiting spontaneous phase 4 depolar-
ization. Dronedarone has a serum half-life
of about 24 hours, compared with 50 days
or longer of amiodarone. The active metabolite
of amiodarone, desethylamiodarone, accumu-
lates in tissues, whereas debutyldronedarone,
the principal metabolite of dronedarone, does
not accumulate signicantly in plasma or tis-
sues. Desethylamiodarone has a strong inhibi-
tory effect on the triiodothyronine (T3)
receptor, whereas debutyldronedarone has a
weak effect [57C].
In two randomized, controlled trials in
1237 patients with atrial brillation or utter,
the European Trial in Atrial Fibrillation or
Flutter Patients Receiving Dronedarone for
the Maintenance of Sinus Rhythm (EURI-
DIS, NCT00259428) and the American-
AustralianAfrican Trial with Dronedarone
in Atrial Fibrillation or Flutter Patients for
the Maintenance of Sinus Rhythm (ADO-
NIS NCT00259376), dronedarone was more
effective than placebo in maintaining sinus
rhythm and in controlling the ventricular
rate during recurrences of atrial brillation
[58M]. At 12 months of follow-up, the rates
of pulmonary, thyroid, and hepatic adverse
effects were not signicantly greater with
dronedarone than with placebo; there was a
higher incidence of raised serum creatinine
Chapter 17 A. Finzi
with dronedarone than with placebo (2.4%
versus 0.2%). However, another study of
dronedarone in patients with advanced
symptomatic congestive heart failure, but
without atrial brillation, was prematurely
terminated because of an excess number of
deaths among those taking dronedarone
[59C]. Adverse effects of dronedarone were
not responsible for this outcome, and an
increased serum creatinine concentration in
eight patients versus none in the placebo
group was the only signicant difference
between the treated and untreated patients.
The ATHENA trial was a placebo-con-
trolled, double-blind, parallel-arm trial to
assess the efcacy of dronedarone 400 mg
bd for the prevention of cardiovascular hos-
pitalization or death from any cause in
patients with atrial brillation/atrial utter
[60C]. Treatment was prematurely with-
drawn in 696 of the 2301 patients (30%) tak-
ing dronedarone, compared with 716 of the
2327 (30.8%) taking placebo. The main rea-
sons were treatment-emergent adverse events
(in 13% of those taking dronedarone versus
8.1% of those taking placebo), gastrointesti-
nal events (26% versus 22%), skin related
events (10% versus 7.6%), raised serum creat-
inine (4.7% versus 1.3%), and QT interval
prolongation (1.7% versus 0.6%).
In a meta-analysis of randomized con-
trolled studies of dronedarone and amiodar-
one for prevention of recurrent atrial
brillation, four placebo-controlled trials of
dronedarone, four placebo-controlled trials
of amiodarone, and one trial of dronedar-
one versus amiodarone were compared
[61M]. Amiodarone was superior to drone-
darone in preventing recurrent atrial brilla-
tion, but there was a trend towards greater
all-cause mortality (OR 1.61; 95% CI
0.97, 2.68) and more overall adverse
events requiring drug withdrawal with amio-
darone than with dronedarone (OR 1.81;
95% CI 1.33, 2.46). Among adverse reac-
tions, thyroid toxicity was more frequent
with amiodarone (7.5% versus 4.0%)
whereas increased serum creatinine was
more frequent with dronedarone (4.0% ver-
sus 0%). For every 1000 patients treated
with dronedarone instead of amiodarone,
the authors estimated that there were about
Positive inotropic drugs and drugs used in dysrhythmias
228 more recurrences of atrial brillation in
exchange for 9.6 fewer deaths and 62 fewer
adverse events requiring drug withdrawal.
This meta-analysis prompted comments
and criticisms with regard to the imbalance
in the number of trials with amiodarone
and dronedarone and their patient popula-
tions [62r]. However, although further con-
rmation from direct comparisons is
needed, dronedarone does seem to be some-
what less efcacious but possibly safer than
amiodarone.
In conclusion, based on the results of an
adequate series of clinical trials, dronedarone
may be a useful alternative to amiodarone,
with similar or slightly less antidysrhythmic
efcacy, but signicantly better tolerability. It
is noteworthy that it seems to have no prodys-
rhythmic effects and has denitely no thyro-
toxic effect. Among its non-cardiac adverse
effects, only a raised serum creatinine seems
to be clinically relevant and deserves careful
monitoring, particularly in patients with
impaired renal function.
Flecainide [SED-15, 1370; SEDA-30,
217; SEDA-31, 330; SEDA-32, 348]
Cardiovascular Flecainide is used diagnos-
tically to uncover latent Brugada syndrome
in patients with the SCN5A mutation.
However, sporadically it can accidentally
reveal a Brugada pattern when used for
therapeutic purposes in other dysrhythmias,
and caution is recommended when select-
ing it for their treatment.
In one case intravenous ecainide for
atrial brillation induced a transient Bru-
gada-like syndrome, sinus arrest, and total
atrioventricular block; an SCN5A mutation
was subsequently identied [63A].
Electrolyte balance Severe ecainide-in-
duced hyponatremia has been described
[64A].
A 67-year-old woman with symptomatic par-
oxysmal atrial tachycardia was given oral e-
cainide 100 mg bd. After 1 month, she
developed dizziness, generalized malaise, and
Chapter 17 387
weakness. She had hyponatremia with a fall
in serum sodium concentration from
136 mmol/l before ecainide to 122 mmol/l.
There were no signs or symptoms of volume
overload or volume depletion. The random
urine osmolality was 242 mOsm/kg, suggesting
an inability to excrete a dilute urine. Serum
osmolality was 282 mOsm/kg (reference range
275290 mOsm/kg), which ruled out the syn-
drome of inappropriate antidiuretic hormone
secretion. The urine random sodium concen-
tration was 41 mmol/l (reference range
< 30 mmol/l), indicative of increased urinary
sodium loss, which was puzzling as the patient
showed no signs of volume depletion. Renal
function was normal. After uid restriction,
the sodium concentration rose to 130 mmol/l
and her symptoms abated. Flecainide was con-
tinued, and 5 days later, she again developed
dizziness, generalized malaise, and weakness.
Once again, the serum sodium concentrations
had fallen to 127 mmol/l. In addition to uid
restriction, ecainide was withdrawn. Her
symptoms improved and the serum sodium
concentration normalized. No further episodes
of hyponatremia occurred over the next
12 months.
In this case, hyponatremia was precipitated
by ecainide and recovered after drug with-
drawal. The authors postulated that the
mechanism was direct inhibition of renal
and intestinal epithelial sodium channels,
leading to reduced sodium reabsorption.
Skin There have been several reports of
various cutaneous adverse effects of ecai-
nide, such as urticaria, ushing, pruritus,
and psoriasis. There has now been a report
of a xed drug eruption [65A].
A 69-year-old man developed a recurrent foot
blister several weeks after starting oral ecai-
nide. The clinical suspicion of a xed drug
eruption was conrmed histologically. The
patient was given clobetasol ointment and
advised to continue taking ecainide despite
the eruption, given the importance of the
medication in treating his dysrhythmia.
Drug overdose Deliberate overdose with
ecainide has been described [66A].
A 37-year-old man took ecainide 1500 mg over
a few minutes and developed chest discomfort,
dyspnea, and a ventricular tachycardia, which
resolved spontaneously. In sinus rhythm, a Bru-
gada pattern on the electrocardiogram became
evident, with right bundle branch block and
388
typical ST segment elevation in the right precor-
dial leads. Hypotension, which occurred after
some hours, was treated with intravenous uids,
and a mild acidosis required sodium bicarbon-
ate. He recovered after 2 days.
Accidental ecainide intoxication, due to a
medication error, occurred in a 2-year-old
toddler who was given intravenous ecainide
4.8 mg/kg/day and nadolol for persistent junc-
tional reciprocating tachycardia [67A]. Car-
diogenic shock with absence of vital signs
required emergency treatment, and ventricu-
lar tachycardia was treated with sodium bicar-
bonate; recovery was uneventful. The serum
ecainide concentration was 0.67 mg/l.
Drugdrug interactions Paroxetine An
interaction of ecainide with paroxetine
has been described.
A 67-year-old patient taking paroxetine 40 mg/
day developed confusion and paranoia
after taking ecainide 200 mg/day for 2 weeks.
The plasma ecainide concentration was
1360 mg/l (usual target range 2001000);
the symptoms subsided after paroxetine was
withdrawn and the dose of ecainide was
reduced [68A].
Paroxetine is a CYP2D6 inhibitor, which
could have explained this interaction.
The effects of CYP2D6 genetic polymor-
phisms on the pharmacokinetics of a single
oral dose of ecainide and on the extent
of its interaction with paroxetine have been
investigated in an open study in 21 healthy
Korean volunteers [69c]. The AUC, termi-
nal half-life, and mean residence time
increased signicantly after paroxetine in
those with the CYP2D6*10 allele, which is
common among Asians.
Lidocaine [SED-15, 1370; SEDA-30,
217; SEDA-31, 330]
Cardiovascular Brugada syndrome has
been attributed to lidocaine [70A].
A 45-year-old black man with no history of car-
diac disease had a seizure associated with a
monomorphic broad-complex ventricular tachy-
cardia. He was given lidocaine 70 mg followed
by a continuous infusion of 1 mg/minute, which
Chapter 17 A. Finzi
led to ST segment elevation in leads V13. The
tachycardia was hemodynamically destabilizing
and was quickly converted electrically.
Lidocaine-induced ST segment elevation and
the fact that the patient had a malignant dys-
rhythmia and ST segment elevation
unmasked by the Na channel blocker led to a
diagnosis of Brugada syndrome. Because of
the unique characteristics of the case, he was
referred for genotyping to look for a channe-
lopathy. He had a double mutation in the
SCN5A gene, capable of altering the interac-
tion of lidocaine with the sodium channels,
conferring class Ic activity on this class Ib drug,
with potent use-dependent blockade of the
sodium channel; there was an additive effect
of the two missense mutations in sensitizing
the sodium channel to lidocaine.
Cardiac arrest occurred after 20 minutes a
52-year-old woman gargled and accidentally
swallowed 20 ml of a 5% lidocaine solution
before laryngoscopy [71A]. She developed
somnolence, bradypnea, hypotension, and
eventual cardiac arrest, which necessitated
external cardiac massage, intubation, and
adrenaline infusion. Recovery was uneventful.
Prolonged use of topical lidocaine can
result in systemic and specically cardio-
vascular toxicity [72A].
A healthy 48-year-old man sprayed lidocaine
solution on his glans penis on several occa-
sions before having sex over a period of
2 weeks and developed chest discomfort and
profound bradycardia, which resolved with
conservative treatment.
Respiratory Topical lidocaine can cause
bronchospasm and airways obstruction in
asthmatics [73R] as can intravenous lidocaine
[74A].
A 17-month-old child was given intravenous
lidocaine 1.5 mg/kg to facilitate endotracheal
intubation and immediately developed broncho-
spasm, which resolved uneventfully after
5 minutes.
Nervous system Nervous system adverse
effects have been reported during treat-
ment with different lidocaine formulations
for analgesia. Intravenous lidocaine in
doses titrated between 1 and 4 mg/minute
Positive inotropic drugs and drugs used in dysrhythmias
was investigated in 68 patients with intrac-
table daily headache for an average
of 8.5 days: 25% obtained complete remis-
sion and 57% partial remission. The
more frequent adverse effects were nausea
and vomiting (n 14) and hallucinations
(n 8); none led to drug withdrawal [75c].
In a comparison with ropivacaine 5 mg/
ml for out-patient knee arthroscopy in 30
patients, lidocaine 10 mg/ml caused pain
and dysalgesia in the buttocks, thighs, or
legs in 40% [76c].
Central nervous system toxicity from local
anesthetics has previously been described.
Lidocaine is usually considered to be safe
up to a total intravenous dose of 3 mg/kg.
However, although the total dose of the local
anesthetic is important, lidocaine injected
directly into the arterial circulation close to
the central nervous system can produce tox-
icity in small doses [77A].
A 26-year-old patient undergoing percutaneous
dilatation tracheostomy was given lidocaine
accidentally into an aberrant carotid artery
underlying the trachea. Generalized convul-
sions immediately occurred, which resolved
after injection of thiopental and extra oxygen.
Mexiletine [SED-15, 1370; SEDA-30,
217; SEDA-31, 330]
Nervous system Mexiletine 6001500 mg/
day has been investigated in nine patients
with refractory chronic headache. Although
it was much more effective or more
effective than previous medications,
adverse effects such as nausea, fatigue,
tremor, dizziness, incoordination, and, to a
lesser extent, palpitation led to withdrawal
in most patients [78c].
Pilsicainide [SEDA-32, 348]
Drug overdose A young woman ingested
many tablets of pilsicainide and atenolol;
her pilsicainide and atenolol plasma con-
centrations were 7.83 and 4.94 mg/l
Chapter 17 389
respectively, far above the usual target con-
centrations [79A].
Procainamide [SED-15, 2923;
SEDA-30, 219]
Cardiovascular Intravenous procainamide
had a prodysrhythmic effect when it was
given as a single 1000 mg bolus during an
electrophysiological study in a patient with
myotonic dystrophy type 1 [80A]. During
ventricular pacing, ventricular tachycardia
and brillation occurred and required DC
cardioversion. By slowing cardiac conduc-
tion, procainamide, as do other sodium
channel blockers, worsens abnormalities
already present in the hearts of patients
with myotonic dystrophy type 1.
Propafenone [SED-15, 2939; SEDA-30,
218; SEDA-31, 331; SEDA-32, 351]
Cardiovascular Propafenone, like all class I
antidysrhythmic agents, can increase the
heart rate in patients with atrial tachydys-
rhythmias, because of its vagolytic effect,
which leads to enhancement of atrioventric-
ular nodal conduction. A case of propafe-
none-mediated 1:1 atrial tachycardia has
been reported [81A].
A 58-year-old man developed sudden onset
rapid palpitation and signicant presyncope
while walking on the at. The previous day
he had undergone DC cardioversion for atrial
brillation, which had been initially successful.
However, 6 hours after cardioversion he
became aware of an intermittently fast but
regular heartbeat. He was well with no hemo-
dynamic compromise. An electrocardiogram
showed an atrial tachycardia instead of atrial
brillation. He had been taking propafenone
300 mg bd, bisoprolol 5 mg at night, and war-
farin. The dose of bisoprolol was increased to
5 mg bd and he was discharged with a plan
for out-patient ablation. He collapsed in the
hospital car park with rapid palpitation, chest
tightness, and vagal symptoms. He was
390
hypotensive with a heart rate of 200/minute.
An electrocardiogram showed an atrial tachy-
cardia with 1:1 atrioventricular conduction,
which promptly improved after intravenous
atenolol.
Immunologic A lupus-like syndrome has
been reported in a patient taking propafe-
none [82A].
A 73-year-old woman developed weakness
and erythematous plaques on the trunk and
limbs after taking propafenone for 2 months.
She had a neutropenia with a predominance
of immature cells in the bone marrow. Skin
biopsy was compatible with subacute cutane-
ous lupus erythematosus. After withdrawal of
all drugs there was complete clinical and ana-
lytical recovery. Her medications were then
sequentially re-introduced, with the exception
of propafenone. After 6 months she remained
asymptomatic.
Drug overdose Deliberate propafenone
overdose has been reported [83A].
A 17-year-old man took about 20 tablets of
propafenone (total 6000 mg) and 24 tablets
of trimethoprim (total 1920 mg) sulfameth-
oxazole (total 9600 mg) with suicidal intent.
Within 1 hour, he started vomiting, and had
nausea, loss of consciousness, cyanosis, mild
acidosis, and eventually cardiorespiratory
arrest. He was resuscitated and sinus rhythm
was restored at a rate of 55/minute, with a
blood pressure of 70/45 mmHg. An electrocar-
diogram showed sinus bradycardia, extreme
widening of the QRS complex (260 msec),
and a right bundle branch block pattern. He
was given intravenous saline, bicarbonate,
and dopamine, and respiration was supported
mechanically, which resulted in rapid restora-
tion of sinus rhythm and improved hemo-
dynamic parameters and acidosis. A subsequent
electrocardiogram showed shortening of the
QRS duration (230 msec).
Drugdrug interactions Carvedilol An
interaction of propafenone with carvedilol
has been reported [84A].
A 76-year-old woman who was taking carvedi-
lol for hypertension and paroxysmal supraven-
tricular dysrhythmias had an attack of
transient syncope after taking a single dose
of propafenone 600 mg. Her blood pressure
was 110/60 mmHg, heart rate 68/minute, and
an electrocardiogram showed left bundle
branch block and rst degree atrioventricular
Chapter 17 A. Finzi
block. Her electrocardiogram normalized over
the next few hours.
Others later commented that since propafe-
none and carvedilol are both metabolized by
CYP2D6, inhibition of propafenone metabo-
lism by carvedilol may have caused the syn-
cope reported in this case [85H].
Citalopram An interaction of propafenone
with citalopram reportedly caused adverse
effects attributable to propafenone, mim-
icked coronary artery disease [86A].
An 80-year-old woman with mild cognitive
impairment, who had taken propafenone
900 mg/day for over 10 years for paroxysmal
atrial brillation without adverse effects, was
given citalopram, and 3 months later had epi-
sodes of chest tightness and dizziness, which
became more frequent, causing several falls
but no acute coronary event. She was given
amlodipine 2.5 mg/day, a glyceryl trinitrate
patch 0.4 mg/hour, and warfarin 5 mg/day.
After one fall, she became delirious. Amlodi-
pine and glyceryl trinitrate were withdrawn
and the dose of propafenone was reduced to
450 mg/day; citalopram 20 mg/day was contin-
ued. She recovered, both cognitively and
physically, and did not have any further symp-
toms after 1 year of follow-up. Coronary
investigations were negative.
Quinidine and derivatives [SED-15,
2997; SEDA-30, 219; SEDA-31, 332;
SEDA-32, 352]
Observational studies In a retrospective
study of oral quinidine for termination of
atrial brillation in 501 consecutive patients
(mean age 66 years, 32% women), quini-
dine 200400 mg was given every 6 hours
until cardioversion or for a maximum of
48 hours [87C]. Quinidine did not have to
be withdrawn because of adverse drug
reactions and there was no signicant QT
interval prolongation and no life-threaten-
ing ventricular dysrhythmias. The mean
total dose of quinidine was 617 mg and
92% of the patients received verapamil or
a beta-blocker to slow the ventricular rate
to below 100/minute. Cardioversion was
successful in 84%. All adverse drug
Positive inotropic drugs and drugs used in dysrhythmias
reactions were minor and transient (diar-
rhea in 13%, rst degree atrioventricular
block in 4%, symptomatic hypotension in
2%, supraventricular and ventricular extra
beats and nausea in 1% respectively; there
was a rash in one patient). Multivariate
analysis showed that female sex (OR 2.62;
CI 1.61, 4.26) and an ejection fraction
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Chapter 17 391
of 4554% (OR 1.97; CI 1.15, 3.36)
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dine for pharmacological cardioversion of
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18
BETA-ADRENOCEPTOR
ANTAGONISTS [SED-15, 452;
SEDA-30, 223; SEDA-31, 339; SEDA-
32, 363]
Sexual function Beta-blockers can cause
erectile dysfunction in men. However, car-
diovascular diseases and thiazide diuretics
can do the same and psychosocial factors
can contribute. Thus, the assumption that
beta-blockers can cause erectile dysfunc-
tion in a large number of treated men needs
to be veried. In a randomized study of 114
hypertensive men (mean age 57 years)
without erectile dysfunction, all were given
metoprolol 100 mg/day; however, one
group were fully informed of the risk of
erectile dysfunction with beta-blockers,
another group were partially informed,
and a third group were not informed at all
[1c]. After 60 days of therapy with metopro-
lol, the incidences of erectile dysfunction
were 32% in group 1, 13% in group 2,
and 8% in group 3. All those who reported
erectile dysfunction were randomized to
tadalal 20 mg/day or placebo in a cross-
over study with 4-week treatment periods
and 1 week of washout between each. Met-
oprolol was continued in the same dosage.
Side Effects of Drugs, Annual 33
J.K. Aronson (Editor)
ISSN: 0378-6080
DOI: 10.1016/B978-0-444-53741-6.00018-0
# 2011 Elsevier B.V. All rights reserved.
M.G. Franzosi and R. Latini
Beta-adrenoceptor
antagonists and
antianginal drugs
At the time of nal evaluation, tadalal
and placebo were equally effective in
reducing erectile dysfunction. These results
conrm that knowledge about the possibil-
ity of erectile dysfunction inuences
its occurrence, and questions the use of
phosphodiesterase-5 inhibitors to correct
erectile dysfunction in patients taking
beta-blockers.
Atenolol [SED-15, 366; SEDA-31, 339]
Drugdrug interactions Thalidomide A 76-
year-old Japanese man with hypertension
and multiple myeloma who was taking
atenolol developed syncope and sinus
bradycardia after thalidomide was added;
his heart rate fell from 70 to 30/minute
[2A]. The heart rate rose to 70/minute a
few days after stopping atenolol. Either
drug alone did not cause bradycardia, but
the combination caused a profound reduc-
tion in sinus heart rate. If thalidomide is
given to patients who are already taking a
beta-blocker, the heart rate should be care-
fully monitored.
Betaxolol [SEDA-32, 363]
Comparative studies In 105 children aged
under 6 years who were randomized for
12 weeks to betaxolol suspension (n 34)
or timolol maleate ophthalmic gel-forming
397
398
solution 0.25% (n 35) or 0.5% (n 36) for
glaucoma, both drugs produced statistically
signicant mean reductions in intraocular
pressure [3C]. Adverse events were predomi-
nantly non-serious and those attributed to
betaxolol were hyperemia, discomfort, and
irritation in the eyes; there was one case of
bradycardia and one of hypotension.
Bisoprolol [SED-15, 522]
Respiratory Although selective beta1-
adrenoceptor antagonists may be better toler-
ated than non-selective ones, adverse respira-
tory reactions have been reported. In the
absence of randomized trials, 27 patients with
heart failure and moderate or severe COPD
were randomized to the highly selective
beta-blocker bisoprolol or placebo over
4 months. There was a signicant reduction
in FEV1 in those who took bisoprolol,
although the number of exacerbations of
COPD, symptoms, and quality of life were
similar in the two groups [4c]. Larger random-
ized controlled trials are needed addressing
the issue of beta-blockade in this large and
often ignored population of patients with
heart failure and COPD.
Carvedilol [SED-15, 676; SEDA-32, 363]
Sexual function Peyronie's disease has been
attributed to carvedilol [5A]. However, the
association of beta-blockers with Peyronie's
disease is not convincing [SED-15, 463].
Drug overdose An 84-year-old man took
total of 60 (6.25 mg) tablets and rapidly
developed hypotension (systolic blood
pressure 70 mmHg), bradycardia (45/
minute), and a junctional rhythm [6A]. He
was given intravenous glucagon and dopa-
mine infusion and recovered after 14 hours.
The carvedilol serum concentration was
472 mg/l, compared with a predicted
steady-state concentration of 8.5 mg/l during
treatment with 6.25 mg bd.
Chapter 18 M.G. Franzosi and R. Latini
Drugdrug interactions Propafenone An
interaction of carvedilol with propafenone
has been reported [7A].
A 76-year-old woman who was taking carvedilol
for hypertension and paroxysmal supraventricu-
lar dysrhythmias had an attack of transient syn-
cope after taking a single dose of propafenone
600 mg. Her blood pressure was 110/60 mmHg,
heart rate 68/minute, and an electrocardiogram
showed left bundle branch block and rst degree
atrioventricular block. Her electrocardiogram
normalized over the next few hours.
Others later commented that since
propafenone and carvedilol are both metabo-
lized by CYP2D6, inhibition of propafenone
metabolism by carvedilol may have caused
the syncope reported in this case [8H].
Celiprolol [SED-15, 687]
Respiratory Even non-asthmatic patients
should be carefully monitored for respira-
tory adverse effects when they are rst given
cardioselective beta-blockers. A 79-year-old
man developed a wheeze without dyspnea
or cough. After withdrawal of celiprolol,
which he had taken for 7 years before the
onset of the wheeze and for 3 years after,
his peak expiratory ow rate improved as
did his respiratory symptoms [9A].
Esmolol [SED-15, 1252]
Comparative studies Blood pressure control
is important after repair of coarctation of
the aorta. In a multicenter trial in 116
children under 6 years of age, esmolol, 125
micrograms/kg (n 36), 250 micrograms/kg
(n 43), and 500 micrograms/kg (n 37),
was effective in reducing systolic blood pres-
sure [10C]. The three dose groups had similar
incidences of adverse events, the most com-
mon being postoperative pain (n 90), post-
operative agitation (24), postoperative anemia
(22), hypokalemia (32), and metabolic acido-
sis (33). In 17 cases in which adverse events
were attributable to esmolol, the reactions
were hypotension (n 10), bradycardia (1),
wheezing (3), and a reaction at the injection
site (1).
Beta-adrenoceptor antagonists and antianginal drugs
Labetalol [SED-15, 1985; SEDA-32, 364]
Body temperature Fever has been attrib-
uted to labetalol [11A].
Drug overdose Death has been attributed
to labetalol overdose.
A 44-year-old woman with a history of depres-
sion and alcoholism was found dead at home
[12A]. An autopsy showed non-specic abnor-
malities (alveolar edema, hepatic steatosis, and
interstitial nephritis). Because several boxes of
medicines had been found near the body, a toxi-
cological analysis was carried out on peripheral
blood and urine samples. Ethanol (1.24 g/l in
blood, 2.63 g/l in urine, and 1.33 g/kg in gastric
content), meprobamate (14 mg/l in blood),
nordiazepam (0.12 mg/l in blood), and labetalol
(1.7 mg/l in blood and 20 mg/l in urine) were
found. Labetalol concentrations in samples of
viscera (liver, heart, kidney, and lung) and gas-
tric contents were also high (14, 7.8, 5.4, 5.2,
and 31 micrograms/g respectively).
Metoprolol [SED-15, 2321; SEDA-32,
364]
Nervous system Sleepwalking is as a rare
adverse effect of metoprolol, possibly facil-
itated by a history of childhood somnambu-
lism [13A].
A 66-year-old woman was referred to the sleep
laboratory because of unusual sleep behavior
shortly after she started to take metoprolol
50 mg/day for hypertension. Her somnambu-
lism completely resolved within 23 weeks after
ramipril was substituted for metoprolol.
Drug withdrawal Transient left ventricular
ballooning syndrome (takotsubo cardio-
myopathy) occurs mostly in post-menopausal
women in response to stressful events
and beta-blockers are used to treat it.
Abrupt withdrawal of beta-blockade can
result in a hyperadrenergic syndrome that
can lead to takotsubo cardiomyopathy, even
in the absence of a stressful precipitating
event [14A].
A 59-year-old woman with hypertension
and left ventricular hypertrophy developed
Chapter 18 399
chest pressure and new ST segment elevation
in the anterior electrocardiographic leads 6 days
after metoprolol had been withdrawn because
of symptomatic bradycardia. After myocardial
infarction had been excluded, takotsubo car-
diomyopathy was diagnosed, based on chest
radiography and echocardiography. Metoprolol
was restarted and her symptoms completely
regressed, as did the left ventricular dilatation.
Susceptibility factors Genetic Metoprolol
plasma concentrations in CYP2D6 poor
metabolizers are higher than in extensive
metabolizers. The effect of this polymorphism
on metoprolol concentrations and effects has
been assessed in a prospective, double-blind
study. Metoprolol caused signicantly and
persistently greater reductions in heart rate,
diastolic blood pressure, and mean arterial
pressure in poor metabolizers than in exten-
sive metabolizers. CYP2D6 therefore has
an effect on interindividual differences in
response to metoprolol [15c].
Sotalol [SED-15, 3170; SEDA-28, 218;
SEDA-29, 195]
Cardiovascular Sotalol can increase the
risk of torsade de pointes, and in all case
series the risk has been reported to be sig-
nicantly higher in women than in men.
This difference suggests that sex hormones
play a role; testosterone may protect men
from QT prolongation [16R].
Timolol [SED-15, 3428; SEDA-32, 365]
Skin Contact dermatitis of the eyelids has
been attributed to timolol eye-drops in a 40-
year-old man, conrmed by patch tests [17A].
Susceptibility factors Genetic The relation
between the effects of timolol and CYP2D6
Arg296Cys and Ser486Thr genotypes has
been studied in 73 patients with primary
open-angle glaucoma [18c]. Topical timolol
signicantly reduced intraocular pressure
and heart rate in all the subjects. There
was no signicant difference in intraocular
pressure in those with different CYP2D6
400
Arg296Cys or Ser486Thr genotypes. How-
ever, timolol had different effects on heart
rate: bradycardia tended to occur in those
with the Arg296Cys CT and TT genotypes
than in those with the CC genotype.
Drugdrug interactions Bevacizumab The
effect of timolol dorzolamide eye-drops,
which reduces aqueous outow from
the eye, on the activity of intravitreal
bevacizumab has been studied in 38 patients
with macular edema after retinal vein obstruc-
tion [19c]. Mean central retinal thickness was
used as a surrogate for the activity of
bevacizumab. Mean central retinal thickness
was signicantly reduced by bevacizumab,
and after 5 weeks the effect was enhanced by
timolol dorzolamide but not after 9 weeks.
The authors suggested that timolol
dorzolamide eye-drops had reduced the
clearance of intravitreal bevacizumab. How-
ever, this needs to be conrmed. If it is a real
effect, it remains to be seen whether it
improves the efcacy of bevacizumab or
increases the risk of adverse effects.
POTASSIUM CHANNEL
ACTIVATORS
Nicorandil [SED-15, 2505; SEDA-31,
340; SEDA-32, 365]
Skin Perianal and other mucosal ulcers
have been reported with chronic use of
nicorandil. Inguinal ulcers have been attrib-
uted to nicorandil without any associated
mucosal ulcers [20A].
An 85-year-old man who had taken nicorandil
20 mg/day for 45 years developed inguinal
ulcers, which did not respond to topical or sys-
temic agents. Near complete healing occurred
8 weeks after withdrawal of nicorandil.
It is important to recognize not only
mucosal, but also cutaneous isolated ulcers
with nicorandil and to stop treatment as
soon as possible.
Chapter 18 M.G. Franzosi and R. Latini
Ulceration of the oral mucosa, perianal
skin, and peristomal skin with nicorandil
has been more often reported than lesions
of the vaginal mucosa. Two elderly women
developed large painful ulcers of the vulva,
which healed in a few days after withdrawal
of nicorandil, which had been prescribed
for angina pectoris [21A]. The mechanisms
of this adverse reaction are unknown. Sim-
ilar ndings have been reported in a series
of ve elderly women [22c], stressing the
importance of taking a careful drug history
in patients with such ulcers. Prompt resolu-
tion after stopping nicorandil is typical.
NITRATES, ORGANIC
[SEDA-15, 2529; SEDA-30, 225;
SEDA-32, 366]
Cardiovascular Local application of exoge-
nous nitric oxide donors, such as glyceryl
trinitrate or isosorbide dinitrate, promotes
healing of chronic anal ssures by reducing
anal resting pressure and improving
anodermal blood ow. However, headache,
due to vasodilatation, which occurs in as
many as 40% of the patients, is a major fac-
tor that limits their use. In any case, nitrates
are barely superior to placebo in producing
complete healing. In an attempt to circum-
vent this adverse reaction, 15 patients with
chronic anal ssures were treated topically
for at least 12 weeks with a gel containing
arginine. There was complete healing after
18 weeks of treatment in 62% of the
patients, and headaches did not occur
[23c]. Placebo-controlled studies are needed
to establish whether arginine is a better
alternative to NO donors in the treatment
of chronic anal ssures.
Glyceryl trinitrate (nitroglycerin)
Nervous system Transdermal glyceryl
trinitrate has been advocated in the treat-
ment of peripheral vascular disease and
Beta-adrenoceptor antagonists and antianginal drugs
frostbite. A 49-year-old elite mountaineer
applied a 10 mg glyceryl trinitrate patch to
each leg in order to prevent frostbite
[24A]. During his last ascent above
8000 meters he developed neurological
symptoms suggestive of acute mountain
sickness, which he had never had before.
His symptoms were relieved shortly after
he removed the patches during the return
trip. The use of glyceryl trinitrate at high
altitude should be strongly discouraged.
Hematologic Methemoglobinemia is a well-
known complication of intravenous glyceryl
trinitrate therapy and has been reported
again in an unusual case [25A].
A 45-year-old man was injured by an exploding
bomb and, apart from burns and various
lesions, had a peak of plasma concentration of
methemoglobin of 42%, because of extensive
transcutaneous absorption of glyceryl trinitrate
from non-combusted particles attached to his
skin. He was given methylthioninium chloride
(methylene blue) serially over 6 days and the
hemoglobin normalized.
Drug formulations Nitrates are often pre-
scribed for Raynaud's phenomenon, but
their use is limited by adverse effects such
as headache, dizziness, and skin irritation.
A new gel formulation of glyceryl trinitrate
(MQX-503) has been tested in 219 patients
with Raynaud's phenomenon, in a double-
blind, randomized, placebo-controlled trial.
MQX-503 was signicantly more effective
than placebo, and had comparable adverse
effects [26c].
CALCIUM CHANNEL
BLOCKERS [SED-15, 598; SEDA-
30, 225; SEDA-31, 340; SEDA-32, 366]
Mouth Gingival enlargement is often asso-
ciated with calcium channel blockers and
ciclosporin. In 93 renal transplant recipients
who had taken ciclosporin (n 31),
ciclosporin nifedipine (n 31), or
ciclosporin amlodipine (n 31), more
Chapter 18 401
of those who took ciclosporin nifedipine
(90%) had gingival enlargement than those
who took ciclosporin amlodipine (58%)
or ciclosporin alone (52%) [27c]. More of
those who took ciclosporin nifedipine
had severe gingival enlargement (23%)
compared with ciclosporin amlodipine
(16%) or ciclosporin alone (0%). This sug-
gests that these combinations should be
avoided, or that amlodipine should be used
instead of nifedipine if a calcium channel
blocker is required in a patient taking
ciclosporin. However, the study was not
randomized and the authors did not report
the reason for the use of calcium channel
blockers in these patients.
Amlodipine [SED-15, 175; SEDA-30,
225; SEDA-31, 340; SEDA-32, 367]
Autacoids The calcium channel blockers
verapamil, diltiazem, and nifedipine have
been associated with angioedema, and a
case has also now been reported in a
patient taking amlodipine [28A].
A 50-year-old AfricanAmerican woman had a
left-sided stroke, with hemiplegia. Her blood
pressure was 214/125 mmHg and she was given
a continuous infusion of labetalol and hemo-
dialysis, but remained hypertensive. The blood
pressure stabilized with intravenous
nicardipine which was switched to oral
amlodipine 10 mg/day. After about 24 hours
she developed swelling of the face and tongue.
Fosphenytoin and famotidine were withdrawn,
but there was still massive edema of the tongue,
causing it to protrude from the mouth.
Amlodipine was withdrawn and about 24 hours
later the oropharyngeal and tongue edema had
reduced signicantly. The angioedema
completely resolved after 10 days.
Nicardipine and amlodipine could have
caused this patient's angioedema; however,
the symptoms continued for 4 days after the
withdrawal of nicardipine. Amlodipine was
started 24 hours before the onset, and the
symptoms began to improve 24 hours after
withdrawal.
Skin Drug hypersensitivity reactions can
cause an atypical lymphoid cell inltrate
402
ranging from a benign condition to a malig-
nant lymphoma. There have been a few
reports of CD30-positive drug-induced
pseudolymphoma in patients taking
amlodipine. Skin inltration of atypical lym-
phoid cells mimicking mycosis fungoides
has now been reported during amlodipine
therapy [29A].
A 74-year-old man developed red solid papules
and erythematous plaques on his abdomen,
chest, the inner aspect of the arms, and the
lower legs after taking amlodipine 5 mg/day
and naftopidil 50 mg/day for 2 months for
hypertension. Histology of the skin lesions after
10 months showed massive inltration of small
lymphocytes and large atypical lymphocytes in
the upper dermis. Large atypical cells were pos-
itive for CD30. The eruption was initially diag-
nosed as lymphomatoid papulosis, but the
papular lesions evolved into scaly erythematous
plaques resembling mycosis fungoides. He was
given intramuscular interferon-gamma and
ultraviolet B in combination, but the eruption
and pruritus worsened. The eruption was there-
fore suspected to be a peculiar form of drug
eruption rather than a cutaneous T-cell lym-
phoma. A lymphocyte stimulation test for
amlodipine and naftopidil was strongly positive
for amlodipine and negative for naftopidil. The
eruption resolved within 2 months of with-
drawal of amlodipine.
Lercanidipine [SED-15, 2024;
SEDA-30, 226]
Serosae Calcium channel blockers have
been rarely associated with chylous ascites
in patients taking peritoneal dialysis. The
mechanism is unknown. Chylous ascites
has been attributed to lercanidipine [30A].
A 41-year-old uremic woman who had taken
lercanidipine 10 mg/day for 3 days developed
a painless peritoneal efuent. She had been
undergoing continuous ambulatory peritoneal
dialysis for 2 weeks for end-stage nephropa-
thy. The only physical nding was mild epigas-
tric tenderness. The turbid peritoneal efuent
contained a high triglyceride concentration
without evidence of micro-organisms or cellu-
lar components, suggestive of chylous ascites.
Lercanidipine was withdrawn and the dialysis
efuent cleared within 24 hours. Re-challenge
with lercanidipine provoked the same adverse
reaction within 16 hours.
Chapter 18 M.G. Franzosi and R. Latini
Nicardipine [SED-15, 2502; SEDA-30,
227; SEDA-32, 367]
Liver Raised liver enzymes have been asso-
ciated with nicardipine [31A].
A 61-year-old man with hypertension had a
right middle cerebral artery infarction and an
evolving stroke, followed by a cerebral hemor-
rhage during angiography and stent place-
ment. After neurosurgery he was given
hypertonic saline, mannitol for cerebral
edema, and a nicardipine infusion for blood
pressure control. After 4 days he developed
a fever with progressively rising liver enzymes.
Other medications included metoprolol and
heparin. The white blood cell count was
13  109/l and there was no evidence of infec-
tion. The liver enzymes continued to rise with-
out changes in protein or bilirubin.
Nicardipine was withdrawn and labetalol
substituted. The fever resolved and the liver
enzymes normalized.
Nifedipine [SED-15, 2516; SEDA-30,
227; SEDA-31, 341]
Susceptibility factors Sex There are differ-
ences in blood pressure between the sexes,
the mechanisms of which are unknown; fur-
thermore, it is not known whether sex can
inuence the response to antihypertensive
therapy. In a prospective study 3535
untreated hypertensive Chinese patients
were randomized to atenolol, sustained-
release nifedipine, captopril, or hydro-
chlorothiazide for 8 weeks [32c]. Women
had signicantly better pressure responses,
but more adverse effects with sustained-
release nifedipine and captopril than men.
The authors suggested that sex should be
taken into account when selecting antihy-
pertensive drugs.
Drugdrug interactions Voriconazole A
clinically relevant drug interaction between
voriconazole and nifedipine eplerenone
has been reported [33A].
A 48-year-old man with myelodysplastic syn-
drome underwent bone marrow transplanta-
tion from an unrelated donor and took
Beta-adrenoceptor antagonists and antianginal drugs
ciclosporin and methylprednisolone for acute
graft-versus-host disease. He had taken regu-
lar candesartan, nifedipine, and eplerenone
for hypertension. He was given intravenous
voriconazole for prophylaxis of fungal infec-
tions. His blood pressure fell to 76/48 mmHg
after 2 days, without evidence of hypovolemia,
acute blood loss, or septicemia. Candesartan,
nifedipine, and eplerenone were withdrawn
and his blood pressure rose after 1 day; at
5 days it was 180/80 mmHg. Candesartan and
nifedipine were started again, with a reduction
in the dose of nifedipine, and eplerenone was
no longer needed to control the hypertension.
Both nifedipine and eplerenone are
metabolized by CYP3A4, which is inhibited
by voriconazole. Other azoles, such as u-
conazole, reportedly also interact with
nifedipine, but such an interaction has not
been demonstrated with eplerenone.
Nimodipine [SED-15, 2526; SEDA-29,
199]
Nervous system Familial hemiplegic
migraine is an autosomal dominant form of
migraine. A prolonged attack of hemiplegic
migraine was worsened by intravenous
nimodipine in a Norwegian family with four
members affected over three generations.
The family had a point mutation in the
ATP1A2 gene that caused a change in valine
to methionine (V628M). One of the affected
individuals, a 16-year-old boy, had
prolonged attacks of migraine and a single
generalized clonictonic seizure, which was
possibly provoked by intravenous
nimodipine [34A]. The authors concluded
that nimodipine is contraindicated in the
management of prolonged attacks of familial
hemiplegic migraine.
Verapamil [SED-15, 3618; SEDA-30,
228; SEDA-31, 342; SEDA-32, 367]
Susceptibility factors Genetic The NOS1AP
gene has been associated with variation in the
duration of the QT interval in several large
populations. NOS1 is presumed to inuence
Chapter 18 403
intracellular calcium. In a prospective popula-
tion-based study, the Rotterdam Study,
the presence of two single nucleotide poly-
morphisms (SNPs) in the NOS1AP gene,
rs10494366 T > G and rs10918594 C > G,
modied the QTc interval-prolonging effect
of calcium channel blockers [35C]. The study
included 16 603 electrocardiograms from
7565 participants, after exclusion of patients
with left ventricular hypertrophy and left
and right bundle branch block, and those with
pacemakers. The use of verapamil was associ-
ated with signicant QTc interval prolonga-
tion (6.0 ms; 95% CI 1.7, 10) compared
with non-users. Furthermore, users of verap-
amil with the rs10494366 GG genotype had
signicantly more QTc prolongation than
users with the TT genotype (25.4 ms; 95% CI
5.9, 45). In other words, the minor alleles of
both NOS1AP SNPs signicantly potentiated
the QTc interval-prolonging effect of verapa-
mil. Amlodipine, isradipine, nifedipine, and
diltiazem did not prolong the QT interval.
Drug overdose In a case of attempted sui-
cide with 7.2 g of sustained-release verapa-
mil, with extremely high initial plasma
concentrations (3600 mg/l 1.5 hours after
ingestion), there was a very long period of
toxicity, with a surprising sudden escalation
of symptoms on the third day, characterized
by extreme hypotension, bradycardia, and
loss of consciousness [36A]. Massive bowel
irrigation, prolonged cardiac pacing, and
invasive hemodynamic monitoring are
advisable when treating toxicity from
sustained-release verapamil. Repeated
doses of activated charcoal have also been
suggested, especially after overdose with
modied-release formulations [37A].
Two patients with serious calcium chan-
nel blocker overdose gradually improved
after being given levosimendan [38A].
A 47-year-old woman who had taken 16 g of
verapamil 1 hour before was given activated
charcoal 50 g orally, a noradrenaline infusion,
and boluses of calcium and atropine. She had
a cardiac arrest and was given boluses of cal-
cium, glucagon, and adrenaline. Because of
refractory shock she was also given
levosimendan, and after 6 hours the doses of
vasopressors were reduced. She gained full
404
consciousness 24 hours after the cardiac arrest
and was sedated with propofol. The infusion
of levosimendan was continued for 30 hours
and sinus rhythm was restored on day 2.
A 38-year-old man was found in his bed
deeply comatose and it was suspected that he
had taken amlodipine 630 mg, zopiclone
300 mg, and uncertain amounts of citalopram
and paracetamol at least 4 hours earlier. He
was given activated charcoal, intravenous
boluses of glucagon and calcium, and dopa-
mine by infusion, followed by noradrenaline
by infusion. Because of persistent hypotension
and heart failure he was given levosimendan
and the dobutamine was withdrawn. After
90 minutes his cardiac function had improved.
The dose of levosimendan was increased and
continued for 24 hours, when his lactic acido-
sis resolved.
These two cases cannot be considered as
providing direct evidence of a benecial
effect of levosimendan. Both patients
received intensive conventional treatment
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ssure by application of L-arginine gel: a
phase II study in 15 patients. Dis Colon
Rectum 2005; 48: 8327.
[24] Mazzuero G, Mazzuero A, Pascariello A.
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2413.
[25] Badii F, Maghelli S, Costa N,
Borreggine D, Zoccali G, Dur D. Acute
methemoglobinemia after nitroglycerine
transcutaneous absorption after bomb
explosion: a case report. J Trauma 2009;
66: 9367.
[26] Chung L, Shapiro L, Fiorentino D, Baron M,
Shanahan J, Sule S, Hsu V, Rotheld N,
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Simms R, Pope J, Kahaleh B, Csuka ME,
Gruber B, Collier D, Sweiss N, Gilbert A,
Dechow FJ, Gregory J, Wigley FM. MQX-
503, a novel formulation of nitroglycerin,
enon. Arthritis Rheum 2009; 60: 8707.
[27] Lpez-Pintor RM, Hernndez G, de
Arriba L, Morales JM, Jimnez C, de
Andrs A. Amlodipine and nifedipine used
with cyclosporine induce different effects
on gingival enlargement. Transplant Proc
2009; 41: 23513.
[28] Southward J, Irvine E, Rabinovich M.
Probable amlodipine-induced angioedema.
Ann Pharmacother 2009; 43: 7726.
[29] Kabashima R, Orimo H, Hino R,
Nakashima D, Kabashima K, Tokura Y.
CD30-positive T-cell pseudolymphoma
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Dermatol Venereol 2008; 22: 15224.
[30] Tsao YT, Chen WL. Calcium channel
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[31] Chaudhry M, Maqsood A, Diab-Agha S,
Rosenberg J. Nicardipine-induced acute
406
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[33] Kato J, Mori T, Nakamura Y, Sakurai M,
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[35] van Noord C, Aarnoudse AJLHJ,
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19 Drugs acting on
the cerebral and
peripheral circulations
DRUGS USED IN THE
TREATMENT OF
ARTERIAL DISORDERS
OF THE BRAIN AND LIMBS
Buomedil [SED-15, 566; SEDA-29,
202; SEDA-32, 371]
Death Data on the efcacy of buomedil in
intermittent claudication were retrieved from
a Cochrane systematic review, and data on
safety were obtained by comparing the num-
ber of reports of serious adverse events and
deaths published in the literature with those
reported in postmarketing surveillance data-
bases [1M]. The authors concluded that the
evidence that buomedil is benecial is
undermined by documented publication bias.
They also concluded that there is bias in
reporting adverse events to international
safety databases, illustrated by the discrep-
ancy between the number of published drug-
related deaths (20), deaths recorded in the
WHO database that were potentially drug
related (20), and deaths that were attributed
to buomedil in the database of the interna-
tional marketing authorization holder (11).
Side Effects of Drugs, Annual 33
J.K. Aronson (Editor)
ISSN: 0378-6080
DOI: 10.1016/B978-0-444-53741-6.00019-2
# 2011 Elsevier B.V. All rights reserved.
P. Verhamme
Cilostazol [SED-15, 773; SEDA-29, 202;
SEDA-30, 231; SEDA-32, 371]
Hematologic A spinal epidural hematoma in
the region of T12 to L3 occurred in a 90-year-
old man after removal of an epidural catheter
while he was taking cilostazol, which was
attributed to reduced platelet function [2A].
Drug withdrawal Thrombosis occurred in a
drug-eluting stent 3 days after withdrawal of
cilostazol and after colonoscopic polypectomy
in the presence of a colorectal adenocarci-
noma in a 78-year-old man; aspirin and
clopidogrel had been continued [3A]. Throm-
bosis in this case may have been at least partly
due to reduced platelet aggregation secondary
to loss of the therapeutic effect of cilostazol
and it is also possible that there was rebound
hyperaggregability of platelets; the contribu-
tion of hypercoagulability because of the pre-
sence of a cancer could not be assessed.
Drugdrug interactions Glycirrhizin
Pseudoaldosteronism occurred after cilostazol
was added to treatment in a 65-year-old man
who had taken glycyrrhizin for 10 years with-
out problems [4A]. His serum potassium con-
centration, which had been over 4 mmol/l,
gradually fell to 2.5 mmol/l during the next 7
months. He had also taken imidapril and
olmesartan for over 1 year, and plasma renin
activity and aldosterone were suppressed.
Urinary potassium excretion was increased,
even when there was severe hypokalemia.
Glycyrrhizin was withdrawn and he was given
oral potassium and spironolactone. The serum
407
408
potassium concentration normalized after 2
weeks, even though the cilostazol was contin-
ued. The mechanism was suggested to be dis-
placement by cilostazol from albumin
binding sites of glycyrrhizin or its metabolites,
glycyrrhetic acid and 3b-monoglucuronyl
glycyrrhetic acid, the second of which is
thought to be responsible for the potassium-
wasting effects of licorice.
Naftidrofuryl
Systematic reviews Naftidrofuryl is still
being marketed in a number of countries
for the symptomatic treatment of intermit-
tent claudication. In a meta-analysis based
on individual patient data provided by the
manufacturers seven randomized controlled
trials published between 1984 and 2001 were
reanalysed [5M, 6M]. Naftidrofuryl signi-
cantly improved walking distance. There
were no signicant differences in serious
adverse events, but naftidrofuryl led to sig-
nicantly poorer gastrointestinal tolerance.
The safety data were conrmed by the indi-
vidual data analysis.
Drug overdose A 52-year-old man was
found dead in his bed [7A]. Autopsy showed
no structural cause of death. Analysis of
post-mortem blood detected valproic acid
in the usual target range and disulram
above the usual target range, but in each
case far below the lethal concentration.
However, naftidrofuryl was present in a very
high concentration (7500 mg/l) and was
thought to have been the cause of death.
DRUGS USED IN THE
TREATMENT OF
MIGRAINE
Triptans [SED-15, 3525; SEDA-31, 346;
SEDA-32, 372]
Cardiovascular Cases of myocardial infarc-
tion in patients taking triptans have been
Chapter 19 P. Verhamme
reviewed in the light of a 54-year-old
woman with no history of coronary artery
disease who had an acute myocardial
infarction 30 minutes after using subcutane-
ous sumatriptan 6 mg; coronary angiogra-
phy was normal [8AR].
Nervous system adverse effects of
triptans
The nervous system adverse effects of triptans
have been reviewed in light of the question of
whether they can enter the brain [9R].
Some patients complain of sleepiness/
tiredness, difculty in thinking, and dizzi-
ness after sumatriptan [10C], and in a
meta-analysis, sumatriptan 100 mg caused
6% more nervous system adverse events
than placebo, and zolmitriptan 2.5 mg
caused 9% more [11M].
In one large randomized controlled trial
[12C] any nervous system adverse events were
more frequent after sumatriptan 100 mg
(30%; n 386) than after rizatriptan 10 mg
(23%; n 385) [13C] despite the fact that
the two drugs were equally efcacious.
In a placebo-controlled study in healthy
women triptans had adverse nervous system
effects, mainly mild sedative effects, which
were less than sedation after temazepam
20 mg; sumatriptan, but not rizatriptan, also
caused a signicant increase in the electro-
encephalographic alpha power compared
with placebo [14C].
Zolmitriptan 5 and 10 mg, but not suma-
triptan 100 mg, had an effect on cortical
auditory-evoked potential in humans [15C].
In a placebo-controlled study in men with
a history of substance abuse, subcutaneous
sumatriptan 8 and 16 mg reduced euphoria
dose relatedly and increased apathetic seda-
tion and disliking [16C].
There have also been rare cases of central
nervous system effects after subcutaneous
and oral sumatriptan, including akathisia
[17A], acute dystonia [18A], and pathologi-
cal laughter [19A].
A seizure has been attributed to
almotriptan [20A].
Drugs acting on the cerebral and peripheral circulations
A 37-year-old woman with a history of migraine
and a strong family history of migraine, in one
case associated with hemiparesis, had a focal left
motor seizure with secondary generalization
and postictal left hemiparesis 20 minutes after
taking almotriptan 12.5 mg for a headache. Six
months later she took ergotamine tartrate 2 mg
and 1 hour later developed weakness in the left
arm for 5 minutes followed 18 hours later by
two generalized tonicclonic seizures.
The authors invoked two mechanisms for
this: drug-induced vasoconstriction and a
genetic susceptibility, since there are gene
mutations (CACNA1A, ATP1A2, SCN1A)
that are associated with familial forms of
migraine with or without aura, hemiplegic
migraine, and epileptic syndromes.
However, the nervous system effects of
triptans can be partly ascribed to unmasking
of the symptoms of migraine, since responders
to eletriptan had more nervous system adverse
events than non-responders [21C].
Gastrointestinal Acute-on-chronic ischemic
colitis has been attributed to rizatriptan
[22A].
A 50-year-old woman with migraine developed
abdominal pain and hematochezia after taking
rizatriptan intermittently for 3 weeks, not
exceeding a total dose of 30 mg/day. She had
severe progressive continuous lower abdomi-
nal pain with nausea and bloody diarrhea, hav-
ing had similar milder intermittent abdominal
pain for the past few months. Her temperature
was 37.7 C, pulse 95/minute, and there was
severe tenderness in the lower abdomen with-
out rebound tenderness. There was bright
blood in the rectum. Colonoscopy showed
moderate to severe colitis in the sigmoid colon,
the descending colon, and the transverse colon,
with patchy erythema in the rectum and ascend-
ing colon, and biopsies showed mild acute and
chronic ischemic changes, with acute inamma-
tion, glandular atrophy, and brosis in the lam-
ina propria; the terminal ileum was normal as
were biopsies from the terminal ileum. The
erythrocyte sedimentation rate (ESR) was nor-
mal and ANA, ASCA, and pANCA were neg-
ative. Rizatriptan was withdrawn and her
symptoms gradually improved.
Drugdrug interactions Moclobemide The
summary of product characteristics for
sumatriptan, under the heading con-
traindication, states concomitant use of
Chapter 19 409
monoamine oxidase inhibitors and the use
of sumatriptan within 2 weeks after discon-
tinuation of therapy with monoamine
oxidase inhibitors [23S]. The systemic
availability of subcutaneous sumatriptan is
nearly 100% and metabolism by mono-
amine oxidase type A (MAOA) leads to
about 40% of the dose appearing in the
urine as indole acetic acid, which is inactive.
In a survey of summary pharmacokinetic
data taken from the literature and from
GlaxoSmithKline's study C92-050, a pharma-
cokinetic compartmental model was used to
generate predicted kinetic parameters after
the perturbation that would be expected to
occur after inhibition by the MAOA inhibitor
moclobemide [24H]. The analysis suggested
that inhibition of MAOA would be expected
to have a trivial effect on the pharmacokinetics
of a 6-mg subcutaneous dose of sumatriptan.
However, these ndings should not be extrap-
olated to other routes of administration.
OTHER PERIPHERAL
VASODILATORS
Inhibitors of phosphodiesterase
type V [SED-15, 3133; SEDA-30, 232;
SEDA-31, 346; SEDA-32, 372]
Respiratory Vasodilatation induced by
PDE-5 inhibitors is responsible for com-
mon undesired effects, such as headache,
ushing, and nasal congestion. The effect of
sildenal on nasal airways has been measured
in 11 young normally potent volunteers using
a double-blind crossover design [25C].
Endonasal volume measured with a nasal
telescope fell signicantly after a dose of sil-
denal, as has previously been shown with
another technique in a few patients.
Nervous system Cerebral vasodilatation,
increasing blood ow, is suspected to have
increased the risk of intracerebral hemor-
rhage in a 62-year-old man 2 hours after a
rst dose of sildenal 50 mg and before
410
any sexual activity; however, a fortuitous
association could not be ruled out [26A].
Sensory systems Adverse effects of PDE-5
inhibitors on the eyes have repeatedly been
reported, but it is unclear whether these
events are coincidental or related to drug-
related effects on the ocular circulation or
on other structures in the eye [27R]. In a
multicenter study 244 subjects were ran-
domized to tadalal 5 mg/day, sildenal
50 mg/day, or placebo for 6 months [28C].
There was one case of retinal artery occlu-
sion in a patient taking placebo and there
were no abnormalities in electroretinogra-
phy or visual function and no treatment-
related ndings suggestive of drug toxicity.
Hematologic Sildenal has been associated
with thrombocytopenia [29A].
A 53-year-old woman with multiple pathology
was admitted to the intensive care unit in
respiratory distress. Sildenal was added
empirically to her extensive drug regimen,
because of pulmonary hypertension. Her
platelet count fell after 1 week. Heparin was
rst suspected and withdrawn, without effect.
Sildenal was then withdrawn and the platelet
count started to rise. Two rechallenges with
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[11] Ferrari MD, Goadsby PJ, Roon KI,
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[14] van der Post J, Schram MT,
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 Jamie J. Coleman, Anthony R. Cox, and
20 Antihypertensive drugs
Antihypertensive drugs and their
adverse effects in the
perioperative period
Introduction A number of risk factors have
been identied for perioperative cardiovas-
cular complications, and are used for risk
stratication of patients for surgery. These
include a history of ischemic heart disease,
myocardial dysfunction, or a history of com-
pensated heart failure, a history of cerebro-
vascular disease, diabetes mellitus, and
renal insufciency. Patients in these risk cat-
egories are very likely to be taking one or
more antihypertensive medications, both to
control arterial hypertension and as therapy
for other underlying diseases. Preoperative
evaluation is an opportunity to optimize
control of cardiovascular risk factors and
review medication requirements.
The rationale for perioperative antihyper-
tensive medication It is clear that periopera-
tive morbidity and mortality gures for
patients with one or more of these risk factors
are higher than for those without, in particu-
lar for high-risk surgical procedures, includ-
ing vascular surgery. Current data show
rates of 2.7% for perioperative mortality and
4.4% for non-fatal myocardial infarction in
patients with cardiovascular risk factors
[1C]. During the perioperative period, there
is a catecholamine surge, leading to increased
myocardial oxygen consumption. The
Side Effects of Drugs, Annual 33
J.K. Aronson (Editor)
ISSN: 0378-6080
DOI: 10.1016/B978-0-444-53741-6.00020-9
# 2011 Elsevier B.V. All rights reserved.
Nicholas J. Cowley
rationale for the use of pharmacological ther-
apy in these patients is to reduce this myocar-
dial stress. However, adverse drug effects may
act to offset this benet, making evaluation of
net benet difcult.
Although arterial hypertension is not itself
an independent risk factor for cardiovascular
complications in non-cardiac surgery, the
presence of a raised blood pressure should
facilitate the identication of patients who
are at risk of associated cardiovascular
pathology, and prompt a search to be under-
taken. In patients with mild to moderate
(grade 1 or 2) hypertension, there is no
evidence that preoperative optimization is
benecial in the short term, although anti-
hypertensive medications already prescribed
should be continued during the perioperative
period [2S]. Guidelines also suggest that
patients with a systolic blood pressure over
180 mmHg or a diastolic blood pressure over
110 mmHg are at increased perioperative
risk, and elective surgery should be deferred
until control is achieved. Control over a
period of weeks allows cardiovascular risk
to be minimized, although rapid control is
preferable if the benet to harm balance
favors early surgery [3C].
Perioperative beta-blockers There is a con-
tinuing debate about the administration of
antihypertensive medications in the peri-
operative period. Particular focus has been
directed at perioperative beta-blockers
because they can reduce the incidence of
perioperative cardiovascular adverse events.
Randomized studies have shown that beta-
adrenoceptor antagonists can reduce peri-
operative myocardial ischemia, as assessed
by continuous ST-segment monitoring [4C].
413
414 Chapter 20 Jamie J. Coleman, Anthony R. Cox, and Nicholas J. Cowley
In order to establish whether this confers any
clinical benet, several multicenter random-
ized controlled trials have been published
[1C,5C,6C,7C,8C,9C,10C]. Half of these trials
included patients at high risk of perioperative
complications, and half did not require the
presence of risk factors. Trials that did not
identify high-risk categories for surgery did
not identify clear benet from perioperative
beta-blockade [5C,6C,9C].
The rst trial, in 200 high-risk patients
who underwent non-cardiac surgery under
general anesthesia using atenolol as the
study drug, showed a signicantly reduced
mortality for up to 2 years of follow up
[7C]. Another study, the Dutch Echographic
Cardiac Risk Evaulation Applying Stress
Echo (DECREASE) trial, selected 112
patients undergoing vascular surgery, care-
fully selected for high risk with positive
dopamine stress echo testing, to receive stan-
dard care or bisoprolol, started 1 week before
surgery, and titrated to heart rate [8C]. There
was an impressive 89% reduction in cardiac
mortality/myocardial infarction in the treat-
ment group (3.4% versus 34%), sustained
up to 3 years. In by far the largest trial, POISE
(PeriOperative ISchaemic Evaluation trial)
8351 patients with cardiovascular risk factors,
undergoing non-cardiac surgery, were ran-
domly assigned to metoprolol succinate or
placebo 24 hours before surgery and to con-
tinue for 30 days [1C]. This resulted in a 17%
reduction in the composite end-point of death,
myocardial infarction, or non-fatal cardiac
arrest at 30 days (5.8% versus 6.9%). How-
ever, the reduction in non-fatal myocardial
infarction was offset by an increase in total
mortality (3.1% versus 2.3%) and double the
numbers of strokes (1% versus 0.5%). There
was more hypotension in the therapy group,
and a post-hoc analysis identied this popula-
tion at most risk of death and stroke.
The most recent meta-analysis, pooling the
available data, did not identify any signicant
reduction in all cause or cardiovascular mor-
tality, but conrmed a reduction in non-fatal
myocardial infarction and myocardial ische-
mia at the expense of an increased risk of stroke
[11M]. Safety outcomes included a high risk of
perioperative bradycardia and hypotension
requiring treatment. However, it should be
borne in mind that two-thirds of the pooled
data arose from the POISE trial. It is possible
that the benet of the beta-blockade in this
group was offset by the method of administra-
tion, with introduction of high-dose metopro-
lol immediately before surgery, leading to
postoperative problems with heart rate and
blood pressure control. Fixed-dose strategies,
used in the majority of trials, do not account
for variations in response to medication within
populations, leading to inadequate dosing in
some patients and too much in others. A more
tailored strategy of titration to response is likely
to lead to fewer postoperative adverse events.
Current advice for using perioperative
beta-blockade With this evidence in mind,
the current advice is to use beta-blockers in
high-risk patients without contraindications
during high risk, usually vascular, surgery
[12S]. Those with intermediate cardiovascular
risk may also benet [13C]. Beta-blockade
should be titrated to achieve a heart rate of
6070/minute. In order to reduce the morbidity
and mortality associated with postoperative
hypotension and bradycardia, it is important
that beta-blockade is started optimally 1 week
to 1 month preoperatively, in order to achieve
safe dosage titration. Treatment with a selective
beta1-adrenoceptor antagonist without intrin-
sic sympathomimetic activity is favored. The
duration of therapy has not been adequately
determined, although the risk of postoperative
cardiovascular events continues for several
months. Preoperative identication of indica-
tions for long-term beta-blockade should lead
to consideration of life-long treatment.
Beta-blockade as long-term therapy When
beta-blockers have been appropriately
titrated to effect for indications other
than surgery, and a maintenance phase has
been achieved, the advice is to continue treat-
ment perioperatively in all groups of patients
and all surgical risk categories. When beta-
blockers are prescribed for hypertension, the
absence of evidence of perioperative cardio-
protective effects of other agents does not sup-
port a change in therapy. Higher mortality
rates have been observed after beta-blocker
withdrawal in observational studies, and so
Antihypertensive drugs Chapter 20
this is not advised [14c,15c]. Certainly, when
beta-blockers are prescribed for patients with
ischemic heart disease, stable heart failure, or
dysrhythmias; they should not be discontin-
ued, as these patients t into high-risk catego-
ries for surgery. Beta-blockers should not be
continued if there are independent indications
to withdraw treatment, such as decompen-
sated heart failure or hypotension [12S].
Drugs acting on the renin-angiotensin sys-
tem (RAS) It is possible that perioperative
treatment with angiotensin converting enzyme
(ACE) inhibitors may have benecial effects
on postoperative outcome. This supposition
stems from information about longer term
benets independent of blood pressure
control, including anti-inammatory actions,
improvements in endothelial function, and
end-organ preservation. Evidence from the
placebo-controlled QUO VADIS study in
patients undergoing cardiac surgery showed
fewer postoperative cardiovascular events in
those who were randomized to quinapril start-
ing 1 month before surgery and continuing for
1 year [16C]. However, the prolonged duration
of treatment may have inuenced the results,
and a more recent systematic review has ques-
tioned these ndings [17M].
Intraoperative hypotension attributed to
drugs acting on the renin-angiotensin sys-
tem A complication is the risk that ACE
inhibitors can cause severe hypotension dur-
ing anesthesia [18c,19R], as can the angioten-
sin receptor blockers (ARBs) [20c], which
can also impair the response to standard
vasopressors used intraoperatively. This
problem can be minimized by drug with-
drawal the day before surgery. However,
treatment should be resumed as soon as prac-
ticable postoperatively, assuming stabilized
intravascular volume. Patients at high risk
of perioperative cardiovascular risk, in par-
ticular those with stable left ventricular dys-
function, may benet from continued ACE
inhibition, although there is still a risk of
intraoperative hypotension [12S,21c]. A more
informed choice may be possible after the
publication of a larger trial, currently recruit-
ing, in which continued ACE inhibition is
415
being compared with a short period of with-
drawal preoperatively [22S].
Other specic considerations of periopera-
tive use of ACE inhibitors The risk of
angioedema with ACE inhibitors is a suscepti-
bility factor in dental and maxillofacial sur-
gery, during which orofacial manipulation
can lead to localized angioedema. This adverse
effect must be recognized when edema of the
face, lips, oral cavity, or larynx occurs peri-
operatively in patients taking ACE inhibitors.
Calcium channel blocking drugs Most of the
work on perioperative outcomes has focused
on reducing myocardial oxygen demand using
beta-blockade. Calcium channel blockers may
be suitable alternatives in high-risk patients
with contraindications to beta-adrenoceptor
antagonists. However, the dihydropyridines
do not offer the protection that those with
heart-rate lowering properties offer, and may
even worsen outcome [23C].
Other antihypertensive agents There is little
direct evidence to support the use of other anti-
hypertensive agents perioperatively, although
advice is to continue drugs already prescribed.
Although diuretics are usually used in low
doses compared with those used in heart fail-
ure, the possibility of electrolyte disturbances
should be remembered, as potassium imbal-
ance can increase the risk of perioperative dys-
rhythmias and worsen outcomes [24c]. The use
of perioperative alpha2 adrenoceptor agonists
may improve outcomes in high-risk patients,
but most of the supportive evidence is conned
to vascular surgery [25M]. However, a ran-
domized trial of moxonidine in patients under-
going major vascular surgery showed no
evidence of a benecial effect on mortality or
perioperative myocardial ischemia [26C].
Conclusion The current evidence does not
support the need to treat moderate arterial
hypertension aggressively perioperatively, but
supports continued medication when possible
unless clinical circumstances dictate otherwise.
Most of the evidence for starting antihyperten-
sive drug treatment relates to risk modication
in patients at high cardiovascular risk. Many
416 Chapter 20 Jamie J. Coleman, Anthony R. Cox, and Nicholas J. Cowley
high-risk patients will have arterial hyperten-
sion, and this should prompt a cardiovascular
risk assessment and drug therapy when there is
a sound evidence base.
ANGIOTENSIN
CONVERTING ENZYME
INHIBITORS [SED-15, 226;
SEDA-30, 234; SEDA-31, 350;
SEDA-32, 379]
Combination studies There is continued
interest in the use of drug combinations
involving angiotensin converting enzyme
(ACE) inhibitors and other inhibitors of
the reninangiotensinaldosterone system
(RAAS). While attempts are being made to
quantify the benecial clinical effects of such
combinations, there are clear concerns about
the potential for renal impairment and electro-
lyte imbalance, including hyperkalemia. The
efcacy and safety of adding another RAAS
inhibitor or blocker to an ACE inhibitor or
an angiotensin II receptor antagonist plus a
beta-adrenoceptor antagonist in heart failure
secondary to left ventricular systolic dysfunc-
tion has been discussed [27r]. It is difcult to
know how much RAAS blockade is too much
in such cases, in view of uncertain benets and
signicant increases in adverse effects. The
combined use of ACE inhibitors and angio-
tensin II receptor antagonists is also consid-
ered to carry limited benets and evidence
of renal adverse effects [28r].
In an analysis of the Valsartan in Heart
Failure Trial (Val-HeFT), focusing on
chronic kidney disease, the benets and
harms of dual blockade of the RAAS have
been explored [29C]. Compared with the
addition of placebo to ACE inhibition, the
addition of valsartan led to higher rates of
discontinuation and hyperkalemia in those
with chronic kidney disease at baseline.
However, the authors argued that the over-
all benets of combined therapy would out-
weigh the risks even in those with chronic
kidney disease.
In a large industry-sponsored randomized
study, the ONTARGET trial (Ongoing Telmi-
sartan Alone and in combination with Rami-
pril Global Endpoint Trial), the effects of
telmisartan, ramipril, alone or in combination
were examined in patients without heart fail-
ure [30C]. Telmisartan and ramipril both
increased the risks of renal impairment, as
measured by the primary renal end-points of
rst occurrence of dialysis, renal transplanta-
tion, doubling of serum creatinine, or death
[31C]. However, combination therapy, while
associated with a lower rate of proteinuria,
was associated with a signicant increase in
the primary renal outcomes. One hypothesis
for the poorer renal outcomes with combina-
tion therapy compared with single therapy is
a greater reduction in glomerular ltration rate
in those with unknown renal artery stenosis.
In an open, randomized, crossover trial
in 18 patients with chronic non-diabetic pro-
teinuric kidney disease, double blockade with
telmisartan and cilazapril plus hydrochloro-
thiazide was compared with triple blockade
(the addition of spironolactone) [32c]. Plasma
renin activity and proteinuria were reduced,
but the risk of hyperkalemia increased.
Respiratory In 199 patients with heart failure
taking enalapril there was a higher incidence
of cough in those with non-severe heart failure
(classes I or II) than in those with classes III
and IV [33c]. An ejection fraction over 40%
or a brain natriuretic peptide (BNP)
concentration under 3000 ng/l predicted
the risk of cough. The authors suggested
that cough may be a marker of non-severe
heart failure and that the highly activated reni-
nangiotensin system in severe congestive
heart failure might prevent bradykinin build-
up, even in the presence of ACE inhibition.
The problems of multiple prescribing in
the elderly have been discussed in the
context of a case of enalapril-associated
dry cough misdiagnosed as pneumonia
[34A]. The prescribed antibiotics caused
pseudomembranous colitis and an opioid-
based syrup contributed to delirium. The
authors drew attention to the effect of the
prescribing cascade that can occur fol-
lowing the failure to identify an adverse
drug reaction.
Antihypertensive drugs Chapter 20
It has been hypothesized that the combi-
nation of ACE inhibitors and aliskiren may
reduce the rate of cough associated with
ACE inhibitors [35H]. The theoretical mech-
anism suggested is that aliskiren reduces
renin activity and plasma concentrations
of angiotensin I, leaving more uninhibited
ACE free to metabolize bradykinin. How-
ever, this hypothesis is based on a non-statis-
tically signicant difference in cough rates
between ramipril and ramipril aliskiren
in a trial that was not primarily designed
to ascertain differences in rates of cough.
Metabolism Hypoglycemia associated with
ACE inhibitors has been a concern, partic-
ularly given their benets in hypertension
in diabetes mellitus. In a systematic review
of drug-induced hypoglycemia, ACE inhib-
itors emerged as one of the most common
groups of drugs associated with hypoglyc-
emia [36M]. However, the evidence base
was considered to be of low quality.
Autacoids There have been many studies
of the association of ACE inhibitors with
angioedema (SEDA-29, 207; SEDA-31,
352; SEDA-32, 380).
EIDOS classication:
Extrinsic moiety ACE inhibitors
Intrinsic moiety Tissues affected by
bradykinin
Distribution Areas of production of
bradykinin
Outcome Tissue swelling (lips and
tongue, larynx and pharynx)
Sequela Angioedema from ACE
inhibitors
DoTS classication:
Dose-relation Hypersusceptibility
reaction
Time-course Intermediate
Susceptibility factors Genetic (blacks;
dipeptidyl peptidase IV deciency); sex
(female); exogenous factors (drugs
NSAIDs, vaccines, immunosuppressants;
surgerydental and maxillofacial
procedures; devicespolyacrylonitrile
membranes in hemodialysis); diseases
417
(a history of angioedema; acquired
dipeptidyl peptidase IV deciency)
The incidence of ACE inhibitor-induced
angioedema has been investigated in a
retrospective study of admissions to an
emergency admissions unit [37c]. In a ran-
domized trial of ramipril 5 mg/day
(n 505) versus placebo (n 503) in
patients with hypertension there was no dif-
ference in the frequency and types of
adverse events and serious adverse events
[38C]. However, cough was more common
with ramipril (4.8%) than placebo (0.4%).
Diagnosis of angioedema can sometimes
be difcult. In a 59-year-old woman taking
long-term enalapril CT and MR, imaging
showed a right peritonsillar/pharyngeal
mass like lesion, suggesting a differential
diagnosis of infection or a tumor [39A].
However, 1 day later, a contrast-enhanced
MR image showed no focal mass and the
tonsils and pharynx were normal. Enalapril
was withdrawn and her symptoms subsided.
The authors advised that clinicians and
radiologists should be aware of the unex-
pected focal nature of angioedema.
Cerebral angioedema has been associ-
ated with enalapril [40A].
A 28-year-old woman with systemic lupus
erythematosus developed angioedema of the
face and lip without airways involvement after
taking enalapril for 2 weeks. Several hours later
she had tonic-clonic seizures, which were con-
trolled with diazepam and phenytoin. A CT scan
showed extensive cerebral edema involving
white matter. Enalapril was withdrawn and she
received supportive treatment and intravenous
dexamethasone 10 mg every 12 hours.
Susceptibility factors Hyperkalemia associ-
ated with ACE inhibitors is often associated
with drugdrug interactions, in particular
with aldosterone antagonists such as spirono-
lactone. In a prospective observational cohort
study of cardiac patients taking ACE inhibi-
tors with interacting drugs [41C], one in 10
patients had hyperkalemia suspected to be
associated with a drugdrug interaction. Pre-
dictive susceptibility factors for hyperkalemia
418 Chapter 20 Jamie J. Coleman, Anthony R. Cox, and Nicholas J. Cowley
included advanced age, renal disease, hepatic
disease, and polypharmacy. The authors
argued that susceptibility factors should trig-
ger more frequent monitoring.
Using the African American Study
of Kidney Disease and Hypertension
(AASK) database, non-diabetic adults were
randomly assigned to ACE inhibitors, beta
adrenoceptor antagonists, or calcium channel
blockers [42C]. Hyperkalemia was associated
with a reduced glomerular ltration rate
(below 41 ml/minute/1.73 m2). Hyperkalemia
was also signicantly more common with
ACE inhibitors. The use of a potassium-wast-
ing diuretic was associated with a 59% reduc-
tion in the risk of hyperkalemia.
Benazepril [SED-15, 420; SEDA-29, 209]
Liver A 32-year-old woman with type 2 dia-
betes and hypertension who had taken bena-
zepril for 14 weeks developed jaundice; a
liver biopsy showed marked cholestasis with
necrosis and inammatory changes [43A].
Captopril [SED-15, 625; SEDA-31, 355;
SEDA-32, 384]
Electrolyte balance Hyperkalemia (6.0
mmol/l) has been reported in an 18-month-
old child who had received long-term capto-
pril after an elective operation on a type 1
truncus arteriosus defect [44A]. The child also
had anemia, presumed to be due to erythroid
hypoplasia.
Skin Contact dermatitis associated with
captopril has been reported on the hands
and eyelids of a 35-year-old mother who
was giving captopril syrup to her child
[45A]. Patch testing isolated captopril as
the causative agent, and the authors sug-
gested that the thiol (sulfhydryl) compo-
nent was the cause. Exposure to captopril
was thought to have occurred during both
administration of the drug and exposure
to unmetabolized captopril in the urine of
the child when changing nappies.
Enalapril [SED-15,1210; SEDA-30, 235;
SEDA-31, 355; SEDA-32, 384]
Musculoskeletal Pseudopolymyalgia has
been associated with enalapril [46A].
A 72-year-old man developed myalgia, morn-
ing stiffness, and polyarthritis after taking
enalapril 10 mg/day for 3 months. There were
no laboratory changes and no changes on CT
scan; the symptoms disappeared within 3
months of withdrawal.
Lisinopril [SED-15, 2071; SEDA-30, 237;
SEDA-31, 357; SEDA-32, 385]
Skin Erythroderma associated with lisino-
pril has been reported [47A].
ANGIOTENSIN II
RECEPTOR ANTAGONISTS
[SED-15, 223; SEDA-30, 238; SEDA-
31, 358; SEDA-32, 387]
Autacoids Angioedema attributed to
angiotensin receptor blockers continues to
be reported [48c].
EIDOS classication:
Extrinsic moiety Angiotensin II
receptor antagonists
Intrinsic moiety Tissues affected by
bradykinin
Distribution Areas of production of
bradykinin
Outcome Tissue swelling (lips and
tongue, larynx and pharynx)
Sequela Angioedema
DoTS classication:
Dose-relation? Collateral
Time-course Time independent
Susceptibility factors Previous
angioedema with an ACE
inhibitor
Antihypertensive drugs Chapter 20
A meta-analysis of the risk of angioedema
associated with angiotensin II receptor
blockers in patients with previous angio-
edema associated with ACE inhibitors has
suggested that the risk of subsequent angioe-
dema is 217% for any subsequent angioe-
dema and 09.2% for conrmed angioedema
[49M].
Teratogenicity In a retrospective analysis of
26 735 pregnant women with hypertension,
only ve had used angiotensin II receptor
antagonists [50c]. In all ve cases the angio-
tensin II receptor antagonist was withdrawn
when pregnancy was conrmed (between
weeks 5 and 23). There were two deliveries
of healthy babies at term and one full-term
baby had an additional nger and toe.
The other two pregnancies were complicated
by oligohydramnios, ending in pre-term
delivery.
Candesartan [SED-15, 612; SEDA-30,
241; SEDA-31, 358; SEDA-32, 386]
Teratogenicity A woman who took cande-
sartan 8 mg for 2 years before and through-
out her pregnancy for idiopathic
hypertension delivered a boy by cesarean
section at 34 weeks who subsequently died
following respiratory difculties [51A]. The
autopsy showed hypoplasia, renal dyspla-
sia, and calvarial hypoplasia with brain
malformation. The authors noted that the
known risk of fetal toxicity associated with
candesartan may be ignored by prescribers.
Losartan [SED-15, 2168; SEDA-30, 242;
SEDA-31, 359; SEDA-32, 000]
Comparative studies In a double-blind
comparison of losartan 50 and 150 mg/day
in patients with heart failure, high-dose
losartan had a benecial effect on mortality
and hospital admissions with heart failure
[52C]. However, hyperkalemia, hypotension,
renal impairment, and angioedema were
more common in the high-dose group.
419
Cardiovascular A woman taking losartan
25 mg/day and carbamazepine was admit-
ted to hospital with head trauma secondary
to syncope; her heart rate was 30/minute
and her serum potassium concentration
6.7 mmol/l [53A]. It was suspected that the
hyperkalemia was associated with losartan,
leading to third-degree sinoatrial block or
complete sinus arrest.
Sensory systems Taste Dysgeusia in a 78-
year-old woman occurred after losartan
was added to her antihypertensive treat-
ment [54A]. She described a constant
unpleasant taste, which resolved within 2
weeks after replacement of losartan by
amlodipine.
Olmesartan [SEDA-32, 387]
Nervous system In a non-interventional
study of olmesartan, with 6 weeks follow-
up, dizziness was the most frequent adverse
reaction (0.19%) [55c].
Fetotoxicity Olmesartan given in the last
month of pregnancy was associated with
oligohydramnios [56A]. The neonate devel-
oped severe renal failure and died at 45
days. A post-mortem showed tubal dysgen-
esis in the kidneys, alveolar damage,
pulmonary hemorrhage, and focal pneumo-
nia. An association with olmesartan in this
case seems unlikely, given its late introduc-
tion in pregnancy.
Telmisartan [SED-15, 3311; SEDA-30,
242; SEDA-31, 360; SEDA-32, 388]
Drugdrug interactions Mycophenolate
mofetil In a pharmacokinetic study of tel-
misartan, valsartan, and candesartan in
combination with mycophenolate mofetil
in renal transplant patients, telmisartan
increased the elimination of mycophenolic
acid; there was no interaction with valsar-
tan or candesartan [57c]. It was suggested
that this was due to activation by
420 Chapter 20 Jamie J. Coleman, Anthony R. Cox, and Nicholas J. Cowley
telmisartan of PPAR-g, leading
to increased glucuronidation of myco-
phenolate. The authors suggested periodic
monitoring of mycophenolate concentra-
tions during co-administration with
telmisartan.
Valsartan [SED-15, 3593; SEDA-30, 242;
SEDA-31, 360; SEDA-32, 388]
Observational studies In an open single-
dose study of valsartan in children and ado-
lescents with hypertension, only minor
adverse effects (such as headache) were
recorded; there were no serious adverse
events or clinically signicant laboratory
results [58c].
Placebo-controlled studies In a double-
blind randomized trial of valsartan in 90
children, with an open follow-up arm, there
were no changes in linear growth, weight
gain, or head circumference, or develop-
mental disorders; drug-related adverse
events were similar with placebo and val-
sartan [59c].
Cardiovascular Prolonged hypotension fol-
lowed an intentional overdose of amlodi-
pine and valsartan [60A].
DIRECT RENIN
INHIBITORS [SEDA-30, 242;
SEDA-31, 360; SEDA-32, 000]
NON-PEPTIDE INHIBITORS
Aliskiren [SEDA-30, 242; SEDA-32, 388]
Systematic reviews Several reviews of alis-
kiren have included information on its
adverse effects [61R,62R,63R]. In addition,
a Cochrane systematic review and meta-
analysis has been conducted, for which the
authors reviewed six trials in 3684 patients
[64M]. Adverse events reported in these
trials included headache, nasopharyngitis,
diarrhea, and back pain; but the rates of
these events were similar between placebo
and all doses of aliskiren.
Cardiovascular Prolongation of the QT
interval and resultant torsade de pointes
and cardiac arrest has been attributed to
aliskiren [65A]. The patient had multiple
co-morbidities and was taking several cardi-
oactive drugs, including sotalol, which pro-
longs the QT interval. However, the QT
intervals measured while the patient was
taking sotalol but before aliskiren was
added led the authors to suggest that alis-
kiren had caused the dysrhythmia. The
potential weaknesses in attributing causal-
ity to this adverse reaction, especially given
the absence of evidence in other post-mar-
keting data were highlighted in an accom-
panying editorial, which concluded with
prudent advice: it is not possible to impli-
cate aliskiren as a sole cause of QT prolon-
gation in this patient, but it may suggest
that patients on sotalol should be moni-
tored when starting aliskiren [66r]. Fur-
thermore, a study of aliskiren (at up to
four times the normal dosing limit) in
nearly 300 healthy volunteers has also
shown no adverse effects on cardiac con-
duction and repolarization [67c].
Urinary tract Acute renal insufciency with
hyperkalemia has been reported in a 76-
year-old hypertensive woman taking both
aliskiren and spironolactone [68A]. Pre-
existing renal impairment and concomitant
use of an aldosterone receptor antagonist
were predisposing factors, and it is not sur-
prising that the same pattern of adverse
effects is seen in cases like this as have been
seen with ACE inhibitors and angiotensin
receptor blockers before.
Drug overdose An accidental single inges-
tion of aliskiren 300 mg in a 12-year-old child
led to falls in systolic and diastolic pressures
of 63 and 40 mmHg respectively without any
permanent adverse consequences [69A].
Drugdrug interactions Several industry-
sponsored interaction studies of aliskiren
Antihypertensive drugs Chapter 20
have been conducted in healthy volunteers
[70c,71c,72c,73c]. These studies have shown
that it is safe to co-administer aliskiren with
acenocoumarol, atorvastatin, digoxin, feno-
brate, ketoconazole, metformin, pioglita-
zone, and modied-release isosorbide
mononitrate. The only co-administered drug
whose exposure was reduced was furosemide,
although the clinical signicance of this inter-
action is uncertain.
ENDOTHELIN RECEPTOR
ANTAGONISTS [SED-15, 1215;
SEDA-30, 245; SEDA-31, 360; SEDA-
32, 389]
The biological basis and clinical data under-
lying the practical use of endothelin recep-
tor antagonists (ERAs) in the eld of
pulmonary hypertension have been
reviewed [74R].
Ambrisentan [SEDA-30, 245;
SEDA-31, 361; SEDA-32, 389]
The clinical pharmacology, use, and
adverse effects of ambrisentan in the man-
agement of pulmonary artery hypertension
have been reviewed [75R]. The adverse
effects of ambrisentan include peripheral
edema, nasal congestion, palpitation, ush-
ing, nasopharyngitis, and sinusitis. In pla-
cebo-controlled trials lasting up to 12
weeks the incidence of liver enzyme func-
tion abnormalities is lower with ambrisen-
tan than with placebo.
Liver The availability of ambrisentan in
patients with pulmonary artery hyperten-
sion who have previously discontinued
other endothelin receptor antagonists
because of liver function abnormalities pro-
vides an important option for patients who
have had adverse reactions to bosentan or
sitaxsentan [76c]. Ambrisentan is a
421
propionic acid-based compound rather than
a sulfonamide, and its adverse hepatic
effects are known to be different. Previous
short-term studies have suggested that
ambrisentan may be associated with a
lower risk of aminotransferase abnormali-
ties. This study supports this view, as none
of the 36 patient had serum transaminase
activities more than three times the upper
limit of normal, although one had a trans-
ient rise that resolved after temporary dos-
age reduction. Most of the other adverse
effects were similar to those in studies of
other endothelin receptor antagonists,
including peripheral edema, ushing, and
headache. However, the results of longer-
term studies have shown that ambrisentan
can cause liver abnormalities and can lead
to treatment withdrawal; at present it is
possible that the differences in reporting
rates of liver enzyme adverse effects with
different agents can be attributed to differ-
ent rates of exposure.
A long-term extension studyARIES-E
(Ambrisentan in Pulmonary Arterial
Hypertension, Randomized, Double-Blind,
Placebo-Controlled, Multicenter, Efcacy
Studies)of the original 12 week random-
ized trials (ARIES-1 and ARIES-2) has
been reported [77c]. From the original 383
patients, 261 patients were still taking
ambrisentan after 2 years, during which
time 42 had died and 22 had withdrawn
because of adverse events, most of which
were consistent with disease progression.
The annual incidence of aminotransferase
abnormalities was about 2%, and although
this rate is low, 12 patients had enzyme
rises to more than 3 times the upper limit
of normal and two withdrew as a result.
Monitoring of liver function is therefore
still advised.
Drugdrug interactions Tadalal The in-
teraction of ambrisentan with tadalal has
been investigated in a crossover study in
26 healthy adults [78c]. In contrast to
bosentan, there was no interaction, and
dosage adjustment is not necessary during
combination therapy.
422 Chapter 20 Jamie J. Coleman, Anthony R. Cox, and Nicholas J. Cowley
Warfarin In a crossover study in 22 healthy
subjects multiple doses of ambrisentan had
no clinically relevant effects on the pharma-
cokinetics and pharmacodynamics of a sin-
gle dose of warfarin [79c].
Bosentan [SED-15, 549; SEDA-30, 245;
SEDA-31, 361; SEDA-32, 389]
Observational studies Experience with
bosentan in the European postmarketing
surveillance program in children has been
described [80c]. The analysis compared
older (12 years and over) and younger
children, most of whom had idiopathic
pulmonary hypertension or secondary to
congenital heart disease. Hepatic amino-
transferase activities were increased in
fewer younger children (2.7% versus
7.8%) and withdrawal rates were also lower
in those under 12 years. As well as conrm-
ing the value of monthly liver function
monitoring, this industry-sponsored analy-
sis may suggest that bosentan is better tol-
erated in children than in adults.
The use of endothelin receptor antago-
nists for pulmonary hypertension has been
examined in 14 high-risk adults with sickle
cell disease [81c]. Most were taking bosen-
tan and three were taking ambrisentan.
There were similar adverse effects as in
previous studies, including rises in serum
alanine aminotransferase (n 2), periph-
eral edema (4), rash (1), headache (3), and
reduced hemoglobin (2), none of which
required drug withdrawal.
In unselected patients with HIV-associ-
ated pulmonary hypertension bosentan
was safe in combination with highly active
antiretroviral therapy; there were no
adverse effects on the control of HIV infec-
tion [82c].
In a study of the long-term effects of
bosentan in pulmonary hypertension asso-
ciated with connective tissue disorders over
a follow-up period of 48 weeks in 53
patients [83c] there were frequent adverse
events, such as peripheral edema, nausea,
and worse dyspnea; serious adverse events
(such as dyspnea and pneumonia) were
not uncommon but were not judged to be
related to bosentan by the investigators;
withdrawals most often involved worse
dyspnea (6%), general deterioration in
physical health (6%), and liver enzyme
increases (6%).
Placebo-controlled studies In a random-
ized placebo-controlled trial of bosentan in
30 patients with severe chronic obstructive
pulmonary disease (COPD) without evi-
dence of severe pulmonary hypertension at
rest there was no evidence of improved exer-
cise capacity; in fact, hypoxemia and func-
tional status deteriorated [84c].
The use of bosentan in patients with
mildly symptomatic pulmonary arterial
hypertension has been studied in a multicen-
ter, double-blind, randomized, placebo-con-
trolled trial (the EARLY study) [85C].
Patients over 12 years of age (n 185) with
less functional compromise (WHO func-
tional class 2) were randomized to bosentan
or placebo and followed for 6 months dou-
ble-blind, followed by an open extension
period. Adverse events were common in
both groups and included nasopharyngitis
and abnormal liver enzymes in the bosentan
arm. Laboratory tests identied increases in
aminotransferases of more than three times
the upper limit of normal in 12 (13%)
patients taking bosentan compared with
two (2%) patients taking placebo. Liver
enzyme abnormalities invariably resolved
on dose reduction or drug withdrawal.
Immunologic Delayed hypersensitivity in a
patient taking bosentan has been described
[86A].
A 44-year-old Hispanic woman with pulmo-
nary hypertension secondary to scleroderma,
but no previous allergic disorders, had a gen-
eralized maculopapular rashafter taking
bosentan for 18 days. Her symptoms subsided
with oral betamethasone for 10 days and 1
month later she underwent skin tests, patch
tests, lymphocyte transformation tests (all of
which were also performed in three controls
who had scleroderma and who had tolerated
bosentan), and a controlled oral provocation
test. The skin and patch tests were negative
Antihypertensive drugs Chapter 20
in both the patient and controls, but the
lymphocyte transformation test was positive
only in the patient. In the oral provocation
test, bosentan at 1% of the therapeutic dose
provoked pruritus, erythema, angioedema,
fever, rash, bronchospasm, eosinophilia, and
hepatic/renal abnormalities within 24 hours,
consistent with drug rash with eosinophilia
and systemic symptoms (DRESS).
Extensive investigation in this case con-
rmed cell-mediated hypersensitivity to
bosentan.
Sitaxsentan [SEDA-30, 245; SEDA-31,
362; SEDA-32, 390]
Observational studies STRIDE-2X is the
1-year open extension study of the 18 week
STRIDE-2 (Sitaxsentan To Relieve ImpaireD
Exercise) investigation that followed patients
taking sitaxsentan or bosentan for pulmonary
artery hypertension [87C]. As well as efcacy
measures, the researchers included time to
withdrawal because of adverse events and
time to rises in hepatic aminotransferases in
the outcome measures. For the analysis popu-
lation, the risk of raised aminotransferases
to more than 3 times the upper limit of normal
at 1 year was 6% with sitaxsentan 100 mg/day
and 14% with bosentan. The cumulative risk
of withdrawal at 1 year with raised amino-
transferases was 3% with sitaxsentan
100 mg/day and 9% with bosentan. Other
adverse events were peripheral edema, naso-
pharyngitis, dyspnea, and cough, consistent
with previous trials in pulmonary artery
hypertension. The overall withdrawal rates
at 1 year were 15% with sitaxsentan 100 mg/
day and 30% with bosentan. Sitaxsentan
therefore seems to have similar efcacy to
bosentan and from this evidence may have
the advantage of causing fewer hepatic
adverse events in longer-term treatment (but
see below).
Liver In addition to the trial evidence, case
studies of sitaxsentan and hepatic dysfunc-
tion have been reported. Liver damage
associated with sitaxsentan progressed
423
despite drug withdrawal, but eventually
responded to glucocorticoid therapy [88A].
A liver biopsy was not obtained in this case,
but the authors surmised that the pattern of
adverse features and response to gluco-
corticoids suggested an immune-mediated
mechanism.
Two other cases of severe liver dysfunc-
tion have been attributed to sitaxsentan
within 12 weeks of treatment [89A]. In both
patients the aminotransferase activities
peaked at up to 30 times the upper limit
of normal and both had protracted periods
of jaundice. Only the rst was symptomatic
at presentation, whereas the second was
detected on routine liver function test
monitoring.
These three cases have been discussed in
the light of an earlier study of two cases and
an unreported case of severe hepatitis [90r].
The author discussed the atypical presenta-
tions and also suggested that these cases
were much more serious (severe progressive
liver dysfunction despite drug withdrawal)
than previous cases of hepatotoxicity
during therapy with endothelin receptor
antagonists.
Therefore although there is direct com-
parative evidence from trial data of possi-
ble benets of sitaxsentan compared with
bosentan, it is possible that despite fewer
cases of raised aminotransferases, there
may be a greater potential for severe and
possibly fatal liver toxicity from sitaxsentan.
Drugdrug interactions Acenocoumarol
Endothelin receptor antagonists and oral
anticoagulants are commonly used in
patients with pulmonary artery hyperten-
sion, and their interaction has been exam-
ined [91c] in a subgroup analysis of
patients who were enrolled in the
STRIDE-3 trial. There were increases in
INR up to 4.0 or more in 26 of 51 patients
taking acenocoumarol, but no signicant
bleeding events, suggesting that with close
dosage adjustment co-administration of
sitaxsentan with acenocoumarol should be
manageable.
424 Chapter 20 Jamie J. Coleman, Anthony R. Cox, and Nicholas J. Cowley
DRUGS THAT ACT ON THE
SYMPATHETIC NERVOUS
SYSTEM [SEDA-30, 245; SEDA-31,
362; SEDA-32, 391]
PRESYNAPTIC ALPHA-
ADRENOCEPTOR AGONISTS
Clonidine [SED-15, 817; SEDA-30, 245;
SEDA-31, 362; SEDA-32, 391]
Cardiovascular In a phase II dose-ranging
study of clonidine in the treatment of acute
organophosphorus poisoning there was a
signicantly higher incidence of hypoten-
sion in the higher dosage group, which
required temporary withdrawal of treat-
ment in several cases [92A].
Nervous system Clonidine has been suc-
cessfully used for impulsive and oppositional
behavior in attention-decit hyperactivity
disorder as well as for its centrally mediated
sedative action when taken late in the day.
A child who took clonidine for this indica-
tion had night terrors shortly after initial
therapy, insomnia during attempts at drug
withdrawal, and depression when the drug
was nally tapered and stopped [93A].
Body temperature Fever has been associ-
ated with clonidine [94A].
A 66-year-old woman with Alzheimer's
disease, morbid obesity, hypertension,
and depression, who was taking memantine,
donepezil, duloxetine, metoprolol, amlodipine,
and clonidine 100 micrograms tds, had a non-
ST segment elevation myocardial infarction
and was given aspirin, atorvastatin, and clopi-
dogrel. The dose of clonidine was doubled to
optimize blood pressure control, after which
she developed a high uctuating fever. Clini-
cal and laboratory examinations did not reveal
a source for the fever, which settled only
after the clonidine dosage reduction and
withdrawal.
Whether it was the increased dose of cloni-
dine alone or interactions with the previous
or new medicines is unclear, but the tempo-
ral relation suggested a probable associa-
tion with clonidine.
Drug overdose A systems error related to
incorrect pharmaceutical preparation of an
epidural solution containing bupivacaine,
adrenaline, and clonidine led to a 100-fold
overdose of the clonidine component in three
infants undergoing surgery [95A]. All three
had prolonged sedation postoperatively but
none required medical interventions or had
any lasting sequelae. The authors suggested
that this overdosing error offered some indi-
cation of the margin of safety for epidural
clonidine dosing in healthy children.
Drugdrug interactions Escitalopram An
interaction of clonidine with escitalopram
has been reported [96A].
Clonidine was given to a 66-year-old critically
ill patient to control agitation, after which her
regular medications including escitalopram
were started 1 day later. Over 3 days she
became more sedated to the level of near
unconsciousness. This resolved when the
escitalopram was withdrawn.
Combinations of centrally acting drugs
with possible sedative effects should be
used cautiously in critically ill patients.
Methyldopa [SED-15, 2291; SEDA-31,
363; SEDA-32, 391]
Hematologic Methyldopa-induced hemolytic
anemia has been described in a young woman
with hypertension [97A].
A 26-year-old woman taking a combined oral
contraceptive took methyldopa for hypert-
ension as she was planning a pregnancy in
the near future. She developed a hemolytic
anemia. The methyldopa was withdrawn and
the anemia resolved within 6 weeks.
Liver Two independent case reports have
described acute hepatitis in pregnancy
related to methyldopa [98A,99A]. Each pre-
sented with jaundice and dark urine; one in
the rst trimester and one in the second tri-
mester. In both cases the hepatitis resolved
quickly, although in one case prednisolone
was given.
Antihypertensive drugs Chapter 20
Fetotoxicity A positive antiglobulin test in a
neonate investigated for jaundice was
related to her mother's use of methyldopa
during pregnancy [100A]. The authors cor-
rectly pointed out that the presence of a
positive direct antiglobulin test in the
absence of blood group incompatibility
should prompt a search for a drug-related
cause.
Drug overdose A mixed overdose of
methyldopa, theophylline, indapamide, and
paracetamol led to prolonged severe hypo-
tension in an 89-year-old man, who required
vigorous intravenous uid replacement and
several days of intravenous noradrenaline
to maintain his vital signs [101A].
POSTSYNAPTIC
a-ADRENOCEPTOR
ANTAGONISTS [SEDA-30, 246;
SEDA-31, 363; SEDA-32, 391]
The use of postsynaptic a-adrenoceptor
antagonists in older patients with benign pros-
tatic hyperplasia has been reviewed [102R].
Cardiovascular Postsynaptic a-adrenoceptor
antagonists cause vasodilatation, and there-
fore, while they are useful as antihyper-
tensive agents, they are associated with
adverse effects such as dizziness, pre-
syncope, and syncope. These adverse
effects are particularly important for
patients with benign prostatic hyperplasia,
who are not hypertensive. A meta-analysis
has shown that the use of postsynaptic
a-adrenoceptor antagonists (including alfu-
zosin, terazosin, doxazosin, and doxazosin
GITS) for benign prostatic hyperplasia
confers an added risk of vascular-related
adverse events compared with placebo
[103M]. Tamsulosin was associated with a
non-statistically signicant trend toward a
higher incidence of such events; vaso-
dilatory adverse effects are likely to be
related to the selectivity proles of indi-
vidual drugs.
425
Sensory systems Intraoperative oppy iris
syndrome (IFIS) in cataract surgery is asso-
ciated with a-adrenoceptor antagonists,
especially tamsulosin. The factors associ-
ated with IFIS have been explored in a
comparative case series [104c]. When stan-
dard criteria for identifying IFIS were used,
4.1% of 660 patients undergoing routine
cataract surgery were affected. The use of
tamsulosin or other a-adrenoceptor antago-
nists correlated with the syndrome. The
association has already been fairly clearly
veried; however, this analysis also showed
that 8 out of 9 patients with IFIS but with-
out evidence of current or past a-adreno-
ceptor antagonist exposure had
hypertension. Given the current evidence
it is impossible to ascertain whether hyper-
tension is an independent susceptibility fac-
tor for IFIS.
Musculoskeletal The association of a-
adrenoceptor antagonists with fractures
has been studied in a Korean casecontrol
study using a health insurance database
[105c]. After adjustment for the use of
other agents (5a-reductase inhibitors, anti-
depressants, antipsychotic drugs, benzo-
diazepines, and calcium channel blockers)
there was an increased risk of fractures in
patients taking doxazosin or tamsulosin,
but not terazosin or alfuzosin.
Sexual function There was a clear associa-
tion between a-adrenoceptor antagonists
and ejaculatory dysfunction (pain/discom-
fort) in an observational study in Spanish
men with benign prostatic hyperplasia
and/or lower urinary tract symptoms
[106c]. The presence and severity of symp-
toms were assessed using the male sexual
health questionnaire; there was an 83%
prevalence of ejaculatory dysfunction in
patients taking a-adrenoceptor antagonists.
Most cases of ejaculatory dysfunction were
mild and severe dysfunction occurred in
only 4% of cases. Although the adverse
effects on sexual function were seen
with all of the a-adrenoceptor antagonists,
alfuzosin was associated with better ejacu-
latory function than tamsulosin, terazosin,
or doxazosin.
426 Chapter 20 Jamie J. Coleman, Anthony R. Cox, and Nicholas J. Cowley
Doxazosin [SED-15, 1188; SEDA-30,
246; SEDA-31, 363; SEDA-32, 392]
Observational studies In a retrospective
review of 97 patients with hypertension,
doxazosin was usually added as a fth agent
in doses of 216 mg/day [107c]. Adverse
effects related to doxazosin were rare and
drug withdrawal was necessary in only ve
patients.
Sexual function Retrograde ejaculation has
been described in a young man with a
pheochromocytoma who took doxazosin
for preoperative blood pressure control
[108A].
Indoramin [SED-15, 1746]
Drug overdose Cardiovascular collapse
and prolongation of the QT interval with
torsade de pointes was been reported in
two cases of self-poisoning with large doses
of indoramin [109A]. The risk of indoramin-
associated cardiotoxicity and torsade de
pointes appears to be high when the dose
is more than 750 mg.
Prazosin [SED-15, 2915; SEDA-32, 392]
Cardiovascular Prazosin, used to treat the
symptoms of sleep-related post-traumatic
stress disorder (PTSD), has been linked to
chest pain [110A].
A 25-year-old male veteran developed PTSD
after deployment in Iraq and was given prazo-
sin 1 mg at night for sleep disturbance. After
only a few doses he developed acute, intermit-
tent, left-sided chest pain. No alternative
cause could be found for the pain and he had
minimal cardiac risk factors. The pain
resolved completely within 1 week after drug
withdrawal.
Causality was not discussed, but while
an adverse reaction to the drug was
possible, there could have been other
explanations.
Tamsulosin [SED-15, 3303; SEDA-30,
246; SEDA-31, 364; SEDA-32, 392]
Sensory systems Eyes The association be-
tween tamsulosin and adverse ophthalmic
events related to cataract surgery has been
examined in two non-randomized studies.
In the rst, patients undergoing cataract
surgery in Turkey were prospectively
examined; 15 patients developed IFIS, 12
of whom were taking systemic tamsulosin
[111c]. The second study was a nested
case-control analysis which used Canadian
linked health-care databases to assess the
risk of adverse events after cataract surgery
[112C]. There were serious adverse ophthal-
mic events up to 14 days after surgery,
including retinal detachment, lost lens or
lens fragment, and endophthalmitis.
Adverse events were signicantly more
common among patients with recent tamsu-
losin exposure (adjusted OR 2.33; 95%
CI 1.22, 4.43). Recent exposure to other
a-adrenoceptor antagonists or prior expo-
sure to tamsulosin was not signicantly
associated with the same events. Because
of the nature of this research, it is not pos-
sible to link the adverse outcomes deni-
tively to episodes of IFIS, but this study is
set apart from previous work as it has
linked tamsulosin exposure to clinically
important postoperative complications,
which one can surmise relate to more
common drug-induced intra-operative
complications.
Sexual function Partial priapism (partial
segmental thrombosis of the corpus caver-
nosum) has been associated with tamsulo-
sin [113A].
A 59-year-old man developed a perineal mass
2 hours after taking a second dose of tamsulo-
sin for lower urinary tract symptoms. The
proximal part of the penis shaft was stiff, con-
sistent with partial priapism. Ultrasound
examination showed no ow in the cavernosal
artery and MR imaging showed edema
towards the base of the penis. Surgical
exploration allowed blood to be aspirated
from the thrombotic segment and a shunt
to be inserted in the corpus cavernosum spon-
giosum. Postoperatively normal sexual func-
tion was restored within 3 months.
Antihypertensive drugs Chapter 20
Priapism has also been described in a 47-
year-old man taking tamsulosin 400 micro-
grams/day as a smooth muscle relaxant for
the off-label indication of a distal urethral
stone [114A].
Sexual function While ejaculatory disorders
have been attributed to a-adrenoceptor
antagonists; it is less clear whether they
affect semen. In a randomized, double-
blind, placebo-controlled 3-way crossover
study of sperm in 48 healthy men after
exposure to tamsulosin, alfuzosin, and pla-
cebo for 5 days each tamsulosin was associ-
ated with negative effects on ejaculate
volume, sperm concentration, total sperm
count, semen viscosity, and sperm motility
compared with placebo; alfuzosin was com-
parable to placebo [115c]. Post-ejaculate
urine sperm concentrations were compara-
tively normal between all agents, suggesting
that retrograde ejaculation is not responsi-
ble for the ejaculatory dysfunction. There
was complete absence of ejaculation in 17
of the 48 men (35%) during treatment with
tamsulosin compared with none in the
other groups.
Urapidil [SEDA-32, 393]
Fetotoxicity Transient respiratory depres-
sion occurred in a neonate after the mother
had received intravenous urapidil for
uncontrolled hypertension in pregnancy
[116A]. The neonate required articial ven-
tilation for a period of 24 hours but recov-
ered fully. Urapidil was found in very high
amounts in the urine.
IMIDAZOLINE RECEPTOR
AGONISTS
Moxonidine [SED-15, 2395; SEDA-30,
247]
Drug overdose Acute moxonidine over-
dose in a 17-year-old woman resulted in
central nervous system reactionsinitial
427
sleepiness and headache then convul-
sionsand a paradoxical increase in blood
pressure [117A]. Symptomatic treatment
with anticonvulsants and mannitol resulted
in a full recovery. Although moxonidine is
an a2-adrenoceptor antagonist, the authors
postulated that during acute overdose the
blood concentration may be high enough
to allow non-selective activation of periph-
eral a1-adrenoceptors on blood vessels.
OTHER CENTRALLY
ACTING DRUGS
Reserpine (and Rauwola
alkaloids) [SED-15, 3034]
In a Cochrane systematic review of four
randomized controlled trials (all conducted
over three decades ago) reserpine was
effective in reducing systolic blood pressure
as a rst-line agent [118M]. The number of
patients included in these trials was small
(237), and none of the trials reported with-
drawals because of adverse reactions.
DIRECT VASODILATORS
Diazoxide [SED-15, 1188;SEDA-32,
393]
Multiorgan damage An infant with persis-
tent hyperinsulinemic hypoglycemia received
diazoxide and developed pulmonary hyper-
tension, heart failure, and neutropenia
[119A].
A girl with macrosomia, who was delivered by
cesarean section at 34 weeks, developed sei-
zures and hypoglycemia in the rst days of life
due to hyperinsulinemia and was given octreo-
tide and diazoxide. After 10 days she became
short of breath with signs of heart failure and
had evidence of pulmonary hypertension on
echocardiography and cardiac catheterization.
There was also neutropenia. Her respiratory
428 Chapter 20 Jamie J. Coleman, Anthony R. Cox, and Nicholas J. Cowley
and hemodynamic status improved after drug
withdrawal, as did the neutrophil count.
The exact mechanism of the pulmonary
hypertension, heart failure, and neutro-
penia was unclear, but it was probably
mediated by direct toxic effects on the pul-
monary vascular resistance, myocardium,
and bone marrow.
Hydralazine and
dimethylhydralazine [SED-15, 1701;
SEDA-31, 365; SEDA-32, 393]
Liver Hydralazine-induced cholestatic jaun-
dice has been reported [120A].
A 63-year-old AfricanAmerican woman with
hypertension and end-stage renal disease on
hemodialysis developed epigastric pain and
jaundice, having taken hydralazine 75 mg tds.
Abdominal ultrasound and CT and MRI
imaging showed no evidence of biliary
obstruction. There was complete clinical and
biochemical recovery after 4 weeks when the
drug was withdrawn.
Immunologic A 50-year-old woman taking
hydralazine for hypertension developed
alveolar hemorrhage and anti-neutrophil
cytoplasmic antibody (ANCA)-positive
pauci-immune glomerulonephritis; despite
the absence of full criteria for drug-induced
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21
CARBONIC ANHYDRASE
INHIBITORS [SED-15, 643;
SEDA-30, 254; SEDA-31, 371;
SEDA-32, 403]
Acetazolamide
Nervous system Glyceryl trinitrate dilates
cephalic arteries without increasing cerebral
blood ow, while acetazolamide increases
cerebral blood ow without dilating cerebral
arteries. The hypothesis that acetazolamide,
by dilating cerebral arterioles but not arteries
and thereby reducing pulsatile stretching of
the wall of the large arteries and their
perivascular sensory nerves, would reduce
or prevent headache due to glyceryl trinitrate
has been tested in 14 healthy volunteers in a
randomized, double-blind, crossover study
[1C]. However, acetazolamide combined with
glyceryl trinitrate caused a more delayed
headache than glyceryl trinitrate alone. Fur-
thermore, in three volunteers a migraine-like
headache occurred after the combination
and not with glyceryl trinitrate alone. The
authors suggested that the triggering of
migraine in individuals with no previous
attacks could be genetically determined.
Because of its effects on regional cere-
bral blood volume, acetazolamide has been
used to study cerebral hemodynamics. In
two men, aged 60 and 72 years, with strokes
due to unilateral internal carotid artery
occlusion, an acetazolamide challenge
resulted in enlargement of the cerebral
Side Effects of Drugs, Annual 33
J.K. Aronson (Editor)
ISSN: 0378-6080
DOI: 10.1016/B978-0-444-53741-6.00021-0
# 2011 Elsevier B.V. All rights reserved.
Jeffrey K. Aronson
Diuretics
infarction; the authors suggested that de-
hydration may have been the precipitating
factor [2A].
Sensory systems Myopia has been attrib-
uted to acetazolamide [3A].
A 27-year-old man developed loss of visual acu-
ity after treating himself with acetazolamide for
acute mountain sickness. His distance vision
deteriorated after a single dose of acetazolamide
250 mg. Fundoscopy was normal, but there was
bilateral reduced acuity for distance vision, while
near vision was unaffected. His visual acuity
returned to normal within 48 hours.
A change in refraction at high altitude, and
thus transient myopia, can occur through
osmotically altered vitreous volume or
altered curvature of the lens secondary to
edema or ciliary muscle spasm. The authors
pointed out that altitude-related hypoxia
(causing corneal swelling) and dehydration
(associated with both exercise and inade-
quate uid intake) could have contributed in
this case. Drugs that can cause transient myo-
pia include aspirin [4A], chlortalidone [5A],
co-trimoxazole [6A, 7A], dapsone [8A], hydro-
chlorothiazide [9A], metronidazole [10A,
11A], prochlorperazine [12A], quinine [13A],
sulfonamides [14A, 15R], tetracyclines [16A],
topiramate [17c, 18A, 19A], triamterene [20A,
21A], and carbonic anhydrase inhibitors, par-
ticularly acetazolamide [22A, 23A, 24A, 25c].
The mechanism may be an allergic reaction
in the ciliary body [26A].
Acidbase balance Acetazolamide causes a
metabolic acidosis, which is usually mild,
but can be associated with hypokalemia.
In nine subjects who took acetazolamide
250 mg or placebo every 8 hours for 3 days
in a double-blind, randomized, crossover
437
438
design, metabolic acidosis due to acetazol-
amide was accompanied by a rise in ventila-
tion, a substantial fall in PaCO2, and a
parallel leftward shift of the ventilatory
CO2 response curve [27c]. Acetazolamide
shifted the concentrationeffect curve relat-
ing hypoxic sensitivity to arterial hydrogen
ion concentration to the left, without alter-
ing its slope, showing that it did not affect
the interaction of O2 and CO2. There was
no specic inhibitory effect of acetazol-
amide on hypoxic sensitivity.
In a 9-year-old girl recombinant human
growth hormone 6 mg/week caused idiopathic
intracranial hypertension (pseudotumor
cerebri), which was treated with acetazol-
A
amide [28 ]. After 4 days the dose was
increased to 30 mg/kg/day, and 2 days later
she developed a severe metabolic acidosis,
with a pH of 7.29.
There has been a previous report of met-
abolic acidosis in a 1-year-old girl who took
5001250 mg of acetazolamide [29A].
Gastrointestinal Adynamic ileus has been
attributed to acetazolamide [30A].
A 75-year-old-man developed abdominal
cramps and constipation after taking acetazol-
amide 125 mg bd and prednisone 25 mg/day
for 2 days. He stopped taking the acetazol-
amide, and the symptoms resolved in 3 days.
Later he started to take acetazolamide again
in a dosage of 250 mg/day, and within 24 hours
the symptoms returned. Acetazolamide was
withdrawn and the symptoms resolved within
48 hours.
Skin Acetazolamide has been implicated in
worsening of pemphigus in a 52-year-old
woman with pre-existing disease who took
the drug for 1 month; however, relapse
could have been coincidental [31A].
Dorzolamide
Sensory systems Choroidal detachment has
been attributed to dorzolamide [32A],
Chapter 21 Jeffrey K. Aronson
adding to previous reports of this rare reac-
tion [33A, 34A, 35A].
A 75-year-old woman developed bilateral ocu-
lar irritation, swollen eyelids, and reduced
visual acuity after using dorzolamide 2% eye-
drops tds for 2 days, in addition to long-term
latanoprost timolol. Her best-corrected
visual acuity deteriorated from 6/9 right and
left, to 6/12 and 6/18 respectively. The eyelids
were erythematous and there was bilateral
conjunctival injection. The anterior chambers
were deep and the intraocular pressure was
22 mmHg in both eyes, with no intraocular
inammation. Fundoscopy showed extensive
bilateral choroidal detachment. Dorzolamide
was withdrawn and the problem resolved
within 2 weeks.
Drugdrug interactions Bevacizumab The
effect of timolol dorzolamide eye-drops,
which reduces aqueous outow from the
eye, on the activity of intravitreal
bevacizumab has been studied in 38 patients
with macular edema after retinal vein
obstruction [36c]. Mean central retinal
thickness was used as a surrogate for the
activity of bevacizumab. Mean central reti-
nal thickness was signicantly reduced by
bevacizumab, and after 5 weeks the effect
was enhanced by timolol dorzolamide
but not after 9 weeks. The authors suggested
that timolol dorzolamide eye-drops had
reduced the clearance of intravitreal
bevacizumab. However, this needs to be
conrmed. If it is a real effect, it remains to
be seen whether it improves the efcacy of
bevacizumab or increases the risk of adverse
effects.
THIAZIDE AND THIAZIDE-
LIKE DIURETICS [SED-15,
3375; SEDA-30, 256; SEDA-31, 372;
SEDA-32, 405]
Electrolyte balance Cases of hyponatremia
and hypokalemia continue to be reported
in patients taking thiazide and thiazide-like
diuretics [37A].
Diuretics Chapter 21
EIDOS classication:
Extrinsic moiety Loop, thiazide, and
thiazide-like diuretics
Intrinsic moiety Na/K/Cl co-
transporters (loop diuretics) or
Na/Cl co-transporters (thiazides)
Distribution Nephrons: loop of Henle
(loop diuretics) or distal convoluted
tubule (thiazides)
Outcome Altered physiology (excess
natriuresis and kaliuresis)
Sequela Hyponatremia and
hypokalemia
DoTS classication:
Dose-relation Collateral
Time-course Time independent, but
typically occurs within weeks of
starting therapy
Susceptibility factors Age; sex (female);
physiological factors (reduced
solute intake); drugs (e.g. licorice
derivatives)
An unusual interaction of hydrochlorothi-
azide with a herbal tea, resulting in
hyponatremia and rhabdomyolysis, has been
reported [38A].
A 45-year-old woman developed muscle
weakness, restlessness, and blurred vision
while taking hydrochlorothiazide 25 mg/day,
having drunk 7 liters of a herbal tea during a
single day. She had severe hyponatremia
(108 mmol/l), hypokalemia, and reduced
plasma and urine osmolality. Creatine kinase
and myoglobin were markedly increased.
In 10 healthy volunteers who took
licorice 32 g alone or in combination with
hydrochlorothiazide 25 mg/day for 2 weeks
in an open, randomized crossover study,
licorice alone had no effects on plasma
potassium, sodium, creatinine, renin activ-
ity, serum aldosterone, blood pressure, or
heart rate [39C]. However, when licorice
and hydrochlorothiazide were combined,
the plasma potassium fell by 0.32 mmol/l,
plasma renin activity rose by 1.6 mg/l/hour,
and weight fell by 0.9 kg; in two
subjects there was hypokalemia, which
439
developed during the rst week of com-
bined treatment.
Hydrochlorothiazide
Sensory systems Retinal phototoxicity with
macular damage immediately after exposure
to UV light in a 40-year-old myopic woman
was attributed to the UV light, compounded
by the photosensitizing effect of hydrochloro-
thiazide; it gradually improved over 1 year
after withdrawal [40A].
Metabolic In 22 non-diabetic, abdominally
obese, hypertensive patients in a multi-
center, three-way, crossover trial who were
given candesartan 16 or 32 mg, hydro-
chlorothiazide 25 or 50 mg, or placebo
followed by intravenous glucose tolerance
tests and euglycemic hyperinsulinemic
clamps, insulin sensitivity was reduced by
hydrochlorothiazide, liver fat content was
increased, the subcutaneous to visceral
abdominal adipose tissue ratio was reduced,
and aminotransferase activities and concen-
trations of glycosylated hemoglobin and
high-sensitivity C-reactive protein were
higher [41C]. The authors suggested that
these ndings could partly explain the
diabetogenic potential of thiazides.
Skin After developing contact dermatitis on
the eyelids to para-phenylenediamine in a
hair dye, a 52-year-old AfricanAmerican
woman with atopy had a similar rash while
taking hydrochlorothiazide for hyperten-
sion [42A].
A lichenoid eruption has been associated
with hydrochlorothiazide; there was possi-
ble cross-reactivity to furosemide [43A].
Immunologic Hydrochlorothiazide was as-
sociated with an allergic reaction that
mimicked septic shock on three separate
occasions in a 78-year-old woman; on the
third occasion it started almost immediately
after a single dose of hydrochlorothiazide
[44A]. She had previously had allergic
reactions to sulfonamides and penicillin.
440
LOOP DIURETICS [SED-15,
567, 1454; SEDA-30, 258; SEDA-31,
375; SEDA-32, 408]
Furosemide
Endocrine Diuretics are sometimes used in
an attempt to accelerate the elimination of
unbound radioiodine in patients who are
given therapeutic radioiodine. However, in
23 patients with differentiated thyroid can-
cer who were given 131I, furosemide 20 mg
3 hours later and then 8-hourly for 3 days,
combined with potassium chloride, signi-
cantly reduced radioiodine excretion com-
pared with 20 patients who were not given
furosemide [45c].
Urinary tract Susceptibility factors for
nephrocalcinosis have been studied in 55
neonates born before 32 weeks of gestation
[46c]. The strongest independent factor was
furosemide therapy above a cumulative dose
of 10 mg/kg, with a 48-fold increased risk
(CI 4, 585). The risk of nephrocalcinosis
was 1.65 (1.07, 2.56) times higher per 100 g
lower body weight and 4.5 (1.14, 18) times
higher per mmol/l of urinary calcium con-
centration. Many other susceptibility factors
were signicant only in univariate analysis
(gestational age, mechanical ventilation,
infection, bronchopulmonary dysplasia,
blood transfusions, intraventricular hemor-
rhage, surfactant therapy, vasopressors, phe-
nobarbital or caffeine, duration of hospital
stay), suggesting indirect effects only. The
authors suggested that if furosemide is pre-
scribed for preterm infants, it should be
given with caution and close monitoring of
calcium excretion; in infants with respiratory
distress syndrome calcium-sparing thiazide
diuretics may be preferred.
Skin Localized bullous pemphigoid has
been associated with furosemide [47A].
A 56-year-old man with chronic renal insuf-
ciency developed irregular atrophic erythema-
tous plaques on his forehead, cheeks, and ear
lobes after taking furosemide for 4 years. His-
tology showed localized bullous pemphigoid
with IgG class autoantibodies to the
Chapter 21 Jeffrey K. Aronson
C-terminal domain of BP180 (Brunsting-Perry
type). Furosemide was withdrawn and he was
given oral prednisolone 10 mg/day. The erup-
tions resolved leaving supercial scars.
The authors suggested that photosensitivity
caused by furosemide may have contrib-
uted to the induction and exacerbation of
these lesions.
Body temperature Repeated bouts of
hyperthermia with skin blisters occurred in
an 18-year-old girl with a severe Myco-
plasma pneumoniae infection during hemo-
dialysis and continuous infusion of
furosemide and other drugs [48A]. When
the medications were withdrawn, the
hyperthermia resolved within 2 days. After
rechallenge with two intravenous doses of
furosemide 5 mg, there was an almost
simultaneous increase in heart rate and
temperature and the blisters reappeared.
Management of adverse drug reactions
Desensitization to drugs is increasingly
being described by the use of initially tiny
doses, gradually increasing to therapeutic
doses, sometimes over very short periods
of time [SEDA-30, 416; SEDA-33, 494].
A rapid oral desensitization protocol for
furosemide has been described (Table 1)
and used successfully in a 44-year-old
woman who developed urticaria while tak-
ing furosemide [49A]. Previous protocols
have involved rapid intravenous adminis-
tration (Table 2) [50A] or oral administra-
tion over 3 days (Table 3) [51A].
ALDOSTERONE
RECEPTOR ANTAGONISTS
Spironolactone [SED-15, 3176; SEDA-
30, 259; SEDA-31, 375; SEDA-32, 409]
Observational studies Of 134 patients with
heart failure, 76 were currently taking
spironolactone or had previously taken it;
spironolactone was withdrawn in 19 mainly
because of hyperkalemia, deterioration in
Diuretics Chapter 21 441

Table 1 A rapid oral desensitization protocol for patients with furosemide

hypersensitivity

Time (minutes) Dose (as oral solution)

0 1 microgram
20 3 micrograms
40 10 micrograms
60 30 micrograms
80 100 micrograms
100 300 micrograms
120 1 mg
140 3 mg
160 10 mg
180 40 mg
200 100 mg
220 100 mg (tablet)

Table 2 An intravenous desensitization protocol for patients with

furosemide hypersensitivity

Time (minutes) Dose (as oral solution)

0 1 microgram
20 3 micrograms
40 10 micrograms
60 30 micrograms
80 100 micrograms
100 300 micrograms
120 1 mg
140 3 mg
160 10 mg
180 40 mg

Table 3 A 3-day oral desensitization protocol for patients with furosemide

hypersensitivity

Time (hours) Dose (as oral solution)

Day 1
0 5 micrograms
3 10 micrograms
6 30 micrograms
9 1000 micrograms
Day 2
0 100 micrograms
3 300 micrograms
6 1 mg
Day 3
0 1 mg
3 1 mg
6 3 mg
9 3 mg
12 100 mg
15 100 mg
442
renal function, and gynecomastia [52c]. The
authors concluded that the adverse effects
of spironolactone are more common than
have been reported in clinical trials.
Metabolism In a prospective study in 27 hir-
sute women (20 with polycystic ovary syn-
drome and seven with idiopathic hirsutism),
mean age 23 years, spironolactone 100 mg/
day for 3 months was associated with a small
but signicant fall in mean HDL cholesterol
by 0.19 mmol/l and a signicant rise in mean
LDL cholesterol by 0.72 mmol/l [53cr]. There
were no signicant changes in total choles-
terol, triglycerides, or fasting blood glucose.
Serum concentrations of testosterone, de-
hydroepiandrosterone, and prolactin fell
signicantly.
Other studies have yielded conicting
results of the effects of spironolactone on
serum lipids. Some have shown no effects
[54c, 55c]; others have variously shown
increased triglycerides [56C, 57c], reduced
triglycerides and HDL cholesterol [58c],
reduced triglycerides [59c], and increased
HDL cholesterol [60c].
OSMOTIC DIURETICS
Mannitol [SED-15, 2203; SEDA-30, 260;
SEDA-32, 409]
Respiratory Inhaled mannitol as a dry
powder has been used to treat patients with
cystic brosis, since it increases mucociliary
clearance by rehydrating the airways. In 39
children with cystic brosis, aged
818 years, a bronchial provocation
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titis 2008; 19(6): E445.
[43] Aouam K, Ali HB, Youssef M,
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[44] Mineo MC, Cheng EY. Severe allergic
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[45] Matovic MD, Jankovic SM, Jeremic M,
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roid 2009; 19(8): 8438.
[46] Gimpel C, Krause A, Franck P, Krueger M,
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Int 2010; 52(1): 516.
[47] Takeichi S, Kubo Y, Arase S, Hashimoto T,
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[48] Ebdrup L, Pedersen CM, Andersen MH,
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[50] Shteinberg M, Karkabi B, Cohen S. Desen-
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[51] Juang P, Page RL, Zolty R. A successful
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[53] Nakhjavani M, Hamidi S, Esteghamati A,
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[54] Garc Puig J, Miranda ME, Mateos F,
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[55] Wild RA, Demers LM, Applebaum-
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[56] Scherstn B, Thulin T, Kuylenstierna J,
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J Korean Med Sci 2009; 24(3): 5324.

22
Aluminium [SED-15, 97; SEDA-30, 262;
SEDA-31, 383; SEDA-32, 413]
Although agents that contain aluminium
are highly efcient as phosphate binders,
they are no longer widely used because of
proven neurotoxicity and osteotoxicity.
They are gradually being replaced by safer
calcium-based salts, or calcium-free com-
pounds, such as sevelamer hydrochloride
and lanthanum carbonate [1R].
Nervous system Neurotoxic effects of alu-
minium are regularly reported as a result
of intravesical treatment of hemorrhagic
cystitis, as a pediatric case illustrates [2A].
A 9-year-old girl with acute lymphoblastic leu-
kemia and a bone marrow transplant devel-
oped hemorrhagic cystitis and clot retention.
Her bladder was irrigated with 1% alum (alu-
minium ammonium sulfate) for 5 days, during
which time she received 15 liters of alum solu-
tion at a rate of 250 ml/hour alternating with
250 ml of isotonic saline. In total, her bladder
mucosa was exposed to 22.5 g of elemental
aluminium. Within 3 days she became very
agitated and confused and over the next
48 hours became violent. The alum was with-
held after 5 days. The maximum serum alu-
minium concentration was 27 mg/l (normal
< 0.6 mg/l). She was given two doses of intra-
venous deferoxamine mesylate 10 mg/kg on
days 8 and 9 and by the next day her psychotic
symptoms had improved.
In a randomized study, preterm infants
who had been exposed to aluminium in
Side Effects of Drugs, Annual 33
J.K. Aronson (Editor)
ISSN: 0378-6080
DOI: 10.1016/B978-0-444-53741-6.00022-2
# 2011 Elsevier B.V. All rights reserved.
Gijsbert B. van der Voet
Metals
parenteral nutrition solutions had reduced
neurodevelopmental scores [3R].
Psychiatric The controversial role of alu-
minium in Alzheimer's disease has recently
been re-evaluated [4R].
Musculoskeletal Bone area and bone min-
eral content in lumbar spine, hip, and whole
body were measured with dual radiograph
absorptiometry in 59 children aged 1315
who had been born preterm and randomly
assigned standard or aluminium-depleted
parenteral nutrition solutions during the
neonatal period. Those who had been ran-
domly assigned to standard parenteral nutri-
tion solutions had lower lumbar spine bone
mineral content, apparently explained by a
reduction in bone size. In nonrandomized
analyses, children who were exposed as neo-
nates to aluminium above the median
(55 micrograms/kg) had lower hip bone min-
eral content, independent of bone or body
size. The authors concluded that neonates
who are exposed to parenteral aluminium
may have reduced lumbar spine and hip
bone mass during adolescence, potential
risk factors for later osteoporosis, and
hip fracture.
It has been suggested that macrophagic
myofasciitis and chronic fatigue syndrome
may be caused by adverse reactions to
alumina-containing adjuvants in vaccines.
Both conditions are characterized by aber-
rant immune responses, have a number of
prominent symptoms in common, and
coincide in many individuals. Vaccine-asso-
ciated chronic fatigue syndrome and macro-
phagic myofasciitis have been described in
an adult with aluminium overload [5c].
447
448
Tumorigenicity In 4316 male aluminium
smelters, who were followed during 1983
2002, cumulative inhalation of dust, cumu-
lative uoride exposure, and cumulative
benzo(a)pyrene exposure were linked to
the risk of respiratory cancers, after adjust-
ment for smoking [6c].
Susceptibility factors Renal disease The
determination of toxic elements in human
biological samples is an important clinical
screening procedure. In 100 men, aged 25
55, with chronic renal insufciency on
maintenance hemodialysis and 150 healthy
volunteers in the same age range, the con-
centrations of aluminium, cadmium, and
lead were determined in blood samples
before and after hemodialysis and the con-
centrations in urine were determined once,
before hemodialysis [7c]. The blood con-
centrations in the patients before hemodial-
ysis were higher than after dialysis. In the
controls the blood concentrations were sig-
nicantly lower than in the patients with
chronic renal insufciency.
Aluminium toxicity has been studied
retrospectively in 36 hospitalized adults
who had a serum creatinine concentration
at least 1.5 times greater than on the rst
day of parenteral nutrition; 12 were under-
going hemodialysis [8c]. Mean aluminium
exposure was 3.8 g/kg/day in the 36
patients, of whom 29 had safe calculated
exposures (5 g/kg/day) and also signi-
cantly higher serum creatinine concentra-
tions than those with high aluminium
exposure. The authors suggested that most
patients with acute kidney disease who
require parenteral nutrition do not receive
excessive exposure to aluminium.
Antimony [SED-15, 316; SEDA-30, 263;
SEDA-31, 384; SEDA-32, 414]
The adverse effects of the pentavalent anti-
monial compounds, sodium stibogluconate
and meglumine antimoniate, that are
widely used to treat leishmaniasis have
been reviewed; they include nausea,
Chapter 22 Gijsbert B. van der Voet
vomiting, weakness and myalgia, abdominal
colic, diarrhea, rashes, hepatotoxicity,
and cardiotoxicity [9R]. Resistance to anti-
monials is important in the treatment of this
disease.
Skin Drug rash with eosinophilia and sys-
temic symptoms (DRESS) has been associ-
ated with antimonial drugs in a 40-year-old
man with cutaneous and mucosal leishman-
iasis [10A].
Arsenic [SED-15, 339; SEDA-30, 263;
SEDA-31, 385; SEDA-32, 414]
Arsenic trioxide continues to be used in the
chemotherapy of acute promyelocytic leuke-
mia. A novel organic arsenic derivative
S-dimethylarsinoglutathione (Darinaparsin)
shows promise for the treatment of a wider
spectrum of hematological malignancies
and solid tumors than arsenic trioxide
[11R,12R].
Sensory systems Vision In 100 patients
with acute promyelocytic leukemia taking
oral arsenic trioxide, there were two cases
of serious visual problems, both in patients
in complete remission with normal platelet
counts [13A].
A 25-year-old man with acute promyelocytic
leukemia in rst complete remission took oral
arsenic trioxide 10 mg/day and all-trans
retinoic acid (ATRA) 45 mg/m2/day for 2
weeks every 2 months over 2 years. After
completion of maintenance, the vision in his
right eye deteriorated to light perception only,
after a basketball injury sustained during the
last course of oral treatment. Fundoscopy
showed a large retinal tear with total
rhegmatogenous detachment. Posterior vitrec-
tomy, lensectomy, retinectomy, endolaser
photocoagulation, and silicone oil injection
did not affect visual recovery. The concentra-
tions of elemental arsenic in the plasma, aque-
ous humor, and vitreous humor were 115, 35,
and 57 nmol/l respectively.
A 35-year-old man with acute promyelocytic
leukemia in relapse achieved a second remis-
sion with oral arsenic trioxide 10 mg/day for
30 days, followed by idarubicin 9 mg/day for
5 days. He was a chronic smoker (3 packs/
Metals Chapter 22
day) with a history of right amaurosis fugax.
Two days after chemotherapy, he developed
sudden blindness in the right eye, due to
central retinal artery occlusion. No sources of
cardiac or carotid embolization were found.
He was treated with anterior chamber
paracentesis, acetazolamide, and timolol eye-
drops, but optic atrophy ensued.
Both patients had clear anatomical causes
for blindness, and unilateral (rather than
bilateral) blindness suggested a limited role
for systemic arsenic toxicity. Nevertheless,
a weak contribution of ocular arsenic toxic-
ity should not be ruled out. Both arsenic tri-
oxide and all-trans retinoic acid can
increase intracranial pressure, resulting in
pseudotumor cerebri and a secondary
increase in intraocular pressure, which
may augment retinal injury. Also, arsenic
trioxide can cause vasoconstriction and
worsen retinal artery occlusion. Finally, ele-
mental arsenic was detected in the eyes at
3050% of the plasma concentration, a
ratio comparable to that in cerebrospinal
uid. This may have direct retinal toxicity,
especially with the high peak concentra-
tions associated with intravenous arsenic
trioxide. Full ophthalmic evaluation is
recommended in patients receiving long-
term or intravenous arsenic trioxide.
Teeth Toothache occurred in a 45-year-old
man taking arsenic trioxide [14A]. The pain
was mainly in the upper right and left
cheeks, but radiated to become more
severe in the lower anterior region. It
increased in intensity, occurred after eating,
and awoke him from sleep. Opioid analge-
sia was required for pain relief. Two days
after a cycle of arsenic trioxide the pain
diminished, and after 4 days it had
completely resolved. The total cumulative
dose of arsenic trioxide was 1590 mg.
Bismuth [SED-15, 518; SEDA-30, 264;
SEDA-31, 385; SEDA-32, 414]
Nervous system In a 67-year-old man,
acute confusion, disorientation, delusions,
verbal aggression, and myoclonic jerks
with intermittent episodes of drowsiness
449
were attributed to bismuth iodoform paraf-
n paste; blood and urine bismuth
concentrations were 340 and 2800 mg/l
respectively [15A]. The symptoms responded
to chelation therapy with intravenous 2,3-
dimercapto-1-propanesulfonic acid (DMPS)
for 27 days followed by oral therapy to a total
of 51 days.
Calcium salts [SED-15, 610;
SEDA-28, 245]
Calcium is the most abundant essential
mineral in the human body, 99% being
located in the bones and teeth. Calcium
salts have been used therapeutically in
many conditions, such as lactose intoler-
ance, osteoporosis, premenstrual syndrome,
colorectal cancer, kidney stones, and multi-
ple sclerosis. Calcium supplementation has
long been regarded as a fundamental part
of the prevention and treatment of post-
menopausal bone loss. Several other health
benets have also been suggested, includ-
ing improvements in blood pressure and
serum cholesterol. Its adverse effects
include constipation, bloating, and gas
[16r], as well as interference with the absorp-
tion of phosphate [17r].
Cardiovascular The effects of calcium sup-
plementation on vascular disease have been
studied in a large, randomized, controlled
trial in healthy postmenopausal women
over 5 years [18C]. There was a substantial
increase in rates of vascular events, particu-
larly myocardial infarction, in women who
were randomized to calcium. These effects
were more marked in those who were
highly compliant with treatment. Calcium
supplementation also appears to accelerate
vascular disease in patients with renal
impairment, including those not yet requir-
ing hemodialysis.
Mineral metabolism Under steady-state
conditions, urinary calcium excretion corre-
sponds to the calcium load in healthy sub-
jects. However, in patients on chronic
450
hemodialysis reliable data are not available.
In these patients, calcium-containing phos-
phate binders are suspected to play a role
in the progression of arteriosclerosis. The
effects of calcium carbonate 500 mg qds
and the calcium-free phosphate binder
sevelamer hydrochloride 800 mg qds on
serum calcium and urinary calcium excre-
tion have been evaluated in 12 healthy
men in a randomized, single-blind, pla-
cebo-controlled, three-way crossover phase
I study for 6 days on each treatment [19c].
Mean daily urinary phosphorus excretion
was signicantly lower in those who took
sevelamer compared with placebo. Mean
daily total urinary excretion of calcium
was signicantly higher in those who took
calcium carbonate compared with placebo.
Chromium [SED-15, 737; SEDA-30,
264; SEDA-31, 386; SEDA-32, 414]
Urinary tract There are major concerns
about infusion of excess chromium during
parenteral nutrition, because of potential
nephrotoxicity [20R].
Cobalt [SED-15, 847; SEDA-30, 264;
SEDA-31, 386; SEDA-32, 415]
Chromiumcobalt alloys are being increas-
ingly used in medical implants, and metal-
on-metal hip resurfacing arthroplasty can
cause the release of large amounts of very
small wear particles and metal ions [21R].
The long-term biological consequences of
exposure to these chromiumcobalt parti-
cles are largely unknown.
Immunologic An aseptic lymphocyte-domi-
nated-vasculitis-associated lesion (ALVAL)
was reported in a patient in whom cobalt sen-
sitization developed after insertion of a chro-
miumcobalt prosthesis [22A].
Allergy to metal components was suspected in
a 71-year-old woman after bilateral total hip
Chapter 22 Gijsbert B. van der Voet
arthroplasty with femoral heads made of cobalt
and chromium. Groin pain soon after surgery
was treated with prednisolone, but when it
was withdrawn the pain recurred and a swelling
in the left groin was noted. A CT scan showed a
cystic collection of uid anterior to the left
iliopsoas muscle and probably communicating
with the hip joint. A large periprosthetic cystic
mass was removed. Histology showed brinoid
necrosis, a chronic inammatory inltrate with
lymphocytes and macrophages, and capillary
proliferation. Patch testing with nickel, cobalt
chloride 1%, and potassium dichromate was
positive with cobalt.
Copper [SED-15, 901; SEDA-30, 265;
SEDA-31, 387; SEDA-32, 415]
Wilson's disease in children has been
reviewed again [23R].
Reproductive system Intrauterine contra-
ceptive devices (IUCDs) can migrate to
unusual locations in the body. Ovarian
penetration by a copper-based device has
again been reported [24AR].
A 22-year-old nulliparous woman developed
lower abdominal pain, severe dysmenorrhea,
and dyspareunia. A T-shaped IUCD (copper
T) that had been inserted 7 years before was
seen in a 2.0
1.4
2.3-cm cyst in the right
ovary and was removed laparoscopically.
Gallium [SED-15, 1477; SEDA-30, 265;
SEDA-32, 416]
The medical applications of gallium
compounds have been reviewed [25R].
Radiogallium compounds continue to be
used for tumor imaging. Gallium compounds
(gallium nitrate, gallium maltolate) are used
as antineoplastic agents in non-Hodgkin's
lymphoma and bladder cancer. Gallium
compounds may have immunosuppressive
and anti-inammatory activity.
Metals Chapter 22
Gold and gold salts [SED-15, 1520;
SEDA-30, 265; SEDA-31, 387; SEDA-32,
416]
The clinical pharmacology and adverse
effects of gold compounds have again been
reviewed [26R]. Their mechanism of action
in rheumatoid arthritis has not been eluci-
dated. The experimental pharmacology of
the auranocyanide anion, a human metabo-
lite of several anti-rheumatic gold com-
plexes, has also been reviewed [27R].
Iron salts [SED-15, 1911; SEDA-30, 265;
SEDA-31, 387; SEDA-32, 417]
Immunologic The frequency of adverse
drug events associated with four different
iron formulations (high and low molecular
weight iron dextran, iron sucrose, and
sodium ferric gluconate complex) in the
management of anemia in chronic kidney
disease has been reviewed [28MR]. In gen-
eral, with the exception of high molecular
weight iron dextran (as Imferon, which is
no longer available, and Dexferrum, which
is not recommended), serious or life-threat-
ening adverse events are rare. The Revised
European Best Practice Guidelines do not
recommend the use of iron dextran
formulations.
Iron sucrose, ferric gluconate, and low
molecular weight iron dextran can be given
without signicant risk of anaphylaxis, but
only the last can be given as a total-dose
infusion. Iron sucrose has the least reported
number of adverse events and high molecu-
lar weight iron dextran the highest; low
molecular weight iron dextran and ferric
gluconate fall between these two.
Comparisons of iron sucrose or iron glu-
conate with low molecular weight iron dex-
tran show no difference in toxicity or
efcacy but greater ease of administration
with low molecular weight iron dextran.
Low molecular weight iron dextran (InFed)
is relatively safe and substantially less
costly than either iron sucrose or iron glu-
conate. Ferric gluconate and iron sucrose
451
may also be safe among patients who are
allergic to or intolerant of iron dextran.
Infection risk Current evidence on the role
of intravenous iron in increasing the inci-
dence of infection and oxidative stress
deserves special consideration, but the clin-
ical data are conicting. Oxidative stress
should not be considered as a barrier to
the administration of intravenous iron.
Lanthanum carbonate [SEDA-31,
389; SEDA-32, 417]
Lanthanum carbonate is an aluminium-
free, calcium-free, phosphate-binding agent
used to control phosphate concentrations in
patients with renal insufciency [29R]. Lan-
thanum carbonate was generally well toler-
ated in short- and long-term clinical studies;
the most common adverse events were gas-
trointestinal (for example nausea, vomiting,
diarrhea, abdominal pain, and constipation)
and they occurred with a similar incidence
to other phosphate binders (including
sevelamer hydrochloride and calcium-
based binders). These adverse events were
minimized by taking lanthanum carbonate
with food, and generally abated over time
with continued administration. The inci-
dence of treatment-related adverse events
did not increase with increased exposure
to lanthanum carbonate, and no new or
unexpected adverse events were reported
in an extension study in which patients with
end-stage renal failure took treatment for
up to 6 years. Lanthanum carbonate was
associated with fewer episodes of hypercal-
cemia than calcium carbonate. With up to 6
years of lanthanum carbonate treatment,
the incidence of fractures was low (4.3%).
Nervous system Nervous system effects of
lanthanum have been reported [30A].
A 75-year-old woman undergoing hemodialy-
sis for end-stage renal disease developed
abdominal pain and dizziness and became
confused. Among her numerous medications
was lanthanum carbonate 750 mg bd.
452
Abdominal radiography showed multiple dif-
fuse calcium-like deposits throughout the
digestive tract, especially in the rectosigmoid
region. Sigmoidoscopy showed diverticular
disease, with mucous membrane inammation
and off-white foreign bodies on the bowel
wall, which were found to be lanthanum car-
bonate tablet residues. Her confusion resolved
after withdrawal of lanthanum, and plasma
lanthanum concentrations fell at the same
time from 2.13 mg/l on the day after with-
drawal to 1.05 mg/l on day 4 and 0.25 mg/l on
day 7.
The authors tentatively suggested a role for
lanthanum tablets in aggravating diverticu-
lar disease and causing confusion. How-
ever, these suggestions were convincingly
rebutted by others [31r].
Magnesium salts [SED-15, 2196;
SEDA-30, 266; SEDA-31, 390; SEDA-32,
417]
Placebo-controlled studies In a random-
ized, double-blind study of the preventive
analgesic efcacy of adding magnesium to a
multimodal regimen of patient-controlled
epidural analgesia, 90 patients undergoing
abdominal hysterectomy were randomly
assigned to (a) a bolus of magnesium 50 mg
epidurally before induction of anesthesia
followed by infusion at 10 ml/hour until the
end of surgery, (b) epidural saline followed
by a bolus of epidural magnesium 50 mg at
the end of surgery, and (c) epidural saline
during all three periods [32C]. There was sig-
nicantly less pain at rest or during movement
in those who were pretreated with magne-
sium. The authors concluded that continuous
epidural magnesium started before anesthe-
sia provided preventive analgesia and an
analgesic-sparing effect, improving post-
operative analgesia without increasing the
incidence of adverse effects.
Metal metabolism Excessive ingestion of
magnesium can cause hypermagnesemia
without kidney dysfunction. In one case
hypomagnesemia paradoxically resulted from
excessive ingestion of magnesium hydroxide.
Chapter 22 Gijsbert B. van der Voet
A 39-year-old woman developed vomiting,
massive watery diarrhea, and carpopedal
spasm 4 hours after taking a handful of mag-
nesium hydroxide tablets (estimated dose
10 g) in a suicide attempt [33A]. The serum
potassium concentration was 3.5 mmol/l, ion-
ized calcium 1.15 mmol/l, and magnesium
0.95 mmol/l, which is near the lower limit of
the reference range. A few hours later she
developed a tingling sensation and muscle
spasm in the arms. The serum ionized calcium
concentration was 0.87 mmol/l and magnesium
0.8 mmol/l. She was given calcium gluconate
1 g intravenously and the diarrhea improved.
After 3 days she was asymptomatic.
Manganese [SED-15, 2200; SEDA-30,
267; SEDA-32, 418]
Fetotoxicity Little is known about the
effects of manganese deciency or excess
on the human fetus [34R]. In two studies
lower maternal blood manganese concen-
trations were associated with fetal intra-
uterine growth retardation [35C] and lower
birth weights [36C]. In the rst of these,
the relation between blood concentrations
of manganese and intrauterine growth
restriction was assessed in 410 apparently
healthy mothers (aged 1835 years) and
their neonates. Whole blood manganese
concentrations in the mothers were signi-
cantly lower when there was intrauterine
growth retardation than in cases in which
the baby was appropriate for gestational
age (mean 17 versus 19 mg/l respectively).
Conversely, umbilical cord blood man-
ganese concentrations were signicantly
higher in neonates with intrauterine growth
restriction than in those who were appro-
priate for gestational age (45 versus
38 mg/l respectively). There was a signi-
cant relation between maternal whole
blood and umbilical cord blood manganese
concentrations in cases with intrauterine
growth retardation.
In the second study the association
between maternal and umbilical cord blood
manganese concentrations and birth weight
was studied in 470 motherinfant pairs born
at term. Non-linear spline and quadratic
Metals Chapter 22
regression models were used to test the
hypothesis of an inverted U-shaped relation
between manganese concentrations and
birth weight. The mean concentrations of
manganese were 24 mg/l in maternal blood
and 42 mg/l in cord blood. Umbilical cord
manganese was not associated with birth
weight. There was a non-linear relation
between maternal manganese and birth
weight after adjusting for potential con-
founders. Birth weight increased with man-
ganese concentrations up to 3.1 mg/l, with a
slight reduction in weight at higher concen-
trations. These ndings suggest that man-
ganese may affect fetal growth.
Mercury and mercurial salts
[SED-15, 2259; SEDA-30, 268; SEDA-31,
391; SEDA-32, 419]
Thimerosal and
neurodevelopment in infants
The debate about the relation between
autism and mercury (as thimerosal) in vac-
cines continues, without useful conclusions
[37R]. In a population-based study of the
pharmacokinetics of mercury after immuni-
zation of 72 premature infants weighing
20003000 g at birth, the mean maximal
blood mercury concentration was 3.6 mg/l,
and it occurred at 1 day after immunization;
the maximal mean stool mercury concentra-
tion was 35 ng/g, and it occurred on day 5;
urine mercury was almost undetectable
[38C]. The blood mercury half-life was 6.3
(95% CI 3.98.8) days, and mercury con-
centrations returned to prevaccination values
by day 30. The blood half-life of intramus-
cular ethyl mercury from thimerosal in vac-
cines given to premature infants is
substantially shorter than that of oral methyl
mercury in adults. Because of the differing
pharmacokinetics, exposure guidelines
based on oral methyl mercury in adults
may not be accurate for children who
receive thimerosal-containing vaccines.
In a study based on the automated Vac-
cine Safety Datalink 278 624 subjects who
453
had received their rst oral polio immuniza-
tion by 3 months of age, the association
between the prevalence of outcomes and
doses of mercury from thimerosal-
containing vaccines was modelled using
Poisson regression analysis [39c]. There
were consistent signicantly increased rate
ratios for autism, autism spectrum disorders,
tics, attention decit disorder, and emotional
disturbances with mercury exposure; in con-
trast, none of the controls had signicantly
increased rate ratios. The authors discussed
the several limitations of this study, includ-
ing possible bias due to incompleteness of
the records and the potential for
confounding.
In a comparison of two groups of 1403
children who had been exposed randomly
to different amounts of thimerosal through
immunization (cumulative dose of
ethylmercury 62.5 or 137.5 micrograms), 10
years later 24 neuropsychological outcomes
were evaluated and only two were signi-
cantly associated with thimerosal exposure,
a result that could have arisen by chance
[40c].
In a study of neurodevelopment in infants
at 6 months who had been exposed in utero
to thimerosal in tetanusdiphtheria vaccines
during pregnancy there were no differences
from infants who had not been exposed
[41c]. Although there was a signicant corre-
lation between the concentration of mercury
in the hair of the mothers and the hair of the
neonates, there was no correlation between
the degree of in utero exposure to
ethylmercury and mercury concentrations
in neonatal hair.
Nickel [SED-15, 2502; SEDA-30, 268;
SEDA-31, 392; SEDA-32, 419]
Cardiovascular Nickel hypersensitivity has
been associated with a pericardial effusion
after cardiac surgery [42A].
A 52-year-old woman underwent percutane-
ous closure of a patent foramen ovale with a
septal occluder device, and on the next morn-
ing noted severe, burning, left-sided chest pain
454
near the anterior axillary line, after which she
had daily chest pain and occasional episodic
bouts of palpitation. A transesophageal echo-
cardiogram 18 months later showed a small,
hemodynamically insignicant pericardial uid
collection posterior to the left atrium in the
transverse pericardial sinus. She also reported
a history of a reaction to inexpensive jewelry,
raising the possibility of previously
unrecognized nickel allergy. Skin patch testing
showed an allergic contact dermatitis to nickel,
with an unusual pustular reaction. The septal
occluder was removed and the foramen ovale
was closed with a pericardial patch.
Selenium [SED-15, 3119; SEDA-30, 269;
SEDA-31, 392; SEDA-32, 420]
Selenium availability from various food-
stuffs has been reviewed [43R], as has its
role in the management of cancers [44R].
Hair and nails Incidental cases reecting
the use of nutritional supplements that
escape regulation and quality control have
been reported; in two cases there were
signs consistent with selenium poisoning
after use of a dietary supplement called
Total Body Formula [45A].
A 45-year-old woman developed a diffuse ery-
thematous, pruritic, exfoliative eruption on
the scalp and progressive hair loss. She also
had discoloration of the nails, dizziness,
fatigue, amenorrhea, and dental caries. The
hair loss had started 7 days after she began
taking a nutritional supplement, Total Body
Formula, but she continued to take it for
about 30 days and nearly nished a 0.95-liter
container. She had seborrhea-like scaling with
some acneiform papules on the scalp. There
was hair loss, and pulled hairs were predomi-
nantly in the anagen phase. There was a gray-
ish-white discoloration in transverse bands in
most of her ngernails 24-mm distal to the
cuticle. Serum and urine selenium concentra-
tions 5 weeks after the last dose were within
the reference ranges. However, the concentra-
tion of selenium in the hair 6 weeks after the
last dose was high, at 3.2 mg/g (reference range
0.41.4 mg/g). The hair and nails began to
improve 5 weeks after the last dose, and most
of her symptoms resolved completely after 6
months.
Chapter 22 Gijsbert B. van der Voet
A 56-year old woman developed hair loss,
discolored nails, metatarsal cramping, fatigue,
and malaise. She had diffuse alopecia, and
pulled hairs were in the anagen phase: the
nails were thickened and yellow distally. The
serum selenium concentration was 166 mg/l
(reference range 110160) 7 weeks after the
last dose of Total Body Formula. The hair
and nails began to improve 2 months after
the last dose and were completely normal
after 7 months.
Susceptibility factors Renal disease Plasma
copper, selenium, and zinc concentrations
and antioxidant metalloenzymes, gluta-
thione peroxidase (GPX) and superoxide
dismutase (SOD), were studied in 17
patients on maintenance hemodialysis, 14
uremic patients, and 14 healthy subjects
[46C]. Plasma selenium concentrations and
erythrocyte GPX were signicantly lower
in those on hemodialysis, and the two were
correlated. There was also a correlation
between reduced plasma zinc and erythro-
cyte SOD activity.
Silver salts and derivatives [SED-15,
3140; SEDA-30, 269; SEDA-31, 393;
SEDA-32, 420]
Skin Argyria has again been reported
[47A,48A].
A 73-year-old man developed slate-gray pig-
mentation on the face after using colloidal sil-
ver on occasion for at least 5 years, the total
amount of ingested colloidal silver having been
0.2 g. Histology of a skin biopsy from the fore-
head showed upper dermal mild perivascular
lymphocyte inltration and brown-black extra-
cellular granules in the upper dermis and be-
tween collagen bundles. Silver concentrations
were 13 mg/l in the urine, 29 mg/l in blood,
36 mg/g in skin tissue. He stopped taking silver
and was encouraged to use sun protection to
help prevent further skin discoloration, after
which he improved rapidly.
A 25-year-old woman developed severe gen-
eralized dystrophic epidermolysis bullosa hav-
ing used a topical silver sulfadiazine 1% cream
under occlusive dressings as an antimicrobial
agent since early childhood. Over the course
of many years her skin had turned a metallic
slate-grey and she had developed loss of pro-
prioception, a tingling sensation in her limbs,
Metals Chapter 22
and impaired coordination. Her serum silver
concentration was markedly raised at
2645 nmol/l. Silver granules were seen in a
previously excised squamous cell carcinoma.
Strontium salts [SEDA-32, 420]
Observational studies In a survey of the
adverse effects of strontium ranelate using
the UK General Practice Research Data-
base (GPRD), age-adjusted rate ratios for
certain adverse reactions were [49c]:
venous thromboembolism1.1 (95% CI 0.2,
5.0);
memory loss1.8 (0.2, 14);
minor skin complaints2.0 (1.3, 3.1);
gastrointestinal disturbances3.0 (2.3, 3.8).
There were no cases of osteonecrosis
of the jaw, toxic epidermal necrosis, Ste-
vensJohnson syndrome, or drug rash with
eosinophilia and systemic symptoms
(DRESS).
Mineral metabolism Strontium is handled
similarly in the body to calcium [50c,51c],
but there have been few reports of altered
calcium balance in patients who have
received strontium salts. Symptomatic
hypocalcemia occurred in a 32-year-old
man after he was given radioactive 89SrCl
(4 mCi, dose of strontium not stated)
[52AH]. He also had vitamin D decien-
cy and hypoparathyroidism, the latter
being attributed by the authors to stron-
tium. They hypothesized that strontium
stimulates calcium-sensing receptors in the
parathyroid glands, kidneys, and bones,
suppressing parathyroid hormone produc-
tion, increasing urinary excretion of
calcium, reducing production of 1,25-
dihydroxycolecalciferol by the kidneys,
inhibiting of calcium release from bones,
and reducing calcium absorption from the
intestines; strontium may also have direct
effects on the kidneys and bones by stimu-
lating calcium-sensing receptors.
455
Skin Toxic epidermal necrolysis has been
attributed to strontium ranelate 2 g/day in a
72-year-old Chinese woman with post-
menopausal osteoporosis. The lesions
resolved after treatment with intravenous
immunoglobulin 1 g/kg/day for 3 days [53A].
A 56-year-old woman developed a severe gen-
eralized rash consisting of erythematous to
violaceous tender conuent papules, symmetri-
cally distributed on the face, trunk, and limbs
after taking strontium ranelate for 2 months
[54A]. There was neither fever nor malaise.
A skin biopsy showed papillary edema, a
perivascular mixed inltrate with eosinophils,
and mild epidermal spongiosis with necrotic
keratinocytes. After withdrawal of strontium
ranelate and treatment with oral and topical
glucocorticoids and oral diphenhydramine,
severe hypopigmentation and patchy alopecia
developed on the scalp, but the other lesions
resolved, leaving brown-gray postinammatory
hyperpigmentation.
Drug rash with eosinophilia and
systemic symptoms (DRESS) has been
attributed to strontium ranelate several
reports [55A,56A], including a case with a
bullous eruption [57A].
Hair Strontium hydroxide has been used as
a depilatory [58c], and it is not therefore
surprising that there have been reports of
alopecia in patients taking strontium
ranelate. In a series of ve cases reported
to the Spanish pharmacovigilance system
[59Ac], the odds ratios (95% CI) for the
risks of alopecia in postmenopausal women
taking various drugs were:
strontium ranelate 14 (5.4, 37);
acitretin 92 (22, 387);
methotrexate 4.7 (1.7, 13);
doxorubicin 3.0 (0.4, 22);
valproic acid 2.4 (0.3, 17).
Genotoxicity and cytotoxicity Incinerated
industrial waste in Taiwan contains stron-
tium, which was genotoxic in green monkey
kidney cells (Vero cells) [60E]. However, in
in vitro studies on human periodontal liga-
ment broblasts from healthy human third
molars strontium ranelate 2.5 mg/ml was
not cytotoxic [61E].
456
Titanium [SED-15, 3434; SEDA-30, 270;
SEDA-31, 394; SEDA-32, 420]
Sensory systems Eyes and vision In 10
patients, orbital adherence syndrome
developed after orbital fracture repair with
titanium mesh along an orbital wall and/or
a titanium plate over the orbital rim [62c].
Six of the patients had cicatricial eyelid
retraction and nine had restriction of
extraocular movements, resulting in diplo-
pia. There was brotic adherence between
the titanium implant and orbital or
periorbital tissues. The diplopia improved
after removal of the titanium and replace-
ment with nylon implants.
Musculoskeletal In two cases of osteolysis
in hips with third-generation alumina
ceramic-on-ceramic couplings, periarticular
tissue contained titanium wear debris (from
impingement of the neck of the titanium
femoral component against the rim of the
titanium shell) and ceramic debris (from
edge loading wear of the ceramic) [63A].
The authors could not decide whether the
titanium debris, the ceramic debris, or both
had caused the osteolysis.
Titanium allergy
Allergic reactions to titanium are reported
from time to time [64A].
Frequency Allergic skin reactions to tita-
nium are rare. In 445 patients who had
received bone-anchored skin-penetrating
titanium implants for anchorage of facial
prostheses or bone-conducting hearing aids,
nine had adverse skin reactions around the
titanium implants; none had delayed hyper-
sensitivity to titanium [65c]. In these and
other cases [66A] skin reactions have been
attributed to infections with Staphylococcus
aureus.
In some cases allergy may be due not to
titanium but to a contaminant, such as nickel
[67A,68E], chromium or cobalt [69A], palla-
dium [70A], or an epoxy resin [71A].
Chapter 22 Gijsbert B. van der Voet
Clinical diagnosis Patch tests are often neg-
ative, in which case a positive lymphocyte
transformation test may give the diagnosis
[72AR]. In 54 patients who had received tita-
nium-based dental or endoprosthetic
implants a lymphocyte transformation test
against 10 metals was positive, with titanium
in 21 cases, ambiguous in 16, and negative in
19 [73c]. All had negative patch tests.
Removal of the implants produced marked
clinical improvement and in 15 who were
retested lymphocyte reactivity normalized.
It has been suggested that a 0.1% solution
of titanium tetrachloride may be preferable
as a patch test reagent for titanium allergy
[74c].
Different titanium containing compounds
have different degrees of immunogenicity;
the in vitro effects of different titanium salts
on the proliferation of cultured human
peripheral blood mononuclear cells and
cytokine release, titanium dioxide was not
immunogenic, titanium oxalate was mark-
edly so; titanocene selectively increased cyto-
kine release but did not affect cell
proliferation, and titanium ascorbate altered
the release of TNF-alpha but not interferon-
gamma [75E].
Histology In 54 patients who had fractures
of the long bones stabilized with limited-
contact dynamic compression plates made
of titanium samples of the soft tissue layer
covering the plate were recovered after 18
months [76c]. The plates were covered by a
connective tissue layer 2 mm thick on aver-
age. In patients with local pain there were
signicantly more round cells and macro-
phages, consistent with chronic granuloma-
tous inammation.
In subepithelial soft tissue and bone spec-
imens from 19 patients in whom implants
(14 stainless steel and 5 titanium) had been
in situ for more than 6 months, there were
scattered T lymphocyte clusters, small num-
bers of macrophages, and abundant expres-
sion of HLA-DR in the soft tissue adjacent
to both types of implant [77c]. There were
immunocompetent cells in the connective tis-
sue lining the periphery of the screw holes
and metal particles in the soft tissues and
bone.
Metals Chapter 22
Biopsy specimens from 17 mandibular
fracture sites treated by open reduction with
titanium in 12 patients showed double-
layered connective tissue, which consisted
of dense brous connective tissue and rela-
tively loose connective tissue containing pro-
liferated blood vessels with hypertrophied
endothelial cells [78c]. The vascular endo-
thelial cells expressed HLA-DR, CD54,
and CD62P antigens; in some cases they
were CD62E-positive. CD68-positive, and
CD11c-positive round or spindle-shaped
macrophages had inltrated around the
small vessels and contained ne cytoplasmic
titanium particles. In some cases CD4 and
CD8 T lymphocytes had inltrated around
venules.
Sources Dental and bone implants Inam-
matory reactions and contact sensitivity have
been reported after insertion of titanium
implants. Osseointegration of the implant
tends to occur, but around the area there can
be an intense inammatory reaction and per-
sistent irritation of soft tissues [79A].
Titanium allergy can reportedly cause
failure of dental implants [80A,81A] and
interfere with the implant/restoration process
in articial joints [82A].
A 49-year old woman had severe reactions to
all six titanium implants that were placed in
her mandible between the left and right mental
foramen. Three types of implants were used,
an LIBB compression implant, a cylindrical
implant, and a Brnemark-like implant. The
tissue reactions were severe enough to warrant
removal of all the implants and the surround-
ing soft tissues showed chronic inammation
with brosis around all the implants and
foreign-body giant-cell reactions around two.
She recuperated and the soft and hard tissues
healed satisfactorily.
A 64-year-old man underwent a total hip
arthroplasty for severe osteoarthritis of his left
hip following avascular osteonecrosis. An
SEM3 type (Science et Mdecine, Montrouge,
France) cementless forged Ti Al6-4V alloy,
with femoral stem size 12, coated with hydroxy-
apatite on the proximal third, with a metallic
head of a diameter 28 mm, and an ultra-high
molecular weight polyethylene (UHMWPE)
insert (liner) with a metal acetabular cup
(50 mm) was inserted. Four years after the
operation, he developed severe pain in the left
457
hip while walking and inability to bear weight.
An X-ray showed a fracture of the femoral
neck without bone loss in the proximal femur
and he underwent a revision of the total hip
arthroplasty. There was an extensive amount
of bone adherent to the device, and the frac-
tured implant was well xed.
Dental implants have been studied in 35
patients, of whom 16 had had symptoms of
allergy after implantation or unexplained
implantation failure and 19 had a history
of other allergies, or were heavily exposed
to titanium during implantation surgery, or
had implantation failure for which the cause
was known [83c]. Nine patients had positive
reactions to titanium allergy tests: eight in the
rst group, in ve of whom there had been
unexplained implant failures, and one in
the other group. None of 35 controls had
positive reactions.
In one case, facial eczema occurred after
titanium dental implantation, with complete
remission after removal [84A]. In another
case, drug rash with eosinophilia and sys-
temic symptoms (DRESS) occurred in a
previously healthy 19-year-old man after
insertion of a titanium bioprosthesis for a
spinal fracture [85A].
Gingival hyperplasia surrounding the
transmucosal portions of titanium implants
has been attributed to titanium allergy [86A].
In two cases exposure to titanium in den-
tal implants caused reactive lesions in the
peri-implant mucosa, diagnosed as epulis,
in which metal-like particles were observed
histologically [87A]. One involved a pyo-
genic granuloma and the other a peripheral
giant cell granuloma.
Tissues from ve patients who underwent
revision operations for failed total hip
replacements contained large quantities of
particulate titanium, abundant macrophages
and T-lymphocytes, and no B-lymphocytes
[88c]. In four cases the titanium had come
from alloy screws. Skin patch tests with
dilute solutions of titanium salts were nega-
tive, but two of the patients had a positive
skin test to a titanium-containing ointment.
Inhaled dust In a furnace feeder for an alu-
minium smelting company, granulomatous
lung disease was associated with pulmonary
458
deposition of various metallic particles
[89A]. The relation between the metallic
dust and the granulomatous process was
investigated by lymphocyte transformation
tests to aluminium sulfate, titanium chloride,
beryllium sulfate, and nickel sulfate were.
There was a positive lymphocyte prolifera-
tive response to titanium chloride on two
separate occasions and no reactions to the
other metals, consistent with hypersensitivity
to titanium.
Pacemakers Dermatitis due to titanium
hypersensitivity has occasionally been
reported after insertion of a pacemaker
[90A,91A,92A,93A,94A].
Surgical clips Exacerbation of atopic der-
matitis has been attributed to titanium in sur-
gical clips [95A].
Ear piercing A 68-year-old man developed
a granulomatous dermatitis after piercing
his ears. There were titanium, aluminium,
and vanadium particles within macrophages
in the lesions [96A].
Topical solutions Contact allergy has been
attributed to topical ammonium titanium
lactate 10% [97A].
Zinc[SED-15, 3717; SEDA-30, 270;
SEDA-31, 394; SEDA-32, 420]
Nervous system Denture adhesives and
creams are a source of zinc and can cause
hyperzincemia and hypocupremia [98A].
A 47-year-old woman developed progressive
knee and back pain, weakness, paresthesia,
sensory loss, ataxia, and falls. Physical, neuro-
logical, and neurophysiological examinations,
T2-weighted MRI scans of the brain and
spine, cerebrospinal uid analysis, and serum
concentration measurements showed that she
had a myeloneuropathy with anemia, due to
copper deciency, secondary to zinc overload
associated with long-term use of denture
cream with a high zinc content, which she
Chapter 22 Gijsbert B. van der Voet
had used for many years. Change to a low-zinc
denture cream and oral copper replacement
resulted in clinical improvement.
Sensory systems Olfaction Zinc nasal
sprays can cause loss of the sense of
smell in animals and humans, and the
FDA has warned consumers and health-
care professionals to stop using zinc-
containing nasal products sold over-the-
counter as cold remedies (Zicam Nasal
Gel and Nasal Swab), because they are
associated with long-lasting or permanent
loss of the sense of smell [99S]. The FDA
has received over 130 reports of anosmia
associated with the use of these products.
Many have stated that loss of the sense of
smell occurred with the rst dose of the
product, while others have reported that it
happened after later doses. According to
the FDA, these products have not been
shown to be effective in reducing the dura-
tion or severity of cold symptoms. This
advice does not relate to oral zinc tablets
and lozenges.
Hematologic Zinc supplementation has
proven benecial in the treatment of acute
child diarrhea and appears to enhance lin-
ear growth. However, there is a theoretical
risk of anemia, due to inhibition of iron
transport because of reduced copper
absorption. Although many zinc supple-
mentation trials have included hematologi-
cal measures, the effect of zinc on these
outcomes has not been comprehensively
reviewed. In a systematic review of 21 ran-
domized studies of the effect of zinc supple-
mentation on hemoglobin concentrations in
3869 apparently healthy children aged 015
years, the duration of treatment was 415
months and dosages were typically 10
20 mg/day [100M]. Zinc supplementation
did not cause changes in hemoglobin con-
centration. There was no evidence of
effects of age, zinc dosage, duration of
treatment, type of control, baseline hemo-
globin, geographical or health-care setting,
or quality of the studies.
Metals Chapter 22
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23 Metal antagonists
IRON CHELATORS
The effectiveness of iron chelators is illus-
trated by the tremendous improvements in
both life expectancy and quality of life in
patients with thalassemia, thanks to struc-
tured and rigorous diagnosis and treatment
schemes, as for example in Cyprus. At the
same time, the chronic use of chelators con-
tinues to pose major challenges, concerns
regarding their best use, and scientic
assessment of their long-term benets and
harms [1R, 2R].
The use of iron chelators has been
reviewed [3R] and some articles have pro-
vided a practical summary comparison of
today's leading chelating drugs [4R, 5R]
(see Table 1). The use of combinations of
these drugs may lessen some problems or
create others [SEDA 31, 399].
In a review of the current outlook of
transfusional iron overload in Latin Amer-
ica, an expert panel formulated a number
of recommendations [5R], which are rele-
vant to the safe and rational use of iron
chelators, including
patient educationthe key to gaining accep-
tance of the need for therapy and in emphasiz-
ing the importance of ensuring adherence to
the dosing schedule;
education of health authorities and physicians
responsible for treating hematological disor-
dersneeded to ensure that iron chelation
therapy is available to all patients who need
it and that it is prescribed at the recommended
doses;
Side Effects of Drugs, Annual 33
J.K. Aronson (Editor)
ISSN: 0378-6080
DOI: 10.1016/B978-0-444-53741-6.00023-4
# 2011 Elsevier B.V. All rights reserved.
R.H.B. Meyboom
education of different social security systems
and health authorities on the importance of
providing iron chelation medication;
inclusion of iron chelation treatments on the
ofcial lists of medicines approved by Medi-
cines Boards.
Suggestions for future studies include the
incidence of hemochromatosis in different
Latin American countries, the efcacy and
safety of iron chelation therapy, and
pharmacoeconomic studies.
Several papers have also illustrated that b-
thalassemia is itself directly or indirectly asso-
ciated with a wide variety of pathologies, for
example skin disorders [6R], infections, hear-
ing loss, osteoporosis, and cholelithiasis. This
needs to be given due attention in attributing
adverse effects to the drugs used in these
patients, while some of these complications
may become more frequent during the use
of a chelator.
New compounds There is a series of new
iron chelators in development. DP-b99 is an
experimental membrane-activated lipophilic
chelator of iron, calcium, and zinc [7r]. In a
double-blind, placebo-controlled, random-
ized multicenter trial in 150 patients with
strokes, the primary end-point of a change in
the clinical neurological scale score (NIHSS)
from baseline to 90 days was not met. Second-
ary end-points, on the other hand, were signif-
icantly improved after 90 days. There were no
clinically signicant differences between
the groups in vital signs and there were no
major safety problems. CP94 (1,2-diethyl-3-
hydroxypyridin-4-one HCl) has been used in
an open controlled study in a mixed topical
formulation together with 5-aminolevulinic
acid to enhance topical photodynamic ther-
apy in six patients with basal cell carcinomas,
without causing any adverse reactions [8c].
465
466 Chapter 23 R.H.B. Meyboom

Table 1 Summary comparison of three iron chelators [4R, 5R]

Description/
Compound pharmacokinetics Dose Monitoring

Deferasirox Tridentate chelator; 20 mg/kg/day orally as a Monthly: renal and

molecular mass 373 362; single dose; dose in hepatic values
half-life 816 hours; increments of 5 or 10 mg/kg Yearly: ophthalmic review
excretion fecal every 36 months according (color vision, cataract
to serum ferritin; maximum visual elds, fundus);
30 mg/kg/day audiometry
Deferiprone Bidentate chelator; 50100 mg/kg/day orally in Every visit: total and
molecular mass 23 divided doses differential cell counts,
139 152 g/m; half-life 2 joint complaints (stiffness,
3 hours; excretion urinary pain, swelling)
Three-monthly: dose,
ferritin, AlT
Deferoxamine Hexadentate chelator; 2040 mg/kg/day as a Three-monthly: mean
molecular mass subcutaneous night-time daily dosesa; serum ferritin
560 684 g/mol; half-life infusion over 810 hours of and creatinine; therapeutic
6 hours; excretion urinary a 10% solution, 57 nights/ serum indexb; compliance
and fecal week indexc; vision
a
Therapeutic index: mean daily dose (in mg/kg)/serum ferritin (keep below 0.025).
b
Mean daily dose (over a week): actual daily dose administered
7.
c
Compliance index: the number of factual administrations over the year/prescribed number of daily treatments.

Cardiovascular Iron-induced cardiac injury continuous administration. Deferiprone is a

is a major cause of morbidity and mortality
in all transfusion-dependent diseases. The
complex processes that determine the entry,
storage, toxicity, and detoxication of iron
in the heart have been reviewed [9R]. Direct
measurement of cardiac iron, using T2-
weighted magnetic resonance imaging rather
than indirect methods, such as measuring
serum ferritin concentrations or liver iron
concentrations, has contributed to earlier
recognition of myocardial iron loading and
the prevention of cardiac injury. Cardiac
T2-weighted MRI predominantly reects
safely stored cardiac iron, which explains
how patients can have abnormal values in
association with normal cardiac function.
However, this safely stored iron pool is in
dynamic equilibrium with labile myocyte
iron, leading to a higher risk of cardiac
decompensation at low values.
The short half-life of deferoxamine limits
its suppression of non-transferrin-bound
serum iron (NTBI) to the hours of drug
administration, so that effective cardiac
iron chelation requires continuous or near-
relatively small molecule and readily enters
myocytes and intracellular compartments. It
is an effective cardiac iron chelator when used
alone or in combination with deferoxamine.
Cardiac iron, cardiac function, and patient
survival all appear to improve with
deferiprone. In vitro evidence shows that
intracellular sites of labile cardiac iron
accumulation are accessed more rapidly by
deferasirox and deferiprone than by
deferoxamine. In addition, deferasirox
restored the contractility of rat cardiac
myocytes after iron loading. All three chela-
tors can remove labile iron from plasma. Ani-
mal experiments also suggest that deferasirox
and deferiprone have comparable access to
intracardiac iron.
Deferasirox [SEDA-30, 273; SEDA-31,
401; SEDA-32, 426]
In patients with bone marrow failure requir-
ing hemopoietic stem cell transplantation,
Metal antagonists Chapter 23
prior iron chelation may improve survival
[10c], and early deferasirox treatment may
result in long-term reduction in transfusion
requirements [11c].
Cost-effectiveness There is uncertainty
about the risk of serious adverse reactions
to deferasirox, the associated susceptibility
factors, and resultant cost-effectiveness
[12R, 13R]. In a cost-utility multiple appraisal
of deferasirox and deferoxamine, the former
was concluded to be cost-effective, with an
incremental cost-effectiveness ratio (ICER)
below 20 00030 000 per QALY gained
[14r]. The rates of serious adverse events
were thought not to be different, and serious
adverse events, but their costs were not
specied or included in the assessment.
In a cost-utility multiple appraisal
of deferasirox, deferoxamine, and
deferiprone, it was concluded that in the
short term there is little clinical difference
between any of the three chelators in terms
of removing iron from the blood and the
liver, and that deferasirox may be cost-
effective compared with deferoxamine but
not compared with deferiprone [15R]. The
authors emphasized that the primary focus
for future research should be on the long-
term benets of chelation therapy, includ-
ing adverse reactions and adherence.
Observational studies In a retrospective
study of dose escalation of deferasirox to
above 30 mg/kg/day in 264 heavily iron-
loaded patients, gastrointestinal hemorrhage
and lenticular opacities developed as
suspected adverse reactions in one patient
each, but no details were given [16c]. There
was no worsening of renal or hepatic function.
Hematologic While blood dyscrasias may
not be established adverse reactions to
deferasirox, the recently revised data sheet
of Exjade reads There have been
postmarketing reports (both spontaneous
and from clinical trials) of cytopenias,
including agranulocytosis, neutropenia and
thrombocytopenia, in patients treated with
Exjade. Some of these patients died. The
relationship of these episodes to treatment
with Exjade is uncertain. Most of these
467
patients had pre-existing hematologic disor-
ders that are frequently associated with
bone marrow failure. Monitor blood counts
regularly. Consider interrupting treatment
with Exjade in patients who develop
unexplained cytopenia. Reintroduction of
therapy with Exjade may be considered,
once the cause of the cytopenia has been
elucidated [17R].
Gastrointestinal The data sheet for Exjade
(deferasirox, Novartis) has been revised and
a boxed warning has been added that gastro-
intestinal hemorrhage can occur and that
deaths have occurred [17S, 18R].
Liver The data sheet for Exjade
(deferasirox, Novartis) has been revised
and a boxed warning has been added that
hepatic failure can occur and that deaths
have occurred [17S, 18S].
The results of a prospective, multicenter, 1-
year, open study (ESCALATOR) in the Mid-
dle East of the use of daily deferasirox in
heavily iron-overloaded patients with b-thal-
assemia have been reviewed [19cr]. Of 237
patients (162 children and 55 adults) 233 com-
pleted 1 year of treatment. The starting dos-
age was 1020 mg/kg/day and the dosage
was increased to 25 or 30 mg/day in most
patients. Adverse events were reported by
180 patients and were judged to be drug
related in 105 (44%). Serious events occurred
in 17 (7.3%), of which only one (obstructive
jaundice) was thought to be drug related.
There were no withdrawals because of
adverse events that were considered to be
drug related.
Metal metabolism Symptomatic hypocalce-
mia has been attributed to deferasirox in a
patient with end-stage renal disease under-
going peritoneal dialysis [20CR].
A 43-year-old woman with sickle cell nephrop-
athy and hypertension, who had undergone
peritoneal dialysis for 1 year, had been given
repeated blood transfusions and erythropoie-
tin, leading to severe iron overload. She was
given deferasirox 20 mg/kg/day, and her other
medications included allopurinol, amlodipine,
atenolol, darbepoetin alfa, folic acid, lantha-
num carbonate, lisinopril, and losartan. The
468
peritoneal dialysate solutions contained ionized
calcium 2.5 mmol/l. The serum calcium fell to
1.47 mmol/l (ionized calcium 1.5 mmol/l), with-
out a change in parathyroid hormone concen-
tration. Despite paricalcitol, oral calcium, and
addition of calcium to the dialysate solution,
the serum calcium continued to fall and she
developed periorbital paresthesia and mental
slowing. The serum calcium concentration nor-
malized with intravenous calcium. Deferasirox
was withdrawn but later restarted. The serum
calcium again fell. Deferasirox was again with-
drawn and the calcium concentration again
increased.
The authors hypothesized that chelation by
deferasirox of iron from bone tissue had led
to increased calcium uptake, the hungry
bone syndrome, and they suggested that
if deferasirox is used in patients on dialysis,
serum calcium should be checked routinely.
Hypocalcemia has previously been
described in connection with deferoxamine
in an 8-month-old infant with aluminium
overload related to parenteral nutrition,
without increased urinary calcium excre-
tion, suggesting bone uptake of calcium
after chelation of aluminium [21A]. A simi-
lar hypocalcemic effect has been observed
in two patients with dialysis-related alumin-
ium-induced osteomalacia treated with
deferoxamine [22A].
Urinary tract The data sheet of Exjade has
been revised and a boxed warning added
that renal impairment and failure may occur
and that deaths have occurred [17S, 18S].
While increases in serum creatinine due to
deferasirox are usually benign, in one of 14
patients with excess iron storage due to
myelodysplasia, deferasirox (dose not speci-
ed) had to be withdrawn after 1 month
because of impaired renal function [23c].
Acute interstitial nephritis and renal failure
have been attributed to deferasirox [24CR].
A 62-year-old man with myelodysplastic syn-
drome, who had received multiple erythrocyte
transfusions, was given oral deferasirox 2 g/
day. He was not taking NSAIDs or other
nephrotoxic drugs, but 2 months later his
serum creatinine had risen from 141 to
194 mmol/l. When it rose to 265 mmol/l, a renal
biopsy was taken. The glomeruli were
unremarkable, but there was a diffuse intersti-
tial mononuclear inltrate with neutrophils
Chapter 23 R.H.B. Meyboom
and increased numbers of eosinophils, intersti-
tial edema, and interstitial brosis with pro-
portional tubular atrophy. Stains for IgG,
IgA, IgM, C3, C1q, k and l light chains, and
brinogen were negative. The diagnosis was
acute interstitial nephritis due to drug hyper-
sensitivity on a background of chronic intersti-
tial nephritis. Deferasirox was withdrawn and
the creatinine concentration fell to 115 mmol/l.
Fanconi syndrome has been attributed to
deferasirox [25Cr].
A 78-year-old man with sideroblastic anemia
and chronic lymphocytic leukemia took
deferasirox 24 mg/kg/day for transfusional iron
overload. He also had diabetes mellitus without
microangiopathy and was also taking
glibenclamide, metformin, and perindopril.
Before deferasirox the serum creatinine was
82 mmol/l and eGFR was 84 ml/minute, without
proteinuria or electrolyte abnormalities. Within
1 month the serum creatinine rose to 122 mmol/l
and the eGFR fell to 35 ml/minute. There was
proximal tubular dysfunction, with hypo-
phosphatemia, low plasma uric acid, a metabolic
acidosis, glycosuria, and increased urinary b2-
microglobulin. There was no monoclonal
gammopathy, and Doppler ultrasonography
showed normal kidneys. Deferasirox and
perindopril were withdrawn, and within 1 month
the serum creatinine fell to 107 mmol/l and the
proximal tubulopathy resolved.
Infection risk The potential therapeutic
role of iron chelation in mucormycosis was
initially obscured by the apparently
increased risk of mucormycosis during the
use of deferoxamine [SEDA-31, 403].
In an open study in eight patients with
biopsy-proven mucormycosis, deferasirox
(520 mg/kg/day for an average of 14 days)
was a safe adjunctive therapy [26cr].
Deferiprone [SED-15, 1054; SEDA-30,
273; SEDA-31, 402; SEDA-32, 427]
Pro-oxidant effects of deferiprone
At sufciently high concentrations
deferiprone forms a stable water-soluble 3:1
complex with Fe3, with a binding constant
of 37, and has antioxidant activity. At lower
concentrations, on the other hand, incom-
plete 1:1 and 1:2 chelatoriron complexes
Metal antagonists Chapter 23
form and the unoccupied coordination sites
of these complexes can paradoxically catal-
yse the formation of hydroxyl radicals and
other reactive oxygen species.
For some time it has been suspected that
the mechanism underlying the development
of characteristic adverse reactions to
deferiprone, such as agranulocytosis, arthri-
tis, and perhaps heart failure, is related to
this paradoxical pro-oxidant action of
deferiprone. The potential for free radical
formation has been studied after a single
oral dose of deferiprone 25 mg/kg in 21
patients with beta thalassemia or hemo-
globin E [27R]. None of the patients had
received a blood transfusion in the preceding
month. In the presence of tert-butylhydro-
peroxide and ascorbic acid, free radicals
were assessed by electron paramagnetic res-
onance (EPR) spectroscopy spin trapping
technique, using 5,5-dimethyl-1-pyrroline-
N-oxide (DMPO). Shortly after administra-
tion of deferiprone, the EPR signal intensi-
ties fell. However, a pro-oxidant activity
was later observed in the sera of several
patients, as indicated by an enhanced EPR
signal, notably at 300, 360, and 480 minutes
after dosing. Most of these patients had
severe iron load and had serum molar
deferiprone/iron ratios below 3. Although
iron status could also have determined free
radical formation; there were signicant cor-
relations between NTBI and the deferiprone/
iron ratio. On the other hand, in almost all
of the patients, a higher ratio was associated
with antioxidant activity throughout the
study. This study has shown for the rst time
in vivo a paradoxical pro-oxidant action of
deferiprone.
In order to avoid adverse effects, a dosage
regimen should be designed that is based on
the iron status of the patient and aimed at
maintaining a sufciently high ratio of the
serum chelator-to-iron concentration. A possi-
ble advance in this respect is the development
of pro-chelators, chelators that bind iron
only when activated by oxidative stress [28E].
Cardiovascular A severe cardiomyopathy
with congestive heart failure has been
reported after withdrawal of deferiprone
for severe arthritis [29c].
469
A 40-year-old man with sideroblastic anemia,
who had had regular erythrocyte transfusions
for 4 years, was given nightly subcutaneous
infusions of deferoxamine subcutaneously 3 g/
day on 5 days/week. After 22 months he devel-
oped vestibular toxicity and deferoxamine was
replaced by oral deferiprone 75 mg/kg/day.
Cardiac ultrasonography was normal and there
were no signs of pulmonary hypertension or
right ventricle dysfunction. After 6 weeks he
suddenly developed severe arthralgia and swell-
ing of the knees and deferiprone was with-
drawn. During the next few days he developed
severe dyspnea and 2 weeks later congestive
heart failure. The ventricular ejection fraction
had fallen to 30% and there was a dilated
hypokinetic cardiomyopathy. No other causes
were found and he died 3 months later.
Heart failure is a common cause of death in
end-stage b-thalassemia, which might have
contributed in this patient. In previous studies
of deferiprone, heart failure occurred in four
out of 51 patients [30C] and nine out of 532
patients [31C], but most of them had had left
ventricular dysfunction before administration
of deferiprone. The mechanism and precipi-
tating factors of deferiprone-induced
cardiotoxicity are uncertain. It could be due
to a direct toxic effect or to an increase in
non-transferrin-bound iron. The heart selec-
tively takes up labile iron species, and labile
plasma iron can generate reactive oxygen spe-
cies and is thought to play a major role in iron-
related heart failure [32c]. The short half-life
of deferiprone may also be inuential. The
observation in these two patients that
cardiotoxicity happened after stopping is of
particular interest, in the light of the recent
observation that in a single-dose study pro-
oxidant effects of deferiprone were mainly
observed at the end of the study period, when
deferiprone blood concentrations had fallen.
Hematologic In a 5-year randomized study
in 213 patients with b-thalassemia,
deferiprone monotherapy 75 mg/kg/day was
compared with deferiprone 75 mg/kg/day on
3 days/week alternating with deferoxamine
50 mg/kg/day on 3 days/week [33C]. While
neutropenia was equally frequent in the two
groups (11 and 15 patients), there was agran-
ulocytosis in three of the patients who received
deferiprone monotherapy and none in the
other group. This may be related to the
470
pro-oxidant action of deferiprone and raises
the question of whether combined use of
deferiprone with deferoxamine reduces the
risk of agranulocytosis.
Nervous system Two patients with neurolog-
ical reactions during the use of excessive doses
of deferiprone, as referred to in the Ferriprox
Dear Dr letter of July 2006, have been
described in more detail [34CR]. These obser-
vations suggest that deferiprone should not
be used in dosages exceeding 100 mg/kg/day.
In a 9-year-old boy who used deferiprone
119 mg/kg/day for 2 years (indication not spec-
ied) the dose was increased to 238 mg/kg/
day. During the next 16 months he developed
a cerebellar syndrome, with dizziness, axial
hypotonia, nystagmus, and diplopia, together
with obsessivecompulsive behavior. Neuro-
logical investigations were normal and there
were no infections, inammation, or immuno-
logical disorders. He started to improve
3 weeks after stopping deferiprone and he
recovered within 1 year.
A 7-year-old girl took deferiprone 232 mg/kg/
day and 2 months later developed a cerebellar
syndrome, with inability to walk in a straight
line, impaired motor coordination, nystagmus,
and dystonia. The symptoms disappeared
1 month after drug withdrawal.
Musculoskeletal Symptoms of arthropathy
are reported to occur in 1320% of patients
who take deferiprone and to require with-
drawal in about 2%. It typically affects the
knees, but the ankles, wrists, elbows, shoul-
ders, and other joints may be affected. It is
more frequent with a high iron load, high
serum ferritin concentrations, and high
deferiprone doses and less common after
the rst year of use [35R]. Arthroscopy has
shown excess iron in the synovium and carti-
lage, but no deferiprone. Synovial biopsy
has shown iron deposition and proliferation
of the synovial lining without inammatory
reactions. The changes in epiphyseal carti-
lage and subchondral bone are unique to
deferiprone-related arthropathy.
The mechanism is uncertain, but it is
thought that deferiprone-related shifts of
iron to the synovium may increase free
Chapter 23 R.H.B. Meyboom
radical formation and local tissue injury
during incomplete complexation of iron.
There are usually no antibodies, rheumatoid
factor, or antinuclear or anti-DNA antibodies
detectable in the serum. The radiographic
and MRI ndings in deferiprone arthropathy
have been characterized [36A].
An 8-year-old boy, who had been receiving
regular blood transfusions since he was
3 months, was given deferiprone 4080 mg/kg/
day at irregular intervals according to serum
ferritin concentrations. He developed pain in
both knees at the age of 4 years. Plain radio-
graphs showed mild irregular subchondral at-
tening of the femoral condyles and beaking of
the patellae. MRI scans showed irregular thick-
ening of the cartilage with subchondral erosions
and cartilage intrusions in the subchondral
defects. Joint effusion was minimal, but there
were hypo-intense bands in the infrapatellar
fat. Except for hemosiderin deposition the
metaphysis and the epiphyseal plate were
grossly normal. The bone marrow appeared
black because of hemosiderin deposition.
Most patients with joint symptoms due to
deferiprone are able to continue taking
it, with or without NSAIDs. In 60 patients
taking deferiprone, arthropathy occurred in
only two, one of whom was described
in detail, illustrating that deferiprone-induced
arthritis can be severe and disabling [37Ar].
A 29-year-old man with b-thalassemia took
deferiprone for 4 years, initially in a dosage
of 75 mg/kg/day, later increased to 100 mg/
kg/day. He developed bilateral arthritis of
the knees, with swelling and pain particularly
in the right knee. There were no infections,
osteoarthrosis, or other abnormalities of the
bone, cartilage, or surrounding soft tissues
and tests for immunological abnormalities
were negative. T2-weighted signals were low
in the bone marrow, because of iron disposi-
tion. Arthritic uid culture was negative.
Triamcinolone was injected into the right
knee joint, deferiprone was replaced by
deferoxamine, and NSAIDs were given.
There was a complete resolution of the arthri-
tis. Deferiprone was not reintroduced.
Another patient, with suspected
deferiprone-related heart failure, had acute
severe bilateral arthritis of the knees 6 weeks
after starting deferiprone, necessitating
drug withdrawal [29C].
Metal antagonists Chapter 23
Deferoxamine [SED-15, 1058; SEDA-
30, 274; SEDA-31, 402; SEDA-32, 429]
Sensory systems Vision Deferoxamine in
high dose has been linked to retinal dam-
age, thought to be due to retinal pigment
epithelium iron deciency. The relation
between iron and pathology of the eye
(for example, in age related macular degen-
eration) and the possible therapeutic use of
chelators has been reviewed, illustrating the
difculty in distinguishing between sponta-
neous ocular adverse events and reactions
to chelating drugs [38r].
The prevalence of ocular toxicity of
deferoxamine has been evaluated retrospec-
tively in 84 children, average age 13 years,
who had received deferoxamine for an
average of 6.6 years for transfusion-related
hemochromatosis in b-thalassemia, E/b-thal-
assemia, or a-thalassemia [39cr]. The standard
dosage was 2550 mg/kg/day, given subcuta-
neously over 10 hours on 57 nights a week;
three patients received short-term intrave-
nous deferoxamine at some time during the
study. Baseline ophthalmic screening was
followed by yearly reviews (a total of 421
examinations; average ve per patient). As a
rule electroretinography and uorescein
angiography were carried out only when the
ophthalmic history or physical examination
was abnormal. Only one patient had abnormal
ndings, with central blurring, retinal pigmen-
tary changes, and a reduced central response
on electroretinography. This patient (age not
mentioned) had a 3-year history of poor
adherence and was temporarily receiving
intravenous deferoxamine 50 mg/kg/day as a
continuous 24-hour infusion; all symptoms
promptly recovered after changing to
subcutaneous administration. The authors
recommended ophthalmic screening only in
patients receiving high doses or intravenous
deferoxamine or in the case of visual
symptoms.
Auditory function In a cross-sectional study
of the frequency of sensorineural hearing loss
in 67 patients (minimum age 5, maximum
24 years) receiving regular deferoxamine by
subcutaneous pump infusion for b-thalasse-
mia the mean dose was 50 mg/kg/day on a
471
mean of 5.5 days/week; the mean duration of
treatment was 11 (range 121) years [40CR].
In ve cases (three girls, two boys) there was
sensorineural hearing loss, which may have
been due to deferoxamine and was otherwise
unexplained. In three patients chelation treat-
ment was changed, but on follow-up there was
no improvement. There were no substantial
differences between these children and those
with normal hearing (for example, age, sex,
dose and duration of drug use, disease param-
eters). Although in these ve cases the mean
exposure time to deferoxamine of 15 years
was longer than in the patients without
hearing loss (10 years) the difference was not
statistically signicant.
It is not always correct to attribute hearing
loss to deferoxamine or other chelators [41A].
A 6-year-old boy with transfusion-dependent
b-thalassemia developed unilateral hearing loss
shortly after low-dose deferoxamine (dose not
specied). Ototoxicity was assumed, but the
decit was later found to be conductive and
due to bone marrow proliferation within the
ossicular chain as a consequence of the disease.
Musculoskeletal In a retrospective series of
84 children receiving deferoxamine for trans-
fusion-related hemochromatosis (b-thalasse-
mia, E/b-thalassemia, or a-thalassemia) bone
dysplasia occurred in 17 [39c]. The standard
dose was 2550 mg/kg/day subcutaneously
over 10 hours on 57 nights a week; three
patients received short-term intravenous
deferoxamine at some point during the study.
Combinations of iron chelators
[SEDA 31, 399; SEDA 32, 426]
Infection risk Reactivation of hepatitis B
infection may have been caused by the
combined use of deferiprone and
deferoxamine [42A].
A 29-year-old man with b-thalassemia
(CD39IVSH-1), who had received
deferoxamine for 19 years, developed co-exis-
tent cholelithiasis, moderate spleen enlarge-
ment, and chronic HBV hepatitis (HBsAg
positive, HBeAg negative, HBV-DNA
472
2.1
103 copies/ml, normal baseline alanine
aminotransferase). Deferiprone 50 mg/kg/day
was added to deferoxamine 30 mg/kg on 3
5 days/week and the alanine aminotransferase
activity increased. Deferiprone was withdrawn
and the enzyme activity fell. Deferiprone was
reintroduced and there was a new sustained
rise in aminotransferase activity to about twice
baseline. There were 139
103 copies/ml of
HBV-DNA. Extensive testing did not identify
autoantibodies. Deferiprone was withdrawn
again and the HBV-DNA cleared partly
within 8 weeks and alanine aminotransferase
activity returned to normal. Later, deferiprone
was reintroduced in the same dosage and
there was no relapse of hepatitis after
24 months.
This patient received regular transfusions,
and the episode of hepatitis activation can-
not be attributed with certainty to the com-
bined administration of deferiprone and
deferoxamine. The rst rechallenge with
deferiprone was followed by prompt relapse,
but the second was not. Iron storage and iron
chelators both have immunomodulating
effects [43c], and this report suggests
that combined use of deferiprone and
deferoxamine may affect the immune
system. Patients with pre-existing viral hepa-
titis should be monitored, but hepatitis
reactivation should not necessarily be mis-
taken for drug-induced liver damage.
PENICILLAMINE AND
RELATED DRUGS [SED-15,
2729; SEDA-30, 274; SEDA-31, 403;
SEDA-32, 430]
Penicillamine
Effective as penicillamine is in excreting
copper, it can also seriously worsen neuro-
logical symptoms early in the treatment of
Wilson's disease. Unfortunately, there is
still a lack of high-quality evidence regard-
ing the best initial treatment in this disease,
and early diagnosis can also be difcult
[44M, 45R]. Since zinc is effective and has
negligible adverse effects, it is probably
the best choice in the initial treatment of
Chapter 23 R.H.B. Meyboom
presymptomatic patients as well as in
patients with neurological involvement,
although in patients with acute hepatic dis-
ease zinc may act too slowly and penicilla-
mine may be needed. Neither trientine nor
tetrathiomolybdate has been studied widely
enough to decide about the best use of
these drugs in the initial treatment of
Wilson's disease.
Observational studies In a retrospective
chart study of 11 children with cystinuria,
penicillamine (goal dose 20 mg/kg) was
effective [46CR]. During a total of 1203
patient-months several patients had minor
transient adverse events, such as arthralgia,
which did not require withdrawal; there
were serious adverse reactions in two
patients. A 7-year-old boy developed gener-
alized amino-aciduria after 3 years; it
resolved on drug withdrawal. Penicillamine
was reintroduced later and there was a sec-
ond episode of amino-aciduria, which
resolved after penicillamine withdrawal. A
22-year-old woman developed elastosis
perforans serpiginosa after taking penicilla-
mine for 15 years.
Respiratory Hypersensitivity pneumonitis
has been attributed to penicillamine [47A].
A 50-year-old woman with Wilson's disease
and hepatic cirrhosis was given penicillamine
1 g/day and pyridoxine 50 mg/day and after
6 weeks developed acute dyspnea. She had a
respiratory rate of 20/minute, a temperature
of 37.5 C, and reduced breath sounds in both
lung bases, with diffuse end-inspiratory
crackles. Oxygen saturation was 93% at rest.
A chest radiograph showed increased intersti-
tial markings and a CT scan showed diffuse
changes in both lungs with ground-glass opac-
ities and thickening of intralobular and
interlobular septa. There were 42% lympho-
cytes, 48% macrophages, and 9% eosinophils
in bronchial lavage uid. When penicillamine
was withdrawn and replaced by trientine her
symptoms improved and the chest radiograph
returned to normal.
Endocrine In pregnant women with
Wilson's disease chelation therapy is
needed throughout pregnancy. The connec-
tion between maternal use of penicillamine
Metal antagonists Chapter 23
and transient goitrous hypothyroidism in
the neonate has been evaluated [48A].
A mother with Wilson's disease gave birth at
35 weeks to a boy weighing 2.4 kg with a palpa-
ble goiter. Neonatal screening and thyroid func-
tion tests at 18 days showed hypothyroidism
without TSH receptor antibodies. He was given
levothyroxine 25 micrograms/day and the
goiter resolved within 5 months; levothyroxine
was continued for 4 years. The mother had used
penicillamine 1.5 g/day for 15 years and during
pregnancy the dose had been increased to 2 g/
day; no other drugs were taken. There was no
family history of thyroid disease.
The same mother gave birth at term to a sec-
ond son, weighing 3.1 kg. The perinatal course
was uneventful, but neonatal screening
showed severe hypothyroidism; serum thyro-
globulin concentrations were extremely high
and a thyroid scan showed a diffusely enlarged
gland. Levothyroxine was effective within
2 months and was withdrawn after 7 months.
After parturition the mother's thyroid func-
tion tests were normal, as were thyroglobulin
and thyroperoxidase; TSH receptor anti-
bodies were undetectable. Her thyroid was
not palpable, but a scan showed diffuse
enlargement and 131I uptake was increased.
She developed a multinodular goiter 4 years
later, but free thyroxine and TSH concentra-
tions remained normal. Three more children
born to mothers using penicillamine all
had subclinical hypothyroidism. The authors
hypothesized that penicillamine inhibits
thyroid hormone iodination and coupling
reactions catalysed by thyroid peroxidase,
and concluded that in utero exposure to
penicillamine may cause congenital goitrous
hypothyroidism and persistent subclinical
hypothyroidism in older children.
Skin Elastosis of the lip has been described
as a possible late sequel of the use of peni-
cillamine [49Ar].
A 45-year-old man with Wilson's disease
developed two 1- to 2-cm annular atrophic
plaques on the mucosa of the lower lip with
a mildly raised hyperkeratotic rim. Histology
showed irregular acanthotic and atrophic epi-
thelium without perforation. There were
markedly increased elastic bers with a bram-
ble-bush morphology, as is typically seen in
penicillamine dermopathy. During previous
473
treatment with penicillamine he had had
elastosis perforans serpiginosa of the skin of
the axillae, leading to withdrawal of penicilla-
mine and replacement by zinc acetate and
trientine. Bilateral hyperpigmented atrophic
plaques with annular slightly raised borders
were still present in the axillae. The patient
was also known to chew tobacco.
Another case of bullous pemphigoid has
been described in a patient taking penicilla-
mine [50A].
A 47-year-old man with Wilson's disease, who
had taken penicillamine 1.5 g/day for about
20 years, developed marked pruritus, large
tense blisters on an erythematous base, ery-
thematous papules, and small plaques on the
trunk and arms. A biopsy of a bullous lesion
showed a subepidermal blister with eosinophils
and lymphocytes in the blister cavity. Direct
immunouorescence showed linear deposits of
C3, IgG, and IgA. There were IgG deposits on
the epidermal roof of the articially induced
separation. The bullous lesions responded to
topical clobetasol and betamethasone, but new
lesions continued to appear. Penicillamine
was replaced by zinc sulfate, and the rash
improved promptly. When penicillamine was
reintroduced, the pruritus and tense blisters
recurred within a few days.
OTHER CHELATORS
DMPS (2,3-dimercapto-1-
propanesulfonic acid)
Skin StevensJohnson syndrome occurred
in a patient with chronic mercury poisoning
who was given DMPS [51Cr].
An 11-year-old boy with chronic non-symp-
tomatic mercury poisoning was treated with
oral DMPS 600 mg/day, and after 1 week
started to feel unwell, with a mild fever and
painful gums; 1 week later he developed a dis-
seminated cutaneous eruption of red pruritic
macules on the chest and back. He was given
levocetirizine 5 mg/day, and 3 days later the
rash had spread all over the body, the macules
had become conuent, and there were ero-
sions and crusts on the lips and blisters in the
oral mucosa. There were no blisters on the
skin or genitals and no corneal lesions. There
were no signs of infection, and serological
tests for Herpes simplex and Yersinia were
negative. DMPS was withdrawn and the
lesions gradually resolved.
474
Edetic acid (ethylene diamine
tetra-acetic acid, EDTA) [SED-15,
1300; SEDA-30, 276; SEDA-31 405; SEDA-
32, 431]
Placebo-controlled studies In a double-
blind, randomized, placebo-controlled
study (40 cases, 40 controls), mesotherapy
with disodium edetate (subcutaneous injec-
tions of a 15% solution procaine 1%)
in combination with pulse-mode 1 MHz
phonotherapy phonophoresis was highly
effective in calcic tendinitis of the shoul-
der; there were no injection-site reactions
or other adverse events [52cr].
Mineral metabolism Errors causing serious
intoxication continue to be reported, because
of confusion between disodium edetate
(which has a strong afnity for calcium) and
calcium disodium edetate (which can be used
in lead poisoning) [53A]. If chelation therapy
is required in children, calcium disodium
edetate, not disodium edetate, should be
used, because of the risk of hypocalcemia.
Skin Edetic acid can cause hypersensitivity
reactions, including contact eczema [54A].
A 75-year-old man with several malignant epi-
thelial tumors used UriageTM SPF50 cream
as a sunscreen, and 10 months later developed
eczematous areas where the cream had been
applied on the face, neck, and the backs of
the hands. A patch test with the cream was
positive after 4 days; of the 24 components of
the product provided by the manufacturer
only tetrasodium edetate (0.2% in water)
was positive; tetrasodium edetate produced
no reactions in ve control subjects.
Trientine [SED-15, 3508; SEDA-32, 431]
Metal metabolism A sensorimotor axonal
peripheral neuropathy and mild bone
marrow suppression occurred as probable
complications of copper deciency, second-
ary to treatment with trientine and zinc
acetate [55A].
Chapter 23 R.H.B. Meyboom
A 43-year-old man with Wilson's disease was
given zinc acetate 400 mg/day, trientine
900 mg/day, and olanzapine 15 mg/day. He
had persistent stable neutropenia 0.94
109
and then developed distal weakness in the
hands and feet. Electrophysiological tests
showed a length-dependent sensorimotor axo-
nal peripheral neuropathy. Compound muscle
and sensory nerve action potentials were
reduced in amplitude. There were brillation
potentials and large motor unit potentials with
reduced recruitment in the distal limb muscles.
The peroneus brevis muscle showed neurogenic
atrophy and the supercial peroneal nerve axo-
nal degeneration. Total serum copper and ceru-
loplasmin were markedly reduced and serum
zinc was raised. There was a reduced copper
concentration in the cerebrospinal uid. Zinc
acetate was withdrawn and the dose of trientine
temporarily reduced to 300 mg/day. The neu-
trophil count normalized, but there was only
mild neurological improvement.
Copper is an essential co-factor for vari-
ous redox enzymes that prevent free
radical formation. Copper deciency is an
established cause of reduced hemopoiesis.
Hypercupremia and paradoxically also
hypocupremia can both cause neuropathy.
POLYSTYRENE
SULFONATES [SED-15, 2894;
SEDA-30, 275; SEDA-32, 433]
Gastrointestinal Ischemic colitis [56A], colo-
nic necrosis [57A, 58A, 59A], colonic perfora-
tion [60A], and ileal perforation [61A] have
again been reported in patients taking sodium
polystyrene sulfonate.
In a review of all gastrointestinal speci-
mens reported as containing crystals of
sodium polystyrene sulfonate from Decem-
ber 1998 to June 2007, 29 patients were
identied; nine were excluded as incidental
ndings with normal mucosa and nine were
excluded as having had symptoms adminis-
tration of sodium polystyrene sulfonate or
because an alternative cause was identied
[62c]. Eleven patients had conrmed intesti-
nal necrosis and a temporal relation to
the administration sodium polystyrene
Metal antagonists Chapter 23
sulfonate suggestive of drug-induced necro-
sis. Only two were postoperative and only
four had end-stage renal disease. All had
had hyperkalemia, had used oral sodium
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475
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2009; 102(5): 4937.

24 Antiseptic drugs and
disinfectants
Disinfectants and bacterial
resistance
The rst observations to suggest that some
quaternary ammonium compounds, such as
benzalkonium chloride, stearalkonium chlo-
ride, and cetylpyridine chloride, have anti-
microbial activity were made in as early as
1916, but their full potential was rst realized
in the 1930s [1E, 2R]. Since then their
uses have steadily increased and include
many industrial purposes, water treatment,
and antifungal treatment in horticulture,
as well as inclusion in pharmaceutical and
everyday consumer products. For example,
benzalkonium chloride, the most commonly
used, is found in products such as eye drops,
articial tears, decongestion nose drops, facial
moistures, facial cleansers, acne treatments,
sun protection creams and lotions, body
lotions, moisturizers, pain relievers, and hand
sanitizers [3R]. Very often good reasons for
their use are lacking and claims are limited to
assertions that they are bug-killers.
The quaternary ammonium compounds
can be looked upon as hard antibacterial
agents. They are poorly metabolized and
irrespective of use will reach the environment
via water. Although there are considerable
variations in their biodegradability, their
environmental half-lives are weeks to months.
Consequently, bacterial resistance has to
be expected. The authors of an extensive
Side Effects of Drugs, Annual 33
J.K. Aronson (Editor)
ISSN: 0378-6080
DOI: 10.1016/B978-0-444-53741-6.00024-6
# 2011 Elsevier B.V. All rights reserved.
Pam Magee
survey, covering 142 references, concluded
that the development of resistance to quater-
nary ammonium compounds in both patho-
genic and non-pathogenic bacteria, related
to practical applications in human medicine
and the food industry, has been well
documented [4R].
The key point is that increasing evidence for
co-resistance and cross-resistance between qua-
ternary ammonium compounds and most anti-
biotics on the market (such as beta-lactams,
chloramphenicol, fusidic acid, macrolides,
quinolones, tetracyclines) has been found in
many pathogenic bacteria, such as Escherichia
coli, Listeria monocytogenes, Salmonella spp.,
and Pseudomonas aeruginosa. It seems reason-
able to assume that resistance may also be pre-
sent in many more species. The efux pumps
that confer resistance in these organisms can
be encoded in plasmids or chromosomally.
Co-resistance and cross-resistance may
also develop with most other disinfectants.
Taken together, unnecessary use of disinfec-
tants may contribute to the persistence and
spread of antibiotic resistance, limiting our
treatment options for bacterial infections.
This is important because resistance is the
most serious adverse effect of all antibiotics.
ALDEHYDES [SED-15, 1439,
1513; SEDA-31, 409; SEDA-32, 437]
Formaldehyde
Tumorigenicity The most recent evaluation
by the International Agency for Research
479
480
on Cancer classied the sterilizing and pre-
servative agent formaldehyde as a known
human carcinogen. It concluded that there
is strong evidence that formaldehyde
causes nasopharyngeal cancer, strong but
not sufcient evidence for leukemia, and
limited evidence for sinonasal cancer.
However this classication has been
debated [SEDA-32, 438].
Excess mortality from lympho-
hemopoietic malignancies, in particular
myeloid leukemia, and brain tumors, has
been found in surveys of anatomists,
pathologists, and funeral workers, all of
whom may have worked with formalde-
hyde. The risk of cancers in the funeral
industry has been investigated by studying
the relation of mortality to work practices
and formaldehyde exposure [5C]. Profes-
sionals employed in the funeral industry
who died between 1960 and 1986 from
lymphohemopoietic malignancies or brain
tumors were compared with deceased
matched controls with regard to work prac-
tices and to estimated levels of formalde-
hyde exposure. Mortality from myeloid
leukemia increased signicantly with
increasing number of years of embalming
and with increasing peak formaldehyde
exposure. These exposures were not
related to other lymphohemopoietic malig-
nancies or to brain cancer.
The biological monitoring of occupa-
tional exposure to formaldehyde is useful
both for investigating genetic damage and
in epidemiological studies of tumorigenic-
ity. To verify the relation between formal-
dehyde human serum albumin conjugate
(FA-HAS), a biological marker of
exposure, and markers of effect, namely
chromosome aberrations, micronuclei, sis-
ter chromatid exchanges, laboratory
workers who had been exposed to high
concentrations of formaldehyde were com-
pared with a reduced exposure group [6C].
There was a signicant relation between
occupational exposure to formaldehyde
and the biological marker of exposure
(FA-HAS). The markers of effect did not
indicate the presence of genetic damage.
Chapter 24 Pam Magee
Glutaral (glutaraldehyde)
Gastrointestinal Ischemic colitis has been
attributed to glutaral [7A].
A 50-year-old woman underwent colonoscopy
and 2 hours later developed pain in the lower
abdomen and left iliac fossa. There was rectal
bleeding and patchy erythema and ulceration
in the upper rectum, and more striking
changes in the distal sigmoid colon, with dif-
fuse inammation and areas of necrosis and
spontaneous bleeding. She was treated symp-
tomatically and recovered over 23 days.
This episode was attributed to inadequate
rinsing after immersion of the endoscope
in a solution of glutaral. Other similar cases
have been reported [8A].
In a review of the medical records of
patients with acute rectocolitis after endos-
copy, seven patients were identied [9c].
All developed a self-limiting syndrome of
abdominal pain and bloody diarrhea within
48 hours of uncomplicated endoscopy.
Glutaral-induced colitis was diagnosed and
attributed to a defect in the procedure for
cleaning the endoscopes.
Skin A 26-year-old applied topical glutaral
to a plantar wart for 5 months and devel-
oped deep ulceration [10A].
BISBIGUANIDES
Chlorhexidine [SED-15, 714;
SEDA-30, 278; SEDA-31, 410; SEDA-32, 439]
Observational studies The use of chlorhex-
idine in bathing patients has been studied in
an evaluation of the effects on the rates of
infections associated with central venous
catheters in patients in coronary care units
[11c]. On one 70-bedded unit all consecu-
tive patients admitted during 9 months
received daily baths with 2% chlorhexidine.
Infections in central venous catheters were
compared with infections before and after
Antiseptic drugs and disinfectants Chapter 24
the intervention period. Despite the limita-
tions of this study, infections were
signicantly less common during the inter-
vention period, and patients tolerated
the chlorhexidine solution well, although
the wound care team observed that about
1% had increased dryness of the skin. This
study also evaluated the effect of the
chlorhexidine bath on the rates of ventila-
tor-associated pneumonia and observed no
change during the pre-intervention and
intervention periods.
Comparative studies In a multicenter ran-
domized controlled comparison of chlor-
hexidine impregnated sponges and
standard dressings in 1653 patients, patients
with a history of allergy to chlorhexidine or
the transparent dressing were excluded
[12C]. The chlorhexidine impregnated
sponges signicantly reduced the rates of
catheter colonization and catheter-related
bloodstream infections. There was severe
contact dermatitis, leading to permanent
removal of the chlorhexidine sponge, in
eight patients (11% of patients and 5.3%
of catheters). There were no systemic
adverse reactions to chlorhexidine. Skin
allergy to the transparent dressing occurred
in two patients. Although the incidence of
skin lesions was low, contact dermatitis will
occur occasionally and requires prompt
removal of the chlorhexidine sponge.
Ventilation-associated pneumonia con-
tinues to be a common and costly complica-
tion of critical care [13c]. It develops after
aspiration of bacteria from the oropharynx
into the lung and subsequent failure of host
defences to clear the bacteria. Dental
plaque biolms are colonized by respira-
tory pathogens in ventilated patients. Thus,
improvements in oral hygiene in these
patients may prevent pneumonia. In a ran-
domized study of the minimum frequency
of application of chlorhexidine gluconate
necessary to reduce oral colonization by
pathogens in 175 intubated patients, decon-
tamination of the oral cavity did not reduce
the total amount of potential respiratory
pathogens. However the chlorhexidine oral
rinse did reduce the number of Staphylo-
coccus aureus organisms in the dental
481
plaque and there was a non-signicant
reduction in pneumonia rates. There was
no evidence of resistance to chlorhexidine
and no adverse effects.
CATIONIC SURFACTANTS
Benzalkonium compounds
[SED-15, 421; SEDA-28, 261;
SEDA-32, 440]
Immunologic In a 31-year-old woman epi-
sodes of ushing, itching, burning and red
eyes, difculty in breathing, and pain after
the use of epinastine eye drops turned out
to be due to benzalkonium chloride as a
preservative [14A].
DYESTUFFS
Triphenylmethane dyes
[SEDA-28, 262]
Triphenylmethane is a hydrocarbon,
(C6H5)3CH, from which synthetic dyestuffs
are derived, including brilliant blue, brilliant
green, bromocresol green, fuchsine, gentian
violet, and malachite green (Figure 1). They
are intensely colored and poorly resistance
to light and chemical bleaches. They have
industrial uses in copying papers and print-
ing inks and in textile applications for which
light-fastness is not important.
Of the triphenylmethane derivatives, gen-
tian violet has been most often used in medi-
cal applications. It is a purple dye, so-called
because its color resembles that of the gentian
ower; it has nothing to do with Gentiana
species. It is a mixture of crystal violet
(hexamethyl-para-rosaniline) 96% and
methyl violet (tetramethyl- and pentamethyl-
para-rosaniline). Methyl violet was rst syn-
thesized by Lauth in 1861 [15E] after Per-
kins discovery of aniline dyes [16R].
Gentian violet has been used in medicine
for over 100 years: as an antiseptic for
482
Triphenylmethane
N Br
Cl
N N+
Gentian violet
Figure 1 Structures of triphenylmethane, malachite green, gentian violet, and bromocresol green.
external use, by local application to treat
oral and vaginal candidiasis and to prepare
the vagina for gynecological operations, as
an antihelminthic agent by oral administra-
tion, as a blood additive to prevent transmis-
sion of Chagas disease [17E, 18E, 19ER,
20ER, 21E] and toxoplasmosis [22E], and in
the management of chronic obstructive par-
otitis [23c]. Although its use is now restricted
in many countries, because of concerns
about its mutagenic and carcinogenic effects,
it remains rst-line medication for oral can-
didiasis in some countries, such as South
Africa. However, in those with HIV/AIDS
it is not preferred, because the visible purple
staining of the mouth leads them to be stig-
matized as HIV-positive. Financial con-
straints have also limited the use of gentian
violet, and lemon juice applied directly in
the mouth or as a lemon juice infusion is
widely used. In a randomized study in 90
patients with oral candidiasis in HIV/AIDS
both lemon juice and lemon grass were more
effective than gentian violet [24c]. Further-
more, because of mucosal staining, adher-
ence to therapy with gentian violet was poor.
Chapter 24 Pam Magee
Cl
+
N N
Malachite green
Br
OH
HO
Br
Br
O
S O
O
Bromocresol green
Brilliant blue has been used to assist inter-
nal limiting membrane peeling during sur-
gery for macular holes and epiretinal
membranes, without adverse reactions [25c,
26c, 27c].
Pararosaniline pamoate has been used in
the treatment of schistosomiasis in the Phil-
ippines in children, and there were few
adverse reactions [28c].
Respiratory Mucosal ulceration and air-
ways obstruction can occur with appli-
cation of gentian violet, and occlusive
laryngotracheitis requiring orotracheal intu-
bation has been reported [29A].
Mucosal lesions consistent with oral candidiasis
developed in a previously healthy, full-term,
exclusively breast-fed, 2-week-old girl. She
was treated with oral nystatin, resulting in an
initial reduction in the severity of the lesions.
After a few days, the thrush became more
prominent. At 4 weeks of age, 1% aqueous
gentian violet was prescribed and the day after
she developed a cough and difculty in feeding.
There was no nasal congestion, fever, or
rhinorrhea. Over the next 7 days her cough
and feeding difculties became progressively
Antiseptic drugs and disinfectants Chapter 24
worse, and she developed a hoarse cry and stri-
dor. Nasal washings for respiratory syncytial
virus were negative. Intravenous uconazole
and ceftriaxone were given for presumed sepsis
and fungal tracheitis. Lateral neck radiographs
showed an absence of air in the cervical tra-
chea. She was intubated with a 3.5 mm oral
endotracheal tube for airway management,
and then had direct laryngoscopy under gen-
eral anesthesia. The supraglottic, glottic, and
subglottic structures were very edematous, but
the vocal cords were mobile. Blood cultures
on the day of admission failed to grow bacteria
or fungi. There were no fungi in the
supraglottic exudate. Nasopharyngeal samples
were negative in viral cultures.
Sensory systems Gentian violet has been
used as a corneal stain; there were only
minor adverse effects in 112 patients and in
40 healthy eyes [30c]. However, corneal
and conjunctival abrasions have been
described [31A], and in one case bilateral
keratoconjunctivitis followed instillation of
a 1% aqueous solution of gentian violet
and was complicated by a secondary uveitis
and Gram-negative conjunctivitis [32A].
Keratoconjunctivitis sicca has also been
described after inadvertent instillation of
gentian violet 1% in both eyes in a 60-year-
old man; in rabbits gentian violet caused
variable thinning of the epithelial lining of
the conjunctivae, with total loss of goblet
cells and subepithelial capillary congestion
with neutrophil inltration [33AE].
Use of a low concentration of gentian vio-
let to stain the anterior lens capsule during
surgery caused no adverse effects [34c].
Hematologic Methemoglobinemia occurred
in a 3-year-old girl after acute ingestion of
malachite green from a commercial aquar-
ium product [35A].
Mouth There have been reports of irritation
in patients who have used gentian violet in
the mouth [36A, 37A, 38A, 39A, 40A, 41r].
Urinary tract Chemical cystitis due to
intravesical installation of gentian violet is
rare. Cases have occurred in adult women
when an undiluted solution was used. Cystitis
has been reported in a child after bladder
483
instillation of diluted gentian violet [42A] and
in a woman after accidental instillation [43A].
A 16-month-old boy developed painful gross
hematuria after a herniorrhaphy. During the
operation, gentian violet solution diluted to
0.1% had been instilled into the bladder to rule
out bladder injury, and hematuria developed
several hours later. There was no pyuria. Ultra-
sonography showed multiseptate structures
resulting from edema and hematoma in the
bladder and bilateral hydronephrosis. The
hematuria responded to intravenous hydration,
and follow-up ultrasonography showed blad-
der wall thickening with resolution of the stric-
tures and less hydronephrosis.
A 32-year-old woman was given gentian violet
to inject into her vagina, but accidentally
injected it into the urethra. Within a few sec-
onds she developed burning pain in the lower
abdomen, followed by urinary frequency and
urgency and dysuria. Cystoscopy showed gross
inammation and edema on the left side of the
bladder with acute ulceration of the overlying
mucosa.
Skin Contact sensitization to brilliant green,
gentian violet, and malachite green has been
described in 11 patients with eczema mainly
on the legs [44c]. There was sensitization to
brilliant green in all 11, with simultaneous
sensitivity to gentian violet in eight and to
malachite green in six; triphenylmethane
and para-rosaniline produced negative reac-
tions. The authors suggested that the proba-
ble determinants of sensitization are the
N(CH3)2 or the N(C2H5)2 moieties in
the para position of the benzene ring struc-
ture and that cross-reactivity is limited to
substances with amino groups substituted
with at least two alkyl groups (see Figure 1).
There are several other anecdotal reports
of contact reactions to gentian violet, particu-
larly in older literature [45A, 46A, 47A], and
to brilliant green [48A]. In one case there
was co-existent nickel sensitivity [49A]. Even
recently, contact dermatitis has been attrib-
uted to gentian violet in a 28-year-old Chinese
woman without a history of allergy [50A].
Necrotic skin lesions have also been
described [51A, 52A, 53A]. Skin necrosis
occurred in a child after the application
of 2% gentian violet to the gluteal fold; the
authors recommended using concentrations
below 1% for the treatment of intertrigo [54A].
484
Musculoskeletal In two patients, injection
of a low concentration of gentian violet into
the glenohumeral joint, in order to visualize
a rotator cuff tear during surgery, resulted in
chondrolysis [55A].
Immunologic An allergic reaction, with
urticaria, edema of the eyelids and lips, and
hypotension, occurred after the use of Patent
Blue Violet dye for lymphangiography
[56A].
Tumorigenicity In the Rosenkranz bacterial
assay gentian violet caused reparable DNA
damage but it was not mutagenic in the
Ames assay [57E]. In experiments in a
DNA polymerase-decient strain of E. coli
the triphenylmethane dyes inhibited growth
in the following order of potency: gentian
violet > crystal violet > malachite green >
methyl violet [58E].
Chronic oral administration of gentian
violet to mice caused a dose-related
increased risk of hepatocellular carcinoma
after 1824 months [59E]. In rats there was
an increased risk of follicular cell adeno-
carcinoma of the thyroid gland and hepato-
cellular adenomas; in females the risk of
mononuclear cell leukemia was also
increased [60E]. However, in another study
in rats there was a reduced incidence of
mononuclear cell leukemia in rats fed mala-
chite green [61E].
The tumorigenic effects of gentian violet
in animals are probably mediated through
a metabolite. It is demethylated in the liver
and is reduced to leukogentian violet by
intestinal microora. Complete demethyla-
tion produces leukopararosaniline, which is
carcinogenic in rats. A free-radical deriva-
tive is also formed in the liver, but its toxicity
is not clear; N-demethylation by peroxidases
and cyclo-oxygenase are other routes of
metabolism [62R].
However, since there is no evidence that
the phenylmethane dyes are carcinogenic in
man, it has been suggested that they are safe
to use [63r].
Chapter 24 Pam Magee
HALOGENS
Hypochlorous acid
Observational studies Hypochlorite is very
unstable, but hypochlorous acid is stable
and is highly microbicidal, active against
bacteria, viruses, and fungi. It has been
used in 30 patients to treat venous leg
ulcers that had not healed with conven-
tional treatment; 10 achieved a 44% ulcer
reduction after 3 weeks [64c]. The other
20 patients were then treated for 12 weeks;
in nine cases there was full healing and in
ve the ulcers were reduced in size by over
60%. All the patients became free of pain.
Adverse effects were not reported.
Sodium hypochlorite [SED-15, 3157;
SEDA-28, 262]
Respiratory Dilute hypochlorite solutions
are currently the most common bleaching
products used in private households around
the world. Acute exposure to chlorine gas,
which is released during the use of hypo-
chlorite, can cause acute respiratory effects.
Furthermore, the low concentrations of
hypochlorite that are used in cleaning can
affect pulmonary function [SEDA-26, 259].
It has been proposed that chloramines,
which are typically released during cleaning
activities when hypochlorite reacts with
organic matter, may be allergens in a form
of irritant-induced asthma. However, hypo-
chlorite is effective as a cleaning agent in
the inactivation of cat and other indoor
allergens.
The association of household use of
hypochlorite with atopic sensitization, aller-
gic disease, and respiratory health status
has been assessed in 3626 participants in
the European Community Respiratory
Health Survey II. Specic serum IgE to
four environmental allergens was available
and all the participants did the cleaning in
their own homes [65C]. The use of
Antiseptic drugs and disinfectants Chapter 24
hypochlorite was associated with less atopic
sensitization. This association was apparent
for specic IgE to both indoor (cat) and
outdoor (grass) allergens and was consis-
tent in various subgroups, including those
without a history of respiratory problems.
There were doseresponse relations for
the frequency of hypochlorite use and sen-
sitization rates. Lower respiratory tract
symptoms, but not allergic symptoms, were
more prevalent among those who used
hypochlorite on four or more days per
week. The use of hypochlorite was not
associated with indoor allergen concentra-
tions. The authors therefore concluded that
people who clean their homes with hypo-
chlorite are less likely to be atopic but are
more likely to have respiratory symptoms.
IODOPHORS [SEDA-15, 1896;
SEDA-30, 279; SEDA-31, 411;
SEDA-32, 440]
Iodine
Although povidone iodine is now more com-
monly used as an antiseptic, iodine has tradi-
tionally been used as a powerful bactericidal
agent. Owing to the problems associated
with the emergence of drug-resistant patho-
gens, new strategies in the design of anti-
microbial agents are investigating the
properties of iodine in novel ways.
An ideal antimicrobial agent should be
non-toxic and possess broad-spectrum
antiviral, antibacterial, and antifungal activ-
ity and exclude resistance. This has led to
the design of a combination agent,
iodinelithiumalpha-dextran [66R]. This
uses the non-specic antimicrobial action
of molecular and ionized iodine and the
systemic immunomodulatory effects of the
polysaccharide complex of iodine and lith-
ium. This new agent has been assessed by
parenteral administration in HIV-infected
patients. The adverse effects of phlebitis of
punctured small veins and subfebrile fever,
485
transient headache, malaise, and sweating
did not lead to withdrawal of therapy. Hep-
atitis was a serious adverse effect and
occurred in 0.11% of subjects with viral
hepatitis.
Polyvinylpyrrolidone (povidone)
and povidone-iodine
Endocrine Hypothyroidism and altered
metabolism of thyroid hormones have been
reported as adverse events in neonates and
children, resulting from the use of antisep-
tics containing povidone-iodine [SED-15,
1896; SEDA-30, 279; SEDA-31, 411;
SEDA-32, 440]. Because of concerns about
possible iodine excess, chlorhexidine-based
antiseptics have replaced povidone-iodine
in some clinical settings. However, this
may not be advantageous for infants and
children who are receiving total parenteral
nutrition (TPN) as iodine is not routinely
added to TPN solutions. Previously, iodine
deciency was considered unlikely in patients
receiving TPN, because of adsorption
from iodine-containing skin disinfectants and
other adventitious sources [67r, 68R].
Immunologic Severe systemic reactions to
povidone-iodine are rare [SEDA-32, 441]
and are more often reported with lavage
or instillation into wounds or body cavities,
although there are individual case reports
of anaphylaxis when povidone-iodine has
been applied vaginally [SEDA-20, 226]
and rectally [69A].
PHENOLIC COMPOUNDS
[SED-15, 2800, SEDA-32, 441]
Pentachlorophenol
Observational studies Pentachlorophenol
is a chlorinated aromatic compound that
has been used extensively as a fungicide.
486
From the 1950s to the late 1980s pentachlo-
rophenol-based fungicides were widely
used in the New Zealand sawmill industry,
and there were persistent claims of long-
term adverse effects on health. In a cross-
sectional study of the surviving members
of a cohort gathered to study mortality in
sawmill workers employed from 1970 to
1990, only 116 of the 293 participants had
been exposed to pentachlorophenol and
all but 10% had low or short-term expo-
sures. However, pentachlorophenol expo-
sure was associated with a number of
physical and neuropsychological health
effects, which persisted long after exposure
had ceased [70c].
Tumorigenicity Pentachlorophenol was rst
registered as a wood preservative in the
USA in 1936, and has also been used in ropes,
paints, adhesives, canvas, insulation, and
brick walls. Use by the general public was
restricted in 1984, and the use of pentachloro-
phenol was limited to industrial areas. In 1990
the International Agency for Research on
Cancer classied pentachlorophenol as a pos-
sible human carcinogen, based on sufcient
information in animal assays but limited data
in humans. More recently, case reports and
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Chapter 24 Pam Magee
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Harding E, Wong KC, Cheng S,
Mannetje A, Ellison-Loschmann L,
Slater T, Shoemack P, Pearce N. Morbidity
in former sawmill workers exposed to
490
pentachlorophenol: a cross-sectional study
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(4): 27181.
[71] Cooper GS, Jones S. Pentachlorophenol
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25 Penicillins, cephalosporins,
other beta-lactam antibiotics,
and tetracyclines
BETA-LACTAM
ANTIBIOTICS [SED-15, 478;
SEDA-30, 280; SEDA-31, 420;
SEDA-32, 447]
CARBAPENEMS [SED-15, 638;
SEDA-30, 246; SEDA-31, 420;
SEDA-32, 448]
Carbapenems and seizures
Like other beta-lactam antibiotics, the carba-
penems can cause seizures, which have been
reported in association with imipenem
cilastatin [1A, 2A, 3A, 4A, 5A, 6A, 7A], dori-
penem [8R, 9R], ertapenem [10R, 11A], and
panipenem [12A].
Mechanisms The mechanisms by which car-
bapenems provoke seizures are unclear. One
mechanism might be competitive inhibition
of the inhibitory neurotransmitter gamma-
aminobutyric acid (GABA), resulting in
reduced suppression of epileptogenic dis-
charges [13R]. Binding of GABA is antago-
nized to various degrees by different
carbapenems, resulting in some cases in ner-
vous system excitation and convulsions [14R].
There may also be interactions with receptors
for excitatory amino acid neurotransmitters,
Side Effects of Drugs, Annual 33
J.K. Aronson (Editor)
ISSN: 0378-6080
DOI: 10.1016/B978-0-444-53741-6.00025-8
# 2011 Elsevier B.V.
Tore Midtvedt
such as a-amino-3-hydroxy-5-methyl-isoxazo-
lepropionate (AMPA) and N-methyl-D-aspar-
tate (NMDA) [15E, 16E].
Animal studies In rabbits imipenem cila-
statin and another carbapenems were
more neurotoxic than benzylpenicillin [17E].
In mice, ataxia and seizures were seen,
with much lower blood concentrations of imi-
penem than cefotaxime or benzylpenicillin
(1900 mg/ml versus 3400 mg/ml and 5800 mg/ml)
[18E]. In mice imipenem also lowered
the convulsive threshold of pentetrazol (penty-
lenetetrazole) more than cefazolin and two
other carbapenems [19E]. In rats, phenytoin
and phenobarbital both suppressed imi-
penem-induced seizures dose dependently,
but only phenobarbital reduced electroenceph-
alographic epileptiform discharges [20E].
In rats imipenem cilastin provoked con-
vulsions dose dependently, with characteristic
electroencephalographic changes [21E].
Audiogenic stimulation did not by itself pro-
voke seizures in untreated rats but did after pre-
treatment with imipenem; however, these
seizures were not accompanied by electroen-
cephalographic changes. The authors proposed
that imipenem-induced seizures involve neuro-
nal networks in the cortex whereas audiogenic
seizures involve networks in the brainstem.
In various types of animals meropenem
[22E] and other carbapenems [23E, 24E] were
less epileptogenic than imipenem. Cilastatin
alone was not proconvulsant, but it increased
the effects of co-administered imipenem.
In dogs, intraventricular injection of imi-
penem, panipenem, and meropenem caused
491
492
seizures, but doripenem had no effect on the
electroencephalogram and behavior [25E].
There was a similar discrepancy between the
doripenem and the other carbapenems in mice
and rats. In in vitro studies, imipenem, merope-
nem, and panipenem inhibited the binding of
muscimol to GABA receptors in mouse brain
homogenates, while doripenem did not.
In addition, doripenem had no effect on the anti-
convulsive action of valproic acid in the pentyle-
netetrazole- or bicuculine-induced convulsive
models.
Frequency Doripenem Doripenem has now
been on the market for about 5 years. Of 263
patients with nosocomial pneumonia 10 had
seizures. In patients with seizure-predisposing
conditions, seizures occurred during treatment
in two of 193 receiving doripenem and in six of
116 receiving imipenem cilastatin [26R].
Ertapenem Ertapenem came on to the market
around 10 years ago. Of 30 patients taking erta-
penem three had seizures [27c]. All had moder-
ate renal insufciency (creatinine clearances
44, 54, and 56 ml/minute) and all had received
intravenous ertapenem 1 g/day. All three had
some kind of nervous system disorder, but only
one had previously had seizures. Two were
given prophylactic antiepileptic drugs.
Imipenem Imipenem is a more common cause
of seizures than other beta-lactam antibiotics,
particularly when high doses are given [28C,
29AR]. Since imipenem cilastatin came on
the market about 25 years ago seizure rates as
high as 6% have been reported, especially
when dosing with respect to renal function is
not carefully monitored and adjusted.
In a review of 1754 patients there was a
similar incidence of seizures with imipenem
cilastatin as with other antibiotic regimens
usually containing another beta-lactam
[30c]. In another study, seven of 21 children
developed seizure activity while receiving
imipenem cilastatin for bacterial meningi-
tis [31c]. However, computer-assisted moni-
toring of imipenem cilastatin dosages in
relation to renal function resulted in a
reduced incidence of seizures [32C].
Of 82 children with various malignancies
who received imipenem cilastatin 143
Chapter 25 Tore Midtvedt
times for neutropenic fever, three had con-
vulsions attributed to the drug [33c].
In a meta-analysis of 37 papers published
between 1984 and 1999 the seizure rate was
1.4% among 6000 adults taking imipenem
cilastatin [34M].
Meropenem In 403 children there was no
meropenem-associated neurotoxicity [35C]
and meropenem was well tolerated in chil-
dren with bacterial meningitis [36C].
In a meta-analysis of studies in more than
5000 patients receiving meropenem and more
than 1880 receiving imipenem cilastatin,
the incidence of drug-related seizures was
0.8% for meropenem and 2.8% for imipenem
cilastatin, despite the fact that patients with
nervous system disorders, including seizures,
were excluded [37M]. A similar low rate of
neurotoxicity with meropenem was observed
in a more recent review [38R].
In summary, a larger dose range of mero-
penem than imipenem appears to be toler-
ated, but when strictly observing known
risk factors for seizure propensity the differ-
ence between the two compounds is very
small [39R, 40R].
Susceptibility factors The proconvulsant
activity of the carbapenems, particularly imi-
penem, has limited their usefulness in patients
at high risk of seizures, such as patients with
nervous system infections, especially meningi-
tis, chronic or acute nervous system damage,
and more generally in patients with compro-
mised renal function and a reduced threshold
for seizure activity. The risk of seizures due to
carbapenems is increased by renal insufciency
[41Ac, 42A] and a previous stroke [43A] and
may be increased by prior intrathecal metho-
trexate therapy [44A] and concomitant treat-
ment with theophylline [45A].
Meropenem reduces plasma valproate con-
centrations, affording two mechanisms for an
increased risk of seizures in patients with epi-
lepsy, epileptogenic effect of meropenem, and
loss of antiepileptic action of valproate [46A,
47A, 48A, 49A, 50A, 51A, 52c]. In 39 patients
who took valproate and meropenem valproate
plasma concentrations fell in all patients within
24 hours by an average of 66% [53A].
Penicillins, cephalosporins, other beta-lactam antibiotics, and tetracyclines
Meropenem
Hematologic Acute intravascular hemolysis,
occurring as a result of drug administration,
is assumed to arise through one of two
mechanisms [54R]. Red cell antibodies can
develop in response to some drugs; recovery
depends on clearance of the autoantibody
from the circulation and can take several
weeks. However, most cases of drug-induced
hemolysis arise through a mechanism in which
the drug acts as a hapten, resulting in comple-
ment-mediated intravascular hemolysis. This
may have been the mechanism in the following
case [55A].
A 64-year-old man with dialysis-dependent renal
insufciency underwent surgery for cecal per-
foration. He had a history of a rash after penicil-
lin. Postoperatively he received cefuroxime,
gentamicin, and metronidazole (doses not
reported) with no adverse reactions. On postop-
erative day 7 he developed peritonitis and septic
shock. A mixture of cephalosporin-resistant bac-
teria was found in his peritoneal uid and he was
given meropenem 1 g bd. After the rst dose the
hemoglobin concentration fell from 8.1 to 5.4 g/dl
over 12 hours. Laboratory tests were consistent
with intravascular hemolysis, including a blood
lm with spherocytes and fragments. During
continuous venovenous hemoltration the
hemoltrate developed a red-brown discolor-
ation. Meropenem was withdrawn and the
hemolysis resolved about 6 hours later.
The authors suggested that the rapid onset
of symptoms, the results of laboratory tests,
and the rapid resolution of symptoms after
withdrawal of meropenem all pointed to a
hapten-mediated mechanism.
CEPHALOSPORINS [SED-15,
688; SEDA-30, 284; SEDA-31, 422;
SEDA-32, 448]
Immunologic Drug-induced hemolytic ane-
mia can be due to many drugs, but is often
not properly diagnosed [56R, 57R], because
when clinicians suspect it they simply with-
draw possible causative agents and switch to
other drugs. Hemolytic anemia in the same
Chapter 25 493
patient due to more than one drug is rare.
However, as second- and third-generation
cephalosporins are often implicated [58R],
this might be of importance if switching from
one cephalosporin to another. One such case
has been reported [59A].
A 49-year-old woman with extensive skin dam-
age after a trafc accident was given cefotiame
for 19 days and then cefoperazone for 15 days
(doses not reported). Her hemoglobin fell to
5.7 g/dl, with a reticulocyte count of 4.8%. She
was given intravenous ceftizoxime 1 g bd and
then intravenous cefoperazone sulbactam
(cefobactam) 1 g tds instead. However, the
hemoglobin did not increase. Ceftizoxime- and
cefobactam-dependent antibodies were found
in her blood. Cephalosporins were withdrawn
and the hemoglobin increased.
The authors proposed that for the prompt
diagnosis of drug-induced hemolytic ane-
mia, tests for all causative drugs should be
conducted by two methods.
Cefotaxime
Biliary tract Inspissated bile syndrome has
been attributed to cefotaxime in a neonate
[60A].
Skin Acute generalized exanthematous pus-
tulosis has been attributed to cefotaxime
after 12 days in a 30-year-old woman and
conrmed by a positive patch test [61A].
Ceftriaxone
Nervous system Encephalopathy with gen-
eralized triphasic waves occurred in a
patient with pre-existing cerebrovascular
disease who was given ceftriaxone for a uri-
nary tract infection [62A].
Hematologic Further cases of hemolytic
anemia have been attributed to ceftriaxone
[63A]. In a 6-year-old girl with sickle cell
disease it resulted in a hemoglobin con-
centration of 0.4 g/dl and extensive
494 Chapter 25 Tore Midtvedt

neurological sequelae; serology conrmed Table 1 An intravenous desensitization protocol

the presence of ceftriaxone antibodies [64A]. for ceftriaxone hypersensitivity

Dose (as intravenous

Biliary tract Biliary pseudolithiasis has Time (minutes) solution) (mg)
been attributed to intravenous ceftriaxone
in a 64-year-old man [65A]. Day 1
0 0.001
20 0.01
Pancreas Acute pancreatitis has been 40 0.1
attributed to ceftriaxone in a Japanese 60 1
adult [66A].
Day 2
0 1
Management of adverse drug reactions 20 5
Desensitization to drugs is increasingly being 40 10
implemented, by the use of initially tiny 60 50
Day 3
doses, gradually increasing to therapeutic
0 100
doses, sometimes over very short periods of 20 250
time [67A; SEDA-30, 416; SEDA-33, 441]. 40 550
Desensitization to ceftriaxone has been
reported in a 60-year-old woman with Lyme Days 430 1000
disease in whom doxycycline treatment had
failed [68A]. After administration of intrave-
nous ceftriaxone 1 g/day for 8 days she devel-
oped a rash on the palms, feet, and neck,
which resolved spontaneously after the infu- MONOBACTAMS AND
sion was stopped. Treatment was re-started MONOCARBAMS [SED-15,
1 day later, and after 8 days she developed 2378; SEDA-30, 286; SEDA-31, 423;
pharyngeal, plantar, and palmar pruritus, a
rash, nausea, and abdominal cramps. SEDA-32, 450]
Because no other drug was suitable she was
desensitized, starting with 0.001 mg and Chemically modied
increasing the dose 10-fold every 20 minutes monobactams and their non-
on the rst day. The full regimen is shown in antimicrobial properties
Table 1; the total dose of 1 g/day was achieved
on day 3, without any adverse reactions, and The monobactams have a single beta-lac-
continued thereafter. tam ring structure. The only clinically used
monobactam is aztreonam. Replacement
Drugdrug interactions Calcium salts The of the 1-sulfonic acids residue in mono-
FDA's warning that calcium-containing bactam with an N-sulphonylated carbonyl
solutions should not be given simultaneously amino moiety yields monocarbams [71R,
with ceftriaxone or within 48 hours of the last 72R]. So far, however, no monocarbam
dose, because of a risk of calcium deposition derivative is on the market, probably
in the lungs and kidneys [69R], has been rein- because their antimicrobial moiety is not
forced in a review, whose authors concluded optimal. Since micro-organisms need iron
that ceftriaxone should be avoided or used in for growth, some siderophore-conjugated
very low doses in neonates, and especially in monocarbams are now under evaluation
those concomitantly receiving intravenous [73E]. It is reasonable to assume that it will
calcium solutions and those with hyperbili- take some time until they are marketed.
rubinemia, and should potentially be One of the many problems not yet solved
restricted in elderly people who are concom- is the in vivo fate of the siderophore itself,
itantly receiving intravenous calcium [70R]. since it may create some new adverse
effects of its own.
Penicillins, cephalosporins, other beta-lactam antibiotics, and tetracyclines
Aztreonam
Immunologic Prospective studies of hyper-
sensitivity reactions have suggested that the
incidence of cross-reactivity between peni-
cillins and carbapenems, judged by skin
tests, is around 1%. It is generally thought
that there is little risk of cross-reactivity
between aztreonam and other beta-lactams
in allergic patients, although ceftazidime
and aztreonam have similar side chains. In
a systematic review of the English-language
literature on the subject of cross-sensitivity
to penicillins, carbapenems, and monobac-
tams, the authors concluded that the use of
aztreonam in a patient with ceftazidime
hypersensitivity may carry an increased risk
of type I reactions and should be undertaken
cautiously [74M]. They also re-emphasized
the importance of obtaining a thorough his-
tory about the previous allergic event.
Drug formulations In February 2010, a
solution of aztreonam for inhalation, for-
mulated with lysine, was approved by the
US FDA for the treatment of respiratory
symptoms in patients with cystic brosis
and infected with Pseudomonas aeruginosa
[75E], a bacterium that has always been dif-
cult to treat with antibiotics, especially
when it grows in biolm, as is the case in
the airways. So far, no new types of adverse
effects have been found [76R]. A key prob-
lem will be the development of resistance
to this new formulation [77R].
Drugdrug interactions Telavancin In a
randomized crossover study in healthy par-
ticipants, telavancin 10 mg/kg did not alter
the pharmacokinetics of intravenous
aztreonam 2 g [78C].
PENICILLINS [SED-15, 2756;
SEDA-30, 286; SEDA-31, 424; SEDA-
32, 450]
Immunologic The JarischHerxheimer re-
action is a series of transient systemic
Chapter 25 495
events, including tachycardia, fever, chills,
arthralgia, and headache; it is common dur-
ing treatment of spirochete infections with
penicillins, but can occur after the use of
other antibiotics and in other infections, such
as toxoplasmosis [79R]. For example, of 1415
cases of tick-borne relapsing fever due to
borreliosis in Iran, 0.8% had a JarischHerx-
heimer reaction during treatment [80c].
During pregnancy 40% or more of women
with syphilis who take penicillin have symp-
toms of a JarischHerxheimer reaction
[81R, 82R]; they can also have uterine con-
tractions, reduced fetal movements, and an
altered fetal heart rate pattern, including
late decelerations. The JarischHerxheimer
reaction was triggered by intrapartum ampi-
cillin in a pregnant woman with undiagnosed
secondary syphilis [83A].
A 24-year-old Hispanic woman developed
uterine contractions at 34 weeks gestation,
having had vaginal ulcers due to herpes infec-
tion during pregnancy. She was given intra-
venous ampicillin 2 g 6-hourly for prevention
of group B streptococcal infection during pre-
term labor, and about 6 hours after the rst
dose began to have fever and chills and a
tachycardia. At the same time, the fetal heart
rate rose from 120 to 150/minute and began
to show late decelerations. Cesarean section
was undertaken, and she delivered a boy
weighing 2.2 kg with Apgar scores of 8 and 9
at 1 and 5 minutes but with respiratory dif-
culties. On the next day a diagnosis of second-
ary syphilis was established, and she was given
one dose of benzathine penicillin G intramus-
cularly. The neonate had congenital syphilis
and was treated with high doses of penicillin
G intravenously for 19 days.
The mechanisms of the JarischHerxheimer
reaction are not known, but some believe that
it occurs as a result of a rapid killing of spiro-
chetes, resulting in an acute inammatory
response caused by release of lipoproteins,
or from an increase in prostaglandins [84A].
Whatever the mechanism(s), the bottom line
in this case is that both the patient and her
son tolerated another beta-lactam antibiotic
when the rst reaction was over.
In another case there was MRI evidence
of cerebral inammation after the use of
penicillin in a patient with tertiary syphilis,
in the absence of systemic symptoms of a
JarischHerxheimer reaction [85A].
496
In one patient with neurosyphilis, demen-
tia, and a JarischHerxheimer reaction after
intravenous penicillin improved with olanza-
pine [86A]. In another similar case a Jarisch-
Herxheimer reaction was accompanied by a
Hoign reaction after the use of high-dose
intravenous penicillin [87A].
Amoxicillin
Teeth The hypothesis that the use of anti-
biotics in early childhood may cause molar
incisor hypomineralization has been tested in
a retrospective study of 141 school children,
23 of whom were affected; the risk was greater
among those who had taken, during the rst
year of life, either amoxicillin (OR 2.06;
95% CI 1.01, 4.17) or erythromycin
(OR 4.14; 95% CI 1.05, 16) than in chil-
dren who had not received treatment [88cE].
In in vitro experiments in mouse E18 teeth,
amoxicillin increased the thickness of the
enamel but not dentine.
Skin The increased risk of a maculopapu-
lar rash after the use of amoxicillin in
patients with infectious mononucleosis has
been illustrated by the case of a 24-year-
old woman who developed such a rash after
a single dose of amoxicillin 500 mg [89A].
Reactivation of human herpesvirus 6 may
also lead to skin reactions, as suggested by
a series of seven cases of amoxicillin-
induced ares in patients with drug reac-
tions with eosinophilia and systemic symp-
toms (DRESS) due to other drugs; in
in vitro studies in a human T lymphoblas-
toid MT4 cell line, amoxicillin increased
replication of human herpesvirus 6 [90cE].
Immunologic The association of an allergic
reaction with angina pectoris (the Kounis
syndrome) has been discussed in the light
of a case in which three episodes of vaso-
spastic angina, two of them related to
amoxicillin, could have been due to other
causes [91A, 92r]. Another case has been
described in a 13-year-old boy, who devel-
oped chest pain 30 minutes after taking an
oral dose of co-amoxiclav [93A].
Chapter 25 Tore Midtvedt
Allergic reactions to penicillins are usually
of classes I and III, but class IV reactions can
also occur, as illustrated by a reaction in a
patient with systemic lupus erythematosus
after the use of amoxicillin [94A].
Ampicillin
Hematologic Ampicillin dose dependently
causes impaired platelet function by both
reversible and irreversible mechanisms
and moderately prolongs the bleeding time
by 6090 seconds. The effect usually takes
24 hours to start. Bleeding time and platelet
function were measured in 15 neonates
(gestation 3341 weeks, weights
17603835 g) who had not been exposed
to maternal beta-lactam antibiotics during
labor and who were given ampicillin
50100 mg/kg every 12 hours [95c]. The rst
dose of ampicillin had no effect, but after
the third (n 5) and fourth (n 4) doses,
bleeding times were prolonged by an aver-
age of 60 (95% CI 37, 83) seconds and
time to platelet aggregation by a non-signif-
icant average of 20 (20, 60) seconds.
Co-amoxiclav and clavulanic acid
Psychiatric An acute psychosis, with visual
hallucinations, persecutory delusions, and
disordered speech, has been attributed to
co-amoxiclav in a 55-year-old woman
[96A, 97A].
Skin A xed drug eruption has been attrib-
uted to co-amoxiclav [98A], as has a linear
IgA bullous eruption [99Ar], acute general-
ized exanthematous pustulosis (AGEP)
[100A], and contact dermatitis [101Ar].
Immunologic Urticaria and angioedema, a
class I reaction, after the use of co-amoxi-
clav in 10 children aged 412 years were
attributed to allergy to clavulanic acid, on
the basis of the IgE response to an oral
challenge and negative skin tests with peni-
cillins [102c].
Penicillins, cephalosporins, other beta-lactam antibiotics, and tetracyclines
Flucloxacillin
Liver The risk of ucloxacillin-associated
cholestatic liver disease has been assessed
in a study of 346 072 rst-time users of u-
cloxacillin, of whom 21 developed chole-
static hepatitis within 145 days after a
prescription; the incidence estimate was
6.1 per 100 000 users (95% CI 3.8, 9.3)
[103C]. In comparison, there were four
cases out of 1 179 360 rst-time users of
penicillin V, an incidence estimate of 0.3
per 100 000 users (95% CI 0.1, 0.9).
Immunologic Acute interstitial nephritis, a
class III reaction, with acute renal failure
has been attributed to ucloxacillin [104A].
Piperacillin tazobactam
Psychiatric Adverse psychiatric effects
have been attributed to piperacillin [105A].
An 87-year-old man who was given piperacil-
lin tazobactam 2 g 250 mg every 12 hours
after hemodialysis developed auditory and
visual hallucinations, bizarre behavior, disori-
entation, and progressive mental confusion
2 hours after the sixth dose. Piperacillin
tazobactam was withdrawn, and he recovered
within 6 hours. The serum piperacillin concen-
tration was 56 mg/l.
Electrolytic balance Severe hypokalemia
secondary to short-term use of piperacillin
tazobactam occurred in a patient with
normal renal function and a normal serum
potassium concentration before antibiotic
therapy; the electrolyte abnormality
resolved after piperacillin tazobactam
had been withdrawn [106A].
Hematologic Cases of penicillin-induced
hemolytic anemia continue to be reported
[107A]. The risk appears to be especially
high in patients with cystic brosis, which
might be explained by the frequent use of
penicillins, including piperacillin, combined
with a hyperimmune state. More cases have
been reported [108A, 109A].
Chapter 25 497
The nature of the interaction of piperacillin
antibodies with erythrocytes has been studied
in the context of six cases of piperacillin-
induced hemolytic anemia [110A]. The
authors suggested that a diagnosis of pipera-
cillin-induced hemolytic anemia should not
be made solely on the reactivity of a patient's
plasma or serum with piperacillin- or pipera-
cillin/tazobactam-coated erythrocytes and
that testing in the presence of piperacillin is
more reliable. Others have made the point
that adequate interpretation of a positive
direct antibody test requires knowledge
of the clinical history, including the drug
history [111A].
Skin Piperacillin and piperacillin tazo-
bactam can cause petechial rashes or pur-
pura by causing thrombocytopenia [112C].
However, a non-thrombocytopenic pete-
chial rash has also been reported [113A].
A 64-year-old African American woman was
given piperacillin tazobactam 2.25 g qds
for 5 days and developed a petechial rash on
the legs; there was no fever, change in bowel
movements, nausea, vomiting, or shortness of
breath. Prothrombin time and partial throm-
boplastin time were normal. A skin biopsy
showed a supercial perivascular mixed der-
matitis with lymphocyte and neutrophil inl-
tration. The rash resolved after 3 days.
The patient fullled all the criteria of the
American Association for Rheumatology
for a diagnosis of a hypersensitivity vasculi-
tis [114R].
Acute generalized exanthematous pustulo-
sis (AGEP) has also been reported [115A].
TETRACYCLINES AND
GLYCYLCYCLINES [SED-15,
3330; SEDA-30, 288; SEDA-31, 419;
SEDA-32, 451]
Tetracyclines and the
environment
Some pharmaceuticals, such as antibiotics,
should be recognized as ubiquitous
persistent environmental contaminants.
498
Antibiotics have been and still are exten-
sively used in animal farms and sh farming
for disease control and sometimes also for
growth promotion. Once administered to
animals or shes, the antibiotic or its metab-
oliteswhich may also have antimicrobial
propertiescan be present in urine and/or
feces and thereby reach the environment.
The use of farm manure and shpond sedi-
ment as organic fertilizers has a long history
in agriculture.
In the history of the use of antibiotics,
some attention has been paid to the spread
of micro-organisms that are resistant to anti-
microbial drugs in this way. Unlike other
environmental pollutants, such as heavy
metals and pesticides, the behavior and fate
of antibiotics in the environment have been
far less well studied. In fact, there is limited
information on the effects of antibiotics on
soil ecosystems. In soil, micro-organisms
and plants have very close functional rela-
tions and constitute a holistic system; there-
fore, any disturbance to the equilibria
among soil micro-organisms and between
micro-organisms and plants may adversely
affect the stability and productivity of soil
ecosystems. In fact, studies of the inuence
of antibiotics on the environment have been
more focused on the spreading of genes that
code for resistance than on the more direct
effects of these compounds on environmen-
tal ecosystems.
However, now the trend is switching to
investigations in which the more direct
impact of antibiotics on soil microbiology
and productivity are being studied, including
some recent reports from China, which is
ranked rst in the world in terms of annual
production of at least two of the most com-
monly used tetracycline derivatives [116R],
and where these compounds are widely
used. For example, Chinese shrimps and
prawns have been banned in Europe and
the USA, because of their high content of
antibiotics, such as tetracyclines [117R],
reecting extensive use of antibiotics that
may have environmental consequences in
China.
A recent Chinese study was designed to
provide better understanding of the inter-
actions among tetracyclines, soil microbes,
Chapter 25 Tore Midtvedt
and plants, with an emphasis on the effects
of tetracyclines on soil microbes and their
environmental fate [118E]. Here I highlight
some of the many interesting results. First,
tetracycline was slowly degraded in soil,
about 30% being degraded after 60 days.
Many factors can affect this degradation,
including temperature and the presence of
tetracycline-degrading microbes in the soil,
but the message is clear: tetracyclines are
slowly degraded. The most serious interac-
tion was that the plant biomass was
adversely affected by tetracyclines, especially
plant roots, with a reduction of 40% com-
pared with controls. Exposure to various
concentrations of tetracycline resulted in sig-
nicant suppression of the growth of wheat
roots and shoots. The authors concluded
that the agricultural use of animal manure
and shpond sediment containing consider-
able amounts of antibiotics may give rise to
ecological risks.
Who canor shouldact? The answer is
simple: regulatory agencies. The time has
come for them to strengthen the rules for
pharmaceutical companies intending to
bring new compounds on the market and
also to scrutinize more closely compounds
that are already in use. Antibiotic-induced
adverse environmental effects are serious
and could be reduced by more adequate
antibiotics policies.
Tetracyclines and glycylcyclines
and their non-antimicrobial
properties [SEDA-32, 451]
Reports of the non-antimicrobial effects of
tetracyclines continue to appear, and the
clinical uses of non-antimicrobial tetra-
cyclines in dermatology have been
highlighted [119R]. In general, when these
drugs are used for non-infectious condi-
tions, adverse reactions seem to be of same
types and frequencies as when they are
used as antimicrobial agents. However, the
adverse effects proles of the chemically
modied tetracyclines have still not been
properly elucidated.
Penicillins, cephalosporins, other beta-lactam antibiotics, and tetracyclines
Doxycycline
Liver Hepatitis has been attributed to
doxycycline in a 37-year-old man with a
strong family history of autoimmune dis-
eases [120A].
Pancreas Pancreatitis has been attributed
to doxycycline in a 75-year-old woman
[121A].
Skin Drug rash with eosinophilia and sys-
temic symptoms (DRESS) is relatively com-
mon in patients taking minocycline, but
seems to be much less so in patients taking
doxycycline. However, a report has
appeared in a 25-year-old woman of Afri-
can origin who had been taking doxycycline
for malaria prophylaxis for 3 weeks [122A].
Sweet's syndrome has been reported in a
41-year-old woman with acne who took
doxycycline for almost 2 weeks [123A].
Immunologic A JarischHerxheimer reac-
tion occurred four times in a 36-year-old
man with Q fever pneumonia after treat-
ment with doxycycline, with an acute rise
in temperature, tachycardia, tachypnea,
hypoxia, hypotension, and temporary dete-
rioration of the chest x-ray; on each occa-
sion the reaction lasted for 6 hours [124A].
Minocycline
Observational studies Tetracyclines, espe-
cially minocycline, inhibit the matrix metal-
loproteinases (MMPs), and this has been
studied in patients with the so-called fragile
X syndrome (MIM 300624), an inherited
form of intellectual disability and autism,
with an estimated prevalence of about 1 in
4000 [125C]. The gene responsible is
located on the X chromosome (Xq27.3)
and is called Fragile X Mental Retarda-
tion-1 (FMR1; MIM 309550) [126E]. Mino-
cycline improved behavioral performance
and reduced anxiety in a FMRI knockout
mouse [127E], and has been studied in an
open trial in 20 patients with the fragile X
syndrome, aged 1332 years [128c]. The
Chapter 25 499
hypothesis was based on the facts that
matrix metalloproteinase activities are
increased in fragile X syndrome, that doxy-
cycline can reduce serum and tissue con-
centrations of MMP-9 (as has been shown,
for example, in women using a levonorges-
trel-releasing subcutaneous implant [129c]),
and that the benets seen in FMR1 knock-
out mice may have come about through a
reduction in excess activity of MMP-9
[130H]. The only treatment-related adverse
effects were diarrhea in three cases and
seroconversion to a positive antinuclear
antibody in another two, both with a 1/80
titer and a nuclear prole. These results
pave the way for the discovery of more spe-
cic inhibitors of human MMP-9, prefera-
bly without antimicrobial activity, rather
than using minocycline in all patients with
the fragile X syndrome.
Cardiovascular In a 63-year-old man with
aortic regurgitation and a 6.0-cm ascending
aortic aneurysm the aortic valve was tricus-
pid and patulous and there was dark discol-
oration of the left ventricular outow tract,
aortic valve leaets, and sinuses of Valsalva
[131A]. Histology showed black granular
pigment in the body of the leaets within
macrophages and in the ground substance
of the leaet. The damage to the aortic
valve was attributed to long-term mino-
cycline therapy.
Respiratory Acute eosinophilic pneumonia
with marked neutrophilia has been attrib-
uted to minocycline [132A, 133Ar].
Nervous system Benign intracranial hyper-
tension has been reported in a 26-year-old
woman who was taking doxycycline for
malaria prophylaxis [134A].
Endocrine Black discoloration of the thy-
roid gland occurred in a 31-year-old woman
who had taken minocycline for 18 months
before presenting with hyperthyroidism
and a palpable thyroid nodule; a concurrent
papillary microcarcinoma was probably
coincidental [135A].
500
Mouth Tetracyclines can stain body tissues,
particularly cartilage and bone and there have
been reports of blue discoloration of a palatal
torus in a 91-year-old woman who had taken
minocycline for 3.5 years [136A] and of
staining over the whole of the palate [137A,
138A]. In one case minocycline-induced pig-
mentation caused a bluish black discoloration
over the medial and lateral aspects of the left
ankle following an avulsion fracture, mimick-
ing persistent ecchymosis [139A].
Liver Autoimmune hepatitis has been
reported in a 20-year-old woman who had
taken minocycline for 1 year [140A], in a
17-year-old-woman who had taken mino-
cycline 50 mg/day and an oral contraceptive
for about 2 years [141A], and in three other
patients [142A].
Skin Skin pigmentation due to minocycline
has been reviewed [143R]. There are three
distinct types:
type Iblue-black/grey pigment on the face in
areas of scarring or inammation associated
with acne; stains for iron and melanin extra-
cellularly and in macrophages in the dermis;
resolves slowly over time;
type IIblue-grey pigment on normal skin on
the shins and forearms; stains for iron and
melanin extracellularly and in macrophages
in the dermis; resolves slowly over time;
type IIIdiffuse muddy-brown discoloration
in areas of sun exposure; shows non-speci-
cally increased melanin in basal keratinocytes
and dermal melanophages staining for mela-
nin only; persists indenitely.
Immunologic An anaphylactic reaction to
minocycline, a rare adverse reaction has
again been reported [144A].
A 56-year-old woman had three episodes of
anaphylaxis during 1 year and within 4 minutes
of an oral challenge with minocycline 50 mg
developed an itching and burning sensation
in her face and forearms, followed by orbital
and lip swelling. Within 10 minutes her symp-
toms had worsened, her heart rate was 55/
minute, respiratory rate 24/minute, and blood
pressure 70/50 mmHg.
The pathogenesis of minocycline-induced
hypersensitivity is unknown. Although it is
not known for certain that minocycline has
Chapter 25 Tore Midtvedt
reactive metabolites, it may generate an imi-
noquinine derivative. Neither tetracyclines
nor doxycycline contain the amino acid
side-chain that has the potential to form
such a metabolite, and therefore hypersensi-
tivity may be specic to minocycline.
A lupus-like syndrome with neutropenia
has been associated with minocycline in an
18-year-old man [145A].
Drug hypersensitivity syndrome has been
attributed to minocycline in a 15-year-old girl
after treatment for acne vulgaris for 4 week;
7 weeks later she developed autoimmune
hyperthyroidism (Graves disease), and
7 months after discontinuing minocycline she
developed autoimmune type 1 diabetes melli-
tus [146A]. She also developed raised titers of
several markers of systemic autoimmune
disease, including antinuclear, anti-Sjgren
syndrome A, and anti-Smith antibodies. The
authors suggested that drug hypersensitivity
syndrome may be associated with other auto-
immune phenomena.
In another case DRESS was accompa-
nied by myocarditis [147A].
Susceptibility factors Genetic A hypersen-
sitivity reaction with marked eosinophilia
occurred in a 62-year-old man with CD30-
positive lymphomatoid papulosis after he
took minocycline 100 mg/day for 3 weeks
[148A]. The authors suggested that he may
have been particularly susceptible because
of a deletion on chromosome 4 (4q12),
resulting in a fusion tyrosine kinase,
FIP1L1/PDGFRA (Fip1-like 1/platelet-
derived growth factor a; MIM 607686),
since there have been reports of the pres-
ence of this fusion gene in patients with
lymphomatoid papulosis who have devel-
oped eosinophilia, because skin inltration
by CD30 cells from lymphomatoid papu-
losis has a Th2 cytokine prole and
produces interleukin 5, which stimulates
eosinophil differentiation and proliferation.
Drugdrug interactions Dapsone Relapse
of toxoplasmic encephalitis in an HIV-
infected patient was attributed to a possible
interaction between dapsone and mino-
cycline [149A].
Penicillins, cephalosporins, other beta-lactam antibiotics, and tetracyclines
Management of adverse drug reactions
Fractional photothermolysis has been used
to treat blue minocycline-associated pig-
mentation of the face [150A].
Tetracycline
Management of adverse effects Teeth dis-
colored from exposure to tetracycline in a
32-year-old Japanese man have been suc-
cessfully bleached using a KTP laser, a type
of neodymium-doped yttrium aluminium
garnet (Nd:YAG) laser [151A].
Tigecycline
Hematologic A 54-year-old woman under-
going hemodialysis developed a severe
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 Natascia Corti, Anne Taegtmeyer, and
26
antibacterial drugs
AMINOGLYCOSIDE
ANTIBIOTICS [SED-15, 118;
SEDA-30, 297; SEDA-31, 427;
SEDA-32, 461]
Sensory systems Auditory and vestibular
function The evidence that ototoxicity due
to aminoglycoside antibiotics is synergistic
with ototoxicity due to noise exposure (as
occurs commonly, for example, on neonatal
intensive care units) has been reviewed
[1R]. The authors concluded that preven-
tion of ototoxic synergy of noise with
aminoglycosides is best achieved by using
non-ototoxic bactericidal drugs and by atten-
uating perceived noise intensity when life-
saving aminoglycoside therapy is required.
Data on the mechanisms of vestibular
toxicity and its development in association
with aminoglycoside exposure have been
extracted from the MEDLINE database
and summarized [2M]. For similarly
designed studies the pooled incidence of
vestibular toxicity was 11% for gentamicin,
7.4% for amikacin, 3.5% for tobramycin,
and 1.1% for netilmicin. The underlying
mechanism appears to be excessive produc-
tion of oxidative free radicals, a time-
dependent mechanism, but not apparently
related to dose or serum concentration.
Side Effects of Drugs, Annual 33
J.K. Aronson (Editor)
ISSN: 0378-6080
DOI: 10.1016/B978-0-444-53741-6.00026-X
# 2011 Elsevier B.V. All rights reserved.
Alexander Imhof
Miscellaneous
The authors concluded that care should be
taken to minimize the duration of exposure
to aminoglycosides, in order to reduce the
risk ototoxicity.
A survey of prescribing practices in 27 cys-
tic brosis units in Australia showed an
increase in the use of once-daily amino-
glycoside dosing and an increase in the
reports of both ototoxicity and renal toxicity
since 1999 (2775% and 1965% respec-
tively) [3c]. Tobramycin was the aminoglyco-
side of choice in all units. Exact details of
these adverse effects were not given.
Electrolyte balance Aminoglycosides cause
uid, electrolyte, and acidbase disorders by
altering renal tubular function in several ways,
leading to hypokalemia and acidosis or alkalo-
sis. Stimulation of the calcium-sensing recep-
tor has been reported to cause a Bartter-like
syndrome (hypokalemic metabolic alkalosis,
hypomagnesemia, hypocalcemia, and normal
serum creatinine concentrations). More
rarely, a proximal renal tubular acidosis
(Fanconi syndrome: non-anion gap meta-
bolic acidosis) can develop. The mechanisms
have been summarized [4R].
Urinary tract In 306 consecutive patients
starting aminoglycoside therapy in an
ITU-independent susceptibility factors for
aminoglycoside-associated nephrotoxicity
were a baseline estimated glomerular ltra-
tion rate (eGFR) under 60 ml/minute/
1.73 m2, diabetes mellitus, treatment with
other nephrotoxic drugs or iodinated con-
trast agents, and hypotension [5C].
509
510 Chapter 26
Amikacin [SED-15, 111; SEDA-31, 427;
SEDA-32, 461]
Sensory systems Vestibular function Mea-
surement of vestibular function in infants
who had received amikacin, using vestibu-
lar evoked myogenic potentials in 28
infants and healthy controls, showed that
the vestibular organ was damaged by ami-
kacin more often than the cochlea (6 versus
0 abnormal ndings) [6c].
Mineral balance Type 5 Bartter-like syn-
drome with severe hypocalcemia has been
attributed to amikacin [7A].
A 39-year-old man with suspected urinary
tract infection received amikacin and after
4 days he developed severe renal tubular dys-
function resulting in refractory hypokalemia,
hypocalcemia, hypomagnesemia, metabolic
alkalosis, and polyuria. This constellation of
biochemical abnormalities mimic Type 5 Bart-
ter's syndrome (activating mutation of the cal-
cium sensing receptor in the thick ascending
loop of Henle and the distal tubule). Labora-
tory values returned to normal 15 days after
discontinuation of amikacin
Urinary tract The prevalence of genta-
micin- and amikacin-induced nephrotoxi-
city has been studied in patients with
normal baseline renal function; eight of 49
patients receiving amikacin developed
nephrotoxicity [8c]. Amikacin-induced
nephrotoxicity did not signicantly depend
on dosing frequency (see also
Gentamicin).
The effect of sex on the development of
aminoglycoside-induced nephrotoxicity has
been studied in men and women receiving
either amikacin or gentamicin. Women
treated with amikacin were much more
likely to develop nephrotoxicity than their
male counterparts (32% versus 6%). How-
ever, the study did not include other sus-
ceptibility factors for nephrotoxicity. Thus
it is not known whether sex is an indepen-
dent susceptibility factor for nephrotoxicity
due to amikacin [9c].
Skin Two children (aged 3 and 6 years)
developed localized lipoatrophy 4 and 2
months respectively after single intramuscular
Natascia Corti, Anne Taegtmeyer, and Alexander Imhof
injections of amikacin [10A]. In both cases
the lipoatrophy showed signs of resolution
with conservative management at follow-up
2 months later.
Susceptibility factors Age In a retrospec-
tive cohort study in 161 children during
the rst day of life, there was a correlation
between lower gestational age and/or birth
weight z score and lower amikacin clear-
ance [11c].
Diagnosis of adverse drug reactions
Urinary N-acetyl-beta-D-glucosaminidase
(NAG) concentrations and lactate de-
hydrogenase and alkaline phosphatase
activities were measured in 32 children
aged 2 months to 2 years treated with ami-
kacin or gentamicin for suspected infections
[12c]. There was a signicant increase in
NAG on day 5 compared with the values
before amikacin treatment (n 18).
Although serum creatinine and urea rose,
there were no signicant differences com-
pared with baseline values. The authors
concluded that urinary NAG is an index
of nephrotoxicity and should be developed
as a single test for the diagnosis and moni-
toring of drug-induced nephrotoxicity.
Gentamicin [SED-15, 1500; SEDA-30,
297; SEDA-31, 427; SEDA-32, 461]
Sensory systems Vision A 75-year-old dia-
betic woman with glaucoma, diabetic reti-
nopathy, and an epiretinal membrane in
the left eye underwent transconjunctival
sutureless 25-gauge vitrectomy of the left
eye and was given subconjunctival genta-
micin sulfate 0.4 mg/ml [13A]. One month
after surgery, when visual acuity had not
recovered, uorescein angiography showed
occlusion of perifoveal capillaries, causing
macular infarction. The authors warned
against using gentamicin when it can gain
access to the inside of the eye, through
thinned sclera or sutureless sclerotomy, as
in the case here.
Miscellaneous antibacterial drugs Chapter 26
Vestibular function Impairment of evoked
vestibulo-ocular reexes (eVOR) in genta-
micin vestibulotoxicity in 12 patients with
gentamicin vestibulotoxicity and 13 healthy
controls suggests that vestibular hair cells,
activated by electrical stimulation, mediate
the eVOR; abnormalities of eVOR, espe-
cially the phasic component, might be a
marker of vestibular injury in gentamicin
vestibulotoxicity [14c].
Mineral balance A 45-year-old woman
developed symptomatic hypocalcemia, with
metabolic alkalosis, hypokalemia, and
hypomagnesemia (Bartter-like syndrome),
several days after a 10-day course of genta-
micin for a urinary tract infection [15A]. Co-
morbidities included ovarian cancer treated
with intraperitoneal cisplatin (in a dose not
thought to cause renal tubular dysfunction).
Recovery took 6 weeks, and sustained high-
dose electrolyte replacement was required
to counteract persistent urinary potassium
and calcium losses. The authors suggested
that a polyvalent toxin of gentamicin
had caused multiple renal tubular
abnormalities.
Urinary tract In a retrospective cross-
sectional study of the incidence of genta-
micin-associated acute kidney damage in
228 patients receiving gentamicin, the
RIFLE criteria were used to stage renal
damage according to serum creatinine con-
centration and urine output pattern using
the following groups: at Risk, Injury,
Failure, Loss, End-stage renal dis- micin has been assessed in a prospective
ease [16c]. The incidence of acute kidney
damage was 24% (any RIFLE category);
18% developed risk, 4.3% developed
injury, 2.4% developed failure, and duration 14 days) and eGFR fell by 8.6%,
none developed end-stage renal disease.
Independent predictors were the number
of gentamicin concentration measurements
over 2 mg/l and higher baseline serum cre-
atinine concentration, but there was no
effect of gentamicin dose. Patients who
developed acute kidney damage had higher
mortality in hospital.
Initial low-dose gentamicin for Staphylo-
coccus aureus bacteremia and endocarditis
and the incidence of a clinically signicant
511
reduction in creatinine clearance have been
studied in 137 patients, based on the results
of a prospective cohort study of safety data
from a randomized, controlled trial in 236
patients from 44 hospitals in four countries
[17C]. They were randomized to either stan-
dard therapy with antistaphylococcal peni-
cillin, or vancomycin plus initial low-dose
gentamicin, or daptomycin monotherapy.
There was a reduced creatinine clearance
in 8% of daptomycin recipients, 22% of
those who received vancomycin plus low-
dose gentamicin, and 25% of those who
received antistaphylococcal penicillin plus
low-dose gentamicin. Independent predic-
tors of a clinically signicant reduction in
creatinine clearance (by 20 ml/minute or
more if the baseline creatinine clearance
was above 50 ml/minute or by 10 ml/minute
or more if the baseline creatinine clearance
was below 50 ml/minute) were age above
64 years and any initial low-dose genta-
micin. On the basis of these ndings, the
authors concluded that initial low-dose
gentamicin as part of therapy for S. aureus
bacteremia and native valve infective endo-
carditis is nephrotoxic and should not be
used routinely. However, concern about
the design of this study has thrown the
validity of these conclusions into question,
as patients not randomized to gentamicin
had in fact received gentamicin before
enrolment [18r]. Also, the study did not
adequately investigate the potential neph-
rotoxic effects of vancomycin.
The severity of nephrotoxicity of genta-
observational cohort study in 373 patients
with infective endocarditis [19C]. Genta-
micin was given to 77% (n 287, median
compared with a 2.3% increase in those
who were not given gentamicin. The reduc-
tion in renal function correlated with the
duration of gentamicin treatment, with a
reduction of 0.55 ml/minute/1.73 m2 in esti-
mated endogenous creatinine clearance per
day of gentamicin treatment. However, renal
impairment during hospitalization was not
related to post-discharge mortality (mean
duration of follow-up 562 days). The authors
concluded that these ndings do not imply
512 Chapter 26
that gentamicin should not be used to treat
infective endocarditis. Patients undergoing
hemodialysis were included in the study (21
in the non-gentamicin group and 10 in the
gentamicin group), although it is not clear
how their data were handled for the purposes
of renal function analysis; they were
excluded from the mortality analysis.
Skin A 74-year-old woman underwent left
knee replacement, which included the
use of gentamicin-loaded bone cement
(Palacos), and developed a spreading pru-
ritic eczematous rash on her left leg 3 days
later [20A]. Subsequent patch tests were
positive to gentamicin.
Immunologic An endotoxin-like reaction
occurred in a 92-year-old man who received
antibiotic prophylaxis with gentamicin
200 mg and teicoplanin before surgery for
a fractured neck of femur [21A]. The
patient was allergic to penicillin. Soon after
uneventful surgery he developed rigors and
hyperthermia (maximum temperature
40 C) requiring active cooling, which the
authors attribute to the single dose of gen-
tamicin. Serum myoglobin concentration
and creatine kinase activity were not
measured.
Drug formulations A patient with an eGFR
of 65 ml/minute/1.73 m2 and multiple co-
morbidities had 120 gentamicin beads
implanted near an infected hip joint during
drainage and irrigation and 10 days later
suddenly developed severe hearing loss
[22A]. The serum gentamicin concentration
was 0.7 mg/l. The beads were changed 4 days
later and a high gentamicin concentration
was again noted. Gentamicin was detectable
for 4 weeks and the concentration was
above 0.5 mg/l for 3 weeks. Ordinarily,
gentamicinpolymethylmethacrylate beads
release gentamicin locally at initially high
concentrations, followed by a period of con-
stant release for up to about 80 days. System-
ically, only extremely low concentrations are
detectable (below 0.1 mg/l), because of a
bloodbone barrier. The authors speculated
that disruption of the barrier and/or
Natascia Corti, Anne Taegtmeyer, and Alexander Imhof
increased blood ow at the site of the wound
had caused altered gentamicin pharmacoki-
netics. However, moderate renal impair-
ment may also have contributed in this case.
In 42 patients who underwent two-stage
revision hip arthroplasty for periprosthetic
infection and were managed with an
interim cement spacer loaded with liquid
gentamicin (480 mg per 10 ml pack of
cement monomer), with or without vanco-
mycin, none had detectable gentamicin in
the blood during the rst week [23c].
Drug overdose After massive gentamicin
overdose in a 14-month-old girl, who
received gentamicin 56 mg/kg for empirical
treatment of fever, the peak serum genta-
micin concentration was 89 mg/l [24A]. She
was treated with 4 hours of hemodialysis
4 hours after the overdose; her renal func-
tion remained stable throughout and there
was no evidence of renal or hearing impair-
ment 3 months later.
Diagnosis of adverse drug reactions
Urinary lipocalin-type prostaglandin D
synthase (L-PGDS) has been used as a bio-
marker for the early phase of gentamicin-
induced renal impairment in a prospective
study in six patients with endocarditis who
were given long-term intravenous genta-
micin plus a beta-lactam/carbapenem anti-
biotic or vancomycin [25c]. Lipocalin-type
prostaglandin D synthase, beta 2 microglobu-
lin, and NAG were measured within 10 days
of the start of therapy and later. Systemic
clearance of gentamicin was reduced by
10% in the late treatment phase compared
to the early phase and urinary excretion of
lipocalin-type prostaglandin D synthase
increased. In contrast there were no signi-
cant changes in the other two markers.
Serum creatinine and eGFR remained
unchanged throughout. The authors pointed
out the limitations of the study, the small
sample size, and lack of controls. The clinical
usefulness of lipocalin-type prostaglandin D
synthase as a biomarker of gentamicin-
induced nephrotoxicity is also limited by
wide interindividual variability.
Miscellaneous antibacterial drugs Chapter 26
Urinary N-acetyl-beta-D-glucosaminidase
(NAG), lactate dehydrogenase, and alka-
line phosphatase activities were measured
in 32 children aged 2 months to 2 years
treated with gentamicin or amikacin for
suspected infections [12c]. All three rose
signicantly on day 5 was found compared.
Serum creatinine and urea also rose, but
there were no signicant differences from
baseline. The authors concluded that uri-
nary NAG activity is an index of nephro-
toxicity and should be developed as a
single test for the diagnosis and monitoring
of drug-induced nephrotoxicity.
Neomycin [SEDA-30, 297; SEDA-32,
462]
Skin Recall dermatitis has been reported
in a 61-year-old man who underwent patch
testing with neomycin; localized allergic
contact dermatitis developed at previous
neomycin-treated sites [26A].
Immunologic A 52-year-old man who had
treated recurrent nasal scabs with a nasal
ointment containing bacitracin, neomycin,
prednisolone, and carrying agents for
10 years had an immediate allergic reaction
to topical nasal neomycin [27A]. On the pre-
vious two occasions on which he had used
the ointment he had developed acute facial
swelling; pruritus of the eyes, nose, ears,
and throat; and generalized urticaria within
3 minutes. Skin prick tests conrmed sensi-
tivity to neomycin sulfate, with negative
responses to tobramycin and gentamicin.
Paromomycin [SEDA-32, 463]
Nervous system Injection site pain was the
most common adverse event (44%) in a
study of intravenous paromomycin given
for 14 or 21 days (n 217 and 112 respec-
tively) for visceral leishmaniasis [28c].
Liver There were grade 2 or greater rises
in alanine aminotransferase activity (>2.5
times the upper limit of the reference
513
range) in 6% and 6.3% of patients treated
with systemic paromomycin 11 mg/kg/day
for 14 and 21 days respectively, and 15%
and 17% rises in aspartate aminotransfer-
ase activity [28C]. However, at baseline
21% and 20% had grade 1 rises in alanine
aminotransferase activity (up to 2.5 times
the upper limit of the reference range).
Four patients with baseline grade 1 hepatic
enzyme rises who received paromomycin
for 14 days developed grade 3 rises
(5.120 times the upper limit of the refer-
ence range), necessitating drug withdrawal.
Tobramycin [SED-15, 3437; SEDA-30,
297; SEDA-31, 428; SEDA-32, 463]
Sensory systems Vestibular function Vesti-
bulotoxicity was assessed in 23 patients with
cystic brosis who had received at least one
dose of systemic tobramycin [29c]. There
was peripheral loss of vestibular function in
30% of patients and central loss in one.
Symptoms of dizziness did not correlate with
objective measures of vestibular loss. The
authors concluded that their results support
vestibular function screening in patients with
cystic brosis during or after tobramycin
exposure, although prospective longitudinal
investigation would be required before a
more specic evidence-based proposal could
be made.
Skin Recurrent transient aquagenic wrin-
kling of the palms has been reported in a
28-year-old woman receiving intravenous
or inhalational tobramycin for management
of cystic brosis [30A]. The palmar eruption
occurred consistently within 12 days of
each dose of tobramycin and typically per-
sisted for 714 days before gradually resolv-
ing. Water exposure severely exacerbated
the eruption, but it persisted in the absence
of exposure. Eruptions were restricted to
the palms. The patient had previously
noted pronounced wrinkling in the absence
of tobramycin, and the authors suspected
an inherent predisposition, exacerbated by
tobramycin.
514 Chapter 26
CHLORAMPHENICOL AND
RELATED DRUGS [SED-15,
706; SEDA-30, 298; SEDA-31, 429;
SEDA-32, 464]
Liver Hepatitis was attributed to conjuncti-
val administration of 0.5% chloramphenicol
eye drops in a 37-year-old male engineer
with conjunctivitis [31A].
FLUOROQUINOLONES
[SED-15, 1396; SEDA-30, 298;
SEDA-31, 429; SEDA-32, 464]
Sensory systems Vision Pharmacovigilance
databases (the National Registry of Drug-
Induced Ocular Side Effects, and databases
of the World Health Organization and the
Food and Drug Administration) have been
interrogated to investigate a possible associ-
ation between diplopia and uoroquino-
lones [32c]. There were 171 cases. The
median time from the start of therapy to
the appearance of the adverse drug reaction
was 9.6 days (range 1 day to 5 months) and
17 subjects had concomitant tendinitis.
There were 53 positive cases of dechallenge
and ve of positive rechallenge. The authors
concluded that according to the World
Health Organization criteria, there is a
possible relation between uoroquinolones
and diplopia. Tendinitis of the extraocular
muscles is a plausible mechanism.
Susceptibility factors Children The evi-
dence for quinolone-induced arthropathy
in children has been reviewed [33R]. Data
from animal studies and case reports,
including tendon-related adverse reactions
seen in adults, support a policy of restrict-
ing the use of uoroquinolones in children
and adolescents. The emergence of uoro-
quinolone-resistant pneumococci is another
reason for restricting their use. The authors
cited statements from the American Acad-
emy of Pediatrics on cases in which
Natascia Corti, Anne Taegtmeyer, and Alexander Imhof
treatment with quinolones in children may
be considered. These are for the treatment
of exacerbations of pulmonary disease in
patients with cystic brosis, complicated
urinary tract infections, enteritis (transmit-
ted by multiresistant Salmonella or Shigella
species), chronic otitis media (caused by
Pseudomonas aeruginosa), prophylaxis of
anthrax, and other severe potentially life-
threatening diseases.
Teratogenicity In a meta-analysis of the
safety of quinolones in the rst trimester
of pregnancy ve studies were included,
representing 984 quinolone exposures, 318
of which were exposures to uoroquino-
lones [34M]. The summary odds ratio was
1.05 (95% CI 0.9, 1.22) for major malfor-
mations, 2.6 (0.36, 19) for stillbirth, 1.15
(0.69, 1.91) for preterm birth, and 0.73
(0.57, 2.2) for low birth weight. The authors
concluded that fears of teratogenicity from
quinolones are not justied.
Drugdrug interactions Warfarin In a
nested casecontrol and casecrossover
study using US Medicaid data, seeking
interactions between warfarin and uoro-
quinolones (ciprooxacin, levooxacin,
gatioxacin), there was an increased risk
of hospitalization for gastrointestinal bleed-
ing in all warfarin users (308 100 warfarin
users and 11 444 warfarin users hospital-
ized with gastrointestinal bleeding) [35M],
but no increased risk in those who took
warfarin with uoroquinolones.
Ciprooxacin [SED-15, 783; SEDA-30,
298; SEDA-31, 429; SEDA-32, 465]
Cardiovascular Long QT syndrome and
torsade de pointes occurred postpartum in
a woman with heart failure who was taking
ciprooxacin for a urinary tract infection.
Other causative factors included hypo-
kalemia and hypomagnesemia [36A]. The
electrolyte disturbances were corrected,
a pacemaker was implanted, and she was
Miscellaneous antibacterial drugs Chapter 26
given propranolol, but the QT interval
remained prolonged at 490 msec.
Nervous system Hemibalismus and altered
mental status occurred in a 59-year-old
patient with cirrhosis who took a prolonged
course of ciprooxacin for a renal abscess
[37A].
Hematologic A 30-year-old man took oral
ciprooxacin 1 g/day for 3 days for a
suspected urinary tract infection and devel-
oped a rapidly fatal hemolytic anemia
and severe thrombocytopenia [38A]. The
authors attributed the hemolysis and
thrombocytopenia to ciprooxacin, but a
non-drug cause could not be ruled, since
hematuria preceded exposure to
ciprooxacin.
A 76-year-old man developed severe
thrombocytopenia after taking ciprooxacin
on two occasions for a community-acquired
pneumonia [39A]. The authors concluded
that ciprooxacin had probably been causa-
tive, since there was improvement on
dechallenge, a positive rechallenge, and
detectable platelet-reactive antibodies
against glycoprotein IIb/IIIa. According to
WHO causality criteria, this constellation
ts the denition of a certain reaction.
Liver A 66-year-old man developed acute
cholestatic hepatitis after receiving intra-
venous ciprooxacin for 3 days for gastro-
enteritis; all other cause of hepatitis were
excluded and alkaline phosphatase and
gamma-glutamyl transferase activities
returned to normal within 3 months of cip-
rooxacin withdrawal [40A].
Skin A 63-year-old man who took ciproox-
acin for a urinary tract infection for 7 days
developed photoinduced acute exanthema-
tous pustulosis after 6 hours of direct sunlight
exposure; withdrawal of the quinolone and
treatment with corticosteroids led to rapid
clinical improvement [41A].
A 66-year-old woman developed Ste-
vensJohnson syndrome, conrmed by skin
biopsy, after taking oral ciprooxacin for
acute pyelonephritis for 10 days [42A]. She
515
was also taking levothyroxine 150 micro-
grams/day and was biochemically hyper-
thyroid. The authors postulated that
excess levothyroxine had caused increased
ciprooxacin concentrations through inhibi-
tion of cytochrome P450 enzymes.
Musculoskeletal Two cases of Achilles ten-
dinitis [43A, 44A] and one case of Achilles
tendon rupture [45A] were reported in
patients who had taken ciprooxacin for
less than a week and another case of Achil-
les tendon rupture 1 week after a 1-week
course of ciprooxacin [46A]. The cases of
Achilles tendon rupture occurred during
exercise and were not preceded by symp-
toms of tendinitis.
Ciprooxacin-induced severe myalgia
necessitating emergency care treatment
with opiate analgesia and a benzodiazepine
occurred within 2 hours of a dose of cipro-
oxacin in a patient who was taking it for
the third time, having had mild myalgia on
the second occasion [47A]. Creatine kinase
activity was not raised and the symptoms
disappeared within 24 hours.
Immunologic Two cases of ciprooxacin-
induced hemorrhagic vasculitis have been
reported in two patients with diabetes and
infected ischemic foot ulcers after treat-
ment with ciprooxacin plus clindamycin
for 4 and 6 days [48A]. The vasculitis
resolved completely 2 weeks after with-
drawal in one case, but progressive infec-
tion and gangrene necessitated below-knee
amputation in the other.
A further two cases of cutaneous vasculi-
tis developed in association with ciprooxa-
cin therapy for 7 and 8 days; the lesions all
regressed on ciprooxacin [49A] withdrawal.
Drug formulations Ciprooxacin extended-
release (Ciprooxacin XR) 1000 mg/day
has been compared with ciprooxacin
500 mg bd in 103 and 109 patients respec-
tively for complicated urinary tract infec-
tions; there were single episodes of
headache, glycosuria, erythema, and raised
gamma-glutamyl transferase activity in the
former [50C].
516 Chapter 26
Drugdrug interactions Clozapine In two
cases ciprooxacin caused a rise in serum
clozapine concentrations to twice the upper
end of the usual target range; one patient
developed rhabdomyolysis [51A]. The
authors recommended avoiding the con-
comitant use of CYP1A2 and CYP3A4
inhibitors, such as ciprooxacin, with cloza-
pine or to monitor serum clozapine concen-
trations and reduce the dose accordingly.
Diclofenac The interaction of ciprooxacin
500 mg with diclofenac 50 mg had been
investigated in a single-dose, two-period,
crossover study in 12 healthy men [52c].
The Cmax of ciprooxacin increased from
2.48 to 3.91 mg/l when it was co-adminis-
tered with diclofenac. The tmax was reduced
from 1.5 to 2.0 hours. There were signi-
cant increases in AUC and half-life and a
signicant reduction in total body clear-
ance. The clinical consequences of this
interaction are unknown. We disagree with
the authors recommendation that this
combination be avoided or continued only
after dosage adjustments, since we do
not believe that the data from this study in
12 healthy men allows such a sweeping
conclusion.
Simvastatin Rhabdomyolysis occurred in a
77-year-old woman taking simvastatin
40 mg/day when she also took ciprooxacin
for a urinary tract infection [53A]. The
symptoms began after the second dose of
ciprooxacin, and 3 days later the creatine
kinase activity was 28 980 U/l. After with-
drawal of ciprooxacin and simvastatin,
the creatine kinase activity returned to nor-
mal within 14 days and functional activity
improved by day 23. The author speculated
that simvastatin toxicity had been caused
by the addition of ciprooxacin, although
the mechanism is unclear, as ciprooxacin
is only a weak inhibitor of CYP3A4, of
which simvastatin is a substrate.
Venlafaxine Inhibition of CYP3A4 by cip-
rooxacin in a 61-year-old man taking
methadone and venlafaxine was thought
to have caused serotonin syndrome after
2 weeks therapy [54A].
Natascia Corti, Anne Taegtmeyer, and Alexander Imhof
Gemioxacin [SED-15, 1487]
Nervous system A 67-year-old woman
became febrile, dysphasic, uncooperative,
and agitated 24 hours after taking a single
dose of gemioxacin 320 mg for a mild
upper respiratory infection [55A]. Electro-
encephalography showed generalized slow-
ing. Her symptoms resolved within 2 days
without denitive treatment. The authors
speculated that she may have had a prodro-
mal convulsive episode and concluded that
gemioxacin had been responsible.
Drugdrug interactions Probenecid The
interaction of gemioxacin with probene-
cid, an inhibitor of renal organic anion
and organic cation transport, has been stud-
ied in 17 healthy volunteers [56c]. Probene-
cid increased plasma concentrations of
gemioxacin, reduced its urinary excretion,
reduced its total clearance by 31%, and
prolonged its half-life from 8.1 to 9.5 hours.
Modelling showed that competitive inhibi-
tion of renal tubular secretion of gemioxa-
cin by probenecid was the most likely
mechanism.
Levooxacin [SED-15, 2047; SEDA-30,
299; SEDA-31, 432; SEDA-32, 467]
Observational studies In a multicenter trial
of levooxacin in 4888 Chinese patients
gastrointestinal disorders occurred in 193
patients (3.9%) and local irritation at the
infusion site in 84 [57C].
Comparative studies In a prospective, dou-
ble-blind, non-inferiority phase 3 trial of
tigecycline versus levooxacin for commu-
nity-acquired pneumonia, the following
adverse events were reported in 212
patients who took levooxacin: headache
in four (1.9%); hypokalemia in eight
(3.8%); leukocytosis and thrombocythemia
in two and four (0.9% and 1.9%); diarrhea,
nausea, and vomiting in 17, 18, and 14 (8,
8.5, and 6.6); and raised aminotransferase
activities in 16 (7.5%) [58C].
Miscellaneous antibacterial drugs Chapter 26
In a phase 3 comparison study of intra-
venous levooxacin with intravenous tige-
cycline, the following adverse events were
reported in 210 patients who took levooxa-
cin: headache in 10 (4.8%); diarrhea, nausea,
and vomiting in 9, 12, and 4 (4.3%, 5.7%,
and 1.9%); anemia and eosinophilia in 7
and 11 (3.3% and 5.2%); raised aminotrans-
ferase activities in 21 (10%); and raised alka-
line phosphatase activity in 3.8%. [59C].
Nervous system A 58-year-old woman who
was taking mirtazapine and metoclopra-
mide started to take levooxacin; 1 day
later she had an episode of loss of con-
sciousness associated with urinary inconti-
nence and on the following day two
tonicclonic seizures [60A]. Levooxacin
and mirtazapine were withdrawn and the
seizure activity stopped. No other cause
for her seizures was found. The authors
concluded that levooxacin is epileptogenic
and had also, by inhibiting CYP1A2,
increased the serum concentrations of mir-
tazapine and metoclopramide, drugs that
also have epileptogenic effects.
A 15-year-old boy developed benign
intracranial hypertension after taking levo-
oxacin for 3 weeks [61A]. Headache, dip-
lopia, and papilledema resolved within
1 week of levooxacin withdrawal.
Psychiatric An 83-year-old man developed
delirium after taking levooxacin for 3 days
for a right lower lobe pneumonia [62A].
The delirium resolved within 2 days of
levooxacin withdrawal. The authors pro-
posed that the underlying mechanism may
be an agonist action at GABA receptors.
Metabolism A 65-year-old woman with
type 2 diabetes, chronic obstructive pulmo-
nary disease, and renal impairment, taking
glipizide [63A], was given intravenous levo-
oxacin 250 mg/day and had several
episodes of severe treatment-refractory
hypoglycemia on the next day, despite with-
drawal of glipizide. Hypoglycemic episodes
(two requiring glucagon in addition to intra-
venous dextrose) continued for 6 days (until
2 days after levooxacin was withdrawn).
Insulin was not suppressed, in keeping with
517
data from animal studies that have shown
that uoroquinolones directly stimulate
insulin secretion from pancreatic beta cells.
The risks of severe hypoglycemia and
hyperglycemia have been studied in patients
taking levooxacin, gatioxacin, ciprooxa-
cin, or azithromycin [64C]. Levooxacin
was associated with a frequency of hypo-
glycemia of 0.19 per 1000 patients and of
hyperglycemia of 0.18 per 1000 patients,
compared with 0.07 and 0.1 respectively
among patients taking azithromycin.
Skin A localized phototoxic reaction and
increased stool frequency occurred in a
63-year-old man with prostate cancer who
had taken two courses of levooxacin dur-
ing the 90 days before radiotherapy [65A].
The low dose of radiation and the lack of
concomitant chemotherapy made a purely
radiation-associated reaction unlikely. The
authors pointed out that photon beam radi-
ation and uoroquinolones can both inhibit
cell growth via free radical production, and
postulated an interaction.
Musculoskeletal A previously healthy 91-
year-old man was given levooxacin for
presumed bacterial pneumonitis and devel-
oped bilateral heel pain within 4 days and
bilateral complete Achilles tendon rupture
after 4 weeks [66A].
In a study of levooxacin plus metronida-
zole in uncomplicated pelvic inammatory
disease there was a single case of myalgia
and Achilles tendonitis among 40 partici-
pants; the symptoms developed 4 days
after treatment began and levooxacin and
metronidazole were withdrawn [67c].
In 117 men who took oral levooxacin
500 mg/day for chronic bacterial prostatitis
there were six cases of musculoskeletal
and connective tissue disorders (5.1%)
[68C].
Immunologic Cutaneous vasculitis has been
reported in a 65-year-old man who took
oral levooxacin and rifampicin for an
epidural abscess [49A]. Palpable purpura
appeared on his skin after 3 days and disap-
peared rapidly when levooxacin was
518 Chapter 26
withdrawn. Histology showed a leukocyto-
clastic small-vessel vasculitis.
Drug-drug interactions Warfarin In a re-
trospective study of 21 patients taking warfa-
rin, levooxacin signicantly increased the
international normalized ratio (INR) [69c].
In some cases there was concomitant renal
failure, which would have raised serum levo-
oxacin concentrations. Three patients had
episodes of bleeding. The authors proposed
that levooxacin had displaced of warfarin
from protein binding sites, reduced in vitamin
K production by gut bacteria, and inhibited
CYP2C9-mediated warfarin metabolism.
They advised careful INR monitoring
when warfarin and levooxacin are co-
administered.
Moxioxacin [SED-15, 2392; SEDA-30,
300; SEDA-31, 434; SEDA-32, 468]
Systematic reviews The adverse effects of
moxioxacin, other uoroquinolones, and
other antibacterial classes have been
compared [70M]. Data were extracted from
published clinical trials, meta-analyses, post-
marketing studies, spontaneous report sys-
tems, and case reports for rare effects
published before March 2009. Global analysis
did not show signicantly more drug-related
adverse effects than with comparators. Ten-
don rupture was infrequent and severe cuta-
neous reactions and allergies were very rare.
Nervous system adverse effects and photo-
toxicity were less common than with other
uoroquinolones. Severe cardiac toxicity
was not reported, although there was a
47 msec prolongation of the QT interval.
Hepatotoxicity was not different from that
observed for other uoroquinolones (exclud-
ing trovaoxacin) and was less frequent
than reported with co-amoxiclav and
telithromycin.
Cardiovascular QT prolongation and tor-
sade de pointes have been reported in a
71-year-old man who received intravenous
moxioxacin for pneumonia [71A]. The
QTc interval, which was 434 msec before
Natascia Corti, Anne Taegtmeyer, and Alexander Imhof
moxioxacin, was prolonged to 565 msec
within hours. He subsequently developed
torsade des pointes, which self-terminated.
After withdrawal of moxioxacin no fur-
ther dysrhythmias occurred and the QTc
interval returned to normal over the next
few days.
The effect of moxioxacin on the QT
interval has been studied in 20 healthy sub-
jects who received either moxioxacin
400 mg (route not specied, although mean
time to maximum concentration was
2.3 hours, implying an oral dose) or placebo
[72c]. A pharmacokineticpharmacodyamic
model estimated a 3.9-msec increase in the
QTc interval for every 1 mg/l increase in
moxioxacin concentration. The mean
peak moxioxacin concentration was
2.24 mg/l. An early increase in QTc interval
reverted almost to baseline values at
56 hours after the dose, and then
increased again and remained above the
predose baseline for up to 48 hours after
the dose. The authors attributed the fall in
QTc interval at 56 hours to artifact.
Gastrointestinal Four patients developed
fatal pseudomembranous colitis after
receiving moxioxacin for pulmonary infec-
tions [73A]. The delay between therapy
with moxioxacin and the development of
Clostridium difcile-associated disease was
526 days. All had signicant co-
morbidities.
Liver In a prospective, randomized, open,
parallel-group, multinational comparison
of sequential intravenous/oral moxioxacin
400 mg/day and sequential intravenous/oral
co-amoxiclav 100 mg/200 mg tds for compli-
cated skin and skin structure infections 406
patients were given moxioxacin, of whom
one had a transient increase in aminotrans-
ferase activity from 35 U/l before treatment
to 448 U/l on day 13 [74c].
Skin Linear immunoglobulin A bullous
dermatosis occurred in a 72-year-old man
who took moxioxacin for 7 days [75A].
Moxioxacin was withdrawn, systemic
steroids were given, and the skin lesions
completely resolved within 3 weeks.
Miscellaneous antibacterial drugs Chapter 26
Acute generalized exanthematous pustu-
losis has been reported after oral moxiox-
acin in a 76-year-old woman [76A].
Moxioxacin-induced drug hypersensitiv-
ity syndrome with features of toxic epidermal
necrolysis has been reported in a 44-year-old
Asian man after he had taken moxioxacin
for 1 week [77A].
Trovaoxacin [SED-15, 46]
Liver Trovaoxacin was withdrawn from
the European market because of liver toxic-
ity and acute liver failure in 1999, but it is
still available under very strong restrictions
in the USA. In experiments in isolated
human hepatocytes trovaoxacin inhibited
expression of hepatic nuclear factor-4a
(HNF-4a), which in turn suppressed the
function of a network of genes that govern
major metabolic processes, lipid and carbo-
hydrate metabolism, and mitochondrial biol-
ogy [78E]. The author concluded that this
is the probable underlying mechanism of
trovaoxacin-induced hepatotoxicity.
GLYCOPEPTIDES [SEDA-30,
435; SEDA-32, 469]
Observational studies In a retrospective
review of medical charts in a Taiwan hospi-
tal, there were 117 patients whose vanco-
mycin treatment had to be stopped
because of drug-induced fever (n 24),
rash (n 77), fever and rash (n 8), or
neutropenia (n 8) [79c]. After treatment
was switched to teicoplanin, only 10%
(112 patients) had a recurrence of the
drug-induced adverse event; four of the
eight patients who had had vancomycin-
induced neutropenia had neutropenia with
teicoplanin.
Systematic reviews In a systematic review
of randomized controlled trials with the
519
primary outcome of all-cause mortality,
teicoplanin caused signicantly fewer
adverse events than vancomycin expressed
as per patient episodes (RR 0.61; 95%
CI 0.50, 0.74) and signicantly less neph-
rotoxicity (RR 0.44; 95% CI 0.32,
0.61); signicantly fewer events required
withdrawal of teicoplanin (RR 0.57;
95% CI 0.33, 0.8) [80M]. Severe nephro-
toxicity requiring hemodialysis and red
man syndrome was reported only with
vancomycin; rashes were not signicantly
different.
Immunologic Vancomycin- and teicoplanin-
induced drug rash with eosinophilia and sys-
temic symptoms (DRESS) was diagnosed in
a 38-year-old woman who had had an emer-
gency aortic valve replacement because of
acute endocarditis [81A]. Vancomycin
500 mg tds had to be withdrawn on day 43
because of rapid-onset neutropenia, and
treatment was continued with rifampicin and
teicoplanin. Severe DRESS with persistent
fever, multiorgan failure, nodal enlargement,
eosinophilia, and upper body erythema
developed and she recovered only after with-
drawal of antibiotics and high-dose intra-
venous glucocorticoid therapy.
Teicoplanin [SED-15, 3305; SEDA-30,
301; SEDA-32, 469]
Skin A 10-year-old girl developed a pig-
mented eruption around the mouth 48 hours
after the start of an infusion of teicoplanin;
she had had a similar episode after teicopla-
nin administration a few years before [82A].
Drug dosage regimens In 36 out-patients
with osteomyelitis and prosthetic infections
who were given teicoplanin either daily or
three times weekly for 60360 days, trough
and peak concentrations were similar in the
two groups and six patients had mild liver
toxicity. The authors conclude that three
times weekly teicoplanin seems a valuable
option [83A].
520 Chapter 26
Telavancin
There have been several reviews of tela-
vancin (Vibativ), which was approved in
November 2009 by the FDA [84R, 85R, 86R,
87R, 88R]. Telavancin is a rapidly bacteri-
cidal lipoglycopeptide, which is active
against Gram-positive organisms, including
meticillin-resistant and vancomycin-resis-
tant S. aureus, multidrug-resistant Streptococ-
cus pneumoniae, and glycopeptide-resistant
enterococci. As telavancin is eliminated
mostly by the kidneys, dosage adjustment in
renal insufciency is needed. The most com-
mon adverse effects are nausea and vomiting.
QT interval prolongation is more common
with telavancin than with comparator agents
and there was renal impairment in trials in
3.1%. Caution is advised when QT interval-
prolonging agents or nephrotoxic drugs are
used concomitantly.
Vancomycin [SED-15, 3593; SEDA-30,
301; SEDA-32, 470]
Respiratory Occupational asthma occurred
in a pharmaceutical employee who worked
for 10 months as a production worker with
vancomycin powder [89A]. After 5 months
he complained of rhinitis, cough, dyspnea,
and chest discomfort. Vancomycin-associ-
ated occupational asthma was diagnosed.
An intradermal test was positive and there
was a signicant increase in histamine
release capacity, but specic IgE or IgG
antibodies were not identied. Direct hista-
mine release by vancomycin was suggested
as the possible mechanism.
Neuromuscular function Neuralgic amyo-
trophy with bilateral shoulder pain and
stiffness developed in a 22-year-old man
with cystic brosis taking vancomycin,
tobramycin, and piperacillin/tazobactam;
the symptoms persisted for 2 months and
recurred when the same antibiotics were
given 8 months later [90A].
Hematologic Possible vancomycin-induced
thrombocytopenia occurred within 15 hours
of treatment with vancomycin in a 61-year-
Natascia Corti, Anne Taegtmeyer, and Alexander Imhof
old man [91A] and vancomycin-dependent
IgG and IgM platelet antibodies were
detected within 7 days in a neonate [92A].
Vancomycin was withdrawn and the plate-
let counts recovered after 410 days.
Urinary tract Treatment with tenofovir in
combination with prolonged administration
of vancomycin caused renal insufciency in
two HIV-positive patients [93A].
In a retrospective cohort study of 80
patients received vancomycin given either
as an intermittent infusion or as a continu-
ous infusion with a similar cumulative dose;
the prevalence of nephrotoxicity was simi-
lar in the two groups (16%) [94c].
When continuous vancomycin in 119
patients was compared with intermittent
administration in 30 patients after elective
cardiac surgery, renal function deteriorated
in 28% and 37% respectively [95c].
Skin Several cases of skin reactions after
vancomycin have been reported. In an 82-
year-old woman with chronic renal insuf-
ciency oral vancomycin 250 mg qds caused
a pruritic rash similar to red man syndrome;
the rash abated after vancomycin with-
drawal and treatment with antihistamines
[96A].
In an elderly woman, who had already
had a maculopapular rash after intravenous
vancomycin in combination with piperacil-
lin/tazobactam and metronidazole, a pru-
ritic rash developed after exposure to oral
vancomycin for C. difcile infection [97A].
A 76-year-old woman with penicillin and
sulfa allergy was given vancomycin for a
pacemaker infection with meticillin-sensi-
tive S. aureus [98A]. On day 4 she devel-
oped a worsening papular rash and a skin
biopsy conrmed a severe leukocytoclastic
necrotizing vasculitis, which resolved 5 days
after vancomycin withdrawal.
A 60-year-old woman with polyarthritis
taking sulfasalazine developed a drug rash
with eosinophilia and systemic symptoms
(DRESS) with acute liver failure after tak-
ing vancomycin for 2 days [99A]. After liver
transplantation and initial recovery, hepati-
tis recurred. Lymphocytes and eosinophils
were detected post-mortem in the
Miscellaneous antibacterial drugs Chapter 26
transplanted liver. The relation between
sulfonamide hypersensitivity and intoler-
ance to vancomycin is unclear; cross reac-
tivity has not been described and
vancomycin is structurally not related to
the sulfonamides.
Immunologic An elderly woman who
received intravenous vancomycin for
endophthalmitis developed oral ulcers,
fever, and a diffuse erythematous body
rash after 1 week. Double-stranded DNA
and antihistone antibodies suggested a
lupus-like syndrome [100A]. The symptoms
improved dramatically after withdrawal of
antibiotics and treatment with oral
prednisone.
Autacoids In an 11-day-old baby red man
syndrome and stridor developed postopera-
tively after intravenous infusion of vanco-
mycin 45 mg (15 mg/kg) [101A].
Drug formulations MRSA bacteremia in a
liver transplant patient did not respond to
generic vancomycin (Vancomycin Abbott),
despite treatment for 10 days in appropri-
ate doses but resolved after switching to
the original product (Vancomycin Lilly)
[102AE]. The generic vancomycin product
had signicantly lower activity against
S. aureus in a neutropenic mouse model,
compared with the original product.
The authors warned that pharmacokinetic
bioequivalence might not predict therapeutic
equivalence in antimicrobials.
Drug administration In two cases gastro-
intestinal disease led to unexpected high
vancomycin concentrations after oral
administration. In a 65-year-old man with
severe colitis and renal insufciency a van-
comycin serum concentration of 50 mg/l
was associated with oral vancomycin 0.5 g
6-hourly [103A]. In another patient with
severe gastrointestinal graft versus host dis-
ease (GVHD) potentially toxic serum con-
centrations were found during treatment
with oral vancomycin [104A]. Monitoring
of vancomycin concentrations should be
considered in patients with impaired gastro-
intestinal mucosa.
521
Drugdrug interactions Furosemide A 77-
year-old woman who was given intravenous
vancomycin 1 g bd and oral furosemide
20 mg/day developed severe hypokalemia
(1.7 mmol/l) with pulseless ventricular tachy-
cardia, necessitating cardioversion [105A].
The potassium concentration remained sta-
ble only after withdrawal of vancomycin.
She had previously taken furosemide
40 mg/day without hypokalemia.
Monitoring therapy A consensus statement
of the American Society of Health-System
Pharmacists (ASHP), the Infectious Dis-
eases Society of America (IDSA), and the
Society of Infectious Diseases Pharmacists
(SIDP) concerning vancomycin monitoring
and dosing recommendations for adult has
been published [106S]. A higher trough van-
comycin serum concentration of 1520 mg/l
is recommended in complicated infections,
such as bacteremia, endocarditis, osteomye-
litis, meningitis, and hospital-acquired pneu-
monias. However, the safety of higher
trough concentrations over a prolonged
period has not been studied and there
are few data suggesting a direct relation
between toxicity and specic serum concen-
trations. Combining vancomycin with other
nephrotoxic drugs (for example aminoglyco-
sides) increases the risk of nephrotoxicity
and would be expected to alter the
concentrationeffect relation. Close moni-
toring of renal function and vancomycin
trough concentrations is recommended with
higher serum vancomycin concentrations.
KETOLIDES [SED-15, 1976;
SEDA-30, 301; SEDA-31, 436;
SEDA-32, 471]
Telithromycin [SEDA-32, 471]
Liver In a retrospective analysis of 42 cases
of hepatotoxicity attributed to telithromycin,
there were four deaths and one liver trans-
plantation; typical clinical features were
short latency (median, 10 days) and abrupt
onset of fever, abdominal pain, and jaundice,
522 Chapter 26
sometimes with ascites, even in cases that
resolved [107c].
Drugdrug interactions Oxycodone In 11
healthy subjects telithromycin clearly
reduced the N-demethylation of oxycodone
to noroxycodone by inhibiting CYP3A4
[108c]. Thus, telithromycin may increase the
risk of opioid adverse effects in patients tak-
ing multiple doses of oxycodone for pain
relief; it may be appropriate to reduce the
dose of oxycodone by 2550%, followed by
readjustment according to clinical response.
LINCOSAMIDES [SED-15, 2063;
SEDA-30, 302; SEDA-31, 437;
SEDA-32, 472]
Clindamycin
Gastrointestinal In a retrospective study in
34 patients who took oral rifampicin
600 mg/day and clindamycin 600 mg/day
for 10 weeks, the most frequent adverse
event was diarrhea [109c].
Observational studies In a retrospective
study in 70 patients with bone and joint
infections, prolonged, continuous, intra-
venous clindamycin therapy (600 mg as a
loading dose infused over 60 minutes,
followed immediately by a continuous
infusion of 3040 mg/kg/day) one patient
developed cytolytic hepatitis and one had
an allergic rash; both resolved after clinda-
mycin withdrawal [110c].
MACROLIDE ANTIBIOTICS
[SED-15, 2183; SEDA-30, 302;
SEDA-31, 437; SEDA-32, 472]
Susceptibility factors Breast-feeding infants
Treatment of infants with macrolides has
been associated with hypertrophic pyloric
stenosis, causing projectile vomiting,
Natascia Corti, Anne Taegtmeyer, and Alexander Imhof
dehydration, electrolyte abnormalities, and
in rare cases death, possibly via an inter-
action of macrolides with gastric motilin
receptors. Large population-based cohorts
have suggested that exposure to macrolides
via breast milk may also be associated with
pyloric stenosis. However, in a prospective
controlled observational study in 55 infants
exposed to macrolide antibiotics in breast
milk compared with 36 infants who were
exposed to amoxicillin, seven of the former
had compared with three of the latter
(OR 1.6; 95% CI 0.38, 6.7) [111c].
The adverse reactions in the infants
exposed to macrolides were rash, diarrhea,
loss of appetite, and somnolence.
Drugdrug interactions Digoxin In a 15-
year, population-based, nested casecontrol
study of the association between hospitali-
zation for digoxin toxicity and recent expo-
sure to individual macrolide antibiotics,
clarithromycin was associated with the
highest risk of digoxin toxicity (adjusted
OR 15; 95% CI 8, 28), whereas there
were much lower risks with erythromycin
(adjusted OR 3.7; 95% CI 1.7, 7.9)
and azithromycin (adjusted OR 3.7;
95% CI 1.1, 13) [112c].
Azithromycin [SED-15, 389; SEDA-30,
302; SEDA-31, 437; SEDA-32, 472]
Cardiovascular Fulminant myocarditis can
rarely result from a hypersensitivity reac-
tion to azithromycin, as in the case of a
48-year-old man [113A].
Respiratory Recurrent alveolar hemor-
rhage was attributed to azithromycin in a
78-year-old man who took azithromycin
for an upper respiratory tract infection
[114A].
Nervous system There are anecdotal
reports of exacerbation of myasthenia gravis
with azithromycin. In a 13-year-old boy
with myasthenia gravis in whom a single
intravenous dose of azithromycin, 500 mg
infused over 1 hour, caused sudden worsen-
ing of motor symptoms necessitating
Miscellaneous antibacterial drugs Chapter 26
endotracheal intubation, the respiratory
weakness and limb power improved within
a few minutes of intravenous calcium gluco-
nate [115A]. Such rapid reversal suggests
that azithromycin probably acts presynapti-
cally, by suppressing acetylcholine release.
Hematologic Although leukopenia is the
one of the most frequent azithromycin-
related laboratory abnormalities in chil-
dren, agranulocytosis has not been reported
in adults. However, an 81-year-old man
who took azithromycin for acute otitis
media developed febrile neutropenia, and
was given granulocyte colony-stimulating
factor and cefepime; his symptoms and neu-
trophil count recovered within 7 days after
azithromycin withdrawal [116A].
Liver Vanishing bile duct syndrome has
been reported in a 62-year-old man who
had had StevensJohnson syndrome
1 month before, after taking azithromycin
500 mg/day for 3 days; liver transplantation
was performed 7 months later [117A].
Drugdrug interactions Statins In a sys-
tematic screening of the World Health
Organization's adverse drug reactions data-
base, 53 cases of rhabdomyolysis with azi-
thromycin and statins were investigated
retrospectively [118c]. Rhabdomyolysis
occurred shortly after initial treatment with
azithromycin in 23% of cases. In 11 patients
an interaction was suggested. With the
exception of one patient, the statins were
prescribed at the recommended daily doses.
Erythromycin [SED-15, 1237; SEDA-
30, 302; SEDA-31, 438; SEDA-32, 474]
Gastrointestinal In 264 (28%) of 942 respon-
dents who took oral erythromycin 1000 mg/
day for 10 days as prophylaxis for pertussis
infection, there were some form adverse
effects, of which the most common involved
gastrointestinal symptoms, for example,
diarrhea (16%), stomach ache (7.5%),
nausea (3.6%), epigastric distress (2.1%), and
abdominal distention (1.8%) [119c].
523
Biliary tract Erythromycin can induce post-
prandial biliary colic [120c].
Clarithromycin [SED-15, 799; SEDA-
30, 302; SEDA-31, 438; SEDA-32, 473]
Comparative studies Clarithromycin and
ciprooxacin have been compared as
third-line drugs added after 2 years of treat-
ment with rifampicin and ethambutol for
pulmonary disease caused by Mycobacte-
rium avium-intracellulare (MAC; n 170),
Mycobacterium malmoense (n 167), and
Mycobacterium xenopi (n 34); an
optional comparison of immunotherapy
with Mycobacterium vaccae versus no
immunotherapy was also performed
[121C]. Progress was monitored annually
during the 2 years of treatment and for
3 years thereafter. If the patient did not
improve by 1 year, the regimen was supple-
mented by the addition of the drug that had
not been used in the original allocation.
The study included 371 patients, of whom
186 received clarithromycin and 185 cipro-
oxacin. Overall, 20% in each group were
unable to tolerate treatment. Ciprooxacin
was associated with more unwanted effects
than clarithromycin (16% versus 9%).
Psychiatric Visual hallucinations associated
with clarithromycin have been reported in
two children who took clarithromycin
in therapeutic dosages; the symptoms
gradually disappeared after clarithromycin
withdrawal [122A].
Mania is an extremely rare psychiatric
adverse drug reaction but has been
reported in a child who took clarithromycin
[123A].
Gastrointestinal In a double-blind, ran-
domized, placebo-controlled study of the
effect of clarithromycin on cardiovascular
events and mortality in patients with
chronic coronary artery disease in 2172
patients who took clarithromycin 500 mg/
day and 2200 who took matching placebo
for 14 days, there was at least one non-
serious adverse event in 40% of the former
524 Chapter 26
compared with 25% of the latter [124C].
Gastrointestinal adverse reactions were
reported 950 times by 697 patients taking
clarithromycin (32%) compared with 485
times by 390 patients taking placebo
(18%). There were no signicant differ-
ences in other non-serious or serious
adverse events during the rst month.
Liver Liver impairment was reported in
patient with systemic sclerosis after con-
comitant administration of bosentan and
clarithromycin [125A], Hoign syndrome in
a patient who took clarithromycin for rosa-
cea [126A], and cholestatic hepatitis in a 64-
year-old patient who took clarithromycin
for Helicobacter pylori eradication [127A].
Musculoskeletal Rhabdomyolysis has been
attributed to clarithromycin without con-
current use of other medications [128A].
Immunologic An anaphylactic reaction
occurred in a child after treatment with
clarithromycin [129A].
Drugdrug interactions Colchicine Rhab-
domyolysis occurred in a 48-year-old Afri-
can-American man with hypertension and
chronic gout, who was taking colchicine
0.6 mg/day and who took clarithromycin
500 mg bd for 3 days for a community-
acquired pneumonia [130A]. The serum ami-
notransferases rose and the serum creatine
kinase activity was 22 996 U/l; the urine con-
tained myoglobin. Withdrawal of colchicine
and clarithromycin resulted in clinical and
biochemical resolution.
Simvastatin Rhabdomyolysis after com-
bined therapy with simvastatin 80 mg/day
and clarithromycin has been recently
reported in two women; they recovered
rapidly, after simvastatin withdrawal
[131A, 132A]. The interacting mechanism
was probably inhibition of CYP3A4; inhibi-
tion of P glycoprotein transport of simva-
statin may also have contributed.
Natascia Corti, Anne Taegtmeyer, and Alexander Imhof
Roxithromycin
Placebo-controlled studies In a double-
blind study, 31 adults with early rheumatoid
arthritis who had not previously received
disease-modifying antirheumatic drugs
were randomized to oral roxithromycin
300 mg/day or placebo for 3 months
[133C]. There were adverse events in 11
who took roxithromycin and seven who
took placebo. The most common adverse
events (>5%) were nausea, abdominal
pain, headache, and dry mouth. There were
no dose-limiting adverse effects. One
patient taking roxithromycin withdrew
because of severe emesis.
NITROFURANTOIN [SED-15,
2542; SEDA-30, 303; SEDA-31, 439;
SEDA-32, 476]
Respiratory Lung disease after long-term
nitrofurantoin therapy has again been
described in [134A, 135A, 136A, 137A]. In two
cases there was bronchiolitis obliterans and
in two cases interstitial lung disease with pneu-
monitis, one with fatal lung brosis. There was
complete or partial resolution of symptoms
after treatment with glucocorticoids.
EIDOS classication:
Extrinsic species Nitrofurantoin
Intrinsic species Cells involved in
allergic reactions (lymphocytes,
eosinophils), broblasts,
pneumocytes
Distribution Lungs
Outcome Fibrosis or inammation
Sequela Nitrofurantoin-induced lung
disease
DoTS classication:
Dose-relation Hypersusceptibility
reaction
Time-course Late
Susceptibility factors Female sex
Miscellaneous antibacterial drugs Chapter 26
Liver Acute toxic hepatitis was associated
with nitrofurantoin for a urinary tract infec-
tion in a pregnant woman at 36 weeks
of gestation [138A]. After induced delivery
because of hypertension, the liver enzymes
normalized only after nitrofurantoin
withdrawal.
Urinary tract Acute renal insufciency due
to granulomatous interstitial nephritis asso-
ciated with long-term prophylactic nitro-
furantoin improved after nitrofurantoin
withdrawal [139A].
Immunologic Hypersensitivity reactions to
nitrofurantoin have been reported.
Diffuse target-shaped lesions of the skin eosin-
ophilia and multiorgan involvement (DRESS)
occurred after 4 days of treatment with nitro-
furantoin for a urinary tract infection in a 77-
year-old woman; she recovered after high-dose
glucocorticoid treatment [140A].
A 57-year-old woman developed a fever after
taking nitrofurantoin for 4 days for a urinary
tract infection. Creatinine, creatine kinase,
and liver enzymes were raised and there was
an eosinophilia; she recovered after nitrofur-
antoin withdrawal [141A].
A 77-year-old woman with a penicillin allergy
had a recurrent fever, malaise, rigor, chills,
and a leukocytosis after several exposures to
nitrofurantoin; no further inammatory
episodes occurred after nitrofurantoin with-
drawal [142A].
OXAZOLIDINONES [SED-15,
2645; SEDA-30, 304; SEDA-31, 439]
Adverse reactions to linezolid have been
reviewed based on data from several phase
II and phase III studies and from prospective
comparative postmarketing studies [143R,
144R]. Trials were restricted to 28 days. With
the continuing emergence of resistant Gram-
positive organisms, against which it is highly
effective, linezolid has been increasingly
used for off-label indications, such as endo-
carditis. These indications necessitate
525
prolonged administration, which predis-
poses to serious adverse events.
Common adverse events in phase III
studies were gastrointestinal complaints
and abnormal liver function tests, which led
to discontinuation in some patients.
Depending on the study and on the time of
administration hematological adverse
events, such as anemia, leukopenia, and
thrombocytopenia, were seen in up to
46%. Pre-existing hematological abnormali-
ties and prolonged treatment are risk factors
for myelosuppression. There have been
more than 40 cases of only partially revers-
ible peripheral neuropathy and fully revers-
ible optic neuropathy, and one case of
reversible Bell's palsy, in most cases with
treatment for more than 28 days. Mitochon-
drial disturbance may be the causative
mechanism. More than 13 cases of lactic aci-
dosis have been reported; the risk is higher
in older patients and during prolonged treat-
ment. Nephrotoxicity has occurred in trials.
Observational studies In a retrospective
study in South Korea of linezolid in combi-
nation with other second-line drugs in 11
patients with intractable multidrug resistant
tuberculosis, nine had serious adverse
events [145c]. Eight patients developed a
peripheral neuropathy in the legs after a
median of 4 months; linezolid was with-
drawn in these cases. Three patients devel-
oped an optic neuropathy, including two
who had a peripheral neuropathy, after a
median of 4 months. Two patients devel-
oped anemia requiring blood transfusion.
Nervous system A 41-year-old patient with
a history of alcohol abuse and heart failure
developed an encephalopathy after taking
linezolid for 2 days, becoming mute and
akinetic and recovering 48 hours after line-
zolid withdrawal [146A].
A 12-year-old girl developed a peripheral
neuropathy after taking linezolid for
4 months for chronic vertebral osteomyeli-
tis, with reduced sensation with painful
burning paresthesia in both legs; there was
526 Chapter 26
nearly complete resolution 10 months after
linezolid withdrawal [147A].
Linezolid-associated seizures occurred in
two patients with a history of epilepsy
[148A, 149A]. One developed recurrent
complex partial seizures, which ended only
after switching linezolid to teicoplanin.
The other, a 45-year-old woman with
intractable seizures, had a signicant rise
in daily seizure frequency and nally almost
constant seizure activity after three doses of
linezolid for a wound infection; 3 days later
her seizures regained their usual frequency
and became more frequent again when
linezolid was restarted.
Sensory systems Vision A patient with
ocular sarcoidosis developed reduced vision
with optic disc hyperemia after long-term
treatment with linezolid for osteomyelitis.
Vision improved and the hyperemia disap-
peared after linezolid withdrawal [150A].
Auditory function Auditory nerve neuropa-
thy in a neonate has been associated with
linezolid [151A]. Although the neonate had
been treated with an aminoglycoside before
switching to linezolid, the authors speculated
that linezolid had been the causative agent.
The hearing loss did not recover and the
baby was assessed for cochlear implants.
Hematologic Anemia has been attributed
to linezolid in two cases. In a patient with
laryngeal cancer the hemoglobin concentra-
tion fell from 12.5 to 5.9 g/dl over 2 months
of linezolid therapy; there were ringed
sideroblasts in the bone marrow and the
hemoglobin slowly increased after linezolid
withdrawal [152A]. A 2-year-old boy with
infective endocarditis took linezolid for
4 weeks and his hemoglobin concentration
fell to 6.5 g/dl with markedly reduced
erythropoiesis; he recovered 19 days after
linezolid withdrawal [153A].
In a retrospective chart review the sus-
ceptibility factors for linezolid-associated
thrombocytopenia were a dose over 22 mg/
kg, a low baseline platelet count, and renal
impairment (creatinine clearance below
30 ml/minute) [154c].
Natascia Corti, Anne Taegtmeyer, and Alexander Imhof
In 33 patients who received linezolid,
creatinine clearance and platelet count
ratio before and after linezolid were line-
arly correlated [155c].
A patient undergoing chronic hemodialy-
sis developed severe thrombocytopenia
after taking linezolid for 7 days; it resolved
after linezolid withdrawal [156A].
Metabolism Four cases of linezolid-associ-
ated lactic acidosis have been described. One
patient developed pancytopenia, deteriorat-
ing renal function, and lactic acidosis (pH
6.93, blood lactate 61 mmol/l) after 34 days;
he recovered fully after switching to imi-
penem [157A]. Two patients with tuberculosis
took linezolid in combination with other anti-
tuberculosis drugs and developed symptom-
atic lactic acidosis [158A, 159A]. One patient
died despite linezolid withdrawal. A renal
transplant recipient developed lactic acidosis
after a short course of linezolid [160A].
Liver Severe hyperbilirubinemia developed
in a patient with decompensated liver cir-
rhosis after linezolid therapy for 5 days;
after linezolid withdrawal the bilirubin con-
tinued to rise, but then gradually improved
over 10 days [161A].
Urinary tract A 21-year-old drug abuser
developed acute interstitial nephritis with a
pruritic maculopapular rash and fever shortly
after starting to take linezolid for osteomyeli-
tis; renal function gradually improved after
8 days of glucocorticoid treatment [162A].
Skin An 88-year-old woman developed a
drug rash with eosinophilia and systemic
symptoms (DRESS), with severe pruritus,
a maculopapular rash, an eosinophilia, liver
enzyme rises, and acute renal insufciency,
after taking linezolid for 7 days; a renal
biopsy showed a tubulointerstitial nephritis
with eosinophils; recovery followed linezo-
lid withdrawal [163A].
A 64-year-old man developed conuent
non-blanching petechiae and purpura over
the entire body after taking linezolid for
9 days for a retroperitoneal abscess; despite
linezolid withdrawal he died [164A].
Miscellaneous antibacterial drugs Chapter 26
Musculoskeletal Creatine kinase activity
rose in a 79-year-old man after switching
from vancomycin to linezolid; only after
linezolid withdrawal did creatine kinase
activity return to baseline [165A].
Drugdrug interactions Linezolid is pri-
marily metabolized by oxidation of the
morpholine ring, resulting in two inactive
ring-opened carboxylic acid metabolites; it
is not metabolized by CYP enzymes and
does not inhibit their activities.
Rifampicin In eight healthy men intrave-
nous rifampicin 600 mg reduced serum line-
zolid concentrations after a single
intravenous dose of 600 mg; after 6 hours,
the concentration was 90% of expected,
after 9 hours, it was 80%, and after
12 hours, it was 65% [166c]. The authors
suggested that this effect might be due to
up-regulation of linezolid intestinal secre-
tion. A similar reduction has been seen in
a critically ill patient who was receiving
linezolid and rifampicin [167A].
The effect of rifampicin on the steady-state
pharmacokinetics of linezolid has also been
evaluated in an open, multiple-dose, cross-
over study in 16 healthy subjects [168cE].
Rifampicin reduced the AUC of linezolid by
32% and the Cmax by 21%, but the tmax and
apparent volume of distribution were unaf-
fected. The apparent oral clearance was
increased and the half-life shortened. Parallel
studies in human hepatocytes showed that
rifampicin increased the metabolism of line-
zolid by about 50% compared with a 19- to
40-fold increase in testosterone metabolism.
These increases were about 50% inhibited
by ketoconazole. Modelling of these data
using Simcyp suggested that rifampicin-induc-
ible drug metabolizing enzymes play a very
minor role in linezolid clearance.
Serotonin reuptake inhibitors Linezolid is a
reversible inhibitor of monoamine oxidase
and can cause drugdrug interactions when
it is combined with monoamine oxidase inhib-
itors, monoamines such as adrenaline and
noradrenaline, tyramine-containing foods,
and other serotonergic agents. Several cases
of serotonin syndrome have been reported
527
with co-administration of serotonin reuptake
inhibitors, including venlafaxine [169A].
Linezolid associated serotonin syndrome
has been reviewed. Combination with an
SSRI increases the risk. Of 29 reports of
serotonin syndrome in the FDA database,
the most common co-medications were
SSRIs, and in 17 published case reports of
serotonin syndrome linezolid was combined
with an SSRI. The time to onset was
<24 hours to 3 weeks and the symptoms
resolved at 15 days.
In a retrospective chart review the inci-
dence of serotonin toxicity in patients taking
linezolid and SSRIs was 3%. No conclusions
about incidence can be drawn from this
small review, but the authors suggested that
the combination of linezolid and an SSRI
should be administered based on an analysis
of the benet to harm balance [170R].
In four other cases linezolid caused sero-
tonin syndrome when it was combined with
serotonergic drugs, such as SSRIs [171A,
172A, 173A], and in one case metoclopra-
mide plus enteral administration of trypto-
phan-rich nutrition [174A].
Sympathomimetic drugs Reversible hyper-
tension has been observed in patients
taking linezolid with sympathomimetic
drugs, such as pseudoephedrine and phenyl-
propanolamine [175c].
POLYMYXINS [SED-15, 2891;
SEDA-31, 441; SEDA-32, 476]
Colistin
Urinary tract The nephrotoxicity of poly-
myxins has been reviewed and is the major
limiting factor in their use [176R]. It has been
speculated that the mechanism is the content
of D-aminobutyric acid and fatty acids, which
increase the permeability of tubular cells and
cause edema, lysis, and tubular necrosis.
Most studies have been observational, with
limited patient numbers (up to 82) and mostly
in patients in ICU given colistimethate
528 Chapter 26
sodium or polymyxin B. These reports show
nephrotoxicity rates of 1555%. There are
higher prevalence rates in older patients, in
patients with pre-existing renal insufciency,
and at higher doses. As other causes might
have caused renal failure in patients in ICU,
the rates of nephrotoxicity associated with
the single polymyxins might be lower.
Intravenous and nebulized colistin in the
treatment of multidrug resistant Gram-nega-
tive infections have been analysed in two ret-
rospective chart reviews of 115 and 121
treatments [177c, 178c]. There was nephrotox-
icity in 8.3% and 14% respectively, and
chronic renal insufciency, diabetes mellitus,
and aminoglycoside use were associated sus-
ceptibility factors. Four patients experienced
neurotoxicity in one study.
In a retrospective study of 66 active sol-
diers without previous renal replacement
therapy receiving colistin mostly intra-
venously, 45% had some degree of renal dys-
function and 21% stopped treatment
because of nephrotoxicity. The authors con-
cluded that the probability of renal toxicity
increases with cumulative dose and duration
of treatment (a fourfold increase with treat-
ment for more than 14 days) [179c].
In a retrospectively assessment of renal
function before and after treatment with
intravenous colistin for Acinetobacter infec-
tion in 54 mainly critically ill patients, there
was a clinically signicant increase in serum
creatinine concentration in six patients, all
of whom had normal renal function at base-
line, but other causes of nephrotoxicity
could not be ruled out; there were no dif-
ferences in patients with pre-existing renal
impairment [180c].
STREPTOGRAMINS [SED-15,
3182; SEDA-28, 285; SEDA-30, 307;
SEDA-31, 442]
Pristinamycin
Immunologic Leukocytoclastic vasculitis
has been reported in association with pristi-
namycin [181A].
Natascia Corti, Anne Taegtmeyer, and Alexander Imhof
SULFONAMIDES,
TRIMETHOPRIM, AND
CO-TRIMOXAZOLE [SED-15,
3216, 3510; SEDA-30, 308; SEDA-31,
442; SEDA-32, 477]
Sulfadiazine
Observational studies The safety of topical
silver sulfadiazine has been reviewed and
the adverse effects of the silver and sulfadi-
azine components discussed [182R]. Aller-
gic reactions with cross-sensitivity to
antibiotic sulfonamides can occur, but there
have been no reports of severe allergic
reactions. Hemolytic anemia in G6PD-de-
cient patients can occur. Methemoglobine-
mia occurred in a 3-year-old child with
burns and a dominant beta thalassemia trait
treated with silver sulfadiazine.
Urinary tract Bilateral ank pain and pro-
gressive oliguria developed over 3 weeks
in a 47-year-old woman who took sulfadia-
zine for toxoplasmosis retinitis [183A]. Only
in a second CT scan (an unenhanced helical
scan with very low attenuation for stones)
was urolithiasis detected; sulfonamide crys-
tals were found in the urine.
Trimethoprim and co-trimoxazole
Nervous system An 82-year-old man devel-
oped a higher level gait disorder and noc-
turnal delirium after taking co-trimoxazole
(trimethoprim 800 mg sulfamethoxazole
160 mg bd) for 37 day; 3 days after co-
trimoxazole withdrawal his gait returned
to normal [184A].
Liver The treatment of Pneumocystis jiro-
vecii pneumonia remains a challenge in
HIV-infected individuals. The drug of
choice in severe cases, co-trimoxazole, must
be given in high doses for effective out-
comes. Adverse effects such as hepatotoxic-
ity, rash, anemia, thrombocytopenia, and
neutropenia are therefore common and a
hindrance to successful therapy. Two
Miscellaneous antibacterial drugs Chapter 26
patients developed liver toxicity and focal
lesions mimicking liver abscesses [185A].
Urinary tract Acute allograft dysfunction,
with features of allergic acute interstitial
nephritis, occurred in 11 renal transplant
patients who were taking co-trimoxazole
for prophylaxis of Pneumocystis pneumo-
nia. All occurred within 1 month after
transplantation, and renal function
improved immediately after co-trimoxazole
withdrawal [186A].
Skin Sweet's syndrome has been attributed
to co-trimoxazole in two cases. A 67-year-
old man with mesothelioma and an
empyema developed tender erythematous
nodules on his arms, hands, and face, with
arthralgia after taking co-trimoxazole for
1 day; a skin biopsy showed neutrophilic
inltrates and the symptoms resolved
48 hours after withdrawal [187A]. A 7-
year-old boy developed diffuse painful
papulonecrotic lesions after taking co-tri-
moxazole for a gastrointestinal infection;
histology showed a neutrophilic inltrate
without vasculitis; systemic glucocorticoid
and antibiotic therapy led to complete heal-
ing [188A].
Erythrodermic psoriasis, a severe dis-
abling variant of psoriasis, which most com-
monly evolves from pre-existing chronic
plaque-type psoriasis, has been associated
with co-trimoxazole [189A].
Other reported skin reactions include a
xed drug eruption in a 47-year-old man
[190A] and a case of StevensJohnson syn-
drome and toxic epidermal necrolysis [191A].
In a retrospective chart review of 50
patients with StevensJohnson syndrome
and toxic epidermal necrolysis, co-trimoxa-
zole was the most commonly implicated
medication (26%); there was seasonal vari-
ation, with a signicant increase in the
number of cases during the spring [192A].
Immunologic A 23-year-old patient with
lupus nephritis had recurrent fever, throm-
bocytopenia, anaphylaxis, and aseptic men-
ingitis after taking co-trimoxazole for
prophylaxis of Pneumocystis pneumonia
[193A].
529
Drugdrug interactions Emtricitabine In
rats trimethoprim reduced the renal clear-
ance of emtricitabine by 60%, and
increased emtricitabine plasma concentra-
tions would be expected when these
compounds are co-administered [194E].
Paliperidone There was no clinically signif-
icant pharmacokinetic interaction of co-tri-
moxazole, an inhibitor of organic cation
transport, and paliperidone, which is an
organic cation that is mainly eliminated by
renal excretion; paliperidone did not affect
steady-state plasma concentrations of
trimethoprim [195c].
Prednisolone In 30 patients with P. jirovecii
pneumonia, there was a higher incidence of
hyperkalemia when co-trimoxazole was
combined with prednisolone (in 7 of 18
patients) compared with co-trimoxazole
alone (none of 12 patients). Although the
authors concluded that hyperkalemia is
more likely when co-trimoxazole is com-
bined with prednisolone, the data have to
be interpreted with caution, because of the
small number of patients studied and
the observational design of the study [196c].
Warfarin In 22 of 40 chronically anticoagu-
lated patients taking either co-trimoxazole
or levooxacin the INR rose signicantly
after 5 days, leading to transient interrup-
tion of warfarin therapy in 12 patients
[197c]. The effect was more pronounced in
those who took co-trimoxazole. In 18
patients in whom the dosage of warfarin
was pre-emptively reduced the INR did
not change signicantly.
OTHER ANTIMICROBIAL
DRUGS
Daptomycin [SED-15, 1053; SEDA-30,
309; SEDA-31, 446; SEDA-32, 478]
Respiratory After a 14-day course of dapto-
mycin for methicillin-resistant S. aureus a
54-year-old man developed a fever and
530 Chapter 26
dry cough. He had a raised white blood cell
count and an eosinophilia [198A]. A CT
scan showed patchy inltrates and periph-
eral opacities. Over the next 24 hours he
developed respiratory failure and needed
intubation. A lung biopsy showed a diffuse
eosinophilic pneumonia. Daptomycin was
withdrawn and he was given a tapering
dose of a glucocorticoid. He recovered fully
within a few days, with complete resolution
of the radiographic ndings within 4 weeks.
Musculoskeletal Rhabdomyolysis and acute
renal failure have been associated with dap-
tomycin 7.2 mg/kg/day in a patient taking
simvastatin 80 mg/day [199A]. After 16 days
creatine kinase activity rose to 8995 IU/l
and there was weakness and diffuse aching
in the forearms, with deterioration of renal
function. Daptomycin was switched to line-
zolid and ciprooxacin and the creatine
kinase activity normalized.
Drug dosage regimens The pharmacokinet-
ics of daptomycin 4 or 6 mg/kg intravenously
as a 2-minute injection were comparable
to those after a 30-minute infusion [200c].
The adverse effects of high-dose dapto-
mycin (mean 8, range 711, mg/kg) have been
assessed in a retrospective chart review in
patients receiving long-term treatment (mean
14, range 1482 days) for complicated and
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 Dominik Schrey, Thomas J. Walsh, and
27
ALLYLAMINES [SEDA-30, 316;
SEDA-31, 457; SEDA-32, 491]
Terbinane [SED-15, 3316; SEDA-30,
316; SEDA-31, 457; SEDA-32, 491]
Nervous system Bilateral anterior optic
neuropathy has been reported in an other-
wise healthy 43-year-old man who took ter-
binane 500 mg/day for onychomycosis
[1A]. Terbinane was withdrawn and his
visual acuity improved considerably within
1 month, but there was slight pallor of the
left optic disc and the visual elds of both
eyes were still concentrically constricted.
One plausible explanation for this effect of
terbinane may be that it is amphiphilic,
which may allow binding to polar lipids
and accumulation within lysosomes. Drug-
induced lysosomal impairment has been
presumed to be the basis of the retinal
changes observed with other amphiphilic
drugs, such as amiodarone, perhexilene,
and suramin.
Skin In a retrospective cohort study of ter-
binane 250 mg/day for cutaneous sporo-
trichosis in 50 patients in whom
itraconazole was contraindicated or resulted
in severe or moderate pharmacological inter-
actions, 47 had co-morbiditieshigh blood
pressure (30), diabetes mellitus (14), dyslipi-
demia (8), depression (5), and migraine, Par-
kinson's disease, peptic ulcer disease, heart
Side Effects of Drugs, Annual 33
J.K. Aronson (Editor)
ISSN: 0378-6080
DOI: 10.1016/B978-0-444-53741-6.00027-1
# 2011 Elsevier B.V. All rights reserved.
Andreas H. Groll
Antifungal drugs
failure, and dysrhythmias (one each) [2c].
Terbinane was withdrawn because of a rash
in one patient. There were no recurrences of
the mycosis during a mean follow-up period
of 37 weeks.
A further case of acute generalized exan-
thematous pustulosis associated with oral ter-
binane has been reported; it was refractory
to oral glucocorticoids but responsive to
high-dose intravenous glucocorticoids [3A].
Terbinane has been associated with a
cutaneous lupus-like syndrome [4A].
Susceptibility factors Children A new pedi-
atric formulation of terbinane hydro-
chloride oral granules 58 mg/kg/day
(n 1040) has been compared with griseo-
fulvin oral suspension 1020 mg/kg/day
(n 509) for 6 weeks in the treatment of
tinea capitis in children aged 412 years
[5c]. Rates of complete cure and mycologi-
cal cure were signicantly higher with terbi-
nane (45% versus 39% and 62% versus
56% respectively). About half of the
patients in each group reported an adverse
event, almost all mild or moderate in inten-
sity. Nasopharyngitis, headache, and pyrexia
were the most common events in both
groups. There were no drug-related serious
adverse events, no deaths, and no signicant
effects on weight or laboratory measure-
ments, including aminotransferases.
Drugdrug interactions Acenocoumarol A
possible interaction of topical terbinane
with acenocoumarol has been reported in a
71-year-old man who took acenocoumarol
13 mg/week for atrial brillation and used
topical terbinane 1% spray solution
once daily for seborrheic dermatitis [6A].
541
542 Chapter 27 Dominik Schrey, Thomas J. Walsh, and Andreas H. Groll
Other medications included diltiazem 60 mg
bd, lansoprazole 30 mg bd, atorvastatin
20 mg/day, and metformin 850 mg tds. The
international normalized ratio (INR) had
been 2.03.0, but after using terbinane for
15 days his INR rose to greater than 8. Ace-
nocoumarol and terbinane were stopped
and he was given a single dose of phytona-
dione 10 mg and then bemiparin 5000 IU/
day. After 6 days, acenocoumarol 13 mg/
week was reintroduced and therapy was
stable thereafter. Topical terbinane could
have displaced acenocoumarol from
plasma protein-binding sites. Alternatively,
although acenocoumarol is mainly metabo-
lized by CYP2C9, other isoenzymes could
also be involved; terbinane is a potent com-
petitive inhibitor of CYP2D6. Finally, terbi-
nane could have inhibited the clearance of
diltiazem, which is metabolized by CYP2D6
and itself inhibits CYP3A4, by which aceno-
coumarol is weakly metabolized.
AMPHOTERICIN [SED-15, 192;
SEDA-30, 317; SEDA-31, 458; SEDA-
32, 493]
Amphotericin B colloidal
dispersion (ABCD)
Observational studies In clinical trials, in
the absence of premedication, the rates of
infusion-related reactions have been higher
with amphotericin B colloidal dispersion
(ABCD) than with other forms of ampho-
tericin B, including amphotericin B deoxy-
cholate [7R]. Data on pre-medication
practices and infusion-related reactions in
170 patients (median age 37 years; 52%
men) who received 1230 infusions of ABCD
(mean dose 2.8 mg/kg/day) have been cap-
tured in a multicenter, worldwide, observa-
tional registry [8c]. Treatment was
according to the site's standard treatment
practice. Common pre-medications included
glucocorticoids, antihistamines, paracetamol
(acetaminophen), and metamizole. The
overall rate of infusion-related reactions
was 12% (147/1230) and was lower in infu-
sions with premedication (11%) versus no
premedication (22%); glucocorticoids were
also associated with a lower incidence, but
paracetamol and antihistamines were not.
The most common infusion-related reac-
tions were chills (7%), fever (7%), and rigors
(5%).
Amphotericin B deoxycholate
(DAMB)
Comparative studies Amphotericin B deoxy-
cholate (DAMB) is still a cornerstone in
the treatment of cryptococcal meningoen-
cephalitis, alone or in combination with
ucytosine or uconazole. In a randomized
comparison, 64 HIV-positive, antiretroviral
therapy-naive patients in Cape Town, with
a rst episode of cryptococcal meningitis,
received either DAMB 0.7 mg/kg/day plus
ucytosine 25 mg/kg qds (n 30), or
DAMB 1 mg/kg/day plus ucytosine
25 mg/kg qds (n 34) [9C]. Regimens were
given for 2 weeks, followed by oral ucona-
zole. The frequency of renal impairment
did not differ between the groups. Anemia
was associated with female sex and less
strongly with the higher dose of DAMB.
Renal impairment and anemia reversed
after the regimen was switched to ucona-
zole. Two- and 10-week mortality rates
were 6% and 24% respectively, with no dif-
ference between the groups. All the adverse
reactions were manageable and reversible.
In a randomized, open, phase II trial in
Thailand and the USA, DAMB 0.7 mg/kg/
day (standard therapy) was compared with
DAMB 0.7 mg/kg/day plus uconazole
400 mg/day (low-dosage combination ther-
apy), or DAMB 0.7 mg/kg/day plus ucona-
zole 800 mg/day (high-dosage combination
therapy) in 143 HIV-positive patients [10c].
All regimens were given daily for 14 days,
followed by uconazole alone in the ran-
domized dosage (400 or 800 mg/day) for 56
days. There were no differences in treat-
ment-related adverse events among the
three arms. Adverse effects were predictable
and most often related to DAMB; they
Antifungal drugs Chapter 27
included electrolyte abnormalities, anemia,
nephrotoxicity, and infusion-related events.
Susceptibility factors Neonates The neph-
rotoxicity of DAMB in neonates has not
been well dened. In a retrospective,
single-center, cohort study, the medical
records of 92 infants aged up to 90 days,
admitted to the neonatal intensive care
unit, who received at least three doses of
DAMB between January 1990 and Decem-
ber 2004 were reviewed [11c]. Nephrotoxi-
city was dened as a rise in serum
creatinine of at least 35 mmol/l any time
during DAMB therapy. Median gestational
age of the infants was 26 (range 2341)
weeks and median birth weight was 863
(range 5464000) g. Overall, 15 infants
had nephrotoxicity, and 16 developed
hypokalemia (below 3.0 mmol/l). Gesta-
tional age, birth weight, sex, underlying
medical conditions, or the use of other
potentially nephrotoxic medications all
had no apparent effect on the risk of neph-
rotoxicity. DAMB exposure and duration
of therapy were similar between the infants
who developed nephrotoxicity and those
who did not, with a mean cumulative dose
of 14 mg/kg and a mean duration of 16 days.
With the exception of one infant, the raised
creatinine concentrations resolved in all
infants by the end of DAMB therapy. The
authors concluded that DAMB does not
appear to be associated with lasting nephro-
toxicity in neonates, although renal function
and potassium concentrations should be
monitored closely during therapy.
Amphotericin B Lipid Complex
(ABLC)
Susceptibility factors Neonates In a retro-
spective, single-center, casecontrol study
in 35 infants of very low birth weights
(mean 764 g) who received ABLC for at
least 2 weeks, and 35 controls matched by
gestational age (mean 26 weeks), ABLC
had no signicant adverse effects on serum
543
creatinine, blood urea nitrogen, sodium, or
potassium [12c].
Drug administration route Aerosol In a
retrospective analysis of 60 patients with
lung transplants, who were given aerosol-
ized ABLC 50 mg postoperatively for pro-
phylaxis once every 2 days for 2 weeks
and then once a week for at least 13 weeks,
only one patient developed a possible inva-
sive fungal infection due to Aspergillus
fumigatus; four had nausea and vomiting,
but aerosolized amphotericin was not dis-
continued [13c].
Management of adverse reactions Ad-
ministration of amphotericin B lipid com-
plex (ABLC) may be associated with
infusion-related reactions, such as fever,
rigors, and chills. Premedication with
hydrocortisone may reduce the incidence
of these reactions, but there are currently
limited conrmatory data from clinical
practice [7R]. In a prospective 18-month
study, patients with cancers were given
intravenous hydrocortisone 100 mg
1530 minutes before each infusion of
ABLC (275 cycles; mean dose per cycle
931 mg) [14c]. There were 44 infusion-
related reactions (16%), most of which fol-
lowed the rst infusion of a cycle (15%;
subsequent infusions 2.9%). The most com-
mon reactions were rigors (15%) and fever
(13). There was no signicant difference
in the rates or types of reactions be-
tween ABLC-nave and previously treated
patients. The dose of ABLC had no effect
on the rate of reactions, but female sex, neu-
tropenia, and being younger were predictive.
Liposomal Amphotericin
(L-AmB)
Observational studies In a retrospective,
multicenter study of the use of LAMB in
179 patients admitted to 30 Spanish inten-
sive Care Units, in which invasive fungal
infections were proven, probable, and
544 Chapter 27 Dominik Schrey, Thomas J. Walsh, and Andreas H. Groll
possible in 44%, 16%, and 25% of cases
respectively, the mean duration of treat-
ment was 15 days and the mean dose was
3.7 mg/kg/day [15c]. LAMB was used as
rescue treatment in 47% of patients and
as rst line in 52%, with a satisfactory clin-
ical response in 54% of all cases. There
were adverse events in 51 patients, but they
were severe in only four.
In a retrospective study in 84 children
and adolescents (median age 11 years)
who received 141 consecutive courses of
LAMB for prophylaxis (n 32), empirical
therapy (83), and possible (19) or proba-
ble/proven (7) invasive infections, LAMB
was given until intolerance or maximum
efcacy at dosages individually determined
by the responsible physician [16c]. The
median duration of therapy was 13 (range
179) days and the median maximum dos-
age was 2.8 (range 0.95.1) mg/kg. There
were mild to moderate adverse events dur-
ing 109 courses (total 77%; hepatic 59%;
electrolyte loss 53%; renal 32%; infusion-
related reactions 8.5%). There were
adverse events that necessitated withdrawal
of LAMB in six courses (three renal, two
anaphylaxis, one hepatic). While median
hepatic aminotransferase and alkaline
phosphatase activities and blood urea nitro-
gen concentrations were slightly higher at
the end of treatment, bilirubin and creati-
nine were not different from baseline.
Comparative studies In a substudy of a dou-
ble-blind, randomized, multinational com-
parison of LAMB 3 mg/kg and micafungin
2 mg/kg as rst-line treatment of invasive
candidiasis in 98 children, 57 were under 2
years old, including 19 who were premature
at birth, and 41 were aged 216 years; 91 of
them had candidemia and seven had other
forms of invasive candidiasis [17c]. There
was a higher incidence of adverse events
leading to withdrawal in those who received
LAMB (9/54, 17%) compared with those
who received micafungin (2/52, 3.8%).
Electrolyte balance Hyperkalemia occur-
red in a 36-year-old man with acute mye-
loid leukemia who was given LAMB 5 mg/
kg/day for an infection with Absidia
corymbifera during voriconazole and caspo-
fungin therapy for invasive pulmonary
aspergillosis [18A]. There were four episodes
of hyperkalemia on days 9, 10, 11, and 24,
and the last episode was characterized by
severe, refractory hyperkalemia and fatal
cardiac arrest. Renal function was normal
and there were no signs of rhabdomyolysis,
hemolysis, or acidosis; a medication error
could not be identied. However, he was
being given concomitant drugs that can
cause hyperkalemia, including ciclosporin,
mycophenolate mofetil, propofol, nadro-
parin, and co-trimoxazole, and the most
likely mechanism was an interaction with
one or more of these drugs.
Urinary tract Urinary tract in a post-hoc
analysis of a phase III trial of LAMB
(3 mg/kg/day) versus micafungin (100 mg/
day for subjects over 40 kg; 2 mg/kg/day
for subjects weighing 40 kg or less), renal
function was signicantly worse in those
who were given LAMB [19c]. The difference
in mean peak change in eGFR was 18 ml/
minute/1.73 m2. Multivariate regression after
controlling for potential confounding factors
suggested that the APACHE II score was a
potential explanatory factor associated with
treatment success, mortality at day 8, and
mortality at day 30.
Although nephrogenic diabetes insipidus
and renal tubular acidosis are known
adverse effects of conventional amphoteri-
cin, nephrogenic diabetes insipidus has been
uncommonly associated with liposomal
amphotericin. An 18-year-old woman with
invasive aspergillosis and aplastic anemia
developed nephrogenic diabetes insipidus
while receiving high-dose liposomal ampho-
tericin 10 mg/kg/day; the symptoms resolved
after withdrawal, but recurred after rechal-
lenge with 5 mg/kg/day, and she was success-
fully treated with diuretics [20A].
Drug administration route Aerosol The
effects of aerosolized LAMB on pulmonary
function have been recorded in a placebo-
controlled trial in the prevention of inva-
sive pulmonary aspergillosis in 77 patients
with chemotherapy-induced neutropenia;
38 (41 episodes) received LAMB and 39
Antifungal drugs Chapter 27
(49 episodes) received placebo [21C]. There
were no differences in the proportions of
patients with a greater than 20% fall in
FEV1 or forced vital capacity between the
groups and most patients (26/38 and 31/
39) had no signicant changes during the
entire treatment period. However, cough
was signicantly more common in those
who received LAMB. There were no differ-
ences between baseline and post-nebuliza-
tion renal function and hepatic enzymes.
The steady-state concentrations of
amphotericin in the respiratory tract and
serum after inhalation of LAMB and its
effects on respiratory function have been
assessed after 32 consecutive bronchos-
copies in 27 lung transplant patients [22c].
At 2 days, mean amphotericin concentra-
tions were 11 mg/l (95% CI 17, 5.7) and
9.0 mg/l (95% CI 14, 3.8), and at 14 days
3.0 mg/l (95% CI 4.4, 1.5) and 4.1 mg/l
(95% CI 6.1, 2.1) in the rst and third
aliquots of the bronchoalveolar lavage uid
respectively. There were traces of ampho-
tericin (0.1 mg/l) in serum samples from
only one patient. Mean FEV1 was similar
before and after LAMB.
ANTIFUNGAL AZOLES
[SED-15, 301; SEDA-30, 320;
SEDA-31, 459; SEDA-32, 497]
For metronidazole see Chapter 28
Drugdrug interactions with
antifungal azoles
Aliskiren In an open, multiple-dose study
in healthy subjects of the pharmacokinetic
interaction of aliskiren 300 mg and keto-
conazole 200 mg bed (n 21), aliskiren
AUCt was signicantly increased by keto-
conazole (by 76%) through mechanisms
that most probably involved transporters
such as P glycoprotein and organic anion-
transporting peptide and possibly through
545
metabolic pathways such as CYP3A4 in the
gut wall [23c].
All-trans retinoic acid Hyperkalemia due
to an interaction of all-trans retinoic acid
(ATRA) and itraconazole has been reported
[24A].
A 38-year-old man with acute promyelocytic
leukemia who was taking itraconazole 200 mg
bd was given all-trans retinoic acid and during
the third course of maintenance therapy devel-
oped acute renal insufciency and symptomatic
hypercalcemia, which was treated with high-
volume crystalloid infusions and furosemide.
Renal function was restored, and the serum cal-
cium concentration returned to normal within 4
days after withdrawal of ATRA. The peak
serum calcium concentration was 3.67 mmol/l.
Serum parathyroid hormone was undetectable,
and there were no increases in the concentra-
tions of prostaglandins or vitamin D metabo-
lites. Hypercalcemia recurred during a fourth
course of ATRA.
The most important pathways of ATRA
metabolism involve CYP2C9 and CYP3A4
and inhibition of ATRA-metabolizing
enzymes induces hypercalcemia, as reported
with inhibitors of CYP2C9, CYP2C19, and
CYP3A4, such as itraconazole is a potent
CYP3A4 inhibitor.
Antiretroviral drugs (see also individual
agents) In a retrospective cohort study of
serum itraconazole concentrations in 10
HIV-positive patients with disseminated his-
toplasmosis taking antiretroviral drugs
(non-nucleoside reverse transcriptase inhibi-
tors, NNRTIs, or protease inhibitors) [25c].
Six itraconazole concentration measure-
ments during concomitant treatment with a
protease inhibitor were in the target range
in contrast with none in those who were tak-
ing an NNRTI, all of whom had undetect-
able serum itraconazole concentrations.
Two patients switched from NNRTI-based
to protease inhibitor-based regimens and
subsequently reached therapeutic itracona-
zole concentrations. Although the sample
size was small, this study has shown that
co-administration of an NNRTI and itra-
conazole results in a signicant reduction
in itraconazole concentrations, probably by
induction of CYP3A4.
546 Chapter 27
Atazanavir In a phase 1, open, random-
ized, crossover study in healthy volunteers
of co-administration of posaconazole
400 mg bd with atazanavir 300 mg/day,
alone and with either ritonavir 100 mg/day
or efavirenz 400 mg/day, posaconazole
increased the Cmax of atazanavir by 2.6
times and the AUC by 3.7 times [26c]. Posa-
conazole increased the Cmax and AUC of
atazanavir when it was given with ritonavir
by 1.5 and 2.5 times respectively. Most of
those who took atazanavir with or without
ritonavir plus posaconazole had clinically
relevant increases in total bilirubin. Co-
administration of posaconazole and efavir-
enz resulted in clinically relevant reductions
of posaconazole Cmax and AUC by about
45% and 50% respectively. As a result, fre-
quent monitoring of adverse events is recom-
mended when posaconazole and atazanavir
are co-administered with or without ritona-
vir. Because of reduced posaconazole expo-
sure, co-administration with efavirenz
should be avoided if possible.
Bortezomib The effect of concomitant
administration of ketoconazole on the phar-
macokinetics and pharmacodynamics of
bortezomib has been investigated in a pro-
spective, multicenter, open, randomized, mul-
tiple-dose, two-way, crossover study in 12
patients (median age 57 years; 14 men) with
advanced solid tumors. All received intrave-
nous bortezomib 1.0 mg/m2 on days 1, 4, 8,
and 11 of two 21-day cycles and were random-
ized to concomitant ketoconazole 400 mg on
days 6, 7, 8, and 9 of cycle 1 or 2 [27c]. Ketoco-
nazole increased exposure to bortezomib by
35% and was associated with a corresponding
increase of 2446% in the blood proteasome
inhibitory effect.
Calcineurin inhibitors See also individual
names. The interaction of oral itraconazole
in solution and calcineurin inhibitors (ciclo-
sporin or tacrolimus) has been retrospec-
tively studied in 10 recipients of allogeneic
hemopoietic stem cell transplants [28c].
Itraconazole signicantly increased the
dose-corrected blood concentrations of the
Dominik Schrey, Thomas J. Walsh, and Andreas H. Groll
calcineurin inhibitors by 94% (range
37328%) at 710 days. The plasma concen-
tration ratio of itraconazole/hydroxyitraco-
nazole correlated signicantly with the
increase in the dose-corrected blood concen-
trations of the calcineurin inhibitors. The
wide interindividual variability in the degree
of interaction may in part be explained by
the variable systemic availability of itracona-
zole in oral solution.
Chloramphenicol Inhibition of voricona-
zole metabolism by chloramphenicol has
been reported in an adolescent with bacterial
meningitis and subsequent central nervous
system aspergillosis [29A]. Intravenous
voriconazole dosage requirements fell sub-
stantially during co-administration of intra-
venous chloramphenicol and rose
considerably after its withdrawal. In agree-
ment with in vitro evidence, these data sug-
gest that chloramphenicol inhibits hepatic
CYP3A4 and/or CYP2C19.
Citalopram Citalopram is a substrate of
CYP2C19, and inhibition of its metabolism
by uconazole can result in serotonin syn-
drome, as occurred in two patients, who
developed prolonged delirium without
tremor, myoclonus, rigidity, or autonomic
instability [30A]. Serotonin toxicity in
patients with cancers may not present with
the classic constellation of signs and symp-
toms and delirium may be the only present-
ing feature.
Darunavir The interaction of ketoconazole
with darunavir alone and in combination
with low-dose ritonavir has been investi-
gated in HIV-negative volunteers, who took
ketoconazole 200 mg bd, darunavir 400 mg
bd, darunavir 400 mg bd plus ketoconazole
200 mg bd, darunavir ritonavir 400/
100 mg bd, or darunavir ritonavir 400/
100 mg bd plus ketoconazole 200 mg bd;
all the treatments were taken with food for
6 days [31c]. Ketoconazole increased the
AUC0!12h, Cmax, and Cmin of darunavir by
155% (80, 261), 78% (28, 147), and 179%
(58, 393) respectively. Darunavir AUC0!12h,
Antifungal drugs Chapter 27
Cmax, and Cmin increased by 42% (23, 65),
21% (4, 40), and 73% (39, 114) respec-
tively during darunavir ritonavir and keto-
conazole co-administration. Ketoconazole
pharmacokinetics were unchanged by co-
administration of darunavir alone. Ketocona-
zole AUC0!12h, Cmax, and Cmin increased by
212% (165, 268), 111% (81, 144), and 868%
(544, 1355) respectively during co-administra-
tion of darunavir ritonavir. The increase in
darunavir exposure by ketoconazole was
lower than that observed previously with rito-
navir. A maximum ketoconazole dose of
200 mg/day is recommended if it is used con-
comitantly with darunavir ritonavir, and
no dose adjustments of darunavir ritonavir
is required.
Ebastine In a study of the effects of itra-
conazole on the pharmacokinetics and phar-
macodynamics of ebastine in a crossover
sequential design with 2-week washout
periods in 10 healthy participants, itracona-
zole pretreatment reduced the oral clear-
ance of ebastine to 10% and increased the
AUC of its active metabolite, carebastine,
threefold [32c].
Efavirenz Voriconazole is not recom-
mended for use in combination with efavir-
enz; however, when they are co-
administered, the dosage of voriconazole
should be increased to 400 mg 12-hourly
and the dosage of efavirenz reduced to
300 mg/day, in order to provide systemic
exposures similar to standard-dose mono-
therapy [SEDA-32, 498]. The combination
of voriconazole and efavirenz in doses
adjusted according to steady-state plasma
concentration monitoring has been studied
in a 40-year-old man with AIDS, cryptococ-
cosis, and mild liver cirrhosis [33A]. Ade-
quate concentrations of voriconazole in
both plasma and cerebrospinal uid were
obtained and target plasma concentrations
of efavirenz were achieved at the nal dos-
age adjustment (oral voriconazole 200 mg
bd plus oral efavirenz 300 mg/day). There
was stable suppression of cryptococcosis
and plasma HIV viremia at long-term fol-
low-up (66 weeks), with no signicant
adverse events.
547
Etoricoxib The effect of oral voriconazole
(400 mg bd on day 1 and 200 mg bd on
day 2) on the pharmacokinetics of a single
dose of etoricoxib 60 mg has been studied
in 12 healthy volunteers [34c]. Etoricoxib
AUC and Cmax were increased by 49%
(90% CI 37%, 61%) and 19% (90%
CI 8%, 31%) respectively, presumably
by inhibition of CYP3A.
Everolimus The management of a pharma-
cokinetic interaction of voriconazole with
everolimus has been described in a 65-year-
old man who underwent orthotopic liver
transplantation complicated by intestinal
perforation, sepsis, and acute renal insuf-
ciency [35A]. He received intravenous u-
conazole 400 mg, followed by 100 mg/day
and oral everolimus 0.75 mg bd; the
steady-state Cmin of everolimus was satisfac-
tory. On day 72 after transplantation,
because of invasive aspergillosis, antifungal
therapy was switched to intravenous vorico-
nazole 400 mg bd on the rst day followed
by 200 mg bd; to prevent drug toxicity the
dosage of everolimus was promptly lowered
to 0.25 mg/day. The dose-corrected Cmin of
everolimus at steady-state was markedly
lower during uconazole versus voricona-
zole co-treatment (mean 3.5 versus 11 mg/l
per mg/kg/day). During everolimus azole
co-treatment, everolimus dosage reduction
is needed to avoid overexposure. Because
of different CYP3A4 inhibitory potencies,
the reduction should be greater during co-
treatment with voriconazole than with
uconazole.
Halofantrine The effect of uconazole
50 mg on the pharmacokinetics of a single
500-mg oral dose of halofantrine, which is
mainly metabolized by CYP3A4 to the active
metabolite N-desbutylhalofantrine, has been
evaluated in 15 healthy volunteers in a Latin
square crossover design [36C]. Co-administra-
tion of uconazole did not alter the pharmaco-
kinetics of halofantrine, but signicantly
altered the pharmacokinetics of its active
metabolite, reducing Cmax, AUC, and the ratio
of N-desbutylhalofantrine to halofantrine by
3541% and increasing the tmax by 50%.
Although the therapeutic consequences of this
548 Chapter 27
interaction are not clear caution should be
taken during co-administration to avoid accu-
mulation and subsequent cardiotoxic effects of
halofantrine, particularly if higher doses of u-
conazole are used.
Lopinavir ritonavir Itraconazole had no
effect on the lopinavir trough concentration
during co-administration with lopinavir
ritonavir in a 34-year-old HIV-positive man
with histoplasmosis [37A].
Meloxicam The effects of voriconazole on
the pharmacokinetics and pharmacodynam-
ics of meloxicam 15 mg have been investi-
gated in 12 healthy volunteers in a
crossover study [38c]. The plasma concen-
trations of meloxicam and voriconazole
and thromboxane B2 generation were moni-
tored. Voriconazole increased the mean
AUC0!72 h of meloxicam by 47% and pro-
longed its mean half-life by 51%, without
affecting its Cmax. Plasma protein binding of
meloxicam was unchanged by voriconazole.
Reduced plasma meloxicam concentrations
during co-administration of itraconazole
phase were associated with reduced pharma-
codynamic effects of meloxicam, as reected
in weaker inhibition of thromboxane B2 gen-
eration. The mechanism was thought to be
impaired absorption of meloxicam.
Methadone Itraconazole-induced torsade
de pointes have been reported in a heroin-
dependent woman taking methadone substi-
tution therapy who was given itraconazole
for vaginal thrush [39A]. She developed
chest discomfort and had an episode of syn-
cope after taking two doses of itraconazole
200 mg. Electrocardiography showed a pro-
longed QTc interval leading to torsade de
pointes. The electrocardiogram returned to
normal after withdrawal of methadone. This
cardiac dysrhythmia was thought to have
resulted from an interaction of methadone
with itraconazole.
Midazolam Midazolam is metabolized
by CYP3A4. In a phase I, randomized,
open, crossover study, 12 healthy volunteers
Dominik Schrey, Thomas J. Walsh, and Andreas H. Groll
(mean age 43 years; mean weight 81 kg;
mean body mass index 26 kg/m2; 11 men)
were randomized to one of two regimens:
posaconazole 200 mg bd for 7 days, posa-
conazole 400 mg bd for 7 days, no drugs
during a 28-day washout, and ketoconazole
400 mg/day for 7 days; or posaconazole
and ketoconazole in the reverse order
[40c]. Oral midazolam 2 mg and intra-
venous midazolam 0.4 mg were given on
consecutive days before the rst phase and
at the end of each phase thereafter. Posaco-
nazole 200 and 400 mg bd were associated
with signicant increases in midazolam Cmax
(up to 1.3 and 2.4 times respectively) and
AUC (up to 4.6 and 6.2 times respectively).
Ketoconazole 400 mg/day was associated
with signicantly increased midazolam Cmax
and AUC (up to 2.8 and 8.2 times respec-
tively). Posaconazole prolonged the half-life
of midazolam. Seven subjects reported at
least one adverse event during the study (ve
with posaconazole alone and four with
posaconazole midazolam). The most
common adverse events were diarrhea (n
3 with posaconazole alone, n 2 with
ketoconazole alone, and n 1 with posaco-
nazole midazolam) and atulence (n 1
with posaconazole alone and n 1 with
midazolam alone).
Morphine In a randomized, placebo-
controlled, crossover study of the effect of
itraconazole, a potent inhibitor of P-glyco-
protein and CYP3A4, on the pharmacoki-
netics and pharmacodynamics of oral
morphine, 12 healthy men took itraconazole
200 mg/day for 4 days and then morphine
0.3 mg/kg [41C]. Itraconazole increased the
mean AUC0!9 h of morphine by 29%, the
AUC0!48 h by 22%, and the Cmax by 28%.
Itraconazole did not signicantly affect the
pharmacokinetics of morphine-3-glucuro-
nide or morphine-6-glucuronide or the
pharmacodynamics of morphine. Thus, itra-
conazole moderately increases plasma con-
centrations of oral morphine, probably by
enhancing its absorption by inhibiting intes-
tinal wall P-glycoprotein.
Antifungal drugs Chapter 27
Nevirapine In a substudy within a large
double-blind, randomized, placebo-con-
trolled study of the use of uconazole
200 mg three times per week in primary pro-
phylaxis of cryptococcal disease in HIV-
infected adults in rural south-western
Uganda, uconazole increased the nevira-
pine AUC0!8h by 29% [42c]. In the larger
cohort from which the participants were
drawn, co-administration of uconazole
did not increase the risk of hepatotoxicity,
despite increased exposure to nevirapine.
Nifedipine Hypotension due to an inter-
action of voriconazole with eplerenone and
nifedipine has been reported [43A].
A 48-year-old man with myelodysplastic syn-
drome and a bone marrow transplant took
ciclosporin and methylprednisolone for acute
graft-versus-host disease while taking candesar-
tan 8 mg/day, nifedipine 40 mg/day, and epler-
enone 50 mg/day for hypertension, and his
blood pressure was maintained at 130146/
7088 mmHg. Intravenous voriconazole was
added for prophylaxis of fungal infections in
a maintenance dosage of 4 mg/kg 12-hourly.
His blood pressure fell to 76/48 mmHg. There
was no evidence of hypovolemia, acute blood
loss, or septicemia. Candesartan, nifedipine,
and eplerenone were withdrawn and his blood
pressure rose to 116124/6480 mmHg after 1
day and to 164180/8084 mmHg 5 days later.
Candesartan and nifedipine were started again,
the dosage of nifedipine was reduced to 20 mg/
day, and eplerenone was no longer needed.
As both nifedipine and eplerenone are
metabolized by CYP3A4, inhibition of the
metabolism of both agents by voriconazole
is plausible.
Omeprazole Omeprazole 40 mg/day signif-
icantly reduced posaconazole serum trough
concentrations in a 58-year-old man with
invasive aspergillosis, and when it was with-
drawn the serum trough concentration of
posaconazole returned to baseline [44A].
Omeprazole probably suppressed gastric
acid production, causing reduced systemic
availability of posaconazole.
Oxycodone The effect of voriconazole for 4
days on the pharmacokinetics and pharma-
codynamics of a single dose of oxycodone
549
10 mg have been investigated in a random-
ized, placebo-controlled, crossover study in
12 healthy subjects [45C]. Voriconazole
increased the AUC of oxycodone 3.6 times
(range 2.75.6) and the Cmax 1.7 times, and
prolonged the half-life two fold. The AUC
ratio of noroxycodone to oxycodone was
reduced by 92% and that of oxymorphone
increased by 108%. The pharmacodynamic
effects of oxycodone were modestly
increased by voriconazole. Thus, voricona-
zole markedly increased exposure to oral
oxycodone by inhibiting CYP3A-mediated
N-demethylation. Lower doses of oxy-
codone may be needed during voriconazole
treatment to avoid opioid-related adverse
effects.
Sirolimus The effect of posaconazole 400 mg
bd on the pharmacokinetics of a single 2-mg
dose of sirolimus, a substrate of CYP3A4,
has been investigated in an open, multiperiod
study in 12 healthy subjects [46c]. Posacona-
zole increased sirolimus Cmax and AUC by
6.7 and 8.9 times respectively, consistent
with inhibition of CYP3A4 by posaconazole.
These two agents should probably not be co-
administered.
Tacrolimus The co-prescription of posaco-
nazole with tacrolimus has been evaluated
in 14 lung transplant recipients with cystic
brosis. Posaconazole inhibited CYP3A4-
mediated tacrolimus metabolism, resulting
in a threefold reduction in tacrolimus dosage
requirements [47c].
The effects of single nucleotide polymor-
phisms (SNPs) in CYP3A4, CYP3A5, and
MDR1 on interactions of tacrolimus with
uconazole have been examined in 29 renal
allograft recipients, who were genotyped for
CYP3A4*1/*1B, CYP3A5*1/*3, MDR1
C3435T, and G2677T/A [48c]. Dose-cor-
rected trough blood tacrolimus concentra-
tions did not change signicantly from
baseline in heterozygous CYP3A5*1 carriers
during exposure to uconazole, in contrast
to homozygous CYP3A5*3 carriers, in
whom there was a 3.3-fold increase. Homo-
zygous CYP3A5*3 carriers had a
signicant reduction in weight-corrected
tacrolimus dosage requirements during
550 Chapter 27
uconazole administration, in contrast to
heterozygous carriers of CYP3A5*1. These
effects were not inuenced by uconazole dose
or duration of administration. Signicantly
more CYP3A5*3/*3 carriers were exposed to
tacrolimus dose-uncorrected trough blood
tacrolimus concentrations of at least 15 mg/l
during administration of uconazole com-
pared with CYP3A5*3/*1 carriers. Thus, in
renal allograft recipients, the CYP3A5*3/*1
genotype is associated with reduced suscepti-
bility for the inhibitory effects of uconazole
on tacrolimus metabolism, thereby identifying
a genetic determinant of the clinical variability
of CYP3A-mediated drug interactions.
Tilidine The effect of voriconazole 400 mg
on the pharmacokinetics and analgesic
effects of tilidine 100 mg have been investi-
gated in 16 healthy volunteers in a placebo-
controlled study [49C]. Voriconazole caused
a 20-fold increase in the serum AUC of tili-
dine and the AUC of nortilidine increased
2.5-fold; the serum concentrations of bisnor-
tilidine were much reduced. The onset of
analgesic activity occurred later with vorico-
nazole, concordant with the prolonged tmax
of nortilidine from 0.78 to 2.5 hours, due to
additional inhibition of nortilidine metabo-
lism to bisnortilidine. After voriconazole
the AUC under the pain withdrawal versus
time curve was reduced compared, mainly
because of a shorter withdrawal time. Thus,
voriconazole signicantly inhibited the
sequential metabolism of tilidine, with
increased exposure to the active metabolite,
nortilidine. Furthermore, the incidence of
adverse events was almost doubled after vor-
iconazole and tilidine.
Tipranavir ritonavir In a controlled,
two-period study in 20 healthy volunteers
who took tipranavir ritonavir 500/
200 mg, uconazole 100 mg increased the
AUC of tipranavir by 50% [50c]. However,
the authors concluded that no dosage adjust-
ments are necessary when tipranavir rito-
navir is combined with uconazole.
Dominik Schrey, Thomas J. Walsh, and Andreas H. Groll
Vincristine Vincristine-associated neurotox-
icity has been reported in association with
posaconazole co-administration in a 9-year-
old girl with acute lymphoblastic leukemia
[51A]. Six days after the last dose of vincris-
tine, she reported symptoms of severe
peripheral neuropathy, abdominal cramps,
and constipation; she then developed uctu-
ating impairment of consciousness and sei-
zures. There was complete resolution
within 7 days after withdrawal of posacona-
zole. Vincristine-related neuropathy was
also exacerbated by voriconazole in a
patient with previously undiagnosed, X-
linked CharcotMarieTooth disease [52A].
In a retrospective cohort study of 50
adults with acute lymphoblastic leukemia
who received vincristine-based chemother-
apy with (n 21) or without (n 29) an
azole, the mean dose of vincristine had to
be reduced by 47% when an azole was
added [53c]. Symptoms of reduced peristal-
sis were more common in those who took
an azole (66% versus 29%) and on average
occurred after the second dose of vincristine.
These symptoms occurred in 50%, 75%,
and 67% of those who took uconazole,
voriconazole, and posaconazole respec-
tively. The course of vincristine was more Au1
likely to take be incomplete when patients
took an azole (48% versus 9.5%).
These studies conrm that caution should
be taken when vincristine and azoles are co-
administered. Moreover, the reduction in
vincristine dosage has uncertain effects in
cancer chemotherapy. Alternatives to azoles
for prophylaxis of fungal infections in this
population are urgently needed.
Warfarin In a nested casecontrol and
casecrossover study using US Medicaid
data and logistic regression to determine
the association between gastrointestinal
bleeding in patients taking warfarin, anti-
bacterial drugs (ciprooxacin, levooxacin,
gatioxacin, co-trimoxazole, uconazole)
were associated with increased odds
ratios compared with cephalexin, which is
not expected to interact with warfarin;
the odds ratio for uconazole when used in
Antifungal drugs Chapter 27
the prior 1115 days was 2.09 (95%
CI 1.34, 3.26) [54c].
Fluconazole [SED-15, 1377; SEDA-30,
325; SEDA-31, 462; SEDA-32, 502]
Placebo-controlled studies In a double-
blind, placebo-controlled, randomized trial
in 26 centers in the USA of the use of intra-
venous uconazole 800 mg/day for 2 weeks
in 249 adults in ICU with a high risk of
invasive candidiasis, seven who were given
uconazole and 10 who were given placebo
had adverse events resulting in withdrawal
of the study drug: there were abnormal
liver function tests in three and ve subjects
respectively [55C].
Cardiovascular Antifungal triazoles, as a
class, can cause QT interval prolongation
and potentially fatal cardiac dysrhythmias
by blocking inward-rectifying potassium
(hERG) channels in the heart. In a phase
II trial, 141 patients with AIDS and crypto-
coccal meningitis were randomly assigned
to amphotericin (0.7 mg/kg/day) alone or
plus uconazole (400 or 800 mg/day) for
14 days [56C]. At day 7 the mean QTc inter-
val adjusted for baseline was similar in all
the treatment arms. However, day 7
median and adjusted mean changes from
baseline were higher with amphotericin
uconazole 800 mg than with amphotericin
alone. Predictive factors were higher base-
line cerebrospinal uid (CSF) opening
pressure, Karnofsky scales, serum potas-
sium, age, and lower CD4 count. There
was a trend to a signicant correlation
between the change in QTc interval from
baseline and the uconazole Cmin on day
14. Nevertheless, the proportions of
patients with clinically signicant abnormal-
ities were comparable in the two groups
The role of electrolyte abnormalities in
cardiac dysrhythmias has been emphasized
in a report of a patient with diabetic keto-
acidosis who developed torsade de pointes
leading to nine episodes of cardiac arrest
secondary to intravenous uconazole on a
551
background of hypokalemia and hypocalce-
mia [57A].
Skin Sclerosing lymphangitis of the penis
has been reported after co-administration
of tadalal 20 mg and uconazole 300 mg
once weekly in a 50-year-old man [58A].
The penile lesion appeared about 24 hours
after the third day of uconazole treatment,
when the patient also took tadalal. Sexual
and pharmacological abstinence were
recommended and 4 weeks later all the
symptoms had resolved.
Immunologic In a case of allergy to ucon-
azole there was no cross-reactivity with vor-
iconazole [59A].
A 65-year-old immunocompetent, HIV-nega-
tive man was given uconazole 400 mg/day
for cerebral cryptococcosis. After 5 weeks he
developed a rash on the abdomen, torso, legs,
and arms, associated with edema periorbitally
and in the right arm. There were no other fea-
tures of anaphylaxis. Fluconazole was with-
drawn and antihistamines were begun. Over
the next week, he had asymptomatic increases
in liver enzymes and an eosinophilia. Skin
biopsy showed an inammatory cell inltrate
with eosinophils, consistent with a drug reac-
tion. After resolution of the eosinophilia and
liver function abnormalities, he underwent a
supervised graded challenge with oral vori-
conazole, starting with a dose of 25 mg on
day 1, 75 mg bd on day 2, 150 mg bd on day
3, 300 mg on day 4, and then 200 mg bd there-
after. There was no recurrence of symptoms,
liver enzyme rises, or eosinophilia.
This case shows that hypersensitivity reac-
tions to uconazole can occur and that vor-
iconazole can be successfully introduced
without cross-sensitization. In cases of azole
hypersensitivity, one could consider using
another azole cautiously before choosing
another class of antifungal agent.
Teratogenicity Fluconazole may be terato-
genic when it is taken in a dosage of
400800 mg/day. Common features include
multiple synostosis (including craniosyn-
ostosis and digital synostosis), congenital
heart defects, skeletal anomalies, and rec-
ognizable dysmorphic facial features. The
association between maternal use of
552 Chapter 27
uconazole during pregnancy and the risk
of congenital malformations has been
assessed in a population-based cohort study
in Northern Denmark in 1079 women who
had a live birth or a stillbirth after 20 weeks
of gestation and who redeemed at least one
prescription for uconazole during the rst
trimester [60]. The controls comprised
170 453 pregnant women who redeemed
no uconazole prescriptions during preg-
nancy. The women were identied through
the Danish Medical Birth Registry and data
on drug use, birth outcomes, and co-vari-
ates were extracted from population-based
health-care databases. The prevalence odds
ratios (POR) for congenital malformations
after uconazole exposure were adjusting
for maternal smoking, parity, maternal
age, and concurrent prescriptions of anti-
epileptic or antidiabetic drugs. Among the
1079 women in the study group, 797
(74%) took a total of 150 mg of ucona-
zole, 235 (22%) took 300 mg, 24 (2%) took
350 mg, and 23 (2%) took 600 mg. These
women gave birth to 44 (4.1%) children
with congenital malformations. The
170 453 controls gave birth to 6152 (3.6%)
children with congenital malformations.
For congenital malformations overall, the
adjusted POR associated with rst tri-
mester use of uconazole was 1.0 (95%
CI 0.8, 1.4).
Itraconazole [SED-15, 1932; SEDA-30,
326; SEDA-31, 463; SEDA-32, 504]
Liver Fatal hepatitis occurred in a 61-year-
old woman 1 week after the last dose of a
course of pulse itraconazole therapy for 24
weeks [61A]. She had no apparent risk fac-
tors for liver damage. Monitoring of liver
enzymes was not performed during the
treatment period. The alanine and aspar-
tate aminotransferases were 3330 and
3250 U/l respectively, and bilirubin was
360 mmol/l. Her liver function continued to
deteriorate, and she underwent liver
Dominik Schrey, Thomas J. Walsh, and Andreas H. Groll
transplantation 17 days after admission.
Histology showed massive panlobular
necrosis.
Immunologic A 36-year-old woman with
acute lymphoblastic leukemia developed
anaphylactic shock after intravenous itra-
conazole 200 mg on day 17 of a course of
treatment; she responded to glucocorticoid
treatment [62A]. On two subsequent days
she had recurrences during itraconazole
administration. Intravenous itraconazole
was replaced by oral voriconazole 200 mg
bd and there was no recurrence. T cell
reduction, caused by immunosuppression,
and itraconazole accumulation in patients
with acute lymphoblastic leukemia are con-
sidered to be important causal factors for
delayed hypersensitivity reactions.
Teratogenesis Women who called two Ital-
ian Teratology Information Services after
being exposed to itraconazole during the
rst trimester and a contemporary group
of pregnant women who contacted the Ser-
vices because they had been exposed to a
non-teratogenic drug during the rst tri-
mester have been compared in a prospec-
tive cohort study [63c]. Information was
obtained by a trained operator via a struc-
tured questionnaire no earlier than 1 month
after delivery. A conducted the interview. Au2
Information about major congenital anom-
alies, type of delivery, birth weight, and
any pregnancy or neonatal complications
was collected on 206 women who had been
exposed to itraconazole and 207 controls.
There were no signicant differences in
major congenital anomalies (3/163 versus
4/190 respectively). There were no statisti-
cal differences in the rates of vaginal deliv-
ery, premature birth, low birth weight, or
high birth weight. However, the rates of
live births (163/206 versus 190/207), sponta-
neous abortions (23/206 versus 10/207), and
termination of pregnancy (19/206 versus 7/
207) were signicantly different. Thus, itra-
conazole exposure in the rst trimester did
Antifungal drugs Chapter 27
not increase the risk of major congenital
anomalies, but did increase the rates of
spontaneous and induced abortion. Given
the relatively small sample size, larger stud-
ies are warranted.
Monitoring therapy The relation of adverse
effects to itraconazole concentration has
been explored in patients taking itraconazole
100400 mg/day for at least 3 weeks for pro-
phylaxis or an Aspergillus-related syndrome
[64c]. Of 216 patients, 99 (46%) had an
adverse event: uid retention (n 46; of
whom 43 had peripheral edema and three
had features suggestive of congestive cardiac
failure); gastrointestinal intolerance (45),
with nausea and/or vomiting in 32 and
abdominal pain, atulence, and diarrhea in
13; sleep disturbances, with frequent waking,
daytime somnolence, and associated low
mood (21); a diffuse non-pruritic maculopap-
ular rash during therapy, which resolved 24
weeks after stopping itraconazole (16); a sen-
sorimotor polyneuropathy of the hands and
feet (11); headache (8); tremor (8); abnormal
liver function (5); and dysgeusia (3). Six who
were taking concomitant oral or inhaled glu-
cocorticoids had features of Cushing's syn-
drome. Withdrawal of therapy was required
in 72 of the 99 patients who had adverse
events. The adverse events resolved with a
50% reduction in dose in 20 patients and with
a 75% reduction in dose in seven. Although
gastrointestinal intolerance resolved rapidly
when itraconazole was withdrawn or when
the dosage was reduced, the resolution of
uid retention, peripheral neuropathy, and
tremor was protracted and took up to 6
months in some patients. In 45 patients
whose itraconazole was withdrawn, an alter-
native antifungal triazole was given without
recurrence. The mean plasma itraconazole
concentration was 16 mg/l in patients who
had at least one adverse event and 7.0 mg/l
in those who did not have any adverse
events. There was a progressive increase in
the probability of toxicity with increasing
itraconazole concentrations. Classication
and regression tree analysis suggested that
17.1 mg/l was the itraconazole concentration
at which the population of patients was
553
separated into two groups, with high and
low probabilities of adverse effects.
Posaconazole [SED-15, 2905; SEDA-
30, 327; SEDA-31, 463; SEDA-32, 504]
Observational studies The efcacy and
safety of posaconazole in patients with
underlying renal impairment has been
determined in a post-hoc subanalysis of a
phase III, multicenter, open trial in 238
patients with invasive fungal infections tak-
ing posaconazole 800 mg/day in divided
doses, including 65 patients with renal
impairment (creatinine clearance under
50 ml/minute or serum creatinine over
177 mmol/l) [65c]. There were adverse
events in 32 of 65 patients with renal
impairment (49%) and in 72 of the 173
others (42%). The most common adverse
events in both groups were nausea (14%
versus 8%), increased serum creatinine
(6% versus 0%), vomiting (6% versus
4%), abdominal pain (5% versus 5%),
and dizziness (5% versus 1%).
Systematic reviews Adverse effects data
from 18 single-dose and multiple-dose trials
of posaconazole in healthy volunteers plus
two additional healthy subsets from other
trials have been pooled and analysed
[66M]. Of 449 healthy volunteers (354
men; 95 women), 327 were white and their
mean ages and weights were similar across
all dosing groups. There were no confound-
ing factors of underlying disease or
concomitant medications. Evaluations
included spontaneously reported adverse
events, clinical laboratory test results, elec-
trocardiography, and vital sign measure-
ments. A total of 448 subjects took
posaconazole in single or multiple doses of
501200 mg/day for up to 14 days; 217 took
at least 800 mg/day and 188 took multiple
doses of 800 mg/day; 231 took less than
800 mg/day; 48 took placebo. The incidence
of treatmentemergent adverse events with
posaconazole was similar to that seen with
placebo (57% versus 63% respectively)
554 Chapter 27 Dominik Schrey, Thomas J. Walsh, and Andreas H. Groll
and was unrelated to dose. The most com-
mon (posaconazole versus placebo) were
headache (17% versus 13%), dry mouth
(9% versus 0%), and dizziness (6% versus
2%). There were no clinically signicant
changes in vital signs or laboratory tests,
except for transient, mild to moderate rises
in liver function tests. Posaconazole also had
minimal effect on the QT interval.
Monitoring therapy In a retrospective
review of 54 adults who took posaconazole
for at least 5 days, low plasma posaconazole
concentrations (dened as below 500 mg/l)
tended to be more frequent in cases of
digestive disease (63% versus 30%) and
were signicantly more frequent among
patients with diarrhea (71% versus 27%)
or mucositis (100% versus 33%) [67c]. Hep-
atotoxicity, which occurred in two patients,
was not related to high plasma drug con-
centrations. Therapeutic drug monitoring
of posaconazole is recommended for immu-
nosuppressed adults, at least for those with
gastrointestinal disorders.
Voriconazole [SED-15, 3688; SEDA-30,
328; SEDA-31, 463; SEDA-32, 505]
Observational studies Of 72 patients
undergoing allogeneic transplantation who
were given voriconazole as antifungal pro-
phylaxis starting from 2 days before trans-
plantation and continuing until withdrawal
of immunosuppression, 10 required inter-
ruption of voriconazole therapy because of
adverse effects: hepatotoxicity (n 6), QT
interval prolongation (n 1), or other
adverse effects (n 4) [68].
Cardiovascular A 57-year-old man with
HIV infection taking abacavir, nevirapine,
tenofovir, voriconazole, and methadone
developed new-onset seizures [69A]. An
electrocardiogram showed sinus bradycar-
dia and a prolonged QTc interval of
690 msec. He had several episodes of tor-
sade de pointes and ventricular tachycardia,
which resolved spontaneously. They were
accompanied by altered cognition and
generalized twitching. Magnesium and
amiodarone terminated the dysrhythmia.
The patient had multiple susceptibility fac-
tors for prolongation of the QT interval,
including HIV infection, methadone ther-
apy, and polypharmacy leading to potential
drug interactions.
Sensory systems Vision Voriconazole
inhibits brain cholesterol 24S-hydroxylase
(CYP46A1) in vitro and in vivo; as
CYP46A1 is also expressed in the neural
retina, it is possible that inhibition of
CYP46A1 contributes to visual distur-
bances associated with voriconazole [70E].
Psychiatric In a prospective cohort study
12 of 72 patients taking voriconazole had
hallucinations [71c]. Symptoms in eight
patients occurred during administration of
the initial two intravenous loading doses
of voriconazole (6 mg/kg every 12 hours)
and symptoms in two patients occurred on
only the rst day when they received
4 mg/kg of voriconazole every 12 hours.
Only two patients reported symptoms
beginning at the end of the rst week, one
of whom had symptoms while taking oral
voriconazole. Four also had auditory hallu-
cinations, three of whom had them on the
rst day of treatment. Although there was
also altered color perception or blurred
vision in some patients in this study, only
three had both hallucinations and altered
vision. A recurring feature was that symp-
toms worsened when the patients eyes
were closed when they tried to sleep, but
in all cases, the patient remained oriented,
alert, and able to recognize hallucinations
as being unreal. Six patients failed to report
their hallucinations spontaneously and
were hesitant to describe them. There was
no temporal relation between voriconazole
infusion and symptoms. No connection
was found between the hallucinations and
the many other drugs administered. None
of the patients needed specic treatment.
Doses of voriconazole were within the
approved range. None of the patients had
a history of psychiatric illness or similar
symptoms, and all had hematological or
other malignancies. In eight cases the
Antifungal drugs Chapter 27
symptoms disappeared soon after treat-
ment was withdrawn. In two cases the hal-
lucinations disappeared after treatment
was changed from intravenous to oral vori-
conazole. Two patients had mild hallucina-
tions only on the rst day despite
continued treatment. There were no resid-
ual symptoms or sequelae after voricona-
zole was withdrawn. Voriconazole trough
blood concentrations on the day of with-
drawal or just before a change from intra-
venous to oral treatment in six of the
patients were 1.977.66 mg/l, and there
may be an increased risk of hallucinations
in patients with above average voriconazole
concentrations (i.e. above 5 mg/l).
Of 20 Japanese patients who took vorico-
nazole after chemotherapy for hematologi-
cal malignancies, six had visual
disturbances, complicated by hallucinations
in four cases [72c]. The authors suggested
that these effects may be associated with a
polymorphism in CYP2C19, but they pre-
sented no evidence to support this
hypothesis.
Liver In a retrospective study of antifungal
prophylaxis in 67 lung transplant recipients,
itraconazole (n 32) was compared with
voriconazole plus inhaled amphotericin
(n 35) to assess the incidence of hepato-
toxicity [73c]. There were no signicant dif-
ferences between groups in demographic
characteristics, co-morbidities, concomitant
use of hepatotoxic medications, or
APACHE scores at the time of transplanta-
tion. There was hepatotoxicity in 12
patients receiving voriconazole and inhaled
amphotericin and in no patients receiving
itraconazole. There was no signicant dif-
ference between the groups with regard to
the percentage of fungal infections.
Skin Five patients who were initially
thought to be having a are of cutaneous
chronic graft-versus-host disease were actu-
ally exhibiting phototoxicity due to vori-
conazole [74c]. A high index of suspicion
of this adverse reaction after bone marrow
transplantation is needed to prevent mis-
diagnosis and avoid immunosuppressive
therapy.
555
Musculoskeletal Drug-induced myopathy
has not been reported with voriconazole,
although it is recognized with other tria-
zoles. A 34-year-old African-American
woman with a renal transplant and a his-
tory of probable statin-induced myopathy
developed severe generalized weakness
with markedly raised muscle enzymes and
inammatory changes on T2-weighted fat-
suppressed STIR-sequence MRI while tak-
ing voriconazole for invasive aspergillosis
[75A]. Her symptoms resolved and the cre-
atine kinase activity normalized when the
drug was withdrawn.
Possible drug-induced periostitis associated
with long-term use of voriconazole after lung
transplantation has been reported in ve
patients [76c]. The diagnosis was made
because of bone pain, raised serum alkaline
phosphatase, and characteristic ndings on
radionuclide bone imaging in the absence of
any identiable rheumatological disease.
The periostitis was similar to hypertrophic
osteoarthopathy, but did not meet all of the
diagnostic criteria. In all patients, the symp-
toms resolved rapidly after voriconazole
withdrawal.
Tumorigenicity Squamous cell carcinoma
has been associated with voriconazole in
four patients who had taken it for 23 years
[77c]. The lesions were preceded by lesions
photosensitization, and were predomi-
nantly in photoexposed areas, particularly
the face. Replacement by posaconazole or
itraconazole did not trigger other photo-
sensitive lesions. Once voriconazole was
withdrawn, preneoplastic lesions regressed.
In a retrospective review of patients who
developed one or more squamous cell carci-
nomas during long-term treatment with vori-
conazole (median duration 47, range 1360,
months), 51 lesions were identied in eight
patients (median age 35, range 954, years)
[78c]. Underlying diagnoses included graft-
versus-host disease, HIV, and Wegener's
granulomatosis. Signs of chronic phototoxic-
ity and accelerated photoageing included ery-
thema, actinic keratoses, and lentigines. A
prospective cohort study is needed to deter-
mine the true population risk of squamous
cell carcinomas associated with voriconazole,
556 Chapter 27
but a high index of suspicion for photosensi-
tivity and squamous cell carcinoma is war-
ranted when voriconazole is used chronically
in patients with immunosuppression.
Drug overdose The effects of voriconazole
during massive intentional poisoning have
been reported [79A].
A middle-aged man with cystic brosis after
lung transplantation intentionally took vori-
conazole 9.8 g, prednisolone 60 mg, sulfameth-
oxazole 4 g, azithromycin 2.5 g, and
bromazepam 120 mg. He was found at home in
a state of altered consciousness and was intu-
bated for airway protection, sedated with mida-
zolam and sufentanil, and mechanically
ventilated. He had moderate rhabdomyolysis
and acute renal failure, with a creatinine clear-
ance of 22 ml/minute. The voriconazole blood
concentration was 30 mg/l. He awoke within
48 hours, but was extremely agitated, and his
renal function improved without respiratory or
hemodynamic failure. Bilirubin, alkaline phos-
phatase, the aminotransferases, and gamma-glu-
tamyl transferase increased slightly every day
until 126 hours after the overdose, but without
any clinical evidence of liver failure. At 144 hours
he was no longer agitated and 1 week later the
blood tests were normal. In this case report the
patient survived the intoxication but presented
with signs of immediate neurological toxicity
and a delayed increase in liver enzymes, but
without any clinical signs of liver failure.
It is difcult to ascertain the role of each
drug in this case, as both voriconazole and
bromazepam can cause neurological toxic-
ity and raised liver enzymes. However, this
report shows that a very large overdose of
voriconazole with high blood concentra-
tions does not necessarily result in severe
clinical complications or death, but that
delayed hepatotoxicity can occur.
Monitoring therapy The treatment of fungal
infections with voriconazole has been moni-
tored in 49 analyses of 34 patients with hema-
tological diseases [80c]. The voriconazole
concentration was highly variable, regardless
of renal function, liver function, or age, and
the effect of changing dose was not constant,
indicating the difculty of predicting voricona-
zole concentration without blood con-
centration monitoring. There was a
concentrationresponse relation only in
Dominik Schrey, Thomas J. Walsh, and Andreas H. Groll
patients without refractory hematological dis-
ease, in whom a concentration over 2 mg/l was
associated with a good response. Rises in
hepatic enzymes were associated with a vori-
conazole concentration over 6 mg/l. The
authors concluded that a voriconazole con-
centration of 26 mg/l should be targeted, in
order to improve efcacy and to reduce the
risk of adverse effects.
ECHINOCANDINS [SED-15,
1197; SEDA-30, 329; SEDA-31, 464;
SEDA-32, 507]
Caspofungin [SEDA-30, 330; SEDA-32,
508]
Observational studies In a prospective,
non-comparative study of the use of caspo-
fungin 50 mg/day as rst-line monotherapy
in invasive aspergillosis in patients with
hematological malignancies, there were no
serious drug-related adverse events or with-
drawals because of drug-related adverse
events [81c].
In a prospective study of caspofungin for
16 (range 446) days for prevention of
intra-abdominal invasive candidiasis in 19
high-risk surgical patients with recurrent
gastrointestinal perforation/anastomotic
leakage or acute necrotizing pancreatitis,
there were no drug-related adverse events
requiring caspofungin withdrawal [82c].
In a prospective, multicenter, non-com-
parative, open trial of the prophylactic use
of caspofungin for at least 21 days in 71
adult liver transplant recipients at high risk
of invasive fungal infections, six stopped
taking caspofungin because of drug-related
altered liver function, but there were no
symptomatic adverse effects [83c]. There
were changes in laboratory data compatible
with grade 4 adverse effects, irrespective of
caspofungin attribution, in 20 patients at
the end of caspofungin prophylaxis and in
11 patients 14 days after end of caspofungin
administration; eight patients died, six dur-
ing caspofungin administration and two
Antifungal drugs Chapter 27
during follow-up, but none was attributed
to fungal infection or caspofungin.
In a retrospective analysis of the medical
records of 63 adults with cancer who had
candidemia treated with caspofungin
alone for at least three consecutive days,
20 of whom had hematological malignan-
cies, caspofungin was well tolerated by all
patients [84c].
Comparative studies The usefulness of
caspofungin has been substantiated by the
results of a double-blind, randomized, phase
III trial, in which 204 patients with proven
invasive candidiasis were randomized to
caspofungin in a standard or high-dose
(150 mg/day) regimen [85C]. There were sig-
nicant drug-related adverse events in 1.9%
of those who received the standard regimen
and 3.0% of those who received the high-
dose regimen; the most common drug-
related adverse events were phlebitis (3.8%
and 2.0% respectively), increased alkaline
phosphatase (6.9% and 2.0%), and increased
aspartate aminotransferase (4.0% and 2.0%).
Immunologic A patient with a hemopoietic
stem cell transplant and a history of an
immediate hypersensitivity reaction to mica-
fungin was considered for a trial of caspo-
fungin, but a caspofungin intradermal skin
test was positive, suggesting cross-reactivity
[86A]. Thus, the cyclic peptide nucleus
chemical structure shared by echinocandins
may be the site of IgE recognition, and it
would be prudent to avoid challenging
patients with history of immediate hypersen-
sitivity to one echinocandin with another.
Susceptibility factors Children Adverse
reactions to caspofungin in ve clinical regis-
tration studies in 171 children have been
analysed [87M]. The median age of the caspo-
fungin recipients was 6.0 years (range 1
week to 17 years). Most (77%) were taking
a maintenance dose of 50 mg/m2/day. The
rest took 1 mg/kg/day (9 patients), 25 mg/
m2/day (18 neonates or infants under
months of age), or 70 mg/m2/day (12
patients). The maximum absolute dose in
all cases was 70 mg/day. The median dura-
tion of treatment was 9 (range 187) days
557
overall and 10 (range 287) days in
patients taking 50 mg/m2/day. The inci-
dences of drug-related clinical and labora-
tory adverse events were 26% and 16%
respectively. The most common drug-
related clinical adverse events were fever,
rash, and headache. Most of these were
mild in intensity and transient. Increased
aminotransferase activities and reduced
potassium were the most common drug-
related laboratory adverse events; these
returned to within the reference range dur-
ing subsequent caspofungin therapy or by
14 days of follow-up visit in 10 of the 13
patients with increased aspartate amino-
transferase, six of the 11 with increased ala-
nine aminotransferase, and four of the six
with reduced potassium. None of these labo-
ratory adverse events was serious or led to
caspofungin withdrawal. Although 37
(22%) of the 171 patients who received cas-
pofungin had a serious clinical adverse
event, only one event (hypotension)
was considered to be related to caspofungin.
Eleven patients (6%) died during or within
14 days of completing the course of caspo-
fungin, but none of the deaths was consid-
ered to be related to caspofungin. Two
patients (1%) stopped taking caspofungin
because of a drug-related adverse event:
moderate hypotension in one patient (see
above) and a moderate rash in the other;
the hypotension resolved after a bolus of iso-
tonic saline, and the rash resolved without
treatment 10 days later. The incidences of
drug-related adverse events in patients tak-
ing caspofungin were generally similar in dif-
ferent age ranges and in patients of different
sex, race, ethnicity, and body weight. The
incidences of drug-related adverse events
were comparable with all dosing regimens.
Caspofungin 50 mg/m2/day has been
studied in a multicenter, prospective, open
study in children aged 3 months to 17 years
with invasive aspergillosis, invasive candidi-
asis, or esophageal candidiasis [88c]. There
were adverse events in seven patients, but
none was considered drug related. There
were laboratory adverse events in ve
patients, which were considered to be drug
related in three. There were no infusion-
related events or withdrawals because of
558 Chapter 27 Dominik Schrey, Thomas J. Walsh, and Andreas H. Groll
adverse effects. The pharmacokinetics of
caspofungin were generally comparable
with those in adults [89C].
In a dose-nding study, patients aged
111 weeks, weighing 0.683.8 kg, gesta-
tional ages 2441 weeks, receiving intrave-
nous amphotericin for documented or
suspected candidiasis, were enrolled in a
single-dose (n 6) or subsequent multi-
ple-dose (n 12) panel; all received caspo-
fungin 25 mg/m2/day as a 1-hour infusion
[90c]. Clinical and laboratory adverse
events occurred in 17 and 8 patients respec-
tively. Five patients had serious adverse
events, none of which was considered drug
related. However, the small number of
patients precluded denitive recom-
mendations.
Drugdevice interactions Sequestration of
caspofungin and voriconazole during extra-
corporeal membrane oxygenation (ECMO)
has been demonstrated in a 31-year-old
woman with fulminant myocarditis [91A].
The system comprised a membrane oxy-
genator (Quadrox Bioline, Jostra-Maquet,
Orlans, France) and a centrifugal pump
(Rotaow, Jostra-Maquet). Continuous
venovenous hemodialtration (PRISMA
machine; respective blood, dialysate, and
ultraltration ows 120 ml/minute, 500 ml/
hour, and 1000 ml/hour) was started
because of acute renal insufciency.
Because of probable invasive pulmonary
aspergillosis, combined intravenous anti-
fungal therapy was introduced, with vori-
conazole 4 mg/kg bd and caspofungin
50 mg/day. Because of persistent extensive
tracheal pseudomembranous lesions, posi-
tive tracheal aspirate cultures, positive
bronchoalveolar lavage, and a galactoman-
nan index of 8, all indicating treatment fail-
ure, treatment was switched on day 15 to
intravenous liposomal amphotericin 3 mg/
kg/day and ucytosine 1.5 g/day. The
patient was weaned from extracorporeal
membrane oxygenation (ECMO) 21 days
after ICU admission, bronchoalveolar
lavage uid cultures became negative 16
days after starting the new regimen, and
the patient was discharged on day 53. Dur-
ing ECMO, voriconazole and caspofungin
concentrations in blood were low to unde-
tectable, suggesting sequestration by bind-
ing to extracorporeal circuit components.
Micafungin [SEDA-30, 331; SEDA-31,
464; SEDA-32, 510]
Observational studies In a prospective
study in 98 hemopoietic stem cell transplant
recipients who received micafungin either
alone (n 8) or in combination with other
licensed antifungal therapies (n 90), 81
had pulmonary aspergillosis, 42 had graft-
versus-host disease, and 26 had neutro-
penia at the start of treatment; there were
no signicant adverse effects [92].
In a prospective multicenter trial of mica-
fungin, mean dosage and duration 171 mg/
day for 22 days, in 277 patients with inva-
sive fungal infections in hematological dis-
orders, 197 were assessed for clinical
efcacy; there were adverse events related
to micafungin in 39 (14%), but most of
them were mild and reversible [93c].
In a multicenter postmarketing study,
micafungin, mean dosage and duration
104 mg/day for 14 days, was given to 180
patients with a temperature exceeding
37.5  C, either with a proven fungal infec-
tion, or who were regarded as having prob-
able or possible fungal infections; 178 (58
with proven candidiasis, one with proven
aspergillosis, and 53 with suspected fungal
infections) were evaluated [94c]. There
were 69 drug-related adverse reactions,
mainly abnormal hepatic function tests, in
37 patients. One adverse reaction, a rash,
was probably causally related to the drug.
Comparative studies In a prospective ran-
domized study, 106 adults undergoing
hemopoietic stem cell transplantation were
randomly assigned to prophylaxis with
either micafungin 150 mg/day (n 52) or
uconazole 400 mg/day (n 52); mica-
fungin did not cause more adverse effects
than uconazole [95C].
Liver Hepatitis associated with micafungin
has been reported in a preterm infant [96A].
Antifungal drugs Chapter 27
Immunologic Micafungin-mediated immune
hemolysis is an uncommon but potentially
life-threatening adverse reaction that can lead
to renal insufciency. Two patients with
hematological diseases had massive intravas-
cular hemolysis followed by renal insuf-
ciency after administration of micafungin
[97A]. An indirect antiglobulin test showed
signicant agglutination when erythrocytes
were exposed to a mixture of micafungin
and either of the patients plasma samples,
suggesting that antibodies directed against
both micafungin and erythrocyte membranes
had caused hemolysis. However, the drug-
dependent antibodies from each patient did
not cross-react with caspofungin, suggesting
the presence of an antibody against a specic
part of the structure of micafungin, not com-
mon to all echinocandins. Another case of
micafungin-induced hemolysis during condi-
tioning therapy for hemopoietic stem cell
transplantation has been reported, in which
the direct antiglobulin test was negative
[98A]. A test for druganti-drug immune com-
plexes against micafungin, phosphate-buff-
ered saline, and complement (fresh serum)
was positive in a reactive system containing
the patient's serum, micafungin, and comple-
ment, but was negative in a system containing
the patient's serum and voriconazole or mica-
fungin and a serum sample from healthy
individual.
Susceptibility factors Neonates The ad-
verse effects and pharmacokinetics of an
high dose of micafungin (15 mg/kg/day for
5 days) have been assessed in a repeated
dose, open study in 12 preterm neonates
(median gestational age 27 weeks), with
suspected systemic infections [99c]. There
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28 Antiprotozoal drugs
ANTIMALARIAL DRUGS
Various public health programs that
involve mass administration of medicines
call for responsive pharmacovigilance sys-
tems to allow identication of signals of
rare or even common adverse reactions.
In developing countries in Africa, these sys-
tems are mostly absent, and where they
exist their performance is difcult to pre-
dict, given shortages of human, nancial,
and technical resources. Nevertheless, there
is no doubt of their importance, and
research to identify problems, with the
aim of offering pragmatic solutions, is
urgently needed.
In order to examine the effects of train-
ing and monitoring of health-care workers,
making supervisory visits, and the availabil-
ity of telecommunication and transport
facilities on the implementation of a phar-
macovigilance system, a descriptive study
has been performed in Mozambique [1c].
The lessons learnt were enumerated, as
were the challenges faced in implementing
a spontaneous reporting system in two rural
districts challenged by remote location,
poor telecommunication services, and poor
education of health professionals. A stan-
dardized yellow card system for spontane-
ous reporting of adverse drug reactions
was instituted after 35 health workers in
the selected districts had been trained to
diagnose, treat, and report adverse drugs
reactions to all medicines. They made rou-
tine site visits to identify and clarify any
Side Effects of Drugs, Annual 33
J.K. Aronson (Editor)
ISSN: 0378-6080
DOI: 10.1016/B978-0-444-53741-6.00028-3
# 2011 Elsevier B.V. All rights reserved.
Oscar Ozmund Simooya
problems in lling in and sending the forms.
One focal person was identied in each dis-
trict to facilitate communication between
the health-care professionals and the
National Pharmacovigilance Unit (NPU).
The report form was assessed for quality
and causality. The availability of telecom-
munications and transport was assessed.
Within the 14 months after the rst training
period, the NPU received 67 reports of sus-
pected adverse drug reactions involving 74
adverse events associated with 25 separate
drugs, 16 of which were causally certainly,
probably, or possibly linked to the reaction.
Most of the reported events were dermato-
logical reactions (83%). Antimalarial drugs
(chloroquine, amodiaquine, quinine, arte-
sunate, and sulfadoxine pyrimethamine)
were mentioned in 33 reports; 14 reactions
were classied as serious and there were
no fatal reactions. There were no reports
on adverse effects of antihelminthic drugs.
4-AMINOQUINOLINES
(CHLOROQUINE AND
CONGENERS) [SEDA-30, 336;
SEDA-31, 469; SEDA-32, 521]
Amodiaquine [SED-15, 178; SEDA-31,
469; SEDA-32, 521]
Liver The risk of hepatitis in patients tak-
ing long-term amodiaquine has been esti-
mated at one in 15 500, and two further
cases have been reported in patients with
malaria who were also given artesunate
[2A].
567
568
Susceptibility factors Children The adverse
effects of amodiaquine have been described
in two children [3A]. In one there was
an acute dystonic reaction and in the
other persistent asymptomatic bradycardia;
in both cases, plasma concentrations of
N-desethylamodiaquine and N-bis-des-
ethylamodiaquine, the main metabolites of
amodiaquine, were normal, despite a sup-
posed inadvertent overdose in the rst case.
Drugdrug interactions Artesunate Arte-
misinin-based combinations, including with
amodiaquine, are being increasingly used in
uncomplicated falciparum malaria. The inter-
action of amodiaquine 10 mg/kg and artesu-
nate 4 mg/kg has been investigated in a
randomized, three-phase, crossover study in
12 healthy volunteers [4c]. When the combi-
nation was used, the mean AUCs for dihy-
droartemisinin and desethylamodiaquine
were both reduced by one-third. There were
adverse events in four volunteers: grade 3
rises in aminotransferase activities (n 1),
neutropenia (n 2), and hypersensitivity
reactions (n 1). The clinical signicance of
these interactions is not known and the mech-
anism is unclear [5r].
Chloroquine and
hydroxychloroquine [SED-15, 722;
SEDA-30, 336; SEDA-31, 470; SEDA-32,
521]
Cardiovascular Cardiac toxicity due to
chronic chloroquine use includes conduc-
tion disorders, congestive heart failure, pro-
longation of the QT interval, myocardial
hypertrophy, and restrictive cardiomyopa-
thy. Third degree atrioventricular block
and sudden cardiac arrest due to ventricular
brillation caused by chloroquine, unusual
reactions, have been reported [6A].
A 21-year-old man who had taken chloroquine
250 mg/day for primary hemosiderosis since the
age of 8, suddenly collapsed with ventricular
brillation and had no spontaneous circulation.
A single shock was delivered and he regained
Chapter 28 Oscar Ozmund Simooya
consciousness, but an electrocardiogram
showed complete atrioventricular block and a
prolonged QT interval. There were no previous
cardiac symptoms and physical examination,
blood gas analysis, biochemistry, hematology,
and echocardiography were unremarkable.
Ten days after stopping chloroquine, he was
still in heart block and a permanent pacemaker
was implanted.
It could be that increasingly prolonged
atrioventricular conduction could have led
to complete heart block with simultaneous
QT interval prolongation, thus triggering
ventricular brillation.
Skin Pigmentation of the oral mucosa is not
uncommon in dark-skinned people and is
due to deposition of melanin. However in
white people, oral pigmentation calls for
robust investigation. Two Caucasians with
oral pigmentation have been described [7A].
A 65-year-old white woman developed diffuse
blue-grey pigmentation on the hard palate
mucosa and on the pretibial skin. She had
taken chloroquine diphosphate for rheuma-
toid arthritis for 3 years.
A 71-year-old woman developed a burning
sensation on the dorsal surface of the tongue.
There were atrophic areas on the tongue and
blue-grey pigmentation on the hard palate
mucosa and on the skin of her arm. She had
taken chloroquine diphosphate for 10 years
for Sjgren's syndrome.
Biopsies in both patients showed dark-
brown granular pigment in the lamina pro-
pria, mainly located in broblasts and in
the subepithelial and perivascular regions.
Together with the clinical appearances,
these ndings conrmed the diagnosis of
drug-induced pigmentation. In Caucasians,
isolated and well-circumscribed pigmented
lesions are usually diagnosed as melano-
cytic nevi, melanotic macules, amalgam
tattoos, or more uncommonly as initial
signs of melanoma. Diffuse pigmentation
may be due to underlying systemic disor-
ders, such as Addison's disease, PeutzJe-
gher syndrome, or HIV infection. It may
also be due to drugs such as antimalarials,
tetracyclines, and non-steroidal anti-inam-
matory drugs.
 Antiprotozoal drugs Chapter 28
Hair Depigmentation of scalp and body
hair following hydroxychloroquine treat-
ment (generalized poliosis) has been
reported [8A].
A 25-year-old Caucasian woman taking
hydroxychloroquine for discoid lupus ery-
thematous developed generalized symmetrical
depigmentation of the scalp and body hair, or
acquired poliosis. Hydroxychloroquine was
withdrawn and she grew new hair in her natu-
ral color within 3 months.
Generalized poliosis in patients with
strawberry blonde hair and in African
patients with vitiligo have been reported
in patients taking antimalarial drugs. The
mechanism is not known but it is said to
be due to binding of antimalarial drugs to
eumelanin and pheomelanin, disturbing
melanogenesis.
Meoquine [SED-15, 2232; SEDA-30,
337; SEDA-31, 471; SEDA-32, 523]
Nervous system The literature on meo-
quine neurotoxicity has been reviewed
[9R]. Nausea, dizziness, sleep disturbances,
anxiety, and psychosis have been reported.
Female patients and patients with a low
body mass index are at greater risk.
It has been hypothesized that the mecha-
nisms whereby meoquine increases the
risk of seizures in patients with a history
of seizures, which may be via altered neuro-
nal calcium homeostasis, altered gap-junc-
tion functioning, and neuronal cell death,
are particularly associated with a mutation
Au1 in EPM1, a gene that is associated with pro-
gressive myoclonic epilepsy type 1, and
hence altered GABA activity [10H]. The
author proposed that meoquine should
be contraindicated in people with the
EPM1 mutation and in those with a history
of myoclonus or ataxia, or a family history
of degenerative neurological disorders that
are consistent with the presence of the
EPM1 mutation.
Psychiatric Psychiatric adverse effects of
meoquine are common in adults, but rare
569
in children. Acute mania has been reported
in an 11-year-old otherwise healthy girl
from Eastern India after a therapeutic dose
of meoquine for Plasmodium falciparum
malaria; she recovered with risperidone
[11A].
PRIMAQUINE AND
CONGENERS [SED-15, 2919]
Tafenoquine and primaquine
Comparative studies Tafenoquine is an 8-
aminoquinoline analogue of primaquine,
which is being developed for treatment and
prevention of malaria. It has been particu-
larly recommended for the radical cure of
Plasmodium vivax, which causes up to 80
million cases of relapsing malaria annually.
Tafenoquine and primaquine, currently the
drug of choice for vivax malaria, have been
compared in an open study in 1512 Austra-
lian military personnel serving in the South
Pacic, who were assigned to one of three
tafenoquine 3-day regimens: 400 mg/day,
200 mg bd, 200 mg/day, or primaquine
22.5 mg/day doxycycline 100 mg/day over
14 days in Bougainville and in Timor Leste
for post-exposure prophylaxis. The most
common adverse effects were nausea,
abdominal discomfort, and diarrhea. There
was a dose-related reduction in adverse
events when the dose of tafenoquine was
reduced: the lowest dosage of 600 mg/day
over 3 days produced rates of adverse events
similar to that of primaquine doxycycline.
A short course of tafenoquine appears to
offer better adherence outcomes than the
longer course of primaquine.
Proguanil hydrochloride and
atovaquone
Skin Bullous erythema multiforme occurred
in a patient who took atovaquone and pro-
guanil hydrochloride (Malarone) [12A].
570
A 55-year-old Kenyan woman with uncompli-
cated malaria and a history of allergies to sul-
fadoxine/pyrimethamine (Fansidar) and
chloroquine was given artesunate 2.4 mg/kg/
day for 3 days, with successful clearance of
symptoms and parasites and no adverse
events. To ensure parasite clearance she was
then given Malarone (atovaquone 250 mg
proguanil hydrochloride 100 mg) once a day
for three consecutive days. The rst dose was
associated with mild generalized pruritus and
within 2 hours of the second she developed
intense whole-body pruritus and erythema of
the nipples and pubic areas. The nal dose
was withheld, but by this time she had devel-
oped a dusky, erythematous, macular rash on
the medial aspects of both arms with early
bullae. By the next day the eruption had
markedly progressed, and an aspirate of
the bulla uid contained primarily eosinophils.
She was given a single intravenous dose
of hydrocortisone 250 mg and gradually
recovered.
Bullous erythema multiforme following
treatment with Malarone is rare. Artesu-
nate was well tolerated by the patient, and
given its short half-life is less likely to have
provoked the bullous eruption.
PYRIMETHAMINE AND
CONGENERS [SED-15, 2984;
SEDA-32, 523]
Observational studies During a surveil-
lance period of 2 years, 1552 patients with
uncomplicated P. falciparum malaria who
had received sulfadoxine pyrimethamine
with artesunate on the Northern coast of
Peru were followed up; 8.8% reported at
least one adverse effect, the most common
being vomiting, nausea, headache, abdomi-
nal pain, dizziness, and fever; there were
no severe adverse effects [13c].
Pregnancy The pharmacokinetics of sulfa-
doxine and pyrimethamine 1500 75 mg
have been studied in Papua New Guinea in
30 women in the second or third trimester
of pregnancy and in 30 age-matched non-
Chapter 28 Oscar Ozmund Simooya
pregnant women [14C]. Pregnancy was asso-
ciated with signicantly lower AUCs of
sulfadoxine and pyrimethamine (both by
33%) and of N-acetylsulfadoxine (by 50%).
The authors recommended that higher doses
than those recommended for non-pregnant
patients should be considered in pregnancy.
QUININE AND
CONGENERS [SED-15, 3002;
SEDA-31, 472; SEDA-32, 524]
Cardiovascular A 5-year-old African-
Nigerian girl was given intravenous quinine
dihydrochloride for uncomplicated malaria,
developed ventricular brillation, and died
within 1.5 hours of the start of the infusion
[15A].
Hematologic Drug-induced immune throm-
bocytopenia can occur when drug-depen-
dent antibodies, themselves non-reactive,
bind to specic platelet membrane glycopro-
teins in the presence of the drug [16E]. When
two murine monoclonal antibodies that rec-
ognized the N-terminus of the glycoprotein
IIb beta-propeller domain only when qui-
nine was present were incubated with plate-
lets in the presence of quinine, both
mimicked the behavior of antibodies from
patients with quinine-induced immune
thrombocytopenia. These antibodies could
be useful in further exploring the mechanis-
tic nature of this adverse reaction.
Thrombocytopenia with or without
microangiopathy and schistocytes in
patients taking quinine can be associated
with deciency of a protease, ADAMTS13,
that cleaves von Willebrand factor. In a ret-
rospective review, of six women (mean age
62, range 4373 years), with quinine-associ-
ated thrombotic microangiopathy, in whom
ADAMTS13 was measured before plasma
exchange was performed, four had renal
failure requiring dialysis; D-dimers were
raised in ve, markedly in four [17c].
Antiprotozoal drugs Chapter 28
ADAMTS13 was normal in four patients
and mildly reduced in two. The authors
concluded that the pathophysiology of qui-
nine-associated thrombocytopenia and
schistocytosis is distinct from that seen in
most cases of idiopathic thrombocytopenia.
They recommended that the term quinine-
associated thrombotic microangiopathy
should be used.
Skin Fixed drug eruptions have been attrib-
uted to quinine [18A,19A].
Management of adverse reactions In a
genome-wide screen using the yeast dele-
tion strain collection, quinine-sensitive
mutants included several that were defec-
tive in tryptophan biosynthesis (trp strains)
[20EH]. This sensitivity was conrmed in
independent assays and was suppressible
with exogenous tryptophan. Quinine also
inhibited [3H]-tryptophan uptake by the
cells, and the quinine sensitivity of a
trp1Delta mutant could be rescued by over-
expression of tryptophan permeases,
encoded by TAT1 and TAT2. The site of
quinine action was identied specically as
the high-afnity tryptophan/tyrosine per-
mease, Tat2p, with which quinine associ-
ated in a tryptophan-suppressible manner.
Quinine also reduced tyrosine concentra-
tions through tyrosine-suppressible hyper-
sensitivity of an aro7Delta deletion strain,
which is auxotrophic for tyrosine (and phe-
nylalanine). The authors therefore sug-
gested that dietary tryptophan
supplements might help to prevent the
adverse effects of quinine.
ENDOPEROXIDES [SED-15,
342; SEDA-30, 338; SEDA-31, 473;
SEDA-32, 525]
There are ve artemisinin derivatives
that are active in malaria: arteether, arte-
mether, artemisinin, artesunate, and
dihydroartemisinin.
571
Uses The antiviral activities of artemisinin
and artesunate have been reviewed, includ-
ing actions on human cytomegalovirus and
other members of the herpesvirus family
(for example, herpes simplex virus type 1
and EpsteinBarr virus), hepatitis B virus,
hepatitis C virus, and bovine viral diarrhea
virus [21R].
Systematic reviews Adverse reactions to
artemisinin derivatives have been reviewed
in a preliminary survey of 188 studies, of
which 108 (9241 patients) fullled criteria
for an analysis that partly used the
Cochrane methods [22M]. They included
healthy volunteers and patients with both
uncomplicated and severe malaria in either
controlled or non-controlled studies.
Adverse events, laboratory measurements
(hematology in 4062 patients and blood
chemistry in 3893 patients), and electrocar-
diography (2638 patients) were analysed.
There were no differences among the vari-
ous derivatives. There were no serious or
severe adverse events. The most commonly
reported adverse events were gastrointesti-
nal. Occasional neutropenia (1.3%), reticu-
locytopenia (0.6%), and raised liver
enzymes (0.9%) were reported. Transient
bradycardia and prolongation of the QT
interval were reported in about 1.1% of
patients. Neurological assessment was per-
formed primarily in patients with severe
malaria; there was no difference from
quinine and four neuropsychiatric adverse
events were reported in patients taking
concomitant meoquine.
Teratogenicity After 62 pregnant Sudanese
women had been given an artemisinin com-
pound during the rst trimester of pregnancy
they were followed until delivery and their
babies were followed for 1 year [23C].
The treatments were artemether injections
(n 48), artesunate sulfadoxine pyri-
methamine (n 11), and artemether
lumefantrine (n 3). Records were available
for 51 of these patients, and in each case
malaria was conrmed. Two of the women
given artemether in the rst trimester had
spontaneous miscarriages; one at 20 weeks of
gestation and the other at 22 weeks, both
572
while receiving quinine for a second attack of
malaria. The other 60 all had normal deliver-
ies of full-term babies. There were no congen-
ital malformations in any one baby and none
died during the rst year of life. This small
study suggests that artemisinin derivatives
are safe during early pregnancy, but further
research is needed.
Arteether
Psychiatric There is still concern about the
potential of artemisinin derivatives to cause
neurotoxic effects, and severe and irrevers-
ible brain damage has been reported in
some animal and human studies. Mania
developed in an adolescent with a family
history of chloroquine-induced psychosis
after treatment with a/b-arteether [24A].
A 16-year-old female student with normal motor
and mental milestones and no previous history of
psychiatric illness developed falciparum malaria
and was given a/b-arteether 150 mg/day for 3
days. A few days later she started talking exces-
sively, boasting about her abilities, appearing
blissful, and always on the move. Her father
and paternal uncle had developed psychoses
after taking chloroquine for malaria, which in
both cases had resolved spontaneously. She had
no motor decits, but she was talkative and
over-familiar, with an elevated mood, thought
acceleration, and grandiose delusions. Blood
chemistry and hematology, liver function tests,
and electroencephalography were normal. She
was treated successfully with sodium valproate
and quetiapine titrated to doses of 500 and
100 mg/day respectively.
Fever and malaria can induce a psychosis, but
in this case, fever was an unlikely cause, as
fever-induced psychosis is usually polymor-
phic and associated with some alteration of
consciousness and orientation, which were
absent; there was also no past history of an
altered mental state after febrile illnesses. Fal-
ciparum malaria leading to psychiatric
sequelae usually presents with cerebral
malaria, which has well-dened neurological
signs. Antimalarial drugs such as chloroquine,
meoquine, and quinine can cause psychoses,
and given substantial evidence of neurotoxic-
ity after exposure to artemisinin compounds,
Chapter 28 Oscar Ozmund Simooya
arteether administration was the most likely
cause in this case. The family history of chlo-
roquine-induced psychosis suggests a possible
hereditary predisposition, which requires fur-
ther investigation.
Artesunate
Nervous system Artesunate and meo-
quine are the recommended rst-line drugs
for uncomplicated malaria in much of South
East Asia. However, there are no detailed
studies of the potential central nervous sys-
tem effects of this combination in very young
children. In 91 children with uncomplicated
malaria, who were randomized to artesunate
monotherapy (n 45) for 7 days or artesu-
nate for 7 days plus meoquine on days 7
and 8 (n 46), coordination and behavior
were assessed on days 0, 7, 9, 10, 14, and 28
[25C]. As controls, 36 non-febrile children
from the same population were tested on
days 0, 7, 14, and 28. The presence of malaria
and fever had signicant negative effects, but
antimalarial treatment did not.
Sensory systems Auditory and vestibular
function In 93 patients with acute uncom-
plicated malaria auditory function was
tested before and after a 3-day course of
artesunate 4 mg/kg/day combined with mef-
loquine 25 mg/kg, using tympanometry,
audiometry, and auditory brain stem
response [26c]. Hearing loss on day 0 was
common (57%) and was associated with
age only. However, no patient had a thresh-
old change exceeding 10 decibels between
day 0 and day 7 at any tested frequency,
and none had a shift in wave III peak
latency of more than 0.3 msec between
baseline and day 7. Thus, there was no evi-
dence of auditory toxicity in these patients
7 days after a course of artesunate and
meoquine.
Drugdrug interactions Amodiaquine See
Amodiaquine above.
Antiprotozoal drugs Chapter 28
DRUGS USED IN THE
TREATMENT OF
PNEUMOCYSTIS JIROVECII
INFECTIONS
For sulfonamides and co-trimoxazole (tri-
methoprim sulfamethoxazole) see Chap-
ter 26; for dapsone see Chapter 30.
DRUGS USED IN THE
TREATMENT OF OTHER
PROTOZOAL INFECTIONS
For the benzimidazoles see Chapter 31.
Metronidazole [SED-15, 2323; SEDA-
30, 339; SEDA-31, 475; SEDA-32, 525]
For regimens used in the eradication of
Helicobacter pylori, see Chapter 36.
Systematic reviews It is estimated that
4050 million people worldwide who are
infected with Entameba histolytica develop
amebic colitis, resulting in up to 100 000
deaths per year. Metronidazole is the drug
of choice and is often given in combination
with other drugs in order to eliminate the
parasites. However, there is insufcient evi-
dence to support combination therapy,
while the occurrence of adverse reactions
to metronidazole and the possibility of par-
asite resistance are other concerns.
The different drugs used against amebic
colitis alone or in combination have been
compared in a systematic review, as have
single-dose regimens compared with longer
regimens [27M]. In all, 37 trials with 4487
participants were included. The key out-
comes were clinical failure (absence of par-
asites in the stool but little or no relief
of symptoms), parasitological failure
(persistence of Entameba histolytica cysts
or trophozoites), relapse (reappearance of
573
parasites in the stool after initial clearance),
and serious adverse events. Metronidazole
was associated with more clinical failures
than tinidazole and with more adverse
events. Combination therapy resulted in
fewer parasitological failures than metro-
nidazole alone. There were more adverse
events in those who took metronidazole
compared with tinidazole; they included
mild to moderate gastrointestinal com-
plaints, such as nausea, reduced appetite,
vomiting, and a metallic or bitter taste.
Placebo-controlled studies Intravaginal and
oral metronidazole have been compared in
the treatment of bacterial vaginosis in a double
blind, randomized, placebo-controlled study
in 129 women (mean age 36 years) who took
oral metronidazole 2 g/day for 2 days and 134
women (mean age 36 years) who used intrava-
ginal metronidazole 1 g/day for 2 days [28C].
There was no difference in cure rates. Nausea
was the most common adverse event; it was
reported in 10% of those who used intravagi-
nal metronidazole and 30% of those who used
oral metronidazole; other adverse events were
abdominal pain (17% versus 32%) and a
metallic taste (8.8% versus 18%). The authors
concluded that intravaginal metronidazole is
as effective as oral metronidazole in the treat-
ment of bacterial vaginosis with signicantly
fewer adverse events.
Skin Contact dermatitis, a rare manifesta-
tion of topical metronidazole, has been
reported in two nurses [29A].
A 67-year-old female community nurse with
rosacea and no history of allergies, but a long his-
tory of a basal cell carcinoma caused by exposure
to X-rays when she was young, used topical met-
ronidazole, as Rozex cream (Galderma Nordic
AB, Bromma, Sweden), for 2 days and devel-
oped a weeping vesicular erythematous dermati-
tis. The cream was discontinued and she was
given systemic tetracycline. Patch tests with
Rozex cream 5% and metronidazole were posi-
tive. She had previously handled metronidazole
tablets and had used metronidazole pessaries
without any adverse reactions.
A 40-year-old nurse with a history of contact
allergy to metronidazole developed rosacea
and used metronidazole cream (Alpharma,
574
Gentoe, Denmark) for a few days. She devel-
oped facial edema, swelling, and itching. Tests
with metronidazole cream 1% and Rozex gel
(0.75% metronidazole) were positive after 3
days. She had handled parenteral metronida-
zole and oral tablets before without any
adverse reactions.
The rapid onset of the facial dermatitis
after topical metronidazole cream in both
patients suggested previous sensitization,
most probably from occupational exposure.
MISCELLANEOUS DRUGS
For praziquantel see Chapter 31.
Eornithine [SED-15, 1207; SEDA- 30,
341; SEDA-32, 526]
Comparative studies A standard regimen
of intravenous eornithine has been
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[16] Bougie DW, Birenbaum J, Rasmussen M,
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 M. Lartey, K. Torpey, and J.K. Aronson
29
Editor's notes: Interferons are covered
in Chapter 37.
Key to abbreviations and alternative names
of some antiviral drugs:
3TC: lamivudine (dideoxythiacytidine)
AZT: zidovudine (azidothymidine)
D4T: stavudine (didehydrodideoxythmidine)
DDI: didanosine (dideoxyinosine)
DDC: zalcitabine (dideoxycytidine)
TMC125: etravirine
DRUGS ACTIVE AGAINST
CYTOMEGALOVIRUS
Cidofovir [SED-15, 771; SEDA-30, 343;
SEDA-31, 477; SEDA-32, 529]
Tumorigenicity The potential carcino-
genicity of cidofovir has been highlighted
in animal and in vitro experiments [1E],
and an invasive squamous cell cancer
has anecdotally been reported to have
arisen from squamous papillomatosis in a
patient who was given multiple injections of
cidofovir [2A]. The adverse effects of intra-
lesional cidofovir in recurrent respiratory
papillomatosis of the larynx have therefore
been the subject of a systematic review of 31
studies involving 188 patients, with particular
attention to concerns about its potential carci-
nogenicity [3MR]. Five patients developed
Side Effects of Drugs, Annual 33
J.K. Aronson (Editor)
ISSN: 0378-6080
DOI: 10.1016/B978-0-444-53741-6.00029-5
# 2011 Elsevier B.V. All rights reserved.
Antiviral drugs
dysplasia of the larynx during treatment
(2.7%), which is similar to the incidence of
spontaneous malignant degeneration in the
condition (23%). The authors concluded
that intralesional cidofovir does not increase
the risk of laryngeal dysplasia. Other
adverse effects of intralesional and intra-
venous cidofovir were also reviewed in this
article.
DRUGS ACTIVE AGAINST
HERPESVIRUSES [SEDA-29,
301; SEDA-30, 343; SEDA-31, 478;
SEDA-32, 530]
Aciclovir
Psychiatric Cotard's syndrome is a rare
psychiatric condition, in which the patient
has a strong delusion of being dead. Two
cases have been reported in patients taking
aciclovir or valaciclovir [4A].
A 35-year-old woman on long-term hemodial-
ysis, taking prednisolone 5 mg/day and ciclo-
sporin 50 mg/day developed herpes zoster
and was given valaciclovir 1 g/day. After two
doses she became restless and on the next
day she was tired, her body felt unfamiliar,
and she felt shut off from the surrounding
world. That night, after the third dose she
developed anxiety and visual and auditory
hallucinations. The next morning she could
barely walk, cried out, and appeared terried.
Her mother reported that this had been pre-
sent for several hours. After 45 minutes of
hemodialysis her condition improvedshe no
longer cried out and could speak. After an
hour of dialysis she explained that she had
been convinced she was dead, but that now
she was not quite so sure. Valaciclovir was
577
578
withdrawn and 30 hours after the last dose her
serum aciclovir concentration before dialysis
was high, at 19.4 mmol/l; the serum concentra-
tion of the main metabolite, 9-carboxymethox-
ymethylguanine (CMMG) was also high, at 90
mmol/l, and fell during dialysis to 21 mmol/l,
which is still high.
A 36-year-old man who had received a bone
marrow transplant was taking ciclosporin 400
mg/day and prednisolone 25 mg/day. He devel-
oped herpes mucositis and was given oral vala-
ciclovir 500 mg bd. After 6 days he developed
diarrhea and dehydration but was afebrile, nor-
motensive, and lucid. His plasma creatinine
concentration was 419 mmol/l. The next day he
was confused but a CT scan of the brain was
normal. On day 8 valaciclovir was replaced with
intravenous aciclovir 500 mg/day. On day 9 he
awoke with fear, anxiety, and slurred speech;
he was screaming and asking if he was dead.
Intravenous diazepam resolved the symptoms
only temporarily. The feeling of being dead
reappeared the following night and he felt
depressed and tired the day after. However,
his confusion had subsided and his speech
improved. During the next night he again
believed that he was dead and considered that
everybody around him was dangerous. His
mental state and renal function nally returned
to baseline on day 12. A blood sample 16 hours
after the nal dose on day 9 contained aciclovir
39 mmol/l and CMMG 29 mmol/l.
Skin In a 20-year-old woman with acute
allergic contact dermatitis of the lips and
perioral skin after the application of a
cream containing aciclovir, scratchpatch
tests (patch tests after scarication of the
epidermis) with aciclovir 1%, 5% petrola-
tum, and the other components of the
cream (Cycloviran) produced strong posi-
tive reactions to aciclovir and petrolatum
only; conventional patch tests had been
negative or doubtful [5A]. Topical 1% fos-
carnet cream did not produce a reaction.
Valaciclovir
Placebo-controlled studies In a double-
dummy, randomized, placebo-controlled
study of 839 patients aged 1875 years
with Bell's palsy, prednisolone, alone and
in combination with valaciclovir, shortened
the time to recovery [6C]. Headache and
Chapter 29 M. Lartey, K. Torpey, and J.K. Aronson
gastrointestinal disturbances were the most
common adverse events, and the frequencies
of all adverse events were similar in all the
groups.
DRUGS ACTIVE AGAINST
HEPATITIS VIRUSES
Adefovir [SED-15, 35; SEDA-30, 344;
SEDA-31, 480; SEDA-32, 530]
Urinary tract In 290 patients with chronic
hepatitis B, of whom 145 had taken adefo-
vir 10 mg/day, and 145 patients matched
for age, sex, and baseline estimated glomer-
ular ltration rate (eGFR), adefovir was a
signicant predictor of renal dysfunction
(HR 3.94) [7C].
There was impaired renal tubular concen-
trating function within 2 years of therapy
with adefovir in 11 recipients of kidney trans-
plants with chronic hepatitis B virus infection
[8c]. There was a signicant rise in serum
creatinine from 125 to 141 mmol/l and a
signicant increase in 24-hour proteinuria.
Urinary pH fell from 6.60 to 5.65 and bicar-
bonaturia from 0.33 to 0.10 mmol/hour.
Urinary hydrogen ion excretion rose from
1.79 to 2.44 mmol/l and there were signicant
falls in phosphatemia, phosphaturia thresh-
old, and tubular phosphorus reabsorption;
the phosphorus index of excretion rose.
In 37 patients with hepatitis B virus
infection, including 17 with hepatic cirrho-
sis, who were given adefovir plus lamivu-
dine, serum creatinine concentrations rose
in 14 cases and serum phosphate concentra-
tions fell in six [9c]. Those who took combi-
nation therapy for 36 months or longer had
a signicantly increased incidence of raised
serum creatinine concentrations. Fanconi
syndrome occurred in a 57-year-old woman
with cirrhosis after adefovir was added to
lamivudine.
A 58-year-old man developed Fanconi syn-
drome and acute renal insufciency after tak-
ing adefovir 10 mg/day for more than 1 year;
there was also generalized osteoporosis
Antiviral drugs Chapter 29
(see Musculoskeletal below) [10A]. The syn-
drome resolved after drug withdrawal.
Musculoskeletal Severe hypophosphatemic
osteomalacia occurred in a 42-year-old
man with hepatitis B virus-related chronic
liver disease after he had taken adefovir
dipivoxil 10 mg/day for 6 months; the bone
lesions resolved when the hypophosphate-
mia was corrected [11A].
Drug resistance Among 65 patients with
hepatitis B e antigen (HBeAg)-positive
chronic hepatitis B who took adefovir dipi-
voxil 10 mg/day for more than 1 year, ade-
fovir resistance mutations A181V or
N236T developed in 13, and were rst
observed after 195 weeks [12c]. Adefovir
caused no serious adverse effects.
Entecavir
Acidbase balance Of 16 patients with
hepatic cirrhosis and chronic hepatitis B
infection, ve developed lactic acidosis
after 4240 days of treatment with enteca-
vir; all ve had highly impaired liver func-
tion [13c]. One patient died, but in the
other four the lactic acidosis resolved after
withdrawal of entecavir. The serum lactate
concentrations were not increased in the
other 11 patients, who all had less severe
liver impairment. ChildPugh scores did
not correlate with the development of lactic
acidosis, but MELD (Model for End-Stage
Liver Disease) scores did, as did serum
bilirubin, creatinine, and international
normalized ratio (INR). The authors sug-
gested that entecavir should be used
cautiously in patients with severely
impaired liver function.
Hematologic A 30-year-old man with hep-
atitis B virus infections took oral entecavir
0.5 mg/day for 2 days and developed a
hoarse voice, erythema with pruritus on
his buttocks, and a leukocytosis, with a sub-
sequent eosinophilia [14A]. Entecavir was
579
withdrawn. Scratch tests and patch tests
were positive with entecavir.
Liver A 49-year-old-man, a healthy carrier
of hepatitis B virus, was given chemo-
therapy for non-Hodgkin's lymphoma, and
entecavir was added when his hepatitis B
virus DNA rose [15A]. However, the liver
function tests rose over threefold and ente-
cavir was withheld; the liver function tests
quickly improved.
Ribavirin
Since ribavirin is almost always used in
combination with interferons, it can be dif-
cult to know whether adverse events, if
drug-induced, are due to one or the other.
In many cases authors do not even discuss
this problem, often attributing the supposed
adverse effects to the interferon. In some
cases withdrawal of one of the agents can
provide evidence, and in other cases there
may be other clues. For example, in cases
of skin pigmentation at the site of injection
of interferons, the adverse effect may be
presumed to be due to interferon [16A], a
type II between-the-eyes adverse effect
[17H]. In one case hemolytic anemia was
attributed to interferon rather than riba-
virin because the patient had previously
taken a course of interferon without
adverse effects [18A]; presumably the infer-
ence was that the patient had been sensi-
tized by the previous course. A systematic
review of cases in which the drugs were
used together and individually can also
yield useful information, as in the case of
pneumonitis in patients being treated with
interferon and ribavirin, attributed to inter-
feron [19AM]. Similarly, in cases of ocular
myasthenia [20A], pleural effusion [21A],
and cataract [22A] the interferon was
blamed because no previous cases were
found in association with ribavirin alone.
In cases in which the adverse event persists
for some time after the withdrawal of pegy-
lated interferon and ribavirin, the long half
580
of peginterferon is cited as a possible expla-
nation, but this is weak evidence in such
cases. In some cases it may be impossible
to tell whether the adverse event, if drug-
induced, was due to one or other of the
drugs or to the combination.
See also Interferons in Chapter 37.
Respiratory A 50-year-old man developed
progressive dyspnea over 4 months, pro-
gressing to a cough followed by frequent
and abundant elimination of bronchial
casts. The symptoms resolved 30 days after
withdrawal and no other causes were found
[23A].
Nervous system A 64-year-old man de-
veloped parkinsonism while taking peg-
interferon alfa-2a and ribavirin for chronic
hepatitis C and did not improve when the
drugs were withdrawn; he responded to
co-beneldopa [24A]. This may have been
coincidental.
Sensory systems Auditory function Senso-
rineural hearing loss has been attributed to
interferon plus ribavirin [25A].
A 57-year-old man developed vertigo, tinni-
tus, bilateral hearing loss, and postural intoler-
ance temporally related to the administration
of pegylated interferon alfa-2b ribavirin for
chronic hepatitis C viral infection. He had
bilateral high-frequency sensorineural hearing
loss, vertigo with saccadic intrusions during
xation and smooth visual pursuit, supine
hypertension and orthostatic hypotension with
inadequate reex compensatory cardiovascu-
lar responses, and a hemolytic anemia. Audi-
ometry showed changes that suggested
damage to the cochlear outer hair cells. With-
drawal of therapy resulted in rapid clinical res-
olution with mild residual hearing loss and
tinnitus.
Other similar cases have been reported,
albeit in some cases with unilateral effects
[26A, 27A], which suggests that the drugs
may not have been responsible.
Psychological Cognitive dysfunction has
been studied in 47 patients with chronic
hepatitis C during treatment with peginter-
feron alfa ribavirin for 48 weeks in stan-
dard doses; cognitive performance was
Chapter 29 M. Lartey, K. Torpey, and J.K. Aronson
signicantly impaired after 12 weeks com-
pared with controls [28C].
In 26 patients with chronic hepatitis C
taking peginterferon alfa-2a or alfa-2b and
ribavirin all aspects of attention were
impaired after 12 weeks and the dysfunc-
tion did not resolve 8 weeks after with-
drawal [29c]. The authors hypothesized
that there may have been irreversible dam-
age to the dorsolateral prefrontal cortex or
anterior cingulate cortex.
Endocrine Of 107 patients with non-cir-
rhotic chronic hepatitis C, who were given
interferon plus ribavirin for 24 weeks, 20
developed thyroid dysfunction compared
with 60 controls awaiting treatment [30C].
Women were at a higher risk (RR 11).
Hypothyroidism was more common than
hyperthyroidism.
Hematologic Factors that could help pre-
dict hematological abnormalities in patients
with chronic hepatitis C taking pegylated
interferon and ribavirin have been studied
in 136 patients over 4 years, of whom 52
developed neutropenia (n 28), anemia
(30), or thrombocytopenia (11). Genotype
1, a history of hypertension, a low baseline
platelet count, a low baseline hemoglobin,
and a raised serum creatinine concentration
were signicant factors [31c].
Pure red cell aplasia has been attributed
to pegylated interferon alfa-2b plus riba-
virin [32A, 33A].
Mouth Hyperpigmentation of the oral mu-
cosa and tongue has been reported in a
40-year-old Caucasian woman with hepati-
tis C infection who had taken peginterferon
alfa-2a 90180 micrograms/week plus riba-
virin 1 g/day for 12 weeks; she had tongue
discomfort and noticed irregular black
patches on the lateral surface of the tongue
and oral mucosa [34A]. Similarly, a 54-year-
old woman developed numerous asymp-
tomatic dark brown macules on her tongue
and oral mucosa after taking peginterferon
alfa-2a and ribavirin for 4 months [35A],
and a 66-year-old woman developed dark
brown, asymptomatic pigmentation on
the dorsum of the tongue after taking
Antiviral drugs Chapter 29
peginterferon alfa plus ribavirin for 32
weeks; her lesions resolved within 6 months
after withdrawal [36A].
Gastrointestinal 53-year-old woman with
hepatitis C infection was given peginter-
feron 180 micrograms/week and ribavirin
1.2 g/day. After 12 weeks she developed a
neutropenia of 550  106/l and a secondary
enterocolitis, with bowel wall thickening
involving the cecum and proximal ascend-
ing colon; she responded to broad-spectrum
antibiotics, supportive treatment, and G-
CSF (lgastrim) [37A].
Skin The addition of ribavirin to interferon
therapy may be associated with an
increased risk of adverse skin reactions
[38c]. The adverse cutaneous events that
can occur in patients taking interferon plus
ribavirin have been reviewed [39R].
In three cases oral lichen planus wors-
ened during treatment of chronic hepatitis
C with pegylated interferon and ribavirin
[40A].
A 58-year-old woman developed a liche-
noid eruption on the hands after taking
interferon alfa-2b and ribavirin for 6 days;
the lesions resolved within 1 week after
withdrawal [41A].
Sexual function In a 37-year-old man tak-
ing ribavirin and pegylated interferon for
hepatitis C, the percentage of progressive
spermatozoa and the number of motile
sperm per ejaculate fell during treatment
[42A]. The round cell/spermatozoa ratio, a
measure of abnormal spermatogenesis, rose
from 2.6% to 24% and returned to baseline
4 months later. The sperm DNA fragmen-
tation index increased markedly during
treatment from 15% to 69% at 7 months
and was still raised 8 months later.
Infection risk The susceptibility factors for
bacterial infections have been studied in
patients co-infected with HIV and hepatitis
C virus taking pegylated interferon with or
without ribavirin [43c]. There were 18 bac-
terial infections in 17 of the 383 patients
who received at least one dose of study
medication. There were two cases of
581
pyelonephritis and one case of prostatitis
(Escherichia coli), one case of diarrhea
(Klebsiella oxytoca), two of septicemia
(one due to Salmonella enterica and one
to Staphylococcus aureus), one case of
Streptococcus pneumoniae meningitis, eight
lower respiratory tract infections (two in
the same patient), one case of sinusitis,
and two cases of cellulitis. Factors that were
independently associated with the risk of
bacterial infection were related to the dura-
tion of hepatitis C infection and to markers
of liver brosis but not to neutropenia or
characteristics of the HIV infection, includ-
ing CD4 cell count.
A 35-year-old man, who had had a splenec-
tomy at age 14 years but had not been immu-
nized against Streptococcus pneumoniae,
developed pneumococcal meningitis while
taking interferon and ribavirin for chronic
hepatitis C [44A].
A similar case has been reported in a 61-
year-old woman, with a fatal outcome
[45A].
Pregnancy Ribavirin is a category X prod-
uct in the US FDA's classication, which
applies when studies in animals or human
beings have demonstrated fetal abnormali-
ties or there is evidence of fetal risk based
on human experience or both, and the risk
of use of the drug in pregnant women
clearly outweighs any possible benet; in
such cases the drug is contraindicated in
women who are or may become pregnant
[46S]. It is also contraindicated in men
whose partners may become pregnant.
The US Ribavirin Pregnancy Registry is a
surveillance system for exposure to riba-
virin during pregnancy or within 6 months
after treatment is stopped; it relies on
patients and health-care providers to pro-
vide voluntary outcome data [47S].
Drugdrug interactions Azathioprine In a
retrospective review of the medical records
of eight patients who developed severe
pancytopenia after-administration of aza-
thioprine, interferon alfa, and ribavirin,
bone marrow suppression reached nadir
after a mean interval of 4.6 weeks, at which
582
time the mean platelet count was 70  109/l,
the mean hemoglobin 7.8 g/dl, and the
mean neutrophil count 450  106/l [48c].
All had a normal thiopurine methyltrans-
ferase genotype. In two patients in whom
azathioprine metabolites were measured,
myelotoxicity was accompanied by raised
total methylated metabolite concentrations
and reduced 6-tioguanine nucleotide con-
centrations. Pegylated interferon alfa and
ribavirin were withdrawn and the full blood
count returned to normal. There was no
recurrence when peginterferon was reintro-
duced with ribavirin or azathioprine alone.
The authors concluded that the combina-
tion of inosine monophosphate dehydroge-
nase inhibitors with purine analogues
should be avoided. Another similar case
has been reported [49A].
Monitoring drug therapy In a systematic
review of the use of plasma ribavirin con-
centrations to monitor therapy in patients
with chronic hepatitis C (30 studies), a pre-
viously published nine-step decision-mak-
ing algorithm was used to help determine
whether measurement is warranted [50M].
Some studies have supported and others
have refuted the usefulness of ribavirin
measurement; most had methodological
limitations, such as small sample size, retro-
spective analyses, and lack of P value
adjustment for multiple analyses.
Interference with diagnostic tests The
HbA1C concentration was falsely reduced
by joint ribavirin and peginterferon alfa-2b
therapy in a 59-year-old man with type 2 dia-
betes mellitus; after treatment was with-
drawn the HbA1C returned to baseline [51A].
Telbivudine
Cardiovascular The effects of telbivudine
600 and 1800 mg/day for 7 days on cardiac
repolarization have been evaluated in 62
healthy volunteers in a randomized, pla-
cebo-controlled crossover study with moxi-
oxacin 400 mg as a positive control [52C].
Chapter 29 M. Lartey, K. Torpey, and J.K. Aronson
Moxioxacin produced the expected signif-
icant prolongation of the QTc interval but
telbivudine did not.
DRUGS ACTIVE
AGAINST HUMAN
IMMUNODEFICIENCY
VIRUS
Adverse metabolic effects of
antiretroviral drugs
Lipodystrophy is a feature of treatment with
antiretroviral drugs, particularly protease
inhibitors and nucleoside reverse transcrip-
tase inhibitors. It has been attributed to in-
hibition of mitochondrial DNA polymerase
g [53H]. It is associated with other metabolic
alterations, such as lactic acidosis, dyslipide-
mia, and insulin resistance, and may in turn
be associated with an increase in the long-
term risk of cardiovascular diseases [54R,
55C]. It causes loss of fat from the face and
limbs and can be accompanied by accumu-
lation of fat in the trunk and the back of
the neck. It affects up to 50% of the patients
taking highly active antiretroviral drug treat-
ment (HAART).
Efavirenz Although non-nucleoside reverse
transcriptase inhibitors have not typically
been associated with lipodystrophy, recent
reports suggest that efavirenz may also be
associated with this complication. Efavirenz
prevents murine pre-adipocytes from accu-
mulating lipids, and at high concentrations
also alters the magnitude of adipocyte differ-
entiation [56E]. However, efavirenz does not
cause mitochondrial DNA depletion or cyto-
kine expression in adipose tissue, in contrast
to the antiretroviral thymidine analogues
[57E]. The clinical trials data have also been
reviewed [58M]. Randomized comparative
trials involving efavirenz suggest that it
causes a small increase (1.49.3%) in limb
fat, more than nelnavir, similar to atazana-
vir, and less than lopinavir. Although
Antiviral drugs Chapter 29
efavirenz increases serum cholesterol it
also increases high-density lipoprotein
(HDL) cholesterol, and the overall effect is
neutral.
Stavudine The patterns of change in body
fat and metabolism caused by stavudine
have been studied in 42 South African sub-
jects [59c]. At baseline, those who went on
to develop lipodystrophy were fatter and
had greater skinfold thickness and higher
insulin concentrations than those who never
developed lipodystrophy. Triglyceride and
cholesterol concentrations increased in both
groups, but in those who developed lipo-
dystrophy blood lactate and glucose concen-
trations increased more and insulin
concentrations increased less.
The lipoatrophy that has been associated
with nucleoside reverse transcriptase inhibi-
tors is accompanied by mitochondrial dys-
function, and in 10 patients who had taken
stavudine, lamivudine, and lopinavir rito-
navir for over 6 years, mitochondrial func-
tion and morphology improved after
switching from stavudine to tenofovir [60c].
Weight gain has been used as a
marker of recovery from stavudine-associated
lipoatrophy in 114 Rwandan women [61c].
Replacement with tenofovir abacavir was
associated with a progressive increase in weight,
but zidovudine was associated with progressive
weight loss. The authors suggested that alterna-
tives such as tenofovir abacavir should be
preferred to zidovudine in such cases.
Similarly, when 62 patients taking stavu-
dine were switched to tenofovir in a prospec-
tive study, without changing any other drug,
median malar fat thickness increased by
0 8 mm within 24 months and total fat mass
increased by 3.9 kg [62c]. Plasma lactate
concentrations fell from 3.05 to 1.19 mmol/l,
mainly in patients with baseline hyperlacta-
temia. There were signicant improvements
in total cholesterol (12%), triglycerides
(31%), and total cholesterol/HDL choles-
terol ratio (11%).
Lopinavir New-onset diabetes mellitus and
exacerbation of pre-existing diabetes mellitus
have been reported during post-marketing
583
surveillance of lopinavir. Treatment of
HIV-negative volunteers with ritonavir-
boosted lopinavir for 4 weeks caused
increases in triglycerides, very low density
lipoprotein (VLDL) cholesterol, and free
fatty acids; it also worsened glucose toler-
ance at 2 hours [63c]. In a 4-year follow-up
of patients taking lopinavir ritonavir,
increased non-fasting lipids was the most
common laboratory abnormality [64C].
After 7 years in the same cohort of 100
patients, the commonest grade 3 and 4 labo-
ratory abnormalities were total cholesterol
over 7.8 mmol/l (cumulative incidence
27%) and triglycerides over 8.5 mmol/l
(cumulative incidence 29%) [65C]. Increases
in total cholesterol and triglycerides occur
within the rst month of starting therapy
and are subsequently relatively stable [66c].
Zidovudine The differential effects of anti-
retroviral drugs on body fat disposition have
been studied in 50 HIV-1 infected men in a
randomized single-blind comparison of
zidovudine lamivudine with lopinavir
ritonavir and nevirapine with lopinavir
ritonavir [67C]. In those who took the zido-
vudine-based therapy limb fat fell progres-
sively from 3 months onward by a mean of
684 g up to 24 months, whereas abdominal
fat increased, but exclusively in the visceral
compartment. In contrast, in those who took
nevirapine-based therapy there was a gener-
alized increase in fat mass. After 24 months
there were no signicant differences in
HDL cholesterol and the total/HDL choles-
terol ratio, but total and low density lipo-
protein (LDL) cholesterol were higher in
those who had taken nevirapine.
The mechanism whereby zidovudine is anti-
adipogenic has been studied in 3T3-F442A
preadipocytes, which were exposed to zidovu-
dine (1, 3, 6, and 180 mmol/l), stavudine (3
mmol/l), and dideoxycytosine (0.1 mmol/l) for
up to 15 days [68E]. When they were induced
to differentiate in the presence of zidovudine,
the cells failed to accumulate cytoplasmic tria-
cylglycerol and failed to express normal
amounts of the later adipogenic transcription
factors, CCAAT/enhancer-binding protein
alpha and peroxisome proliferator-activated
584
receptor gamma. Zidovudine inhibited the
completion of the mitotic clonal expansion,
which resulted in incomplete cell differentiation
and a reduction in the degree of adiponectin
expression. It also impaired constitutive prolif-
eration. In contrast, dideoxycytosine and
stavudine had no effects.
In a study of subcutaneous fat samples
from 32 HIV-positive treatment-nave
patients before and 6 months after randomi-
zation to zidovudine lamivudine efavir-
enz (n 15) or tenofovir emtricitabine
efavirenz (n 17) and 15 HIV-negative
matched controls, the expression of genes
involved in adipocyte differentiation, lipid
metabolism, mitochondrial function, and
glucocorticoid generation were proled
using real-time PCR [69c]. Lipoprotein
lipase and hepatic lipase activity were
assessed before treatment. Zidovudine was
associated with signicant increases in vis-
ceral adipose tissue and the ratio of visceral
adipose tissue to subcutaneous adipose tis-
sue, down-regulation of cytochrome B and
cytochrome oxidase-3 gene expression, and
up-regulation of NADH dehydrogenase
and nuclear-encoded cytochrome oxidase-4
(complex IV) gene expression. Genes
involved in adipocyte cortisol generation,
fatty acid metabolism, and the tricarboxylic
acid cycle were up-regulated. In those who
took tenofovir, there were no signicant
changes in regional body fat or mitochon-
drial genes. Changes in the expression of
genes involved with cortisol and fatty acid
metabolism were less marked with tenofovir.
In a 48-week, open, randomized compari-
son of continuation of twice-daily zidovudine
lamivudine or replacement with once-daily
tenofovir emtricitabine in 100 individuals
taking successful efavirenz-based antiretro-
viral therapy, limb fat mass was assessed by
dual X-ray absorptiometry [70C]. Fat was
preserved or increased in the switch group
but fell in the continuation group (mean dif-
ference 448 g, 95% CI 57, 839). The loss
of limb fat was attributed to zidovudine.
Genetic factors The adverse effects of
nucleoside reverse transcriptase inhibitors,
Chapter 29 M. Lartey, K. Torpey, and J.K. Aronson
including myopathies, lactic acidosis, and
peripheral neuropathy, have been associated
with inhibition of human mitochondrial
DNA polymerase g [71E, 72E, 73E], and an
autosomal recessive mutation, arginine 964
to cysteine (R964C), has been suggested to
confer a predisposition to stavudine-induced
mitochondrial toxicity. In steady-state
enzyme kinetic studies, the R964C polymer-
ase g holoenzyme was only 67% efcient in
incorporating deoxythymidine triphosphate
(dTTP), its natural substrate, and
three times less discriminatory for 2',3'-di-
dehydro-3'-deoxythymidine-5'-triphosphate
(d4TTP), the active phosphorylated metabo-
lite of stavudine (d4T), relative to the wild-
type enzyme [74E].
Lipoatrophy due to long-term use of
zidovudine and stavudine may occur
through different mechanisms. Surgical
biopsies from 18 HIV-1 patients, 10 of
whom were taking zidovudine and eight
stavudine, showed that zidovudine was asso-
ciated with lower adipogenesis gene expres-
sion, while stavudine was associated with
signicantly lower expression of genes asso-
ciated with mitochondrial biogenesis [75c].
DRUGS ACTIVE
AGAINST HUMAN
IMMUNODEFICIENCY
VIRUS: COMBINATIONS
Cardiovascular A previously healthy young
man had several episodes of syncope while
taking tenofovir, emtricitabine, and nevira-
pine for primary HIV-1 infection. The symp-
toms resolved after withdrawal of
antiretroviral therapy [76A].
An HIV-infected patient developed right
leg edema while taking tenofovir and emtri-
citabine, which was attributed to a transient
drug-induced vefold increase in periph-
eral arterial ow caused by reduced
peripheral arterial resistance attributable
Antiviral drugs Chapter 29
to the antiretroviral drugs [77A]. However,
that this effect was unilateral suggests that
it may not have been drug-induced.
Musculoskeletal Changes in bone mineral
density and bone turnover have been
studied in 50 patients taking lopinavir rito-
navir with either zidovudine lamivudine or
nevirapine [78c]. Bone mineral density rap-
idly fell in both the femoral neck and lumbar
spine after the start of therapy, and there was
greater loss after 24 months in those who
took zidovudine lamivudine. Osteocalcin
and the urine deoxypyridinoline:creatinine
ratio increased to the same extent in both
groups. Changes in parathyroid hormone
did not explain the greater bone loss with
zidovudine lamivudine.
In a comparison of changes in bone min-
eral density in 106 HIV-1 infected, antire-
troviral drug-naive patients, who were
randomized to zidovudine lamivudine
with either efavirenz (n 32) or lopinavir
ritonavir (n 74) for 96 weeks, the mean
changes from baseline in total bone mineral
density were 2.5% (lopinavir ritonavir)
and 2.3% (efavirenz) [79c]. The authors
concluded that loss of bone mineral density
during antiretroviral drug therapy is inde-
pendent of the drug regimen.
Body temperature Within 5 hours of tak-
ing the rst dose of an antiretroviral drug
regimen of tenofovir 245 mg emtricita-
bine 200 mg abacavir 600 mg, a 45-year-
old man developed a fever of 39.3 C, felt
unwell, and had nausea and abdominal
pain; there was no rash [80A]. The symp-
toms subsequently resolved, but the fever
remained. During the next 13 days, he had
temperatures exceeding 39 C every day,
with no specic diurnal variation. The regi-
men was changed to lamivudine zidovu-
dine tenofovir lopinavir ritonavir
and within hours his temperature normal-
ized and remained so thereafter. He was
HLA-B*5701 negative.
585
DRUGS ACTIVE
AGAINST HUMAN
IMMUNODEFICIENCY
VIRUS: NUCLEOSIDE
ANALOGUE REVERSE
TRANSCRIPTASE
INHIBITORS (NRTI) [SED-15,
2586; SEDA-30, 349; SEDA-31, 482;
SEDA-32, 534]
Abacavir [SED-15, 3; SEDA-30, 348;
SEDA-31, 482; SEDA-32, 524]
Cardiovascular Several studies have sug-
gested that abacavir is associated with a high
risk of cardiovascular disease [81R]. In a
study of the past use of zidovudine, didano-
sine, stavudine, lamivudine, and abacavir in
relation to myocardial infarction during
157 912 person-years of therapy in 33 347
patients, adjusted for cohort, calendar year,
the use of other antiretroviral drugs, and car-
diovascular risk factors that are unlikely to
be affected by antiretroviral drug therapy,
517 patients had a myocardial infarction
[82C]. There were no associations between
the rates of myocardial infarction and cumu-
lative or recent use of zidovudine, stavudine,
or lamivudine, but recent use of abacavir or
didanosine was associated with an increased
rate (RR for abacavir 1.90; 95% CI 1.47,
2.45; RR for didanosine 1.49; CI 1.14,
1.95); the rates were not signicantly
increased in those who had stopped taking
these drugs more than 6 months before.
After adjustment for the predicted 10-year
risk of coronary heart disease, recent use of
both didanosine and abacavir was still asso-
ciated with an increased rate of myocardial
infarction. These results have been criticized
on the grounds of possible confounding by
chronic kidney disease [83r]; however,
adjustment for a low eGFR did not alter
the ndings [84r]. This study conrms a sig-
nal that was earlier generated by a data-min-
ing study of 4 million spontaneous reports in
the WHO database, VigiBase [85c].
586
Based on these data it has been calcu-
lated that the NNTH for myocardial infarc-
tion due to abacavir changes with the
underlying individual risk; for example, in
smokers with a systolic blood pressure of
160 mmHg and a 5-year risk of myocardial
infarction of 1.3% the NNTH is 85, but it
increases to 277 if the patient is a non-
smoker and to 370 if the systolic blood
pressure is below 120 mmHg [86C].
The association between the use of aba-
cavir and an increased risk of myocardial
infarction has been conrmed in a prospec-
tive nationwide cohort study that included
2952 Danish HIV-infected patients taking
highly active antiretroviral therapy
(HAART) from 1995 to 2005 [87C]. Hospi-
talization rates for myocardial infarction
were 2.4 per 1000 person-years (95% CI
1.7, 3.4) for abacavir non-users and 5.7
per 1000 person-years (95% CI 4.1, 7.9)
for abacavir users. The risk of myocardial
infarction increased after abacavir was
started (unadjusted IRR 2.22; 95% CI
1.31, 3.76; IRR adjusted for confounders
2.00; 95% CI 1.10, 3.64; IRR adjusted
for propensity score 2.00; 95% CI
1.07, 3.76). This effect was also observed
among patients who started to take abaca-
vir within 2 years after the start of HAART
and among patients who started to take
abacavir as part of a triple nucleoside
reverse transcriptase inhibitor (NRTI)
regimen.
In contrast to these ndings, a retrospec-
tive investigation of the clinical trials data-
base held by the manufacturer showed no
association of abacavir with myocardial
infarction [88c, 89M].
Markers associated with cardiovascular dis-
ease may alter during therapy with abacavir.
For example, there was a 20% increase in C-
reactive protein and interleukin-6 (IL-6)
[90C]. However, in 11 patients there were no
consistent changes in concentrations of D-
dimers, IL-6, IL-8, TNFa, MCP-1, HGF, hs-
CRP, leptin, or adiponectin [91c].
Nervous system The ParsonageTurner
syndrome, an idiopathic brachial plexus
neuritis, has been reported during a hyper-
sensitivity reaction to abacavir in a 35-year-
Chapter 29 M. Lartey, K. Torpey, and J.K. Aronson
old man, positive for HLA B*5701, after 2
weeks of therapy [92A]. The cause of this
syndrome is unknown; it could have been
coincidental in this case, since it has occa-
sionally been reported during seroconver-
sion in HIV infection.
Hematologic Neutropenia (neutrophil count
80  106/l) occurred in a 38-year-old woman
who took abacavir lamivudine with lopina-
vir ritonavir for 3 weeks [93A]. She had a
fever and mild erythema and edema on the
face, trunk, and arms. She was positive for
HLA-B*5701. Subsequent therapy with teno-
fovir emtricitabine and lopinavir ritona-
vir was uneventful.
Liver Liver function tests became abnormal
in two young HLA B*5701-negative
women shortly after they switched to aba-
cavir; they had no history of underlying
liver abnormalities or concurrent suscepti-
bility factors for liver disease [94A].
Susceptibility factors Genetic The associa-
tion of HLA B*5701 with the risk of abacavir
hypersensitivity skin reactions has been
repeatedly reviewed [95R, 96R, 97R, 98R,
99R]. It provides an excellent example of
the successful translation of a pharmaco-
genetic test into clinical practice and affords
insights into why other tests have not been
successful [100R]. However, testing may not
be necessary in all communities; for example
of 534 Koreans none had the HLA B*5701
polymorphism [101C]; this suggests that the
incidence of hypersensitivity in this popula-
tion is likely to be less than 0.6%, and testing
would not be cost-effective.
Nevertheless, hypersensitivity reactions
to abacavir can occur in individuals who are
negative for HLA B*5701, as in the case of
a 41-year-old Caucasian woman who devel-
oped a fever and a severe rash after taking
abacavir for 10 weeks [102A]. In one case
even a patch test to abacavir was negative,
in a 61-year-old man who took abacavir for
10 days before developing a fever over
40 C, muscle aches, watery diarrhea, a rash,
and rhabdomyolysis; the authors suggested
that another genetic association may be
waiting to be found [103A].
Antiviral drugs Chapter 29
In populations with European ancestry,
an HCP5 single-nucleotide polymorphism
(SNP), rs2395029, is in linkage disequilib-
rium with HLA-B 5701 [104C]. In 1103
HIV-positive individuals the HCP5 SNP
was present in all 98 HLA-B 5701-positive
individuals and was absent in 999 of
1005 HLA-B 5701-negative individuals;
rs2395029 was over-represented in 25
individuals with clinically probable abacavir
hypersensitivity, compared with its fre-
quency in 175 abacavir-tolerant individuals
(80 versus 2%). The authors therefore
suggested that HCP5 genotyping could
serve as a simple screening tool for abacavir
hypersensitivity, particularly when sequence-
based HLA typing is not available.
Polymorphisms at position 245 of HIV
type 1 (HIV-1) reverse transcriptase are
associated with HLA B*5701, and in a study
of 1179 sequences from 752 patients infected
with HIV-1 mutant amino acid residues were
found in 31% of sequences [105C]. Among
239 patients with multiple longitudinal geno-
types, residues at position 245 varied in 37
(16%) from wild type to mutant and/or
vice versa. All these changes appeared dur-
ing antiretroviral drug treatment. Of 229
patients who took abacavir, 15 (6.5%) devel-
oped a hypersensitivity reaction; all carried
B subtypes. There was no signicant differ-
ence in the prevalence of mutants at position
245 between those with hypersensitivity
(27%) and those without (29%), even after
limiting the analysis to carriers of subtype
B. The authors concluded that the large var-
iability in residues at position 245 and the
lack of association with hypersensitivity
reactions argue against using them as viral
genetic markers to exclude patients at risk.
Didanosine [SED-15, 1113; SEDA-30,
348; SEDA-31, 483; SEDA-32, 535]
Cardiovascular See Abacavir.
Liver Long-term didanosine therapy was
associated with non-cirrhotic portal hyperten-
sion in three HIV-positive individuals with
chronic hepatitis C, mild liver brosis, and
587
normal liver function tests, who presented
with bleeding from esophageal varices [106A].
In a nested casecontrol study conducted
by the Swiss HIV Cohort there was a strong
association between prolonged exposure to
didanosine and non-cirrhotic portal hyper-
tension [107C]. In 15 patients with non-cir-
rhotic portal hypertension and 75 controls
matched for duration of HIV infection,
absence of viral hepatitis, and duration of
follow-up, cumulative exposure to antiretro-
viral drug therapy (OR per year 1.3; 95%
CI 1.0, 1.6), nucleoside reverse transcrip-
tase inhibitors (OR 1.3; 95% CI 1.1,
1.7), didanosine (OR 3.4; 95% CI 1.5,
8.1), ritonavir (OR 1.4; 95% CI 1.0,
1.9), and nelnavir (OR 1.4; 95% CI
1.0, 1.9) were longer in the patients with por-
tal hypertension. Exposure to non-nucleo-
side reverse transcriptase inhibitors and
other protease inhibitors were not different.
Lamivudine [SED-15, 1989, SEDA-30,
344; SEDA-31, 480; SEDA-32, 531]
Hematologic Pure red cell aplasia has been
attributed to lamivudine in a 29-year-old
woman; it improved rapidly after drug with-
drawal [108A]. In another case a patient
with lamivudine-associated pure red cell
aplasia required 15 units of blood over 3
weeks but recovered swiftly after with-
drawal of lamivudine [109A]. The onset of
pure red cell aplasia due to lamivudine is
variable and occurs at any CD4 count;
rapid improvement after withdrawal of
lamivudine is a consistent feature.
Pancreas Pancreatitis occurred in a 59-year-
old man with a history of chronic hepatitis B
infection after he had taken lamivudine 150
mg/day for 15 days [110A].
Stavudine [SED-15, 3180; SEDA-32,
535]
Nervous system A distal sensory poly-
neuropathy is a complication of HIV
588
infection and is often difcult to distinguish
from stavudine-associated polyneuropathy,
the mechanism of which is most probably
mitochondrial toxicity. Of 102 HIV-positive
individuals who took stavudine-based
HAART, 30 developed peripheral neuro-
toxicity, which was attributed to stavudine
[111c]. In 96 patients in Jakarta who had
taken stavudine, the prevalence of neurop-
athy (symptoms and signs) was 34%
[112c]. The neuropathy was associated with
increasing age, increasing height, and the
TNFA-1031*2 gene allele. Isoniazid expo-
sure was not associated with neuropathy
and all those taking isoniazid had also
taken pyridoxine. The authors suggested
that based on these observations it should
be possible to predict the individual risk of
symptomatic neuropathy before prescribing
stavudine.
In patients in Melbourne, Kuala Lum-
pur, and Jakarta the prevalence of neurop-
athy was 42% in Melbourne (n 100),
19% in Kuala Lumpur (n 98), and 34%
in Jakarta (n 96); increasing age and
height were independently associated with
the risk of neuropathy, explaining some of
these differences [113c].
Acidbase balance A 42-year-old woman
with advanced HIV disease who had taken
stavudine, lamivudine, nevirapine, and pro-
phylactic co-trimoxazole for 9 months
developed a high anion gap metabolic aci-
dosis with a pH of 7.15, due to lactic acido-
sis [114A]. She was also discovered to have
persistent glycosuria, phosphaturia, and
aminoaciduria, in keeping with proximal
renal tubular dysfunction. The lactic acido-
sis was attributed to the stavudine and the
Fanconi syndrome to the combination of
stavudine and lamivudine.
Zidovudine [SED-15, 3713; SEDA-31,
485; SEDA-32, 536]
Nervous system Palpebral ptosis in a patient
taking zidovudine was attributed to mitochon-
drial toxicity from zidovudine; it resolved
when the treatment was changed [115A].
Chapter 29 M. Lartey, K. Torpey, and J.K. Aronson
Hematologic Of 1089 adults taking stavu-
dine-containing HAART (median observa-
tion time, 3 years), 290 (27%) had
zidovudine substituted for didanosine, after
which there were higher frequencies of ane-
mia and leukopenia [116c]. Conversely, in
158 patients taking zidovudine, 77 of whom
switched to another drug, the switch occa-
sioned a net increase in hemoglobin of 1.1
g/dl and a net increase in neutrophil count
of 541  106/l [117c].
Pure red cell aplasia occurred in a 27-
year-old woman who had taken zidovudine,
lamivudine, and nevirapine for 1 year; it
resolved when zidovudine was replaced by
stavudine [118A].
DRUGS ACTIVE
AGAINST HUMAN
IMMUNODEFICIENCY
VIRUS: NUCLEOTIDE
ANALOGUE REVERSE
TRANSCRIPTASE
INHIBITORS
Tenofovir [SED-15, 3314; SEDA-30,
349; SEDA-31, 485; SEDA-32, 537]
Urinary tract Tenofovir can cause renal
tubular damage, with or without small
changes in glomerular ltration [119c,
120c]. Fanconi syndrome and nephrogenic
diabetes insipidus have again been reported
in three patients, who developed poly-
dipsia, polyuria, weight loss, anorexia, and
wasting while taking tenofovir disoproxil
fumarate and didanosine [121c].
The tubular abnormalities that tenofovir
can cause may be due to down-regulation
of a variety of ion transporters. Because
rosiglitazone, a PPAR-g agonist induces
the expression of many of these trans-
porters, it has been successfully used to
ameliorate tenofovir-induced nephrotoxi-
city in rats [122E].
Tenofovir can also cause impaired glo-
merular function [123c]. In 99 patients
Antiviral drugs Chapter 29
taking antiretroviral drug therapy that
included tenofovir, the fall in GFR during
treatment was least in those who responded
best [124c]. The authors suggested that
improvement in GFR that occurs as a result
of viral suppression may more than offset
any adverse effects of tenofovir on renal
function. However, tenofovir-induced renal
damage may be potentiated by co-adminis-
tration with a ritonavir-boosted protease
inhibitor [125c].
A 31-year-old HIV-positive woman de-
veloped progressive renal insufciency while
taking tenofovir and emtricitabine in combi-
nation with efavirenz; she was also taking
oral glucocorticoids, low-dose colecalciferol
25 micrograms/day, and calcium 500 mg/day,
which resulted in hypercalcemia and contrib-
uted to the renal impairment [126A].
Two 16-year-old African-Americans with
HIV infection developed tenofovir-associated
nephropathy and renal rickets [127A].
Musculoskeletal Tenofovir can sometimes
cause osteomalacia and bone fractures
because of renal tubular impairment and
phosphaturia [128A, 129A]. Of 22 patients,
12 had bone pain due to osteomalacia asso-
ciated with abnormal tubular function,
including tubular proteinuria, a reduced
tubular transport maximum of phosphate,
and glycosuria, all consistent with abnormal
proximal tubular function [130c].
Susceptibility factors Genetic Polymor-
phisms in the transporter proteins that are
involved in the renal elimination of tenofo-
vir, such as organic anion transporter 1 or
multidrug-resistant proteins 2 or 4, may
confer an increased risk of renal tubulopa-
thy [131R]. Twelve single-nucleotide poly-
morphisms (SNPs) in the ABCC2,
ABCC4, SCL22A6, SLC22A11, and
ABCB1 genes have been analysed in 115
HIV-infected patients, of whom 19 had
renal tubular dysfunction [132c]. There
were more patients with tubular dysfunc-
tion among those with genotype CC at posi-
tion 24 of ABCC2 than among those with
genotypes CT and TT (24 versus 6%). In
a multivariate analysis, older age (OR
1.1; 95% CI 1.0, 1.2), lower body weight
589
(OR 0.9; 95% CI 0.8, 0.9), and geno-
type CC at ABCC2 position 24 (OR 5;
95% CI 1.2, 21) were independently
associated with renal tubular dysfunction.
The authors suggested that homozygosity
for the C allele at position 24 of the
ABCC2 gene may help to identify patients
who are at greater risk of tenofovir-associ-
ated tubulopathy.
Pregnancy In a retrospective study of 15
pregnant HIV-infected women who took
regimens containing tenofovir during 16
pregnancies (median in utero exposure
127, range 6259, days) there were 15 suc-
cessful deliveries at a median of 36
(3040) weeks, with a median birth weight
of 3255 (11353610) g [133c]. There was
one spontaneous abortion, not attributed
to tenofovir. Eleven women had abnormal
laboratory results, including six with grade
1 hemoglobin abnormalities; four of them
had pre-existing anemia. There were no
major effects on renal function.
Drugdrug interactions Amprenavir See
below.
Diclofenac An HIV-1-positive patient who
had taken long-term tenofovir developed
severe acute tubular necrosis with proximal
tubular dysfunction when she also started
to take diclofenac [134A]. Since she had tol-
erated tenofovir well for several years, the
authors suggested that diclofenac had inter-
fered with tenofovir clearance, thereby caus-
ing nephrotoxicity. However, the effect
could have been due to the diclofenac alone.
Oral contraceptives In a 30-day, xed-
sequence, open study in 20 non-pregnant
and non-lactating women aged 1945 years
who were taking norgestimate ethinyl-
estradiol, tenofovir had no effect on the
pharmacokinetics of deacetylnorgestimate
or ethinylestradiol [135c]. Although tenofo-
vir is unlikely to affect the pharmacokinet-
ics of hormonal oral contraceptives, a
study of this size cannot rule out an inter-
action in a small susceptible subset of
women.
590
Vancomycin Renal failure developed after
a prolonged course of vancomycin in two
patients who were also taking tenofovir
[136A]. The authors implied that the effects
of these two nephrotoxic drugs had been
additive.
DRUGS ACTIVE
AGAINST HUMAN
IMMUNODEFICIENCY
VIRUS: NON-NUCLEOSIDE
REVERSE TRANSCRIPTASE
INHIBITORS (NNRTI) [SED-
15, 2553; SEDA-30, 349; SEDA-31, 486;
SEDA-32, 537]
Liver In 296 patients, of whom 151 took
efavirenz and 145 nevirapine, there was
severe hepatotoxicity (grade 3 to 4 rises in
aspartate and/or alanine aminotransfer-
ases) in two of the former and three of the
latter, and mild-to-moderate hepatotoxicity
(grade 2 rises) in 6.0% and 3.4% [137c].
The only susceptibility factor for mild-to-
moderate hepatotoxicity was hepatitis C
co-infection.
Skin Rashes are common in patients
taking nevirapine, and efavirenz is often
substituted. The factors that predict unsuc-
cessful switching from have been studied ret-
rospectively in 109 HIV-infected patients
who developed a rash after taking nevirapine,
of whom 20 subsequently developed an efavir-
enz-associated rash [138r]. A history of drug
allergy apart from nevirapine (OR 11) and
a CD4 cell count below 100  106/l (OR 6)
were signicant predictive factors.
Efavirenz [SED-15, 1204; SEDA-30, 349;
SEDA-31, 486; SEDA-32, 537]
Nervous system and psychiatric The most
common neuropsychiatric adverse reactions
Chapter 29 M. Lartey, K. Torpey, and J.K. Aronson
to efavirenz have been reviewed [139R].
Status epilepticus and severe neuropsychiat-
ric symptoms have been reported in
an HIV-infected patient with cirrhosis
and a high plasma efavirenz concentration;
the presence of a mutation in the gene
for CYP2B6 may have been relevant
[140A].
The frequencies of adverse neuropsychi-
atric reactions have been evaluated in a
comparison of two dosage regimens in a
randomized, double-blind, controlled trial
in 114 HIV-infected patients [141A]. They
were given efavirenz either in a stepped
dosage regimen (200 mg/day on days 16,
400 mg/day on days 713, and 600 mg/day
on day 14 and after) or an immediate full
dosage regimen (600 mg/day). In both cases
two nucleoside or nucleotide reverse tran-
scriptase inhibitors were added. The full-
dose group had higher incidences and
intensities of dizziness (66 versus 33%),
hangover (46 versus 21%), impaired con-
centration (23 versus 8.9%), and hallucina-
tions (6.1% versus 0%) during the rst
week. From week 2, the incidences were
similar, although the intensities were
greater in the full-dose group. This implies
that these adverse reactions are of the early
tolerant time-course in the DoTS classica-
tion (see p. xxxiii).
Liver A 9-year-old boy developed liver
impairment leading to hepatic encephalopa-
thy after taking lamivudine, efavirenz, and
zidovudine for 13 weeks, attributed to the
antiretroviral drugs and requiring liver
transplantation; he was subsequently given
lamivudine, zidovudine, and raltegravir, in
addition to immunosuppressants, without
incident [142A].
Sweat glands Some patients taking efavir-
enz report excessive nocturnal sweating,
which resolves after dosage reduction. A
man taking efavirenz 600 mg at night devel-
oped hyperhidrosis and was found to have
a high serum concentration of efavirenz;
the hyperhidrosis abated with reduction of
the dose to 400 mg at night and eventually
stopped [143A].
Antiviral drugs Chapter 29
Musculoskeletal Osteomalacia in a 45-year-
old woman has been attributed to induction
of vitamin D metabolism by efavirenz
[144A].
Susceptibility factors Genetic The ethnic
and pharmacogenetic variants that affect
the pharmacokinetics and actions of efavir-
enz have been reviewed; genetic variation
is more important than ethnic variation
[145R]. Efavirenz is mainly metabolized by
CYP2B6, which has two important alleles,
516G and 516T. The 516T/T genotype is
more frequent in Americans of African
descent than in those descended from
Europeans; it is associated with higher
plasma concentrations of efavirenz and
nevirapine and with nervous system
adverse effects of efavirenz. The 16G>T
polymorphism is also associated with higher
plasma efavirenz concentrations, regardless
of ethnic background. However, since there
is a poor correlation of efavirenz concentra-
tions with effects such as adverse neuro-
psychiatric reactions [146C], it is hard to
know how to interpret these differences.
In a UK study the 516GT polymorphism
was more prevalent in Blacks than in Cau-
casians [147c]. There were no signicant
differences in the distributions of genotypes
between 31 individuals who had discontin-
ued efavirenz and 74 who had continued
taking it.
CYP2B6516G>T polymorphisms signi-
cantly affect the metabolism of efavirenz.
In 63 HIV-infected children, median age
12 (range 319) years, who took efavirenz
for at least 4 weeks, CYP2B6516 G/G,
G/T, and T/T genotypes were found in
48%, 41%, and 11% respectively [148c].
The516G>T allele frequency was 32%.
The mean concentrations of efavirenz for
children with the G/G, G/T, and T/T geno-
types were 1604, 2635, and 11 582 ng/ml
respectively. There was a correlation
between efavirenz concentrations over
4000 ng/ml and psychiatric adverse effects,
but no association with rashes, hepatotoxic-
ity, or central nervous system disturbances.
591
In men from South China there was no
association between efavirenz concentrations
and adverse reactions; however, the authors
postulated that accumulation of efavirenz
can occur, causing toxicity in TT and GT
genotypes [149c].
The effect of CYP2B6 genetic variation
on the steady-state pharmacokinetics of
efavirenz 600 mg/day in patients also taking
the enzyme inducer rifampicin has been
studied in 26 patients, in whom the
CYP2B6 c. 516GG, GT, and TT genotype
frequencies were 0.27, 0.50, and 0.23
respectively [150c]. Mean plasma efavirenz
AUC was four times higher and the appar-
ent oral clearance four times lower in
patients with the c. 516TT variant than in
those with the GT or GG genotypes. The
authors concluded that the c. 516TT geno-
type can be used to identify efavirenz poor
metabolizers in patients co-treated with
rifampicin.
The effects of rifampicin co-administra-
tion on the steady-state pharmacokinetics
of efavirenz 600 mg/day have been studied
in 72 patients with HIV-1 infection in South
India [151c]. Peak and trough concentra-
tions and exposure to efavirenz were signif-
icantly higher in patients with the CYP2B6
TT genotype than in those with the GT
and GG genotypes. Although rifampicin
co-administration reduced the peak and
trough concentrations and exposure to efa-
virenz by 18%, 20%, and 19% respectively,
the differences were not statistically signi-
cant. The trough concentration of efavirenz
was subtherapeutic (less than 1.0 mg/l) in
six patients. Thus, the CYP2B6 G516T
polymorphism signicantly altered the
pharmacokinetics of efavirenz, but rifampi-
cin did not.
Liver disease In 134 HIV-infected patients,
35 co-infected with hepatitis C virus and 22
with hepatitis B virus, who took efavirenz
600 mg/day in combination with other anti-
retroviral drugs, the presence of hepatitis
and the stage of brosis affected efavirenz
592
plasma concentrations [152c]. The authors
suggested that it would be helpful to moni-
tor plasma efavirenz concentrations in such
patients.
Drugdrug interactions Antifungal azoles
In a phase I, open, randomized, crossover
study in healthy volunteers of co-adminis-
tration of posaconazole 400 mg bd with
atazanavir 300 mg/day, alone and with
either ritonavir 100 mg/day or efavirenz
400 mg/day, co-administration of posacona-
zole and efavirenz resulted in clinically
relevant reductions of posaconazole Cmax
and AUC by about 45% and 50% respec-
tively [153c]. Because of reduced posacona-
zole exposure, co-administration with
efavirenz should be avoided if possible.
Voriconazole is not recommended for
use in combination with efavirenz; how-
ever, if they are co-administered, the dos-
age of voriconazole should be increased to
400 mg 12-hourly and the dosage of efavir-
enz reduced to 300 mg/day, in order to pro-
vide systemic exposure similar to standard-
dose monotherapy [SEDA-32, 498]. The
combination of voriconazole and efavirenz
in doses adjusted according to steady-state
plasma concentrations has been studied in
a 40-year-old man with AIDS, cryptococco-
sis, and mild liver cirrhosis [154A]. Ade-
quate concentrations of voriconazole in
both plasma and cerebrospinal uid were
obtained and target plasma concentrations
of efavirenz were achieved at the nal dos-
age adjustment (oral voriconazole 200 mg
bd plus oral efavirenz 300 mg/day). There
was stable suppression of cryptococcosis
and plasma HIV viremia at long-term fol-
low-up (66 weeks), with no signicant
adverse events.
Antimalarial drugs There were lower con-
centrations of atovaquone proguanil in
HIV-infected individuals taking efavirenz.
The authors compared the pharmacokinet-
ics of atovaquone proguanil between
healthy volunteers and HIV-infected
patients taking efavirenz and found that
the geometric mean ratio AUC0!t for
Chapter 29 M. Lartey, K. Torpey, and J.K. Aronson
atovaquone in patients taking efavirenz.
Relative to the healthy volunteers was
0.25 (95% CI 0.16, 0.38). Proguanil
plasma concentrations were also signi-
cantly lower (3843%) [155c].
Ginkgo biloba Virological failure in a 47-
year-old HIV-infected patient who had
taken antiretroviral drug therapy for 10
years was associated with falling efavirenz
plasma concentrations after he started to
take Ginkgo biloba [156A].
Etravirine
Etravirine is an antiretroviral drug of the
non-nucleoside reverse transcriptase inhibi-
tor (NNRTI) family that has been
approved by the regulatory agencies for
the treatment of patients with evidence of
active viral replication who have prior
experience with antiretroviral drugs and
who harbor multidrug-resistant strains of
HIV-1.
Observational studies In clinical assess-
ments of etravirine, the main adverse
effects were rash, nausea, vomiting, and
hypercholesterolemia [157r]. In the random-
ized double-blind DUET studies, rash was
more common in those who took etravirine,
and led to withdrawal in 2% of patients
[158C].
Drugdrug interactions Etravirine is me-
tabolized by cytochrome P450 enzymes
and interacts in vitro with high-dose ritona-
vir, atazanavir, fosamprenavir, rifampicin,
and some antiepileptic drugs [159E].
Darunavir ritonavir The interaction of
etravirine 100 or 200 mg bd with darunavir
low-dose ritonavir 600/100 mg bd has
been evaluated in an open, randomized,
two-way crossover phase I study in 23
HIV-negative volunteers [160c]. Darunavir
ritonavir reduced the AUC0!12h of etra-
virine 100 mg bd by 37%, the Cmax by 32%,
Antiviral drugs Chapter 29
and the Cmin by 49%. The AUC0!12h of
etravirine 200 mg bd was 80% greater than
that of etravirine 100 mg bd when daruna-
vir ritonavir were co-administered, and
the Cmax was 81% greater, and the Cmin
67% greater (i.e. less than one would
expect). The pharmacokinetics of darunavir
ritonavir were not altered, except for a
15% increase in AUC0!12h when etravirine
200 mg bd was co-administered. The
authors suggested that no dosage adjust-
ment of etravirine is needed when it is com-
bined with darunavir ritonavir.
Nevirapine
Skin Nevirapine has again been associated
with fatal toxic epidermal necrolysis [161A]
and StevensJohnson syndrome extensive
enough to have been called toxic epidermal
necrolysis [162A, 163r]. Based on studies in
rats, it has been suggested that the mole-
cule that is responsible for such reactions
is formed from nevirapine by hydroxylation
to a reactive quinone methide, and co-
treatment with a CYP enzyme inhibitor,
1-aminobenzotriazole, resulted in a lower
incidence of reactions [164E]. The authors
proposed that the hepatotoxicity of nevira-
pine is due to the quinone methide after
its formation in the liver, and that rashes
may be due to the quinone methide formed
in the skin by sulfation of the 12-hydroxy
metabolite followed by loss of the sulfate
species.
Pregnancy In 103 HIV-positive women who
took nevirapine-based HAART (n 56) or
non-nevirapine-based HAART (n 47)
during pregnancy, there were adverse
reactions necessitating withdrawal in six
of the former and in only one of the
latter [165c].
Susceptibility factors Genetic In HIV-
infected Thai patients HLA-B*3505 had a
99% specicity in identifying nevirapine-
induced rashes [166c].
593
DRUGS ACTIVE
AGAINST HUMAN
IMMUNODEFICIENCY
VIRUS: PROTEASE
INHIBITORS [SED-15, 2586;
SEDA-30, 351; SEDA-31, 487;
SEDA-32, 541]
Drugdrug interactions Cat's claw In a 45-
year-old HIV-positive woman with cirrhosis
due to hepatitis C infection the serum
trough concentrations of atazanavir, ritona-
vir, and saquinavir increased when she took
cat's claw (Uncaria tomentosa), perhaps
because of inhibition of CYP3A4 [167A].
The respective concentrations with and
without cat's claw were 0.30 and 1.22 mg/l
(atazanavir), 0.92 and 6.13 mg/l (ritonavir),
and 0.64 and 3.4 mg/l (saquinavir).
Amprenavir/fosamprenavir
Liver The incidence of hepatotoxicity has
been evaluated in 636 HIV-positive
patients with a high frequency of viral hep-
atitis co-infection taking fosamprenavir
ritonavir 700/100 mg bd; 341 (54%) had
hepatitis C virus antibodies, 38 (5.6%) had
serum HBsAg, and 93 (27%) of those with
hepatitis C virus antibodies had an AST to
platelet ratio index higher than 1.5, consis-
tent with signicant hepatic brosis [168c].
After a median (range) follow-up time of
7 (0.521) months, three patients developed
grade 3 rises in alanine aminotransferase
activity; all had hepatitis virus co-infections.
The frequency of grade 3 rises in alanine
aminotransferase activity in patients with
hepatitis C antibodies was 0.58% and in
those with HBsAg it was 2.6%. Four
patients developed liver decompensation
and one died. None of the patients with
hepatic brosis had grade 3 rises in alanine
aminotransferase activity.
Drugdrug interactions Atazanavir The
pharmacokinetic interaction of fosamprenavir
594
1400 mg/day with atazanavir 400 mg/day for 14
days have been studied in a randomized,
open, three-way crossover study in 11 men
and 10 women who were HIV-seronegative
[169C]. Atazanavir signicantly increased
exposure to amprenavir by about two times
after fosamprenavir and the Cmax of amprena-
vir increased by about 60%. In contrast,
the AUC and Cmax of atazanavir fell
signicantly by about 30% when fosamprena-
vir was co-administered. The authors recom-
mended that this combination should not be
used.
Tenofovir In an open, three-period
study of the interaction of tenofovir
disoproxil fumarate 300 mg/day with
either fosamprenavir 1400 mg bd or fos-
amprenavir ritonavir 700/100 mg for 14
days in 36 healthy subjects, steady-state
plasma amprenavir and tenofovir pharma-
cokinetics were minimally or not signi-
cantly altered [170C].
Atazanavir
Drugdrug interactions Antifungal azoles
In a phase 1, open, randomized, crossover
study in healthy volunteers of co-adminis-
tration of posaconazole 400 mg bd with ata-
zanavir 300 mg/day, alone and with either
ritonavir 100 mg/day or efavirenz 400 mg/
day, posaconazole increased the Cmax of
atazanavir by 2.6 times and the AUC by
3.7 times [153c]. Posaconazole increased
the Cmax and AUC of atazanavir when it
was given with ritonavir by 1.5 and 2.5
times respectively. Most of those who took
atazanavir with or without ritonavir plus
posaconazole had clinically relevant
increases in total bilirubin. Co-
administration of posaconazole and efavir-
enz resulted in clinically relevant reductions
of posaconazole Cmax and AUC by about
45% and 50% respectively. As a result, fre-
quent monitoring of adverse events is
recommended when posaconazole and ata-
zanavir are co-administered with or without
ritonavir.
Chapter 29 M. Lartey, K. Torpey, and J.K. Aronson
Cat's claw See above.
Fosamprenavir See above.
Nevirapine Co-administration of atazanavir
ritonavir (300 100 mg/day) plus nevira-
pine 200 mg bd resulted in a reduction in
the Cmin of atazanavir by nearly half
[171c]. Monitoring of trough atazanavir
concentrations is recommended in patients
taking this drug combination, and it may
be necessary to increase the dose of
atazanavir.
Darunavir
Darunavir is a protease inhibitor with activ-
ity against wild-type and protease inhibitor-
resistant viruses. It is indicated for
treatment-experienced patients and is co-
administered with ritonavir 600/100 mg bd
to improve its systemic availability.
Observational studies In a study of 44
treatment-experienced children who were
given darunavir in doses that were based
on a prior pharmacokinetic study, one with-
drew because of grade 3 anxiety that was
not thought to be drug-related [172C].
Comparative studies In an open random-
ized comparison of darunavir ritonavir
and lopinavir ritonavir in 689 patients
the former was associated with fewer possi-
bly treatment-related grade 24 gastrointes-
tinal adverse events (7 versus 14%) and
specically treatment-related moderate-to-
severe diarrhea (4 versus 10%); adverse
events that led to withdrawal occurred in
3% and 7% respectively [173c].
In the TITAN and POWER series of
studies [174c, 175c, 176c], the following
adverse reactions were reported: naso-
pharyngitis, increases in triglycerides, low
density lipoprotein, total cholesterol, and
blood glucose, neutropenia, nausea and
diarrhea, often a cause of withdrawal,
rashes, and raised aminotransferase, pancre-
atic lipase, and amylase activities. There was
an increase in adverse events affecting the
Antiviral drugs Chapter 29
liver in patients co-infected with hepatitis B
or C [177c].
Drugdrug interactions Atazanavir Hyper-
bilirubinemia and jaundice occurred during
administration of atazanavir in all 23
healthy volunteers taking part in a 30-day
follow-up study; there was a 52% increased
minimum plasma concentration with co-
administration of darunavir [178c].
Etravirine See above.
Nevirapine Nevirapine has no clinically
important interaction with darunavir
[179C].
Oral contraceptives Norethindrone and
ethinylestradiol concentrations were con-
siderably reduced by the combination
of darunavir ritonavir in healthy volun-
teers [180c].
Saquinavir The combination of saquinavir
with darunavir ritonavir is not recom-
mended, as plasma concentrations of daru-
navir are increased [181c].
Indinavir
Susceptibility factors Genetic Of 40
patients eight with the *1B/*1B genotype
for the CYP3A4 gene had a 70% reduction
in absorption compared with those with the
*1A/*1B or *1A/*1A genotypes; those with
the *1B/*1B genotype also had a signi-
cantly lower indinavir Cmax than those with
the *1A/*1B or *1A/*1A genotypes and a
lower increase in triglycerides during the
rst 4 weeks of treatment [182c].
Protease inhibitors can inhibit UDP glu-
curonosyl transferases (UGT) and UGT1A
gene variants can inuence gene transcrip-
tion, inducibility, and glucuronidation activ-
ity. Indinavir can cause hyperbilirubinemia
in Gilbert's syndrome, which is associated
with the UGT1A1*28 polymorphism.
Among 125 HIV-positive patients taking
indinavir and 427 healthy blood donors
who were genotyped for the presence of
595
UGT1A1*28, UGT1A3 66T/C, UGT1A7
57T/G, and UGT1A7(N129K/R131K),
there was hyperbilirubinemia in 42%.
UGT1A1*28 frequencies did not differ
between HIV-positive patients and controls
but were signicantly more common in
patients with hyperbilirubinemia [183c].
The frequency of homozygous carriers of
the four UGT1A marker haplotype
increased with hyperbilirubinemia, and
affected all patients with bilirubin concen-
trations over 85 mmol/l. The authors con-
cluded that in patients taking indinavir the
risk of severe hyperbilirubinemia is associ-
ated with genetic variants of the UGT1A3
and UGT1A7 genes in addition to Gilbert's
syndrome (UGT1A1*28) and that this hap-
lotype is a useful predictor of protease
inhibitor-induced adverse effects.
Drugdrug interactions American ginseng
In 13 healthy volunteers American ginseng
had no effect on the pharmacokinetics of
indinavir 800 mg tds [184c].
Lopinavir
Pregnancy Among 955 live births prena-
tally exposed to lopinavir ritonavir
reported to the Antiretroviral Pregnancy
Registry, 23 had birth defects (2.4%);
among 267 live births with rst-trimester
exposure, ve had birth defects (1.9%)
[185c]. These rates are similar to the popu-
lation rate of 2.7% and the rate in infants
with second- or third-trimester exposure
(2.6%). There was no common pattern of
birth defects.
Drug formulations The heat-stable formu-
lation of lopinavir ritonavir has a better
gastrointestinal adverse effects prole than
the soft gel capsule [186c].
Drugdrug interactions Oxycodone Co-
administration of oral oxycodone with lopi-
navir increases the oxycodone concentra-
tion [187c].
596
Nelnavir
Nelnavir has been largely displaced by
second-generation protease inhibitors but
is thought to inhibit experimentally induced
tissue degeneration or cell damage by pre-
venting loss of the mitochondrial mem-
brane potential, and may even protect
mitochondria in cancer cells. However, con-
versely, it selectively induces mitochondria-
independent cell death in cancer cells by
the so-called endoplasmic reticulum/
unfolded protein stress response, allowing
nelnavir to act on otherwise chemoresis-
tant cancer cells [188R].
Cardiovascular The effect of nelnavir on
the QT interval has been evaluated in a
randomized, four-way crossover, third-
party-blinded study in 68 healthy subjects
with moxioxacin as a positive control. Nel-
navir had no effect on the QT or QTc
intervals or the RR interval, even in poor
metabolizers of CYP2C19, in whom expo-
sure was high [189C].
Ritonavir
Endocrine In a systematic review of 25
cases (15 adults and 10 children) of signi-
cant adrenal suppression secondary to an
interaction between ritonavir and inhaled
uticasone, and three cases involving rito-
navir and intranasal uticasone, cases with
other steroids were not reported [190M].
The authors concluded that the combina-
tion of long-term uticasone with ritonavir
should be avoided and if ritonavir is
required, another inhaled glucocorticoid,
such as low-dose budesonide or beclo-
methasone, can be used cautiously. When
inhaled glucocorticoids are withdrawn, the
patient should be closely monitored for
adrenal insufciency.
The risk of iatrogenic Cushing's syn-
drome followed by secondary adrenal
failure, which is unusual after only a sin-
gle-dose of a synthetic glucocorticoid, may
Chapter 29 M. Lartey, K. Torpey, and J.K. Aronson
be increased by previous exposure to rito-
navir, as has been suggested by three cases
of patients in whom this sequence of events
occurred after they were given a single
intra-articular injection of triamcinolone
acetonide 40 mg [191A]. Other cases of
Cushing's syndrome in patients taking
ritonavir have been reported after intra-
articular triamcinolone [192A], epidural tri-
amcinolone [193A], and inhaled uticasone
[194A, 195A].
Drugdrug interactions Interactions of
ritonavir with other drugs have been sys-
tematically reviewed [196M]. Ritonavir
inhibits the metabolism of medications that
are substrates of CYP3A and CYP2D6. It
also induces CYP3A, CYP1A2, CYP2B6,
CYP2C9, and CYP2C19, and glucuronyl
transferase. It also has a biphasic, time-
dependent effect on P glycoprotein, rst
inhibiting then inducing its activity. These
effects have been observed at both thera-
peutic and boosting doses, but most of the
studies of low-dose ritonavir have involved
a second protease inhibitor, such as daruna-
vir, lopinavir, or tipranavir, making it dif-
cult to distinguish the relative effects of
additional medications. The inhibitory
effect of ritonavir on CYP3A activity is
increased in patients with HIV infection
with chronic viral hepatitis [197c].
Albendazole and mebendazole In 16
healthy volunteers the pharmacokinetics
of single oral doses of albendazole 400 mg
or mebendazole 1000 mg were not changed
by short-term ritonavir; however, long-term
ritonavir resulted in signicant changes in
albendazole and mebendazole disposition,
with signicant reductions in AUC0!24h
(27% and 43% of baseline respectively)
and Cmax (26% and 41% of baseline)
[198c].
Cat's claw See above.
Quinine Downward dosage adjustment of
quinine may be necessary when it is co-
administered with ritonavir [199c].
Antiviral drugs Chapter 29
Saquinavir
Drugdrug interactions Cat's claw See
above.
Tipranavir
Nervous system A 55-year-old HIV-infected
patient ritonavir-boosted tipranavir as part
of HAART developed intracranial hemor-
rhage during the acute phase of cryptococcal
meningitis [200A]. After this, 10 cases of intra-
cranial hemorrhage in patients taking tiprana-
vir were identied in the Food and Drug
Administration's Adverse Events Reporting
System from July 2006 to March 2007 [201c].
This resulted in a black box warning
stating that tipranavir has been associated
with reports of both fatal and non-fatal intra-
cranial hemorrhage, based on 2.6 events
per 1000 person-years of surveillance, a
10-fold higher rate than that observed in an
older, HIV-negative population.
In a cohort study of 16 541 HIV-positive
veterans, matched with 34 305 demographi-
cally similar HIV-negative veterans receiv-
ing care, and 28 023 HIV-positive Medi-
Cal recipients, 33 HIV-negative veterans,
33 HIV-positive veterans, and 373 HIV
Medi-Cal recipients received incident care
for intracranial hemorrhage [202C]. The
crude event rates were:
HIV Medi-Cal cohort4 cases per 1000 per-
son-years (95% CI 3.6, 4.5);
HIV-positive veterans0.4 cases per 1000
person-years (95% CI 0.3, 0.6);
HIV-negative veterans0.1 cases per 1000
person-years (95% CI 0.1, 0.2).
Overall HIV status was associated with
an IRR of 2.48 (95% CI 1.53, 4.02).
Other independent associations were with
age over 50 years (IRR 1.46; 95% CI
1.16, 1.85), minority status (IRR 1.38;
95% CI 1.14, 1.67), vascular disease
(IRR 1.92; 95% CI 1.57, 2.35), alcohol
abuse or dependence (IRR 1.53; 95% CI
1.18, 1.97), and liver disease (IRR 2.30;
95% CI 1.59, 3.33). The NNTH for one
event per year of treatment with tipranavir
was 4555000, although the authors
597
thought that they had probably overesti-
mated the risk.
Metabolism Tipranavir is associated with
raised triglyceride concentrations [203C].
Liver The most common laboratory abnor-
malities observed in the RESIST trials were
raised aminotransferase activities [203C,
204C, 205c]. Susceptibility factors included
infection with hepatitis B or C and high
baseline aminotransferases.
In a review of the adverse hepatic effects
of tipranavir in ve phase IIb/III trials, there
were grade 3/4 rises in aminotransferases in
144/1299 (11%) patients; 123/144 of these
were asymptomatic and in most cases treat-
ment was either temporarily interrupted or
continued, and the aminotransferase activi-
ties returned to grade 2 or better [206M].
After 96 weeks the incidence of grade 3/4
rises was higher among those with liver dis-
ease (17%) than among those without
(10%). The risk was greatest during the rst
24 weeks (6.1%) and it fell thereafter (2448
weeks: 3.4%; 4872 weeks: 2.0%; 7296
weeks: 2.2%). Four of the 144 patients
developed serious hepatic adverse events
and overall, 14/1299 patients (1.1%) had
serious events, including six with hepatic fail-
ure. Independent susceptibility factors for
grade 3/4 rises in aminotransferases included
co-infection with hepatitis B and/or C and a
CD4 count over 200  106/l at baseline.
Skin Toxic epidermal necrolysis has been
attributed to tipranavir in a 45-year-old
man; desensitization was successfully car-
ried out using incrementally increasing oral
doses over a very short period of time
(Table 1) [207A].
Drugdrug interactions Tipranavir rito-
navir In some studies co-administration of
rifabutin and tipranavir ritonavir
increased the concentrations of rifabutin
and its main metabolite 25-O-desacetyl-
rifabutin; this combination should be used
with caution and adverse effects should be
monitored [208r, 209c, 210c].
598 Chapter 29 M. Lartey, K. Torpey, and J.K. Aronson

Table 1 An oral desensitization protocol for depression (which was the most frequent
tipranavir hypersensitivity adverse effect that led to withdrawal)
[213C, 214C].
Time (hours) Dose Enfuvirtide does not require dosage
adjustment in chronic renal insufciency
0.5 3.125 micrograms [215c].
1 6.25 micrograms
1.5 12.5 micrograms
2 50 micrograms Skin Local injection site reactions are com-
2.5 100 micrograms mon with enfuvirtide. In the TORO 2
3 200 micrograms study, among the 338 patients given enfu-
3.5 400 micrograms virtide 98% had at least one injection site
4 900 micrograms reaction. The common signs and symptoms
4.5 1.9 mg
of injection site reactions were induration,
5 3.9 mg
5.5 7.8 mg
erythema, nodules, and cysts; only 3.3%
6 15.6 mg discontinued treatment as a result [213C].
6.5 31.25 mg There were similar and consistent ndings
7 65.25 mg in the TORO 1 study, which was conducted
7.5 125 mg in North and South America [214C]. Biop-
8 250 mg sies of the lesion showed an inammatory
8.5 500 mg response consistent with a localized hyper-
sensitivity reaction [216C]. In a 47-year-old
man amyloidosis occurred at the injection
site [217A].

DRUGS ACTIVE
AGAINST HUMAN
IMMUNODEFICIENCY
VIRUS: INHIBITORS OF HIV
FUSION [SEDA-28, 337; SEDA-29,
310]
Enfuvirtide
Enfuvirtide is a 36 amino acid synthetic
peptide used for managing HIV treat-
ment-experienced patients. It is in powder
form and must be reconstituted with sterile
water for subcutaneous administration. The
adult dose is 90 mg bd. Absorption does
not vary by site of injection (for example,
thigh, arm, or abdomen) [211C]. Enfuvir-
tide binds to HR 1, blocking a conforma-
tional change on gp41 required for the
fusion of the lipid envelope of HIV to the
cytoplasmic membrane of CD4 T lympho-
cytes, thus preventing viral entry [212R].
In trials adverse effects have included
diarrhea and nausea, eosinophilia, and
Immunologic Of the 663 patients who took
enfuvirtide group in the TORO 1 and 2
studies, two had systemic hypersensitivity
reactions. Both recurred on rechallenge. In
the rst case, the reaction occurred after
8 days of treatment and was associated with
a rash, fever, and vomiting [214C]. Delayed
hypersensitivity reactions can occur [218A].
Drugdrug interactions Niacin Caution
should be exercised when co-administering
niacin and enfuvirtide in HIV-infected
patients, in the light of a single report of a
possible interaction [219A].
A 47-year-old HIV-infected man with dilated
cardiomyopathy, a prolonged QT interval,
and an automatic implantable cardiovascular
debrillator device was given subcutaneous
enfuvirtide 90 mg bd and oral extended-
release niacin 500 mg/day. After 1 week he
developed extreme redness, edema, and swell-
ing at the injection site that corresponded with
the ushing sensation due to niacin. The nia-
cin was withdrawn and no further problems
occurred with enfuvirtide alone.
Antiviral drugs Chapter 29
Tipranavir ritonavir Co-administration
of enfuvirtide with tipranavir ritonavir
was associated with markedly higher tipra-
navir and ritonavir trough concentrations
[220c].
DRUGS ACTIVE
AGAINST HUMAN
IMMUNODEFICIENCY
VIRUS: INTEGRASE
INHIBITORS
Raltegravir
Raltegravir is the rst HIV integrase inhib-
itor approved for treatment of HIV infec-
tion. Integration of proviral DNA into
human DNA is a multi-step process, which
involves binding of the enzyme to viral
DNA, formation of a preintegration com-
plex, movement of the preintegration com-
plex from the cytoplasm to the nucleus,
and then transfer of viral strands to human
DNA [221R]. Raltegravir blocks the strand
transfer step, by blocking the active site of
the enzyme [222R]. Raltegravir is thought
to have some activity against HIV-2 [223A].
Nervous system Two middle-aged men
developed insomnia soon after starting to
take raltegravir; it resolved rapidly after
withdrawal in both cases [224Ar].
Psychiatric There have been four cases of
exacerbation of depression in treatment-
experienced patients with HIV infection,
who were taking antidepressants when ral-
tegravir was introduced; the mechanism is
not known [225A].
Gastrointestinal Gastrointestinal reactions,
such as nausea, atulence, and constipation,
have been reported [226C].
Liver Increased aminotransferase activities
have been associated with raltegravir
[226C, 227C]. In a prospective study of 218
599
HIV-positive patients who took raltegravir,
of whom 126 were HIV mono-infected and
92 had co-infection with hepatitis C, any
degree of rises in liver enzymes occurred
in 10 (7.9%) and 23 (25%) respectively
(RR 3.1; 95% CI 2.9, 3.4) [228C].
There was severe hepatotoxicity (grade
34) in three patients (1.4%), all co-infected,
but in all three cases it was probably not due
to raltegravir. Hepatitis C co-infection was
the only independent variable associated
with any degree of hepatotoxicity during ral-
tegravir therapy.
Musculoskeletal Rhabdomyolysis has been
associated with raltegravir in a 46-year-old
African-American man with multidrug-
resistant HIV [229A].
Tumorigenicity In the BENCHMRK trials,
16 of 462 patients (3.5%) who took ralte-
gravir, compared with four of 237 (1.7%)
who took placebo had a diagnosis of a
new, recurrent, or progressive cancer
[230C]. All the cancers were reported as
serious adverse events not related to the
study drug, except for a lymphoma in the
placebo group that was thought to have
been possibly drug-related. When adjusted
for person-years of follow-up, the relative
risk of cancer in those who took raltegravir
was 1.54. The cancers included Kaposi's
sarcoma, non-Hodgkin's lymphoma, anal
and laryngeal squamous cell carcinomas,
rectal adenocarcinoma, hepatocellular car-
cinoma, and skin carcinoma.
Susceptibility factors Hepatic and renal
disease Neither moderate hepatic disease
nor severe renal disease alters the pharma-
cokinetics of raltegravir [231C].
Drugdrug interactions The pharmaco-
kinetics and interactions of raltegravir have
been reviewed [232R]. It is mainly elimi-
nated by UGT1A1-mediated glucuronida-
tion and it does not inhibit or induce CYP
isoenzymes; there is therefore minimal risk
of interactions with most commonly used
drugs. This may even include drugs that
are glucuronidated; for example raltegravir
600
did not affect the glucuronidation of lamo-
trigine in 12 health volunteers [233C].
Indeed, in a systematic review of 14
drugdrug interaction studies none showed
an adverse effect of raltegravir [234M].
Etravirine In an open study in 20 healthy
adults etravirine had no signicant effect
on the steady-state pharmacokinetics of ral-
tegravir 400 mg bd [235c].
Rifampicin Rifampicin induces drug
metabolizing enzymes, leading to lower ral-
tegravir concentrations [236c].
Tipranavir ritonavir In an open study in
18 healthy adults tipranavir ritonavir had
no signicant effect on the steady-state
pharmacokinetics of raltegravir 400 mg bd
[237c].
DRUGS ACTIVE
AGAINST HUMAN
IMMUNODEFICIENCY
VIRUS: CHEMOKINE
RECEPTOR CCR5
ANTAGONISTS
Maraviroc
Maraviroc is a cell surface chemokine
receptor CCR5 antagonist, approved for
the treatment of HIV-1 infection in treat-
ment-experienced patients with CCR5
tropic HIV-1. It is used in combination with
other antiretroviral drugs. It has no activity
against CXCR4 tropic virus [238C]. Inhibi-
tion of CCR5 blocks the entry of HIV-1
into the cell.
Cardiovascular Postural hypotension em-
erged as a dose-limiting event during the
development of maraviroc. In a phase I sin-
gle-dose study, there was orthostatic hypoten-
sion in four of nine patients who took a dose of
1200 mg [239c].
Chapter 29 M. Lartey, K. Torpey, and J.K. Aronson
In a single-dose, double-blind, placebo-
controlled, crossover study in healthy sub-
jects, with moxioxacin 400 mg as an active
control, maraviroc 100, 300, and 900 mg
had no signicant effect on the QT interval
[240C].
Respiratory In the MOTIVATE trials,
upper respiratory infections were more
common in those who took maraviroc com-
pared with placebo [241C].
Liver Maraviroc carries a black box warn-
ing regarding hepatotoxicity [242S]. This
warning is included because the develop-
ment of aplaviroc, an investigational
CCR5 antagonist, was halted because of
reports of hepatotoxicity [243C]. There is
currently no evidence of an increased risk
of hepatotoxicity associated with maraviroc
[244C].
Tumorigenicity A concern related to the
use of CCR5 antagonists is the potential
risk of malignancies, as suggested by
ACTG 5211, a trial of vicriviroc [239R]. In
the MOTIVATE trials, 12 malignancies
were reportedthree cases of Kaposi's sar-
coma and four of lymphoma in those who
took maraviroc, compared with three cases
of Kaposi's sarcoma and two of lymphoma
in those who took placebo; this represented
a lower incidence of malignancy with mara-
viroc [241C].
Drugfood interactions Food reduces mar-
aviroc absorption by about 50% [245C].
When possible it should be taken on an
empty stomach.
Drugdrug interactions Maraviroc is a sub-
strate of P glycoprotein and CYP3A4, by
which it is about 65% metabolized. Mara-
viroc should therefore be used with caution
when inhibitors of CYP3A4 are used con-
comitantly. Potent CYP 3A4 inhibitors,
such as ketoconazole and protease inhibi-
tors, except tipranavir ritonavir, increase
maraviroc exposure; dosage reduction can
compensate [246c]. Conversely, enzyme
inducers, such as rifampicin and efavirenz,
reduce exposure [247C]. In contrast, drugs
Antiviral drugs Chapter 29
that are inhibitors of renal transporters,
such as co-trimoxazole and tenofovir, do
not affect the pharmacokinetics of mara-
viroc [248C].
Co-administration of ritonavir-boosted
elvitagravir and maraviroc leads to a 24 times
increase in maraviroc concentrations, pre-
sumably because of ritonavir-mediated inhibi-
tion of CYP3A and P glycoprotein [249C].
Yellow fever vaccine The mechanism of
action of maraviroc is based on the fact that
a homozygous mutation of the gene encod-
ing for CCR5 (CCR5d32) results in almost
complete resistance to HIV-1 infection.
However, this mutation is associated with
increased severity of infection with avi-
viruses, such as West Nile virus and to a
lesser extent tick-borne encephalitis virus.
A heterozygous mutation has been
described in a patient with yellow fever vac-
cine-associated viscerotropic disease and it
has therefore been suggested that maraviroc
might potentiate the risk of this adverse
effect of yellow fever vaccine [250Hr].
DRUGS ACTIVE AGAINST
INFLUENZA VIRUSES:
NEURAMINIDASE
INHIBITORS [SED-15, 2436;
SEDA-30, 352; SEDA-31, 489; SEDA-
32, 544]
Oseltamivir
Systematic reviews In a review of 20 trials
(four in prophylaxis, 12 in treatment, and
four in postexposure prophylaxis), oseltami-
vir caused nausea (OR 1.79; 95% CI
1.10, 2.93); evidence of rarer adverse events
from pharmacovigilance data was of poor
quality and such events may in any case have
been under-reported [251M].
In seven trials involving 7021 partici-
pants, nausea and vomiting were more
common among those who took oseltamivir
(RR 1.48; CI 1.86, 2.33). All the trials
601
were company-sponsored and no study
was powered to detect rare adverse events
[252M].
Psychiatric There is some controversy
about the potential of oseltamivir to cause
adverse neuropsychiatric effects, since con-
cerns were raised about the risk of halluci-
nations, delirium, and abnormal activity
[253S, 254S]. Even deaths have been
reported [255c].
The relation between oseltamivir and
adverse behaviors was investigated in a
large epidemiological study in Japan in the
winter of 20062007 and the preliminary
results were reported in Japanese; oseltami-
vir had no adverse effects [256c]. However,
the statistical analysis of the results has
been criticized, and it has been suggested
that a more appropriate analysis shows that
the rate ratio of psychiatric adverse reac-
tions to oseltamivir was 1.57 (95% CI
1.34, 1.83) [257r]. Two other studies have
since been published.
In a retrospective study using electronic
health-care service and pharmacy records
in children aged 121 years with inuenza
there was no evidence that oseltamivir
increased the risk of adverse neuropsychi-
atric outcomes [258c]. Similarly, in a retro-
spective study of patients with inuenza
with and without exposure to oseltamivir
(n 60 267 and 175 933 respectively) and
stratied according to age (17 years or
under and 18 years or over), there were
no increases in the incidences of claims-
based neuropsychiatric events in those for
whom oseltamivir was dispensed [259c]. It
should be noted that the second of these
studies was carried out by the marketing
authorization holder.
In a cross-sectional online survey of osel-
tamivir prophylaxis in 95 school children
with conrmed inuenza A (H1N1) in Lon-
don in AprilMay 2009, only 48% of the
primary schoolchildren completed a full
course, compared with 76% of the second-
ary school children [260c]. Mild neuro-
psychiatric adverse effects were reported
by 18% of the children.
It is still not clear what the balance of
benet to harm is in this case [261cr].
602
Susceptibility factors Genetic Oseltamivir
phosphate is an ethyl ester prodrug that is
hydrolysed by carboxylesterase 1 (CES1) to
an active metabolite, oseltamivir carboxyl-
ate. Two functional CES1 variants have
been identied in a subject who had signi-
cantly reduced ability to metabolize the
selective CES1 substrate, methylphenidate;
they are called p.Gly143Glu and p.Asp260fs.
In vitro functional studies have shown that
the presence of either of the two mutations
can result in greatly reduced catalytic ef-
ciency of CES1 for methylphenidate, and a
similar nding has been shown for the con-
version of oseltamivir to oseltamivir carbox-
ylate [262E]. The Vmax of the p.Gly143Glu
variant was about 25% of that of the wild-
type enzyme and the catalytic activity of the
p.Asp260fs variant was negligible. The
authors suggested that the therapeutic ef-
cacy of oseltamivir could be compromised
in patients who express either functional
CES1 mutation and that there may be an
increased risk of adverse effects in those
who are thus exposed to high concentrations
of the non-hydrolysed prodrug.
Drug overdose The pattern of cases of osel-
tamivir self-poisoning reported to Texas poi-
son centers during 20002008 has been
reported, in the expectation of an increase
during the inuenza season [263c]. Of 298
total ingestions, 92% occurred in Decem-
berMarch, 77% involved patients aged
019 years, 73% resulted from therapeutic
errors, 90% were managed on-site, and
80% had no effect. The most common
adverse reactions were vomiting (7.5%),
nausea (3.8%), and abdominal pain (3.8%).
Drugdrug interactions Probenecid In a
three-arm, open study 48 healthy volunteers
were randomized to oral oseltamivir 75 mg/
day, oseltamivir 75 mg every 48 hours pro-
benecid 500 mg qds, or oseltamivir 75 mg
every 48 hours probenecid 500 mg bd for
15 days. Probenecid reduced the systemic
availability of oseltamivir by about 30%
and the steady-state apparent oral clearance
by about 25% [264c]. The authors noted that
alternate-day dosing of oseltamivir plus pro-
benecid four times a day achieved trough
Chapter 29 M. Lartey, K. Torpey, and J.K. Aronson
oseltamivir concentrations adequate for
neuraminidase inhibition in vitro.
The effects of probenecid on the pharma-
cokinetics of four doses of oseltamivir have
been studied in healthy Thai adults [265c].
The median half-lives were 1.0 hour for osel-
tamivir and 5.1 hours for oseltamivir carbox-
ylate. In one subject there was markedly
reduced hydrolysis of oseltamivir to its car-
boxylate, consistent with impaired carboxy-
lesterase activity. Co-administration of
probenecid resulted in a mean 40% reduc-
tion in the apparent volume of distribution
of oseltamivir carboxylate and a 61% reduc-
tion in its renal elimination, with a conse-
quent 154% increase in the AUC. The
AUC increase in saliva was about three
times less than the AUC increase in plasma.
The authors concluded that probenecid co-
administration may reduce oseltamivir dose
requirements considerably.
However, there is also evidence that
adverse reactions may be more common
when this combination is used. During a phar-
macokinetic study in healthy volunteers a
68-year-old woman developed severe throm-
bocytopenia after taking the combination,
and no other drug therapy, for 2 weeks
[266A]. Her platelet count fell from 200 to 15
 109/l. The two drugs were discontinued
and her platelet count returned to normal
within 1 week. In a review of the FDA's
Adverse Event Reporting System database
there were 93 cases of reduced platelet counts
associated with oseltamivir and 24 associated
with probenecid. Signal detection analyses
were signicant for oseltamivir but not
probenecid.
DRUGS ACTIVE AGAINST
INFLUENZA VIRUSES: ION
CHANNEL INHIBITORS
[SED-15, 105, 3051; SEDA-31, 489;
SEDA-32, 544]
Amantadine and corneal edema
Corneal edema has occasionally been attrib-
uted to amantadine, and since the rst
Antiviral drugs Chapter 29
reports appeared in 1977 [267A, 268A] and
the early 1990s [269A, 270A, 271A] sporadic
cases have continued to be reported. It may
be due to direct damage to endothelial cells,
but its pathogenesis is not fully understood.
Case reports Three patients who took aman-
tadine developed diffuse corneal edema
[272A]. In two cases the symptoms started
within a few weeks and in the third case after
6 years. In the rst two cases withdrawal of
amantadine resulted in resolution of the cor-
neal edema. However, the other patient
received a full-thickness corneal transplant
while still taking amantadine, and edema devel-
oped in the grafted cornea; withdrawal of
amantadine then resulted in resolution of the
corneal edema in both eyes, but the ungrafted
corneal eventually also became edematous,
requiring transplantation. Histopathology
showed signicant loss of endothelial cells. As
in the last of these cases, another report docu-
mented corneal edema in a corneal transplant
until amantadine withdrawn [273A].
A 14-year-old boy with a tremor took amanta-
dine and developed corneal edema. The cor-
neal thickness was over 900 mm [274A]. The
edema rapidly resolved after withdrawal and
the corneal thickness returned to normal.
A 61-year-old man with Parkinson's disease
took amantadine 300 mg/day for 8 months
and developed corneal endothelial edema; with-
drawal of amantadine resulted in rapid
improvement of visual acuity [275A].
A 74-year-old woman took amantadine for
8 years without problems; after a break she
started taking it again and after a further 2
years developed bilateral corneal edema, which
resolved within 1 month of withdrawal [276A].
A 52-year-old woman with Parkinson's disease
who had taken amantadine for 6 years devel-
oped bilateral corneal edema for 2 months;
amantadine was withdrawn and the edema
resolved; amantadine was reintroduced and
the corneal edema recurred; amantadine was
then permanently withdrawn and the corneal
edema again resolved [277A].
A 12-year-old girl took amantadine HCl 100
mg bd for 4 months and developed bilateral
blurred vision which progressed. She had cor-
neal edema and the central corneal thicknesses
were 851 mm in the right eye and 886 mm in
the left eye (reference range 509613) [278A].
A 55-year-old woman took amantadine HCl
100 mg bd for several years and developed
severe corneal edema in both eyes; central cor-
neal thicknesses were 930 and 934 mm [278A].
603
A 39-year-old woman developed bilateral cor-
neal edema after taking amantadine for 2
months [279A]. Corneal thicknesses were 940
mm in the right eye and 802 mm in the left.
There was diffuse stromal edema, folds in Des-
cemet's membrane, and microcystic subepithe-
lial edema. Specular microscopy showed
signicant pleomorphism and polymegathism
with an endothelial cell count of 1504 cells in
the right eye and 1596 in the left eye.
A 68-year-old woman with Parkinsonism took
amantadine HCl 100 mg bd for 2 years and
developed corneal edema, with central corneal
thicknesses of 871 mm in the right eye and 746
mm in the left eye [280A]. There was bilateral dif-
fuse stromal and epithelial edema with marked
folds in Descemet's membrane. The amantadine
was withdrawn and topical prednisolone acetate
1% and sodium chloride eye-drops were given.
There was complete resolution within 3 weeks,
and the corneal thicknesses resolved (592 mm
in the right eye and 567 mm in the left eye).
A 45-year-old woman developed amantadine-
associated corneal edema, which did not
resolve despite withdrawal of amantadine and
treatment with glucocorticoids [281A]. She
therefore underwent sequential phakic Desce-
met's stripping automated endothelial kerato-
plasty (DSAEK), with signicant. Histology
of Descemet's membrane by light microscopy
showed a paucity of endothelial cells.
A 61-year-old woman with Parkinson's disease
was given amantadine, followed over the next 6
years by pramipexole, ropinirole, co-careldopa,
and entacapone [282A]. She subsequently devel-
oped severe corneal edema. Amantadine was
withdrawn and within 1 month the corneal
edema had completely resolved. The corneal
thicknesses improved from 810 to 640 mm in the
right eye and from 780 to 660 mm in the left eye.
Post-marketing surveillance In a post-mar-
keting surveillance study of patients with a
new diagnosis of corneal disease and new
prescriptions for amantadine over 2 years,
36 (0.27%) of 13 137 patients developed
corneal edema [283C]. The relative risk of
corneal edema was 1.7 (95% CI 1.1,
2.8); in 12 patients (0.09%) the diagnosis
was made in the rst month.
However, it has been suggested that the
specic keratopathy that is associated with
a pseudoexfoliation (PEX) syndrome,
caused by direct involvement of the corneal
endothelium is part of the differential diag-
nosis of corneal edema in such cases. The
authors of this suggestion reported that they
had found that about 10% of patients diag-
nosed as having corneal edema (also called
604
Fuchs dystrophy) in fact had PEX kerato-
pathy [284r]. In response, the authors of
the original study replied that they agreed
that it was not possible to be sure whether
amantadine causes corneal decompensation,
or if it merely accelerates an underlying
endothelial process, and that the pathogene-
sis of amantadine-associated corneal edema
is obscure and may be multifactorial. How-
ever, they were condent that none of their
patients had any clinical ndings that would
have suggested a diagnosis of PEX kerato-
pathy. Furthermore, in support of a direct
effect of amantadine, they cited clear cases
in which dechallenge and rechallenge had
resulted in corneal edema [285r].
Psychiatric A 19-year-old man took aman-
tadine 100 mg bd for inuenza and the next
developed auditory and visual hallucina-
tions, which resolved after withdrawal of
amantadine [286A]. Altered mental status
has also been attributed to amantadine in
a 27-year-old woman with a kidney trans-
plant [287A].
Endocrine A 66-year-old woman with Par-
kinson's disease developed muscle weak-
ness, anorexia, weight loss, and had severe
hyponatremia due to the syndrome of in-
appropriate ADH secretion (SIADH) after
taking amantadine; after withdrawal the
symptoms disappeared and the sodium con-
centration returned to normal [288A].
Urinary tract A 69-year-old woman devel-
oped seizures and acute renal insufciency
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single hemodialysis, with reduction of
amantadine concentrations, resolved the
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Skin Livedo reticularis has again been
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the amantadine was withdrawn and the
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cardiovascular effects [291A].
A 47-year-old woman took 10 g of amantadine
(150 mg/kg) and had a pulseless cardiac arrest
with ventricular tachycardia; she was resusci-
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took 10 g of amantadine hydrochloride; her
QTc interval was 526 msec and the serum
potassium 3.0 mmol/l; she recovered after
potassium repletion.
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tadine developed generalized seizures fol-
lowed by status epilepticus, with alternating
generalized tonicclonic and partial seizures,
over 7 hours; he also had a sinus tachycardia
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 M.S. Jawahar and V.V. Banu Rekha
30 Drugs used in tuberculosis
and leprosy
Multidrug-resistant tuberculosis
and extensively drug-resistant
tuberculosis
Despite the availability of effective anti-myco-
bacterial agents and many technological
advances in the diagnosis and treatment of
tuberculosis over the past 65 years, the disease
still continues to cause major morbidity and
mortality, especially in developing countries.
The HIV epidemic and the increasing resis-
tance of strains of Mycobacterium tuberculo-
sis to antituberculosis drugs are posing
potent threats to global control. During
2008, there were an estimated 8.99.9 million
new cases and 1.552.32 million deaths in
patients with tuberculosis [1S].
The phenomenon of drug resistance in
tuberculosis is not new. Soon after the ef-
cacy of streptomycin against Mycobacterium
tuberculosis was discovered, the UK's Medi-
cal Research Council reported that deaths in
patients were the same irrespective of
whether they were treated with streptomycin,
and most of the deaths in the treated group
occurred in those who were suffering a
relapse due to streptomycin-resistant strains
[2c]. Standard short-course chemotherapy
using multiple drugs kills all bacilli located
in different environments (pulmonary cavi-
ties, pus, solid caseous material, macro-
phages), including naturally occurring
Side Effects of Drugs, Annual 33
J.K. Aronson (Editor)
ISSN: 0378-6080
DOI: 10.1016/B978-0-444-53741-6.00030-1
# 2011 Elsevier B.V. All rights reserved.
monodrug-resistant strains (killed by the
other drugs) and controls the further emer-
gence of resistance [3R].
Multidrug-resistant (MDR) tuberculosis,
dened as disease caused by Mycobacterium
tuberculosis resistant to isoniazid and rifam-
picin, the two most potent antituberculosis
drugs rst attracted global attention in the
late 1980s and early 1990s with a rash of
institutional outbreaks of MDR tuberculosis
in predominantly HIV-infected patients in
the USA [4C]. Since then there have been
reports of outbreaks in other parts of the
world, fuelling global apprehension of
increasing levels of drug resistance in tuber-
culosis. Extensively drug-resistant (XDR)
tuberculosis was rst described in South
Africa in 2006 [5C], and is dened as
MDR tuberculosis with additional resistance
to any of the uoroquinolones and to any of
the following injectable agents: kanamycin,
capreomycin, amikacin.
Commissioned by the WHO and the
International Union against Tuberculosis
and Lung Diseases, the Global Project on
Antituberculous Drug Resistance Surveil-
lance published a series of reports in 1997,
2001, 2006 and 2008. According to the last
report, between 390 000 and 510 000 new
cases of MDR tuberculosis emerged globally
(best estimate 440 000 cases) in 2008 [6S].
Among all incident cases of tuberculosis,
3.6% (95% CI 3.0, 4.4) were estimated
to have MDR tuberculosis. Almost 50% of
these cases are estimated to have occurred
in India and China. In the same year MDR
tuberculosis caused an estimated 150 000
deaths. Data from 46 countries that have
continuous surveillance or representative
623
624
surveys of second-line drug resistance among
patients with MDR tuberculosis suggests that
5.4% of this category of patients have XDR
tuberculosis. Eight countries reported XDR
tuberculosis in more than 10% of cases of
MDR tuberculosis. A total of 58 countries
have conrmed at least one case of XDR
tuberculosis. Considering that these gures
are most probably underestimates of the real
prevalences, it would be fair to say that this
issue is of alarming signicance.
Diagnosis of multidrug-resistant tuber-
culosis The building of laboratory capacity
to diagnose MDR tuberculosis and undertake
surveillance of antituberculosis drug resis-
tance is one of the most important challenges
in scaling-up care for MDR and XDR tuber-
culosis. The rapid detection of drug resistance
facilitates effective treatment and limits fur-
ther development of resistance to additional
drugs. Conventional phenotypic methods
require culture and detection of growth of
Mycobacterium tuberculosis in the presence
of antituberculosis drugs on solid media. This
may take up to 6 weeks, a delay that is expen-
sive in terms of denial of appropriate treat-
ment and continued transmission of drug-
resistant disease in the community. Recent
research has signicantly shortened this time
lag by introducing improved diagnostic tech-
niques, using both conventional (phenotypic)
and molecular (genotypic) methods.
The radiometric BACTEC TB system
using broth-based media makes drug sus-
ceptibility test results available in 412 days
from primary cultures [7E]. Recently, non-
radiometric fully automated liquid culture
systems have been developed, of which the
most important is the BACTEC MGIT sys-
tem [8M]. However, these automated liquid
culture systems are expensive for resource-
poor countries. The microscopic observation
drug susceptibility (MODS) test is a low-
cost, rapid, and direct assay for detection
and susceptibility testing of Mycobacterium
tuberculosis in sputum specimens, results
being available within 2 weeks [9E]. Calori-
metric methods, based on redox indicators
that are added to the culture medium during
in vitro growth of Mycobacterium
Chapter 30 M.S. Jawahar and V.V. Banu Rekha
tuberculosis, are also available [10R]. These
are the tetrazolium salt-based assay, used
for direct detection of rifampicin resistance
from sputum samples, the risazurin microti-
ter assay and the nitrate reduction assay,
which provides rapid, accurate, and cost-
effective diagnosis of MDR tuberculosis.
Phage-based assays use mycobacterio-
phages to infect live Mycobacterium tuberculo-
sis in the absence or presence of antituberculosis
drugs and detect the bacilli using either a
phage amplication assay (FAST Plaque
tuberculosis-response assay) or production of
light, using luciferase reporter mycobacterio-
phages [11E]. These methods provide results
in 2 days.
Molecular genotypic susceptibility testing
methods detect resistance-associated mutations
in target genes of Mycobacterium tuberculosis
and can be performed on clinical samples
directly [12E]. Genotypic methods have been
developed for all rst-line and many second-
line drugs. Since 9095% of rifampicin-resis-
tant strains contain mutations in a small region
of a single gene (rpoB), and rifampicin resis-
tance is a surrogate marker for MDR tubercu-
losis, the detection of resistance to rifampicin
is a priority [13E]. For other drugs the sensitiv-
ity of resistance detection varies widely, owing
to the number of gene loci involved and the
diversity of mutations [14R].
The PCR-restriction fragment length
polymorphism (PCR-RFLP) analysis is a sim-
ple and rapid method for detecting polymor-
phisms at a single or few codons that are
mutated. The test is used to detect mutations in
katG315 for isoniazid resistance [15E] and in
embB306 for ethambutol resistance [16E].
DNA sequencing is the most reliable method
of detecting mutations that may contribute to
resistance, and is most practical if the majority
of drug-resistant strains contain mutations in
a limited region of a single gene, such as with
the rpoB gene for rifampicin resistance. DNA
sequencing is still considered impracticable
in most developing countries for analysing
large volume of samples. However, recent tech-
nological advances may result in rapid, accu-
rate, and cost-effective analysis of DNA
sequences for diagnosis of MDR tuberculosis
[17R]. A commercial real-time PCR-based
assay is now available for detection of
Drugs used in tuberculosis and leprosy Chapter 30
rifampicin resistance (Xpert MTB, Cepheid).
Another important technology that has
emerged is the reverse hybridization based
Line Probe Assay (macro-arrays) and micro-
array-based assays for detection of MDR
strains directly from clinical specimens. The
INNO-LiPA Rif TB assay (Immunogenetics)
detects mutations in the rpoB gene [18E]. The
GenoType MTBDRplus assay (Hain Life-
sciences) detects MDR tuberculosis by simulta-
neously detecting mutations in the rpoB gene
for rifampicin resistance, and the katG315
and inhA genes for isoniazid resistance [19E].
Results are available within one working day.
Line probe assays have also been developed
for detecting resistance of Mycobacterium
tuberculosis to pyrazinamide [20E] and uoro-
quinolones [21E].
Multidrug-resistant tuberculosis and HIV
The association between MDR tuberculosis
and HIV infection is still not clear. A system-
atic review has suggested no clear associa-
tion between MDR tuberculosis and HIV
infection across time and geographic loca-
tions. In the 32 eligible studies the prevalence
ratios for MDR tuberculosis were 0.2141
[22M]. The summary prevalence ratios for
acquired and primary MDR tuberculosis
were 1.17 (95% CI 0.86, 1.6) and 2.72
(95% CI 2.03, 3.66), respectively. How-
ever, the studies qualifying for review were
few, and most studies were not adjusted for
confounders and heterogeneity. Of 270
South African patients with XDR tuberculo-
sis, 55% were HIV negative [17R].
Management There is evidence that an ef-
ciently organised and implemented TB control
programme with rational use of rst line anti-
TB drugs can prevent the emergence of drug
resistance in the community. While the treat-
ment of drug-susceptible tuberculosis is efca-
cious and cost-effective, the management of
MDR tuberculosis is a therapeutic challenge.
Second line antituberculosis drugs are mainly
bacteriostatic, less effective, and costly and
have more adverse effects. The treatment costs
for MDR tuberculosis are prohibitive, and
many developing countries can ill afford this.
Current guidelines for management of
MDR tuberculosis require the availability of
625
rapid diagnostic facilities and susceptibility
testing for rst-line and second-line antituber-
culosis drugs. Because of the poor prognosis,
rapid diagnosis of MDR tuberculosis is even
more crucial in HIV co-infected individuals.
The susceptibility prole is useful for tailor-
ing individual treatment regimens and for
monitoring responses to treatment. There is
evidence that individual treatment regimens
guided by susceptibility results have better
clinical outcomes [23C]. Regimens should
include a uoroquinolone, an injectable agent
from among kanamycin, amikacin, and
capreomycin, and three or four other sec-
ond-line drugs for a minimum of 24 months.
The best results are achieved with in-patient
treatment [24C]. However, recent studies have
shown that successful outcomes can also be
obtained in community settings [25C]. Com-
munity-based treatment, apart from the
advantage of not disrupting routine activities,
also reduces the chances of nosocomial trans-
mission of infection.
Many developing countries are now imple-
menting a DOTS Plus component that pro-
vides diagnosis and treatment of MDR
tuberculosis with a standardized regimen,
under the aegis of national tuberculosis control
programs. The WHO's Green Light Commit-
tee has subsidized drug prices, but still only
about 10% of patients with MDR tuberculosis
in developing countries are currently being
treated under the GLC program [17R].
The treatment of XDR tuberculosis is
even more difcult, as the choice of effective
drugs is severely limited. Chemotherapy with
appropriate drugs, close monitoring for
adherence and adverse reactions, and other
interventions, such as surgery, will be
required. XDR tuberculosis is virtually
untreatable, and every effort should be made
to minimize its emergence by effectively
treating MDR tuberculosis.
The most recent specic tuberculosis drug,
rifampicin, was introduced more than 40
years ago. The challenges posed by the
HIV epidemic and drug resistance over the
past two decades have nally prompted a
search for new tuberculosis drugs. Initiatives
such as the Global Alliance for New TB
Drug Development have ensured that efforts
are now in place to develop new agents with
626
novel modes of action. The Global Alliance
is an NGO that facilitates the development
of new drugs for tuberculosis. A number of
promising new drugs are in the pipeline,
and some are in advanced stages of clinical
testing. These are TMC 207, a diarylquino-
line that inhibits ATP synthase [26R], and
PA-824, a nitro-imidazo-oxazine [27E], both
of which are undergoing phase II clinical tri-
als; OPC 67683, a nitro-imidazo-oxazone
[28E]; and SQ-109, an ethylenediamine
related to ethambutol [29E]. However, it will
be many years before these drugs become
available for clinical use. Meanwhile, prop-
erly designed clinical trials to evolve optimum
regimens for the treatment of MDR tubercu-
losis and XDR tuberculosis are sorely needed.
Conclusions Mycobacterium tuberculosis
has been in existence for many centuries and
has adapted to the many challenges it has
faced over time, including the development
of resistance to the agents used against it.
The many recent advances in the manage-
ment of tuberculosis are being threatened by
the emergence of drug resistance and the
HIV epidemic. The rational treatment of drug
susceptible tuberculosis and the establishment
of adequate laboratory support is essential in
combating the threat of drug resistance. The
lessons of the past have to be borne in mind
to manage this challenge better. Initiatives
for new rapid diagnostics and the handful of
new antituberculosis drugs that are in the
pipeline are belated but nevertheless welcome
developments to combat this threat. Sustained
activities in these and other elds are manda-
tory if the millennium goals for global tuber-
culosis control are to be achieved.
Liver The incidence and susceptibility fac-
tors for antituberculosis drug-induced hepa-
totoxicity have been assessed in a
prospective cohort study in 100 Egyptian
patients with active pulmonary and extra-
pulmonary tuberculosis [30c]. Therapy
included daily doses of isoniazid, rifampi-
cin, ethambutol, and pyrazinamide, or
streptomycin. There was drug-induced hep-
atotoxicity in 15 patients within 1560
(median 30) days from the onset of therapy.
Chapter 30 M.S. Jawahar and V.V. Banu Rekha
Liver function normalized in 10 of these
within 2 weeks from the end of therapy.
Drug-induced hepatotoxicity did not recur
after reintroduction of therapy. Only one
patient died from fulminant hepatic failure,
despite withdrawal of all antituberculosis
drugs. Univariate analysis showed that
patients with drug-induced hepatotoxicity
had more pre-existing liver disease (OR
3.60; 95% CI 1.16, 11), a lower body
mass index (OR 3.73; 95% CI 1.04,
11), a lower serum albumin (OR 3.31;
95% CI 1.04, 11), and more extensive
disease (OR 3.50; 95% CI 1.11, 11).
Age, sex, raised baseline aminotransferase
activities, the use of pyrazinamide, and
inactive hepatitis B or C carrier state were
not signicant susceptibility risk factors.
Multivariate regression analysis showed
that only pre-existing liver disease and a
lower body mass index (20 kg/m2 or under)
were independent predictors of drug-
induced hepatotoxicity. The authors con-
cluded that antituberculosis drug-induced
hepatotoxicity is not uncommon, needs
early recognition and treatment, and is
more common in patients with pre-existing
liver disease and a low body mass index.
Tuberculosis chemoprophylaxis has been
retrospectively evaluated in 63 Spanish
patients with latent tuberculosis out of 497
with inammatory bowel disease who were
candidates for anti-TNFa therapy [31C].
Skin tests for tuberculosis were positive in
86% after a single exposure, but 14%
needed a booster. There were no suscepti-
bility factors for hepatotoxicity. All but
one was treated with isoniazid alone for 6
or 9 months, and only one required chemo-
prophylaxis withdrawal because of hepato-
toxicity. There were no cases of active
tuberculosis in the patients who were trea-
ted with anti-TNFa therapy. The authors
concluded that chemoprophylaxis is safe in
patients with inammatory bowel disease,
even in those taking concomitant, poten-
tially hepatotoxic drugs.
Susceptibility factors HIV infection The
effect of HIV co-infection on the frequency
of serious adverse events of antituberculosis
drugs has been studied retrospectively in 400
Drugs used in tuberculosis and leprosy Chapter 30
South African patients, of whom 141 were co-
infected with HIV, 23 taking antiretroviral
drugs [32c]. Details of serious adverse events
were ascertainable in 331 patients and
occurred in 27% of HIV-infected and 13%
of HIV-uninfected individuals. The excess
was attributable to increase incidences of
peripheral neuropathy (8.3% versus 1.9%)
and persistent vomiting (13% and 3.3%).
The occurrence of serious adverse events
was not related to antiretroviral drug use,
although median CD4 cell counts were lower
in those with adverse effects (130 versus
259  106/l).
Antituberculosis drug treatment in
transplant recipients
Renal transplant recipients The character-
istics of tuberculosis in renal transplant
recipients have been analysed in a retrospec-
tive study in China [33c]. There were 41
documented post-transplant tuberculosis
cases out of the 2333 patients who received
kidney transplants between 1991 and 2007.
Tuberculosis in these patients had the fol-
lowing characteristics: (i) a high incidence
within a short time after transplantation, the
median interval between renal transplanta-
tion and diagnosis of tuberculosis being
8 (range 1156) months and 56% were
diagnosed within the rst year after trans-
plantation; (ii) a high prevalence (51%) of
extra-pulmonary tuberculosis; (iii) a high
co-infection rate with other pathogens
(20%), including Candida albicans, Pseudo-
monas aeruginosa, Staphylococcus aureus,
Acinetobacter hemolyticus, and cytomegalo-
virus; (iv) fever (83%), cough (56%), and
sputum production (39%) were the most
common clinical manifestations; (v) PPD
skin testing had little diagnostic value, with
negative results in all 41 cases; (vi) acute
rejection (29%) and liver function damage
(17%) were the main adverse effects of anti-
tuberculosis chemotherapy; (vii) mortality
among patients with tuberculosis after trans-
plantation was 22%. The authors concluded
that renal transplant recipients face a high risk
627
of tuberculosis because of their immunocom-
promised state and the prevalence of the
disease. Balancing the benets and disadvan-
tages of antituberculosis treatment is of
importance for this specic population.
The incidence of tuberculosis among
renal transplant recipients between 1984
and 2007 has been analysed in a retrospec-
tive study in Brazil [34c]. Of 1342 renal
transplant recipients, 31 received treatment
for clinical tuberculosis (n 23) or as pro-
phylaxis (n 8). The overall incidence of
tuberculosis was 1.71%, diagnosed at a
mean of 53 months after transplantation.
The indications for tuberculosis prophylaxis
were a previous history of tuberculosis
(n 6) or direct contact with a tuberculosis
carrier (n 1). The most common clinical
presentation was extrapulmonary tuberculo-
sis (n 13). Classical treatment was effec-
tive in 16 cases. However, seven cases of
drug-resistant tuberculosis required addi-
tional ethambutol. Adverse events included
liver toxicity (n 1) and peripheral neurop-
athy (n 1). Three patients died with tuber-
culosis-related complications. There was
graft loss in three patients after the end of
antituberculosis drug treatment. None of
those on prophylaxis developed clinical dis-
ease. Thus, the incidence of tuberculosis
was signicantly higher among renal trans-
plant recipients compared with the local
population, with a higher incidence of extra-
pulmonary disease. Tuberculosis prophy-
laxis in selected cases was effective in
avoiding new infections.
Heart transplant recipients The incidence
of tuberculosis among 315 heart transplant
recipients has been studied in Taiwan [35C].
Clinical records were reviewed for demo-
graphic data, clinical presentation, treatment,
and outcomes. Ten patients who had received
heart transplants (3.17%) developed pulmo-
nary and/or extrapulmonary tuberculosis, a
higher rate than that reported for the general
Taiwan population (0.067%). Treatment
consisted of isoniazid, rifampicin, ethambu-
tol, pyrazinamide, streptomycin, ciprooxa-
cin, and levooxacin. Seven patients
completed treatment, with a median treatment
duration of 1 year. Three patients developed
628
hepatitis. There was no tuberculosis-related
mortality. The authors concluded that tuber-
culosis in heart transplant recipients may be
completely treated by a combination of at
least three drugs, except pyrazinamide
because of adverse effects and tolerance.
Liver transplant recipients The efcacy of
isoniazid in latent and active Mycobacterium
tuberculosis infection in liver transplant recipi-
ents has been studied in a systematic review
[36M]. Treatment was evaluated in seven stud-
ies, including 139 cases of active tuberculosis
infection in liver transplant recipients. Isonia-
zid was associated with reduced tuberculosis
reactivation in transplant patients with risk fac-
tors for latent tuberculosis (0.0% versus 8.2%),
and there was isoniazid-related hepatotoxicity
in 6% of treated patients, with no reported
deaths. The prevalence of active tuberculosis
infection in transplant recipients was 1.3%.
Nearly half of all the recipients with active
tuberculosis had an identiable pre-transplant
tuberculosis risk factor. Among recipients
who developed active tuberculosis infection,
extrapulmonary involvement was common
(67%), including multiorgan disease (27%).
The short-term mortality rate was 31%. Sur-
viving patients were more likely to have
received three or more drugs for tuberculosis
induction therapy, more likely to have had the
diagnosis within 1 month of symptom onset,
less likely to have multiorgan disease, and less
likely to have had episodes of acute transplant
rejection. The authors concluded that com-
pared with the general population, liver trans-
plant recipients have an 18-fold increase in
the prevalence of active tuberculosis infection
and a fourfold increase in the case-fatality rate.
For high-risk transplant candidates, isoniazid
appears to be safe and is probably effective in
reducing tuberculosis reactivation.
In a retrospective study in Brazil in 319
patients who underwent liver transplant and
survived more than 1 month tuberculosis was
identied in ve women, mean age 40 years
[37C]. None received chemoprophylaxis
before or after liver transplant. Two had dis-
seminated tuberculosis, two had pulmonary
disease, and one had extrapulmonary disease.
Cultures were positive in four. Four patients
received isoniazid, rifampicin, and
Chapter 30 M.S. Jawahar and V.V. Banu Rekha
pyrazinamide for 612 months, with good tol-
erance, but one had a recurrence. Another had
raised hepatic enzyme activities after the start
of therapy. In this series, the frequency of
tuberculosis after liver transplantation was
1.57%, and there was no conrmed hepatotox-
icity with conventional treatment. The survival
rate was 100%.
Problems in interpreting
interaction studies with protease
inhibitors in patients co-infected
with tuberculosis and AIDS
Pharmacokinetic studies in healthy volun-
teers have shown an unexpectedly high inci-
dence of gastrointestinal intolerance and
liver enzyme rises. For example, some stud-
ies of the interaction of rifampicin with lopi-
navir ritonavir in healthy volunteers have
also shown increased hepatotoxicity, but
some observational studies have reported a
lower incidence. The methodological prob-
lems of pharmacokinetic studies, which
could affect the incidence of hepatotoxicity,
have been discussed [38r].
Time course Rifampicin induces CYP3A4
at about 15 days, and interaction studies
have generally started treatment with prote-
ase inhibitors within 15 days of the start of
rifampicin therapy. Furthermore, pharmaco-
logical tolerance to effects can occur. The
problems of variations in pharmacokinetics
with time have been illustrated by a study
of the effects of rifampicin on the pharmaco-
kinetics of nevirapine in 16 patients co-
infected with HIV-1 and tuberculosis [39c].
They took standard antituberculosis therapy
and a xed-dose combination of stavudine,
lamivudine, and nevirapine. The median
AUC of nevirapine was reduced by rifampi-
cin by 26% at 4 weeks, but by only 7.5% at
10 weeks. The median Cmin was reduced by
20% at 4 weeks and by 7.1% at 10 weeks.
The authors concluded that the effect of
rifampicin on the pharmacokinetics of nevi-
rapine substantially decreases over time.
Drugs used in tuberculosis and leprosy Chapter 30
Overlapping adverse effects Both rifampi-
cin and protease inhibitors produce hepato-
toxicity, more often within the rst week of
treatment.
Body weight There are well-known phar-
macokinetic differences between healthy vol-
unteers and patients who are co-infected
with tuberculosis and HIVpatients with
co-infection may absorb drugs less well and
be of lower body weight than healthy
volunteers.
In a prospective randomized comparison
of standard doses of efavirenz-based and
nevirapine-based antiretroviral drug ther-
apy, 142 patients with concurrent HIV-1
infection and tuberculosis who were taking
rifampicin were randomized to antiretroviral
drug therapy that included either efavirenz
600 mg/day or nevirapine 400 mg/day
[40C]. Efavirenz and nevirapine concentra-
tions at 12 hours after dosing were moni-
tored at weeks 6 and 12. CD4 cell counts
and HIV-1 RNA concentrations were
assessed every 12 weeks. At weeks 6 and
12, the mean efavirenz concentrations were
4.3 and 3.5 mg/l respectively, and the mean
nevirapine concentrations were 5.6 and
5.6 mg/l respectively. At week 12, 3.1% of
patients taking efavirenz group and 21% of
those taking nevirapine had concentrations
that were less than the recommended mini-
mum concentrations (OR 8.4; 95% CI
1.8, 39). Intention-to-treat analysis
showed that 73% and 72% respectively of
patients taking efavirenz or nevirapine
achieved HIV-1 RNA concentrations below
50 copies/ml at week 48, with respective
mean CD4 cell counts of 274 and
252  106/l. Multivariate analysis showed
that patients with low concentrations and
those with a body weight below 55 kg were
respectively 3.6 and 2.4 times more likely to
develop all-cause treatment failure. Anti-
retroviral therapy regimens containing efa-
virenz were less compromised by
concomitant use of rifampicin than those
that contained nevirapine in patients with
concurrent HIV-1 infection and tuberculo-
sis. Low drug exposure and low body weight
were important predictive factors for treat-
ment failure.
629
Pharmacokinetic variability Plasma con-
centrations of protease inhibitors have high
interindividual and intraindividual variabil-
ity; sequential design is a better option than
parallel group design, because of reduced
interindividual variability.
Co-medication Co-medications in co-
infected patients could result in interactions
with CYP3A4 and P glycoprotein; excessive
alcohol consumption is not unusual in co-
infected patients.
Co-morbidities About 30% of HIV-infected
patients also have hepatitis C infection.
Conclusions It is therefore difcult to gener-
alize the conclusions of studies in healthy
volunteers to patients co-infected with tuber-
culosis and HIV.
Diagnosis of adverse drug reactions The
usefulness of the drug-lymphocyte stimula-
tion test to identify the antituberculosis drugs
that caused adverse effects in 436 patients
with tuberculosis has been studied in Japan
[41C]. Lymphocyte stimulation was per-
formed in patients who had had adverse drug
reactions during antituberculosis drug treat-
ment and the causative drug was identied
by a drug provocation test. The tested drugs
were mainly isoniazid, rifampicin, ethambu-
tol, and pyrazinamide. Of 436 patients,
69 (16%) had adverse reactions to antituber-
culosis drugs. Of the 261 agents that were
tested, 28 (11%) in 20 patients (29%) were
positive by the lymphocyte stimulation test,
and 67 (26%) in 46 patients (67%) were iden-
tied as causative drugs by the drug provoca-
tion test. The sensitivity of the lymphocyte
stimulation test was only 15% for all drugs
(isoniazid 14%, rifampicin 14%, ethambutol
14%, pyrazinamide 0%). The authors con-
cluded that lymphocyte stimulation offers lit-
tle contribution to the detection of causative
agents in patients with adverse reactions to
antituberculosis drugs.
630
Cycloserine [SED-15, 1033]
Nervous system A 69-year-old woman
developed hypersomnolence and asterixis
while taking cycloserine; an MRI scan of
the brain showed bilateral symmetrical tha-
lamic hyperintensities, which resolved after
withdrawal of cycloserine as did her symp-
toms [42A].
Dapsone [SED-15, 1050; SEDA-29, 315;
SEDA-30, 357; SEDA-31, 406]
Observational studies In a retrospective
study of the effects of dapsone 100 mg/day
for at least 30 days in 52 adults with immune
thrombocytopenic purpura, in whom rst-
line therapy with glucocorticoids had failed
[43c]. Dapsone resulted in a sustained
increase in platelet count in 23 patients after
a median follow-up of 21 months and none of
those who responded required splenectomy
compared with 20 of the other 29. Dapsone-
related adverse events were mild and were
promptly reversed by withdrawal.
Cardiovascular Complete atrioventricular
block has been reported in the context of
dapsone hypersensitivity [44A].
A 45-year-old woman took dapsone 150 mg/
day for 5 weeks for pustular palmoplantar
psoriasis and developed dyspnea, numbness
of all four limbs, and syncope. She had multi-
ple enlarged mobile cervical and retroauricu-
lar lymph nodes measuring 1.53.0 cm and
an itchy maculopapular rash. Her liver
enzymes were raised but urea and electrolytes
were normal. An electrocardiogram showed
sinus rhythm and left anterior fascicular block.
She had three further episodes of syncope, on
each occasion associated with bradycardia.
Dapsone was withdrawn and she was given
atropine, dopamine, and isoprenaline, but
her heart rate and blood pressure remained
low and eventually a pacemaker was inserted.
It is not clear whether dapsone could be
incriminated in the heart block that
occurred in this case.
Chapter 30 M.S. Jawahar and V.V. Banu Rekha
Dapsone-induced hematological
abnormalities and their
management
EIDOS classication:
Extrinsic species Dapsone
N-hydroxylated metabolites
Intrinsic species?
Distribution Erythrocytes
Outcome (pathophysiological adverse
effect) Hemolysis and/or
hemoglobin reduction
Sequela (adverse reaction) Hemolytic
anemia and/or methemoglobinemia
DoTS classication:
Dose-relation Collateral
Time-course Intermediate
Susceptibility factors Genetic (G6PD
deciency; cytochrome b5
reductase deciency); diseases
(?renal insufciency)
The most common hematological adverse
effects of dapsone are hemolytic anemia and
methemoglobinemia. Agranulocytosis [45A,
46A] can also occur, as can rarely sulfhemo-
globinemia [47A, 48A], aplastic anemia
[49A], and pure red cell aplasia [50A].
Pathogenesis Dapsone is metabolized either
by acetylation to non-toxic acetyldapsone or
by N-hydroxylation by multiple CYP iso-
enzymes to toxic hydroxylamines [51E]. The
latter are thought to be responsible for methe-
moglobinemia and hemolysis.
Agranulocytosis due to dapsone occurs
particularly in the rst 3 months of therapy,
and the risk is increased in patients with der-
matitis herpetiformis [52R]. The mechanism
is not known, but it has been proposed that
selective preservation of basophils, as found
in a patient with severe dapsone-induced
agranulocytosis, could be relevant [53A].
A 40-year-old woman took dapsone 100 mg/
day for 3 weeks for discoid lupus and devel-
oped a fever, sweats, and severe pharyngitis
associated with dysphagia for solids and uids.
She was also taking atorvastatin, codeine phos-
phate, indometacin, and lansoprazole. Her
Drugs used in tuberculosis and leprosy Chapter 30
throat was congested, with ulceration of the
uvula and white exudates covering the palate
and tonsils. Her leukocyte count was
0.4  109/l, hemoglobin 9.7 g/dl, platelet count
534  109/l, C reactive protein 441 mg/l, and
erythrocyte sedimentation rate 80 mm/hour.
On blood smear there was a complete absence
of neutrophils and eosinophils, but basophils
were preserved. The bone marrow contained
no myeloid precursors, but erythroid, megakar-
yocytic, and lymphoid lineages were present in
normal numbers. All medications, including
dapsone, were withdrawn and she was given
antibiotics and subcutaneous G-CSF 300 mg/
day. The clinical features and neutrophil count
gradually returned to normal.
These observations suggest that if dapsone
was responsible for the agranulocytosis in
this case, the pathogenetic process was oper-
ating at the myeloid progenitor stage. It could
also be that preservation of basophils, which
lack signicant peroxidase activity, is an indi-
cation that dapsone-induced agranulocytosis
may be due to a hypersensitivity reaction
caused by active metabolites of dapsone,
mediated by myeloperoxidases.
Susceptibility factors The association of
dapsone-induced hemolysis with G6PD
deciency is well known [SED-15, 1051].
Cytochrome b5 reductase deciency
can be associated with an increased risk
of methemoglobinemia [54c].
Dapsone-induced hemolytic anemia in lung
transplant recipients who received dapsone for
prophylaxis of Pneumocystis jirovecii pneu-
monia has been reported in a retrospective
study of 43 patients, of whom 10 had hemolytic
anemia without G6PD deciency [55c]. The
mean fall in hemoglobin from baseline was
2.7 g/dl (95% CI 1.9, 3.5). The odds ratio
for hemolysis was 4.75 for each 1.0 mg/dl
increase in serum creatinine (95% CI 1.07,
21). The authors concluded that the prevalence
of dapsone-induced hemolytic anemia in lung
transplant recipients is ve times higher
than the reported rates for other groups
who routinely use dapsone prophylaxis for
Pneumocystis pneumonia and that individuals
with renal insufciency or low body weight
and for whom the dose exceeds 1.5 mg/kg
may be at increased risk of dapsone-induced
hemolytic anemia.
631
Topical TMdapsone The use of dapsone 5% gel
(Aczone ) in acne vulgaris has been reviewed
[56R]. In a 12-month, open study and
two open, phase I pharmacokinetic studies
the serum concentrations of dapsone and N-
acetyldapsone remained low and did not accu-
mulate over time after steady state was reached.
Of 50 patients with G6PD deciency in all the
studies, only two had a fall in hemoglobin con-
centration, consistent with uctuations
observed in other study participants. The risk
of hemolysis in 64 patients, aged 12 years or
over, with G6PD deciency and acne vulgaris
has been reported from a double-blind, ran-
domized, vehicle-controlled, crossover study
of topical dapsone gel 5% bd [57c]. There
was a 0.32 g/dl fall in hemoglobin concentra-
tion from baseline to 2 weeks during dapsone
treatment. It was not accompanied by changes
in other laboratory parameters, including retic-
ulocytes, haptoglobin, bilirubin, or lactate
dehydrogenase activity, and was not apparent
at 12 weeks as treatment continued. The num-
ber of subjects with a 1-g/dl fall in hemoglobin
concentration was similar between treatment
groups at weeks 2 and 12. The largest falls in
hemoglobin concentration were 1.7 g/dl with
the vehicle and 1.5 g/dl with dapsone gel. There
were no signs or symptoms of hemolytic
anemia.
Management Cimetidine The use of cimeti-
dine to reduce dapsone-dependent hemato-
logical adverse effects in a patient with
mucous membrane pemphigoid has been
reported [58A].
A 77-year-old man with COPD who was using
long-term oxygen developed mucous mem-
brane pemphigoid, which did not respond to
high-dose oral glucocorticoids, azathioprine,
and minocycline. He was given dapsone
50 mg in the morning and 25 mg at night in
place of azathioprine, and there was clinical
improvement. His G6PD activity was normal.
However, within 4 weeks, he developed a
hemolytic anemia (hemoglobin 10.2 g/dl, abso-
lute reticulocyte count 206  109/l) and methe-
moglobinemia of 9.4% with mild cyanosis. He
was given cimetidine 400 mg tds and over the
next 4 months his blood counts gradually
improved and the cyanosis resolved. There
was no interference with the efcacy of dap-
sone, and the disease was controlled with dap-
sone 75 mg/day and prednisolone 5 mg/day.
632
Cimetidine increases plasma dapsone con-
centrations without increased hemolysis,
reduces methemoglobin concentrations by
selective inhibition of dapsone N-hydroxyl-
ation, and does not interfere with the control
of the skin disorder. These features seem to
be detectable within weeks and are sustained.
The effects of cimetidine appear to be greatest
on methemoglobin concentrations.
Darbepoetin alfa Darbepoetin alfa has been
used to treated dapsone-induced hemolysis
[59A].
An 84-year-old man with linear IgA disease
was given dapsone 25 mg/day. In a few days
his hemoglobin concentration fell from 12.1 to
10.7 g/dl. There was no therapeutic effect, so
the dose was increased to 50 mg/day. His
hemoglobin concentration fell further to 9.8 g/
dl and he became pale, with cyanotic lips, but
not icteric. The dose of dapsone was reduced
to 50 and 25 mg on alternate days and the
lesions became worse. He was given subcutane-
ous darbepoetin alfa 50 micrograms/week
and the dosage of dapsone was gradually
increased to 150200 mg/day. His hemoglobin
concentration rose and was on average 13.0 g/
dl during 3 years of follow-up, during which
time the total bilirubin was normal. Haptoglo-
bin was undetectable during treatment with
darbepoetin alfa.
Control of anemia with darbepoetin alfa
has been reported in association with cancer
chemotherapy, treatment of renal insuf-
ciency, to control anemia due to inamma-
tory bowel disease, and in diabetes-induced
anemia. However, this appears to be the rst
time it has been used successfully to control
a drug-induced anemia.
Hemodialysis Severe dapsone poisoning,
which resulted in methemoglobinemia and
hemolytic anemia, improved after hemodialy-
sis [60A].
A 19-year-old man with a depressive disorder,
taking olanzapine, lorazepam, and aripipra-
zole, took an intentional overdose of 4045 tab-
lets of dapsone 100 mg (a total of 44.5 g). He
became drowsy but was conscious and
responded to oral commands. There were signs
of cyanosis and sinus tachycardia. The serum
methemoglobin concentration was increased at
Chapter 30 M.S. Jawahar and V.V. Banu Rekha
51 g/dl and a peripheral blood smear showed
Heinz bodies, indicating oxidative stress. He
was treated with hemodialysis for 3 days. Dur-
ing the second day, the methemoglobin concen-
tration fell from 51 to 11.5 g/dl and on the third
day was 0.9 g/dl. However, there was a progres-
sive fall in hemoglobin concentration from
12.6 g/dl on the rst day to 6.5 g/dl on the fth
day. He was given three units of erythrocytes
and the hemoglobin concentration rose to
10.6 g/dl.
Dapsone is 5080% bound to plasma
proteins and the remainder is probably
available in the free form for dialysis.
Skin Dapsone-induced photosensitivity has
been reported in an Indian patient with
leprosy [61A].
A 37-year-old man with borderline leproma-
tous leprosy was given multidrug therapy
according to the WHO guidelines and after 5
weeks developed redness and a burning sensa-
tion with erythema and tiny papules over the
face, the neck, the ears, and the extensor sur-
faces of the arms. The lesions progressed over
34 days. He was afebrile. There was no pallor
or icterus, hepatosplenomegaly or lymph-
adenopathy. The natural skin folds were
spared, as were the other photoprotected
areas of the body. Routine hematology, bio-
chemistry, including anti-nuclear antibody,
and a chest X-ray, were normal. He was given
oral prednisolone, an antihistamine, and a
sunscreen lotion. The drug therapy was con-
tinued without dapsone and after 1 week, the
lesions started to improve and the redness
abated signicantly. Prednisolone was gradu-
ally tapered over 3 weeks and withheld. He
was later challenged with dapsone 50 mg, after
which he developed a rash similar to the previ-
ous episode.
Dapsone-induced photosensitivity is a
rare hypersusceptibility reaction to sulfones
and can occur in patients with inammatory
skin disorders treated with dapsone. Only
12 cases have been reported. Photoallergic
reactions are based on an immunological
mechanism and can be provoked by UV radi-
ation in a minority of people, with prior sen-
sitization to the molecule. The characteristic
sulfone group (C SO2 C) present in the
parent molecule, as well as its metabolites,
is responsible.
Drugs used in tuberculosis and leprosy Chapter 30
Immunologic In the dapsone syndrome (or
sulfone syndrome) there is fever, exfoliative
dermatitis and photosensitivity, jaundice,
hepatosplenomegaly, generalized lymph-
adenopathy, and pruritus. In one case there
was a bullous skin eruption with circulating
190 and 230 kDa autoantibodies [62A].
A 44-year-old Korean woman developed gen-
eralized, pruritic, erythematous, edematous
patches associated with vesicles and bullae
on the limbs, with fever and tenderness in
the right hypochondrium. She had been taking
dapsone 100 mg/day, prednisolone 10 mg/day,
and ebastine 10 mg/day for urticarial vasculitis
for 1 month. There was edema with diffuse
erythema over the entire body, and tense vesi-
culobullous lesions on the forearms. The oral
and genital mucosae were intact. Multiple
enlarged cervical lymph nodes were palpable.
She had a persistent fever (> 38  C), a leuko-
cytosis (white blood cell count 16.2  109/l),
abnormal liver function tests (aspartate ami-
notransferase 248 U/l, alanine aminotransfer-
ase 196 U/l, gamma-glutamyl transferase
214 U/l, total bilirubin 65 mmol/l), and lactate
dehydrogenase. There was an atypical lym-
phocytosis 1015% and an eosinophilia of
14%. Viral markers for acute hepatitis were
negative. Abdominal ultrasonography showed
parenchymal liver disease. Biopsy of a vesicle
from the forearm showed subepidermal bullae
with marked edema in the upper dermis and
perivascular lymphocytic inltrates with eosin-
ophils. Indirect immunouorescence on nor-
mal human foreskin showed deposition of
immunoglobulin G linearly along the base-
ment membrane zone. Immunoblotting using
human epidermal extracts showed IgG anti-
bodies bound to polypeptides of 190 and
230 kDa. ELISA using antidesmoglein-1, anti-
desmoglein-3, anti-bullous pemphigoid
180NC16a, and anti-BP230 was negative.
HHV-6 gene-nested PCR (GenBank acces-
sion No. S57540) using the patient's serum
was negative.
The pathophysiology of the dapsone syn-
drome is unclear, but dapsone metabolites
may act as haptens, resulting in the forma-
tion of antidapsone antibodies. Dapsone is
metabolized primarily via N-acetylation
and N-hydroxylation. The N-hydroxylation
pathway is thought to be the initial step
in the formation of toxic intermediate
633
metabolites, including hydroxylamine. These
metabolites bind covalently to or modify var-
ious molecules, including major histocompat-
ibility complex peptides, so that drug-specic
T-cell recognition contributes to the dapsone
syndrome. Reactive metabolites act as hap-
tens and bind to endogenous proteins to
form a compound that triggers an immune
reaction. Haptenated compounds may also
be directly toxic to cells.
The incidence of the dapsone syndrome
is estimated to be 2% in patients with lep-
rosy, but it can occur in patients without
leprosy. In a retrospective Taiwanese study
of 361 patients without leprosy, of whom
126 (35%) had vascular diseases, who were
given dapsone between June 2001 and
December 2005, the average duration of
therapy was 126 days and the average dos-
age was 110 (range 50300) mg/day [63c].
Dapsone syndrome developed in six
(1.66%) during the rst 6 weeks of treat-
ment (mean time to onset 20, range 836,
days), necessitating hospitalization and
withdrawal of dapsone. There was no cor-
relation between the risk of the dapsone
syndrome and the primary clinical diagno-
sis. None of the patients received rifampi-
cin. All had fever and a rash, either
maculopapular or vesiculopapular. All but
one had evidence of hepatic damage. There
was lymphadenopathy in three and hepa-
tosplenomegaly and pedal edema in one.
All six had a low hemoglobin, ve had
raised activities of serum liver enzymes
and alkaline phosphatase, there was a
lymphocytosis with atypical cells, raised
bilirubin, or raised C-reactive protein con-
centration in four patients each, hypoalbu-
minemia and leukocytosis in three patients
each, and eosinophilia in two. Biopsy of
inamed skin in one patient showed a pre-
dominantly mononuclear cell inltrate
around small blood vessels. Dapsone was
withdrawn and ve patients were managed
with systemic glucocorticoids. The syn-
drome abated in 514 days and all had
favorable outcomes. Rechallenge was not
performed.
634
Ethambutol [SED-15, 1282; SEDA-29,
316; SEDA-30, 358; SEDA-31, 407]
Sensory systems Optic neuropathy
EIDOS classication:
Extrinsic species Ethambutol
Intrinsic species Not Known
Distribution Optic nerve bers and
retinal ganglion cells
Outcome Altered physiology initially;
later nerve cell degeneration
Sequela Optic neuropathy and
retinopathy due to ethambutol
DoTS classication:
Dose-relation Collateral
Time-course Intermediate
Susceptibility factors Diseases (renal
impairment, zinc deciency)
Reduced visual acuity and central or centro-
cecal scotomas on visual eld testing have
been reported as the usual presentation of eth-
ambutol-induced optic neuropathy. Bilateral
temporal hemianopia has been reported in a
case of ethambutol toxicity [64A].
A 75-year-old woman developed progressively
worse peripheral vision in both eyes after tak-
ing ethambutol 1200 mg/day for almost 1 year,
plus clarithromycin and rifampicin for infec-
tion with Mycobacterium avium complex and
Mycobacterium kansasii. Best corrected visual
acuity was 20/80 in the right eye and 20/60
in the left eye. Eye movements were full. Slit
lamp exam showed 1 nuclear sclerosis in
both eyes. On fundoscopy the optic discs were
not swollen or pale. A 302 Humphrey visual
eld showed bitemporal hemianopia. An
MRI scan of the brain was normal, as was
optical coherence tomography.
The mechanism of ethambutol-induced
optic neuropathy is unclear. It has been pos-
tulated that it is caused by a disturbance in
mitochondrial metabolism. Ethambutol is
also a strong chelator of copper, a co-factor
of cytochrome c oxidase, which is required
for axonal transport in the optic nerves, fail-
ure of which, secondary to mitochondrial
insufciency, results in optic neuropathy.
Ethambutol is specically toxic to retinal
Chapter 30 M.S. Jawahar and V.V. Banu Rekha
ganglion cells and may affect only the small
papillomacular bundle of axons, resulting in
normal initial fundoscopy, delayed optic
atrophy, and normal MR imaging.
In a retrospective study of 857 Korean
patients who took ethambutol, 89 had
impaired vision [65c]. Ethambutol-induced
optic neuropathy was diagnosed in during a
mean follow-up period of 13 months. The
average dose of ethambutol was 18 mg/kg/
day and the duration of therapy was 9.4
months. Ophthalmic ndings included
reduced visual acuity (n 58), abnormal
visual elds (n 58), abnormal color vision
(55), optic disc pallor (34), and increased
latency on VEP tests (58). Slightly less than
one-third of the patients had improved visual
function after discontinuing ethambutol.
The mean time to recovery was 5.4 months.
However, no patient with optic disc pallor
at the time of diagnosis had improved visual
function. Renal dysfunction and the daily
dose of ethambutol, but not the duration of
treatment, contributed. The authors esti-
mated the incidence of ethambutol-induced
optic neuropathy in Koreans to be under
2%. Thus, visual function after withdrawal
of ethambutol is reversible in only a minority
of patients and does not occur if optic disc
pallor is present.
Two patients who developed reduced
visual acuity after taking ethambutol for
several months for Mycobacterium avium-
intracellulare infection had bitemporal
visual eld defects that suggested damage
to the optic chiasm [66A].
A 48-year-old woman developed progressively
blurred vision, difculty in identifying colors,
and peripheral visual eld loss after taking clar-
ithromycin and ethambutol 16 mg/kg/day for 7
months for pulmonary Mycobacterium avium
intracellulare infection. Ethambutol was
promptly withdrawn. The best-corrected visual
acuities were 20/50 in the right eye and 20/60
in the left eye. She correctly identied 7/8 and
5/8 Ishihara color plates in the right and left
eyes respectively. Automated (Humphrey)
visual eld testing showed bilateral superotem-
poral defects that respected the vertical merid-
ian and extended to xation. However, the
probability map of the total deviation plot
crossed the vertical meridian, which made it
unlikely that the pattern of visual loss was
caused solely by a chiasmal lesion. Multifocal
Drugs used in tuberculosis and leprosy Chapter 30
electroretinography was performed on the
VERIS system using 103 hexagons. Multiple
hexagons showed responses with signicantly
reduced amplitudes in the central and nasal
macular regions in both eyes that corresponded
to the visual eld defects. Her visual acuity
recovered to 20/30 in both eyes 7 months after
withdrawal ethambutol.
A 78-year-old woman developed blurred vision,
impaired color vision, new oaters, and soreness
in her left eye after taking ethambutol 19.6 mg/
kg/day, clarithromycin, rifampicin, anastrozole,
zolpidem, and felodipine for 6 months. Etham-
butol was withdrawn. Her best-corrected visual
acuities were 20/80 in the right eye and 20/400
in the left eye. She was able to identify only the
test plate on Ishihara color testing. Automated
(Humphrey) visual eld testing showed reduced
sensitivity in the temporal paracentral aspect of
the visual elds in both eyes. The threshold
abnormalities of the total deviation plot crossed
the vertical meridian, which made it unlikely that
the pattern of visual loss was solely attributable
to a chiasmal lesion. Dilated stereoscopic oph-
thalmoscopy showed temporal pallor of both
optic discs. There were retinal pigment epithelial
changes in the nasal mid-peripheral retina in the
right eye and in the nasal peripheral area in the
left eye. There were several ame hemorrhages
along the inferior temporal arcade in the left
eye. Full-eld electroretinography showed
reduced B wave amplitudes; on multifocal elec-
troretinography multiple hexagons showed
reduced amplitude responses in the central and
nasal macular regions in both eyes, correspond-
ing to the visual eld defects. Her visual acuities
improved to 20/30 in both eyes 7 months after
ethambutol withdrawal.
These results suggested that visual dysfunc-
tion due to ethambutol may be entirely attrib-
utable to retinal rather than optic nerve
toxicity. These are the rst reports to show
abnormalities in multifocal electroretinogra-
phy that correspond to bitemporal visual eld
defects and add to the growing evidence that
ethambutol damages the retina.
In a prospective evaluation of various
visual parameters for early detection of eth-
ambutol toxicity in 52 patients with tubercu-
losis attending a Directly Observed
Treatment Strategy Centre [67c] visual acu-
ity, visual elds, visual-evoked responses,
stereoacuity, and retinal nerve ber layer
thickness on optical coherence tomography
were assessed after 1 and 2 months of treat-
ment, and 1 month after withdrawal. There
was no visual functional defect at baseline.
On follow-up, visual acuity, color vision,
635
contrast sensitivity, fundoscopy, and stereo-
acuity were not affected in any patient.
Visual eld defects developed in eight
of the 104 eyes. Pattern visual-evoked
responses showed an increased mean latency
of the P100 wave after 1 and 2 months of ther-
apy, and 15 eyes had more than a 10-msec
increase in latency. Optical coherence
tomography showed signicant loss of mean
temporal retinal nerve ber layer thickness
in three eyes. There was subclinical toxicity
in 20 eyes, with reversal of this in 80% within
1 month of ethambutol withdrawal, although
mean visual-evoked response latencies
remained delayed. The authors concluded
that pattern visual-evoked responses and
visual eld examinations are sensitive tests
in the detection of early ethambutol toxicity.
Together with optical coherence tomogra-
phy, they may help to identify patients who
are likely to develop clinical toxicity.
Isoniazid [SED-15, 1923; SEDA-29, 317,
SEDA-30, 359; SEDA-31, 498]
Systematic reviews In a meta-analysis of
published studies of compliance, toxicity,
and cost-effectiveness, comparing isoniazid
monotherapy for 9 months and rifampicin
for 4 months [68M] in a total of 3586
patients, the latter was associated with a
signicant reduction in the risk of non-com-
pletion (RR in a random-effects model
0.53; 95% CI 0.44, 0.63). Non-comple-
tion rates were lower among patients who
took rifampicin for 4 months (range
8.628) than in those who took isoniazid
for 9 months (range 2447%). Rates of hep-
atotoxicity (dened as grade 3 or 4 liver fail-
ure leading to drug withdrawal) were lower
in patients who took rifampicin (range
00.7% versus 1.45.2%), and rifampicin
was associated with signicant reduction in
the risk of hepatotoxicity (RR 0.12;
95% CI 0.05, 0.3).
Nervous system Central nervous system
toxicity due to isoniazid has been reported
in a child [69A].
636
A 5-year-old girl with pulmonary tuberculosis
was given isoniazid, rifampicin, pyrazinamide,
and ethambutol and within 1 week developed
somnolence, reduced appetite, and vomiting.
A few days later she had two seizures lasting
about 5 minutes each. She was afebrile, had
normal vital signs, and was alert but had a
uctuating level of consciousness over the
next 48 hours, with times when she was rousa-
ble only by painful stimuli. Blood culture was
sterile and cerebrospinal uid culture was neg-
ative for bacteria, mycobacteria, and viruses.
An MRI scan of the brain showed symmetri-
cal, strikingly increased signal intensity in the
thalami. MR angiography, venography, and
MR spectroscopy were normal, and there
was no abnormal enhancement or mass to sug-
gest meningeal disease or a tuberculoma on
either CT or MR imaging. The serum isonia-
zid concentration taken 12 hours after the
seizures was 20 mg/l (147 mmol/l) and fell
to 1 mg/l (5.3 mmol/l) 19 hours later. The
calculated half-life of isoniazid was 3.9 hours.
Investigation of the abnormally raised concen-
tration of isoniazid established that a dispens-
ing error had been made. Rather than 100-
mg tablets she had received 300-mg tablets
and had taken 750 mg/day (43 mg/kg/day).
All medications were withheld and she had
no further seizures. Within 7 weeks the imag-
ing abnormalities had resolved.
The mechanism of isoniazid-induced neu-
rotoxicity is believed to be reduced concentra-
tions of GABA by inhibition of pyridoxine
(vitamin B6) metabolism. Human studies
describing white matter changes in isoniazid
toxicity have also corroborated a potential
toxic effect on myelin. Rapid resolution of dif-
fusion-restricted lesions in this patient sug-
gested a similar process of intramyelinic
edema. In addition, the half-life of isoniazid
was 3.9 hours, suggestive of the slow acetyla-
tor phenotype, with increased susceptibility
to adverse effects of isoniazid.
Liver Isoniazid-induced liver damage is
histologically indistinguishable from viral
hepatitis and is related to individual suscep-
tibility in patients who hydrolyse the drug
to isonicotinic acid at different rates. Histo-
logically proven isoniazid hepatotoxicity in
complicated tuberculous salpingitis has
been reported [70A].
A 49-year-old woman with tuberculous salpingi-
tis was given isoniazid 300 mg/day, rifampicin
600 mg/day, pyrazinamide 2.0 g/day, and
Chapter 30 M.S. Jawahar and V.V. Banu Rekha
ethambutol 1.5 g/day. She developed fever and
disseminated joint pain after 21 days. Liver
aminotransferases rose and the drugs were with-
held. When she resumed isoniazid, the fever
returned, with chills and ushing. Liver histology
showed prominent hepatocellular damage and
bilirubin accumulation, compatible with a diag-
nosis of drug-induced liver toxicity, which was
attributed to isoniazid. Acetylator status and
CYP polymorphisms were not measured.
Drugdrug interactions Clozapine
Increased plasma concentrations of cloza-
pine have been reported after the addition
of isoniazid [71A].
A 65-year-old man with paranoid schizophre-
nia, generalized anxiety disorder, social anxi-
ety disorder, hypertension, frequent
constipation, and mild anemia, taking cloza-
pine 200 mg bd, venlafaxine XR 150 mg bd,
metoprolol 25 mg bd, docusate 100 mg bd,
and milk of magnesia 30 ml when necessary,
was given isoniazid 300 mg/day for 9 months.
Clozapine and norclozapine concentrations
were measured before he started to take isoni-
azid, because it was anticipated that isoniazid
might increase clozapine concentrations. After
3 days the clozapine and norclozapine concen-
trations rose from 397 and 384 mg/l respec-
tively to 569 and 520 mg/l and after 9 days
756 and 725 mg/l. The patient did not have
any signicant adverse effects, except for
excess sedation. The dose of clozapine was
reduced to 150 mg bd and 11 days later the
clozapine and norclozapine concentrations
had fallen to 527 and 614 mg/l respectively.
The dose of clozapine was reduced again to
100 mg bd and 21 days later, the clozapine
and norclozapine concentrations were 385
and 379 mg/l respectively. After 9 months iso-
niazid was withdrawn and after 54 the cloza-
pine and norclozapine concentrations were
239 and 221 mg/l respectively at a clozapine
dosage of 100 mg/day.
This case shows the affect that isoniazid can
have on serum clozapine and norclozapine
concentrations. Isoniazid inhibits CYP
isoenzymes, including CYP1A2, of which
clozapine is a substrate.
PA-824
PA-824 is a novel nitroimidazo-oxazine, a
prodrug that requires activation by a
bacterial F420-dependent glucose-6-
Drugs used in tuberculosis and leprosy Chapter 30
phosphate dehydrogenase (Fgd) and nitro-
reductase to activate components that
then inhibit bacterial mycolic acid and protein
synthesis [72E]. It has a minimum
inhibitory concentration (MIC) as low as
0.0150.250 mg/l against drug sensitive and
multidrug resistant Mycobacterium tuberculo-
sis. Pharmacokinetic studies of PA-824 in rats
have shown that it has excellent tissue pene-
tration [73E]. In animals, it was active against
non-growing bacilli, even in microaerophilic
conditions, and its activity is comparable to
that of isoniazid, rifampicin, and moxioxacin.
PA-824 had bactericidal activity in mice in the
rst 2 months of treatment and also in the con-
tinuation phase, which suggests that it has sig-
nicant activity against non-growing
persistent bacilli in vivo.
Urinary tract The effects of PA-824 on renal
function have been evaluated in 47 healthy
volunteers, who took PA-824 800 or
1000 mg/day or matching placebo for 8 days
[74c]. The serum creatinine concentration
increased and there were trends towards
reductions in creatinine clearance and extra-
glomerular creatinine excretion (dened as
creatinine clearance minus glomerular ltra-
tion rate). All the changes resolved within 1
week of withdrawal. Thus, the reversible
increase in serum creatinine observed in this
and earlier studies of PA-824 did not appear
to result from a pathological effect on renal
function. That extraglomerular creatinine
excretion fell maximally when drug concen-
trations were highest suggests that PA-824
causes creatinine concentrations to rise by
inhibiting renal tubular creatinine secretion.
Such an effect, considered clinically benign,
has been described for several drugs.
Pyrazinamide [SED-15, 2979;
SEDA-32, 563]
Sensory systems Olfaction Alterations in
taste and smell function, which are rare, have
been reported for pyrazinamide when com-
bined with other drugs. Reversible olfactory
637
impairment related to pyrazinamide, with
positive rechallenge, has been reported
[75A].
A 53-year-old woman with diabetes was given
isoniazid 300 mg/day, rifampicin 600 mg/day,
pyrazinamide 1500 mg/day, and streptomycin
1 g/day for skeletal tuberculosis. On the rst
day she had a sensation of smelling something
burning 15 minutes after taking her medica-
tions and had the same sensation every day
thereafter. The sensation lasted 45 hours
and then spontaneously ceased completely.
Three weeks later she had equilibrium disor-
ders, with rotatory dizziness when shaking
her head; investigations localized it to a vestib-
ular origin. Streptomycin was withdrawn and
replaced by ethambutol, but the dysosmia per-
sisted. Pyrazinamide and ethambutol were
withdrawn and the olfactory effects resolved
completely. She then inadvertently took a
single dose of pyrazinamide 1500 mg and
15 minutes later experienced the olfactory
symptoms as before. She continued to take
isoniazid and rifampicin without recurrence.
Olfactory disorders are often caused by
affections of the nose and sinuses, such as
rhinitis, sinusitis, nasal polyps, nasal septal
deviation, and less frequently diabetes,
hepatic diseases, or renal insufciency. In
this case, even though pyrazinamide was
the probable cause, a role of diabetes can-
not be totally excluded. Altered sense of
smell has been associated with pyrazina-
mide plus levooxacin [76c] and altered
taste or smell has been reported with pyra-
zinamide plus isoniazid plus rifampicin and
with gatioxacin [77c].
RIFAMYCINS [SED-15, 3040;
SEDA-30, 359; SEDA-31, 498;
SEDA-32, 563]
Rifabutin
Skin Acute generalized exanthematous pus-
tulosis (AGEP) is a clinical reaction pattern
that is principally drug induced; more than
90% of cases are drug induced, mainly by
antibiotics, especially b-lactams and macro-
lides. It has also been attributed to rifabutin
638
[78A]. The incidence is probably underesti-
mated, because many cases are either
unrecognized or confused with pustular
psoriasis.
Drugdrug interactions Lopinavir rito-
navir The steady-state pharmacokinetics
of rifabutin and its active metabolite 25-
desacetyl-rifabutin have been examined
before and after the addition of lopinavir
ritonavir in 10 patients with HIV infection
and active tuberculosis [79c]. Samples were
collected at 24 weeks after starting rifa-
butin 300 mg thrice weekly without lopina-
vir ritonavir, 2 weeks after the addition
of lopinavir ritonavir 400/100 mg bd to
rifabutin 150 mg thrice weekly, and (if rifa-
butin plasma concentrations were below
the target range) 2 weeks after an increase
in rifabutin dosage to 300 mg thrice weekly
with lopinavir ritonavir. Lopinavir
ritonavir reduced the Cmax of total rifabutin
and most unbound rifabutin Cmax values
were below the tuberculosis MIC. For most
patients, the AUC was low or lower than
associated with treatment failure or relapse
and with acquired rifampicin resistance.
The authors concluded that the recom-
mended doses of rifabutin for use with lopi-
navir ritonavir may be inadequate in
many patients and recommended monitor-
ing of plasma concentrations.
Rifampicin
Comparative studies In a prospective com-
parison of a combination of rifampicin and
linezolid with a combination of rifampicin
and co-trimoxazole in the treatment of
bone and joint infections in 56 adults, 36
had infected orthopedic devices and 20
had chronic osteomyelitis [80c]. Patients
who discontinued antibiotic therapy within
4 weeks of starting treatment were consid-
ered to be cases of treatment failure
and were excluded. The rates of adverse
effects were similar in the two groups;
43% versus 46% respectively, and led to
Chapter 30 M.S. Jawahar and V.V. Banu Rekha
treatment discontinuation in four and six
patients.
Liver In a retrospective cohort study of the
effect of adding rifampicin to standard ther-
apy in 42 cases of S. aureus endocarditis on
native valves, conrmed by modied Duke
criteria in a large urban hospital between
2004 and 2005 and 42 controls, the cases
received a rifampicin for median of 20
(range 1448) days [81c]. Rifampicin-resis-
tant S. aureus isolates emerged in nine
patients who had received rifampicin
before clearance of bacteremia (56%),
while there were signicant rises in hepatic
aminotransferases in nine cases, all of
whom had hepatitis C infection. Unrecog-
nized signicant drugdrug interactions
with rifampicin were common (52%). Cases
were more likely to have a longer duration
of bacteremia than controls (5.2 versus 2.1
days) and were less likely to survive (79%
versus 95%). The authors concluded that
the potential for hepatotoxicity, drugdrug
interactions, and the emergence of resistant
S. aureus isolates warrants a careful assess-
ment of the benet-to-harm balance before
adding rifampicin to standard antibiotic
treatment in such cases.
Both linezolid and co-trimoxazole are
antibiotics that are well suited for oral ther-
apy of bone and joint infections caused by
otherwise resistant Gram-positive cocci
(resistant to uoroquinolones, macrolides,
beta-lactams).
Hematologic Two patients developed
severe intravascular hemolysis during daily
low-dose rifampicin treatment of meticil-
lin-resistant Staphylococcus aureus
(MRSA) [82A].
A 14-year-old girl with cystic brosis, who was
taking ciprooxacin, amikacin, co-trimoxazole,
and rifampicin for a chronic pulmonary infec-
tion with culture-proven MRSA, was given oral
rifampicin 16 mg/kg/day (300 mg bd) and after 5
weeks developed fatigue and weight gain and
had marked dependent edema. There was no
splenomegaly or jaundice. She had an anemia
(hemoglobin 6.6 g/dl), reticulocytopenia (0.3%),
thrombocytopenia (platelets 64  109/l), and
Drugs used in tuberculosis and leprosy Chapter 30
acute renal insufciency. Renal biopsy showed
acute tubular necrosis. All antibiotics were
stopped and then restarted 48 hours later at renal
doses. However, even after dialysis, the anemia
did not improve and she required erythrocyte
transfusions. A peripheral blood smear showed
occasional echinocytes and rare schistocytes.
Her lactate dehydrogenase activity and bilirubin
were raised and haptoglobin mildly reduced.
Specic antibody testing showed a specic hemo-
lytic anti-rifampicin antibody. Rifampicin and all
antibiotics were withdrawn and the hemoglobin
and platelet count recovered within 2 months.
A 6-month-old boy with trisomy 21, hypo-
thyroidism on replacement therapy, and a
repaired atrioventricular canal was given
parental vancomycin and oral rifampicin
35 mg bd for MRSA bacteremia. He had had
hematuria and a non-hemolytic normocytic
anemia before starting rifampicin. He was
transfused with packed erythrocytes to hemo-
globin of 12.2 g/dl, but returned 2 weeks later
with hemoglobin of 7.3 g/dl, MCV 88 , and
reticulocyte count 6.9%. He had no jaundice,
splenomegaly, or tachycardia. An antibody
that reacted with erythrocytes in the presence
of rifampicin and complement was found.
Rifampicin was withdrawn and his hemo-
globin rose to 11.0 and 15.5 g/dl at 1 and 9
months respectively.
Hemolytic anemia associated with rifampi-
cin was hypothesized to be hapten medi-
ated, as the patient's serum xed
complement in the presence of rifampicin.
However, subsequent studies identied cir-
culating erythrocyte-specic antibodies in
the serum with specicity for both the
Lutheran (Lu) and I antigens. The presence
of the I antigen on the surface of leuko-
cytes, platelets, and renal tubular epithelial
cells may have accounted for the hemolysis,
thrombocytopenia, and renal failure with
acute tubular damage observed in the rst
patient.
Drugdrug interactions Atazanavir
ritonavir In a phase I, open, one-arm study,
14 HIV-seronegative volunteers rst took
rifampicin 600 mg/day for 8 days and then
added atazanavir 300 mg bd and ritonavir
100 mg bd; however, when atazanavir and
ritonavir were added, the rst three subjects
developed vomiting and rises in aminotrans-
ferases and the study was terminated [83c].
639
Atorvastatin Both atorvastatin and rifampi-
cin are substrates of OATP1B1 (organic
anion transporting polypeptide 1B1),
encoded by the SLCO1B1 gene. Rifampicin
is a potent inhibitor of SLCO1B1 (IC50
1.5 mmol/l) and the SLCO1B1 521T>C func-
tional genetic polymorphism alters the kinet-
ics of atorvastatin in vivo. The hypothesis
that rifampicin might inuence atorvastatin
kinetics in a SLCO1B1 polymorphism-
dependent manner has been evaluated in a
two-phase crossover study in 16 subjects with
known SLCO1B1 genotypes (six c.521TT,
six c.521TC, and four c.521CC) [84c]. Rifam-
picin increased atorvastatin plasma concen-
trations in accordance with SLCO1B1
521T>C genotype, while the increases in
AUC0!48 among c.521TT, c.521TC, and
c.521CC individuals were 833%, 468%, and
330% respectively. In contrast, SLCO1B1
521T>C had no effect on rifampicin
pharmacokinetics.
Lopinavir ritonavir The interaction of
rifampicin with lopinavir ritonavir has
been assessed in 34 patients, of whom 23
took a non-adjusted dose of lopinavir
ritonavir (400/100 mg bd or 800/200 mg/
day), six took a slightly adjusted dose (500/
125 or 533/133 mg bd), and ve took a
recommended dose (400/400 or 800/200 mg
bd) [85c]. Seven prematurely stopped taking
the combination within 4 weeks because of
acute adverse events (4/23, 1/6, and 2/5 in
the three respective dosage groups). Com-
bined use of lopinavir ritonavir and rifam-
picin is challenging, as it implies a balance
between suboptimal efcacy and toxicity.
Oxycodone Oxycodone is metabolized
mainly in the liver by CYP3A and
CYP2D6, which rifampicin induces. The
interaction of rifampicin 600 mg/day for 7
days with a single dose of oxycodone,
0.1 mg/kg intravenously or 15 mg orally,
has been studied in a four-session, paired,
placebo-controlled crossover study in 12
volunteers [86C]. Concentrations of oxy-
codone and its metabolites noroxycodone,
oxymorphone, and noroxymorphone were
determined for 48 hours. Psychomotor
640
effects were characterized for 12 hours by
several visual analogue scales. Analgesic
effects were characterized by measuring
the heat pain threshold and cold pain sensi-
tivity. Rifampicin reduced the oxycodone
intravenous and oral AUCs by 53% and
86% respectively. The systemic availability
of oxycodone was reduced from 69% to
21%. Rifampicin greatly increased the
plasma metabolite-to-parent drug ratios
for noroxycodone and noroxymorphone.
The pharmacological effects of oral oxyco-
done were attenuated. To maintain ade-
quate analgesia, dosage adjustment of
oxycodone may be necessary when it is
used concomitantly with rifampicin.
Protease inhibitors For problems in inter-
preting drug interactions studies in patients
who are co-infected with tuberculosis
and AIDS, see the special review above. See
also individual drug names in this section.
Ritonavir saquinavir The effects of
rifampicin 600 mg/day on the steady-state
pharmacokinetics of co-administered saquin-
avir ritonavir 1000/100 mg bd have been
evaluated in 28 healthy HIV-negative sub-
jects in an open, randomized, one sequence,
two-period crossover study [87c]. Following
substantial rises (grade 2) in hepatic amino-
transferases in those who took the co-admin-
istered agents, the study was discontinued
prematurely. Nausea, vomiting, abdominal
pain, and headache were common. The symp-
toms abated and the aminotransferases nor-
malized after drug withdrawal. There was a
possible relation between the rises in amino-
transferases and raised rifampicin and desa-
cetyl-rifampicin concentrations. Although
they have not been conrmed in HIV-
infected patients, these data suggest that
rifampicin should not be co-administered
with saquinavir ritonavir.
Roumilast Roumilast is metabolized by
CYP3A4 and CYP1A2, with further
involvement of CYP2C19 and extrahepatic
CYP1A1. The effects of rifampicin on the
pharmacokinetics of roumilast and rou-
milast N-oxide have been studied in 16
healthy men in an open, three-period,
Chapter 30 M.S. Jawahar and V.V. Banu Rekha
xed-sequence study [88c]. They took a sin-
gle oral dose of roumilast 500 mg on days
1 and 12 and oral rifampicin 600 mg/day on
days 515. Rifampicin the AUC of roumi-
last by 80% and the Cmax by 68%; it
reduced the AUC of roumilast N-oxide
by 56% and increased the Cmax by 30%;
total phosphodiesterase PDE4 inhibitory
activity due to roumilast fell by 58%.
Rifaximin
Immunologic Rifaximin is widely used for
the local treatment of intestinal infections
because of its very poor absorption in the
gastrointestinal tract (less than 0.4%).
IgE-mediated reactions to rifaximin are
rare, but one has been reported [89A].
A 64-year-old man had a severe anaphylactic
reaction (cough, dyspnea, convulsions, and
transient loss of consciousness) a few minutes
after topical medication of a surgical wound
with rifamycin SV solution (Rifocin, Sano-
Aventis, Milan). He had a history of generalized
urticaria after the removal of stitches after
saphenectomy 4 years before, but no informa-
tion was available about the drug used for disin-
fection. Three months before the life-
threatening episode, he had had severe abdom-
inal pain, dyspnea, and urticaria, requiring
emergency admission, about 10 minutes after
taking one tablet of rifaximin (Norntix, Alfa
Wassermann, Bologna, Italy) for diverticular
disease. His serum was studied twice, 1 month
and 1 year after the anaphylactic reaction. On
the rst occasion serum IgE to rifamycin SV
and rifampicin, but not to rifaximin, was
detected; total IgE was 415 kU/l. However,
there were specic IgE antibodies to rifaximin,
because pre-incubation of serum with rifaximin
almost completely inhibited the binding of IgG
to the rifampicinsepharose complex. One year
later, serum-specic IgE to rifampicin, rifa-
butin, and rifapentin was still present; total
IgE was 102 kU/l.
The time-course of the reactions suggested
that the small amount of rifaximin absorbed
not only provoked the rst, relatively mild
systemic reaction, but could have had a
booster effect on IgE synthesis in response
to rifampicin (probably present since the
rst reaction, 4 years earlier), which
enhanced the subsequent severe reaction
to rifamycin SV.
Drugs used in tuberculosis and leprosy Chapter 30
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 P.J.J. van Genderen

31 Antihelminthic drugs

Metabolism In a systematic review of the BENZIMIDAZOLES [SED-15,

literature on drug-induced hypoglycemia 424; SEDA-30, 364; SEDA-31, 508;
electronic databases (MEDLINE,
EMBASE, Web of Science, and SCOPUS) SEDA-32, 572]
and the drug information system Micro-
medex were searched and additional refer- Albendazole [SED-15, 48; SEDA-30,
ences were sought from experts [1M]. 364; SEDA-31, 508; SEDA-32, 572]
Studies were eligible if they reported hypo-
Observational studies In a study in Sri
glycemia as an adverse effect of a drug not
Lanka, 2319 patients, aged 1090 years, were
used to treat hyperglycemia, regardless of
randomly selected from urban and rural areas
their design, size, or follow-up duration, or
and interviewed about the type and severity of
the language of the report. Hypoglycemia
adverse reactions to mass drug administration
caused by industrial exposures, non-phar-
of albendazole and diethylcarbamazine,
macological chemical exposures, alcohol,
which is a component of the World Health
herbs, and nutritional supplements were
Organization's efforts to eliminate lariasis
excluded, as were in vitro and animal stud-
worldwide [2C]. Seeking medical treatment
ies. There were 448 eligible studies, describ-
and requiring hospitalization were used as
ing 2696 cases of hypoglycemia associated
indicators of the severity of infection. Almost
with 164 different drugs. The quality of evi-
64% (n 1478) of the population said that
dence supporting the associations was
they had taken the drug and 36% had not.
mostly very poor, with methodological lim-
Adverse drug reactions were reported by
itations and imprecision. The most com-
187 patients (13%), the proportions being
monly reported offending drugs were
similar in urban and rural areas; the total num-
quinolones, pentamidine, quinine, beta-
ber of reactions was 268 (range 14 per per-
blockers, angiotensin-converting enzyme
son). Commonly reported symptoms were
inhibitors, and insulin-like growth factor.
drowsiness (35%), headache (23%), gastro-
These data suggest that antihelminthic
intestinal symptoms (19%), and dizziness and
drugs are not associated with signicant
faintness (12%). Most of the symptoms were
drug-related hypoglycemia.
mild and only one person was hospitalized
(with abdominal pain). Persons those aged
3150 years had more adverse reactions than
those younger than 20 years. Women had
more adverse reactions than men, but more
men sought medication for their symptoms.

Placebo-controlled studies In a double-

Side Effects of Drugs, Annual 33
J.K. Aronson (Editor)
ISSN: 0378-6080
DOI: 10.1016/B978-0-444-53741-6.00031-3
# 2011 Elsevier B.V. All rights reserved.
blind, randomized, placebo-controlled trial
in Kenya [3C] of the effect of treating helminth
and HIV co-infection, 208 antiretroviral drug-
naive adults were given albendazole 400 mg/
day for 3 days or placebo. Albendazole
647
648
resulted in signicantly higher CD4 cell
counts among individuals with Ascaris lum-
bricoides infection after 12 weeks but there
was no benet in those with infections due to
other species of soil-transmitted helminths.
There were no adverse events reported.
In a randomized placebo-controlled trial
[4C] of the effects of albendazole on cyst dis-
appearance, reduction of the number of cysts,
and seizure recurrence in 178 patients with
new-onset symptoms due to active or transi-
tional neurocysticercosis, antiepileptic drugs
were given with or without albendazole
15 mg/kg/day in two divided doses for 28 days;
all patients also received prednisone. Active
cysts were identied in 59 of 88 patients who
were randomized to albendazole and 57 of
the 90 patients in the placebo arm. By
1 month, 31% were free of active cysts in
the treatment group compared with 7% in
the placebo group. In addition, albendazole
group produced a greater reduction in the
number of active cysts than placebo. How-
ever, albendazole had little effect on cysts in
the transitional stage or on calcied cysts.
There was no difference in symptoms
between albendazole and placebo during
treatment or in seizure recurrence during
the 12 months after treatment. The three
most common symptoms reported during
treatment and the rst month after treatment
were headache, seizures, and stomach prob-
lems, which were comparable in the two
groups. During the 8 days of treatment, three
patients developed intracranial hypertension,
all in the placebo group.
The efcacy of combining albendazole
15 mg/kg/day for 7 days with either prazi-
quantel 75 mg/kg/day (n 53) or placebo
(n 50) for 1 day has been studied in a dou-
ble-blind, placebo-controlled, randomized
study in North India in children with seizures
and single-lesion neurocysticercosis [5C].
Repeat CT scans were performed after 1, 3,
and 6 months. Seizure control and adverse
reactions were similar in the two groups.
Adverse effects were mild. There was no evi-
dence of raised intracranial pressure and
none of the patients reported epigastric dis-
comfort or other gastrointestinal symptoms.
None of the patients required drug with-
drawal because of adverse reactions.
Chapter 31 P.J.J. van Genderen
Hematologic In unresectable cases of alve-
olar echinococcosis, liver transplantation
has been undertaken. A technically difcult
liver transplant was performed in a 68-year-
old man with end-stage liver disease after
treatment with albendazole was tried for a
short period but had to be stopped because
of pancytopenia [6A].
Liver In two cases of alveolar echinococco-
sis with multiple-organ involvement (the
liver, lungs, and bone) resection of the
bone lesion was complete in one case but
incomplete in the other [7A]. Albendazole
caused no adverse reactions other than
mild disturbances of liver function tests.
Albendazole 10 mg/kg/day has been used
to treat cystic echinococcosis (hydatid dis-
ease) in 11 children aged 414 years, with at
least 10 cysts in the same organ [8c]. The chil-
dren had a total of 296 cysts located mostly in
the liver (178 cysts) and the lungs (78 cysts).
With exclusive albendazole therapy, 58% of
pulmonary cysts, 96% of peritoneal cysts,
but only 32% of hepatic cysts were cured.
There were no adverse events related to
treatment, apart from slight rises in serum
aminotransferase activities in two cases,
which normalized without withdrawal of
albendazole. The high rate of viable cysts
after medical therapy is problematic and in
this case was attributed to poor diffusion of
albendazole into the cysts, because of their
multiplicity and contiguity, variable sensitiv-
ity of each cyst to albendazole, and/or insuf-
cient duration of treatment; resistance to
albendazole was unlikely.
Benznidazole [SED-15, 426]
Benznidazole, a nitroheterocyclic com-
pound, was developed early in the 1970s
and acts by direct toxic inhibition of the
DNA synthesis of Trypanosoma cruzi, act-
ing on both amastigotes and trypomasti-
gotes. Its main adverse effects, which have
been reviewed [9R] are related to the enzy-
matic activity of nitroreduction and the
generation of free radicals. This enzymatic
activity is very low in children and young
adults, which explains the fewer adverse
Antihelminthic drugs Chapter 31
reactions in these age groups. The main
adverse reactions to benznidazole include:
nervous systempolyneuritis, which is dose
related and occurs at dosages of over 18 g;
gastrointestinaldigestive intolerance consist-
ing of vomiting and abdominal pain;
liverhepatitis, which occurs in 0.8% of
patients taking benznidazole;
skindermatitis from hypersensitivity, the
principal undesirable adverse effect of benzni-
dazole, which affects 2025% of patients; it is
a hypersusceptibility reaction that occurs
10 days after the start of treatment;
bone marrowdepression of the bone marrow
is rare; it has been proposed that neutropenia,
agranulocytosis, and thrombocytopenia could
be dose related;
tumorigenicityanimal studies suggest that at
high doses, benznidazole may induce the
development of lymphomas.
Other adverse effects include anorexia,
chronic headache, fatigues, myalgia, and
insomnia. In order to prevent these adverse
reactions, and hence improve adherence to
benznidazole, the following measures are
recommended: a low fat and hypoallergenic
diet, daily administration, patient education,
and treatment for no more than 30 days. In
particular, patients should be reassured that
the adverse effects that benznidazole causes
are reversible and non-life-threatening.
Diethylcarbamazine [SED-15, 1115;
SEDA-31, 365; SEDA-32, 574]
See Albendazole.
Ivermectin [SED-15, 1946; SEDA-30,
365; SEDA-31, 509; SEDA-32, 575]
Observational studies The use of oral iver-
mectin has been evaluated in eight Egyptian
patients with crusted scabies who took a sin-
gle oral dose of ivermectin 200 micrograms/
kg and were re-examined at 2, 4, 6, and
8 weeks [10c]. A second dose of ivermectin
was given if there was treatment failure at
the end of the second week, and a third dose
649
of ivermectin, combined with permethrin
5% and salicylic acid 5%, was given at the
end of the fourth week for non-responders
to the second dose. Two patients were
completely cured after a single dose of iver-
mectin, four required a second dose, and
two patients were cured after combined
therapy. There were no recurrences at the
end of 8 weeks. There was an inverse rela-
tion between the response to ivermectin
and the severity of immunosuppression,
crust thickness, and mite burden. No major
adverse effects or changes in laboratory data
were reported after ivermectin.
Levamisole [SED-15, 2028; SEDA-30,
366; SEDA-31, 510; SEDA-32, 575]
Skin Drug rash with eosinophilia and sys-
temic symptoms (DRESS) has been studied
in an observational study of 30 patients
aged 1378 years in Taiwan [11c]. The most
common offending drug was allopurinol,
followed by carbamazepine. In one case it
was associated with levamisole, but details
were not given. In the 30 cases the most
common pathological changes were liche-
noid dermatitis, erythema multiforme,
pseudolymphoma, and vasculitis. Impair-
ment of liver and renal functions and blood
dyscrasias were frequent complications.
There was active infection or reactivation
of human herpesvirus-6 in seven of 11
patients who were studied serologically.
Two patients developed type 1 diabetes
mellitus. The mortality rate was 10%.
Myrrh (Commiphora molmol)
[SED-15, 2409; SEDA-31, 511]
Uses The use of myrrh in treating human
trematode infections in Egypt has been
reviewed [12R].
Placebo-controlled studies Guggul 2160
mg/day has been studied in a double-blind,
650
randomized, placebo-controlled trial in 43
Norwegian women and men, aged
2770 years, with moderately increased
cholesterol [13C]. After 12 weeks, mean
concentrations of total cholesterol and
HDL cholesterol were signicantly reduced
by guggul, but mean concentrations of LDL
cholesterol, triglycerides, and total choles-
terol/HDL ratio did not change signi-
cantly. Ten guggul users (versus four with
placebo) reported adverse effects: mild gas-
trointestinal discomfort (n 7), possible
thyroid problems (n 2), and a generalized
rash (n 1); the latter resulted in with-
drawal from the trial.
Praziquantel [SED-15, 2911; SEDA-30,
366; SEDA-31, 511]
Comparative studies The combination of
artemether with praziquantel in different
regimens has been studied in 205 Chinese
subjects with acute Schistosoma japonicum
infection, who were randomly assigned to
four regimens: praziquantel 60 mg/kg
artemether 6 mg/kg; praziquantel 60 mg/kg
placebo; praziquantel 120 mg/kg arte-
mether 6 mg/kg; placebo praziquantel
120 mg/kg [14C]. All the participants were
followed up for 45 days. Treatment was
efcacious in over 96% in all the groups,
although the rst group had a faster fever
clearance time, resulting in shorter hospital-
ization. Pain in the upper abdominal region,
accompanied by diarrhea, occurred in 26%
of those who took praziquantel; other
adverse events included headache, nausea,
and lower abdominal discomfort. Adverse
events in patients who took artemether
included allergy, nausea, vomiting, and
abdominal pain. The authors concluded
that combining artemether and praziquan-
tel did not improve treatment efcacy com-
pared with praziquantel alone.
The use of praziquantel in the treatment
of Schistosoma hematobium has been stud-
ied in 767 patients in Zimbabwe [15C].
Two single oral doses of praziquantel
40 mg/kg were given 6 weeks apart, and
Chapter 31 P.J.J. van Genderen
624 participants were available for follow-
up 6 weeks later. The overall cure rate
was 89% and the egg reduction rate was
98%; 72 individuals remained infected at
6 weeks after treatment, 46 of whom
resolved after a second round of treatment,
and the remainder after a third round of
treatment 6 months later. The most com-
mon adverse events reported 24 hours after
treatment were stomach discomfort and
nausea; they were mild and transient.
Suramin [SED-15, 3249; SEDA-30, 367;
SEDA-31, 512]
Uses Human African trypanosomiasis, also
known as sleeping sickness, has been
reviewed [16R]. All four main drugs used
are toxic, and melarsoprol, the only drug
that is effective for both types of central
nervous system disease, kills 5% of patients
who take it. Eornithine, alone or com-
bined with nifurtimox, is being used
increasingly as rst-line therapy for gam-
biense disease. There is a pressing need
for an effective, safe oral drug for both
stages of the disease, but this will require
a signicant increase in investment for
new drug discovery from Western govern-
ments and pharmaceutical companies.
Suramin is the drug of choice for the
early hemolymphatic stage of both Trypa-
nosoma brucei gambiense and Trypano-
soma brucei rhodesiense infections before
nervous system invasion occurs [17R]. The
dose is 1520 mg/kg/week, given intra-
venously, up to a maximum single dose of
1 g. Suramin, which is excreted by the kid-
neys, binds to plasma proteins and can per-
sist in the circulation in low concentrations
for as long as 3 months. A single course
for an adult is usually 5 g, never to exceed
7 g. The primary adverse reactions are
fever, rash, conjunctivitis, renal insuf-
ciency, abdominal pain, paresthesia, and
muscle pain.
Observational studies The potential of
non-cytotoxic doses of suramin to reverse
Antihelminthic drugs Chapter 31
chemotherapy resistance in advanced
chemonaive and chemoresistant non-small-
cell lung cancer has been evaluated in
a phase II study [18c]. Patients received
paclitaxel 200 mg/m2 and carboplatin
(AUC 6 minutes mg/ml) every 3 weeks.
The total dose of suramin per cycle was
calculated using a nomogram derived
from a preceding phase I trial to
obtain the desirable plasma concentration
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 S. Dittmann

32 Vaccines

Editors note: Abbreviations used in this GENERAL

and previous issues of SEDA:

aP: Acellular pertussis HZV vaccine: Herpes Surveillance The applicability, reliability,
AVA: Anthrax vaccine zoster virus vaccine sensitivity, and specicity of six standard-
adsorbed IPV: Inactivated
ized case denitions for adverse events fol-
BCG: Bacillus polio vaccine
CalmetteGurin JE vaccine: Japanese
lowing immunization (AEFI) (for fever,
DTP: Diphtheria encephalitis vaccine generalized convulsive seizures, hypotonic
tetanus toxoids MCV4: Meningococcal hyporesponsive episodes, intussusception,
pertussis vaccine conjugate vaccine, nodules, and persistent crying) developed
DTaP: 4-valent by the Brighton Collaboration using the
Diphtheria tetanus MMR: Measles US Vaccine Adverse Event Reporting Sys-
toxoids acellular mumps rubella tem (VAERS) have been evaluated [1H].
pertussis MR: Measles rubella The evaluation included: (a) the develop-
DTaP-Hib-IPV-HB: MMRV: Measles ment of codied search strings using stan-
Diphtheria tetanus mumps rubella
dardized coding terminology, and (b) for
toxoids acellular varicella
pertussis IPV OPV: Oral polio
sensitivity and specicity analyses, the
Hib hepatitis B vaccine development of a gold standard for case
(hexavalent vaccine) PRP-D-Hib: Conjugated determination by clinical expert reviews,
DTwP: Hib vaccine (Hib and its comparison with the application of
Diphtheria tetanus capsular antigen the denitions to VAERS reports by non-
toxoids whole cell polyribosylphosphate clinicians. Application of the case deni-
pertussis covalently linked to a tions in an automated approach proved to
HAV: Hepatitis A virus mutant polypeptide be valid, feasible, and unlikely to miss con-
HbOC (also called of diphtheria toxin) rmed cases of the reported clinical event.
PRP-CRM): SV40: Simian virus 40
The denitions had variable but generally
Conjugated Hib Td: Diphtheria
vaccine (Hib tetanus toxoids
high sensitivity and specicity compared
capsular antigen (adult formulation) with clinician review, which in itself yielded
polyribosylphosphate Tdap: Tetanus toxoid inconsistent case determination. These
covalently linked to reduced results demonstrate the need for standard-
the non-toxic diphtheria diphtheria toxoid ized denitions for AEFI and their useful-
toxin variant CRM197) acellular pertussis ness in surveillance.
HBV: Hepatitis B wP: Whole cell pertussis
virus YF vaccine: Yellow
Hib: Haemophilus fever vaccine Cardiovascular A systematic review of the
inuenzae type b YFV: Yellow fever virus literature on immunization myocarditis
or pericarditis after immunization identied
37 publications, in which 269 cases
Side Effects of Drugs, Annual 33 were reported during the search period
J.K. Aronson (Editor)
ISSN: 0378-6080
(19662007); the cardiac symptoms occurred
DOI: 10.1016/B978-0-444-53741-6.00032-5 at 130 days after immunization [2MA].
# 2011 Elsevier B.V. All rights reserved. Eosinophilic myocarditis was also reported

653
654
in two cases of single administrations of con-
jugate meningococcal C vaccine or hepatitis
B vaccine. The histological ndings strongly
supported hypersensitivity reactions and
there was no evidence of a viral etiology,
which is typically characterized by a lympho-
cytic inltrate. Both episodes resolved with
glucocorticoid therapy. Cardiac complica-
tions, including myopericarditis, can also
occur with smallpox vaccine (see below).
Nervous system Five patients developed
symptoms of paresthesia within 1 day to
2 months after immunization against rabies,
varicella, or Lyme disease [3c]. There was
mild sensory loss in the legs, preserved
strength, normal or minimally abnormal
electrodiagnostic ndings, and reduced
epidermal nerve ber densities per skin
biopsy. Empirical immunomodulatory
therapy was tried in two patients but was
ineffective. The symptoms improved spon-
taneously in all the patients but did not
fully resolve.
Skin Discoloration of the leg after immuni-
zation is a relatively unknown entity, which
has been studied during a 10-year period
after immunization of infants in the Dutch
National Vaccination Program [4R]. Disco-
lored leg syndrome was dened as an even
or patchy red, blue, or purple discoloration
of the leg(s) and/or petechiae with or with-
out swelling. In all, 1162 reports of adverse
events after immunization were made to
the passive surveillance system between
1994 and 2003. Red, blue, or purple discol-
oration and isolated petechiae were
reported in 39%, 19%, 27%, and 14% of
these cases respectively; 1105 cases were
considered to be related to immunization,
based on a predened risk window with
the onset of symptoms after immuniza-
tion48 hours for discoloration and
2 weeks for petechiae. Of the 1105 cases,
about 50% occurred after DTP-IPV
Hib1 immunization, and 30% occurred
after DTP-IPV Hib2 immunization. Dis-
colored leg syndrome was often accompa-
nied by erce crying (78%). The median
interval between immunization and the
occurrence of the syndrome was 3.8 hours
Chapter 32 S. Dittmann
and the median duration was short
(2 hours). Changing the immunization
schedule from 3 to 2 months of age caused
a small increase in the frequency of disco-
lored leg syndrome. The syndrome mani-
fested mainly after the rst and/or second
dose. In addition to dose it may be slightly
age-dependent. The pathophysiology is
unknown but it may be the result of a vaso-
motor reaction.
Nicolaus syndrome, or embolia cutis
medicamentosa, is a rare condition that is
characterized by acute cutaneous and soft-
tissue necrosis after intramuscular injection
of drugs, including modied-release formu-
lations of penicillin, NSAIDs, and glucocor-
ticoids [5RH]. In a retrospective study of
seven children (mean age 9.8 months) who
developed Nicolaus syndrome after intra-
muscular immunization, the reactions were
observed after the use of different combi-
nations of vaccine antigens, and were no
more common after repeated than after pri-
mary injections of the vaccines [6c]. Three
children developed scars without functional
impairment, two made a full recovery, and
the nal outcome was unknown in four.
Taken into account the large number of
intramuscular injections during infancy,
Nicolaus syndrome seems to be rare, but
there is a possibility of under-reporting of
less severe reactions.
Immunologic In a prospective trial in
neonates, in which an acellular pertussis
vaccine was administered at 25 days
of age, the vaccine was well-tolerated
and immunogenic; however, there were
reduced antibody responses, predominantly
to Haemophilus inuenzae type b [7C].
Infection risk Some have hypothesized that
the simultaneous administration of combi-
nations of vaccines might overload the
immune system and therefore facilitate the
development of bacterial and viral infec-
tions. In a case-series analysis of bacterial
and viral infections during risk periods of
030, 3160, and 6190 days after the
administration of either MMR vaccine
or MMR vaccine plus serogroup C
meningococcal conjugate vaccine (given
Vaccines Chapter 32
concomitantly), there was a reduced risk at
030 days after the administration of MMR
vaccine for both bacterial infections (rela-
tive incidence 0. 68; 95% CI 0.54,
0.86) and viral infections (relative incidence
0.68; 95% CI 0.49, 0.93) [8c]. There
was no increased risk in any period when
looking at combined viral or bacterial infec-
tions or for individual infections, with the
single exception of an increased risk at
3160 days after immunization for herpes-
virus infections (relative incidence 1.69;
95% CI 1.06, 2.70). In the children given
meningococcal group C vaccines concomi-
tantly there was no signicantly increased
risk in either bacterial infections (relative
incidence 0.54; 95% CI 0.26, 1.13) or
viral infections (relative incidence 0.46;
95% CI 0.11, 1.93). These results con-
rm that these vaccines do not increase
the risk of invasive bacterial or viral infec-
tion in the 90 days after immunization and
do not support the hypothesis that there is
an induced immune deciency due to over-
load from combinations of vaccines.
Susceptibility factors Preterm infants Sev-
eral investigators have reported an
increased incidence of cardiorespiratory
events in preterm infants after immuniza-
tion. For example, of 64 preterm infants of
very low birth weights, 33 had a cardio-
respiratory event after the rst immuniza-
tion, and six of these had a recurrence
after the second immunization, including
two who had previously been discharged
home; a cardiorespiratory event associated
with the rst vaccination was the sole sus-
ceptibility factor for recurrence identied
[9C]. However, the American Academy of
Pediatrics recommends immunization of
preterm infants with diphtheriatetanusa-
cellular pertussis vaccine at a chronological
age of 2 months, regardless of birth weight
and gestational age. The relation between
the use of diphtheriatetanusacellular per-
tussis vaccine and objectively assessed car-
diorespiratory events has been examined
in 191 preterm infants aged 5660 days,
who had been born before 37 weeks, in a
randomized controlled study in 10 hospitals
655
[10C]. The infants were randomly assigned
to diphtheriatetanusacellular pertussis
vaccine (n 93) at 2 months or a control
group (n 98). Recording monitors were
used continuously during the next 48 hours
to document prolonged apnea and pro-
longed bradycardia. In the immunized
group, 16% had at least one episode
of prolonged apnea compared with 20% of
the controls. One or more episodes
of prolonged bradycardia occurred in 58%
of immunized infants and 56% of the con-
trols. The frequency of episodes was not sig-
nicantly different, with an average of 0.5
episodes of prolonged apnea in each group.
The mean numbers of episodes of prolonged
bradycardia were 2.6 and 2.7 respectively.
These results support the recommendation
of the American Academy of Pediatrics
that diphtheriatetanusacellular pertussis
immunization should be offered to preterm
infants at 2 months of age.
BACTERIAL VACCINES
Anthrax vaccine [SED-15. 260;
SEDA-28, 357; SEDA-29, 357]
Observational studies Anthrax vaccine
adsorbed (AVA) is the only US licensed
AVA vaccine approved by the Food and
Drug Administration. In recent years, the
safety of anthrax vaccine has been contro-
versial, stimulating reviews of its safety
and efcacy. During 1 March 1998 to 14
January 2007, about 6 million doses of
AVA vaccine were administered. As of 16
January 2007, 4753 reports of adverse
events after the use of AVA had been sub-
mitted to the Vaccine Adverse Event
Reporting System (VAERS) [11C]. The
most commonly reported were: myalgia,
arthralgia, pain, headache, depression,
asthenia, rash, anxiety and insomnia, and
back pain. Reports to VAERS did not
denitively link any serious unexpected
risks to this vaccine, and a review of deaths
656
and serious reports did not show a distinc-
tive pattern suggestive of a causal relation
with AVA.
Bacille CalmetteGurin (BCG)
vaccine [SED-15, 397; SEDA-30, 372]
Although intravesical therapy is an integral
part of the management of non-muscle inva-
sive bladder cancer, both intravesical chemo-
therapy and BCG have potential adverse
effects that may lead to treatment withdrawal
and incomplete treatment courses. An Inter-
national Bladder Cancer Group has reviewed
the current literature on adverse events asso-
ciated with intravesical therapy [12R]. They
concluded that cystitis, hematuria, contracted
bladder, and ureteral obstruction are adverse
reactions that can follow both chemotherapy
and BCG. BCG-specic adverse events
include granulomatous prostatitis, epididymo-
orchitis, systemic BCG reactions, and
allergic reactions. Adverse reactions that are
specic to intravesical chemotherapy include
contact dermatitis, bladder calcication,
and myelosuppression. Preventive strategies
include instructing health-care professionals
about proper treatment techniques, prophy-
lactic use of antibiotics, and the possibility of
BCG dose reduction.
Hematologic Lymphadenitis due to dissem-
inated BCG-itis has been described in a
patient with X-linked chronic granulomatous
disease 25 years after immunization [13c].
Skin BCG-induced keloid has been investi-
gated in 60 patients [14c]. The mean length
of the maximum dimension was 42.4 mm
and the length increased proportionally to
age at rst visit. Keloids grew rapidly between
the ages of 20 and 40 years. The authors
recommended early therapeutic intervention,
which might prevent keloids from growing
larger, and underlined the need to provide
adequate information.
The complications of BCG immunization
were reviewed in SED-15 (p. 397). Recent
Chapter 32 S. Dittmann
case reports have included lupus vulgaris
[15c], osteomyelitis [16c], and psoriasis
[17c]. Extensive ulcerating vasculitis after
BCG immunization has been reported in
a 12-year-old girl, who developed extensive
primary ulceration involving most of
her left upper arm at the site of BCG
immunization [18c]. Over a period of
18 months, secondary lesions developed
on her forehead, prompting further investi-
gation of a systemic disease process.
Vaccine-induced granulomatous vasculitis
was diagnosed and she responded to a
combination of antituberculosis therapy
and glucocorticoids. Skin grafting of the
ulcerated area achieved wound closure.
Susceptibility factors HIV infection At its
meeting on 34 December 2009, the Global
Advisory Committee on Vaccine Safety
(GACVS) reviewed data from studies in
Argentina and South Africa, which con-
rmed the signicantly high risk of dissem-
inated BCG disease in HIV-positive
infants, with rates approaching 1% [19S].
Other studies have shown that infection
with HIV severely impairs BCG-specic
T-cell responses during the rst year of life.
Thus, BCG may provide little, if any, pro-
tection against tuberculosis in HIV-infected
infants. Considering the signicant risk of
disseminated BCG disease, these data
strongly support the WHO recommenda-
tion that BCG should not be given to
children who are infected with HIV.
Meningococcal vaccine [SED-15,
2250; SEDA-30, 372; SEDA-31, 519;
SEDA-32, 580]
Observational studies At its meeting on
34 December 2009, the Global Advisory
Committee on Vaccine Safety (GACVS)
reviewed the safety prole on meningococ-
cal A conjugate vaccine (MenAfri-VacTM
vaccine) from clinical trials [20S].
MenAfri-VacTM vaccine is a lyophilized
meningitis A conjugate vaccine developed
Vaccines Chapter 32
by the Meningitis Vaccine Project and man-
ufactured in the Serum Institute of India,
Poona. Its reactogenicity and safety have
been evaluated in four clinical studies and
two other studies are in progress. A phase
I study was conducted in volunteers in
India aged 1834 years and phase II and
II/III studies were performed in Africa
and India in people aged 129 years. To
date, 1126 subjects have been followed for
adverse events after immunization for at
least 1 month and for serious adverse
events up to at least 1 year. The vaccine
did not cause any adverse reactions beyond
4 days after immunization; the adverse
events observed were comparable between
study and control vaccine groups, except
for injection site tenderness, which was more
common (13%) among those who received
the vaccine. None of the 137 serious adverse
events (including 14 deaths) reported in the
vaccine studies were thought to be related
to the study vaccines. The committee con-
cluded that the available data for MenAfri-
VacTM vaccine do not indicate any special
cause for concern. However, further studies,
particularly postmarketing surveillance, are
needed to assess the safety prole of the
vaccine better.
Pertussis vaccine (including
diphtheriatetanuswhole cell
pertussis vaccine [DTwP]) [SED-
15, 2780; SEDA-31, 520; SEDA-32, 580]
In the early 1980s there were concerns
about the safety of whole cell pertussis vac-
cines; in particular, it was claimed by some
that the vaccine was associated with sudden
infant death syndrome and encephalopathy
[21H]. Immunization rates fell, and many
vaccines were withdrawn from the market.
However, epidemiological studies have
consistently failed to identify an associa-
tion. It has been recently argued that such
reactions may have occurred in metaboli-
cally vulnerable children, specically those
with defects in fatty acid oxidation, in
whom the combination of anorexia and
fever due to the vaccine may have resulted
657
in hypoglycemia and possibly death.
Of course, this argument presupposes that
the postulated association was a true one.
Observational studies A combined tetanus
toxoid, reduced diphtheria toxoid, and acel-
lular pertussis (Tdap) vaccine containing
three pertussis antigens (Boostrix, Tdap3v)
or ve pertussis antigens (Adacel, Tdap5v)
has been evaluated in 2284 healthy adults
aged 1964 years in a randomized study
[22C]. Injection site reactions (pain, redness,
and swelling) and fever of at least 37.5 C
were signicantly more common in those
who received the pentavalent pertussis
and fatigue was slightly more common in
those who received the trivalent pertussis.
VIRAL VACCINES
Hepatitis B vaccine [SED-15, 1600;
SEDA-30, 374; SEDA-31, 520]
Immunologic The medical records of 10
patients, mean age 35 (2644) years who
developed systemic lupus erythematosus
after hepatitis B immunization, have been
analysed retrospectively, to determine the
prevalence of different manifestations and
the time course after immunization [23C].
Two patients had received one dose, two
had received two doses, and six had
received three doses. The mean interval
between the rst dose and the onset of
autoimmune symptoms was 56 days. The
authors concluded that data from this
case-series, and previously documented
cases, could only demonstrate a temporal
relation between hepatitis B immunization
and the appearance of systemic lupus
erythematosus and not a causative one.
Human papilloma virus (HPV)
vaccine [SED-15, 1698; SEDA-30, 374]
Cervical cancer is the second most common
cause of cancer deaths in women world-
wide. It is almost invariably associated with
658
human papilloma virus (HPV) infection.
Two HPV vaccines have been developed
and licensed. Both vaccines, Gardasil and
Cervarix, are highly effective in prevent-
ing persistent infections with HPV types
16 and 18, two high-risk viruses that cause
70% of all cervical cancers. Gardasil also
prevents infection with HPV types 6 and
11, which cause 90% of all genital warts.
Before licensing the vaccines were trialled
in over 60 000 women and assessed as safe,
within the statistical constraints of the trials
to detect very rare events.
Observational studies In June 2006, the
Food and Drug Administration licensed
the quadrivalent human papilloma virus
(qHPV) (types 6, 11, 16, and 18) recombi-
nant vaccine in the USA for use in girls
and women aged 926 years; the Advisory
Committee on Immunization Practices then
recommended a qHPV vaccine for routine
immunization of girls aged 1112 years.
Reports to the Vaccine Adverse Event
Reporting System (VAERS) after the use
of qHPV from 1 June 2006 to 31 December
2008 have been summarized [24R]. The
authors performed additional analyses for
some adverse effects following immuniza-
tion (AEFIs) in prelicensing trials, those
of unusual severity, or those that had
received public attention. The VAERS
received 12 424 reports of AEFIs after the
use of qHPV, a rate of 54 reports per
100 000 doses distributed. A total of 772
reports (6.2% of all reports) described seri-
ous AEFIs, including 32 deaths. The report-
ing rates per 100 000 doses distributed were
8.2 for syncope; 7.5 for local site reactions;
6.8 for dizziness; 5.0 for nausea; 4.1 for
headache; 3.1 for hypersensitivity reactions;
2.6 for urticaria; 0.2 for venous thrombo-
embolic events, autoimmune disorders, and
GuillainBarr syndrome; 0.1 for anaphy-
laxis and death; 0.04 for transverse myelitis
and pancreatitis; and 0.009 for motor neu-
ron disease. Data mining revealed dispro-
portionate reporting of syncope and
venous thromboembolism. The authors
concluded that most of the AEFI rates
were not greater than the background rates
associated with other vaccines, apart from
Chapter 32 S. Dittmann
syncope and venous thromboembolism.
The signicance of these ndings must be
tempered by considering the limitations of
the reporting system, notably the high like-
lihood of under-reporting.
Nervous system Several vaccines have
been reported as potential triggers of acute
disseminated encephalomyelitis, including
HPV [25A].
A 15-year-old girl developed acute dissemi-
nated encephalomyelitis 23 days after receiv-
ing a second dose of HPV vaccine. She had
no history of other recent diseases, immuniza-
tion, or infections. She was given high-dose
glucocorticoids, which produced rapid neuro-
logical improvement and complete recovery
after 3 weeks.
The authors cautioned that a single case
report should not lead to unjustied mis-
perceptions about the safety of a vaccine.
A 19-year-old girl developed left brachial
plexus neuritis after immunization with a
qHPV vaccine [26A].
Pregnancy The pregnancy outcomes in
20 551 women aged 1545 years, enrolled
in ve phase III placebo-controlled studies
of two doses of qHPV 6/11/16/18 vaccine
at 2 and 6 months, have been analysed
[27M]. Urine pregnancy tests were per-
formed immediately before each injection
and participants with positive tests were
not immunized. Women who became preg-
nant after enrolment were withdrawn
from further immunization until resolution
of the pregnancy. During the studies,
1796 vaccine recipients and 1824 placebo
recipients became pregnant, resulting in
2008 and 2029 pregnancies with known
outcomes. There were no signicant differ-
ences in the proportions of pregnancies that
resulted in live births, fetal losses, or spon-
taneous abortions. A total of 40 neonates
born to women given the vaccine and 30
born to women given placebo had one or
more congenital anomalies, which were
diverse and consistent with those most com-
monly observed in the general population.
The authors concluded that the administra-
tion of qHPV vaccine to women who
Vaccines Chapter 32
became pregnant during phase III clinical
trials did not appear to affect pregnancy
outcomes negatively.
The effects of HPV vaccine on preg-
nancy outcomes (live births, abortions, fetal
deaths, and congenital anomalies) have
been analysed using postmarketing data
from the USA, France, and Canada [28R].
Among the 517 prospective reports with
known outcomes, 451 (87%) were live
births, including three sets of twins. Of 454
neonates, 439 (96.7%) were normal. The
overall rate of spontaneous abortions was
6.9 per 100 outcomes. The prevalence of
major birth defects was 2.2 per 100 live-
born neonates. There were seven fetal
deaths (1.5 per 100 outcomes). Rates of
spontaneous abortions and major birth
defects were not greater than in the
unexposed population.
Although no adverse signals have been
identied to date, HPV vaccines are not
recommended for use in pregnant women.
Inuenza vaccine [SED-15, 1753;
SEDA-30, 374; SEDA-32, 581]
Pandemic inuenza H1N1
vaccines
At its meeting on 34 December 2009, the
Global Advisory Committee on Vaccine
Safety (GACVS) preliminarily reviewed the
safety of pandemic A (H1N1) inuenza vac-
cines [29S]. From 21 September to 2 Decem-
ber 2009, tens of millions of doses of the
2009 H1N1 vaccine were administered, pro-
viding the basis for this rst safety review
by the GACVS. Pandemic inuenza vac-
cines include live attenuated vaccines, inacti-
vated unadjuvanted vaccines (split, subunit
virion, or whole virion), and inactivated
adjuvanted vaccines (split or subunit virion).
At the time of the GACVS review, it was
estimated that nearly 150 million doses of
vaccine had been distributed in many coun-
tries around the world. About 30% of those
150 million doses were adjuvanted vaccines.
659
No unexpected safety concerns were identi-
ed for any of the pandemic H1N1 vaccines.
In these immunization campaigns, deaths in
temporal association with immunization
have been reported in many countries.
Given the large number of people who have
been immunized, it is expected that deaths
that were unrelated to immunization would
occur in temporal association with immuni-
zation. Investigation of deaths that have
been reported after immunization have iden-
tied that the cause of death has been unre-
lated to immunization in all but a few
instances. There have been a few individual
reports of deaths associated with anaphylac-
tic reactions to immunization. Immediate
hypersensitivity reactions have been reported
after the use of all types of 2009 pandemic
H1N1 vaccines. These events include urti-
caria, angioedema, and anaphylaxis, with
reactions ranging from mild to serious. The
overall reporting rates for anaphylaxis range
from 1 per 1 000 000 to 1 per 100 000 doses
distributed. Anaphylaxis is a rare but poten-
tially life-threatening adverse reaction to all
vaccines, and immunization providers must
be prepared to recognize such reactions and
treat them appropriately. Although some
cases of GuillainBarr syndrome have been
reported after the use of pandemic H1N1 vac-
cines, the evidence to date is reassuring, with
no increase in reporting rates above what is
expected, based on background rates. Sur-
veillance for GuillainBarr syndrome has
been instituted in several countries and
should provide additional information by
the rst quarter of 2010.
Concerns have been raised about the use
of adjuvanted pandemic vaccines in patients
with immune disorders, such as immuno-
deciency, autoimmune disorders, and solid
organ transplants. To date, postmarketing
surveillance has not found evidence for cau-
sality of any adverse reactions in such
patients. Viral infections, such as inuenza,
can lead to severe complications in immuno-
compromised patients.
Conclusion Ten weeks into the worldwide
immunization campaign against pandemic
H1N1 in 2009, the GACVS reviewed the
safety of the vaccines that are currently in
660
use. To date, the safety data are reassuring.
Most of the adverse events that have
been reported after immunization have not
been serious. To date, no unexpected safety
concerns have been identied.
Observational studies In October 2003 the
Advisory Committee on Immunization
Practices (ACIP) recommended inuenza
immunization for all children aged
623 months [30R]. The safety of this rec-
ommendation has been evaluated using
the Vaccine Adverse Event Reporting Sys-
tem (VAERS) to study serious adverse
events reported between 1 July 2003 and
30 June 2006 in children aged 623 months
who had been given trivalent inactivated
inuenza vaccine. There were 104 serious
adverse events at a median time after
immunization of 1 day. The two most com-
mon serious adverse events were fever (52
reports) and seizures (35 reports). Causality
assessment suggested that none was de-
nitely related to inuenza vaccine. No new
or unexpected concerns were identied.
Nervous system A 44-year-old man who
developed a stroke with a left hemiparesis
after inuenza immunization had a large,
contrast-enhancing brainstem lesion, and
multiple punctate lesions suggesting micro-
hemorrhages in both cerebral hemispheres
[31A]. Detailed diagnostic studies failed to
yield any results to support inammatory
or demyelinating diseases, suggesting that
inuenza immunization may have been
associated with the event. The patient had
a remarkable response to high-dose gluco-
corticoid treatment.
Immunologic There is controversy about
whether autoimmune or rheumatic diseases
can be precipitated by immunization. Vas-
culitis after inuenza vaccines have been
discussed as a possible new entity [32H].
Four cases of new or relapsing vasculitis
associated with antineutrophil cytoplasmic
antibodies (ANCA) have been described
after inuenza immunization [33c]. Several
trials in patients with pre-existing auto-
immune diseases failed to show an
Chapter 32 S. Dittmann
increased risk of disease recurrence after
inuenza immunization, but these studies
were probably underpowered to detect
very rare adverse reactions. The authors
concluded a causal relation between immu-
nization and vasculitis has not been proved,
but it seems possible that in rare cases vac-
cines might cause vasculitis.
Pregnancy In the USA, routine inuenza
immunization is recommended for all
women who are or will be pregnant during
the inuenza season. During pandemics
and seasonal epidemics of inuenza, preg-
nancy places otherwise healthy women at
increased risk of serious complications from
inuenza, including death. The evidentiary
basis for recommending immunization in
women who will be pregnant during the
inuenza season and the adverse reactions
to inuenza immunization during preg-
nancy have been reviewed [34R]. No study
to date has shown an increased risk of
either maternal complications or adverse
fetal outcomes associated with inactivated
inuenza vaccine. Moreover, there is no sci-
entic evidence that vaccines that contain
thimerosal cause adverse reactions among
children born to women who received
inuenza vaccine during pregnancy.
Drugdrug interactions Anticoagulants
Although most reports of concomitant war-
farin therapy and inuenza immunization
have shown no signicant change in the
average degree of anticoagulation, there
have been reports of individuals who may
have had increased anticoagulation after
inuenza immunization, as illustrated by
another such report [35A].
A 64-year-old man with a 2-day history of
bleeding from the rectum became unrespon-
sive. He had taken long-term warfarin because
of atrial brillation and had received an inacti-
vated inuenza vaccine 1 month before admis-
sion. The INR was raised, after having been
stable for at least 6 months. A CT scan
showed a large parenchymal hemorrhagic
infarct involving the left temporal, parietal,
and occipital lobes. He died about 17 hours
after admission.
Vaccines Chapter 32
The authors considered the raised INR in
this case to have been due to an interaction
of warfarin with the inuenza immuniza-
tion. They suggested that the INR should
be measured more often during the
46 weeks after inuenza immunization.
Measlesmumpsrubella (MMR)
vaccine [SED-15, 2207; SEDA-30, 375;
SEDA-31, 521; SEDA-32, 581]
Nervous system In 2003, a 4-week national
measlesrubella immunization program was
implemented in Iran, during which the inci-
dence of GuillainBarr syndrome was stud-
ied among children aged 514 years, using
the national surveillance system for acute
accid paralysis from 2002 to 2004 [36R].
There were 370 conrmed case reports.
The annual incidence was relatively constant
over the 3-year period, and ranged from 0.65
per 100 000 population in 2004 to 0.76 per
100 000 population in 2003. In comparison
with other 10-week periods, there was no
increase in the incidence of GuillainBarr
syndrome during 20022004.
Autism and vaccines
The controversy about vaccines as a possible
cause of autism is not over. In the USA, some
doctors and scientists, some groups represent-
ing families with autistic children, and many
parents fervently believe that there is a con-
nection. More than 4800 such US families
(Autism Omnibus) have petitioned the Fed-
eral Vaccine Injury Compensation Program
(VICP) for compensation, based on the claim
that their childrens autism/autistic spectrum
disorder was caused through vaccines, either
caused by MMR vaccine alone or in combi-
nation with thimerosal-containing vaccines
(Theory 1) or through thimerosal-containing
vaccines (Theory 2).
Autism decisions and background infor-
mation on the Omnibus Autism processing
(OAP) can be accessed on the US Court of
Federal Claims website [37S].
661
Cases under Theory 1 In February 2009,
special masters of the US Court of Federal
Claims ruled in favor of the United States
Department of Health and Human Services
(HHS) on general causation and three test
cases under this theory. All three test cases
were appealed to judges of the CFC and all
three were afrmed in July and August,
2009. Two of the three test cases, Hazlehurst
and Cedillo, were then appealed to the Fed-
eral Circuit. On 13 May 2010, the US Court
of Appeals for the Federal Circuit released
its decision in Hazlehurst. The Federal
Circuit afrmed the decision of the HHS.
The Hazlehurst family may next seek review
by the Supreme Court. On 27 August 2010
the US Court of Appeals to the Federal
Circuit afrmed the denial of Cedillos
petition for compensation.
Cases under Theory 2 On 12 March 2010,
special masters decided in favor of the
HHS on general causation and three test
cases for Theory 2. None of the three test
cases was appealed by petitioners.
Hematologic The risk of immune thrombo-
cytopenia purpura during 42 days after
MMR immunization has been studied in chil-
dren aged 1215 months, 1223 months, and
118 years, using the Vaccine Safety Datalink
[38C]. Those affected had a platelet count of
less than 50  109/l with bleeding and normal
erythrocyte and leukocyte indices. The study
comprised 1 036 689 children who received
1 107 814 doses of MMR vaccine; 259
had immune thrombocytopenia purpura.
Because only ve exposed cases occurred
after the age of 2 years, analyses were limited
to children aged 1223 months; they had
lower median platelet counts than those who
were not exposed and had a similar median
duration of illness (11 versus 10 days). The
incidence rate ratio was highest for children
aged 1215 months, at 7.10, with a sex differ-
ence: 14.6 in boys and 3.22 in girls. In children
aged 1223 months 76% of cases were attrib-
utable to MMR. The authors concluded
that MMR immunization in the second year
of life is associated with an increased risk
662
of immune thrombocytopenia purpura and
causes one case per 40 000 doses.
Measlesmumpsrubellavaricella
(MMRV) vaccine
Nervous system Pre-licensing clinical trials
data have shown a signicant increase in
the risk of fever during days 512 after
MMRV immunization compared with the
vaccines given separately (MMR vari-
cella). The incidence of febrile convulsions
after MMRV immunization has been stud-
ied in a retrospective cohort study in chil-
dren aged 1260 months, who received a
rst dose of MMRV from February 2006
to June 2007, matched by age, sex, and cal-
endar date of immunization with children
who received separate MMR varicella
vaccines concomitantly from November
2003 to January 2006, before MMRV was
licensed [39C]. During the 30 days after
immunization, there were respectively 128
and 94 cases of potential convulsions
among the 31 298 children in the MMRV
and MMR varicella cohorts. Review of
the available medical charts resulted in 84
cases of conrmed febrile convulsions, 44
(1.41 per 1000) and 40 (1.28 per 1000) in
the two groups. During days 512 after
immunization, the pre-specied period of
interest, the respective numbers were 22
(0.70 per 1000) and 10 (0.32 per 1000).
The authors concluded that the risk of
febrile convulsions is increased during
days 512 after immunization with MMRV
compared with MMR varicella given
separately at the same visit, when post-
immunization fever and rash are also
increased in clinical trials. However, there
was no evidence of an increase in the
month after immunization.
Mumps vaccine
Infection risk Transmission of the Lenin-
gradZagreb mumps vaccine strain from a
vaccinee to a susceptible contact has been
described [40c].
Chapter 32 S. Dittmann
A 14-month-old boy developed unilateral par-
otitis after immunization with MMR vaccine
containing the LeningradZagreb mumps
strain. Six weeks later his 32-year-old mother
developed fever, unilateral parotitis, and
meningism, having never had mumps nor hav-
ing received mumps immunization. Mumps
virus was isolated from cerebrospinal uid
and conrmed by indirect immunouores-
cence assay. The isolate was subsequently
characterized as LeningradZagreb mumps
vaccine strain by genomic sequencing and
comparing the genome with the reference
sequences (GenBank NIH, Bethesda). Both
patients were treated symptomatically and
recovered completely.
This was a denitive (between-the-eyes)
adverse reaction of type 4 [41H]. In addition
to a few other reports, the report of
virologically conrmed parotitis and menin-
gitis in a fully immunocompetent family
member provides further strong evidence
that horizontal transmission after mumps
immunization with the LeningradZagreb
strain can occur.
Rabies vaccine [SED-15, 301;
SEDA-32, 582]
Observational studies An adsorbed human
diploid cell rabies vaccine (Rabivax) has
been tested in a post-licensing study in 150
cases of suspect rabid animal bites [42c].
Adverse events included pain at the injec-
tion site (3.4%), swelling with induration
(2.8%), and fever and headache (1.4%);
there were no serious adverse events.
Rotavirus vaccine [SED-15, 3082;
SEDA-27, 338; SEDA-28, 365; SEDA-30,
376; SEDA-31, 376]
Gastrointestinal Reports of intussusception
after RotaTeq immunization have been
assessed, using data from the VAERS and
the Vaccine Safety Datalink, in children
enrolled in managed care [43R]. Observed
versus expected rate ratios were determined
using vaccine dose distribution data and
Vaccines Chapter 32
Vaccine Safety Datalink background rates
of intussusception. Between 1 February
2006 and 25 September 2007, the VAERS
received 160 reports of intussusception.
Assuming that reporting completeness was
75% and that 75% of the distributed doses
of RotaTeq were administered, the observed
versus expected rate ratios were 0.53 and
0.91 during 121 and 17 days after immuni-
zation respectively. There were three cases
of intussusception within 30 days after
111 521 RotaTeq immunizations, compared
with six cases after 186 722 non-RotaTeq
immunizations during the same period. The
authors concluded that these data do not
suggest that RotaTeq is associated with
intussusception.
Smallpox vaccine [SED-15, 3150;
SEDA-32, 582]
Cardiovascular Following a federal cam-
paign to vaccinate US military personnel
and civilians in 2002, to counter a possible
bioterrorism attack, more than 1 200 000 mil-
itary personnel and about 40 000 civilians
were vaccinated [44AR]. The incidence of
myopericarditis exceeded calculated back-
ground rates, prompting discussion about
cardiac inammation and other potential
vaccine-associated cardiac complications
such as dilated cardiomyopathy and myocar-
dial ischemia. A causal relation between
smallpox-associated myopericarditis and
dilated cardiomyopathy has not been demon-
strated, since there have been only a few
cases, while historical and current data have
not substantiated a causal association with
myocardial ischemia.
Tick-borne meningoencephalitis
vaccine [SEDA-15; 3423]
Hematologic There have been several
reports of the development or reactivation
of immune thrombocytopenic purpura after
immunization. Most of them have
been related to MMR immunization in
663
childhood, but a case has also been
reported after immunization against tick-
borne encephalitis [45c].
A 34-year-old woman with immune thrombo-
cytopenic purpura was treated with
splenectomy and was immunized against pneu-
mococci, meningococci, and Haemophilus
inuenzae type b. She had been well for 3 years,
but 2 weeks after a rst dose of tick-borne
encephalitis vaccine (FSME-Immun, Baxter),
her platelet count fell to 37  109/l. She was
given dexamethasone 40 mg/day for 4 days
and her platelet count normalized and
remained stable.
Varicella vaccine and Herpes
zoster vaccine [SED-15, 3606;
SEDA-31, 522; SEDA-32, 584]
Varicella vaccine
See also Measlesmumpsrubellavaricella
(MMRV) vaccine above.
Sensory systems Eyes Interstitial keratitis
has been reported after varicella immuniza-
tion [46A].
Infection risk Recurrent herpes zoster in
an immunocompetent 2-year-old child was
associated with the vaccine strain of vari-
cella zoster virus by polymerase chain reac-
tion; this is a rare complication [47A].
A previously healthy boy who had
received varicella vaccine developed herpes
zoster with meningitis [48A]. The vaccine
strain recovered from scabs of three skin
lesions had the wild-type allele at position
108111, a vaccine marker never previously
associated with vaccine-associated adverse
events. The vaccine strain from cerebro-
spinal uid also contained mutations never
previously observed at vaccine-associated
single nucleotide polymorphisms that
would alter amino acid sequences in
ORF54 and ORF59. The presence of dis-
tinct strains in the skin lesions and
664
cerebrospinal uid suggested that more
than one variant strain can reactivate and
cause herpes zoster.
A 19-month-old child developed vari-
cella caused by co-infection with two geno-
types of varicella zoster virus 3 days after
immunization with live varicella vaccine
[49A]. The presence of two different wild-
type viruses in vesicular uid was conrmed
by amplication from single virus genomes
and genotyping of single nucleotide poly-
morphisms that distinguish the ve differ-
ent genotypes of varicella zoster virus.
This nding has important implications for
recombination of the wild-type virus.
Yellow fever vaccine [SED-15, 3703;
SEDA-30, 336; SEDA-31, 523; SEDA-32,
586]
Observational studies Adverse events after
yellow fever immunization reported to the
US Vaccine Adverse Event Reporting Sys-
tem (VAERS) from 2000 to 2006 have
been reviewed [50C]. There were 660
adverse events that met the inclusion cri-
teria, 627 (95%) of which were reported
to have occurred after primary immuniza-
tion. Most of them occurred in female
recipients (61%) and in recipients aged
1949 years. Adverse events occurred
within a median of 1 day after immuniza-
tion (range 050 days), and 60% occurred
within 2 days. The most commonly
reported adverse event coding terms
included fever, pain, pruritus, headache,
injection site erythema, urticaria, rash, nau-
sea, dizziness, dyspnea, and fatigue. Local
inammatory events accounted for a larger
proportion of the adverse events reported
by female than by male recipients. Most of
the events (71%) occurred after administra-
tion of yellow fever vaccine given at the
same time as one or more other vaccines;
29% of the events occurred after yellow
fever vaccine given alone. The age and sex
distributions of events reported after yellow
fever immunization given alone were simi-
lar to those reported after immunization in
combination with other vaccines. In 72
cases (11%) adverse events were classied
Chapter 32 S. Dittmann
as severe, including 12 cases of vaccine-
associated neurological disease, six cases
of vaccine-associated viscerotropic disease,
and four deaths, two of which were attrib-
uted to viscerotropic disease. All but three
of the severe adverse events occurred after
primary vaccination and all the cases of
neurological and viscerotropic disease
occurred in primary vaccinees.
Nervous system Longitudinal myelitis
occurred in a 56-year-old man 45 days after
yellow fever immunization [51c]. There was
no history of other immunization or infec-
tion. An MRI scan of the spine showed
longitudinal intramedullary hyperintense
signals (D512) without gadolinium
enhancement. There was a high concentra-
tion of yellow fever vaccine-specic IgM
antibody in the cerebrospinal uid. Sero-
logical tests for other aviviruses were neg-
ative. His symptoms improved 5 days later.
Infection risk On 10 April 2009, during a
routine record review in connection with a
subsequent blood drive, a blood bank
supervisor learned of a breach in the defer-
ral protocol for blood products collected
from trainees [52c]. Further investigation
showed that the blood that had been
obtained during the previous drive had
been from trainees who had been immu-
nized with yellow fever vaccine 4 days
before the drive. All of those blood prod-
ucts had already been processed and incor-
porated into the inventory at the hospitals
blood bank. The blood bank supervisor
reviewed the blood banks records and
identied 87 units of whole blood and three
units of platelet that had been obtained
from the recently immunized trainees.
Blood products that had been released for
transfusion were tracked forward to iden-
tify the patients who had received the
implicated blood products. Unused blood
products were identied and destroyed.
Five patients had received six blood prod-
ucts (three units of platelets, two units of
fresh frozen plasmas, and one unit of
packed erythrocytes) from six of the
trainees, who had no previous history of
immunization or travel consistent with
Vaccines Chapter 32
exposure to wild-type yellow fever virus.
An 82-year-old man with terminal prostate
cancer and a B-cell lymphoma died 20 days
after receiving one of the implicated units
of platelets. The other four recipients had
no documented laboratory abnormalities
or symptoms attributable to yellow fever
vaccine. Three of the four had IgM anti-
bodies to yellow fever virus 2637 days
after transfusion, but no avivirus IgM
and IgG antibodies; of these, two had been
immunized with yellow fever vaccine at
least 20 years before. A booster response
was identied in these two previously
immunized donor recipients by the pres-
ence of IgM antibodies to yellow fever
virus and high neutralizing antibody titers.
This report has documented for the rst
time serological evidence for transmission
of yellow fever vaccine virus through
infected blood products.
Yellow fever vaccine virus can be trans-
mitted via breast-feeding [53A].
Meningoencephalitis occurred in an infant
whose mother had recently received yellow
fever vaccine during a postpartum visit. The
mother had headache, malaise, and low fever
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Sings HL, Ciprero KL, Saah A, Marino D,
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Vaccines Chapter 32
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[30] Rosenberg M, Sparks R, McMahon A,
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[31] Turkoglu R, Tuzun E. Brainstem encepha-
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[32] Zafrir Y, Agmon-Levin N, Shoenfeld Y.
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[33] Birck R, Kaelsch I, Schnuelle P, Flores-
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[34] Tamma PD, Ault KA, del Rio C,
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[35] Carroll DN, Carroll DG. Fatal intracranial
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[44] Mora LF, Khan AH, Sperling LS. Cardiac
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 P.F.W. Strengers and K.J. Velthove
33 Blood, blood components,
plasma, and plasma products
The risks of infections from
transfusions
The administration of blood, blood compo-
nents, plasma, and plasma products always
carries the potential risk of transmission of
infectious agents [1R, 2R]. Owing to increased
standards of donor screening, serological test-
ing, and nucleotide amplication testing
(NAT), resulting in reduced window periods,
transmission of blood-borne infections by
blood products has become very rare in West-
ern countries [3R]. This is especially the case
for plasma products, with the continuing
development of dedicated viral inactivation/
reduction methods, including heat (pasteuri-
zation and dry heat), cold ethanol fraction-
ation, solventdetergent processes, low pH,
addition of pepsin or caprylic acid, and nano-
ltration [1R, 2R].
The risk of ABO-incompatible blood
transfusion, although completely prevent-
able, is 1000 to 10 000 times higher than
the risk of viral infection from blood. How-
ever, geographical location is important in
evaluation of the risk of transfusion-related
infections [3R].
Bacteria Transfusion-related infections are
mainly caused by contamination with skin-
commensal bacteria [3R]. One in every
3000 donated blood units is contaminated
with bacteria. The estimated prevalence of
Side Effects of Drugs, Annual 33
J.K. Aronson (Editor)
ISSN: 0378-6080
DOI: 10.1016/B978-0-444-53741-6.00033-7
# 2011 Elsevier B.V. All rights reserved.
contaminated blood products varies from 1
in 20 000 to 1 in 30 000, with an aseptic
transfusion reaction in between 1 in 20 000
and 1 in 250 000, depending on the specic
product [3R, 4c].
As platelet concentrates are stored at
room temperature, these products are most
susceptible to bacteria growth. Because of
the short shelf-life of platelet concentrates,
these products are sometimes already trans-
fused before the results of bacterial culture
have been evaluated. In a study of 121 402
platelet concentrates, 544 cultures (0.45%)
were agged positive, of which 181 units
had already been transfused, with 160 truly
positive units (from two patients, clinical
data were lacking). Two of 158 patients
developed a transfusion reaction. In both
cases Propionibacterium was cultured from
the transfused platelet concentrates, but both
events were classied as being unrelated to
the platelet concentrate [4c]. One case of a
near-fatal septic transfusion reaction was
reported with a platelet concentrate unit that
did not undergo bacterial detection [5A].
Viruses The risk of transfusion-related viral
infection is signicantly lower than the risk
of bacterial infections [3R]. Of all human
herpesviruses, cytomegalovirus (CMV) is
the most signicant cause of transfusion-
related morbidity and mortality. Because
CMV may be associated with leukocytes in
blood products, the incidence of transfu-
sion-related CMV infection is signicantly
reduced after the use of leukocyte reduction
techniques. The residual risks of transfu-
sion-related infection with hepatitis B virus,
hepatitis C virus, and HIV are respectively
669
670
estimated to be 1 per 153 000 donations, 1
per 2.3 million donations, and 1 per 7.8 mil-
lion donations [3R].
Despite cases of transmission of hepatitis
C associated with intravenous immunoglob-
ulin in the 1990s, no cases of transmission
of hepatitis, HIV, or CreutzfeldtJakob dis-
ease have since been reported with immuno-
globulins [6R]. Before 1996, PCCs
(prothrombin complex concentrates) were
associated with minimal risk of transmission
of infective agents [7R]. There are no docu-
mented cases of viral transmission in patients
with von Willebrand disease or hemophilia A
treated with Haemate P/Humate P in over
25 years of clinical experience in Europe
and more than 17 years in the USA [8R]. In
the IMPACT-1 and IMPACT-2 trial in 124
patients there were no cases of HIV, hepatitis,
or human B19 virus conversion. Further-
more, no cases of viral transmission have
been reported during 30 years of post-market-
ing surveillance of C1-esterase inhibitor con-
centrate [9R, 10C].
No cases of transmission of HIV or hepa-
titis have been associated with the use of
brin sealants, but there have been reports
of transmission of parvovirus B19 [11M].
Transmission of parvovirus B19 in blood
products and its resistance to common viral
inactivation techniques raises concern about
blood safety [3R].
Protozoa In Western countries transfusion-
related malaria is rare. However, on a global
scale malaria remains one of the most com-
mon transfusion-related infections [3R].
Prions The use of bovine thrombin in brin
sealants increases the risk of transmission of
bovine spongiform encephalitis (BSE) [11M].
However, the risk of transmitting prion dis-
eases by giving human blood or blood prod-
ucts is theoretical at present. Because of the
long incubation time it is challenging to evalu-
ate the risk [2R]. In 168 UK cases of variant
CreutzfeldtJakob disease (vCJD), nine
patients had received fractionated plasma
products on 12 occasions, intramuscular
immunoglobulins for travel on four occasions;
Rh(D) immunoglobulin for rhesus
Chapter 33 P.F.W. Strengers and K.J. Velthove
isoimmunization on seven occasions (in one
case in 1970, before the start of the at-risk
period for vCJD in 1980); and one dose of
albumin [12c]. The authors considered it
unlikely that plasma products had been the
source of vCJD disease in these cases, but
could not rule out the possibility that the use
of plasma products may result in vCJD trans-
mission in the future. Because of this uncer-
tainty, steps have been taken to reduce the
risk. Donors who have spent more than
6 months in the UK during the period 1986 to
the present are excluded from donating blood
or plasma in the USA and Europe [2R].
ALBUMIN AND
DERIVATIVES [SED-15, 54;
SEDA-30, 381; SEDA-31, 527;
SEDA-32, 591]
Albumin [SEDA-30, 381; SEDA-31, 527;
SEDA-32, 591]
The use of 20% albumin infusion in the
treatment of neonatal hypoalbuminemia is
controversial, because of lack of evidence-
based guidelines. In a retrospective study
of 30 neonates, no adverse effects of albu-
min infusion were registered [13c].
Albumin-derived hemostatics
BioGlue, which is based on albumin and glu-
taraldehyde, was introduced into the Euro-
pean market in 1998. In patient studies, no
related adverse events have been reported;
however, there has been one report of severe
active inammatory response. In 75 pediatric
neurosurgical patients there was a strong
association between BioGlue and postopera-
tive wound complications. Embolization and
stenosis have also been associated with Bio-
Glue. Other reports include valve malfunc-
tion because of BioGlue migration, an
aseptic mediastinal cyst, massive lung brosis,
and an anastomotic pseudoaneurysm [11M].
Blood, blood components, plasma, and plasma products
ANTICOAGULANT
PROTEINS [SED-15, 266; SEDA-
30, 381; SEDA-31, 527; SEDA-32, 591]
Drotrecogin alfa (activated)
(recombinant human activated
protein C) [SEDA-32, 591]
Hematologic In 100 consecutive patients
who received drotrecogin alfa for severe
sepsis, 30 of whom underwent surgery and
70 of whom did not, seven fullled pre-set
criteria for bleeding complications (transfu-
sion of more than 3 units of blood, an intra-
cranial hemorrhage, or other serious
adverse bleeding events), four of the former
and three of the latter [14c]. There were no
deaths. All the bleeding complications were
due to falls in hemoglobin or platelets.
In a retrospective review of the medical
records of 73 patients who had received
drotrecogin alfa for sepsis, there were seri-
ous bleeding events in 7 of 20 with any
baseline susceptibility factor for bleeding
and only two of 53 patients without; more
of the former died and they had higher
APACHE II scores and more bloodstream
infections [15c].
In a review of six large phase III and
phase IV post-approval clinical studies (two
placebo-controlled studies and four open
studies), involving 8615 adults with severe
sepsis, serious bleeding events were ana-
lysed according to the drug infusion period
and during the overall study (28 days)
[16MR]. The rates of serious bleeding during
the infusion period were consistent at about
2.4% compared with a background bleeding
rate in severe sepsis of about 1.1%; the 28-
day serious bleeding rates were 3.16.5%
compared with 1.72.2% in the placebo
group. Central nervous system bleeding
occurred in 0.20.6% during infusion and
in 0.21.5% during the entire 28-day study,
compared with placebo rates of 00.2%
and 0.10.4% respectively.
Drugdrug interactions Heparin Heparin
increases the risk of bleeding in patients
Chapter 33 671
who are receiving drotrecogin. In a dou-
ble-blind, randomized, placebo-controlled
trial of prophylactic heparin in patients with
severe sepsis treated with drotrecogin
24 micrograms/kg/hour for 96 hours, patients
were randomized to unfractionated heparin
5000 units bd (n 511), enoxaparin 40 mg/
day (n 493), or placebo (n 990) every
12 hours [17C]. There were more bleeding
events overall during infusion of drotrecogin
in those who also received heparin compared
with placebo (11% versus 8.1%), but serious
bleeding events were similar (2.3% versus
2.5%), and central nervous system bleeds
were uncommon in both groups (0.3% versus
0.3%).
BLOOD TRANSFUSION
[SED-15, 529; SEDA-30, 381;
SEDA-31, 528; SEDA-32, 593]
Adverse events related to transfusion of
blood components have been reported,
including febrile non-hemolytic transfusion
reactions, mild febrile reactions, acute and
delayed hemolytic transfusion reactions,
transfusion-related acute lung injury
(TRALI), anaphylactic and other allergic
reactions, graft-versus-host disease (GvHD),
transfusion-associated circulatory overload
(TACO), viral infections, post-transfusion
bacteremia, transfusion-associated sepsis
(TAS), hemosiderosis, post-transfusion pur-
pura, and new allo-antibody formation
[18S, 19S]. Whole blood, erythrocytes, leu-
kocytes, platelets, and plasma for trans-
fusion (fresh frozen plasma, FFP) are
involved. Quite a number of these adverse
effects, such as TRALI, TACO, TAS, and
allergic/anaphylactic reactions can be dif-
cult to evaluate.
Susceptibility factors Children In pediatric
practice, such as intensive treatment of mal-
ignant disease, cardiac surgery including
extracorporeal membrane oxygenation,
672
transplant surgery, and transfusion support
for neonates and for children with hemo-
globinopathies, the availability of blood
has enabled enormous advances. Of all
erythrocyte transfusions, 4.2% are in
patients under 18 years and 1.7% in chil-
dren under 12 months. Adverse outcomes
are estimated to occur in 18 per 100 000
erythrocyte transfusions in children under
18 years and 37 per 100 000 in those under
12 months, compared with 13 per 100 000
in adults [20C].
Erythrocytes
In several studies, transfusion of older
compared with fresh erythrocytes
has been associated with increased mortal-
ity, prolonged hospitalization, intensive care
treatment, mechanical ventilation, an
increased risk of postoperative pneumonia,
infection at any site, and multiorgan failure
[21C, 22C]. However, most studies suffered
from not adjusting the data for the number
of units transfused. Patients who received
old erythrocytes often received more
cells on average than recipients of fresh
erythrocytes. The amount of cells trans-
fused reects the severity of the illness,
co-morbidity, and a poorer baseline prog-
nosis [23R]. A meta-analysis did not sup-
port the suspicion that old erythrocytes
are associated with common adverse mor-
bidity/mortality outcomes [24M].
Leukocyte contamination has been asso-
ciated with increased transfusion associated
mortality as a result of transfusion-related
immune modulation, with cancer growth
and impaired immunity against infections
as suspected consequences. However, in
two randomized studies, cancer growth
was not found to be inuenced by trans-
fusion of leukodepleted and non-depleted
erythrocytes [25R]. The association with
postoperative infections and leukocyte-
containing transfusions could not be con-
rmed in a meta-analysis [26M].
Chapter 33 P.F.W. Strengers and K.J. Velthove
BLOOD SUBSTITUTES
[SEDA-30, 383; SEDA-31, 531;
SEDA-32, 593]
Hemoglobin-based oxygen
carriers
Hemoglobin-based oxygen carriers are
infusible oxygen-carrying uids prepared
from puried human or animal hemoglo-
bin; they do not need to be refrigerated
and cross-matching is unnecessary [27R,
28R]. However, small amounts of residual
cell membranes are very toxic. The rst-
generation of compounds, prepared from
modied tetrameric hemoglobin molecules,
was mainly associated with vasoconstriction
and renal dysfunction. Clinical trials were
stopped because of increased mortality,
myocardial infarction, and stroke [28R,
29C]. A meta-analysis of 16 trials involving
a total of 3711 patients showed that hemo-
globin-based oxygen carriers are associated
with a 30% increased risk of death (RR 1.3;
95% CI 1.11.6) and a 2.7-fold increased
risk of myocardial infarction (RR 2.7; 95%
CI 1.74.4) [30M], although other authors
have debated these results [29C]. Other
adverse effects that are associated with
hemoglobin-based oxygen carriers include
abdominal pain, diarrhea, skin rash, jaun-
dice, hemoglobinuria, oliguria, fever, and
interference with laboratory assays [28R,
31R]. Increases in the activities of serum
liver enzymes and lipase may be related to
interference with clearance of these pro-
teins by the reticuloendothelial system
[32C]. In phase III clinical trials in 171
patients undergoing surgery, the use of
human polyhemoglobin was not associated
with adverse effects [27R]. In 714 patients
hypertension, coagulopathy, and myocar-
dial infarction occurred more in those who
were given hemoglobin-based oxygen car-
riers than in the controls [29C]. Although
polymerized hemoglobin products appear
to have a better safety prole, their safety
remains a topic of considerable debate.
Blood, blood components, plasma, and plasma products
Cardiovascular Tetrameric hemoglobin can
cause vasopressor effects. It is hypothesized
that it enters the interstitial space through
the intercellular junctions of the endothelial
lining of the vascular wall, where it binds
nitric oxide, which is needed for maintaining
normal muscle tone in smooth muscles, lead-
ing to vasoconstriction. Binding of nitric
oxide also leads to increased platelet aggre-
gation. To avoid vasopressor or cardiac
effects, polyhemoglobin products must con-
tain less than 2% of tetrameric hemoglobin
[27R, 28R, 29C]. Liposome-encapsulated
hemoglobin-based oxygen carriers can acti-
vate the reticuloendothelial system and the
complement and coagulation pathways, and
can cause platelet aggregation [31R].
Gastrointestinal Binding of nitric oxide by
tetramer hemoglobin leads to smooth mus-
cle dysfunction and gastrointestinal adverse
effects such as abdominal pain, diarrhea,
nausea, and vomiting [28R, 31R].
Pancreas Pancreatitis has been reported as
an adverse event in three studies of hemo-
globin-based oxygen carriers; the most
plausible mechanism is production of reac-
tive oxygen species [31R].
Urinary tract Hemoglobin tetramers rap-
idly degrade into dimers and monomers,
which are ltered by the kidney and can
damage renal tubular cells; this is pre-
vented by polymerization of free hemo-
globin molecules [28R].
Susceptibility factors In a phase III trial in
688 patients there were more adverse events,
primarily affecting the cardiac and nervous
systems, reported with hemoglobin-based
oxygen carriers than with erythrocyte trans-
fusions. Three main factors were considered
to have contributed: age over 80 years, vol-
ume overload, and undertreatment. Patients
with pre-existing cardiac disease are more
vulnerable to adverse effects at lower total
hemoglobin concentrations [32C]. A re-anal-
ysis of the same data showed that cardiac
adverse events and mortality were much
more common among patients aged over
Chapter 33 673
70 years [33c]. The authors hypothesized that
younger patients tolerate vasoconstriction
and persistent anemia related to hemoglo-
bin-based oxygen carriers better because of
larger physiological reserve, a lower inci-
dence of co-morbid cardiovascular disease,
and better microvascular compensatory
properties.
Peruorocarbons [SEDA-30, 383;
SEDA-31, 531; SEDA-32, 594]
Peruorocarbons are completely synthetic
molecules made of 810 carbon molecules
with uorine atoms replacing hydrogen
atoms. They are immiscible with water
and can dissolve oxygen and carbon diox-
ide. Unlike hemoglobin, which binds oxy-
gen covalently, peruorocarbons require a
high PaO2 (300 mmHg) to be effective
[31R]. Second-generation peruorocarbons
that have been developed include Oxygent,
Oxyuor, Oxycyte, and Perftoran. There is
limited clinical experience. A phase III
study of Oxygent was terminated because
of a possible increase in strokes. Oxyuor
was associated with mild thrombocytopenia
and u-like symptoms in phase I and II tri-
als, but its development has been ended.
The u-like symptoms may be due to
immunological activation of macrophages
by the particle size of the product. Perf-
toran was associated with hypotension and
pulmonary complications in about 1% of
cases in a randomized trial. Clinical experi-
ence with large volumes of Perubron
(Oxygent) yielded few adverse events, diar-
rhea being the most common. Peruorocar-
bons interfere with laboratory assays such
as CO oximetry [31R].
Cardiovascular Peruorocarbons that un-
load oxygen in a linear manner can cause
excessive tissue oxygenation, which could lead
to reex vasoconstriction, increased blood pres-
sure, a reduced heart rate, and a reduced cardiac
output [31R].
674
PLASMA AND PLASMA
PRODUCTS [SED-15, 2847;
SEDA-30, 383; SEDA-31, 532;
SEDA-32, 594]
Alpha1-antitrypsin [SEDA-31, 532]
Augmentation therapy for alpha1-antitryp-
sin uses partially puried plasma, which is
highly enriched with alpha1-antitrypsin.
Adverse reactions to this are rare (under
0.03 events per patient-month) and gener-
ally mild. They include headache, dizziness,
nausea, and dyspnea [34R].
A non-smoking 61-year-old man with severe
emphysema due to alpha1-antitrypsin de-
ciency was given intravenous human alpha1-
antitrypsin 60120 mg/kg once a week or
every second week for 10 years [35A]. His
plasma alpha1-antitrypsin concentration was
restored. There were no signicant changes
in FEV1, vital capacity, or the ratio of FEV1
to vital capacity, and the emphysema pro-
gressed, but there were fewer exacerbations.
There were no adverse reactions.
Drug administration route Six healthy sub-
jects, seven patients with alpha1-antitrypsin
deciency, and seven patients with cystic
brosis were given alpha1-antitrypsin by
nebulization. One healthy subject devel-
oped tongue vesicles and dysphagia and
one patient with cystic brosis had mild
headache, which was possibly related to
alpha1-antitrypsin [36c].
Antithrombin III [SEDA-32, 594]
Observational studies In a retrospective
cohort analysis, using an intensive care unit
database, of the effect of antithrombin III
compared with standard therapy on out-
comes and erythrocyte transfusion rates in
545 postoperative surgical patients with
severe sepsis, antithrombin III therapy
was associated with a signicantly higher
frequency of erythrocyte transfusion (22
versus 9 units); there was no benecial
effect on mortality [37c].
Chapter 33 P.F.W. Strengers and K.J. Velthove
C1 esterase inhibitor concentrate
[SEDA-30, 383; SEDA-31, 532;
SEDA-32, 594]
In the IMPACT-1 trial of C1-esterase
inhibitor, 39 patients received 10 U/kg, 46
received 20 U/kg, and 41 received placebo
[10C]. In the 4 hours after the dose, eight
of the 10 U/kg recipients, ve of the 20 U/
kg recipients, and eight of the placebo
recipients reported adverse events that
were considered at least possibly related
to treatment; none was considered serious.
The difference in the rates of reported
adverse events between 20 U/kg and pla-
cebo can be explained by the fact that most
of the patients had attacks of abdominal
pain, which were recorded as adverse
events [10C]. The most commonly reported
adverse events with 20 U/kg included nau-
sea, diarrhea, abdominal pain, and muscle
spasms, all of which occurred less often in
the 20 U/kg group compared with placebo.
In the IMPACT-2 trial, an extension of
IMPACT-1 [9R], 16 of 39 patients who
were given 20 U/kg reported adverse
events, of which four were considered at
least possibly related to the drug, including
dry mouth, inuenza-like symptoms, infu-
sion-related reactions, dizziness, and head-
ache. During almost 20 years of post-
marketing surveillance, few adverse events
have been reported, including injection-site
redness, fever, chills, headache, and anaphy-
lactic reactions. These events are rare and
mostly related to over-rapid infusion or giv-
ing the product before it has reached room
temperature.
Fibrin glue [SED-15, 1363]
The compositions of brin sealants differ: all
consist of brinogen in combination with
thrombin and in some cases they include fac-
tor XIII and/or an antibrinolytic agent,
which stabilizes the clot. Their adverse effects
have been highlighted [11M]. Bovine throm-
bin is potentially immunogenic and can cause
immunological sequelae, anaphylaxis, and
Blood, blood components, plasma, and plasma products
coagulopathy. Coagulopathy is hypothesized
to be related to cross-reactive antibodies
against bovine products, which react with
human products, especially factor V. How-
ever, not all cases of coagulopathy result in
hemorrhage, and spontaneous resolution is
common. The antibrinolytic drugs in the
product can also be associated with adverse
events. Bovine aprotinin has been associated
with anaphylactic reactions in case reports
[11M, 38A] and tranexamic acid has been
reported to be neurotoxic. Completely
patient-derived (autologous) brin products
without antibrinolytic drugs minimize these
risks. Lastly, higher concentrations of throm-
bin in brin sealants are associated with a
higher risk of thrombosis [11M].
Plasma [SEDA-30, 384; SEDA-31, 532]
Respiratory Transfusion-related acute lung
injury (TRALI) can be a serious adverse
event after transfusion of plasma that contains
antibodies against the recipient's leukocytes,
and is the most common cause of transfu-
sion-related mortality. About 90% of cases
of TRALI are associated with human leuko-
cyte antigen (HLA) antibodies from the
donor [39A, 40A]. Two mechanisms of
TRALI have been suggested: (1) an antige-
nantibody reaction leads to a series of
events; (2) neutrophils are primed and
become activated [7R].
A 79-year-old woman with myasthenia gravis
developed TRALI after being given plasma
exchange therapy for 4 days; she recovered
completely [39A].
A 25-year-old man with factor V deciency
developed TRALI after receiving 5 units of
plasma; he recovered completely [40A]. How-
ever, recurrent TRALI developed after he
was given 2 units of plasma 5 months later.
The second case shows that the risk of
recurrent TRALI may persist longer than
previously thought. The authors suggested
screening donors that are at risk of allo-
immunization to HLA antigens and exclud-
ing donations from positive donors.
Chapter 33 675
Fluid balance Because of the low concen-
tration of coagulation proteins in fresh fro-
zen plasma, large volumes may be needed
when it is used to reverse excess oral antic-
oagulation treatment, with a risk of uid
overload [41R, 42R].
Susceptibility factors There is no correla-
tion between the risk of TRALI and age,
history of transfusions, previous transfusion
reactions in the recipient, or ABO compat-
ibility of donor and recipient; the volume of
donor plasma correlates poorly with the
risk [39A].
PLASMA SUBSTITUTES
[SEDA-30, 384; SEDA-31, 533;
SEDA-32, 594]
Dextrans [SEDA-32, 595]
Immunologic Dextran 70 has been used as
stabilizer in a measlesmumpsrubella
(MMR) vaccine product named Morupar.
This vaccine was associated with dextran-
driven hypersensitivity reactions with high
concentrations of dextran-specic IgG
[43r]. The most probable mechanism is
immune complex-mediated reactions
caused by naturally occurring dextran-
specic antibodies. Morupar was with-
drawn from the market.
Etheried starches [SED-15, 1237;
SEDA-30, 384; SEDA-31, 533; SEDA-32,
595]
Hydroxyethyl starch has been widely used as
plasma volume expander in bleeding
patients. Each product is characterized by its
molecular weight, concentration, molar sub-
stitution, origin, and solvent [44C]. Adverse
reactions include excessive intravascular vol-
ume expansion, metabolic acidosis, anaphy-
laxis, renal dysfunction, hepatic dysfunction,
and coagulopathy [45A]. It has been sug-
gested that adapting the formulation to the
676
electrolytic composition of plasma will yield a
safer product, but this is debated [46r, 47r,
48c].
[Authors note: Among those who have
taken part in the debate about the usefulness
of etheried starches is Joachim Boldt. How-
ever, many papers authored by Dr. Boldt
have been retracted by the Editors of the jour-
nals in which they have appeared, namely
Acta Anaethesiologica Scandinavica, Anaes-
thesia, Ansthesiologie Intensivmedizin Not-
fallmedizin Schmerztherapie, Anesthesia &
Analgesia, Anesthesiology, Annals of Tho-
racic Surgery, British Journal of Anaesthesia,
Canadian Journal of Anesthesia, Der An-
sthesist, European Journal of Anaesthesiol-
ogy, Intensive Care Medicine, Journal of
Cardiothoracic and Vascular Anesthesia,
Journal of Cranio-Maxillo-Facial Surgery,
Medical Science Monitor, Minerva Anestesio-
logica, Thoracic and Cardiovascular Surgeon,
and Vox Sanguinis [49S]. The Editors wrote
that The retraction of the 88 articles for lack
of IRB (Institutional Review Board)
approval means that the research was unethi-
cal, and that IRB approval for the research
was misrepresented in the published article.
It does not mean that the research results
per se are fraudulent. Klinikum Ludwigsha-
fen has commissioned an investigating com-
mittee to systematically assess the veracity of
the ndings presented in Dr. Boldt's articles
against patient and laboratory records.]
Hematologic Colloid plasma expanders are
associated with coagulopathy and increase
the risk of bleeding and the need for trans-
fusion. The coagulatory effects of hydro-
xyethyl starch are dose-related in the
therapeutic range (i.e. they are collateral
adverse effects), and they may be associated
with higher molecular weights and higher
degrees of saturation [44C, 45A]. The mecha-
nism of the coagulopathy is unknown and is
the subject of debate. Hydroxyethyl starch
molecules of high molecular weights inter-
fere with brinogen, factor VIII, and von
Willebrand factor more than expected from
hemodilution only [45A, 48c]. It has been
hypothesized that hydroxyethyl starch
Chapter 33 P.F.W. Strengers and K.J. Velthove
impairs thrombinbrinogenfactor XIII
interactions, with enhanced brinolysis and
reduced platelet activity, which may play a
role [45A]. From the results of a study in 20
bleeding patients with substitution of hydro-
xyethylstarch 130/0.4 up to a target level of
30%, it seems that this coagulopathy is pre-
dominantly caused by acquired brinogen
deciency [50c]. Earlier reports suggested
that hydroxyethyl starch 130/0.4 would be
safer than hydroxyethyl starch 200/0.5, but
these were contradicted by later reports
[46r, 47r, 48c]. In 45 patients undergoing car-
diac surgery, 6% hydroxyethyl starch 200/0.5
and 6% hydroxyethyl starch 130/0.4 pro-
duced similar impairment of brin formation
and clot strength [47r].
Two neonates underwent major opera-
tions and received hydroxyethyl starch
along with albumin, fresh frozen plasma,
erythrocytes, and thrombocytes; there were
no changes in coagulation status and no
other adverse events [51A].
Urinary tract Renal dysfunction has been
associated with hydroxyethyl starch.
A 67-year-old man developed acute renal
insufciency after the administration of over
10 liters of 10% pentastarch over 2 months
[52A]. Renal biopsy showed hydropic changes
in the renal tubular cells, compatible with col-
loid-induced damage. These changes were
long-lasting and irreversible.
In a cohort study of 563 adults undergo-
ing cardiac surgery, pentastarch 10% with
an intermediate molecular weight (hydro-
xyethyl starch 200/0.5) was identied as an
independent risk factor for acute kidney
injury at doses as low as 14 ml/kg, the man-
ufacturer's maximally recommended dos-
age being 28 ml/kg [44C]. The authors
proposed that the mechanism is hypervisc-
osity of the urine, resulting in stasis of tubu-
lar ow and obstruction of the tubular
lumen with nephrosis-like lesions. Formula-
tions with higher molecular weights and
degrees of substitution are more likely to
cause renal damage [52A].
Blood, blood components, plasma, and plasma products
GLOBULINS
Immunoglobulins [SED-15, 1719;
SEDA-30, 385; SEDA-31, 534; SEDA-32,
595]
Intravenous immunoglobulin
Intravenous immunoglobulin is being used
for a wide range of other disorders beyond
its licensed indications [53R]. This increased
use has resulted in an increased number of
reported adverse reactions. Systemic reac-
tions include fever, malaise, ushing, chills,
fatigue, myalgia, arthralgia, u-like symp-
toms, and very rarely life-threatening events,
such as anaphylaxis and death [1R, 6R, 53R,
54r, 55c, 56c].
Intravenous immunoglobulin products
differ in excipients and physicochemical
characteristics. Each may have slightly dif-
ferent proles of efcacy and adverse reac-
tions. The reported adverse reaction rate
varies between 2% and 25% of all infusions,
depending on the disease being treated and
the patient population. There is a higher
incidence rate after a rst exposure. Most
of the adverse reactions are classied as
being of mild-to-moderate intensity [1R,
54r, 57c, 58c]. In one prospective study in
almost 400 patients with immunodeciency
(over 13 000 infusions), the adverse reaction
rate was 0.8%; none of these events was
classied as severe [54r]. In 38 children there
was an adverse reaction rate of 9% of all
infusions; none was life-threatening [59c].
In 70 patients who received 1085 infusions
there was an adverse events rate of 4.3%
of all infusions (33% of all patients); none
was serious [58c]. In one study of 341 infu-
sions, severe adverse reactions led to discon-
tinuation of therapy in 4% of all treatment
courses [53R].
Cardiovascular Hypotension, hypertension,
chest pain, and rarely dysrhythmias or myo-
cardial infarction have been associated with
the use of intravenous immunoglobulin [1R,
53R, 54r, 55c, 57c]. In a small crossover
study in patients with multifocal motor neu-
ropathy there was one case of phlebitis
Chapter 33 677
during intravenous immunoglobulin treat-
ment [60c].
Respiratory Dyspnea, cough, and broncho-
spasm have been reported during intra-
venous immunoglobulin treatment. Rare
adverse effects include pleural effusion, pul-
monary edema, and TRALI [1R, 53R, 54r,
61A].
Nervous system The most common adverse
reactions to intravenous immunoglobulin
are neurological, headache being the most
frequent, occurring in 3067% of all patients
[1R, 19c, 53R, 54r, 57c, 61A, 62A]. Headache
may be associated with increased serum vis-
cosity [62A], and is mostly mitigated by pre-
treatment with analgesics [54r]. Other
reported adverse reactions are migraine, diz-
ziness, meningism, and back pain. Rare
adverse reactions include aseptic meningitis,
dysesthesia, weakness, convulsions, and a pos-
terior reversible encephalopathy syndrome
[1R, 53R, 54r, 55c, 57c].
A 14-year-old Japanese girl with Guillain-
Barr syndrome was given intravenous immu-
noglobulin 0.4 g/kg/day and after 3 days
developed severe headaches without disturbed
consciousness [62A]. An MRI scan of the brain
showed characteristics consistent with posterior
reversible encephalopathy syndrome. After the
end of the course of intravenous immunoglobu-
lin she recovered.
Hematologic Hematological adverse eve-
nts are rare; they include hemolysis, venous
thrombosis and stroke, hyperviscosity, leu-
kopenia, and anemia [1R, 54r, 57c].
A 40-year-old Caucasian woman with systemic
lupus erythematosus received intravenous
immunoglobulin 2 g/kg on three consecutive
days monthly [63A]. This treatment was effec-
tive for 12 months, but after switching to a
new batch of the same product she developed
a hemolytic anemia, with mild abdominal
pain, fatigue, and a rash. She was given gluco-
corticoids and the hematocrit returned to nor-
mal within 4 weeks. However, 1 month later
she was again given intravenous immunoglob-
ulin (the same dose and batch as 1 month
before) and had the same adverse reactions.
Again she was given glucocorticoids and
recovered in 4 weeks.
678
The authors considered it probable that
the patient's AB blood type had increased
the risk of hemolysis and they concluded
that patients with severe hemolysis can
switch from one batch of intravenous
immunoglobulin to another batch of the
same product after recovery.
Gastrointestinal Gastrointestinal adverse
events include nausea, vomiting, anorexia,
diarrhea, and cramping [1R, 53R, 54r, 55c,
57c]. Necrotizing enterocolitis after photo-
therapy and intravenous immunoglobulin
for hemolytic disease of the newborn has
been reported in three cases [64A].
Urinary tract Renal insufciency and hema-
turia are rare after the administration of intra-
venous immunoglobulin, and most often
occur in patients with pre-existing renal
impairment. Products that contain sucrose
carry a higher risk of renal adverse events
[1R, 53R, 54r].
Skin Cutaneous reactions associated with
intravenous immunoglobulin are uncommon,
but include pruritus, non-specic eruptions,
erythema, urticaria, eczema, pompholyx, pete-
chiae, and skin hemorrhage [53R, 54r, 55c, 57c,
59c].
A 54-year-old woman with carbamazepine-
induced StevensJohnson syndrome was given
intravenous immunoglobulin 1 g/kg/day for
3 days and topical glucocorticoids to the non-
erosive skin lesions [65A]. However, 3 days
later she developed multiple non-pruritic vesi-
cobullae with clear uid contents on the palms
after most of the previous lesions had
resolved. The new lesions resolved spontane-
ously within 1 week without treatment.
A 26-year-old Korean man with GuillainBarr
syndrome was given intravenous immunoglobu-
lin 0.4 g/kg/day for 3 and 6 days later developed
multiple reddish severely pruritic vesicles on
both palms, diagnosed as pompholyx [66A].
The vesicles resolved after treatment with topi-
cal diucortolone valerate ointment.
Immunologic The risk of anaphylaxis in
patients with anti-IgA antibodies is not pre-
cisely known. Although 1025% of patients
with common variable immunodeciency
have anti-IgA antibodies, anaphylaxis is
Chapter 33 P.F.W. Strengers and K.J. Velthove
rare after administration of intravenous
immunoglobulin [54r]. Differences in prod-
uct tolerance because of IgA content could
be explained by the presence of an Fc-a on
leukocytes that is activated by interaction
with IgA. Activation of IgA receptors could
result in infusion-related fevers after the use
of products with a high IgA content [59c].
Susceptibility factors Most adverse reac-
tions occur after the rst dose of intravenous
immunoglobulin [1R, 54r, 59c]. Furthermore,
adverse events are associated with several fac-
tors including the presence of infection, a high
concentration of IgG in the product (which
carries a risk of immunoglobulin aggregate
formation), a switch of product, a high dosage,
and a rapid infusion rate [1R, 54r, 55c, 67c].
Severe adverse reactions are very rare and
occur mainly in patients who repeatedly
receive high-dose infusions for diseases other
than primary immune deciencies [1R]. In a
casecontrol study of the susceptibility factors
that are associated with thromboembolic
adverse reactions in 19 patients and 38 age-
matched controls, no single cardiovascular
susceptibility factor increased the risk of
thrombosis, but the risk was signicantly
higher in patients with four or more suscepti-
bility factors [68c].
Children In 38 children with juvenile derma-
tomyositis the rate of adverse events, partic-
ularly fever, fatigue, nausea, and vomiting,
was higher with intravenous immunoglobu-
lin containing more than 15 mg/ml of IgA
[59c]. Children may be more sensitive to
immunological triggers than adults [59c].
Subcutaneous immunoglobulin
One of the advantages of subcutaneous over
intravenous administration is a more stable
plasma IgG concentration, because some
adverse effects of intravenous administra-
tion are possibly associated with high peak
serum IgG concentrations. Subcutaneous
administration of immunoglobulin leads to
fewer systemic adverse effects compared
with intravenous immunoglobulin. Local
adverse reactions, such as redness, swelling,
Blood, blood components, plasma, and plasma products
and pain are common but mild [1R, 54r, 69R,
70c]. Other advantages of subcutaneous
immunoglobulin are a better quality of life,
less emotional stress, improved convenience,
less absence from school or work, and lower
costs [1R, 69R, 70c]. In a 6-month open pilot
intervention study, nine patients switched
from intravenous to subcutaneous immuno-
globulins once or twice a week. All had local
adverse effects after subcutaneous treatment
during 330 treatments, with a reduced fre-
quency of adverse effects during prolonged
treatment. Swelling and redness of the skin
occurred more often, followed by induration
of the skin and soreness. Systemic adverse
effects included fever, malaise, palpitation,
and rash. There were no serious adverse
events. The intensity of adverse effects was
comparable between subcutaneous and
intravenous treatment, but there were fewer
systemic adverse effects with subcutaneous
immunoglobulin [70c]. A limitation of sub-
cutaneous administration is the large volume
that needs to be injected, requiring multiple
injection sites [69R].
Drug formulations Studies of premedication
with hyaluronidase to allow the administra-
tion of larger volumes of subcutaneous immu-
noglobulin at one injection site or the use of a
20% concentration product in order to mini-
mize the volume showed similar rates of
adverse reaction as with established subcuta-
neous immunoglobulin [69R].
Drug administration route Rapid bolus
dose administration of subcutaneous immu-
noglobulin 320 ml per dose was associated
with a similar adverse event rate to pump
administration; local infusion-site reactions
were the most common adverse effects [69R].
Intravenous anti-D
immunoglobulin
Respiratory Transfusion-related acute lung
injury (TRALI) occurred 5 hours after
treatment with intravenous anti-D immuno-
globulin in a 14-year-old girl with idiopathic
Chapter 33 679
thrombocytopenic purpura; there were no
pulmonary sequelae [71A].
Hematologic Extravascular hemolysis is the
major complication of treatment with anti-D
immunoglobulin. Usually, the hemoglobin
falls to a nadir at 67 days after infusion
and normalizes after 1542 days. However,
hemolysis can be delayed when concurrent
glucocorticoids are used [72A]. There have
been 15 previous cases of acute hemoglobine-
mia or hemoglobinuria associated with intra-
venous anti-D immunoglobulins [73c] and six
cases of disseminated intravascular coagula-
tion, of whom ve died [74c], both severe
unpredictable adverse effects but very rare.
COAGULATION PROTEINS
[SED-15, 845; SEDA-30, 387; SEDA-
31, 537; SEDA-32, 596]
Factor VIIa [SED-15, 1318; SEDA-30,
387; SEDA-32, 596]
Hematologic Recombinant factor VIIa
(rFVIIa) is being investigated as a possible
reversal agent for new anticoagulants. In
general, the risk of thrombosis is increased
with products that contain activated factor
VII. However, the incidence of thrombotic
complications is reported as low as 48 per
100 000 infusions [7R]. Because of its short
half-life, repeated dosing may be needed,
increasing the risk of thrombosis, which
complicates treatment in up to 79% of
cases [41R, 42R]. However, a similar rate
was found in neonates who received fresh
frozen plasma only, and neonates with coa-
gulopathy and/or bleeding may be at a sig-
nicant risk of thrombosis [75M].
Factor VIII [SED-15, 1319; SEDA-30,
387]
In 171 patients with hemophilia A and inhib-
itors, treated with factor VIII concentrate,
680
adverse events were reported during 10
courses, six of these events were allergic reac-
tions [76R].
Factor IX [SED-15, 1324; SEDA-30,
388; SEDA-32, 596]
Adverse events, mainly allergic reactions,
occurred in 11 of 16 courses of immune tol-
erance induction therapy in patients with
hemophilia B and inhibitors. Three cases
of nephritic syndrome were also reported,
with edema, proteinuria, and hypoalbumi-
nemia 79 months after they had received
factor IX 100 U/kg/day [76R].
Prothrombin complex concentrate
[SEDA-31, 537; SEDA-32, 596]
Several prothrombin complex concentrate
products are available, with different
amounts of vitamin K-dependent factors.
Products that contain therapeutic concen-
trations of factors II, IX, and X are referred
to as three-factor concentrates; those with
additional factor VII are called four-factor
concentrates. The clinical differences
between these types are unclear, but four-
factor concentrates should more effectively
correct the international normalized ratio
(INR) [41R].
Hematologic Historically, there was con-
cern that prothrombin complex concen-
trates were associated with thrombotic
events such as stroke, myocardial infarction,
pulmonary embolism, deep venous throm-
bosis, and disseminated intravascular coagu-
lation. These events resulted mainly from
the use of prothrombin complex concen-
trates as source of factor IX in patients with
hemophilia B, and in particular after sur-
gery, but the reported incidence is low and
there is considerable evidence that the risk
of thrombosis has been minimized with cur-
rent prothrombin complex concentrates by
reduced use of activated factors and the
Chapter 33 P.F.W. Strengers and K.J. Velthove
inclusion of coagulation inhibitors [7R,
42R, 77c]. However, it is still possible that
activated coagulation factors could increase
the risk of thrombosis and myocardial
infarction in patients with susceptibility fac-
tors. Most current products contain one or
more coagulation inhibitors (antithrombin,
protein C, protein S, protein Z, or heparin)
to maintain hemostatic balance while the
coagulation factors are increased. Unfortu-
nately, many products do not mention the
inhibitor concentrations in the label [7R].
In two studies in 24 and 8 patients undergo-
ing surgery, there were no thrombotic com-
plications or other adverse events, and
several other studies have reported similar
safety [7R, 77c]. Pharmacokinetic studies of
factor IX 50 U/kg in healthy volunteers
have shown rapid increases in coagulation
factors, no increase in D-dimer concentra-
tions, and no clinical evidence of thrombo-
sis. On the other hand, a review revealed
seven thrombotic complications in 460
patients. It has been suggested that the risk
of thrombosis is due to a high concentration
of factor II (thrombin) [7R].
A 72-year-old man with diabetes mellitus,
hypertension, a recent ischemic stroke,
chronic renal disease, and a deep venous
thrombosis developed severe hypoglycemia
and was found to have an INR over 12.8
[78A]. An echocardiogram showed cardiac
tamponade. It was decided to reverse anticoa-
gulation rapidly with prothrombin complex
concentrate 50 U/kg, vitamin K 10 mg, and
desmopressin acetate 24 micrograms, and to
drain the pericardial effusion. Immediately
after the pericardiocentesis he developed
a right-sided ventricular thrombus occupying
the entire right side of the ventricle and died.
The authors suggested that thrombus had
formed from a combination of the effects
of prothrombin complex concentrate, des-
mopressin acetate, which releases von Will-
ebrand factor and factor VIII from
endothelial cells, and blood stasis of on
re-expansion of the right ventricle following
pericardiocentesis, creating a hypercoagul-
able state. The failure of the prothrombin
complex concentrate to correct the INR
was probably due to consumption of the
active factors by the ventricular thrombus.
Blood, blood components, plasma, and plasma products
Von Willebrand factor/factor VIII
concentrates [SEDA-30, 388; SEDA-32,
597]
Von Willebrand factor/factor VIII concen-
trates play a key role in the treatment of
patients with von Willebrand disease. The
von Willebrand factor multimer fraction is
very effective in achieving hemostasis. The
available products differ in production tech-
niques, von Willebrand factor multimer con-
tent, and activity. No serious adverse events
have been related to Haemate P/Humate P
in clinical trials. Non-serious adverse events
include allergic symptoms in under 6% of
patients, chills, phlebitis, edema, pain in the
limbs, and pseudothrombocytopenia in a few
patients. No cases of thrombosis have been
reported in clinical trials, although caution
should be taken in patients with von Wille-
brand disease who have other thrombotic risk
factors [8R].
ERYTHROPOIETIN AND
DERIVATIVES [SED-15, 1243;
SEDA-30, 388; SEDA-31, 538;
SEDA-32, 597]
Erythropoietin derivatives, such as epoetin
alfa, epoetin beta, epoetin delta, and darbe-
poetin alfa, have been used to correct the
anemia of chronic renal insufciency and
in the management of a variety of refrac-
tory anemias, including the anemia of
chronic diseases, anemias in patients with
various neoplasms undergoing chemother-
apy, in patients with multiple myeloma,
and in some patients with myelodysplasia,
in aplastic anemia, and in anemia associ-
ated with the use of antiretroviral drugs.
The dosages required in these anemias are
signicantly higher than in the anemia of
chronic renal insufciency. Erythropoietin
derivatives have also been successfully used
to stimulate blood production in patients
without anemias who have to undergo fre-
quent phlebotomy to accumulate blood for
Chapter 33 681
autologous blood transfusion at the time
of orthopedic surgery [79R].
Observational studies The European Med-
icines Agency's Committee for Medical
Products for Human use (CHMP) has
reviewed new data from studies that
showed an increased risk of tumor progres-
sion, venous thromboembolism, and
shorter overall survival in patients with can-
cer who received erythropoietin derivatives
compared with patients who did not [80S].
The CHMP concluded that the benets of
erythropoietin derivatives continue to out-
weigh their harms in the approved indica-
tions. However in patients with cancer and
a reasonably long life-expectancy, the bene-
t of using erythropoietin derivatives does
not outweigh the risk of tumor progression
and shorter overall survival. The CHMP
therefore concluded that in these patients
anemia should be corrected with blood
transfusions.
Death Several groups have published evi-
dence that erythropoietin derivatives main-
tain normal hemoglobin concentrations but
also shorten the overall survival of patients
with cancers or multiple myeloma [81M,
82C, 83r, 84r]. Although the explanation is
uncertain, thromboembolic events, inter-
actions of erythropoietin derivatives with
erythropoietin receptors on tumor cells,
and stimulation of angiogenesis by actions
on erythropoietin receptors on endothelial
cells have been suggested. Guidelines
based on these results limit the use of
erythropoietin derivatives to patients with
chronic kidney disease and cancers under-
going chemotherapy, with a target hemo-
globin concentration of 12 g/dl [85S, 86M].
Susceptibility factors Children Studies on
the use of erythropoietin derivatives in chil-
dren have suggested that although children
need almost the same doses of erythropoie-
tin derivatives as are used in adults range
and should be dosed according to the hemo-
globin decit and not according to body
weight, there is no evidence of unexpected
serious adverse events attributable to eryth-
ropoietin derivatives [87r, 88c, 89c].
682
Darbepoetin alfa
Several studies on the use of erythropoietin
stimulating agents in the treatment of ane-
mia in patients with cancers with or without
chemotherapy or radiotherapy, the most
common adverse reactions to darbepoetin
alfa were myalgia, rash, pruritic rash, and
cardiovascular and thrombotic events, such
as dysrhythmias, congestive heart failure,
strokes, myocardial infarction/coronary
artery disorders, embolism/thrombosis (arte-
rial and venous), hypertension, and seizures
[90C, 91C, 92C]. Switching from subcutane-
ous to intravenous administration can
maintain hemoglobin in the dened range
of 1013 g/dl at comparable dose require-
ments without compromising safety and tol-
erability [93C].
Susceptibility factors Elderly In elderly
patients with chronic renal disease once-
monthly darbepoetin alfa for anemia was
not associated with different rates of
adverse events in patients aged under 65,
6574, or 75 years and over [94c].
Epoetin alfa
The most frequently reported adverse
events are headache, polycythemia, tired-
ness, common cold, diarrhea, nausea, stom-
ach pains, chest pressure sensation, back
pain, leg pain, and dizziness, as conrmed
in a phase I open bioequivalence parallel
group study of two recombinant human
epoetin alfa products; the pattern of the
adverse events revealed no relevant differ-
ences between the erythropoietin deriva-
tives [95c]. Patients who were randomized
to early intervention with immediate epoe-
tin alfa (n 68) or to standard intervention
with epoetin alfa (n 68), and a further 50
who were not randomized, pain, injection-
site pain, bone pain, and deep vein thrombo-
sis were observed [96c].
Chapter 33 P.F.W. Strengers and K.J. Velthove
Epoetin beta
Erythropoietin derivatives are associated
with an increased frequency of thrombo-
vascular events in a variety of tumor types
[97C]. However, whether patients with sus-
ceptibility factors should receive prophylac-
tic antithrombotic treatment has not been
conrmed. The adverse effects of combina-
tion therapy with epoetin beta and all-trans
retinoic acid (ATRA) in 59 patients with
myelodysplastic syndromes were muscle
pain, raised liver enzymes without hepatic
failure, fatigue, headache, dry skin, and dry
mucosa [98c].
Epoetin delta
Epoetin delta differs from the other eryth-
ropoietin derivatives in that it is produced
in a human cell line using gene-activation
technology. It has been approved in
Europe but not in the USA for the treat-
ment of anemia associated with chronic kid-
ney disease. In patients with cancer and
anemia who were given epoetin delta, pos-
sible treatment-related serious adverse
events were hypertension, increased serum
creatinine, and peripheral vascular disease
[99C]. There was a correlation with higher
doses, suggesting that a dose of 150 IU/kg
would be most appropriate to start with
for this indication.
STEM CELLS [SEDA-30, 389;
SEDA-31, 539; SEDA-32, 599]
Cardiovascular There is a high rate of stent
restenosis if intra-coronary infusion of stem
cells is carried out within 4 weeks after cor-
onary stenting [100C, 101C, 102C, 103C,
104C]. It should be possible to mitigate this
effect by delaying stem cell injection [105c].
Blood, blood components, plasma, and plasma products
The release of biomarkers of myocardial
damage has been studied in 71 patients with
severe coronary artery disease, after direct
intramyocardial injection of vascular endo-
thelial growth factor genes or mesenchymal
stromal stem cells [106c]. Plasma creatine
kinase MB fraction rose from 2 to 6 mg/l
after 8 hours and normalized to 4 mg/l after
24 hours. Eight patients who received a vol-
ume of 0.3 ml per injection had rises exceed-
ing three times the upper limit, whereas
none of those who received 0.2 ml had a
more than two-fold rise. No patient devel-
oped new electrocardiographic changes,
and there were no ventricular dysrhythmias
or deaths. The authors suggested that injec-
tion volumes of 0.2 ml are probably safer
than 0.3 ml.
The possibility that stem cells are pro-
dysrhythmic has been reviewed [107R] and
disputed [108R].
Gastrointestinal Nausea and vomiting are
common during infusion of cryopreserved
peripheral blood stem cells, but the symp-
toms were signicantly attenuated by the
use of a strawberry-avored lollipop during
infusion in 158 patients with malignancies
[109c]. Other infusion-related adverse events
were hypoxia, cough, dyspnea, abdominal
cramping, tachycardia, hiccup, fever, chills,
chest pain, hypotension, hypertension, agita-
tion, sore throat, and dysrhythmias.
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[99] Krzakowski M. Epoetin delta: efcacy in
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Lee W, Kang WJ, Koo BK, Kim YJ,
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intracoronary infusion of mobilized
peripheral blood stem cells by granulocyte
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[101] Mansour S, Vanderheyden M, De
Bruyne B, Vandekerckhove B, Delrue L,
Van Haute I, Heyndrickx G, Carlier S,
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[102] Kang HJ, Kim HS, Zhang SY, Park KW,
Cho HJ, Koo BK, Kim YJ, Soo Lee D, [109]
Sohn DW, Han KS, Oh BH, Lee MM,
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RAVEL Study Group. Randomized Study
Chapter 33 689
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 M.C. Allwood and J.K. Aronson

34 Vitamins, intravenous
solutions, and drugs and
formulations used in nutrition

VITAMIN A Vitamin A supplementation in

(CAROTENOIDS) [SED-15, infants at times of immunization
3642; SEDA-31, 548; SEDA-32, 607] The WHO has recommended the use of
high-dose vitamin A supplements at times of
The adverse effects of vitamin A in so-called
immunization after 6 months of age, since it is
tolerable upper intake levels have been
associated with reduced morbidity and mortal-
reviewed [1R]. Chronic hypervitaminosis A
ity [2S, 3C, 4C]. Consequently, the expanded
is relatively rare. Its effects are varied and
programme on immunization has been estab-
non-specic. In adults they include central
lished to provide the opportunity of giving vita-
nervous system effects, skin disorders, con-
min A supplements to young infants [5S, 6S].
junctivitis, nausea, vomiting, teratogenicity,
This has given rise to three concerns: rst,
and hepatotoxicity. In infants and young
whether vitamin A supplementation interferes
children, skeletal and intracranial (e.g. tran-
with immune responses to vaccines; this has
sient bulging fontanelle) abnormalities can
not been shown to be the case [7C, 8C, 9C,
occur. There are conicting data on the risks
10C, 11C, 12C, 13C]; secondly, whether high
of bone fractures from high chronic dosing
doses of vitamin A cause adverse effects during
in industrialized countries.
immunization; the main adverse reaction that
Prolonged high doses of beta-carotene
has been reported is transient bulging of the
can cause carotenodermia, a yellow-orange
anterior fontanelle, which is uncommon and
discoloration of the skin, which is harmless.
not associated with neurological complications
There have been reports of increased fre-
[14C, 15C, 16C, 17C]; thirdly, whether high-
quencies of lung cancer in heavy tobacco
dose vitamin A is associated with increased
smokers and asbestos workers associated
mortality at the time of immunization.
with beta-carotene supplements of 30 and
The effects of vitamin A given with differ-
20 mg/day respectively, but these are very
ent vaccines have been studied in 982 chil-
high doses, exceeding those normally
dren aged 617 months in GuineaBissau,
available in the diet.
who were given DTP or DTP measles
The authors reviewed models for
vaccine and were followed until they were
minimizing the risks of these adverse effects.
18 months of age; 20 died during follow-up
and the mortality rate ratio (MRR) for vita-
min A with DTP measles vaccine or with
DTP was 3.43 (1.36, 8.61) compared with
Side Effects of Drugs, Annual 33 vitamin A alone [18C]. There were no deaths
J.K. Aronson (Editor) among those who received vitamin A with
ISSN: 0378-6080
measles vaccine alone. Children who
DOI: 10.1016/B978-0-444-53741-6.00034-9
# 2011 Elsevier B.V. All rights reserved. received vitamin A with DTP had a higher

691
692
mortality than non-participants who did not
receive vitamin A (3.04; CI 1.31, 7.07).
In 3349 infants randomized to vitamin A
50 000 IU or placebo with BCG immuniza-
tion adverse events were monitored by daily
clinical examinations by a doctor during the
rst 3 days and by weekly interviews by a
trained assistant during the rst month
[19C]. Vitamin A supplementation was asso-
ciated with a relative risk of bulging fonta-
nelles of 1.16 (95% CI 0.82, 1.65). There
were more local reactions to BCG in boys,
but not in girls.
However, concerns have been raised
about the safety of administering high dose
vitamin A supplements to infants less than
6 months of age in developing countries.
The safety and immunogenicity of 15 mg of
retinol equivalents of vitamin A with a
pentavalent vaccine containing diphtheria,
polio, tetanus, Haemophilus inuenzae b,
and hepatitis B at 6, 10, and 14 weeks of
age have been studied in a randomized con-
trolled trial in 1077 infants in the Kintampo
Health Research Centre [20C]. There were
signicantly fewer reports of fever and ill-
nesses in infants who had been given vitamin
A compared with infants in the control
group. However, there were six deaths, ve
in the intervention group and one in the con-
trol group (RR 4.65; CI 0.55, 40).
Although this was not statistically signicant,
because of the large condence interval, the
authors urged caution in giving young
infants high doses of vitamin A with the
pentavalent vaccine.
On the other hand, a systematic review
of six randomized, quasi-randomized, or
cluster-randomized placebo-controlled stud-
ies of the effect of prophylactic neonatal
supplementation with synthetic vitamin A
in developing countries has shown no effect
on mortality (RR 0.92; 95% CI 0.75,
1.12) or morbidity, including bulging fonta-
nelle (RR 1.16; CI 0.81, 1.65) [21M].
Skin The use of topical tretinoin 0.075%
cream once at night to treat mild photo-
ageing in middle-aged Japanese women
was associated with skin irritation in only
Chapter 34 M.C. Allwood and J.K. Aronson
three cases; 0.04% cream for 13 weeks
was less benecial but there was minimal
irritation [22c].
Musculoskeletal The risk of hip and total
fractures has been determined in 75 747
women from the Women's Health Initiative
Observational Study [23C]. After adjust-
ment for covariates such as age, protein,
vitamin D, vitamin K, calcium, caffeine,
and alcohol intake, body mass index use
of therapeutic hormones, smoking, and eth-
nicity, the association between vitamin A
and retinol intake and the risk of fractures
was not statistically signicant. However,
there was an association with the highest
dose of retinol in conjunction with low vita-
min D status. Women with lower vitamin
D intake had a modest increased risk of
total fracture if they were in the highest
quintile of vitamin A intake (HR 1.19;
95% CI 1.04, 1.37) and retinol intake
(HR 1.15; 95% CI 1.03, 1.29).
Drug overdose The hepatotoxicity of
the retinoids is well known. Fulminant
hepatic failure followed an intentional
overdose of acitretin 600 mg, with poor
prognostic criteria at 66 hours after over-
dose, but there was rapid improvement
thereafter and liver transplantation was
not required [24A].
It has been national government policy
in India, via the Integrated Child Develop-
ment Programme, which covers 90% of
rural India, to provide nutrition education
to mothers, nutritional supplements in
physiological doses to children under 6
years of age, and mega-doses of vitamin
A. A total of nine massive doses of syn-
thetic vitamin A are given to children
between the ages of 9 and 60 months.
While the programme undoubtedly
reverses and prevents deciency it has been
criticized on account of the risks of adverse
effects of the high doses of vitamin A
(200 000 units) that are commonly used
[25r].
Vitamins, intravenous solutions, and drugs and formulations used in nutrition
VITAMINS OF THE B
GROUP [SED-15, 2700; SEDA-31,
548; SEDA-32, 608]
Cobalamins
Cardiovascular In 41 healthy volunteers
who received single intravenous doses of
hydroxocobalamin 2.5, 5, 7.5, or 10 g over
7.530 minutes there were transient
increases in blood pressure, which returned
nearly to baseline after 4 hours [26c]. The
changes in mean arterial pressure corre-
lated with changes in plasma total and
unbound cobalamins-(III).
Nervous system Three infants developed
movement disorders during vitamin B12
administration, with a combination of
tremor and myoclonus affecting the face,
tongue, and limbs; in two cases the involun-
tary movements resolved with clonazepam
and in the other with piracetam [27A].
Folic acid
Respiratory Data from experimental ani-
mals suggest that folic acid given to the
mother during pregnancy may be associ-
ated with an increased risk of asthma in
the offspring by an epigenetic effect involv-
ing altered DNA methylation [28E].
In an analysis of data from the Mother and
Child Cohort study in Norway, where foods
are not fortied, wheezing and lower respira-
tory tract infections during the rst 18 months
of life were examined in 32 077 children born
between 2000 and 2005 in relation to mater-
nal reported intake of folic acid 400 mg/day
and cod liver oil 5 ml/day [29C, 30r]. The rela-
tive risks in the infants of mothers who took
folate supplements during the rst trimester
were 1.06 (95% CI 1.03, 1.10) for wheez-
ing, 1.09 (95% CI 1.02, 1.15) for lower
respiratory tract infections, and 1.24 (95%
CI 1.09, 1.41) for hospitalization associ-
ated with lower respiratory tract infections.
Although small, these relative risks were
statistically signicant.
Chapter 34 693
In a study of the effect of the timing,
dose, and source of folate during pregnancy
on childhood asthma, using data from an
Australian prospective birth cohort study
from 1998 to 2005, 490 and 423 mothers
and children took part at 3.5 and 5.5 years
respectively [31c]. Asthma was reported in
12% of children at both 3.5 years (n 57)
and 5.5 years (n 50). Supplementary folic
acid taken during late pregnancy was asso-
ciated at 3.5 years with an increased risk
of childhood asthma (RR 1.26; 95%
CI 1.08, 1.43) and persistent asthma
(RR 1.32; 95% CI 1.03, 1.69). The
effect sizes did not change with adjustment
for potential confounders. The association
was similar at 5.5 years but did not reach
statistical signicance (RR 1.17; 95%
CI 0.96, 1.42).
In contrast, in 8083 women of childbear-
ing potential in the 20052006 US National
Health and Nutrition Examination Survey,
higher serum folate concentrations were
associated with a lower risk of high total
serum IgE concentrations, atopy, and
wheezing [32C]. There was a doseresponse
relationship between higher serum folate
concentrations and lower risks of these out-
comes, and the associations were indepen-
dent of age, sex, race/ethnicity, and poverty.
Immunologic Hypersusceptibility reactions
to folic acid are very rare, but new cases
have been reported [33A].
A 42-year-old woman developed generalized
urticaria and dyspnea 2 hours after taking a
folic acid-containing supplement; 2 years
before she had taken folic acid for 2 months
without any symptoms. Skin prick tests were
positive for the supplement and one of its
ingredients, folic acid, but not any other ingre-
dients, including riboavin, biotin, niacin, thia-
mine, pyridoxine hydrochloride, pantothenate
calcium, or yeast. There was also a positive
reaction to methotrexate, but not to folinic
acid. Folic acid and methotrexate stimulated
basophils to release signicant amounts of
histamine, but folinic acid did not.
A 72-year-old woman developed urticaria
after taking folic acid, 400 micrograms/day
for 2 years. Folic acid was withdrawn, and a
few days later the urticaria disappeared. Intra-
dermal tests with folic acid 1 and 5 mg/ml were
694
negative, but single-blind oral challenge tests
with increasing doses of folic acid at 30-minute
intervals (0.25, 0.50, and 1 mg) were positive.
Ten minutes after the 1-mg dose she devel-
oped red pruriginous wheals and 2 hours later
generalized urticaria, facial and lingual edema,
and bilateral conjunctival congestion. Folic
acid-specic IgE was not detected. Three
weeks after the folic acid challenge, a single-
blind parenteral challenge test with intramus-
cular folinic acid 50 mg/5 ml was performed;
after 1 hour she developed a red pruriginous
macule over her torso. There were no reac-
tions at the site of injection.
Tetrahydrobiopterin and
sapropterin [SEDA-32, 609]
Observational studies In 80 patients aged
at least 8 years, who had taken part in a
6-week, randomized, placebo-controlled
study of sapropterin, and who were
enrolled in a 22-week, multicenter, open,
extension study there were dose-related
reductions in plasma phenylalanine concen-
trations from 844 to 645 mmol/l; 68 patients
had at least one adverse event, all but one
of which were mild or moderate in intensity
[34c]. Neither the one severe event nor any
of the three serious events was considered
related to sapropterin. No adverse event
led to treatment withdrawal.
VITAMIN C (ASCORBIC
ACID) [SED-15, 351; SEDA-30, 394;
SEDA-31, 548; SEDA-32, 611]
Cardiovascular In a systematic review of
seven studies of the effect of combined vitamin
C and vitamin E supplements in 5969 preg-
nant women at risk of pre-eclampsia, of whom
2982 received vitamin C vitamin E and
2987 received placebo, there were increased
risks of gestational hypertension (RR 1.3;
95% CI 1.08, 1.57) and low birth weight
Chapter 34 M.C. Allwood and J.K. Aronson
(RR 1.13; 95% CI 1.004, 1.27) [35M].
Pre-eclampsia (RR 0.7; 95% CI 0.58,
1.08) and preterm delivery (RR 1.12; 95%
CI 0.96, 1.32) were not affected.
Sensory systems Vision In a prospective
study of the effect of high doses of vitamin
C supplements (about 1 g/day) and multi-
vitamins containing vitamin C (about
60 mg/day) on the risk of age-related cata-
racts in 24 593 women aged 4983 years
(184 698 person-years of follow up) the mul-
tivariable hazard ratio for vitamin C users
compared with non-users was 1.25 (95% CI
1.05, 1.50) [36C]. The hazard ratio for
those who had used vitamin C for over 10
years was 1.46 (95% CI 0.93, 2.31). The
hazard ratio for the use of multivitamins con-
taining vitamin C was 1.09 (95% CI 0.94,
1.25). Vitamin C supplements increased the
risk of cataract by 38% among women aged
at least 65 years, by 56% among those who
used hormone replacement therapy, and by
97% among glucocorticoid users.
Urinary tract Vitamin C can rarely cause
nephrotoxicity due to oxalate crystal deposi-
tion. This can be fatal, as in the case of a
patient who chose to forgo treatment and
failed to disclose his use of high-dose vita-
min C; intra-renal oxalate crystal deposi-
tion was demonstrated at autopsy [37A].
Infection risk The effects of vitamin E and
beta-carotene supplements on the risk of
tuberculosis have been studied using data
from the Alpha-Tocopherol Beta-Carotene
Cancer Prevention (ATBC) Study, a
6-year, randomized, controlled trial in
which the effects of vitamin E (50 mg/day)
and beta-carotene (20 mg/day) on lung can-
cer were studied in Finland in 19851993 in
29 023 male smokers aged 5069 years, at
baseline [38C]. Vitamin E supplementation
had no overall effect on the incidence of
tuberculosis (RR 1.18; 95% CI 0.87,
1.59) and neither had beta-carotene (RR
1.07; 95% CI 0.80, 1.45). However,
dietary vitamin C signicantly modied
the vitamin E effect. Among participants
Vitamins, intravenous solutions, and drugs and formulations used in nutrition
who took vitamin C 90 mg/day or more in
food (n 13 502), vitamin E supplementa-
tion increased the risk of tuberculosis by
72% (95% CI 4, 185). This effect was
restricted to participants who smoked
heavily. The authors concluded that vita-
min E transiently increased the risk of
tuberculosis in those who smoked heavily
and had a high dietary intake of vitamin
C. However, confounding factors were not
ruled out [39r].
In 21 657 participants in the Alpha-Tocoph-
erol Beta-Carotene Cancer Prevention
(ATBC) Study vitamin E supplementation
had no effect on the risk of pneumonia in those
whose body weights were 7089 kg (n 12
495; RR 0.99; 95% CI 0.81, 1.22), but
increased the risk of pneumonia in those who
weighed under 60 kg (n 1054; RR 1.61;
CI 1.03, 2.53) and in those who weighed
over 100 kg (n 1328; RR 2.34;
CI 1.07, 5.08); these effects were restricted
to those with dietary vitamin C intakes above
the median [40C].
VITAMIN D ANALOGUES
[SED-15, 3669; SEDA-30, 394;
SEDA-31, 549; SEDA-32, 612]
Systematic reviews In a systematic review
of 23 randomized controlled trials of the
effects of calcitriol and alfacalcidol on the
risks of fractures and fall in 2139 partici-
pants, of which 16 trials had sufcient
data for meta-analysis, vertebral fractures
were not signicantly reduced, although
subgroup analyses showed a signicant
reduction with alfacalcidol (13 trials; OR
0.50; 95% CI 0.25, 0.98) [41M]. There
was a signicant reduction in non-vertebral
fractures (six trials; OR 0.51; 95% CI
0.30, 0.88), and falls (two trials; OR
0.66; 95% CI 0.44, 0.98). There was
an increased risk of hypercalcemia (OR
3.63; 95% CI 1.51, 8.73) and a trend
toward an increased risk of hypercalciuria.
Chapter 34 695
In contrast, a systematic review of dou-
ble-blind randomized controlled trials,
eight dealing with falls (n 2426) and 12
with non-vertebral fractures (n 42 279),
there was a signicant doseresponse rela-
tion between the dose of 25-hydroxycole-
calciferol and prevention of falls and
fractures and no association between serum
25-hydroxycolecalciferol concentrations of
75110 nmol/l and serum calcium concen-
trations [42M]. The authors suggested
that the ideal oral dose of 25-hydroxycole-
calciferol is in the range of 18004000 IU/
day.
Mineral metabolism Milk-alkali syndrome
(hypercalcemia, metabolic alkalosis, and
impaired kidney function) has been
reported in an 85-year-old Japanese woman
who had taken oral alfacalcidol plus large
doses of magnesium oxide without calcium-
containing drugs or supplements [43A]. She
had severely impaired renal function (serum
creatinine 386 mol/l; eGFR 10 ml/minute/
1.73 m2), hypercalcemia (serum calcium
3.62 mmol/l), hypermagnesemia (serum
magnesium 4.20 mmol/l), and a metabolic
alkalosis (pH 7.445; serum bicarbonate
36 mmol/l). She responded to uid replace-
ment and furosemide. The coexistence of
hypercalcemia and hypermagnesemia in this
case was unusualthe syndrome tends to
present with hypomagnesemia. The authors
suggested that the syndrome should be
renamed calciumalkali syndrome, although
they confusingly ended by pointing out that
the syndrome can be caused by factors other
than ingestion of large amounts of calcium
and alkali.
Immunologic A leukocytoclastic vasculitis
has been attributed to cinacalcet in an 80-
year-old woman on maintenance hemodial-
ysis therapy [44A]. After taking cinacalcet
for 3 days she developed palpable purpura
on all four limbs, which resolved after with-
drawal of cinacalcet and administration of
glucocorticoids.
696
VITAMIN E
(TOCOPHEROL) [SED-15, 3677;
SEDA-30, 395; SEDA-31, 549;
SEDA-32, 612]
Cardiovascular See also Vitamin C.
There are discordant results between the
effects of vitamin E supplements in obser-
vational studies, in which they seem to
reduce the risk of cardiovascular disease,
and the results of interventional studies, in
which they seem to have the opposite
effect. In an extensive review of the bene-
ts and adverse effects of vitamin E, the
authors, employees of IdeaSphere Inc.,
which markets vitamins and nutrients, con-
cluded that healthy consumers should not
change their current use of vitamin E sup-
plements since most of the studies
included in the three recent neutral to unfa-
vorable meta-analyses were not conducted
on free-living healthy individuals . . . [and]
only four of 28 studies included in these
meta-analyses involved healthy individ-
uals [45R]. They urged that the guidelines
set forth by the Institute of Medicine [in
2000] should still be embraced and that
healthy individuals should not use more
than 1000 mg of vitamin E daily. They
concurred with the ndings of the HOPE
study, a randomized, placebo-controlled
study of the use of vitamin E 400 IU/day
over 7 years [46C], that vitamin E did not
prevent cancer or major cardiovascular dis-
ease events in subjects with pre-existing
vascular disease or diabetes mellitus, and
may have increased the risk of heart failure,
and that, as the authors of the HOPE study
concluded, such individuals should be
warned to beware of natural products.
However, the possibility that the differ-
ences between observational studies and
interventional studies may be due to differ-
ences between healthy subjects and those
with pre-existing cardiovascular disease
has not been supported by the results of a
Framingham Study in 4270 subjects strati-
ed by baseline cardiovascular disease
status [47C]. In those with pre-existing car-
diovascular disease, there were 28 (44%)
Chapter 34 M.C. Allwood and J.K. Aronson
and 20 (32%) incident cases of cardiovascu-
lar disease and all-cause mortality in the
vitamin E supplement users versus 249
(47%) and 202 (38%) respectively in the
non-users. In those without pre-existing
cardiovascular disease there were 51
(13%) and 47 (12%) cases of cardiovascu-
lar disease and all-cause mortality in the
vitamin E supplement group versus 428
(13%) and 342 (10%) respectively in the
non-vitamin E supplement group. The
authors concluded that cardiovascular dis-
ease status has no effect on the risks of sup-
plementation with vitamin E.
Infection risk See Vitamin C.
Death In a Bayesian meta-analysis of stud-
ies that had previously been included in
meta-analyses of the relation between dose
of vitamin E and all-cause mortality there
was no evidence of an increases risk in
those taking vitamin E [48M]. The weak-
nesses of the Bayesian approach have been
discussed [49r], as have problems with other
types of meta-analysis [50M].
Teratogenicity In a casecontrol study in
276 mothers of children with congenital
heart defects and 324 control mothers with
healthy children, dietary vitamin E intake
was higher in the former and the risk
increased with increasing dietary vitamin
E intake [51C]. Retinol intake was not sig-
nicantly different between the groups
and was not associated with a risk of con-
genital heart defects.
Drugdrug interactions Vitamin K The
mechanism by which vitamin E interferes
with vitamin K activity is not known, but
it has been hypothesized that it involves
vitamin K metabolism [52R]. Phylloquinone
(vitamin K1) is converted to menaquinone,
the most potent extrahepatic form of vita-
min K by truncation of the side chain and
replacement with geranylgeranyl. Possible
mechanisms for the interaction of vitamin
E with vitamin K include: competition for
the as yet undiscovered enzyme that trun-
cates the K1 side chain; competition with
vitamin K1 for the hypothetical CYP
Vitamins, intravenous solutions, and drugs and formulations used in nutrition
isoenzyme that omega-hydroxylates the K1
side chain, thereby preventing its beta-oxi-
dation and its conversion to menaquinone;
increased hepatic metabolism and excretion
of all forms of vitamin K.
Warfarin In a Canadian survey of the pre-
valence of the use of complementary and
alternative medicines (CAM) among
patients taking warfarin and of the effect
on the risk of warfarin-related adverse
effects, 314 patients completed the survey,
of whom 139 (44%) reported using CAM
at least weekly [53C]. Potentially interacting
medicines were used by 107 (34%) of the
respondents, or 57 (18%) respondents if
vitamin E was excluded. Vitamin E was used
by 76 (24%) of all respondents, or 71% of
those who used potentially interacting med-
icines. It was recommended that health-care
professionals should stay abreast with the
literature on complementary and alternative
medicines and routinely query the use of
these and other non-prescription products
when documenting medication histories of
patients taking warfarin.
PARENTERAL NUTRITION
[SED-15, 2700; SEDA-31, 549;
SEDA-32, 613]
Cardiovascular In a study of the risk of pul-
monary embolism in 64 patients aged 3
months to 22 years. receiving parenteral
nutrition, 25 (39%) had an abnormal ventila-
tionperfusion scan and 29 episodes of pul-
monary embolism were diagnosed. The
median age at time of diagnosis was 4.6 years
[54C]. Pulmonary embolism was bilateral in
56% and unilateral in 44% and was the main
cause of two of 15 recorded deaths.
Respiratory A unilateral pleural effusion
occurred during parenteral nutrition in an 8-
week-old preterm boy because of intra-
Chapter 34 697
abdominal extravasation of parenteral uid
with leakage into the pleural cavity [55A].
Bilateral pleural effusions and respira-
tory distress have also been reported [56A].
A 79-year-old Japanese woman with advanced
gastric carcinoma developed dyspnea and a
massive right-sided pleural effusion during
postoperative nutritional management. Her
symptoms resolved after thoracentesis, but
she again developed severe respiratory dis-
tress and required mechanical ventilation.
The tip of the central venous catheter had
become displaced out of the wall of the
superior vena cava, causing mediastinitis and
leakage of intravenous uid. The patient
recovered after removal of the catheter.
In a prospective survey of 2346 patients
aged 16 years and over who underwent
mechanical ventilation within the rst
48 hours of admission after trauma, 404
(17%) were exposed to parenteral nutrition
and 192 (8.2%) met criteria for late adult
respiratory distress syndrome (ARDS)
[57C]. The incidence of late ARDS among
those exposed to parenteral nutrition was
29% (116/404) compared with 3.9%
(76/1942) among those not so exposed. The
authors concluded that parenteral nutrition
is independently associated with late ARDS.
Metabolism Exposure to light of total par-
enteral nutrition solutions increases oxida-
tion products such as lipid peroxides and
hydrogen peroxide and oxidative stress
impairs glucose uptake and affects lipid
metabolism [58c]. In a secondary analysis
of a prospective study in which preterm
infants were allocated to light-exposed
(n 32) or light-protected (n 27) paren-
teral nutrition solutions, blood glucose was
higher and accumulation of triglycerides
with increasing lipid intake was twice as high
in those who received the light-exposed solu-
tions. The authors concluded that shielding
parenteral nutrition solutions from light pro-
vides a potential benet for preterm infants
by avoiding hypertriglyceridemia and allow-
ing increased substrate delivery.
Hyperglycemia has been reported in two
children who developed severe insulin
resistance requiring intravenous insulin
698
therapy at doses up to 13 units/kg/hour dur-
ing parenteral nutrition [59A]. In 276
patients who received parenteral nutrition
for a mean of 15 days, after adjustment
for age, sex, and diabetes status, mortality
was independently predicted by pretreat-
ment blood glucose concentrations of
6.728.33 mmol/l (OR 2.2; 95% CI
1.1, 4.4), 8.349.99 mmol/l (OR 3.41;
CI 1.3, 8.7), and 10 mmol/l or over (OR
2.2; CI 0.9, 5.2) and by blood glucose
concentrations within 24 hours of 10 mmol/l
or over (OR 2.8; CI 1.2, 6.8) [60c]. A
blood glucose concentration 10 mmol/l or
over within 24 hours was associated with
increased risks of pneumonia (OR 3.1;
95% CI 1.4, 7.1) and acute renal insuf-
ciency (OR 2.3; CI 1.1, 5.0).
Metabolomics of the urine from an 8-
year-old patient with epilepsy and an 11-
year-old patient with malignant lymphoma
who was being treated with methotrexate,
both of whom were receiving parenteral
nutrition, showed identical metabolic pro-
les to that of phenylketonuria [61A]. Neop-
terin concentrations were markedly raised
and in one case the biopterin concentration
was also above normal. The metabolic pro-
les were normal when they were not
receiving parenteral nutrition.
Mineral metabolism Refeeding hypophos-
phatemia is a risk during parenteral nutri-
tion. In 70 patients with refeeding
hypophosphatemia who were matched with
controls the independent susceptibility fac-
tors were: signicant malnutrition; a dose
of less than 12 mmol of total phosphate
during the rst day; and an initial rate of
infusion of more than 70% of calculated
requirements [62C]. Increasing amounts of
non-lipid phosphate in the rst day's regi-
men were protective.
Metal metabolism Aluminium toxicity dur-
ing parenteral nutrition has been studied ret-
rospectively in 36 adults with impaired renal
function, of whom 12 received hemodialysis
[63c]. Mean aluminium exposure was
3.8 micrograms/kg/day in the 36 patients.
Of these, 29 had safe calculated aluminium
exposure (less than 5 micrograms/kg/day)
Chapter 34 M.C. Allwood and J.K. Aronson
and seven had high exposure (over 5 micro-
grams/kg/day). The former had signicantly
higher serum creatinine concentrations.
The authors concluded that most patients
with acute kidney damage who require par-
enteral nutrition do not receive excessive
exposure to aluminium.
Bone area and bone mineral content were
measured in the lumbar spine, hip, and
whole body with dual radiograph absorpti-
ometry in 59 children aged 1315 years who
were born preterm and randomly assigned
standard or aluminium-depleted parenteral
nutrition solutions during the neonatal
period [64c]. Those who were randomly
assigned to standard parenteral nutrition
had lower lumbar spine bone mineral con-
tent, explained by a reduction in bone size.
Those who were exposed to neonatal alu-
minium intakes above the median (55 micro-
grams/kg) had lower hip bone mineral
content (by 7.6%; 95% CI 0.12, 14) inde-
pendent of bone or body size.
Liver In a 5-day, randomized, double-blind
comparison of the effects of structured tri-
glycerides, a mixture of medium- and
long-chain triglycerides, and an emulsion
of long-chain triglycerides on liver function
in 45 patients undergoing abdominal sur-
gery, the structured triglycerides were asso-
ciated with preserved liver function,
whereas both of the other formulations
caused subclinical hepatic damage [65C].
The role of phytosterols in the hepato-
toxicity of parenteral nutrition has been
studied in 27 adults [66c]. Total plasma
phytosterol concentrations correlated with
total bilirubin and aspartate aminotransfer-
ase activity. A poor oral diet and the
infused dose of phytosterols were suscepti-
bility factors. Biopsies showed moderate
to severe liver impairment in ve patients.
Progression of liver disease during par-
enteral nutrition in two infants with intesti-
nal failure was rapidly exacerbated by
ischemic liver damage [67A].
In a prospective study of 994 patients who
required parenteral nutrition, hepatic dys-
function was identied by a greater than 1.5-
fold increase above of the top reference range
Vitamins, intravenous solutions, and drugs and formulations used in nutrition
of alkaline phosphatase (40450 U/l) and
gamma-glutamyltranspeptidase (1149 U/l)
associated with increased aminotransferases
(532 U/l) and a total bilirubin over
20 mmol/l [68C]. The incidence of hepatic
dysfunction was 4.9% (n 49). The sus-
ceptibility factors were the critical patient
condition, the duration of parenteral nutri-
tion, and a total calorie contribution over
25 kcal/kg, specically carbohydrates in
excess of 3 g/kg, lipids 0.8 g/kg, and nitrogen
0.16 g/kg.
Currently approved parenteral lipid
emulsions generally contain safower or
soybean oils, which are both rich in
omega-6 polyunsaturated fatty acids, which
may contribute to liver damage [69R]. Fish
oil-based lipid emulsions, which are primar-
ily composed of omega-3 polyunsaturated
fatty acids, have been used to reduce hepa-
totoxicity (see also biliary tract below).
Biliary tract In a study of 66 infants with
cholestasis associated with parenteral nutri-
tion, there were 10 deaths and one referral
for liver transplant in the rst year of life,
all of whom had at least one positive blood
culture after the onset of cholestasis [70c].
Maximum conjugated bilirubin in these 11
infants was 270 mmol/l, compared with
145 mmol/l in babies who recovered. A max-
imum conjugated bilirubin concentration
over 170 mmol/l was a susceptibility factor
for death or transplantation.
In a 2-year retrospective study of liver
damage and cholestasis in premature
babies with cholestasis associated with par-
enteral nutrition, 17 received ursodeoxy-
cholic acid and 7 did not [71c]. In the
treated group there were signicant reduc-
tions in gamma-glutamyltranspeptidase
activity and conjugated bilirubin after 45
weeks of treatment. There was a signicant
correlation between conjugated bilirubin
and duration of total parenteral nutrition.
The susceptibility factors for cholestasis
associated with parenteral nutrition have
been studied in 62 premature infants in a
neonatal intensive care unit, of whom 11
(18%) developed cholestasis [72c]. There
were signicant differences in terms of
Chapter 34 699
gestational age, weight at birth, duration of
parenteral nutrition, septic episodes, and
average energy intake during the second
and third weeks of life between those with
and without cholestasis; the duration of par-
enteral nutrition was most signicant factor.
A sh oil-based intravenous lipid emul-
sion in the treatment of liver disease associ-
ated with parenteral nutrition has been
compared with soybean oil in an open
study in 42 infants with short-bowel syn-
drome who developed cholestasis [73c].
There were three deaths and one liver
transplantation in those who received the
sh oil, compared with 12 deaths and 6
transplants in those who received soybean
oil. The sh oil was not associated with
hypertriglyceridemia, coagulopathy, or
deciency of essential fatty acids.
In another study a lipid emulsion based
on soybean oil, medium-chain triglycerides,
and olive and sh oil was compared with
one based on olive and soybean oil in a
double-blind, randomized trial in 44 post-
operative patients [74C]. On days 2 and 5,
there were signicantly lower aminotrans-
ferase and alpha-glutathione S-transferase
activities with the former.
Musculoskeletal When 45 patients using
parenteral nutrition at home were asked
about adverse reactions to their treatment
they reported that muscle cramps were the
most common minor adverse reaction (12/
45; 27%); the frequency in patients with
inammatory bowel disease was 24%
[75c]. The cramps were of sufcient severity
to warrant pharmacological intervention in
nine patients.
Skin A rash with subsequent urticaria in an
infant receiving parenteral nutrition, con-
rmed by positive rechallenge, resolved
after the amino acid solution was replaced
with a non-bisulte-containing product
[76A]. The authors speculated that the
bisulte additive in the amino acid solution
may have interacted with the lipid emulsion
to sensitize the patient.
Infection risk In a study of biolms and
micro-organisms adhering to 39 central
700
venous catheters used for parenteral nutri-
tion in patients with and without clinical
signs of infection, those with signs of infec-
tion had more positive cultures [77c]. How-
ever, scanning electron microscopy showed
that there were biolms in all catheters
used, and 55% of them showed structures
that suggested central venous catheters
colonization by micro-organisms. About
53% of the catheter infections evolved to
systemic infections, conrmed by blood
cultures.
The epidemiology of catheter-related
bloodstream infections during parenteral
nutrition has been reviewed [78R]. They
occur in 1.326% of patients with central
venous catheters used to administer.
Contamination during preparation and
handling is rare in hospitals and home-infu-
sion pharmacies but may be difcult to
control in the home. The risk of infection
is increased in hospitalized patients because
of immunosuppression associated with mal-
nutrition, hyperglycemia exacerbated by
dextrose infusion, microbial colonization/
contamination of catheter hubs and the
skin surrounding insertion site, and poor
nursing care. During long-term catheter
use, an intraluminal biolm, catheter-tip
brin sheath or tail, or central venous throm-
bosis creates sites for microbial seeding and
infection. In hospital the most common infec-
tive organisms are coagulase-negative staphy-
lococci, Staphylococcus aureus, Enterococcus,
Candida spp., Klebsiella pneumoniae, and
Pseudomonas aeruginosa. In patients receiv-
ing long-term parenteral nutrition, about
60% of catheter-related bloodstream infec-
tions are caused by coagulase-negative
staphylococci.
Parenteral nutrition was a susceptibility
factor for central venous catheter-related
bloodstream infections in 109 patients who
received chemotherapy after surgery for
colorectal cancer for a total of 5558 cathe-
ter-days in a retrospective database evalua-
tion (OR 13; 95% CI 2.5, 62).
Similarly, early administration of paren-
teral nutrition after severe injury was asso-
ciated with an increased risk of
nosocomial infections in a retrospective
cohort study of 567 patients, of whom 95
Chapter 34 M.C. Allwood and J.K. Aronson
(17%) received early parenteral nutrition
(RR 2.1; 95% CI 1.6, 2.6); mortality
tended to be higher in patients who
received additional enteral nutrition and
parenteral nutrition versus enteral nutrition
alone (RR 2.3; 95% CI 1.0, 5.2) [79c].
Catheter-related sepsis is the most fre-
quent complication in patients receiving
home parenteral nutrition for short bowel
syndrome. A low-grade systemic inamma-
tory state and an altered mucosal immune
response, as well as diminished intestinal
barrier function have been characterized
in these patients. The possibility of systemic
immunocompromise has only recently been
suggested.
Catheter-related sepsis in patients on
parenteral nutrition is usually caused by
Gram-positive or Gram-negative bacteria
or by Candida species. However, other
organisms can be involved in patients who
are immunocompromised [80A].
A 45-year-old woman with short-bowel syn-
drome, asplenia, and insulin-dependent diabe-
tes mellitus developed catheter-related sepsis
with a large skin ulcer on the left calf. A chest
X-ray and a CT scan showed multiple sub-
pleural pulmonary inltrates consistent with
bacterial or fungal dissemination. Blood cul-
tures from the catheter port and the periph-
eral blood grew Staphylococcus haemolyticus
and Fusarium oxysporum. The catheter was
removed, and she was given ucloxacillin and
voriconazole. The sepsis resolved slowly.
ENTERAL NUTRITION
[SED-15, 1221; SEDA-30, 396]
Metabolism Refeeding syndrome is nor-
mally associated with large calorie loads
delivered by parenteral or enteral feeding.
Acute respiratory failure has been attrib-
uted to refeeding syndrome induced by
hypocaloric enteral tube feeding [81c].
A 60-year-old man with esophageal carcinoma
and local metastases was fed via a jejunal tube
at a rate of 4.4 kcal/kg/day, increased over 2
days to 27 kcal/kg/day. By day 4 his serum
Vitamins, intravenous solutions, and drugs and formulations used in nutrition
potassium, magnesium, and phosphate had
fallen to below normal, the last being particu-
larly low. He developed abdominal pain and
acute respiratory failure. Intravenous therapy
successfully normalized the serum electrolytes
over the next 4 days, and enteral feeding was
restarted 36 hours after ITU admission. He
was gradually weaned from the ventilator.
Refeeding syndrome is a series of meta-
bolic complications linked to articial nutri-
tional support in patients who are severely
malnourished, with conditions such as
kwashiorkor, chronic malnutrition, or
anorexia nervosa. This study shows that
even hypocaloric feeding should be consid-
ered a susceptibility factor for the refeeding
syndrome.
The prevalence of undiagnosed diabetes
mellitus in elderly patients received enteral
nutrition was 21%; in 79% of them hemo-
globin A1c concentrations were over 7%,
and in 24% over 8% [82c].
Skin An allergic skin reaction to casein and
soy has been described [83A].
A 13-year-old girl who had had skin lesions on
her limbs for 12 years was found to be allergic
to the enteral feeding formulation that she had
received during that time (Ensure Liquid;
Abbott Japan Co, Ltd, Tokyo, Japan), which
contains casein and soy. Patch, prick, and
scratch patch tests with Ensure Liquid,
casein, and soy were all negative, as was a
radioallergosorbent test for immunoglobulin
E to both casein and soy. However, a drug-
induced lymphocyte stimulating test was
strongly positive with Ensure Liquid (stimulat-
ing index of 316%), casein (471%), and soy
(378%). In addition, challenge tests by oral
provocation with all three items were positive.
The skin lesions disappeared without any
other treatment after changing from Ensure
Liquid to another enteral nutrition formula-
tion containing neither casein nor soy.
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Chapter 34 701
Infection risk Patients with severe acute
pancreatitis are always at a high risk of
infectious complications, which contributes
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function appears to lead to local and sys-
temic infectious complications. Enteral
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35 Drugs that affect blood
coagulation, brinolysis,
and hemostasis
Editors note: The clotting factors and anti-
coagulant proteins are included in Chapter
33.
COUMARIN
ANTICOAGULANTS [SED-15,
983; SEDA-30, 399; SEDA-31, 553;
SEDA-32, 617]
Cardiovascular The incidence of mitral and
aortic valve calcication has been studied in
1155 patients with atrial brillation, of
whom 725 were taking warfarin [1c]. There
was a signicant association between the
use of warfarin and the risk of calcication
(unadjusted OR 1.71; 95% CI 1.34,
2.18), and the association remained after
adjustment for confounding factors.
In contrast, in a cross-sectional analysis
of the extent of coronary artery calcication
in 70 patients without coronary heart dis-
ease, currently taking or referred for warfa-
rin therapy, univariate analysis showed a
non-signicant trend to increased coronary
artery calcication with increasing warfarin
Side Effects of Drugs, Annual 33
J.K. Aronson (Editor)
ISSN: 0378-6080
DOI: 10.1016/B978-0-444-53741-6.00035-0
# 2011 Elsevier B.V. All rights reserved.
J.K. Aronson
exposure, but bivariate analysis showed no
correlation between warfarin duration and
coronary artery calcication [2c].
Calciphylaxis, a rare, usually fatal disor-
der characterized by cutaneous ischemia
and necrosis due to calcication of arterioles,
has been described in a 63-year-old Poly-
nesian woman who was taking warfarin
[3A]. Enoxaparin was used instead and after
40 sessions of hyperbaric oxygen therapy her
leg ulcers resolved. The authors attributed
the calciphylaxis in this case to warfarin.
Respiratory Respiratory complications can
occur due to bleeding in patients taking
warfarin. An 84-year-old woman developed
hemoptysis due to diffuse alveolar hemor-
rhage when her INR rose to 6 during treat-
ment with phenprocoumon [4A] and an
83-year-old woman with an INR of 10
developed upper airway obstruction due to
hemorrhage in the epiglottis and arytenoid
cartilages [5A].
Nervous system The association between
cerebral microbleeds and the risk of recur-
rent hemorrhagic stroke in patients who
have taken warfarin after cerebral embolic
strokes associated with atrial brillation
has been studied in 87 patients [6c]. Micro-
bleeds were more common in patients with
intracerebral hemorrhage than in those
with cerebral infarction (87% versus 39%)
and there were more of them per patient
(8.4 versus 2.1). The mean INR was higher
in patients with intracerebral hemorrhage
(2.2 versus 1.4), as was the frequency of
707
708
hypertension (87% versus 46%). Multivari-
ate analysis showed that the presence of
cerebral microbleeds (OR 7.38; 95% CI
1.05, 52) was associated with intracere-
bral hemorrhage independent of an
increased INR and hypertension.
Similarly, among 24 patients more of
those with intracerebral hemorrhage had
microbleeds than the controls (79% versus
23%) and there were more microbleeds in
each patient (9.0 versus 0.5) [7c]. The num-
ber of microbleeds correlated signicantly
with the presence of warfarin-related intra-
cerebral hemorrhage. Conditional logistic
regression analysis showed that increased
prothrombin time and the presence of
microbleeds were independently related to
the incidence of warfarin-related intracere-
bral hemorrhage.
In contrast, in 141 patients with ischemic
strokes taking warfarin therapy and 105
controls, there were cerebral microbleeds
in 31 patients (22%) and 17 controls
(16%), a non-signicant difference [8c].
Sensory systems Eyes A spontaneous hy-
phema has been attributed to over-anti-
coagulation with warfarin [9A].
The risk of subconjunctival hemorrhages
in patients taking warfarin has been
assessed in a retrospective chart review of
4334 patient visits over 2 years; there were
15 events, giving an event rate of 0.35%
[10c].
Nutrition The effect of warfarin therapy
for 6 months on folate status has been stud-
ied in 114 patients, using measurements of
erythrocyte folate and 5-methyltetrahydro-
folate and plasma folate, total homocyste-
ine, phylloquinone, vitamin B12, and
methylmalonic acid [11c]. There were sig-
nicant falls in total erythrocyte folate and
5-methyltetrahydrofolate and a concurrent
increase in plasma phylloquinone, attrib-
uted to altered vitamin K metabolism.
Hematologic Rebound coagulation after
warfarin withdrawal is supposed not to be
a major risk, since the action of warfarin is
only slowly reversible. However, rapid
occurrence of an intraluminal thrombus
Chapter 35 J.K. Aronson
and secondary myocardial ischemia has
been described after a brief period of with-
drawal of warfarin in a 15-year-old with a
Kawasaki-related chronic giant coronary
aneurysm [12A]. In another case splenic
infarction occurred after withdrawal of war-
farin for atrial brillation [13A].
Liver In 30 patients with suspected phen-
procoumon-induced liver disease periph-
eral blood mononuclear cells were
subjected to an in vitro lymphocyte trans-
formation test for reactivity with phenpro-
coumon; 15 had sensitized lymphocytes
[14c]. One of 20 controls, who either had
not taken phenprocoumon or had taken it
without adverse reactions, had sensitized
lymphocytes. The authors suggested that
immune mechanisms may play a part in
phenprocoumon-induced liver disease.
Urinary tract The pathological ndings in
kidney biopsy specimens from nine patients
with warfarin overdose (mean INR 4.4),
hematuria, and acute kidney damage have
been reported [15c]. In each case there
was evidence of acute tubular damage, glo-
merular hemorrhage, and chronic kidney
damage.
Skin Skin necrosis due to warfarin has
been reviewed, emphasizing the occasional
difculty that can arise in diagnosis; skin
biopsy typically shows diffuse dermal
microthrombi with endothelial cell damage
and red cell extravasation, with progression
to full-thickness coagulative necrosis
[16AR].
Two patients, a 60-year-old man and a
51-year-old woman, developed dark purple
lesions on the arms and legs distal to the
elbows and knees after taking warfarin for
a few days; the authors hypothesized that
these lesions were precursors of skin necro-
sis [17A]. However, it has also been sug-
gested that purple toes in patients taking
warfarin are due to microembolism of cho-
lesterol crystals in small blood vessels [18A].
Musculoskeletal In a casecontrol survey
of bone density in 70 patients taking warfa-
rin, there was a marked reduction in bone
Drugs that affect blood coagulation, brinolysis, and hemostasis
mineral density in the lumbar spine com-
pared with 103 randomly selected matched
controls; duration of warfarin use was the
only susceptibility factor of signicant
importance [19c].
Death In a retrospective review of 27 812
patients admitted to trauma centers, 2791
were aged 65 or over and had fallen from
a standing position; the use of warfarin
(mean INR 2.8) increased the risk of death
after such falls (OR 1.54; 95% CI 1.09,
2.19), the deaths being attributed to head
injuries [20c].
Teratogenicity A 35-year-old woman took
warfarin 9 mg/day for 17 weeks before real-
izing that she was pregnant, when she
stopped taking it; she gave birth at full term
to a girl with bilateral corneal opacities and
microphthalmia, which the authors thought
was most probably due to warfarin, even
though the child had no other features of
warfarin embryopathy, such as optic atro-
phy, cataracts, large prominent eyes, small
eyelids, hypertelorism, small orbital arches,
palpebral ptosis, mesodermal dysgenesis,
antimongoloid slants, Peters anomaly,
optic nerve dysfunction, and goniodysgen-
esis [21A].
Fetotoxicity Although warfarin can be
used for anticoagulation during the second
and early third trimesters of pregnancy, it
can occasionally cause fetal hemorrhage,
as has again been reported [22A, 23A].
Susceptibility factors Genetic In a system-
atic review of randomized trials of geno-
type-guided dosing of warfarin in reducing
the occurrence of serious bleeding events
and over-anticoagulation, three studies
(423 patients) met the inclusion and exclu-
sion criteria [24M]. Summary estimates
showed no statistically signicant difference
in bleeding rates or time within the INR
target range. The highest quality study
showed no signicant difference in primary
or secondary outcomes, although there was
a trend towards more rapid achievement of
a stable dose (14 versus 20 days) in the
pharmacogenetic arm.
Chapter 35 709
Decision-tree modeling to simulate the
effects of genotype-guided dosing accord-
ing to CYP2C9 and VKORC1 genotyping
has shown that it is not a cost-effective
strategy, with mean ICERs of US$347 059
per QALY gained, $170 192 per adverse
event averted, and $1 106 250 per life
saved [25M]. Monte Carlo simulations
showed that 62% of the time the ICER
per QALY gained was over $50 000. The
authors concluded that the cost-effective-
ness of genotype-guided dosing could be
improved by reducing the cost of geno-
typing, improving effectiveness of the
genotype-guided dosing algorithm in con-
trolling the INR, and using the algorithm
in places where high out-of-range INRs
are common.
A Markov model has been used to eval-
uate whether and under what circum-
stances genotype-guided warfarin dosing
could be cost-effective for patients with
atrial brillation [26H]. The cost-effective-
ness depended greatly on the assumed
effectiveness of genotyping in increasing
the amount of time patients spend in the
INR target range. The ICER would be over
$100 000 per QALY if genotyping
increased the time spent by less than 5%
and below $50 000 per QALY if the time
increased by 9%. The authors concluded
that, given current uncertainty surrounding
genotyping efcacy, caution should be
taken in advocating the widespread adop-
tion of this strategy.
In a non-randomized study the addition
of CYP2C9 pharmacogenetic testing
improved the time spent in the target range
by 7% overall (4% supratherapeutic and
3% subtherapeutic); the hazard ratio for
adverse reactions was reduced (HR
0.54; 95% CI 0.29, 0.97); VKORC1 con-
tributed to only 1% of the variability [27c].
Not surprisingly, the algorithm that best
predicted the therapeutic dosage require-
ments included the rst three doses and
the INR on day 4. Use of statins, smoking,
and a history of liver disease were not sig-
nicant predictors.
In a systematic review of 39 studies
in 7907 patients, compared with the
CYP2C9*1/*1 genotype, the CYP2C9*1/*2,
710 Chapter 35 J.K. Aronson

CYP2C9*1/*3, CYP2C9*2/*2, CYP2C9*2/ may be suspected; however, in the case of

*3, and CYP2C9*3/*3 genotypes required an 86-year-old woman who took an over-
warfarin doses that were respectively 20%, dose of warfarin, slow recovery, despite
34%, 36%, 57%, and 78% lower; the effect large repeated doses of vitamin K, was
of CYP2C9 genotype tended to be larger attributed to the fact that her CYP2C9
in patients without interacting drugs [28M]. genotype was CYP2C9*3/*3 [35A].
A new CYP2C9 polymorphism, G1078A
coding for a D360N in the cDNA coding
Drugdrug interactions Ambrisentan In an
region of exon 7, one codon downstream
open crossover study in 22 healthy subjects,
from the I359L coding change seen in
ambrisentan 10 mg/day for 8 days had no
CYP2C9*3, has been associated with gas-
effects on the pharmacokinetics and phar-
trointestinal bleeding in a 63-year-old Afri-
macodynamics of the enantiomers of warfa-
canAmerican man [29A].
rin after a single dose of racemic warfarin
Deciencies of anticoagulant proteins
25 mg [36c].
can increase the risk of skin necrosis due
to warfarin. In a 19-year-old man with pro-
Cannabinoids An interaction of warfarin
tein C deciency, recurrent (stuttering)
with marijuana smoking has been reported
priapism attributed to warfarin was compli-
in a 56-year-old man, in whom the INR
cated by skin necrosis, presumably because
rose from 1.8 to 12 and who had a constant
of paradoxical hypercoagulability [30A].
nose-bleed and increased bruising [37A].
Activated protein C concentrate can be
During the next 9 months, while he did
used to treat such cases [31A]. In another
not smoke marijuana, his INR was
case, skin necrosis occurred on the pinna
1.084.40 and there were no bleeding com-
of an 82-year-old man with protein S de-
plications. The authors suggested that
ciency after warfarin therapy for 2 weeks
marijuana may have inhibited the metabo-
[32A].
lism of warfarin and to a lesser extent
displaced it from protein-binding sites.
Renal disease The effect of renal function
on warfarin dosage, anticoagulation con-
Duloxetine In a steady-state study of once-
trol, and the risk of hemorrhagic complica-
daily warfarin and once-daily duloxetine in
tions has been evaluated in a secondary
60 healthy subjects with a stable INR of
analysis of a prospective cohort of 578
1.52.0, duloxetine had no clinically or sta-
patients [33c]. Patients with severe chronic
tistically signicant effects on the pharma-
kidney disease (eGFR < 30 ml/minute/
codynamics or pharmacokinetics of
1.73 m2) required signicantly lower warfa-
warfarin [38c].
rin dosages, spent less time with their INR
in the target range, and were at a higher
risk of over-anticoagulation, compared with Fibrates An interaction of gembrozil with
patients with no, mild, or moderate disease. warfarin has been described in a 62-year-
In those with severe disease the risk of old man, whose INR rose to 5.8 within 3
major hemorrhage was more than double weeks of the addition of gembrozil 600
that in those with lesser degrees of renal mg bd. The authors recommended a dosage
dysfunction (HR 2.4; 95% CI 1.1, 5.3). reduction of 20% and close monitoring dur-
ing administration of this combination
Drug overdose Two cases of overdose of [39Ar].
phenprocoumon have been reported, in a
57-year-old woman and a 76-year-old man,
fatal in the former; there were multiple Fluoroquinolone antibiotics Moxioxacin
hemorrhages in both cases [34A]. 400 mg/day markedly increased the action
In patients who take a long time to of warfarin in a 74-year-old patient with a
recover from warfarin overdose the use of prosthetic mitral valve, whose INR rose to
a long-acting superwarfarin [SED-15, 984] 12 [40A].
Drugs that affect blood coagulation, brinolysis, and hemostasis
In a retrospective study of 21 patients
taking warfarin there was a signicant
increase in INR after the addition of levo-
oxacin [41c].
Getinib In a retrospective study of 296
patients taking getinib for non-small-cell
lung cancer, 12 also took warfarin; there
was a raised prothrombin time in six, asso-
ciated with liver dysfunction [42c]. It is not
clear to what extent a direct interaction of
getinib with warfarin was responsible in
these cases, as opposed to liver impairment.
Gemcitabine Gemcitabine caused a rise in
INR during warfarin therapy in a 70-year-
old woman with pancreatic cancer [43A].
Hormonal contraceptives An interaction of
warfarin with hormonal contraceptives has
been described in a 33-year-old woman
[44A]. While taking warfarin 38.5 mg/week
she switched from a monophasic combined
oral contraceptive (ethinylestradiol nor-
ethindrone) to an implantable progesto-
gen-only contraceptive (etonogestrel); 19
days later her INR fell to 1.8 and she
required an increase in warfarin dose to
60 mg/week. After 10 months she decided
to have the implant removed, and 9 days
later her INR rose to 6.5. The warfarin
dose was reduced to 55.5 mg/week. She
then started to use an oral progestogen-
only contraceptive (norethindrone) and
the effective warfarin dose was 53.5 mg/
week. The authors hypothesized that the
predominant mechanism of this interaction
was inhibition of CYP1A2 and CYP2C19
by ethinylestradiol.
Inuenza vaccine Most reports of inuenza
immunization in patients taking warfarin
have shown no signicant changes in anti-
coagulation. A 64-year-old man had gastro-
intestinal bleeding and a large cerebral
hemorrhage while taking warfarin (INR >
15) 4 weeks after inuenza immunization,
when his INR had previously been 2.0
[45A]. It is likely that something other than
the immunization was responsible in this
case.
Chapter 35 711
Laropiprant Multiple-dose laropiprant had
no effects on the pharmacokinetics and
pharmacodynamics of the enantiomers of
warfarin after a single dose of 30 mg in 13
subjects [46c].
Methylsalicylate Topical methylsalicylate
50% has been reported to have enhanced
the action of warfarin in a 53-year-old
man, resulting in a large right retroperito-
neal hematoma and right iliac intramuscu-
lar hematoma after trauma [47A].
Nitazoxanide In a phase I, open, random-
ized, two-way crossover study in 14 healthy
men, nitazoxanide administration for 6 days
had no effect on the pharmacokinetics or
pharmacodynamic actions of a single dose
of warfarin 25 mg [48c].
Oxcarbazepine Resistance to warfarin has
been described in a 16-year-old boy with
the VKORC1 1173CC genotype and
CYP2C9 *2 allele [49A]. It is not clear what
the mechanism was in this case, nor the
relevance of the pharmacogenetic
polymorphisms.
Paracetamol (acetaminophen) In a study
of the interaction of warfarin with paraceta-
mol, using a large post-mortem toxicology
database, the contribution of anticoagulant
use to death was evaluated from death cer-
ticates based on medicolegal autopsies
[50c]. In 33% of the 328 warfarin-positive
cases, at least one interacting drug was pre-
sent, and paracetamol was the most
frequent, accounting for 49% (n 53).
When paracetamol and warfarin were
detected simultaneously, the numbers of
fatal bleeds were 4.6 higher than with para-
cetamol alone and 2.7 times higher than
with warfarin alone. An NSAID was used
in combination with warfarin in only six
cases. The authors concluded that the
results supported the clinical evidence that
suggests that warfarinparacetamol inter-
actions may create signicant life-threaten-
ing conditions.
Proton pump inhibitors Proton pump
inhibitors increase the INR when they are
712
taken concomitantly with warfarin. Of 240
patients who took warfarin after surgery,
114 also took rabeprazole 10 mg/day and
126 took lansoprazole 15 mg/day; there
were delayed cardiac adverse effects in
those who took lansoprazole (tamponade
in six and hemothorax in one) [51C].
Selective serotonin reuptake inhibitors
(SSRIs) In a cohort study, 117 patients tak-
ing warfarin for atrial brillation and an
SSRI were compared with 117 controls
matched for age and sex [52C]. Bleeding
occurred in 17 exposed patients (23 epi-
sodes) and in two unexposed patients (two
episodes). The incidences of bleeding epi-
sodes per 1000 treatment years were 51 and
24 respectively, and the unadjusted inci-
dence rate ratio was 2.15 (95% CI 0.88,
5.11). Cox regression analysis including rst
episodes showed an adjusted hazard ratio
of 3.49 (1.37, 8.91) for bleeding during com-
bined treatment with warfarin and an SSRI.
Sorafenib A 70-year-old man had a rise in
INR during warfarin therapy when sorafe-
nib 200 mg/day was added [53A].
Tamoxifen The literature on the potential
interaction of tamoxifen with warfarin,
based on the possibility that tamoxifen
inhibits CYP2C9, has been reviewed
[54M]. Of 31 patients taking warfarin and
tamoxifen concomitantly, described in two
letters, two case reports, and two retrospec-
tive reviews, eight had bleeding complica-
tions. The authors concluded that evidence
about this supposed interaction is limited.
Torsemide The anticoagulant effect of war-
farin was potentiated by torsemide in a
43-year-old Hispanic woman; the authors
postulated that this was due to inhibition
of CYP2C9 and protein binding displace-
ment of warfarin [55A].
Drugfood interactions Cranberry juice
Another case of increased anticoagulation
in a patient taking warfarin and cranberry
juice has been reported, with fatal internal
hemorrhage in an elderly man [56A].
Chapter 35 J.K. Aronson
However, despite anecdotal reports,
small formal studies have failed to show
any interaction of warfarin with cranberry
juice. In 30 patients taking warfarin with
stable INRs of 1.73.3, who were random-
ized to 240 ml of cranberry juice or a pla-
cebo beverage, matched for color and
taste, once daily for 2 weeks, cranberry
juice had no effect on plasma S- or R-war-
farin plasma concentrations, and there were
only minimal changes in INR on one day
during the study [57C]. However, a study
of this size does not rule out an effect in a
susceptible subpopulation, and a larger
casecontrol study may be the only way to
settle the apparent discrepancy between
formal studies and anecdotal reports.
Pomegranate juice In mice consumption of
pomegranate juice reduced total hepatic
content of cytochrome P450 enzymes and
reduced the expression of CYP1A2 and
CYP3A [58E]. Pomegranate juice also
inhibited carbamazepine 10,11-epoxidation
by CYP3A in human liver microsomes
and inhibited enteric CYP3A in rats [59E];
it also inhibited diclofenac 40 -hydroxylation
by CYP2C9 in human liver microsomes
[60E]. Now an interaction of pomegranate
juice with warfarin has been described in a
64-year-old woman, in whom the INR was
in the target range while she was drinking
pomegranate juice 23 times/week and then
became subtherapeutic when she stopped
drinking the juice, requiring an increase in
the dosage of warfarin [61A]. The presump-
tion was that the pomegranate juice had
inhibited the metabolism of warfarin.
Enteral feeding Resistance to warfarin in
patients receiving enteral feeding has been
attributed to vitamin K. However, it has
been suggested that other mechanisms
may be responsible, since reducing the vita-
min K content of enteral feeding solutions
has not eradicated the problem [62R]. For
example, there is evidence of binding of
warfarin in the gut by enteral nutrition
solutions. The author recommended that
enteral feeding should be withheld for 1
hour before and after warfarin administra-
tion and that the feeding rate should be
Drugs that affect blood coagulation, brinolysis, and hemostasis
increased slightly, to compensate for the
reduced duration of infusion. In contrast,
there is also evidence that o-3 polyunsatu-
rated fatty acids in sh oil supplements
can impair platelet aggregation and reduce
factor VII, increasing anticoagulation [63c].
Drugdevice interactions Photodynamic
therapy Massive suprachoroidal hemorrhage
in a 78-year-old woman after photodynamic
therapy may have been made more likely
by concurrent warfarin therapy [64A].
Management of adverse drug reactions In
417 patients from 22 centers with a mean
initial INR of 7.7, 85% of whom had an
INR under 9.0 or were not bleeding and
15% had serious bleeding, treatment did
not adhere to guidelines in 170 cases
(41%); 15% were undertreated and 48%
over-treated [65c]. Lack of adherence was
attributed primarily to excessive doses of
vitamin K1 (mean initial dose 6.9 mg)
and inappropriate routes of administration
(subcutaneous or intramuscular).
Factor VII Rapid reversal of warfarin
over-anticoagulation can be achieved with
factor VII [66A].
Factor IX complex In a retrospective chart
review of 28 patients treated with intrave-
nous factor IX complex for warfarin-
induced coagulopathy, the INR was
reduced from 5.1 to 1.9 within a mean of
14 minutes; there were no early thrombotic
events or allergic reactions [67c].
Prothrombin complex concentrates In a ret-
rospective chart review of 72 patients who
received activated prothrombin complex con-
centrate factor VIII inhibitor bypassing activ-
ity and 69 patients who received fresh-frozen
plasma to reverse the effects of warfarin dur-
ing life-threatening bleeding, the former
resulted in lower INR and a shorter time from
drug administration to an INR of 1.4 or less
[68c]. There were no signicant differences
in survival or in the length of hospital stay.
There were ve adverse events that could
have been related to the prothrombin
Chapter 35 713
complex concentrate: a perioperative myo-
cardial infarction, a deep vein thrombosis,
chest pain with a raised serum troponin, a
raised troponin, and ventricular brillation;
however, the authors considered that none
of the ve events was directly related to pro-
thrombin complex concentrate.
In contrast, in 40 patients with INRs over
5.0, of whom 29 were bleeding and 11 were
at high risk of bleeding, who were treated
with a three-factor prothrombin complex
concentrate and were compared with 42 his-
torical controls treated with plasma alone,
the prothrombin complex concentrate did
not satisfactorily reduce the INR, because
of a low factor VII content [69c]. Treatment
with plasma alone lowered the INR to below
3.0 in 63% of the controls, while low-dose (25
U/kg) and high-dose (50 U/kg) prothrombin
complex concentrate alone lowered the INR
to below 3.0 in 50% and 43% of patients
respectively. Additional transfusion of a
small amount of plasma improved these rates
to 89% and 88%.
Vitamin K In a multicenter, randomized,
placebo-controlled trial of low-dose vitamin
K 1.25 mg/day in 724 non-bleeding patients
with INRs of 4.510.0, 56 patients (16%) in
the vitamin K group and 60 patients (16%)
in the placebo group had at least one bleed-
ing complication; there were major bleed-
ing events in nine patients (2.5%) and
four patients (1.1%) respectively and
thromboembolism in four (1.1%) and three
(0.8%) patients [70C].
HEPARINS [SED-15, 1590; SEDA-
30, 404; SEDA-31, 556; SEDA-32, 626]
Electrolyte balance Heparin-induced hyper-
kalemia is usually associated with intravenous
heparin, but it can occasionally occur during
subcutaneous administration, as in the case
of a 75-year-old woman, whose serum potas-
sium rose from 5.0 to 6.9 mmol/l when she
was given unfractionated heparin 5000 units
bd subcutaneously for 6 days [71A].
714
Hematologic
EIDOS classication:
Extrinsic species Heparin
Intrinsic species Platelet factor 4
Distribution Plasma
Outcome Formation of platelet factor
4/heparin antibodies
Sequela Heparin-induced
thrombocytopenia (HIT), type II
DoTS classication:
Dose-relation Hypersusceptibility
Time-course Early persistent
Susceptibility factors Renal disease for
some forms of heparin
Incidence Platelet factor 4/heparin anti-
bodies are not always associated with
thrombocytopenia. In 135 children who
underwent cardiac surgery and were given
unfractionated heparin (60 neonates under-
going rst-time surgery and 75 older chil-
dren undergoing re-operations), platelet
factor 4/heparin antibodies were not
detected preoperatively in either group
[72c]. However, there were antibodies in
one neonate on postoperative days 5 and
10, and in 12 of the older children on day
5 and 39 on day 10. Seroconversion in the
older children on day 10 was signicantly
associated with previous exposure to hepa-
rin, and one patient seroconverted and
developed HIT without thrombosis or skin
lesions. The authors concluded that in older
children the incidence of antibodies is simi-
lar to that reported in adults, that HIT is
rare, and that both age and previous expo-
sure to unfractionated heparin correlated
with seroconversion; in contrast, the rate
of seroconversion in neonates undergoing
rst-time surgery was substantially lower.
In a prospective analysis of antibodies in
31 pregnant women who received dalteparin
250010 000 IU/day for 645 (median 33)
weeks, IgG, IgM, and IgA antibodies were
not detected and there were no thrombo-
embolic events [73c]. One woman developed
a prolonged fall in platelet count to less than
Chapter 35 J.K. Aronson
50% of baseline after 35 weeks, with sponta-
neous resolution after delivery.
In a retrospective study, 37 women with
high-risk pregnancies were given tinzaparin
175 IU/kg/day; there were no episodes of
recurrent venous thromboembolism but
there were two unusual thrombotic compli-
cations, a parietal infarct in one patient and
a postpartum cerebral venous thrombosis in
another [74c].
However, false positive tests for platelet
factor 4/heparin antibodies can occur in
patients with the phospholipid antibody
syndrome or systemic lupus erythematosus,
as illustrated by the results of a study in 42
such patients, of whom 32 were positive for
platelet factor 4/heparin IgG antibodies and
24 were positive for platelet factor 4 anti-
bodies [75c]. However, there were no
abnormalities in heparin-induced platelet
activation or aggregation.
Time-course The time-course of production
of heparin-induced antibodies has been
studied in 435 patients receiving heparin
thromboprophylaxis [76c]. Antibodies
formed in 56%, and in over 90% of cases
they appeared at 414 days. After reaching
maximum reactivity by days 1012, the
antibody titers fell, despite heparin continu-
ation, even in two patients with HIT. Indi-
vidual IgG, IgA, and IgM classes had
identical times of onset (median day 6).
Most of the antibody-positive patients
(59%) developed all three immunoglobulin
classes; only 11% lacked an IgG response,
and all three immunoglobulins usually
increased simultaneously.
In a study of IgG, IgA, and IgM anti-
bodies in 12 patients with HIT and 36
patients who formed antibodies but did
not develop HIT, the antibodies became
detectable in the former at a median of 4
days after the start of treatment and pre-
ceded the fall in platelet count by a median
of 2 days [77c]. Patients with HIT produced
higher titers of IgG antibodies than the
seropositive controls, but similar IgA and
IgM titers.
Of 500 patients treated with unfractio-
nated heparin 131 (26%) developed plate-
let factor 4/heparin antibodies, which
Drugs that affect blood coagulation, brinolysis, and hemostasis
persisted for a median of 90 (IQ range
31186) days [78c]. At 30 days, patients
with antibodies had a higher incidence of
thrombotic events (28% versus 15%) and
death/myocardial infarction (15% versus
7.8%). Of the 131 patients with antibodies,
78 had already developed antibodies before
cardiac surgery, and they became serologi-
cally negative more slowly than those who
developed antibodies after surgery. Over
3 years of follow-up, the patients with
antibodies had 65 thrombotic events; 25
developed deep vein thrombosis and/or
pulmonary embolism and 20 had a myocar-
dial infarction.
Management It has been suggested that
platelet transfusions are contraindicated in
HIT, because of the risk of thrombosis.
However, no complications occurred in
four patients with clinically suspected HIT
who received platelet transfusions [79cM].
The authors also reviewed the literature
and found no cases of complications clearly
attributable to platelet transfusion and con-
cluded that platelet transfusions should not
be withheld when indicated in patients with
HIT.
Treatment with plasmapheresis to
remove the antibodies was effective in a
60-year-old man with HIT after cardiac sur-
gery [80A] and has also been described in a
series of 11 patients, in whom a single
plasmapheresis reduced titers by 5084% [81c].
Reports and reviews continue to appear
on the successful use of other anticoagu-
lants in patients with a history of HIT,
including argatroban [82A, 83A, 84A, 85A,
86A, 87A, 88A, 89c, 90R, 91R, 92R], bivali-
rudin [93A, 94A, 95c, 96M], danaparoid
[97A], fondaparinux [98A, 99A, 100c, 101c,
102M], hirudin [103A], lepirudin [104A,
105c, 106R, 107M], and rivaroxaban [108A].
In 82 adults there was no signicant differ-
ence in outcomes between argatroban and
lepirudin [109c].
Skin Of 320 patients, 24 (7.5%; 95% CI
4.7, 11) had heparin-induced skin lesions,
which were delayed-type hypersensitivity
reactions in all cases [110c]. The
Chapter 35 715
susceptibility factors were a body mass
index greater than 25 (OR 4.6; 95% CI
1.7, 15), duration of heparin therapy lon-
ger than 9 days (OR 5.9; 95% CI 1.9,
26), and female sex (OR 3.0; 95% CI
1.1, 8.8).
Skin necrosis can occur occasionally in
patients receiving heparin, in association with
heparin-induced thrombocytopenia [111A].
Recall urticaria occurred in a 42-year-old
woman at previous dalteparin injection
sites in the abdomen when she was given
intracutaneous dalteparin and certoparin
in the forearms [112A].
Subcutaneous calcinosis occurred in two
patients with renal failure who developed
erythematous nodules with calcium deposi-
tion in the dermis and hypodermis [113A], a
between-the-eyes reaction of type 1a [114H].
Bullous hemorrhagic dermatosis is a rare
adverse reaction to subcutaneous heparin
[115A, 116A].
Musculoskeletal Long-term heparin can
cause osteoporosis, as illustrated by the case
of a 19-year-old woman with protein C de-
ciency, who had a fracture of the right wing
of the sacrum after receiving low-molecu-
lar-weight heparin daily during her preg-
nancy [117A].
The effect of low-molecular-weight hepa-
rin on bone mineral density has been assessed
in a multicenter multinational randomized
study in pregnant women with thrombophilia
[118c]. There was no signicant difference in
mean bone mineral density between those
who were given low-molecular-weight hepa-
rin prophylaxis and those who were given
no prophylaxis, but the study was not ade-
quately powered to detect differences in the
absolute risk of fractures.
Pregnancy In a prospective study of 130
pregnancies in 114 women treated with pro-
phylactic or therapeutic low-molecular-
weight heparins, there was one allergic skin
reaction in a patient with hereditary throm-
bophilia treated with enoxaparin and then
with nadroparin in the third trimester of preg-
nancy, hemorrhagic complications in a
patient with dysbrinogenemia and placental
abruption, and one case of minor epistaxis in
716
a patient treated with heparin and aspirin
[119c]. There were no pathological fractures,
signicant reductions in platelet counts, or
episodes of arterial thrombosis.
Drug formulations A multimatrix oral for-
mulation of parnaparin sodium, MMX,
releases heparin in the colon, avoiding sys-
temic absorption and has been used for
8 weeks to treat left-sided ulcerative colitis
in 10 patients with mild-to-moderate
relapses [120c]. There were no adverse
reactions and at the end of treatment, seven
patients were in clinical remission, although
only one achieved endoscopic healing.
A heparin-coated stent was associated
with a giant aneurysm in the left anterior
descending coronary artery immediately
distal to the stent, which had been in place
for 3 years, in a 79-year-old woman [121A].
Drug contamination Adverse reactions to
heparin contaminated with oversulfated
chondroitin sulfate have been evaluated in
a US casecontrol study of patients in dial-
ysis facilities who had signs and symptoms
of allergic reactions after 1 November
2007 [122C]. There were 152 adverse reac-
tions associated with heparin in 113
patients from 13 states from 19 November
2007 to 31 January 2008. The use of hepa-
rin manufactured by Baxter Healthcare
was the factor most strongly associated with
reactions, which occurred in 100% of 21
facilities in which cases were reported ver-
sus 4.3% of 23 control facilities. Vials of
heparin manufactured by Baxter from facil-
ities that reported reactions contained a
contaminant identied as oversulfated
chondroitin sulfate. Adverse reactions to
the contaminated heparin were often char-
acterized by hypotension, nausea, and
shortness of breath within 30 minutes of
administration. Of 130 reactions for which
information on the heparin lot was avail-
able, 128 occurred in a facility that had con-
taminated heparin on the premises. Of 54
reactions for which the lot number of the
heparin was known, 52 occurred after the
administration of contaminated heparin.
Plasma samples obtained from dialysis
patients in 2006 and 2007 had a low (5%)
Chapter 35 J.K. Aronson
prevalence of platelet factor 4/heparin anti-
bodies, whereas in samples from 78 patients
on maintenance hemodialysis who had been
potentially exposed to contaminated heparin
there were antibodies in 15 (19%); there
was also a higher prevalence of IgG anti-
bodies [123c]. The authors suggested that
the contaminant in the recalled heparin may
have triggered an immunogenic response
not seen with non-contaminated heparin.
Management of adverse drug reactions
Heparin allergy, which caused a pruritic
urticaria-like rash on the back in a 55-year-
old man, without associated angioedema,
wheezing, ushing, or anaphylaxis, has been
successfully managed with an intravenous
desensitization protocol (Table 1) [124Ar].
Two earlier protocols, which were used in a
34-year-old man [125A] and a 55 year-old
woman [126A], are also shown in Table 1 for
comparison. An even faster protocol has also
been described [127A]. A combined subcuta-
neous and intravenous protocol that was used
in a 55-year-old woman is shown in Table 2
[128A].
In four patients with delayed hypersensi-
tivity reactions to different forms of heparin,
prick tests, intradermal tests, and patch tests
were performed using unfractionated sodium
heparin, low-molecular-weight heparins
(nadroparin, enoxaparin, bemiparin, and dal-
teparin), and fondaparinux [129A]. There
were different patterns of cross-reactivity; all
were sensitive to at least two forms of heparin
and one patient was sensitive to all ve drugs.
Danaparoid sodium [SEDA-32, 631]
Immunologic A patient with delayed-type
hypersensitivity to heparins was given dana-
paroid subcutaneously for thrombosis pro-
phylaxis after orthopedic surgery and after
the rst few injections developed eczematous
plaques followed by generalized eczema
despite treatment with topical and oral gluco-
corticoids; danaparoid was replaced by intra-
venous heparin, and there was rapid
resolution of the skin lesions [130A].
Drugs that affect blood coagulation, brinolysis, and hemostasis Chapter 35 717

Table 1 Intravenous heparin desensitization protocols described in three different reports

Desensitizing dose (U/h)

Ar
Time of administration (hours) [124 ] [125A] [126A]

012 0.5 4.2 0.42

1224 1.5 4.2 0.42
2436 4.5 42 4.2
3648 13.6 42 4.2
4860 40.8 208 42
6072 122.5 8 208 42
7284 367.4 < 210
8496 1008 5000 U bd subcutaneously 210
:
96120 500

Table 2 A combined subcutaneous and intravenous heparin desensitization protocol [128A]

Time of administration Desensitizing dose (units) Route

Day 1 50 Subcutaneous
Day 1 after 40 minutes 250 Subcutaneous
Day 1 after 80 minutes 500 Subcutaneous
Day 2 500 Subcutaneous
Day 2 after 40 minutes 1500 Subcutaneous
Day 2 after 80 minutes 3000 Subcutaneous
Day 3 500 Intravenous
Day 3 after 40 minutes 1500 Intravenous
Day 3 after 80 minutes 3000 Intravenous
Day 4 5000 Intravenous

Pregnancy In 91 pregnancies in 83 patients termination, and one neonatal death. In 13

with a history of thrombophilia and/or cases a maternal, but no fetal, adverse
intra-uterine growth retardation, all of event was attributed to danaparoid.
whom had intolerance to heparins, subcuta-
neous and/or intravenous danaparoid
10007500 U/day was started in the rst,
second, and third trimesters in 60%, 19%,
and 21% respectively and was continued
for a median of 105 (range 1252) days dur-
DIRECT THROMBIN
ing pregnancy and for 7 (range 256) days INHIBITORS [SED-15, 1142;
post-partum [131c]. The live birth rate was SEDA-30, 409; SEDA-31, 559;
90% (75/81) and danaparoid was restarted SEDA-32, 632]
after 37 deliveries. Maternal adverse events
in 46% of the pregnancies included two Argatroban [SEDA-32, 632]
post-cesarean deaths, three non-fatal major
bleeds, three thromboembolic events unre- Pregnancy Argatroban has been used in a
sponsive to an increased dose of danapar- 26-year-old pregnant woman with portal vein
oid, and 10 recurrent rashes. There were thrombosis and thrombocytopenia from the
seven early miscarriages, one therapeutic 33rd to the 39th week, when labor was
718
induced; argatroban was discontinued 7 hours
before epidural anesthesia, and there were no
adverse events attributable to it [132A].
Dabigatran [SEDA-32, 633]
Susceptibility factors Liver disease The
effects of moderate hepatic impairment on
the pharmacokinetics and pharmacodynam-
ics of a single oral dose of dabigatran etexi-
late 150 mg have been evaluated in an
open, parallel-group study in 12 healthy sub-
jects and in 12 patients with hepatic impair-
ment (ChildPugh classication B) [133c].
Conversion of the dabigatran intermediate
BIBR1087 to active dabigatran was slower
in patients with hepatic impairment, but
total drug exposure was comparable
between the groups. Dabigatran glucuroni-
dation was unchanged by liver disease. The
activated partial thromboplastin time, ecarin
clotting time, and thrombin time were essen-
tially identical in the two groups.
Drugdrug interactions HMG Co-A reduc-
tase inhibitors (statins) The interaction of
dabigatran etexilate with atorvastatin has
been studied in 22 healthy men and women
in an open, randomized, multiple-dose,
three-way crossover study [134c]. They took
dabigatran 150 mg bd on days 13 and 150
mg/day on day 4, or atorvastatin 80 mg/day
on days 14, or both treatments together
on days 14. During co-administration, the
steady-state AUC of dabigatran fell by
18% and the plasma atorvastatin concentra-
tion increased by 18%. Exposure to
20 -hydroxyatorvastatin was unchanged
and exposure to 40 -hydroxyatorvastatin
increased by 15%. The small changes
observed were thought to be of little clinical
relevance, given the overall interindividual
variability in the metabolism of atorvastatin.
Lepirudin [SEDA-32, 633]
Hematologic Thrombocytopenia has been
attributed to lepirudin in a 61-year-old
Chapter 35 J.K. Aronson
man with a history of heparin-induced
thrombocytopenia (HIT) due to enoxa-
parin [135A].
INDIRECT FACTOR XA
INHIBITORS [SEDA-30, 412;
SEDA-31, 563; SEDA-32, 636]
Fondaparinux [SEDA-32, 636]
Hematologic The association between
major bleeding and death at 30 days has
been derived from individual patient data
from eight large randomized controlled
comparisons of fondaparinux with either
low-molecular-weight heparin or placebo in
prophylaxis of venous thromboembolism in
13 085 hospitalized patients [136M]. Those
who had major bleeding were older, were
more likely to be men, had lower body
weights and lower creatinine clearances,
and were more likely to be receiving fonda-
parinux. At 30 days, the risk of death was 7
times higher among patients with a major
bleeding event (8.6% versus 1.7%; adjusted
HR 6.96; 95% CI 4.60, 11). There was
a consistent pattern of reduced mortality in
patients treated with fondaparinux, irrespec-
tive of whether the patients had major
bleeding (6.8% versus 11%; HR 0.58;
95% CI 0.27, 1.23) or not (1.5% versus
1.9%; HR 0.77; 95% CI 0.59, 1.02).
Idraparinux [SEDA-32, 636]
Skin The Amadeus comparison of a vita-
min K antagonist and a weekly subcutane-
ous injection of idraparinux was stopped
early because of excessive bleeding in
patients assigned idraparinux. There were
also unusual skin lesions in 15 of 56 partic-
ipants who were assigned to idraparinux
compared with none of 59 patients assigned
to warfarin at one center [137c]. There were
raised, blood-lled vesicles 0.52.0 cm in
Drugs that affect blood coagulation, brinolysis, and hemostasis
diameter, remote from the subcutaneous
injection sites. Most of the patients had
28 lesions, usually on the arms and legs,
which appeared on average 3 (range 28)
months after starting idraparinux. After
that, new lesions continued to appear, but
the severity of the lesions did not increase,
despite continuing medication. On rst
appearance the lesions were bright red,
suggesting fresh blood. They would then
darken before gradually resolving over 2
weeks. They were not painful or itchy.
DRUGS THAT ALTER
PLATELET FUNCTION
[SEDA-30, 413; SEDA-31. 564;
SEDA-32, 637]
Anagrelide [SEDA-32, 637]
Cardiovascular In a database study cardio-
myopathy was temporally associated with
the use of anagrelide in six patients, all of
whom had symptomatic and/or objective
improvement after drug withdrawal [138c].
Mid-ventricular takotsubo syndrome (see
also p. 313) has also been described in a
75-year-old woman taking anagrelide
[139A]. The authors hypothesized that
accumulation of anagrelide, a phospho-
diesterase type II inhibitor, had caused
major inotropic stimulation and sympa-
thetic hyperactivation in a vulnerable
myocardium.
Dipyridamole [SED-15, 1140; SEDA-
30, 413; SEDA-31, 564; SEDA-32, 638]
Cardiovascular Asystole has been reported
during the administration of dipyridamole
[140A].
A 67-year-old woman with hypertension, who
was taking metoprolol 50 mg bd, underwent
dipyridamole stress testing, and during the
infusion of dipyridamole developed nausea,
dizziness, and sudden loss of consciousness.
Chapter 35 719
Electrocardiography showed asystole, which
resolved after 20 seconds, with return of con-
sciousness. She was given theophylline, which
was associated with a brief period of atrial
brillation followed by chest discomfort. Her
electrolytes were normal, and there was no
rise in cardiac enzymes nor electrocardio-
graphic evidence of myocardial infarction.
Angiography showed normal coronary arter-
ies and echocardiography showed normal car-
diac function.
It has been suggested that dipyridamole
inhibits cardiac conduction by autonomic
dysregulation [141A]. An interaction with
beta-blockers has also been described
[142c] and that may have been the case
here.
Nervous system The susceptibility factors
for dipyridamole-induced headache have
been studied in an analysis of data from
the European/Australasian Stroke Preven-
tion in Reversible Ischaemia Trial
(ESPRIT) and the Second European
Stroke Prevention Study (ESPS 2). In
ESPRIT, dipyridamole-induced headache
was signicantly associated with female
sex, absence of hypertension, and non-
smoking, and in ESPS 2 with female sex
and absence of ischemic lesions on imaging
[143C].
The risk of dipyridamole-induced head-
ache can be reduced by slow upward titra-
tion of the dose. The susceptibility factors
for headache during such a regimen have
been studied in 20 stroke units in Sweden,
where 174 patients with newly diagnosed
strokes and transient ischemic attacks were
offered a titration regimen of the combina-
tion of aspirin 25 mg/day dipyridamole
200 mg/day for 5 days followed by 200 mg/
day bd [144c]. Headache of any kind was
reported in 70 patients (40%), and 37
(21%) assessed it as moderate/severe; six
stopped taking the medication because of
headache. The headache subsided over a
mean of 3.1 days. Patients who had tran-
sient ischemic attacks had a signicantly
higher risk of headache than those with
strokes, regardless of localization. There
was a trend towards a higher risk in youn-
ger patients and women.
720
Glycoprotein IIbIIIa inhibitors
[SED-15, 4; SEDA-30, 414; SEDA-31, 565;
SEDA-32, 638]
Cardiovascular Cardiac tamponade result-
ing from hemorrhagic pericarditis has been
attributed to abciximab [145A].
A 66-year-old man had a myocardial infarc-
tion and was given intravenous heparin, and
oral aspirin 200 mg/day, clopidogrel 75 mg/
day, and cilostazol 200 mg/day. After 5 days
he was given abciximab 10 mg during percuta-
neous coronary intervention followed by 10
micrograms/minute for 12 hours, but 11 hours
after coronary intervention he developed
chest discomfort and dyspnea, his blood pres-
sure fell to 60/30 mmHg, and the ST segment
elevation increased. Echocardiography show-
ed a scanty pericardial effusion with no evi-
dence of tamponade. Three days later he
complained of chest discomfort and dyspnea,
and again developed shock. Echocardiography
showed a large pericardial effusion, with tam-
ponade. A bloody pericardial effusion of
about 950 ml was aspirated.
A 56-year-old man developed acute tran-
sient phlebitis during an intravenous injec-
tion of eptibatide; the eptibatide was
withdrawn and the signs of phlebitis disap-
peared within minutes [146A].
Hematologic Thrombocytopenia has again
been attributed to eptibatide [147A,
148A, 149A, 150AM] and tiroban [151A,
152A, 153A].
THIENOPYRIDINES [SED-15,
821; SEDA-30, 415; SEDA-31, 566;
SEDA-32, 639]
Observational studies Cross-reactivity bet-
ween clopidogrel and ticlopidine, which
are structurally very similar, has been stud-
ied by reviewing the medical records of 76
patients who had an allergic or hematologi-
cal adverse reaction to either drug and who
were subsequently given the other [154c].
In 14 patients who had allergic or
Chapter 35 J.K. Aronson
hematologic adverse reactions to clopido-
grel there was a similar reaction to ticlopi-
dine; none was life-threatening and the
most common reaction was a rash (93%).
Hematologic In a systematic review of the
English-language literature on thrombotic
thrombocytopenic purpura associated with
thienopyridines, epidemiological studies
identied recent initiation of antiplatelet
drugs as the most common susceptibility
factor, and ticlopidine and clopidogrel were
the two most common drugs implicated in
FDA safety databases [155M]. Most cases
associated with thienopyridines involve an
antibody to ADAMTS13 metalloprotease,
which is present in severe thrombocyto-
penia and responds to therapeutic plasma
exchange; in a minority of cases there is
severe renal insufciency, due to direct
endothelial cell damage.
Clopidogrel [SEDA-32, 639]
Nervous system In a retrospective case-
control study of 3817 patients with closed
head trauma, of 131 who were taking clopi-
dogrel, aspirin or warfarin, those taking clo-
pidogrel (n 21) were more likely to die
(OR 15; 95% CI 2.3, 94) and be dis-
charged to an in-patient long-term facility
(OR 3.25; 95% CI 1.06, 9.96). Mortal-
ity in those taking aspirin (n 90) or warfa-
rin (n 20) did not differ from controls,
although those taking warfarin had longer
hospital and ICU stays [156c].
Psychological In a double-blind, placebo-
controlled, balanced, between-subject study
in 54 young healthy volunteers, single oral
doses of clopidogrel 37.5 mg had no signi-
cant effects on psychomotor performance
[157C].
Hematologic In a retrospective review of
453 patients who underwent off-pump
bypass graft surgery and who received clo-
pidogrel preoperatively (n 101) or not
(n 352), clopidogrel was associated with
higher intraoperative and postoperative
Drugs that affect blood coagulation, brinolysis, and hemostasis
bleeding and with more platelet transfu-
sions; however, in those in whom clopido-
grel was withdrawn 3 days before surgery
there was similar blood loss compared with
controls [158c].
In a retrospective chart study of 50
patients who underwent a general surgical
procedure, patients who took clopidogrel
within 6 days before surgery (n 28) were
compared with those who stopped taking it
for 7 days or more (n 22); more patients
who took their last dose of clopidogrel
within 1 week of surgery (21% versus
9.5%) had signicant bleeding after surgery
requiring blood transfusion [159c].
In 4794 patients who underwent bypass
grafting, treatment with clopidogrel within 5
days before the operation was modestly asso-
ciated with erythrocyte transfusion (OR
1.40; 95% CI 1.04, 1.89), but more weakly
than other factors, including which surgeon
performed the procedure; it was not associ-
ated with re-operation for bleeding [160c].
However, in a secondary post-hoc analy-
sis of inhibition of platelet aggregation and
bleeding complications, as assessed by the
TIMI, GUSTO, and BleedScore scales, in
patients with coronary artery disease (n
246) and previous ischemic strokes (n
117), inhibition of platelet aggregation of
over 50% correlated strongly with minor
but not severe bleeding [161c]. The authors
concluded that chronic oral combination
antiplatelet regimens are associated with a
very high prevalence of episodes of super-
cial bleeding (5761%), which they
thought to be greatly underestimated in tri-
als and registries.
Acute severe pancytopenia has been
associated with clopidogrel [162A].
Gastrointestinal There was an increased
risk of major gastrointestinal bleeding, but
not other major or minor bleeding events,
in the year after percutaneous coronary
intervention in 1816 patients in whom clo-
pidogrel or placebo was added to aspirin
after 4 weeks [163C].
Liver Clopidogrel can occasionally cause
liver damage, as has again been reported
[164Ar].
Chapter 35 721
A 78-year-old woman developed mixed hepa-
tocellular and cholestatic liver damage after
taking clopidogrel and aspirin for 3 weeks.
Clopidogrel was withdrawn, and her liver
function tests improved. Clopidogrel was re-
introduced and her liver enzyme activities
again rose. Clopidogrel was again withdrawn
and her liver function tests gradually started
to improve after 3 days.
Skin A xed drug eruption has been
reported in a 68-year-old man, who devel-
oped a few well-circumscribed, darkly pig-
mented, oval-shaped lesions in his shoulder,
forehead, and trunk after taking clopido-
grel 75 mg/day for 4 days. A patch test with
clopidogrel was negative, but oral rechal-
lenge with a dose of 18.75 mg caused the
appearance of similar lesions over the exact
sites of the previous lesions within a few
hours [165A].
Infection risk In a retrospective cohort
study of 1677 patients undergoing coronary
artery bypass surgery, in which preopera-
tive aspirin clopidogrel was compared
with aspirin alone, clopidogrel was associ-
ated with an increased risk of postoperative
surgical site infection and bacteremia, both
unadjusted (HR 1.51; 95% CI 1.09,
2.08) and after adjustment for demo-
graphic, socioeconomic, preoperative, and
intraoperative risk factors (HR 1.42;
95% CI 1.01, 2.00) and propensity score
(HR 1.43; 95% CI 1.01, 2.01) [166c].
Susceptibility factors Genetic The pharma-
cogenetic determinants of the response to
clopidogrel have been studied in 2208
patients with acute myocardial infarction,
of whom 225 died [167c]. None of the
selected single-nucleotide polymorphisms
(SNPs) in CYP3A5, P2RY12, or ITGB3
was associated with a risk of an adverse
outcome during follow-up. Patients with
two variant alleles of ABCB1 (TT at
nucleotide 3435) had a higher rate of car-
diovascular events at 1 year than those with
the ABCB1 wild-type genotype (CC at
nucleotide 3435) (16% versus 11%;
adjusted HR 1.72; 95% CI 1.20,
2.47). Patients carrying any two CYP2C19
loss-of-function alleles (*2, *3, *4, or *5)
722
had a higher event rate than patients with
none (22% versus 13%; adjusted HR
1.98; 95% CI 1.10, 3.58). Among the
1535 patients who underwent percutaneous
coronary intervention during hospitaliza-
tion, the rate of cardiovascular events
among patients with two CYP2C19 loss-of-
function alleles was 3.58 times the rate
among those with none (95% CI 1.71,
7.51).
The association between functional
genetic variants in CYP genes, plasma con-
centrations of active metabolite, and plate-
let inhibition in response to clopidogrel
has been studied in 162 healthy subjects,
and the association between these genetic
variants and cardiovascular outcomes in a
separate group of 1477 subjects with acute
coronary syndromes who were taking clopi-
dogrel [168C]. Carriers of at least one
CYP2C19 reduced-function allele (about
30% of the population) had a relative
reduction of 32% in plasma exposure to
the active metabolite of clopidogrel com-
pared with non-carriers. Carriers also had
an absolute reduction in maximal platelet
aggregation in response to clopidogrel. Car-
riers had a relative increase of 53% in the
composite primary efcacy outcome of the
risk of death from cardiovascular causes,
myocardial infarction, or stroke, compared
with non-carriers (12% versus 8.0%; HR
1.53; 95% CI 1.07, 2.19) and an
increased risk of stent thrombosis (2.6%
versus 0.8%; HR 3.09; 95% CI 1.19,
8.00).
In 60 patients undergoing elective percu-
taneous coronary intervention who were
genotyped for polymorphisms in the
CYP2C19, CYP2C9, CYP3A4, CYP3A5,
ABCB1, P2Y12, and CES genes,
CYP2C19*1*1 carriers had greater platelet
inhibition 2 hours after a dose of 600 mg
compared with carriers of CYP2C19*2, *4,
or *17 [169c].
In a prospective observational study of
15 603 patients in Singapore, of whom
12 502 (80%) were white, 486 (3.1%)
black, 775 (5.0%) Asian, and 1613 (10%)
Hispanic, ethnicity was not a signicant
predictor of the primary composite cardio-
vascular event, but it was a signicant
Chapter 35 J.K. Aronson
independent predictor of the secondary
outcomes, cardiovascular and all-cause
mortality (blacks and Hispanics) and mod-
erate bleeding complications (blacks and
Asians) [170C].
Drug overdose A 49-year-old woman had
a pulmonary hemorrhage and hemothorax
after taking an overdose of clopidogrel
1875 mg [171A].
Drugdrug interactions Aprotinin In 15
patients with acute coronary syndrome tak-
ing clopidogrel and undergoing coronary
surgery, aprotinin increased platelet aggre-
gation in 11 cases from 84% to 94% and
reduced it in two [172c].
Calcium channel blockers In 200 patients
undergoing percutaneous coronary inter-
vention, platelet reactivity was increased
in patients taking clopidogrel and calcium
channel blockers compared with clopido-
grel alone; the effect was not related to car-
diovascular risk factors and was attributed
to inhibition of CYP3A4, since in vitro
incubation with amlodipine, nimodipine,
diltiazem, and verapamil had no effect on
aggregation of platelets from patients tak-
ing clopidogrel [173c].
Similarly, the addition of calcium channel
blockers in patients taking clopidogrel
increased platelet reactivity in 162 patients
after percutaneous intervention with stent
implantation [174c].
HMG Co-A reductase inhibitors (statins)
In a cohort study of 10 491 patients who
took clopidogrel after percutaneous coro-
nary intervention, the co-prescription of
CYP3A4-metabolized statins was not asso-
ciated with an increased risk of adverse out-
comes (HR 1.16; 95% CI 0.91, 1.47)
[175C].
In patients with coronary artery disease
who took part in a double-blind compari-
son of atorvastatin 2080 mg/day (n 22)
and rosuvastatin 1040 mg/day (n 24),
the platelet inhibitory effects of clopidogrel
were not altered [176C].
In an open, randomized, crossover, two-
arm, parallel-group study in 69 healthy
Drugs that affect blood coagulation, brinolysis, and hemostasis
men aged 1860 years, atorvastatin 80 mg/
day had no clinically signicant effects on
the pharmacokinetics or pharmacodynam-
ics of clopidogrel or prasugrel [177c].
Proton pump inhibitors A systematic
review of the evidence has suggested that
omeprazole reduces the antiplatelet effects
of clopidogrel, probably by competitive
inhibition of CYP2C19, that the interaction
is clinically signicant, and that it may not
be shared by other proton pump inhibitors
[178M]. Other reviewers have concluded
similarly [179R, 180R]. New studies have
mostly supported these conclusions.
In a nested casecontrol study of 734
patients aged 66 years or older who were
given clopidogrel following an acute myo-
cardial infarction and had a second admis-
sion within 90 days, and 2057 controls,
current use of proton pump inhibitors was
associated with an increased risk of rein-
farction (adjusted OR 1.27; 95% CI
1.03, 1.57) [181C]. In a stratied analysis,
pantoprazole, which does not inhibit
CYP2C19, was not associated with readmis-
sion for myocardial infarction (adjusted OR
1.02; 95% CI 0.70, 1.47).
Similarly, in a retrospective cohort study
of 8205 patients with acute coronary syn-
drome who took clopidogrel after dis-
charge, of whom 5244 also took a proton
pump inhibitor, combined use was associ-
ated with an increased risk of death or
rehospitalization for acute coronary syn-
drome (adjusted OR 1.25; 95% CI
1.11, 1.41) [182c].
In a study of the effect of pantoprazole,
omeprazole, and esomeprazole on platelet
responses to clopidogrel in 1000 patients,
of whom 268 were taking a proton pump
inhibitor at the time of platelet function
testing with adenosine diphosphate (panto-
prazole, n 162; omeprazole, n 64;
esomeprazole, n 42), platelet aggregation
was signicantly greater in those taking
omeprazole, but not pantoprazole or
esomeprazole, compared with patients
who were not taking proton pump inhibi-
tors [183C].
However, other studies have shown small
effects or none. In 18 565 clopidogrel users,
Chapter 35 723
2.6% of those who were also taking a pro-
ton pump inhibitor versus 2.1% of non-
users were hospitalized with a myocardial
infarction; 1.5% versus 0.9% died and
3.4% versus 3.1% underwent revasculariza-
tion [184C]. The propensity score-adjusted
rate ratios were: 1.22 (95% CI 0.99,
1.51) for the primary end-point of myocar-
dial infarction or death; 1.20 (95% CI
0.84, 1.70) for death; and 0.97 (95% CI
0.79, 1.21) for revascularization. The
authors concluded that if there is an inter-
action, it is unlikely to exceed a 20%
increase in risk.
In the PRINCIPLE-TIMI 44 trial, 201
patients undergoing elective percutaneous
coronary intervention were randomly
assigned to prasugrel (n 102) or high-
dose clopidogrel (n 99); mean inhibition
of platelet aggregation was signicantly
lower in patients taking a proton pump
inhibitor at 6 hours after a loading dose of
clopidogrel 600 mg and there was a smaller
difference after a loading dose of prasugrel
60 mg [185C]. However, in the TRITON-
TIMI 38 trial, in which 13 608 patients with
an acute coronary syndrome were ran-
domly assigned to prasugrel (n 6813) or
clopidogrel (n 6795), there was no associ-
ation between the use of proton pump
inhibitors and the risk of the primary end-
point in those taking clopidogrel or
prasugrel.
Ranitidine In an open, two-period, two-
treatment, crossover study in 47 healthy
men, ranitidine had no clinically signicant
effects on the pharmacokinetics of the
active metabolites of either prasugrel or
clopidogrel [186c].
Drugsmoking interactions In 259 patients
who underwent coronary stenting and were
taking clopidogrel, 104 were current
smokers and 155 were non-smokers. Smok-
ing was independently associated with
reduced platelet aggregability and lower
active glycoprotein IIb/IIIa expression,
and smokers had greater platelet inhibition
with clopidogrel [187c]. This was probably
due to a pharmacodynamic interaction,
although smoking also induces the activity
724
of CYP1A2, which is involved in the con-
version of clopidogrel to its active
metabolite.
When platelet aggregation was studied in
102 patients taking dual antiplatelet ther-
apy 24 hours after peripheral, coronary, or
carotid artery stenting, current smokers
had signicantly lower P2Y12 Reaction
Units compared with non-smokers, and in
a multivariate regression analysis smoking
was an independent inuencing variable
for ADP-inducible platelet reactivity;
smoking was associated with enhanced clo-
pidogrel-mediated but not aspirin-mediated
inhibition of platelet aggregation [188c].
In a study of the relation between smok-
ing status (current smoker, former smoker,
or never smoker) and treatment with clopi-
dogrel on the risk of mortality in 12 152
patients, current smoking was associated
with an increase in all-cause mortality
(adjusted HR 2.58; 95% CI 1.85,
3.60), cardiovascular mortality (HR 2.26;
95% CI 1.48, 3.45), and cancer-related
mortality (HR 3.56; 95% CI 1.96,
6.46) compared with never smoking
[189C]. Among current smokers, clopido-
grel was associated with a reduction in all-
cause mortality (HR 0.68; 95% CI
0.49, 0.94), but it did not reduce all-cause
mortality among former smokers (HR
0.95; 95% CI 0.75, 1.19) or never
smokers (HR 1.14; 95% CI 0.83,
1.58); there was a similar pattern for cardio-
vascular mortality but not for cancer-
related mortality. Clopidogrel was also
associated with a signicantly increased risk
of severe or moderate bleeding among cur-
rent smokers. The authors concluded that
in current smokers clopidogrel may be
more effective but may also be associated
with a greater risk of bleeding.
Management of adverse drug reactions
Desensitization in a case of clopidogrel
and ticlopidine allergy has been described
in a 55-year-old man; he was given increas-
ing oral doses of clopidogrel from 0.005 to
75 mg at half-hour intervals over 7 hours
[190A].
In a retrospective study of the efcacy of
an out-patient oral clopidogrel
Chapter 35 J.K. Aronson
desensitization protocol, eight patients
were successfully desensitized using 10
doses given during 23 half-day clinical
visits and were able to go home between
desensitization sessions without complica-
tions [191c]. There were no recurrences of
allergic reactions 3 months after the proce-
dure. The authors suggested that out-
patient desensitization is cheaper than in-
patient desensitization.
Of 2701 patients who underwent percu-
taneous coronary intervention, 20 had
adverse skin reactions to clopidogrel and
were treated with a combination of oral
prednisolone 30 mg/day for 5 days and
chlorphenamine 4 mg tds for 7 days, while
clopidogrel was continued [192c]. There
was complete resolution in most of the
patients within an average of 3.2 days; one
had partial resolution and one had no
response to treatment, but both were able
to continue clopidogrel.
Ticlopidine [SEDA-32, 642]
Hematologic Neutropenia due to ticlopi-
dine usually occurs within the rst 3 months
(i.e. has an intermediate time course), but
has also been reported after about 18
months [193A].
Liver Acute cholestatic hepatitis has been
attributed to ticlopidine in a 68-year-old
woman [194A].
HEMOSTATIC AGENTS
Aprotinin [SED-15, 331; SEDA-31, 566;
SEDA-32, 642]
Aprotinin and renal function
The use of aprotinin in patients undergoing
surgery has been reported to increase the
Drugs that affect blood coagulation, brinolysis, and hemostasis
risk of renal impairment (SEDA-32, 642),
and the authors of a review of data from
basic science studies in tissues, animals, and
man, as well as data from observational
studies and randomized controlled trials,
concluded that aprotinin causes a transient
small rise in plasma creatinine concentration
in some patients, but that there is no evi-
dence of an increased risk of new renal
insufciency requiring renal replacement
therapy [195R].
Further reports have appeared, many
being comparisons between aprotinin and
either tranexamic acid or aminocaproic acid.
The results have been conicting.
Studies showing renal impairment In a sys-
tematic review of 11 studies, including 10
that studied renal function and seven that
studied deaths, aprotinin was associated with
renal dysfunction (risk ratio, RR 1.42;
95% CI 1.13, 1.79) and long-term mortal-
ity (HR 1.22; 95% CI 1.08, 1.39)
[196M]. Pooled estimates were lower for
short-term mortality (RR 1.16; 95% CI
0.84, 1.58) and renal failure requiring
dialysis (RR 1.17; 95% CI 0.99, 1.38).
Time on bypass was a signicant source of
heterogeneity, with a 29% increased risk of
renal dysfunction for every 10-minute
increase in bypass time.
In a prospective comparison of aprotinin (n
1507) and aminocaproic acid (n 1830) in
patients undergoing surgery, postoperative
renal failure was signicantly more common
in the former (6.2% versus 2.7%) and at
median 5.4-year follow-up (up to 12 years)
mortality was higher (KaplanMeier failure
rates 44% versus 24% at 8 years), with a step-
wise relation between weight-based aprotinin
dose and mortality [197C].
In a non-randomized prospective study of
1188 patients who underwent cardiac sur-
gery, the rst 596 received aprotinin and
the next 592 received tranexamic acid
[198c]. Postoperatively, in those who under-
went primary valve surgery, tranexamic acid
was associated with signicantly higher inci-
dences of seizures (4.6% versus 1.2%), per-
sistent atrial brillation (7.9% versus
2.3%), and renal insufciency (9.7% versus
1.7%). In those who underwent primary
Chapter 35 725
coronary artery bypass surgery and received
aprotinin, there were more cases of acute
myocardial infarction (5.8% versus 2.0%)
and renal dysfunction (23% versus 15%).
In a follow-up database study of 3535
patients who underwent cardiac surgery,
635 were treated with aprotinin and 2900
with tranexamic acid. Those who received
aprotinin had an increased risk of postoper-
ative dialysis (adjusted RR 1.76; 95% CI
1.15, 2.70) [199c].
Studies showing no renal impairment In a
non-randomized study in 2101 patients
who underwent coronary artery bypass
grafting and valve surgery, alone or com-
bined, and who received either aprotinin
(n 1898) or aminocaproic acid (n
203), operative mortality was higher with
aprotinin in univariate analysis (4.3% versus
1%) but not propensity score-adjusted
multivariate analysis (4% versus 0.9%)
[200c]. In propensity score-adjusted analy-
sis, aprotinin was also associated with a
lower rate of blood transfusion (39% versus
50%), a lower rate of hemorrhage-related
re-exploration (3.7% versus 7.9%), a higher
risk of in-hospital cardiac arrest (3.7% ver-
sus 0%), and a marginally but not statisti-
cally signicantly higher risk of acute renal
failure (6.8% versus 2.6%). In Cox propor-
tional hazards regression analysis, the risk
of late death was higher with aprotinin
(HR 4.33, 95% CI 1.60, 12).
In a non-randomized study, 391 patients
who were given aprotinin after median
sternotomy for non-bypass surgery were
compared with 370 controls; postoperative
cardiac, renal, neurological, and respiratory
complications and hospital mortality were
similar in the two groups [201c].
In a matched cohort study, in which 200
patients who received high-dose aprotinin
were compared with 200 age- and sex-
matched patients who received tranexamic
acid during primary isolated coronary sur-
gery, there were no signicant differences in
fractional change in creatinine clearance or
any other assessments of postoperative renal
function between the two groups [202c].
Adverse events rates were also similar for
early mortality (3.5% versus 4.5%), stroke
726
(1.5% versus 2%), re-operation for bleeding
(3.5% versus 2.5%), and 5-year survival
(87% versus 84%). Patients in the aprotinin
group needed fewer transfusions (48% ver-
sus 61%) and fewer units of packed erythro-
cytes (2.0 versus 1.4) and plasma (1.3 versus
0.5), but more units of platelets (0.2 versus
0.1).
In a single-center non-randomized study
in patients undergoing primary cardiac
operations, 3334 were given aprotinin and
3417 were not [203c]. The former were
older, and had more unstable symptoms,
lower ejection fractions, more preoperative
hemodynamic support, more urgent opera-
tions, and more combined coronary or val-
vular operations. Postoperative bleeding
and blood product transfusion were consid-
erably reduced by aprotinin, as was median
duration of mechanical ventilation. Apro-
tinin was not related to postoperative myo-
cardial infarction, renal insufciency,
neurological dysfunction, or operative
death.
In a placebo-controlled study of 26 neo-
nates who underwent cardiac surgery, apro-
tinin was not efcacious and had no
deleterious effect on renal function; the
authors suggested that it is unclear whether
adverse reactions data on aprotinin from
studies in adults are relevant to neonates
[204c]. Similarly, in a controlled study in
31 patients who underwent neuromuscular
scoliosis surgery, aprotinin reduced total
blood loss and did not cause renal impair-
ment. However, these studies were too small
to draw any conclusions.
In a retrospective survey of 200 neonates
scheduled for palliative or corrective con-
genital cardiac surgery requiring cardiopul-
monary bypass, 156 were given aprotinin
and 44 were not [205c]. There was more
renal dysfunction in those who received
aprotinin, although the difference was not
statistically signicant. Time on bypass and
age were signicant predictors of postopera-
tive renal dysfunction irrespective of the use
of aprotinin.
In a retrospective cohort study of 395 chil-
dren who underwent cardiac surgery, 55%
received aprotinin and 45% did not; 17%
were neonates [206c]. Although there was a
Chapter 35 J.K. Aronson
signicant difference in the unadjusted risk
of renal dysfunction, adjustment with the
preoperative propensity score showed that
there was no association between aprotinin
and renal dysfunction (OR 1.32; 95% CI
0.55, 3.19). The duration of bypass was
the only independent variable associated
with renal dysfunction (OR 1.0; 95% CI
1.00, 1.01).
Conclusions On the whole, although not
exclusively, the positive associations of apro-
tinin with impaired renal function have
come from systematic reviews and large ran-
domized studies, while the negative studies
have tended to be small or retrospective.
Immunologic Allergic reactions to intra-
venous aprotinin continue to be reported,
as in the case of a 67-year-old man who
had been treated with an aprotinin-contain-
ing brin sealant and 3 years later had an
anaphylactic reaction after intravenous
administration of aprotinin, associated with
aprotinin-specic IgG and IgE antibodies
[207A], and a 66-year-old man who had
anaphylactic shock within 2 minutes of a
rapid infusion of aprotinin 4 million units
following two previous infusions of 2 mil-
lion units each [208A].
Death In a double-blind, randomized, pla-
cebo-controlled trial, 298 patients sched-
uled for low- or intermediate-risk rst-
time cardiac surgery with cardiopulmonary
bypass were randomized to tranexamic
acid, high-dose aprotinin, or placebo. Nei-
ther antibrinolytic agent increased the
incidence of death [209C]. However, a
meta-analysis, updated in the light of these
data, still showed increased mortality attrib-
utable to aprotinin (OR 1.50; 95% CI
1.04, 2.27) [210M].
The problems with meta-analyses that
include small trials whose primary aims
were not relevant to the analyses have been
highlighted, throwing doubts on meta-ana-
lyses that have not shown an increased
mortality in patients who have received
aprotinin [211H].
Drugs that affect blood coagulation, brinolysis, and hemostasis
Protamine [SED-15, 2964; SEDA-30,
417; SEDA-32, 646]
Cardiovascular In 242 consecutive patients
(mean age 58 years, 193 men) with drug
refractory atrial brillation who underwent
catheter ablation and received protamine
immediately after catheter ablation to
reverse the effects of heparin, 58 had prior
exposure to protamine; three developed
an adverse reaction to protamine (1.2%),
each with profound hypotension [212c].
Life-threatening pulmonary vasoconstric-
tion occurred in a 62-year-old male chronic
smoker with long-standing systemic hyper-
tension and hypercholesterolemia within
10 minutes of an intravenous infusion of
protamine 4 mg/kg after coronary artery
bypass graft surgery; the authors attributed
this to the formation of large heparinpro-
tamine complexes after rapid infusion of
protamine [213A]. In another case acute
pulmonary hypertension induced by prot-
amine during elective coronary artery
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 Corrado Blandizzi and Carmelo Scarpignato
36 Gastrointestinal drugs
ANTACIDS [SED-15, 243; SEDA-
30, 423; SEDA-31, 573; SEDA-32, 665]
Drugdrug interactions Eltrombopag The
effects of food and an antacid containing alu-
minum hydroxide and magnesium carbonate
on the pharmacokinetics of eltrombopag
have been studied in two single-dose, open,
randomized-sequence, crossover studies in
18 and 26 healthy adults. Mean plasma
AUC and Cmax fell by about 70% when
eltrombopag was given with the antacid [1c].
Pirfenidone In an open, single-dose, cross-
over study of the effects of food and an ant-
acid (Mylanta Maximum Strength Liquid)
on the pharmacokinetics of pirfenidone
in 16 healthy adults, co-administration with
food reduced the rate and, to a lesser
degree, the extent of pirfenidone absorption;
the antacid had no signicant effect [2c].
ANTIEMETICS AND DRUGS
THAT AFFECT
GASTROINTESTINAL
MOTILITY [SEDA-30, 423;
SEDA-31, 573; SEDA-32, 665]
Cannabinoids (see also Chapter 4)
Systematic reviews In a systematic review of
the evidence for using cannabinoids in the
Side Effects of Drugs, Annual 33
J.K. Aronson (Editor)
ISSN: 0378-6080
DOI: 10.1016/B978-0-444-53741-6.00036-2
# 2011 Elsevier B.V. All rights reserved.
management of chemotherapy-induced nau-
sea and vomiting in patients with cancer,
nabilone, dronabinol, and levonantradol
were superior to placebo and neuroleptic
drugs [3M]. However, the cannabinoids
caused adverse effects in some patients, even
when they were given orally and even when
their use was limited to 24 hours. Some unto-
ward reactions occurred almost exclusively
in patients who were exposed to them: para-
noid delusions (5%), hallucinations (6%),
and dysphoria and/or depression (13%).
Although the patients had more adverse
effects and greater intensity of symptoms
during treatment with cannabinoids, most of
the dropouts, associated with these events
which were responsible for almost 30% of
the nearly 400 dropouts in all the studies
included in the systematic review, were
probably not due to cannabinoid toxicity.
Cisapride [SED-15, 789; SEDA-31, 573]
Cardiovascular The possible association
between cisapride and ventricular dysrhyth-
mias has been evaluated in a nested case
control study of 145 cases and 7520 controls
exposed to cisapride, metoclopramide, or
proton pump inhibitors [4C]. Cases included
hospitalized patients with sudden cardiac
death or ventricular dysrhythmias. Cisa-
pride, but not metoclopramide, was associ-
ated with a two- to threefold increased risk
of hospitalization for ventricular dysrhyth-
mias, with a nearly eightfold risk during the
initial prescription period. In this analysis,
the risk associated with cisapride seemed
not to be dose related, which implies one of
four different interpretations:
741
742 Chapter 36
The effect was not real.
The effect had its doseresponse curve at
much lower doses than the authors studied,
and the reported observations were made at
the top of the dose-response curve; this is
unlikely in this case.
The interindividual variability was so large
that it obscured the dose responsiveness; how-
ever, in that case the mean estimates of effect
at each dose should have been dose-related,
even if the overall relation was not apparently
signicant.
The doseresponse curve for the effect was
very shallow compared with the range of
doses being studied.
In addition, the use of potentially dys-
rhythmogenic CYP3A4 inhibitors was asso-
ciated with an increased risk, but this
appeared to depend on a direct dysrhyth-
mogenic effect of the drugs themselves,
rather than on an interaction with cisapride.
Clebopride
Nervous system An 83-year-old woman
developed acute hemifacial dystonia,
involving the masticatory and tongue mus-
cles, after self-medication with clebopride
1.5 mg/day for constipation [5A]. She had
a dystonic facial posture, with torsion and
mouth deviation, while cranial/neck MRI
and electroencephalography showed no
abnormalities. The event persisted after
reduction of the dosage of clebopride to
0.5 mg/day for 2 weeks, but resolved within
2 days after drug withdrawal. This event
was interpreted as having resulted from
extrapyramidal effects of clebopride, but a
possible diagnosis of a transient ischemic
attack was not considered.
Domperidone [SED-15, 1178;
SEDA-30, 423; SEDA-32, 665]
Comparative studies Regurgitation and
gastroesophageal reux are common pediat-
ric problems, and cisapride is no longer
available for this indication in several coun-
tries. Domperidone (0.8 mg/kg/day; n 10)
Corrado Blandizzi and Carmelo Scarpignato
and cisapride (0.8 mg/kg/day; n 10) have
been compared in a single-blind, random-
ized trial in infants. Cisapride caused QT
interval prolongation in one infant [6c].
Systematic reviews The efcacy of domperi-
done in diabetic gastroparesis has been evalu-
ated in a systematic review of 28 clinical trials
in a total of 1016 patients [7M]. Domperidone
improved symptoms, enhanced gastric emp-
tying, and reduced hospital admissions in
6070% of trials. None of the studies assessed
the risk of adverse reactions to domperidone
versus comparators. The most common
adverse reaction was hyperprolactinemia,
but in no case was it serious.
Metoclopramide [SED-15, 2317;
SEDA-30, 423; SEDA-31, 574]
Comparative studies In a double-blind,
randomized comparison of a single intra-
venous bolus dose of metoclopramide
10 mg or midazolam 2 mg in reducing eme-
sis in 80 women undergoing elective cesar-
ean delivery under spinal anesthesia (0.5%
bupivacaine 10 mg), the frequency of
intraoperative nausea and vomiting was
lower with midazolam than with metoclo-
pramide [8C]. However, sedation scores
and the frequency of respiratory depression
were higher with midazolam17 of those
who were given midazolam had a respira-
tory rate below 10/minute. Neonatal out-
comes were similar in the two treatment
groups, and all the neonates had Apgar
scores over 8, evaluated at 1 and 5 minutes
after delivery.
Cardiovascular A 17-year-old man with a
3-year history of ulcer symptoms, diarrhea,
and bouts of abdominal colic developed
severe hypotension (50/20 mmHg) after
receiving intravenous metoclopramide for
acute vomiting with diarrhea [9A]. He then
developed pneumonia, rhabdomyolysis,
renal tubular necrosis, and disseminated
intravascular coagulation. A diagnosis of
gastrinoma was made. During hormonal
assessment, he received a second dose of
Gastrointestinal drugs Chapter 36
metoclopramide for abdominal pain and
vomiting. His condition then deteriorated
again; his blood pressure fell to
90/50 mmHg, and he was resuscitated with
plasma expanders and inotropic drugs.
Although positive rechallenge in this case
suggested a drug-related effect, the under-
lying neuroendocrine disorder with its auto-
nomic consequences made it very difcult
to interpret this particular adverse event.
An 86-year-old man with a history of
hypertension, hypothyroidism, and gastro-
esophageal reux developed symptoms of
cardiac failure while taking lisinopril,
levothyroxine, and metoclopramide 10 mg
qds [10A]. Furosemide administration was
associated with renal impairment, and fol-
lowed by QT interval prolongation, which
evolved into torsade de pointes. After suc-
cessful debrillation, the QT interval pro-
longation persisted and resolved only after
metoclopramide withdrawal.
Nervous system A 40-year-old man was trea-
ted with metoclopramide by intravenous infu-
sion of 10 mg over 5 minutes and famotidine
20 mg as premedication for elective endo-
scopic sinus surgery. About 1015 minutes
after metoclopramide administration, he
developed agitation, tachycardia, and hyper-
tension, which resolved after treatment with
oxygen 2 liters/minute and intravenous
diphenhydramine 25 mg [11M].
Endocrine Metoclopramide can cause
gynecomastia, and has been reported to do
so in a neonate.
A full-term male neonate with trisomy 21, pat-
ent ductus arteriosus, stridor, and feeding
intolerance was thought to have irritation of
the airways due to gastroesophageal reux
[12A]. He was given metoclopramide
0.15 mg/kg every 8 hours for 45 days. Owing
to symptom persistence, lansoprazole 1.5 mg/
kg/day was added and the dose of metoclopra-
mide was increased to 0.2 mg/kg every 6 hours.
Two weeks later, he was noted to have prom-
inent breasts (asymmetrical gynecomastia,
greater on the right than on the left) with milk
outow. Serum prolactin concentrations were
two times higher than the upper limit of the
reference range, but scrotal ultrasound was
normal. Metoclopramide was withdrawn and
both the gynecomastia and galactorrhea
743
resolved within 1 week. The prolactin concen-
trations returned within the reference range 2
weeks after withdrawal
Drug dosage regimens The effect of the
rate of infusion of metoclopramide on the
incidence of acute akathisia has been inves-
tigated in a double-blind, randomized trial
in 68 adults with acute nausea, vomiting,
or migraine [13C]. They were randomized
to one of two dosage regimens, in which
metoclopramide 10 mg was given either as
a 2-minute bolus or as an intravenous
infusion over 15 minutes. They all received
isotonic saline as a placebo in a double-
dummy design, to maintain blinding.
Of those who received bolus doses 11%
developed akathisia, compared with none
in the infusion group, supporting the con-
clusion that giving metoclopramide by infu-
sion, rather than by bolus injection, will
reduce the incidence of akathisia.
Prucalopride
Prucalopride is the rst of a new class
(dihydrobenzofurancarboxamide deriva-
tives) of highly selective 5HT4 receptor
agonists, with strong enterokinetic activity
and efcacy in patients with chronic consti-
pation in whom laxatives do not provide
adequate relief [14R]. It has afnity for
other receptors, ion channels, and trans-
porters at concentrations that exceed its
5HT4 receptor-afnity by at least 150 times,
suggesting a wide safety margin at thera-
peutic doses.
Placebo-controlled studies The efcacy
and safety of prucalopride 2 or 4 mg/day
for 12 weeks has been assessed in a
double-blind, placebo-controlled trial in
patients with severe chronic constipation
[15C]. The most common drug-related
adverse events included headache, abdomi-
nal pain, nausea, and diarrhea (which
occurred mainly on day 1 of treatment).
However, there were no differences in the
incidences of serious adverse effects or car-
diovascular events compared with placebo.
744 Chapter 36
In a double-blind, randomized, placebo-
controlled trial of prucalopride 2 or
4 mg/day for 12 weeks in 716 patients with
chronic constipation, the most common
drug-related adverse events were headache,
nausea, abdominal pain, and diarrhea [16C].
The overall incidence of prolongation of
the QT interval was low and similar among
all treatment groups. Withdrawals as a
result of these adverse events accounted
for a higher dropout rate in those who took
prucalopride 4 mg/day (15%), than in the
other treatment groups (6.3% and 6.7%
with 2 mg/day and placebo respectively).
In a phase II, double-blind, randomized,
dose-escalation study of prucalopride 0.5,
1, and 2 mg/day for 28 days in 89 elderly
chronically constipated patients in nursing
homes, the most common adverse events,
which were probably related to prucalo-
pride, were diarrhea and abdominal pain
[17C]. Relative to placebo, there were no
differences in vital signs, electrocardiogra-
phy, and the incidence of dysrhythmias.
Tegaserod
Tegaserod is a selective partial agonist at
5HT4 receptors, which normalizes gastro-
intestinal function by stimulating neuro-
transmitter release from enteric nerves.
The resulting effects include increased
intestinal secretions and contractility,
enhancement of peristaltic and secretory
reexes, and inhibition of visceral afferent
responses involved in abdominal pain sig-
nal transmission. Tegaserod has been used
in women with irritable bowel syndrome
associated with constipation and in patients
with idiopathic constipation [18R]. How-
ever, marketing was suspended at the
request of regulatory authorities after they
had reviewed reports of ischemic cardiovas-
cular events in patients who had been
enrolled in double-blind trials [19R],
although these ndings were not conrmed
in a matched case-control study [20C].
Observational studies In two prospective
cohort studies of tegaserod 6 mg bd for
Corrado Blandizzi and Carmelo Scarpignato
1 year in 780 women with functional dys-
pepsia, the most commonly reported
adverse events occurred in the rst 6
months and consisted mainly of diarrhea,
headache, nausea, abdominal pain, vomit-
ing, and constipation, all of which were
mostly transient and mild or moderate in
intensity [21C]. One patient developed
bradycardia, dizziness, and hypoglycemia.
There was no association of tegaserod with
adverse cardiovascular events.
Placebo-controlled studies The efcacy of
tegaserod 6 mg bd for 6 weeks in 2667
women with dysmotility-like functional dys-
pepsia has been evaluated in two random-
ized, double-blind, placebo-controlled
trials [22C]. There were some improve-
ments in symptom severity and quality of
life in those who took tegaserod, although
the clinical implication of these improve-
ments is uncertain. Diarrhea, requiring drug
withdrawal, was more common with tega-
serod than with placebo.
5HT 3 RECEPTOR
ANTAGONISTS [SED-15, 1365;
SEDA-30, 423; SEDA-31, 575;
SEDA-32, 666]
Comparative studies Azasetron versus
ondansetron Intravenous azasetron 10 mg
and ondansetron 8 mg have been compared
in a double-blind, randomized trial in 98
patients with postoperative nausea and
vomiting after gynecological laparoscopic
surgery under general anesthesia [23C]. Aza-
setron was more efcacious in the intermedi-
ate postoperative period (1224 hours). Both
drugs caused headache, dizziness, and consti-
pation and the frequencies were similar.
Granisetron versus palonosetron In a ran-
domized, double-blind comparison of a
single intravenous dose of palonosetron
0.25 mg and granisetron 3 mg in 208
patients with cancer who were about to
Gastrointestinal drugs Chapter 36
receive highly emetogenic chemotherapy,
palonosetron was non-inferior to granise-
tron and there were no clinically relevant
differences in the overall incidences of
adverse events [24C]. The main adverse
events were: headache (1% in both
groups), constipation (1% in both groups),
and hypokalemia (1.9% versus 1%).
Single-dose intravenous palonosetron
0.75 mg and granisetron 40 micrograms/kg
(both combined with intravenous dexa-
methasone and given 30 minutes before
highly emetogenic chemotherapy) have
been compared in a double-blind, random-
ized study in 1114 patients with cancer
[25C]. Palonosetron was non-inferior to
granisetron in the acute phase of vomiting,
but signicantly better in the delayed
phase. The main adverse events were con-
stipation (17% versus 16%), raised serum
aminotransferases activities (aspartate
aminotransferase 4.3% versus 6%; alanine
aminotransferase 2.9% versus 5.9%), head-
ache (3.2% versus 3.7%), and QT interval
prolongation (2.7% versus 3.2%). One
patient developed hepatitis possibly related
to palonosetron.
Granisetron versus ramosetron In a double-
blind, randomized comparison of ramose-
tron or granisetron 3 mg, each given with
dexamethasone 20 mg, for the prevention
of acute chemotherapy-induced nausea and
vomiting in 285 patients with cancer who
were scheduled to receive cisplatin, doxo-
rubicin, epirubicin, or oxaliplatin, the ramo-
setron combination was non-inferior to the
granisetron combination in preventing nau-
sea and vomiting [26C]. Seven patients
(2.46%; 3 in the ramosetron group and 4 in
the granisetron group) had drug-related
adverse effects of mild to moderate intensity,
which included raised liver enzymes and uric
acid, hiccups, rash, and constipation.
Ondansetron versus ramosetron In a dou-
ble-blind, randomized study of intravenous
ramosetron 0.3 mg and ondansetron 4 mg
followed by 12 mg in preventing nausea
and vomiting related to opioid-based
patient-controlled analgesia in 94 women
745
subjected to lumbar spine surgery, ramose-
tron was superior to ondansetron, and the
proportion of patients who had headache,
drowsiness, and dizziness was higher in
those who received ondansetron [27C].
Alosetron [SEDA-29, 372; SEDA-30,
423; SEDA-31, 575; SEDA-32, 666]
A quantitative benet-harm balance analy-
sis of alosetron for the treatment of irrita-
ble bowel syndrome from the patient's
perspective has been reported [28C]. There
was greater than 99% chance that both the
incremental benet and the incremental
risk associated with alosetron are greater
than with placebo. The incremental net
benet of alosetron was greatest in patients
with the worst quality of life at baseline.
Azasetron
Azasetron, a potent selective 5HT3 recep-
tor antagonist, is a benzamide derivative
that has a different chemical structure and
a longer duration of action than other
5HT3 receptor antagonists, such as granise-
tron, ondansetron, and tropisetron [29E].
For a comparison of azasetron with ondan-
setron, see above.
Dolasetron
Drugdrug interactions See Neurokinin
NK1 receptor antagonists below.
Granisetron
Drugdrug interactions See Neurokinin
NK1 receptor antagonists below.
Ondansetron
Cardiovascular There have been reports of
bradycardia attributed to ondansetron [30A].
An 8-year-old child with a perianal abscess
was given intravenous ondansetron 2 mg and
746 Chapter 36
within 23 minutes developed severe sinus
bradycardia (16/minute), which resolved after
intravenous atropine 0.2 mg and ventilation
with 100% oxygen.
A 60-year-old man with gastric carcinoma was
given intravenous glycopyrrolate 10 mg/kg fol-
lowed by ondansetron 4 mg as pre-medication
for surgical operation. Within 2 minutes from
ondansetron administration, the patient
developed severe bradycardia (20 beats/min)
associated with respiratory arrest and loss con-
sciousness, which was resolved by intravenous
administration of atropine 0.6 mg and ventila-
tion with 100% oxygen.
Other cardiac dysrhythmias have also
been reported [31A].
Postoperatively, a 51-year-old man was given
intravenous ondansetron 4 mg and glycopyr-
rolate 0.3 mg, followed by intravenous ondan-
setron 4 mg about 3 hours later. Immediately
after the second dose he vomited and com-
plained of chest pain. Electrocardiography
showed ST segment elevation and new-onset
atrial brillation. The systolic blood pressure
fell from 160 to 90 mmHg, and the QTc inter-
val increased from 416 to 457 ms. Cardiac
investigations, including troponin concentra-
tions, catheterization, and transesophageal
echocardiography, were normal. Electrical
cardioversion restored sinus rhythm. His
symptoms and cardiac dysrhythmia did not
recur during the next 3 years.
Nervous system A 26-year-old woman
undergoing emergency cesarean delivery
under spinal anesthesia with bupivacaine
10 mg was pre-medicated with intravenous
ranitidine 50 mg and metoclopramide
10 mg, and received intramuscular diclo-
fenac for postoperative analgesia [32A].
Starting at 12 hours postoperatively she
was given intravenous ondansetron 6 mg
every 12 hours for nausea and vomiting.
About 2 hours after the rst dose she devel-
oped a severe headache, which persisted for
over 90 hours and was characterized by
aggravation of symptoms in coincidence
with doses of ondansetron. The headache
resolved completely a few hours after
ondansetron withdrawal.
Ondansetron has both proconvulsant and
anticonvulsant effects in animals. Seizures
have been reported in two women and
one man (ages 3856 years) after
Corrado Blandizzi and Carmelo Scarpignato
intravenous administration of ondansetron
4 mg in order to manage severe nausea and
vomiting associated with migraine, gastritis,
and diabetic ketoacidosis [33A]. They had
generalized tonicclonic seizures 12, 15, and
22 minutes after the injection. In all cases,
brain MRI and electroencephalography
were normal, the seizures resolved sponta-
neously, and there were no relapses.
Liver Rises in serum aminotransferases
have been attributed to ondansetron [34A].
A 44-year-old woman with extensive coronary
artery disease developed nausea, shortness of
breath, and angina unrelieved by sublingual
glyceryl trinitrate. Her other drug therapy
consisted of gembrozil 600 mg bd, aspirin
81 mg/day, clopidogrel 75 mg/day, omepra-
zole 20 mg/day, and duloxetine 60 mg/day.
She was given intravenous ondansetron 4 mg
and morphine 4 mg, sublingual glyceryl trini-
trate 0.4 mg, oral aspirin 325 mg and clopido-
grel 75 mg, and heparin 60 U/kg. The chest
pain resolved. On the next day her amino-
transferase activities increased to nearly 18
times the upper limit of the reference range,
in the absence of other abnormalities of liver
function or liver ultrasonography. Ondanse-
tron was withdrawn and the aminotransferases
promptly fell and normalized within a
few days.
Immunologic Hypersensitivity reactions to
ondansetron are rare but have been
reported, including both IgE- and non-
IgE-mediated anaphylactic reactions.
A 44-year-old woman was given ondansetron,
vecuronium, and propofol at induction for
elective surgery and immediately became
hypotensive (60/30 mmHg) [35A]. There were
no accompanying skin or systemic symptoms,
and the episode resolved completely after
treatment with intravenous adrenaline,
promethazine, hydrocortisone, and uids.
Subsequent skin prick tests with ondansetron,
vecuronium, and propofol were negative,
but intradermal testing with ondansetron
0.02 mg/ml produced a positive wheal reaction.
Drug overdose Severe toxicity occurred in
a 12-month-old boy who unintentionally
took 7 or 8 tablets of ondansetron 8 mg
(5.66.4 mg/kg against a therapeutic dosage
of 0.15 mg/kg), and developed obtundation
and myoclonic movements of the limbs
Gastrointestinal drugs Chapter 36
within 20 minutes [36A]. He then developed
seizures, hepatotoxicity, QT interval pro-
longation, and serotonin syndrome, which
required endotracheal intubation and
treatment with intravenous midazolam,
morphine, and suxamethonium. A brief gen-
eralized tonicclonic seizure, associated with
signicant oxygen desaturation, was treated
with lorazepam. His conditions improved
over the course of 24 hours with supportive
care and there were no sequelae.
Drugdrug interactions Droperidol In a
double-blind, randomized, crossover study
16 healthy volunteers were treated with sin-
gle intravenous doses of ondansetron 4 mg,
droperidol 1 mg, or ondansetron 4 mg
droperidol 1 mg, in order to assess the effects
of these drugs on QT interval duration [37C].
Droperidol and ondansetron, alone and in
combination, induced signicant QT interval
prolongation. However, the combination did
not signicantly increase QT prolongation
compared with droperidol alone.
Palonosetron
Palonosetron is a second-generation, potent,
highly selective 5HT3 receptor antagonist,
with high binding afnity to the receptor
and a long terminal half-life (about
40 hours), which is effective as a single-dose
treatment in preventing both acute and
delayed nausea and vomiting associated
with both moderately and highly emetogenic
chemotherapy [38R]. The most common
adverse reactions in clinical trials include
headache (9%) and constipation (5%). Less
frequent adverse effects (<1%) involved
the cardiovascular system (tachycardia,
sinus dysrhythmia, supraventricular extra
beats, and QT interval prolongation), the
gastrointestinal system (diarrhea, dyspepsia,
abdominal pain, dry mouth, and atulence),
the nervous system (dizziness, somnolence,
insomnia, hypersomnia, and paresthesia),
and altered hearing and vision.
Nervous system A seizure has been attrib-
uted to palonosetron [39A].
747
A 43-year-old woman with breast cancer and
no history of seizures was scheduled to
undergo chemotherapy with cyclophospha-
mide, 5-uorouracil, and epirubicin and to
receive antiemetic treatment with intravenous
dexamethasone 8 mg and palonosetron
0.25 mg. During the fourth cycle of chemo-
therapy, she developed a generalized tonic
clonic seizure, which lasted 8 minutes and
was followed by a period of drowsiness. She
was given intravenous diazepam 10 mg and a
saline infusion. Detailed investigations,
including brain CT scan, did not reveal
abnormalities, and she recovered completely.
Although other 5HT3 receptor antagonists
(particularly ondansetron) have been previ-
ously reported to cause seizures, in this case
the role of palonosetron was uncertain.
Drug dosage regimens Different single
intravenous doses of palonosetron (0.025,
0.050, and 0.075 mg) have been compared
with placebo in a double-blind, randomized
study of its use in preventing postoperative
nausea and vomiting in 489 patients under-
going either outpatient abdominal or gyne-
cological laparoscopic surgery [40C]. There
was a doseresponse trend in the proportion
of patients with a complete antiemetic
response, and the effect over placebo was
signicant at the highest dose. Most of the
adverse events were of mild to moderate
intensity, and they were not apparently dose
related. The most common treatment-
related adverse events with placebo and
the three doses of palonosetron were head-
ache (4%, 4%, 7%, and 3% respectively)
and constipation (3%, 2%, 4%, and 3%).
No patients withdrew because of serious
adverse events. QT intervals were similar
in all the groups.
Ramosetron
Ramosetron is a selective 5HT3 receptor
antagonist, which has a high receptor bind-
ing afnity due to a slow dissociation rate,
resulting in more potent and more pro-
longed receptor blockade and antiemetic
effects compared with older 5HT3 receptor
antagonists [41R].
748 Chapter 36
Drugdrug interactions Fluvoxamine In an
open crossover study in healthy men and
women who took a single dose of ramose-
tron 10 micrograms, steady-state uvoxa-
mine 50 mg/day increased the Cmax and
AUC of ramosetron by 42% (90% CI 35,
49) and 178% (90% CI 153, 205) respec-
tively [42c].
NEUROKININ NK 1
RECEPTOR ANTAGONISTS
[SEDA-32, 667]
Aprepitant and fosaprepitant
A single intravenous dose of fosaprepitant
115 mg, a prodrug of aprepitant, is
bioequivalent to oral aprepitant 125 mg.
Cardiovascular In a double-blind, active-
controlled, randomized, three-treatment,
three-period, crossover study in young
healthy subjects fosaprepitant 200 mg had
no effect on the QT interval; moxioxacin
400 mg had the expected effect [43C].
Casopitant
Drugdrug interactions 5HT3 receptor ant-
agonists The effects of casopitant, a neuro-
kinin NK1 receptor antagonist, on the
pharmacokinetics of dolasetron 100 mg/day
for 3 days and granisetron 2 mg/day for 3
days have been studied in a phase I, open,
single-sequence study in 18 and 19 healthy
subjects respectively [44c]. The largest
changes in exposure to hydrodolasetron
after co-administration with casopitant were
seen in CYP2D6 extensive metabolizers,
with a 24% increase in AUC on day 1 and
a 30% increase in Cmax on days 1 and 3;
these changes were not considered to be
clinically important. Granisetron exposure
was not signicantly altered.
Corrado Blandizzi and Carmelo Scarpignato
HISTAMINE H 2 RECEPTOR
ANTAGONISTS [SED-15, 1629;
SEDA-30, 423; SEDA-31, 576;
SEDA-32, 667]
Cimetidine
Hematologic There have been a few reports
of immune hemolytic anemia in association
with cimetidine, but without convincing evi-
dence of an association. Now there has been
a report of a hemolytic anemia in which the
direct antiglobulin test was positive (C3
only) and a serum antibody to cimetidine
was detected; an eluate from the patient's
erythrocytes was non-reactive [45A].
Famotidine
Liver Famotidine has been associated with
acute hepatitis in a 47-year-old man with a
history of hepatitis C [46A].
Ranitidine
Immunologic The incidence of anaphylac-
tic reactions to ranitidine has been reported
to be 0.30.7%. Two cases of anaphylactic
shock have been attributed to intravenous
ranitidine, in one case fatal.
A 51-year-old man had a prostate resection
under epidural anesthesia and 24 hours later
was given a single intravenous dose of raniti-
dine 50 mg in isotonic saline as prophylaxis
for stress ulceration [47A]. Within a few
minutes he developed a combination of wheez-
ing, dyspnea, and hypotension, followed by loss
of consciousness. Despite intensive resuscita-
tion attempts, he died 30 minutes later.
Autopsy showed pulmonary congestion with
widespread upper airway edema and petechial
hemorrhages and brain swelling with diffuse
petechial hemorrhages. Histology conrmed
the presence of widespread hypolaryngeal and
pharyngeal edema with an inammatory cell
inltrate and abundant mast cells.
A 47-year-old woman developed an anaphy-
lactic reaction to ranitidine used as intra-
venous premedication before induction of
anesthesia [48A]. She had previously used oral
Gastrointestinal drugs Chapter 36
ranitidine for peptic ulceration without any
adverse reactions. An intradermal test with
ranitidine at a dilution of 1:100 was intensely
positive.
Drugdrug interactions Clopidogrel and
prasugrel In an open crossover study in 47
healthy men, ranitidine had no signicant
effect on the AUC, Cmax, or tmax of the
active metabolites of clopidogrel 75 mg/
day or prasugrel 10 mg/day for 7 days [49c].
HELICOBACTER PYLORI
ERADICATION REGIMENS
[SED-15, 1586; SEDA-30, 425;
SEDA-31, 579]
Lansoprazole amoxicillin
metronidazole or clarithromycin
There is limited information on Helicobacter
pylori eradication in children in developing
countries. In a study of 2-week triple therapy
in Vietnam, 238 H. pylori infected children
aged 315 years (mean 8.6) were divided into
two weight categories 1322 and 2345 kg
[50C]. The former received lansoprazole
15 mg/day amoxicillin 500 mg bd either
metronidazole 250 mg bd or clarithromycin
250 mg/day. The latter received twice daily
lansoprazole 15 mg amoxicillin 750 mg
either metronidazole 500 mg or clarithro-
mycin 250 mg. Adverse events included a
burning sensation in the mouth, a metallic taste
in the mouth, abdominal pain, nausea,
vomiting, dizziness, headache, and rash.
PROTON PUMP
INHIBITORS [SED-15, 2973;
SEDA-30, 424; SEDA-31, 577;
SEDA-32, 667]
Comparative studies Esomeprazole versus
lansoprazole In an open, randomized, com-
parative study of esomeprazole 40 mg/day
749
and lansoprazole 30 mg/day in patients with
Barrett's esophagus, the most common
adverse events in those taking esomepra-
zole were pharyngolaryngeal pain, sinusitis,
and headache [51c]. In contrast, the most
common adverse events in those taking
lansoprazole were diarrhea, nausea, anxiety,
and headache. Only two patients had
treatment-related adverse events, both
while taking lansoprazole; these included
three cases of diarrhea and one of abdomi-
nal pain.
Esomeprazole versus rabeprazole In a
multicenter, double-blind, double dummy,
randomized, non-inferiority comparison of
rabeprazole 20 mg/day and esomeprazole
20 or 40 mg/day for 4 weeks in primary care
in 1392 patients with gastroesophageal
reux disease complaining of heartburn,
with or without regurgitation, 800 adverse
events were recorded in 464 patients and
13 required hospitalization (rabeprazole
20 mg: 1.7%; esomeprazole 20 mg: 2.7%;
esomeprazole 40 mg: 0.4%) [52C]. The
most common adverse events for rabepra-
zole 20 mg/day, esomeprazole 20 mg/day,
and esomeprazole 40 mg/day respectively
were: gastrointestinal signs and symptoms
(n 86, 77, 80), gastrointestinal motility
and defecation disorders (n 26, 40, 32),
headache (n 22, 32, 30), and infections
(n 22, 29, 10). There was a statistically
signicant difference between treatments
for the number of adverse events consid-
ered by the investigator to be treatment
related; the highest proportion of therapy-
related adverse events occurred with
esomeprazole 20 mg/day. However, no
plausible biological mechanism could be
proposed for these ndings.
In an open study of lansoprazole in the
prevention of relapse of erosive esophagi-
tis, 206 of 241 patients (85%) healed after
treatment with lansoprazole 30 mg/day for
8 weeks [53c]. They then received double-
blind maintenance treatment with lansopra-
zole 15 mg/day or ranitidine 150 mg bd for
up to 1 year. During the 8-week treatment
period, 37 (15%) of 241 patients taking lan-
soprazole reported at least one adverse
event that was considered to be possibly
750 Chapter 36
or probably related to treatment. The only
event reported by more than 5% of
patients was diarrhea (6% of patients).
Seven patients discontinued treatment
because of the following adverse events:
abdominal pain (two patients); myalgia;
abdominal and chest pain; abdominal pain
and atulence; anorexia and nausea; head-
ache. During the comparative phase of the
study, the most frequently reported adverse
events were abdominal pain (5%) and
headache (5%) with lansoprazole, and
headache (6%) with ranitidine.
Systematic reviews Laboratory and clinical
evidence suggest that the increase in gastric
pH caused by proton pump inhibitors may
be linked to increased bacterial coloniza-
tion of the stomach and may predispose
patients to an increased risk of respiratory
infections. The association of proton pump
inhibitors (esomeprazole, rabeprazole,
pantoprazole, and omeprazole) with respi-
ratory infections has been studied in a
systematic review of seven studies, four of
which showed a trend towards an associa-
tion, although most of the studies failed to
show a signicant correlation [54M].
Dexlansoprazole
Dosage formulations Dexlansoprazole MR
is a modied-release formulation of dex-
lansoprazole, an enantiomer of lansopra-
zole, which uses an innovative dual delayed
release (DDR) technology designed to pro-
long the plasma dexlansoprazole concentra-
tion versus time prole and provide
extended duration of acid suppression with
once-daily dosing [55R]. The DDR formula-
tion uses different types of granules with
pH-dependent dissolution proles that
release dexlansoprazole at different times
and over a longer period of time. Dexlanso-
prazole MR must therefore be administered
at a higher daily dose than conventional
delayed-release lansoprazole.
In a randomized, placebo-controlled
study, 451 patients who had had their ero-
sive esophagitis healed in two previous
Corrado Blandizzi and Carmelo Scarpignato
dexlansoprazole MR healing trials took pla-
cebo or lansoprazole MR 60 or 90 mg/day
for 6 months [56C]. The most common
treatment-emergent adverse events respec-
tively were: diarrhea (<1%, 6%, and 7%);
gastritis (<1%, 6%, and 4%); gastrointesti-
nal and abdominal pain (1%, 6%, and
4%); atulence, bloating, and distension
(0%, 5%, and 2%); and respiratory tract
infections (4%, 3%, and 7%). The increases
in fasting serum gastrin concentrations with
dexlansoprazole MR 60 and 90 mg were
within the range expected with proton
pump inhibitors; however, no patients
developed neuroendocrine cell prolifera-
tion, enterochromafn-like cell hyperplasia,
or adenocarcinomas.
Esomeprazole
Gastrointestinal Lansoprazole has been
associated with diarrhea and microscopic coli-
tis, but this association has not been clearly
established with other proton pump inhibi-
tors. Microscopic colitis has been reported
after treatment with esomeprazole (two
cases) and omeprazole (two cases) [57A].
Lansoprazole [SEDA-31, 578;
SEDA-32, 668]
Observational studies The long-term clini-
cal safety of dose-titrated lansoprazole
15120 mg/day as maintenance therapy
has been assessed in an open study for up
to 82 months in 195 subjects who had
achieved healed erosive reux esophagitis
in a phase III multicenter trial [58C]. There
were 2825 treatment-emergent adverse
events in 189 subjects (97%); most of them
occurred during the rst year of treatment,
were mild or moderate in intensity, and
resolved during treatment. Of 155 serious
adverse events in 74 patients, only two (coli-
tis and rectal hemorrhage in one subject)
were considered to have been treatment
related. There were 187 treatment-related
adverse events in 69 subjects (35%),
Gastrointestinal drugs Chapter 36
diarrhea (10%), headache (8%), and abdom-
inal pain (6%) being the most common.
Serum gastrin concentrations over 400 pg/
ml were recorded in 9%. However, in these
patients hypergastrinemia was not associ-
ated with any gastrointestinal adverse event
or presence of gastric nodules/polyps.
Placebo-controlled studies In a 4-week
multicenter, double-blind, parallel-group,
randomized study of lansoprazole in 162
infants aged 112 months with persistent
symptoms attributed to gastroesophageal
reux disease there was no difference
between lansoprazole and placebo in terms
of efcacy [59C]. However, serious adverse
events, particularly lower respiratory
tract infections, occurred in 12 infants, and
were signicantly more common with
lansoprazole.
Urinary tract Acute tubulointerstitial nephri-
tis has been reported with proton pump
inhibitors, and although it is rare it tends to
occur more commonly in elderly patients.
A 70-year-old Caucasian developed nausea,
and loose stools after taking lansoprazole for
4 days, and stopped taking it. He had also
taken omeprazole intermittently, and had
taken the last dose of 4 weeks earlier. He
was taking lisinopril for hypertension. The
blood urea nitrogen and creatinine concentra-
tions were raised but urine analysis and renal
ultrasound were normal. Lisinopril was
withdrawn. A renal biopsy showed diffuse
inltration with lymphocytes, monocytes, and
occasional eosinophils, normal glomeruli, and
mild changes suggestive of acute tubulointer-
stitial nephritis.
Based on literature data and the tempo-
ral relationship, this adverse event was
attributed to lansoprazole, although the
association was by no means clear [60A].
Immunologic Kounis syndrome (acute
myocardial infarction following an allergic
reaction) has been associated with lanso-
prazole [61A].
A 52-year-old-man developed generalized
itching, malaise, shortness of breath, difcult
in swallowing, abdominal pain, and numbness
751
all over the body. He had an erythematous
rash covering the whole body and facial
edema. He was pale, sweating, and agitated.
His symptoms started 10 minutes after a dose
of lansoprazole 30 mg for abdominal pain.
After treatment with intravenous hydrocorti-
sone sodium succinate 500 mg and dimetiri-
dene 4 mg plus an inhaled glucocorticoid, he
suddenly developed severe retrosternal pain
radiating to both arms and started vomiting.
There was ST segment elevation, compatible
with an acute inferior myocardial infarction.
The serum troponin T and creatinine kinase
were increased. The blood eosinophil count
was 9%. Coronary angiography showed a
90% right coronary artery lesion, which
was successfully stented. A skin prick test with
lansoprazole elicited a wheal of 3 mm at
20 minutes; there was no reaction with
omeprazole, pantoprazole, ranitidine, or buff-
ered saline, conrming only lansoprazole
hypersensitivity.
Omeprazole and esomeprazole
[SED-15, 1252, 2615; SEDA-30, 424;
SEDA-31, 578; SEDA-32, 668]
Mineral and metal metabolism Severe
hypomagnesemia impairs parathyroid hor-
mone (PTH) secretion and is a recognized
cause of hypocalcemia. Proton pump
inhibitors have been associated with cases
of symptomatic hypocalcaemia and hypo-
magnesemia [62A] and with refractory
chronic hypokalemia and hypocalcemia sec-
ondary to hypomagnesemia, which resolved
after withdrawal of omeprazole [63A].
Gastrointestinal Two cases of microscopic
colitis associated with omeprazole have
been reported [57A].
Urinary tract Severe acute tubulointerstitial
nephritis with tubular atrophy and minimal
brosis has been reported in a 69-year-old
Caucasian man who was taking irbesartan,
hydrochlorothiazide, ezetimibe, and omep-
razole [64M]. Withdrawal of irbesartan and
hydrochlorothiazide had no effect. Omep-
razole was withdrawn, and there was
dramatic improvement.
752 Chapter 36
Immunologic Allergic reactions have been
attributed to omeprazole [65A].
Itching of the palms, facial angioedema, gen-
eralized urticaria, bronchospasm, dizziness,
and collapse occurred in a 37-year-old woman
15 minutes after taking a capsule of omepra-
zole. She had previously taken omeprazole
several times without problems, and had no
history of atopy. Skin prick tests with commer-
cial common inhalant, food allergens, other
imidazole derivatives (ketoconazole, metro-
nidazole), lansoprazole, pantoprazole, rabe-
prazole, and esomeprazole were negative, but
skin prick and intradermal tests with omepra-
zole were positive. A serum analysis was
negative for specic IgE to omeprazole. Oral
challenges with lansoprazole, pantoprazole,
and the capsule shell caused no reactions.
A 58-year-old man developed generalized urti-
caria, vomiting, and diarrhea 1 hour after tak-
ing an omeprazole capsule; 15 days later he
received an intravenous injection of pantopra-
zole before a surgical operation and 5 minutes
later developed generalized itching, shock,
and loss of consciousness. Skin prick and intra-
dermal tests were positive with omeprazole and
pantoprazole, while skin prick tests with
esomeprazole, lansoprazole, and rabeprazole
were negative, as was an oral challenge with
esomeprazole. Of note, this patient, who was
sensitive to omeprazole, tolerated esomepra-
zole, the S-enantiomer of omeprazole.
The second case highlights cross-reactivity
among the drugs of this class, which is at
variance with previous reports of anaphylac-
tic reactions to proton pump inhibitors.
Pantoprazole
Observational studies Stress ulcer prophy-
laxis with ranitidine has been associated
with an increased risk of ventilator-associ-
ated pneumonia. The use of proton pump
inhibitors has also been linked to an
increased risk of community-acquired
pneumonia, and pantoprazole is commonly
used in stress ulcer prophylaxis. In a retro-
spective observational study the database
of a cardiothoracic surgery unit was used
to identify all patients who had received
stress ulcer prophylaxis with pantoprazole
or ranitidine; 887 patients met the inclusion
criteria [66c]. Nosocomial pneumonia was
Corrado Blandizzi and Carmelo Scarpignato
found to have developed in 35 of 377
patients (9.3%) who had received panto-
prazole, compared with 7 of the 457
patients (1.5%) who had received raniti-
dine (OR 6.6; 95% CI 2.9, 15). After
propensity-adjusted multivariate logistic
regression, pantoprazole was found to be
an independent risk factor for nosocomial
pneumonia (OR 2.7; 95% CI 1.1, 6.7).
Hematologic Some reports have highlighted
cases of thrombocytopenia associated with
proton pump inhibitors in adults and possible
pantoprazole-induced thrombocytopenia
has also been reported in an infant [67A].
In an 8-week, open, prospective, multi-
center, community-based, post-marketing
study of oral rabeprazole 20 mg/day in
2579 patients with erosive esophagitis the
most commonly reported adverse events
included abdominal pain (1.2%), chest pain
(0.5%), diarrhea (1.5%), dizziness (0.7%),
dyspepsia (0.6%), belching (0.5%), headache
(1.6%), nausea (1.0%), rash (0.5%), and
upper respiratory tract infection (0.5%)
[68c]. At least one adverse event was
reported by 15% of patients, 2.4% withdrew
because of adverse events, and 1.4%
reported a serious adverse event. All serious
adverse events were considered to be un-
related to rabeprazole, except for one case
of esophageal spasm. Three patients died
during the study, but the deaths were judged
to be unrelated to the study drug. A total of
2.2% of patients were hospitalized after the
initiation of rabeprazole treatment. Some
of these hospitalizations occurred as a result
of serious adverse events, most commonly
involving the cardiovascular system; how-
ever, none of these were considered by
investigators to be related to rabeprazole.
OTHER ULCER-HEALING
AGENTS
Bismuth compounds [SED-15, 518]
Mouth Black tongue has been associated
with bismuth compounds, and has again
been reported, this time in a 55-year-old
Gastrointestinal drugs Chapter 36
man with metastatic melanoma who chewed
two Pepto-Bismol (bismuth subsalicylate)
tablets before going to sleep [69A]. His black
tongue was then noticed on the following
morning. The patient agreed to a re-chal-
lenge and chewed two tablets at 23.00 h;
there was no change in the color of his
tongue 2 hours later, but at 10.00 hours the
next morning his tongue was black again;
later that night, it had spontaneously
regained its normal pink color.
LAXATIVES AND ORAL
BOWEL PREPARATIONS
[SED-15, 2008; SEDA-30, 426;
SEDA-31, 581; SEDA-32, 668]
Comparative studies In a randomized
study, patients took Pico-Salax (a small-
volume, osmotically active laxative contain-
ing sodium picosulfate 10mg magnesium
oxide 3.5 g) at 17.00 and 22.00 hours the
night before colonoscopy, having taken
bisacodyl 10 mg at 17.00 hours on the two
previous evenings (n 105), or Pico-Salax
alone at 17.00 and 22.00 hours the night
before colonoscopy (n 109), or oral
sodium phosphate at 17.00 and 22.00 hours
the night before colonoscopy (n 101). All
were encouraged to drink 34 liters of
Gatorade or other clear uids the night
before the colonoscopy. More of the
patients who took oral sodium phosphate
reported nausea compared with Pico-Salax
alone (40% versus 22%) and Pico-Salax
bisacodyl (19%). There was a rise in serum
phosphate and a reciprocal fall in serum cal-
cium in a signicant number of those who
took oral sodium phosphate. Signicantly
more of those who took oral sodium phos-
phate than Pico-Salax had hypokalemia
(oral sodium phosphate 73% versus
Pico-Salax bisacodyl 10%) [70M].
Anthraquinones
Cardiovascular A 42-year-old woman, who
for 2 years had been accustomed to boil
753
dried senna leaves and drink about
200 ml/day, developed epigastric pain,
anorexia, episodic vomiting, and intermit-
tent fever [71A]. A color Doppler scan
showed a thrombus occluding the portal
vein bifurcation and the right branch, with
complete interruption of blood ow. Treat-
ment with tissue plasminogen activator
(intravenous infusion of 50 mg total over
48 hours), followed by enoxaparin sodium
4000 IU/day for 14 days and then warfarin
7.5 mg/day for 2 months failed to resolve
the portal obstruction.
Gastrointestinal A 74-year-old woman
developed severe melanosis coli of the
whole colon after using anthraquinone lax-
atives over many decades [72A]. Endoscopy
showed marked black pigmentation of the
colonic mucosa, which was conrmed by
histology as widespread lipofuscin granula-
tion. Several adenomatous lesions were
found, although no colorectal cancer was
detected.
Bisacodyl
Comparative studies A high oral dose of
bisacodyl (30 mg) plus water lavage
(2 liters) and oral sodium phosphate
(90 ml in divided doses) has been evaluated
in a randomized study in 276 adults under-
going elective colonoscopy [73c]. There
was more nausea in those who took sodium
phosphate compared with bisacodyl (28%
versus 7%). There were no signicant dif-
ferences between the two groups in overall
tolerance (95% versus 96%), vomiting (4%
versus 2%), or abdominal cramps (31%
versus 34%).
Drug dosage regimens Three low-volume
regimens, consisting of an oral sodium
phosphate solution 45/45 ml, a reduced-
dose oral sodium phosphate solution
45/30 ml, and polyethylene glycol bisaco-
dyl have been evaluated in a single-blind,
randomized study in 121 adults who were
scheduled to undergo screening colonos-
copy [74c]. Thirst was reported more often
754
by those who took in the sodium phosphate
45/45 than in those who took sodium
phosphate 45/30 or polyethylene glycol
bisacodyl. There was a signicant interac-
tion of sex by regimen for the incidence of
vomiting, which was reported by more of
the women who took polyethylene glycol
bisacodyl. There was also a signicant sex
difference in the incidences of nausea,
weakness, anal irritation, indigestion, and
overall discomfort among regimens
women reported these adverse events more
often than men, regardless of regimen
assignment.
Bran
Gastrointestinal Bran is a natural ber
which undergoes considerable expansion
and thickening when hydrated, and is cur-
rently being used for weight loss as tablets,
which undergo expansion in the stomach
and are expected to cause early satiety.
These products can rarely cause severe
adverse reactions, such as sudden esopha-
geal obstruction [75A].
A 45-year-old woman developed acute dys-
phagia, with retrosternal pain, difcult in swal-
lowing and drinking, and a sensation of air
hunger, after taking two capsules of a dietetic
bran product before lunch. She was given
intravenous hyoscine butylbromide, but the
symptoms persisted. After a plain X-ray of
the upper gastrointestinal tract, which was
negative, a contrast esophagogram with
water-soluble medium showed an esophageal
obstruction by a pair of radiotransparent soft
masses in the region of upper esophagus.
Complete resolution of symptoms was
obtained by pushing the obstructing masses
downward during endoscopy.
Lactulose
Placebo-controlled studies The efcacy of
lactulose in preventing the recurrence of
hepatic encephalopathy has been the subject
of an open, randomized, placebo-controlled
trial in 140 patients with cirrhosis [76c].
Chapter 36 Corrado Blandizzi and Carmelo Scarpignato
Lactulose was administered at a dose of
3060 ml in 23 divided doses, in order to
allow patients to pass 23 semisoft stools
per day. Lactulose was effective in this set-
ting. Of 61 patients, 14 (23%) had diarrhea,
6 (10%) had abdominal bloating, and
8 (13%) had distaste for lactulose; in these
patients, the dose of lactulose was reduced
but not stopped. In the placebo group, con-
stipation was reported in 10 (16%) and was
managed by dietary modications.
Magnesium salts [see also Chapter 22]
Metal metabolism Magnesium hydroxide is
widely used as laxative, and it can therefore
cause diarrhea, which can be followed by
excessive magnesium loss [77A].
A 39-year-old woman developed severe
watery diarrhea and carpopedal spasm after
taking at least 20 tablets of magnesium
hydroxide in a suicidal attempt; each con-
tained magnesium hydroxide 500 mg. Labora-
tory tests detected hypomagnesemia,
hypocalcemia, and normokalemia. She was
given calcium gluconate, but her symptoms
did not improve. The adverse event disap-
peared spontaneously 2 days after the watery
diarrhea had subsided.
Senna
Gastrointestinal High-dose senna is supe-
rior to polyethylene glycol-electrolyte solu-
tion (PEG-ES) for the quality of bowel
cleansing, but its acceptance may be inu-
enced by the incidence of abdominal pain.
In a randomized investigator-blinded study
of a combination of PEG-ES and senna in
ensuring adequate bowel preparation in
296 patients scheduled for elective colonos-
copy, the patients were assigned to either
12 tablets of senna 12 mg 2 liters of
PEG-ES (half-dose group) or 24 tablets of
senna divided in two doses (senna group)
the day before colonoscopy [78C]. The
cleansing activity was excellent in both
groups. There was moderate-to-severe
abdominal pain in 6% of patients in the
half-dose group and 15% in the senna
Gastrointestinal drugs Chapter 36
group. However, there were no statistically
signicant differences in the frequency and
intensity of nausea, vomiting, dizziness, or
headache.
Phosphates [SED-15, 2820; SEDA-30,
427, SEDA-31, 581; SEDA-32, 668]
Observational studies The use of oral
sodium phosphate and polyethylene glycol
solutions as bowel cleansing preparation
for radiological examination of the colon
has been evaluated in an observational sur-
vey in 592 adults [79c]. Sodium phosphate
was rated superior to polyethylene glycol
by both patients and physicians. There were
similar patterns of adverse reactions, in par-
ticular nausea (26% and 24% respectively)
and cramps (20% and 27%). Abdominal
bloating was more frequent with polyethyl-
ene glycol (35% versus 17%), while dry
mouth occurred more frequently with
sodium phosphate (16% versus 8%).
Mineral balance Hypocalcemia and hyper-
phosphatemia have been attributed to a
phosphate enema [80A].
A 37-year-old woman with suspected celiac
disease was prepared for colonoscopy using
sodium phosphate solution (Fleet Phospho-
Soda) 90 ml. About 12 hours later, she devel-
oped perioral paresthesia, Chvostek's sign,
numbness in the limbs, and carpopedal spasm.
Blood tests showed hypocalcemia and hyper-
phosphatemia. She was treated immediately
with repeated doses of intravenous calcium
gluconate and her electrolyte balance normal-
ized over the next 2 days.
Urinary tract Acute phosphate nephropathy
has been described as a possible complica-
tion after the use of oral sodium phosphate
or phosphorus-containing medications.
A 13-year-old boy with Costello syndrome
(neonatal macrosomia with subsequent slow
growth, developmental delay, coarse facial
dysmorphisms, gingival hyperplasia, skeletal
anomalies, and hypertrophic cardiomyopathy)
and chronic constipation developed signs and
symptoms of acute renal insufciency, after
having received four phosphate-containing
enemas (125 ml containing sodium
755
biphosphate 28 g and sodium monophosphate
12.5 g) [81A]. He had reduced consciousness,
with a low blood pressure, tachycardia,
increased respiratory rate, and room air satu-
ration of 88%. There was severe hypertonic
dehydration, hyperphosphatemia, and hypo-
calcemia. He was given uids and electrolytes.
His urine ow started immediately and his cre-
atinine and blood urea nitrogen normalized
within the next few days.
A 64-year-old man took oral sodium phos-
phate tablets in preparation for endoscopic
colon polyp resection [82A]. He had a history
of hypertension, which was being managed
with a calcium channel blocker, and had a nor-
mal serum creatinine concentration. One day
after the bowel preparation and colonoscopic
intervention, his serum creatinine concentra-
tion rose. With supportive treatment the creat-
inine gradually normalized over the course of
8 weeks after reaching a peak concentration
of 270 mmol/l on day 4.
A 76-year-old woman with rectal bleeding
underwent sigmoidoscopy after taking two
sachets of sodium phosphate solution (Fleet
Phospho-Soda) and sodium phosphate
enema (Fleet Ready-To-Use) [83A]. She
was then given mesalazine for chronic active
ulcerative colitis and 2 days later developed
acute renal insufciency, with normocalcemia
and mild hyperphosphatemia. Mesalazine
was replaced with prednisolone enemas.
Renal biopsy showed normal glomeruli but
widespread tubular calcication with high
phosphate content; the tubules were dilated
and the tubular epithelium was attened, with
minimal lymphocytic inltration.
As the last case shows, this adverse reac-
tion is accompanied by the presence of
phosphate in the renal tubules. This is
therefore a type 1a between-the-eyes
adverse reaction [84H].
From July 2006 to September 2008, 10
cases of acute phosphate nephropathy,
associated with sodium phosphate tablets
for bowel cleansing, were reported to the
FDA's Adverse Event Reporting System
database [85c]. Renal biopsy in these
patients showed nephrocalcinosis (calcium
phosphate crystal deposition in the distal
tubules and collecting ducts). All these
patients had at least one underlying suscep-
tibility factor for acute renal insufciency,
such as pre-existing renal impairment,
hypertension, diabetes mellitus, advanced
age, underlying electrolyte imbalance, and
756 Chapter 36
concomitant medications that affect renal
perfusion or function (for example, angio-
tensin-converting enzyme inhibitors, angio-
tensin receptor antagonists, non-steroidal
anti-inammatory drugs, or diuretics).
Moreover, the reduction in intravascular
volume, caused by bowel cleansing, is likely
to have promoted increased phosphate con-
centrations in the renal tubular uid. Some
patients, especially those with underlying
susceptibility factors, developed acute
phosphate nephropathy with doses as low
as 30 g of sodium phosphate. In addition,
some patients who developed renal damage
did not present with symptoms of acute
phosphate nephropathy for up to several
months after using sodium phosphate tab-
lets. There is currently insufcient informa-
tion to make global recommendations
regarding standard pre- and post-proce-
dural renal function testing for patients
who may be at risk. However, the impor-
tance of taking sodium phosphate correctly
(i.e. with adequate hydration and separat-
ing the two doses by 12 hours) should be
stressed in order to reduce the risk of
developing acute phosphate nephropathy
and acute renal insufciency.
Sodium picosulfate
Electrolyte balance Electrolyte distur-
bances are well-recognized complications
of all bowel preparations. Rarely, they can
be of clinical signicance, as in one case of
seizures secondary to hyponatremia [86A].
An 80-year-old woman underwent bowel
cleansing before colonoscopy. She was taking
no regular medications and did not have any
susceptibility factors for hyponatremia. Within
3 hours of the rst dose of sodium picosulfate
magnesium citrate she became confused
and dysphasic, and within 6 hours developed
generalized seizures due to hyponatremia.
She was treated with slow intravenous hydra-
tion with isotonic saline. Within 72 hours, she
was fully alert and oriented with no neurolog-
ical decit, and her blood sodium concentra-
tion had normalized. A brain MRI scan was
normal.
Corrado Blandizzi and Carmelo Scarpignato
AMINOSALICYLATES
[SED-15, 138; SEDA-30, 428;
SEDA-31, 583; SEDA-32, 669]
Observational studies Mesalazine (mesala-
mine, 5-aminosalicylic acid) has been
linked with tubulointerstitial nephritis in
patients with inammatory bowel disease.
In a retrospective analysis of renal impair-
ment during long-term use of aminosalicy-
lates in 171 patients with inammatory
bowel disease, the mean daily dose was
3.65 g/day and the mean treatment duration
8.4 years; treatments included mesalazine
(74%), sulfasalazine (15%), and the combi-
nation (11%) [87c]. Serum creatinine con-
centrations increased signicantly during
treatment, from 77 to 89 mmol/l, and creati-
nine clearance fell signicantly from 105 to
93 ml/minute. The fall in creatinine
clearance correlated positively with the
mean daily dose. There was one case of
interstitial nephritis.
Balsalazide [SEDA-31, 583; SEDA-32,
669]
Cardiovascular Myocarditis has been
attributed to balsalazide [88A].
A 38-year-old man with ulcerative colitis who
had taken mesalazine for many years was
switched to balsalazide 2.25 g tds and prednis-
olone 15 mg/day. However, 14 days later,
while his bowel symptoms were improving,
he developed intermittent chest pain (not typ-
ical of ischemia or pericarditis). Cardiac tropo-
nin I and C reactive protein were raised and
there was widespread T wave inversion.
Echocardiography showed apical and poste-
rior segment wall motion abnormality with
no effusion. A diagnosis of myocarditis was
made, and balsalazide was withdrawn. His car-
diac symptoms resolved within 48 hours.
Drug dosage regimens In a randomized,
double-blind study of two oral dosage regi-
mens of balsalazide, 6.75 or 2.25 g/day for
8 weeks, in 68 children (age range 517
years) with mild-to-moderate ulcerative
Gastrointestinal drugs Chapter 36
colitis, there was clinical improvement in
45% and 37% and clinical remission in
12% and 9% of those who took 6.75 and
2.25 g/day respectively [89C]. The most com-
mon treatment-related adverse events were
headache (15% versus 14%), abdominal
pain (12% versus 11%), vomiting (3% ver-
sus 17%), and diarrhea (6% versus 11%).
Mesalazine (5-aminosalicylic acid,
mesalamine) [SEDA-30, 428; SEDA-31,
583; SEDA-32, 669]
Placebo-controlled studies In a double-
blind, randomized study, 122 children with
Crohn's disease took either mesalazine
50 mg/kg/day or placebo for 1 year after
successful treatment of are-ups [90C].
Mesalazine did not appear to be effective.
Most of the reported adverse events were
not considered to be serious, and there
was no difference between mesalazine and
placebo. However, there was one case of
interstitial nephritis among those who took
mesalazine.
Cardiovascular Myocarditis has been
attributed to mesalazine [91A].
A 36-year-old man with Crohn's disease tak-
ing long-term mesalazine and low doses of
prednisone developed repeated bouts of syn-
cope. He had trifascicular block (a prolonged
PR interval, anterior hemiblock, and complete
right bundle branch block), and predomi-
nately anterior and septal hypertrophy. An
MRI scan with gadolinium also showed intera-
trial septal hypertrophy with nodular forma-
tion in the lowest section, myocardial edema,
a perfusion defect in the hypertrophic areas, epi-
cardial late enhancement in the anterior wall,
and transmural extension in the interventricular
and interatrial septa. Mesalazine was withdrawn
and a pacemaker implanted. One year later the
electrocardiogram was normal and echocardiog-
raphy showed thinning with dyskinesia of the
previously hypertrophic areas.
The type I variant of Kounis syndrome
has been attributed to mesalazine [92A].
A 12-year-old boy with an exacerbation of
ulcerative pancolitis was given mesalazine
757
800 mg tds and prednisone 20 mg/day fol-
lowed by intravenous 6-methylprednisolone
8 mg 6 hourly). While his symptoms of colitis
were improving, he complained of chest pain.
There were non-specic ST-T wave changes
with T wave inversion, and echocardiography
showed low-normal to mildly depressed left
ventricular systolic function. The left main
coronary artery and left anterior descending
artery were mildly prominent, and measured
5 and 4.7 mm respectively. The chest pain
resolved completely within 2436 hours after
mesalazine withdrawal. Echocardiography 2
days later showed normal left ventricular func-
tion with normal coronary arteries (<3.5 mm).
This variant of the Kounis syndrome
includes patients of any age, with normal
coronary arteries, without predisposing fac-
tors for coronary artery disease, in whom
the acute release of inammatory media-
tors from mast cells can cause either
sudden coronary artery narrowing, without
increases in cardiac enzymes or troponins,
or coronary artery spasm that progresses
to acute myocardial infarction, with raised
cardiac enzymes and troponins [93A].
Respiratory Lung toxicity is rare in
patients taking mesalazine; a hypersensitiv-
ity pneumonitis can occur.
A 23-year-old man with ulcerative proctitis
was treated successfully with topical mesala-
zine and beclometasone dipropionate [94A].
After 1 month the treatment was stopped,
but 5 years later, a relapse was treated with
topical mesalazine and then oral mesalazine
2.4 g/day. After 3 days the patient developed
pleuritic chest pain, exertional dyspnea, fever
(38 C), and arthralgias, in particular in the
shoulders and spine. Chest X-ray showed a
right-sided basal pleural effusion. He was
given intramuscular ceftriaxone 1 g/day and
oral methylprednisolone 16 mg/day and after
11 days the chest symptoms resolved; 1 month
later mesalazine and glucocorticoid treatment
were withdrawn, but 1 month later a relapse
was treated again with oral mesalazine 2.4 g/
day. After 3 days the same pleuritic symptoms
occurred and disappeared promptly on with-
drawal of mesalazine.
A 25-year-old woman, with an 8-year history
of ulcerative colitis limited to the distal colon,
during which time she had taken mesalazine
900 mg/day, developed a non-productive
cough accompanied by a high-grade fever
[95A]. The white blood cell count, ESR, and
758 Chapter 36
C reactive protein were increased. Chest X-ray
and a CT scan showed bilateral inltrates and
large peripheral pulmonary nodules with cavi-
tation. There were mild increases in antinuclear
antibodies and antiproteinase-3, and cytoplas-
mic antineutrophil cytoplasmic antibodies
(c-ANCA) were positive. There was complete
resolution of both clinical and radiological
ndings after mesalazine withdrawal and
treatment with ciprooxacin and clindamycin.
Hematologic Eosinophilia has been attrib-
uted to mesalazine [96M].
A 9-year-old boy with inammatory bowel
disease, without pathognomonic signs of ulcer-
ative colitis or Crohn's disease, was given oral
mesalazine 30 mg/kg/day, rectal mesalazine
250 mg/day, and oral metronidazole 30 mg/
kg/day for 15 days, and the disease activity
was partly controlled. However, after 2 years
of mesalazine therapy, he developed a severe
eosinophilia and an increased leukocyte count,
together with a are-up of his bowel symp-
toms. A peripheral smear and a bone marrow
aspirate showed 74% and 16% eosinophils
respectively. Parasite infestation, hypereosino-
philic syndrome, and eosinophilic leukemia
were excluded by appropriate tests. Mesala-
zine was withdrawn and he was given a gluco-
corticoid. The eosinophilia resolved and did
not relapse during the next 2 years.
Aplastic anemia has been attributed to
mesalazine [97A].
A 52-year-old woman with ileocolonic Crohn's
disease took mesalazine 1 g tds for several
years before developing progressive lethargy,
fatigue, and bright red blood in her stools.
She had small macular petechiae on the palate
and bilaterally on the legs. The white blood
cell count was 3.4  109/l, the platelet count
10  109/l, and hemoglobin 9 g/dl. The
absolute neutrophil count was 550  109/l,
and the absolute reticulocyte count was
20  1015/l. Bone marrow biopsy showed a
hypocellular marrow composed of erythroid
precursors, lymphocytes, and plasma cells;
myeloid precursors were signicantly reduced.
It is not clear whether mesalazine was the
culprit in this case.
Gastrointestinal Mesalazine has report-
edly, and paradoxically, exacerbated ulcer-
ative colitis [98A].
A 30-year-old woman with distal ulcerative
colitis and joint involvement was initially
Corrado Blandizzi and Carmelo Scarpignato
given sulfasalazine 4 g/day, but this was poorly
tolerated, because of fever and a rash. It was
replaced by oral prednisolone 60 mg/day for
8 weeks. The abdominal symptoms did not
subside, and she was given azathioprine which
was hepatotoxic and was withdrawn. Inixi-
mab stabilized the disease, but there was
residual activity in the distal 20 cm of large
bowel. She was given a mesalazine enema
and 3 days later developed nausea, abdominal
pain, and blood-stained diarrhea. Colonos-
copy showed conuent disease activity up to
the descending colon with granular mucosa
and contact hemorrhage. The patient was then
subjected to proctocolectomy, which was
followed by a complete uneventful recovery.
Liver Hepatitis has been attributed to
mesalazine [99A].
A 45-year-old man, who had taken mesalazine
1.6 g/day for 8 years for ulcerative colitis,
developed right upper abdominal pain, jaun-
dice, and pale stools. He had a raised white
cell count with eosinophilia, and raised bili-
rubin, alkaline phosphatase, and alanine
aminotransferase. Abdominal ultrasonogra-
phy showed a normal liver without ductal dila-
tation. A liver biopsy showed eosinophil
inltration in the sinusoids, parenchyma, and,
in particular, the central veins and portal
tracts, consistent with drug-induced hepatitis.
Mesalazine was withdrawn and the blood tests
improved or normalized over the next week.
After 3 years, liver function tests and blood
cell counts were normal.
Urinary tract Nephritis has been attributed
to mesalazine [100A].
A 15-year-old boy with idiopathic proctocolitis
took sulfasalazine for 1 year and then mesala-
zine 3 g/day, azathioprine up to 3 mg/kg, and
prednisolone in a tapering daily dose of
8 mg/kg. He developed weight loss of 4.5 kg,
a high ESR, anemia, and a raised blood urea
nitrogen and borderline serum creatinine.
Mesalazine was withdrawn, but the laboratory
ndings did not improve and he then devel-
oped a fever with erythema nodosum. There
was proteinuria and creatinine clearance was
reduced. Renal scintigraphy showed a bilat-
eral diffuse non-homogeneous pattern with
multifocal defects in isotope uptake. Renal
biopsy showed chronic tubulointerstitial
involvement with sclerosed glomeruli. There
was remarkable improvement after 21 days
of therapy with glucocorticoids.
It is not clear whether mesalazine was the
culprit in this case.
Gastrointestinal drugs Chapter 36
Musculoskeletal A toxic non-inammatory
myopathy has been attributed to mesala-
zine [101A].
An 11-year-old girl with ulcerative colitis
developed muscle pain in the limbs while tak-
ing oral mesalazine 2 g/day and prednisolone.
She had also received a sulfasalazine supposi-
tory as initial therapy. Serum creatine kinase
activity was markedly raised, and 98% of the
enzyme originated from skeletal muscle. The
peripheral eosinophil cell count was normal
and there were no signs or autoantibodies to
suggest dermatomyositis or systemic lupus.
There was no cardiomegaly or cardiac hypo-
kinesis, but there were ST-T wave changes
on the electrocardiogram. An adverse reac-
tion to mesalazine was hypothesized, and it
was withdrawn, resulting in prompt and spon-
taneous resolution of the muscle pain, raised
creatine kinase activity, and electrocardio-
graphic abnormalities. Biopsy of the left rectus
femoris muscle showed atrophy of both type 1
and 2 bers, focal myobrillar degeneration,
necrosis, regenerative changes, and phago-
cytosis of degenerative and necrotic bers,
with a few intermyseal lymphocytes. She was
given azathioprine and prednisolone. After
withdrawal of prednisolone, a drug-induced
lymphocyte stimulation test for mesalazine
was strongly positive, suggesting that the
myopathy had resulted from a hypersensitivity
reaction to mesalazine.
Drug formulations Mesalazine formulated
with the MMX Multi Matrix System tech-
nology contains 1.2 g per tablet for once-
daily administration [102R]. The MMX
technology comprises hydrophilic and lipo-
philic excipients enclosed within a gastrore-
sistant, pH-dependent coating. This system
is designed to prolong exposure of the
colonic mucosa to the drug. In an open
study, 304 patients with active, mild-to-
moderate ulcerative colitis, who had not
achieved clinical and endoscopic remission
after 8 weeks of treatment with MMX
mesalazine (2.4 or 4.8 g/day), or delayed-
release mesalazine (Asacol, tablets 2.4
g/day), or placebo, were treated with
MMX mesalazine 4.8 g/day for 8 weeks
[103c]. There was disease remission in
60%, but 27 patients (8.7%) had a total of
60 treatment-related adverse reactions, of
which 15 were gastrointestinal in nature,
including aggravated ulcerative colitis, diar-
rhea, nausea, and vomiting. Nine patients
759
(2.9%) had adverse effects that led to with-
drawal; four of these had a total of four
treatment-related adverse effects, including
two cases of aggravated ulcerative colitis,
one case of pancreatitis, and one case of
aggravated headache.
Sulfasalazine
Immunologic There have been further
reports of drug rash with eosinophilia and
systemic symptoms (DRESS) in patients
taking sulfasalazine, a 47-year-old white
Brazilian woman who developed DRESS
after 8 weeks [104A], a 60-year-old man
with polyarthritis who also developed ful-
minant liver failure after additional vanco-
mycin treatment [105A], and a 68-year-old
woman in whom the reaction may have
been precipitated by the addition of sulbac-
tam ampicillin [106A]. In another case,
drug-induced hypersensitivity syndrome
was associated with reactivation of an infec-
tion with human herpesvirus-6 in a 15-year-
old boy with juvenile rheumatoid arthritis
who was taking sulfasalazine [107A].
ANTISPASMODIC AGENTS
Hyoscine (scopolamine)
butylbromide
Nervous system Patients with migraine can
develop migraine-like headaches after the
administration of hyoscine butylbromide.
The clinical features have been evaluated
in 54 adults with history of migraine, who
developed a headache within 20 minutes
after a single intramuscular dose of hyosci-
nebutylbromide 20 mg during gastric
X-ray examination [108C]. There was pul-
sating/throbbing pain in diffuse or bilateral
areas of the head. The headache worsened
at 2030 minutes after onset, persisted for
618 hours, and gradually ameliorated after
8 hours. All the subjects had repeated nau-
sea and vomiting. Assessment of intensity
760 Chapter 36
showed that 50 subjects had a severe head-
ache, requiring complete bed rest. The hyo-
scine-induced headache had characteristics
similar to migraine without aura. Of 1865
non-migraineurs, only one had a mild
degree of migraine-like headache triggered
by hyoscine butylbromide. The pathophysi-
ological basis of hyoscine-induced head-
ache is not clear. Studies in preclinical
models support the notion that migraine is
associated with the cholinergic neuronal
network, in addition to serotonergic
pathways in the central nervous system.
Accordingly, an abnormal interaction
between cholinergic and serotonergic neu-
rons could play a role in the pathogenesis
of migraine-like headache triggered by
hyoscine butylbromide.
ANTIDIARRHEAL AGENTS
Loperamide
Gastrointestinal In a retrospective review
of the clinical records of patients admitted
to hospital during 1 year, Clostridium dif-
cile-associated diarrhea was diagnosed
using the following criteria: (i) loose stools
or diarrhea more than twice per day and
(ii) stool positive for Clostridium difcile
toxin A or identication of the organism
by stool culture [109c]. Six patients with
Clostridium difcile-associated diarrhea
had taken loperamide and 80 others were
chosen as controls matched for age, dura-
tion of hospitalization, and ward of admis-
sion. There were no differences in the
duration of fever over 37.5 C, the intensity
of the diarrhea, white blood cell count or
C-reactive protein concentration; however,
in those who had taken loperamide the
duration of twice-daily diarrhea was longer
(9.0 versus 3.7 days), the maximum number
of episodes of diarrhea per day was greater
(9.2 versus 5.6 episodes), and the duration
of the disease was longer (13 versus 5.6
days). The authors reiterated the
Corrado Blandizzi and Carmelo Scarpignato
observation that drugs that are often used
to treat diarrhea, such as loperamide,
diphenoxylate, and bismuth compounds,
worsen the clinical course of Clostridium
difcile-associated diarrhea, and recom-
mended that antimotility agents should not
be used in such cases.
CHOLELITHOLYTIC
AGENTS, BILE ACIDS
Ursodeoxycholic acid
Respiratory Pegylated interferon alfa com-
bined with ribavirin is currently the stan-
dard treatment for hepatitis C virus
infection, and ursodeoxycholic acid is used
as a supportive treatment in patients who
are non-responders or develop severe
adverse reactions. Interstitial pneumonia
has been attributed to this [110A].
A 65-year-old man with chronic hepatitis C
developed a cough, exertional dyspnea, and
an increase in serum Krebs Von den Lungen-
6 (KL-6), a marker of interstitial pneumonia,
while receiving peginterferon alfa-2b 40
80 micrograms once a week and ribavirin
400 mg/day. A chest X-ray and a CT scan
showed bilateral linear and reticular pulmo-
nary inltration, suggestive of interstitial
pneumonia. The signs of pneumonia abated
and KL-6 normalized after peginterferon and
ribavirin were withdrawn. Ammonium glycyr-
rhizate 300600 mg/day and ursodeoxycholic
acid 300 mg/day were then introduced and
although the aminotransferase activities
improved, the productive cough and exer-
tional dyspnea returned along with an
increase in KL-6. Ursodeoxycholic acid was
withdrawn, but the symptoms persisted and
ursodeoxycholic acid was restarted. However,
the KL-6 increased and there was a further
reduction in blood oxygen saturation. There
was complete relief of the respiratory
symptoms and normalization of KL-6 after
ursodeoxycholic acid had been withdrawn
and prednisolone 15 mg/day was given.
The association in this case was not
convincing.
Gastrointestinal drugs Chapter 36
OTHER
GASTROINTESTINAL
AGENTS
Mercaptamine (cysteamine)
[SED-15, 2258]
Immunologic Drug-induced lupus has been
attributed to cysteamine [111A].
A girl with nephropathic cystinosis was given
cysteamine bitartrate 3045 mg/kg/day. How-
ever, despite adequate intracellular cystine
depletion, her renal function declined and
she was given enalapril for proteinuria. When
she was 14 years old she was found to have a
persistently positive lupus anticoagulant with
anticardiolipin, antinuclear, and antihistone
antibodies, weakly positive double-stranded
DNA antibodies, negative extractable nuclear
antibodies, an increased ESR, and low serum
complement concentrations. Cysteamine was
withdrawn and 1 month later the ESR and
complement had fallen and the antibody titers
had become weakly positive.
Cysteamine is structurally similar to pen-
icillamine, a known cause of drug-induced
lupus.
Ion-exchange resins [SED-15, 1902]
See also Chapter 23 for polystyrene
sulfonates
Acidbase balance Sevelamer hydrochlo-
ride is an ion-exchange resin, used to reduce
serum phosphorus concentrations in patients
with chronic kidney disease, that can cause a
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 D. Spoerl and Andreas J. Bircher
37 Drugs that act on the
immune system: cytokines
and monoclonal antibodies
COLONY-STIMULATING
FACTORS [SEDA-30, 435;
SEDA-31, 589; SEDA-32, 675]
Granulocyte colony-stimulating
factor (G-CSF) and granulocyte-
macrophage colony-stimulating
factor (GM-CSF) [SED-15, 1542;
SEDA-30, 435; SEDA-31, 589; SEDA-32,
675]
Comparative studies It is of concern that
biosimilars may have different efcacy and
safety proles. In a comparison of a bio-
similar (XM02) with lgrastim, the former
had equivalent efcacy and a similar safety
prole as lgrastim. It ameliorated severe
neutropenia and febrile neutropenia in
patients with non-Hodgkin's lymphoma
receiving chemotherapy and was compara-
ble to lgrastim [1C].
Systematic reviews A meta-analysis of
eight randomized controlled trials on the
use of granulocyte colony-stimulating factor
(G-CSF) for cardiac repair after acute myo-
cardial infarction has yielded divergent
results [2M]. The effect of G-CSF therapy
on left ventricular function and structure
in these patients is unclear. There were no
Side Effects of Drugs, Annual 33
J.K. Aronson (Editor)
ISSN: 0378-6080
DOI: 10.1016/B978-0-444-53741-6.00037-4
# 2011 Elsevier B.V. All rights reserved.
signicant differences in the incidence of
death or recurrent myocardial infarction
between patients who received G-CSF
and controls. The pooled analysis of 328
patients showed no difference in the risk
of in-stent restenosis.
Filgrastim
Observational studies In 2408 unrelated
donors of peripheral blood stem cells,
adverse events associated with lgrastim
were evaluated using the Cancer and
Leukemia Group B (CALGB) criteria
[3c]. The events assessed included allergy,
anorexia, chills, fever, sweats, fatigue, head-
ache, myalgia, nausea, vomiting, other
u-like symptoms, local reactions, rashes,
pain, and infections. Women had higher
rates of adverse events, obese donors had
more bone pain, and heavy donors had
higher rates of adverse reactions. There
were grade 34 adverse reactions in 6% of
donors, and 0.6% had adverse reactions
that were considered serious and unex-
pected. Nearly all donors have bone pain,
1 in 4 have signicant headache, nausea, or
citrate toxicity, and a small percentage have
serious short-term adverse reactions.
Although the short-term safety prole of
recombinant human (rh)G-CSF seems to
be acceptable, there are minimal data
on its long-term safety. In a questionnaire
study 95 donors (64%) responded, but only
69 of them (46%) reported on their actual
769
770
health status and quality of life, which was
good to very good in the majority [4c].
Two donors developed malignancies in the
post-donation course. In general, collection
of peripheral blood progenitor cells after
rhG-CSF mobilization was well tolerated
by the responding donors. Although the
reported events after donation do not seem
to be associated with rhG-CSF administra-
tion or the collection procedure, lifelong
follow-up of donors should be obligatory.
Cardiovascular Concerns about adverse
cardiac reactions to lgrastim could not be
substantiated in a prospective study in a
selected population of neutropenic patients,
other than a signicant reduction in mean
heart rate [5c].
A 54-year-old man with squamous cell
carcinoma of the lung developed abdomi-
nal aortitis after the use of G-CSF [6A].
Hematologic G-CSF stimulates myeloid
progenitors and is routinely used to acceler-
ate neutrophil recovery in the treatment of
hematological malignancies and blood or
marrow transplantation. However, lgras-
tim has never been conclusively proven to
produce a survival benet in allogeneic
human stem cell transplantation. Filgrastim
may cause enhanced leukemic transforma-
tion through actions mediated by the G-
CSF receptor. G-CSF receptor mutations
predispose to expansions of clonal popula-
tions by exogenous G-CSF, and it is there-
fore best avoided in all patients with
abnormalities of chromosome 7. In the nal
analysis of the benet to harm balance, the
immediate benets of G-CSF related to
recovery of the leukocyte count, which
were substantial in the case of cord blood
grafts, may be insignicant for a peripheral
blood progenitor graft [7R].
Susceptibility factors Sickle cell disease Of
11 patients with sickle cell disease who
were given G-CSF, seven had severe
adverse reactions, including vaso-occlusive
episodes, acute chest syndrome, multiorgan
system failure, and death [8c]. This suggests
that G-CSF should not be used in individ-
uals with sickle cell disease except in the
Chapter 37 D. Spoerl and Andreas J. Bircher
absence of alternatives and after full disclo-
sure of the risks involved.
Lenograstim
Observational studies In 184 healthy donors
who were mobilized using lenograstim and
were assessed with a median follow-up of 62
(range 2155) months, bone pain was the most
frequent short-term adverse reaction (71%)
[9c]. Other common short-term symptoms
included headache (28%), insomnia (22%),
fatigue (19%), nausea (12%), and fever
(5.4%). Spleen size increased in 4.3% of the
donors. There were no vascular disorders or
cardiac diseases. Long-term follow-up
included a transient ischemic attack in one
donor at 39 months. There were no cases of
hematological disease. There was one case
of ankylosing spondylitis at 28 months. One
donor with chronic obstructive pulmonary
disease developed secondary polyglobulia at
50 months. One donor developed lung cancer
at 19 months after donation.
Peglgrastim
Observational studies There have been
several studies of peglgrastim in prevent-
ing infections in patients with different
cancers [10c, 11M]. In 14 patients with con-
genital neutropenia, peglgrastim replaced
G-CSF (lgrastim or lenograstim) after a
median of 6.9 years of G-CSF therapy
[12c]. The absolute neutrophil count tended
to increase more with peglgrastim than G-
CSF, but the difference was not statistically
signicant. During peglgrastim therapy,
four patients had severe infections and
bone pain was reported by nine. WHO
grade 3 reactions (anemia, thrombocyto-
penia, or chronic urticaria) occurred in two
patients. A patient with glycogen storage
disease type Ib received developed respira-
tory distress after one injection and died 15
days later. Peglgrastim is more difcult to
use in congenital neutropenia, with more
frequent adverse reactions and sometimes
poor efcacy.
Drugs that act on the immune system: cytokines and monoclonal antibodies
Sargramostim
Observational studies Six patients with mo-
derately to severely active Crohn's disease
were enrolled in an open, phase I study of
subcutaneous sargramostim followed in ve
cases by an open study of tolerability of
subcutaneous sargramostim over 8 weeks
[13c]. Drug-related adverse events included
injection site reactions, pyrexia, back pain,
and bone pain.
Long-term adverse reactions to sargra-
mostim over 3 years have been evaluated
in 98 patients with melanoma [14c]. There
were grade 1 or 2 reactions in 82% and
no grade 3 or 4 treatment-related reactions.
Two patients developed acute myelogenous
leukemia after completing 3 years of GM-
CSF treatment.
Human keratinocyte growth
factor
Palifermin (Kepivance; Amgen Inc., Thou-
sand Oaks, CA, USA) is a truncated,
recombinant form of human sickle cell dis-
ease (KGF) that specically stimulates the
growth of epithelial cells that express KGF
receptors, thereby reducing mucosal injury
due to chemotherapy and radiation. Palifer-
min is approved for use in reducing the
incidence and duration of severe mucositis
in patients with hematological malignancies
who receive myelotoxic chemotherapy with
autologous stem-cell support.
Observational studies In 30 patients who
underwent allogeneic stem-cell transplanta-
tion for leukemia and a retrospectively
matched group of controls, the palifermin
recipients who received a transplant from
an unrelated donor had reduced severity,
incidence, and duration of oral mucositis
WHO grades 24, reduced need for opioid
analgesics, and a shorter duration of total
parenteral nutrition [15c]. However, there
was no benecial effect of palifermin on
the incidence and severity of acute graft-
versus-host disease. Febrile neutropenia,
Chapter 37 771
infections, hemopoietic recovery, and over-
all survival were unchanged. The most
common adverse reactions included rashes
or erythema, white coating of the oral
mucosa, and altered taste, which was gener-
ally mild and transient.
In 15 patients who underwent autologous
stem-cell transplantation and who received
sickle cell disease, oral and intestinal mucosi-
tis were signicantly less severe [16c].
Adverse reactions that were attributable to
the drug included erythema, mild rashes, pru-
ritus, nasal congestion, and low-grade fever.
All the complications were easily manageable
and resolved after completion of treatment.
Placebo-controlled studies Ten once-
weekly doses of palifermin 60 micrograms/kg
were well tolerated compared with placebo in
patients who received concurrent chemo-
radiotherapy for advanced head and neck
squamous cell carcinomas [17c]. Palifermin
appeared to reduce the incidences of mucosi-
tis, dysphagia, and xerostomia during hyper-
fractionated radiotherapy (n 40) but not
during standard radiation therapy (n 59).
Adverse events were similar in the two
treatment groups.
Skin Five patients (aged 5363 years, 3
men) with malignant hematological dis-
eases developed exural hyperpigmentation
after treatment with palifermin [18c]. All
had ill-dened symmetrical hyperpigmen-
ted papillomatous plaques with slight ery-
thema in the skin folds, especially
affecting the axillae and inguinal areas.
The most striking histological nding was
a thickened granular layer and an increase
in cytoplasmic laggrin staining in the stra-
tum granulosum in all patients.
A patient who had an autologous hemo-
poietic stem cell transplantation and was
given palifermin developed erythema and
lichenoid papules that were distributed
primarily in intertriginous areas [19A].
Histology of the papules showed a striking
resemblance to verrucae, but in situ
hybridization studies were negative for
human papillomavirus. Immunohistochemi-
cal staining with antibodies to Ki-67 and
cytokeratin 5/6 showed increased
772
keratinocyte proliferation in lesional skin.
The eruption did not required treatment
and resolved spontaneously.
Human epidermal growth factor
(rhEGF)
Human epidermal growth factor (EGF) is a
polypeptide growth hormone that plays an
important role in the regulation of growth,
proliferation, and differentiation of a wide
range of cells by binding to EGF receptors.
By binding to cell-surface receptors, EGF
activates an extensive network of signal trans-
duction pathways that include the PI3K/
AKT, RAS/ERK, and JAK/STAT pathways.
Recombinant human EGF (rhEGF) may
enhance growth of new epidermal and stem
cells and promote cell metabolism.
Uses Topical rhEGF has been used to treat
exfoliated lesions on the penis and scrotum
in a 79-year-old man with StevensJohnson
syndrome; within 1 day the pain in the area
of the external genitalia had markedly
reduced and the rash had improved [20A].
Adverse reactions were not reported. The
rhEGF was also applied to the left axillary
area and the eruption resolved after 10
days. The rhEGF cream was prepared by
the local pharmacy department by mixing
lyophilized rhEGF powder 0.02% with a
plain cream base.
Comparative studies In a double-blind study
of two doses of rhEGF in 41 patients with type
1 or 2 diabetes and Wagner's grade 3 or 4 foot
ulcers, with a high risk of amputation, intrale-
sional injections of 25 or 75 micrograms were
given three times a week for 58 weeks with
standard good wound care [21C]. The rates
of adverse events were similar with the two
doses. The most frequent were sepsis (33%),
burning sensations (29%), and tremors, chills,
and local pain (25% each).
Placebo-controlled studies Topical rhEGF
has been evaluated in patients with head
and neck cancers with oral mucositis
Chapter 37 D. Spoerl and Andreas J. Bircher
induced by radiotherapy, with or without
chemotherapy [22C]. Patients were assigned
to a placebo group or to one of three con-
centrations of EGF (10, 50, or 100 micro-
grams/ml). The grade of mucositis was
evaluated using the Radiation Therapy
Oncology Group (RTOG) scoring criteria.
Of 113 patients, 28 used placebo, 29 used
EGF 10 micrograms/ml, 29 used 50 micro-
grams/ml, and 27 used 100 micrograms/ml.
EGF signicantly reduced the incidence of
severe oral mucositis at the primary end-
point (a 64% response with EGF 50 micro-
grams/ml versus a 37% response in the
control group). The frequency of minor and
serious adverse events was similar in all the
groups and there were no systemic adverse
reactions, based on the numbers of periph-
eral blood leukocytes and granulocytes.
In a multicenter, double-blind, placebo-
controlled study of intralesional inltration
of rhEGF in Wagner's grade 3 or 4 diabetic
foot ulcers in 149 patients who were ran-
domized to EGF 25 or 75 micrograms or
placebo three times per week for 8 weeks
and standard good wound care, the main
endpoint was granulation tissue covering
at least 50% of the ulcer at 2 weeks [23C].
This occurred in 19/48 controls versus 44/
53 with 75 micrograms (OR 7.5; 95%
CI 2.9, 19) and 34/48 with 25 micrograms
(OR 3.7; 1.6, 8.7). Most of the adverse
events were mild and there were no drug-
related severe adverse reactions.
Insulin-like growth factor
(mecasermin) [SED-15, 1792;
SEDA-32, 676]
Injectable recombinant human insulin-like
growth factor (rhIGF-I; rINN mecasermin)
has been available for nearly 20 years for
treatment of the rare instances of growth hor-
mone (GH) insensitivity caused by GH
receptor defects or GH-inhibiting antibodies.
It has also been used as an insulin-sensitizing
agent in severe insulin-resistant conditions.
Adverse reactions to mecasermin have been
reviewed [24R]. The most common adverse
reaction is hypoglycemia, which is readily
controlled by administration with meals.
Drugs that act on the immune system: cytokines and monoclonal antibodies
Other common adverse reactions involve
hyperplasia of lymphoid tissue, which may
require tonsillectomy/adenoidectomy, accu-
mulation of body fat, and coarsening of the
facies.
Drug abuse Since IGF-I mediates many of
the anabolic actions of growth hormone, it
is on the World Anti-Doping Agency list
of prohibited substances [25R].
INTERFERONS [SED-15, 1841;
SEDA-30, 436; SEDA-31, 591;
SEDA-32, 676]
Since interferons are almost always used in
combination with ribavirin in patients with
hepatitis C infection, it can be difcult to
know whether adverse events, if drug-
induced, are due to one or the other. In
many cases authors do not even discuss this
problem, often attributing the supposed
adverse effects to the interferon. In some
cases withdrawal of one of the agents can
provide evidence, and in other cases there
may be other clues. For example, in cases
of skin pigmentation at the site of injection
of interferons, the adverse effect may be
presumed to be due to interferon [26A], a
type II between-the-eyes adverse effect
[27H]. In one case hemolytic anemia was
attributed to interferon rather than riba-
virin because the patient had previously
taken a course of interferon without
adverse effects [28A]; presumably the infer-
ence was that the patient had been sensi-
tized by the previous course. A systematic
review of cases in which the drugs were
used together and individually can also
yield useful information, as in the case of
pneumonitis in patients being treated with
interferon and ribavirin, attributed to inter-
feron [29AM]. Similarly, in cases of ocular
myasthenia [30A], pleural effusion [31A],
and cataract [32A] the interferon was
blamed because no previous cases were
found in association with ribavirin alone.
In cases in which the adverse event persists
Chapter 37 773
for some time after the withdrawal of pegy-
lated interferon and ribavirin, the long half-
life of peginterferon is cited as a possible
explanation, but this is weak evidence in
such cases. In some cases it may be impos-
sible to tell whether the adverse event, if
drug-induced, was due to one or other of
the drugs or to the combination.
See also Ribavirin in Chapter 29.
Susceptibility factors Genetic Genetic poly-
morphisms associated with or hematological
adverse reactions to interferon-based com-
bination therapy in Japanese patients with
chronic hepatitis C have been identied
[33c]. Single nucleotide polymorphisms were
detected in all exonic regions of the 12 genes
involved in the interferon signalling pathway
in 32 healthy Japanese. Of 167 identied
polymorphisms, 35 were genotyped and
tested for an association with the efcacy of
interferon plus ribavirin or adverse reactions
in 240 patients with chronic hepatitis C. Mul-
tiple linear regression analyses showed that
two polymorphisms (IFNAR1 10848-A/G
and STAT2 4757-G/T) were signicantly
associated with interferon-induced neutro-
penia. Thrombocytopenia was associated
with IRF7 789-G/A.
Interferon alfa [SED-15, 1793; SEDA-
30, 436; SEDA-31, 591; SEDA-32, 676]
Systematic reviews In a systematic review
of antiviral drug therapy in 16 studies, in
which pegylated interferon alfa was used
in combination with ribavirin for recurrent
hepatitis C after liver transplantation, the
mean sustained viral response rate was
30% (range 850%) [34M]. Dosage reduc-
tion and withdrawal of treatment were
common (73% and 28% respectively).
Respiratory In a patient with chronic hepa-
titis C, peginterferon alfa-2b was associated
with interstitial pneumonia, which was exac-
erbated by ursodeoxycholic acid [35A].
After a rst course failed, a second course
of antiviral therapy achieved normalization
of serum aminotransferases and hepatitis
774
C viral RNA, but also caused interstitial
pneumonia, which improved after with-
drawal of peginterferon. When ursodeoxy-
cholic acid was started 4 months later for
relapsing hepatitis the interstitial pneumo-
nia recurred.
A 62-year-old Japanese man with a renal
cell carcinoma and multiple metastases,
who had had inactive idiopathic interstitial
pneumonia for 5 years without treatment,
was given three intramuscular injections of
standard-dose interferon-alfa and had an
acute exacerbation of the interstitial pneu-
monia [36A].
A rare case of desquamative interstitial
pneumonitis occurred during treatment
with peginterferon alfa and ribavirin in a
man with hepatitis C infection; it responded
to glucocorticoids [37A].
Nervous system Interferon alfa has been
used to investigate pathways by which
innate immune cytokines affect the brain
and behavior [38c]. There were reduced
motor speed and reaction times and slower
response times in the rapid visual informa-
tion processing task in patients who were
treated with interferon alfa and ribavirin.
Reduced motor speed correlated with
increased symptoms of depression and
fatigue.
Sensory systems Eyes When conjunctival
and corneal intraepithelial neoplasia were
treated with topical interferon alfa-2b there
was complete clinical resolution in 27 of the
28 eyes treated after a median of 2 months;
adverse reactions included mild conjuncti-
val hyperemia and follicular conjunctivitis
in three patients [39c].
In 15 patients with ocular surface squa-
mous neoplasia treated with topical inter-
feron alfa-2b, one developed follicular
conjunctivitis, but treatment was continued
[40c].
The frequency of ophthalmological com-
plications was determined in a retrospective
analysis of 183 patients with hepatitis C
virus infection, of whom 29 had diabetes
and 85 had hypertension; 71 received inter-
feron alfa-2a, 100 received interferon alfa-
2b, and 12 received consensus interferon
Chapter 37 D. Spoerl and Andreas J. Bircher
[41c]. Seven had retinal changes on follow-
up and treatment was discontinued in three.
Of seven with ocular changes, two had
hypertension and one had both hyperten-
sion and diabetes.
Ocular sarcoidosis has been reported in
three patients, in two of whom conven-
tional interferon alfa was used and in one
peginterferon alfa-2b; all had granuloma-
tous panuveitis with choroidal granulomata
of various sizes [42c]. All had also taken
ribavirin. The intraocular inammation
was managed by reducing the dose of inter-
feron and all patients received topical
glucocorticoids.
A 56-year-old black woman developed
with bilateral orbital swelling in the region
of the lacrimal glands after taking inter-
feron-alfa ribavirin for 4 months for
occupationally acquired hepatitis C infec-
tion [43A]. Bilateral lacrimal gland biopsies
showed granulomatous inammation. All
other tests were negative for sarcoidosis.
Auditory function Cochlear damage has
been attributed to interferon alfa [44A].
A 57-year-old man developed vertigo, tinni-
tus, bilateral hearing loss, and postural intoler-
ance temporally related to administration of
peginterferon alfa-2b ribavirin for chronic
hepatitis C viral infection. He had bilateral
sensorineural hearing loss, subjective vertigo
with saccadic intrusions during xation and
smooth visual pursuit, and supine hyperten-
sion followed by orthostatic hypotension with
inadequate reexive compensatory cardiovas-
cular responses. There was also a marked
hemolytic anemia. Formal audiometry showed
high-frequency sensorineural hearing loss with
abnormal high-frequency distortion product
otoacoustic emissions, suggestive of damage
to the cochlear outer hair cells. Withdrawal
of therapy resulted in rapid resolution with
mild residual hearing loss and tinnitus.
A 51-year-old man with chronic obstruc-
tive pulmonary disease and hepatitis C
genotype 2b suddenly developed left-sided
acute sensorineural hearing loss after taking
peginterferon ribavirin for 6 weeks [45A].
Endocrine Treatment of chronic hepatitis
C with interferon is associated with thyroid
dysfunction in 514% of patients. Among
Drugs that act on the immune system: cytokines and monoclonal antibodies
511 patients, 45 with thyroid dysfunction
were identied (8.8%) [46c]. Pegylated
interferon alfa was associated with higher
rates of thyroid dysfunction than interferon
(14% versus 6.0%). Female sex and Asian
ethnicity were independent predictors.
There was persistent thyroid dysfunction
in 16 patients by the end of the follow-up
period, predicted by female sex, non-Asian
ethnicity, a prior history of thyroid dysfunc-
tion, and peroxidase antibodies.
The occurrence and distribution of thy-
roid antibodies and non-organ-specic auto-
antibodies before, during, and after
treatment with daily high-dose consensus
interferon alfa-1 (interferon alfacon-1) have
been reported in 217 patients with chronic
hepatitis C [47c]. TSH concentrations were
abnormal (over 3.0 or under 0.4 mU/l)
before treatment in 16% and signicantly
more often in women (25%). Thyroid anti-
bodies were detected in only 2.6% and
non-organ-specic autoantibodies in up to
30% (47% women versus 24% men). During
induction therapy, there were low TSH con-
centrations in 14%, whereas there were
raised TSH concentrations later (week 48)
in up to 16%, again preferentially in women
(42%). In 1.4% of all the patients, treatment
had to be withdrawn because of symptom-
atic hyperthyroidism. Thyroid antibodies
were detected in 11% (31% women) and
non-organ-specic autoantibodies in up to
58% during treatment.
Interferon alfa-2b can cause both hyper-
thyroidism and hypothyroidism, the com-
monest cause being thyroiditis. Seven
women and four men developed thyroiditis
over 30 months while using peginterferon
alfa-2b and ribavirin for hepatitis [48c].
The average time to the development of
thyroid disease was 10 weeks and the dura-
tion of the disease was 9 weeks. All eventu-
ally recovered normal biochemical thyroid
function, although two required short-term
supplementation.
Thyroid function and changes in ultra-
sound morphology have been studied in
59 patients with chronic hepatitis C during
antiviral therapy with pegylated interferon
and ribavirin [49c]. All had ultrasonography
of the thyroid gland before treatment, and
Chapter 37 775
after 1, 3, and 6 months of antiviral drug
therapy. Before and during the course of
therapy, 11 patients developed thyroid dys-
function (one hypothyroidism, nine hyper-
thyroidism, and one hyperthyroidism
followed by hypothyroidism). Hyperthy-
roidism was due to Graves disease in one
patient and destructive thyroiditis in nine.
There was reduced echogenicity suggestive
of a destructive process in the thyroid gland
even before changes in thyroid function or
antibodies were detected. Susceptibility fac-
tors for thyroid dysfunction were age,
female sex, pre-treatment thyroid volume,
pre-existing thyroglobulin/thyroid peroxi-
dase antibodies, and viral load.
Liver In a 38-year-old man who took peg-
interferon alfa-2b plus ribavirin for hepatitis
C, the aminotransferase activities normal-
ized [50A]. However, repeated treatment
resulted in both a low hepatitis C RNA
titer and an increase in aminotransferases.
Immunostaining of the liver showed accu-
mulation of peginterferon alfa-2b and when
it was withdrawn and recombinant inter-
feron alfa-2a was used instead, the amino-
transferases normalized within about 2
months. The authors suggested that the rise
in aminotransferase activities was related to
polyethylene glycol.
A 55-year-old man with hepatitis C virus
(genotype 1a) infection, which did not
respond to peginterferon alfa (type not
mentioned) and ribavirin, was subsequently
treated with interferon alfacon-1 riba-
virin [51A]. He developed raised amino-
transferase activities, despite a reduced
viral load. The aminotransferases returned
to baseline when interferon alfacon-1 was
withdrawn and rose again after rechallenge.
Interferon alfacon-1 differs from interferon
alfa-2b in 19/166 amino acids (88% homol-
ogy), and from interferon alfa-2a in 18/166
amino acids (88% homology).
Skin A patient developed two histologically
conrmed subcutaneous sarcoid nodules 15
months after starting adjuvant therapy with
interferon for lymph node metastatic mela-
noma in which the primary tumor was not
known [52A]. As imaging techniques do
776
not necessarily differentiate between sar-
coidosis and the radiological signs of metas-
tases, histological evaluation is essential.
Oral lichen planus can appear or be exac-
erbated during treatment of chronic hepati-
tis C. Improvement after withdrawal of
therapy suggests that interferon can cause
or worsen these lesions in some patients. In
three patients oral lichen planus worsened
during treatment of chronic hepatitis C with
pegylated interferon and ribavirin [53c].
Linear IgA bullous dermatosis has been
associated with interferon alfa-2a in a
patient with Kaposi's sarcoma [54A].
Immunologic A large variety of auto-
immune adverse reactions have been
reported during interferon alfa therapy.
A 46-year-old man with chronic hepatitis C
developed antiphospholipid syndrome after tak-
ing peginterferon alfa ribavirin for 12 weeks;
the presentation was primary adrenal insuf-
ciency secondary to bilateral adrenal hematoma
and subclavian vein thrombosis [55A].
Dermatomyositis occurred in a 57-year-old
patient who took interferon beta for multiple
sclerosis [56A]. Immunohistochemical staining
of skin biopsies for myxovirus-resistance pro-
tein A (a surrogate marker of cutaneous type
I interferon signalling) showed increased
staining that correlated temporally with inter-
feron beta treatment and subsequent disease
activity. In vitro treatment with interferon
beta of peripheral blood mononuclear cells
isolated from this patient showed enhanced
type I interferon signaling, assessed by inter-
feron-induced gene expression proles.
A 64-year-old woman developed polymyositis
associated with chronic hepatitis C after tak-
ing peginterferon-alfa ribavirin [57A]. She
had raised serum CK, aminotransferases, and
LDH activities after 28 weeks of treatment.
Further investigations suggested polymyositis,
possibly triggered by the peginterferon. She
was given prednisolone and the polymyositis
remained in remission.
A lupus-like syndrome occurred during
therapy with peginterferon alfa-2b for chronic
hepatitis B virus infection after 8 months
[58A] and other cases have been reported.
A 43-year-old man developed a lupus-like
syndrome, including life threatening myoperi-
carditis and vasculitis, after receiving
Chapter 37 D. Spoerl and Andreas J. Bircher
peginterferon alfa and ribavirin for chronic
hepatitis C, with eight features of the Ameri-
can Rheumatological Association's diagnostic
criteria, including high titers of antinuclear
antibodies, and anti-double-stranded DNA
antibodies [59A].
A 20-year-old woman with chronic hepatitis C
virus infection and end-stage renal disease due
to systemic lupus erythematosus was admitted
to hospital with fever, pain in the abdomen,
seizures, and altered consciousness [60A]. She
was on maintenance dialysis and was receiving
peginterferon monotherapy. Investigations
showed activation of systemic lupus erythema-
tosus with cerebritis after peginterferon. Man-
agement included temporary withdrawal of
peginterferon and pulse methylprednisolone
500 mg/day for 3 days followed by oral pred-
nisolone 40 mg/day.
Interferon beta [SED-15, 1793;
SEDA-30, 437]
Immunologic Vasculitis has been attributed
to interferon beta.
A 52-year-old woman with an oligoastro-
cytoma received postoperative radiotherapy
and intravenous interferon beta [61A]. She
continued to have a high fever and impaired
consciousness, and an MRI scan showed mul-
tiple enhanced lesions in the residual tumor.
A biopsy showed vasculitis in the residual
tumor. She improved quickly with glucocorti-
coid treatment. Radiotherapy produced com-
plete remission of the tumor.
A 38-year-old woman with relapsing-remitting
multiple sclerosis received subcutaneous inter-
feron beta-1b and developed disseminated
cutaneous lesions after three injections, reap-
pearing after drug readministration [62A]. His-
topathology conrmed non-specic cutaneous
lymphocytic vasculitis. She improved with
glucocorticoids and withdrawal of interferon
beta.
Systemic sclerosis developed in a 38-year-
old woman with multiple sclerosis after
treatment with interferon beta [63A].
Infection risk A 43-year-old woman with
multiple sclerosis treated with subcutane-
ous interferon beta developed right lower
abdominal quadrant pain, fever, and an
indurated McBurney point [64A]. An
Drugs that act on the immune system: cytokines and monoclonal antibodies
abdominal CT scan showed inammatory
subcutaneous fat inltration reaching the
surface of the right lateral rectus muscle.
Laparoscopic appendectomy produced no
improvement, and the inltration near a
site of subcutaneous injection progressed
with areas of liquefaction. A deep cutane-
ous biopsy specimen showed septal panni-
culitis without vasculitis.
Teratogenicity There are controversial and
discrepant results on the risk of spontane-
ous abortions and teratogenesis induced
by interferon in 38 patients with multiple
sclerosis who became pregnant in 10 year
period [65c]. Neonates who had been
exposed in utero had slightly lower birth
weights, but the difference was not statisti-
cally signicant, Developmental milestones
were within the reference ranges in all
groups. The authors concluded that inter-
feron beta should be withdrawn until deliv-
ery and should not be considered to be a
reason for interrupting an intact pregnancy.
INTERLEUKINS [SED-15, 1831;
SEDA-30, 438; SEDA-31, 592;
SEDA-32, 676]
Aldesleukin (interleukin-2, IL-2)
[SED-15, 58; SEDA-30, 438; SEDA-32,
676]
Observational studies In 19 patients with
acute lymphoblastic malignancies who
received interleukin-2 for recurrence after
hemopoietic stem cell allotransplantation,
adverse reactions were mainly fever, pain,
redness, and swelling at the injection site; four
patients withdrew because of fever [66c].
In 17 patients with pancreatic adenocar-
cinoma adverse reactions to preoperative
interleukin-2 were mild, and included injec-
tion site reactions in all 17, fever in 15, and
hypotension in one patient; the symptoms
resolved completely within 24 hours [67c].
Of 259 patients with metastatic renal cell
carcinoma, who were treated with high-
Chapter 37 777
dose interleukin-2, 23 had a complete
response and 30 a partial response [68c].
There were two treatment-related deaths.
Adverse reactions, including hematological
and hepatic reactions, were generally lim-
ited to grade 1 and grade 2. Other grade 1
and grade 2 reactions included edema,
chills, fatigue, dyspnea, rashes, diarrhea,
and nausea. Because of the capillary leak
syndrome, vasodilatation, and diarrhea,
patients often had hypotension and oliguria.
Confusion and impaired consciousness were
among the other major grade 3 and grade 4
reactions. All these reactions were readily
reversible after withdrawal of interleukin-2.
Patients aged 60 years and older with
acute myeloblastic leukemia in complete
remission were randomly assigned to no
further therapy or a 90-day regimen of 14-
day cycles of low-dose rIL-2 (n 66); of
the latter, 24 stopped early because of
adverse reactions or relapse [69C]. Grade
4 reactions during rIL-2 therapy included
thrombocytopenia (65%) and neutropenia
(64%), and grade 3 reactions included ane-
mia (33%), infections (24%), and malaise/
fatigue (14%).
Cardiovascular In 23 patients with advanced
renal cell carcinoma 15 of whom had previ-
ously received tyrosine kinase inhibitors and
eight bevacizumab none achieved a partial
or complete response to therapy, and the inci-
dence of severe cardiac adverse reactions in
those who had previously received tyrosine
kinase inhibitors was 40%. This suggests that
interleukin-2 cannot be safely given to
patients who have previously received a tyro-
sine kinase inhibitor [70c].
Reversible left posterior fascicular block
occurred in a 50-year-old man with meta-
static clear-cell renal carcinoma when he
was given two doses of high-dose interleu-
kin-2; it resolved 18 hours after the second
dose [71A]. He had similar electrocardio-
graphic changes during two subsequent
cycles of high-dose interleukin-2, both of
which resolved spontaneously
Hematologic In chronically HIV-infected
adults taking antiretroviral drugs and inter-
leukin-2 there were signicant increases in
778
high-sensitivity C-reactive protein (hsCRP)
and D dimers by the end of the rst cycle
of treatment, returning to baseline by the
end of study [72c]. Although this suggests
the possibility of an increased risk of throm-
botic events, there were no serious throm-
botic or cardiovascular adverse events
during interleukin administration.
In a phase I study in 10 patients with meta-
static renal cell carcinoma who were given
intravenous Innacell gd, an autologous cell-
therapy product based on g9d2 T lympho-
cytes, combined with a low dose of subcuta-
neous interleukin-2, one patient developed
disseminated intravascular coagulation [73c].
Other treatment-related adverse events
included gastrointestinal disorders and u-like
symptoms (fatigue, pyrexia, rigors). Hypoten-
sion and tachycardia also occurred. During
interleukin-2 administration there was fever
in 60%, grade 12 weakness and fatigue
(25%), grade 12 anemia (13%), neutropenia
(11%), and thrombocytopenia (11%), and
reversible episodes of grade 34 anemia
(4.3%) and thrombocytopenia (11%). There
were episodes of nausea/vomiting in 6.5%
and grade 12 diarrhea and mucositis in
17%. Clinical signs of autoimmunity
appeared at 49 months in six cases, discoid
lupus erythematosus in one, and mono/oligo-
articular arthritis accompanied by fever and
increased inammatory markers in ve.
Anti-double-stranded DNA antibodies, anti-
nuclear antibodies, and anticyclic citrulline
peptide antibodies were always in the refer-
ence ranges. There were increases in circulat-
ing immune complexes in two cases.
Tumorigenicity Concerns about a possible
excess risk of lymphomas in HIV-infected
patients exposed to interleukin-2 were
not conrmed in a large observational
study [74C].
Interleukin-11 (IL-11; oprelvekin)
[SED-15, 1845; SEDA-30, 438]
Observational studies Recombinant hu-
man interleukin-11 (rhIL-11) is a gp-130
signalling cytokine with hemopoietic and
Chapter 37 D. Spoerl and Andreas J. Bircher
anti-inammatory activity. In an open trial
of three dosage regimens of subcutaneous
rhIL-11 in nine patients with mild von
Willebrand's disease, concentrations of
von Willebrand factor and factor VIII
increased gradually and progressively over
7 days and returned to baseline by day 14
[75c]. Adverse reactions were limited to less
than grade-1 hypertension, hypokalemia,
and uid retention.
In 14 patients with chronic myeloid leu-
kemia and thrombocytopenia associated
with tyrosine kinase inhibitors, interleukin-
11 increased the platelet count in eight
cases and allowed an increased in the dose
of imatinib in one [76c]. One patient
stopped taking interleukin-11 because of
grade 4 fatigue. Grade 1 or 2 peripheral
edema was the most common adverse event
(n 6) and was manageable with diuretics
in all but one patient with grade 2 edema,
who required dosage reduction. One
patient developed grade 1 blurred vision,
and one developed a grade 1 rash.
Interleukin-12 (IL-12) [SED-15,
1848; SEDA-32, 677]
Observational studies Mucosal immuniza-
tion offers potential protection against
pneumococcal disease, but the lack of a
suitable adjuvant for use in humans is an
obstacle. In animals interleukin-12 has been
successfully used as an adjuvant. The use
of interleukin-12 in humans has been
reviewed, with suggested approaches by
which it could be developed as a mucosal
adjuvant [77R]. However, in 48 patients
with multiple myeloma who were initially
given intravenous interleukin-12 there was
an unexpectedly high rate of adverse reac-
tions and although the subcutaneous route
was used instead, with some improvement,
the adverse reactions were also unaccept-
able [78c]. Changing the route of adminis-
tration from intravenous to subcutaneous
improved the rate of grade 3 and 4 non-
hematological reactions from 63% to 31%;
there were no deaths.
Drugs that act on the immune system: cytokines and monoclonal antibodies
Interleukin-18 (IL-18)
Interleukin-18, a member of the IL-1 super-
family of cytokines, is an immunostimula-
tory cytokine that regulates both innate
and adaptive immune responses. It is pro-
duced by several cells, including macro-
phages, dendritic cells, microglial cells, and
keratinocytes. It enhances the production
of interferon gamma by T cells and natural
killer cells, augments the cytolytic activity
of natural killer cells and cytolytic T lympho-
cytes, and promotes the differentiation of
activated CD4 T cells into helper effector
cells. It acts synergistically with IL-12 to
induce interferon gamma production and
stimulate Th1 immune responses. Its role in
cardiac disease has been reviewed [79R].
The effects of prolonged therapy with
rhIL-18 in escalating doses have been
described in patients with advanced cancer
[80c]. Common adverse reactions included
chills, fever, headache, fatigue, and nausea.
Common laboratory abnormalities included
transient asymptomatic grade 13 lympho-
penia, grade 14 hyperglycemia, grade 12
anemia, neutropenia, hypoalbuminemia, rises
in liver enzymes, and rises in serum creatinine.
In a phase 2 study of rhIL-18 in stage IV
melanoma, 64 patients were randomized to
three doses [81c]. Five patients had 10 grade
3 drug-related adverse events: polyarthritis;
deep vein thrombosis, pulmonary embolism;
cognitive disorder; fatigue, dyspnea, pleural
effusion, and lymphopenia. One patient
had a grade 4 increase in lipase activity, which
led to permanent withdrawal from the study.
Anakinra (interleukin-1 receptor
antagonist) [SED-15, 215; SEDA-31,
592; SEDA-32, 677]
Skin An interstitial granulomatous reaction
to anakinra resulted in pink dermal plaques
and nodules in the periaxillary region which
resolved after withdrawal of anakinra and
recurred on rechallenge [82A]. Biopsy
showed diffuse dermal inltration of lym-
phocytes and histiocytes with interspersed
neutrophils and eosinophils, and
Chapter 37 779
fragmentation and degeneration of collagen
and elastic bers.
Immunologic An IgE-mediated anaphylac-
tic reaction has been attributed to anakinra
in a 46-year-old Indian woman with rheu-
matoid arthritis who had had an urticarial
rash and infusion reactions after three
doses of iniximab, and autoantibodies,
worsening Raynaud's phenomenon, and
digital microinfarcts after treatment with
etanercept for 1 year [83A]. Skin prick tests
were positive to both anakinra and hista-
mine. She then had an urticarial reaction
to adalimumab.
Infection risk Two injection site reactions
to subcutaneous anakinra have been
reported: Wells cellulitis of the thigh and a
bacterial cellulitis with deep necrosis [84A].
TUMOR NECROSIS
FACTOR ALFA (TNF-a)
AND ITS ANTAGONISTS
[SEDA-30, 439; SEDA-31, 592;
SEDA-32, 677]
Tumor necrosis factor
The effect on tumor progression of tumor
necrosis factor (TNF), a peptide produced
by macrophages with cytostatic and cyto-
lytic effects, has recently raised concern,
since tumor inhibiting and stimulating
properties have been identied [85R]. The
best option may be to combine it with other
treatments [86R].
Observational studies Recombinant TNF
(rTNF) and dactinomycin have been stud-
ied in 19 patients with recurrent or refrac-
tory Wilms tumor. Three had a complete
response, ve had stable disease, and 11
had progressive disease. After 59 patient
treatment cycles, the most common grade
3/4 adverse reactions were thrombocyto-
penia (41%), raised aminotransferases
780
(24%), neutropenia (20%), leukopenia
(14%), anemia (12%), and myalgias (10%).
Nervous system Peripheral nerve damage
has been reported in 148% of patients,
including a 49-year-old man in whom hyper-
thermic isolated limb perfusion was per-
formed with TNF-alpha and melphalan for
an irresectable desmoid tumor and caused
extensive local edema and a common pero-
neal nerve palsy, which was still severe 10
months later [87A]. In such cases emergency
compartmental pressure measurement may
guide the need for fasciotomy
Tumor necrosis factor antagonists
Nervous system Demyelinating neuropathy
is a rare adverse reaction to anti-TNF ther-
apy, including adalimumab, etanercept, and
iniximab; improvement usually occurs
after drug interruption and/or in association
with usual treatments for demyelinating
neuropathies [88Ar].
Hematologic During treatment with TNF
antagonists in 67 patients, four had thrombo-
cytopenia. The platelet count recovered after
withdrawal in three patients and recurred
after re-exposure in two. The overall esti-
mated frequency of thrombocytopenia in
this study was 4.3% (95% CI 0,6.2%).
Liver Reactivation of hepatitis B virus has
been reported in patients who are chronic
carriers and who are receiving TNF antago-
nists [89c]. Use of these agents in patients
with hepatitis virus infections can be associ-
ated with transient increases in aminotrans-
ferases but appears to be safe overall.
Skin Cutaneous adverse reactions to TNF
antagonists have been studied in 252
patients with rheumatoid arthritis (146 trea-
ted with iniximab, 72 with adalimumab,
and 34 with etanercept) and in 183 with
spondyloarthropathies (138 treated with
iniximab, 37 with etanercept, and 8 with
Chapter 37 D. Spoerl and Andreas J. Bircher
adalimumab) [90C]. Of the former, 11 devel-
oped psoriatic skin lesions and 10 granuloma
annulare; there were ve cases of vasculitis,
two of alopecia areata, two of discoid lupus
erythematosus, one of lichen planus,
and one vitiligo. Of the 183 patients with
spondyloarthropathies, six developed psori-
atic skin lesions, one developed granuloma
annulare one lichen planus, and one alopecia
areata; there was one case of vasculitis.
A 49-year-old woman with seronegative rheu-
matoid arthritis developed pustular psoriasis
while taking etanercept and subsequently
developed disseminated herpes simplex during
iniximab therapy, with fever, a widespread
itchy vesicular rash, and worsening inamma-
tory arthritis [91A].
Infection risk Fatal disseminated systemic
nocardiosis with Nocardia farcinica, involv-
ing the brain, lymph nodes, and adrenal
glands, occurred in a 66-year-old woman
with psoriasis after sequential therapy with
alefacept and then iniximab [92A].
Adalimumab [SED-15, 2380; SEDA-30,
439; SEDA-31, 597; SEDA-32, 679]
Observational studies In an open pilot study
in 41 patients with rheumatoid arthritis who
had previously failed iniximab therapy, nei-
ther former adverse reactions to iniximab
nor baseline human antichimeric iniximab
antibodies had an effect on adverse event fre-
quency or severity [93c].
Cardiovascular A severe cardiomyopathy
occurred 1 week after a single dose of ada-
limumab in a 25-year-old woman with
Crohn's disease [94A].
Ear, nose, throat A possible link between
sinusitis and adalimumab has been reported
[95A].
Nervous system MillerFisher syndrome has
been reported in a patient with rheumatoid
arthritis taking adalimumab [96A]. Bilateral
Drugs that act on the immune system: cytokines and monoclonal antibodies
phrenic nerve palsy has been reported after
adalimumab therapy for psoriasis in 65-year-
old woman [97A].
Skin Lichen planus-like eruptions have been
attributed to adalimumab and iniximab
[98A].
In a comparative study, patients with
rheumatoid arthritis treated with adalimu-
mab had a signicantly higher rate of inci-
dent psoriasis than patients who used
etanercept and iniximab [99c].
Musculoskeletal Severe myalgia associated
with adalimumab has been reported in a
patient with Crohn's disease [100A].
Reproductive system Menorrhagia and
severe dysmenorrhea have been reported
after adalimumab [101A].
Immunologic Two patients with worsening
injection site reactions to adalimumab have
been described [102A]. Skin tests suggested
immediate type I hypersensitivity reactions.
Exposure of peripheral blood leukocytes to
adalimumab caused signicant histamine
release and passive transfer of serum from
one of the allergic patients to basophils
from a non-atopic, healthy donor sensitized
those cells to release signicant amounts of
histamine after exposure to adalimumab.
Lupus erythematosus has also been
reported [103A].
In a retrospective study in 30 patients with
Crohn's disease, the presence of antibodies
to adalimumab in 17 patients was related
to non-response to adalimumab [104c].
Infection risk There have been reports of
tuberculosis in patients receiving adalimu-
mab, in most cases extrapulmonary [105c].
The risk of tuberculosis was higher in
patients receiving anti-TNF monoclonal
antibodies than those who were receiving
soluble TNF receptors. Some patients who
have previously received treatment for
latent or active tuberculosis have devel-
oped active tuberculosis while being treated
with adalimumab.
Chapter 37 781
Etanercept [SED-15, 1279; SEDA-30,
440; SEDA-31, 600; SEDA-32, 681]
Hematologic In a postmarketing Swedish
cohort study (n 820) the incidence of
hematological disorders in patients treated
with etanercept was 3.4 per 1000 patient-
years [106C]. However, half of these patients
were using at least one other disease-modify-
ing anti-rheumatic drug (DMARD), in
most cases methotrexate, and attribution
was not clear.
Gastrointestinal New Crohn's disease or
non-specic inammatory bowel disease
has been attributed to etanercept [107c].
Skin Angiokeratomata have been attrib-
uted to etanercept [108A].
A 43-year-old man used acitretin, photother-
apy, methotrexate, ciclosporin, and iniximab
and had an initially good response, but then
relapsed. Etanercept 50 mg twice a week for
3 months, then 25 mg twice a week, was intro-
duced, and after 14 months he noticed black
lesions over injection sites, initially on the
abdomen. He then carried out injections into
the thigh, where the same reactions occurred.
A biopsy of a black papule was consistent with
angiokeratoma.
Hypopigmented mycosis fungoides Hypo-
pigmented mycosis fungoides is a rare vari-
ant of mycosis fungoides, which occurs
mostly in patients of Asian or African
descent, as in the case of a 61-year-old
AfricanAmerican woman in whom a
hypopigmented T-cell dyscrasia evolved to
hypopigmented mycosis fungoides during
treatment with etanercept [109A]. Because
of the risk of lymphoma, TNF inhibitors
are typically avoided in patients with
history of systemic lymphoma.
Injection site reactions Etanercept recall
reactions bear some similarity to xed-drug
eruptions [110A].
A 50-year-old woman with psoriasis devel-
oped an erythematous edematous plaque at
the site of a second injection and simulta-
neously at a previous injection site, both on
the abdomen. The lesions regressed after 1
782
week with topical glucocorticoids, oral anti-
histamines, and withdrawal of etanercept.
After resolution, etanercept was restarted
and there were no further local reactions.
Pemphigus vulgaris Pemphigus has been
attributed to etanercept [111A]
A 51-year-old man presented with plaque-type
psoriasis took etanercept and 2 years later
developed painful ulcers in the mouth and on
the penis, shoulders, chest, and back. Etaner-
cept was withdrawn and most of the lesions
cleared within a few weeks. Several months
later, etanercept was started again, but within
3 months he developed more lesions on the
chest and back, in the mouth, and in new areas
in the inguinal region and on the limbs. A
biopsy showed suprabasal acantholysis and
intercellular deposition of IgG and C3.
Squamous cell carcinomas A penile cuta-
neous squamous cell carcinoma developed
rapidly in a 71-year-old man who took eta-
nercept for psoriasis [112A].
Infection risk Virus infections can develop
during treatment with TNF antagonists, as
in a case of varicella zoster infection [113A].
A 58-year-old man with severe chronic plaque
psoriasis used etanercept 50 mg subcutaneously
twice a week, and after 1 month about 15 scat-
tered, symptomless, erythematous, slightly
edematous macules with central papulovesicles
appeared on the trunk, arms, and face, without
dermatomal clustering. PCR of the vesicle uid
was strongly positive for varicella zoster virus
DNA, and there were specic IgG and IgM.
He had had chickenpox at the age of 4 years.
Iniximab [SED-15, 1747; SEDA-30,
440; SEDA-31, 601; SEDA-32, 683]
Respiratory Exacerbations of brosing
alveolitis, interstitial pneumonitis, and bron-
chospasm in patients using iniximab have
been described [114A, 115A].
Nervous system Iniximab has been associ-
ated in rare cases with optic neuritis [116A]
and other nervous system disorders, includ-
ing GuillainBarr syndrome [117A] and
LewisSumner syndrome [118A].
Chapter 37 D. Spoerl and Andreas J. Bircher
Liver Reactivation of hepatitis B virus in
patients who are chronic carriers who are
receiving TNF antagonists, including inixi-
mab, has been reported [119A]
Toxic hepatitis has been attributed to
iniximab in a 38-year-old woman with
rheumatoid arthritis [120A].
Skin Eczema-like eruptions In a prospec-
tive cohort study in 92 patients treated with
iniximab for a variety of disorders, with
the exception of cutaneous psoriasis, 15
developed eczema [121C]. In univariate
analyses, a personal history of atopic symp-
toms was the only predictive factor (OR
3.6); sex, age, principal diagnosis, dose and
duration of iniximab, and concomitant
use of other immunosuppressant had no
effect.
Pityriasis lichenoides chronica Pityriasis
lichenoides chronica has been attributed to
iniximab in a patient with psoriasis [122A].
A 58-year-old man with severe recalcitrant
psoriasis was treated with intravenous inixi-
mab and after 10 weeks developed new
lesions affecting both lower legs and feet. His-
tology was consistent with pityriasis liche-
noides chronica. His psoriatic plaques cleared
progressively, and 5 months after the rst infu-
sion of iniximab his skin was clear of psoria-
sis; however, the crop of lesions of pityriasis
lichenoides chronica had still not resolved.
Primary cutaneous melanoma A 70-year-
old man with rheumatoid arthritis devel-
oped a malignant melanoma after taking
iniximab for 12 months [123A].
Psoriasis New-onset psoriasis is a paradox-
ical adverse effect of TNF antagonists and
has been described with iniximab [124c],
for example in a young woman who devel-
oped pustular psoriasis for the rst time
while receiving iniximab for Crohn's
disease [125A], and a 14-year-old girl with
Crohn's disease who developed guttate
psoriasis [126A].
Immunologic Iniximab-induced lupus-like
syndrome has been reported in a patient
with ankylosing spondylitis [127A].
Drugs that act on the immune system: cytokines and monoclonal antibodies
Infection risk Patients receiving iniximab
are more susceptible to serious infections,
including mycobacterial infections [128A]
and pneumonia [129A]. Concomitant treat-
ment with glucocorticoids was the only
independent susceptibility factor for infec-
tions in patients with inammatory bowel
disease treated with iniximab [130C].
Atypical acute infectious mononucleosis
has been reported in a patient with juvenile
ankylosing spondylitis who was treated with
iniximab [131A].
Mucormycosis has been reported in a
patient with Crohn's disease receiving
iniximab [132A].
Leprosy A 58-year-old man with ankylosing
spondylitis, receiving iniximab, developed
multiple plaques on the face, chest, and
limbs, a thickened, tender ulnar nerve,
and severe neuritis of the feet; biopsy
showed lepromatous Hansen's disease
[133A]. In this case the use of iniximab
may have resulted in either a new infection
or reactivation of a latent infection with
Mycobacterium leprae.
Tuberculosis In a case-control analysis,
exposure to iniximab versus etanercept
was an independent susceptibility factor
for tuberculosis. The authors concluded
that the risk of tuberculosis is higher in
patients receiving anti-TNF monoclonal
antibodies than in those receiving soluble
TNF receptors [105c].
Before starting therapy with iniximab,
all patients must be evaluated for both active
and inactive (latent) tuberculosis infection.
The interferon gamma release assay is pre-
ferred over tuberculin skin testing [134c].
Varicella infection A 36-year-old man with
plaque psoriasis developed a generalized
pruritic vesicular eruption, weakness, a high
fever, myalgias, anorexia, and progressive
respiratory insufciency after being treated
with iniximab for 15 months [135A]. He
had never had chicken pox. A Tzanck smear
and a skin biopsy from a vesicle showed
typical signs of herpetic infection involving
Chapter 37 783
the epidermis and the follicular epithelia
with ballooning degeneration and multi-
nucleated giant cells containing intra-
nuclear inclusions; PCR showed varicella
zoster virus DNA in the vesicle.
Tumorigenicity In a 9-year, single-center,
cohort study of 147 patients with inamma-
tory bowel disease, 60 episodes of hospital-
izations were at least possibly related to the
use of iniximab [136C]. Nine patients
developed malignancies: four cases of colo-
rectal carcinoma, one carcinoid tumor with
another primary signet-ring cell carcinoma
of the small bowel, one breast cancer, two
skin cancers, and one supercial melanoma;
eight died, six as a result of malignancies,
one as a result of a complication of short
bowel syndrome, and one patient for
unknown reasons. In studies with iniximab
in which 5780 patients were treated, repre-
senting 5494 patient years, there were ve
cases of lymphomas and 26 non-lymphoma-
tous malignancies, compared with no
lymphomas and one non-lymphomatous
malignancy in 1600 placebo-treated patients
representing 941 patient years.
Interference with diagnostic tests In a
study of iniximab in patients with cancer,
there was neutralization of serum TNF-a
after 1 hour, while plasma concentrations
of the leukocyte activating chemokine
CCL2 and interleukin-6 and serum CRP
were reduced at 24 and 48 hours after
iniximab administration [137c].
MONOCLONAL
ANTIBODIES [SED-15, 2380;
SEDA-30, 442; SEDA-31, 602;
SEDA-32, 686]
Abciximab
See Chapter 35.
784
Adalimumab
See TNF-a antagonists above.
Alemtuzumab (Campath-1H)
[SED-15, 71; SEDA-30, 442; SEDA-31,
602; SEDA-32, 686]
Uses Alemtuzumab is indicated for the
treatment of patients with B-cell chronic
lymphocytic leukemia for whom udarabine
combination chemotherapy is not appropri-
ate. Alemtuzumab may also be effective in
early multiple sclerosis [138C], as induction
therapy before transplantation [139c, 140C],
and in vasculitis associated with anti-neutro-
phil cytoplasmic antibodies (ANCA) [141c].
Nervous system Infusion-related headache
affected more than 50% of treated individ-
uals in a cohort of patients with multiple scle-
rosis [138C]. Anxiety, syncope, vertigo,
dizziness, tremor, paresthesia, and hypesthe-
sia are common undesirable reactions during
treatment or within 30 days after the comple-
tion of treatment with alemtuzumab. Guil-
lainBarr syndrome and its chronic form,
chronic inammatory demyelinating polyra-
diculoneuropathy, have also been reported.
Sensory systems There was an increased
incidence of cytomegalovirus retinitis in
four unrelated patients undergoing
hemopoietic stem cell transplantation using
a non-myeloablative alemtuzumab-based
conditioning regimen [142c].
Liver There were abnormal liver function
tests in 2.3% of patients with multiple scle-
rosis treated with alemtuzumab [138C].
Skin Infusion-related rashes affected more
than 90% of treated patients with multiple
sclerosis [138C]. Urticaria is one of the com-
monest types of rash during alemtuzumab
therapy.
Immunologic Serious infusion reactions
occurred in 1.4% of patients with multiple
sclerosis treated with alemtuzumab [138C].
Chapter 37 D. Spoerl and Andreas J. Bircher
Patients should be premedicated with an
oral or intravenous glucocorticoid, an anti-
histamine, and an analgesic 3060 minutes
before each infusion of alemtuzumab
during dose escalation.
Infection risk Recurrent oral herpes sim-
plex virus type 1 was seen in 1.4% of
patients with multiple sclerosis immediately
after each cycle of alemtuzumab [138C].
Inactive tuberculosis was incidentally
identied in one patient who received
alemtuzumab 24 mg. There were no cases
of progressive multifocal leukoencephalo-
pathy, cytomegalovirus infection, or pneu-
mocystis pneumonia.
In a study of graft-versus-host disease
prevention strategies in patients after bone
marrow transplantation for aplastic anemia,
a signicantly higher proportion of alem-
tuzumab-treated patients developed cyto-
megalovirus reactivation compared with
control patients [139c]. Prophylaxis with
aciclovir has been recommended [143R].
Asymptomatic laboratory positive cyto-
megalovirus viremia should not necessarily
be considered a serious infection requiring
interruption of therapy.
In a study in Korean patients receiving
alemtuzumab as part of a conditioning reg-
imen for allogeneic hemopoietic stem cell
transplantation, alemtuzumab recipients
had a high incidence of cytomegalovirus
disease as well as BK virus-associated hem-
orrhagic cystitis compared with recipients
of antithymocyte globulin [144c].
In renal and pancreas transplant
recipients, infections and malignancies were
similar after alemtuzumab versus anti-
thymocyte globulin induction [140C].
In a phase II study of alemtuzumab,
symptomatic cytomegalovirus reactivation
occurred in six of 20 patients; there were
two deaths, one from bacterial pneumonia
and one from an adenovirus infection [145c].
Tumorigenicity Lymphoproliferative disor-
ders have been reported after pancreas
transplantation following alemtuzumab
induction in 100 patients [146c]. Epstein
Barr virus-positive immunodeciency
lymphoma after therapy with alemtuzumab
Drugs that act on the immune system: cytokines and monoclonal antibodies
CHOP for peripheral T-cell lymphoma
has also been reported in three of 20
patients [147c].
In a study of alemtuzumab for the treat-
ment of acute rejection in 15 kidney trans-
plant recipients, the rates of malignancies
in alemtuzumab-treated patients were not
increased during 12 years follow-up; in
particular, no patients treated with
alemtuzumab for acute rejection developed
post-transplantation lymphoproliferative
disorders [148c].
Basiliximab [SED-15, 418; SEDA-30,
443; SEDA-31, 603; SEDA-32, 687]
Uses Basiliximab is indicated for the pro-
phylaxis of acute organ rejection in de novo
allogeneic renal transplantation in adults
and children, and is used concomitantly
with ciclosporin for microemulsion-based
and glucocorticoid-based immunosuppres-
sion, in patients with panel reactive
antibodies less than 80%, or in triple main-
tenance immunosuppressive regimens con-
taining ciclosporin, glucocorticoids, and
either azathioprine or mycophenolate
mofetil. Basiliximab has also been studied
in 221 liver transplant recipients [149c] and
in nine patients with metastatic cancer
[150c].
Observational studies Adverse events have
been studied in a 2-year, non-placebo-con-
trolled trial in 164 children and adolescents
undergoing renal transplantation [151C],
who were randomized to tacrolimus, azathi-
oprine, and glucocorticoids or tacrolimus,
azathioprine, glucocorticoids, and two
doses of basiliximab. Basiliximab conferred
no additional benet. There were no differ-
ences between the groups in mean eGFR,
blood pressure, or serum cholesterol
concentrations, and no differences in the
incidences of infections or malignancies.
Respiratory Basiliximab-induced non-
cardiogenic pulmonary edema has been
described in two pediatric renal transplant
recipients [152A].
Chapter 37 785
Infection risk In a comparison of anti-
thymocyte globulin and basiliximab after renal
transplantation in 12 children, there were no
cases of opportunistic infections [153c].
Bevacizumab
See also Chapter 47.
Possible adverse reactions to bevacizu-
mab and their management have been
reviewed [154R].
Uses Bevacizumab, in combination with
uoropyrimidine-based chemotherapy, is
indicated: for patients with metastatic carci-
noma of the colon or rectum [155c, 156C,
157C, 158C]; in combination with paclitaxel
or docetaxel for rst-line treatment of
patients with metastatic breast cancer
[159c, 160R]; in addition to platinum-based
chemotherapy, for rst-line treatment of
patients with unresectable, advanced, meta-
static or recurrent non-small cell lung
cancer, other than with predominantly
squamous cell histology [161C, 162R]; and
in combination with interferon alfa-2a, for
rst-line treatment of patients with
advanced and/or metastatic renal cell can-
cer [163R, 164C].
Bevacizumab has been approved in some
countries for the treatment of recurrent
glioblastoma after rst-line treatment with
temozolomide [165c, 166M].
Bevacizumab has been studied in
advanced carcinoid tumors [167c], prostate
cancer [168c], high-risk corneal transplanta-
tion [169c], diabetic retinopathy [170c, 171C,
172R], ischemic retinal diseases [173c],
refractory choroidal neovascularization
secondary to uveitis [174c], macular edema
secondary to branch retinal vein occlusion
[175c], retinal angiomatous proliferation
[176c], choroidal neovascularization attrib-
utable to pathological myopia [177c, 178],
exudative age-related macular degenera-
tion [179M], multifocal lymphangioendothe-
liomatosis with thrombocytopenia [180A],
in combination with chemotherapy for the
treatment of recurrent ovarian cancer
[181c], advanced melanoma [182c], malig-
nant pleural mesothelioma [183c],
786
metastatic pancreatic cancer [184c, 185c],
unresectable hepatocellular carcinoma
[186c, 187c], poor-prognosis head and neck
cancer [188c, 189c], persistent or recurrent
squamous cell carcinoma of the cervix
[190c], and ovarian cancer [191c, 192c]. This
list is not meant to be exhaustive.
Cardiovascular There was an increased
incidence of hypertension in bevacizumab-
treated patients [159c]. Clinical safety data
suggest that the incidence of hypertension
is likely to be dose-related. Arterial hyper-
tension has been suggested to correlate
with clinical outcomes in patients with
colorectal cancer treated with rst-line
bevacizumab [193c].
In randomized clinical trials, the inci-
dence of arterial thromboembolic events,
including strokes, transient ischemic
attacks, and myocardial infarctions, was
higher in patients receiving bevacizumab
in combination with chemotherapy com-
pared with those who received chemother-
apy alone [194R].
Events consistent with congestive heart
failure have been reported in clinical trials
[154R]. The symptoms ranged from asymp-
tomatic reductions in left ventricular ejec-
tion fraction to symptomatic congestive
heart failure, requiring treatment or hospi-
talization. Most of the patients who had
congestive heart failure had metastatic
breast cancer and had received previous
treatment with anthracyclines or prior
radiotherapy to the left chest wall, or had
other risk factors for congestive heart fail-
ure, such as pre-existing coronary heart dis-
ease or concomitant cardiotoxic therapy.
Sinusoidal obstruction syndrome (veno-
occlusive disease) has been reported in a
patient receiving bevacizumab for meta-
static colorectal cancer [195A]. Venous
thromboembolism in general has been
reported to occur with a higher incidence
during bevacizumab treatment [196M].
Nervous system There have been rare
reports in bevacizumab-treated patients of
signs and symptoms that are consistent with
reversible posterior leukoencephalopathy
syndrome (RPLS), a rare neurological
Chapter 37 D. Spoerl and Andreas J. Bircher
disorder, which can present with the follow-
ing signs and symptoms among others: sei-
zures, headache, altered mental status,
visual disturbances, or cortical blindness,
with or without associated hypertension
[154R].
Sensory systems Adverse reactions have
been reported from unapproved intravitreal
use. These reactions included infectious
endophthalmitis, intraocular inammation
(such as sterile endophthalmitis, uveitis,
and vitritis), retinal detachment, retinal pig-
ment epithelial tears, increased intraocular
pressure, and intraocular hemorrhage (such
as vitreous hemorrhage or retinal hemor-
rhage and conjunctival hemorrhage) [197c,
198c]. Vitreous hemorrhage has also been
reported during treatment with bevacizu-
mab for metastatic rectal cancer [199A].
Hematologic Patients treated with
bevacizumab have an increased risk of
hemorrhage, especially tumor-associated
hemorrhage [154R]. Major or massive pul-
monary hemorrhage/hemoptysis has been
observed primarily in trials in patients with
non-small cell lung cancers, who were
excluded from subsequent phase III trials.
Gastrointestinal Patients may be at in-
creased risk of stulae when treated with
bevacizumab [188c, 200A]. In clinical trials,
gastrointestinal stulae have been reported
with an incidence of up to 2% in patients
with metastatic colorectal cancer, but were
also reported less commonly in patients
with other types of cancers.
Diarrhea, nausea, and vomiting are very
common adverse reactions [187c].
Urinary tract Patients with a history of
hypertension may be at increased risk of
proteinuria when treated with bevacizumab
[159c]. Progressive bevacizumab-associated
renal thrombotic microangiopathy has been
reported [201A].
Skin Bevacizumab can adversely affect
wound healing [202c]. There was an
increased incidence of postoperative bleed-
ing or wound healing complications within
Drugs that act on the immune system: cytokines and monoclonal antibodies
60 days of major surgery if patients were
being treated with bevacizumab at the time
of surgery. The incidence was 1020%. In
locally recurrent and metastatic breast can-
cer, wound healing complications were
observed in up to 1.1% of patients receiv-
ing bevacizumab compared with up to
0.9% of patients in the control arms.
Hand-foot skin reactions have been
reported as an adverse reaction to bevaci-
zumab [203c].
Musculoskeletal Reversible skeletal changes
after treatment with bevacizumab in a
child with cutaneovisceral angiomatosis
and thrombocytopenia have been reported
[204A].
Immunologic Patients may be at risk of
infusion/hypersensitivity reactions [154R],
which have occurred in up to 5% of
patients.
BG9588
BG9588 is a humanized anti-human CD40L
antibody that blocks antigen-specic IgG
responses in non-human primates (baboons
and rhesus monkeys) immunized with a
variety of T-dependent antigens.
Observational studies BG9588 has been
studied in humans with lupus glomerulo-
nephritis, but the study was terminated
prematurely because of thromboembolic
events [205c]. CD40L stabilizes arterial
thrombi by a b3 integrin-dependent mecha-
nism; inhibition of these interactions by
anti-CD40L may make platelet plugs unsta-
ble and thus ready to embolize. This prob-
lem has not been further evaluated and
the project was abandoned by the com-
pany. There were no statistically signicant
changes in neutrophil or total lymphocyte
counts (including T cell subsets, such as
CD4 and CD8 cells), hematocrit, plate-
let counts, or serum anticardiolipin anti-
bodies after therapy. Serum concentrations
of immunoglobulins (IgA, IgG, and IgM)
were transiently reduced from baseline to
Chapter 37 787
28 days after the last dose. Of 18 patients
in whom efcacy could be evaluated, two
had a 50% reduction in proteinuria without
worsening of renal function. There was a
signicant reduction in anti-dsDNA titers
and a signicant increase in mean serum
C3 concentrations after treatment.
Daclizumab [SED-15, 1047; SEDA-30,
444; SEDA-31, 605; SEDA-32, 687]
Daclizumab is a recombinant humanized,
IgG1 antibody to the alpha subunit of the
IL-2 receptor of T cells. It is produced in
a murine NSO myeloma cell line using a
glutamine synthetase expression system by
recombinant DNA technology. It was rst
approved for the prophylaxis of acute
organ rejection in de novo allogenic renal
transplantation. However, on 27 November
2006, the marketing authorization holder
responsible for daclizumab, Roche, notied
the European Commission of its decision to
withdraw the marketing authorization for
daclizumab voluntarily, for commercial rea-
sons. Roche stated that this decision was
not related to any safety concerns. Daclizu-
mab was withdrawn from the market in the
European Union on 1 January 2009.
Uses Daclizumab has been studied in cases
of active posterior uveitis [206c]; in children
with refractory and steroid-resistant/depen-
dent graft-versus-host disease [207c, 208c];
for recalcitrant ocular inammatory disease
[209c]; in multiple sclerosis [210c, 211c]; and
in patients with moderate to severe persis-
tent asthma [212C]. Daclizumab has been
used as induction therapy before liver
transplantation [213c, 214C] and renal trans-
plantation [215c], as well as in active ante-
rior uveitis associated with juvenile
idiopathic arthritis [216c].
Hematologic Two patients developed
adverse events that required transient with-
drawal of daclizumab because of lympho-
penia and generalized lymphadenopathy in
an open baseline versus treatment phase
II clinical trial of daclizumab in patients
788
with multiple sclerosis with an inadequate
response to interferon beta [211c].
Skin One participant among six studied in
a trial of high-dose daclizumab for the
treatment of juvenile idiopathic arthritis-
associated active anterior uveitis developed
a rash possibly induced by daclizumab
[216c].
Musculoskeletal In a study of intravenous
daclizumab for recalcitrant ocular inam-
matory disease adverse reactions to daclizu-
mab included fatigue and muscle aches
[209c].
Immunologic Two patients developed sys-
temic immune responses 12 months after
withdrawal of interferon beta, character-
ized by mouth ulcers, a photosensitivity
rash, and transient formation of autoanti-
bodies that required glucocorticoid therapy
for resolution in an open baseline versus
treatment phase II clinical trial of daclizu-
mab in patients with multiple sclerosis and
an inadequate response to interferon beta
[211c]. In rare cases severe hypersensitivity
reactions after daclizumab have been
reported.
Edrecolomab
Edrecolomab is a murine monoclonal anti-
body to the cell-surface glycoprotein 17-
1A, which is expressed on epithelial tissues
and on various carcinomas. This 17-1A
antigen is also known as EGP-2, Ep-
CAM, CO17-1A, or GA733-2. Preliminary
data suggested that it might be of use in
the adjuvant treatment of patients with
resected stage III colon cancer.
In the initial clinical study, which focused
on patients with minimal residual disease
because of the presumption that overt
metastatic disease might overwhelm the
capacity of the immune system, 189 patients
with stage III colon or rectal cancer were
randomized to edrecolomab or no treat-
ment [217c]. On the strength of the results
the drug was approved by the regulatory
Chapter 37 D. Spoerl and Andreas J. Bircher
authorities in Germany and was available
there by prescription for the treatment of
patients with stage III colorectal cancer.
To our knowledge no other countries
approved the agent for routine use on the
basis of these data [218R]. All studies
reported to date, with the exception of the
Riethmller trial, have been negative
[219C, 220C, 221C].
In the last of these trials, the most com-
mon hematological adverse reaction was
neutropenia, the most common non-hemato-
logical adverse reactions were diarrhea
(80%) and nausea (72%), and there were
hypersensitivity reactions, dened as any
adverse events possibly involving an
immune response and occurring within 1
day of edrecolomab infusion, in 31% of
patients, including fever (8% overall), ush-
ing (6%), hypotension (<1%), rashes (3%),
and breathing disorders (<1%). Edrecolo-
mab has been withdrawn from the German
market and production has been suspended.
Efalizumab [SEDA-30, 445; SEDA-31,
605; SEDA-32, 688]
On 9 April 2009, Genentech announced
that the company was voluntarily withdraw-
ing efalizumab from the marketplace
because of continuing concerns about its
association with progressive multifocal
leukoencephalopathy.
Hematologic In post-marketing surveil-
lance, isolated cases of severe hemolytic
anemia have been reported during treat-
ment with efalizumab. Thrombocytopenia
can occur [222A, 223A] and thrombocytosis
has also been attributed to efalizumab
[224A].
Skin A localized papular rash or aggrava-
tion of psoriasis in an edematous or even
pustular form are the two most commonly
observed complications of treatment with
efalizumab [223A]. Efalizumab can cause
exacerbation of psoriasis, including pustu-
lar, erythrodermic, and guttate subtypes
[225A], and rebound can also occur after
Drugs that act on the immune system: cytokines and monoclonal antibodies
withdrawal of the drug [226c]. The occur-
rence of autoimmunity during an immuno-
modulating therapy blocking T-cell
activation is paradoxical and might be
related to disruption of immune balance
rather than a specic drug-induced pathway
requiring simultaneous binding of the drug
to the target molecule, as in a case of bul-
lous pemphigoid attributed to efalizumab
in an 82-year-old patient with diabetes and
psoriasis who received efalizumab for 6
weeks [227A]. A patient with psoriasis
developed typical lesions of familial benign
chronic pemphigus after four doses of efali-
zumab [228A]. In another case there was
exacerbation of psoriasis during efalizumab
treatment, associated with a reversible lym-
phocytosis with a normal total leukocyte
count [229A]. In another study, an inam-
matory are occurred in six cases after 23
72 weeks, with pronounced worsening of
the cutaneous psoriatic lesions accompa-
nied by severe musculoskeletal involve-
ment in all cases [230c].
Lymphomatoid papulosis occurred in a
60-year-old woman after treatment with
efalizumab for psoriasis taking for 8 months,
with red crusted papules and plaques on
the forearms and back. Biopsies of the
lesions were consistent with CD30 lym-
phomatoid papulosis. Efalizumab was with-
drawn and the lesions resolved during a 6-
week course of narrowband ultraviolet B
phototherapy. However, 4 months later a
red ulcerated plaque formed in her left
axilla and a biopsy was again consistent
with CD30 lymphomatoid papulosis,
which resolved over 2 months with intra-
lesional triamcinolone.
Seborrheic keratoses have been reported
in a 56-year-old man with recalcitrant psori-
asis that had responded to efalizumab
[231A].
Urticaria associated with a raised serum
IgE concentration has been associated with
efalizumab in a 50-year-old man with psori-
asis, perhaps due to the formation of anti-
bodies against efalizumab or other
epitopes [232A].
Chapter 37 789
Autacoids Recurrent angioedema has been
reported in a 63-year-old man with severe
plaque psoriasis after efalizumab treatment
for 15 weeks [233A]. There was swelling of
the periorbital area, cheek, tongue, and
lips, and after the next dose he developed
the same symptoms as well as acute abdom-
inal pain. Efalizumab was withdrawn and
the swelling and abdominal pain resolved
within 3 weeks.
Infection risk Efalizumab can increase the
risk of infections or at least their severity,
for example tuberculous pneumonia, and
reactivate latent chronic infections, such as
JC virus infection. However, in an open
extension of a phase IIIb trial, the inci-
dence of infections was 1015% during the
12-week segments of efalizumab therapy,
compared with 19% in placebo-treated
patients [234c].
Tumorigenicity It is not known whether
efalizumab increases the risk of lympho-
proliferative disorders or other malignancies
in patients with psoriasis. Of the 15 malig-
nancies that were reported in 418 efalizu-
mab-treated patients in a phase IIIb clinical
trial, four were basal cell carcinomas and
nine were squamous cell carcinomas [234c].
Gemtuzumab ozogamicin [SED-15,
1488; SEDA-30, 446; SEDA-32, 689]
Combination studies The effects of gemtu-
zumab in combination with other treat-
ments have been studied in patients with
relapsed CD33-positive acute myeloid leu-
kemia [235c, 236c, 237c, 238c] and in
patients with acute promyelocytic leukemia
[239c]. The Committee for Medicinal Prod-
ucts for Human Use (CHMP) noted that
there were adverse reactions associated
with gemtuzumab. These included severe
and long-lasting bone marrow suppression
causing reduced leukocyte and platelet
counts, liver problems, and adverse reac-
tions related to the infusion, such as chills,
790
fever, and low blood pressure. In a study of
gemtuzumab in advanced childhood mye-
loid leukemia ve patients had infections
[240c]. On 20 September 2007, the CHMP
recommended refusal of the marketing
authorization for the medicinal product
because of an unfavorable benet to harm
balance.
HA-1A (Centoxin)
HA-1A (Centoxin; Centocor, Malvern,
PA) is a human IgM monoclonal antibody
that binds to the lipid A domain of endo-
toxin and is produced by the stable hetero-
myeloma cell line A6(H4C5). This
hybridoma was created by fusion of a
murinehuman heteromyeloma line with
splenic B lymphocytes sensitized in vivo
by immunization with killed Escherichia
coli J5 cells and subsequently transformed
in vitro by EpsteinBarr virus.
HA-1A was developed for use in the
treatment of sepsis. However, it was volun-
tarily withdrawn by the manufacturer in
1992 because of excess mortality in patients
without Gram-negative bacteremia [241S].
Placebo-controlled studies In a multicenter,
double-blind, randomized, placebo-con-
trolled, phase III trial in 543 patients with
sepsis, no overall benet of HA-1A could
be demonstrated [242C]; however, among
102 patients with Gram-negative bacteremia
and shock, the 28-day all-cause mortality
rate was signicantly reduced from 56%
among patients receiving placebo to 33%
among those receiving HA-1A. These results
were not conrmed in a second study, a large,
group-sequential, placebo-controlled trial
that enrolled 2199 patients, of whom 621
(28%) had Gram-negative bacteremia
[243C]. In a later double-blind, randomized,
placebo-controlled trial (n 269), the
authors compared the effectiveness of HA-
1A and placebo in reducing the 28-day all-
cause mortality rate among children with a
presumptive diagnosis of meningococcal
septic shock; there was no signicant benet
[244C].
Chapter 37 D. Spoerl and Andreas J. Bircher
Ibalizumab
Ibalizumab (formerly TNX-355) is a
humanized monoclonal antibody that binds
CD4, the primary receptor for HIV-1, and
inhibits the viral entry process [245R]. It
has been studied for the potential treat-
ment of HIV infection [246R]. The most
common adverse event in a phase I study
in HIV-infected individuals was headache
[247c]; there were mean increases from
baseline in CD4 T-cell counts during the
9-week infusion period, with the largest
mean increases at week 1. However, there
was no evidence of CD4 T-cell and ibali-
zumab was not immunogenic. There were
no serious drug-related adverse events.
Iniximab
See TNF-a antagonists above.
Natalizumab [SEDA-30, 447; SEDA-32,
690]
Assessment of the benet to harm balance
of natalizumab continues [248R].
Nervous system Subclinical reactivation
of JC virus is common in patients with mul-
tiple sclerosis who are treated with natalizu-
mab [249c] and there is an increased risk of
JC virus-associated progressive multifocal
leukoencephalopathy, which can be fatal or
result in severe disability. The risk appears
to increase with treatment duration, espe-
cially beyond 2 years. There is limited
experience in patients who have received
natalizumab for more than 3 years and the
risk in these patients cannot therefore
currently be estimated.
Hematologic Natalizumab increases the
percentage of activated leukocytes produc-
ing proinammatory cytokines in the blood,
presumably due to sequestration of acti-
vated cells in the peripheral circulation
[250c]. It can increase circulating lympho-
cytes, monocytes, eosinophils, basophils,
and nucleated erythrocytes, without
Drugs that act on the immune system: cytokines and monoclonal antibodies
affecting neutrophils. Increases from base-
line for lymphocytes, monocytes, eosino-
phils, and basophils were 35140% for
individual cell types, but mean cell counts
remained within the reference ranges.
Immunologic Hypersensitivity reactions oc-
curred in up to 4% of patients with multiple
sclerosis in 2-year controlled trials; anaphy-
lactic or anaphylactoid reactions occurred
in under 1%. Among 234 consecutive nata-
lizumab-treated patients, followed for at
least 3 months, there were nine anaphylac-
toid reactions, mainly urticarial [251c].
Hypersensitivity reactions usually occurred
during infusion or within the 1 hour after
the completion of the infusion. In post-mar-
keting experience there have been reports
of hypersensitivity reactions in association
with one or more of the following symp-
toms: hypotension, hypertension, chest
pain, chest discomfort, dyspnea, and
angioedema, in addition to more usual
symptoms, such as urticaria. The risk of
hypersensitivity reactions was greatest in
patients who were re-exposed to natalizu-
mab after an initial short exposure (one or
two infusions) or after an extended period
(3 months or more) without treatment. In
10% of patients antibodies against natalizu-
mab were detected. Persistent anti-natalizu-
mab antibodies (one positive test
reproducible on retesting at least 6 weeks
later) developed in 36%.
Immune reconstitution inammatory syn-
drome is a reported rebound phenomenon
after withdrawal of natalizumab [252A,
253A].
Tumorigenicity A primary central nervous
system lymphoma has been reported in a
patient treated with natalizumab [254A].
Omalizumab [SED-15, 2614; SEDA-30,
447; SEDA-32, 690]
Skin During clinical trials in adults and
adolescents the most commonly reported
adverse reactions were injection site
Chapter 37 791
reactions [255C, 256C], including injection
site pain, swelling, erythema, and pruritus.
Immunologic Type I local or systemic aller-
gic reactions, including anaphylaxis and
anaphylactic shock, can occur during omali-
zumab therapy, but also after a long dura-
tion of treatment [257R]. Most of these
reactions occurred within 2 hours after the
rst and subsequent injections of omalizu-
mab, but some started beyond 2 hours and
even beyond 24 hours. Serum sickness and
serum sickness-like reactions have been
seen, typically 15 days after administration
of the rst or subsequent injections, but
also after longer durations of treatment.
The suggested mechanism includes
immune-complex formation and deposition
due to development of antibodies against
omalizumab.
Ranibizumab
See Chapter 47.
Rituximab [SED-15, 3069; SEDA-30,
448; SEDA-31, 607]
Uses Rituximab has been studied in a wide
range of diseases, including different vascu-
litic disorders [258R, 259C, 260c, 261c],
chronic immune thrombocytopenic
purpura [262c], collapsing glomerulopathy
with dominant C1q-containing mesangial
immune deposits [263A], severe glucocorti-
coid- or ciclosporin-dependent nephrotic
syndrome [264c, 265c], immune-mediated
neuropathies [266C], treatment-refractory
myasthenia gravis and inammatory myop-
athies [267c, 268R], systemic lupus erythe-
matosus [269c, 270c, 271R, 272M], Sjgren's
syndrome [273c, 274M], autoimmune bul-
lous diseases [275c, 276A], relapsing Graves
disease [277c], chronic graft-versus-host
disease [278M], primary gastric lymphoma
[279c], autoimmune hemolytic anemia
[280c], and thrombotic thrombocytopenic
purpura [281cM].
792
Respiratory Cases of interstitial lung dis-
ease, dyspnea, and pneumonitis associated
with rituximab, some fatal, have been
reported [282M, 283A, 284A, 285A, 286A,
287c].
Infection risk Serious infections, including
deaths, can occur during therapy with ritux-
imab. Infectious events (predominantly
bacterial and viral) occurred in 3055% of
patients with non-Hodgkin's lymphoma
and in 3050% of patients with chronic
lymphocytic leukemia. In other therapeutic
indications, the risk of infections seems
to be less, but still increased compared
with placebo [272M, 288c, 289c, 290M,
291M].
Hepatitis B reactivation has been
reported in subjects receiving rituximab
including fulminant hepatitis with a fatal
outcome [292c, 293c]. Localized candidiasis
and herpes zoster infection have been
reported [279c].
Nervous system Rituximab can be associ-
ated with an increased risk of progressive
multifocal leukoencephalopathy [294A, 295R].
Hyperammonemic encephalopathy has
been reported after chemotherapy includ-
ing rituximab for solid and hematological
malignancies [296A].
Hematologic Catastrophic multiple organ
ischemia due to an anti-Pr cold agglutinin
has been reported in a patient with mixed
cryoglobulinemia after treatment with
rituximab [297A].
Gastrointestinal Gastrointestinal perfora-
tion, in some cases fatal, has been observed
in patients receiving rituximab for malig-
nant disease; in most of these cases, rituxi-
mab was administered with chemotherapy
[295R, 298A].
Immunologic The most common adverse
drug reactions in patients receiving rituxi-
mab are infusion-related reactions, which
occur during the rst infusion in most cases
Chapter 37 D. Spoerl and Andreas J. Bircher
[274M, 299c]. The symptoms are mainly
fever, chills, and rigors. Other symptoms
include ushing, angioedema, broncho-
spasm, vomiting, nausea, urticaria, fatigue,
headache, throat irritation, rhinitis, pruri-
tus, pain, tachycardia, hypertension, hypo-
tension, dyspnea, dyspepsia, weakness,
and features of tumor lysis syndrome.
Severe infusion-related reactions (such as
bronchospasm and hypotension) occur in
up to 12% of cases. The incidence of infu-
sion-related symptoms falls substantially
with subsequent infusions and is less than
1% after eight doses of rituximab.
Human antichimeric antibodies develop
in some patients after a rst course of ritux-
imab and can be associated with worsening
of infusion or allergic reactions after subse-
quent infusions. In one case, there was fail-
ure to deplete B-cells after further courses
[270c].
The safety of immunization with live
viral vaccines after rituximab therapy has
not been studied in patients with non-
Hodgkin's lymphoma or chronic lympho-
cytic leukemia, and immunization with live
virus vaccines is not recommended. Immu-
nization with other non-live vaccines seems
to be impaired following rituximab therapy
[270c], but immunization is not
contraindicated.
Common variable immunodeciency has
been reported in an 8-year-old boy treated
with rituximab for idiopathic thrombocyto-
penia [300A].
Autacoids Rituximab vials contain poly-
sorbate 80 (polyoxyethylene-sorbitan-20-
monooleate, Tween 80), a solubilizing
agent that can cause severe non-IgE-medi-
ated anaphylactic reactions [301Ar].
Fetotoxicity There are no adequate and
well-controlled data from studies of rituxi-
mab in pregnant women; however, tran-
sient B-cell depletion and lymphopenia
have been reported in an infant born to a
mother exposed to rituximab during preg-
nancy [302A].
Drugs that act on the immune system: cytokines and monoclonal antibodies
Trastuzumab [SED-15, 3480]
Cardiovascular Heart failure (New York
Heart Association classes IIIV) has been
observed in patients receiving trastuzumab,
alone or in combination with paclitaxel or
docetaxel, particularly after chemotherapy
containing an anthracycline (doxorubicin
or epirubicin) [303M, 304M, 305R, 306c]. It
can be moderate or severe and can be fatal.
The results of many randomized trials have
shown that the degree of cardiotoxicity is
generally acceptable; the incidence of car-
diac damage caused by trastuzumab was
0.44.1% [307R]. Older age, lower left ven-
tricular ejection fraction, and antihyperten-
sive medications are associated with an
increased risk of cardiac dysfunction in
patients receiving trastuzumab [308C]. The
cardiac dysfunction associated with trastu-
zumab is usually reversible on withdrawal
and standard medical therapy [309R]. In
one case, trastuzumab-associated cardio-
myopathy presented with complete left
bundle-branch block mimicking acute coro-
nary syndrome [310A].
Respiratory Severe pulmonary events,
such as interstitial lung disease [311A], have
been reported with trastuzumab in post-
marketing surveillance and can occasionally
be fatal.
Hematologic Febrile neutropenia has been
observed very commonly in trastuzumab-
treated patients; anemia, neutropenia, and
thrombocytopenia were common labora-
tory ndings in these patients [312c].
Gastrointestinal In 10 patients treated with
trastuzumab, diarrhea, vomiting, nausea, or
abdominal pain were each reported in
more than one case. In a retrospective
study there were gastrointestinal adverse
reactions after 12% of administrations,
including nausea and vomiting, diarrhea,
abdominal pain, and bloating [313c]; muco-
sitis was more rare [314c, 315c].
Liver Trastuzumab-induced hepatotoxicity
has been reported [316A].
Chapter 37 793
Visilizumab
Visilizumab is a humanized anti-CD3
monoclonal antibody characterized by a
mutated IgG2 isotype, lack of binding to
Fcg receptors, and the ability to induce
apoptosis selectively in activated T cells.
Observational studies In 17 patients with
steroid-refractory acute graft-versus-host
disease, there were no consistent variations
in chest X-ray ndings or electrocardio-
grams after visilizumab therapy; there was
no difference in liver function tests, or
serum creatinine, and human antibodies
against visilizumab were not detected; there
were no allergic reactions [317c]. Three of
53 visilizumab infusions were followed by
single transient grade 1 adverse events
(facial ushing, upper limb weakness, and
a low-grade fever). None of the 17 patients
had serum cytokine concentrations above
1 ng/ml and those without postinfusional
adverse events did not have detectable
peaks in cytokines.
In an open phase I study of intravenous
visilizumab 15 micrograms/kg in 32 patients
with ulcerative colitis, the dose was reduced
to 10 micrograms/kg in 24 because of
adverse reactions [318c]. Mild to moderate
symptoms of cytokine release occurred in
100% and 83% of patients in the 15 and
10 micrograms/kg dose groups respectively.
One patient had chest pain and had a mod-
est rise in serum troponin I concentration
30 minutes after a second infusion; the
symptoms resolved within 20 minutes. One
patient had mild bilateral blurring of vision
on the rst day; ophthalmologic examina-
tion 1 month later showed several small
peripheral retinal hemorrhages in one eye.
After visilizumab administration, the fall
in the numbers of peripheral T-cells was
associated with increased EpsteinBarr
virus DNA titers in the blood in most of
the patients and 34% of patients reported
eight types of infections, including urinary
tract infections, cellulitis, candidiasis, naso-
pharyngitis, rhinitis, tonsillitis, and upper
respiratory tract infections; all were mild
or moderate and resolved with out-patient
management.
794
In two prospective studies in 34 patients
with Crohn's disease who received intra-
venous visilizumab 10 micrograms/kg on
two consecutive days, there were symptoms
of cytokine release at a median of 45
minutes after the infusion [319c]. The cyto-
kine prole was characterized by increases
interferon-inducible protein-10, monocyte
chemotactic protein 1, tumor necrosis fac-
tor-alpha, interferon gamma, interleukins
2, 6, 8, and 10, and interleukin 1 receptor
antagonist. TNF-alpha and IL-2 peaked at
1 hour and all the others at 6 hours. In
86% of the patients there were transient
rises above the upper limit of the reference
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38 Drugs that act on the
immune system:
immunosuppressive and
immunostimulatory drugs
Ciclosporin [SED-15, 743; SEDA-30,
452; SEDA-31, 619; SEDA-32, 705]
Nervous system A posterior reversible
encephalopathy syndrome in a child with
Langerhans cell histocytosis resolved
completely when ciclosporin was withdrawn
[1A]. Similar cases have been reported in a
27-year-old man with collapsing focal glo-
merulosclerosis [2A] and in a 68-year-old
woman and a 19-year-old man after heart
transplantation [3A].
Several cases of parkinsonism have been
attributed to ciclosporin.
A 42-year-old man developed parkinsonism
after taking ciclosporin for 10 days; after con-
version of ciclosporin to tacrolimus the condi-
tion resolved [4A].
A 51-year-old man developed parkinsonism
after taking ciclosporin 3 mg/kg/day for 2
months; an MRI scan showed only bilateral
chronic frontal subdural hematomas and with-
drawal of ciclosoporin led to complete resolu-
tion within 2 months [5A].
Disabling parkinsonism occurred in a 59-
year-old Thai woman who had taken ciclo-
sporin for several years and began to resolve
within a few days of withdrawal [6A].
Side Effects of Drugs, Annual 33
J.K. Aronson (Editor)
ISSN: 0378-6080
DOI: 10.1016/B978-0-444-53741-6.00038-6
# 2011 Elsevier B.V. All rights reserved.
J.K. Aronson
Mouth Of 50 patients taking ciclosporin 32
developed minimal gingival overgrowth and
18 had clinically signicant overgrowth; the
mutated C3435T genotype of the MDR1
gene was signicantly more frequent in
the latter and a signicant association
between gingival overgrowth and the
3435TT genotype was conrmed by logistic
regression analysis [7c].
The involvement of cystatin C in gingival
overgrowth has been studied in human gin-
gival samples, comparing 15 samples from
patients with gingival overgrowth and ve
normal samples [8cE]. Cystatin C staining
in gingival tissue was stronger in those with
ciclosporin-induced overgrowth, and inten-
sive staining for cystatin C expression was
seen mainly in the cytoplasm of broblasts,
epithelial cells, and inammatory cells.
Cystatin C expression was also signicantly
increased in samples with greater degrees
of inammatory inltration. The addition
of ciclosporin 200 mg/l increased cystatin C
expression in human gingival broblasts,
and this effect was increased by addition
of periodontal pathogens and proinamma-
tory cytokines.
Biliary tract See Tacrolimus below.
Pancreas There was biochemical evidence
of acute pancreatitis in a 49-year-old
woman after she had taken ciclosporin for
20 days, although an abdominal CT scan
815
816
and ultrasonography showed a normal pan-
creas; it responded to dosage reduction and
supportive care [9A].This may simply have
been hyperamylasemia.
Urinary tract In 53 patients with steroid-
dependent nephrotic syndrome taking
ciclosporin, there was nephropathy in 22
biopsies; nephropathy was positively associ-
ated with the use of angiotensin-converting
enzyme inhibitors, angiotensin II receptor
blockers, and hyperuricemia [10c].
In 18 patients with minimal change
nephrotic syndrome or IgA nephropathy
taking ciclosporin, tubular expression of
Toll-like receptors was increased, as were
TLR4 mRNA and protein expression in a
dose-related fashion [11cE].
In a retrospective review of 235 childhood
liver transplant recipients with no known
risk factors for formation of renal cysts and
no evidence of cysts at the time of transplan-
tation, 26 (11%) developed at least one cyst
and had a reduced mean GFR [12c].
Two (1.4%) of the 146 patients who took
tacrolimus and 24 (27%) of the 89 patients
who took ciclosporin acquired renal cysts,
and ciclosporin was the only independent
variable associated with renal cysts.
Hemolyticuremic syndrome occurred in
a 41-year-old Chinese man with diffuse-
type systemic sclerosis when he took
ciclosporin for 12 months; it responded to
plasma exchange [13A].
Skin Acne with cysts and nodules on the
face in a 9-month-old boy was attributed
to ciclosporin; it resolved after withdrawal
of ciclosporin and administration of isotret-
inoin [14A].
Hair Hypertrichosis and darkening of the
hair occurred in a 59-year-old man who took
ciclosporin 2.5 mg/kg/day for 2 months [15A].
Musculoskeletal Bone pain occurred in a 6-
year-old boy during infusion of ciclosporin
[16A]. An MRI scan showed periosteal soft
tissue changes and mild bone marrow
edema of the femora and tibiae. Ciclo-
sporin was replaced by tacrolimus, and
after 9 days the pain had abated; it resolved
Chapter 38 J.K. Aronson
completely when tacrolimus was with-
drawn. The authors suggested that the bone
changes had been mediated by calcineurin-
induced vascular changes, leading to
intraosseous vasoconstriction and bone
marrow edema.
Genotoxicity Sister chromatid exchange
was signicantly increased in 20 renal trans-
plant recipients who were taking ciclo-
sporin; there were no changes in 17
patients taking tacrolimus [17c].
Tumorigenicity A digital brokeratoma
occurred in association with gingival over-
growth in a 39-year-old Chinese woman
who had taken ciclosporin for 6 years [18A].
Susceptibility factors Genetic The associa-
tions between ABCB1 genotypes (in exons
12, 21, and 26) and ciclosporin-related out-
comes have been studied in 147 renal trans-
plant recipients [19C]. Carriers of T allelic
variants in exons 21 or 26 had a threefold
increased risk of delayed graft function, a
trend to slower recovery of renal function
and a lower GFR at study end, and signi-
cantly higher incidences of new-onset dia-
betes and cytomegalovirus reactivation
compared with carriers of the wild-type
genotype. T variants in both exons 21 and
26 were independently associated with 3.8-
fold and 3.5-fold respectively higher risks
of delayed graft function.
Age Patients taking ciclosporin aged over 65
years (n 11, mean 73 years) were com-
pared with patients aged 1864 years
(n 14, mean 43 years), with measure-
ments of ciclosporin concentrations in whole
blood and T lymphocytes [20c]. The older
patients achieved target concentrations with
lower doses because of a lower clearance
and had 44% higher ratios of intracellular
to whole blood ciclosporin concentrations.
The CYP3A5*1 and ABCB1 genotypes
had no effect on ciclosporin pharmacokinet-
ics. The authors suggested that in elderly
recipients it might be safe to aim for lower
whole blood target concentrations than cur-
rent guidelines recommend.
Drugs that act on the immune system Chapter 38
Drugdrug interactions Escitalopram A
case of serotonin syndrome in an 84-year-
old woman has been attributed to co-admi-
nistration of escitalopram and ciclosporin;
the authors suggested that ciclosporin
inhibited the metabolism of escitalopram
by CYP3A4 [21A].
HMG CoA reductase inhibitors Rhabdo-
myolysis and renal failure in a 55-year-old
man has been attributed to inhibition by
concomitant ciclosporin and risperidone of
the metabolism of simvastatin by CYP3A4
[22A].
Nifedipine The incidence of gingival hyper-
plasia has been studied in 31 patients taking
ciclosporin, 31 taking ciclosporin amlodi-
pine, and 31 taking ciclosporin nifedipine
[23c]. There was gingival hyperplasia in 16,
18, and 28 respectively; furthermore, more
of those who took ciclosporin nifedipine
had severe hyperplasia (n 7), compared
with ciclosporin alone (n 0) and ciclo-
sporin amlodipine (n 5).
Rimonabant The pharmacokinetic inter-
action of ciclosporin with rimonabant has
been studied in 10 stable renal transplant
recipients [24c]. Rimonabant caused a mod-
erate but signicant increase in ciclosporin
AUC0!12h, with non-signicant rises in
Cmax and C2 concentrations. Tacrolimus
pharmacokinetics were not signicantly
affected by rimonabant in eight patients.
Everolimus (SDZ-RAD) [SED-15,
1306; SEDA-30, 453; SEDA-31, 622;
SEDA-32, 708]
Respiratory Pneumonitis occurred in a 57-
year-old renal transplant recipient taking
everolimus, whose trough blood concentra-
tions were in the usual target range; it
resolved completely after drug withdrawal
[25A]. Interstitial pneumonitis has also been
attributed to everolimus in ve heart trans-
plant recipients [26A, 27A] and a liver trans-
plant recipient [28A].
817
Of 1471 adult renal transplant recipients,
205 were switched from calcineurin inhibi-
tors to sirolimus (n 88) or everolimus
(n 117) [29c]. Six (2.9%) developed pneu-
monitis, one associated with sirolimus and
ve with everolimus. Median times from
conversion to the onset of pneumonitis
were 34 days in four patients (range 2446
days) and 491 days in 2 subjects (range
454528 days). The most common symp-
toms were dry cough (n 6), fever (n
5), and dyspnea (n 4). Imaging tests
showed lower lobe involvement in all cases.
Bronchoalveolar lavage in four patients
showed lymphocytic alveolitis. All recov-
ered completely after drug withdrawal.
In a retrospective study of 64 patients
taking everolimus 10 mg/day, 24 had radio-
graphic evidence of pneumonitis; in 16
cases it was thought to be either possibly
(n 12) or probably (n 4) related to
everolimus [30c]. The most common radio-
graphic ndings were focal areas of consol-
idation at the lung bases or ground-glass
opacities.
Metabolism Before heart transplantation
in 15 patients the mean concentration of
serum triglycerides was 1.55 mmol/l; after
transplantation it rose to 2.12 mmol/l; and
after treatment with sirolimus or everoli-
mus there was a further rise to 4.00 mmol/l
[31c]. After treatment with omega-3 fatty
acids for 4 months the triglyceride concen-
tration fell to 2.55 mmol/l.
Drugdrug interactions Antifungal azoles
The management of a pharmacokinetic
interaction of voriconazole with everolimus
has been described in a 65-year-old man
who underwent orthotopic liver transplan-
tation complicated by intestinal perfora-
tion, sepsis, and acute renal insufciency
[32A]. He received intravenous uconazole
400 mg followed by 100 mg/day and
oral everolimus 0.75 mg bd; the steady-state
Cmin of everolimus was satisfactory. On day
72 after transplantation, because of invasive
aspergillosis, antifungal therapy was
switched to intravenous voriconazole 400
mg bd on the rst day followed by 200 mg
bd; to prevent drug toxicity the dosage of
818
everolimus was promptly lowered to 0.25
mg/day. The dose-corrected Cmin of evero-
limus at steady-state was markedly higher
during co-treatment with voriconazole than
with uconazole (mean 11 vs. 3.5 mg/l per
mg/kg/day). During everolimus azole
co-treatment, everolimus dosage reduction
is needed to avoid overexposure. Because
of different CYP3A4 inhibitory potencies,
the reduction should be greater during co-
treatment with voriconazole than with
uconazole.
Leunomide [SED-15, 2015; SEDA-30,
454; SEDA-31, 625; SEDA-32, 709]
Respiratory More cases of respiratory
adverse reactions to leunomide have been
reported, manifesting as interstitial pneumo-
nitis [33A], diffuse alveolar damage with sec-
ondary organizing pneumonia [34A], and
diffuse alveolar hemorrhage [35A]. A review
counted 32 cases of leunomide-induced
pneumonitis (not including the one men-
tioned above) reported in the English lan-
guage literature [36R].
Of 5043 patients in the postmarketing
surveillance of leunomide in Japan, 61
had lung damage, and 24 died as a result.
Multivariate regression analysis showed
that pre-existing interstitial lung disease,
the use of a loading dose, a history of smok-
ing, and a body weight of 40 kg or less were
susceptibility factors. Based on these nd-
ings, it has been proposed that leunomide
should only be used as a second-line drug,
that it should not be used in those with
pre-existing interstitial lung disease, and
that a loading dose should not be used in
those with other susceptibility factors [37R].
The prevalence and susceptibility factors
for new and/or exacerbated interstitial lung
disease have been studied in a post-market-
ing surveillance review of 5054 Japanese
patients with rheumatoid arthritis taking
leunomide [38C]. Interstitial lung disease
developed and/or was exacerbated in 61
patients (1.2%). Pre-existing interstitial
lung disease (OR 8.17; 95% CI 4.63,
Chapter 38 J.K. Aronson
14), cigarette smoking (OR 3.12; 95%
CI 1.73, 5.60), a low body weight (OR
2.91; 95% CI 1.15, 7.37), and the use
of a loading dose (OR 3.97; 95% CI
1.22, 13) were independent susceptibility
factors. The authors suggested that leuno-
mide should not be prescribed for patients
with rheumatoid arthritis complicated by
interstitial lung disease.
The factors associated with a poor prog-
nosis in leunomide-induced lung injury
have been studied in 22 patients with rheu-
matoid arthritis, of whom 9 died and 13
recovered [39c]. The patients who died
tended to have pre-existing interstitial
pneumonia (8/9 vs. 6/13). The loading and
maintenance doses, the serum concentra-
tion of the leunomide metabolite
A771726, and the duration of treatment
did not differ between the groups. The
patients who died had more frequent hyp-
oxemia and mechanical ventilation, had a
high serum CRP concentration (190 vs.
100 mg/l), and had a low albumin concen-
tration (27 versus 33 g/l). The lymphocyte
count was persistently low in those who
died, but recovered in those who survived.
Colestyramine wash-out therapy has
been used to treat a 32-year-old Chinese
woman with leunomide-induced pneumo-
nitis [40A].
Nervous system Leunomide-associated
progressive multifocal leukoencephalopathy
has been reported in a 68-year-old man [41A].
Gastrointestinal Persistent diarrhea and
weight loss occurred during therapy with
leunomide, with histological evidence of
lymphocytic colitis; leunomide was with-
drawn, the diarrhea settled, and histologically
there was no colitis 3 months later [42A].
Skin Toxic epidermal necrolysis has been
attributed to leunomide in a patient with
rheumatoid arthritis [43A].
A 36-year-old woman with seropositive rheu-
matoid arthritis was given leunomide 20 mg/
day, and 2 weeks later developed a painful,
febrile, maculopapular rash involving the face
and upper torso. The skin lesions had a
bull's-eye appearance with a dark center and
Drugs that act on the immune system Chapter 38
spread rapidly to the rest of her body. After 4
days the lesions coalesced into large areas of
epidermal detachment involving 55% of the
body surface area. There was catarrhal con-
junctivitis and symblepharon. Liver enzymes
were raised. All medications were stopped
and colestyramine and prednisolone were
started. The patient was eventually left
completely blind as a result of punctuate
keratitis with keratinization of the cornea.
Another case has been reported in a 36-
year-old woman 1 week after a 3-week
course of leunomide [44A].
Cutaneous ulceration occurred after
treatment with leunomide 20 mg/day for
1 month in two patients with psoriasis
[45A, 46A], including a 31-year-old woman
with psoriatic arthropathy who took leu-
nomide 20 mg/day for 1 month.
Musculoskeletal Polymyositis occurred in a
53-year-old woman after leunomide treat-
ment for rheumatoid arthritis [47A].
Teratogenicity Healthy twins born were
born after maternal exposure to leuno-
mide [48A].
Susceptibility factors Genetic Isoforms of
cytochromes P450, mainly CYP1A2 and
CYP2C19, may be involved in leunomide
activation. Genotyping in 105 patients with
rheumatoid arthritis suggested that the
CYP1A2*1F allele may be associated with
leunomide toxicity [49c]. In addition, the
dihydro-orotate dehydrogenase A40C poly-
morphism was associated with leunomide
toxicity in 105 patients with rheumatoid
arthritis [50c].
Mycophenolate mofetil [SED-15,
2402; SEDA-30, 455; SEDA-31, 627;
SEDA-32, 710]
Drugdrug interactions Ciclosporin In 18
kidney transplant recipients taking myco-
phenolate mofetil, ciclosporin in concentra-
tion-related fashion increased trough
concentrations of the acyl glucuronide
and phenol glucuronide metabolites of
819
mycophenolate; tacrolimus had no effect
on mycophenolate or its metabolites in 17
patients [51c].
Pimecrolimus [SED-15, 2833; SEDA-
30, 456; SEDA-31, 628; SEDA-32, 712]
Observational studies In 52 patients with
seborrheic dermatitis who used pimecro-
limus 1% cream bd, the most frequent
adverse reaction was a burning-tingling sen-
sation, which abated after 7 days (i.e. it was
of the early tolerant variety, see p. xxxiii)
[52c].
Placebo-controlled studies In a double-
blind, randomized, placebo-controlled
study in 68 patients with vitiligo, the only
adverse reaction to pimecrolimus in combi-
nation with narrow-band ultraviolet B irra-
diation was self-limited erythema and
pruritus [53C].
Tumorigenicity The rates of tumors among
patients with atopic dermatitis or eczema
who used topical pimecrolimus have been
evaluated in a retrospective cohort study
of 953 064 subjects and controls [54c]. The
age- and sex-adjusted hazard ratio for all
cancers was 1.15 (95% CI 0.99, 1.31).
T-cell lymphoma was the only tumor asso-
ciated with a signicantly increased
risk (HR 3.76; 95% CI 1.71, 8.28).
However, after exclusion of patients who
had had suspicious lesions before exposure
the hazard ratio fell to 2.32 (95% CI
0.89, 6.07).
In a cohort study of 92 585 patients with
dermatitis, who used pimecrolimus for 121
289 person-years of follow-up, there was
no increased risk of lymphoma compared
with tacrolimus (rate ratio, RR 1.16;
95% CI 0.74, 1.82) and glucocorticoids
(RR 1.15; 95% CI 0.49, 2.72) [55c].
All three topical treatments were associ-
ated with an increased risk of lymphoma
compared with the general population, sug-
gesting increased detection of pre-existing
tumors.
820
Drugalcohol interactions See Tacrolimus
below.
Sirolimus (rapamycin) [SED-15,
3148; SEDA-30, 457; SEDA-31, 628;
SEDA-32, 712]
Respiratory More cases of sirolimus-associ-
ated interstitial pneumonitis have been
reported (see also Everolimus) [56Ar, 57A].
A 50-year-old man developed bronchiol-
itis obliterans with organizing pneumonia
after taking sirolimus monotherapy 2
mg/day for 8 days [58A].
Hematologic Severe, sustained, unilateral
and bilateral lymphedema has been
reported in eight patients taking sirolimus
[59A]. In six cases it was unilateral and in
seven cases there was no improvement
after withdrawal; both of these factors
throw some doubt on a causative relation.
Metabolism The rate of new-onset diabetes
mellitus has been studied in 20 124 patients
taking sirolimus after kidney transplanta-
tion, using data from the US Renal Data
System, compared with patients taking
ciclosporin, mycophenolate mofetil, or aza-
thioprine [60c]. Those who took sirolimus
were at increased risk of diabetes, whether
it was used in combination with ciclosporin
(adjusted HR 1.61; 95% CI 1.36, 1.90),
tacrolimus (adjusted HR 1.66; 95% CI
1.42, 1.93), or mycophenolate mofetil or
azathioprine (adjusted HR 1.36; 95% CI
1.09, 1.69).
Mouth Mouth ulcers are common in
patients who take sirolimus. In a study of
the case notes of 37 renal transplant recipi-
ents who took sirolimus, eight had mouth
ulcers [61c]. Painful conuent aphthous
ulcers on the tongue and lower lip in a 45-
year-old man taking sirolimus 2 mg/day
resolved when everolimus 0.75 mg bd was
used instead [62A].
Urinary tract Factors that affect protein-
uria in patients taking sirolimus have been
Chapter 38 J.K. Aronson
elucidated in 48 patients, of whom 25 had
new-onset proteinuria or a greater than
25% increase in proteinuria after starting
sirolimus; men were more likely to have
proteinuria and those taking statins were
less likely; those with proteinuria had a
higher rate of acute rejection [63c].
Skin In 148 patients taking sirolimus after
transplantation, wound complications were
more common (46% versus 19%) in those
who continued to take glucocorticoids, as
follows: lymphocele 32% versus 5%; dehis-
cence 10% versus 0%, leakage 8.8% versus
6.2%, seromas 7.5% versus 1.4% [64c]. A
multivariate analysis suggested that the
addition of glucocorticoids to sirolimus
increases the risk of wound complications
about fourfold. Avoiding overweight sub-
jects (BMI over 30 kg/m2), using closed suc-
tion drains, and avoiding a loading dose of
sirolimus may reduce the risk of wound
complications [65c].
Musculoskeletal Growth retardation in an
11-year-old girl occurred when she started
to take sirolimus; before treatment her
growth rate had been 5.5 cm/year and it slo-
wed down to 2.2 cm/year [66A]. The authors
attributed this to the anti-proliferative and
anti-angiogenic properties of sirolimus.
Reproductive function In a questionnaire
study of men aged 2040 years who
received a kidney transplant and used siro-
limus throughout the post-transplant
period, there was a signicantly reduced
total sperm count compared with patients
who did not use sirolimus (29  106 versus
292  106) and a reduced proportion of
motile spermatozoa (22% versus 41%)
[67c]. The fathered pregnancy rates (preg-
nancies/1000 patient years) were 5.9 (95%
CI 0.8, 42.1) and 93 (95% CI 66, 130)
respectively. Of six patients in whom siroli-
mus was withdrawn, only three had signi-
cant improvement in sperm parameters.
Of 170 kidney transplant patients, nine
(six men and three women) were taking sir-
olimus; four of the men developed gonadal
dysfunction and infertility on average 512
months after transplantation [68c].
Drugs that act on the immune system Chapter 38
Sirolimus was withdrawn in all four, with
full recovery and restoration of fertility.
Two of the women developed amenorrhea
after transplantation, and withdrawal of sir-
olimus in one resulted in resumption of
menstrual cycles.
In a retrospective chart review of 57 islet
transplant recipients, ovarian cysts were
found in 31 of 44 premenopausal women
and only two of 13 postmenopausal women
[69c]. No woman who used combined oral
contraception developed ovarian cysts. Sir-
olimus withdrawal was associated with a
reduction in cyst size and resolution of cysts
in 80% of subjects.
Body temperature Fever occurred in a
renal transplant recipient after he took siro-
limus for 1 month [70A]. During treatment
with broad-spectrum antibiotics the inam-
matory markers and fever worsened. Other
causes were ruled out and the fever and
other symptoms disappeared within 24
hours of withdrawal of sirolimus.
Drugdrug interactions Antifungal azoles
The effect of posaconazole 400 mg bd on
the pharmacokinetics of a single 2-mg dose
of sirolimus, a substrate of CYP3A4, has
been investigated in an open, multiperiod
study in 12 healthy subjects [71c]. Posacona-
zole increased sirolimus Cmax and AUC by
6.7 and 8.9 times respectively, consistent
with inhibition of CYP3A4 by posacona-
zole. These two agents should probably
not be co-administered.
Tacrolimus [SED-15, 3279; SEDA-30,
458; SEDA-31, 630; SEDA-32, 714]
Observational studies In a retrospective
study in 42 patients who took tacrolimus
for a mean of 288 days, tacrolimus was
withdrawn in 28 patients, because of
adverse reactions in 21 cases [72c]. Gastro-
intestinal symptoms were the most common
adverse reactions (19/42 patients), followed
by infections and hyperglycemia; nausea
and vomiting led to withdrawal in seven
821
patients, within 60 days of starting treat-
ment in six cases. The incidence of gastro-
intestinal symptoms was higher in patients
taking a daily dose of 2 mg or more.
Systematic reviews In a systematic review
of adverse reactions to tacrolimus ointment
in patients with atopic dermatitis who used
it for at least 6 months, there were no
increased risks of cancer or immunosup-
pression during follow-up for up to 4 years
[73M]. Short-term adverse events included
increased burning and stinging of the skin
and a temporary increase in skin infections.
Nervous system Brachial neuritis in an 8-
year-old boy resolved after tacrolimus was
withdrawn and everolimus used instead
[74A].
Akinetic mutism has been reported in a
66-year-old man who was given intravenous
methylprednisolone and tacrolimus after
liver transplantation [75A]. On day 3 he
developed acute onset mutism, akinesia,
and waxy rigidity of passive limb move-
ments. The serum tacrolimus concentration
was 21 mg/l. Tacrolimus was replaced with
ciclosporin and mycophenolate mofetil,
and his symptoms resolved completely over
the next few days.
A reversible leukoencephalopathy have
been attributed to tacrolimus in several
cases.
A 62-year-old, liver transplant recipient devel-
oped posterior reversible encephalopathy syn-
drome after taking tacrolimus 2 mg/day and
metoprolol 150 mg/day; when her serum
tacrolimus concentration fell to 1.5 mg/l she
recovered [76A].
Posterior reversible encephalopathy syndrome
occurred in an 18-year-old woman who had
taken tacrolimus for 14 days; an MRI scan 4
weeks after withdrawal of tacrolimus showed
almost complete resolution of all the changes
that were noted in a scan that was taken at
the time of presentation [77A].
A 68-year-old woman who had taken tacroli-
mus 4 mg/day for 7 months developed a post-
erior reversible leukoencephalopathy, which
resolved within 6 months of tacrolimus with-
drawal [78A].
A 22-year-old woman who developed post-
erior leukoencephalopathy while taking tacro-
limus recovered completely after drug
withdrawal [79A].
822
There has also been a report of a pro-
gressive necrotic encephalopathy following
tacrolimus therapy in a 57-year-old man;
although there was some improvement
after drug withdrawal, he was left with a
residual hemiplegia [80A].
Metabolism In a retrospective analysis of
122 non-diabetic patients taking tacroli-
mus-based triple drug immunosuppression
55% developed abnormal glycemic control
and 33% required drug therapy, of whom
only 5.5% required insulin [81c].
In 25 renal transplant recipients who
took tacrolimus, of whom nine also took a
statin, tacrolimus signicantly increased
plasma triglyceride concentrations, which
the authors attributed to reduced lipopro-
tein lipase activity [82c].
Hematologic Thrombotic microangiopathy
occurred in a 56-year-old woman after ther-
apy with tacrolimus for 6 days, associated
with a high trough concentration [83A].
Thrombotic thrombocytopenic purpura
has been attributed to tacrolimus in a 61-
year-old woman [84A].
Gastrointestinal Severe new-onset colitis
occurred in two kidney transplant recipi-
ents shortly after the introduction of a mod-
ied-release formulation of tacrolimus
instead of standard twice-daily tacrolimus
in one case and ciclosporin in the other
[85A]. Both developed severe, intermittent
bloody diarrhea, with abdominal pain,
weight loss, dehydration, and worsening
graft function. The symptoms did not abate
after dosage reduction or withdrawal of
mycophenolate.
Biliary tract The frequencies of gallbladder
sludge and cholelithiasis in 25 patients tak-
ing tacrolimus and 51 taking ciclosporin
have been compared [86c]. With tacrolimus
the incidence of biliary sludge was 4% (1 of
25) and of gallstones 28% (7 of 25); the
rates with ciclosporin were 4% (2 of 51)
and 25% (13 of 51).
Urinary tract In 15 transplant recipients a
diagnosis of chronic tacrolimus-associated
Chapter 38 J.K. Aronson
nephrotoxicity was established at an aver-
age of 55 months postoperatively [87c].
The mean dosage at the time of diagnosis
was 0.054 mg/kg, with a mean whole blood
trough concentration of 5.09 mg/l, which is
within the usual target range. There was
moderate to severe arteriosclerosis of
medium-sized arteries in 12 cases, and the
authors concluded that arteriosclerosis in
medium-sized arteries was more likely to
be associated with chronic nephrotoxicity
than the dosage or whole blood trough
concentration of tacrolimus.
Skin Granuloma annulare has been attrib-
uted to topical tacrolimus 0.1% in three
women aged 37, 55, and 43 [88A].
Tumorigenicity The rates of tumors among
patients with atopic dermatitis or eczema
who used topical tacrolimus have been
evaluated in a retrospective cohort study
of 953 064 subjects and controls [89c]. The
age- and sex-adjusted hazard ratio for all
cancers was 0.93 (95% CI 0.81, 1.07).
T-cell lymphoma was the only tumor asso-
ciated with a signicantly increased risk
among those who used tacrolimus (HR
5.04; 95% CI 2.39, 11). Even after exclu-
sion of patients who had had suspicious
lesions before exposure the hazard ratio
remained signicant at 5.44 (95% CI
2.51, 12).
Susceptibility factors Genetic In 51 chil-
dren with liver transplants taking tacro-
limus, there was a higher incidence of
ABCB1 variant-alleles among patients with
at least a 30% reduction in eGFR at 6 months
after transplantation (1236T allele: 63% ver-
sus 38% in controls; 2677T allele: 63% versus
36%; 3435T allele: 60% versus 39%). Car-
riers of the G2677>T variant allele also had
a signicant 23% reduction in eGFR at 12
months after transplantation [90c]. Haplo-
type analysis showed a signicant association
between TTT haplotypes and an increased
incidence of nephrotoxicity at 6 months after
transplantation (haplotype frequency
53% in nephrotoxic patients versus 29% in
controls). Furthermore, G2677>T and
C3435>T polymorphisms and TTT
Drugs that act on the immune system Chapter 38
haplotypes correlated signicantly with
higher tacrolimus dose-adjusted trough
concentrations.
A genetic factor that may predispose to
post-transplantation diabetes mellitus in
patients taking tacrolimus is polymorphism
in the calpain-10 gene (CAPN10), which is
associated with an increased risk of type 2
diabetes in the general population. Of 214
non-diabetic kidney transplant recipients
taking tacrolimus, 56 developed diabetes
and 158 did not, and they were genotyped
for CAPN10 gene variants (SNP-43:
rs3792267:G>A, SNP-19: rs3842570 ins/
del, and SNP-63: rs5030952:C>T) [91c].
The frequency of the SNP-63 minor allele
was slightly increased in those who devel-
oped post-transplantation diabetes mellitus,
and there was an association of SNP-63 het-
erozygosity with the risk of diabetes (OR
2.45). There was an increased risk of diabe-
tes in patients carrying the 112 haplotype
(rs3792267:G-rs3842570:ins-rs5030952:T)
compared with non-carriers (OR 2.35). A
higher body mass index and SNP-63 minor
T allele carrier status were independent
susceptibility factors.
Drug overdose A 3-year-old girl with an
acute overdose of tacrolimus developed
abdominal pain, a poor appetite, vomiting,
diarrhea, headache, tachypnea, leg pains,
gingival bleeding, easy bruisability, epi-
staxis, and ecchymoses all over the body
[92A]. The hemoglobin was 10 g/dl, plate-
lets 307  109/l, prothrombin time 13.6 sec-
onds, partial thromboplastin time 98
seconds, and bleeding time 12.5 seconds.
The tacrolimus trough concentration was
28 (target 712) ng/ml.
An accidental overdose of tacrolimus,
prescribed instead of thiamine, in a 42
year-old woman resulted in non-oliguric
renal failure and a metabolic acidosis; the
tacrolimus concentration 27 hours after
the last dose was 97 (usual target range
520) mg/l and she recovered without
sequelae [93A].
Drugdrug interactions Amlodipine A
19-year-old woman, who took tacrolimus
after renal transplantation and amlodipine
823
5 mg/day, developed galactorrhea and mas-
talgia; the dose of tacrolimus was reduced,
but her symptoms persisted until amlodi-
pine was withdrawn [94A]. Her serum pro-
lactin concentration was slightly raised.
When amlodipine was reintroduced her
symptoms returned within 5 days.
Antifungal azoles The co-prescription of
posaconazole with tacrolimus has been
evaluated in 14 lung transplant recipients
with cystic brosis. Posaconazole inhibited
CYP3A4-mediated tacrolimus metabolism,
resulting in a threefold reduction in tacroli-
mus dosage requirements [95c].
The effects of single nucleotide polymor-
phisms (SNPs) in CYP3A4, CYP3A5, and
MDR1 on interactions of tacrolimus with
uconazole have been examined in 29 renal
allograft recipients, who were genotyped
for CYP3A4*1/*1B, CYP3A5*1/*3,
MDR1 C3435T, and G2677T/A [96c].
Dose-corrected trough blood tacrolimus
concentrations did not change signicantly
from baseline in heterozygous CYP3A5*1
carriers during exposure to uconazole, in
contrast to homozygous CYP3A5*3 car-
riers, in whom there was a 3.3-fold increase.
Homozygous CYP3A5*3 carriers had a sig-
nicant reduction in weight-corrected
tacrolimus dosage requirements during u-
conazole administration, in contrast to het-
erozygous carriers of CYP3A5*1. These
effects were not inuenced by uconazole
dose or duration of administration. Signi-
cantly more CYP3A5*3/*3 carriers were
exposed to tacrolimus dose-uncorrected
trough blood tacrolimus concentrations of
at least 15 mg/l during administration of u-
conazole compared with CYP3A5*3/*1
carriers. Thus, in renal allograft recipients,
the CYP3A5*3/*1 genotype is associated
with reduced susceptibility for the inhibi-
tory effects of uconazole on tacrolimus
metabolism.
Carbamazepine In a pharmacokinetic
investigation in a woman in her 40s, tacroli-
mus trough concentrations fell within 7
days of treatment with carbamazepine 200
mg/day, and a 3040% increase in tacroli-
mus dosage was required to maintain
824
adequate blood concentrations [97A]. The
dose-corrected AUC0!12h after 11 days
was about 50% of the value before carba-
mazepine and apparent oral clearance was
about twice as high.
Mirtazapine In a 68-year-old woman with
renal failure on chronic hemodialysis, the
combination of tacrolimus with mirtazapine
resulted in asymptomatic hypotension after
2 hours; the tacrolimus blood concentration
was over 15 mg/l [98A]. The authors hypoth-
esized that tacrolimus, in a high concentra-
tion, had inhibited the metabolism of
mirtazapine via CYP3A4.
Drugalcohol interactions In 25 patients
who applied either pimecrolimus 1%
cream (n 13) or tacrolimus 0.1% oint-
ment (n 12) to lesions of vitiligo on the
face twice daily for 24 weeks and then took
small quantities of beer or wine, facial
ushing occurred in two of the former and
ve of the latter [99c]. There was an itch-
ing-burning sensation, quickly followed by
ushing within 510 minutes after alcohol
and at 24 weeks after the start of treat-
ment; it disappeared after 2030 minutes.
This reaction has previously been described
in 67% of patients using topical tacrolimus
[100C, 101c]. The authors proposed three
hypotheses for this interaction: release of
neuropeptides, causing extreme vasodilata-
tion; local accumulation of acetaldehyde
due to inhibition of aldehyde dehydroge-
nase by the calcineurin inhibitors; and an
interaction at the calcineurincalmodulin
calcium complex.
Temsirolimus [SEDA-32, 716]
Observational studies In 208 patients with
advanced renal cell carcinoma who were
randomized to subcutaneous interferon up
to 18 MU thrice weekly, intravenous tem-
sirolimus 25 mg/week, or intravenous tem-
sirolimus 15 mg/week subcutaneous
interferon 6 MU thrice weekly, the most
common temsirolimus-related grades 34
Chapter 38 J.K. Aronson
adverse events were anemia (13%), hyper-
glycemia (9%), and weakness (8%) [102c].
Grades 34 hypercholesterolemia (1%),
hypertriglyceridemia (3%), and hypo-
phosphatemia (4%) also occurred. Pneu-
monitis was infrequent.
In 32 patients with advanced renal cell
carcinoma who were treated with temsiroli-
mus 25 mg/week, common adverse events
included weakness/fatigue (44%), increased
creatinine (41%), mucositis (31%), second-
ary diabetes (28%), hypothyroidism (13%),
rashes (13%), and hypercholesterolemia
and hypertriglyceridemia (9.3%) [103c].
Urinary tract A 58-year-old man with
advanced renal cell carcinoma developed
grade 3 proteinuria (8.5 g/24 hours) without
microscopic hematuria or renal insuf-
ciency 5 days after an infusion of temsiroli-
mus [104A]. Kidney biopsy showed
ischemic glomeruli and focal segmental glo-
merulosclerosis. His proteinuria fell to 2.8
g/day 2 weeks after temsirolimus
withdrawal.
Skin A 73-year-old woman with metastatic
renal cell carcinoma developed a pruritic
rash after receiving two infusions of tem-
sirolimus 25 mg/week; the rash was located
on both antecubital areas and the backs of
the knees [105A]. Biopsy showed spongiotic
dermatitis with eosinophils. The authors
hypothesized that temsirolimus, an mTOR
kinase inhibitor, has a direct inhibitory
effect on signalling pathways that regulate
cell growth and tissue repair.
THIOPURINES
Cross-reactivity between
thiopurines
Azathioprine, 6-(1-methyl-4-nitroimidazole-
5-yl)-thiopurine, is a prodrug that is con-
verted non-enzymatically to mercaptopurine
(Figure 1) and subsequently to thioguanine
nucleotides. It is therefore not unexpected
Drugs that act on the immune system Chapter 38
Imidazole 8-hydroxy 8-hydroxy
derivatives azathioprine mercaptopurine
AO AO
HPRT
Azathioprine Mercaptopurine
XO/XDH TMPT
Inhibited by Thiouric acid Methylmercapto-
allopurinol purine
AO
Methylmercapto-
8-hydroxypurine
Figure 1 The metabolism of azathioprine and mercaptopurine. Key: AO, aldehyde oxidase; GMPS, guanine
monophosphate synthetase; HPRT, hypoxanthine phosphoribosyl transferase; IMPDH, inosine mono-
phosphate dehydrogenase; ITPA, inosine triphosphate pyrophosphohydrolase; TPMT, thiopurine
methyltransferase; XO/XDH, xanthine oxidase/dehydrogenase; dark shading: thiopurines; light shading:
active metabolites.
for patients who have experienced adverse
reactions to azathioprine to have similar
reactions to the other thiopurines. However,
in some cases mercaptopurine [106c] and
thioguanine [107A] do not elicit the same
adverse reactions.
Observational studies Patients with Crohn's
disease (n 14) or ulcerative colitis (n 15)
with previous hypersensitivity reactions to
azathioprine were given gradually increasing
doses of mercaptopurine from 0.5 to 1.01.5
mg/kg/day [108c]. In nine patients mercapto-
purine was withdrawn in the rst 2 weeks
because of early hypersensitivity reactions;
the other 20 patients tolerated it.
Of 135 patients with Crohn's disease (n
88) or ulcerative colitis (n 47), 65 stopped
taking it because of adverse events after 25
(892) days; the other 70 patients tolerated
mercaptopurine and were followed up for
736 (3621080) days [109c]. Mercapto-
purine was tolerated in 12 of 17 patients with
hepatotoxicity and in 13 of 19 with arthral-
gia/myalgia during azathioprine treatment.
Previous abdominal surgery was more
common in those who had adverse reactions
to mercaptopurine (39/65 vs. 27/70), and
thiopurine methyltransferase activity was
higher in those who were tolerant of
mercaptopurine.
Of 32 patients with inammatory bowel
disease who had adverse reactions to
825
Inhibited by Thioxanthosine Thioxanthosine
ribavirin triphosphate diphosphate
ITPA
Thioinosine IMPDH Thioxanthosine
GMPS Thioguanine
monophosphate monophosphate nucleotides
TMPT Kinase
Thioguanine
Methyl thioinosine
monophosphate AO
8-hydroxy
thioguanine
azathioprine or mercaptopurine, thiogua-
nine 20 or mg/day was well tolerated in 26;
in three patients there were adverse reactions
that were probably or obviously related
to thioguanine and that necessitated with-
drawal [110c].
Of 95 patients in whom thioguanine
0.30.4 mg/kg/day was used after adverse
reactions to azathioprine or mercaptopurine,
only 20 had adverse reactions that required
withdrawal [111c]. The main reasons were
gastrointestinal complaints (31%), malaise
(15%), and hepatotoxicity (15%). There
were hematological events in three patients
and seven cases of hepatotoxicity.
In 22 patients with inammatory bowel
disease who had adverse reactions to aza-
thioprine, mercaptopurine was tolerated for
longer (median 219, range 3503 days) than
azathioprine (median 14, range 2180 days)
[112c]. The adverse reactions to azathio-
prine were nausea and vomiting (n 14),
u-like symptoms (n 5), myalgia/arthral-
gia (n 6), headaches (n 6), and diarrhea
(n 2).
Gastrointestinal adverse effects In 15
patients (11 with Crohn's disease and four
with ulcerative colitis) azathioprine caused
epigastric pain, nausea, and vomiting, which
developed within the rst weeks of treatment
[113c]. Azathioprine was withdrawn and
mercaptopurine substituted; 11 patients
826
tolerated mercaptopurine and only two
patients had to stop taking it because of
adverse effects.
In two patients with severe intestinal toxic-
ity, which was life-threatening in one after
rechallenge, there was no recurrence after
the use of mercaptopurine [114A].
Hepatotoxicity In two boys, aged 11 and
15, liver damage that resolved after with-
drawal of azathioprine did not occur when
mercaptopurine was introduced [115A].
Either there was no cross-reactivity in these
cases or azathioprine was not responsible
for the liver damage.
A 50-year-old man had a severe hyper-
sensitivity reaction to azathioprine resulting
in hepatitis; however, he tolerated mercapto-
purine for 6 years without hepatotoxicity,
despite high concentrations of methyl-
mercaptopurine [116A].
In a retrospective study of 31 patients (14
with Crohn's disease and 17 with ulcerative
colitis), in whom azathioprine (mean dose
2.2 mg/kg/day) was withdrawn because of
liver damage (cytolytic in 32%, cholestatic
in 39%, and mixed in 29%), mercapto-
purine (mean dose 1.3 mg/kg/day) was used
instead [117c]. In 27 patients there was no
further liver damage; of these, 24% tolerated
full doses of mercaptopurine. In four
patients liver damage recurred 13 months
after the onset of exposure to
mercaptopurine.
Hypersensitivity reactions In 21 patients
with inammatory bowel disease who had
hypersensitivity reactions to azathioprine or
mercaptopurine within 6 weeks, thioguanine
1040 mg/day elicited hypersensitivity reac-
tions in only four, after a median of 9 days;
pancreatitis did not recur [118c].
A 56-year-old woman with chronic intermittent
urticarial vasculitis was given oral azathioprine
100 mg/day for 10 days, but developed severe
nausea and vomiting [119c]. Oral re-challenge
1 year later caused similar symptoms. A second
re-challenge with a single intravenous dose of
50 mg caused an immediate hypersensitivity
reaction, with severe vomiting, fever, urticaria,
and hypotension, followed by myalgia. A prick
Chapter 38 J.K. Aronson
test was strongly positive with azathioprine but
not mercaptopurine. Subsequent therapy with
mercaptopurine was uneventful.
Conclusions In some cases reactions to aza-
thioprine may be due to azathioprine itself,
or to metabolites that are not formed after
conversion to mercaptopurine, such as 8-
hydroxyazathioprine (Figure 1) or a imidaz-
ole glutathione conjugate [120A]. In such
cases the adverse reactions may not occur
when mercaptopurine or thioguanine are
used instead. In some cases in which cross-
reactivity did not apparently occur, the orig-
inal adverse event may not have been due to
the thiopurine to which it was attributed.
Pancreas During 82 episodes of acute
pancreatitis, most cases were attributed to
drug exposure: azathioprine/mercapto-
purine (n 46) and mesalazine (n 6)
[121c]. In those with acute pancreatitis due to
thiopurines, female sex (OR 3.4; 95% CI
1.3, 9.3) and Crohn's disease (OR 5.8;
95% CI 1.6, 21) were susceptibility factors.
Skin Sweet's syndrome (neutrophilic der-
matosis) has been attributed to thiopurines
[122A].
A 55-year-old man developed a fever with a
non-pruritic rash 1 week after starting to take
azathioprine 2.5 mg/kg/day. There were ery-
thematous, edematous plaques, with painful
pseudovesicles scattered over the face, neck,
back, palms, soles, and limbs, three painless
ulcers in the mouth, and bilateral conjunctivi-
tis. He then developed right knee and bilateral
elbow pain associated with erythema, warmth,
and swelling. A biopsy conrmed Sweet's syn-
drome, which was treated with an anti-TNFa
antibody. Azathioprine was withdrawn and
then re-introduced; 6 hours later he developed
a high-grade fever, arthralgia, a papular erup-
tion, and unilateral conjunctivitis. Azathio-
prine was immediately withdrawn and he
recovered completely within 48 hours. He
was then given mercaptopurine 1.6 mg/kg/
day and the symptoms of Sweet's syndrome
recurred after 7 hours and on two subsequent
occasions after oral challenge.
Sweet's syndrome has been reported in
other cases [123A, 124A].
Drugs that act on the immune system Chapter 38
Azathioprine [SED-15, 377; SEDA-30,
459; SEDA-31, 635; SEDA-32, 717]
Observational studies in 106 patients with
Crohn's disease taking azathioprine, there
was at least one adverse reaction in 56,
and 18 had to stop taking it, often because
of hypersensitivity reactions; there was
nausea and vomiting in 29 and leukopenia
in 36 [125c].
Hematologic Eryptosis is a process of sui-
cidal cell death undergone by erythrocytes,
in which the process known as scrambling
of the cell membrane occurs; there is eryth-
rocyte shrinkage, exposure of membrane-
bound phosphatidylserine, and annexin
binding, mimicking features of apoptosis
in nucleated cells [126R]. Erythrocytes from
patients taking azathioprine showed signi-
cantly increased exposure of phosphatidyl-
serine within 1 week of treatment, and
in vitro exposure to azathioprine in concen-
trations of 2 mg/l and over for 48 hours
increased cytosolic Ca2 activity and
annexin V binding and reduced forward
scatter [127cE]. The effect of azathioprine
on both annexin V binding and forward
scatter was signicantly blunted in the
absence of extracellular Ca2. The authors
proposed that eryptosis might contribute
to azathioprine-induced anemia.
Liver A 48-year-old patient with Crohn's
disease developed hepatic nodular regener-
ative hyperplasia, with fatigue, icterus,
hepatosplenomegaly, and ascites, accompa-
nied by pancytopenia; liver histology sug-
gested a drug-induced cause and after
withdrawal of azathioprine he improved
substantially [128A].
A 50-year-old man with ulcerative colitis
developed severe acute cholestatic hepatitis
after taking azathioprine for 20 days. Despite
withdrawal of azathioprine and methylpred-
nisolone therapy it persisted for 2 months
and may have been coincidental [129A].
Skin In ve patients the minimal erythema
dose for UVB, UVA, and solar-simulated
radiation was determined before and after
827
azathioprine therapy for at least 12 weeks
[130c]. Azathioprine was associated with
increased sensitivity of the skin and
reduced minimal erythema doses to UVA
and solar-simulated radiation; there were
no changes in UVB-induced erythema or
minimal erythema dose. DNA from the
skin during azathioprine therapy contained
the metabolite 6-thioguanine. The authors
concluded that the interaction of 6-thio-
guanine with UVA results in abnormal
cutaneous photosensitivity.
An unusual case of contact hypersensitiv-
ity to azathioprine has been reported
[131A].
A man in his early 30s developed an intermit-
tent eczematous eruption over the shaft of his
penis and scrotum coinciding with his wife's
intermittent courses of azathioprine for
Crohn's disease. During four courses of such
treatment over 4 years her vaginal secretions
were yellow, and the authors thought that vag-
inal secretion of azathioprine or its metabo-
lites could have led to allergic contact
dermatitis in the husband. Patch testing with
azathioprine and mercaptopurine was positive
in the husband but not the wife.
Nails Beau's lines, transverse depressions on
the nails, developed in two patients taking aza-
thioprine, a 68-year-old AfricanAmerican
woman and a 62-year-old man; in each case
there was evidence of an associated hypersen-
sitivity reaction, in one case with neutropenia
and raised aminotransferase activities and in
the other raised aminotransferase activities
[132A].
Infection risk In 230 taking azathioprine
who were studied prospectively and com-
pared with patients who were not taking
azathioprine, there was no difference in
the incidence of upper respiratory tract
infections, but the incidence of herpes ares
was signicantly increased in those taking
azathioprine and there were signicantly
more patients with new or worsening viral
warts [133c].
Tumorigenicity The increased risk of squa-
mous cell carcinoma in patients who are
immunosuppressed by azathioprine has
been reviewed [134R].
828
PTCH gene mutations have been ana-
lysed in 60 basal cell carcinomas, 39 from
patients taking azathioprine and 21 from
individuals who had never used it [135cM].
PTCH was mutated in 55% of all tumors,
independent of azathioprine treatment. In
both the azathioprine and non-azathioprine
groups, transitions at dipyrimidine
sequences, considered to indicate mutation
by ultraviolet-B radiation, were frequent
in tumors from chronically sun-exposed
skin. In basal cell carcinomas from non-
sun-exposed skin there was an over-repre-
sentation of unusual G:C to A:T transitions
at non-dipyrimidine sites only in those who
had taken azathioprine, and all in the same
TGTC sequence context at different posi-
tions within PTCH. Meta-analysis of 247
basal cell carcinomas from published stud-
ies showed that these mutations are rare
in sporadic cases and have never previously
been reported in this specic sequence con-
text. The authors suggested that exposure
to azathioprine may be associated with
PTCH mutations, particularly in tumors
from non-sun-exposed skin.
Reversible Hodgkin's lymphoma associ-
ated with EpsteinBarr virus infection dur-
ing azathioprine therapy for systemic lupus
erythematosus in a 47-year-old woman was
attributed to azathioprine, which she had
taken for several years [136A]. A locally
invasive mass associated with lymphadenop-
athy in the neck regressed signicantly after
withdrawal of azathioprine, and after about
5 months had almost completely resolved
without the need for chemotherapy.
Unbalanced whole-arm chromosomal
translocations, including der(1;7)(q10;p10),
der(1;15)(q10;q10), der(1;16)(q10;p10), and
der(1;19)(q10;p10), have been reported in
hematological malignancies, but der(1;7)
(q10;p10) has rarely been associated
with acute erythroleukemia. A 64-year-old
Korean woman with severe neutropenia
and erythroid hyperplasia during azathio-
prine therapy had an unbalanced transloca-
tion between the whole arms of
chromosomes 1 (long arm) and 7 (short
arm); the detailed karyotype was 46,XX,1,
der(1;7)(q10;p10),inv(9)(p11q13)c [137A].
Chapter 38 J.K. Aronson
The authors suggested that der(1;7)(q10;
p10) may be a susceptibility factor in aza-
thioprine-associated acute erythroleukemia.
A 67-year-old renal transplant recipient
developed a nodular malignant melanoma
after 30 years of immunosuppression with
azathioprine and prednisolone [138A].
Teratogenicity In the infants of 476 Swed-
ish women who reported using azathioprine
in early pregnancy, mostly for inammatory
bowel disease, the rate of congenital mal-
formations was 6.2%, compared with 4.7%
among all infants born (adjusted OR
1.41; 95% CI 0.98, 2.04) [139C]. Exposed
infants were also more likely to be preterm,
to weigh under 2500 g, and to be small for
gestational age.
Aplasia cutis congenita involving over
90% of body surface area occurred in a
baby born to a mother with pemphigus vul-
garis who had taken oral prednisolone and
azathioprine during pregnancy [140A].
Susceptibility factors Genetic In 50 patients
with systemic lupus erythematosus taking
azathioprine, the erythrocytic concentra-
tions of thioguanine nucleotides that were
associated with clinical responses were
lower than the target range established for
inammatory bowel disease [141c].
The frequencies of four common TPMT
mutant alleles, TPMT*2, *3A, *3B, and
*3C have been determined in 150 Chinese
patients who had taken azathioprine, 30 of
whom had stopped taking it or were taking
a reduced dosage because of adverse reac-
tions [142c]. The mean TPMT activity in
those who had never had adverse reactions
was 38 (range 1768) units and the mean
value in 12 patients with hemotoxicity was
signicantly lower (23 units). However,
there was no signicant difference in 18
patients with hepatotoxicity. There were
no cases of TPMT deciency, and TPMT*2,
*3A, and *3B were not detected.
TPMT*3C heterozygous alleles were found
in seven patients, all of whom had inter-
mediate TPMT activity, and the mean
activity was 17 units, much lower than other
TPMT wild-type patients; of these seven,
Drugs that act on the immune system Chapter 38
four had adverse reactions. The authors con-
cluded that TPMT activity is reduced in Chi-
nese patients with the TPMT*3C mutation.
In a study of the association between gene
polymorphisms in TPMT and ITPA (see
Figure 1) and drug intolerance in 157 renal
transplant recipients taking azathioprine,
each was genotyped for variant TPMT
alleles (*2, *3A, *3B, and *3C) and ITPA
alleles (94C>A and IVS221A>C) [143c].
Mean azathioprine dose, mean white
blood-cell count, and platelet count during
treatment were lower in carriers of variant
TPMT alleles compared with those with the
TPMT wild-type genotype. Leukocyte num-
bers fell below 4.0  109/l in 41% of TPMT
heterozygotes compared with 18% of the
wild-type patients. In contrast, the ITPA
genotype did not inuence azathioprine,
hematology, or the risk of leukopenia.
TPMT genotype polymorphisms
(TPMT*2, *3A, *3B, and *3C) have been
studied in 108 patients with vasculitis associ-
ated with positive antineutrophil cytoplasmic
antibodies (ANCA), who were given azathio-
prine and followed for 47 months [144c].
Adverse reactions (leukopenia, anemia,
thrombocytopenia, gastrointestinal adverse
reactions including hepatitis, and hypersensi-
tivity reactions) did not differ between
patients who were heterozygous and those
who were homozygous or between the ter-
tiles of patients who were homozygous.
The frequencies of TPMT mutant alleles
have been studied retrospectively in 147
Japanese patients with inammatory bowel
disease taking azathioprine, of whom 144
were wild-type for TPMT (TPMT*1/*1)
and three carried a mutant TPMT allele
(TPMT*1/*3C) [145c]. The incidence of
adverse reactions to azathioprine was 38/
114 in the wild-type group. Leukopenia
occurred in 16% of the patients with wild-
type TPMT. The authors concluded that
determination of TPMT genotype may not
be useful in Japanese patients in predicting
adverse reactions to azathioprine.
In contrast, in 139 kidney transplant
recipients in Thailand, nine of whom were
heterozygous for the TPMT*1/*3C
829
genotype, TPMT activity in those patients
was signicantly lower than in those with
the homozygous wild-type genotype [146c].
The risk of azathioprine-induced myelosup-
pression in the patients with the hetero-
zygous TPMT*1/*3C genotype was
signicantly higher than in those with the
wild-type genotype. The sensitivity and
specicity of TPMT*3C genotyping for pre-
dicting azathioprine-induced myelosuppres-
sion were 27% and 97% respectively.
Genetic polymorphisms in aldehyde
oxidase (AOX1), xanthine dehydrogenase
(XDH) (see Figure 1), and MOCOS (the
product of which activates the essential co-
factor for aldehyde oxidase and xanthine
dehydrogenase) have been studied in
patients with inammatory bowel disease
taking azathioprine [147c]. The single nucle-
otide polymorphism AOX1 c.3404A>G
(Asn1135Ser, rs55754655) predicted a lack
of response to azathioprine, and combined
with TPMT activity allowed stratication of
a patient's chance of response, ranging from
86% in patients in whom both markers were
favorable to 33% in those in whom they were
unfavorable. There was also a weak protec-
tive effect against adverse drug reactions
from the single nucleotide polymorphisms
XDH c.837C>T and MOCOS c.2107A>C,
which was stronger when they coincided.
Drugdrug interactions Ribavirin The
interaction of ribavirin, an inosine mono-
phosphate dehydrogenase inhibitor (see
Figure 1), with azathioprine has been retro-
spectively studied in eight patients who
developed severe pancytopenia after con-
comitant use [148c]. All had normal thio-
purine methyltransferase (TPMT) activity.
Bone marrow suppression reached a nadir
after a mean of 4.6 weeks. Myelotoxicity
was accompanied by raised total concentra-
tions of the methylated metabolites and
reduced concentrations of 6-thioguanine
nucleotides. The authors suggested that ino-
sine monophosphate dehydrogenase inhibi-
tors, such as ribavirin, should not be used
in combination with purine analogues.
830
Mercaptopurine
Skin Hand-foot syndrome (acral erythema,
palmoplantar erythrodysesthesia) has been
attributed to mercaptopurine in a 4-year-
old child with acute lymphoblastic leukemia
who developed dry painful palmar and
plantar erythema with ssures after receiv-
ing mercaptopurine for 3 weeks [149A].
Hair Myelosuppression that occurred after
treatment with mercaptopurine for 6 weeks
in a 15-year-old woman with Crohn's dis-
ease was preceded by alopecia, which
occurred after only 3 days [150A].
Drug overdose Accidental overdose
occurred when a woman with hypothyroid-
ism was erroneously given mercaptopurine
100 mg tds instead of propylthiouracil
[151A]. Her symptoms began on day 3,
when she developed fatigue, night sweats,
headaches, chest pain, hair loss, aching in
the thighs, neck, and back, nausea, and
one episode of non-bloody, non-bilious
vomiting. She also developed drooping of
the right eyelid without change in vision
or diplopia. The symptoms progressively
worsened, and she stopped taking mercap-
topurine on day 6 (total dose 1800 mg).
She had raised aminotransferase activities
and a prolonged prothrombin time with an
INR of 1.7. This is not the rst time that
this error has been made [152A, 153A].
Drugdrug interactions Methotrexate The
pharmacokinetic interaction between meth-
otrexate and mercaptopurine has been
studied in 20 children with acute lympho-
blastic leukemia [154c]. High-dose metho-
trexate (5 g/m2 over 24 hours) produced a
rapid reduction in erythrocyte concentra-
tions of thioguanine within 24 hours, and
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39 Corticotrophins,
corticosteroids, and
Editor's notes: In this chapter adverse effects
arising from the oral or parenteral adminis-
tration of corticosteroids (glucocorticoids
and mineralocorticoids) are covered in the
section on systemic administration. Other
routes of administration are dealt with in the
sections after that; inhalation and nasal
administration are dealt with in Chapter 16,
topical administration to the skin in Chapter
14, and ocular administration in Chapter 47.
All the uses of prostaglandins are covered in
this chapter, apart from topical administration
to the eyes, which is covered in Chapter 47.
SYSTEMIC
GLUCOCORTICOIDS [SED-15,
906; SEDA 30, 463; SEDA-31, 651;
SEDA-32, 723]
Systematic reviews In a pooled analysis of
data from ve double-blind, randomized,
placebo-controlled, multicenter trials of
budesonide capsules 6 mg in Crohn's disease,
the most common adverse reactions were
gastrointestinal and endocrine (budesonide
6 mg/day, n 208; placebo, n 209) [1M].
The frequencies were similar, except for a
Side Effects of Drugs, Annual 33
J.K. Aronson (Editor)
ISSN: 0378-6080
DOI: 10.1016/B978-0-444-53741-6.00039-8
# 2011 Elsevier B.V. All rights reserved.
J. Costa and M. Farr
prostaglandins
higher incidence of endocrine disorders when
comparing budesonide with placebo, caused
by a higher overall occurrence of cutaneous
reactions with budesonide. Patients who used
budesonide had an increased incidence of
acne, moon face, and viral infections com-
pared with placebo, but at signicantly
lower frequencies than with systemic gluco-
corticoids, such as prednisolone. The number
of patients with normal adrenal function was
signicantly lower at 13 weeks (in three of ve
studies), but not at 52 weeks (two studies)
when comparing budesonide with placebo.
Sepsis, cataracts, and adrenal insufciency
were rare and similar in the two groups.
Cardiovascular Early initiation of glucocor-
ticoids in cardiac sarcoidosis, as soon as the
diagnosis is made and before the onset of
heart failure, is considered to be crucial to
prevent permanent damage and improve
prognosis. A patient with cardiac sarcoidosis
had a non-sustained ventricular tachycardia,
mimicking right ventricular cardiomyopathy
[2A]. Glucocorticoid therapy was not effec-
tive and the dysrhythmia deteriorated into
multifocal and sustained prolonged ventricu-
lar tachycardia. The authors suggested that
the glucocorticoid may have converted gran-
ulomatous inammation into brosis and
aggravated the dysrhythmias, which were
nally controlled by catheter ablation.
Nervous system A 67-year-old woman with
a dural arteriovenous stula developed acute
paraparesis 2 hours after receiving an intra-
venous bolus of methylprednisolone 1 g [3A].
841
842
She complained of pain in the legs and weak-
ness and developed a paraparesis and L2 level
hypoalgesia. The treatment was temporarily
withdrawn and 48 hours later she had recov-
ered. However, when glucocorticoid therapy
was restarted the same effect occurred. It is
uncommon for a dural arteriovenous stula
to manifest with acute clinical effects. Since
vasogenic edema is the main pathogenic fac-
tor in dural arteriovenous stula, one would
have expected a glucocorticoid to produce
clinical benet. However, in this patient it
aggravated the symptoms. The authors
hypothesized that rapid infusion of saline, in
which the methylprednisolone was diluted,
and uid retention produced by the drug,
could have resulted in hypervolemia and a
secondary increase in venous pressure.
Hypokalemic periodic paralysis is a rare
heterogeneous disorder characterized by
paroxysmal attacks of accid muscle weak-
ness associated with low serum potassium
concentrations. It is due to mutations in
transmembrane voltage gated ion channels
in skeletal muscle, with familial autosomal
dominant inheritance or sporadic occur-
rence. In one report of 12 cases, a single
dose or short-term use of glucocorticoids
caused periodic paralysis associated with
hypokalemia in patients with a variety of
genotypes [4c]. The authors hypothesized
that glucocorticoids cause hypokalemia in
patients with periodic paralysis by stimulat-
ing the NaK ATPase.
Sensory systems Vision Steroid cataract is
one of the most serious adverse reactions
to glucocorticoids, because it affects quality
of life. The risk factors for steroid cataracts
in children with rheumatic diseases were
initiation of glucocorticoid therapy in chil-
dren under 12 years of age and intravenous
methylprednisone pulse therapy [5c].
Unilateral severe visual loss occurred in
a 51-year-old woman after injection of
triamcinolone acetonide into the nasal
mucosa, resulting in permanent and severe
visual disturbance with marked retinal
atrophy [6A].
Chapter 39 J. Costa and M. Farr
Psychiatric The French Association of
Regional Pharmacovigilance Centers has
summarized the results of spontaneous
reports submitted from 1 January 1985 to
30 March 2007 to the French Pharmaco-
vigilance Database, in which glucocorticoids
were suspected of causing psychiatric and/
or behavioral adverse reactions in patients
aged under 18 years [7S]. Among the 455
spontaneous reports there were psychiatric
and/or behavioral reactions to glucocorti-
coids in 95 (21%) patients under 18 years
of age, including 136 adverse reactions; 15
were classied as serious (one death and
14 hospitalizations). The mean age of the
patients was 5.9 years and 57 were under
6 years of age. The glucocorticoid dosage
was unknown in 16 cases. Adverse reac-
tions occurred in 29 cases (31%) after pre-
scription or administration errors (16 cases
of overdose and 13 of high doses). They
were observed in 13 other children (14%)
after the use of high doses (n 8) or
supratherapeutic doses (n 5) for differ-
ent therapeutic indications (serious asthma,
nephrotic syndrome, or leukemia). In four
cases the indications were as recommended
in the Summary of Product Characteristics,
and there was off-label prescription or
administration in 25 cases (26%) (21 cases
of overdose and four off-label indications).
The most frequent adverse reactions were
agitation or excitation and sleep distur-
bances. Adverse reactions occurred most
often with oral administration (n 72),
but were also reported after administration
of intravenous or inhaled forms. In 75% of
cases, the time to onset was less than 7 days.
Most of the adverse reactions (82 cases,
86%) resolved completely after glucocorti-
coid withdrawal. The glucocorticoids
that were most often involved were
betamethasone (n 38), prednisolone
(n 21), and prednisone (n 17). The
authors suggested that these results should
be interpreted with caution, because of the
low reporting rate of adverse drug reactions
in France.
Glucocorticoids can cause severe emo-
tional and even psychiatric disturbances.
There is a great deal of controversy about
Corticotrophins, corticosteroids, and prostaglandins
whether emotional and psychiatric adverse
reactions to glucocorticoids are linked to
patients pre-existing mental health. The
ndings from a pilot study that explored
prior mental health and the effects of gluco-
corticoids in 10 hematology patients in
Australia have provided evidence that emo-
tional disturbances associated with the use
of glucocorticoids result directly from the
drugs used and are not expressions of the
individual's prior emotional health [8c].
Endocrine The prevalence of adrenal
insufciency after systemic glucocorticoid
therapy has been evaluated in 16 infants
with hemangiomas, using a combined low-
dose/high-dose corticotropin stimulation
test [9c]. They were given prednisolone at
a starting dose of 23 mg/kg/day for
4 weeks, followed by a tapering period.
The mean duration of glucocorticoid treat-
ment was 7.2 months. Corticotropin testing
at a mean of 13 days after the completion
of therapy showed that only one of the 16
infants had adrenal insufciency.
Skin Lichen planus has been attributed to
intramuscular triamcinolone [10A].
A 21-year-old Japanese man with alopecia
multiplex developed pruritic linear eruptions
on the left thigh. He was given intramuscular
triamcinolone acetonide 40 mg once a month,
and after 10 such injections developed numer-
ous eruptions on his left thigh consisting of
multiple pigmented brownish macules and
papules with a tendency to disseminate. Skin
biopsy was consistent with lichen planus. He
used topical 0.05% diuprednate ointment
for more than 1 year, without improvement.
The onset in this case was during the
administration of triamcinolone for alopecia
areata. Although glucocorticoids have not
been previously reported to have caused
lichen planus, the possibility that triamcino-
lone might have affected the immune system
cannot be excluded.
Patients with psoriasis who become
exposed to high doses of systemic glucocor-
ticoids (7.5 mg prednisolone equivalents or
more per day) for more than 710 days
may develop generalized pustular psoriasis
during tapering of the dosage or complete
Chapter 39 843
withdrawal. Four cases of generalized pustu-
lar psoriasis attributed to systemic gluco-
corticoids have been reported, with
recommendations for treatment [11cr].
Musculoskeletal Osteonecrosis As the use
of glucocorticoids increased in acute lym-
phoblastic leukemia, osteonecrosis became
an increasingly frequent complication. To
further explore genetic predictors of
osteonecrosis, 12 candidate polymorphisms
potentially involved in osteonecrosis have
been studied by the Children's Cancer
Group (CCG1882); there was a relatively
high incidence of osteonecrosis in children
10 years and older [12c]. Candidate genes
(TYMS, MTHFR, ABCB1, BGLAP, ACP5,
LRP5, ESR1, PAI-1, VDR, PTH, and
PTHR) were chosen based on putative mech-
anisms underlying the risk of osteonecrosis.
A polymorphism in PAI-1 (rs6092) was asso-
ciated with a risk of osteonecrosis in a univar-
iate analysis (OR 2.79) and a multivariate
analysis (OR 2.89) (adjusted for age, sex,
and treatment arm). Overall, 21 (27%) of 78
children with PAI-1 GA/AA genotypes,
versus 25 (12%) of 214 children with GG
genotype, developed osteonecrosis.
There has been a report of Kienbck dis-
ease (osteonecrosis of the lunate bone)
resulting from local glucocorticoid injec-
tions in a 51-year-old man [13A].
Osteoporosis
EIDOS classication:
Extrinsic species Glucocorticoids
Intrinsic species Osteoblasts and
osteoclasts
Distribution Bone
Outcome Atrophy
Sequela Osteoporosis from
glucocorticoids
DoTS classication:
Dose-relation Collateral reaction
Time-course Late
Susceptibility factors Age (elderly
patients); sex (female sex,
postmenopausal)
844
Quality of studies Many studies of glucocor-
ticoid-induced osteoporosis are of moderate
(37%) or poor (31%) quality, and the quality
of a study is an independent predictor for the
degree of prevention for glucocorticoid-
induced osteoporosis reported in the study
[14M]. It is apparent that patients who take
glucocorticoids often do not receive appropri-
ate prophylaxis. However, there has been a
noticeable improvement from earlier studies,
which were conducted in the mid-1990s, par-
ticularly if specic interventions have been
undertaken. Future intervention studies that
assess prophylaxis should aim to recruit only
patients who require prophylaxis according
to the prevalent guidelines. Furthermore,
these studies should state clearly which part
(s) of the decision-making steps, as stated in
the prevalent guideline at the time of the
study, have been assessed for adherence.
Future interventions should comply with
ve major quality criteria. A multifaceted
approach involving health providers who care
for glucocorticoid users, public education,
and increased access to absorptiometry is
required in order to make an impact on the
underprescribing of prophylaxis of gluco-
corticoid-induced osteoporosis.
Susceptibility factors Inammatory bowel
disease is a susceptibility factor for abnor-
mal bone metabolism, with a large amount
of evidence of increased incidences of
osteopenia and osteoporosis in adults.
However, only a few studies of bone min-
eral density have been performed in chil-
dren and adolescents with inammatory
bowel disease. Bone mineral density in the
lumbar spine has been evaluated in 40 chil-
dren and adolescents with inammatory
bowel disease, mean age 12 years, 26 with
ulcerative colitis and 14 with Crohn's dis-
ease, in order to identify the associated suscep-
tibility factors [15c]. There was a low bone
mineral density (Z-score worse than 2) in
25% of patients, with equal prevalences in
Crohn's disease and ulcerative colitis. Height
for age, basal metabolic index, and cumulative
glucocorticoid dose had independent effects,
and these effects remained signicant after
adjustment for disease duration.
Chapter 39 J. Costa and M. Farr
Children The effects of systemic glucocorti-
coids on acute changes in bone formation
and resorption markers (amino-terminal
type I collagen propeptide (PINP) and
carboxyterminal telopeptide of type I colla-
gen (ICTP)), and markers of inammation
have been studied in 22 children, mean age
12 years, with inammatory bowel disease,
before and during treatment [16c]. In addi-
tion, GH-related IGF-I and sex hormone-
binding protein (SHBG) were measured.
The control group comprised 22 patients
with inammatory bowel disease in remis-
sion. Serum PINP and IGF-I concentrations
were already lower before glucocorticoid
treatment in the children with active inam-
matory bowel disease, and PINP fell further
after 2 weeks of glucocorticoid treatment;
serum ICTP and SHBG also fell. In con-
trast, serum IGF-I increased. One month
after the withdrawal of the glucocorticoid,
all the bone markers had returned to control
values. The authors concluded that bone
formation in children with active inamma-
tory bowel disease is compromised and sys-
temic glucocorticoid treatment further
suppresses bone turnover.
Prevention Recommendations for the regis-
tration of agents for the prevention and
treatment of glucocorticoid-induced osteo-
porosis were produced by the Group for
the Respect of Ethics and Excellence in Sci-
ence (GREES) in 1996 and updated in
2005. The 2005 update mainly addressed
the design of clinical studies in glucocorti-
coid-treated postmenopausal women and
its authors concluded that for agents with
proven efcacy in postmenopausal osteo-
porosis, a placebo-controlled trial with
measurement of lumbar spine bone mineral
density at 1 year as the primary endpoint
was required. This work has since been
updated [17H], with the aim of considering
separately the appropriate recommenda-
tions for registering agents for use in gluco-
corticoid-induced osteoporosis in men and
in premenopausal and postmenopausal
women. At present etidronate, alendronate,
risedronate, and teriparatide are approved
for the prevention and treatment of gluco-
corticoid-induced osteoporosis in Europe.
Corticotrophins, corticosteroids, and prostaglandins
Risedronate (the only compound that has
been centrally registered) is limited to post-
menopausal women.
Zoledronic acid (5 mg intravenous infu-
sion) and risedronate (5 mg/day orally) for
the prevention and treatment of glucocorti-
coid-induced osteoporosis have been evalu-
ated in a 1-year double-blind, double-
dummy, randomized, non-inferiority study in
833 patients in 54 centers in 12 European
countries, Australia, Hong Kong, Israel, and
the USA [18C]. The treatment subgroup
consisted of those treated for more than
3 months (272 patients with zoledronic acid
and 273 with risedronate), and the prevention
subgroup consisted of those treated for less
than 3 months (144 patients on each drug);
62 patients did not complete the study
because of adverse events, withdrawal of
consent, loss to follow-up, death, mis-
randomization, or protocol deviation.
Adverse events were more frequent in
patients taking zoledronic acid. The authors
of an accompanying editorial commentary
commented that although a once-yearly intra-
venous infusion of zoledronic acid would
seem to have obvious advantages over an oral
regimen, the best dosing strategy for
zoledronic acid is not currently known in terms
of cost-effectiveness and the adverse effects of
long-term regimens in glucocorticoid-induced
osteoporosis. This information is especially
important in view of the long duration of
action of zoledronic acid and concerns about
possible deleterious effects from long-term
oversuppression of bone turnover [19r].
Immunologic Immediate hypersensitivity to
glucocorticoids is rare. To date, about 100
cases have been reported, mostly in adults
who had anaphylaxis within several minutes
of oral or intravenous administration. There
has also been a report in a child [20A].
A 2-year-old boy had used inhaled uticasone-
dipropionate 100 micrograms/day for frequent
episodes of asthma and had also intermittently
received prednisone suppositories (Recto-
deltTM) for acute bronchopulmonary obstruc-
tion with no adverse outcomes. During a bout
of severe bronchospasm he was given intra-
venous prednisolone-21-hydrogen succinate
50 mg (Solu-DecortinTM) and within a few
Chapter 39 845
minutes developed generalized urticaria, facial
angioedema, nausea, and severe dyspnea, and
required nasal oxygen. The prednisolone was
withdrawn and his symptoms resolved within
30 minutes. A subsequent skin prick test
was positive with prednisolone-21-hydrogen
succinate in a dilution of 1:10; there were
no reactions with prednisone (RectodeltTM),
betamethasone (Celestamine N liquidumTM),
or dexamethasone (FortecortinTM).
Infection risk Aspergillosis is a well-known
complication in patients using long-term
glucocorticoids, but until now, there have
been only two reports of pulmonary and
cerebral aspergillosis in patients using
short-term course of glucocorticoids for
idiopathic thrombocytopenic purpura. In
both cases, the patient survived without any
sequelae. A fatal case of pulmonary and
cerebral aspergillosis has now been reported
in a 24-year-old man who took a short
course of glucocorticoids for idiopathic
thrombocytopenic purpura [21A].
When a 26-year-old man was infected with
Cladophialophora bantiana, a dematiaceous
fungus found in soil in a worldwide distribu-
tion, the fungus was unable to proliferate and
was controlled by a local immune response
[22A]. However, the residual multiple scars
were initially managed 4 months later with
serial injections of intralesional glucocorti-
coids, after which he developed erythema,
edema, and tenderness around the largest scar.
A biopsy from the area of erythema showed
the presence of septate fungal hyphae.
Severe Cytomegalovirus esophagitis
occurred after short-term glucocorticoid
therapy in a patient with no other apparent
cause of immune deciency, such as human
immunodeciency virus infection, neopla-
sia, or previous organ transplantation [23A].
Two cases of Strongyloides stercoralis
hyperinfection after glucocorticoid therapy
have been reported [24A].
Pregnancy The rst large UK population-
based study to assess the risk of maternal
asthma and exposure to current asthma
treatments during pregnancy on overall
and system-specic major congenital
malformations in their offspring has been
reported [25C]. It was a matched case-control
846 Chapter 39 J. Costa and M. Farr

study using The Health Improvement Net- 1 and 5 minutes. He cried normally and his
work primary care database. Children with breathing was effortless. However, 3 hours
after birth he developed respiratory distress
malformations were matched with control syndrome and a mild metabolic acidosis, and
children by year of birth, general practice, became hemodynamically unstable, with falls
and singleton or twin delivery. There were in blood pressure and anuria. An ACTH stim-
5124 live-born children with major congeni- ulation test conrmed profound adrenal
tal malformations and 30 053 controls. The suppression.
risk of any malformation in children born to
An adverse effect of the hydrocortisone
women with asthma was marginally higher
acetate enemas in this case cannot be either
than that in children born to women without
conrmed or excluded. Since the concen-
asthma (adjusted OR 1.10, 95% CI
tration of methylprednisolone or its metab-
1.01, 1.20). However, there was no associ-
olites in the blood was not measured, the
ation in children born to mothers who had
relation between adrenal insufciency in
received asthma treatment in the year before
the child and maternal exposure to methyl-
or during pregnancy (OR 1.06; 95% CI
prednisolone was not unequivocal.
0.94, 1.20). In assessing the teratogenicity
Twin pregnancies have a much higher rate
of the medications that had been used, there
of glucose intolerance and/or gestational dia-
were no increases in the risks of malforma-
betes than singleton pregnancies. In a study
tion with gestational exposure to short- or
of maternal glucose concentrations after the
long-acting b-adrenoceptor agonists, inhaled
administration of dexamethasone in singleton
or oral glucocorticoids, other bronchodila-
versus twin pregnancies, 10 patients with sin-
tors, or cromones. These ndings were
gleton pregnancies and nine patients with
similar for each of 11 system-specic
twin pregnancies who needed glucocorticoids
malformations, except for an increase in
were enrolled at 2434 weeks of gestation and
musculoskeletal system malformations asso-
received four doses of intramuscular dexa-
ciated with exposure to cromones. The nd-
methasone 6 mg 12 hours apart [27c]. Mean
ings suggest that gestational exposure to
glucose concentrations were signicantly
commonly used asthma medications is safe
higher in the twin group at 4 hours (6.33 ver-
overall, although a moderate teratogenic risk
sus 5.31 mmol/l), 8 hours (6.34 versus
of cromones cannot be excluded. There was
5.00 mmol/l), and 24 hours (6.44 versus
some evidence of a small increased risk of
4.50 mmol/l).
congenital malformation in children born to
women with asthma, but this was not
explained by gestational exposure to asthma
drugs.
Methylprednisolone is used for the treat-
ment of acute exacerbations of Crohn's dis-
ease in pregnancy, since its use is PROSTAGLANDINS AND
considered to be less harmful than the ANALOGUES [SED-15, 2955;
effect of the active disease on the fetus. SEDA-30, 465; SEDA-31, 651; SEDA-
However, adrenal suppression in a fetus
32, 729]
has been associated with administration of
methylprednisolone [26A].
Alprostadil (prostaglandin E1)
A 29-year-old pregnant woman with active [SED-15, 94; SEDA-32, 729]
Crohn's disease received high doses of methyl-
prednisolone (32 mg/day) and a daily enema Cardiovascular Unstable angina has been
containing hydrocortisone acetate 100 mg for reported after intracavernous injection of
at least 1 month before labor. She delivered alprostadil in a 72-year-old man; there was
a boy at 37 weeks of gestation by elective
cesarean section. At delivery the infant's inferolateral ST segment depression and a
weight was 3380 g, length 53 cm, head circum- tight stenosis of the rst marginal coronary
ference 36 cm, and the Apgar score was 10 at artery [28A].
Corticotrophins, corticosteroids, and prostaglandins Chapter 39 847

Bimatoprost [SED-15, 517; SEDA-31, Iloprost [SED-15, 1716; SEDA-32, 729]

655; SEDA-32, 729]
Comparative studies Studies of prostanoids
See Chapter 47. in intermittent claudication have yielded
inconsistent results. In a multicenter com-
parison of three doses of oral iloprost,
pentoxifylline, and placebo, conducted in
Epoprostenol [SED-15, 1228; SEDA- 19981999 but published only in 2008, oral
30, 465; SEDA-30, 465] iloprost did not improve exercise perfor-
mance or quality of life [31C]. Serious
Hematologic The risk of thrombocytopenia
adverse events did not differ among the
has been studied in 47 patients with advanced
groups and neither did any specic cardio-
pulmonary arterial hypertension during intra-
vascular events. However, oral iloprost
venous epoprostenol therapy, and compared
was poorly tolerated and therapy was often
with 44 patients with an inadequate response
interrupted because of headache, ushing,
to initial therapy with oral agents in a cross-
nausea, or diarrhea.
sectional study [29c]. There was thrombo-
cytopenia in 34% of patients treated with
Skin A curious but non-serious local
epoprostenol, compared with 15% of patients
adverse reaction to iloprost, a linear ery-
receiving oral therapy (OR 2.9), and
thematous facial rash, has been described
the association between epoprostenol and
in an 11-year-old boy with severe pulmo-
thrombocytopenia remained signicant after
nary hypertension associated with right
adjustment for differences in hemodynamics
ventricular failure, who was given iloprost
(OR 5.0). Right atrial pressure
by inhalation [32A]. On one occasion, the
(OR 1.12 per mmHg) and mixed venous
child removed the mouthpiece and cham-
oxygen saturation (OR 0.92 per percent-
ber lid and applied iloprost directly to his
age) were also associated with thrombocyto-
cheek. A few minutes later, he developed
penia in univariate analyses; after logistic
two erythematous linear skin lesions
regression analysis, both epoprostenol and
spreading over his face and neck, which
oxygen saturation were independently associ-
resolved spontaneously within 3 days.
ated with thrombocytopenia. In a separate
analysis including only patients with current
or prior epoprostenol use, epoprostenol dose
and right atrial pressure were inversely associ-
ated with platelet count.
Latanoprost [SED-15, 2002; SEDA-30,
465; SEDA-31, 655; SEDA-32, 729]

Nervous system The headache eliciting See Chapter 47.

effect of prostacyclin (PGI2) has been studied
in 12 healthy subjects in a double-blind, cross-
over, study [30c], in which epoprostenol
10 nanograms/kg/minute was infused for
25 minutes. During the immediate phase
(030 minutes) and the post-infusion phase
(3090 minutes) 11 subjects reported head-
ache after epoprostenol and none reported
headache on the placebo day. The headache
was associated with dilatation of the super-
cial temporal artery but there was no dilata-
tion of the middle cerebral artery. These data
suggest that PGI2-induced headache may be
due to activation and sensitization of sensory
afferents around extracranial arteries.
Misoprostol [SED-15, 2357; SEDA-30,
466; SEDA-31, 655; SEDA-32, 730]
Systematic reviews Sublingual and vaginal
misoprostol administration in the third tri-
mester of pregnancy for induction of labor
has been studied in women with a live,
full-term fetus and an unripe cervix [33M].
There were no signicant differences
between the two groups with respect to
the rate of vaginal delivery not achieved
within 24 hours (OR 1.27; 95%
848
CI 0.87, 1.84), uterine hyperstimulation
syndrome (OR 1.20; 95% CI 0.61,
2.33), or cesarean section (OR 1.33;
95% CI 0.96, 1.85). There was an
increased risk of uterine tachysystole with
sublingual misoprostol (OR 1.70; 95%
CI 1.02, 2.83). When the studies were
grouped according to the initial dose of
misoprostol, there was no signicant differ-
ence between sublingual or vaginal admin-
istration. The authors concluded that the
sublingual route of administration is as
effective as the vaginal route in inducing
labor in full-term pregnancies with
live fetuses. However, the adverse effects,
optimal dose, and perinatal outcomes
related to this route of administration
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Dermatol 2009; 34(8): e1014.
[33] Souza ASR, Amorim MMR, Feitosa FEL.
Comparison of sublingual versus vaginal
misoprostol for the induction of labour: a
systematic review. BJOG 2008; 115(11):
13409.
[34] Hagenaars M, Knape JTA, Backus EMJM.
Pulmonary oedema after high infusion rate
of sulprostone. Br J Anaesth 2009; 102(2):
2812.

40 Sex hormones and related
compounds, including
hormonal contraceptives
Author's note: Sex hormones, particularly
estrogens and progestogens, can be used sep-
arately or in combination, and for various
purposes. It is often not possible to deter-
mine to which compound or combination a
particular adverse reaction can be attributed;
information on particular types of adverse
reactions may therefore need to be sought
under a series of differing headings.
GONADOTROPINS [SED-15,
1536; SEDA-30, 468; SEDA-31, 656;
SEDA-32, 735]
Cardiovascular Human chorionic gonado-
trophin has been used for two generations
in patients with cryptorchidism, in the
hope of inducing testicular descent. Fail-
ures are common (in which case one
resorts to corrective surgery) but complica-
tions are not. In one case injection of
human chorionic gonadotrophin was fol-
lowed by a stroke and hemiparesis, the
mechanism being unclear [1A]. There have
been occasional earlier reports of ischemic
reactions. Cerebral infarction is seen in
both boys and girls given gonadotrophin;
Side Effects of Drugs, Annual 33
J.K. Aronson (Editor)
ISSN: 0378-6080
DOI: 10.1016/B978-0-444-53741-6.00040-4
# 2011 Elsevier B.V. All rights reserved.
M.N.G. Dukes
since cerebrovascular disorders are increas-
ingly being recognized as important causes
of mortality and morbidity in children, this
possible complication deserves to be taken
seriously.
Reproductive system Attempts to avoid
severe ovarian hyperstimulation and its
accompanying risks during gonadotrophin
therapy continue, without notable success.
There is some preliminary evidence that
the joint use of dopamine receptor agonists
and gonadotrophin-releasing hormone
antagonists, administered as soon as hyper-
stimulation is diagnosed, rapidly suppress
the symptoms of the complication, but fur-
ther study of the method is called for [2c].
Drug formulations Whatever the relative
merits of recombinant (rh) as against uri-
nary (uh) chorionic gonadotrophin, safety
does not seem to be a determinant factor.
When the two were compared using gener-
ally recognized doses, the resulting preg-
nancy rates were similar; of 64 women
who received rhCG, 30% became pregnant;
of the 61 patients who received uhCG, 25%
became pregnant [3c]. No adverse effects
were noted in either group.
851
852
ESTROGENS [SED-15, 1253;
SEDA-30, 469; SEDA-31, 657;
SEDA-32, 736]
Autacoids Angioedema is a disease of
women that is often but not always aggra-
vated by exogenous estrogens. In four
women who had attacks of angioedema of
the pharynx and limbs, some episodes were
apparently precipitated by local trauma,
upper respiratory tract infections, and preg-
nancy [4A]. A maternal aunt of one patient
had suffocated during an attack at age 20.
These patients had normal concentrations
of C1 esterase inhibitor at baseline. During
attacks, their C1 esterase inhibitor activity
fell, but the inhibitor concentrations them-
selves remained normal. Concentrations of
the complement proteins C1q, C3, and C4
also remained normal during attacks, which
is considered strong evidence against classic
hereditary angioedema. The women had
reduced kallikrein concentrations during
episodes, suggesting activation of the con-
tact system, which generates bradykinin
and allows vascular leakage of plasma and
the development of angioedema. One
patient had a mutation related to a gain-
of-function of Hageman factor, which has
been suggested as the genetic basis of this
disease.
Tumorigenicity Over the years there has
been a lack of consistent evidence as to
the possible association between combined
oral contraceptives (or other estrogen-con-
taining hormonal formulations) and the
occurrence of melanoma. In the Nether-
lands, material from a large pharmacy data-
base and a pathology database have now
been brought together to examine possible
links [5C]. Women aged 18 years or over
who were the subject of database entries
for primary cutaneous melanoma recorded
during the years 19912004 and followed
up for not less than 3 years were the pri-
mary study population, and controls were
matched for age and geographic region. In
Chapter 40 M.N.G. Dukes
all, 778 cases and 4072 controls were
included. The risk of cutaneous melanoma
was signicantly associated with use for
6 months or more (adjusted OR 1.42;
95% CI 1.19, 1.69). This effect was dose
related with respect to the cumulative dose
taken. The risk of melanoma was also signif-
icantly associated with the use of hormone
replacement therapy (HRT) for more than
6 months (OR 2.08; 95% CI 1.37,
3.14) and oral contraceptives (OR 1.28;
95% CI 1.06, 1.54).
Diethylstilbestrol [SED-15, 1119;
SEDA-31, 657; SEDA-32, 739]
Urinary tract In data from a collaborative
follow-up of three US cohorts of diethylstil-
bestrol-exposed sons, prenatal exposure
was not associated with varicocele, struc-
tural abnormalities of the penis, urethral
stenosis, benign prostatic hyperplasia, or
inammation/infection of the prostate, ure-
thra, or epididymis [6C]. However, there
were increased risks of cryptorchidism
(RR 1.9; 95% CI 1.1, 3.4), epididymal
cysts (RR 2.5; CI 1.5, 4.3), and test-
icular inammation/infection (RR 2.4;
CI 1.5, 4.4). There were stronger associa-
tions with exposure that began before the
11th week of pregnancy: cryptorchidism
(RR 2.9; 95% CI 1.6, 5.2), epididymal
cysts (RR 3.5; CI 2.0, 6.0), and testicular
inammation/infection (RR 3.0; CI 1.7,
5.4). The authors suggested that these nd-
ings support the hypothesis that endocrine
disrupting chemicals may contribute to the
increased prevalence of cryptorchidism that
has been seen in recent years.
Tumorigenicity A clear cell adenocarci-
noma of the ovary has been linked to early
diethylstilbestrol exposure in utero in a 45-
year-old woman; her mother had taken
diethylstilbestrol throughout the pregnancy
[7A].
Acute monocytic leukemia occurred in a
neonate whose mother had been exposed
Sex hormones and related compounds, including hormonal contraceptives
to diethylstilbestrol in utero; the child pre-
sented with leukemia cutis, hemorrhagic
skin lesions, a leukocytosis, and dissemi-
nated intravascular coagulation [8A].
In a database study of 3140 diethylstilbes-
trol-exposed and 826 unexposed women,
those who had been exposed in utero to di-
ethylstilbestrol were more likely than unex-
posed women to receive recommended or
additional screening examinations for breast
cancer (adjusted OR 2.20; 95% CI 1.04,
4.67) among women without a history of
benign breast disease compared with unex-
posed women [9c]. There were no other statis-
tically signicant differences between
exposed and unexposed women. Most of
the exposed women received breast
cancer screenings at least at recommended
intervals, but over two-thirds did not perform
monthly self-examination. The authors
concluded that future efforts should be
focused on education about the benets of
screening examinations of at-risk populations
through mailed reminders and during patient
consultations.
Epigenetic effects In 4029 sons and 3808
daughters of women whose mothers had
used diethylstilbestrol during pregnancy
(i.e. the third generation) and a subcohort
of 793 third generation daughters, overall
birth defects were more common in both
the sons (OR 1.53; 95% CI 1.04, 2.23)
and in the daughters (OR 2.35; 95%
CI 1.44, 3.82) [10C]. Most estimates of
association were imprecise, but the daugh-
ters appeared to have an excess of heart con-
ditions (OR 4.56; 95% CI 1.27, 16).
These data suggest a possible association
between the mother's prenatal exposure
and birth defects in their offspring, particu-
larly in their daughters. However, the
authors could not rule-out reporting bias.
Equine estrogens [SEDA-32, 739]
See next section
Chapter 40 853
Hormone replacement therapy
(HRT) [SED-15, 1684, 1686, 1692;
SEDA-30, 469; SEDA-31, 659; SEDA-32,
740]
Attitudes to the use of hormone
replacement therapy
With half a century of experience of various
forms of HRT, well-documented reviews con-
tinue to appear regarding the safety or other-
wise of this treatment [11R]. When one
recalls the initial enthusiasm with which oral
HRT was originally greeted the caution now
widely expressed about its use is striking,
although there is still some doubt as to its
long-term effects, especially when very low
doses are used [12R]. The authors of one
recent review concluded that the risk of
venous thrombosis is increased 2.5 times in
current users of oral formulations, although
the risk is not increased in those using trans-
dermal hormone patches. Several large trials
have now shown that oral estrogens do not
protect against, and might even increase, the
risk of coronary heart disease, and slightly
increase the risk of breast cancer after pro-
longed use. On the basis of such results,
HRT is no longer considered to be indicated
for long-term use: short-term use to alleviate
menopausal symptoms seems defensible,
and skin patches are likely to be safer than
orally administered hormones [13R].
There has naturally been some criticism of
the move away from HRT. For example,
some have argued that the ndings in the
Women's Health Initiative were wrongly
interpreted [14R]; however, this is a minority
view, and it seems fair to conclude that for
many women the risks of this treatment out-
weigh the possible benets.
Helpful reviews continue to provide guid-
ance on the use of HRT in individual cases,
bearing in mind both objective risks and the
fears expressed by individual women [15R].
Here too, HRT still has its champions, who
consider that this form of treatment as a
whole has been unfairly condemned. Some
854
among them point to the extent to which
heart disease presents differently between
the sexes, non-obstructive coronary disease
and angina unrelated to exercise being con-
siderably more prevalent in women than in
men. When the outcomes of large controlled
trials failed to demonstrate cardiac risk pro-
tection, many women and their physicians
abandoned HRT as primary or secondary
prevention for cardiovascular disease.
However, some believe that insufcient dis-
tinction has been made between the cardio-
vascular actions of estrogen, progesterone,
and medroxyprogesterone acetate. In their
opinion one can already distil from the liter-
ature mounting evidence that progesterone
improves cardiovascular function, and pro-
posals have been advanced for further
research on this issue [16R].
Placebo-controlled studies Preliminary
placebo-controlled studies of the use of a
combination of the selective estrogen
receptor modulator (SERM) bazedoxifene
(1040 mg/day) and conjugated estrogens
(0.450.625 mg/day) given daily for up to
2 years for menopausal symptoms have sug-
gested that the method provides relief with-
out inducing any detectable degree of
endometrial hyperplasia [17c].
Cardiovascular The extent to which certain
genetic subgroups of women may be at
greater risk of thromboembolic complica-
tions than others when using HRT is not
well-dened. However, one may note that
such an effect might be modulated by the
expression of CYP3A5 and CYP1A2,
which are involved in the hepatic metabo-
lism of estrogens. In a French study of
women with such adverse effects it
appeared that women with the CYP3A5*1
allele using oral estrogens comprised a sub-
group at high risk of venous thromboembo-
lism [18C]. CYP1A2 polymorphism was not
associated with any increased risk. These
ndings provide only a preliminary pointer;
as the investigators themselves stressed,
further data are needed to assess the rele-
vance of this genetic biomarker in the
Chapter 40 M.N.G. Dukes
medical management of the menopause
and policy regarding the use of HRT.
In a population register study in Den-
mark 698 098 healthy women aged 5169
were followed over 6 years with respect to
the use of HRT and the incidence of myo-
cardial infarction [19C]. There were 4947
cases of myocardial infarction. There was
no increased risk in current HRT users
compared with women who had never used
HRT. However, there was an increased risk
with longer duration of HRT among youn-
ger women only. The highest risk of infarc-
tion was found with a continuous HRT
regimen. There was no increase in risk with
unopposed, cyclic combined therapy or
with tibolone. There was a signicantly
lower risk with the transdermal route than
with oral unopposed therapy. There were
no associations with a particular progesto-
gen type or estrogen dose.
Psychiatric Postmenopausal conjugated
equine estrogens increase the risk of cogni-
tive impairment in women aged 65 years or
older and are associated with smaller
regional brain volumes. Of 1403 women
aged 6580 years, studied 14 years after
they had participated in randomized pla-
cebo-controlled clinical trials of conjugated
equine estrogens, during which they had
been free of dementia and mild cognitive
impairment when originally enrolled, 53
developed mild cognitive impairment or
probable dementia during follow-up [20c].
Among women who had taken conjugated
equine estrogens, cognitive impairment
was associated with relatively smaller
hippocampal and total brain volumes.
Among those who had taken placebo cog-
nitive impairment was associated with
greater ischemic lesion volume in the fron-
tal lobe and overall. The authors proposed
that conjugated equine estrogens may
cause cognitive impairment through
increased brain atrophy.
Brain MRI scans have also been
recorded in a subset of 1403 women
aged 7189 years who participated in the
Women's Health Initiative Memory
Study, an ancillary study to the Women's
Health Initiative, which consisted of two
Sex hormones and related compounds, including hormonal contraceptives
randomized, placebo-controlled trials
involving conjugated equines 0.625 mg with
or without 2.5 mg medroxyprogesterone
acetate in one daily tablet [21C]. The scans
were performed, on average, 3.0 years after
the trial for the combined therapy (average
follow-up interval 4.0 years) and 1.4 years
after the trial for the conjugated estrogens
alone (average follow-up interval 5.6 years).
Compared with placebo, mean frontal lobe
volume was 2.37 ml lower among women
assigned to HRT, mean hippocampal vol-
ume was slightly but still signicantly lower
(0.10 ml), and the difference in total brain
volume approached signicance. The
results were similar for both regimens.
HRT-associated reductions in hippocampal
volumes were greatest in women with the
lowest baseline Modied Mini-Mental State
Examination scores (scores <90). The
authors concluded that conjugated equine
estrogens with or without a progestogen
are associated with greater brain atrophy
among women aged 65 years and older;
however, the adverse effects are most evi-
dent in women who have cognitive decits
before they start hormone therapy.
This work has drawn international atten-
tion [22r]. It is disappointing, to say the
least, that this form of treatment, which
was at the outset intended to attenuate the
ageing process, now appears at least in this
respect to accentuate it.
Gastrointestinal Ischemic colitis has been
reported as a complication of both estro-
gens and progestogens and must be
expected to occur in some women taking
HRT. In a Greek study of women who
had used various forms of HRT for several
months before the complication developed,
none had a history of bowel disorders [23c].
Fasting, parenteral nutrition, intravenous
antibiotic treatment with metronidazole,
and withdrawal of HRT brought about
recovery; the antibiotics were continued
after the patients were discharged from
the hospital. Follow-up colonoscopy at
34 months after the initial episode was
normal in all cases.
Raised concentrations of estrogen and
progesterone can increase the chance of
Chapter 40 855
gastroesophageal reux, although one must
bear in mind that this is not an unusual phe-
nomenon in the general population. In an
analysis of data on 51 637 postmenopausal
women, enrolled in the Nurses Health
Study, who provided data on the use of
postmenopausal hormone treatment, no
fewer than 12 018 women (23%) had symp-
toms of reux [24C]. Compared with
women who were not taking hormone ther-
apy, the multivariate odds ratio was 1.46
(95% CI 1.36, 1.56) for past hormone
users, 1.66 (95% CI 1.54, 1.79) for cur-
rent users of estrogen only, and 1.41 (95%
CI 1.29, 1.54) for current users of com-
bined estrogen and progesterone. The risk
of symptoms of gastroesophageal reux
increased signicantly with increasing
estrogen dosage and increasing duration of
estrogen use. Moreover, current users of
selective estrogen receptor modulators
(SERMs) had an odds ratio of 1.39 (95%
CI 1.22, 1.59) for symptoms and women
currently using over-the-counter hormone
formulations had an odds ratio of 1.37
(95% CI 1.16, 1.62).
Breasts Susceptibility factors for benign
proliferative epithelial disorders of the breast
have been the subject of a cohort study of
68 132 postmenopausal women who were
prospectively followed; those who had an
open surgical biopsy or a core needle
biopsy had histological sections obtained
for centralized pathology review. Over an
average of 7.8 years of follow-up, 1792
women with benign proliferative disorders
were identied. Women who had used
postmenopausal hormones for 15 years or
more had a twofold increase in the risk
of such disorders of the breast compared
with women who had never used post-
menopausal hormones (HR 2.03; 95%
CI 1.73, 2.38) and the increase in risk
was observed both for proliferation without
atypia and for atypical hyperplasia. Fur-
thermore, the risk of such complications
decreased with time since cessation of use
so that there was essentially no increase in
risk ve or more years after withdrawal of
HRT [25C].
856
Tumorigenicity Breast cancer The risk of
invasive breast cancer as a consequence of
hormonal replacement therapy varies
markedly with the drugs and combinations
used. A group in France has sought to char-
acterize the risk more precisely, using data
from the French E3N cohort study, in the
course of which 80 391 postmenopausal
women were followed for an average of
8.1 years, and 2265 histologically conrmed
invasive breast cancers were traced [26C].
Compared with non-users of HRT in the
same age group, ever-use of additional pro-
gesterone was not signicantly associated
with the risk of any breast cancer subtype,
but increasing duration of a combined
estrogen progesterone regimen was asso-
ciated with increasing risks of lobular and
estrogen receptor-positive/progesterone
receptor-negative (ER/PR) tumors.
Estrogen dydrogesterone was associated
with a signicant increase in the risk of lob-
ular carcinoma (RR 1.7; 95% CI 1.1,
2.6). Estrogen other progestogens was
associated with signicant increases in the
risks of ductal carcinomas (RR 1.6; 95%
CI 1.3, 1.8), lobular carcinomas
(RR 2.0; 95% CI 1.5, 2.7), ER/PR substantially reduced by giving a progesto-
carcinomas (RR 1.8; 95% CI 1.5,
2.1), and ER/PR carcinomas (RR 2.6;
95% CI 1.9, 3.5), but not of ER/PR
or ER/PR carcinomas. The authors con-
cluded that the increased risk of breast can-
cer with combined HRT other than
estrogen progesterone and estrogen
dydrogesterone seems to apply preferen-
tially to ER carcinomas, especially those
that are ER/PR, and to affect both duc-
tal and lobular carcinomas.
Endometrial cancer In an unusually large
investigation into the incidence of endo-
metrial cancer as a complication of various
forms of HRT in Finland, using data from
the country's Cancer Registry and Medical
Reimbursement system, all postmeno-
pausal women who during the years
19942006 had been treated with HRT for
at least 6 months were identied and com-
pared with the general population [27C].
Continuous estradiol progestogen ther-
apy for 3 years or more was associated with
Chapter 40 M.N.G. Dukes
a 76% reduction in the risk of type 1 can-
cers (95% CI 6, 60%). In contrast, use
of a sequential estradiol progestogen
regimen for at least 5 years was accompa-
nied by a 69% increase (95% CI 43,
96%) if the progestogen was added
monthly, and with a signicantly higher
increase in risk of 276% (95% CI 190,
379%) if a progestogen was added at 3-
month intervals. The use of a continuous
rather than a sequential estradiol proges-
togen regimen reduces the risk of endome-
trial cancer, whereas the route of
administration or type of progestogen used
do not affect the risk.
Ovarian cancer The evidence that HRT in
postmenopausal women signicantly
increases the risk of ovarian cancer is now
incontrovertible (SEDA-32, 740). In partic-
ular, there is evidence of a substantial
increase in risk if unopposed estrogens are
used. However, a Danish study has also
shown an increase in risk irrespective of
the nature of the product used. In view of
this, one must be cautious in accepting the
view that the risk of ovarian cancer can be
gen alongside the estrogen. That is, how-
ever, still the approach favored, albeit
hesitantly, by some writers, as reected in
a recent review [28R], pointing to ndings
suggesting that whereas treatment with
unopposed estrogen for more than 5 years
increases the risk of ovarian cancer by
some 20% compared with controls, peri-
odic addition of a progestogen to the regi-
men reduces the risk to some 10% above
control values, although the effect remains
signicant; the reviewers suggest that the
risk might be further reduced by giving a
progestogen daily, though this is still
unproven.
Can HRT activate latent
breast cancer?
One of the various reasons that has caused
physicians and their patients to turn away
Sex hormones and related compounds, including hormonal contraceptives
in recent years from HRT is the likelihood
that, in one way or another, it is associated
with an increased incidence of cancer of
the breast. There is evidence of an increased
risk among American women of Asian ori-
gin, in whom the use of HRT increased the
risk by 26% for every 5 years of estrogen
and progestogen treatment. Many other
studies have come to similar conclusions,
and workers in the eld have been some-
what reluctant to accept the ndings of a
French paper that concluded in 2006, in the
light of earlier results from the MISSION
study, that among HRT users the risk of
breast cancer is unchanged, or perhaps even
very slightly reduced [29C].
In seeking an explanation as to why the risk
mightas is widely believedbe increased
among HRT users, Horwitz and Sartorius
have advanced an unusual hypothesis [30H].
Their starting point is the observation that
experimental estrogen receptor-positive
(ER) and progesterone receptor-positive
(PR) human breast cancers contain a
rare subpopulation of ER,PR cancer stem
cells. Especially in small, nascent ER,PR
tumor colonies, progestogens (but not estro-
gens) reactivate cells with ER,PR stem
cell-like properties. In addition there may be
a reservoir of occult, undetected, preinvasive
breast cancer in some women who are candi-
dates for HRT. The hypothesis is that women
who develop breast cancer while taking estro-
gens progestogens harbour nascent but
undiagnosed disease before the start of ther-
apy. The progestogen component, in a
non-proliferative step, reactivates receptor-
negative cancer stem cells within such germi-
nal, perhaps even dormant, tumors. After
reacquiring receptors, these tumor cells are
expanded by the mitogenic properties of
estrogens. In their view, screening methods
need to be improved so that they can detect
small, pre-existing malignancies before the
start of HRT. Women who harbor such
malignancies could and should then be
excluded from regimens that include systemic
progestogens. It is a theory that at the very
least merits consideration and further study.
In the meantime one may note the nd-
ings of a German study whose authors
Chapter 40 857
sought to examine the effect of the decline
in HRT on the incidence of breast cancer,
using population-based surveys [31M]. Pre-
scription of HRT started to decline in Ger-
many in 1999; about 2 years later, there
was a parallel decline in the incidence of
breast cancer. The number of HRT prescrip-
tions fell by 69% up to 2006, and the inci-
dence of breast cancer fell by 6.8% in all
age groups (in 20022005) and by 13% in
those aged 5069 years. The reductions in
HRT prescriptions and the incidence of
breast cancer were markedly correlated
across the federal states in Germany. While
there is still much to be learnt about the epi-
demiology of breast cancerthe incidence
of which, for example, varies between the
various states of Germany and for unknown
reasonsthe success achieved in reducing its
incidence across the board by adopting a
more critical approach to the feminine for-
ever fable of the 1960s is a monument to
good sense.
Susceptibility factors HIV infection Meta-
bolic dysregulation is a common long-term
complication associated with HIV infection,
but it is also observed as a complication of
HRT and is difcult to manage. There are
still no clear guidelines for dealing with this
problem when HIV-positive women take
HRT, but the need to be alert for the occur-
rence of metabolic dysregulation is clear
[32R].
Drugdrug interactions Tacrolimus A seri-
ous interaction has been described between
HRT and tacrolimus [33A].
A 65-year-old woman with a renal transplant
was taking tacrolimus 9 mg/day, mycophenolic
acid 540 mg/day, prednisolone 4 mg/day, lisi-
nopril 20 mg/day, atorvastatin 10 mg/day,
levothyroxine 100 micrograms/day, and
alprazolam 0.5 mg/day. After transplantation
renal function was good, but after 10 days
her renal function suddenly deteriorated and
the tacrolimus plasma concentration was very
high (trough concentrations of 1418 ng/ml).
The serum creatinine increased and eGFR
fell to 28 ml/minute/m2. She had been taking
858
HRT (Estreva 0.1%) comprising estradiol
0.5 mg/day (one-third of the recommended
dose). The serum creatinine fell and eGFR
rose to 44 ml/minute/m2 2 weeks after a pro-
gressive 60% reduction in tacrolimus dosage
(trough concentration 6.4 ng/ml).
Both tacrolimus and estradiol are metabo-
lized by CYP3A4 and tacrolimus is a potent
inhibitor of 2-estradiol metabolism. Con-
versely, estradiol inhibits hepatic and intesti-
nal CYP3A4 and reduces tacrolimus
metabolism. Transdermal administration
avoids hepatic rst-pass metabolism, which
explains why even small doses have a sys-
temic effect. Co-administration of tacroli-
mus is possible, but close monitoring of
tacrolimus trough concentrations and renal
function is necessary.
Ecotoxicity The possible environmental
health implications of conjugated equine
estrogens, including discharge into the envi-
ronment, their uptake, potency, and ability
to induce biological effects in wildlife, have
been evaluated. Inuents and efuents
from four UK sewage treatment works
and the bile of efuent-exposed sh were
screened for six equine estrogens [34E].
Low concentrations of the equine estrogen
equilenin and its metabolite 17-beta-
dihydroequilenin were detected by tandem
GCMSMS in all sewage inuent samples
and 83% of efuent samples and were
taken up by efuent-exposed sh. These
estrogens bound to and activated the sh
estrogen receptors. Exposure of sh for
21 days to equilenin and 17-beta-dihydro-
equilenin induced estrogenic responses,
including hepatic growth and vitellogenin
production at concentrations as low as
0.64.2 ng/l. Hepatic ERa and ERb1
gene expression was induced. The authors
suggested that these compounds may
contribute to feminization of exposed
wildlife.
*Editorial note: In SED-15 there is a transcription error in the rst column on page 1646. The sentence 16
lines from the bottom of the page, which cites an incidence of thromboembolism of 15 per 100 000 women
per year should refer to the second generation of products and not to the third generation; the correct state-
ment appears at the bottom of the page.
Chapter 40 M.N.G. Dukes
HORMONAL
CONTRACEPTIVES [SED-15,
1642; SEDA-30, 473; SEDA-31, 663;
SEDA-32, 741]
Cardiovascular The risk of thrombo-
embolic complications, especially as regards
the third generation of hormonal contra-
ceptives, is considered in some detail in
the Side Effects of Drugs Essay that opens
this Annual. The overall conclusion must
be essentially the same as that presented
in SED-15 at pages 16451652, namely that
the two-component oral contraceptives that
are currently in use most widely, with deso-
gestrel or gestodene as their progestogenic
component, present an appreciably greater
risk of thromboembolic complications than
the products that were in use a generation
earlier. This added risk must be a matter
of public health concern, particularly in
view of the scale on which these formula-
tions are used by healthy women world-
wide.*
Drug formulations and administration
route Although most forms of hormonal
contraception, including combination tab-
lets, progestogens alone, and injections,
have now been in use for several decades,
physicians still have difculty in advising
individual women on the method that they
are likely to tolerate best, and comparisons
continue to be carried out. In a US study,
menstrual, physiological, and psychological
symptoms were examined over 2 years in
608 women who used depot medroxypro-
gesterone acetate or an oral contraceptive
formulation containing 20 micrograms of
estrogen and in untreated controls [35C].
The oral contraceptives protected against
mastalgia, cramping, hair loss, acne, nervous-
ness, and mood swings. Depot medroxy-
progesterone acetate protected against
bloating and mood swings (OR 0.7)
Sex hormones and related compounds, including hormonal contraceptives
but it tended to cause weight gain (OR
2.3), bleeding episodes lasting more than
20 days (OR 13.4), and missed periods
(OR 96.9). Both methods caused inter-
menstrual bleeding.
Drugdrug interactions Warfarin In a sin-
gle case an interaction of hormonal contra-
ceptives with warfarin made dosage
changes necessary [36A].
A 33-year-old women who required long-term
anticoagulation following an aortic valve
replacement, and who was taking warfarin
38.5 mg/week, changed from a monophasic
combined oral contraceptive (ethinylestradiol
norethindrone) to an implantable progesto-
gen-only contraceptive (etonogestrel); 19 days
later her INR fell to 1.8 and she required an
increase in warfarin dosage to 60 mg/week.
Within 10 months, she elected to have the
implant removed because of vaginal bleeding,
and 9 days later had a transient increase in
INR to 6.5. Her INR returned to within the
target range after the dosage of warfarin was
reduced to 55.5 mg/week.
In the light of literature data the authors
suggested that the predominant mechanism
of interaction was inhibition of CYP1A2
and CYP2C19 by ethinylestradiol.
Emergency contraception [SEDA-
32, 742]
Skin A 28-year-old woman developed a
fever, rash, and sore throat, followed by
ulceration of the mucosae, dysuria, and
conjunctivitis [37A]. Over the next 4 days,
she developed a purulent conjunctival dis-
charge and bullae over 80% of her body
surface area, consistent with toxic epidermal
necrolysis. She had used four contraceptive
pills (each containing levonorgestrel
0.125 mg ethinylestradiol 0.03 mg) as a
single dose 5 days before her visit as a
morning after agent to avoid becoming
pregnant. Treatment included intravenous
immunoglobulin and she made a full recov-
ery within 14 days.
Chapter 40 859
ANTIESTROGENS AND
SELECTIVE ESTROGEN
RECEPTOR MODULATORS
(SERMS) [SEDA-30, 474; SEDA-31,
664; SEDA-32, 743]
While tamoxifen remains an important
component of endocrine therapy for breast
cancer, major clinical trials of the aroma-
tase inhibitors anastrozole, letrozole, and
exemestane suggest that these agents are
more effective and better tolerated than
tamoxifen. On the other hand, some com-
parative studies have suggested that the
aromatase inhibitors have less favorable
effects than tamoxifen on cardiovascular
risk. An occasional review puts the contro-
versy into perspective [38R], but the debate
is obscured by the publication of many
papers that appear biased in favor either
of tamoxifen or the inhibitors as regards
efcacy, safety, or both.
Psychiatric Estrogens have long been con-
sidered to have some type of positive effect
on cognitive function, and it is not surpris-
ing that occasional reports have described
a contrary effect of antiestrogens. The pos-
sibility of such a negative effect appears to
have been examined systematically for the
rst time in a study undertaken at the Neth-
erlands Cancer Institute in Amsterdam and
published in 2009 [39c]. Postmenopausal
patients with breast cancer who had
received doxorubicin cyclophosphamide
were randomized to follow-up with tamoxi-
fen (n 30) or exemestane (n 50); an
average of 2 years after completion of the
original chemotherapy they were inter-
viewed, answered questionnaires, and were
subjected to cognitive tests; 48 healthy con-
trols were similarly tested. Memory com-
plaints were reported by 28% of those
who had used tamoxifen, 24% of those
who had used exemestane, and 6% of the
healthy controls. Both patient groups per-
formed signicantly less well than the
healthy controls on verbal uency and
information processing speed. Cognitive
testing showed no statistically signicant
860
differences between tamoxifen and exemes-
tane, but suggested that tamoxifen is possi-
bly related to poorer verbal functioning,
while exemestane is possibly related to
slower manual motor speed. Tamoxifen
users had lower scores in executive func-
tioning (which includes such things as being
able to shift attention between two
different parts of a task) than did women
without breast cancer. Women taking exe-
mestane had smaller falls and the changes
were not statistically signicant, compared
with the healthy women. There were no
substantial differences between any of the
three groups in terms of visual memory,
working memory, reaction speed, or motor
speed.
Not surprisingly, this work has elicited
much comment and some criticism [40r].
Noting the less satisfactory test results with
tamoxifen, one commentator pointed out
that the research was sponsored by the
manufacturer of exemestane, apparently
implying some form of bias in the study
design. However, most reviewers remarked
that, as the investigators themselves sug-
gested, further work is needed, and that
the mechanism of the effects observed
needs to be understood. Victor G. Vogel,
of the American Cancer Society, said the
results were not surprising, and although
the reason why women on tamoxifen had
more cognitive decline is not known, he
said a logical though unproven explanation
is that it may just not be good for your
brain not to have estrogen [41r].
Management of adverse drug reactions
Zoledronic acid has been used to counter
the adverse effects of aromatase inhibitors
on bone density [SEDA-32, 753]. It seems
very likely that the risk of accelerated bone
loss and consequent fractures during adju-
vant aromatase inhibitor therapy would
similarly be reduced by the use of denosu-
mab, a fully human monoclonal antibody
against receptor activator of NFk-B. A US
group has reported on a group of 252
patients with breast cancer and low
bone mass (but no osteoporosis) taking
aromatase inhibitors for long periods
[42C]. All received supplementary calcium
Chapter 40 M.N.G. Dukes
and vitamin D, but beyond that they
were randomly assigned to either placebo
(n 125) or subcutaneous denosumab
60 mg (n 127) every 6 months. At 12
and 24 months, bone mineral density in
the lumbar spine increased by 5.5% and
7.6% respectively in those who took deno-
sumab compared with those who took pla-
cebo. Increases were observed as early as
1 month and were not inuenced by the
duration of aromatase inhibitor therapy.
There were also increases in bone mineral
density at the total hip, total body, femoral
neck, and the predominantly cortical one-
third radius. Bone turnover markers fell
with denosumab treatment. The overall
incidence of treatment-emergent adverse
events was similar in the two treatment
groups.
Anastrozole
Musculoskeletal Susceptibility factors for
arthralgia and arthritis have been studied
in 9366 postmenopausal women who were
assigned to anastrozole 1 mg/day, tamoxi-
fen 20 mg/day, or a combination of the
two; 5433 of them were examined for joint
symptoms [43C]. Of 1914 women in this
subgroup who had earlier taken HRT, 777
(41%) developed joint symptoms, com-
pared with 1001 of 3519 women (28%)
who had not used HRT, a highly signicant
difference. Women with hormone-receptor-
negative breast cancer developed signi-
cantly fewer joint symptoms than those
with hormone-receptor-positive tumors.
As one might have expected, obese women
reported more joint symptoms than others.
Women who took anastrozole reported
more joint symptoms than those taking
tamoxifen (35% versus 30%).
The tenosynovial changes and the associ-
ated functional impairment seen when
tamoxifen or an aromatase inhibitor
adversely affects the small joints of the
hand and wrist have been studied in 17
patients [44c]. At 6 months, patients taking
an aromatase inhibitor had reduced grip
strength and signicant tenosynovial
Sex hormones and related compounds, including hormonal contraceptives
changes, as assessed by MSI scanning, and
worsening of morning stiffness and an
increase in intra-articular uid. There were
only minor changes in patients taking
tamoxifen.
The Arimidex, Tamoxifen, Alone or in
Combination (ATAC) trial, with its median
follow-up of 68 months, has provided the
best evidence to date that an adjuvant ana-
strozole regimen is better tolerated (and
more effective) than tamoxifen alone, but
the problem remains that anastrozole
reduces circulating estrogen, and that low
estradiol concentrations cause reduced bone
mineral density and hence an increased risk
of fractures. In a substudy of the ATAC trial,
the effects of prolonged long-term aroma-
tase inhibitor therapy on bone mineral den-
sity have been examined in 197 patients,
who took anastrozole 1 mg/day or tamoxifen
20 mg/day as adjuvant therapy for 5 years
[45CR]. Anastrozole-treated women had
reduced median bone mineral density com-
pared with those who took tamoxifen, but it
is striking that no patients with normal bone
mineral density at the outset developed
osteoporosis at 5 years. The real risks with
anastrozole thus seem to be limited to
women who have osteopenia at the start of
treatment.
Reproductive system Further analysis of
the ndings in the ATAC trial has quantied
the extent to which tamoxifen was clearly
associated in that study with a signicantly
higher incidence of gynecological adverse
events compared with anastrozole (34% ver-
sus 21%) [46C]. This led to more diagnostic
and/or therapeutic interventions, including
an almost fourfold increase in the number
of hysterectomies (5.1% versus 1.3%). Most
of the gynecological adverse events in those
taking tamoxifen occurred during the rst
2.5 years of treatment.
Clomifene [SED-15, 812; SEDA-30, 474;
SEDA-31, 665; SEDA-32, 743]
Tumorigenicity A study involving the
major Swedish clinics providing treatment
Chapter 40 861
for female infertility was designed to deter-
mine the possible effect of such treatment
on the incidence of breast cancer [47c].
Among 1135 women who had taken treat-
ment at some time over a 15-year review
period, 54 had breast cancer, which was
essentially as expected. However, users of
high-dose clomiphene citrate had an almost
twofold increase in risk (standardized inci-
dence ratio 1.90; 95% CI 1.08, 3.35).
This association was more pronounced
among women who were referred for non-
ovulatory factors, with a threefold increased
risk (standardized incidence ratio 3.00;
95% CI 1.35, 6.67).
Exemestane [SEDA-31, 665; SEDA-32,
744]
Comparative studies Exemestane 25 mg/
day and raloxifene 60 mg/day and the
combination have been compared in 11
postmenopausal women with hormone-
receptor-negative breast cancers [48C]. Ini-
tial therapy with one drug was for 2 weeks,
and the patients then took combination
therapy for a minimum of 1 year. Plasma
concentration-time proles for each drug
were the same during monotherapy and
combination therapy. Raloxifene mono-
therapy did not affect plasma estrogen con-
centrations, but plasma estrogen
concentrations were suppressed below the
lower limit of detection by exemestane
both as monotherapy and when combined
with raloxifene. The most common adverse
events of any grade included arthralgias,
hot ushes, vaginal dryness, and myalgias.
Liver Severe prolonged cholestatic hepatitis
has been attributed to exemestane [49A].
A 47-year-old woman was given exemestane
25 mg daily and after 3 weeks reported
fatigue, jaundice, and pruritus, associated with
rises in total bilirubin, aminotransferases, and
alkaline phosphatase. Hepatitis serology,
including hepatitis A IgM, hepatitis B surface
antigen, hepatitis B core IgM, and hepatitis
C antibody, was negative, as were autoanti-
bodies associated with autoimmune hepatitis,
862
including antimitochondrial antibodies and
antinuclear antibodies. Exemestane was with-
drawn, but although the aminotransferases fell
quickly, the serum bilirubin concentration
continued to rise for another 4 weeks, before
resolving.
This case was complicated by the use of
other medications, and it is not clear that
exemestane was to blame.
Musculoskeletal Changes in bone mineral
density from baseline to 24 months have
been studied in 167 women taking either
exemestane 25 mg/day or tamoxifen
20 mg/day [50C]. There was more bone loss
at both the spine and the hip with exemes-
tane during the rst 12 months, but by
2 years the differences were less apparent
and the bone loss with exemestane had
slowed, the difference being signicant only
at the hip.
Letrozole
Observational studies The most common
adverse effects letrozole are, as might be
expected, those of estrogen deprivation.
The frequencies of unwanted effects based
on clinical trials do not necessarily parallel
those subsequently seen in long-term prac-
tical use. The adverse effects seen over
2 years of treatment have been studied in
185 women who took letrozole after breast
cancer surgery [51C]. The most prominent
problem was musculoskeletal pain (see also
below). In addition hot ushes, increased
fatigue, nausea, vomiting, anorexia, mood
disturbances, vaginal dryness, hair loss,
and rashes were recorded. In contrast to
the ndings in prospective randomized clin-
ical trials, there was a high drop-out rate
(20%), mainly due to the fact that arthral-
gia interfered signicantly with daily life.
Musculoskeletal Musculoskeletal symptoms
have been studied in 100 women who took
letrozole or exemestane and were followed
up for at least 6 months [52C]. Of 97 eligible
patients 44 met predetermined criteria for
referral to a rheumatologist. No baseline
Chapter 40 M.N.G. Dukes
characteristics were signicantly associated
with referral. The median time to onset
of symptoms was 1.6 months (range
0.410 months). Clinical and laboratory
evaluation of patients suggested that most
developed either non-inammatory muscu-
loskeletal symptoms or inammation local-
ized to tenosynovial structures. Letrozole
was withdrawn in 13 cases because of mus-
culoskeletal effects after a median 6.1
(range 2.213) months. The etiology of this
complication remains elusive.
Raloxifene [SEDA-31, 666; SEDA-32,
745]
Susceptibility factors Renal disease In a
randomized study of raloxifene in 7707
postmenopausal women with chronic kid-
ney disease, the incidence of adverse reac-
tions was similar to that in a control group
without kidney disease [53C].
Tamoxifen [SED-15, 3296; SEDA-30,
475; SEDA-31, 667; SEDA-32, 745]
Uses Although tamoxifen increased bone
mineral density in clinical trials, it is less
clear whether this signicantly affects frac-
ture rates in ordinary practice. In a popula-
tion-based casecontrol study in women
aged 50 years or over in one Canadian
Province, 11 096 women with osteoporotic
fractures (involving the vertebrae, wrist, or
hip) were compared with 33 209 women
who had not had fractures [54C]. There were
fewer osteoporotic fractures in those taking
current tamoxifen (univariate OR 0.68;
95% CI 0.55, 0.84). After controlling for
demographic and medical diagnoses known
to affect the risk of fractures, current use of
the drug was associated with a signicantly
reduced overall risk of osteoporotic frac-
tures (adjusted OR 0.68). However,
neither recent nor remote past tamoxifen
use was associated with a reduced risk.
Sex hormones and related compounds, including hormonal contraceptives
Metabolism The effects of adjuvant tamox-
ifen on the lipid prole have been com-
pared with those of exemestane in 142
postmenopausal patients with breast cancer
in the Greek substudy of the Tamoxifen
and Exemestane Adjuvant Multicenter
International trial [55c]. Total cholesterol
and LDL cholesterol were consistently
and signicantly reduced by tamoxifen
only. The mean HDL cholesterol concen-
tration was higher in those taking tamoxi-
fen compared with exemestane. Neither
drug had a signicant effect on
triglycerides.
Hematologic Pseudolymphoma as a com-
plication of tamoxifen treatment has been
reported briey [56A].
Reproductive system Endometrial polyps
during tamoxifen treatment can be pre-
vented by the simultaneous use of intra-
uterine levonorgestrel (the Mirena
system), but the method is of limited useful-
ness, since its effects lasts only as long as
the Mirena is in place; once it is removed,
and while tamoxifen is continued, the
polyps recur [57c]. There are differing opin-
ions on this form of administration (see the
special review below).
Autacoids Exacerbation of hereditary
angioedema has been attributed to tamoxi-
fen [58A].
A 69-year-old woman with hereditary angio-
edema type I used danazol 200 mg three times
a week and had only occasional crises requir-
ing tranexamic acid. She developed breast
cancer and took tamoxifen, after which the
severity and frequency of episodes of angio-
edema rapidly increased, despite maintenance
of her usual treatment. After replacement of
tamoxifen by letrozole, her symptoms
improved.
Tumorigenicity Uterine cancer Although it
is widely considered that tamoxifen increases
the risk of uterine corpus cancer, the evidence
has been derived from a series of small studies
that have thrown little light on the degree of
risk or the prognosis. In a retrospective
cohort study in 332 patients who developed
Chapter 40 863
such cancers after treatment with tamoxifen
for breast malignancy, follow-up data on 309
cases studied earlier were also examined
[59C]. Long-term tamoxifen users had a
higher proportion of non-endometrioid
tumors than non-users (33% versus 17%),
especially serous adenocarcinomas and carci-
nosarcomas. There was also an increased pro-
portion of International Federation of
Gynecology and Obstetrics (FIGO) stage III
and IV tumors (20% versus 11%). Within
FIGO stage I, both short-term and long-term
tamoxifen users had a higher proportion of
tumors limited to the endometrium than
non-users (36% versus 23%). Uterine corpus
cancers in long-term tamoxifen users were
more often steroid receptor-negative (ERa,
PRA, and PRB) and P53-positive. The 3-year
uterine corpus cancer-specic survival was
worse for long-term tamoxifen users than
for non-users (82% versus 93%). The sur-
vival difference remained after adjustment
for histological and immunohistochemical
characteristics.
The unwanted effects of tamoxifen on
the endometrium have long been a source
of concern, and cases continue to be
reported, sometimes with a range of associ-
ated complications affecting the ovary and
the adnexa as well. Effects that have been
observed include malignancy, endometri-
osis, leiomyomata, endometrial polyps,
and apparently benign endometrial hyper-
plasia, and cases continue to be reported
in detail [60c]. Repeated attempts have
been made to reduce or reverse these com-
plications. An Italian study has continued
this work, notably in a series of 70 post-
menopausal patients with estrogen recep-
tor-positive breast tumors who were
switched to anastrozole after a course of
tamoxifen [61c]. The introduction of ana-
strozole was associated with reversal of
both the thickening of the endometrium
and the histological changes caused by
tamoxifen.
The mechanism by which tamoxifen
induces endometrial neoplasms is not
known. Possible associations with the MSI,
PTEN, beta-catenin, and KRAS genes have
been sought in 18 cases of endometrial
carcinoma after the use of tamoxifen
864
compared with various other cases of endo-
metrial cancer in which the drug had not been
used [62C]. A control group included 15
patients with endometrial carcinoma unasso-
ciated with the use of the drug. There was a
direct relation between tamoxifen exposure
and overexpression of beta-catenin oncopro-
tein, which plays a major role in the pathogen-
esis of estrogen-driven type I endometrial
adenocarcinoma. Patients with tamoxifen
exposure also had more K-ras mutations and
fewer PTEN mutations and MSI compared
with controls, but these results were not statis-
tically signicant.
Among the less common complications
attributed, anecdotally but credibly, to the
use of tamoxifen is the development of an
extrauterine leiomyoma [63A].
Teratogenicity Animal studies have shown
evidence of teratogenicity of tamoxifen,
and hence the FDA classies it in category
D. In 1994 a report appeared of apparent
induction of Goldenhar's syndrome (the
oculo-auriculo-vertebral syndrome), a rare
defect that is characterized by incomplete
development of the ear, nose, mandible,
soft palate, and lip, and the authors stated
that the manufacturer of tamoxifen knew
of two earlier cases associated with congen-
ital craniofacial defects. The Pierre Robin
sequence, which comprises severe micro-
gnathia and cleft palate, has now also been
described [64Ar]. Both this and Goldenhar's
syndrome have earlier been observed in
infants exposed in utero to isotretinoin.
However, it must be emphasized that with
tamoxifen these complications are very
rare; most infants exposed to the drug
before birth appear to be entirely normal.
Susceptibility factors Genetic The occur-
rence of hot ushes during tamoxifen treat-
ment has long been recognized, but only
recently has there been evidence that a
woman's susceptibility to this effect can be
inuenced by her phenotype, as well as by
her menopausal status and her earlier treat-
ment. In a US study in premenopausal
women, women with the alleles ESR1 PvuII
and XbaI CG had higher baseline hot ush
scores after 4 months of tamoxifen
Chapter 40 M.N.G. Dukes
treatment than in those who had other hap-
lotypes [65c]. Women with the ESR1 PvuII
CC and ESR2-02 GG genotypes had
increased hot ush scores 4.6 times more
often than other postmenopausal women
(56 versus 12). Women who had the ESR2-
02 AA genotype were signicantly less
likely to have tamoxifen-induced hot ushes
than women with at least one ESR-02 G
allele (HR 0.26; 95% CI 0.10, 0.63).
Bearing in mind the evidence that there
is a genetic predisposition to thrombo-
embolic complications of hormonal contra-
ceptives (see above), it is not unexpected
that there is a similar predisposition to
thrombotic complications of antiestrogenic
treatment with tamoxifen. Banked DNA
obtained from tamoxifen-treated individ-
uals with breast cancer was tested for an
association between the incidence of
tamoxifen-associated thromboembolic
events and single nucleotide polymor-
phisms encoding the estrogen receptors
1,2 (ESR1, ESR2) or the drug metabolizing
enzymes CYP2D6 and aromatase (CYP19)
[66C]. There were thromboembolic events
in 16/220 subjects, and there was an associ-
ation with the XbaI (rs9340799) genotype
and the ESR1 Xbal/PvuII diplotype
(rs9340799 and rs2234693) (HR 3.47;
95% CI 0.97, 12). The association per-
sisted after adjusting for classical suscepti-
bility factors, including age at diagnosis
and body mass index at enrolment.
The same group of investigators also
found an association between CYP2D6
genotype and tamoxifen-induced hot
ushes in 297 women who took tamoxifen
for 12 months [67C]. At 4 months, there
was a trend to fewer severe hot ushes
in poor metabolizers compared with
intermediate and extensive metabolizers
combined.
Renal disease Tamoxifen has been found to
be safe and effective in patients with nor-
mal renal function, but until recently there
was no evidence regarding its safety or oth-
erwise in women with impaired renal func-
tion. A study in 29 patients in whom
impaired renal function ranged from mild
to severe has suggested that a tamoxifen
Sex hormones and related compounds, including hormonal contraceptives
dose of 20 mg/day every 4 weeks is well tol-
erated, adverse effects being no more
severe or frequent than in women with nor-
mal kidney function [68c].
Drugradiation interactions There have
been few experimental or clinical studies of
the combined effects of hormone and radia-
tion therapy. Although data from in vitro
studies have supported the notion that there
is an antagonistic effects of concurrent tamox-
ifen and radiotherapy on tumor cells, in vivo
research has suggested that there is a syner-
gistic effect that could be attributable to
micro-environmental changes in tumor
responsiveness to ionizing radiation and hor-
mone therapy [69R]. Retrospective studies
have suggested that concurrent use of tamox-
ifen and radiotherapy does not compromise
local control but might increase toxicity. Fur-
ther studies are needed to clarify possibly
undesirable interactions.
PROGESTOGENS [SED-15,
2930; SEDA-30, 477; SEDA-31, 669;
SEDA-32, 747]
Hematologic Sideroblastic anemia with
iron overload has been previously reported
shortly after the administration of proges-
terone [70A]. Removal of the progestogen
led to prompt disappearance of the anemia
as well as the ringed sideroblasts. There
was enhanced sensitivity of erythroid pro-
genitors to progesterone. This complication
must be excessively rare, but a further case
has been described, this time in a pregnant
woman, in whom sideroblastic anemia fol-
lowed the use of progesterone [71A].
Drug administration route During in vivo
fertilization, progesterone in an oily solution
is commonly given to provide luteal-phase
support [72C]. An unusual case has been
reported in which a 35-year-old primigravida
treated in this way developed acute eosino-
philic pneumonia. She was given glucocorti-
coids, and the remaining course of
Chapter 40 865
progesterone treatment was given intravagin-
ally, resulting in marked improvement and
complete recovery. The incident appears to
have represented an allergic reaction, but it
is not clear whether this was due to the pro-
gesterone itself or the solvent.
Intrauterine administration of
levonorgestrel
The Mirena system for intrauterine adminis-
tration of levonorgestrel is estimated to
release some 20 micrograms of the drug
daily. This has been the subject of some
sharply differing assessments. In a mailed
questionnaire study of 1056 British women
who had been treated with this product for
menstrual disorders, 73% had continued
using the system, having found that it pro-
vided relief; the most common adverse effect
was menstrual spotting (19%) [73c].
The possible long-term effects of a levonor-
gestrel-releasing intrauterine system on the
endometrium and lipid prole have been
examined in 142 postmenopausal women with
breast cancer who took tamoxifen and were
studied for 36 months. At the end of this period
there were only very minor changes in serum
lipids, fewer endometrial polyps, and no endo-
metrial hyperplasia in the study group com-
pared with a control group taking tamoxifen
alone. The authors concluded that use of the
levonorgestrel-releasing intrauterine system
may reduce the need for investigation of
adverse effects in women taking tamoxifen
and may also reduce patient discomfort while
improving adherence to treatment [74C].
However, some women express a dislike for
the levonorgestrel intrauterine releasing sys-
tem, declaring that they have an excessive inci-
dence of adverse reactions. When another
hospital sent questionnaires to 203 British
women in whom the device had been inserted
over a 5-year period it was found that the con-
tinuation rate fell progressively from 85% after
the rst 6 months to 50% after 4 or 5 years
[75c]. The median duration of use was only
270 days. The principal reasons for requesting
removal were unscheduled bleeding, progesto-
genic adverse effects, or abdominal pain.
866
This may well prove to be one of the situa-
tions in which patient satisfaction with a
method of treatment appears to differ mark-
edly from one place to another, and especially
between countries. Differences in the tradition
of treatment or in the manner in which a phy-
sician presents a proposed therapy to the
patient may be important factors determining
patients expectations. The British report
(published under the heading Why do some
people dislike it?) needs to be set alongside
an Austrian study of 180 000 users of the
intrauterine system, many of them apparently
very satised with the method. To cite a group
of 13 Austrian authors: Reliability, comfort,
excellent compatibility and less severe, shorter
and less painful monthly periods were the
most frequently named advantages of the
levonorgestrel-releasing [intrauterine sys-
tem]. Medication-induced cervical priming
before insertion can be carried out on a rou-
tine or selective basis (for example in nulli-
para, in women who have undergone
cervical conisation or in women who have
previously experienced painful insertion).
There is, at present, no evidence of an
increased rate of breast cancer . . . A directly
comparative study with oral contraceptives
in young nullipara showed excellent results
for the levonorgestrel-releasing [intrauterine
system] [76c]. A Spanish group similarly
considered that the system meets the effec-
tiveness and tolerability criteria for being con-
sidered as a rst choice treatment option for
women with idiopathic menorrhagia [77c].
Drospirenone [SEDA-31, 670;
SEDA-32, 748]
See Hormonal contraceptives above.
Medroxyprogesterone [SED-15,
2225; SEDA-32, 749]
Skin The pigmented purpuric dermatoses
are a group of chronic diseases of mostly
unknown cause that have a very distinctive
clinical appearance. They are characterized
by extravasation of erythrocytes in the skin,
Chapter 40 M.N.G. Dukes
with marked hemosiderin deposition.
Although the condition is more common
in men, a number of cases have in the
course of the years occurred in women,
either early or late after administration of
medroxyprogesterone acetate [78A, 79A].
Megestrol acetate [SED-15, 1679,
2932; SEDA-31, 670; SEDA-32, 749]
Endocrine In some centers, megestrol ace-
tate is being used to promote weight gain
in malnourished elderly patients. The suspi-
cion that this might lead to impaired adre-
nal function has been incidentally voiced
in the past, and a US group has described
such a case in detail [80Ar].
An 80-year-old woman with worsening dys-
pnea was transferred to a university clinic from
a psychiatric hospital where she was being trea-
ted for major depressive disorder with psy-
chotic features. She had weight loss and
anorexia, and 1 month before she had been
given megestrol acetate 400 mg/day to stimu-
late her appetite and improve her nutritional
state. Her dyspnea worsened and she rapidly
became hypotensive. A cosyntropin stimulation
test elicited a suboptimal response, and the
ACTH concentration was 8 pg/ml (reference
range 1060 pg/ml). Megestrol was withdrawn
and she was given corticosteroids. Her blood
pressure normalized and she improved slowly.
Two months later a repeat cosyntropin stimula-
tion test was normal.
PROGESTERONE
ANTAGONISTS [SEDA-30, 477;
SEDA-31, 671; SEDA-32, 749]
Mifepristone [SED-15, 2344; SEDA-30,
477; SEDA-31, 671; SEDA-32, 749]
Uses There is currently increasing interest in
the use of mifepristone as a once-a-month oral
contraceptive. In a study in which 86 women
took mifepristone 200 mg in tablet form on
the 16th day of the menstrual cycle, while a
control group of 92 women took a combined
oral contraceptive, the latter had worse
Sex hormones and related compounds, including hormonal contraceptives
biochemical parameters [81c]. Much larger
studies will be needed to assess the benet to
harm balance of this contraceptive method.
Observational studies In a phase 2 trial of
mifepristone 200 mg/day in women with
advanced or recurrent endometrioid adeno-
carcinoma or low-grade endometrial stro-
mal sarcoma, there were no partial or
complete responses [82c]. The most fre-
quent grade 1 and 2 adverse reactions were
anorexia, fatigue, and mood alterations
which occurred in 50%, 50%, and 58% of
patients respectively. The most common
grade 3 adverse reactions were fatigue and
dyspnea, which occurred in 25% and 17%
of patients respectively. One patient had
grade 4 dyspnea. There were asymptomatic
rises in corticotrophin in 33%.
SEX HORMONE AGONISTS
Tibolone [SEDA-30, 485; SEDA-31, 671;
SEDA-32, 750]
Cardiovascular In some cases tibolone pre-
vents bone loss in elderly subjects, although
after 40 years of use some questions regarding
its clinical role remain unanswered. In a ran-
domized study in the US, in which 4538 older
women took either tibolone 1.25 mg/day or
placebo, tibolone reduced the risk of verte-
bral fractures and of breast cancer. However,
there was an increased risk of stroke (relative
hazard 2.19; 95% CI 1.14, 4.23); the
study was stopped after a mean treatment
period of 34 months at the recommendation
of the data and safety monitoring board
[83Cr]. There were no signicant differences
between the two groups in the risks of either
coronary heart disease or venous
thromboembolism.
However, as others have pointed out, the
long-term safety and efcacy of tibolone on
major health outcomes in younger postmeno-
pausal women are unknown [84r]. In older,
mostly white, women with osteoporosis, tibo-
lone 1.25 mg/day for 3 years seemed in earlier
studies to have a benecial effect on the breast
Chapter 40 867
and skeleton without any deleterious effect on
cardiovascular outcomes or thrombosis. How-
ever, that study was not adequately powered
to evaluate the effect of tibolone on these out-
comes. The use of tibolone should be avoided
in older women, those at a high risk of stroke,
and those who have breast cancer or are at
high risk of the disease.
Reproductive system The endometrial
effects of tibolone 1.3 mg/day have been
examined in a 3-year placebo-controlled
study in 635 elderly women with osteoporosis
[85C]. During the rst year, mean endometrial
thickness increased signicantly by 1 mm in
women taking tibolone, but there were no
further increases during the next 2 years.
Diagnostic biopsies in 499 women taking tibo-
lone and 136 who taking placebo showed
cumulative incidences of endometrial hyper-
plasia of less than 1%. Among the 15% of
women whose biopsies showed an endome-
trial polyp (with similar rates in the tibolone
and placebo groups), those taking tibolone
were more than twice as likely to have hyper-
plasia within the polyp. There was a marginal
increase in grade 1 endometrioid adenocarci-
noma in women taking tibolone. Prevalences
of vaginal bleeding during the study were
11% with tibolone and 2.8% with placebo.
All these effects were regarded as minimal.
Tumorigenicity The possible risks of tibo-
lone when it is used to attenuate the
unwanted effects of adjuvant treatment for
breast cancer have been studied in a multi-
center investigation, with particular atten-
tion to the possibility that it might increase
the risk of cancer recurrence [86C]. Women
who had been surgically treated for histolog-
ically conrmed breast cancer with vasomo-
tor symptoms were randomly assigned to
either tibolone 2.5 mg/day or placebo at
245 centers in 31 countries (1556 in the tibo-
lone group and 1542 in the placebo group).
The mean age at randomization was 53 years
and the mean time since surgery was
2.1 years. Of 3098 women, 1792 (58%) were
node-positive and 2185 (71%) were recep-
tor-positive. At study entry, 2068 women
(67%) used tamoxifen and 202 (6.5%) used
aromatase inhibitors. After a median
868
follow-up of 3.1 years, 237 of 1556 women
taking tibolone (15%) had a cancer recur-
rence, compared with 165 of 1542 (11%)
taking placebo (HR 1.40; 95% CI 1.14,
1.70). Tibolone was not different from pla-
cebo with regard to other safety outcomes,
such as mortality, cardiovascular events, or
gynecological cancers. The authors con-
cluded that tibolone increased the risk of
recurrence in breast cancer patients,
although it relieved vasomotor symptoms
and prevented bone loss.
The signicance of these ndings has been
stressed by Patricia Goodwin [87R], particu-
larly in view of the fact that the increased
recurrence rate of breast cancer led the inves-
tigators to stop the trial. It is worrying, she
noted, that over 70% of the recurrence
events were distant metastases, since these
metastases will ultimately lead to death. The
effect of tibolone seemed to be highest in indi-
viduals with hormone-receptor-positive
breast cancer, although there were not
enough study participants with hormone-
receptor-negative breast cancer to conclude
that tibolone use was safe in that group. No
other subgroups were identied where the
power of the study was sufcient to conclude
tibolone use was safe. . . An adverse effect of
tibolone on the recurrence of breast cancer
was also reported in the HABITS trial. With
its unusual mixture of hormonal effects, tibo-
lone has always been a puzzling compound,
seeking as it were a role for itself. At least in
the treatment of women who have undergone
surgery for breast cancer, that quest seems, on
present evidence, to have been unsuccessful.
SEX HORMONE
ANTAGONISTS
Danazol [SEDA-31, 672; SEDA-32, 750]
Cardiovascular The short-term and long-
term effects of danazol on proatherogenic
intermediate end-points have been evalu-
ated in 15 healthy volunteers and 17
patients with hereditary angioedema in a
Chapter 40 M.N.G. Dukes
4-week, crossover, placebo-controlled trial
[88C]. Short-term danazol treatment in the
former was associated with a 21% reduc-
tion from baseline in apolipoprotein A-I
and a 23% reduction in HDL cholesterol.
Long-term danazol treatment in the
patients with hereditary angioedema did
not adversely affect HDL cholesterol,
HDL-related transfer proteins such as
paraoxonase-1, cholesteryl-ester transfer
protein mass, lecithin cholesterol acyltrans-
ferase activity, plasma phospholipid trans-
fer protein activity or apolipoproteins.
However, the patients who used danazol
had increased coagulation compared with
controls.
Liver In a study of the potential hepato-
toxic or liver tumor-inducing effects of
long-term danazol prophylaxis in 92
patients with hereditary angioedema, half
of whom took danazol [89c]. There were
no clinically important differences between
the liver function parameters in years
0 and 5 in the two groups. Abdominal ultra-
sound did not detect neoplastic or other
potentially treatment-related alterations in
the liver parenchyma.
Drugdrug interactions Lovastatin As
monotherapies, both danazol and lovastatin
have been reported to cause myopathy and
pancreatitis, and a case report suggests that
the combination may do likewise [90A].
ANABOLIC STEROIDS,
ANDROGENS, AND
RELATED COMPOUNDS
[SED-15, 216; SEDA-30, 477;
SEDA-31, 672; SEDA-32, 751]
Anabolic steroids
Uses Among the very few medical uses of
anabolic steroids that continue to be
defended by certain centers is in promoting
recovery in cases of severe burns, even in
Sex hormones and related compounds, including hormonal contraceptives
children. The published evidence, exam-
ined in a recent critical review of eight pro-
spective controlled studies in which
oxandrolone was used for this purpose, sug-
gests that oxandrolone stimulates protein
synthesis by binding to androgen receptors
[91R]. During the rehabilitation period,
oxandrolone 0.1 mg/kg/day improved mus-
cle strength, especially when combined with
exercise. Based on clinical studies, oxandro-
lone 0.1 mg/kg bd is safe when it is used for
up to 12 months in such cases. However,
there were mild increases in serum amino-
transferase activities and reversible sexual
changes during therapy. As the reviewers
pointed out, limitations of the available data
are that they originated from a single study
center and that measurement of wound heal-
ing is lacking in children with severe burns. If
oxandrolone and other compounds of this
type are to be used in children, close moni-
toring of liver function, sexual development,
and growth is recommended during
treatment.
Cardiovascular Over the years there have
been repeated reports of cardiac enlarge-
ment and associated complications in ath-
letes who have attempted to improve their
performance with anabolic steroids. In
bodybuilders using anabolic steroids there
were smaller diastolic velocities in both
ventricles compared with sedentary coun-
terparts [92c].
Cases of dilated cardiomyopathy have
been reported [93AR, 94A], but most of
them were at least partially reversible after
withdrawal. However, fatal cases of hyper-
trophic cardiomyopathy have been
reported in the past [95A].
Abuse of anabolic steroids and the
justication of control measures
Although anabolic androgenic steroids
are widely misused, their relative abuse and
dependence liability have not been fully
characterized. As Wood has pointed out in
Chapter 40 869
an extensive review, it is difcult in humans
to separate the direct psychoactive effects of
these compounds from physical reinforce-
ment due to their systemic anabolic effects
[96R]. However, studies in animals using
conditioned place preference and self-
administration techniques show that ana-
bolic steroids have a reinforcing effect,
even in a context in which athletic perfor-
mance is irrelevant. They also have brain
receptor sites and neurotransmitter systems
in common with other drugs of abuse. Some
recent evidence has shown that in this
respect they are analogous to the opioids;
indeed, anabolic steroid abuse is sometimes
associated with use of prescribed opioids.
In animals, overdose of anabolic steroids
produces symptoms resembling opioid over-
dose, and these compounds have been found
to modify the activity of the endogenous opi-
oid system.
Continuing concerns regarding the social
consequences of the widespread and still
increasing misuse of anabolic steroids, par-
ticularly by young people, have led in many
countries to imposition of controls. In Janu-
ary 2008, the UK's Advisory Council on the
Misuse of Drugs wrote to the Home Ofce
(the UK Government's ministry for internal
affairs) proposing the compilation and sub-
mission of an expert report titled Consider-
ation of the Anabolic Steroids. The report
appeared 2 years later [97R] and was sub-
mitted to the Secretary of State for Health
in September 2010 [98R].
Reliable data on the extent of misuse in
England and Wales proved to be elusive,
but in the British Crime Survey published
in 2010 it was estimated that in the 1659 age
group some 226 000 people had admitted to
ever having used anabolic steroids, with
50 000 users in the year preceding the survey
and 19 000 in the most recent month [99R].
The UK Report (2010) The expert report
provided evidence that by the mid-1960s
the use of anabolic steroids was an accepted
practice among weightlifters and body-
builders (including amateurs). During the
1980s a number of reports began to appear
870
about the use of these drugs in health and
tness clubs, while newspaper reports at
the time described a thriving black market
in the buying and selling of anabolic steroids
in and around such centers. The number of
people who report using anabolic steroids
is relatively low by comparison with some
other illicit drugs, but similar to rates
reported for heroin and crack cocaine. The
numbers of women reporting anabolic ste-
roid use are relatively small; the ratio of
men to women has been reported as ranging
from 3:1 to as high as 10:1. Among school-
children aged 1115 years, 2% had been
offered anabolic steroids at some stage.
Anabolic steroids are generally used in pat-
terns called cycling, in which they are taken
for a period of time (for example 612 weeks),
known as an on cycle, followed by a similar
period of steroid-free training, known as an
off cycle. Such a cyclical method is practiced
in the belief that it prevents tolerance to the ste-
roids, reduces the risk of adverse effects from
prolonged use, and allows the hypothalamic-
pituitarygonadal axis time to resume normal
function. Users also often combine several dif-
ferent types of anabolic steroids in a process
known as stacking. Here, two or more ana-
bolic steroids are taken at the same time (using,
for example, oral and injectable products).
Users believe that stacking will have specic
additional, or synergistic, effects, although this
theory has not been scientically evaluated.
The report goes on to provide an extra-
ordinarily detailed account of the adverse
physical, mental, and social ill effects of ana-
bolic steroid misuse. Some of the harmful
physical effects are commonly self-reported,
for example acne, endocrine effects, and
gynecomastia in men; however, others are
rarer and therefore the causal link to use of
anabolic steroids is equivocal. Most of the
harmful effects of anabolic steroids are not
life-threatening, although a few deaths have
been attributed to liver damage associated
with long term steroid use.
Many, but not all, of the adverse effects
are reversible on withdrawal of anabolic ste-
roids. However, there are special concerns
about the use of anabolic steroids by young
people, as the use of these substances can
lead to virilization and, more broadly,
Chapter 40 M.N.G. Dukes
potentially disrupt the normal pattern of
growth and behavioral maturation. Adult
women are exposed to virilization, which
can involve marked physical effects, such
as hirsutism, deepening of the voice, amen-
orrhea/anovulation, clitoral enlargement,
atrophy of breast tissue, and changes in
libido. These changes can be pronounced
and in some cases permanent.
Most users administer anabolic steroids
by injection. As a consequence, they are
potentially at risk of a number of serious
forms of harm that can include damage to
the injection site as a result of poor injection
technique, bacterial and fungal infections (as
a result of using contaminated drug prod-
ucts, sharing vials, and/or reusing injecting
equipment) and blood-borne virus infec-
tions, such as HIV, hepatitis B, and hepatitis
C (again largely as a result of sharing
equipment).
Use of anabolic steroids has been associ-
ated with a range of psychological and
behavioral effects in case reports, such as
hypomania, mania, aggression, violence,
depression, and, after withdrawal, suicide.
Although there is not enough evidence to
connect chronic anabolic steroid use with sub-
stance dependence, the positive psychological
effects experienced by many users and other
positive effects (including increased training
capacity or strength, enhanced appearance,
and feelings of well-being) appear to
reinforce the continuing use of steroids in
some individuals.
Finally, the expert report notes the exis-
tence of a market in substandard and coun-
terfeit anabolic steroids; the composition
and purity of which are unknown.
Recommendations In the light of this
report, the Advisory Council on the Misuse
of Drugs recommended in September 2010
that anabolic steroids should continue to be
controlled as Class C drugs under the Mis-
use of Drugs Act 1971. In essence this would
retain the possibility of prescribing these
compounds for certain medicinal purposes,
but severe measures would be maintained
to prevent, so far as possible, their importa-
tion outside the medical sector. Supplemen-
tary measures would be required to
Sex hormones and related compounds, including hormonal contraceptives
discourage the use of these substances other
than on prescription, including personal
custody provisions and educational mea-
sures. Severe penalties would be retained
for illegal possession of anabolic steroids
(up to 2 years imprisonment and/or an
unlimited ne) and for illegal supply (up to
14 years imprisonment and/or a ne).
General conclusions The data provided by
the UK report greatly exceed the scope of
this review. It can be highly recommended
as a current source of information and
informed opinion on the problems posed
by anabolic steroids. It is clear that in vari-
ous circumstances the misuse of these prod-
ucts has given rise to social problems as
well as purely medical complications, and
that on both counts society is now obliged
to look for effective solutions.
Androgens
Uses Use in men with hypogonadism
While the debate on the acceptability of
androgen replacement therapy in elderly
men as a group shows no sign of dying
down, there is some agreement that in
men who have severe hypogonadism as a
consequence of successful treatment for
prostate cancer there can be a sufcient
argument for cautious androgen supple-
mentation as a means of improving the
quality of life [100R]. So long as there is
any possibility of residual cancer, the use
of androgens remains rmly excluded; how-
ever, a somewhat different view of this
issue, advanced by Morgenthaler, is noted
below.
Use in women This topic was considered in
detail in SEDA-29 (p. 510) and the contro-
versy shows no sign of abating. The authors
of an extensive review have again con-
cluded that testosterone replacement in
women can be used safely without an
increased risk of endometrial or breast can-
cer [101R]. However, the available evidence
on long-term use remains limited, and the
Chapter 40 871
widely held view that such treatment
should not last more than 2 years still
appears to hold good.
Respiratory Peliosis is a rare lesion of
unknown incidence and cause, character-
ized by the presence of blood-lled cysts.
It has been most often reported to affect
the liver (peliosis hepatis), sometimes in
association with the use of anabolic ste-
roids, but it has also been localized else-
where in the mononuclear phagocytic
system, such as the spleen, bone marrow,
and lymph nodes, and occasionally at other
sites. Pulmonary peliosis has been reported
in a 29-year-old man who was abusing tes-
tosterone [102A]. This appears to be only
the third published case involving the lungs,
and it is highly unusual in that no other
organ system was affected.
Tumorigenicity There is still uncertainty
regarding the belief (which originated with
a single case report) that androgen replace-
ment therapy in men might increase the
risk of prostatic neoplasms, but there have
been two reports arguing that the risk was
in fact negligible or absent (SEDA-32,
751). A critical and very extensive system-
atic review of the literature now seems to
have underpinned this optimistic conclu-
sion. Of 44 studies that met the authors
strict inclusion criteria, none showed that
testosterone therapy for hypogonadism
increased the risk of prostate cancer or
increased the Gleason grade of cancer
detected in treated versus untreated men
[103M]. Testosterone therapy did not have
a consistent effect on prostate-specic anti-
gen concentrations.
Susceptibility factors Prostate cancer And-
rogen treatment of men has a striking num-
ber of champions, ready to spring to its
defence whenever critics express reserva-
tions. That is the case regarding the widely
expressed view [SEDA-30, 477] that admin-
istration of androgens is undesirable in men
with a history of prostatic cancer. In a
recent review, Morgenthaler has argued
872
for a less absolute attitude [104R]. Hesita-
tion regarding the use of testosterone in
these cases is, in his opinion, based on a
model that assumes that androgen sensitiv-
ity of prostate cancer extends throughout
the range of testosterone concentrations.
Although it is clear that prostate cancer is
exquisitely sensitive to changes in serum
testosterone at low concentrations, he nds
considerable evidence that prostate cancer
growth becomes androgen indifferent at
higher concentrations. The most likely
mechanism for this loss of androgen sensi-
tivity at higher testosterone concentrations
is the nite capacity of the androgen recep-
tor to bind androgen. This saturation model
explains why serum testosterone appears to
be unrelated to the risk of prostate cancer
in the general population and why testos-
terone administration in men with meta-
static prostate cancer causes rapid
progression in castrated but not hormonally
intact men. Worrisome features of prostate
cancer, such as a high Gleason score, extra-
capsular disease, and biochemical recur-
rence after surgery, have been reported in
association with low but not high testoster-
one. Anecdotal evidence suggests that tes-
tosterone therapy does not necessarily
cause increased prostate-specic antigen
concentrations, even in men with untreated
prostate cancer. Morgenthaler has con-
cluded that although no controlled studies
have been performed to date to document
the safety of testosterone therapy in men
with prostate cancer, the limited available
evidence suggests that such treatment may
not pose an undue risk of prostate cancer
recurrence or progression.
Drug administration route Published expe-
rience with testosterone pellets of an older
type has noted relatively high rates of pellet
extrusion (8.512%) and infection
(1.46.8%). A study in 80 men with long-
acting testosterone implants (Testopel),
which are smaller and have a smooth sur-
face, has shown that with this formulation
extrusion occurred in only 0.3% of cases
and infection also in only 0.3% [105c].
Chapter 40 M.N.G. Dukes
ANTIANDROGENS [SEDA-29,
510; SEDA-30, 479; SEDA-31, 673;
SEDA-32, 755]
Bicalutamide
Quality of life The positive effects that can
be achieved with intensive androgen block-
ade (using a drug such as bicalutamide)
need to be weighed against the possibility
of such adverse effects as gynecomastia
and breast pain, but also against possible
deterioration in the quality of life as a whole.
A Japanese group sought to evaluate the
latter, using a standard questionnaire in
203 previously untreated cases of prostate
cancer, who were questioned at intervals
during 24 weeks of maximum androgen
blockade, involving use of bicalutamide
together with an LH agonist; a control
group was receiving an LH agonist only
[106C]. The patients on maximum androgen
blockade had a better therapeutic response
and there was no evidence that their quality
of life was in any way impaired compared
with the controls.
Cyproterone acetate
Drugalcohol interactions An apparently
unprecedented case has been reported in
which cyproterone induced disulram-like
interference with the metabolism of alcohol
[107A].
A 31-year-old woman who had had bacterial
vaginosis while using of an intrauterine con-
traceptive device was instead given the oral
contraceptive Diane, which contains cyprot-
erone acetate 2 mg and ethinylestradiol
35 micrograms. She developed a reaction to
alcohol, marked by facial ushing, sweating,
palpitation, abdominal pain, nausea, vomiting,
and diarrhea within about 10 minutes of
taking a drink. Each reaction lasted for
34 hours. When Diane was replaced by a com-
bination of drospirenone ethinylestradiol the
adverse reaction to alcohol disappeared.
There is evidence that certain drugs that
interfere with the metabolism of alcohol
appear to do so by inducing a toxic
Sex hormones and related compounds, including hormonal contraceptives
serotonin syndrome [108c], and it has been
suggested that this may be the case with
cyproterone [109r].
Finasteride [SED-15, 3132; SEDA-30,
480; SEDA-31, 675; SEDA-32, 755]
Musculoskeletal Reversible myalgia associ-
ated with raised creatine kinase activity has
been attributed to nasteride [110A]
A 30-year-old man who had been taking nas-
teride 5 mg/day for 10 years for frontal bald-
ness developed diffuse muscle aches
associated with a raised creatine kinase activ-
ity to 10 117 IU/l; there were no signs of
weakness or pigmenturia. His symptoms
resolved and his creatine kinase activity fell
to 256 IU/l 3 weeks after nasteride
withdrawal.
Skin A xed drug eruption has been attrib-
uted to nasteride [111A].
A 39-year-old Japanese male with a 2-month
history of a pruritic sore erythematous spot
on the dorsal surface of the shaft of the penis
used a topical steroid, but the eruption
remained almost unchanged. It consisted of a
solitary violaceous erythematous macule with-
out erosions or blisters. Finasteride was with-
drawn; topical steroid therapy was restarted.
The erythema rapidly resolved leaving mild
pigmentation.
Sexual function Adverse effects of naste-
ride on male sexual function are not
uncommon (SEDA-30, 480). These effects
are dose related, and in the low doses used
to treat hair loss (1 mg/day) they are
unusual. However, they can occur in certain
instances, as in two patients with azoosper-
mia and severe oligospermia resulting in
infertility when they took nasteride 1 mg/
day for hair loss; the drug was withdrawn
and the sperm count recovered within
36 months [112A].
The use of nasteride and other 5-alpha
reductase inhibitors in benign prostatic
hyperplasia has been associated with
adverse sexual outcomes, including dys-
function of erection or ejaculation and
Chapter 40 873
reduced libido. In an extensive literature
review of these complications it was con-
cluded that in clinical trials they have
occurred at rates of 2.138%, the most
common problem being erectile dysfunc-
tion [113R]. These effects occur early in
therapy and attenuate over time. A pro-
posed mechanism for sexual dysfunction
involves impaired nitric oxide synthase
activity, due to reduced dihydrotestoster-
one concentrations.
Drugdrug interactions St John's wort The
effects of St John's wort on nasteride and
its metabolites, hydroxynasteride and
carboxynasteride, have been studied in
12 men, in whom nasteride 5 mg was
administered directly into the intestine via
a catheter before and after 14 days of treat-
ment with St John's wort 300 mg bd [114c].
St John's wort signicantly reduced the
Cmax, the AUC0!24h, and the half-life of
nasteride; the kinetics of carboxynaster-
ide were also signicantly altered.
Flutamide [SED-15, 1427; SEDA-30,
484; SEDA-31, 675; SEDA-32, 755]
Observational studies Although utamide
is effective in treating hirsutism, adverse
reactions are very frequent and long-
term adherence is poor. In one study
over 7 years, of 83 women who took uta-
mide 250 mg/day alone or in combination
with an oral contraceptive containing ethi-
nylestradiol 20 micrograms and desogestrel
150 micrograms, 34 had one or more
adverse reaction during follow-up, 28 had
at least one adverse reaction that was possi-
bly related to the study drug, and 20 with-
drew because of adverse reactions,
hepatotoxicity being the most troublesome;
during follow-up, as many as 59% aban-
doned the study [115c].
Liver The use of utamide for hirsutism in
premenopausal women over 15 years has
been reported [116c]. The dosage of uta-
mide, alone or in combination with oral
874
contraceptives, was reduced yearly (250,
125, and 62.5 mg/day), and individual
women were treated for up to 8 years. Dur-
ing the rst year, 6% abandoned the study
because of hepatic disorders, but as the
dosage was reduced, tolerance improved.
The authors considered that this is a satis-
factory therapeutic regimen for any form
of hirsutism in the long term, but if one
seeks to achieve minimal adverse reactions
and a high degree of adherence, the lowest
dose should be used.
A 26-year-old woman developed hepato-
toxicity while taking a low dose of uta-
mide, 250 mg/day [117A].
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41 Thyroid hormones, iodine,
and antithyroid drugs
Thyrotropin (thyroid-stimulating
hormone, TSH) [SEDA-31, 683;
SEDA-32, 763]
Uses Recombinant human TSH (rhTSH) is
used to increase the efcacy of radioiodine
(131I) administration in the treatment of
symptomatic non-toxic goiter. This
approach can achieve a doubling in thyroid
131
I uptake, reducing the volume of the goi-
ter by 3556%, at the expense of a vefold
higher rate of permanent hypothyroidism
[1R, 2c]. In addition rhTSH is used in the
preparation of patients with differentiated
thyroid cancer undergoing thyroid remnant
ablation, and this is effective even in patients
undergoing low dose ablative 131I therapy
[3c]. Furthermore, this approach results in
lower extra-thyroidal irradiation. Reduced
rates of transient headaches, thrombocyto-
penia, neutropenia, hyperamylasemia, and
acute sialoadenitis were reported when 30
patients treated with rhTSH were compared
with 64 subjects who underwent levothyrox-
ine withdrawal before receiving 3.7 GBq of
ablative 131I [4c].
Side Effects of Drugs, Annual 33
J.K. Aronson (Editor)
ISSN: 0378-6080
DOI: 10.1016/B978-0-444-53741-6.00041-6
# 2011 Elsevier B.V. All rights reserved.
Kristien Boelaert
THYROID HORMONES
[SED-15, 3409; SEDA-30, 490;
SEDA-31, 687; SEDA-32, 763]
Uses Thyroid hormones (levothyroxine,
T4, and liothyronine, T3) are used to treat
overt hypothyroidism. In addition, supra-
physiological doses of levothyroxine are
widely used to reduce the risk of thyroid
cancer recurrence by suppressing serum
TSH concentrations. The use of levothyrox-
ine suppressive therapy to induce shrinkage
of benign thyroid nodules remains contro-
versial and its routine use is not recom-
mended in view of its low efcacy and
potential long-term effects on the cardio-
vascular system and the skeleton caused
by the induction of subclinical hyper-
thyroidism [5C].
Non-immune fetal goitrous hypothyroid-
ism can cause obstetric and/or neonatal com-
plications as well as neurodevelopmental
impairment. Intra-amniotic levothyroxine
administration in doses of 200800 micro-
grams per injection every 14 weeks from 24
weeks gestation onward resulted in signicant
goiter size reduction in eight out of nine
fetuses. Nevertheless, all the babies were
hypothyroid at birth despite reductions in
intra-amniotic TSH concentrations in more
than 50% of cases [6c].
Liothyronine is used to accelerate and
enhance the response to antidepressants,
especially in patients with major depression
who have not responded to conventional
therapy. Randomized controlled trials and
meta-analyses have demonstrated the bene-
t of using liothyronine in conjunction with
881
882
tricyclic antidepressants, although the evi-
dence base for combined use of selective
serotonin reuptake inhibitors (SSRIs) and
liothyronine is more limited. A review of
ve randomized controlled trials suggested
that liothyronine was well tolerated and
adverse reactions did not impede its clinical
use. However, the overall efcacy of combi-
nation treatment with SSRIs and liothyro-
nine remains unclear and requires further
investigation [7R].
Two separate reports have suggested that
supraphysiological doses of liothyronine
may be benecial in refractory major depres-
sion when combined with both tricyclic anti-
depressants and SSRIs [8c, 9c]. Preliminary
evidence suggests that the presence of a
functional polymorphism in the type 1 de-
iodinase enzyme, resulting in reduced
peripheral conversion of T4 to T3, may be
associated with increased benet from com-
bination therapy of antidepressants with
liothyronine [10c].
The systematic treatment of subclinical
hypothyroidism remains controversial. In a
double-blind, randomized, controlled study
of patients with co-existing iron deciency
anemia and subclinical hypothyroidism, a
combination of levothyroxine 75 micro-
grams/day and oral iron 240 mg/day resulted
in increased serum iron, hemoglobin, and
serum ferritin concentrations compared with
subjects who took oral iron monotherapy.
These ndings suggest that normalization
of serum TSH concentrations may be bene-
cial if patients with subclinical hypothyroid-
ism are found to have iron deciency
anemia [11c].
Nervous system Iatrogenic subclinical
hyperthyroidism is induced in patients with
differentiated thyroid cancer in order to
reduce the risk of recurrence. Long-term
exogenous subclinical hyperthyroidism
causes autonomic nervous system abnor-
malities, and lower heart rate variability
and increased urinary catecholamine excre-
tion are common. After restoration of
euthyroidism for a minimum of 6 months
in 12 patients who underwent TSH suppres-
sive therapy for more than 10 years,
autonomic nervous system abnormalities
Chapter 41 Kristien Boelaert
remained unchanged, suggesting irrevers-
ible changes or adaptation during long-term
exposure [12c].
Electrolyte balance In patients with meta-
static thyroid carcinoma undergoing treat-
ment with 131I, levothyroxine is withdrawn
and a low iodine diet prescribed to improve
treatment efcacy. Signicant hyponatremia,
associated with symptoms including weak-
ness, dizziness, fainting spells, lethargy, and
nausea, has been reported in ve patients dur-
ing levothyroxine withdrawal and a low iodine
diet. Combined low sodium intake and the
syndrome of inappropriate antidiuretic hor-
mone secretion secondary to hypothyroidism
or metastatic disease were proposed as poten-
tial underlying mechanisms [13c].
Drug dosage regimens The timing of admin-
istration in relation to food affects the effects
of levothyroxine on thyroid functionnon-
fasting regimens are associated with higher
and more variable serum TSH concentrations
[14c]. If a specic serum TSH goal is desired,
in order to avoid iatrogenic subclinical
thyroid disease, fasting administration of
levothyroxine ensures that serum TSH
concentrations remain within the narrowest
therapeutic target range.
There has been a report of thyrotoxic
periodic paralysis due to excessive replace-
ment with levothyroxine in a patient with
panhypopituitarism secondary to a cranio-
pharyngioma [15A].
Choreoathetosis due to excessive doses
of levothyroxine has been reported [16A].
The patient had an underlying diagnosis of
autoimmune hypothyroidism and tripled
her daily dose of levothyroxine during a 6-
month period.
Drugdrug interactions Sunitinib and
paracetamol Acute fatal liver failure fol-
lowing the addition of levothyroxine in a
patient taking sunitinib and paracetamol
for a metastatic gastric stromal tumor has
been reported. Sunitinib can cause hypo-
thyroidism, and it is plausible that correc-
tion of the hepatic hypothyroidism with
levothyroxine resulted in potentiation of
Thyroid hormones, iodine, and antithyroid drugs
the hepatotoxicity of paracetamol, thereby
triggering hepatic necrosis [17A].
Susceptibility factors There is impaired
absorption of levothyroxine, due to
reduced acid secretion, in patients with
Helicobacter pylori gastritis, suggesting that
screening for H. pylori in patients taking
thyroxine replacement should be consid-
ered at the start of therapy [18M].
IODINE AND IODIDES
[SED-15, 1896; SEDA-30, 490;
SEDA-31, 688; SEDA-32, 764]
Fetotoxicity Excess iodine ingestion can
cause goiter and hypothyroidism. Congenital
goiter and increased iodide uptake in a neo-
nate is considered diagnostic of dyshormono-
genesis, a permanent form of congenital
hypothyroidism. Eight cases of congenital
goiter, caused by ingestion of large amounts
of iodine by mothers who took prenatal vita-
min supplements, have been reported [19c].
The vitamin supplements were found to have
errors in their formulation, resulting in 400
times the recommended dose of iodine. The
presence of goiter was associated with bio-
chemical hypothyroidism in three infants
who required temporary thyroid hormone
supplements. There was complete resolution
of goiter in all babies within the rst 30 days
of life. The differentiation between excess
maternal iodine intake and dyshormono-
genesis is important and may prevent lifelong
use of thyroxine supplements in babies with
transient abnormalities.
Radioactive iodine
Uses Radioiodine (131I) is widely used in
the treatment of hyperthyroidism and thy-
roid cancer. It is also used to reduce thyroid
volume in patients with large multinodular
Chapter 41 883
goiters that are not amenable to surgery.
In 34 women who received four separate
doses of 131I 800 MBq at 3-monthly inter-
vals, the highest response of thyroid vol-
ume was observed after the rst course of
treatment; 24 months after the completion
of treatment, 60% of the patients remained
euthyroid and 40% were hypothyroid [20c].
Endocrine Patients with moderate- or
high-risk differentiated thyroid cancer
undergo postsurgical 131I therapy for rem-
nant ablation. In a comparison of 68
patients who received 131I in a dose of
1110 MBq and 115 patients who were given
a dose of 3700 MBq there were similar
ablation success rates, with a reduction in
the frequency and severity of radiation thy-
roiditis in those treated with lower doses
[21c].
Radiation-induced thyroiditis can also
occur in patients who receive radioiodine
for hyperthyroidism. In a retrospective
review of 1333 patients with Graves dis-
ease who received an empirical xed dose
of 131I (185370 MBq), insufcient doses
of radioiodine resulted in early and para-
doxical exacerbation of Graves disease in
ve patients. The clinical course of these
patients was distinct from those with radia-
tion-induced thyroiditis and all ve
required treatment with antithyroid drugs
[22C].
Salivary glands A wide spectrum of salivary
gland complaints, ranging from mild tran-
sient discomfort to permanent xerostomia
and tooth decay, have been described after
the administration of radioiodine. In a retro-
spective study of 262 patients who under-
went remnant ablation with 131I there were
signicant salivary gland adverse reactions
in 40%. In most cases the reactions were
transient, and after a median follow-up of 7
years the incidence of persistent adverse
reactions was only 5% [23C].
Drugdrug interactions Diuretics Diuretics
are often used in patients who receive high
doses of 131I, in an attempt to accelerate the
884
elimination of unbound radioiodine, in
order to reduce the risk of adverse reac-
tions and to shorten the time spent in hospi-
tal. However, in a study of the use of low-
dose furosemide (20 mg) in 23 patients
3 hours after 131I compared with 20 control
patients, who received the same dose of
131
I, there was signicantly reduced urinary
excretion of radioiodine and higher blood
concentrations in those who received furo-
semide, in contrast to expectations [24c].
The authors therefore did not recommend
the use of furosemide as adjuvant to
radioiodine.
ANTITHYROID DRUGS
[SEDA-15, 3387; SEDA-30, 490;
SEDA-31, 689; SEDA-32, 765]
Uses The optimal treatment of Graves dis-
ease in children is controversial, although
antithyroid drugs are usually favored ini-
tially. In 51 children induction of euthyroid-
ism within 3 months of starting propyl-
thiouracil treatment was an independent
predictor of remission. Other factors that
predicted cure included lower serum free
T3 concentrations at presentation and older
age [25c].
Cardiovascular The serum free thyroxine
(fT4) concentration is associated with QT
interval prolongation, which is a susceptibil-
ity factor for sudden cardiac death. Investi-
gation of a prospective population-based
cohort and a casecontrol study have
shown a threefold increased risk of sudden
cardiac death in patients taking antithyroid
drugs. Although a direct link between the
use of thionamides and sudden cardiac
death cannot be ruled out, these ndings
could more readily be explained by under-
lying poorly controlled hyperthyroidism,
since patients who died had low serum
TSH concentrations before death [26C].
Chapter 41 Kristien Boelaert
Hematologic Drug-induced agranulocyto-
sis is the most serious disorder associated
with thionamide therapy; it can be life
threatening, with a reported mortality of
515%.
EIDOS classication:
Extrinsic species: Thionamides
Intrinsic species: White blood cells
Distribution: Bone marrow
Outcome: Not known
Sequela: Agranulocytosis due to
thionamides
DoTS classication:
Dose-relation: Collateral
Time-course: Intermediate
Susceptibility factors: Exogenous (other
drugs that can cause
agranulocytosis)
In a large multinational casecontrol study
in Latin America there was a relatively low
overall incidence of agranulocytosis (0.38
cases per million inhabitant-years). Patients
who developed agranulocytosis more often
took medications already associated with
agranulocytosis than controls, mainly methi-
mazole (OR 44; 95% CI 6.8, 1) [27C].
The development of aplastic anemia fol-
lowing treatment with thionamide drugs
has been reviewed [28R]. At least 34 cases
have been described previously in addition
to two further reports of this condition in
subjects undergoing treatment with methi-
mazole or carbimazole. Patients usually
developed symptoms suddenly after a rela-
tively short time (50% of cases occurred
within the rst 15 weeks of therapy) and
concomitant agranulocytosis was present
in all patients. Most of the subjects recov-
ered rapidly after withdrawal of the thiona-
mide and supportive treatment with broad
spectrum antibiotics, glucocorticoids, gran-
ulocyte-colony stimulating factor (G-CSF),
granulocyte macrophage-colony stimulating
factor (GM-CSF), androgens, and intra-
venous immunoglobulin. Only two deaths
related to thionamide-induced aplastic ane-
mia have been reported.
Thyroid hormones, iodine, and antithyroid drugs
Liver The association between propylthi-
ouracil and hepatocellular inammation is
well described. During the past 20 years, there
have been 33 published reports of severe
propylthiouracil-related liver failure in adults
and 14 in children, resulting in 16 liver trans-
plants in adults and seven in children between
1990 and 2007. In addition propylthiouracil-
induced liver injury has resulted in death both
among adults and children [29r]. This has led to
the recommendation that propylthiouracil
should not be prescribed as a rst-line agent
in children or adults. The settings in which
propylthiouracil is preferred before methima-
zole include the rst trimester of pregnancy,
life-threatening thyrotoxicosis or thyroid
storm (because of inhibition of peripheral
conversion of T4 to T3 by propylthiouracil),
and if patients have had adverse reactions
(other than agranulocytosis) to methimazole.
Patients taking propylthiouracil should be
counseled regarding the risk of liver failure,
and liver function tests should be monitored
in symptomatic patients [30r].
Methimazole can also cause liver dam-
age, although this is typically characterized
by cholestatic dysfunction [31A] and no
cases of liver damage resulting in transplan-
tation or death have been described.
Skin A 38-year-old man developed purpura
fulminans on both breast areas and the abdo-
men after having taken propylthiouracil for 7
years; after withdrawal of propylthiouracil
and administration of methylprednisolone
he made a full recovery [32A].
Topical methimazole is used as a skin
depigmenting agent for conditions that
include epidermal melasma. In 20 patients
who used this treatment once daily for 6
weeks there were no signicant changes in
circulating thyroid hormone or thyroid-
stimulating hormone (TSH) and no signi-
cant cutaneous adverse reactions [33c].
Immunologic Vasculitis associated with
myeloperoxidase antineutrophil cytoplas-
mic antibodies (MPO-ANCA) caused by
Chapter 41 885
thionamides is well described. In 92
patients with thionamide-induced vasculitis
there was a variable time of onset (1372,
median 42, months) after the start of treat-
ment [34c]. The median dose at onset was
15 (range 2.545) mg/day for methimazole
and 200 (range 50450) mg/day for
propylthiouracil. The intensity and the
number of organs involved did not corre-
late with the MPO-ANCA titer, indicating
a need for vigilance even when the MPO-
ANA titer is only weakly positive.
There have been separate case reports of
alveolar hemorrhage secondary to
propylthiouracil-induced vasculitis [35A]
and central nervous system vasculitis attrib-
uted to methimazole [36A].
Withdrawal of thionamides results in res-
olution of vasculitis in many cases, although
immunosuppressive therapy may be indi-
cated. In a study of the long-term outcomes
in 15 patients with propylthiouracil-induced
vasculitis who received immunosuppressive
therapy for up to 12 months there was com-
plete remission in 12 patients, partial remis-
sion in one, and progression to end-stage
renal failure in two [37c].
Teratogenicity During pregnancy, propyl-
thiouracil is considered the treatment of
choice, especially during the rst trimester.
Methimazole has been associated
with fetal abnormalities, including aplasia
cutis and choanal atresia. In a controlled
cohort study of 115 propylthiouracil-
exposed pregnancies and 1141 controls
there were similar rates of major abnor-
malities in both groups (13% versus
3.2%). Hypothyroidism was found in
9.5% of fetuses/neonates and was associ-
ated with goiter in 57%. Goiters diagnosed
prenatally by ultrasound were successfully
treated in utero by maternal dosage
adjustments. Median neonatal birth weight
was lower in the propylthiouracil group
compared with controls (3145 g versus
3300 g) [38c].
886
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Stricker BH. Population-based studies of
antithyroid drugs and sudden cardiac death.
Br J Clin Pharmacol 2009; 68(3): 44754.
[27] Hamerschlak N, Maluf E, Biasi
Cavalcanti A, Avezum Jnior A, Eluf-
Neto J, Passeto Falco R, Lorand-Metze IG,
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Goldenberg D, Leite Santana C, de Oliveira
Werneck Rodrigues D, Nascimento da Motta
Passos L, Oliveira de Miranda Coelho E,
Tostes Pinto MC, Moraes de Souza H,
Borbolla JR, Pasquini R. Incidence and risk
factors for agranulocytosis in Latin American
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9219.
[28] Thomas D, Moisidis A, Tsiakalos A,
Alexandraki K, Syriou V, Kaltsas G. Anti-
thyroid drug-induced aplastic anemia. Thy-
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[29] Cooper DS, Rivkees SA. Putting propyl-
thiouracil in perspective. J Clin Endocrinol
Metab 2009; 94(6): 18812.
[30] Bahn RS, Burch HS, Cooper DS,
Garber JR, Greenlee CM, Klein IL,
Laurberg P, McDougall IR, Rivkees SA,
Ross D, Sosa JA, Stan MN. The role of
propylthiouracil in the management of
Graves disease in adults: report of a meet-
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Administration. Thyroid 2009; 19(7): 6734.
[31] Gallelli L, Staltari O, Palleria C, De Sarro G,
Ferraro M. Hepatotoxicity induced by
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Curr Drug Saf 2009; 4(3): 2046.
[32] Akman A, Dicle O, Ciftcioglu MA,
Alpsoy E. Unusual location of purpura ful-
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deciency and administration of propyl-
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e4634.
[33] Kasraee B, Safaee Ardekani GH,
Parhizgar A, Handjani F, Omrani GR,
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Eshraghian A, Sorg O, Saurat JH. Safety
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[34] Noh JY, Yasuda S, Sato S, Matsumoto M,
Kunii Y, Noguchi Y, Mukasa K, Ito K,
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[35] El-Fakih R, Chehab BM, Shaver T. Thiona-
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[36] Tripodi PF, Ruggeri RM, Campenni A,
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Baldari S, Trimarchi F, Cucinotta D,
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[37] Gao Y, Chen M, Ye H, Yu F, Guo XH,
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[38] Rosenfeld H, Ornoy A, Shechtman S, Diav-
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42 Insulin, other hypoglycemic
drugs, and glucagon
GLUCAGON [SED-15, 1510;
SEDA-31, 689; SEDA-32, 769]
Cardiovascular Transient branch hepatic
artery vasospasm followed the intravenous
administration of glucagon 1 mg on two
separate occasions during visceral angiogra-
phy in a 69-year-old man with a vasculitis
[1A].
Gastrointestinal Glucagon affects the smo-
oth muscle of the gastrointestinal tract. In 10
healthy volunteers, mean age 32 years, intra-
venous glucagon 1 mg resulted in paralysis
of small bowel motility after about 13.4 sec-
onds; motility returned after 18 minutes [2c].
INSULIN [SED-15, 1761; SEDA-30,
494; SEDA-31, 689; SEDA-32, 769]
Metabolism Hypoglycemia When 97
patients mean age 53 years with severe
brain injury were randomized to an insulin
infusion when their blood glucose concen-
trations exceeded 12 mmol/l or to maintain
blood glucose concentrations between 4.4
and 6.7 mmol/l, those who received more
intensive insulin therapy not surprisingly
Side Effects of Drugs, Annual 33
J.K. Aronson (Editor)
ISSN: 0378-6080
DOI: 10.1016/B978-0-444-53741-6.00042-8
# 2011 Elsevier B.V. All rights reserved.
R.C.L. Page
had more episodes of hypoglycemia
(median 15 versus 7 per patient), however
duration of stay in intensive care was
shorter (7.7 versus 10 days). Mortality was
similar in the two groups [3c].
In a study of critically ill patients in
intensive care, mean age 60 years, 3054
were randomized to intensive blood glu-
cose control (4.56 mmol/l) and 3050 to
blood glucose concentrations of less than
10 mmol/l. Mortality at 90 days was higher
in those who had been randomized to tight
blood glucose control (28% versus 25%);
severe hypoglycemia, dened as a blood
glucose concentration less than 2.2 mmol/l,
was also more common (6.8% versus
0.5%) [4C].
Patients admitted to hospital with acute
myocardial infarction between 2000 and
2005 were identied from a database; those
who had a blood glucose concentration on
admission of less than 7.8 mmol/l were
excluded [5C]. Of 7820 patients with a mean
age of 72 years, 482 had hypoglycemia dur-
ing admission, of whom 346 were treated
with insulin. Mortality was higher in those
who developed hypoglycemia but had not
been treated with insulin. Thus, spontane-
ous hypoglycemia appeared to be a marker
of increased mortality, but insulin did not
appear to increase the risk of mortality.
Intensive treatment of blood glucose con-
centrations in critically ill patients with
insulin increases the risk of hypoglycemia
and may increase mortality.
In 175 children, mean age 13 years, who
were randomized to insulin glargine
(n 85) or an intermediate-acting insulin
(n 90), with insulin lispro at meal times,
889
890
the adjusted event rate per patient year of
blood glucose concentrations less than
3.9 mmol/l was 116 for those who used insu-
lin glargine and 94 for those who used an
intermediate-acting insulin [6c]. However,
the patients who used insulin glargine and
had a higher initial HbA1c concentration
appeared to have greater reductions in
HbA1c.
Data from three studies of patients with
type 2 diabetes, aged 3080 years, in whom
hypoglycemia was dened as a blood glu-
cose less than 3.5 mmol/l, and all of whom
were treated with metformin and insulin,
showed that there was an inverse relation
between the frequency of hypoglycemia
and HbA1c concentration, whether insulin
lispro mixtures or glargine was used [7M].
This reinforces the difculty of trying to
achieve tight blood glucose control with
insulin.
Skin Lipodystrophy at the site of insulin
injection is well documented, although the
mechanism remains unknown, and cases
continue to be reported [8A]. However,
other effects can occur at the site of
injection.
A 40-year-old man with insulin-dependent
diabetes, who was using Humulin insulin,
developed a lump on his upper arm at the site
of his injections [9A]. It was thought to be a
lipoma but histology suggested amyloid
deposition.
The skin manifestations of continuous
subcutaneous insulin infusion have been
studied in 40 children aged under 6 years
(mean age 2.3 years) compared with 38
children over 6 years (mean age 8.4 years)
[10c]. Small scars of less than 3 mm were
the most commonly reported events, and
there were slightly fewer in the younger
children: 20 (50%) compared with 27
(71%). Lipohypertrophy was also common
at the insertion sites: 18 (45%) and 18
(47%) respectively. Erythema and blisters
were less common, but occurred more often
in those who had reported an allergic pre-
disposition before starting subcutaneous
Chapter 42 R.C.L. Page
infusion. Overall, young children did not
have an increased risk of skin problems.
Immunologic Insulin allergy is rare but as
insulin is often an essential therapy it can
cause major clinical problems. Sometimes
a change to a less immunogenic insulin is
helpful, and if not continuous subcutaneous
insulin infusion has been tried [11R]. In one
case desensitization was successful [12A].
A 68-year-old man with type 2 diabetes trea-
ted with insulin and oral hypoglycemic agents
developed pruritic plaques of more than
15 cm diameter at the site of his insulin injec-
tions. Skin biopsy showed an Arthus type
reaction. Various insulin therapies, including
insulin glargine, insulin detemir, and human
insulin, produced the same response. Intra-
dermal tests were positive to a variety of insu-
lins and protamine. He was desensitized using
subcutaneous human insulin and orally fexofe-
nadine 180 mg bd and was then successfully
treated with insulin glargine. The fexofena-
dine was stopped 6 months later.
Drug overdose The duration of action of in-
sulin glargine is dose related, and this should
be remembered when treating patients who
have taken a massive overdose [13A].
A 31-year-old woman deliberately injected in-
sulin glargine 1000 units subcutaneously. Her
blood glucose concentration was 2.4 mmol/l
and she was treated with oral feeding and con-
tinuous intravenous dextrose. The last docu-
mented hypoglycemic episode on trying to
withdraw dextrose occurred 106 hours after
the overdose. Intravenous dextrose was
stopped at 130 hours.
Is there an increased risk of
cancer in patients using insulin?
In 127 031 patients without known malig-
nancies, mean age 68 years, who had
received human insulin exclusively or only
one type of analogue insulin (lispro, aspart,
or glargine), who were identied from the
German health insurance fund and followed
for a mean of 1.6 years, the insulin dose was
Insulin, other hypoglycemic drugs, and glucagon
positively associated with the risk of malig-
nancy [14C]. This risk was higher with insu-
lin glargine than human insulin, but not
higher among those who used insulin lispro
or insulin aspart. The hazard ratios for insu-
lin glargine compared with human insulin
were 1.19 with 10 units/day of glargine and
1.31 with 50 units/day.
Although the methods of analysis in this
study were thought to have been inappropri-
ate, the results raised a question that resulted
in further investigation [15r]. In Sweden
malignancies that occurred between 1 Janu-
ary 2006 and 31 December 2007 were
recorded in 114 841 people who had had a
prescription for insulin between 1 July and
31 December 2005 [16C]. Women who had
used only insulin glargine had an increased
risk of breast cancer, with an incidence ratio
of 1.9 compared with those who used other
insulins. Those who used insulin glargine
in combination with other insulins did not
have an increased risk.
In an analysis of the pharmacovigilance
database of the manufacturer, Sano Aven-
tis, 5657 patients using insulin glargine were
compared with 5223 patients who had used
other therapies [17R]. The data included
patients with type 1 and type 2 diabetes.
There were no differences in the rates of
malignancy, with 52 events in those using
glargine compared with 48 controls. The
most common cancers were skin, colorectal,
and breast. Most of the trials that formed the
basis of this analysis were for 6 months,
although one was for 5 years.
In a similar study, 3983 patients who used
insulin detemir were compared with 2661
who used NPH insulin, and 1219 who used
insulin detemir were compared with 830 who
used insulin glargine [18M]. The patients had
type 1 and type 2 diabetes and the mean age
was 50 years. The exposure in weeks was
0.1114. There was no difference in cancer
rates between those who used insulin detemir
(n 8; 0.87 per 100 exposure years) and
those who used insulin glargine (n 8; 1.27
per 100 exposure years).
In a 5-year study of 1017 patients ran-
domized to insulin glargine or NPH insulin,
there were 57 neoplasms in those who used
insulin glargine (11%) compared with 62
Chapter 42 891
(12%) in those who used NPH insulin
[19c]. The numbers of patients with breast
cancer was small (three of those who used
insulin glargine compared with ve of those
who used NPH) and did not suggest an
excess risk.
These studies have mostly been too short
to be conclusive. The current data are dif-
cult to interpret, because the risks of cancer
are complex and include increasing age
and obesity, which are common features of
type 2 diabetes, along with many other con-
founding factors. The possibility that insulin
is associated with a risk of cancer requires
longer exposure data to be collected to pro-
vide useful information.
Pregnancy In a retrospective cohort study
of 112 women with both pregestational dia-
betes (n 53) and gestational diabetes
(n 59) pregnancy outcomes were reported
in relation to the use of NPH insulin and insu-
lin glargine [20c]. Women with pregesta-
tional diabetes were signicantly more
likely to have used insulin glargine (37 com-
pared with 16). Insulin glargine did not
increase the risk of, pre-eclampsia, maternal
hypoglycemia, maternal weight gain, or
cesarean delivery. Neonatal outcomes were
also similar. Of the women with pregesta-
tional diabetes, those who had used insulin
glargine had fewer large-for-dates babies
(19% versus 50%). This is reassuring, as
insulin glargine has a high afnity for insu-
lin-like growth factor receptors [21E].
In a similar study, 114 women, 67 of whom
used insulin glargine, of whom 47 had pre-
gestational diabetes, were compared with
49 patients who used NPH insulin, of whom
37 had pregestational diabetes. The out-
comes were similar in the two groups, with
the exception of shoulder dystocia, which
was more frequent in those who used NPH
(8.2% compared with 0%) [22c]. Prospective
safety data with long-term follow-up are
required to conrm the safety of insulin glar-
gine in pregnancy.
Drug administration route Continuous
subcutaneous insulin infusion (CSII)
There are limited data about the use of
892
CSII in patients with type 2 diabetes. In a
meta-analysis of the use of CSII in patients
with type 2 diabetes hypoglycemia, including
severe hypoglycemia, was as common as
with multiple injection insulin therapy
[23M]. Another similar analysis showed sim-
ilar outcomes in patients using CSII com-
pared with multiple daily injections [24R].
In a retrospective study in which data
were collected from 16 European countries
and Israel, of 1098 patients with type 1 dia-
betes, mean age 12 years, who were treated
with CSII for a mean of 2 years, 18 had a
single episode of severe hypoglycemia (6.6
events per 100 patient-years) [25C]. The
event rate for diabetic ketoacidosis was 6.2
events per 100 years. There was no compar-
ison group. It has been suggested that in
adults CSII can help improve HbA1c
slightly, but the impact on hypoglycemia
compared with multiple injections of ana-
logue insulin is not clear [24R].
Skin infections at the infusion site vary
from 0.06 to 12 events per patient per year
and are a major reason for discontinuing
pump therapy [11R].
Pump failure continues to be a problem.
Of 640 consecutive new pumps used from
2001 to 2007 by 252 adults with type 1 dia-
betes, 232 broke down after 0.164 months;
103 had complete failure and were immedi-
ately unusable [26c]. There was hyperglyce-
mia in 40 patients, with ketones in 10; none
required admission to hospital. Pump fail-
ure is frequent and it is important that
patients know what to do when it occurs.
Inhaled insulin AIR insulin given pre-
prandially as an inhalation has been studied
in 208 patients with type 2 diabetes and
compared with 203 patients receiving pre-
prandial injections of insulin [27c]. The
study was stopped early owing to the with-
drawal of AIR insulin. The mean age was
56 years, and just over 50% of patients
were men. FEV1 fell compared with base-
line in those who received AIR insulin. This
change was observed at 1 month and per-
sisted, but did not decline further. Forced
vital capacity (FVC) was also lower. There
was no change in lung diffusion capacity.
Cough was the most frequently reported
Chapter 42 R.C.L. Page
adverse effect (20% of those using AIR com-
pared with 10% injecting insulin). In all, 175
patients completed 6 months of AIR, 141
patients completed 12 months, and only
one patient completed the planned 2 years.
In a similar study, which was also
stopped, in patients with type 1 diabetes,
82 of 193 patients who used prandial AIR
insulin and 84 of 192 who used injections
completed the 2-year study [28c]. The mean
age was 39 years. AIR insulin was associ-
ated with signicantly greater reductions
in diffusion capacity, but not FVC. Hypo-
glycemia was the most frequent signicant
adverse event in those using AIR and
injected insulin, and it occurred at a similar
frequency (5.3 events per patient per
30 days).
Intranasal insulin Intranasal insulin has
been studied in 25 patients with Alzhei-
mer's disease; 12 received placebo and 13
received Novolin R 20 units using a Via-
nase Electronic Atomizer [29c]. Fasting glu-
cose and insulin concentrations did not
change, but there was a reduction in post-
prandial insulin concentrations in those
who used insulin. At 21 days those who
used insulin appeared to have improved
attention compared with controls.
In six children with 22q13 deletion syn-
drome, Actrapid insulin given intranasally
via an Aero pump was gradually titrated
to 0.51.5 units/kg/day in three divided
doses [30c]. Blood glucose concentrations
did not change. One patient had intermit-
tent nose bleeds. The children were
assessed after 6 weeks and 12 months of
treatment and were thought to have had
improved cognitive function. There was no
control group.
Drugdrug interactions The manufacturer
of insulin glargine does not recommend
mixing it with rapid-acting insulin ana-
logues. In 19 children with type 1 diabetes,
mean age 11 years, who used insulin glar-
gine mixed with a rapid-acting analogue
and who were compared with 17 children
who used NPH insulin mixed with a rapid-
acting analogue for 3 months, those who
Insulin, other hypoglycemic drugs, and glucagon
used insulin glargine had better blood glu-
cose control [31c].
ALPHA-GLUCOSIDASE
INHIBITORS [SED-15, 85; SEDA-
30, 496; SEDA-31, 691; SEDA-32, 772]
Acarbose
Metabolism German guidelines have re-
minded us that if acarbose is combined with
insulin in the treatment of diabetes, hypo-
glycemia must be treated with glucose and
not with oligosaccharides [32S].
Skin Acute generalized exanthematous pus-
tulosis has been attributed to acarbose in a
38-year-old woman, using the EuroSCAR
Study Group criteria [33A].
AMYLIN ANALOGUES
[SEDA-30, 496; SEDA-31, 692;
SEDA-32, 773]
Pramlintide
Metabolism In 10 people, aged 1317 years,
who were randomized unblinded to pram-
lintide in addition to insulin or to continue
taking their usual insulin, the initial dose
of pramlintide was 15 micrograms/day sub-
cutaneously, titrated to 30 micrograms/day
after 4 days [34c]. At 4 weeks those who
used pramlintide had reduced weight by
0.8 kg compared with a gain of 0.9 kg in
those who used insulin alone, although this
was not statistically signicant. The dose of
insulin fell in those who used pramlintide,
without an increase in blood glucose
concentrations.
Susceptibility factors Age The use of pram-
lintide in adolescents with type 1 diabetes
has been evaluated in small studies. The
results suggest that the effects of
Chapter 42 893
pramlintide in adolescents are similar to
those found in adults.
BIGUANIDES [SED-15, 506;
SEDA-30, 497; SEDA-31, 692;
SEDA-32, 773]
Metformin
Acidbase balance In 42 patients with met-
formin-associated lactic acidosis between
1998 and 2007, who were identied from a
database, all of whom had type 2 diabetes,
13 had taken an intentional overdose and
all survived; 29 developed lactic acidosis in
association with circulatory or respiratory
failure, of whom 14 died [35c]. A predictive
factor for death was prothrombin time at
the time of admission. The difference in
mortality rates was highly signicant. Met-
formin increases lactate by stimulating
anerobic glucose metabolism, even in the
presence of adequate oxygen. In overdose
large amounts of lactate are produced.
Blood concentrations of metformin corre-
lated with pH but the concentrations of lac-
tate in these circumstances do not appear to
correlate with mortality. Patients treated
with metformin with other signicant ill-
nesses need early recognition of the possi-
bility of lactic acidosis and intensive
treatment. The outcome is often poor.
In a similar retrospective study over
5 years, 30 patients with metformin-associ-
ated lactic acidosis were admitted to inten-
sive care; three had taken an overdose; 21
survived [36c]. Prothrombin time was also
related to survival, which may imply that
liver function is particularly important.
Not all patients received hemodialysis, but
there was no difference in survival between
those who did and did not.
Of 21 patients with lactic acidosis between
2001 and 2005, 13 were taking metformin; 18
had acute gastrointestinal problems and three
had congestive heart failure [37c]. None of the
patients stopped taking metformin, despite
having had several days of illness before
894
admission; four patients died within hours,
despite intensive medical therapy.
Two case reports have demonstrated the
importance of withdrawing metformin at
the time of anesthesia and ensuring that
the patient is well before restarting.
A 64-year-old woman with mild chronic renal
impairment who was taking metformin 3 g/day,
allopurinol 300 mg/day, verapamil 120 mg/day,
irbesartan 300 mg/day, and furosemide 25 mg/
day, developed nausea, vomiting, and abdomi-
nal pain 6 days after a surgical procedure [38A].
The serum creatinine concentration had risen
to 500 mmol/l, and the pH was 7.16 with a serum
bicarbonate of 11 mmol/l. She was treated with
sustained low-efciency daily dialysis (SLEDD)
with GENIUS. Acidbase balance returned to
normal after three treatments.
A 49-year-old woman who was taking metfor-
min, losartan, bendroumethiazide, and aten-
olol, developed diarrhea and vomiting after
general anesthesia for a minor procedure
[39A]. Her symptoms continued for 5 days
and worsened with the development of dys-
pnea. Her pH was less than 6.8 and the serum
creatinine concentration was 769 mmol/l. She
was treated with continuous hemoltration
for 4 days and made a good recovery.
Patients taking metformin should be
reminded to discontinue therapy when they
have another illness and to seek medical
help [40R].
Hematologic Metformin-induced hemolytic
anemia is rare and generally not fatal; the
time to onset of symptoms after starting
metformin is about 10 days. A fatal case
has been reported [41A].
A 56-year-old man with type 2 diabetes and a
hemoglobin of 14.7 g/dl took metformin
500 mg bd for 4 days, in addition to pantopra-
zole, levothyroxine, and glibenclamide. The
day after starting metformin he developed pal-
pitation and labored breathing and discontin-
ued the therapy. On the next day he was
given ciprooxacin for hematuria. Two days
later his hemoglobin had fallen to 6.6 g/dl.
There was severe hemolysis and a direct anti-
globulin test was positive for anti-IgG. Despite
intensive treatment the hemoglobin fell to
3.3 g/dl and the patient died 12 hours later.
It was thought that metformin may
have been the cause of the hemolytic
Chapter 42 R.C.L. Page
anemia, although ciprooxacin was also a
possibility.
Susceptibility factors Genetic An epidemi-
ological study has suggested that genetic
susceptibility may alter the effectiveness of
metformin. Polymorphisms in MATE1
may be important in the pharmacokinetics
of metformin. Impairment of the MATE1
transporter leads to increased metformin
plasma concentrations, owing to reduced
efux of metformin at the renal brush bor-
der. In 116 people with type 2 diabetes
using metformin, the SNP rs2289669 in the
SLC47A1 gene that encodes the MATE1
transporter was associated with a 0.3%
reduction in HbA1c for each copy of the A
allele [42c].
Drug overdose There have been two fur-
ther reports of self-poisoning with metfor-
min, both associated with acidosis.
A 30-year-old woman took 85 g of metformin
about 6 hours before admission to hospital.
Her pH was 6.88 and bicarbonate 7.3 mmol/l;
she was hemodialysed with bicarbonate and
plasma exchange and made a complete recov-
ery [43A].
A 28-year-old pregnant woman took 40 g of
metformin at 24 weeks of pregnancy [44A].
Her pH was 7.07. She was treated with intra-
venous 0.9% saline and sodium bicarbonate
and activated charcoal via nasogastric tube.
After 10 hours of treatment her pH was 7.3.
A healthy baby was delivered 8 weeks later
and had no signicant health problems after
2 years.
DIPEPTIDYL PEPTIDASE 4
(DDP-4) INHIBITORS [SEDA-
30, 498; SEDA-31, 693; SEDA-32, 774]
The DDP-4 inhibitors are chemically
variable and their metabolic pathways are
different. Sitagliptin, (2R)-4-oxo-4[3-(tri-
uoromethyl)-5,6-dihydrol[1,2,4]triazolol[4,
3-a]pyrazin-7(8H)-yl]-1-(2,4,5-triuorophe-
nyl)butan-2-amine, is primarily eliminated
unchanged, 80% being excreted in the
Insulin, other hypoglycemic drugs, and glucagon
urine. Vildagliptin, 1-[[(3-hydroxy-1-ada-
mantyl)amino]acetyl]-2-cyano-(S)-pyrolidine,
is largely metabolized by the kidney, and
only 23% is found unchanged in the urine.
Saxagliptin is metabolized by CYP isoen-
zymes, and its metabolite is half as potent
[45S].
In reviews of trials of sitagliptin and vil-
dagliptin there were no cases of signicant
hypoglycemia. Nasopharyngitis, upper
respiratory tract infections, urinary tract
infections [46R], and headache [47R] were
the most commonly reported adverse
reactions.
Studies of saxagliptin and vildagliptin
have taken place in patients without signif-
icant heart failure and so there are no
safety data in this patient group.
Alogliptin
Skin In a 26-week randomized placebo-
controlled study in 527 patients, mean age
55 years, with type 2 diabetes taking met-
formin, alogliptin 12.5 or 25 mg/day was
associated with skin-related adverse events
in 7.7% of those taking placebo compared
with 12% in both alogliptin groups. Dry
skin, pruritus, rashes, and eczema were
reported; one patient stopped taking alo-
gliptin because of an eruption [48C].
Saxagliptin
Fluid balance In a study of 768 patients,
mean age 55 years, with type 2 diabetes
taking glibenclamide, who were random-
ized to additional saxagliptin or 5 mg/day
or placebo for 24 weeks, patients were
excluded if they had had a cardiovascular
event in the preceding 6 months or a diag-
nosis of congestive heart failure, signicant
renal or liver disease, or had taken potent
CYP3A4 inhibitors or inducers. There were
two cases of localized edema, one in a
patient taking saxagliptin 2.5 mg/day and
one taking 5 mg/day; both continued ther-
apy [49C]. In a similar study combining
Chapter 42 895
saxagliptin with pioglitazone or rosiglita-
zone, 565 patients with a mean age of
54 years were randomized [50C]. Peripheral
edema was more common in those taking
saxagliptin 5 mg/day than with 2.5 mg/day
or placebo (8%, 3%, and 4% respectively).
Sitagliptin
Immunologic Serious hypersensitivity reac-
tions, including anaphylaxis and angio-
edema, have occurred in patients taking
sitagliptin [51A]. These are individual case
reports and the frequency is unknown.
Vildagliptin
Ear, nose, and throat A 52-week study was
extended for a further 52 weeks with a dou-
ble-blind extension for those who agreed to
continue; 569 people completed the initial
study and 402 completed the extension
[52c]. The patients had type 2 diabetes and
had not taken drug therapy before the
study. In 304 predominantly Caucasian
patients, mean age 54 years and BMI 33,
who took vildagliptin 100 mg/day, the most
common adverse reaction was nasopharyn-
gitis (16%). Upper respiratory tract infec-
tions occurred in 10%. Headache was
reported in 13%.
Metabolism A conrmed case of hypo-
glycemia was reported in one of 304
patients who took vildagliptin for 2 years;
it was of moderate intensity and was precip-
itated by strenuous exercise [52c].
Liver Rare case reports of liver abnormali-
ties have been reported in patients taking
vildagliptin; liver function returns to normal
on withdrawal; it is recommended that liver
function be checked before starting therapy
and 3-monthly during the rst year [53S].
896
INCRETIN MIMETICS [SEDA-
30, 49; SEDA-31, 695; SEDA-32, 775]
Gastrointestinal The most frequent adv-
erse reactions reported with incretin
mimetics are gastrointestinal symptoms.
These include nausea, vomiting, and diar-
rhea, which occur in 1015% of patients,
are dose-related, and tend to abate during
the rst few weeks of treatment [54R].
EIDOS classication:
Extrinsic species Incretin mimetics
Intrinsic species Not known
Distribution ?Stomach, ?brain
Outcome Altered function
Sequela Nausea and vomiting due to
incretin mimetics
DoTS classication:
Dose-relation Collateral
Time-course Intermediate
Susceptibility factors None known
In a systematic review of 17 controlled
trials of subjects with poorly controlled dia-
betes nausea was the most common adverse
event in placebo-controlled trials. The rates
of hypoglycemia were similar in compari-
sons of exenatide and insulin, but were
more common with exenatide 10 micro-
grams bd than with placebo; hypoglycemia
occurred predominantly when a sulfonyl-
urea was co-administered with exenatide
[55M].
Exenatide
Pancreas Acute pancreatitis has been
attributed to exenatide in a woman with
type 2 diabetes [56A].
Urinary tract It has been suggested, on the
basis of a single case, that exenatide may
cause further impaired renal function in
patients with type 2 diabetes and pre-exist-
ing mild to moderate renal impairment
[57A].
Chapter 42 R.C.L. Page
A 66-year-old man with type 2 diabetes, who
was already using insulin, was given exenatide
5 micrograms bd, and in the next 4 weeks his
serum creatinine rose 192 to 244 mmol/l, with
a reduction in CockcroftGault calculated cre-
atinine clearance from 53 to 42 ml/minute.
There was no evidence of urinary tract infec-
tion, obstruction, or dehydration. Exenatide
was withdrawn, and within the next 2 weeks
his renal function returned to pretreatment
values (creatinine 196 mmol/l, creatinine clear-
ance 52 ml/minute).
In four patients with type 2 diabetes (three
men and one woman; ages 5273 years), who
were taking stable doses of ACE inhibitors
and diuretics, exenatide was associated with
renal impairment [58c]. The time between
starting exenatide and the diagnosis of renal
failure was 29 months, and the drug was
withdrawn within 3 months after diagnosis
except in one patient, whose symptoms
improved after dosage reduction. In three
cases recovery of renal function was incom-
plete after drug withdrawal or dosage reduc-
tion. The authors proposed that exenatide
could contribute to extracellular volume
contraction by causing nausea, vomiting, or
reduced uid intake, which, in combination
with diuretics and ACE inhibitors, could
lead to impaired renal function. They also
pointed out that glucagon-like peptide
causes a natriuresis, which could reduce
renal perfusion, an effect that could be
shared by incretin mimetics.
Liraglutide
Liraglutide is a GLP-1 analogue, adminis-
tered subcutaneously once a day as an iso-
tonic solution. It has a substitution of
lysine to arginine at position 34 and attach-
ment of a C16 fatty acid at position 26. The
tmax and half-life are both about 12 hours.
Steady state occurs at about 4 days [59R,
60R].
Pancreas In the LEAD (Liraglutide Effect
and Action in Diabetes) studies, nine cases
of pancreatitis were reported, eight of which
were in those taking liraglutide. The rates
were: 2.2, 0.0, 0.9, and 0.6 events per 1000
Insulin, other hypoglycemic drugs, and glucagon
subject-years of exposure for total liraglu-
tide, placebo, active comparator, and total
comparator respectively. Patients who take
exenatide are warned of the risk of pancre-
atitis similar warnings are required for lira-
glutide [61R] [59R].
Immunologic It has been reported that
antibodies to liraglutide do not develop
[46R]. However, in the LEAD-5 study,
which was a 26-week study of 581 patients
with type 2 diabetes, mean age 57 years,
in which patients were randomized to lira-
glutide 1.8 mg/day, placebo, or insulin glar-
gine, antibodies were present in 9.8% [62C].
However, the antibodies did not appear to
impair the blood glucose-lowering effect of
liraglutide.
Tumorigenicity Rodents who are given lir-
aglutide have an increased risk of thyroid
C-cell tumors and increased concentrations
of calcitonin [63E]. In the LEAD-6 study,
which was an open comparison of liraglu-
tide (n 233) and exenatide (n 231), in
patients with type 2 diabetes, mean age
56 years for 26 weeks, calcitonin concentra-
tions fell slightly in both groups [64C]. Cal-
citonin screening is not thought to be
necessary. Papillary thyroid cancer has
been reported to occur at a rate of 1.6%
per 1000 patient-years of exposure in
patients who use liraglutide, compared with
0.6% in those who use exenatide. Longer-
term data are required to determine the
importance of these ndings [65r].
Susceptibility factors Renal disease Of 30
subjects, aged 3182 years, three with type
2 diabetes, who received a single subcuta-
neous dose of liraglutide 0.75 mg, six had
normal renal function, six mild renal impair-
ment (creatinine clearance 5080 ml/
minute), seven moderate renal impairment
(creatinine clearance 3050 ml/minute), ve
severe renal impairment (creatinine clear-
ance less than 30 ml/minute), and six end-
stage renal failure treated with CAPD [66c].
Concentration proles were similar in all
groups. Cmax varied from 7.9 nmol/l in those
with mild renal impairment to 10.5 in those
with end-stage renal failure, but there was
Chapter 42 897
no consistent trend. The half-life varied from
11 hours in those with end-stage renal failure
to 14 hours in healthy subjects.
MEGLITINIDES [SED-15, 2238;
SEDA-31, 695; SEDA-32, 776]
Metabolism The use of meglitinides has
been evaluated in China in patients with
type 2 diabetes, 433 of whom used nategli-
nide and 436 repaglinide, mean age 55 years
and BMI 25 kg/m2. There was no statisti-
cally difference in the rates of adverse
events, but the risk of an event was 0.59
times higher in those who took nateglinide;
the most common adverse event was hypo-
glycemia [67R].
The incidence of episodes of hypoglycemia
and the patterns of their occurrence during
the rst 9 months of treatment with four oral
hypoglycemic drugs, rosiglitazone, pioglita-
zone, nateglinide, and repaglinide, have been
studied in a prescription-event monitoring
(PEM) study in 14 373, 12 768, 4549, and
5727 patients respectively, of whom 276 had
at least one episode of hypoglycemia [68C].
The incidence rate was 50100% higher in
patients taking meglitinides compared with
those taking thiazolidinediones (9.94, 9.64,
15.7, and 20.3 per 1000 patient-years for rosi-
glitazone, pioglitazone, nateglinide, and repa-
glinide respectively). The person-time in days
was 999 060 for nateglinide and 1 275 333 for
repaglinide. Hypoglycemia occurred more
often soon after starting treatment, and the
risk fell with time.
Repaglinide
Metabolism Hypoglycemia has again been
reported [69A].
An 82-year-old man developed dizziness and
confusion due to hypoglycemia and was given
one ampoule (quantity not specied) of 50%
intravenous dextrose. His symptoms resolved.
Laboratory tests showed high concentrations
898
of C-peptide and insulin and he was therefore
given 75 micrograms of octreotide subcutane-
ously and remained well over the next 6 hours.
Octreotide is useful in the management of
prolonged hypoglycemia due to sulfonyl-
ureas. Repaglinide has a short half-life and
there was no suggestion of overdose in this
case. Whether the octreotide added to the
management is uncertain.
Drugdrug interactions Gembrozil Gem-
brozil increases the blood glucose-lower-
ing effect of repaglinide. The timing of the
last dose of gembrozil has been studied
in 10 healthy volunteers who took repagli-
nide 0.25 mg without gembrozil and then
again 0, 3, 6, or 12 hours after gembrozil
600 mg [70c]. The AUC was increased for
all doses taken with or after gembrozil,
gradually falling from a sevenfold increase
when taken simultaneously to a vefold
increase when taken 12 hours after. Thus,
taking tablets at different times of day does
not alter the effect of gembrozil on the
pharmacokinetics of repaglinide.
SODIUM GLUCOSE
TRANSPORTER TYPE 2
(SGLT2) INHIBITORS
SGLT2 inhibitors block the transport of glu-
cose into the renal tubule. Sergliozin etabo-
nate [71E, 72R, 73M] and dapagliozin [74R,
75R] are two such drugs under development.
SULFONYLUREAS [SED-15,
3230; SEDA-30, 500; SEDA-31, 695;
SEDA-32, 777]
Tumorigenesis In a casecontrol study of
the tumorigenic effect of sulfonylureas,
1919 people with type 2 diabetes, mean age
64 years, 1092 men, were followed for
6.5 years [76C]. There were 195 cases of
Chapter 42 R.C.L. Page
cancer, of which gastrointestinal cancer was
most common (n 48). When cases were
compared with controls identied from the
same cohort, there appeared to be an
increased risk of cancer in those receiving
glibenclamide. The odds ratio for those who
had used glibenclamide for at least 36 months
was 2.62. This was not found for gliclazide,
which had an odds ratio of 0.4. This study
was small and the data were partly self-
reported, so further studies are warranted.
Glibenclamide
Pregnancy When 99 women with gestational
diabetes were randomized to either insulin or
glibenclamide (n 49) for blood glucose
control, 82 of their neonates, 41 in each group,
were examined for adiposity using measures
such as skin-fold thickness and BMI [77c].
There were no differences between the
groups. However, 22% of babies whose
mothers took glibenclamide had macrosomia,
dened as a birth weight above 4 kg, com-
pared with 2% of those who used insulin.
Gliclazide
Drug overdose In a case of overdose with gli-
clazide there was severe hypoglycemia with-
out adrenergic or autonomic responses [78A].
Glimepiride
Respiratory Asthma has been attributed to
glimepiride in a 40-year-old woman with
type 2 diabetes but no allergies or history
of asthma [79A]. It occurred 2 hours after
the rst dose. A subsequent drug-induced
lymphocyte stimulating test against glime-
piride was positive, and tests against pio-
glitazone, gliclazide, and glibenclamide
were negative.
Insulin, other hypoglycemic drugs, and glucagon
THIAZOLIDINEDIONES
(GLITAZONES) [SED-15, 3380;
SEDA-30, 501; SEDA-31, 697; SEDA-
32, 779]
Cardiovascular Previous reports have sug-
gested that pioglitazone may have better
cardiovascular safety than rosiglitazone
[SEDA-31, 697; SEDA-32, 779]. Further
studies have supported this nding [80R].
Out-patients (n 39 736) aged 66 years
or older who had used either pioglitazone
or rosiglitazone were identied from the
Ontario Public Drug Benet Program pre-
scription records [81C]. Those who had taken
pioglitazone had a lower risk of death or hos-
pital admission for either acute myocardial
infarction or heart failure compared with
rosiglitazone, with an adjusted hazard ratio
of 0.8. Further analysis showed that this was
due to a reduction in death (adjusted hazard
ratio 0.86) and heart failure (0.77). There
was no difference in the risk of acute myocar-
dial infarction (0.95).
In a population-based retrospective cohort
study, which used data from the National
Health Insurance database in Taiwan in
473 483 patients who had newly diagnosed
type 2 diabetes and who had taken oral anti-
hyperglycemic agents at least three times
from 2001 to 2005, those who had received
rosiglitazone alone (n 2093) had a higher
risk of any cardiovascular event than those
who had received pioglitazone alone
(n 495): 13% (n 266) compared with
8.9% (n 44) [82C]. However, the differ-
ences between the drugs when they were used
as additional therapy were not signicant.
In a casecontrol study of 9870 cases and
29 610 controls, mean age 63 years, there
was difference in the risk of myocardial
infarction in those taking pioglitazone com-
pared with rosiglitazone [83C]. Data were
obtained from the Integrated Healthcare
Information Services claims database.
Cases were dened as people with a diag-
nosis of myocardial infarction at least
3 months after developing diabetes.
In a further similar study, patients with type
2 diabetes were identied from electronic
Chapter 42 899
records at the Cleveland Clinic between
1998 and 2006; 1079 had used rosiglitazone
monotherapy and 1508 pioglitazone [84C].
There was no difference in the risk of coro-
nary artery disease or mortality.
Studies of adipocytes have suggested that
there is only 40% concordance between pio-
glitazone and rosiglitazone in gene expres-
sion; 23 genes are commonly regulated,
with 12 additional genes only regulated by
pioglitazone and ve only regulated by rosi-
glitazone. These differences may explain
some of the variation in clinical outcomes in
studies [85R, 86R].
Heart failure in those taking thiazolidine-
diones has been explained by uid reten-
tion in susceptible individuals; PPAR-g
receptors are present in the distal renal
tubule collecting ducts [87R].
Sensory systems Vision An increased risk
of macular edema is a recognized adverse
reaction to thiazolidinediones. Using data
obtained from a US Kaiser Permanente
diabetes database 996 new cases of macular
edema were recorded in 2006 in 59 013
patients with diabetes [88c]. Those who
took a thiazolidinedione (98% pioglita-
zone) and or insulin were at an increased
risk of macular edema compared with
patients who took other oral agents. Odds
ratios were 1.6 for thiazolidinediones and
2.8 for insulin, compared with odds ratios
of 0.8 for sulfonylureas and 0.9 for
metformin.
Musculoskeletal Reduced bone density and
risk of fracture
EIDOS classication:
Extrinsic species Thiazolidinediones
Intrinsic species Osteoclasts
Distribution Bone
Outcome Atrophy
Sequela Reduced bone density and
increased risk of fractures due to
thiazolidinediones
DoTS classication:
Dose-relation Collateral
Time-course Late
900
Susceptibility factors Age (elderly
patients); sex (female sex,
postmenopausal)
Data from a prospective cohort study of
84 339 patients in Canada, mean age
59 years, 43% women, have conrmed the
increased risk among women of peripheral
fractures when taking thiazolidinediones;
the NNTH for one additional peripheral
fracture in patients taking a thiazolidine-
dione for 3 years was 86 [89c]. The data also
suggested an increased risk in men using
pioglitazone compared with sulfonylureas.
Pioglitazone
Observational studies In a general practice
study in England using prescription-event
monitoring, 34 151 patients were given pio-
glitazone between November 2000 and
June 2001. Useful data were available for
12 772 patients (53% male, median age
62 years); 3690 discontinued treatment,
most commonly because of hyperglycemia
(n 1143) and lack of hypoglycemic effect
(n 831). Other reasons included edema
(n 121) and weight gain (n 118) [90C].
The most common adverse events were
malaise and lassitude (0.23%; n 30),
nausea and vomiting (0.22%; n 28), and
dizziness (0.17%; n 22).
Systematic reviews In a meta-analysis of
ve randomized, controlled trials in 9965
patients taking pioglitazone, in which data
on myocardial infarction were available,
the relative risk of myocardial infarction
was 0.86 (95% CI 0.69, 1.07) [91M]. The
relative risks for stroke and revasculariza-
tion were 0.79 (0.61, 1.02) and 0.40 (0.13,
1.23) respectively. The authors concluded
that pioglitazone does not increase the risk
of myocardial infarction.
Cardiovascular In 518 patients with type 2
diabetes and New York Heart Association
functional heart failure class II/III, mean
Chapter 42 R.C.L. Page
age 64 years, who were randomized to pio-
glitazone 30 mg/day (n 262) or glibencla-
mide 10 mg/day (n 256) for 6 months,
those who took pioglitazone had a higher
incidence of heart failure; 30 required hos-
pitalization or acute attendance at hospital
compared with 15 taking glibenclamide,
but there was no difference in death rates
[92C].
Metabolism Weight gain is a well-recog-
nized adverse effect of pioglitazone ther-
apy. In 31 Japanese patients with type 2
diabetes who took pioglitazone 15 mg/day
for 3 months, increasing to 30 mg/day for
a further 9 months, 14 of whom also took
the alpha-glucosidase inhibitor voglibose
0.9 mg/day, those who took voglibose
gained 0.1 kg compared with 2.5 kg in the
control group [93c]. Voglibose is an alpha-
glucosidase inhibitor. It is unclear why
there should be less weight gain in those
taking pioglitazone and voglibose.
Liver Patients aged 1880 years (mean
54 years) with type 2 diabetes were ran-
domized to either pioglitazone 1545 mg/
day (n 1063) or glibenclamide 515 mg/
day (n 1057). Liver enzymes were mea-
sured every 2 months in the rst year of
the study and then every 3 months for the
remaining 2 years [94C]. Only 411 and 413
patients completed the study in the two
groups. Those who took pioglitazone had
fewer hepatobiliary events (n 15; 1.4%)
compared with those taking glibenclamide
(n 26; 2.5%). Two patients stopped tak-
ing pioglitazone because of abnormal liver
function compared with eight taking gliben-
clamide. Statin therapy was used by about
33% of the patients. These results suggest
that pioglitazone does not cause more
problems with liver function than glibencla-
mide and can be safely used in conjunction
with statins. However, the withdrawal rate
was high.
In the PROactive study of patients with
type 2 diabetes and pre-existing cardiovas-
cular disease, the frequency of serious liver
disorders was similar in those taking pio-
glitazone (n 4 of 2605) compared with
those taking placebo (n 5 of 2633) [95C].
Insulin, other hypoglycemic drugs, and glucagon
Urinary tract In 10 patients with type 2 dia-
betes treated with hemodialysis, mean age
67 years, who were taking pioglitazone
15 mg/day, which was increased after 4 weeks
to 30 mg/day for a further 8 weeks, there
were no signicant adverse reactions [96c].
Tumorigenicity In the PROactive study,
which randomized 5238 people with type 2
diabetes, mean age 62 years, to pioglita-
zone (n 2605) or placebo (n 2633),
the incidence of any malignant neoplasm
was similar in the two groups, 3.7% and
3.8%. The types of neoplasia differed
between the groups. There were 14 cases
of bladder neoplasm compared with six in
the placebo group, but only three cases of
breast cancer compared with 11 in the pla-
cebo group [95C]. Whether long-term use
of pioglitazone carries a risk of bladder
neoplasia continues to be explored.
Pregnancy Two pregnancies have been
reported in women taking pioglitazone
[90C]. One woman gave birth to a live baby
at term; exposure had been only in the rst
month of pregnancy. The other woman,
whose exposure had been during the rst
6 weeks, gave birth to a baby with sireno-
melia, who died within 3 hours of birth.
Rosiglitazone
Cardiovascular In September 2010, the
European Medicines Agency completed a
review focused on cardiovascular safety
and decided that medicines containing rosi-
glitazone should stop being available in
Europe.
In patients with type 2 diabetes aged
4075 years (mean 58 years) with a BMI
of more than 25 kg/m2 (mean 31 kg/m2)
taking metformin and a sulfonylurea, who
were randomly allocated to additional rosi-
glitazone or metformin or sulfonylurea,
there was no difference at 5 years between
those taking rosiglitazone (n 2220) and
those taking the metformin and sulfonylurea
combination (n 2227) for all causes of
Chapter 42 901
death (136 compared with 157). However,
the risk of heart failure doubled (HR 2.1;
61 compared with 29), and although cardio-
vascular death rates were similar (60 com-
pared with 71), deaths due to heart failure
were signicantly increased.
In a multicenter, open trial in 4447
patients with type 2 diabetes taking met-
formin or sulfonylurea monotherapy, who
were randomized to additional rosiglita-
zone (n 2220) or to a combination of
metformin and a sulfonylurea (n 2227),
there was a non-signicant excess of myo-
cardial infarction (HR 1.14) [97C].
The safety of rosiglitazone has continued
to be examined. The 2010 FDA meta-
analysis did not include large trials, but
included data from 52 studies of 2 months
to 2 years duration in a total of 12 069
patients, mean age 58 years, 59% men, with
a mean BMI of 30 kg/m2 [98M]. The odds
ratio for myocardial infarction in those tak-
ing rosiglitazone was 1.8 and for congestive
heart failure 1.93. These data support the
continued concern about the use of rosigli-
tazone in type 2 diabetes.
Liver In 63 patients with non-alcoholic
steatohepatitis who were randomized to
rosiglitazone 4 mg/day for 1 month, increas-
ing to 8 mg/day for 11 months (n 32,
mean age 53 years, 19 men) or placebo
(n 31, mean age 54 years, 18 men),
rosiglitazone did not cause adverse liver
reactions [99C].
Susceptibility factors Renal disease A
study of the Dialysis Outcomes and Prac-
tice Patterns Study (DOPPS) identied
2393 patients taking oral hypoglycemic
agents, of whom 177 were taking rosiglita-
zone and 118 pioglitazone. Mean age was
63 years and about 47% were men. Those
taking rosiglitazone had an increased risk
of all-cause mortality (HR 1.38) and
cardiovascular mortality (HR 1.59) com-
pared with those taking non-thiazolidine-
dione oral hypoglycemic agents [100C].
Drugdrug interactions Fibrates Case
reports have reinforced the need to
902
monitor HDL concentrations when rosigli-
tazone is combined with a brate [SEDA-
32, 781; 101A].
A 66-year-old woman with raised triglycerides
and type 2 diabetes taking metformin, rosi-
glitazone, aspirin, metoprolol, uvastatin, and
hydrochlorothiazide had the dose of metformin
increased and fenobrate added. The HDL
cholesterol fell from 1.19 to 0.26 mmol/l. Rosi-
glitazone was changed to pioglitazone and the
HDL cholesterol increased to 1.22 mmol/l.
A 71-year-old man with type 2 diabetes taking
amlodipine, warfarin, valsartan, hydrochloro-
thiazide, atenolol, and rosiglitazone was given
fenobrate. The HDL cholesterol fell from
0.96 to 0.60 mmol/l but rose to 0.80 mmol/l
on changing the rosiglitazone to pioglitazone.
A 64-year-old woman with type 2 diabetes tak-
ing metoprolol, aspirin, niacin, warfarin, simva-
statin, rosiglitazone, and metformin was given
fenobrate. The HDL cholesterol fell from
1.09 to 0.44 mmol/l. The fenobrate was with-
drawn and the HDL rose to 1.09 mmol/l.
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PROLIFERATOR-
ACTIVATED DUAL
RECEPTOR AGONISTS
[SEDA-32, 782]
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43 Miscellaneous hormones
Calcitonin [SED-15, 595; SEDA-30, 507;
SEDA-31, 703; SEDA-32, 789]
The adverse effects of salmon calcitonin
have again been reviewed [1R]. Salmon cal-
citonin nasal spray is thought to be safe.
Hypersensitivity is the only contraindication.
The systemic adverse reactions of ushing
and nausea that occur with injections are
rare. Local reactions due to nasal irritation
are the most common adverse reactions.
Gonadotropins (gonadorelin,
GnRH, and analogues) [SED-15,
1536; SEDA-30, 507; SEDA-31, 703;
SEDA-32, 789]
A review of the use of gonadorelin analogues
for precocious puberty showed that in general
they were well tolerated [2R]. Headache and
hot ushes were usually short-term problems.
Local adverse events at the injection site occa-
sionally required a change of therapy. Ana-
phylaxis has been described. Bone mineral
density was not thought to be adversely
affected in this group. In contrast gonadorelin
therapy alone was not recommended for the
management of idiopathic short stature,
when the delay in puberty can compromise
bone mineral density.
Cardiovascular In 945 men with prostate
cancer who were randomly allocated to
Side Effects of Drugs, Annual 33
J.K. Aronson (Editor)
ISSN: 0378-6080
DOI: 10.1016/B978-0-444-53741-6.00043-X
# 2011 Elsevier B.V. All rights reserved.
R.C.L. Page
external beam radiotherapy combined with
goserelin acetate or to radiotherapy fol-
lowed by goserelin only if there was relapse,
the mean period of follow-up was 8.1 years,
during which there were 574 deaths, 117 of
which were due to cardiovascular disease
[3C]. There was no increased risk of cardio-
vascular mortality in men who used adjuvant
goserelin compared with those not using
goserelin (8.4% versus 11%). The risk of
cardiovascular disease has previously been
reported to increase in men using GnRH
agonists for prostate cancer.
Nervous system Drug-induced chorea has
previously been described with the use of
the combined oral contraceptive, but the
mechanism is uncertain. A case involving
goserelin has been reported [4A].
A 77-year-old man complained of involuntary
movements after taking goserelin for prostate
cancer for 6 weeks. He continued therapy for
about 10 months and his symptoms persisted,
but 3 months after stopping goserelin the
abnormal movements stopped.
Reproductive system Ovarian hyperstimu-
lation syndrome has been attributed to trip-
torelin [5A].
A 35-year-old woman with infertility received
triptorelin 3.75 mg on day 21 of her menstrual
cycle and 10 days later a scan showed 12 folli-
cles measuring 1619 mm in both ovaries. She
had symptoms of nausea and abdominal
bloating.
A 26-year-old woman with infertility received
triptorelin 3.75 mg and 2 weeks later devel-
oped abdominal heaviness; a scan showed
bilateral follicles of 1521 mm in both ovaries.
Ovarian hyperstimulation has been previ-
ously been reported but is uncommon after
the sole administration of triptorelin.
909
910
In an uncontrolled study in 13 patients
aged 3042 years with endometriosis or
menorrhagia, who took the aromatase
inhibitor letrozole 2.5 mg/day for the rst
5 days after receiving leuprolide acetate
3.75 mg intramuscularly, the initial increase
in estrogen concentrations was not appar-
ent [6c]. In a randomized study in healthy
subjects, mean age 30 years, who received
triptorelin 3.75 mg (two injections 4 weeks
apart), with or without oral exemestane
25 mg/day for 56 days, there was no effect
on the initial are of FSH, LH, and estro-
gen, although there was subsequent
increased suppression of estrogen [7c]. Of
the 14 women who received placebo with
triptorelin, 11 had hot ushes compared
with nine of the 15 who took exemestane.
Musculoskeletal Gonadorelin has been
used for the management of endometriosis
in adolescents [8R]. In this group the effect
on bone mineral density can be minimized
by using norethindrone acetate with or
without estrogen at the same time.
Tumorigenicity In an analysis of data from
54 362 women referred to Danish hospitals
between 1963 and 1968 with infertility
problems (median age at rst evaluation
30 years), there were 156 patients with epi-
thelial ovarian tumors, who were compared
with a randomly selected subcohort [9C].
Various infertility therapies had been used.
The risk of ovarian cancer was not
increased after any use of gonadotropins
(rate ratio 0.83).
Drug formulations In patients, mean age
73 years, with prostate cancer, a study of
the use of leuprorelin acetate 11.25 mg
injections every 3 months for 12 months
(n 58), compared with six monthly injec-
tions of depot leuprorelin acetate contain-
ing either 22.5 or 30 mg (n 120), the
results suggested no differences in adverse
reactions [10C]. Flushing was the most com-
mon adverse reaction; it occurred in 43% of
those who received 11.25 mg and in 34% of
those who received 30 mg. Increased sweat-
ing was also slightly more common in those
who received 11.25 mg. Injection site
Chapter 43 R.C.L. Page
reactions were more common in those who
received 30 mg, 12% versus 2%. Overall
the frequency of adverse reactions was
similar.
Somatropin (human growth
hormone, hGH) [SED-15, 3163;
SEDA-30, 508; SEDA-31, 705; SEDA-32,
791]
Cardiovascular In 14 patients with growth
hormone deciency (aged 3362 years, four
men), who were given growth hormone at
an initial dose of 0.015 mg/kg/week, the
dose was then titrated depending on IGF-
1 concentrations [11c]. Echocardiography
was performed at baseline and at 24, 48,
and 60 months. There was progressive
increase in left ventricular mass from 116
to 174 g. The long-term effects of growth
hormone replacement in adults are
unknown.
In 122 men, mean age 70 years, who
were randomized to testosterone gel 5 g/
day (n 61) or 10 g/day with different
doses of growth hormone (0, 3, or 5 micro-
grams/kg/day) for 12 weeks, there was an
increase in blood pressure, which persisted
4 weeks after the study ended [12c]. The
blood pressure at 16 weeks was 130/
76 mmHg compared with 117/68 mmHg at
baseline.
In 10 patients (mean age 58 years, one
man) with acromegaly, which was thought
to have been cured, who were treated with
growth hormone with the dose adjusted to
normalize IGF-1 concentrations, and 10
patients with previous non-functioning pitu-
itary adenomas, who also received growth
hormone (mean age 54 years, one man),
three of the former had cardiovascular
events during 2 years; one patient died with
a myocardial infarction after 5 months; two
had cerebral infarctions at 2 and 6 weeks
and continued growth hormone therapy
[13c]. None of the patients with non-func-
tioning pituitary disease had cardiovascular
events. The numbers were small in this
study, and the safety of using growth
Miscellaneous hormones Chapter 43
hormone in patients with previous acro-
megaly needs further evaluation.
Metabolism A review of growth hormone
therapy for adults with growth hormone
deciency has shown a correlation of growth
hormone dose and duration with the devel-
opment of impaired glucose tolerance [14R].
A meta-analysis of studies of growth hor-
mone therapy for obesity in adults showed
a small but signicant increase in fasting
plasma glucose concentrations [15M].
Pancreas Pancreatitis has been attributed
to growth hormone.
A 40-year-old man used growth hormone
0.6 mg/day for 2 weeks to enhance muscle
development. He developed pancreatitis
10 days later. There was no other apparent
risk factor [16A].
A 13-year-old girl with a craniopharyngioma
was using growth hormone 0.033 mg/kg/day
subcutaneously six times per week, levothyr-
oxine, hydrocortisone, and an antidiuretic hor-
mone analogue [17A]. She developed severe
abdominal pain and was admitted 1 month
later with persistent symptoms. The diagnosis
was pancreatitis. Growth hormone was with-
drawn and she recovered. Six months later
growth hormone was restarted without recur-
rence of pancreatitis.
In the second case the authors speculated that
the pancreatitis might have been related to a
high cholesterol concentration (6.5 mmol/l)
caused by the use of growth hormone.
Musculoskeletal Of 19 patients with de
Quervain's tenosynovitis, mean age
33 years, nine were using growth hormone
for body building purposes [18c]. Four
stopped using growth hormone when
requested. The patients who were not using
growth hormone responded to non-surgical
treatment. Four of the ve patients who
continued growth hormone therapy
required surgical therapy, compared with
two of the four who stopped. Growth hor-
mone may make de Quervain's tenosynovi-
tis more difcult to treat.
Eight children with Hurler's syndrome,
mean age 9 years, were treated with growth
hormone, mean dose 0.32 mg/kg/week
911
[19c]. There was radiographic data for six
children. There was progression of scoliosis
in one, kyphosis progression in one, and
worsening of genu valgum in one. One
child discontinued therapy owing to a
slipped capital femoral epiphysis, which is
not a typical feature of Hurler's syndrome.
In 39 children with isolated growth hor-
mone deciency and ve with multiple pitui-
tary hormone deciencies (aged 816 years,
30 boys), who were treated with growth hor-
mone 33 micrograms/kg/day, Southwick's
angle was measured using pelvic X-rays at
baseline, 1 year, and 2 years [20c]. Data were
available for 28 patients at 1 year, of whom
17 had an increased angle. Data at 2 years
were available for 10 patients, of whom nine
had further progression. It is thought that an
increased Southwick's angle is a marker for a
risk of slipped capital femoral epiphysis, and
growth hormone can increase the risk of
epiphysiolysis.
Drug administration route Inhaled growth
hormone In a randomized crossover trial,
somatotropin inhalation powder was given
to 22 children with growth hormone de-
ciency, mean age 11 years [21c]. Eight
received inhaled growth hormone 8.4 mg/
day or subcutaneous growth hormone
0.5 mg per day; six received inhaled growth
hormone 16.8 mg/day or subcutaneous
growth hormone 1.0 mg/day; and eight
received inhaled growth hormone 33.6 mg/
day or subcutaneous growth hormone
2.0 mg/day. Each treatment was given for
7 days. There were no effects on lung func-
tion in this short study.
Growth hormone receptor
antagonists [SEDA-30, 510; SEDA-31,
707; SEDA-32, 794]
Liver In a 40 week, open, randomized,
controlled study in patients with acro-
megaly, who were inadequately treated
with long-acting octreotide, adding pegviso-
mant therapy to octreotide was compared
with changing to pegvisomant alone [22c].
912
The mean age of the 25 patients random-
ized to pegvisomant alone was 49 years,
10 of whom had diabetes. The 26 patients
randomized to combined therapy had a
mean age of 40 years and four had diabetes.
Pegvisomant was begun at 10 mg/day and
titrated, according to IGF-1 concentrations,
to a maximum of 30 mg/day and a mini-
mum of 5 mg/day. There were signicant
increases in liver enzymes to more than
three times the upper limit of the reference
range in one patient who received pegviso-
mant alone and in four who received com-
bination therapy. Three patients using
combination therapy had activities more
than 10 times the upper limit, and they
returned to normal or near normal on with-
drawal. Liver function should be moni-
tored, especially when combination
therapy is used. Current recommendations
suggest monthly liver function tests for the
rst 6 months of treatment, followed by 6-
monthly tests [23R].
Tumorigenicity Two boys and one girl with
pituitary gigantism, who were not cured by
surgery, a somatostatin analogue, and a
dopamine receptor agonist, were given peg-
visomant [24A]. One child, aged 5 years
received 10 mg/day subcutaneously; the
others, aged 10 and 11 years, received
20 mg/day. One child had a documented
increase in tumor size and stopped taking
pegvisomant after about 3 years; 3 months
after the end of therapy there was no fur-
ther increase in tumor size.
One patient in each group of a random-
ized control comparison of pegvisomant
alone with pegvisomant plus long-acting
octreotide had an increased pituitary vol-
ume at 40 weeks [22c]. Long-term surveil-
lance of pituitary volume is required for
patients receiving pegvisomant.
Melatonin and analogues [SED-15,
2245; SEDA-31, 708; SEDA-32, 794]
Melatonin analogues are under develop-
ment with varying binding afnities for
Chapter 43 R.C.L. Page
melatonin receptors [25R]. Large-scale evi-
dence for their use in circadian rhythm
sleep disorders is not yet available.
Ramelteon, (S)-N-[2-(1,6,7,8-tetrahydro-
2H-indeno-[5,4-b]furan-8-yl)ethyl]propio-
namide (TAK-375), has four times the
potency as melatonin at MT1 receptors
and 17 times the potency at MT2 receptors.
Adverse effects in trials so far suggest
effects similar to placebo.
Agomelatine, N-[2-(7-methoxy-1-
naphthyl)ethyl]acetamide, is a melatonin
MT1 and MT2 receptor agonist. It is also
an antagonist at 5-HT2C receptors.
Tasimelteon, (1R-trans)-N-[[2-(2,3-dihy-
dro-4-benzofuranyl)cycloproplyl]methyl] pro-
panamide, has high afnity for melatonin
MT1 and MT2 receptors.
Melatonin has been used in neonates at
pharmacological doses without apparent
adverse reactions, although studies are usu-
ally small [26R].
Circadin is a prolonged-release tablet con-
taining melatonin 2 mg. It has received Euro-
pean Medicine Agency approval for
treatment of primary insomnia. Adverse
reactions are uncommon, but include head-
ache, pharyngitis, back pain, and weakness.
There do not appear to be withdrawal effects.
Drugdrug interactions Melatonin is meta-
bolized mainly by CYP1A, but CYP2C19
is also involved to a lesser extent [27r].
Melatonin concentrations can be increased
by cimetidine, quinolones, and estrogens.
They are reduced by carbamazepine and
cigarette smoking.
Oxytocin and analogues [SED-15,
2657; SEDA-30, 511; SEDA-31, 708;
SEDA-32, 795]
Observational studies The use of oxytocin
in low income countries has been reviewed
[28R]. The use of oxytocin compared with
no use of oxytocin in normal labor had a
relative risk of 1.9 for stillbirth. The
adjusted relative risk for neonatal resuscita-
tion was 25.6. Oxytocin is useful for the
Miscellaneous hormones Chapter 43
management of postpartum hemorrhage,
but it is important that in low resource set-
tings its use does not result in increased
harm to the neonate.
In 80 women, mean age 31 years, under-
going cesarean section, who were random-
ized to oxytocin 2 or 5 units as an
intravenous bolus over 510 seconds after
the delivery of a baby and cord clamping,
followed by a continuous infusion of oxy-
tocin 10 units/hour over 4 hours, 13
reported nausea after receiving 5 units com-
pared with two who received 2 units [29C].
Mean arterial pressure fell more in those
who were given 5 units (13 compared with
6 mmHg), and six patients had a reduction
of more than 30 mmHg.
Electrolyte balance Hyponatremia has
been attributed to oxytocin [30A].
A 26-year-old woman in the second stage of
labor received an infusion of oxytocin 10 U/l in
5% dextrose at a variable rate of 10150 ml/
hour. In the 5 hours after delivery, which was
complicated by a retained placenta requiring
general anesthesia for removal, she received iso-
tonic uid 5500 ml, 5% dextrose 3500 ml with
oxytocin 50 U/l, hydroxyethyl starch 1000 ml,
and 4 units of blood. She then received 5% dex-
trose 7500 ml with oxytocin 100 U/l over
15 hours; 24 hours later her serum sodium con-
centration was 113 mmol/l. She became uncon-
scious and had a generalized convulsion. She
subsequently made a full recovery.
Consideration of how oxytocin is infused to
minimize the risk of hyponatremia is
essential.
Skin Extravasation of concentrations of
oxytocin in the hand has reportedly caused
vasoconstriction [31A].
A 24-year-old woman had vaginal bleeding at
15 weeks gestation. She received 2 units of
packed erythrocytes and then 3 units of oxy-
tocin through a cannula on the back of the
hand. Within 30 minutes the hand had become
edematous and cyanotic. Extravasation was
apparent. The radial and ulnar pulses were
not palpable and were faint on a Doppler
scan. The hand was elevated and the symp-
toms gradually abated, with improvement of
the pulses.
913
Thyrotropin-releasing hormone
and thyrotropin
See Chapter 41.
Parathyroid hormone [SED-15, 2689;
SEDA-32, 796]
Potential novel uses of parathyroid hor-
mone therapy are being explored through
its effects on the cardiovascular system,
which include arterial vasodilatation [32R].
Observational studies Women aged more
than 45 years with low bone mineral den-
sity were randomized to hormone replace-
ment therapy with (n 90) or without
(n 90) 100 micrograms of subcutaneous
PTH 184 [33c]. Those who received PTH
184 had more hypercalciuria (43%),
hypercalcemia (14%), nausea (25%), vomit-
ing (11%), and dizziness (10%). It was
thought that they might not have had as
great an increase in calcium concentrations
as would have been expected, because of a
tendency of hormone replacement therapy
to lower calcium concentrations.
Somatostatin (growth hormone
release-inhibiting hormone) and
analogues [SED-15, 3160; SEDA-30,
510; SEDA-31, 709; SEDA-32, 796]
Adverse reactions to somatostatin ana-
logues have been extensively reported.
The asymptomatic effects have been
reviewed [23R, 34R]. There are asymptom-
atic gallstones in 2040, bradycardia in up
to 25%, and conduction abnormalities in
10%. Somatostatin analogues may alter
the absorption of other drugs, especially
oral hypoglycemic agents, b blockers, cal-
cium channel blockers, and ciclosporin,
while effects on CYP isoenzymes may alter
concentrations of quinidine, terfenadine,
and warfarin. Somatostatin analogues
914
should not be used with drugs that prolong
the QT interval, such as cisapride.
Nervous system In one case a high dose of
octreotide may have altered the balance
between brain dopamine and GABA, and
thus caused Parkinson-like symptoms [35A].
A 31-year-old woman with carcinoid syn-
drome was given octreotide in doses that grad-
ually increased over the years, so that after
4 years she was receiving 30 mg intramuscu-
larly every 2 weeks and an additional 68 mg
of subcutaneous octreotide each month. She
developed slowness of movement and a ten-
dency to bump into things. The dose of
octreotide was reduced to 10 mg every 2 weeks
and her neurological symptoms improved. The
dose of octreotide was temporarily increased
to 30 mg 2 weekly with a recurrence of
symptoms.
Metabolism In 112 patients with acro-
megaly (mean age 47 years, 51 men), who
were treated with somatostatin analogues,
there was an increase in fasting plasma
glucose concentrations after 1 month, which
correlated with a reduction in insulin
concentrations [36C]. The fasting glucose
concentration had returned to baseline by
3 months. At the end of 12 months the most
important predictor of blood glucose con-
centration was control of growth hormone
concentrations; 11 patients had improved
their glucose tolerance status and 17 had
worsened.
Octreotide [SEDA-30, 510; SEDA-31,
709; SEDA-32, 797]
Hematologic Thrombocytopenia has been
attributed to octreotide [37A].
A 53-year-old man with hematemesis and
melena due to variceal bleeding was given
octreotide 50 micrograms as an initial intra-
venous bolus, followed by 50 micrograms/hour
as a continuous intravenous infusion. His
platelet count fell from 144 to 4  109/l over
the next 50 hours. The platelet count gradu-
ally increased after the octreotide was with-
drawn at 72 hours. He was again given
octreotide 3 months later, and the platelet
count fell from 214 to 89  109/l. The
Chapter 43 R.C.L. Page
octreotide was withdrawn and the platelet
count returned to 221  109/l.
The mechanism of this effect is unknown.
Gastrointestinal In 125 patients being trea-
ted with pelvic radiation for various cancers
of the pelvis, randomly allocated to sub-
cutaneous octreotide 100 micrograms on
day 1 followed by depot octreotide 20 mg
on days 2 and 29, or placebo, octreotide
did not improve symptoms and may have
worsened abdominal cramps, nocturnal
bowel movement, and melena [38C].
Biliary tract Nine subjects with Prader
Willi syndrome (mean age 15 years)
received either octreotide 30 mg or saline
intramuscularly every 4 weeks for 16 weeks.
After a 24-week wash-out period, they then
received the alternative therapy. Three
developed gallbladder abnormalities on
ultrasound by the end of the octreotide
phase; two went on to have cholecystec-
tomy 1224 months later [39c].
Nails Beau's lines, or onychomadesis, are
seen in patients receiving certain drugs,
and has been associated with octreotide
[40A].
Beau's lines were noted in a 72-year-old lady
with carcinoid syndrome who was receiving
subcutaneous octreotide every 28 days. The
distance of the lines from the proximal nail
fold suggested that they had developed at
around the time of octreotide injection,
although there were only two lines when she
had received four injections.
VASOPRESSIN RECEPTOR
ANTAGONISTS
There are three subtypes of arginine vaso-
pressin receptor, V1A, V1B, and V2. The
V2 receptor is mainly situated in the kidney
and is important in free water reabsorption
[41R]. The V1B receptor mediates adreno-
coticotropin release in the anterior pitui-
tary. The V1A receptor has multiple
Miscellaneous hormones Chapter 43
functions, including vasoconstriction and
glycogenolysis. Drugs that block activation
of the V2 receptor have been developed
for the management of hyponatremia. This
induces excretion of free water without
changed electrolyte excretion. Lixivaptan,
satavaptan, and tolvaptan are all V2 recep-
tor antagonists that are taken orally.
Conivaptan is a V1A and V2 receptor antag-
onist that has been licensed by the FDA for
intravenous use.
Conivaptan
Although oral conivaptan, [1,10 -biphenyl]-2-
carboxamide, N-[4-[(4,5-dihydro-2-methylimi-
dazo[4,5-d][1]benzazepin-6(1H)-yl)carbonyl]
phenyl] monohydrochloride, was efcacious,
drug development has been discontinued
because of signicant inhibition of CYP3A4.
In 84 adults with hyponatremia (euvole-
mic or hypervolemic) who were random-
ized to a bolus of conivaptan 20 mg
followed by a 4-day continuous infusion of
40 mg/day (n 29) or 80 mg/day (n 26)
compared with placebo (n 29), the main
adverse reactions were infusion site reac-
tions [41R].
Tolvaptan
Tolvaptan, 40 -[(7-chloro-2,3,4,5-tetrahydro-
5-hydroxy-1H-1-benzazepin-1-yl) carbonyl]-
o-tolu-m-toluidide, has been approved by
the FDA and EMA for management of
hyponatremia. It is taken orally in a dose
of 15 mg/day and is titrated to a maximum
of 60 mg, depending on sodium concentra-
tions and volume status. Tolvaptan is metab-
olized by the liver. Blood concentrations of
tolvaptan are increased when it is co-admin-
istered with CYP3A4 inhibitors such as dil-
tiazem, ketoconazole, and grapefruit juice,
and reduced when it is co-administered with
CYP3A4 inducers such as rifampicin.
Placebo-controlled studies Patients, mean
age 66 years, with hyponatremia were
915
randomized to tolvaptan (n 15) or pla-
cebo with uid restriction (n 8). The
underlying diagnoses were heart failure,
hepatic cirrhosis, and the syndrome of in-
appropriate antidiuretic hormone secretion.
The numbers in this study were small and
the adverse events were not fully documen-
ted, but thirst scores between the groups
were not different [42c].
In two randomized placebo-controlled
trials of tolvaptan 1560 mg in patients with
either euvolemic or hypervolemic hypo-
natremia, adverse events were similar to
those with placebo [43C]. The most com-
mon adverse reactions were thirst (14%
versus 5%) and dry mouth (13% versus
4%). Death rates were similar: 14 of 223
patients who took tolvaptan compared with
13 of 220 patients who took placebo. Four
patients who took tolvaptan had an
increased serum sodium concentration to
over 146 mmol/l, and in four patients the
rate of increase of sodium was more rapid
than clinically appropriate. Close monitor-
ing of serum sodium concentrations and
plasma volume status is essential. Fluid
restriction is not required. Polyuria is
common.
VASOPRESSIN AND
ANALOGUES [SED-15, 3609;
SEDA-30, 511; SEDA-31, 710;
SEDA-32, 798]
Cardiovascular Bradycardia has been
attributed to intrauterine vasopressin [44A].
A woman who underwent laparoscopic myo-
mectomy had 56 ml of diluted vasopressin
(0.2 units/ml) injected into the uterine wall.
Within 2 minutes her pulse rate had fallen
from 58 to 35/minute. She had a cardiac arrest
a short time later, from which she recovered.
Electrolyte balance In 24 children (11
boys, median age 3 years) with non-septic
critical illnesses, who were randomized to
either vasopressin 0.5 milliunits/kg/minute
916
or 0.9% sodium chloride 1 ml/hour for
48 hours, there was hyponatremia in eight
of the former compared with one of the
latter [45c]. Blood pressure increased in
normotensive children who received vaso-
pressin, with rebound hypotension on with-
drawal. Urine output fell in those who were
given vasopressin.
Death In a randomized study, 35 children
(mean age 9 years, 19 boys) with vasodila-
tory shock were given arginine vasopressin
at a starting dose of 0.5 milliunits/kg/minute
and were compared with 34 children (mean
age 11 years, 17 boys) who were treated
with saline as a placebo. Although not sta-
tistically signicant, there were 10 deaths
in the vasopressin group and only ve in
the placebo group (relative risk 1.94).
Vasopressin did not appear to confer
benet.
In a subgroup analysis of a comparison
of vasopressin 40 IU adrenaline 1 mg
(n 1442) with adrenaline alone
(n 1452) in cardiopulmonary resuscita-
tion, when the initial electrocardiogram
showed pulseless activity the rate of sur-
vival was higher in those treated with
adrenaline alone (5.8% compared with
0%) [46C]. Overall, 1-year survival was
1.3% versus 2.1% respectively; although
this was a non-signicant difference, it was
clear that vasopressin in addition to adren-
aline was not benecial and could be
harmful.
Desmopressin (N-deamino-8-D-
arginine vasopressin, DDAVP) [SED-15,
1076; SEDA-30, 512; SEDA-31, 710;
SEDA-32, 798]
Electrolyte balance The risk of hyponatre-
mia as a consequence of inappropriate uid
administration after a single dose of desmo-
pressin has been highlighted [47A].
A 48-year-old woman received intravenous
desmopressin 0.4 micrograms/kg over
30 minutes as part of assessment for a bleed-
ing tendency and 4 hours later drank large
Chapter 43 R.C.L. Page
amounts of water. The serum sodium concen-
tration fell to 116 mmol/l and she had seizures
and became unconscious. She was treated with
hypertonic saline. On recovery she had mild
impairment of short-term memory for
3 months.
Hematologic Another report of the
increased risk of thrombosis when desmo-
pressin is used in von Willebrand's disease
has highlighted the need for caution [48A].
A 52-year-old woman with von Willebrand's
disease was admitted for a surgical procedure.
Preoperatively she received intravenous
desmopressin 0.3 micrograms/kg and on the
day after surgery she developed bilateral pul-
monary emboli and an acute ischemic stroke.
Echocardiography showed a small patent
foramen ovale. She was anticoagulated and
recovered without clinical sequelae.
Terlipressin [SEDA-30, 512; SEDA-31,
710; SEDA-32, 798]
Cardiovascular QT interval prolongation
and torsade de pointes have been attributed
to terlipressin [49A].
A 50-year-old man with alcohol problems had
endoscopy, which showed multiple ulcers at
D1 and D3. He had a small amount of cof-
fee-ground vomit and was given intravenous
terlipressin 1 mg 6 hourly. Electrocardiogra-
phy showed gradual prolongation of the QTc
interval from 0.34 to 0.44 seconds. He devel-
oped melena and signs of incipient shock
9 days later. Bleeding at D2 was identied at
endoscopy and treated with embolization.
Intravenous terlipressin 1 mg 6 hourly was
restarted. The next day he collapsed and an
electrocardiogram showed torsade de pointes.
One hour before that the QTc interval was
0.49 seconds.
Minor electrolyte abnormalities at the time
of bleeding may have increased the risk of
ventricular dysrhythmia in this case.
Skin Two further case reports of thrombo-
sis of supercial dermal capillaries have
been reported. One patient presented with
widespread lesions and the other had more
localized involvement [50A].
Miscellaneous hormones Chapter 43
A 68-year-old man with alcoholic cirrhosis,
hepatocellular carcinoma, esophageal varices,
and hepatorenal syndrome was given intra-
venous boluses of terlipressin 1 mg qds and
3 days later developed diffuse purpuric necrotic
plaques all over his body, including the tongue
and scrotum. A week later the reticulated
erythema of the trunk and the purpuric plaque
on the scrotum became necrotic. He died
3 weeks later from staphylococcal septicemia.
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917
A 74-year-old man with multiple metastases
and an unknown primary developed acute
renal failure. He was given terlipressin
0.5 mg/hour via an infusion pump together
with albumin and antibiotics and 4 days later
developed an isolated large erythematous pla-
que on the scalp. Biopsy showed thrombosis
of dermal capillaries. He died a few days later
from tumor progression.
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 Paul Nestel

44 Drugs that affect lipid

metabolism

Ezetimibe [SED-15, 1308; SEDA-30, trial, in which ezetimibe was compared with
515; SEDA-31, 715; SEDA-32, 803] extended-release niacin in 208 patients with
coronary heart disease or a coronary heart
Ezetimibe has been the subject of recent disease risk equivalent, who had previously
criticism, arising from clinical trials that taken statin monotherapy and were given
have cast doubt on its efcacy to improve extended-release niacin (target dose
outcomes and unsubstantiated suggestions 2000 mg/day) or ezetimibe (10 mg/day)
of a possible carcinogenic effect. [3C]. The primary end-point was the
between-group difference in the change from
baseline in the mean common carotid intima-
Comparative studies A disappointing study
media thickness after 14 months. It was
of the efcacy of ezetimibe, the ENHANCE
expected that both interventions would lower
trial, raised the possibility of unidentied
LDL cholesterol beyond the reduction pro-
adverse effects that nullied its LDL lowering
duced by previous statin monotherapy, but
effect. This trial tested the efcacy of either
that niacin would increase HDL cholesterol
reducing or slowing the progression of carotid
more than ezetimibe. This proved correct,
intima-media thickness (CIMT), a surrogate
and the trial was terminated early, after
for cardiovascular events, in 720 subjects with
14 months, when it was discovered that
heterozygous hypercholesterolemia, who
extended-release niacin caused signicant
were randomized to simvastatin 80 mg/day
regression of carotid intima-media thickness
alone or simvastatin ezetimibe 10 mg/day
when combined with a statin and that niacin
[1C]. The combination achieved signicantly
was superior to ezetimibe. The greater bene-
lower LDL concentrations than simvastatin
t with niacin in this study has cast further
alone. However, there was no difference in
doubt on the usefulness of ezetimibe, an
the progression of CIMT over 2 years. In
interpretation that appears to be unjustied.
the absence of an adverse proatherogenic
Several studies in which ezetimibe was
effect of ezetimibe, the favored explanation
co-administered with a statin in comparison
lies in the virtually normal CIMT parameters
with the statin alone, for example atorva-
at baseline in the trial participants, which
statin, have shown no signicant differences
appears to have resulted from long-term
between the two treatments in serious
statin therapy before the trial began [2C].
adverse events involving the liver or muscle
The most recent large ezetimibe trial,
[4C].
which also appears to have been initially mis-
interpreted, was the ARBITER 6-HALTS
Musculoskeletal Serious myopathy has been
studied in a systematic review of PubMed
Side Effects of Drugs, Annual 33 listed studies of ezetimibe alone or combined
J.K. Aronson (Editor)
ISSN: 0378-6080
with a statin. The frequency of musculoskele-
DOI: 10.1016/B978-0-444-53741-6.00044-1 tal disorders was identical with placebo or, in
# 2011 Elsevier B.V. All rights reserved. the case of combination therapy, with the

921
922
frequency associated with the statin [5M]. It
should be noted that these reports relate to
serious events dened as myopathies and
not to the occurrence of myalgia, in which no
objective measure of muscle damage is
demonstrable.
Tumorigenicity In the SEAS trial simva-
statin 40 mg ezetimibe 10 mg was com-
pared with placebo in 1873 elderly
subjects with mild to moderately severe
aortic stenosis [6C]. The hypothesis was that
intensive lipid lowering would reduce the
rate of progression of stenosis. The result
over 4.1 years did not support the hypothe-
sis, despite a 50% reduction in LDL choles-
terol. However, there was a statistically
signicant increase in the incidence of can-
cers (93 versus 65 cases in the placebo
group). There were several types of cancer
but no temporal relation between therapy
and diagnosis. Nevertheless, this led to fur-
ther interim investigations in two larger
studies of the combination of simvastatin
ezetimibe, the SHARP trial [7C] and the
IMPROVE-IT trial [8C]. Analysis of the
incidences of cancers in all three trials
established an overall absence of increased
cancer risk compared with placebo in
SHARP and compared with simvastatin
alone in IMPROVE-IT [9M]. The rates of
some cancers rose slightly but the rates of
others fell. A very large post-marketing sur-
vey based on cancer adverse event reports
led with the FDA did not show excess
cancer rates linked to 52 million prescrip-
tions for ezetimibe and 55 million prescrip-
tions for ezetimibe simvastatin [10S].
Fibrates [SED-15, 1358; SEDA-30, 515;
SEDA-32, 804]
Observational studies In a large interven-
tional study of the use of fenobrate in
patients with mostly uncomplicated type 2
diabetes, in which cardiovascular mortality
was not reduced, several potentially life-
threatening complications occurred, namely
Chapter 44 Paul Nestel
signicantly increased incidences of pulmon-
ary thromboembolism and acute pancreatitis
[11C]. However, unpublished presentations
at major meetings have revealed that these
two complications were no longer observed
at signicant rates in subjects who had contin-
ued taking fenobrate for several more years.
However, three clinical laboratory
abnormalities that were initially documen-
ted in the FIELD study, namely raised con-
centrations of homocysteine and creatinine
(which were correlated) and increased albu-
minuria have been conrmed in smaller
studies. The importance of these potentially
serious adverse ndings is uncertain. In fur-
ther analyses of the FIELD study, clear
benets on microvascular complications
have become apparent. The need for laser
therapy of the retina for diabetic retinopa-
thy and the risk of amputation of the legs
(because of both macrovascular and micro-
vascular damage) were signicantly less in
those who took fenobrate [12C, 13C].
Systematic reviews In a meta-analysis of 18
prospective randomized controlled trials of
brates, involving 45 058 patients, the fre-
quency of serious adverse events was not
signicantly increased; furthermore, the
risk of progression of albuminuria was sig-
nicantly reduced, despite a rise in serum
creatinine [14M].
Bezabrate
Cardiovascular In a 2-year, double-blind,
placebo-controlled study of 108 patients
with coronary artery disease and class III
heart failure, enrolled in the Bezabrate
Infarction Prevention Study, bezabrate
caused a small increase in the concentration
of N-terminal pro-B type natriuretic peptide
(ProBNP) [15C]. However, the patients
who took bezabrate were older and had
lower baseline ProBNP concentrations,
and there were no signicant differences
in ProBNP concentrations between the
groups after 2 years.
Drugs that affect lipid metabolism Chapter 44
Fenobrate
Musculoskeletal The major concern about
myopathy when brates are combined with
statins, as in the cerivastatin gembrozil
disaster, has largely abated. Several large
analyses have not shown an increased risk
of serious adverse events when fenobrate
was co-administered with a statin. Speci-
cally, the frequency of myopathy was not
increased when fenobrate was added to a
statin [16c]. The frequencies of raised crea-
tine kinase activities to more than 510
times the upper limit of the reference
range, signifying probable muscle damage,
were the same with fenobrate a statin
as with a statin alone; however, raised liver
transaminases (more than three times the
upper limit of the reference range)
appeared to occur slightly more often with
additional brate [17C].
Gembrozil
Musculoskeletal Myositis has been described
in a patient with normal renal function
taking gembrozil monotherapy [18A].
Drugdrug interactions Tiagabine An in-
teraction of gembrozil with tiagabine has
been reported [19A].
A 39-year-old man took oral tiagabine 16 mg
tds and carbamazepine 500 mg bd for complex
partial seizures secondary to mesial temporal
sclerosis. He was given gembrozil for type
IV hypertriglyceridemia and reported severe
confusion and altered consciousness soon after
a single dose of 600 mg. Later, after a con-
trolled challenge with a single dose of gem-
brozil 300 mg, he developed lightheadedness,
and the total tiagabine serum concentrations
rose by 59% and 75% at 2 and 5 hours respec-
tively, without a signicant change in baseline
carbamazepine concentrations.
Warfarin An interaction of gembrozil
with warfarin [SED-15, 1361] has again
been described and the interaction
reviewed [20AR].
In a 62-year-old man who was taking warfarin
45 mg/week for paroxysmal atrial brillation
923
the INR rose from a stable value of 2.03.0
to 5.8 after he had taken gembrozil 600 mg
bd for 3 weeks. He denied any changes in die-
tary vitamin K or alcohol use or the use of
non-prescription or herbal agents. No other
causes could be found. The dose of warfarin
was reduced to 3537.5 mg/week (a 22%
reduction) and a therapeutic INR was main-
tained until gembrozil was later withdrawn
because of myalgia. After consecutive sub-
therapeutic INRs, the dose of warfarin was
increased to 45 mg/week and a therapeutic
INR was maintained.
The exact mechanism of the proposed
interactions between bric acid derivatives
and warfarin is not known but may be inhi-
bition of CYP isoenzymes, displacement
from protein binding sites, or changes in
coagulation factor synthesis. The authors
recommended that, regardless of the bric
acid derivative chosen, a dosage reduction
of 20% and close INR monitoring are war-
ranted in patients taking warfarin.
Fish oils [SED-15, 1364; SEDA-30, 515;
SEDA-32, 806]
Cardiovascular In a systematic review of
deaths in 12 randomized controlled trials of
sh oil as dietary supplements in 32 779
patients there was no benecial effect in three
studies (n 1148) of implantable cardiac
debrillators (OR 0.90; 95% CI 0.55,
1.46) or in six studies (n 31 111) of sudden
cardiac death (OR 0.81; 0.52, 1.25). In 11
studies (n 32 439 and n 32 519) there
was a reduction in deaths from cardiac causes
(OR 0.80; 0.69, 0.92) but no effect on dys-
rhythmias or all-cause mortality [21M]. How-
ever, it was later pointed out that there is
some evidence that sh oils may be dysrhyth-
mogenic in some subgroups of patients with
heart disease [22r]. These include an
increased risk of ventricular tachycardia in
patients with implantable cardiovertor de-
brillators whose primary dysrhythmia was
ventricular tachycardia [23C], and an
increased risk of cardiac death in patients with
angina [24C].
924
HMG-CoA reductase inhibitors
[SED-15, 1632; SEDA-30, 516; SEDA-31,
715; SEDA-32, 807]
The safety of HMG-CoA reductase inhibi-
tors (statins) has been assessed repeatedly
in studies involving hundreds of thousands
of patients. Those who have participated
in trials have included healthy people in
primary prevention trials, but they have
mostly been patients at increased risk, vary-
ing from very high to relatively low risk, but
still exceeding that among healthy subjects.
Included in the high-risk category are those
with a previous cardiovascular event; more
recently patients with diabetes mellitus
have been included in this category,
although not with absolute unanimity.
Many studies have compared different
statins at different dosages, often in con-
junction with other lipid-modifying agents
that alter the risk. Recent concern has
centred on the likelihood of a small but sig-
nicant increase in the incidence of diabe-
tes. Concern about an increased risk of
cancer arises regularly, but has again been
recently refuted in a large analysis (see
below).
Comparative studies Adverse events have
been studied in 10 384 patients taking rosu-
vastatin and 14 854 taking other statins
[25C]. There were two cases of myopathy,
one with rosuvastatin and one with another
statin. The relative risk of myopathy in
patients taking rosuvastatin compared with
other statins was 1.31 (95% CI 0.13,
13). There were two cases of rhabdomyoly-
sis among current rosuvastatin users, i.e. 2.9
per 10 000 person-years (95% CI 0.8, 11)
and no cases of acute liver injury. There
were 17 cases of acute renal insufciency
(ve with rosuvastatin, 12 with other sta-
tins) and the relative risk in rosuvastatin
users compared with other statins was 0.49
(95% CI 0.16, 1.50). There were 285
deaths (87 among rosuvastatin users, 198
among those taking other statins), and the
relative risk was 0.42 (95% CI 0.32,
0.57). The same group found similar results
in a study of 10 289 patients taking
Chapter 44 Paul Nestel
rosuvastatin and 117 102 taking other sta-
tins, using the UK General Practice
Research Database (GPRD) [26C].
Combination studies Statins brates
Fibrates, such as gembrozil or fenobrate
are valuable in the management of disor-
ders that are characterized by hypertrigly-
ceridemia as the major abnormality or
more frequently together with a statin or
other lipid-modifying drug when LDL chol-
esterol concentrations are also increased.
The adverse effects of combinations of sta-
tins and brateshave been reviewed [27R,
28R]. Furthermore, in a recent large study
of fenobrate, the FIELD study, there were
unexpected adverse events, albeit in very
few individuals, that have led to debate
about the cost-benet of brate therapy
[11C]. Nevertheless subsequent analysis
showed signicant protection against pro-
gressive retinopathy in this trial [13C].
Comparative studies Reports of the recog-
nized adverse effects of statins on muscle
and liver have been published as compari-
sons of the most recent statins (rosuvasta-
tin, atorvastatin, pitavastatin) or from
meta-analyses. A comparison of rosuva-
statin and atorvastatin included some
20 000 patients studied in 25 trials [29M].
There were no differences between the
two statins at any doses or at any dose ratio
of the two. The incidences of myalgia and
of rises in liver and muscle enzymes were
similar and resembled the incidences
reported in earlier studies. There were no
cases of rhabdomyolysis, which was not sur-
prising, since the expected incidence is in
the region of one case per 100 000. Since
adverse effects on renal function were sug-
gested during the initial process of register-
ing rosuvastatin, several of the reports
focused on glomerular ltration rate
(GFR); however, both statins improved
GFR to about the same extent.
Pitavastatin, which is marketed in Japan,
has been compared with atorvastatinin in a
randomized trial in 250 subjects; the
authors claimed that there were signi-
cantly fewer adverse effects with pitava-
statin in terms of raised liver enzymes
Drugs that affect lipid metabolism Chapter 44
[30C]. This may reect differences in
metabolismCYP3A4 for atorvastatin
and CYP2C9 for pitavastatin.
Metabolism Of considerable importance is
the consistency with which small but impor-
tant increments in the incidence of new dia-
betes mellitus have been reported in
patients taking statins. This adverse effect
was noted in the early Heart Protection
Study with simvastatin (although it was
not statistically signicant) and in the
ASCOT Trial with atorvastatin; in both tri-
als the hazard ratio for type 2 diabetes was
1.15 [31R]. Atorvastatin at different dosages
(1080 mg/day) compared with placebo
reduced insulin sensitivity signicantly
within 2 months as glycemia increased.
Conrmation that statins can be associ-
ated with new-onset diabetes came with
the publication of the JUPITER trial, a pri-
mary prevention trial of rosuvastatin in
17 802 apparently healthy subjects [32C].
The trial was stopped after a median period
of only 1.9 years, because of a clear reduc-
tion in cardiovascular outcomes in the trea-
ted group. However, physician-reported
type 2 diabetes was reported signicantly
more often with rosuvastatin than placebo
(270 versus 216 cases). This nding stimu-
lated a meta-analysis of 13 randomized
statin trials involving 91 140 patients, of
whom 4278 developed newly diagnosed
diabetes; 2226 had been assigned to a statin
and 2052 to placebo. The odds ratio of 1.09
was not statistically signicant. The authors
concluded that the risk of diabetes was
small in relation to the large benet in
reducing cardiovascular events.
Urinary tract The initial concern with rosu-
vastatin, which has now abated, was the
occurrence of minimal proteinuria (which
was subsequently shown to occur with
other statins) and a rise in serum creatinine
concentration. In a placebo-controlled study
of the role of rosuvastatin 10 mg/day in
about 2500 patients in heart failure, a minor
rise in creatinine after treatment for 1 year
was similar to the rise in the placebo group
[33C].
925
Musculoskeletal Myalgia, myopathy, and
rhabdomyolysis due to statins.
EIDOS classication:
Extrinsic species HMG Coenzyme A
reductase inhibitors
Intrinsic species Skeletal muscle
mitochondria
Distribution Skeletal muscle
Outcome Necrosis
Sequela Myalgia, myopathy, and
rhabdomyolysis due to statins
DoTS classication:
Dose-relation Collateral
Time-course Intermediate
Susceptibility factors Genetic (the
C-allele of the rs4149056 SNP in
SLCO1B1 on chromosome 12;
COQ2 mutations); age (over
65 years); drugs (brates;
compounds that inhibit statin
metabolism, e.g. grapefruit);
diseases (hypothyroidism; trauma
and physical exertion; nephrotic
syndrome)
The classication and management of
muscle disorders due to statins are begin-
ning to become clearer. It is now recog-
nized that as many as 10% of patients
who take a statin will develop muscle symp-
toms of varying severity. Myalgia remains
the main therapeutic problem, and
although it is not a major health concern,
it occurs with sufcient frequency to affect
adherence to therapy. However, most
reviews of adverse effects focus on the
much rarer myopathy or the very rare but
potentially fatal rhabdomyolysis.
Statins are mostly well tolerated, and
minor myalgia is rarely a reason for with-
drawal [34M]. Muscle-related problems
include myalgia without raised muscle crea-
tine kinase activity, raised creatine kinase
activity alone, and severe muscle pain with
or without a raised creatine kinase activity
to more than 10 times the upper level of
the reference range. Exercise can cause
myalgia and increased serum creatine
kinase activity in patients taking even low
926
doses of a statin [35C]. Substantial muscle
damage or rhabdomyolysis can cause acute
renal failure and death. Serious adverse
effects are more likely in elderly patients
and in those with diabetes and pre-existing
hepatic or renal impairment. Serious myop-
athy has been estimated to occur once in
about 30 000 treatments and rhabdomyoly-
sis about three times less often.
Statin-induced muscle disorders are asso-
ciated with one candidate gene, which has
been reported in several publications. A
variant of the SLCO1B1 gene can lead to
suboptimal hepatic uptake of statins, result-
ing in high circulating concentrations at
conventional dosages. The gene encodes a
polypeptide that regulates the uptake of
statins by the liver. The variant affects
15% of the population, giving an odds ratio
for myopathy of 4.5 [36C]. Patients with this
variant can be successfully treated by titrat-
ing the dosage to very small amounts and/
or administering the drug only every sec-
ond day.
In one patient with myopathy associated
with pravastatin, the function of a novel
mutation (c.1628T>G, p.Leu543Trp)
in the SLCO1B1 gene was studied
[37AE]. OATP1B1 variants with the
mutation (OATP1B1*1ac.1628T>G or
*1bc.1628T>G) had reduced transporting
activity for typical substrates and prava-
statin compared with other variants
(OATP1B1*1a or *1b), with a reduction
in the Vmax of transport and a normal KM.
The variant was normally expressed on
the plasma membrane of HEK293 cells,
suggesting that the mutation reduced the
function of OATP1B1, probably by reduc-
ing its turnover rate.
Tumorigenicity The remote possibility that
cancers may be attributable to statins has
been constantly under watch, and several
studies have shown that there is no
increased risk. In a 26-year prospective
study in the UK in patients who took statins
for 46 580 person-years, 90 subjects died
from cancers, one-third fewer than the
fatality rate from cancers in the general
population [38C]. In a meta-analysis of 15
Chapter 44 Paul Nestel
controlled trials involving 437 017 person-
years, a metaregression analysis showed
that statins did not affect the risk of cancers
across all concentrations of LDL choles-
terol [39M].
Susceptibility factors Ethnicity The special
risk of adverse effects among Asians has
been conrmed, as Asians participate more
widely in trials of statins. It had been
claimed for some time that Asians appear
to require lower doses than Caucasians in
order to achieve optimal LDL targets, and
it now seems likely that clearance of statins
from plasma among Asians is less efcient
than among Caucasians [40c].
Atorvastatin
Placebo-controlled studies Atorvastatin
10 mg/day has been compared with placebo
in 2838 patients with type 2 diabetes melli-
tus and no history of coronary heart disease
over 3.9 years [41C]. The percentages of
patients with treatment-associated adverse
events, serious adverse events, and who
withdrew because of adverse events respec-
tively were 23% versus 25%, 1.1% versus
1.1%, and 2.9% versus 3.4%. The most
common treatment-associated adverse
events were gastrointestinal (8.9% versus
10%) and there was myalgia in (5.0% and
6.0%).
Endocrine In 77 men with coronary heart
disease atorvastatin 4080 mg/day and for
12 weeks had no signicant effects on
serum total testosterone, free testosterone,
sex hormone-binding globulin, luteinizing
hormone, or follicle stimulating hormone
compared with 83 men who took
1020 mg/day [42C].
Liver Severe acute hepatitis with symptom-
atic cholestasis has again been attributed
to atorvastatin. This is a rare adverse effect,
which cause mixed hepatotoxicity and cana-
licular cholestasis [43Ar]. In another case,
that of a 68-year-old man who was taking
Drugs that affect lipid metabolism Chapter 44
atorvastatin 20 mg/day, there was repeated
cholestatic liver damage without evidence
of bile obstruction but with positive serol-
ogy for antinuclear antibodies, antimito-
chondrial antibodies, M2 autoantibodies; a
liver biopsy showed non-specic changes
and the association with the drug was not
clear [44A].
Urinary tract A 77-year-old woman took
atorvastatin 5 mg/day for 1 week and devel-
oped hemorrhagic cystitis, which resolved
on withdrawal [45A].
Immunologic A vasculitis with a positive
titer of P-ANCA (1:160) in a 45-year-old
man has been attributed to atorvastatin
10 mg/day, which he had taken for 6 months
[46A].
A drug reaction with eosinophilia and
systemic symptoms (DRESS) has been
attributed to atorvastatin in a 58-year-old
woman after 6 weeks of therapy [47A].
Genotoxicity Lymphocytes exposed in
vitro to the peak concentration of atorva-
statin that would be achieved in a patient
weighing 70 kg and taking 80 mg/day
showed genotoxic changes, using comet
assays to evaluate basal DNA damage and
possible oxidative DNA damage produced
by reactive oxygen species [48E]. Tail
length, tail intensity, and tail moment were
signicantly increased, which suggests that
oxidative stress is likely to be responsible
for the DNA damage that was detected.
Drugdrug interactions Dabigatran In an
open, randomized, three-way crossover
study in 22 healthy volunteers, atorvastatin
80 mg/day had no effect on the pharmaco-
kinetics or pharmacodynamics of dabiga-
tran 150 mg bd, and vice versa [49C].
Istradefylline In 20 subjects who took a sin-
gle dose of atorvastatin 40 mg before and
after steady-state therapy with istradefyl-
line 40 mg/day (n 16) or placebo (n 4)
for 14 days, istradefylline increased atorva-
statin Cmax by 53%, the AUC by 54%,
and the half-life by 27%; it increased the
AUC of orthohydroxyatorvastatin by
927
18%, but had no signicant effect on its
Cmax or half-life; it had minimal effect on
parahydroxyatorvastatin AUC [50C]. The
authors suggested that these results could
be explained by inhibition of P-glyco-
protein by istradefylline.
Omega-3-acid ethyl esters In a randomized,
open, repeated-dose, two-way crossover,
interaction study omega-3-acid ethyl esters
4 g/day had no effect on the steady-state
pharmacokinetics of atorvastatin 80 mg/
day in 50 healthy adults [51c].
Thienopyridines In an open, randomized,
crossover, two-arm, parallel-group study in
69 health men, aged 1860 years, atorva-
statin 80 mg/day had no effects on the anti-
platelet actions of the thienopyridines
prasugrel and clopidogrel [52C].
Pravastatin
Gastrointestinal Colitis has been attributed
to pravastatin in an 80-year-old woman
within 48 hours of starting treatment
[53A]. Colonoscopy showed diffuse ulcera-
tion throughout the colon with relative
sparing of the rectum, and biopsies showing
ulceration and inammation. The authors
thought that the combination of pravastatin
with amitriptyline could have caused this
uncommon complication.
Skin An erythematous pigmented rash has
been attributed to olanzapine in a severely
depressed 55-year-old woman, who was
also taking lithium and pravastatin [54A].
The authors proposed that pravastatin and
lithium had aggravated the rash.
Drugdrug interactions Rifampicin In a
single-blind, placebo-controlled, crossover
study in 12 healthy Chinese men a single
oral dose of rifampicin 600 mg increased
the Cmax and AUC and reduced the appar-
ent oral clearance of pravastatin 20 mg/day
[55c]. Since rifampicin is an enzyme
inducer, it would normally have been
expected to do the opposite; the authors
928
proposed that it inhibited the hepatic
uptake and biliary secretion of pravastatin.
Rosuvastatin
Drugdrug interactions Omega-3-acid
ethyl esters In an open, randomized, two-
way crossover study omega-3-acid ethyl
esters 4 g/day had no effect on the steady-
state pharmacokinetics of rosuvastatin
40 mg/day in 48 adults [56c].
St John's wort Reduced efcacy of rosuva-
statin 10 mg/day has been attributed to
enzyme induction by St John's wort in a
59-year-old black man [57A].
Simvastatin
Immunologic Dermatomyositis with posi-
tive Mi-2 antibodies has been attributed to
simvastatin in a 71-year-old woman [58A].
Drug overdose Rhabdomyolysis occurred
in a 57-year-old woman who accidentally
took four times the prescribed dose of
simvastatin for 18 days [59A].
In another case, a 39-year-old woman
mistakenly took simvastatin for weight
reduction and developed a bilateral leg
compartment syndrome and acute renal
insufciency due to myonecrosis [60A].
Drugdrug interactions Erlotinib Rhabdo-
myolysis due to an interaction of simva-
statin with erlotinib in a 75-year-old woman
has been attributed to inhibition of
CYP3A4 by erlotinib [61A].
Podophyllotoxin In four patients concur-
rent administration of a podophyllotoxin-
containing cytotoxic drug and simvastatin
caused muscle pain, soreness, fatigue, or
weakness, and in some cases rhabdomyoly-
sis. These effects were attributed to com-
petitive inhibition of CYP3A4-mediated
metabolism of simvastatin [62A].
Chapter 44 Paul Nestel
NICOTINIC ACID
DERIVATIVES [SED-15, 2512;
SEDA-32, 815]
Niacin
Observational studies In 71 subjects with
low HDL cholesterol, 12 months of treat-
ment with niacin signicantly reduced
carotid plaque wall area [63c].
Comparative studies In the ARBITER 6-
HALTS ER niacin simvastatin was com-
pared with ezetimibe simvastatin [3C]. It
was expected that both interventions would
lower LDL cholesterol beyond that due to
the statin but that niacin would additionally
raise HDL cholesterol more than ezeti-
mibe. This proved correct, and in fact the
trial was halted prematurely at 14 months
when the progression of carotid intima-
media thickness among the 208 patients
was signicantly slowed only in the niacin
group. It should be noted that this study
does not diminish the benets attributable
to lowering LDL cholesterol but focuses
on the additional value of raising HDL
cholesterol, which will be the major target
in future with nicotinic acid formulations,
especially those that are associated with tol-
erable degrees of ushing.
Niacin has also been trialled in combina-
tion with a statin and its safety compared
with a statin alone [64C]. Flushing occurred
in 67% of patients and was the most com-
mon treatment-related adverse effect; 21%
of patients stopped taking niacin for a vari-
ety of symptoms and the incidence of
adverse effects apart from ushing was
85%. There were three cases of chest pain,
which were regarded as serious adverse
events. Gastrointestinal discomfort was not
uncommon. Fasting blood glucose concen-
trations rose by 7.7% over the 12 weeks of
the study. In contrast in another study there
was improved whole-body insulin sensitiv-
ity in an open study over 6 months [65c].
Drug formulations The development of an
extended-release formulation of nicotinic
acid, named ER niacin has been an
Drugs that affect lipid metabolism Chapter 44
advance. The circulating concentrations of
the drug, when it is given once or twice a
day in this formulation, are much less vari-
able, and severe ushing does not occur in
the majority of patients. The demonstration
of a specic prostanoid receptor in the skin,
with which prostaglandin PGD2 interacts to
cause ushing, has led to the use of a com-
bination of ER niacin with laropiprant (a
specic antagonist at prostaglandin D1
receptors), which has further reduced the
adverse effects of niacin [66c]. This combi-
nation has been accepted in some major
countries in Europe and Asia but not in
the USA. To date there have been no
reports of serious adverse effects attribut-
able to laropiprant, but its usage is recent.
Efcacy and safety studies with ER nia-
cin have shown benet, albeit with some
safety concerns that were reported many
years ago with nicotinic acid, such as small
increased risks of hyperglycemia and
hyperuricemia.
The addition of laropiprant to ER niacin
signicantly reduced the frequency of ush-
ing in a worldwide, multicenter, double-
blind, randomized 24-week study in 800
subjects with dyslipidemia randomized to
active treatment (n 543) compared with
placebo (n 270), using an electronic diary
to record and transmit the incidence and
severity of ushing episodes [67C]. Never-
theless, 29% withdrew, compared with
11% of those taking placebo. The addition
of laropiprant to ER niacin did not affect
the reduction in LDL cholesterol (20%)
and triglycerides (25%) or the increase
in HDL (20%); lipoprotein(a) was also
reduced, nicotinic acid being one of the
few drugs capable of a signicant effect.
The laboratory safety data showed that
about 1% of those taking either ER niacin
or ER niacin laropiprant had increases
in hepatic aminotransferase activities to
more than three times the upper limit of
the reference range. Creatine kinase activity
increased to more than 10 times the upper
limit of the reference range in three of 762
patients taking the combined therapy. Five
of 661 taking the combined therapy devel-
oped diabetes mellitus compared with none
of those taking placebo. There was
929
worsening of pre-existing diabetes in 19 of
78 taking ER niacin alone and in 23 of
137 taking ER niacin laropiprant; how-
ever none of these was signicantly differ-
ent from placebo (two of 38). There were
no cases of myopathy. Six patients, three
in each treatment group, developed gout,
and uric acid rose by 40 mmol/l in both
groups.
In a 12-week study of 1398 patients tak-
ing ER niacin 2 g/day and laropiprant
20 mg/day, plus increasing doses of simva-
statin, the maximum reduction in LDL cho-
lesterol was 48% and the maximum
increase in HDL cholesterol was 27%
[68C]. Flushing and gastrointestinal symp-
toms were the main reasons for withdrawal,
but the rate was regarded as low. The low
incidence rates of increased hepatic trans-
aminase and creatine kinase activities were
similar across the treatment groups. Fasting
blood glucose rose by 0.22 mmol/l and uric
acid by 20 mmol/l.
Torcetrapib [SEDA-32, 817]
Cardiovascular As was reported in SEDA-
32 (p. 817), ILLUMINATE, an outcome
study that recruited around 15 000 statin-
eligible patients with coronary heart disease
or type 2 diabetes mellitus was terminated
after a median follow-up of only 550 days,
because of a small but signicant increase
in major cardiovascular events in those tak-
ing torcetrapib atorvastatin compared
with those taking atorvastatin alone (49
versus 35 cardiovascular deaths) [69C].
This occurred despite a 72% increase in
HDL cholesterol and a 25% reduction in
LDL cholesterol compared with the statin
alone. This was almost certainly correctly
attributed to activation of the reninangio-
tensinaldosterone system, resulting in
increments in blood pressure and aldo-
sterone and reduced potassium.
In a placebo-controlled study (RADI-
ANCE 2) in 752 subjects, torcetrapib failed
to improve carotid-intima thickness and con-
rmed the blood pressure raising effect [70C].
930
This experience is worth revisiting. Does
it suggest that such large effects on HDL
cholesterol cannot overcome the adverse
effects of a modest increase in blood pres-
sure? Does that itself cast some doubt on
the HDL hypothesis, or will other inhibi-
tors of cholesterol ester transfer protein
(CETP) reveal problems not associated
with blood pressure? Several major compa-
nies are advanced in their trials of CETP
inhibitors. One, anacetrapib, has been
found to be free of the mineralocorticoid-
related blood pressure effects and is equi-
potent with torcetrapib and another com-
pound already in a large outcome trial.
These inhibitors bind CETP to HDL and
there are differences between the com-
pounds to the extent of the reversibility of
the binding [SEDA-32, 816].
The failure of torcetrapib has led to a re-
examination of the safety of raising HDL
concentrations excessively and the possibil-
ity that high concentrations of the very large
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 Avinash Gupta and Mark Middleton
45 Cytostatic and cytotoxic
drugs
Editors note: The wide range of cytostatic
and cytotoxic drugs, the multitude of their
adverse effects, and the fact that they are
generally used in combinations of several
agents all make it impossible to provide as
detailed a review of adverse reactions to all
the drugs in this eld as the Annual gives
in others. This year this chapter is devoted
to a special review of the taxanes and other
microtubule stabilizing agents and a short
additional review on the use of carboxypep-
tidase in the treatment of methotrexate
toxicity.
Previous special reviews of anticancer
drugs in the SEDA series have been as
follows:
Anthracyclines (SEDA-25, 533)
Antimetabolites (SEDA-29, 551): Purine
antagonists, pyrimidine antagonists, antifolate
drugs, phosphatidylcholine antagonists, adeno-
sine deaminase inhibitors
DNA alkylating N-Lost derivatives (SEDA-31,
721)
Fluorouracil (SEDA-23, 476)
Inhibitors of topoisomerase I and topoisomer-
ase II (SEDA-27, 477)
Monofunctional alkylating agents (dacarbazine
and temozolomide) (SEDA-32, 827)
Paclitaxel (SEDA-21, 463)
Platinum compounds (SEDA-26, 490)
Tyrosine kinase inhibitors (SEDA-30, 520)
Vinca alkaloids (SEDA-28, 538)
Side Effects of Drugs, Annual 33
J.K. Aronson (Editor)
ISSN: 0378-6080
DOI: 10.1016/B978-0-444-53741-6.00045-3
# 2011 Elsevier B.V. All rights reserved.
Taxanes and other microtubule
stabilizing agents
Microtubules play an important role in vari-
ous cellular functions, including intracellular
transport, maintenance of cell shape and
polarity, cell signaling, and cell division by
mitosis. Their role in cell division in particu-
lar makes them suitable as targets for anti-
cancer drugs. The taxane chemotherapy
drugs paclitaxel and docetaxel exert their
cytotoxic effect by stabilizing microtubules,
promoting polymerization, and suppressing
microtubule dynamics. This leads to cell
cycle arrest and apoptosis. Both paclitaxel
and docetaxel have signicant antitumor
activity against a variety of solid tumors,
both as monotherapy and in combination
with other chemotherapeutic drugs. More
recently, a new class of microtubule stabiliz-
ing agents has emerged, called epothilones.
These also have antitumor activity against
various solid tumors, including taxane-resis-
tant cancers. Although taxanes and epothi-
lones have a similar mechanism of action,
there are important differences in both
efcacy and toxicity proles [1R].
Paclitaxel
Paclitaxel (Taxol) is a complex plant prod-
uct derived from the bark of the yew tree,
Taxus brevifolia. It is currently indicated
for rst-line treatment of advanced and
metastatic ovarian cancer, metastatic breast
cancer (in which it can be given in combina-
tion with trastuzumab in patients who
935
936
overexpress HER2), non-small cell lung
cancer (in combination with platinum
agents), and as a single agent for the treat-
ment of AIDS-related Kaposis sarcoma in
patients who have failed prior liposomal
anthracycline therapy [2S].
Paclitaxel, given 3-weekly, was previously
indicated in the adjuvant treatment of node-
positive breast cancer, following anthra-
cycline and cyclophosphamide chemother-
apy, but a large randomized study showed
that weekly paclitaxel or 3-weekly docetaxel
regimens are superior [3C]. Thus, in the
UK NICE recommends the use of docetaxel
rather than paclitaxel as adjuvant treatment
for lymph node-positive breast cancer [4S].
Paclitaxel has also been investigated in the
treatment of other carcinomas, including
melanomas, head and neck cancers, and
leukemia.
The recommended dosage for the treat-
ment of ovarian and breast cancer is gener-
ally 175 mg/m2 given intravenously over
3 hours every 21 days, although various
other dosage and administration schedules
have been investigated and are appropriate
in different settings. In the treatment of
AIDS-related Kaposis sarcoma the recom-
mended dose is 100 mg/m2 given intra-
venously over 3 hours every 14 days [2S].
Paclitaxel is poorly water-soluble and so
is conventionally administered via a poly-
oxyethylated castor oil derivative, Cremo-
phor EL, which is a micelle-forming
vehicle. This has now been found to affect
the pharmacokinetics of paclitaxel, as well
as its adverse reactions, as detailed below.
More recently, two new formulations have
been developed: albumin-bound paclitaxel
(marketed as Abraxane) and docosahexae-
noic acid paclitaxel (DHA paclitaxel, mar-
keted as Taxoprexin). Both have different
pharmacokinetics and adverse reactions
from conventional paclitaxel, as discussed
separately below.
Mechanism of action Paclitaxel acts by
enhancing microtubule assembly and stabi-
lizing microtubules [5R, 6R]. Microtubules
consist of polymers of tubulin in dynamic
equilibrium with tubulin heterodimers. The
principal function of microtubules is
Chapter 45 Avinash Gupta and Mark Middleton
formation of the mitotic spindle during cell
division, but they are also active in many
interphase functions, such as cellular motil-
ity, intracellular transport, and signal
transmission. Paclitaxel inhibits the depoly-
merization of tubulin, and the microtubules
formed in the presence of paclitaxel are
extremely stable and dysfunctional. This sta-
bilization impairs the essential assembly and
disassembly required for dynamic cellular
processes, and death of the cell results
through disruption of the normal micro-
tubular dynamics required for interphase
processes and cell division. In tumor cells
cytotoxicity is represented by the appearance
of abnormal microtubular bundles, which
accumulate during G2 and mitosis, blocking
the cell cycle [7R].
There is also increasing evidence that
paclitaxel has antiangiogenic effects, via
selective inhibition of endothelial cell
proliferation, migration, and tube formation
[8E, 9R].
Pharmacokinetics The pharmacokinetics of
paclitaxel depend on both its schedule of
administration and its formulation.
Conventional paclitaxel administered in
Cremophor EL has non-linear pharmaco-
kinetics [10r]. Both biphasic [11c] and
triphasic [12C] models have been reported.
Peak plasma concentrations and drug
exposure increase disproportionately with
increasing doses. For a 30% increase in dose
from 135 to 175 mg/m2, the Cmax and AUC
increase by 75% and 81% respectively [2S].
The duration of paclitaxel infusion also
inuences the peak plasma concentration,
as well as the half-life. In 25 patients treated
with paclitaxel 100 mg/m2 weekly, adminis-
tered over 1 hour or 3 hours there was a sig-
nicantly longer half-life and higher Cmax in
patients who received the shorter infusion
[13c].
The half-life of paclitaxel in plasma has
been estimated to be 353 hours [2S].
The frequency of dosing of paclitaxel also
affects its pharmacokinetics, through induc-
tion of CYP2C8 and CYP3A4 [14E]. This
may have signicance as weekly paclitaxel
regimens become more popular, because of
Cytostatic and cytotoxic drugs Chapter 45
better tolerability and demonstrable
responses in patients refractory to 3-weekly
regimens [15c, 16R].
Traditionally both saturable distribution
and elimination were thought to be the main
mechanisms underlying the non-linear phar-
macokinetics of paclitaxel [17R]. However,
the formulation vehicle Cremophor EL also
has a major effect. The clearance of Cremo-
phor EL increases signicantly and dispro-
portionately with prolongation of the
infusion [18r, 19r]. Indeed, unbound pacli-
taxel has linear pharmacokinetics, with a
half-life of about 22 hours [20r, 21r].
The rate of infusion also has an effect on
the adverse reactions prole of paclitaxel.
Shorter infusions are associated with less
myelotoxicity but more acute hypersensitiv-
ity and peripheral neuropathy [22r].
After intravenous administration pacli-
taxel is widely distributed, despite extensive
binding to plasma proteins (89%) [6R].
There is no evidence for accumulation of
paclitaxel with multiple treatment courses
[2S].
The routes of elimination of paclitaxel
have not been fully established in humans.
Only a small proportion of the drug
(1.313%) is excreted unchanged in the
urine [23c]. The main route of elimination
appears to be via hepatic metabolism (spe-
cically CYP3A4 and CYP2C8 activity)
and biliary clearance. The three major
metabolites of paclitaxel are 6a-hydroxy-
paclitaxel, 30 -para-hydroxypaclitaxel, and
6a-30 -para-dihydroxypaclitaxel [24E]. After
intravenous administration of paclitaxel, the
amounts of each metabolite excreted via the
feces were 26%, 2%, and 6% respectively
[2S]. The metabolites of paclitaxel do not
have signicant cytotoxic properties them-
selves [25E].
The effect of reduced renal function on
paclitaxel elimination has not been fully
established. However, as renal clearance
accounts for only a small proportion of total
clearance, dosage modications are not con-
sidered necessary in patients with renal
impairment [2S].
Hepatic impairment reduces the elimina-
tion of paclitaxel, which in turn results in
greater toxicity, particularly hematological
937
toxicity and mucositis [26c]. Caution is
required in patients with hepatic impairment,
and dosage reductions or avoidance are
recommended, depending on the severity of
liver dysfunction. Total bilirubin in particu-
lar is a good predictor of paclitaxel elimina-
tion and potential toxicity in patients with
liver dysfunction.
Based on a study in 35 patients with mod-
erate to severe liver dysfunction treated with
paclitaxel monotherapy given over 3 hours,
recommendations on dosage adjustments,
based on total bilirubin, have been pro-
posed, as outlined in Table 1.
Paclitaxel does not penetrate the central
nervous system [27c]. It can be detected in
ascitic uid after intravenous administration.
There is no evidence that it is secreted in
human breast milk, but in lactating rats
given radiolabelled drug, concentrations of
radioactivity in breast milk were higher than
those in plasma and fell in parallel with
plasma concentrations.
Cardiovascular Paclitaxel has been associ-
ated with disturbances in cardiac rhythm,
but the relevance of these effects has not
been fully established. Originally, all
patients in trials of paclitaxel were under
continuous cardiac monitoring, owing to
the risk of hypersensitivity reactions. Car-
diac disturbances were therefore more likely
to be detected. Many trials limited eligibility
to patients without a history of cardiac
abnormalities and to those who were not
taking medications likely to alter cardiac
conduction. The incidence of cardiac dys-
rhythmias without paclitaxel treatment is
unknown, and it is therefore not always
Table 1 Proposed dosage adjustments for
paclitaxel in liver impairment
Total serum Recommended initial
bilirubin dose of paclitaxel (mg/m2)
1.25  ULN 175
1.262.0  ULN 115
2.13.5  ULN 100
3.610  ULN 70
ULN, upper limit of normal (i.e. the reference range).
938
possible to attribute dysrhythmias in these
patients to paclitaxel. One mechanism by
which paclitaxel affects the heart appears to
be through impairment of the autonomic
modulation of heart rate [28c].
The most common cardiovascular
adverse reactions observed in patients
receiving paclitaxel are hypotension and
bradycardia [29R]. Hypotension has been
observed in up to 23% of patients and is
thought to be mostly secondary to hyper-
sensitivity reactions [30r]. Asymptomatic
bradycardia occurs in 929% of patients,
usually starting several hours after the start
of infusion and resolving spontaneously on
withdrawal [31r]. It is recommended that vital
signs should be monitored regularly during
the rst hour of an infusion [2S]. However,
bradycardia is not an indication for with-
drawal of treatment altogether, unless it is
associated with atrioventricular conduction
disturbances or clinically signicant effects
(such as symptomatic hypotension).
The authors of a review of the cardiac
toxicity associated with paclitaxel treatment
concluded that the overall incidence of seri-
ous cardiac events is low (0.1%). The causal
relation of paclitaxel to atrial and ventricular
dysrhythmias and cardiac ischemia is not
entirely clear [32r]. Reported events include
ventricular tachycardia, Mobitz I (Wencke-
bach syndrome), Mobitz II atrioventricular
block, complete atrioventricular block
(requiring pacemaker insertion), acute myo-
cardial infarction, supraventricular tachy-
cardia, and atrial brillation.
One patient died in heart failure 7 days
after receiving paclitaxel by infusion; this
patient had no prior history of cardiac prob-
lems, apart from mild hypertension [33A].
Cremophor EL may be implicated in the
incidence of dysrhythmias, particularly as a
result of hypotension associated with hyper-
sensitivity reactions [34R]. Another mecha-
nism may be through histamine release,
which in animals results in conduction dis-
turbances and dysrhythmias [35R].
Routine cardiac monitoring is considered
unnecessary in patients without a history of
cardiac conduction abnormalities. If a
patient has a history of serious cardiac dys-
rhythmias or develops cardiac dysrhythmias
Chapter 45 Avinash Gupta and Mark Middleton
that are clearly associated with paclitaxel
treatment, suitable treatment should be
started and paclitaxel should be adminis-
tered with continuous cardiac monitoring
[2S].
Further studies are needed to determine
the risks in patients with predisposing car-
diac risk factors who are being treated with
paclitaxel. A retrospective review of patients
with major cardiac risk factors who were
treated with paclitaxel (either monotherapy
or in combination with cisplatin or carbo-
platin) did not nd any evidence of reduced
cardiac function after treatment with pacli-
taxel. However the series only consisted of
15 patients [36c].
Respiratory The effects of paclitaxel on the
respiratory system are mostly related to
hypersensitivity reactions, causing dyspnea,
with or without bronchospasm. There have
been reports of patients who have developed
pulmonary inltrates or interstitial pneumo-
nia after paclitaxel treatment, with an inci-
dence of 3% in one phase II study [37c].
These inltrates usually resolve spontane-
ously or after glucocorticoid therapy; once
resolved, patients can be successfully rechal-
lenged with paclitaxel without developing
recurrent pneumonitis [38A]. There has been
one reported death, possibly secondary to
paclitaxel-related interstitial pneumonia, in
a 71-year-old Japanese man with stage IV
non-small cell lung carcinoma [39A]. How-
ever, whether death was secondary to pro-
gressive disease or interstitial pneumonia
was unclear.
There have been reports of radiation
pneumonitis after chemotherapy with pacli-
taxel. However, a large phase III study in
breast cancer patients showed no signicant
difference in clinically relevant radiation
pneumonitis between patients treated with
radiotherapy with or without prior exposure
to paclitaxel [40C].
Nervous system Neurotoxicity associated
with paclitaxel is dose-related, cumulative,
and characterized principally by a sensory
peripheral neuropathy, although motor
weakness has occasionally been reported
[41c]. In patients treated with paclitaxel 135
Cytostatic and cytotoxic drugs Chapter 45
or 175 mg/m2 (depending on whether they
had had three previous chemotherapy regi-
mens or only one or two respectively),
administered over 3 hours every 21 days,
grade 12 sensory neuropathy occurred in
52%, and grade 34 neuropathy occurred
in 9% [42C]. Toxicity appears to be related
to axonal degeneration and demyelination
and is usually reversible after withdrawal
[43c]. While withdrawal of therapy is rarely
required, peripheral neuropathy has been
the dose-limiting adverse reaction in some
phase I trials of paclitaxel monotherapy
[11c, 21c, 44c].
The intensity of neurotoxicity increases
with higher doses [31r, 34c]. While doses
up to 725 mg/m2 have been found to be tol-
erable (when administered as a one-off
infusion in combination with other chemo-
therapy drugs as part of a high-dose chemo-
therapy treatment regimen) [45c], most cases
of neurotoxicity occur at doses over 200 mg/
m2 and particularly after multiple courses
monotherapy [11c, 34c, 43c].
Peripheral neuropathy presents as numb-
ness, burning, and tingling in a glove-and-
stocking distribution. Symptoms usually
begin 2472 hours after treatment with pacli-
taxel, with a symmetrical distal loss of sensa-
tion. Once treatment is stopped, the
symptoms generally subside within several
weeks to months [34c].
Previous exposure to potentially neuro-
toxic chemotherapeutic agents, such as plati-
num compounds and vinca alkaloids, does
not appear to increase the risk of neurotoxic-
ity with paclitaxel [5R]. However, patients
with co-existing medical illnesses associated
with peripheral neuropathy, such as diabetes
mellitus and alcohol abuse, may be more
likely to develop a peripheral neuropathy.
A pre-existing neuropathy as a result of
prior therapy is not a contraindication to
paclitaxel, but in severe cases of peripheral
neuropathy a dosage reduction of 20% is
recommended for subsequent courses.
Tricyclic antidepressants, in particular
amitriptyline and venlafaxine, are helpful in
relieving symptoms of paclitaxel-induced
peripheral neuropathy [5R, 46A].
Other rare neurological adverse reactions
include development of autonomic
939
neuropathy, resulting in paralytic ileus, optic
nerve and/or visual disturbances, ototoxicity
(hearing loss and tinnitus), dizziness, head-
aches, and convulsions [2S, 44c].
Sensory systems Vision Transient scintillat-
ing scotomata have been observed in the
visual elds of both eyes in nine patients
receiving paclitaxel infusions in doses of
175 and 225 mg/m2 [47r]. Involvement of
the optic nerve was conrmed, and this is
likely to have been related to optic nerve
conduction abnormalities associated with
the neurological effects of paclitaxel. The
abnormalities were not progressive and there
was some degree of recovery, although one
patient had permanently impaired vision.
Hematologic Bone-marrow suppression is
the most common dose-limiting adverse
reaction to paclitaxel. Neutropenia occurs
most commonly 810 days after treatment,
and recovery usually occurs by days 1521.
Paclitaxel is relatively platelet sparing, and
thrombocytopenia and anemia are rare
[21c]. There is no evidence that neutropenia
is cumulative, suggesting that paclitaxel
may not irreversibly damage hemopoietic
stem cells [5R].
Neutropenia is dose- and schedule-
related, and is less common with shorter
infusion schedules. At doses of
110250 mg/m2 over 24 hours, neutropenia
is generally severe, and grade 4 neutropenia
(absolute neutrophil count below 0.5  109/
l) develops in a large proportion of patients
[21c, 48R]. Paclitaxel given as a 3-hour infu-
sion causes less severe neutropenia [41c,
49R]. In a large randomized trial, in which
patients received either a 3-hour or a 24-
hour infusion of 135 or 175 mg/m2, grade 4
neutropenia was more common with the
24-hour infusion regimen; 75% of patients
developed severe neutropenia and episodes
of fever [50C].
The duration of neutropenia is usually
brief, and treatment delays for unresolved
adverse hematological reactions on day 21
are rare. Paclitaxel-induced neutropenia
does not always lead to infectious complica-
tions, and therefore a dosage reduction for
940
neutropenia alone is not considered neces-
sary [51C, 52c].
Prior myelotoxic chemotherapy appears
to be a major susceptibility factor in deter-
mining the severity of neutropenia [5R,
34R]. Doses of 200 and 250 mg/m2 over
short infusion times cause minimal myelo-
suppression in patients who have had mini-
mal prior therapy [21C, 52C]; however,
seven patients (1.6%) died because of toxic-
ity in another study in patients with ovarian
cancer who had received extensive previous
chemotherapy; deaths were due to sepsis or
severe neutropenia [34R]. Prior radiother-
apy has also been reported to be associated
with increased severity of myelosuppression,
but this does not appear to be the case.
Paclitaxel administered in a weekly regi-
men rather than the more common 3-weekly
schedule has been found to be better toler-
ated, with less myelosuppression (as well as
fewer non-hematological adverse reactions)
and comparable, if not improved, efcacy
[16R, 53C].
The incidence of neutropenia has also
been investigated in combination schedules.
Patients who receive paclitaxel in combina-
tion with cyclophosphamide have severe
neutropenia more often than with monother-
apy (72% of patients). Paclitaxel given as a
24-hour infusion before cyclophosphamide
is more likely to cause severe neutropenia
compared with patients who receive cyclo-
phosphamide rst [54R]. Conversely, in
studies of paclitaxel and cisplatin combina-
tion chemotherapy, myelosuppression is
worse when paclitaxel is given after cisplatin
rather than before. This appears to be due to
reduced plasma clearance of paclitaxel when
cisplatin is administered rst.
Attempts to overcome neutropenia
include the use of human granulocyte col-
ony-stimulating factor (G-CSF). The abso-
lute neutrophil counts are generally higher
and the duration of severe neutropenia is
shorter when G-CSF is given 24 hours after
paclitaxel and continued until there is recov-
ery of the neutrophil count. When paclitaxel
is given in combination with G-CSF, doses
of 250 mg/m2 given over 24 hours every
3 weeks are possible without causing dose-
limiting neutropenia [49C]. Three-hour
Chapter 45 Avinash Gupta and Mark Middleton
infusion schedules have also been successful
using doses of 250 mg/m2 in combination
with G-CSF and doxorubicin [55c]. Other
dose-limiting adverse reactions, such as
neurotoxicity and gastrointestinal adverse
reactions, tend to predominate when pacli-
taxel is given in higher doses in combination
with G-CSF.
Recommendations currently specify that
patients should not be re-treated with pacli-
taxel until the neutrophil count recovers to
2.5  109/l and the platelet count recovers
to over 100  109/l.
Gastrointestinal Severe nausea, vomiting,
and diarrhea are uncommon with paclitaxel
[5R]. Although about half of the patients in
one study had vomiting or diarrhea, under
5% were severe [31R]. In another phase II
trial there were 11 episodes of nausea and
vomiting in 281 courses [48R]. Four patients
developed diarrhea, but this was not consid-
ered clinically signicant.
Mucositis and stomatitis have been com-
monly reported with paclitaxel. Mucositis is
characterized by ulceration of the lips, phar-
ynx, and oral cavity, occurring 37 days
after paclitaxel treatment [21c, 34R, 48R,
49R, 50C, 56C]. Mucositis appears to be
more common during treatment of acute leu-
kemias than with solid tumors, when doses
above 390 mg/m2 are used [41c]. Severe
mucositis occurred during second and third
courses, suggesting a cumulative effect, and
was more severe if treatment was given at
15 days or earlier after previous courses.
Patients with hematological malignancies
are more susceptible to breakdown of the
mucosal barrier, and this may account for
the increased incidence of mucositis. Nar-
cotic analgesics are effective in controlling
the pain associated with mucositis [5R].
In a phase I study of intraperitoneal pacli-
taxel in patients with advanced ovarian can-
cer, severe abdominal pain was the dose-
limiting toxicity at doses over 175 mg/m2
[57c]. Signicant gastrointestinal adverse
reactions have been noted in other trials of
intraperitoneal paclitaxel chemotherapy,
and this has limited its usefulness as a means
of administering chemotherapy via this route
[58C, 59r].
Cytostatic and cytotoxic drugs Chapter 45
Transient paralytic ileus occurred in two
patients in one study [50C]. Both patients
had diabetes mellitus, and these symptoms
may have been an additional manifestation
of autonomic neuropathy.
Post-mortem examination of patients trea-
ted with paclitaxel has shown mucosal ulcers
in the esophagus, stomach, small intestine,
and colon [60c]. Changes associated with
epithelial necrosis and mitotic arrest were
most prominent in patients who had recently
been treated with paclitaxel. These ndings
suggest that paclitaxel causes transient
mitotic arrest associated with cell necrosis.
Similar ndings have been found in studies
of the gastrointestinal tract of patients who
have received taxane chemotherapy treat-
ment at some time [61c].
Urinary tract Reversible renal insufciency
has been reported in one patient who was
treated with paclitaxel by the intraperitoneal
route [57c].
Skin Local venous effects, including ery-
thema, tenderness, and discomfort, can
occur at the injection site during paclitaxel
infusion [34R]. Inammation is usually evi-
dent within hours and normally resolves
within 21 days. Inammation occurs in
areas of drug extravasation along with pro-
longed soft tissue injuries. Necrotic changes
have been reported in one patient at the site
of extravasation [62r]. A soft tissue injury
occurred in one patient at the site of previous
extravasation after treatment with paclitaxel
in a different limb [63c]. This resolved
within 7 days. Inammation is most likely
to be due to the drug, but the Cremophor
EL vehicle may also be implicated, as it pro-
duces mild inammation in animals.
There is little information on the treatment
of extravasation of paclitaxel, as it has not
been common during clinical trials.
Radiation dermatitis has been reported in
a patient who received a single infusion of
paclitaxel [64A]. This was attributed to
potentiation of radiation effects by pacli-
taxel, because of the close time relation
between the radiotherapy and paclitaxel
therapy.
941
Hair Alopecia occurs in nearly all patients
who receive paclitaxel, but it has unique
characteristics. Hair loss is sudden and com-
plete, and many patients often lose all body
hair, including axillary and pubic hair, eye-
lashes, and eyebrows [42R, 65c]. The loss
of body hair often occurs with cumulative
therapy and is more severe after longer infu-
sion times.
Nails Onycholysis occurred in ve of 21
patients who received more than six doses
of paclitaxel 100 mg/m2/week [66cr]. The
authors provided a useful review of onycho-
lysis caused by other chemotherapy drugs.
Subungual hemorrhages after paclitaxel
treatment have also been reported [67A].
A felon (a closed space infection of the
ngertip pulp) was reported in one case
[68A]. The infection resolved after removal
of the nail to allow drainage of pus, followed
by intravenous antibiotics.
Musculoskeletal Arthralgia and/or myalgia
have been reported in 2030% of patients
receiving paclitaxel; they typically occur
25 days after chemotherapy [5R]. Symp-
toms commonly occur at doses above
170 mg/m2 [50C]. Symptoms of myalgia usu-
ally involve the shoulder and paraspinal
muscles, while arthralgia is commoner in
the large joints of the arms and legs [5R,
34R]. Symptoms can be controlled by non-
steroidal anti-inammatory drugs [34R]
and prophylactic gabapentin [69r]. The inci-
dences of arthralgia and myalgia are also
increased in patients who receive G-CSF, in
whom symptoms occurred in 86% of
patients compared with 28% of patients
who received similar doses without growth
factor support [51C].
The intensity of myalgia and arthralgia
correlated signicantly with the total cumu-
lative dose of paclitaxel 210 mg/m2/cycle by
3-hour infusion in 247 patients with a
median cumulative dose of 630 mg/m2 [70r].
Immunologic Acute hypersensitivity reac-
tions were common during phase I trials of
paclitaxel, and this caused delays in the com-
pletion of many trials. Early in the develop-
ment of paclitaxel, premedication with
942
glucocorticoids and antihistamines was
introduced to counter these reactions [71r].
Since then, the incidence of mild hypersensi-
tivity reactions has been reported as occur-
ring in under 44% of cases and severe
reactions in under 10% [72r]. Symptoms
consist of cutaneous ushing, urticaria,
bronchospasm, bradycardia, and hypo-
tension; the reactions mostly occur within
the rst 10 minutes of infusion, usually after
either the rst or second dose [73r]. Fatal
reactions are rare [72r].
Longer infusion schedules are associated
with a reduced incidence of hypersensitivity
reactions; the frequency of severe reactions
is reduced from 12% or more to 5% with
longer infusion times [11c, 31R, 73c]. Infu-
sions of less than 1 hour have been found
to be intolerable, even with appropriate pre-
medication [74r].
The mechanism of paclitaxel-induced
hypersensitivity reactions is uncertain. The
symptoms suggest histamine release from
mast cells to be a likely cause. Cremophor
EL is thought to play a signicant role in
inducing hypersensitivity reactions. Cremo-
phor EL causes similar reactions in dogs
by direct release of histamine [17R]. Hyper-
sensitivity reactions have also been directly
linked to complement activation secondary
to binding of naturally occurring anticholes-
terol antibodies to the hydroxyl-rich surface
of Cremophor EL micelles [75E]. However,
there is evidence that paclitaxel alone, with-
out the Cremophor EL vehicle, can also
cause hypersensitivity reactions [76E].
Premedication regimens of glucocorti-
coids and histamine H1 and H2 receptor
antagonists have been used to try to prevent
or reduce hypersensitivity reactions. Various
phase I trials have been successfully com-
pleted using infusion schedules of
1120 hours and doses of 135390 mg/m2,
with a lower incidence of hypersensitivity
reactions [31R, 49R, 42R, 50C, 56c, 65C,
71r]. However, the use of premedication
does not completely prevent such reactions.
There were incidences of 16%, 13%, and
7% with 3, 6, and 24-hour infusion sched-
ules respectively, despite premedication
[71r], while only 1.5% of patients developed
Chapter 45 Avinash Gupta and Mark Middleton
reactions in a trial with doses of
125250 mg/m2 over 24 hours, with gluco-
corticoid and histamine receptor antagonist
pre-treatment [50C]. Only one patient out
of 26 developed a hypersensitivity reaction
with doses of 150250 mg/m2 over 24 hours
[21c]. In one study of paclitaxel 175275 mg/
m2 infused over 6 hours without premedica-
tion there was only one hypersensitivity reac-
tion in 32 patients [73c], while patients who
received paclitaxel administered over 1 hour
with premedication had no serious hyper-
sensitivity reactions [56C]. There were no
hypersensitivity reactions in 40 patients who
received fractionated doses of paclitaxel
administered over 35 days, with cumulative
doses of 120250 mg/m2 [77R]. In a ran-
domized comparison of two doses of pacli-
taxel given by 3-hour or 24-hour infusions,
premedication alone was sufcient to pre-
vent hypersensitivity reactions with either
infusion duration [50C].
Premedication consisting of dexametha-
sone 20 mg intravenously 12 and 6 hours
before the infusion, and diphenhydramine
50 mg and cimetidine 300 mg intravenously
30 minutes before the infusion are now rou-
tinely given before patients are treated with
paclitaxel, and this, as well as a recom-
mended infusion time of 3 hours, has
reduced the incidence and severity of hyper-
sensitivity reactions. Single-dose dexametha-
sone 16 mg given 30 minutes before
paclitaxel was effective in preventing hyper-
sensitivity reactions in 43 patients [78r] and
is now commonly used, although there
remain concerns about the effectiveness of
this shorter course of premedication [72r].
In a large single-institution study, there
was a 9% incidence of clinically important
hypersensitivity reactions to paclitaxel in
450 women with gynecological malignancies
treated with paclitaxel alone or in combina-
tion regimens [79C]. All patients were even-
tually able to be re-treated with paclitaxel,
although in ve cases a desensitization regi-
men was required rst. There was also a sig-
nicant association between bee sting or
animal allergy and paclitaxel hypersensitiv-
ity in 57 patients with a variety of tumors
[80c].
Cytostatic and cytotoxic drugs Chapter 45
Drugdrug interactions Interactions with
paclitaxel have been reviewed [81R, 82R].
The most important of these are pharmaco-
dynamic interactions with other cytostatic
drugs, but pharmacokinetic interactions
have also been described.
Paclitaxel is metabolized by CYP2C8 and
CYP3A4 [23r, 83E], and drugs that inhibit
or induce these isoenzymes would be
expected to alter the metabolism of pacli-
taxel. In vitro ranitidine, diphenhydramine,
vincristine, vinblastine, and doxorubicin
had little or no effect on the metabolism of
paclitaxel, but barbiturates stimulated
hydroxylation of the side-chain by induction
of CYP3A isoforms [83E]. Although cimeti-
dine and famotidine have quite different
CYP-modulating abilities, a clinical study
showed no difference in paclitaxel clearance
or associated neutropenia when cimetidine
or famotidine were used as part of the pre-
medication regimen [84c].
Anthracyclines Paclitaxel given in combina-
tion with anthracyclines increases cardiac
toxicity. In one study, 35 women with
chemotherapy-naive metastatic breast cancer
were treated with increasing doses of pacli-
taxel and doxorubicin in combination. After
a median cumulative anthracycline dose of
480 mg/m2, 50% of the patients had a reduced
left ventricular ejection fraction and 18%
developed reversible congestive cardiac fail-
ure [85c]. Paclitaxel also dose-dependently
increased the plasma concentrations of
doxorubicin and its metabolite doxorubici-
nol; this was attributed to competition for bil-
iary excretion of taxanes and anthracyclines
mediated by P-glycoprotein [86E].
With epirubicin, excretion of the active
metabolite epirubicinol is reduced. Two
studies of the combination of epirubicin plus
paclitaxel have shown less reduction in left
ventricular ejection fraction and no clinical
evidence of cardiac failure [87c, 88c].
The cumulative dose of anthracyclines
remains important and should be lower in
combination regimens with paclitaxel, com-
pared with monotherapy [89r].
Platinum-containing cytotoxic drugs In 21
patients with advanced non-small cell lung
943
cancer, carboplatin had no effect on the
pharmacokinetics of paclitaxel 135200 mg/
m2 as a 24-hour intravenous infusion [90c].
Peripheral neuropathy occurred in 13 of 37
patients treated with paclitaxel 175 mg/m2
carboplatin [91c]. The authors concluded
that clinically important neurotoxicity
increases with every cycle of chemotherapy.
The peripheral neuropathy mainly affected
sensory bers, without involving motor
nerves. The same paclitaxel carboplatin
chemotherapy in 28 women caused no signs
of acute central neurotoxicity or neuro-
psychological deterioration; however, 11
patients had a peripheral neuropathy [92c].
Albumin-bound paclitaxel
In recent years, a Cremophor-free formula-
tion of paclitaxel has been developed, with
the trade name Abraxane. It uses nano-
particle albumin-bound (nab) technology
as a vehicle for the delivery of paclitaxel.
Abraxane is a Cremophor-free, 130-nano-
meter particle form of paclitaxel, which
delivers paclitaxel as a suspension of albu-
min particles in saline. It therefore avoids
the adverse reactions that are associated with
Cremophor EL. It does not need premedica-
tion with glucocorticoids and antihistamines.
In animals albumin-bound paclitaxel has
increased and prolonged antitumor activity
and more effective intratumor accumulation
of paclitaxel, compared with Cremophor-
based paclitaxel [93E]. It is currently
licensed for second-line treatment of meta-
static breast cancer.
Pharmacokinetics The apparent volume of
distribution and clearance of albumin-
bound paclitaxel are signicantly higher
than Cremophor-based paclitaxel, in both
animals and humans [94E]. Albumin-bound
paclitaxel has linear pharmacokinetics over
a dosage range of 135300 mg/m2 [95c].
The half-life is 22 hours, which is similar to
that of Cremophor-based paclitaxel [96R].
Cardiovascular In most studies to date there
has been no signicant evidence of
944
cardiotoxicity associated with albumin-
bound paclitaxel. However, in one phase II
study in which the drug was administered
in a dose of 300 mg/m2 one patient death
was considered to have been possibly due
to treatment-related cardiac ischemia or
infarction [97c].
Nervous system Most studies of albumin-
bound paclitaxel have used a higher dose
of paclitaxel than with Cremophor-based
paclitaxel, and this has correlated with a
higher incidence of peripheral neuropathy.
In phase II studies, 1138% of patients had
grade 2 or worse sensory neuropathy [97c,
98c, 99c]. In a phase II comparison of 3-
weekly cycles of albumin-bound paclitaxel
260 mg/m2 and conventional Cremophor-
based paclitaxel 175 mg/m2, grade 3 periph-
eral neuropathy was reported in 10% versus
2% of cases [100C]. Neuropathy typically
occurs in a glove-and-stocking distribution,
with symptoms of numbness or pain. Peri-
oral numbness has also been reported
[95c]. No cases of motor neuropathy have
been reported so far.
Sensory systems Vision Ocular adverse
reactions have been reported in phase I stud-
ies, with symptoms of blurred or smoky
vision, ashing lights, and photosensitivity position on the paclitaxel molecule [101E].
at a dose of 300 mg/m2 and supercial kera-
topathy during the rst cycle of treatment at
375 mg/m2, which constituted the dose-limit-
ing adverse reaction in this study [95c].
Hematologic Although regimens with albu-
min-bound paclitaxel involve higher doses
of paclitaxel, the incidence of myelosuppres-
sion is less than with Cremophor-based pac-
litaxel. This is in keeping with evidence that
some of the myelotoxicity of conventional
paclitaxel is related to the Cremophor vehi-
cle. Adverse reactions are dose-related. In
phase II studies to date, the incidence of
grade 2 or worse neutropenia was 2851%
[97c, 98c, 99c]. The risk of grade 2 or worse
anemia is reported at 731%. Thrombocyto-
penia is rare. In a direct comparison of albu-
min-bound paclitaxel and Cremophor-based
paclitaxel, the incidences of grade 4 neutro-
penia were 9% and 22% respectively [100C].
Chapter 45 Avinash Gupta and Mark Middleton
Gastrointestinal Nausea and diarrhea have
been reported in 810% of cases, with grade
3 diarrhea in 13% of patients in one phase II
trial [97c, 98c, 99c].
Hair In phase II trials alopecia was reported
in 6067% of patients [97c, 98c, 99c].
Musculoskeletal Myalgia and/or arthralgia
have been reported in about 710% of cases
in clinical trials to date [97c, 98c, 99c].
Immunologic In clinical studies albumin-
bound paclitaxel has been administered
without glucocorticoid or antihistamine pre-
medication. In phase I and phase II studies
there were no reported hypersensitivity reac-
tions. In a phase III study in patients with
breast cancer there was a <1% incidence
of hypersensitivity reactions and no grade 3
or 4 reactions [100C].
Docosahexaenoic acid (DHA)
paclitaxel
DHA paclitaxel is a novel formulation of
paclitaxel, made by covalently conjugating
the essential fatty acid DHA to the 20 -OH
Preclinical studies have suggested that there
is increased uptake of fatty acids by cancer
cells, for use as biochemical precursors and
energy sources [102c]. DHA paclitaxel has
been developed as a prodrug that harnesses
this process to target tumor cells selectively.
It has no cytotoxic activity until it is metabo-
lized intracellularly to the active molecule
paclitaxel by hydrolysis [101E]. Animal
studies have conrmed higher concentra-
tions of DHA paclitaxel compared with con-
ventional paclitaxel within tumor cells after
equimolar dosing [103E]. Pharmacokinetic
studies suggest that DHA paclitaxel has a
long half-life of 85 hours [102c]. Thus,
higher doses of paclitaxel can be delivered
to tumor cells for prolonged periods com-
pared with conventional paclitaxel.
DHA paclitaxel has been tested in a num-
ber of solid tumors so far in phase I and
phase II trials and has shown some efcacy
Cytostatic and cytotoxic drugs Chapter 45
in esophagogastric cancer [104c] and non-
small cell lung cancer [105c]. In a phase III
trial in patients with metastatic melanoma
there was no signicant difference in efcacy
between 3-weekly DHA paclitaxel and stan-
dard dacarbazine [106C].
Both weekly and 3-weekly regimens have
been investigated in phase I and phase II tri-
als [107c]. Doses of 9001100 mg/m2 admin-
istered 3-weekly have been reasonably well
tolerated. The dose-limiting adverse reac-
tions in phase I and phase II trials have been
neutropenia and hyperbilirubinemia [108c].
Signicant anemia and thrombocytopenia
are relatively uncommon. In a phase II
study, two out of four deaths were thought
to have been related to DHA paclitaxel, with
one death due to neutropenic sepsis and the
other secondary to cardiac failure. Post-
mortem examination in the second case
showed diffuse alveolar damage consistent
with drug-related pneumonitis [104c]. In a
phase III trial three patients died from
adverse events thought to be related to
DHA paclitaxel. One had congestive cardiac
failure, the second had a cardiopulmonary
arrest, and the third developed congestive
heart failure, pneumonia, and renal failure
[106C]. However, the authors did not go into
further details regarding these patients and
why the deaths were considered to be related
to DHA paclitaxel. Other adverse reactions
in the phase III study included rashes
(24% of patients), fatigue (54%), nausea
(39%), diarrhea (18%), constipation
(25%), and peripheral edema (13%).
In phase I and phase II studies DHA pac-
litaxel has been administered with glucocorti-
coid and antihistamine premedication [104c,
108c]. However, there have been reports of
hypersensitivity reactions despite this [104c].
A signicant difference compared with con-
ventional paclitaxel is the relatively small inci-
dence of peripheral neuropathy and no
reports of alopecia so far [102c, 106C].
Docetaxel
Docetaxel is a water-soluble, semisynthetic
analogue of paclitaxel, synthesized from the
945
needles of the European yew tree (Taxus
baccata).
Docetaxel is indicated, in combination
with doxorubicin and cyclophosphamide,
for adjuvant treatment of node-positive
breast cancer and, in combination with
doxorubicin, for treating locally advanced
or metastatic breast cancer. It is also indi-
cated as monotherapy or in combination
with capecitabine for the treatment of locally
advanced or metastatic breast cancer in
patients who have relapsed or progressed
after previous anthracycline or alkylating
agents. It can be administered concurrently
with trastuzumab, with which it is synergistic
in vitro [109r], unlike paclitaxel, which
appears to have simply an additive effect
with trastuzumab [110E].
Docetaxel in combination with cisplatin is
indicated as rst-line treatment for advanced
non-small cell lung cancer. Docetaxel mono-
therapy is indicated as second-line treatment
for advanced non-small cell lung cancer, fol-
lowing previous platinum-based
chemotherapy.
Docetaxel in combination with predniso-
lone is indicated for the treatment of hor-
mone-refractory metastatic prostate cancer.
Docetaxel in combination with cisplatin
and uorouracil is indicated in the treatment
of gastric adenocarcinoma and locally
advanced squamous cell carcinoma of the
head and neck [111S].
The recommended dose of docetaxel is
generally 75100 mg/m2, administered intra-
venously over 1 hour once every 3 weeks.
Premedication with dexamethasone is gener-
ally given; for example, dexamethasone
8 mg bd for 3 days, starting the day before
treatment with docetaxel. This helps to
reduce uid retention, as well as hypersensi-
tivity reactions.
Weekly docetaxel regimens have also been
investigated, but there are mixed reports
regarding tolerability; some studies have
reported a fairly similar adverse reactions
prole to 3-weekly docetaxel [112C], while
others have reported signicantly less myelo-
suppression with the weekly regimens [113R].
Mechanism of action Like paclitaxel,
docetaxel promotes tubulin assembly in
946
microtubules and inhibits their depolymeri-
zation [114R]. Compared with paclitaxel,
docetaxel has greater afnity for the tubu-
lin-binding site, accumulates in tumor cells
to a greater extent, and remains in cells for
longer [115R, 116R]. Thus, a lower dose of
docetaxel is required to produce the same
cytotoxic effect, compared with paclitaxel.
Pharmacokinetics Docetaxel administered
intravenously over 12 hours has linear
pharmacokinetics and the AUC increases
proportionately with dose [117R]. Plasma
protein binding is 7689% [118R]. The
half-life is 11 hours. Elimination is mainly
by biliary excretion into the feces [119R].
In patients with raised bilirubin and/or liver
aminotransferases, there is a 1227% reduc-
tion in docetaxel elimination, and dosage
reductions should be considered [117R]. In
patients with raised bilirubin concentrations
or aminotransferases more than 3.5 times
the upper limit of the reference range, and
alkaline phosphatase more than six times,
no recommendations for dosage reduction
can be made and docetaxel should be
avoided [111S].
Docetaxel is mainly metabolized by
CYP3A4. Its metabolism is inhibited by
inhibitors of CYP3A4, such as ketoconazole
and ritonavir [120c, 121E]. Renal excretion
is minimal (<5%) [117R].
Pregnancy There are no data on the use of
docetaxel in pregnant women. However, in
animals, docetaxel is both embryotoxic and
fetotoxic and, like other cytotoxic com-
pounds, it should not be used in pregnancy
unless clearly indicated [111S].
Lactation Docetaxel is lipophilic, but it is
not known whether it is secreted into breast
milk. However, because of the potential for
adverse reactions in nursing infants, breast-
feeding must be stopped while the mother
is receiving docetaxel [111S].
Cardiovascular There are no signicant
reports of cardiotoxicity associated with
docetaxel. The combination of docetaxel
trastuzumab is not associated with signi-
cant cardiotoxicity [122R]. Patients who are
Chapter 45 Avinash Gupta and Mark Middleton
receiving trastuzumab should undergo regu-
lar cardiac monitoring, but there is no indi-
cation that increased monitoring is required
when it is given in combination with
docetaxel.
Respiratory There are reports of interstitial
pneumonitis after treatment with docetaxel
[123r, 124A]. In one case series four patients
developed symptoms within 12 weeks of
receiving docetaxel. All ended up requiring
mechanical ventilation and two died from
progressive pulmonary disease [123r]. The
risk of interstitial pneumonitis appears to
be greater when docetaxel is given in combi-
nation with gemcitabine or radiotherapy
[125R].
Nervous system About 30% of patients
treated with docetaxel develop symptoms of
peripheral neuropathy [112C]. Generally,
the symptoms settle within months. Periph-
eral neuropathy is less frequent with doce-
taxel than with paclitaxel; grade 3/4 sensory
neuropathy occurs in about 5% of patients
treated with docetaxel 100 mg/m2 [126C].
Proximal and distal muscle weakness has
also been reported (about 5% in a review
of 186 patients in phase I and phase II stud-
ies) [127C]. The pathogenesis, incidence,
susceptibility factors, diagnosis, characteris-
tics, and management of taxane-induced
peripheral neuropathy have been critically
reviewed [128R].
Sensory systems Eyes Blockage of the lacri-
mal ducts, resulting in epiphora (overow of
tears on to the face due to disturbed outow)
is a little known but common adverse reac-
tion to weekly docetaxel, and required cor-
rective surgery in 30 out of 71 patients in
one study [129C]. The incidence of epiphora
was much less in patients treated with 3-
weekly docetaxel; only three of 72 patients
required surgery in the same study.
Fluid balance Fluid retention has been
reported in up to 50% of patients treated
with docetaxel, usually after cumulative
doses. This commonly manifests as periph-
eral edema, but pleural effusions and ascites
have also been reported [130c]. As a result,
Cytostatic and cytotoxic drugs Chapter 45
docetaxel is usually administered with gluco-
corticoid cover, which is very effective at
reducing the incidence and severity of uid
retention. Some believe that the development
of uid retention depends on the dose and
the duration of infusion, and that high con-
centrations of M4, the cyclized oxazolidine-
dione metabolite of docetaxel, cause more
pronounced uid retention [130R, 131c].
Hematologic Neutropenia was the dose-
limiting adverse reaction in most phase I
and phase II studies of docetaxel, with a
median duration to nadir counts of 7 days
[132R]. This appears to be dose-related, but
not schedule-related (unlike paclitaxel). In
a large phase III trial, 9.6% of patients
receiving 3-weekly docetaxel 75 mg/m2
developed grade 3/4 neutropenia [112C].
Anemia is also commonly reported and
dose-related, affecting up to 97% of patients
[133C]. Thrombocytopenia is less common,
occurring in 7.412% of patients [131C].
Docetaxel can cause a signicant but
reversible non-specic lymphopenia.
Patients treated with docetaxel-containing
regimens have been found to be at increased
risk of non-neutropenic infections, com-
pared with patients treated with paclitaxel
or non-taxane-based chemotherapy [134C].
Gastrointestinal Nausea/vomiting, diar-
rhea, and mucositis are commonly reported
adverse reactions to docetaxel, affecting
about 40%, 30%, and 20% of patients
respectively [112C, 130R]. Neutropenic
enterocolitis is a rare but severe consequence
of docetaxel treatment and, while it is more
commonly reported during treatment of
hematological malignancies, there have been
cases reported after docetaxel chemotherapy
for solid tumors as well [135r]. It is charac-
terized by segmental cecal and ascending
colon ulceration and is often fatal, because
of rapid progression to sepsis and shock.
Non-neutropenic colitis and ischemic colitis
associated with docetaxel and vinorelbine
combination chemotherapy have also been
reported [136A].
Skin In one study, of 99 patients who
received low-dose docetaxel (60 mg/m2
947
every 3 or 4 weeks), 25 had skin toxicity,
mainly erythema and nail changes [137c].
Of a subset of 25 patients who received irra-
diation before docetaxel, four had recall der-
matitis during their rst infusion of
docetaxel. All had previously been treated
with doxorubicin, which may in part have
explained some of the toxicity.
In a phase II trial in patients with non-
small cell lung cancer, docetaxel 100 mg/m2
resulted in at least a grade 2 rash in 41%
of cases. In a further study with docetaxel
75 mg/m2 plus prednisolone cover there
was a 25% reduction in rashes. However,
whether this was due to the prednisolone or
the lower dose of docetaxel was unclear
[138c].
Palmarplantar erythrodysesthesia syn-
drome (commonly called handfoot syn-
drome) has been reported to be associated
with docetaxel, although various patterns of
spread, from solitary erythematous plaques
to widespread involvement of the trunk,
have been observed [139c, 140A].
There has been one report of increased
photosensitivity with docetaxel. A 58-year-
old man with prostate cancer developed
lichenoid eruptions on the forearms and face
23 days after each docetaxel infusion
[141A]. The lesions would fade within
2 weeks, but then recur after the next infu-
sion, and were associated with pruritus
which increased on exposure to the sun.
Nails Nail changes have been reported in up
to 44% of patients treated with docetaxel,
with manifestations including onycholysis,
subungual hemorrhages, and subungual
abscesses [142R, 143R].
Hair Docetaxel is commonly associated
with signicant and sometimes complete hair
loss [130R, 144R]. This usually develops by
the second cycle of treatment of a 3-weekly
regimen.
Musculoskeletal Docetaxel is associated
with arthralgias and myalgias, usually start-
ing 12 days after infusion and lasting up
to 5 days [142R]. As with paclitaxel, gaba-
pentin given prophylactically controls symp-
toms in some patients [69r].
948
Immunologic Hypersensitivity reactions to
docetaxel occur in about 2030% of cases,
usually within a few minutes of starting an
infusion [142R]. They most commonly occur
during the rst or second cycle of treatment.
The symptoms may be minor, such as ush-
ing or localized cutaneous reactions, or
more severe, such as severe hypotension,
bronchospasm, or generalized rash/
erythema. Patients who develop severe
hypersensitivity reactions should not be
rechallenged with docetaxel [111S].
In one phase II study, infusion-related
reactions were reported in 34% of patients
treated with docetaxel 100 mg/m2. This was
reduced by 25% after the use of oral pred-
nisone (100 mg orally before treatment and
50 mg once on the morning of treatment
and the following 2 days) [136c].
Drugdrug interactions Anthracyclines
Unlike paclitaxel, docetaxel does not appear
to affect the metabolism of doxorubicin.
Thus, the combination of docetaxel and
doxorubicin does not increase the risk of
cardiotoxicity, compared with doxorubicin
alone [145r] or doxorubicin cyclophos-
phamide combination chemotherapy [146C].
Epothilones
The naturally occurring products epothilone
A and B were originally isolated from the
myxobacterium Sorangium cellulosum. The
epothilones are 16-membered macrolides
with a similar mechanism of action to tax-
anes, stabilizing microtubules and promot-
ing tubulin polymerization, thus inducing
mitotic arrest in the G2M phase of the cell
cycle, resulting in apoptosis [147R]. Their
name is derived from their molecular struc-
ture, which includes an epoxide, methyl
thiazole, and a ketone [1R]. Epothilones
compete with paclitaxel for the same binding
sites to tubulin, although they interact with
the binding sites in a different way to pacli-
taxel [1R]. In in vitro studies epothilone A
and paclitaxel have similar activity in induc-
ing tubulin polymerization, while epothilone
B is a more potent microtubule stabilizer
Chapter 45 Avinash Gupta and Mark Middleton
[148E]. Furthermore, compared with pacli-
taxel, the potency of the epothilones appears
to be signicantly less affected by cells that
overexpress the P-glycoprotein efux pump,
which is considered a key mechanism by
which cells become resistant to chemo-
therapy drugs [149E]. Ixabepilone, patuli-
pone, and sagopilone are the main
epothilones to be investigated so far,
although others are in development.
Ixabepilone
Ixabepilone is a semisynthetic derivative of
epothilone B. It has been approved by the
US FDA, for use as monotherapy or in com-
bination with capecitabine for the treatment
of locally advanced or metastatic breast can-
cer that is resistant or refractory to standard
chemotherapy options (anthracyclines, tax-
anes, capecitabine) [1R]. It also has activity
in prostate, renal, and pancreatic cancers
and in non-small cell lung cancer.
Pharmacokinetics Ixabepilone is more sta-
ble than natural epothilone B and has a
half-life of 1672 hours [150c, 151R]. Like
taxanes, ixabepilone is mostly metabolized
in the liver, by CYP3A4/5. The clearance
of ixabepilone is reduced in patients with
hepatic impairment and dosage reductions
are required [156R].
General adverse reactions The adverse
reactions to ixabepilone are similar to those
seen with standard taxanes. Most data so
far come from phase II studies, although
there has been one large phase III study with
ixabepilone given in combination with cape-
citabine [152C].
Nervous system Peripheral neuropathy has
been common in studies to date and in some
cases has been the dose-limiting adverse
reaction. Sensory neuropathy is most com-
mon, of grade 2 or greater intensity in about
45% of cases. However, motor neuropathy
and autonomic neuropathy have also been
reported [153c, 154c, 155c, 156c]. In some
phase II studies, some patients already had
Cytostatic and cytotoxic drugs Chapter 45
grade 1 neuropathy on entering the study,
due to residual toxicity from previous
chemotherapy.
Hematologic Neutropenia is the most com-
monly reported hematological adverse reac-
tion, and is of grade 2 or worse in 7179%
of cases [153c, 154c, 155c, 156c]. Grade 2
or worse anemia has been reported in about
35% of cases. Thrombocytopenia is less
common (grade 2 or worse in 812% of
cases), but severe thrombocytopenia with
subsequent hemorrhage has been reported
[153c].
Gastrointestinal Nausea and vomiting has
been reported in 4157% of patients. Bowel
disturbances are common; diarrhea has been
reported in 2247% of patients (grade 2 or
worse in 610%) and constipation in
2056% [153c, 154c, 155c, 156c]. Mucositis
or stomatitis has been reported in 1029%
of patients (grade 2 in 214%).
Musculoskeletal Arthralgia/myalgia has been
reported in 3065% of patients [153c, 154c,
155c, 156c].
Skin, nails, hair Rash and/or palmarplan-
tar erythema has been reported in 822%
of cases. Nail changes are reported in
956% of cases. Alopecia of varying severity
has been reported in 4392% of cases [153c,
154c, 155c, 156c].
Immunologic Ixabepilone is formulated in
Cremophor EL and so is usually adminis-
tered with premedication using histamine
H1 and H2 receptor antagonists. There have
been reports of hypersensitivity in about
58% of cases, but these are usually mild
and not treatment-limiting [153c, 154c, 155c,
156c].
Drugdrug interactions Like taxanes, ixa-
bepilone is metabolized by CYP3A4/5 and
inhibitors of this enzyme, such as ketocona-
zole, inhibit its clearance and increase drug-
related adverse reactions [151R].
949
Patupilone
Patupilone is naturally occurring epothilone
B. It is twice as potent in promoting tubulin
polymerization in vitro, compared with pac-
litaxel and epothilone A [147R]. Phase I/II
studies have been conducted in patients with
non-small cell lung cancer, renal cell cancer,
and ovarian cancer. Patupilone crosses the
bloodbrain barrier and has activity in
patients with non-small cell lung cancer
and cerebral metastases [1R].
The major dose-limiting adverse reaction
to patupilone is diarrhea, rather than neu-
ropathy. Other signicant adverse reactions
include fatigue and nausea. In phase I/II
studies severe diarrhea has been reported in
1419% of patients [157R, 158c]. Hemato-
logical toxicity appears to be minimal
[158c]. Grade 3 peripheral neuropathy was
the dose-limiting adverse reaction in one
phase I study, along with grade 3 diarrhea
[159c]. Premedication has not been required
and there have been no reports of hyper-
sensitivity reactions so far.
Sagopilone
Sagopilone is a fully synthetic epothilone B
analogue that has efcacy in ovarian cancer,
melanoma, and prostate cancer [160R]. In
in vitro studies sagopilone induces tubulin
polymerization more rapidly than paclitaxel
or patupilone [161E]. In animals sagopilone
crosses the bloodbrain barrier and has
activity against glioblastomas and nervous
system metastases [162E].
In phase I studies, sagopilone has a similar
adverse reactions prole to those of taxanes
and ixabepilone; neuropathy and neutro-
penia are the most commonly reported adverse
events [163c]. Motor neuropathy has not been
reported so far, although in one phase I study,
two patients reported symptoms of central
ataxia [164c]. Diarrhea is less common with
sagopilone than with ixabepilone and patupi-
lone. Premedication is not routinely given with
sagopilone and hypersensitivity reactions have
not been reported so far.
950
OTHER CYTOTOXIC
DRUGS
Methotrexate
Use of carboxypeptidase in the
treatment of methotrexate toxicity
Carboxypeptidases are regulatory peptide-
processing enzymes that are secreted by
human cells [165E]. Carboxypeptidase G2,
which is produced by Pseudomonas strain
RS-16, hydrolyses the glutamate residue from
methotrexate and other folate analogues
[166Ec] and rapidly hydrolyses methotrexate
to the inactive metabolite DAMPA (4-[[2,4-
diamino-6-(pteridinyl)methyl]-methylamino]-
benzoic acid) and glutamate. It has been used
when unexpected toxicity or renal insuf-
ciency occurs during high-dose methotrexate
therapy [167A, 168A, 169A, 170A, 171A,
172c, 173c], including intrathecal administra-
tion [174c], and for example when folinic
acid and other interventions have failed
[175c, 176c]. High-dose methotrexate has suc-
cessfully been used again after rescue with
carboxypeptidase G2 [177c].
Observational studies In four patients with
recurrent primary nervous system lympho-
mas who were given methotrexate 3.0 g/m2
infused over 2 hours and carboxypeptidase
G2, 50 U/kg 12 hours later, followed by a
second dose 6 hours after the rst, plasma
methotrexate concentrations fell to the sub-
therapeutic range within 5 minutes of the
rst dose of carboxypeptidase G2, but the
second dose had no further effect [178c]. In
contrast, cerebrospinal uid methotrexate
concentrations were not altered. Anti-car-
boxypeptidase antibodies were not detected.
Comparative studies In 20 patients with
high-dose methotrexate-induced renal dys-
function, who received one to three doses
of carboxypeptidase G2, 50 U/kg intra-
venously, thymidine 8 g/m2/day by
Chapter 45 Avinash Gupta and Mark Middleton
continuous intravenous infusion, and stan-
dard pharmacokinetically guided leucovorin
rescue, carboxypeptidase G2 and thymidine
resulted in a rapid 95.699.6% reduction in
the plasma methotrexate concentration;
renal function recovered after a median of
22 days [179c].
Urinary tract Methotrexate-induced renal
damage appears to be physicochemical in
nature. Both the parent compound and its
major metabolite, 7-hydroxymethotrexate,
are less soluble at acidic pH values, increas-
ing the risk of precipitation in the kidneys,
particularly at high dosages. An amorphous
yellow materialvery probably metho-
trexatehas been isolated in the kidneys of
patients who died as a result of metho-
trexate-induced renal dysfunction. For physi-
cochemical reasons, it is recommended that
the urine be alkalinized (target urinary pH
above 7.5) before intensive methotrexate regi-
mens are started. Supportive agents include
sodium bicarbonate orally or intravenously,
acetazolamide 500 mg qds, or both in combi-
nation [180c, 181c, 182A]. If there is acute
renal insufciency despite appropriate
urinary alkalinization, one may need to use
carboxypeptidase G2 as an antidote, which is
also appropriate in cases of accidental intrathe-
cal overdose of methotrexate [183A, 184A].
A 14-year-old Hispanic boy (59 kg, 1.78 m)
with non-metastatic osteosarcoma of the right
tibia was given methotrexate 12 000 mg/m2
weekly together with doxorubicin. High-dose
methotrexate was administered over 4 hours
and leucovorin rescue (12 mg/m2 intravenously
6-hourly) was started 20 hours after metho-
trexate and was intended to be continued until
methotrexate concentrations were below
0.2 mmol/l. During the sixth cycle, the metho-
trexate plasma concentration was 657 mmol/l
(compared with 3.3 mmol/l during the rst
cycle) 24 hours after methotrexate had been
started. Acute renal insufciency and cytolytic
hepatitis developed. The dose of leucovorin
was increased to 35 mg/m2 6-hourly, and furo-
semide and aminophylline were given. How-
ever, 4 days later, the serum creatinine, blood
urea, uric acid, and methotrexate concentra-
tions were still abnormal, with a creatinine
clearance of 10 ml/minute. The next day, he
Cytostatic and cytotoxic drugs Chapter 45
was given carboxypeptidase G2 50 units/kg,
which resulted in a reduction in methotrexate
plasma concentrations from 614 mmol/l to
24 mmol/l within 16 hours. However, 5 days
after methotrexate infusion, renal insufciency
was still severe. Although the dosage of leucov-
orin was increased again to 90 mg/m2 6-hourly
and a second dose of carboxypeptidase G2 was
given, he worsened on the following day, with
grade 2 mucositis and jaundice. However,
15 days after the start of the sixth methotrexate
cycle, renal and hepatic function had
normalized.
Drugdrug interactions Leucovorin Leuco-
vorin is used to antagonize the effects of
methotrexate on purine metabolism, but its
protective effect is antagonized by carboxy-
peptidase G2, which should therefore be
administered to patients with caution
[185Er].
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46 Radiological contrast agents
and radiopharmaceuticals
Iodinated contrast agents and CT scanning
have been compared with gadolinium-
enhanced MRI scanning in a review of con-
trast medium-induced nephropathy [SEDA
32, 846], nephrogenic systemic brosis
[SEDA 32, 852], extravasation of contrast
media, allergy and allergic-type reactions
to contrast media, and the role of contrast
agents in pregnancy [1R].
Comparative studies In a retrospective
review of 456 930 doses of iodinated and
gadolinium-containing contrast media,
there were 522 adverse reactions (0.11%
of the total), of which 458 were to low-
osmolar iodinated media and 64 to gadolin-
ium [2c]. Urticaria, which occurred in 274
patients, was the commonest reaction.
Management of adverse reactions The use
of intravenous adrenaline in patients with
reactions to contrast media has been retro-
spectively reviewed in nine of 456 930
patients who received either an intravenous
iodinated contrast medium or intravenous
gadolinium over a 5-year period [3R].
Seven had reactions to intravenous low-
osmolar contrast media and two to gadolin-
ium. Laryngeal edema was the most
frequently documented reason for adrena-
line administration (six of nine patients).
Transient cardiovascular adverse reactions
to adrenaline, including vague chest
Side Effects of Drugs, Annual 33
J.K. Aronson (Editor)
ISSN: 0378-6080
DOI: 10.1016/B978-0-444-53741-6.00046-5
# 2011 Elsevier B.V. All rights reserved.
Julie Olliff and Peter Riley
tightness and labile hypertension, were
recorded in four patients. One had a car-
diac arrest and died; autopsy showed retro-
peritoneal hemorrhage.
Water-soluble intravascular
iodinated contrast agents [SED-15,
1848; SEDA-29, 573; SEDA-30, 533;
SEDA-31, 731]
There are four types of iodinated water-sol-
uble contrast media, classied according to
their physicochemical properties (Table 1).
They are mainly used intravascularly, but
can also be injected into body cavities, par-
ticularly the low-osmolar contrast agents.
Some are also used for oral or rectal admin-
istration, and the high-osmolar water-solu-
ble contrast agent diatrizoate is suitable
only for these purposes. Low-osmolar and
iso-osmolar iodinated contrast media have
almost completely replaced high-osmolar
agents for intravascular use and administra-
tion into body cavities.
Observational studies There were 57
adverse events after the use of non-ionic
contrast media in 12 494 consecutive chil-
dren or young adults aged under 21 years,
an incidence of 0.46% [4c]. There were no
serious adverse events, and the authors
noted a signicant relation between age
and the incidence per 1000 studies, inde-
pendent of sex, season, or year of study,
with an increase in the frequency of reac-
tions to contrast media with increasing age.
963
964 Chapter 46 Julie Olliff and Peter Riley

Table 1 Some iodinated water-soluble contrast media

Properties Examples (INNs) Brand names

High-osmolar ionic monomers Diatrizoate Angiogran, Hypaque, Gastrogran,

Renogran, Urogran
Iotalamic acid Conray
Ioxitalamic acid Telebrix
Metrizoate Isopaque, Triosil
Low-osmolar ionic dimers Ioxaglic acid Hexabrix
Low-osmolar non-ionic monomers Iobitridol Xenetrix
Iohexol Omnipaque
Iomeprol Iomeron
Iopamidol Isovue, Niopam, Solutrast
Iopentol Imagopaque
Iopromide Ultravist
Ioversol Optiray
Metrizamide Amipaque
Iso-osmolar non-ionic dimers Iodixanol Visipaque
Iosimenol Iosmin
Iotrolan Isovist

Nervous system Intracranial hemorrhage
has been reported after injection of con-
trast medium through microcatheters dur-
ing intra-arterial thrombolysis for acute
ischemic stroke in a study in 98 patients
[5C]. After the procedure CT scans were
reviewed for evidence of contrast extrava-
sation or intracranial hemorrhage (dened
as a hyperdensity suggestive of contrast
medium, Hounseld units >90 at 24 hours
or present before 24 hours and persisting
or replaced by intracranial hemorrhage at
24 hours). There were intracranial hemor-
rhages in 57 of the 98 patients. There were
more microcatheter injections in those with
intracranial hemorrhage (median 2 versus
1). The authors concluded that the effect
may be due to an adverse reaction to con-
trast medium in this small subset of
patients, although the effect could also have
been secondary to a pressure effect follow-
ing injection.
Salivary glands Iodide-induced sialadenitis
(iodide mumps) is the name given to
swelling of the salivary glands due to com-
pounds that contain iodine [SEDA-32,
845]. Further cases have been reported
[6A, 7A]. The EIDOS and DoTS descrip-
tions of this reaction are shown in Figure 1.
Urinary tract Contrast-induced nephrotoxi-
city has been reviewed in successive vol-
umes of SEDA [SEDA-29, 575; SEDA-30,
535; SEDA-31, 731; SEDA-32, 846]. The
EIDOS and DoTS descriptions of this reac-
tion are shown in Figure 2. Susceptibility
factors include: age (over 70 years), drugs
(nephrotoxic drugs, such as non-steroidal
anti-inammatory drugs; metformin; man-
nitol, and diuretics, particularly loop
diuretics; multiple repeat exposures to con-
trast media within 72 hours), and diseases
(pre-existing renal insufciency, particu-
larly if it is associated with diabetes melli-
tus, congestive heart failure, dehydration).
There is also an increased risk in organ
transplant recipients.
Contrast-induced nephrotoxicity is
dened as an acute rise in serum creatinine
by at least 44 mmol/l (0.5 mg/dl), or 25%
above baseline within 4872 hours after
the administration of an intravascular con-
trast agent, in the absence of any other
cause.
Radiological contrast agents and radiopharmaceuticals Chapter 46 965

EIDOS Extrinsic species (E) Intrinsic species (I)

lodine-containing compounds Not known

Distribution
Salivary glands

Manifestations (test results) Outcome (the adverse effect)

Ultrasonography/histology Oedema, increased vascularity

Manifestations (clinical) Sequela (the adverse reaction)

Salivary gland swelling Sialadenitis (iodide mumps)

DoTS
Dose-responsiveness Time-course Susceptibility factors
024 h
Hypersusceptibility First-dose lodine hypersensitivity

Dose-responsiveness Time-course Susceptibility factors

>24 h
Toxic/hypersusceptibility Intermediate Renal impairment

Figure 1 The EIDOS and DoTS descriptions of iodide-induced sialadenitis.

EIDOS Extrinsic species (E) Intrinsic species (I)

lodinated water-soluble contrast media Renal tubular cells

Distribution
Kidney

Outcome (the adverse effect)

Inhibition of apoptosis
Manifestations (test results)
Impaired renal function
Sequela (the adverse reaction)
Manifestations (clinical) Contrast medium-induced nephrotoxicity
Clinical effects of renal failure

DoTS
Dose-responsiveness Time-course Susceptibility factors
Collateral Intermediate Age, drugs, and
diseases (see text)

Figure 2 The EIDOS and DoTS descriptions of contrast-induced nephrotoxicity.

The number of comparisons of different use of prophylactic drugs and various

contrast agents and potential methods of
prevention is increasing with increasing
awareness of clinicians. Several authors
have described potential mechanisms of
injury, compared different contrast agents,
and discussed prevention, including the
hydration regimens [8R, 9R, 10r].
In a retrospective casecohort study in
809 patients who developed contrast-
induced nephrotoxicity after either intra-
arterial or intravenous contrast administra-
tion and 2427 patients who did not,
966
nephrotoxicity was signicantly associated
with both mortality at 30 days (OR 3.37;
95% CI 2.58, 4.41) and overall mortality
(HR 1.57; 95% CI 1.32, 1.86), after
adjustment for other susceptibility factors
[11C].
Choice of contrast agent Several studies
have compared the use of non-ionic low-
osmolar agents with the iso-osmolar agent
iodixanol, given either intra-arterially or
intravenously, in patients at risk of con-
trast-induced nephrotoxicity. Previous stud-
ies have supported the use of an iso-
osmolar agent in susceptible patients
undergoing intra-arterial injection of con-
trast material when compared with a low-
osmolar agent. However, more recent
studies have suggested that there is little
difference between the two, particularly
when they are given intravenously.
In a meta-analysis of 25 randomized con-
trolled trials involving 3270 patients, iodixa-
nol was not associated with a signicantly
reduced risk of contrast-induced nephro-
toxicity compared with all low-osmolar
media pooled together (RR 0.80; 95%
CI 0.61, 1.04) [12M]. There were no sig-
nicant risk reductions in subgroups after
intravenous administration (RR 1.08;
95% CI 0.62, 1.89) or intra-arterial
administration (RR 0.68; 95% CI
0.46, 1.01), or in the subgroup with pre-
existing renal insufciency (RR 0.59;
95% CI 0.33, 1.07). However, there was
an increased risk after intra-arterial admin-
istration in patients with pre-existing renal
insufciency for iohexol compared with
iodixanol (RR 0.38; 95% CI 0.21,
0.68). There was no signicant difference
between iodixanol and other low-osmolar
media.
In a comparison of the effects of iso-osmo-
lar media and low-osmolar media on renal
function in high-risk patients undergoing
intravenous contrast medium-enhanced CT
scanning, intravenous contrast media were
unlikely to be associated with permanent
adverse outcomes [13C]. There were no sig-
nicant effects of either iodixanol or iopro-
mide on serum creatinine concentrations
over the subsequent 3 days. Iodixanol
Chapter 46 Julie Olliff and Peter Riley
increased eGFR and iopromide reduced it
on all 3 days, but the changes were not signif-
icant. Fewer patients who were given iodixa-
nol (8.5%) compared with iopromide (28%)
had an increase in serum creatinine of
44 mmol/l (0.5 mg/dl) or more. The authors
concluded that serum creatinine concentra-
tions after contrast administration are lower
after iodixanol than after iopromide.
Prevention Several agents have been tried
in the past in order to prevent contrast-
induced nephrotoxicity. These have all
been directed at various proposed methods
of causation [SEDA-32, 848]. The most
effective to date has been intravenous
hydration before and after administration
of the iodinated contrast medium, either
with 0.9% saline or sodium bicarbonate;
bicarbonate is superior to saline.
Some practitioners advocate the use of
oral N-acetylcysteine, although the evi-
dence is conicting. In a randomized pla-
cebo-controlled study of 200 patients who
were given iodixanol, oral N-acetylcysteine
600 mg bd the day before and on the day
of the procedure or placebo were combined
with intravenous saline 1 ml/kg/hour
1224 hours before the procedure and
1224 hours after [14C]. The rates of con-
trast-induced nephrotoxicity were 8.1% in
those who were given acetylcysteine and
5.9% in those who were given saline, a
non-signicant difference. The authors con-
cluded that acetylcysteine did not prevent
contrast-induced nephrotoxicity in patients
who received iso-osmolar contrast media
with adequate hydration.
Skin Acute generalized exanthematous pus-
tulosis has been described in an 84-year-
old man on two separate occasions after
infusions of an ioversol-containing contrast
medium [15A].
Immunologic Acute and delayed allergic
reactions after the intravenous administra-
tion of iodinated low-osmolar contrast
media are well documented but rare. They
range in intensity from mild, involving urti-
caria, rash, and pruritus, to severe, includ-
ing cardiopulmonary arrest and death.
Radiological contrast agents and radiopharmaceuticals
The medical records of 545 patients who
received intravenous non-ionic contrast
media out of a total of 84 928 injections
over 6 years have been reviewed; 418
(77%) of the reactions were classied as
mild, 116 (21%) as moderate, and 11
(2%) as severe; 221 (41%) received treat-
ment [16C]. The most frequent mild reac-
tion was urticaria (n 286) followed
by pruritus (n 131) and erythema or rash
(n 114). Moderate reactions included
shortness of breath (n 55), cardiac-like
symptoms (n 48), and laryngeal edema
(n 38). Severe reactions included the
aforementioned and either hypotension,
tachycardia, bronchospasm, and/or a neuro-
logical event. Follow-up data on 402 of the
patients with a mild reaction showed that
51% resolved within 1 hour and 48%
resolved at 124 hours. In those with a
moderate reaction, the symptoms resolved
within 1 hour in 53%; in the other 47%
the symptoms had resolved within 24 hours.
Only two patients with severe reactions had
documented sequelae lasting more than
24 hours and there were no deaths.
It has been proposed that the mechanism
of these hypersensitivity reactions is related
to a connection between antibodies to con-
trast media, in the light of a single case
[17A].
A 75-year-old man developed an acute reac-
tion after injection of amidotrizoate for retro-
grade ureteropyelography. He developed a
sinus bradycardia and hypotension, which
responded quickly to resuscitation. Subse-
quent intradermal testing was positive to ami-
dotrizoate, with cross reactivity with iomeprol.
Basophil activation tests conrmed the pres-
ence of anti-amidotrizoate basophils and upre-
gulation of CD203c antibodies.
In 32 patients with a history of rashes
after injection of iodinated contrast media,
skin tests in six cases strongly suggested a
delayed-type allergic hypersensitivity to
three different contrast agents; in four
patients alternative non-ionic monomers
were identied by controlled challenge tests
[18c].
Chapter 46 967
Barium sulfate [SED-15, 414]
Gastrointestinal Barium appendicitis is
rare but several cases have recently been
reported.
A 48-year-old woman developed a fever and
pain in the right lower quadrant of the abdomen
8 hours after a barium study that was performed
through an ileostomy stoma [19A]. Her temper-
ature was 38.5 C and there was tenderness and
rebound tenderness over McBurney's point.
The white cell count was raised. A supine plain
abdominal X-ray showed retained barium in
the cecum and appendix, which was conrmed
by a CT scan, which also showed mild swelling
of the appendiceal wall. The appendix was
resected. It was red and edematous and there
was barium in the lumen.
An 18-year-old man developed right lower
quadrant pain 2 weeks after upper gastrointes-
tinal imaging [20A]. A CT scan of the abdo-
men and pelvis appeared to show a foreign
body in the region of the terminal ileum, but
a plain X-ray of the abdomen showed radio-
paque appendicoliths. Pathology conrmed
the diagnosis of barium appendicitis.
A 75-year-old woman had a double-contrast
barium examination of her colon and devel-
oped severe right lower quadrant pain [21A].
There was tenderness in the right lower abdom-
inal quadrant with a positive McBurney's sign.
The white blood cell count was 16.3  109/l,
with 88% neutrophils. A plain abdominal X-
ray showed a densely radio-opaque tubular
lesion in the right lower quadrant and CT scans
showed dense barium retention in the appendix
with surrounding prominent fatty inltration.
The appendix was enlarged and erythematous
with a perforation near the base.
In another case, chronic right lower
quadrant pain, which persisted for 1 year
after an upper gastrointestinal contrast
study, was attributed to retained barium in
a 47-year-old woman; her appendix was
mildly inamed and the lumen was lled
with barium [22A].
Breasts Opacication seen on mammogra-
phy in a 60-year-old woman with a right
breast lump, thought to be microcalcica-
tion in a ductal carcinoma, turned out to
be barium particles [23A]. She had previous
968 Chapter 46 Julie Olliff and Peter Riley

drainage of an abscess in the same region of iodinated contrast in a small casecontrol

the right breast 10 years before, and the study [24A]. In a prospective study of MR
authors thought that the source of the bar- arthrography in 1085 patients using
ium had been dressings used at the time, 2 mmol/l gadopentetate dimeglumine
since dressings sometimes have barium (Magnevist; Bayer-Schering-Pharma) in
incorporated as a radio-opaque marker. the shoulder, elbow, hip, knee, and ankle
and 5 mmol/l gadoterate (Dotarem; Guer-
bet, Aulnaysous-Bois, France) in the wrist,
there were no signs of joint infection [25c].
None of the patients had any other major
adverse reactions, including anaphylactic
MRI CONTRAST MEDIA reactions, cellulitis, or vascular complica-
tions. Increased pain was most pronounced
Gadolinium salts [SED-15, 1469;
4 hours after the procedure, and patients
SEDA-29, 578; SEDA-30, 538; SEDA-31,
under 30 years were more severely
734] affected. The authors concluded that MR
arthrography temporarily increases joint-
The gadolinium salts that are used as con-
related pain, depending on age, but not on
trast media in magnetic resonance imaging
sex, joint type, or contrast medium volume.
(MRI) and have been assigned Interna-
In a retrospective review of adverse reac-
tional Non-proprietary Names (INNs) by
tions over 4 years in 158 439 patients who
the WHO are listed in Table 2.
received gadolinium, there were only 64
The gadolinium chelates, the most com-
cases and only 15 required treatment; four
monly used MR contrast agents, are avail-
had a severe reaction and there were no
able in three forms: extracellular uid
deaths [2c].
agents, which are excreted unchanged by
the kidneys, liver agents, which are taken
Cardiovascular Data from two multicenter
up by hepatocytes and excreted via the
phase II studies of the use of gadoverseta-
hepatobiliary system, and blood pool
mide (OptiMARK Tyco Healthcare/Mal-
agents, which remain longer in the vascular
linkrodt. St Louis MO) in 577 patients
space than the extracellular uid agents.
with acute and chronic myocardial infarc-
Gadolinium has been used successfully
tion trials have been reviewed [26C]. They
as the contrast agent for hysterosalpingog-
were randomly assigned to four dosage
raphy performed on women allergic to
groups (0.05, 0.1, 0.2, or 0.3 mmol/kg) for
delayed hyperenhancement MRI. There
Table 2 Gadolinium salts that are used as contrast were 164 adverse events in 124 patients;
media in magnetic resonance imaging 139 were mild or moderate. Electrocardio-
graphic changes were the most frequent
Name (INN) Brand name adverse events. The investigators judged
that eight adverse events were likely to
Gadobenic acid Multihance
Gadobutrol Gadovist have been due to the contrast agent. No
Gadocoletic acid serious adverse event was thought to have
Gadodenterate been due to gadoversetamide.
Gadodiamide Omniscan
Gadofosveset Ablavar Immunologic Two cases of anaphylactic
Gadomelitol Vistarem shock after rst exposure to gadoterate
Gadopenamide meglumine (Gd-DOTA; Dotarem; Guer-
Gadopentetic acid Magnevist bet, Roissy, France) have been reported
Gadoteric acid Dotarem
[27A], with the implication that the tetra-
Gadoteridol Prohance
azacyclododecane derivative ligand of mac-
Gadoversetamide OptiMARK
Gadoxetic acid Eovist, Primovist
rocyclic MRI contrast agents are involved
in the genesis of anaphylactic reactions, as
Radiological contrast agents and radiopharmaceuticals Chapter 46 969

demonstrated by (1) positive skin tests with
contrast media sharing the same macro-
cyclic ligand, (2) negative skin tests with lin-
ear MRI contrast media, and (3) the
tolerance of intravenous linear Gd-DTPA.
The authors suggested that patients who
are allergic to macrocyclic MRI contrast
media can still tolerate linear contrast
media, and they emphasized the theory that
the structures of these contrast media pre-
dict allergenicity [28r].
Multiorgan damage Systemic brosis due
to gadolinium-based contrast agents was
reviewed in SEDA-31 (p. 735) and many
other reviews have appeared [SEDA-32,
852]. The EIDOS and DoTS descriptions
of this reaction are shown in Figure 3; the
susceptibility factors include drugs (epoetin
therapy, sevelamer) and diseases (renal
insufciency, acidosis, inammatory events,
hyperphosphatemia). The risks from differ-
ent contrast agents are shown in Table 3.
Susceptibility factors Renal disease In a
retrospective study of 61 subjects who had
received at least 40 ml of gadodiamide dur-
ing a single imaging (median dose 80 ml,
range 40200 ml), who were followed for
at least 1 year and had moderate to severe
end-stage renal disease (median eGFR 30,
range 357 ml/minute/1.73 m2), nephro-
genic systemic brosis eventually devel-
oped in one patient, yielding a prevalence
of 1.6% [29c]. Among 33 patients who were
not undergoing dialysis eGFR within 5 days
of contrast medium injection changed by
8.8 to 43 ml/minute/1.73 m2, with a sta-
tistically signicant median improvement of
2.4 ml/minute/1.73 m2. The authors con-
cluded that although the use of a gadolin-
ium-based contrast agent was a
prerequisite for the development of
nephrogenic systemic brosis, it was not
the only factor, even in patients receiving
very high doses.
The renal adverse effects of gadolinium-
based contrast agents have been reviewed
in patients with chronic renal insufciency
[30R]. The authors suggested that gadolin-
ium chelates are safe and not nephrotoxic
when used intravenously for MRI or
MRA in patients with normal renal func-
tion, or in patients with pre-existing renal
insufciency when they are used in doses
similar to those recommended for MRI.
They also suggested that renal function is
likely to deteriorate in most cases after
intra-arterial administration of gadolinium-
based media at doses over 0.2 mmol/kg

EIDOS Extrinsic species (E) Intrinsic species (I)

Gadolinium-containing contrast media Fibroblasts

Distribution
Skin, lungs, liver, serous membranes, skeletal, cardiac muscle

Manifestations (test results) Outcome (the adverse effect)

Histology [SEDA-32, 852] Fibrosis

Manifestations (clinical) Sequela (the adverse reaction)

Changes in skin and hair Skin symptoms (e.g. pain, pruritus,
[SEDA-32, 852] stiffness); hair loss; sleeplessness

DoTS
Dose-responsiveness Time-course Susceptibility factors
Collateral Late Drugs and diseases
(see text)

Figure 3 The EIDOS and DoTS descriptions of systemic brosis due to gadolinium-based contrast agents.
970 Chapter 46 Julie Olliff and Peter Riley

Table 3 Risks of systemic brosis from gadolinium-containing salts

Name (INN) Chelate Charge Structure Risk

Gadodiamide DTPA-BMA Non-ionic Linear High (37%)

Gadopentetic acid DTPA Ionic Linear High (0.11%)
Gadoversetamide DTPA-BMEA Non-ionic Linear High
Gadobenic acid BOPTA Ionic Linear Intermediate
Gadofosveset DTPA-DPCP Ionic Linear Intermediate
Gadoxetic acid EOB-DTPA Ionic Linear Intermediate
Gadobutrol BT-DO3A Non-ionic Cyclic Low
Gadoteric acid DOTA Ionic Cyclic Low
Gadoteridol HP-DO3A Non-ionic Cyclic Low

DPTA, diethylene triamine penta-acetic acid; BMA, 5,8-bis(carboxymethyl)-11-[2-(methylamino)-2-oxoethyl]-3-oxo-2,5,8,-

11-tetra-azatridecan-13-oic acid; BMEA, N,N'-bis[methoxyethylamide); BOPTA, benzyloxypropionic tetra-acetic-acid;
DPCP, N,N'-bis[pyridoxal-5-phosphate)-trans-1,2-cyclohexyldiamine-N,N'-diacetic acid; EOB-DTPA, ethoxybenzyl-
diethylene triamine penta-acetic acid; BT-DO3A, 10-[2,3-dihydroxy-1-hydroxymethylpropyl)-1,4,7,10-tetra-azacyclo-
dodecane-1,4,7-triacetic acid; HP-DO3A, 10-[2-hydroxypropyl)-1,4,7-tetra-azacyclododecane-1,4,7-triacetic acid;
DOTA, 1,4,7,10-tetra-azacyclododecane-N,N',N",N"'-tetra-acetic acid.

for diagnostic or interventional angiogra- Superparamagnetic iron oxide

phy in patients with renal insufciency (cre-
atinine clearance less than 60 ml/minute/
1.73 m2), which is often associated with
diabetes mellitus and/or hypertension.
Therefore, although high doses of
gadolinium-based contrast media (over
0.20.3 mmol/kg) can be used safely in
patients with renal insufciency, doses over
0.2 mmol/kg for angiography should be
avoided in these patients, especially when
the intra-arterial route is chosen.
Dialysis In a 26-month observational study,
fever, chills, and nausea were recorded in
13 of 136 patients undergoing hemodialysis
or CAPD within hours of a dose of gadolin-
ium DTPA used for cardiovascular evalua-
tion before transplantation [31c]. No other
susceptibility factor was identied. The
authors suggested that such reactions may
be relevant to the poorly understood patho-
genesis of skin reactions to some gadolin-
ium-containing products in patients with
end-stage renal disease.
Several late sequelae of the use of gado-
linium-containing MRI contrast agents
have been described in patients with
advanced renal failure, for example
nephrogenic systemic brosis [SEDA 32,
852].
(SPIO) MRI contrast agents
[SEDA-28, 564]
Iron oxide-containing contrast agents consist
of suspended colloids of iron oxide nanoparti-
cles, which reduce T2 MRI signals. They are
taken up by the reticuloendothelial system.
Superparamagnetic iron oxide (SPIO) con-
trast agents are taken up into the liver and
spleen. The ultrasmall superparamagnetic
iron oxide (USPIO) contrast agents have a
longer plasma circulation time and have
greater uptake into marrow and lymph nodes.
They also have a greater T1 shortening effect
than SPIO contrast agents. Some examples
are listed in Table 4; of these, feruglose and
ferumoxtran have been discontinued.
Table 4 Some superparamagnetic and ultrasmall
superparamagnetic iron oxide agents for use as
contrast media in magnetic resonance imaging
Name (INN) Brand name
Ferucarbotran Cliavist, Resovist
Feruglose Clariscan
Ferumoxide Endorem, Feridex
Ferumoxtran Combidex, Sinerem
Ferumoxytol Feraheme
Radiological contrast agents and radiopharmaceuticals
Observational studies In a questionnaire
study about unwanted symptoms over
7 days after injection of ferucarbotran, an
SPIO contrast agent, in 315 patients who
underwent MRI scans of the liver, here
were 169 adverse events in 78 patients, of
which 70 adverse events in 45 patients were
judged to be adverse reactions to the con-
trast agent, dened as possibly or denitely
related to ferucarbotran [32c]. All the reac-
tions were of mild intensity. However, the
incidence of all adverse events was less
than that of baseline symptoms.
In a multicenter study of 375 patients who
received a lymph node-specic contrast
agent (USPIO) ferumoxtran-10 (Sinerem,
Guerbet, France) by intravenous infusion,
there were no serious adverse events [33C].
In six patients low back pain during the infu-
sion resolved after the infusion was stopped
and did not recur when the infusion was
restarted about 10 minutes later. Other
minor adverse events were diarrhea and
abdominal cramps (n 9), pruritus and
urticaria (n 4), and headache (n 2).
Carbon dioxide [SED-15, 642]
Observational studies In 18 patients who
underwent endovascular repair of abdomi-
nal aortic aneurysms using angiography
with CO2 delivered through the endograft
sheath, there were no ischemic or systemic
complications related to CO2 administra-
tion and there was no signicant deteriora-
tion in renal function [34c].
ULTRASOUND CONTRAST
AGENTS [SED-15, 3543; SEDA-30,
540; SEDA-32, 855]
Ultrasound contrast agents contain micro-
bubbles of air, nitrogen, or uorocarbon gas,
coated with a thin shell of material such as
Chapter 46 971
albumin, galactose, or lipid. Their acoustic
impedance is markedly different from that
of blood or tissues. The contrast is usually
injected intravenously and the bubbles must
measure less than 7 microns if they are to
cross the lungs and reach the arterial circula-
tion. They remain intact for only a short time.
Modication of the composition of the
microbubble shell and the use of a lower
solubility substance can improve resistance
to pressure and make the microbubbles
more resilient and able to resist destruction
by the ultrasound beam.
Adverse reactions to ultrasound contrast
agents (SonoVue 46% and Luminity 54%)
have been assessed in 3704 patients, of
whom 1150 underwent stress echocardiog-
raphy with exercise or dobutamine [35C].
There was no excess of adverse events in
those with stable chest pain or suspected
acute coronary syndrome.
Peruorocarbons
Observational studies In a retrospective
analysis of 26 774 patients who underwent
stress echocardiography the 10 792 patients
who comprised the contrast cohort received
second-generation peruorocarbon-based
agents for left ventricular opacication
[36C]. The controls comprised 15 982
patients who had their rst stress echocar-
diography during the same period but with-
out contrast agents. Short-term end-points
(< 72 h and <30 days) and long-term end-
points (up to 4.5 years) were death and
myocardial infarction. The patients in the
contrast cohort were older (mean ages 66
versus 63 years), with higher percentages
of men (57% versus 53%), and higher-risk
patients. In addition, patients who under-
went dobutamine stress echocardiography
had greater cardiac risk than those who
underwent exercise stress echocardiogra-
phy. Abnormal ndings in patients who
received contrast agents were more fre-
quent (32% versus 28%). There was no sig-
nicant difference in the incidences of
972
short-term events (death and myocardial
infarction). Within 72 hours, one patient in
the contrast cohort and two controls died;
three and seven respectively had myocar-
dial infarctions. Within 30 days, 37 patients
(0.34%) in the contrast cohort and 57
patients (0.36%) controls; 17 patients
(0.16%) in the contrast cohort and 16 con-
trols (0.10%) had a myocardial infarction.
Adjusted hazard ratios were not different
between cohorts for death (HR 0.99;
95% CI 0.88, 1.11) or myocardial infarc-
tion (HR 0.99; 95% CI 0.80, 1.22).
Comparative studies Perubutane micro-
bubbles have been used in 190 patients to
assess their efcacy and safety in the use of
contrast-enhanced ultrasound and to com-
pare it with unenhanced ultrasound and
dynamic CT in the detection and characteri-
zation of focal liver lesions [37C]. The micro-
bubbles consisted of peruorobutane
(C4F10) stabilized by a monomolecular
membrane of hydrogenated egg phosphatidyl
serine. When the liver is imaged in the phase-
modulation harmonic mode, contrast-
enhanced ultrasound with perubutane
microbubbles has two phases: the vascular
and Kupffer phases. The vascular phase of
enhancement occurs soon after intravenous
injection and can be used to characterize
lesions using patterns of contrast enhance-
ment. The perubutane microbubbles are
then taken up by the Kupffer cells in normal
liver, allowing recognition of abnormal tis-
sues that are not part of the reticuloendothe-
lial system. The patients received Sonazoid
(GE Healthcare), a lyophilized formulation
reconstituted for injection containing 16 ml
of perubutane microbubbles in one vial.
The contents of each vial were resuspended
in 2 ml of water for injection. Each patient
received a single injection of 0.12 ml/kg of
microbubbles (0.015 ml/kg of the reconsti-
tuted suspension) into a forearm vein, fol-
lowed by a 10-ml saline ush. There were no
deaths or serious or severe adverse events.
Adverse events occurred in 49% of patients
and adverse drug reactions in 10%; they were
self-limiting. The authors graded the adverse
reactions as mild in intensity and thought that
the high incidence of adverse events could
Chapter 46 Julie Olliff and Peter Riley
mostly be attributed to factors other than
the contrast agent.
Perubutane polymer microspheres (Ima-
gifyTM, Acusphere Inc, Watertown, MA,
USA) have been used to assess myocardial
perfusion and wall motion in patients with
chest pain, in two phase III studies [38C].
Perfusion stress echocardiography was per-
formed with Imagify and compared with
stress perfusion imaging using 99mTc single-
photon emission computed tomography
(SPECT). There were serious adverse
events in four of 662 patients (0.6%); none
was life threatening, and all occurred at least
1 hour after contrast administration and
resolved without residual effect. Adverse
events were reported in 454 patients (69%).
Most (98%) were mild or moderate in inten-
sity, were not serious, and resolved. There
were adverse events in 10% of patients after
the rst dose of Imagify, before dipyrida-
mole administration. The most common
adverse events (in at least ve patients each)
before dipyridamole were headache (2.6%),
ushing (1.8%), and hypotension (0.8%).
Overall, the most frequently reported
adverse events were headache (34%), chest
pain (10%), nausea (10%), ushing (9%),
and chest discomfort (8%); they mainly
occurred after dipyridamole infusion. The
investigators were more likely to attribute
these events to dipyridamole rather than
the imaging agent.
Sulfur hexauoride
Cardiovascular Sinus bradycardia with
hypotension has been attributed to sulfur
hexauoride [39A].
A 55-year-old man was given sulfur hexauor-
ide (Sonovue, Bracco Imaging, Plan-les-
Ouates, Geneva, Switzerland) via a VuJect
pump (Bracco) at a rate of 0.8 ml/minute
[40A]. Within 3 minutes he became unrespon-
sive, with sinus bradycardia and hypotension.
The hypotension did not improve with atro-
pine, although the heart rate normalized. This
was followed by a tonic-clonic seizure and a
rash with edema. He was successfully treated
with intravenous hydrocortisone and chlor-
phenamine, followed by intravenous boluses
of phenylephrine 100 micrograms.
Radiological contrast agents and radiopharmaceuticals
The authors discussed the safety record
of ultrasound contrast agents and stressed
that they are generally safe, with no
increase in the risk of death seen in a regis-
try of over 4 million patients exposed [41C].
THOROTRAST [SED-15, 3401;
SEDA-28, 565]
Tumorigenicity Induction by Thorotrast of
a primary cerebral angiosarcoma has been
reported 62 years after previous cranial sur-
gery for a childhood cerebral abscess [42A].
It was thought that Thorotrast had been
instilled into the cavity of the abscess for
future monitoring. The histology of the
tumor showed a well differentiated angio-
sarcoma with a background consistent with
a so-called Thorotrast granuloma. The
authors suggested that the histology, the
conrmation of radioactivity in the material
obtained from within the tumor, and the
latency period provided compelling support
for tumor induction by Thorotrast.
RADIOPHARMACEUTICALS
[SED-15, 3017]
99m
Technetium sestamibi
Autacoids Angioedema, with signicant
tongue swelling, drooling, and difculty in
speaking, occurred 6 hours after adminis-
tration of 99mTc sestamibi tracer during
adenosine nuclear stress testing in a 63-
year-old woman [43A]. The authors thought
that the short half-life of adenosine (10 sec-
onds) made it unlikely to have been the
causative drug.
Chapter 46 973
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[25] Saupe N, Zaneti N, Prrmann CWA,
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[27] Hasdenteufel F, Luyasu S, Renaudin JM,
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[28] Hasdenteufel F, Luyasu S, Renaudin JM,
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[30] Ledneva E, Karie S, Launay-Vacher V,
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[31] Steen H, Giannitsis E, Sommerer C,
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47 Drugs used in ocular
DRUGS USED IN THE
MANAGEMENT OF
AGE-RELATED MACULAR
DEGENERATION [SEDA-30,
545; SEDA-31, 739; SEDA-32, 865]
Bevacizumab [SEDA-30, 545;
SEDA-32, 865]
Observational studies The short-term and
long-term safety of topical bevacizumab
5 mg/ml for progressive corneal neovascu-
larization secondary to a variety of corneal
diseases and not responding to conven-
tional anti-inammatory treatment have
been evaluated in 30 eyes of 27 patients
[1c]. Five patients (ve eyes) developed
new corneal epithelial defects. The authors
warned against using bevacizumab in
patients with epithelial defects and neuro-
trophic keratopathy. There were no allergic
reactions, ocular drug-related complaints,
or systemic adverse reactions.
Pegaptanib [SEDA-31, 739;
SEDA-32, 865]
Comparative studies The safety of pegap-
tanib has been studied in two randomized
trials in 161 patients with exudative age-
Side Effects of Drugs, Annual 33
J.K. Aronson (Editor)
ISSN: 0378-6080
DOI: 10.1016/B978-0-444-53741-6.00047-7
# 2011 Elsevier B.V. All rights reserved.
J.S.A.G. Schouten
treatment
related macular degeneration during their
third year, who had been using pegaptanib
throughout years 1 and 2 and had received
at least one dose in year 3; they received
0.3, 1, or 3 mg intravitreally every 6 weeks
[2C]. There were ocular adverse events in
114 subjects (71%) in the primary safety
population in year 3, and most of the events
were associated with the injection proce-
dure. There were serious ocular or non-
ocular adverse events in 27 (17%) subjects
and 3% withdrew because of an adverse
event. There were two cases of endophthal-
mitis, one of rhegmatogenous retinal detach-
ment, and one of vitreous hemorrhage. One
case of loss of vision of at least four lines
was related to the injection procedure, and
one case of retinal and vitreous hemor-
rhages was related to the injection proce-
dure. Intraocular pressure rose after the
injection procedure in some cases, but
remained stable throughout the 3 years in
those who received pegaptanib 0.3 or
1 mg for 3 years. There were no thrombo-
embolic cerebrovascular accidents; two sub-
jects had myocardial infarctions and one
had angina. The incidence of these throm-
boembolic events was the same among the
entire cohort of 422 subjects treated with
pegaptanib sodium in year 3 and was simi-
lar to those observed in the pegaptanib
and sham groups in years 1 and 2. There
were no serious non-ocular hemorrhagic
events. Among the entire cohort of 422
subjects treated with pegaptanib sodium in
year 3, the most common serious adverse
events were neoplasms and cardiac
disorders, each experienced by 12 subjects,
gastrointestinal disorders (10 subjects),
977
978
and vascular disorders (nine subjects). With
the exception of one case of hypertension
none was related to the injection procedure
or the study drug. There were six deaths
among the 422 subjects who received
pegaptanib sodium in year 3 (including also
those who had not received pegaptanib in
year 1 or 2); none of the deaths was consid-
ered to be related to the study drug or
injection procedure. The adverse events
associated with these deaths were glio-
blastoma, cardiac arrest, Clostridium colitis,
cardiorespiratory arrest, hypotension, and
metastatic lung cancer (one case each).
There were no ndings in relation to elec-
trocardiography or vital signs performed
at each clinical assessment that suggested
a relation to treatment with pegaptanib
sodium; in particular, there was no evi-
dence of an increase in mean blood pres-
sure over the 3 years of treatment. There
were no laboratory test ndings suggestive
of adverse reactions to pegaptanib sodium.
Pegaptanib (0.3 mg intravitreally every
6 weeks for 30 weeks) has been studied in
an open, randomized, controlled study in
10 patients with proliferative diabetic reti-
nopathy and compared with 10 patients
who received panretinal photocoagulation
[3c]. The eyes that were exposed to pegap-
tanib had mild to moderate transient ocular
adverse events, including most commonly
subconjunctival hemorrhages after injec-
tion. One eye developed an epiretinal mem-
brane. There were no other ocular adverse
events. Fellow eyes in this group developed
an epiretinal membrane (one eye), a vitre-
ous hemorrhage (two eyes), cataract (one
eye), and diabetic macular edema (one
eye). Study eyes that had been treated with
panretinal photocoagulation developed
epiretinal membranes (four eyes), vitreous
hemorrhages (two eyes), iritis (one eye),
and a macular hole (one eye). The fellow
eyes in this group developed an epiretinal
membrane (one eye), vitreous hemorrhages
(two eyes), and diabetic macular edema
(one eye).
Sensory systems Eyes A case of culture-
proven endophthalmitis after intravitreal
pegaptanib for exudative age-related
Chapter 47 J.S.A.G. Schouten
macular degeneration presented as frosted
branch angiitis [4A].
Ranibizumab [SEDA-30, 545;
SEDA-31, 739; SEDA-32, 867]
Comparative studies Adverse reactions
have been studied in 32 patients with exu-
dative age-related macular degeneration
who received standard uence photo-
dynamic therapy with verteporn at
baseline and months 3, 6, and 9 and ranibi-
zumab 0.5 mg at baseline and months 1, 2,
and 3 [5c]. The main adverse reactions out-
come measure was severe loss of vision (a
loss of best-corrected visual acuity of at
least 30 letters). There was no severe loss
of vision due to ocular inammation or uve-
itis. One patient had moderate loss of
vision (of at least 15 letters). Three patients
had mild/moderate uveitis. There were two
serious ocular adverse events (a retinal pig-
ment epithelial tear and a moderate reduc-
tion in best-corrected visual acuity). There
were no systemic adverse events.
In an open, prospective, uncontrolled
study, 10 patients with macular edema due
to central retinal vein occlusion were ran-
domly assigned to ranibizumab 0.3 or
0.5 mg and adverse reactions were studied
[6c]. There were no severe adverse events.
Ranibizumab has been studied in 4300
patients with choroidal neovascularization
secondary to age-related macular degenera-
tion [7c]. One group was randomized to
ranibizumab 0.3 or 0.5 mg and the second
group received open ranibizumab 0.5 mg.
Some 82% of the rst group and 50% of
the second group completed the 12-month
study. The average total numbers of ranibi-
zumab injections were 4.9 and 3.6 re-
spectively. The incidences of vascular and
non-vascular deaths during the 12 months
were 0.9% and 0.7% in those who took
0.3 mg, 0.8% and 1.5% in those who took
0.5 mg in the rst group, and 0.7% and
0.9% in those who took 0.5 mg in the sec-
ond group. The incidence of death due to
unknown cause was 0.1% in all the groups.
The numbers of vascular deaths and deaths
Drugs used in ocular treatment Chapter 47
due to unknown causes did not differ across
the groups. Stroke rates were 0.7%, 1.2%,
and 0.6% in the three groups. The rates of
individual key ocular serious adverse
events in the rst group were less than
1%; two of those who took 0.3 mg and ve
of those who took 0.5 mg developed
endophthalmitis or presumed endophthal-
mitis (i.e. ocular infection treated with anti-
biotics), and one subject in each dosage
group had a serious cataract event. The
rates of individual key ocular serious
adverse events in the second group were
less than 1%; one subject developed
endophthalmitis, and one had a serious cat-
aract event. The incidences of ocular
inammation, including iritis, uveitis, vitri-
tis, and iridocyclitis, were 1.0% in those
who took 0.3 mg, 1.5% in those who took
0.5 mg in the rst group, and 0.5% in the
second group. The overall incidences of cat-
aract were 5.4%, 6.0%, and 2.8%. The rates
of key non-ocular serious adverse events
were similar across the two dosages in the
rst group, but non-vascular deaths,
strokes, and hemorrhages were numerically
higher in the 0.5 mg group. Eight subjects
who took 0.3 mg and 15 who took 0.5 mg
had a stroke during the 12 months. The
incidences of myocardial infarctions and
Antiplatelet Trialists Collaboration
(APTC) three arterial thromboembolic
events, which included vascular deaths and
deaths of unknown cause, non-fatal myo-
cardial infarctions, and non-fatal cardiovas-
cular accidents, were similar across the two
dosages. The rates of key non-ocular seri-
ous adverse events in the second group
were generally lower than those in the rst
group, which may have been a result of
under-reporting, because of the large num-
ber of subjects in the second group who
withdrew. The incidence of non-ocular
adverse events that were potentially related
to VEGF inhibitors was low and compara-
ble across all the groups. A prior stroke, a
history of dysrhythmias, and a history of
congestive heart failure were signicant
susceptibility factors for stroke. Although
the numbers were small, there was a non-
statistically signicant trend toward a
higher incidence of stroke in those in the
979
rst group who took 0.5 mg with a history
of stroke. Seven of the 73 subjects with a his-
tory of stroke who took 0.5 mg had a stroke
during the study compared with two of the
73 subjects with a history of stroke who took
0.3 mg. None of the subjects in the second
group with a history of stroke had a stroke
during the study. There were 82 deaths
during the study (20, 29, and 33 subjects
in the respective groups);.the numbers of
vascular deaths and deaths due to unknown
causes did not differ across the groups.
In the ANCHOR study of ranibizumab
0.3 and 0.5 mg versus photodynamic ther-
apy for neovascular age-related macular
degeneration in 423 patients the adverse
events were reported after 2 years [8C].
Overall, there was no imbalance among
the three treatment groups in the rates of
serious and non-serious ocular adverse
events in the study eye. The percentages
of patients with any serious ocular adverse
event in the study eye were similar among
those who received photodynamic therapy
(7.7%), ranibizumab 0.3 mg (7.3%), and
ranibizumab 0.5 mg (9.3%). Presumed
endophthalmitis occurred in three of 277
patients (1.1%) in the pooled ranibizumab
groups and in none in the photodynamic
therapy group. Vitreous hemorrhage was
reported in two of 277 patients (0.7%) in
the former and none of 143 patients in the
latter. Rhegmatogenous retinal detachment
occurred in two (0.7%) and one patient
(0.7%) respectively and the rates per ocular
injection were two out of 5921 (0.03%) and
two out of 2571 (0.07%). The percentage of
patients who had any serious or non-serious
intraocular inammation in the study eye
was higher in the ranibizumab groups
(12% with 0.3 mg and 17% with 0.5 mg)
than in the photodynamic therapy group
(3.5%). As in all previous trials of ranibizu-
mab, transient increases in intraocular pres-
sure in the study eye were common in the
hour after intravitreal injection. No cases
of traumatic lens damage were reported.
There was a trend to a higher rate of cata-
ract in the study eye with ranibizumab
(17% with 0.3 mg and 20% with 0.5 mg)
compared with photodynamic therapy
(11%); post hoc analysis showed that the
980
difference between ranibizumab 0.5 mg and
photodynamic therapy was statistically sig-
nicant. Cataract surgery was performed
during the 24 months in ve of 137 patients
(0.3 mg), ve of 140 patients (0.5 mg), and
one of 143 patients (photodynamic ther-
apy). Overall, there was no imbalance
among the three treatment groups in the
rates of serious non-ocular adverse events,
including those known to be potentially
associated with systemic administration of
VEGF inhibitors in patients with cancers.
The rates of arterial thromboembolic
events (dened using the Antiplatelet Trial-
ists Collaboration criteria) were similar
across the groups 4.4% (0.3 mg), 5.0%
(0.5 mg), and 4.2% (photodynamic ther-
apy). Although the rate of arterial throm-
boembolic events with ranibizumab 0.5 mg
(3.6%) was slightly higher than with rani-
bizumab 0.3 mg and photodynamic therapy
(2.2% and 2.1% respectively) during the
rst treatment year, it was slightly lower
than in the other two groups during the sec-
ond year: 1.6% (2/128) compared with
2.4% (3/127) and 2.3% (3/128) respectively;
none of these differences was statistically
signicant. There were no deaths from myo-
cardial infarction or stroke during the study.
Rates of non-fatal strokes were 2.2%, 0%,
and 1.4% respectively. Hypertension was
not more common with ranibizumab than
photodynamic therapy. Non-ocular hemor-
rhages were more common with ranibizu-
mab (8.8% with 0.3 mg, 9.3% with 0.5 mg,
4.9% with photodynamic therapy), although
these differences were not statistically signif-
icant. The incidence of serious non-ocular
hemorrhage was also slightly higher with
ranibizumab (2.9% with 0.3 mg, 2.1% with
0.5 mg, and 0.7% with photodynamic ther-
apy). Serious hemorrhages with ranibizu-
mab included gastrointestinal hemorrhage
(n 4), traumatic subdural hematoma
(n 2), and duodenal ulcer hemorrhage
(n 1). The temporal pattern of these
events in relation to ranibizumab dosing
did not suggest a causal association. No rani-
bizumab-treated patient had proteinuria.
The risks of strokes and myocardial
infarctions have been calculated in patients
who received ranibizumab (0.3 or 0.5 mg
Chapter 47 J.S.A.G. Schouten
intravitreally) for age-related macular
degeneration in three large randomized tri-
als (MARINA, ANCHOR, and FOCUS)
in a total of 859 subjects who were treated
with monthly ranibizumab, and 434 subjects
who were sham-treated [9M]. During the 2-
year observation period, 19 of those who
received ranibizumab (2.2%) had strokes
and 16 (1.9%) had myocardial infarctions.
Of the sham-treated subjects, three (0.7%)
had strokes and 13 (3.0%) had myocardial
infarctions. Intravitreal ranibizumab was
associated with an increased risk of stroke
(OR 3.24; 95%CI 0.96, 11), whereas
there was no apparent association between
intravitreal ranibizumab and myocardial
infarction.
In a randomized controlled trial in
patients with diabetic macular edema who
were randomised to intravitreal ranibizu-
mab 0.5 mg, focal or grid laser, and a com-
bination of these interventions, there was
one serious adverse event (a stroke in a
high-risk patient), which was presumed to
be unrelated to the use of ranibizumab
because it occurred 6 weeks after the injec-
tion [10C]. There was no difference in blood
pressure. Eight patients across the groups
had vitreous hemorrhages, and in one
patient it was combined with worsening of
the macular edema, while in the others it
was mild and had cleared at 6 months.
Sensory systems Eyes In 138 patients with
subfoveal choroidal neovascular age-
related macular degeneration who received
ranibizumab 0.5 mg the observed adverse
events were vitreous hemorrhage (n 1),
extrafoveal tears in the retinal pigment epi-
thelium (n 13; 9%), conjunctival hemor-
rhages (n 33; 24%), small oaters
(n 42; 30%), and mild pain without
inammation (n 37; 27%); there were
no systemic adverse events [11c].
Retinal pigment epithelium tears can
complicate exudative age-related macular
degeneration or its treatment. An 81-year-
old woman with retinal angiomatous prolif-
eration and pigment epithelial detachment
had a retinal pigment epithelial tear 10 days
after an intravitreal injection of ranibizu-
mab [12A].
Drugs used in ocular treatment Chapter 47
Verteporn and photodynamic
therapy [SEDA-30, 545; SEDA-31, 739;
SEDA-32, 868]
Observational studies No adverse reactions
were observed in 31 patients with choroidal
hemangioma who received photodynamic
therapy with verteporn (6 mg/m2) and a
light dose of 50 J/cm2 at 692 nm [13c].
In a case series of 21 patients (22 eyes)
with exudative age-related macular degener-
ation with a suspected chorioretinal anasto-
mosis or age-related macular degeneration
that was resistant to prior photodynamic
therapy alone, photodynamic therapy was
given combined with intravitreal triamcino-
lone 2 mg [14c]. The patients were followed
for 12 months. The incidence of adverse
reactions accompanying treatment was not
as high as that reported previously for com-
bined therapy that used higher doses of
intravitreal triamcinolone.
Comparative studies Reduced-uence pho-
todynamic therapy has been compared with
standard photodynamic therapy, in both
cases with intravitreal triamcinolone, in a
randomized controlled trial in 40 patients
with exudative age-related macular degen-
eration [15C]. The reduced-uence inter-
vention gave better visual outcomes and
fewer patients had choroidal hypoperfusion
(three versus 14).
Photodynamic therapy with intravitreal
triamcinolone has been compared with
photodynamic therapy alone in a random-
ized study in patients with exudative age-
related macular degeneration [16C]. There
was a better short-term effect on visual acu-
ity in the combined treatment group, but
not at 24 months. Areas with reduced/
absent fundus autouorescence within the
photodynamic therapy spot area were sig-
nicantly greater with the combined ther-
apy. The number of operations for cataract
was higher in the combined therapy group
(49% versus 20%). In the combined ther-
apy group four patients (9.3%) had an
intraocular pressure higher than 24 mmHg;
they were treated successfully with addi-
tional therapy.
981
Full-uence verteporn photodynamic
therapy has been compared with photo-
dynamic therapy in combination with intra-
vitreal triamcinolone in a double-blind,
randomized, sham-controlled trial in 100
patients with exudative age-related macular
degeneration and subfoveal neovasculariza-
tion [17C]. There was no difference in visual
acuity after 1 year and visual acuity was
reduced in both groups. Fewer retreat-
ments with verteporn photodynamic
therapy were needed in those who received
triamcinolone. Intraocular pressure rose
more in those who received triamcinolone,
but it could be treated with topical ocular
antihypertensive drugs.
In a study of verteporn photo-
dynamic therapy combined with intravitreal
bevacizumab 1.25 mg for neovascular
age-related macular degeneration in 1196
patients, most of the serious adverse events
(26/30, 22 non-ocular, eight ocular) were
judged by the investigators not to have
been related to the treatments [18C]. Three
ocular events were judged to have been
possibly related to bevacizumab alone,
and one ocular event was to both bevacizu-
mab and photodynamic therapy. The latter
was a reduction loss of vision of 20 letters
within 7 days after photodynamic therapy
with standard light uence; vision slowly
improved to baseline after 6 months. The
other four ocular events (a suspected infec-
tion in the right eye, attributed to dry eyes,
a cataract extraction, an advanced cataract,
and reduced vision) were judged not to
have been related to either bevacizumab
or verteporn. All eight patients recovered
from the ocular adverse events. There were
22 reports of non-ocular serious adverse
events; they occurred over 11435 days
with bevacizumab and 42423 days with
verteporn. No non-ocular serious adverse
events were judged to have been related
to either bevacizumab or photodynamic
therapy. The serious adverse events
reported were myocardial infarctions
(n 4), respiratory failure (n 3),
unknown cause of death (n 3), transient
ischemic attacks (n 3), stroke (n 1
event), and one event each of renal
failure, renal cell carcinoma, colon cancer,
982
gastrointestinal hemorrhage, hepatic cirrho-
sis, accidental fall, hip osteoarthritis, and hip
dislocation; 11 of these patients died. Eight
of the 22 non-ocular serious adverse events
were cardiovascular, four of which had a
temporal relation to treatment. However,
the Registry Oversight Board reviewed the
context of these events, and based on the
available information judged that none was
associated with either treatment.
Placebo-controlled studies In a randomized
placebo-controlled trial (n 64; 21 placebo)
of verteporn photodynamic therapy in acute
symptomatic central serous choroidopathy
with half-dose verteporn (3 mg/m2) and
83 seconds laser treatment 10 minutes after
the start of the infusion, there were no ocular
or systemic adverse reactions [19C].
Sensory systems Eyes Half-uence verte-
porn photodynamic therapy (300 mW/cm2
light intensity) for central serous chorioretino-
pathy is generally regarded as safer than full-
uence photodynamic therapy (600 mW/cm2
light intensity). However, in one case a pig-
ment epithelial tear occurred after half-uence
verteporn photodynamic therapy in central
serous chorioretinopathy [20A].
In 11 patients with exudative age-related
macular degeneration who received verte-
pron pdt and ranibizumab, optical
coherence tomography showed that subret-
inal and intraretinal leakage increased with
verteporn but resolved after 2 weeks
[21c]. Non-perfusion of small/medium cho-
roidal vessels occurred, and although reper-
fusion began after 1 month it was not
restored completely.
ADRENOCEPTOR
AGONISTS [SEDA-31, 740;
SEDA-32, 869]
Apraclonidine [SEDA-32, 869]
Observational studies Adverse reactions to
apraclonidine 0.5% have been studied
Chapter 47 J.S.A.G. Schouten
retrospectively in 75 children with glau-
coma who underwent 179 treatment ses-
sions, 91% during or after angle surgery
[22c]. The glaucoma was congenital or
infantile in 53% of cases. The median age
was 5.3 months (range 017 year). The
median number of apraclonidine exposures
was 15 (range 45745). There were non-
threatening adverse reactions in 8%
(6/75): topical allergy (n 2), lethargy
(n 3), and reduced appetite (n 1). The
authors concluded that in contrast to bri-
monidine, topical apraclonidine 0.5% can
safely be used in short-term treatment of
most infants and children undergoing angle
surgery for glaucoma, and that it rarely
causes systemic adverse reactions. How-
ever, care should be taken, since the study
group was too small to detect (severe)
adverse events with a low incidence.
ANTI-GLAUCOMA DRUGS
Observational studies In a German registry
of 20 506 patients with glaucoma who used
anti-glaucoma drugs, 57% had dry eyes
[23C]. The occurrence of dry eyes was
related to the duration of glaucoma and
the number of anti-glaucoma drugs used.
Systematic reviews In a meta-analysis of
studies of adverse reactions to anti-glau-
coma drugs, conjunctival hyperemia was
more common in patients who used travo-
prost [24M]. The authors noted that this
was in contrast to the results of trials in
which there was a higher incidence of this
adverse reaction in patients who used bima-
toprost. Travoprost also caused more sting-
ing/burning and dry eye sensations and
timolol had a higher incidence of supercial
punctuate keratopathy.
Sensory systems Eyes The frequency of
nasolacrimal duct obstruction has been
studied in 384 patients [25c]. There was lac-
rimal drainage obstruction, especially upper
Drugs used in ocular treatment Chapter 47
lacrimal duct obstruction, in 20% of those
who used anti-glaucoma drugs compared
with 8.6% of the controls. The combina-
tions of timolol dorzolamide and timolol
dorzolamide pilocarpine were related
to this adverse reaction.
BETA-ADRENOCEPTOR
ANTAGONISTS [SEDA-31, 740;
SEDA-32, 870]
Comparative studies In 105 children who
were treated with either betaxolol hydro-
chloride ophthalmic suspension 0.25% or
timolol maleate ophthalmic gel-forming
solution 0.25% and 0.5% after randomiza-
tion, adverse events were mostly non-seri-
ous and mild to moderate in intensity
[26C]. No patient stopped treatment
because of adverse events, which were
hyperemia of the eye, discomfort, irritation
of the eye, discharge from the eye, lid margin
crusting, pruritus of the eye, a sticky sensa-
tion, bradycardia, and hypotension.
In 148 of 286 long-term users of beta-
blockers, prostaglandins, or the combination
there was no statistically signicant differ-
ence between the beta-blockers and prosta-
glandins in the risks of falls, orthostatic
hypotension, or dizziness [27c].
Timolol [SED-15, 3428; SEDA-31, 741;
SEDA-32, 870]
Comparative studies In 29 patients with
normal blood pressures, the intraocular
pressure and blood pressure were mea-
sured during several times in a 24-hour
period during the use of either a xed com-
bination of latanoprost timolol or timolol
[28c]. The patients received the drugs in a
crossover design for two periods of 8 weeks.
There were no statistical differences
between untreated and treated 24-hour sys-
tolic, diastolic, or mean blood pressures,
983
heart rate, or nocturnal dip in blood pres-
sure with either medication.
CARBONIC ANHYDRASE
INHIBITORS
See Chapter 21.
GLUCOCORTICOSTEROIDS
[SED-15, 906; SEDA-30, 548;
SEDA-31, 741; SEDA-32, 871]
Comparative studies In a randomized, sin-
gle-masked, controlled trial in 315 patients
with persistent macular edema, the patients
were randomized to intravitreal surgical
placement of a dexamethasone drug deliv-
ery system 350 or 700 micrograms or obser-
vation [29C]. The patients with uveitis or
IrvineGass syndrome (n 41) were eval-
uated. There was an increase in intraocular
pressure of 10 mmHg or more in ve of 13
patients who took 700 micrograms, in one
of 12 patients who took 350 micrograms,
and in no patients in the control group.
There were no reports of endophthalmitis.
Endocrine Adrenal insufciency and obe-
sity occurred as a result of continuous use
of topical corticosteroids for uveitis in a
child [30A].
Drug administration route Intravitreal
The two main adverse reactions to intravi-
treal inserts of sustained-release glucocorti-
coids are cataracts and increased
intraocular pressure [31R]. Glucocorticoids
can also be associated with central serous
chorioretinopathy or exacerbation of exist-
ing chorioretinopathy, a disorder that is
characterized by serous detachment of the
neurosensory retina at the posterior pole
of the fundus. Central serous chorioretino-
pathy has been reported in a 42-year-old
984
man after intravitreal injection of triamcin-
olone acetonide 4 mg in 0.1 ml for the treat-
ment of macular edema secondary to
branch retinal vein occlusion [32A].
PROSTAGLANDIN
ANALOGUES (SEE ALSO
CHAPTER 39) [SEDA-32, 871]
Systematic reviews Adverse reactions to
prostaglandin analogues have been reviewed
[33M]. Common adverse reactions include
conjunctival hyperemia, elongation and dark-
ening of the eyelashes, iris darkening, and
periocular skin pigmentation. Uncommon
adverse reactions with no denitive causal
relation are iris cysts, cystoid macular edema,
anterior uveitis, and reactivation of herpes sim-
plex keratitis.
In a meta-analysis of all clinical trials
with a direct comparison of prostaglandins
(latanoprost, bimatoprost, and travoprost)
in which adverse events were reported,
there was a higher incidence of conjunctival
hyperemia in patients who used bimato-
prost 0.03%. [34M].
Sensory systems Eyes In a retrospective
case series in 84 consecutive patients with
uveitis, prostaglandins did not increase the
frequency of anterior uveitis or cystoid
macular edema compared with other anti-
glaucoma drugs [35c].
A lower rate of conjunctival hyperemia has
been reported with latanoprost in compari-
son with bimatoprost and travoprost, and
there has been a meta-analysis of 13 random-
ized clinical trials in 2222 patients with ocular
hypertension and/or glaucoma, comparing
latanoprost with bimatoprost and travoprost,
either together or in separated studies [36M].
Five of the studies compared latanoprost
and travoprost, seven compared latanoprost
and bimatoprost, and one compared latano-
prost, travoprost, and bimatoprost. The com-
bined results showed that latanoprost was
associated with a lower incidence of conjunc-
tival hyperemia than both travoprost
Chapter 47 J.S.A.G. Schouten
(OR 0.51; 95% CI 0.39, 0.67) and bima-
toprost (OR 0.32; 95% CI 0.24, 0.42).
Bimatoprost [SED-15, 517; SEDA-31,
655; SEDA-32, 729]
Sensory systems Eyes Conjunctival hyper-
emia has been studied in patients using
bimatoprost 0.03% as initial therapy and com-
pared with that in patients in whom latano-
prost was replaced by bimatoprost; changes
in hyperemia scores from baseline were highly
signicant only in rst-line therapy [37c].
Skin Periorbital fat atrophy has been
observed after treatment with bimatoprost
0.03%, with deepening of the upper eyelid
sulcus [38A].
In ve patients using bimatoprost 0.03%
unilaterally for glaucoma, the following
adverse events were reported: periorbital
fat atrophy, deepening of the upper eyelid
sulcus, relative enophthalmos, loss of lower
eyelid fullness, and involution of dermato-
chalasis compared with the fellow
untreated eye [39c]. These events were
assumed to be related to the use of bimato-
prost, because the effects were unilateral
and were conrmed by inspecting old
photographs not to have been present
before the use of bimatoprost. The changes
were partly reversible after drug withdrawal.
Latanoprost [SED-15, 2002; SEDA-30,
465; SEDA-31, 655; SEDA-32, 729]
Respiratory A 51-year-old woman devel-
oped a chronic cough after using latano-
prost for glaucoma [40A]. A citric acid
cough challenge was performed while she
was using latanoprost and repeated after
the drug had been withdrawn. The initial
cough challenge showed marked hypersen-
sitivity of the cough reex, and this was sig-
nicantly reduced after latanoprost had
been withdrawn for 10 days. After 3 days
of restarting latanoprost, cough sensitivity
again increased.
Drugs used in ocular treatment Chapter 47
Sensory systems Eyes Progression of kera-
toconus has been attributed to latanoprost,
which is known to affect metalloproteinases
[41A].
A 47-year-old man with keratometric values
of 42.75 D at 30 degrees and 45.00 D at
120 degrees had mild keratoconus in the right
eye; the left eye was normal. The right eye was
treated with latanoprost for normal-tension
glaucoma for 2 years. The keratometric values
were 40.75 D at 42 degrees and 48.25 degrees
at 132 degrees. There was more advanced ker-
atoconus. Latanoprost was changed to timolol
and no further progression was observed.
Adverse reactions to latanoprost have
been studied in 115 children who had used
latanoprost for a mean of 20 months [42c].
The reported adverse reactions were eye-
lash growth (in all eyes exposed for at least
6 months; latanoprost was withdrawn in
one case), conjunctival hyperemia/irritation
(n 6; two withdrawn), headache (n 3),
and difculty in focusing, iris pigmentation,
and sleep disturbances (n 1 each).
Travoprost [SED-15, 3481; SEDA-30,
466; SEDA-31, 655; SEDA-32, 731]
Observational studies Adverse events dur-
ing the administration of travoprost have
been studied in 75 eyes of 57 children in a
retrospective medical record review [43c].
Eyelash thickening and elongation occurred
in all 75 eyes, conjunctival injection in 13
(17%); ocular irritation in 4 (5%), and eye-
lid swelling and blurring of vision in one
each. There was no iris heterochromia or
periorbital skin pigmentation.
Skin A patient with unilateral normal-ten-
sion glaucoma and another with unilateral
primary open-angle glaucoma, both of
whom used travoprost monotherapy unilat-
erally for 2 years, gradually developed
deepening of the eyelid superior sulcus, with
hyperpigmentation in the eyelid skin of the
treated eye [44A]. The disparity between
the treated eye and the fellow eye was
clearly visible and resolved after
985
withdrawal of travoprost for 15 months.
The authors suggested that the mechanism
could be fatty degeneration and reduced
collagen bers in the levator complex; how-
ever, the exact mechanism remains to be
determined.
PROCEDURES
Intravitreal injection [SEDA-29, 581;
SEDA-32, 874]
The rise in intraocular pressure after intravi-
treal injections of pegaptanib (0.09 ml, 27-
gauge needle), bevacizumab (0.05 ml, 30-
or 32-gauge needle), ranibizumab (0.05 ml,
30- or 32-gauge needle), or triamcinolone
(0.1 ml, 27-gauge needle) has been investi-
gated in 213 consecutive injections [45C].
Mean preinjection intraocular pressure
was 14 (range 722) mmHg. Mean baseline
intraocular pressure was 14 (range 722)
mm Hg. Mean intraocular pressure directly
after injection was 44 (range 487) mmHg,
when all but one eye had at least hand-
movement vision and a perfused optic
nerve. Intraocular pressure fell to less than
30 mmHg in 70% by 5 minutes, in 96% of
injections by 15 minutes, and in 100% by
30 minutes. Eyes with a history of glaucoma
took signicantly longer to normalize intra-
ocular pressure. There were statistically sig-
nicant spikes in intraocular pressure with
smaller needle bore sizes, even though this
was related to smaller injected volumes,
and in eyes with a history of glaucoma.
Adverse reactions to intravitreal injec-
tions of VEGF inhibitors have been
reviewed [46R] There is circumstantial evi-
dence that systemic adverse events could
occur in patients who receive intravitreal
injections, especially thromboembolic
events. Moreover, VEGF inhibitors are
detectable in the circulation after intra-
vitreal injection. Since adverse events are
infrequent, the authors proposed using sev-
eral highly sensitive methods to identify
them.
986
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 K. Chan, H.W. Zhang, and Z.X. Lin
48 Treatments used
in complementary and
alternative medicine
Pharmacovigilance in complementary and
alternative medicine Pharmacovigilance in
complementary and alternative medicine
has attracted much attention worldwide.
The awareness of the need for surveillance
of adverse reactions to natural health prod-
ucts has stimulated the implementation of a
reporting system for suspected adverse
reaction in Italy [1C]. From April 2002 to
March 2007, 233 spontaneous reports of
suspected adverse reactions to natural
health products were collected. A large
proportion of the suspected adverse reac-
tions were serious: hospitalization was
reported in 35% of cases; 6% reported
life-threatening clinical events, and there
were two fatal events. Most of the reported
cases involved herbal products (66%); 21
reports were associated with 27 homeo-
pathic preparations, most of which con-
tained a mixture of substances; 14 reports
attributed the suspected reactions to prod-
ucts containing propolis.
A review in China has shown that tradi-
tional Chinese medicine (TCM) led to sev-
eral adverse drug reactions during the past
few years and that pharmacovigilance in
TCM remains problematic, although great
efforts have been made to improve it [2R].
In order to report adverse effects of inter-
ventions in randomized controlled trials
Side Effects of Drugs, Annual 33
J.K. Aronson (Editor)
ISSN: 0378-6080
DOI: 10.1016/B978-0-444-53741-6.00048-9
# 2011 Elsevier B.V. All rights reserved.
transparently, it has been suggested that
Consolidated Standards of Reporting Trials
(CONSORT) for TCM should include
background information on adverse reac-
tions to each intervention, specic outcome
assessments of adverse effects, and inter-
pretation of the occurrence of adverse reac-
tions in a structural report [3R].
In South India, a pharmacist-coordinated
program has been initiated to improve the
reporting of adverse reactions to comple-
mentary and alternative medicines [4C].
ASIAN HERBAL
MEDICINES [SED-15, 1609;
SEDA-32, 879]
Ling yang gan mao capsule
Immunologic Ling yang gan mao capsule is
a commonly used over-the-counter Chinese
herbal mixture for the treatment of colds
and u. It contains Cornu Saigae Tataricae
(antelope horn, ling yang jiao), Fructus Arc-
tii (achene of great burdock, niu bang zi),
glycine max (fermented soybean, dan dou
chi), Flos Lonicerae Japonicae (honey-
suckle ower, jin yin hua), Herba Schizonepe-
tae (neleaf schizonepeta herb, jing jie),
Fructus Forsythiae (lian qiao), Herba
Lophatheri (dan zhu ye), Radix Platycodo-
nis (platycodon root, jie geng), Oleum
Menthae (peppermint oil, bo he you), and
989
990
Radix Glycyrrhizae (liquorice root, gan cao).
An allergic reaction has been reported to Ling
yang gan mao capsule [5A].
A 62-year-old woman took Ling yang gan mao
capsule three times in 2 days to treat a cold.
She gradually developed increasing numbness,
distension and itching of the lips, pain in the
palms, swollen ngers, and erythema and itch-
ing in the hands. After she took cyprohepta-
dine, triprolidine, and dexamethasone her
symptoms gradually disappeared.
Shen ling bai zhu san
Skin Shen ling bai shu san, an over-the-
counter Chinese herbal formula that is com-
monly used to help digestion, consists of 10
herbs: Radix Ginseng (ren shen), Poria (fu
ling), Rhizoma Atractylodis macrocephalae
(bai zhu), Tuber Dioscores opposita (shan
yao), Semen Lablab album (bai bian dou),
Semen Nelumbo nucifere (lian zi), Semen
Coicis (yi yi ren), Fructus Amomi xanthioidis
(sha ren), Radix Platycodonis (jie geng), and
Radix Glycyrrhizae (gan cao). It has been
reported to cause erythema multiforme [6A].
A 5-month-old girl developed swollen red skin
around her eyes and mouth 1 day after taking
three doses of Shen ling bai zhu san. After
stopping the medication, her skin lesion wors-
ened and spread to the whole body, with ery-
thema multiforme and exfoliation. She
became agitated, and cried and moved rest-
lessly. She was given hydrocortisone, penicil-
lin, promethazine, vitamin C, and calamine
lotion, and her skin condition gradually
resolved after 1 week.
An 8-month-old boy developed similar symp-
toms after two doses of the same brand of
Shen ling bai zhu san. The skin lesion also
included bullae, which was easily ruptured.
He made a gradual recovery treatment with
hydrocortisone, ceftriaxone, calamine lotion,
a sedative, and medications for anaphylaxis.
Zhi xue capsule
Liver Zhi xue capsule, a preparation that
contains two Chinese medicinal herbs,
Chapter 48 K. Chan, H.W. Zhang, and Z.X. Lin
Cortex Dictamnus dasycarpus (bai xian pi)
and Radix Sophora avescens (ku shen), is
commonly used to treat hematochezia, anal
bulge, and constipation caused by hemor-
rhoids. The State Food and Drug Adminis-
tration of China (SFDA) has received
several reports of adverse reactions to Zhi
xue capsule in recent years [7A, 8S]. Up to
September 2008, 35 cases of adverse reac-
tions associated with Zhi xue capsule had
been reported, of which 21 were associated
with abnormal liver function, cholestatic
hepatitis, and drug-induced liver damage.
After withdrawal and symptomatic treat-
ment, there was full recovery in eight cases,
and the rest improved markedly.
Zhuang gu guan jie wan
Liver Zhuang gu guan jie wan is a com-
pound herbal preparation consisting of Rhi-
zoma Cibotii (gou ji), Flos Epimedium
brevicornum (yin yang huo), Radix Angeli-
cae biseratae (du huo), Rhizoma Drynariae
fortuei (gu sui bu), Radix Dipsaci asperoidis
(xu duan), Fructus Psoralea corylifolia (bu
gu zhi), Herba Taxilli Chinensis (sang ji
sheng), Caulis Spatholobus suberectus Dunn
(ji xue teng), Radix Rehmanniae preparata
(shu di huang), Radix Aucklandiae (mu
xiang), Boswellia carterii (ru xiang), and
Commiphora myrrha (mo yao). It is com-
monly used in the treatment of osteoarthritis
and lumbar muscle strains. Since 2001, there
have been increasing numbers of reports of
adverse reactions to zhuang gu guan jie wan
[9S, 10A]. The most common adverse reac-
tion is liver damage, of which 47 cases have
been recorded among 158 patients moni-
tored. The other adverse reactions include
rashes, pruritus, nausea and vomiting, stom-
ach ache, abdominal pain, diarrhea, and high
blood pressure. After drug withdrawal there
is good recovery. No drug-related deaths
have been reported. It has been speculated
that olibanum and myrrh are the main hepa-
totoxic ingredients in zhuang gu guan jie
wan, and Fructus Psoraleae may also have
detrimental effects on liver function [11E].
Treatments used in complementary and alternative medicine
INJECTABLE
FORMULATIONS OF
CHINESE MEDICINES
Ci wu jia injection
Skin Allergic skin reactions have been
reported to be associated with the use of
ci wu jia injection [12A].
A 40-year-old woman with vertebrobasilar
insufciency was given an intravenous infu-
sion of ci wu jia 250 ml for vertigo after an
injection of xue sai tong (Panax notoginseno-
sides as the main ingredients) in isotonic saline
250 ml. Nearly 40 minutes into the infusion
she developed a pruritic maculopapular rash
from the neck to the chest, and then spreading
all over the body. The rash resolved with oral
cetirizine hydrochloride 10 mg, intravenous
dexamethasone sodium phosphate 5 mg, and
intravenous calcium gluconate 20 ml.
Ku die zi injection
Immunologic Ku die zi injection is made
from Herba Ixertis Sonchifoliae, which is
believed to improve blood circulation and
is generally used to treat coronary heart
disease and angina pectoris in China. How-
ever, it has been reported to cause serious
allergic reactions [13A].
A 65-year-old woman with coronary heart dis-
ease and unstable angina pectoris was treated
with an intravenous infusion of Ku die zi injec-
tion 40 ml in 5% dextrose. On the third day of
the treatment, she suddenly developed shiver-
ing, cold limbs, and palpitation. The infusion
was stopped immediately, and she gradually
recovered after a combination treatment of
dexamethasone, promethazine, and bro-
misoval and procaine injection.
Lian bi zhi injection
Urinary tract Lian bi zhi injection is a ster-
ilized uid that contains andrographolide
sodium bisulfate, which has antibacterial
and anti-inammatory effects and is com-
monly used to treat bacillary dysentery,
Chapter 48 991
pneumonia, and acute tonsillitis. It has
been associated with acute renal failure,
and the SFDA has issued warnings on its
clinical use [14A, 15A, 16S].
Shu xue ning injection
Immunologic Shu xue ning injection is a
sterilized uid made from Ginkgo biloba
leaves, with total avonol glycosides and
ginkgolides as the main active principles.
It is generally used in China for the treat-
ment of ischemic cardiovascular and cere-
brovascular diseases. Eight cases of
adverse effects have been reported. Aller-
gic reactions, such as urticaria, broncho-
spasm, macular rashes, palpitation, nausea,
and chest distension, were observed in six
cases after an intravenous infusion of Shu
xue ning injection [17A, 18A]. Two cases
of anaphylactic shock were observed
23 minutes into the infusion, and the
patients gradually recovered after treat-
ment [19A, 20A].
Xing nao jing injection
Immunologic Xing nao jing injection, a
sterilized aqueous extract of Calculus bovis
(niu huang), Moschus (she xiang), Dry
Obalanopsaromatica Gwaertn. (bing pian),
and Fructus Gardeniae (zhi zi), is com-
monly used in China to treat coma in stroke
or traumatic injuries. It has been reported
to cause serious allergic reactions [21A].
A 73-year-old man developed shivering and
spasm 25 minutes into an intravenous infusion
of Xing nao jing injection 20 ml in isotonic
saline 250 ml for cerebral infarction. The infu-
sion was stopped immediately. He gradually
recovered 40 minutes later after receiving oxy-
gen, adrenaline, and promethazine.
A 62-year-old man was given Xing nao jing
injection 30 ml in 5% dextrose 250 ml. About
10 minutes into the infusion, he developed
chest distension, shortness of breath, a ushed
complexion, a tachycardia, and a raised blood
pressure. The infusion was stopped immedi-
ately. After receiving oxygen, dexamethasone,
and promethazine he made an uneventful
recovery.
992
Zedoray tumeric oil and glucose
injection
Zedoray tumeric oil and glucose injection is
an oil/water lipid emulsion made from the
naphtha of Rhizoma Curcumae aeruginosae,
Rhizoma Curcumae Kwangsiensis (or Rhi-
zoma Curcumae Wenyujin) and is commonly
used to treat virus infections. It has been
reported to cause adverse effects such as
allergic reactions, rashes, dyspnea, and even
anaphylactic shock, and the SFDA has issued
warnings on its clinical use [22S, 23A].
INDIAN MEDICINES
Kadda
Drug contamination In India, a 39-year-old
man with jaundice developed vomiting and
severe abdominal pain after consuming
1015 ml of kadda (in local language) every
morning on an empty stomach for 10 days
[24A]. Lead poisoning was conrmed when
the blood lead concentration was measured.
A combination of chelation therapy and
nutritional supplements reduced the body
lead burden. The original syrup had been con-
sumed and could not be tested for lead
content.
SPECIFIC PLANTS
Actaea racemosa
(Ranunculaceae, black cohosh;
formerly Cimicifuga racemosa)
Systematic reviews There has been a system-
atic review of adverse reactions to black
cohosh as reported in 13 clinical trials, three
postmarketing surveillance studies, four case
series, and eight single case reports [25M].
Three studies reported no serious adverse
events. In one trial one of 21 patients had joint
pain in the hands. Another trial reported
Chapter 48 K. Chan, H.W. Zhang, and Z.X. Lin
gastrointestinal complaints in 0.1% of patients.
A crossover study reported no difference in
the occurrence of adverse events between
black cohosh and placebo, without providing
further details. In two uncontrolled trials there
were bleeding episodes in 59 women (36 spot-
ting, eight mild bleeding, nine moderate bleed-
ing, and six major bleeding) and in four women
respectively. In three postmarketing surveil-
lance studies involving 5405 patients, adverse
events included stiff limbs, gastric pain, allergic
reactions, breast tenderness, bleeding, and
gastrointestinal complaints. Case reports
included liver damage, seizures, muscle dam-
age, and pseudolymphoma. Of all these effects,
hepatotoxicity was most often reported.
Liver Cases of liver damage associated with
black cohosh continue to appear [26c, 27c].
The hepatotoxic effects of black cohosh
have been analysed by the Dietary Supple-
ment Information Expert Committee of the
US Pharmacopeia's Council of Experts.
Reports were obtained from diverse sources,
including the European Medicines Agency
[28S]. There were 30 reports, all of which
were considered to be possibly associated
with the plant, using Naranjo's algorithm.
The Expert Committee proposed that black
cohosh products should be labeled with a
cautionary statement. This is a change from
a previous in 2002, which required no such
statement. Meanwhile, other national regu-
latory authorities have issued similar warn-
ings [29S, 30S, 31S, 32S].
In contrast, in a prospective study of 87
postmenopausal women who took a dry
extract of black cohosh 40 mg/day for
12 months total hepatic blood ow, assessed
by color Doppler ultrasound, was unaffected
as were prothrombin time and concentration,
serum albumin and bilirubin concentrations,
and gamma-glutamyltransferase, alkaline
phosphatase, and aminotransferase activities
[33c]. However, these results do not rule out
an incidence of hepatotoxicity of up to 3.4%.
The use of a causality algorithm in four
subjects with liver disease suggested that it
was not related to the black cohosh that they
had taken [34c]. Another group with the
same rst authors used the same methods in
nine patients, in whom they judged that
Treatments used in complementary and alternative medicine
causality was excluded (n 4) or unlikely
(n 4) and possible in only one case [35c].
Pursuing the same theme, the same group
analysed data from 69 reported cases of liver
disease in patients taking black cohosh, using
the same method [36c]. They considered that
causality had been excluded or was unlikely,
unrelated, or unassessable in 68 cases; in the
other case causality was possible. A major
problem with these analyses was that in gen-
eral the cases were poorly documented. Fur-
thermore, the drawbacks of causality
algorithms are well known [37M].
Agauria salicifolia (Ericaceae)
See Rhododendron spp. below
Allium sativum (Liliaceae,
garlic bulb)
Hematologic A renal hematoma after
extracorporeal shock-wave lithotripsy was
attributed to the antiplatelet action of a
garlic extract that the patient was taking
[38A]. The authors suggested that herbal
medications, such as garlic, ginkgo, and gin-
seng, should be withdrawn for up to 15 days
before urological surgery or shock-wave
lithotripsy, in order to minimize the risk of
bleeding.
Gastrointestinal A 60-year-old woman had
severe sustained chest pain due to bullous
necrosis of the esophagus when a piece of
raw garlic measuring 2.7  1.5 cm
impacted and had to be removed at endos-
copy [39A].
Skin The application of fresh garlic to the
skin can cause erythema and blistering
(garlic burns), as has been reported in
three young people in whom topical garlic
was used as an analgesic by naturopaths;
they all felt a burning sensation in the area,
but did not remove the bandage, even
when the burning sensation became severe
[40cr]. The risks of garlic burns depend on
various factors, such as the concentration,
Chapter 48 993
freshness of the garlic, duration of
exposure, the area of application, the pre-
existing skin condition, and individual reac-
tivity [41r].
Artemisia vulgaris (Asteraceae,
mugwort, moxa)
Tumorigenicity The formation of a basal
cell carcinoma on a burn scar has been
reported after repeated exposure to moxa
cautery for 10 years, with occasional acci-
dental burns [42A]. Malignant degeneration
can occur in long-standing burn scars, and
the authors proposed that moxa had
encouraged the formation of the tumor in
this case.
Camellia sinensis (Theaceae;
green tea)
Liver See Garcinia gambogia below.
Crataegus orientalis (Rosaceae,
Anatolian hawthorn)
Urinary tract Crataegus orientalis contains
avonoids and oligomeric procyanthins as
its main active constituents. A multisystem
hypersensitivity reaction and progressive
acute renal failure has been associated with
consumption of this plant [43A].
A 68-year-old man developed weakness,
fatigue, difculty in breathing, reduced urine
output, and epistaxis after eating 1 or 2 kg of
raw Crataegus orientalis and drinking ve cups
of tea made from its leaves. He developed
acute renal failure with moderate metabolic
acidosis and uid overload and hemodialysis
was performed. A renal biopsy showed acute
tubulointerstitial nephritis.
Cynomorium songaricum Rupr.
(Cynomoriaceae)
Urinary tract Cynomorium songaricum
(also called Herba cynomorii) is commonly
994
used to treat kidney disorders in traditional
Chinese medicine. A high oral dose has
been associated with acute renal insuf-
ciency [44A].
A 49-year-old woman developed nausea and
vomiting after self-administering a decoction
made by boiling 100150 g of Cynomorium son-
garicum for about 30 minutes. She developed
acute renal failure after 7 days and required
hemodialysis.
Datura stramonium (Solanaceae,
Jimson weed, thorn apple, angel's
trumpet)
Nervous system Datura stramonium has
been traditionally used in North America,
East Asia, and Africa to treat asthma,
chronic bronchitis, arthritis, and pain. All
parts of the plant contain poisonous alka-
loids, including atropine, hyoscyamine, and
hyoscine (scopolamine). The highest con-
centration of anticholinergic alkaloids is
present in the seeds (equivalent to 0.1 mg
of atropine per seed). Adverse anticholiner-
gic effects can occur [45A].
Two elderly women developed agitation, con-
fusion, urinary retention, dry mouth, and
dilated pupils within 3 hours of taking the
dried seeds of Datura stramonium. They
recovered completely after symptomatic treat-
ment for 5 days.
Ecballium elaterium
(Cucurbitaceae, squirting
cucumber)
Ear, nose, and throat A 42-year-old man
had a perforation of the nasal septum after
using nasal drops prepared from Ecballium
elaterium [46A]. Within minutes of using the
drops, he started to have a burning sensation
in the nose and the pharynx, followed by a
watery and then a purulent discharge from
the nose. After 2 months of regular use he
reported not being able to breathe through
the nose with excessive crusting. There was a
Chapter 48 K. Chan, H.W. Zhang, and Z.X. Lin
perforation of 23 cm in the anterocaudal part
of the septal cartilage. The right inferior and
middle conchae were hypertrophic, and the
remaining parts of the septum were deviated
to the left.
In another case, a 22-year-old man devel-
oped a headache, shortness of breath, and a
sore throat 1.5 hours after aspirating an
unknown amount of the undiluted juice of
Ecballium elaterium intranasally [47A]. He
responded to oxygen, methylprednisolone
1 g intravenously, and adrenaline 2 mg
subcutaneously.
Ephedra
See Chapter 13.
Garcinia gambogia (Clusiacaeae;
brindleberry, gamboge)
Liver In recent years, there have been
many reports of hepatotoxicity associated
with herbal products used for weight reduc-
tion. These products, which are sold as die-
tary supplements, do not usually undergo
safety tests before they are marketed [48R].
Proprietary formulations such as
Hydroxycut (MuscleTech Research and
Development, Inc; Iovate Health Sciences
Research, Oakville, Ontario, Canada) and
Exilis (Fusion Health Products, Houston,
Texas) contain mixtures of ingredients,
including Garcinia gambogia. Hydroxycut
is said to contain Garcinia gambogia, L-car-
nitine, chromium picolinate, and guaran
extract; some preparations have also con-
tained MaHuang extract. Exilis is said to
contain Garcinia gambogia, Gymnema Syl-
vestre, calcium, L-carnitine fumarate, chito-
san, green tea extract, conjugated linoleic
acid, magnesium chelate, and white kidney
bean extract. The US Food and Drug
Administration (FDA) has issued warnings
that Hydroxycut products should not be
used [49S], because of the possibility of liver
damage, of which there have been several
reports [50A, 51A, 52A, 53A, 54A, 55Ar,
56cr, 57r]. In one case an interaction with
montelukast was postulated [58A].
Treatments used in complementary and alternative medicine
There has been a review of eight patients
who developed liver injury after taking
Hydroxycut; all were hospitalized, and
three required liver transplantation [59cr].
Nine other cases with adequate clinical
information were obtained from the FDA
MedWatch database, including one fatal
case of acute liver failure. The usual symp-
toms were jaundice, fatigue, nausea, vomit-
ing, and abdominal pain. Most patients had
hepatocellular liver damage.
Exilis has also been associated with ful-
minant hepatic failure [60A].
A 25-year-old man presented to a walk-in
clinic with tea-colored urine and fatigue. He
had taken Exilis for less than 3 weeks, and
after taking it for 1 week he had developed
nausea, vomiting, aches, and fever. His serum
aspartate aminotransferase, alanine amino-
transferase, and total bilirubin were 1394 U/l,
2362 U/l, and 180 mmol/l (10.5 mg/dl) respec-
tively. He underwent cadaveric liver
transplantation.
The principal hepatotoxic ingredient
of Garcinia gambogia is thought to be
hydroxycitric acid. However, it has been
pointed out that 14 different formulations
of Hydroxycut have been marketed, that
only eight contained hydroxycitric acid,
and that products of this sort contain
numerous ingredients [61r]. For example,
green tea (Camellia sinensis), present in
some of these formulations, has also been
associated with hepatotoxicity [SEDA-28,
575; 62A, 63A, 64A, 65c, 66C].
Ginkgo biloba (Ginkgoaceae,
maidenhair)
Placebo-controlled studies An adequately
powered placebo-controlled trial of the
effect of Ginkgo biloba in the primary pre-
vention of dementia included over 3000
volunteers aged 75 years and over [67C].
They were randomized to twice daily doses
of either Ginkgo biloba extract 120 mg or
placebo and were followed for a median
of 6.1 years. The extract had no effect on
the incidence of dementia. The adverse
Chapter 48 995
events proles for Ginkgo and placebo
were similar and there was no statistically
signicant difference in the rate of serious
adverse events. The rates of major bleeding
did not differ between the groups, nor in
individuals who combined the study drug
with regular aspirin. There were twice as
many hemorrhagic strokes in the Ginkgo
group, but the number of cases was too
low (16 versus eight) to reach signicance.
Drugdrug interactions Antiplatelet and
anticoagulant drugs A systematic review
of the potential interaction of Ginkgo
biloba with antiplatelet or anticoagulant
drugs has shown that concerns about the
safety of Ginkgo when used in combination
with anticoagulants or antiplatelet drugs
are not supported by the currently available
evidence [68M]. The author also pointed to
the discrepancy between controlled trials
of the EGb 761 extract, which has consis-
tently been found to have no signicant
effect on hemostasis and case reports of
episodes of bleeding with Ginkgo, which
have rarely implicated this well-dened
extract.
Efavirenz Virological failure in a 47-year-
old HIV-infected patient who had taken
antiretroviral drug therapy for 10 years
was associated with falling efavirenz plasma
concentrations after he started to take
Ginkgo biloba [69A].
Hypericum perforatum
(Clusiaceae, St John's wort)
Drugdrug interactions Finasteride The
effects of St John's wort on nasteride and
its metabolites, hydroxynasteride and
carboxynasteride, have been studied in
12 men, in whom nasteride 5 mg was
administered directly into the intestine via
a catheter before and after 14 days of treat-
ment with St John's wort 300 mg bd [70c].
St John's wort signicantly reduced the
Cmax, the AUC0!24h, and the half-life of
nasteride; the kinetics of carboxynaster-
ide were also signicantly altered.
996
Morinda citrifolia (Rubiaceae)
Liver Hepatotoxicity related to the con-
sumption of noni juice, prepared from the
fruits of Morinda citrifolia, has again been
reported [71R].
A 43-year-old white man with a glioblastoma
underwent surgery and was scheduled for
radiation and chemotherapy. After drinking
noni juice 20 ml bd for 2 weeks, he developed
raised aminotransferases in routine pre-
chemotherapy blood tests. The aminotransfer-
ases returned to normal as soon as he stopped
drinking noni juice.
The hepatotoxic potential of noni fruit juice
has been assessed in in vitro tests in the
HepG2 cell line of human liver cells and in
subchronic oral toxicity tests in rats [72E].
Freeze-dried ltered noni fruit puree did not
alter the viability of HepG2 cells or cause neu-
tral lipid accumulation and phospholipidosis
and there were no changes in liver function
tests in the rats. The authors therefore sug-
gested that consumption of noni fruit juice is
unlikely to cause adverse liver reactions.
Panax ginseng (Araliaceae, Asian
ginseng)
Drugdrug interactions Getinib It has
been reported in Korea that the use of
complementary herbal medicines caused
getinib treatment failure [73r].
A 36-year-old woman with a stage IV adeno-
carcinoma of the lung was given oral getinib
250 mg/day as the rst-line chemotherapy.
Within 9 weeks she became progressively
short of breath. She had simultaneously taken
multiple complementary herbal medicines
including ginseng, Fomes fomentarius, Ino-
notus obliquus, Phellinus linteus, and selenium
along with getinib without notifying her phy-
sician. After all the complementary herbal
medicines were withdrawn, her symptoms
improved signicantly.
Previous studies have suggested that gin-
seng may increase the clearance of getinib
by inducing the activity of CYP3A4 [74E].
Warfarin The interaction between warfarin
and Panax ginseng has been investigated in
Chapter 48 K. Chan, H.W. Zhang, and Z.X. Lin
25 patients with ischemic strokes in a ran-
domized, open, controlled study [75c]. The
results suggested that co-administration of
Panax ginseng did not affect the pharmaco-
logical action of warfarin.
Panax notoginseng (Araliaceae)
Sanqi pian, a tablet made from Panax noto-
ginseng, is a widely used traditional Chi-
nese medicinal herb. It is commonly used
to treat bleeding disorders and traumatic
injuries and has been associated with ana-
phylactic shock [76A].
A 20-year-old man developed limb weakness,
chills, cold sweats, and shortness of breath
about 30 minutes after taking two tablets of
Sanqi pian. He was given oxygen, dexametha-
sone, and promethazine, and made a complete
recovery.
Panax quinquefolius (Araliaceae,
American ginseng)
Drugdrug interactions Indinavir In 13
healthy volunteers American ginseng had
no effect on the pharmacokinetics of indin-
avir 800 mg tds [77c].
Warfarin In a randomized, controlled trial
in healthy volunteers, American ginseng
reduced the effect of warfarin [78c].
Rhododendron spp. (Ericaceae,
rhododendron)
Cardiotoxicity of mad honey
Certain species of rhododendron contain
grayanotoxins (andromedotoxins), which
open sodium channels. In the heart this
effect can trigger the BezoldJarisch reex
and cause bradycardia, heart block, asystole,
and hypotension [79R].
Treatments used in complementary and alternative medicine
Case reports There have been several
reports of these complications in people
who have eaten honey prepared by bees
from Rhododendron luteum, Rhododen-
dron mucronulatum, Rhododendron
ponticum, or Castanea sativa [80A95A];
myocardial infarction has also been reported
[96A]. In the eastern Black Sea region of
Turkey, where most cases have been
reported, such honey is called bitter honey
or mad honey, which is often used as a
household remedy for various conditions,
including stomach pains, bowel disorders,
hypertension, and erectile dysfunction
[97R]. Because of variations in the plant
content of grayanotoxins, poisoning with
honey made in the spring is more severe
[97r]. However, honey poisoning is rarely
fatal and the effects generally last for no
more than 24 hours. This type of poisoning
is thought to have been described by Xeno-
phon 2400 years ago [98R].
In one case poisoning from Rhododen-
dron simsii occurred when a baby's grand-
mother prepared a decoction of this plant
in milk [99A]. Poisoning from eating rhodo-
dendrons has also been reported in animals
such as sheep and goats [100R].
Other Ericaceae can do likewise, as has
been reported in a series of cases of poison-
ing with Agauria salicifolia from Reunion
Island [101c]and a case from the Mascarene
Islands, where a 28-year-old woman mistak-
enly drank a herbal tea made with leaves of
Agauria salicifolia and developed symptoms
characteristic of grayanotoxin intoxication,
with vomiting, hypotension, and bradycar-
dia. [102Ar].
Case series In a retrospective series of 19
patients poisoned by mad honey, all had
nausea, vomiting, sweating, dizziness, and
weakness several hours after ingestion
[103c]. There was hypotension in 15, sinus
bradycardia in 15, and complete atrioven-
tricular block in four. The hypotension and
conduction disorders resolved with atropine
treatment, resulting in complete recovery
within 24 hours.
In 66 patients symptoms that occurred
several hours after the ingestion of small
amounts of mad honey included nausea,
Chapter 48 997
vomiting, salivation, dizziness, weakness,
hypotension, bradycardia, and syncope
[104c]. All had hypotension and most had
bradycardia. These features resolved
completely in 24 hours with intravenous
uids and atropine; none died.
In a review of 47 patients who had
ingested mad honey 0.59 (mean 2.8)
hours before presentation, the heart rate
was 3077 (mean 47) per minute and the
systolic blood pressure was 50140 (mean
47) mmHg [105c]. Cardiac rhythms on
arrival were sinus bradycardia (n 37),
nodal rhythm (6), sinus rhythm (3), and
complete atrioventricular block (1). All were
given atropine 0.52 mg.
In a prospective study of 42 patients (33
men; median age 49 years) who had been
hospitalized with mad honey intoxication,
all had nausea, vomiting, dizziness, fainting,
and sweating; ve had syncope [106c]. The
mean blood pressure was 73/52 mmHg and
the mean heart rate 38/minute; 18 had sinus
bradycardia, 15 had complete atrioventricu-
lar block, and nine had nodal rhythm. None
needed temporary pacing and all were dis-
charged without complications.
In 33 patients (30 men, median age
52 years) the most common effects of poi-
soning with mad honey were sinus brady-
cardia (91%), nausea and vomiting (82%),
and dizziness (79%); average heart rate
was 55/minute and mean blood pressure
was 78/46 mmHg [107c].
In seven cases of grayanotoxin poisoning
due to consumption of wild honey that was
brought from the Himalayan belt of Nepal,
most had blurring of vision, diplopia,
and nausea and vomiting; two had cardiac
effects [108c].
Chronic mad honey intoxication syn-
drome has also been described in a prospec-
tive evaluation of 173 patients with
bradycardia or atrioventricular conduction
abnormalities; in ve cases there was a his-
tory of ingestion of non-commercial honey
made by different amateur beekeepers in
the eastern Back Sea region of Turkey
[109c]. When they stopped taking the
honey there was prompt normalization of
conduction and signicant symptomatic
improvement.
998
Although most cases of poisoning are
accidental, in a few cases deliberate self-
poisoning has occurred. In 21 patients (18
men) with acute grayanotoxin poisoning,
enhancement of sexual performance was
the reason for the would-be therapeutic use
of mad honey [110c].
Incidence This type of poisoning is said to
be rare, but the incidence is not known. In
one report 69 published reports were
reviewed [111M].
Management Muscarinic M2 receptors in
the vagus are involved in the cardiotoxicity
of grayanotoxin [112AE, 113AE], and brady-
cardia and heart block in these cases
respond to atropine, as in toxicity with vera-
trum alkaloids. However, temporary pacing
may sometimes be required [114Ar].
Tripterygium wilfordii Hook. f.
(Celastraceae, bittersweet)
Skin Tripterygium wilfordii, also called
Lei-gong-teng in Chinese (literally meaning
thunder vine god), is a common herb
used in traditional Chinese medicine for
the treatment of many autoimmune disor-
ders. The multiglycosides derived from this
plant have been made into tablet form as
over-the-counter herbal products in China.
Lei-Gong-Teng Multiglycosides tablets
have immunodepressant and anti-inam-
matory effects, and are widely used to treat
rheumatoid arthritis, nephrotic syndrome,
and some systemic autoimmune diseases.
However, it has been reported to cause skin
pigmentation [115A].
A 35-year-old woman with nephrotic syn-
drome developed brown to dark pigmented
spots on the face after taking Lei-Gong-Teng
Multiglycosides tablets 20 mg tds for 20 days.
She stopped taking the medication for about
1 month, and the pigmentation gradually
disappeared.
Chapter 48 K. Chan, H.W. Zhang, and Z.X. Lin
Uncaria tomentosa (Rubiacaeae,
cat's claw)
Drugdrug interactions HIV protease
inhibitors In a 45-year-old HIV-positive
woman with cirrhosis due to hepatitis C infec-
tion, the serum trough concentrations of ata-
zanavir, ritonavir, and saquinavir increased
when she took cat's claw (Uncaria tomentosa),
perhaps because of inhibition of CYP3A4
[116A]. The respective concentrations with
and without cat's claw were 0.30 and
1.22 mg/l (atazanavir), 0.92 and 6.13 mg/l
(ritonavir), and 0.64 and 3.4 mg/l (saquinavir).
Vaccinium macrocarpon
(Ericaceae, cranberry)
Drugdrug interactions Warfarin The pos-
sible effects of two commonly used herbal
medicines, garlic and cranberry, on the phar-
macokinetics and pharmacodynamics of
warfarin have been investigated in an open,
three-treatment, randomized, crossover trial
in 12 healthy men [117c]. They took a single
oral dose of warfarin 25 mg alone or after
2 weeks of pretreatment with either garlic
or cranberry. Pretreatment with cranberry
signicantly increased the area under the
INR versus time curve by 30% compared
with warfarin alone. Co-administration of
garlic did not signicantly alter warfarin
pharmacokinetics or pharmacodynamics.
Both herbal medicines showed some evi-
dence of VKORC1 (but not CYP2C9) geno-
type-dependent interactions with warfarin.
Co-administration of warfarin and cranberry
requires careful monitoring.
ANIMAL DRUGS
Carp gallbladder
Urinary tract Fish gallbladder has long
been used as a folk remedy in China, and
its consumption has been linked to acute
renal failure [118A].
Treatments used in complementary and alternative medicine
A 67-year-old woman developed nausea and
epigastric pain 2 hours after taking grass carp
gallbladder stewed with honey. She also had
raised alanine aminotransferase activity after
8 hours. On day 3 she developed oliguria,
and hemodialysis was performed on day 5, fol-
lowing which she gradually recovered and was
discharged on day 26.
Toad extract (Chan Su)
Toad extract, obtained from the secretions
of the salivary and skin glands of Chinese
toads, is commonly used in Chinese medi-
cine. It contains bufotenine and a series of
bufadienolides that are structurally similar
to cardiac glycosides [119E].
A 24-year-old man collapsed and died soon
after an intravenous injection of 3540 ml of
what was thought to be ecstasy [120A].
MDMA was not detected in toxicological ana-
lyses, but a low concentration of bufotenine
was identied instead. In addition, resibufo-
genin, cinobufagin, and bufalin, which are
bufadienolides present in toad venom, were
found in the injected material.
ACUPUNCTURE
Observational studies In a Korean retro-
spective cross-sectional survey of 1095 sub-
jects who used acupuncture, 75 (6.8%)
described negative short-term acupuncture
reactions, including feelings of pain in 37
(3.4%), tiredness in 24 (2.2%), and dizzi-
ness in nine (0.8%). The only adverse event
reported was bleeding in 92 (8.4%) of the
participants [121c].
In a German observational study of
503 397 treatments documented between
July 2001 and June 2003, physicians
recorded at least one adverse effect in
7.8% of all patients, the most frequent
being needling pain in 3.9% [122C]. Serious
adverse events were reported in 17 cases,
the most frequent event being pneumo-
thorax (ve cases).
Of 6140 patients who received acupunc-
ture, 9.3% reported adverse reactions, and
Chapter 48 999
a quarter of these were considered to be
troublesome. The most frequent adverse
reactions were pain, fatigue, and circulatory
disturbances. In 20 patients who received
acupuncture for acute non-penetrating limb
injuries, only minor complications were
reported, including local pain at the acu-
puncture site, light-headedness, sweating
and pruritus, erythema, and minor bleeding
at the acupuncture site [123c].
In a review of case reports and prospective
surveys of adverse events focusing on Japa-
nese acupuncture, almost all of the adverse
reactions commonly seen in acupuncture
practice, such as fatigue, drowsiness, aggrava-
tion of existing symptoms, minor bleeding,
pain on insertion, and subcutaneous hemor-
rhage, were mild and transient [124R].
Anecdotal reports Some serious adverse
events have also been reported in individ-
ual patients who have received
acupuncture.
A 52-year-old woman presented with a 3-day
history of anorexia and jaundice after receiving
acupuncture twice a day for 7 weeks, performed
bilaterally at the Zusanli (ST36) acupoint to a
depth of 22 mm [125A]. Electrical stimulation
was performed, with the stimulation frequency
xed at 5 Hz for 20 minutes. Her aspartate
aminotransferase and alanine aminotransfer-
ase activities and total bilirubin concentrations
were 84 U/l, 109 U/l, and 216 mmol/l respec-
tively She developed pale stools, dark urine,
pruritus, pedal edema, and diarrhea during
the next 12 days. Her laboratory results contin-
ued to worsen. No specic therapy was pro-
vided for the severe cholestatic jaundice. Over
the next 12 weeks, her symptoms and the labo-
ratory results gradually improved.
A 42-year-old man received acupuncture at the
Jiaji (EX-B2, L4 & 5) and Weizhong (BL40) acu-
points, with electrical stimulation for about
30 minutes 2 days after a back sprain [126A].
While he was walking from the clinic to a hospital
pharmacy, he suddenly felt dizzy, blacked out,
and became ustered; he sweated heavily and
his face was pale. After receiving oxygen and
intravenous dextrose, he made a full recovery.
A 35-year-old woman received conventional
acupuncture and stauntoniae injection 2 ml at
Jiaji points (EX-B2, C6 & 7) for the treatment
of pain and numbness in the right neck
1000
and arm [126A]. After about 3 minutes, she
developed dizziness, chest distension, shortness
of breath, and a hot ush. Her face was ushed,
and her eyelids and mouth were swollen.
The needles were removed immediately and
she was given intramuscular dexamethasone
10 mg. She then began to lose consciousness
and had a blood pressure of 75/55 mmHg.
Several minutes after being given oxygen
and a series of anti-allergy treatments, she
regained consciousness. The swellings on the
eyelids and mouth disappeared after 2 days.
A 43-year-old woman suddenly developed a
headache, dizziness, and heavy sweating with
vomiting during the second acupuncture treat-
ment for low back and leg pain [126A]. The
needles were removed immediately and she
was helped to lie down. Most of her symptoms
resolved but the headache persisted for 2 days.
A subarachnoid hemorrhage was later con-
rmed by CT scan.
Immunologic Allergic reactions to the
metal used in acupuncture needles have
been reported [127A].
A 72-year-old man who received acupuncture
for neck and shoulder pain developed ery-
thema, pruritus, and swelling on the needling
region after the needles had been removed
from Jiaji points (EX-B2, C5, 6, & 7), which
had been stimulated with electrical pulsation
for 30 minutes. The next day he developed
mung bean-sized blisters on the needling
region. He was found to be allergic to the
metal in the needle. Acupuncture was stopped
and the blisters disappeared after symptomatic
treatment for 1 week.
A 49-year-old woman with cervical spondylo-
pathy developed pruritus at the needling region
1 day after acupuncture at Jiaji points (EX-B2,
C5, 4, 5, & 6) with electronic stimulation. She
then developed rice grain-sized blisters at the
needling region on the third day. She was aller-
gic to the metal in the needle. Acupuncture was
discontinued and the blisters disappeared after
symptomatic treatment for 5 days.
CHIROPRACTIC
Observational studies In a casecontrol
and case-crossover study there was no dif-
ference in the risk of vertebrobasilar artery
stroke associated with chiropractic care
and primary care [128C].
Chapter 48 K. Chan, H.W. Zhang, and Z.X. Lin
In a cross-sectional survey of pediatric
chiropractic, chiropractors reported three
adverse events per 5438 ofce visits involv-
ing the treatment of 577 children. The par-
ents reported two adverse events from
1735 ofce visits involving the care of 239
children [129C].
Systematic reviews A systematic review of
the reported adverse events of chiropractic
procedures has shown that most of the
adverse events reported were benign and
transient; however, there were reports of
complications that were serious or life threat-
ening, such as arterial dissection, myelopathy,
vertebral disc extrusion, and epidural hema-
toma [130M]. The frequency of adverse
events was 3361%, while the frequencies
of serious adverse events were 5 strokes/
100 000 manipulations, 1.46 serious adverse
events per 10 000 000 manipulations, and
2.68 deaths per 10 000 000 manipulations.
Nervous system Chiropractic has been
reported to be associated with a case of
quadriparesis [131A].
A 41-year-old man with chronic neck pain
developed weakness of the legs a few hours
after undergoing chiropractic manipulation.
He recalled hearing a snapping sound during
the manipulation and felt tingling and numb-
ness in his arms and legs immediately after. He
had no power in the legs, 2/5 in the arms,
reduced sensation for light touch over all four
limbs, bilateral extensor plantar responses,
reduced anal sphincter tone, and urinary reten-
tion. He rapidly developed complete quadripar-
esis. An MRI scan showed a large paracentral
C6C7 disc herniation with marked cord
edema. After intravenous injection of methyl-
prednisone and an emergency C6C7 anterior
cervical discectomy and fusion, he had partial
improvement, but remained paraplegic
3 months after the incident.
SKIN BRANDING
Branding refers to a process whereby third-
degree burns are inicted on the skin with a
hot iron rod or metallic object. Branding
uses the phenomenon of counter-irritation,
by briey using moderately intense pain to
Treatments used in complementary and alternative medicine
relieve chronic pain. Branding is used by
faith healers in some developing countries
for therapeutic purposes. Some methods,
which are very crude and inhumane, carry
a high risk of complications. Four Pakistani
patients aged 2560 years developed severe
medical complications after being branded
with a red-hot iron rod for various medical
reasons [132cr]. The mean duration
between the procedure and presentation
to the hospital was 6 days. At the time of
admission, two had septic shock, one had a
cavernous sinus thrombosis, and one
had multiple splenic abscesses. All received
standard care for wound management and
systemic infections. Two eventually died.
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49 Miscellaneous drugs,
materials, medical devices,
and techniques
Alcohol [SEDA-31, 757; SEDA-32, 891]
Cardiovascular Heavy drinking may be the
commonest cause of reversible hyperten-
sion, and reducing heavy alcohol intake
plays an important public health role in
management. In addition to the mecha-
nism, which is not known, unresolved ques-
tions include whether there is a threshold
dosage of alcohol for the association with
hypertension, the sequelae of alcohol-asso-
ciated hypertension, and the role of interac-
tions with sex, ethnicity, other lifestyle
traits, drinking pattern, and choice of bev-
erage. These areas have been reviewed,
including new data about the effects of dif-
ferent types of beverage [1R].
Nervous system It has been hypothesized
that the right hemisphere of the brain is
more sensitive to alcohol-related damage
than the left hemisphere. This hypothesis
has been tested by using functional MRI
to determine whether the pattern of right
hemispheric activity is different in alcohol-
dependent patients, compared with healthy
individuals [2HC]. Two different types of
memory-encoding tasks were performed
separately: word and face encoding. The
data from the healthy volunteers suggested
that the left prefrontal region is more active
Side Effects of Drugs, Annual 33
J.K. Aronson (Editor)
ISSN: 0378-6080
DOI: 10.1016/B978-0-444-53741-6.00049-0
# 2011 Elsevier B.V. All rights reserved.
N.H. Choulis
during word encoding, whereas the right
parahippocampal region is more active dur-
ing face encoding. However, in the patients
there was left lateralization in the pre-
frontal area during word encoding, and no
right lateralization in the parahippocampal
region during face encoding. Thus, alcohol-
ism appears to have no effect on left hemi-
spheric activity, since the activation pattern
was similar to that observed in healthy indi-
viduals. However, the absence of right
hemispheric lateralization in alcohol-
dependent patients was consistent with the
hypothesis that the right hemisphere is
more vulnerable to alcohol-related damage
than the left.
In another study, the neuromotor effects
of acute alcohol ingestion, postural sway,
hand tremor, and reaction time were mea-
sured before and after ingestion of alcohol
or fruit juice in 13 healthy volunteers aged
2022 years [3A]. The mean dose of ethanol
was 590 mg/kg and the blood ethanol con-
centrations were 860 mg/l at 30 minutes;
880 mg/l at 70 minutes, and 740 mg/l at
130 minutes. The 1-hour and 2-hour
changes in sway area and total transversal
sway with eyes closed were signicantly
larger after alcohol. Similarly, the 2-hour
changes in sway area with eyes open were
signicantly larger after alcohol. There
were no differences between alcohol and
fruit juice regarding changes in hand
tremor or reaction time. These data suggest
that static balance due to acute alcohol
ingestion is characterized mainly by trans-
versal sway of low frequency with the eyes
1009
1010
closed, which seems to differ from the char-
acteristics of postural sway in alcoholics.
Sensory systems Balance Otolith function
is signicantly affected by alcohol, and the
higher the dosage, the greater the effect.
The effect of alcohol on ocular counter-
rolling has been studied in 20 subjects,
who were tested before and after drinking
80 proof vodka, and three measures of ocu-
lar counter-rolling were considered [4A].
Blood alcohol concentrations after a dose
of 150 ml were 0.090.18%. The amplitude
of ocular counter-rolling was signicantly
reduced after alcohol; disconjugacy was sig-
nicantly increased; smoothness was not
signicantly affected. In contrast, a study
of a lower dose, 90 ml, produced blood
alcohol concentrations of 0.040.09% and
resulted in signicantly reduced amplitude,
no signicant change in disconjugacy, and
a signicant improvement in smoothness.
An increase in blood alcohol concentra-
tions produced further impairment of
amplitude and conjugacy but eliminated
the benet of smoothness.
Psychological Alcohol consumption has
been associated with increased aggressive
behavior. However, experimental evidence
of a direct association is equivocal, and pos-
sible mechanisms are poorly understood.
One mechanism by which alcohol consump-
tion may increase aggressive behavior is by
altering the processing of emotional facial
cues. The effects of acute alcohol consump-
tion on sensitivity to facial expressions of
emotion have been investigated in three
experimental sessions during which partici-
pants took a drink of alcohol (0, 200, or
400 mg/kg) and completed a psychophysical
task to distinguish expressive from neutral
faces [5c]. The level of emotion in the
expressive face varied across trials and the
threshold at which the expressive face was
reliably identied was measured. There
was a signicant three-way interaction
involving emotion, the sex of the partici-
pant, and alcohol use. Men had signicantly
higher perceptual thresholds for sad facial
expressions compared with women after
Chapter 49 N.H. Choulis
consumption of the highest dose of alcohol.
There was no evidence that alcohol altered
the processing of angry facial expressions.
Liver Alcoholic hepatitis has been
reviewed [6r]. This association has been
well documented, although cirrhosis of the
liver develops in only a small proportion
of heavy drinkers. Since up to 40% of
patients with severe alcoholic hepatitis die
within 6 months after the onset of the clini-
cal syndrome, appropriate diagnosis and
treatment are essential.
Death The changes in Russian mortality
rates during the past two decades are
unprecedented in a modern industrialized
country. These uctuations have attracted
much interest, and trends for major groups
of causes of death might shed light on the
underlying determinants. Cause-specic
mortality in Russia for the period
19912006 has been studied, using the
records of 24 836 forensic autopsies carried
out during 19902004 in a specic city, and
then analysed with respect to blood alcohol
concentration [7M]. Cardiovascular diseases
(in those aged 3569 years) and external
causes (in those aged 1534 years) were
the main contributors to the uctuations in
mortality rates. The largest relative changes
were for conditions directly related to alco-
hol. Among cardiovascular diseases, uctu-
ations were due to other forms of acute
and chronic ischemia and atherosclerotic
heart disease, while rates of myocardial
infarction were low and relatively constant.
In the autopsy series a very high proportion
of deaths were attributed to other or not
classied cardiovascular diseases and
lethal or potentially lethal blood ethanol
concentrations. The increases in mortality
in 19911994 and in 19982003 coincided
with the economic and societal crisis, while
decreases in 19941998 and 20032006 cor-
related with economic improvements.
Excessive alcohol intake is a major cause
of premature male mortality in Russia,
although many alcohol-related deaths are
wrongly attributed to cardiovascular
diseases.
Miscellaneous drugs, materials, medical devices, and techniques Chapter 49 1011

Articial sweeteners [SED-15, 348;
SEDA-32, 892]
Tumorigenicity The possible association of
articial sweeteners and urinary tract
tumors is controversial. In a case-control
study in Argentina in 197 patients with his-
tologically conrmed transitional urinary
tract tumors and 397 controls with acute,
non-neoplastic, and non-urinary tract dis-
eases between 1999 and 2006, 51 of the for-
mer (26%) and 87 of the latter (22%) had
used articial sweeteners [8C]. The risk of
urinary tract tumors was signicantly
increased in long-term users (10 years or
more). The odds ratio for long-term con-
sumers was 2.18 (95% CI 1.22, 3.89)
and for short-term users 1.10 (0.61, 2.00)
after adjustment for age, sex, BMI, social
status, and years of tobacco use.
The role of articial sweeteners on the
risks of cancers of the stomach, pancreas,
and endometrium has been studied in 230
patients with histologically conrmed can-
cers of the stomach and 547 controls, 326
cancers of the pancreas and 652 controls,
and 454 cancers of the endometrium and
908 controls [9C]. After allowing for various
confounding factors, the odds ratios for
ever users of sweeteners versus non-users
were 0.80 (95% CI 0.45, 1.43) for gastric
cancer, 0.62 (0.37, 1.04) for pancreatic can-
cer, and 0.96 (67, 1.40) for endometrial can-
cer. Corresponding odds ratios for
saccharin were 0.65, 0.19, and 0.71, and
for other sweeteners 0.86, 1.16, and 1.07
respectively for the three cancer sites. The
authors concluded that low-calorie sweet-
eners (including aspartame) do not increase
the risk of common neoplasms.
Bisphosphonates [SED-15, 523;
SEDA-30, 561; SEDA-32, 893]
Uses Bisphosphonates encourage osteo-
clasts to undergo apoptosis [10r] and in
addition to their other uses have been used
to reduce fracture rates in children with
osteogenesis imperfecta [11r] and in the
treatment of otosclerosis [12r].
Musculoskeletal Osteonecrosis of the jaw
Osteonecrosis of the jaw is becoming more
common (SEDA-32, 893). It is most often
identied in patients with multiple mye-
loma or other malignancies, but cases have
also been reported in patients taking
bisphosphonates for non-oncological dis-
eases. The EIDOS and DoTS descriptions
of this reaction are shown in Figure 1.

EIDOS Extrinsic species (E) Intrinsic species (I)

Bisphosphonates (especially zoledronate) Osteoclasts

Distribution
Bone

Manifestations (test results)

Osteolytic lesions; soft- Outcome (the adverse effect)
tissue edema (x-ray, MRI) Increased apoptosis

Manifestations (clinical)
Bone pain, paresthesia, Sequela (the adverse reaction)
dehiscence of bone Osteonecrosis of the jaw

DoTS Dose-responsiveness Time-course Susceptibility factors

Collateral Delayed Tooth extraction; diseases
(dental disease; myeloma and
breast cancer)

Figure 1 The EIDOS and DoTS descriptions of bisphosphonate-induced osteonecrosis of the jaw.
1012
In a 4-year study of 102 patients with
osteonecrosis of the jaw associated with
bisphosphonates, 24 had non-neoplastic dis-
eases, and had used bisphosphonates mainly
for postmenopausal osteoporosis (n 20)
[13c]. The duration of therapy before the
diagnosis of osteonecrosis was 1140 months
and the most common triggering event was
dentoalveolar surgery. All were non-
smokers; six had multiple lesions and only
three had possible co-morbidities. Surgical
debridement was performed in 19 patients
for a total of 22 lesions; there was complete
remission in 21 of the lesions.
The prevalence of osteonecrosis of the
jaw has been studied in 75 patients with
breast cancer taking bisphosphonates for
osseous metastases [14M]. Four patients
(5.3%) developed osteonecrosis; three had
used zoledronate only and one had rst
used pamidronate followed by zoledronate
and ibandronate. Tooth extraction was
identied as a trigger factor for osteonecro-
sis in two patients.
The susceptibility factors and the poten-
tial outcomes have been further categorized
in a retrospective study in 310 patients with
metastatic bone disease who were treated
with intravenous bisphosphonates between
1996 and 2006; 28 had osteonecrosis of the
jaw at presentation and osteonecrosis was
subsequently diagnosed in another seven
[15R]. Statistically signicant factors that
were associated with an increased likeli-
hood of osteonecrosis of the jaw included
the type of cancer, the duration of bis-
phosphonate therapy, sequential intrave-
nous treatment with pamidronate followed
by zoledronic acid, co-morbid osteoarthritis
or rheumatoid arthritis, and benign hema-
tological conditions. The data did not sup-
port glucocorticoid use or oral health as
predictors. The clinical outcomes were var-
iable; only 11 patients had improvement or
healing with conservative management.
The incidence and susceptibility factors
in cases of bisphosphonate-induced osteo-
necrosis of the jaw have been studied in
patients with breast cancer and gynecologi-
cal malignancies [16c]. Of 345 patients, 10
(2.9%) developed osteonecrosis while tak-
ing bisphosphonates. Six had a history of
Chapter 49 N.H. Choulis
recent dental procedures. All had taken
zoledronic acid. The time of exposure to
bisphosphonates and the number of treat-
ment cycles were signicant susceptibility
factors (27 versus 12 in those without
osteonecrosis).
Susceptibility factors for osteonecrosis of
the jaw have been sought in 34 cases [17C].
The most frequently used bisphosphonate
was zoledronic acid (n 29). Microbiologi-
cal data obtained in 25 patients showed that
72% of these were infected or colonized by
an actinomycete. Eight of the 14 patients
who received only medical treatment were
cured. Of the 20 patients who underwent
surgical treatment, only four were
completely cured. Osteonecrotic lesions
smaller than 1 cm were associated with a
better prognosis in terms of treatment out-
comes. Local treatments combined with
long-term antibiotics also correlated with a
better prognosis.
In a study of the records of 638 patients
who were treated with intravenous bis-
phosphonates [18r] there was osteonecrosis
in six (0.94%). There was no signicant
relation between the incidence of osteone-
crosis and demographic parameters, the
primary tumor, the cumulative drug dose,
or dosing intervals. However, those who
developed osteonecrosis had received a sig-
nicantly greater mean number of infusions
and signicantly more mean hours of infu-
sion time. These ndings suggest a positive
correlation between the risk of osteonecro-
sis and overall drug exposure. However,
the relatively low incidence of osteonecro-
sis precluded denition of the dosere-
sponse relation.
The effects of a prevention program in
186 patients with cancer and bone involve-
ment using pamidronate or zoledronate
have been studied in two different groups
of patients treated from 2003 to 2005 and
from 2005 to 2007, based on examination
of the oral cavity and education of dentists
and patients. The prevention program
started for all patients in June of 2005; 16
developed osteonecrosis of the jaw, eight
before and eight after June 2005 [19M].
There was a consistent difference in the
evolution of the disease in the two groups:
Miscellaneous drugs, materials, medical devices, and techniques
in the rst group, four patients underwent
major surgery (one partial maxillectomy;
two partial mandibulectomy; one segmental
mandibular resection), with important
impairment in quality of life; on the other
hand, the eight patients with osteonecrosis
of the jaw diagnosed after June 2005 were
successfully treated without aggressive den-
tal interventions and achieved good control
of symptoms. The authors therefore con-
cluded that bisphosphonate-related osteo-
necrosis of the jaw is common (8.6%) and
that the monitoring program was very ef-
cient in improving the clinical outcomes,
avoiding aggressive treatment and using a
conservative approach and medical
therapy.
It has been suggested that parathyroid
hormone may be of benet in the manage-
ment of osteonecrosis of the jaw [20A].
A 74-year-old woman, who was referred for
evaluation of pain and persistently abnormal
exposure of jaw bone after extraction of teeth,
had been using weekly oral alendronate for
osteoporosis for about 5 years. She had the
clinical features of bisphosphonate-associated
osteonecrosis of the mandible, which was pre-
cipitated by extraction of teeth 14 months
before she was referred for assessment. She
had multiple susceptibility factors for osteo-
necrosis of the jaw, including older age, type
2 diabetes mellitus, and a long duration of
bisphosphonate therapy. The mandibular
lesions did not improve despite repeated oper-
ations over 14 months. Bisphosphonate ther-
apy was withdrawn and parathyroid hormone
therapy was started; after 2 months the oral
mucosa had healed, after 4 months the pain
had completely subsided, and after 6 months
the patient's eating and drinking habits had
returned. The serum concentration of osteo-
calcin, a marker of bone formation, which
was initially suppressed, increased by 174%
from baseline after 6 months of treatment with
parathyroid hormone.
Fractures Rarely, long-term combined
antiremodelling therapy in patients with
osteoporosis can be associated with skeletal
damage. Atypical skeletal fragility occurred
in three subjects after long-term combined
antiremodelling therapy [21c]. Despite
minimal or no trauma they had chalk-stick
type metadiaphysial femoral fractures while
taking long-term bisphosphonates. The
Chapter 49 1013
fracture location, type, bilaterality, pro-
dromal pain, and delayed healing were
atypical for uncomplicated postmenopausal
osteonecrosis. All three had concomitant
factors (endogenous estrogens) or were
taking medications (glucocorticoids, hor-
mone replacement therapy, and raloxifene)
that probably suppressed bone remodelling
beyond the effect of the bisphosphonate
alone. Biochemical markers of bone turn-
over were very low or in the low premeno-
pausal rate. Double tetracycline-labelled
bone biopsies showed a very low activation
frequency in one subject and limited single
tetracycline labelling in a second patient
was consistent with severely suppressed
bone turnover.
While nitrogen-containing bisphospho-
nates reduce the risk of fractures in men
and postmenopausal women, their safety
in the period after a fracture is unclear. In
fully adjusted multivariable regression
models, the use of bisphosphonates in the
period after a fracture was associated with
an increased probability of non-union. The
risk of non-union associated with bis-
phosphonates after a fracture has been
studied in older adults after fracture of the
humerus in a nested case-control study
[22M]. Cases of non-union were dened as
those who had an orthopedic procedure
related to non-union 91365 days after the
initial fracture. Exposure to bisphospho-
nates was assessed during the 365 days
before non-union among cases or the
matched date for controls. Among 19 731
patients with fractures, 81 (0.4%) had
non-union, of whom 13 had used bispho-
sphonates (16%); 69 of the 810 controls
(8.5%) had used bisphosphonates. In fully
adjusted multivariable regression models,
the use of a bisphosphonate after the frac-
ture was associated with an increased risk
of non-union; the increased risk persisted
in the subgroup of patients without a his-
tory of osteonecrosis or prior fractures.
Drug formulations Patients with Paget's
disease of bone who use daily oral
bisphosphonates can have serious upper
gastrointestinal adverse events, and a
1014
once-weekly oral dose of a bisphosphonate
in buffered solution may be as effective,
better tolerated, and more convenient. In
63 patients who were randomized to either
oral alendronate solution 280 mg once a
week or tablets of alendronate 40 mg/day
in a double-blind, randomized, controlled
trial, the primary end-point was the mean
percentage reduction in total serum alka-
line phosphatase activity from baseline
after 6 months [23C]. There was no signi-
cant difference between the groups, but
there was a higher incidence of adverse
events, including drug-related adverse
events, in those who took the weekly oral
solution, and the study was terminated.
Cyanoacrylates [SED-15, 1022;
SEDA-32, 894]
Cyanoacrylates are a common class of
household substances used as adhesives
and are commonly sold under brand names
such as Super Glue, Krazy Glue, and
others. N-butyl-2-cyanoacrylate (rINN
enbucrilate) is used to arrest bleeding in
gastrointestinal ulcers and elsewhere and
occasionally to help wound closure.
Cardiovascular Enbucrilate is often com-
bined with lipiodol (lipid-soluble ethiodized
oil) for injection of bleeding gastrointesti-
nal ulcers; the advantage of this com-
bination is slower polymerization of
enbucrilate, with more accurate administra-
tion of the glue, but a potential disadvan-
tage is a higher frequency of embolism,
several cases of which have been reported.
Injection of 0.5 ml of enbucrilate and lipiodol
in a 79-year-old woman resulted in extravasa-
tion of sclerosant along the left subphrenic
area, causing epigastric pain [24A].
Embolism of cyanoacrylate occurred in an 87-
year-old man occurred 5 days after injection of
a bleeding duodenal ulcer with a 5:3 mixture
of enbucrilate and lipiodol [25A]. A CT scan
showed linear opacication of the common
hepatic artery, its right branch, some splenic
branches, and lesions in the head of the pan-
creas suggestive of infarction.
Chapter 49 N.H. Choulis
A 36-year-old man had a pulmonary embolus
after percutaneous embolization of a varico-
cele with enbucrilate (Histoacryl) lipiodol
[26A].
In a 47-year-old woman in whom a gastric
varix was injected with enbucrilate lipiodol,
cyanoacrylate migrated into the inferior vena
cava and left renal vein; thrombus formation
on the plug surface in the stomach caused a
pulmonary embolus, which became infected
with vancomycin-resistant enterococci, and
she died with multiple lung abscesses [27A].
A 77-year-old man died after an acute episode
in which multiple pulmonary emboli arose
from an injection of enbucrilate (Glubran)
diluted 50/50 with lipiodol into gastric varices
[28A].
A 70-year-old Chinese woman had a gastric
varix injected with enbucrilate plus lipiodol
followed by transarterial chemoembolization
for hepatocellular carcinoma, at which time
radio-opaque lipiodol was noted in the gastric
varix and in several branches of the right pul-
monary artery [29A].
A 48-year-old woman who had endoscopic
injection of enbucrilate for variceal bleeding
rapidly had portal and splenic vein emboli,
causing intestinal ischemia secondary to
abdominal compartment syndrome, with
raised intra-abdominal pressure [30A]. There
were no enbucrilate emboli in the mesenteric
arteries.
A 36-year-old woman with esophageal varices
injected with a 1:2 mixture of enbucrilate plus
lipiodol and 4 days later had a right-sided
stroke [31A]. A CT scan of the brain showed
an acute infarction in the left middle cerebral
artery territory with evidence of embolic
lipiodol and glue.
A 58-year-old man had bleeding gastric vari-
ces injected with a 50/50 mixture of enbucri-
late and lipiodol, but a follow-up X-ray
showed radiopaque material in the left lobe
of the liver and a CT scan showed cyanoacry-
late embolization via the right gastric vein into
the main and left portal veins [32A]. A CT
scan 2 years later showed atrophy of the left-
lateral segment of the liver, with portal-vein
thrombosis and little residual lipiodol
retention.
A 46-year-old woman had an internal iliac
arteriovenous malformation obliterated using
enbucrilate mixed with lipiodol and 3 days
later had a pulmonary embolism [33A].
An 11-year-old boy had fundal varices
injected with enbucrilate plus lipiodol and
soon afterwards developed hypotension and
bradycardia associated with a pulmonary
embolism [34A].
A 50-year-old man had a bleeding esophageal
varix injected three times with enbucrilate
plus lipiodol, but 2 weeks later developed an
esophageal ulcer, which was thought to be
Miscellaneous drugs, materials, medical devices, and techniques
secondary to the glue. A CT scan 5 weeks
later showed a sealed perforation in associa-
tion with the injection site and a right-sided
empyema. He subsequently developed a s-
tula between the esophagus and the pulmo-
nary vein and died of hemorrhage [35A].
A 77-year-old woman had an injection of a 50/
50 mixture of enbucrilate (Histoacryl) and
lipiodol for esophageal varices, and immedi-
ately developed epigastric pain and fever asso-
ciated with portal-vein thrombosis [36A].
A 58-year-old man had a gastric varix injected
twice with a mixture of enbucrilate plus lipio-
dol and subsequently needed anticoagulant
therapy for four episodes of venous thrombo-
embolism. A CT scan showed a linear hyper-
dense lesion in the left renal vein due to the
presence of enbucrilate and renal vein throm-
bosis. The thrombus extended into the inferior
vena cava and there was splenic infarction
[37A].
A 60-year-old man had a gastric varix injected
with a 50/50 mixture of enbucrilate
(Histoacryl) and lipiodol and within 1 week
developed acute hepatic failure associated
with multiple emboli in the portal vein and
its branch [38A].
A 62-year-old man had bleeding gastric vari-
ces injected with enbucrilate (Histoacryl)
and 4 weeks later developed hepatic impair-
ment associated with cyanoacrylate in the
aorta and iliac arteries [39A]. He then devel-
oped a diffuse ascending spondylodiscitis, with
osteolysis of the fth lumbar vertebra, proba-
bly as a result of septic emboli and died
10 months later.
A 56-year-old man had a bleeding ulcerative
gastric tumor injected with a 50/50 mixture of
enbucrilate plus lipiodol and 3 days later a
CT scan showed high-density material extend-
ing from the gastric wall to the splenic hilum,
near-total occlusion of the splenic artery and
its branches, and a cystic mass with an air
uid cavity in the spleen, due to splenic infarc-
tion with abscess formation [40A].
Respiratory A 25-year-old woman devel-
oped symptoms of rhinoconjunctivitis and
asthma, attributed to an allergy to cyano-
acrylate in a ngernail adhesive gel, which
as a manicurist she had used for 6 months
[41A]. Skin prick tests were positive with
dog and cat dander and grass pollens. Patch
tests were positive with nickel, cadmium,
and silver salts. An inhalation challenge
with cyanoacrylate for 30 minutes elicited
a late asthmatic response, with a 24% fall
in FEV1, with rhinorrhea and asthma that
worsened progressively until she received
short-acting b2-adrenoceptor agonists.
Chapter 49 1015
Nervous system Embolization of a spinal
dural arteriovenous stula with enbucrilate
resulted in progressive venous congestion,
which was treated with antithrombin ther-
apy, and dual antiplatelet therapy and
resolved after more than 2 months [42A].
Gastrointestinal A 30-year-old man had
selective embolization of a bleeding sig-
moid artery with N-butyl cyanoacrylate
and 6 months later developed colonic
occlusion due to an ischemic stricture that
required surgical treatment [43A].
Skin The use of enbucrilate (Indermil)
for closing the incision after parotidectomy
in 100 patients resulted in hypertrophic
scars in eight and keloid scars in nine; the
authors quoted a frequency of 516% in
such cases after the use of sutures [44c].
Infection risk A glue plug provides an ideal
surface for bacterial colonization. Injection
of an arteriovenous malformation with
enbucrilate (Hystoacryl glue) in a 24-year-
old non-immunocompromised man resulted
in multiple granulomatous brain abscesses,
with which he presented 4 years later
[45A]. In one case portosplenic vein throm-
bosis after injection of gastric varices led to
a persistent fatal septicemia with Klebsiella
pneumoniae [46A].
Drug overdose Accidental aspiration of a
cyanoacrylate adhesive by a toddler was
complicated by tracheal and bronchial
obstruction [47A]. At bronchoscopy several
pieces of glue were removed from both
main-stem bronchi and the child made a
full recovery.
Dimethylsulfoxide (DMSO)
[SED-15, 1131; SEDA-32, 894]
Systematic reviews In a systematic review
of the evidence from randomized con-
trolled trials in patients with osteoarthritis
of the knee, six studies were included,
involving 681 patients treated with DMSO
1016
(297 on active treatment) and 168 patients
treated with methylsulfonylmethane (52
on active treatment) [48M]. Two of the four
studies of DMSO and both of the studies of
methylsulfonylmethane reported signicant
improvement in pain outcomes in the treat-
ment group. However, no denitive conclu-
sions can currently be drawn; the ndings
from all the studies of DMSO need to be
viewed with caution, because of poor
methods, including possible unblinding
and questionable treatment duration and
dosage.
Mutagenicity DMSO increases mutation
rates in the polymerase chain reaction
(PCR) [49r].
Disulram [SED-15, 1148; SEDA-31,
760; SEDA-32, 895]
Psychiatric Punding, a type of complex
repetitive stereotyped behavior with com-
pulsive features, has been attributed to
disulram in a 39-year-old woman who took
it for 4 months; it persisted for 2 months
until disulram was withdrawn [50A].
Drug overdose An acute peripheral neu-
ropathy with quadriparesis, lancinating
pain, sensory loss, paresthesia of the distal
limbs, and a vocal fold palsy occurred
1 month after a disulram overdose of 130
tablets in a 49-year-old woman [51A]. A
severe toxic encephalopathy with coma,
convulsions, and quadriparesis occurred in
a 35-year-old man who took an overdose
of disulram [52A].
In another case, a 49-year-old woman
developed cardiogenic shock after taking
60 disulram tablets (15 g), 16 clonazepam
tablets (8 mg), and six maprotiline tablets
(450 mg) in association with alcohol [53A].
Drugdrug interactions Alcohol An acute
myocardial inferior infarction has been
attributed to the formation of acetaldehyde
in a 22-year-old chronic alcoholic man who
Chapter 49 N.H. Choulis
took oral disulram and alcohol together
[54A]. Coronary angiography showed nor-
mal coronary arteries.
Cocaine As well as inhibiting acetaldehyde
dehydrogenase, disulram inhibits dopa-
mine beta-hydroxylase, increasing dopamine
and reducing noradrenaline concentrations.
A 31-year-old man with cocaine dependence
was given disulram 250 mg/day to prevent
relapse, but 8 months later started to use
cocaine again. A few minutes after taking 1 g
of cocaine nasally his pulse rate increased.
He became sensually more sensitized, com-
plained about the radio being too loud and
the headlights of cars being too bright. He
took another dose of cocaine 1 g nasally and
30 minutes later started to feel very sick and
anxious, with paranoid delusions and illusions.
He had irregular breathing and began sweat-
ing profusely. The next day his speech was dis-
turbed and his body was shaking. He thought
that his face was very small and he felt
exhausted. The next morning he had
recovered.
The authors hypothesized that this interac-
tion had resulted in increased dopamine
activity [55A].
Colchicine Acute colchicine intoxication
occurred after co-administration of disul-
ram in a 44-year-old man; it was attributed
to inhibition of CYP3A4 and P glyco-
protein by disulram [56A].
DYESTUFFS
Fluorescein [SEDA-29, 607; SEDA-32,
895]
Nervous system Leakage of cerebrospinal
uid (CSF) may be iatrogenic (for example,
after otolaryngological or neurological sur-
gery), traumatic (from blunt or penetrating
trauma), non-traumatic (from bony erosion
by tumor, infection, empty sella syndrome,
meningoencephaloceles, and congenital
defects), and spontaneous. An important
component in the management of any CSF
Miscellaneous drugs, materials, medical devices, and techniques
leak is proper identication and localization
of the dural defect, which can originate from
the anterior, middle, or posterior cranial fos-
sae [57r]. Fluorescein is a uorochrom dye
that is occasionally administered by intra-
thecal injection to identify and localize CSF
leaks. Although it is generally considered
to be benign, intrathecal administration of
uorescein has resulted in adverse events,
such as status epilepticus [58A].
A 59-year-old woman with progressive left
periorbital pain and edema 2 days after exten-
sive endoscopic sinus surgery and reconstruc-
tion for recurrent paranasal sinusitis was
thought to have leakage of CSF and was given
intrathecal uorescein 50 mg as 0.5 ml of a
10% solution diluted in 9.5 ml of CSF, and
70 minutes later had seizure-like shaking of
the legs while under anesthesia. She was given
intravenous dextrose, midazolam 1 mg, and
thiopental 125 mg and the shaking resolved.
After another episode 20 minutes later thiopen-
tal 250 mg and dextrose were effective within
seconds. A third episode of generalized stiff-
ness and shaking occurred about 40 minutes
later and resolved spontaneously after 10 sec-
onds. After a third dose of thiopental 250 mg
she was taken to the intensive care unit, intu-
bated, and sedated, but continued to have inter-
mittent episodes of decerebrate posturing and
generalized tremors lasting up to 20 seconds.
She had intermittent seizure activity through-
out the rst postoperative day and frequent epi-
sodes of decerebrate posturing. She recovered
after 5 days and was given phenytoin.
Indocyanine green [SED-15, 2595;
SEDA-31, 760; SEDA-32, 896]
Sensory systems Eyes Subretinal migration
of indocyanine green dye and subsequent
retinal pigment epithelial atrophy has been
reported during macular surgery for serous
macular detachment in a 65-year-old
woman [59A].
Fluoride [SED-15, 1395; SEDA-32, 892]
Skeletal uorosis is endemic in some parts
of the world owing to life-long ingestion of
high amounts of uoride in the drinking
Chapter 49 1017
water. It is characterized by dental changes
and diffuse densication of bones, with
ossication of many ligaments and inter-
osseous membranes.
Nervous system Neurological complica-
tions of uoride occur in 10% of patients,
mostly in the late stages of uorosis [60r].
High cervical myelopathy caused by ossi-
cation of the posterior longitudinal liga-
ment and ligamentum avum has been
reported in a patient from an area endemic
for skeletal uorosis [61c].
A 48-year-old man developed stiffness and
weakness of upper and lower limbs, which
started insidiously with slowly progressive
stiffness of the neck and back. After 1 year
he started to have difculty in walking, and a
few months later developed symmetrical
weakness of both hands with urinary inconti-
nence. There was a severe spastic quadripar-
esis with spasticity as the dominant nding,
accompanied by signs of posterior column
involvement and generally brisk deep tendon
reexes with clonus. There were diffuse opa-
que white areas with brownish mottling and
discrete pitting on his teeth. A urodynamic
study showed an overactive urinary bladder.
Plain X-rays of the cervical and thoracic spine
showed markedly increased bond density and
ossication of the ligamentum avum, and
ossication of the patellar tendons and inter-
osseous membranes of the ribs. The urine
uoride concentration was 11.2 mg/l (refer-
ence range 0.21.1 mg/l) with normal renal
function. The uoride concentration in drink-
ing water was 4.5 mg/l (permitted concentra-
tion less than 1.5 mg/l). Somatosensory-
evoked potentials showed slowing of posterior
column conduction in all limbs. Decompres-
sive laminectomy at T1112 followed by
median corpectomy at C23 with a bone graft
fusion 1 month later resulted in slight recov-
ery. At the last neurological examination,
2 years later, he was unable to stand without
support, was severely spastic and incapaci-
tated by frequent exor spasms, and required
intermittent catheterization.
Glycols [SED-15, 1516; SEDA-30, 567]
Observational studies Exposures to the
potentially harmful pharmaceutical excipi-
ents benzyl alcohol and propylene glycol
1018
present in parenteral medications routinely
administered in neonatal and pediatric
intensive care units have been examined
in 170 episodes of exposure to parenteral
medications [62C]. Patients who received
medications by continuous infusion
received signicantly higher doses of the
excipient than those who received medica-
tions intermittently. In this subset of
patients, the median cumulative doses of
the excipients were about 21 and 180 times
the acceptable daily intakes of benzyl alco-
hol and propylene glycol respectively, and
exceeded the doses above which adverse
reactions have been reported in infants.
There was no signicant correlation
between the duration of medication admin-
istration and cumulative excipient expo-
sure. The authors concluded that critically
ill neonates, especially those receiving med-
ication by continuous infusion, are at risk of
being exposed to benzyl alcohol and pro-
pylene glycol at potentially toxic doses dur-
ing routine medication administration.
Metabolism Probable propylene glycol tox-
icity has been reported in a patient receiv-
ing a continuous infusion of pentobarbital
for refractory status epilepticus [63c].
A 59-year-old woman with worsening mental
status developed status epilepticus. She was
given a continuous infusion of propofol, but
this failed to achieve the therapeutic end-point
of electroencephalogram burst suppression
and she was given a continuous infusion of
pentobarbital instead, starting with a loading
dose of 450 mg and followed by a mainte-
nance infusion of 10 mg/kg/hour to achieve
burst suppression. After 12 hours she devel-
oped an anion gap metabolic acidosis, a raised
serum lactate concentration, hyperosmolality,
and an increased osmolal gap. The pento-
barbital was withdrawn, and the acidosis and
hyperosmolality resolved.
Pentobarbital contains 40% v/v propyl-
ene glycol, which was thought to have
caused this patient's metabolic derange-
ments. Reports of toxicity with drugs con-
taining propylene glycol, particularly
intravenous lorazepam, have been well
described, but this is one of few reports
involving intravenous pentobarbital.
Chapter 49 N.H. Choulis
Latex [SED-15, 2005; SEDA-31, 761]
Immunologic Exposure to latex is associ-
ated with three clinical syndromes: irritant
dermatitis, delayed hypersensitivity reac-
tions, and the most serious, but least com-
mon, immediate or type 1 hypersensitivity.
Exposure to latex can occur through the
skin, mucous membranes, or airways.
Gloves used for examination, surgical or
household, are often the cause of allergic
reactions.
Natural rubber latex has also become a
major cause of occupational asthma (OA)
in workers using natural rubber latex gloves.
The time course of occupational asthma due
to natural rubber latex in Belgium and the
relation to the different types of gloves used
in hospitals have been studied over 5 years
[64r]. Based on the results of diagnostic pro-
cedures, occupational asthma due to natural
rubber latex was categorized as denite,
probable, unlikely, or indeterminate. The
patterns of glove usage were characterized
through a questionnaire survey in hospitals.
A total of 298 claims for occupational asthma
due to natural rubber latex were identied,
including 127 subjects with denite and 68
with probable occupational asthma. As a
result, the use of powdered natural rubber
latex gloves fell from 81% to 18% over the
5 years and they were predominantly
substituted by latex-free gloves, especially
for non-sterile procedures.
Methylthioninium chloride
(methylene blue) [SED-15, 2314;
SEDA-30, 569; SEDA-32, 896]
Skin Methylthioninium chloride has been
used for lymphatic mapping/sentinel
lymphadenectomy in staging melanoma
and breast cancer. It can cause skin
necrosis, but more mild adverse reactions
from intraparenchymal breast injection
are not well characterized. Of patients under-
going staging for breast cancer and mela-
noma, 95 received intraparenchymal breast
injected of methylthioninium chloride [65R].
Miscellaneous drugs, materials, medical devices, and techniques
There was no frank skin necrosis in any case,
but six patients who underwent breast conser-
vation had local inammatory changes; four
had changes indistinguishable from infectious
cellulitis, two had skin telangiectases before
radiotherapy, and two had fat necrosis. Most
of these effects resolved with conservative
management. The authors concluded that
methylthioninium chloride can cause cutane-
ous changes that are more subtle than have
been previously described.
Drugdrug interactions Methylthioninium
chloride is a monoamine oxidase inhibitor,
and can cause serotonin toxicity when it is
combined with drugs that increase central
serotonin neurotransmission. It has been
associated with a toxic metabolic encepha-
lopathy in 26 cases [66r]. Autonomic, neu-
rological, and neuromuscular instability
has been reported after infusion of
methylthioninium chloride for parathyroid-
ectomy, and the authors suggested that this
was due to serotonin syndrome [67A].
A 58-year-old woman, with a background of
obsessive compulsive disorder treated with
paroxetine, underwent parathyroidectomy
under general anesthesia and was given
methylthioninium chloride. Postoperatively
she had symptoms and signs of serotonin syn-
drome and specically tachycardia, agitation,
dystonia, and abnormal eye movements.
These spontaneously resolved over the next
48 hours.
Nicotine [SED-15, 2508; SEDA-30, 571;
SEDA-31, 571; SEDA-32, 987]
Observational studies In a study of the use
of nicotine replacement therapy, smokers
were followed by phone at 2 weeks (n 33
690), and a randomly selected subsample
was followed for 3 months (n 1187)
[68C]. Among those who reported having
used nicotine replacement therapy after
2 weeks, about one in four reported an
adverse reaction; this rate increased to
about 42% among those surveyed at
3 months. The prevalence and specic types
Chapter 49 1019
of adverse effects reported were consisted
with ndings from clinical trials of nicotine
replacement therapy and varied in relation
to the type of formulation used (patches,
gum, lozenges). Most of the adverse reac-
tions were rated mild, and only about 5%
of subjects (across the 2-week and 3-month
follow-ups) reported having stopped using
nicotine replacement therapy as a result of
adverse reactions.
Psychiatric The association of smoking,
smoking cessation, and cessation medica-
tions with suicide has been reviewed [69r].
Current smoking has been associated with
an increase in the risk of suicide in both
case-control and cohort studies. The three
most plausible (but relatively untested)
explanations for this association are that
smokers have pre-existing conditions that
increase their risk of suicide, that smoking
causes painful and debilitating conditions
that might lead to suicide, and that smoking
reduces serotonin concentrations and
monoamine oxidase activity. Stopping
smoking appears to lead to major depres-
sion in some smokers, which could result
in suicide; however, smoking cessation has
not been associated with suicide in the few
studies available. Regulatory agencies have
stated that bupropion, rimonabant, and
varenicline appear to be associated with
suicide; however, the data for these state-
ments have not been presented in sufcient
detail to assess their validity.
Genotoxicity Genotoxic effects of nicotine
have been reported in tumor-free salivary
gland cells in 10 patients with parotid gland
tumors [70E]. Single cells were prepared by
enzymatic digestion immediately after sur-
gery and exposed for 1 hour to nicotine
0.1254.0 mmol/l. Nicotine caused a signi-
cant concentration-related increase in
DNA migration in parotid gland single
cells. The lowest concentration that caused
signicant DNA damage, 0.25 mmol/l, was
only 10-fold higher than the maximal con-
centrations of nicotine reported in the
saliva after unrestricted smoking. Although
conclusive evidence of a carcinogenic
potential of nicotine is still lacking, the
1020
effects of long-term nicotine replacement
therapy should be carefully monitored.
Tumorigenicity The effects of smoking and
drinking on the development of squamous
cell carcinoma of head and neck have been
investigated in 152 patients and 157 healthy
controls matched for age and sex, and ana-
lyses were performed to evaluate possible
differences in cancer susceptibility among
the anatomical subregions of the head and
neck [71r]. The association between ve
single nucleotide polymorphisms (SNPs) in
the homologous recombination DNA
repair pathway and the risk of carcinomas
was also investigated. Stratication accord-
ing to smoking habits and alcohol consump-
tion highlighted the importance of tobacco
and alcohol as two susceptibility factors
for squamous cell carcinoma of head and
neck. Stratication according to the ana-
tomical region of the tumor showed site-
specic differences in sensitivity to tobacco
smoke, with an increase in cancer suscepti-
bility from the oral cavity down to the phar-
ynx and larynx.
Pregnancy In a retrospective review of the
medical records of participants in the Baby
Steps Trial, a study of nicotine replacement
therapy, data that were abstracted from 157
records were combined with baseline char-
acteristics for logistic regression modeling
of serious adverse events and adjusted to
co-variates [72c]. There were serious
adverse events in 31% of those who took
nicotine replacement therapy and 17% of
the controls. Black race, an adverse preg-
nancy history, and use of analgesic medica-
tions during pregnancy were signicant
predictors of adverse events.
Teratogenicity The association between
maternal smoking and alcohol use during
the periconceptional period and the risk of
congenital defects in the offspring has been
studied in a case-control study of fetuses
and live-born infants with orofacial clefts,
neural tube defects, and conotruncal heart
defects [73r]. Information on smoking and
alcohol consumption was obtained via tele-
phone interviews with mothers of 1355
Chapter 49 N.H. Choulis
cases and 700 non-malformed, live-born
controls. Smoking more than ve cigarettes
was associated with higher risks of neural
tube defects and the risk associated with
higher consumption of cigarettes was lower
for conotruncal heart defects.
Oleic acid
Uses Oleic acid is a mono-unsaturated
omega-9 fatty acid found in various animal
and vegetable sources. Triglyceride esters
of oleic acid comprise the majority of olive
oil. Oleic acid is used as an excipient in
pharmaceuticals and as an emulsifying or
solubilizing agent in aerosol products. It
may hinder the progression of adrenol-
eukodystrophy, a fatal disease that affects
the brain and adrenal glands, and it may
help boost memory [74r]. Oleic acid may
also be responsible for the hypotensive (or
blood pressure reducing) effects of olive
oil [75r].
Placebo-controlled studies Oleic acid pre-
meal supplements have been used to trigger
the ileal brake and thus lengthen transit
time and the opportunity for nutrient
absorption in patients with short bowel syn-
drome and it affects diarrhea and weight. In
a double-blind, controlled, random-order,
crossover trial in eight participants with
long-standing severe short bowel syn-
drome, blue food color appearance, breath
hydrogen testing, and radio-opaque
markers were used as measures of transit
time [76r]. Only seven completed the study.
Transit time was not signicantly different
affected by oleic acid, although peptide
YY concentrations tended to be increased.
Energy absorption was reduced 14% by
oleic acid, signicantly more than the 3%
reduction by placebo. Fat, protein, and
uid absorption were not signicantly chan-
ged. Neither diarrhea nor weight was
affected. The authors concluded that
energy absorption is reduced by oleic acid
supplements in severe short bowel syn-
drome, although the study may have lacked
Miscellaneous drugs, materials, medical devices, and techniques
the power to determine whether oleic acid
affects diarrhea or body weight.
Tumorigenicity Oleic and mono-unsatu-
rated fatty acid concentrations in erythro-
cyte membranes have been associated with
an increased risk of breast cancer [77r].
Polyvinyl alcohol
Observational studies Polyvinyl alcohol
bers and lms are used in medicine and
pharmacology because of their ability to
swell, absorb toxic products, decompose
necrotic masses, and reduce blood loss
[78r]. A mixture of polyvinyl alcohol with
ketoprofen has been used to reduce pelvic
pain after uterine artery embolization
[79C] in a randomized prospective study in
80 patients, 40 of whom received keto-
profen mixed with polyvinyl alcohol particles
and 40 polyvinyl alcohol alone. During
embolization, only ve patients recorded a
pain score of 12. One had an allergic reac-
tion to the contrast medium; 13 of the
patients who received polyvinyl alcohol
alone reported severe or very severe pain,
compared with none of those who received
ketoprofen plus polyvinyl alcohol.
Sclerosants [SED-15, 3107]
Foam sclerotherapy is a technique that
involves injecting sclerosant drugs into a
blood vessel. The sclerosant drug (sodium
tetradecyl sulfate or polidocanol) is mixed
with air or a physiological gas (carbon diox-
ide) in a syringe or mechanical pump. This
increases the surface area of the drug.
Foam sclerosants are more efcacious than
liquid sclerosants in causing sclerosis (thick-
ening of the vessel wall and sealing off
blood ow) [80r], as they do not mix with
the blood in the vessel and in fact displace
it, thus avoiding dilution of the drug and
causing maximal sclerosant action. They
are therefore useful for longer and larger
Chapter 49 1021
veins. Thick foam, like tooth-paste, has rev-
olutionized the non-surgical treatment of
varicose veins [81r].
Observational studies Transcatheter foam
sclerotherapy has been studied retrospec-
tively in 38 patients (mean age 37 years)
with pelvic congestion syndrome [82C]. Pel-
vic pain was associated with dyspareunia in
23 patients, urinary urgency in nine, and
worsening of pain during menstruation
and at the end of the day of work in seven
and 38 respectively. Pelvic and transvaginal
color Doppler ultrasonography showed
ovarian or pelvic varices with a diameter
over 5 mm preventing venous reux. Foam
sclerotherapy was performed in all patients,
using 3% sodium tetradecyl sulfate foam.
Pelvic colicky pain occurred immediately
after injection in three patients and disap-
peared spontaneously after a few minutes.
Hemodynamic changes after sclerother-
apy have been evaluated in a prospective
observational trial in 53 patients, in whom
67 sites were treated with polidocanol foam
[83C]. With the exception of two sites, all
the treatments resulted in at least an
improvement, and about 80% of the trea-
ted veins were completely occluded as dem-
onstrated by duplex ultrasonography.
Patients with post-thrombotic syndrome
had poorer results.
In a study of the use of transthoracic
echocardiography and middle cerebral
artery transcranial Doppler performed dur-
ing ultrasound-guided foam sclerotherapy
circulating emboli were detected in super-
cial, perforating, communicating, and deep
veins and the central circulation [84C].
Transthoracic echocardiography detected
bright echoes in the right heart after every
injection and in the left heart in up to 655
of selected patients. Transcranial Doppler
high-intensity transient signals were
detected in 1442% of patients, with an
incidence higher than patient reports of
adverse events: the incidence of high-inten-
sity transient signals was independent of
the volume of foam injected.
Placebo-controlled studies In a multicenter
controlled study in which patients were
1022
treated with foam sclerotherapy for trunk
incompetence of the great and small saphe-
nous veins in 1025 patients the saphenous
trunk was occluded in 90.3% [85C]. There
were 27 (2.6%) adverse reactions reported:
migraine (n 8), visual disturbances alone
(n 7), chest pressure alone (n 7), and
chest pressure associated with visual distur-
bances (n 5). There were 10 cases of
deep vein thrombosis and one case of pul-
monary embolism 19 days after foam
sclerotherapy without deep vein thrombo-
sis. There was one transient ischemic stroke,
with complete clinical recovery in
30 minutes, and one case of septicemia with
a satisfactory outcome.
Systematic reviews Foam and liquid sclero-
therapy for primary varicose veins in the legs
have been compared in a review of the liter-
ature [86M]. For treatment of saphenous
veins, six trials were considered. Despite
containing much less sclerosing agent, foam
sclerotherapy was markedly more effective,
the difference being 2050%. In a meta-
analysis of four comparisons, foam sclero-
therapy had an efcacy of 77% and liquid
sclerotherapy 40%. The adverse reactions
that were reported did not differ between
the two forms of sclerotherapy, although
visual disturbances seemed to be more com-
mon with foam sclerotherapy.
In a literature survey of randomized con-
trolled trials, meta-analyses, and observa-
tional studies using survival analysis for
long-term outcomes, foam was more effec-
tive than liquid for ultrasound-guided
sclerotherapy [87R]. The two types of scler-
osants are equally effective for sclerother-
apy of small veins, but little else is known,
according to this study, about the optimal
preparation of foam sclerosants and the
best technique for administering foam.
Drug dosage regimens The proportion of
sclerosant that enters deep veins after injec-
tion of polidocanol foam has been studied
in 107 patients with supercial venous
incompetence; they were randomized to
multiple small-dose injections of 1% poli-
docanol foam (less than 0.5 ml per
Chapter 49 N.H. Choulis
injection) or a few injections of 1% polido-
canol foam (more than 0.5 ml per injec-
tion), for the treatment of varicose
tributaries [88C]. All then received ultra-
sound-guided foam sclerotherapy for reux-
ing great saphenous veins using 3%
polidocanol foam. Ultrasonography immedi-
ately after sclerotherapy showed that there
was less foam in the deep veins after the mul-
tiple small-volume injections, but there were
no signicant differences in the success rates
between the groups at 6 months. Two patients
developed migraine during the procedure.
These ndings suggest that multiple small-
volume injections can reduce the amount of
foam sclerosant and the risk of foam sclero-
sant entering the deep veins in patients with
supercial venous insufciency.
Silicone [SED-15, 3137; SEDA-31, 766]
Sexual function Penile augmentation with
liquid injectable silicone has been reported
and the literature reviewed [89cr]. The
injection of medical grade silicone for soft
tissue augmentation has a role in carefully
controlled settings. Traditionally, the use
of liquid injectable silicone for penile aug-
mentation has had poor outcomes and sur-
gical interventions are often required to
correct complications. The authors discour-
age its use for penile augmentation until
carefully designed and evaluated trials have
been completed.
Sodium metabisulte [SEDA-30, 572]
Respiratory Three cases of occupational
airways disease with episodes of increased
breathlessness and symptoms typical of
asthma have been attributed to sodium
metabisulte exposure [90r].
A 44-year-old trawlerman and a 43-year-old
man and a 39-year-old woman working as
prawn processors developed work-related
Miscellaneous drugs, materials, medical devices, and techniques
airways disease due to exposure to sodium
metabisulte, the rst with irritant-induced
asthma with a positive-specic bronchial chal-
lenge associated with very high sulfur dioxide
exposures, the second with occupational
asthma, and the third with vocal cord dysfunc-
tion and underlying asthma.
Of nine reported cases, most were non-
atopic and responses to specic bronchial
challenge when undertaken showed an
immediate response. Exposure to sulfur
dioxide in these settings is very high, in
excess of 30 ppm and the authors con-
cluded that sodium metabisulte should be
regarded as a cause of occupational airways
disease and that its use in the sh- and
prawn-processing industry should be inves-
tigated further to identify the risks of expo-
sure and handling of the agent in the
workplace.
Sultes [SED-15, 3215]
Nervous system It has been hypothesized
that amyotrophic lateral sclerosis of the
non-mutant superoxide dismutase type
may be caused by adverse effects of gluta-
mate and cysteine, which are reduced gluta-
thione precursors, and by sulte (a
metabolite of cysteine), which accumulate
when one or more of the enzymes needed
for glutathione synthesis are defective. In
one case there was a raised sulfur concen-
tration in the hair, a raised blood cysteine,
a positive urine sulte, a raised urine gluta-
mate, and a low whole blood glutathione
concentration [91c]. When strict dietary
and supplement measures normalized the
patient's whole blood glutathione, blood
cysteine, and urine sulte, there was no
additional physical decline. Patients with
the non-mutant superoxide dismutase type
of amyotrophic lateral sclerosis should be
tested for sulte toxicity and for cysteine,
glutamate, and glutathione concentrations,
and for enzymes involved in glutathione
metabolism.
Chapter 49 1023
Talc [SED-15, 3592; SEDA-32, 898]
Respiratory In a retrospective review of
the use of the combination of talc and
doxycycline for pleurodesis in 33 sequential
patients (20 women and 13 men; average
age 64 years) over 2 years, the doses of talc
(2.5 g) and doxycycline (250 mg) were half
the usual doses [92c]. There were no imme-
diate perioperative complications. Chest
tube duration average 4.2 and the total
amount drained averaged 880 ml. Mean
length of stay after the procedure in out-
patients was 4.8 days. There was persistent
or worsening dyspnea in 11 patients in the
immediate postoperative period. Only two
developed respiratory distress and neither
had any parenchymal changes on chest
radiology or required ventilatory support.
Other immediate postoperative events
included chest pain in 18 patients and fever
in three. Follow-up imaging was available
in 29 patients, an average of 3.9 months
postoperatively; 20 had complete pleuro-
desis, four had partial pleurodesis, and ve
failed. In no case did follow-up imaging
show new adult respiratory distress-like
inltrates.
Tumorigenicity Several studies have estab-
lished preliminary links between talc and
pulmonary issues [93r], lung cancer [94r],
and skin cancer and ovarian cancer [95r].
This is a major concern, considering the
widespread commercial and household uses
of talc. Epidemiological evidence also sug-
gests a possible association between genital
use of talcum powder and the risk of epi-
thelial ovarian cancer; however, the biolog-
ical basis for this association is not clear.
The interactions between talc and genes in
detoxication pathways, glutathione S-
transferase M1 (GSTM1), glutathione S-
transferase T1 (GSTT1), and N-acetyltrans-
ferase 2 (NAT 2) have been analysed, in
order to assess whether the association of
talc with ovarian cancer is modied by var-
iants of genes that are potentially involved
in the response to talc [96M]. The analysis
included 1175 cases and 1202 controls from
1024
a New England case-control study and 210
cases and 600 controls from a prospective
Nurses Health Study. Regular talc use
was associated with an increased risk of
ovarian cancer in the combined study popu-
lation. Independent of talc, the genes exam-
ined were not clearly associated with an
increased risk. However, the association of
talc with ovarian cancer varied by GSTT1
genotype and combined GSTM1/GSTT1
genotype. n the pooled analysis, the associ-
ation with talc was stronger among women
with the GSTT1-null genotype, particularly
in combination with the GSTM1-present
genotype. There was no clear evidence of
an interaction with GSTM1 alone or
NAT2. These results suggest that women
with certain genetic variance may have a
higher risk of ovarian cancer associated
with genital use of talc.
Toluene [SEDA-32, 899]
Nervous system The results of 30 studies of
long-term exposure to toluene in humans,
using neuroimaging and neuropsychologi-
cal methods, have been reviewed [97M].
There were nine case studies, 11 group
studies with controls, and 10 without
controls. Toluene preferentially affects
white matter relative to gray matter and
periventricular/subcortical regions relative
to cortical regions. The lipid-dependent dis-
tribution and pharmacokinetic properties of
toluene appear to explain the pattern of
MRI abnormalities as well as the common
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A Actaea racemosa
abacavir
liver function tests, 586
myocardial infarction, 585
neutropenia, 586
ParsonageTurner
syndrome, 586
ABCD
see amphotericin B colloidal
dispersion
abciximab
see also glycoprotein
IIbIIIa inhibitors
hemorrhagic pericarditis, 720
ABLC
see amphotericin B lipid
complex
acarbose
acute generalized
exanthematous pustulosis
(AGEP), 893
hypoglycemia, 893
acetazolamide
adynamic ileus, 438
cerebral blood ow, 437
ciliary muscle spasm, 437
corneal swelling, 437
edema, 437
hypokalemia, 4378
hypoxic sensitivity, 4378
metabolic acidosis, 4378
migraine-like headache, 437
myopia, 437
pemphigus, 438
acetylsalicylic acid
asthma, 248
DRESS, 248
drug overdose, 249
hematospermia, 248
mortality, 248
peptic ulceration, 248
spinal epidural hematoma,
248
utricaria, 248
aciclovir
allergic contact dermatitis,
578
Cotard's syndrome, 5778
acitretin
darkening hair previously
white hair, 339
fulminant hepatic failure,
340
Index of drugs
allergic reactions, 992
bleeding episodes, 992
breast tenderness, 992
gastrointestinal complaints,
992
joint pain, hand, 992
liver damage, 992
muscle damage, 992
pseudolymphoma, 992
seizures, 992
stiff limb, 992
acupuncture
allergic reactions, 1000
anorexia, 999
bleeding, 999
dizziness, 999
erythema and minor
bleeding, 999
fatigue and circulatory
disturbances, 999
jaundice, 999
light-headedness, sweating,
and pruritus, 999
neck and shoulder pain, 1000
neck numbness, 999
pain, 999
pale stools, dark urine,
pruritus, pedal edema, and
diarrhea, 999
pneumothorax, 999
subcutaneous hemorrhage, 999
tiredness, 999
adalimumab, 784
Crohn's disease, 781
lichen planus-like eruptions,
781
lupes erythematosus, 781
menorrhagia and
dysmenorrhea, 781
MillerFisher syndrome,
7801
myalgia, 781
sinusitis, 780
Adderall
cardiomyopathy, 2
adefovir
Fanconi syndrome, 5789
hypophosphatemic
osteomalacia, 579
impaired renal tubular
concentrating function,
578
renal dysfunction, 578
adenosine and analogues
atrial brillation, 379
chest discomfort, 379
dyspnea, 379
esophageal distensibility
reduced, 379
ventricular tachycardia, 379
visceral hyperalgesia, 379
adenosine receptor agonists
body mass index, 380
chest pain, 380
dizziness and dyspnea, 380
ushing, 37980
gastrointestinal discomfort, 380
headache, 380
tachycardia, 37980
adrenaline (epinephrine)
acute macular
neuroretinopathy, 316
atrial brillation, 315
corneal endothelial
decompensation, 316
denervation hypersensitivity,
316
dysrhythmias, 315
Kounis syndrome, 316
paradoxical hypotension,
316
sinus tachycardia, 317
splenic infarction, 316
thrombosis, coronary stent,
315
Agauria salicifolia, 993
agomelatine
back pain, 33
constipation, 33
headache, 33
albendazole
drowsiness, 647
faintness, 647
gastrointestinal symptoms,
647
headache, 647
liver function tests, 648
pancytopenia, 648
albumin-bound paclitaxel
alopecia, 944
cardiotoxicity, 9434
metastatic breast cancer, 943
myalgia and arthralgia, 944
nausea and diarrhea, 944
numbness or pain, 944
1031
1032
albumin-derived hemostatics
anastomotic
pseudoaneurysm, 670
aseptic mediastinal cyst, 670
embolization, 670
massive lung brosis, 670
postoperative wound
complications, 670
severe active inammatory
response, 670
stenosis, 670
alcohol
aggressive behavior, 1010
blood alcohol, 1010
chronic ischemia and
atherosclerotic heart
disease, 1010
hepatitis, 1010
hypertension, 1009
myocardial infarction, 1010
aldesleukin (interleukin-2,
IL-2)
anemia, infection, and
malaise, 777
capillary leak syndrome, 777
confusion and impaired
consciousness, 777
disseminated intravascular
coagulation, 778
dyspnea, rashes, diarrhea,
and nausea, 777
edema, chills, fatigue, 777
fever, pain, redness, 777
u-like symptoms, 778
gastrointestinal disorders, 778
hypotension, 777
left posterior fascicular
block, 777
mono/oligoarticular arthritis,
778
neutropenia, 777
oliguria, 777
swelling at the injection
site, 777
thrombocytopenia, 777
alemtuzumab
abnormal liver function, 784
anxiety, syncope, vertigo,
784
aplastic anemia, 784
chronic inammatory
demyelinating
polyradiculoneuropathy,
784
cyomegalovirus retinitis, 784
dizziness, tremor,
paresthesia, and
hypesthesia, 784
GuillainBarr syndrome,
784
infusion reaction, 784
lymphoproliferative
disorders, 7845
Index of drugs
multiple sclerosis, 784 amantadine
urticaria, 784 auditory and visual
alfentanil hallucinations, 604
apnea, 209 cardiovascular effects, 604
emergence agitation, 209 Fuchs dystrophy (corneal
nausea, 209 edema), 6024
vomiting, 209 livedo reticularis, 604
aliskiren syndrome of inappropriate
acute renal insufciency, 420 ADH secretion (SIADH),
back pain, 420 604
diarrhea, 420 urinary retention, 604
furosemide, interaction, ambrisentan
4201 aminotransferase
headache, 420 abnormalities, 421
nasopharyngitis, 420 ushing, 421
prolongation of the QT nasal congestion, 421
interval, 420 nasopharyngitis, 421
Allium sativum palpitation, 421
bullous necrosis, esophagus, peripheral edema, 421
993 sinusitis, 421
erythema and blistering, tadalal, interaction, 421
993 warfarin, interaction, 422
garlic burns, 993 amfebutamone
renal hematoma, 993 see bupropion
allopurinol amfetamine
DRESS, 250 blood pressure and heart
oral ulceration, 250 rate, increased, 12
toxic epidermal necrolysis, mortality rate, 1
250 American ginseng
all-trans retinoic acid see Panax quinquefolius
see tretinoin amikacin
alogliptin lipoatrophy, 510
dry skin, pruritus, rashes, nephrotoxicity, 510
and eczema, 895 type 5 Bartter-like
alosetron syndrome, 510
irritable bowel syndrome, vestibular function, 510
benet to harm balance, aminoglycoside antibiotics
745 hypokalemia and acidosis/
alpha1-antitrypsin alkalosis, 509
dizziness, 674 proximal renal tubular
dysphagia, 674 acidosis, 509
dyspnea, 674 vestibular toxicity, 509
headache, 674 aminolevulinic acid
nausea, 674 erosive pustular dermatosis,
tongue vesicles, 674 3389
alprostadil (prostaglandin E1) pain, 338
unstable angina, 846 phototoxic reactions, 339
aluminium aminosalicylates
Alzheimer's disease, 447 inamatory bowel disease,
bone area and bone mineral 756
content, 447 renal impairment, 756
chronic fatigue syndrome, tubulointerstitial nephritis,
447 756
kidney disease, 448 amiodarone
lumbar spine and hip bone acute cardiogenic shock, 381
mass, 447 chest trauma, 381
macrophagic myofasciitis, congenital heart defects,
447 380
neurotoxicity and cornea verticillata, 382
osteotoxicity, 447 fever and leukocytosis, 382
reduced glucocorticoids, 383
neurodevelopmental hepatotoxicity, 3834
scores, 447 ischemic heart disease, 381
Index of drugs
liver cirrhosis, 381
liver injury, 3834
lymphoplasmacytic
inltrates, 381
nodular goiter, 382
peripheral neuropathy and
cognitive impairment, 382
plasma concentrations, 383
QT interval prolongation,
381
steatohepatitis, 384
thyroid hormone resistance
syndrome, 382
torsade de pointes, 381
tremor and gait ataxia, 382
thyroid-stimulating hormone
(TSH), 382
ventricular
tachydysrhythmias, 381
amisulpride
extrapyramidal adverse
effects, 99
amlodipine
angioedema, 401
blood pressure, 401
mimicking mycosis
fungoides, 4012
skin inltration of atypical
lymphoid cells, 4012
amodiaquine
artesunate, interaction, 568
hepatitis, 567
amoxicillin
allergic reaction, 496
Kounis syndrome, 496
maculopapular rash, 496
molar incisor
hypomineralization, 496
vasospastic angina, 496
amphotericin B colloidal
dispersion (ABCD)
chills, fever, rigors, 542
amphotericin B deoxycholate
(DAMB)
anemia, 5423
electrolyte abnormality,
5423
infusion-related events,
5423
neonates, 543
nephrotoxicity, 5423
renal impairment, 542
amphotericin B lipid complex
(ABLC)
infusion-related reactions,
543
nausea, 543
neonates, 543
vomiting, 543
ampicillin
impaired platelet function,
496
platelet aggregation, 496
amprenavir/fosamprenavir
atazanavir, interaction,
5934
tenofovir, interaction, 594
anabolic steroids
acne, 870
amenorrhea/anovulation, 870
cardiac enlargement, 869
clitoral enlargement, 870
dilated cardiomyopathy, 870
gynecomastia, 870
hepatitis B, 870
hepatitis C, 870
HIV, 870
anagrelide
cardiomyopathy, 719
sympathetic hyperactivation,
719
takotsubo syndrome, 719
Anatolian hawthorn
see Crataegus orientalis
anakinra (interleukin-1
receptor antagonist)
anaphylactic reaction, 779
bacterial cellulitis, 779
interstitial granulomatous
reaction, 779
Wells' cellulitis, 779
anastrozole
arthralgia and arthritis, 860
fractures, 861
reduced bone mineral
density, 861
tenosynovial changes, 8601
androgens
endometrial or breast
cancer, risk of, 871
hypogonadism, 871
peliosis, 871
prostate cancer, 871
prostatic neoplasms, risk of,
871
angel's trumpet
see Datura stramonium
angiotensin converting enzyme
(ACE) inhibitors
angioedema, 417
cholestasis, 418
contact dermatitis, 418
cough, 416
electrolyte imbalance, 416
erythroderma, 418
hyperkalemia, 41618
hypoglycemia, 417
pseudopolymyalgia, 418
renal impairment, 416
aniline derivatives
paracetamol
(acetaminophen), 2445
antacids, 741
anthranilic acid derivatives
etofenamate, 245
mefenamic acid, 245
1033
anthraquinones
anorexia and episodic
vomiting, 753
epigastric pain, 753
intermittent fever, 753
melanosis coli, 753
anthrax vaccine
anxiety, 6556
arthralgia, 6556
asthenia, 6556
back pain, 6556
depression, 6556
headache, 6556
insomnia, 6556
myalgia, 6556
pain, 6556
rash, 6556
anticholinergic drugs
agitation, 324
anxiety, 324
confusion, 324
desaturation, 26970
hallucinations, 324
heart failure, 364
insomnia, 324
lung function, 364
migrainous headaches, 324
myocardial infarction, 3645
nausea and vomiting, 324
sedation, 324
stroke, 3645
urinary tract, 268
antidepressant drugs
see also individual names
cardiac disease, 25
anti-D immunoglobulin
see intravenous anti-D
immunoglobulin
antiepileptic drugs
see also individual names
anticonvulsant
hypersensitivity syndrome,
129
antipsychotic drugs, 128
bipolar disorder, 128
cognitive adverse effects, 127
constipation, 126
drug-resistant epilepsy, 125
gestational hypertension, 130
glaucoma, 126
hip bone mineral density,
129
hypersensitivity, 129
hyponatremia, 126
hypothyroidism, 126
idiopathic epilepsy, 1267
immunoallergic mechanism,
129
initima media thickness, 126
lamotrigine, 126, 132
(see also lamotrigine)
lamotrigine and phenytoin,
131
1034
levetiracetam, 126 (see also
levetiracetam)
liver injury, 129
metabolic acidosis, 132
nausea, 126
osteopenia, 130
osteoporosis, 126
oxcarbazepine, 131 (see also
oxcarbazepine)
oxcarbazepine monotherapy,
130
pre-eclampsia, 130
psychiatric diagnosis, 128
psychiatric disorder, 127
StevensJohnson syndrome,
132
teratogenic effect, 131
thyroid hormone deciency,
126
valproate-induced liver
injury, 129
weight gain, 129
antiestrogens and selective
estrogen receptor
modulators (SERMs)
breast cancer, 85960
cognitive function, 85960
antifungal azoles
aliskiren, interaction, 545
all-trans retinoic acid,
interaction, 545
antiretroviral drugs,
interaction, 545
atazanavir, interaction, 546
bortezomib, interaction, 546
calcineurin inhibitors,
interaction, 546
chloramphenicol,
interaction, 546
citalopram, interaction, 546
darunavir, interaction, 5467
ebastine, interaction, 547
efavirenz, interaction, 547
etoricoxib, interaction, 547
everolimus, interaction, 547
halofantrine, interaction,
5478
lopinavir and ritonavir,
interaction, 548
meloxicam, interaction, 548
methadone, interaction, 548
midazolam, interaction, 548
morphine, interaction, 548
nevirapine, interaction, 549
nifedipine, interaction, 549
omeprazole, interaction, 549
oxycodone, interaction, 549
sirolimus, interaction, 549
tacrolimus, interaction, 549
tilidine, interaction, 550
tipranavir and ritonavir,
interaction, 550
vincristine, interaction, 550
warfarin, interaction, 5501
anti-glaucoma drugs
conjunctival hyperemia, 982
dry eyes, 982
lacrimal drainage
obstruction, 9823
stinging/ burning, 982
supercial punctuate
keratopathy, 982
antihelminthic drugs
hypoglycemia, 647
antimony
abdominal colic, 448
diarrhea and rashes, 448
hepatotoxicity and
cardiotoxicity, 448
nausea, 448
vomiting, 448
weakness and myalgia, 448
antipsychotic drugs
bipolar disorder, 95
carbohydrate intolerance,
945
catract formation, 94
coronary heart disease, 93
diabetes mellitus, 956
dyslipidemia, 90
extrapyramidal acute
symptoms, 8990
extrapyramidal effects, 93
genetic factors and
metabolic reactions, 98
hyperlipidemia, 96
hyperprolactinemia, 8990
involuntary movements,
934
ischemic priapism, 99
metabolic abnormalities, 95
metformin, 979
obesity/weight gain, 90
orthostatic hypotension, 90
parkinsonism risk, 91
psychosis, 95
schizophrenia, 901
sedation, 8990, 934
seizures, 934
sudden cardiac death, 93
tardive dyskinesia, 8990
type 2 diabetes, 90
urinary retention, 99
weight gain, 90, 969
antiretroviral drugs
see also individual names
fever, 585
edema, 5845
musculoskeletal changes, 585
syncope, 584
antithrombin III
sepsis, 674
antithyroid drugs
agranulocytosis, 884
alveolar hemorrhage, 885
anemia, 884
Index of drugs
aplasia cutis and choanal
atresia, 885
goiter, 885
Graves' disease, 884
hepatocellular inammation,
885
purpura fulminans, 885
QT interval prolongation,
884
vasculitis, 885
antituberculosis drugs
HIV co-infection, 6267
Mycobacterium tuberculosis,
623, 624
appetite, drugs that suppress
see also individual names
apraclonidine
lethargy, 982
reduced appetite, 982
topical allergy, 982
aprotinin
acute myocardial infarction,
725
allergic reactions, 726
aminocaproic acid, 725
anaphylactic reactions, 726
atrial brillation, 725
blood transfusion, 725
cardiopulmonary bypass, 726
coronary artery bypass
surgery, 725
death, 725
ejection fraction reduced,
726
heterogeneity, 725
neurological dysfunction,
725, 726
non-bypass surgery, 725
plasma concentrations,
7245
postoperative cardiac, 725
postoperative renal failure,
725
renal function, 725
renal replacement therapy,
7245
tranexamic acid, 725
argatroban
epidural anesthesia, 71718
portal vein thrombosis,
71718
thrombocytopenia, 71718
aripiprazole
akathisia, 99101
anxiety, 99101
body weight changes, 99
cellulitis, 1001
chest pain, 1001
cocaine interaction, 102
depression, 99100
extrapyramidal disorders, 99
fatigue, 1001
u-like symptoms, 101
Index of drugs 1035

headache, 101 fosamprenavir, interaction, vanishing bile duct

hepatic impairment, 1002 594 syndrome, 523
insomnia, 1001 nevirapine, interaction, 594 aztreonam
metamfetamine, interaction, atenolol cystic brosis, 495
102 bradycardia, 397 hypersensitivity reaction, 495
migraine, 1001 sinus heart rate, 397
nausea, 101 atomoxetine B
neuroleptic malignant aggression, 7 Bacille Calmette-Gurin
syndrome, 101 agitation and suicidal (BCG) vaccine
prolactin concentration, 99 ideation, 7 allergic reactions, 656
restlessness, 1001 alcohol abuse and bladder calcication, 656
sedation, 101 dependence, 7 contact dermatitis, 656
sinusitis, 99100 bruxism, nocturnal, 7 contracted bladder, 656
somnolence, 99101 methylphenidate, cystitis, 656
thrombosis, 1001 interactions, 7 epididymo-orchitis, 656
tremor, 99 mydriasis, 7 granulomatous prostatitis, 656
upper respiratory infection, QT interval prolongation, 7 hematuria, 656
99100 transient ischemic attack, 7 keloid, 656
arsenic atorvastatin lupus vulgaris, 656
acute promyelocytic coronary heart disease, 926 lymphadenitis, 656
leukemia, 448 DNA damage, 927 myelosuppression, 656
blindness, 449 gastrointestinal, 926 osteomyelitis, 656
intraocular pressure, 449 hemorrhagic cystitis, 927 psoriasis, 656
retinal damage, 449 hepatitis, 9267 systemic reactions, 656
systemic arsenic toxicity, istradefylline, inhibition, 927 ulcerating vasculitis, 656
449 myalgia, 926 ureteral obstruction, 656
toothache, 449 vasculitis, 927 baclofen
arteether ATRA abdominal discomfort, 3023
mania, 572 see tretinoin back pain due to worsening
Artemisia vulgaris azasetron, 745 scoliosis, 3023
basal cell carcinoma, 993 azaspirones, 71 constipation, 3023
artesunate azathioprine drooling and swallowing
amodiaquine, interaction, acute erythroleukemia, 828 difculties, 3023
572 anemia, 829 head balance, reduced,
articial sweeteners aplasia cutis congenita, 828 3023
endometrial cancer, 1011 ascites, 827 increased tolerance of
gastric cancer, 1011 Beau's lines, 827 baclofen, 3023
non-neoplastic diseases, cholestatic hepatitis, 827 Mycobacterium fortuitum,
1011 Crohn's disease, 827 303
pancreas and endometrium, eryptosis, 827 paralytic ileus, 303
1011 fatigue, icterus, 827 transient drowsiness, 303
pancreatic cancer, 1011 hepatitis, 829 balsalazide
stomach cancer, 1011 herpes ares, 827 bowel symptoms, 756
urinary tract tumors, 1011 Hodgkin's lymphoma, 828 cardiac symptoms, 756
arylalkanoic acid derivatives hypersensitivity reaction, 829 chest pain, 756
bufexamac, 245 inammatory bowel disease, diarrhea and vomiting, 7567
diclofenac, 2456 829 headache and abdominal
urbiprofen, 246 leukopenia, 827 pain, 7567
ibuprofen, 246 nausea and vomiting, 827 ischemia or pericarditis, 756
ketoprofen, 246 nodular malignant myocarditis, 756
ketorolac, 246 melanoma, 828 ulcerative colitis, 756
loxoprofen, 246 pancytopenia, 827 barium sulfate
ascorbic acid ribavirin, interactions, 829 appendicitis, 967
see vitamin C squamous cell carcinoma, breast lump, 9678
Asian ginseng 827 ductal carcinoma, 9678
see Panax ginseng thrombocytopenia, 829 lower quadrant pain, 967
aspart azithromycin upper gastrointestinal, 967
see insulins agranulocytosis, 523 basiliximab
aspirin alveolar hemorrhage, 522 non-cardiogenic pulmonary
see acetylsalicylic acid exacerbation of myasthenia edema, 785
atazanavir gravis, 5223 BCG vaccine
antifungal azoles, myocarditis, 522 see Bacille Calmette-Gurin
interaction, 594 statins, interaction, 523 (BCG) vaccine
1036 Index of drugs

benazepril discomfort, 3978 delusions and verbal

see also angiotensin
converting enzyme (ACE)
inhibitors
cholestasis, 418
benzalkonium compounds
breathing and pain, 481
burning, 481
episodes of ushing, 481
itching, 481
red eyes, 481
benznidazole
agranulocytosis, 649
anorexia, 649
chronic headache, 649
dermatitis, 649
digestive intolerance, 649
fatigue, 649
hepatitis, 649
insomnia, 649
lymphoma, 649
myalgia, 649
neutropenia, 649
polyneuritis, 649
thrombocytopenia, 649
benzocaine
contact dermatitis, 290
methemoglobinemia, 289
benzodiazepine antagonists
umazenil, 7982
benzodiazepine-like drugs
see also individual names
benzodiazepines
delirium, 72
teratogenicity, 72
benzydamine (benzindamine)
agitation, 249
convulsions, 249
dizziness, 249
hallucinations, 249
nausea, 249
vomiting, 249
benzylpiperazine
seizures, increased
frequency, 545
3-triuoromethylphenyl
piperazine, interaction, 55
bepridil
interstitial pneumonia, 384
beta-adrenoceptor antagonists
bradycardia, 983
discomfort, 983
erectile dysfunction, 397
eye discharge, 983
eye hyperemia, 983
eye irritation, 983
eye pruritus, 983
hypotension, 983
lid margin crusting, 983
sticky sensation, 983
betaxolol
bradycardia and
hypotension, 3978
hyperemia, 3978
irritation in the eyes, 3978
bevacizumab
breast cancer, 785
carcinoid tumors, 7856
congestive heart failure, 786
corneal epithelial defects,
977
diarrhea, nausea, and
vomiting, 786
stulae, 786
glioblastoma, 785
high risk corneal
transplantation, 7856
hypertension, 786
infectious endophthalmitis,
intraocular inammation,
786
infusion/hypersensitivity
reaction, 787
ischemic retinal diseases,
7856
leukoencephalopathy
syndrome, 786
pancreatic cancer, 7856
postoperative bleeding or
wound healing
complications, 7867
prostate cancer, 7856
proteinuria, 786
sinusoidal obstruction
syndrome, 786
systemic adverse reactions,
977
thromboembolic events, 786
bezabrate
coronary artery disease, 922
heart failure, 922
BG9588
lupus glomerulonephritis,
787
bicalutamide
breast pain, 872
gynecomastia, 872
prostate cancer, 872
bimatoprost, 847
conjunctival hyperemia, 984
dermatochalasis involution,
984
lower eyelid fullness, loss, 984
periorbital fat atrophy, 984
relative enophthalmos, 984
upper eyelid sulcus,
deepening, 984
bisacodyl
abdominal cramps, 753
indigestion, 7534
nausea and vomiting, 753
weakness and anal irritation,
7534
bismuth
acute confusion, 449
aggression, 449
disorientation, 449
myoclonic jerks, 449
bismuth compounds
black tongue, 7523
bisoprolol
FEV1, reduction, 398
bisphosphonates
breast cancer, 1012
metadiaphysial femoral
fractures, 1013
metastatic bone, 1012
multiple myeloma, 1012
non-neoplastic, 1012
non-oncological, 1011
osteonecrosis of jaw, 1011
Paget's disease, 101314
parathyroid hormone, 1013
tetracycline-labelled bone,
1013
tooth extraction, 1012
upper gastrointestinal,
101314
bittersweet
see Tripterygium wilfordii
Hook
black cohosh
see Actaea racemosa
blood substitutes
abdominal pain, 672, 673
blood pressure, increased,
673
diarrhea, 672, 673
fever, 672
u-like symptoms, 673
hemoglobinuria, 672
hypotension, 673
increased mortality, 672
interference with laboratory
assay, 672
jaundice, 672
myocardial infarction, 672
nausea, 673
oliguria, 672
pancreatitis, 673
pulmonary complications, 673
renal dysfunction, 672
stroke, 672, 673
thrombocytopenia, 673
vasoconstriction, 672, 673
vasopressor effects, 673
vomiting, 673
blood transfusion
acute and delayed hemolytic
transfusion reactions, 671
anaphylactic and other
allergic reactions, 671
bacteremia, 671
febrile non-hemolytic
transfusion reaction, 671
graft-versus-host disease
(GvHD), 671
Index of drugs
hemosiderosis, 671
hospitalization prolonged, 672
infection at any site, 672
intensive care treatment, 672
mechanical ventilation, 672
mortality increased, 672
multiorgan failure, 672
new allo-antibody formation,
671
pneumonia, postoperative,
increased risk, 672
purpura, 671
transfusion-associated
circulatory overload
(TACO), 671
transfusion-associated sepsis
(TAS), 671
transfusion-related acute
lung injury (TRALI), 671
viral infections, 671
bosentan
dyspnea, 422
edema, peripheral 422
headache, 422
hemoglobin, reduced, 422
hypersensitivity, delayed
4223
liver enzymes, abnormal 422
nasopharyngitis, 422
nausea, 422
rash, 422
botulinum toxins
anal ssure, 304
chronic pain, 304
muscle hypertrophy, 305
muscle weakness, 3045
Parkinson's disease, 304
brachial plexus anesthesia
Horner's syndrome, 283
motor block, 283
bran
acute dysphagia, 754
esophageal obstruction, 754
retrosternal pain, 754
weight loss, 754
brindleberry
see Garcinia gambogia
bufexamac
pigmented purpuric
dermatosis, 245
bupivacaine
cardiac arrest, 290
dysrhythmia, 290
buprenorphine
constipation, 225
dizziness, 225
drug formulations, 226
drug overdose, 2267
hepatitis, 225
mortality, 226
nausea, 225
during pregnancy, 226
sedation, 225
sweating, 225
transdermal administration,
226
withdrawal symptoms, 226
bupropion (amfebutamone)
see also antidepressant
drugs
angioedema and serum
sickness-like reactions, 33
CYP2D6 metabolism, 33
seizures, 33
buspirone
dizziness, 71
dry mouth, 71
ushing/sweating, 71
butorphanol
dizziness, 227
drug withdrawal, 227
nausea, 227
sedation, 227
vomiting, 227
C defects, 133
caffeine
hyperkinetic disorder risk,
112
lactic acidosis, 12
orofacial clefts, 12
calcitonin
ushing and nausea, 909
local reactions, 909
calcium channel blockers
see also individual names
gingival enlargement, 401
calcium salts
absorption of phosphate,
449
bloating and gas, 449
constipation, 449
myocardial infarction, 449
camphor
bag-valve-mask ventilation,
334
cold, 334
seizures, 3334
candesartan
calvarial dysplasia, 419
hypoplasia, 419
renal dysplasia, 419
cannabinoids
Aspergillus infection, 58
cerebellar-dependent
learning, 567
cognitive function
worsening, 57
depression, 741
dizziness, 55
dysphoria, 741
gray matter loss, 55
hallucinations, 741
hallucinations and
dysphoria, 55
multiple sclerosis, 55
1037
myocardial infarction, 56
nausea and vomiting, 741
paranoid delusions, 55, 741
periodontal disease, 57
steatosis, 578
captopril
see also angiotensin
converting enzyme (ACE)
inhibitors
contact dermatitis, 418
hyperkalemia, 418
carbamazepine
see also antiepileptic drugs
acute interstitial
pneumonitis, 133
acute mania, 1323
acute pulmonary failure, 135
adjunctive therapy, 132
anaplastic large cell
lymphoma, 134
aripiprazole, interaction, 135
atrioventricular conduction
bipolar disorder, 1334
comparative efcacy, 1323
corpus callosum lesion, 133
diplopia, 132
DRESS, 134
drug hypersensitivity
syndrome, 134
erythema multiforme, 1345
hyperammonemia, 1334
hypertension, 132
hyponatremia, 132
leukoencephalopathy, 133
paracetamol, interaction,
135
rashes, 132
schizophrenia, 135
serum thyroxine, 133
StevensJohnson syndrome,
134
tachycardia, 134
tacrolimus, interaction,
1356
toxic epidermal necrolysis,
134
valproate, 1345
carbapenem
audiogenic seizure, 491
compromised renal function
and renal insufciency,
492
doripenem, 492
epilepsy, 492
inhibitory neurotransmitter
gama-aminobutyric acid
(GABA), 491
meningitis, chronic or acute
nervous system damage,
492
methotrexate, prior
intrathecal therapy, 492
1038
nervous system excitation
and convulsions, 491
nervous system infection,
492
seizures, 491, 492
stroke, 492
theophylline, 492
valproate, 492
carbon dioxide
abdominal aortic aneurysms,
971
renal function, 971
carbonic anhydrase inhibitors
see also individual names
cardiac glycosides
see also individual names
atrioventricular block, 377
bradydysrhythmias, 377
chronic heart failure, 377
hyperkalemia, 378
carp gallbladder
acute renal failure, 998
nausea and epigastric pain,
999
carvedilol
blood pressure, 398
Peyronie's disease, 398
caspofungin
alkaline phosphatase
increased, 557
aspartate aminotransferase
increased, 557
hypersensitivity, immediate,
557
hypotension, 557
phlebitis, 557
voriconazole, interaction,
558
cat's claw
see Uncaria tomentosa
cefotaxime
acute generalized
exanthematous pustulosis
(AGEP), 493
inspissated bile syndrome,
493
positive patch test, 493
ceftriaxone
acute pancreatitis, 494
biliary pseudolithiasis, 494
calcium deposition, 494
cerebrovascular disease, 493
encephalopathy, 493
hemolytic anemia, 4934
hyperbilirubinemia, 494
hypersensitivity, 494
Lyme disease, 494
neurological sequelae, 4934
palmar pruritus, rashes,
nausea, and abdominal
cramp, 493
sickle cell disease, 4934
urinary tract infection, 493
celecoxib
anaphylaxis, 246
docetaxel, interaction, 247
drug overdose, 2467
celiprolol
wheeze, 398
Centoxin
see HA-1A
cephalosporins
see also individual names
hemolytic anemia, 493
cetirizine
acute dystonia, 345
anaphylactic shock, 345
anaphylaxis, 345
chelators
see also individual names
contact eczema, 474
distal limb muscles, 474
electrophysiological test, 474
herpes simplex, 473
hypocalcemia, 474
hypocupremia, 474
pruritic rash on chest and
back, 473
StevensJohnson syndrome,
4734
Yersinia, 473
chiropractic therapy
arterial dissection,
myelopathy, vertebral disc
extrusion, and epidural
hematoma, 1000
chronic neck pain, 1000
quadriparesis, 1000
vertebrobasilar artery
stroke, 1000
chloramphenicol
hepatitis, 514
chlorhexidine
bloodstream infection, 481
central venous catheters,
4801
contact dermatitis, 481
dental plaque biolms, 481
pneumonia, 4801
skin allergy, 481
skin dryness, 481-2
Staphylococcus aureus, 481
chloroform
carbon monoxide poisoning,
257
dysrhythmias, 257
hepatitis, 257
chloroquine and
hydroxychloroquine
depigmentation, 569
pigmentation of oral mucosa,
568
third-degree atrioventricular
block, 568
ventricular brillation, 568
chlorphenamine
Index of drugs
contact dermatitis, 346
generalized convulsion,
3456
sedation, 345
cibenzoline
chewing difculty and
dyspnea, 385
headache, dull 385
kidney disease, chronic 385
myasthenia, 385
ciclosporin
bone pain, 816
digital brokeratoma, 816
gingival overgrowth, 815
hair, dark, 816
hemolyticuremic syndrome,
816
hyperplasia, 817
hypertrichosis, 816
pancreatitis, 81516
parkinsonism, 815
posterior reversible
encephalopathy syndrome,
815
renal cysts, 816
renal failure, 817
rhabdomyolysis, 817
serotonin syndrome, 817
cidofovir
dysplasia, 577
cilomilast
exacerbation of COPD,
3678
cilostazol
glycyrrhetic acid, 4078
spinal epidural hematoma,
407
thrombosis, 407
cimetidine
hemolytic anemia, 748
Cimicifuga racemosa
see Actaea racemosa
ciprooxacin
Achilles' tendinitis, 515
Achilles' tendon rupture,
515
acute generalized
exanthematous pustulosis
(AGEP), 515
clozapine, interaction, 516
hemibalismus, 515
hemolytic anemia, 515
hemorrhagic vasculitis, 515
hepatitis, cholestatic, 515
myalgia, 515
serotonin syndrome, 516
simvastatin toxicity, 516
StevensJohnson syndrome,
515
thrombocytopenia, 515
torsade de pointes, 51415
tuberculosis, 6278
urinary tract infection, 515
Index of drugs 1039

cisapride antiplatelet, 723 cocaine

ventricular dysrhythmias, bleeding, 7201 aortic dissection, 58
7412 carotid artery stenting, 724 cerebral blood ow, 61
citalopram and escitalopram cholestatic liver damage, 721 exogenous lipoid
herpes zoster infection, 29 coronary artery disease, 721, pneumonia, 59
propafenone interactions, 722 fetotoxicity, 601
2930 death, 723 bromuscular dysplasia, 61
seizures, 29 xed drug eruption, 721 lung cavitation, 59
torsade de pointes, 29 gastrointestinal bleeding, 721 myocardial infarction, 58
ci wu jia injection head trauma, 720 osteonecrosis, 60
allergic skin reactions, 991 hemothorax, 722 panhypopituitarism, 60
vertigo, 991 liver damage, 721 peripheral vasospasm, 59
clarithromycin myocardial infarction, 7212 pleural empyema, 59
anaphylactic reaction, 524 pancytopenia, 721 pneumothorax, 59
cholestatic hepatitis, 524 peripheral, 724 vasculitides and purpura, 60
chronic coronary artery pharmacodynamic codeine, 209-10
disease, 5234 interaction, 7234 colchicine, 250
colchicine, interaction, 524 plasma concentrations, 722 colistin
Hoign syndrome, 524 platelet inhibition, 722 Acinetobacter infection, 528
mania, 523 platelet transfusions, 7201 nephrotoxicity, 5278
rhabdomyolysis, 524 prasugrel, 723 neurotoxicity, 528
visual hallucinations, 523 proton pump inhibitors, 723 Commiphora molmol
clebopride psychomotor performance, see myrrh
hemifacial dystonia, 742 720 complementary and alternative
ischemic attack, 742 pulmonary hemorrhage, 722 medicine
clavulanic acid ranitidine, 723 adverse reactions, 989
see co-amoxiclav revascularization, 723 C1 esterase inhibitor
clenbuterol smoking, 7234 concentrate
adulteration, 53 ticlopidine allergy, 724 abdominal pain, 674
blood and urine symptoms, clozapine anaphylactic reactions, 674
323 agranulocytosis, 103 chills, 674
chest pain, 323 benzodiazepines, diarrhea, 674
dyspnea, 323 interactions, 103 dizziness, 674
hyperglycemia, 323 and haloperidol, 1023 dry mouth, 674
hypokalemia, 323 leukopenia, 103 fever, 674
nausea, 323 neutropenia, 103 headache, 674
palpitation, 323 and olanzapine, 102 inuenza-like symptoms, 674
tachycardia and venous thromboembolism, infusion-related reactions,
hypotension, 323 103 674
tremor, 323 coal tar injection-site redness, 674
clindamycin skin-to-skin and skin-to- muscle spasms, 674
allergic rash, 522 mouth contact, 334 nausea, 674
cytolytic hepatitis, 522 co-amoxiclav and clavulanic conivaptan
diarrhea, 522 acid see vasopressin receptor
clobazam acute generalized antagonists
StevensJohnson syndrome, exanthematous pustulosis copper
72 and contact dermatitis, 496 ovarian penetration, 450
clomifene xed drug eruption, 496 Wilson's disease, 450
breast cancer, 861 linear IgA bullous eruption, co-trimoxazole
clonazepam 496 see trimethoprim
drug abuse, 73 psychosis, 496 coumarin anticoagulants
hair loss, 73 urticaria and angioedema, see also individual names
malignant catatonia, 73 496 acute kidney damage, 708
psychomotor performance cobalamins (vitamin B12) acute tubular damage, 708
impairment, 72 blood pressure, 693 allergic reactions, 713
clonidine movement disorders, 693 atrial brillation, 7078, 709
escitalopram, interaction, 424 tremor and myoclonus, 693 bleeding, 707
fever, 424 cobalt bone mineral density,
hypotension, 424 aseptic lymphocyte- reduction, 7089
clopidogrel dominated vasculitis- calciphylaxis, 707
acute coronary syndromes, associated lesion carbamazepine, 712
722 (ALVAL), 450 cardiac, 7112
allergic reactions, 724 groin pain, 450 cerebral hemorrhage, 711
1040
cerebral microbleeds, 7078
chest pain, 713
chronic giant coronary
aneurysm, 708
chronic kidney damage, 708
coagulopathy, 713
coronary artery calcication,
707
cutaneous ischemia, 707
cytochrome P450 (CYP), 712
deep vein thrombosis, 713
endothelial cell damage, 708
folate status, 708
gastrointestinal bleeding, 710
hemoptysis, 707
hepatic, 712
hypertension, 7078
hyphema, 708
inuenza, 711
intracerebral hemorrhage,
7078
life-threatening bleeding, 713
liver disease, 708
lung cancer, 711
mitral and aortic valve
calcication, 707
myocardial, infarction, 713
myocardial ischemia, 708
optic nerve dysfunction, 709
pancreatic cancer, 711
paracetamol interaction,
711
photodynamic therapy, 713
prothrombin, 713
prothrombin time, increased,
708
proton pump inhibitors,
7112
rebound coagulation, 708
renal dysfunction, 710
retroperitoneal hematoma,
711
serum troponin, 713
skin necrosis, 708
SSRIs, 712
subconjunctival hemorrhage,
708
suprachoroidal hemorrhage,
713
tamoxifen, 712
thromboembolism, 713
trauma, 711
upper airway obstruction, 707
ventricular brillation, 713
COX-2 selective inhibitors
see also individual names
cranberry
see Vaccinium macrocarpon
Crataegus orientalis
acute renal failure, 993
acute tubulointerstitial
nephritis, 993
epistaxis, 993
cyanoacrylates
abdominal compartment
syndrome, 1014
acute hepatic failure, 1015
acute infarction, 1014
anticoagulant therapy, 1015
antithrombin therapy, 1015
aorta and iliac arteries, 1015
bradycardia, 1014
brain abscesses, 1015
dual antiplatelet therapy, 1015
embolism, 1014
epigastric pain, 1014
esophageal ulceration, 1014
fever, 1015
gastrointestinal bleeding,
1014
hemorrhage, 1014
hepatic artery, 1014
hepatocellular carcinoma,
1014
hypertrophic scars, 1015
intestinal ischemia, 1014
ischemic stricture, 1015
pulmonary embolus, 1014
rhinoconjunctivitis and
asthma, 1015
septicemia, 1015
tracheal and bronchial
obstruction, 1015
variceal bleeding, 1014
cyclobenzaprine
serotonin syndrome, 305
torticollis, 305
cycloserine
asterixis, 630
hypersomnolence, 630
Cynomorium songaricum
acute renal insufciency,
9934
nausea and vomiting, 994
cyproterone acetate
abdominal pain, nausea,
vomiting, 872
facial ushing, sweating, 872
serotonin syndrome, 8723
cysteamine
drug-induced lupus, 761
D coronary artery disorders,
dabigatran
atorvastatin, 718
enoxaparin, 718
liver disease, 718
thrombin time, 718
thrombocytopenia, 718
thromboplastin time, 718
daclizumab
fatigue and muscle aches, 788
lymphopenia and
generalized
lymphadenopathy, 7878
rash, 788
Index of drugs
DAMB
see amphotericin B
deoxycholate
danaparoid sodium
eczema, 716
glucocorticoids, 716
hypersensitivity,
delayed-type, 716
neonatal death, 717
orthopedic surgery, 716
skin lesions, 716
thromboembolism, 717
thrombophilia, 717
thrombosis, 716
danazol
angioedema, 868
lovastatin, interaction, 868
myopathy and pancreatitis,
868
dantrolene sodium
acneiform eruption, 305
dapsone
agranulocytosis, 630, 631
aplastic anemia, 630
cimetidine, interaction, 631
complete atrioventricular
block, 630
darbepoetin alfa, interaction,
632
dermatitis herpetiformis, 630
hemolytic anemia, 6302
methemoglobinemia, 630,
632
photosensitivity, 632
platelet count, increased, 630
pure red cell aplasia, 630
sulfhemoglobinemia, 630
sulfone syndrome (dapsone
syndrome), 633
daptomycin
eosinophilic pneumonia, 529
rhabdomyolysis, 530
darbepoetin alfa
congestive heart failure, 682
dysrhythmias, 682
embolism/thrombosis, 682
hypertension, 682
myalgia, 682
myocardial infarction/
682
rash, 682
seizures, 682
strokes, 682
darunavir
amylase activity, 5945
atazanavir, interaction, 595
blood glucose, 594
diarrhea, 594
etravirine, interaction, 595
low density lipoprotein, 594
nasopharyngitis, 594
nausea, 594
Index of drugs
neutropenia, 594
nevirapine, interaction, 595
oral contraceptives,
interaction, 595
pancreatic lipase, 594
raised aminotransferase, 594
rashes, 594
saquinavir, interaction, 595
total cholesterol, 594
triglycerides, raised, 594
Datura stramonium
anticholinergic effects, 994
confusion, 994
dilated pupils, 994
dry mouth, 994
urinary retention, 994
deferasirox
agranulocytosis, 497
blood dyscrasias, 467
Fanconi syndrome, 468
gastrointestinal hemorrhage,
467
hepatic failure, 467
hungry bone syndrome, 468
hypocalcemia, 468
impaired renal function, 468
interstitial nephritis and
renal failure, 468
lenticular opacities, 467
mucormycosis, 468
neutropenia, 467
obstructive jaundice, 467
renal impairment and
failure, 468
symptomatic hypocalcemia,
467
thrombocytopenia, 467
deferiprone
agranulocytosis, 469
arthritis, 469, 470
arthropathy, 470
axial hypotonia, 470
cardiotoxicity, 469
cerebellar syndrome, 470
dilated hypokinetic
cardiomyopathy, 469
dizziness, 470
heart failure, 469
hydroxyl radicals, 4689
neurological reactions, 470
nystagmus and diplopia,
470
reactive oxygen species,
4689
sideroblastic anemia, 469
deferoxamine
bone dysplasia, 471
central blurring, 471
reduced central response on
electroretinography, 471
retinal damage, 471
retinal pigmentary changes,
471
sensorineural hearing loss,
471
dental anesthesia
multiple sclerosis,
precipitation, 287
desferrioxamine
see deferoxamine
desloratadine
xed drug eruption, 346
oral ulceration, 346
pruritic lesions, 346
desmopressin
hyponatremia, 916
seizures, 916
thrombosis, 916
desvenlafaxine
see venlafaxine and
serotonin and
noradrenaline re-uptake
inhibitors (SNRIs)
detemir
see insulins
dexlansoprazole
adenocarcinomas, 750
diarrhea, 750
atulence, bloating, and
distension, 750
gastrointestinal and
abdominal pain, 750
hyperplasia, 750
respiratory tract infection,
750
dextrans
hypersensitivity reactions,
675
dextromethorphan
agitation, 210
nausea, 210
paranoia, 210
psychosis, 210
vomiting, 210
dextropropoxyphene, 210
diacerein (diacetylrhein)
soft stools, 249
yellow discoloration of the
urine, 249
diamorphine (heroin)
drug overdose, 211
hallucinations, 211
myocarditis, 2101
respiratory depression, 211
rhabdomyolysis, 211
seizures, 211
spongiform
leukoencephalopathy, 211
diarylquinoline
tuberculosis, 6256
diazepam
drug resistance, 73
transient pain, 73
watery eyes, 73
diazoxide
heart failure, 4278
1041
neutropenia, 4278
pulmonary hypertension,
4278
diclofenac
allergic contact dermatitis,
245
aminotransferases, rises, 245
anastomotic leakage, 245
gastrointestinal bleeding, 246
Kounis syndrome, 245
photoallergic contact
dermatitis, 245
didanosine
non-cirrhotic portal
hypertension, 587
diethylstilbestrol
acute monocytic leukemia,
8523
adenocarcinoma of the
ovary, 852
breast cancer, 853
cryptorchidism, 852
inammation/infection of the
prostate, 852
inammation/infection of the
testicles, 852
dihydrocodeine
convulsions, 211
dimethylfumarate
contact dermatitis, 336
dimethylhydralazine
see hydralazine
dimethylsulfoxide (DMSO)
101516
dipeptidyl peptidase 4 (DDP-
4) inhibitors
see also individual names
headache, 894
nasopharyngitis, 420
upper respiratory tract
infection, 895
urinary tract infection, 895
diphenhydramine
allergic contact dermatitis,
3467
blood pressure fall, 347
cardiogenic shock, 347
death, 347
dry skin, 347
manifestation of coma, 347
metabolic acidosis, 347
muscle tone, 347
pulmonary edema, 347
status epilepticus, 347
dipyridamole
asystole, 719
atrial brillation, 719
cardiac enzymes, 719
chest discomfort, 719
dizziness, 719
headache, 719
loss of consciousness, 719
myocardial infarction, 719
1042
nausea, 719
non-smoking, 719
theophylline, 719
transient ischemic attacks,
719
disopyramide
myasthenia gravis, 385
disulram
alcohol, 1016
colchicine intoxication, 1014
lancinating pain, 1016
myocardial infarction, 1014
paresthesia of distal limbs,
1016
peripheral neuropathy, 1014
punding, 1016
dobutamine
chest pain, 319
compelete heart block, 319
coronary artery spasm, 319
empty ventricle syndrome,
31920
heart block, 319
myocardial infarction, 319
serpentine tongue, 320
splenic artery aneurysm,
reputure, 320
transient global amnesia, 320
docetaxel
adverse reactions, 946
anemia, 947
arthralgia and myalgia, 947
bronchospasm, 948
cardiotoxicity, 948
colon ulceration, 947
cytotoxic effect, 9456
epiphora, 946
erythema, 947
uid retention, 9467
ushing, 948
gastric adenocarcinoma, 945
generalized rash/erythema,
948
hair loss, 947
localized cutaneous
reactions, 948
lymphopenia, 947
metastatic breast cancer, 945
muscle weakness, 946
nausea/vomiting, diarrhea,
and mucositis, 947
neutropenia, 947
neutropenic enterocolitis,
947
non-neutropenic colitis and
ischemic colitis, 947
non-small-cell lung cancer,
945, 947
onycholysis, 947
palmarplantar
erythrodysesthesia
syndrome, 947
peripheral neuropathy, 946
pneumonitis, 946
prostate cancer, 947
pruritus, 947
recall dermatitis, 947
reduce uid retention, 945
renal excretion, 946
severe hypotension, 948
squamous cell carcinoma,
945
subungual hemorrhages and
subungual abscesses, 947
docosahexaenoic acid (DHA)
paclitaxel
constipation, 945
diarrhea, 945
esophagogastric cancer,
9445
fatigue, 945
metastatic melanoma, 9445
nausea, 945
neutropenia and
hyperbilirubinemia, 945
non-small-cell lung cancer,
9445
peripheral edema, 945
peripheral neuropathy, 945
rashes, 945
dofetilide
heart failure, 386
torsade de pointes, 385
dolasetron
see neurokinin NK1 receptor
antagonists
domperidone
diabetic gastroparesis, 742
gastroesophageal reux, 742
hyperprolactinemia, 742
QT interval prolongation,
742
donepezil
anemia, 15
delusions, 15
dizziness, 15
gait disorder, 15
headache, 1516
insomnia, 15
dopamine
brotic heart valve disease,
321
panic attacks and
pramipexole, 322
Parkinson's disease, 321
restless legs syndrome, 322
sleep attacks, 322
syncope, 321
tachypnea, 322
dorzolamide
bevacizumab interaction, 438
choroidal detachment, 438
doxazosin
retrograde ejaculation, 426
doxycycline
DRESS, 499
Index of drugs
hepatitis, 499
JarischHerxheimer
reaction, 499
malaria prophylaxis, 499
pancreatitis, 499
Sweet's syndrome, 499
tachycardia, tachypnea,
hypoxia, hypotension, 499
drospirenone
see hormonal contraceptives
drotrecogin alfa
bleeding complication, 671
heparin, interaction, 671
duloxetine
binge eating, 31
dry mouth, 31
encephalastrapy, 31
hyponatremia, 31
nausea, 31
sexual desire, increased, 31
suicide, 31
tachycardia, 31
warfarin interaction, 32
E
Ecbalium elaterium
headache, 994
nasal septum perforation,
994
shortness of breath, 994
sore throat, 994
ecstasy
anaphylactic reaction, 64
angle closure, 62
cardiac valvular disease, 62
cognitive function and
impulsivity, 634
prospective memory, 63
sex differences, 64
working memory, 63
edrecolomab
breathing disorders, 788
colon cancer, 788
diarrhea and nausea, 788
fever, 788
ushing, 788
hypotension, 788
efalizumab
angioedema, 789
familial benign chronic
pemphigus, 7889
lymphomatoid papulosis, 789
lymphoproliferative
disorders, 789
progressive multifocal
leukoencephalopathy, 788
seborrheic keratoses, 789
thrombocytopenia, 788
thrombocytosis, 788
urticaria, 789
efavirenz
antifungal azoles,
interaction, 592
Index of drugs 1043

antimalarial drugs, Ephedra and ephedrine gastrointestinal symptoms,

interaction, 592 anencephaly, 31718 523
dizziness, 590 aortic stenosis, 31718 erythropoietin and derivatives
Ginkgo biloba, interaction, weight loss, 31718 see also epoetin alfa, epoetin
592 epinephrine beta, and epoetin delta
hallucinations, 590 see adrenaline back pain, 682
hangover, 590 epidural anesthesia bone pain, 682
hepatic encephalopathy, 590 hiccups, 284 chest pressure sensation, 682
impaired concentration, 590 Horner's syndrome, 2834 common cold, 682
limb fat, increased, 5823 leg pain, 284 congestive heart failure, 682
nocturnal sweating, 590 epoetin alfa deep vein thrombosis, 682
osteomalacia, 591 see also erythropoietin and diarrhea, 682
status epilepticus, 590 derivatives dizziness, 682
eornithine back pain, 682 dry mucosa, 682
confusion, 574 bone pain, 682 dry skin, 682
fever, 574 chest pressure sensation, 682 dysrhythmias, 682
infections, 574 common cold, 682 embolism/thrombosis, 682
seizures, 574 deep vein thrombosis, 682 fatigue, 682
Trypanosoma brucei diarrhea, 682 headache, 682
gambiense, 574 dizziness, 682 hypertension, 682
emergency contraception headache, 682 injection-site pain, 682
dysuria, 859 injection-site pain, 682 leg pain, 682
toxic epidermal necrolysis, leg pain, 682 liver enzymes, raised, 682
859 nausea, 682 muscle pain, 682
EMLA pain, 682 myalgia, 682
see prilocaine polycythemia, 682 myocardial infarction/
enalapril stomach pains, 682 coronary artery disorders,
see also angiotensin tiredness, 682 682
converting enzyme (ACE) epoetin beta nausea, 682
inhibitors see also erythropoietin and pain, 682
pseudopolymyalgia, 418 derivatives peripheral vascular disease,
endoperoxides dry mucosa, 682 682
see also individual names dry skin, 682 polycythemia, 682
bradycardia, 571 fatigue, 682 pruritic rash, 682
liver enzymes, raised, 571 headache, 682 rash, 682
neutropenia, 571 liver enzymes, raised, 682 seizures, 682
QT interval, 571 muscle pain, 682 serum creatinine, increased,
reticulocytopenia, 571 thrombovascular events, 682 682
enfuvirtide epoetin delta stomach pains, 682
depression, 598 see also erythropoietin and strokes, 682
diarrhea, 598 derivatives thrombovascular events, 682
eosinophilia, 598 hypertension, 682 tiredness, 682
hypersensitivity reactions, peripheral vascular disease, escitalopram
598 682 see citalopram
injection site reactions, 598 serum creatinine, increased, esmolol
nausea, 598 682 bradycardia, 398
niacin, interaction, 5989 epoprostenol hypokalemia, 398
tipranavir and ritonavir, headache, 847 hypotension, 398
interaction, 599 hypertension, 847 injection site reactions, 398
entecavir thrombocytopenia, 847 metabolic acidosis, 398
eosinophilia, 579 epothilones postoperative agitation, 398
lactic acidosis, 579 apoptosis, 948 postoperative anemia, 398
leukocytosis, 579 mitotic arrest, 948 postoperative pain, 398
enteral nutrition eptibatide systolic blood pressure, 398
abdominal pain, 700 see glycoprotein IIbIIIa wheezing, 398
allergic skin reaction, 701 inhibitors esomeprazole
diabetes mellitus, 701 equine estrogens, 853 see omeprazole
esophageal carcinoma, 700 ertapenem estrogens
organ failure, 701 antiepileptic drugs, 492 angioedema, 852
pancreatic infections, 701 nervous system disorder, 492 melanoma, 852
refeeding syndrome, 700 renal insufciency, 492 etanercept
respiratory failure, 700 erythromycin angiokeratomata, 781
serum potassium, 700 biliary colic, 523 Crohn's disease, 781
1044
non-specic inammatory extrapleural anesthesia
bowel disease, 781
varicella zoster, 782
ethambutol
bilateral temporal
hemianopia, 634
central/centrocecal
scotomas, 634
drug-resistant tuberculosis,
627
liver toxicity, 627
Mycobacterium avium-
intracellulare infection,
634
reduced visual acuity, 634
tuberculosis, 6278
etheried starches
anaphylaxis, 6756
coagulopathy, 6756
excessive intravascular
volume expansion, 6756
hepatic dysfunction, 6756
metabolic acidosis, 6756
renal dysfunction, 6756
ethosuximide
see also antiepileptic drugs
behavioral changes, 136
loss of appetite, 136
sleep disturbance, 136
somnolence, 136
systemic lupus
erythematosus, 136
vomiting, 136
etofenamate, 245
etomidate
adrenal insufciency,
2623
adrenal suppression, 263
etravirine
darunavir and ritonavir,
interaction, 5923
hypercholesterolemia, 592
nausea, 592
rash, 592
vomiting, 592
everolimus
aspergillosis, invasive,
81718
pneumonitis, 817
serum triglycerides, 817
exemestane
arthralgias, hot ushes, 861
bone mineral density, 862
cholestatic hepatitis, 861
fatigue, jaundice, and
pruritus, 861
myalgia, 861
vaginal dryness, 861
exenatide
acute pancreatitis, 896
impaired renal function, 864
Exilis
see Garcinia gambogia
Horner's syndrome, 287
ezetimibe
cancers, 922
carotid intima-media
thickness (CIMT), 921
coronary heart disease, 921
myopathy, 9212
F transformation, 770
factor VIIa (coagulation
proteins)
thrombosis, 679
factor VIII (coagulation
proteins)
allergic reactions, 67980
factor IX (coagulation
proteins)
allergic reactions, 680
edema, 680
hypoalbuminemia, 680
nephritic syndrome, 680
proteinuria, 680
famotidine
acute hepatitis, 748
febuxostat
diarrhea, 250
dizziness, 250
fenuramine
thrombocytopenia, 6
valvular disease, 6
fenobrate
liver transaminases, raised,
923
myopathy, 923
fentanyl
adrenal insufciency, 212
bradycardia, 212
bradykinesia and rigidity,
212
bronchospasm, 21213
cough, 212
erythema, 21213
hypotension, 21213
and ketamine, 213
muscle rigidity, 212
nebulizer administration, 213
paroxetine interaction, 213
and propofol, 21314
ropivacaine interaction, 213
transdermal administration,
213
brates
albuminuria, increased, 922
diabetes, 922
homocysteine and creatinine
concentrations, raised, 922
pancreatitis, 922
pulmonary
thromboembolism, 922
brin glue
anaphylactic reactions, 6745
coagulopathy, 6745
Index of drugs
immunological sequelae,
6745
thrombosis, 6745
lgrastim
abdominal aortitis, 770
allergy, anorexia, chills,
fever, 769
citrate toxicity, 769
enhanced leukemic
local reactions, rashes, pain,
and infections, 769
nausea, vomiting, u-like
symptoms, 769
sickle cell disease, 770
sweats, fatigue, headache,
myalgia, 769
nasteride
azoospermia, 873
erythema, 873
xed drug eruption, 873
hair loss, 873
myalgia, 873
oligospermia, 873
sh oils
cardiac death, 923
ventricular tachycardia, 923
ecainide
Brugada syndrome, 387
chest discomfort, 387
xed drug eruption, 387
hyponatremia, 387
ucloxacillin
acute interstitial nephritis,
497
cholestatic hepatitis, 497
uconazole
allergy, 551
congenital malformation,
5512
liver function tests,
abnormal, 551
QT interval prolongation, 551
sclerosing lymphangitis, 551
ucytosine
anemia, 559
umazenil
adrenocorticotrophic
responses, reduced, 81
ballismus, 81
depressive mood, 80
drug overdose, 82
drug withdrawal, 81
dysrhythmias, 81
heart block, 81
myoclonic-like movements,
81
nausea, 80
opisthotonos, 81
psychosis, 81
seizures, 81
shivering, 80
ventricular brillation, 801
Index of drugs 1045

ventricular tachycardia, 801 squamous cell carcinoma, anaphylactic reactions,

vomiting, 80 337 cellulitis, or vascular
unitrazepam furosemide complications, 968
acute ischemia, 734 bronchopulmonary anaphylactic shock, 9689
road trafc accidents, 74 dysplasia, 440 contrast media, 968
uorescein bullous pemphigoid, 440 diabetes mellitus, 96970
empty sella syndrome, hypersensitivity, 441 electrocardiographic
101617 hyperthermia, 440 changes, 968
status epilepticus, 10167 nephrocalcinosis, 440 fever, chills, and nausea, 970
uoride reduced radioiodine hepatocytes, 968
brisk deep tendon reexes, excretion, 440 hypertension, 96970
1017 respiratory distress myocardial infarction, 968
high cervical myelopathy, syndrome, 440 nephrogenic systemic
1017 urticaria, 440 brosis, 969
ligamentum avum, 1017 fusidic acid non-proprietary names, 968,
overactive urinary bladder, urticaria, 530 968
1017 renal insufciency, 96970
skeletal uorosis, 1017 G skin reactions, 970
symmetrical weakness, 1017 gabapentin systemic brosis, 969, 969,
uoroquinolones see also antiepileptic drugs 970
arthropathy, 514 alopecia, 138 gamboge
diplopia, 514 androgen deprivation see Garcinia gambogia
tendinitis, 514 therapy program, 1367 gamma-hydroxybutyric acid
tuberculosis, 6245 chemotherapy-induced (GHB)
upirtine, 249 neuropathic pain, 136 confusion, 645
urazepam, 74 chorea, 137 drug abuse, 65
urbiprofen clonazepam, 137 drug overdose, 65
xed drug eruption, 246 delirium, 138 euphoria, 645
utamide delirium tremens, 136 xed, dilated, asymmetric
hepatotoxicity, 873 diabetic neuropathy, 138 pupils, 65
hirsutism, 8734 diabetic polyneuropathy, 136 sedation and dizziness, 645
folic acid dry mouth, 136 somnolence, 645
asthma, increased risk, 693 encephalopathy, 137 garlic
dyspnea, 693 fatigue/somnolence, 137 see Allium sativum
generalized urticaria, 693 fever, 137 gembrozil
hypersusceptibility reactions, xed drug eruption, 1378 hypertriglyceridemia, 923
693 hearing loss, 137 myositis, 923
lower respiratory tract imbalance and dizziness, 137 paroxysmal atrial brillation,
infections, 693 lorazepam, 136 923
methotrexate reaction, 693 loss of appetite and seizures, 923
red pruriginous macules, 693 constipation, 1367 gemioxacin
wheezing, 693 monotherapy, 136 probenecid, interaction, 516
fondaparinux myoclonus, 137 prodromal convulsive
bleeding, 718 myoglobinuria, 138 episode, 516
death, 718 myopathy, 138 gemtuzumab ozogamicin
venous thromboembolism, nausea, 1389 bone marrow suppression,
718 nortriptyline, 136 78990
formaldehyde Parkinson's disease, 137 chills fever, and low blood
brain tumors, 480 post-herpetic neuralgia, 136 pressure, 78990
leukemia, 47980 pruritus, 136 liver problems, 78990
lymphohemopoietic psychomotor retardation, gentamicin
malignancies, 480 vertigo and sedation, Bartter-like syndrome, 511
nasopharyngeal cancer, 1389 endotoxin-like reaction, 512
47980 renal disease, 137, 138 macular infarction, 510
sinonasal cancer, 47980 rhabdomyolysis, 138 nephrotoxicity, 5112
formoterol sedation, 136 pruritic eczematous rash, 512
asthma exacerbations, 3601 seizure, 136 Staphylococcus aureus, 511
cardiac mortality, 360 syncope, 136 vestibular function, 511
fosphenytoin tremulousness and geraniol
see phenytoin dizziness, 137 allergic contact dermatitis,
fumaric acid esters urticaria, 136, 138 3367
psoriasis, 337 gadolinium salts leg ulcers, 3367
1046
Ginkgo biloba
dementia, 995
hemostasis, 995
virological failure, 995
glargine
see insulins
glibenclamide
gastrointestinal cancer, 898
macrosomia, 898
gliclazide
hypogycemia, 898
glimepiride
asthma, 898
glucagon
hepatic artery vasospasm, 889
paralysis, 889
short bowel syndrome, 889
glucocorticosteroids
see also individual names
Achilles' tendinitis, 355
acne, 841
adrenal suppression/
insufciency, 355, 843, 983
anaphylaxis, 845
Aspergillus infection, 845
asthma, 355, 842, 845
bone mineral accretion, 356
bone mineral density, 356
bowel disease, 844
cataract, 355, 842
chorioretinopathy, 9834
Cladophialophora bantiana,
845
Crohn's disease, 841
cytomegalovirus esophagitis,
845
death, 353, 354
emotional disturbances,
8423
fracture risk, 356
hypokalemia, 842
hypokalemic periodic
paralysis, 842
intraocular pressure,
increased, 983
Kienbck disease, 843
leukemia, 842
lichen planus, 843
moon face, 841
muscle weakness, 842
nephrotic syndrome, 842
oropharyngeal candidiasis,
354
osteonecrosis, 843
osteoporosis, 356, 844
paraparesis, 8412
pharyngitis, 354
psoriasis, 843
psychiatric effects, 842
retinal vein occlusion, 9834
rheumatic disease, 842
skin bruising, 354
Strongyloides stercoralis, 845
Index of drugs
throat irritation/soreness, ushing, 910
354 headache and hot ushes,
ventricular tachycardia, 841 909
viral infections, 841 infertility, 910
visual loss, 842 injection site reactions, 910
voice, weakness/hoarseness, ovarian hyperstimulation
354 syndrome, 909
glutaral (glutaraldehyde) prostate cancer, 909
abdominal pain, 480 sweating, 910
bloody diarrhea, 480 granisetron
deep ulceration, 480 see neurokinin NK1 receptor
iliac fossa, 480 antagonists
ischemic colitis, 480 granulocyte colony-stimulating
necrosis, 480 factor (G-CSF)
patchy erythema, 480 acute myocardial infarction,
rectal bleeding, rectocolitis, 769
480 non-Hodgkin's lymphoma,
glycols 769
acidosis and green tea
hyperosmolality, 1018 see Camellia sinensis
anion gap metabolic growth hormone receptor
acidosis, 1018 antagonists
benzyl alcohol and liver enzymes, increased,
propylene glycol, 10178 9112
intravenous lorazepam, pituitary gigantism, 912
1018 pituitary volume, increased,
status epilepticus, 1018 912
glycopeptides
see also individual names H
all-cause mortality, 519 HA-1A (Centoxin)
DRESS, 519 sepsis, 790
fever and rash, 519 hair dyes
neutropenia, 519 basal cell carcinoma, 336
glycoprotein IIbIIIa inhibitors halothane
see also individual names hepatitis, 257
blood pressure, 720 henna
bloody pericardial effusion, contact allergy, 336
720 contact leukoderma, 336
chest discomfort and hypertrichosis, 336
dyspnea, 720 immediate hypersensitivity
coronary intervention, reactions, 336
720 heparins
hemorrhagic pericarditis, see also individual names
720 allergy, 716
myocardial infarction, 720 anaphylaxis, 716
phlebitis, 720 angioedema, 716
thrombocytopenia, 720 arterial thrombosis, 7156
gold and gold salts bone mineral density, 715
auranocyanide anion, 451 bullous hemorrhagic
rheumatoid arthritis, 451 dermatosis, 715
gonadotropin cardiac, 714
cryptorchidism, 851 cerebral venous thrombosis,
hemiparesis, 851 714
morbidity, 851 certoparin, 715
mortality, 851 death/myocardial infarction,
ovarian hyperstimulation, 7145
severe, 851 dermis and hypodermis,
stroke, 851 715
gonadotropins (gonadorelin, enoxaparin, 7156
GnRH, and analogues) epistaxis, 7156
anaphylaxis, 909 ushing, 716
bone mineral density, 910 fracture, 715
chorea, 909 hemodialysis, 716
Index of drugs
hemorrhagic complications,
7156
hyperkalemia, 713
hypersensitivity reactions,
715, 716
hypotension, 716
immunoglobulins, 714
myocardial infarction, 714
osteoporosis, 715
pathological fractures, 7156
phospholipid antibody
syndrome, 714
plasma, 716
plasmapheresis, 715
platelet, 714
pulmonary embolism, 7145
recall urticaria, 715
renal failure, 715
serum potassium, 713
skin lesions, 714
skin necrosis, 715
spontaneous, 714
subcutaneous calcinosis, 715
systemic lupus
erythematosus, 714
thrombocytopenia, 714
thromboembolic events, 714
thrombophilia, 715
thrombotic complications, 714
wheezing, 716
hepatitis B vaccine
systemic lupus
erythematosus, 657
Herba cynomorii
see Cynomorium songaricum
heroin
see diamorphine
HIV, drugs active against
see antiretroviral drugs
HMG-CoA reductase
inhibitors
see also individual names
cancers, risk, 926
diabetes mellitus, 924
liver and muscle enzymes,
rises, 924
myalgia, 924
myopathy, 924
proteinuria, 925
renal insufciency/failure,
924, 9256
retinopathy, 924
rhabdomyolysis, 925
serum creatinine
concentration rise, 925
honey
see Rhododendron
hormonal contraceptives
acne, 858
hair loss, 858
mood swings, 8589
nervousness, 8589
thromboembolism, 858
warfarin, interactions, 859
weight gain, 8589
hormone replacement therapy
(HRT)
beneign proliferative
epithelial disorders, 855
breast cancer, 853
cognitive impairment, 854
coronary heart disease, 853
endometrial cancer, 856
gastroesophageal reux, 855
HIV infection, 857
hyperplasia, 854
ischemic colitis, 855
myocardial infarction, 856
ovarian cancer, 854
skin patches, 853
tacrolimus interaction, 857
thromboembolism, 854
5HT3 receptor antagonists
see also individual names
anesthesia, 744
drowsiness, 745
headache, dizziness, and
constipation, 744
hepatitis, 745
hiccups, 745
hypokalemia, 7445
liver enzyme and uric acid,
rises, 745
nausea, 745
QT interval prolongation,
745
rash, 745
serum aminotransferase
activities, rises, 745
vomiting, 745
human epidermal growth
factor (rhEGF)
chills and local pain, 772
sepsis, burning sensations,
and tremors, 772
StevensJohnson syndrome,
772
human immunodeciency
virus, drugs active against
see antiretroviral drugs
human keratinocyte growth
factor
erythema and lichenoid
papules, 7712 hyoscine (scopolamine)
febrile neutropenia, 7712
exural hyperpigmentation,
771
nasal congestion, 771
rashes or erythemia, 771
white coating of the oral
mucosa, 771
human papilloma virus (HPV)
vaccine
acute disseminated
encephalomyelitis, 658
anaphylaxis, 658
1047
autoimmune disorders, 658
brachial plexus neuritis, 658
death, 658
dizziness, 658
GuillainBarr syndrome,
658
headache, 658
hypersensitivity reactions, 658
local site reactions, 658
motor neuron disease, 658
nausea, 658
pancreatitis, 658
syncope, 658
transverse myelitis, 658
urticaria, 658
venous thromboembolism,
658
hydralazine and
dimethylhydralazine
cholestatic jaundice, 428
drug-induced lupus, 428
vasculitis, 428
hydrochlorothiazide
allergic reaction, 439
contact dermatitis, 439
insulin sensitivity, 439
lichenoid eruption, 438
retinal phototoxicity, 439
hydromorphone
bradycardia, 214
nausea, 214
oxygen desaturation, 214
pruritus, 214
vomiting, 214
hydroxychloroquine
see chloroquine
Hydroxycut
see Garcinia gambogia
hydroxyethylmethacrylate and
ethylmethacrylate
inammation and swelling,
335
nodules, 335
hydroxyisohexyl-3-
cyclohexene carboxaldehyde
see Lyral
hydroxyzine
QT interval prolongation,
3478
syncope, 348
butylbromide
migraine-like headaches,
75960
nausea and vomiting, 75960
Hypericum perforatum
nasteride, interactions, 995
hyperzine
arthralgia, 16
bradycardia and headache, 16
tachycardia, dry mouth, and
hypertension, 16
hypochlorous acid, 484
1048
I infectious mononucleosis,
ibalizumab
HIV infection, 790
ibuprofen
acute localized
exanthematous pustulosis,
246
esophageal perforation, 246
hyperbilirubinemia, 246
idraparinux
bleeding, 7189
subcutaneous injection,
7189
iloperidone
dizziness, 104
and haloperidol, 1034
nasal congestion, 104
orthostatic hypotension, 104
tachycardia, 104
weight gain, 104
iloprost
headache, ushing, 847
linear erythematous facial
rash, 847
nausea, diarrhea, 847
imipenem
bacterial meningitis, 492
cilastatin, 492
malignancies, 492
neutropenic fever, 492
renal function, 492
immunoglobulin
see intravenous
immunoglobulin and
subcutaneous
immunoglobulin
incretin mimetics
see also individual names
hypoglycemia, 896
nausea, 896
vomiting and diarrhea, 896
indacaterol
cough, 3612
indinavir
American ginseng,
interaction, 595
indocyanine green
retinal pigment epithelial
atrophy, 1017
indometacin, 247
indoramin
cardiotoxicity, 426
torsade de pointes, 426
inltration anesthesia
pain, 286
iniximab
bowel syndrome, 783
bronchospasm, 782
brosing alveolitis, 782
GuillianBarr syndrome,
782
Hansen's disease, 783
783
inammatory bowel disease,
783
interstitial pneumonitis, 782
leprosy, 783
LewisSumner syndrome,
782
lupes-like syndrome, 782
mucormycosis, 783
optic neuritis, 782
pityriasis lichenoides
chronica, 782
psoriasis, 782
toxic hepatitis, 782
varicella infection, 783
inuenza vaccines
see pandemic inuenza
H1N1 vaccines
insulins
allergy, 480
Alzheimer's disease, 483
brain injury, severe, 479
breast cancer, risk of, 481
erythema and blisters, 890
hypoglycemia, 479
ketoacidosis, 483
lipodystrophy, 480
myocardial infarction, 479
pre-eclampsia, 482
insulin-like growth factor
(mecasermin)
accumulation of body fat and
coarsening of the facies,
7723
hyperplasia of lymphoid
tissue, 7723
hypoglycemia, 7723
interferon alfa
cochlear damage, 774
conjunctival hyperemia and
follicular conjunctivitis,
774
depression and fatigue, 774
granulomatous
inammation, 774
Graves' disease, 775
hemolytic anemia, 773
hyperthyroidism and
hypothyroidism, 775
interstitial pneumonia, 7734
Kaposi's sarcoma, 776
linear IgA bullous
dermatosis, 776
lupus-like syndrome, 776
ocular sarcoidosis, 774
oral lichen planus, 776
sensorineural hearing loss,
774
subcutaneous sarcoid
nodules, 7756
thyroid antibodies, 775
Index of drugs
thyroid dysfunction, 7745
interferon beta
systemic sclerosis, 776
vasculitis, 776
interleukin-11 (IL-11,
oprelvekin)
fatigue, 778
hypertension, 778
hypokalemia and uid
retention, 778
pheripheral edema, 778
interleukin-12 (IL-12)
pneumococcal disease, 778
interleukin-18 (IL-18)
anemia, 779
chills fever, headache,
fatigue, and nausea, 779
cognitive disorder, 779
deep vein thrombosis, 779
fatigue and dyspnea, 779
hypoalbuminemia, 779
liver enzymes, increased, 779
neutropenia, 779
plueral effusion and
lymphopenia, 779
polyarthritis, 779
pulmonary embolism, 779
serum creatinine, increased,
779
intravenous anti-D
immunoglobulin
disseminated intravascular
coagulation, 679
extravascular hemolysis, 679
hemoglobinemia/
hemoglobinuria, 679
transfusion-related acute
lung injury (TRALI), 679
intravenous immunoglobulin
anaphylaxis, 677, 678
anemia, 677
anorexia, 678
arthralgia, 677
aseptic meningitis, 677
back pain, 677
bronchospasm, 677
chest pain, 677
chills, 677
convulsions, 677
cough, 677
cramping, 678
death, 677
diarrhea, 678
dizziness, 677
dysesthesia, 677
dyspnea, 677
dysrhythmias, 677
eczema, 678
erythema, 678
fatigue, 677, 678
fever, 677, 678
u-like symptoms, 677
Index of drugs 1049

ushing, 677 osteoporosis and nausea and vomiting, 949

headache, 677 cholelithiasis, 465 neutropenia, 949
hematuria, 678 reactivation of hepatitis B non-small-cell lung cancer,
hemolysis, 677 infection, 4712 948
hypertension, 677 thalassemia, 465 peripheral neuropathy, 9489
hyperviscosity, 677 toxicity and detoxication, prostate, renal, and
hypotension, 677 466 pancreatic cancers, 948
leukopenia, 677 iron salts rash and/or palmarplantar
malaise, 677 anaphylaxis, 451 erythema, 949
meningism, 677 kidney desease, 451 sensory neuropathy, 9489
migraine, 677 isourane thrombocytopenia, 949
myalgia, 677 generalized chorea and
myocardial infarction, 677 hallucinations, 258 J
nausea, 678 tremor and facial tremor, Jimson weed
necrotizing enterocolitis, 678 258 see Datura stramonium
non-specic eruptions, 678 isoniazid
petechiae, 678 clozapine, interaction, 636 K
phlebitis, 677 hepatotoxicity, 628, 635 ketamine
pleural effusion, 677 liver damage, 636 agitation, 2646
pompholyx, 678 Mycobacterium tuberculosis, avoidance, 263
posterior reversible 623 blood presure increased, 264
encephalopathy syndrome, neurotoxicity, 636 bradycardia, 266
677 tuberculosis, 6278 bradypnea, 266
pruritus, 678 isotretinoin breath holding, 2645
pulmonary edema, 677 central retinal vein clonic movement, 264
renal insufciency, 678 occlusion, 340 desaturation, 264
skin hemorrhage, 678 corneal steepening, 340 dizziness, 266
stroke, 677 homocysteine emergence delirium, 267
urticaria, 678 concentrations, 340 hallucinations, 264
venous thrombosis, 677 inammatory bowel disease, heart rate increased, 264
vomiting, 678 340 hyperarousal, 263
weakness, 677 liver enzymes increased, 340 hypotension, 266
intravenous regional melena, 340 hypoxia, 265
anesthesia panenteritis, 340 nervous system, 267
cardiac event, 287 serum lipids increased, 340 opioid, 263
seizures, 287 tear secretion and tear oversedation, 266
intravitreal injection quality, 340 postoperative nausea and
glaucoma, 985 itraconazole vomiting, 265
intraocular pressure, 985 anaphylactic shock, 552 post-traumatic stress
systemic adverse events, Aspergillus, 553 disorder, 263
985 congenital anomalies, 5523 psychotomimetic effects,
iodinated contrast agents dysgeusia, 553 266
see water-soluble uid retention, 553 salivation excessive, 2645
intravascular iodinated gastrointestinal intolerance, sedation, 263
contrast agents 553 shivering, 266
iodine headache, 553 tachycardia, 2656
fever, 485 hepatitis, 552 vomiting, 264
serum creatinine, increased, liver function, abnormal, ketoprofen
779 553 erythema multiforme, 246
headache, 485 maculopapular rash, 553 ketorolac
hepatitis, 485 sensorimotor acute asthma, 246
malaise, 485 polyneuropathy, 553 khat
phlebitis, 485 sleep disturbances, 553 chest pain, 66
sweating, 485 tremor, 553 headache, 66
ion-exchange resins ivermectin, 649 hypertension, 66
chronic kidney disease, 761 ixabepilone intracerebral hemorrhage,
metabolic acidosis, 761 adverse reactions, 949 66
iron chelators arthralgia/myalgia, 949 myalgia, 66
see also individual names bowel disturbances, 949 myocardial ischemia, 66
autoantibodies, 471 breast cancer, 948 nausea, 66
basal cell carcinomas, 465 constipation, 949 pulmonary edema, 66
intracellular compartment, diarrhea, 949 smoking during pregnancy,
466 mucositis or stomatitis, 949 66
1050
substance use and misuse,
65
sympathomimetic effect, 65
tachycardia, 66
violent expression, 656
vomiting, 66
ku die zi injection
allergic reactions, 991
cold limbs, 991
palpitation, 991
L binge-eating disorder, 142
labetalol
alveolar edema, 399
fever, 399
hepatic steatosis, 399
interstitial nephritis, 399
peripheral blood and urine
samples, 399
lacosamide
see also antiepileptic drugs
adjunctive therapy, 139
antidysrhythmic drugs, 139
behavioral or cognitive
effect, 1401
cardiac arrest, 140
central nervous system
adverse effects, 1401
depression, 13940
diarrhea, 140
distal diabetic neuropathy,
139
dizziness, 13940
double vision, 13940
drug-resistant focal epilepsy,
13940
fatigue, 13940
headache, 140
irritability, 13940
memory impairment, 1401
nausea, 13940
neuropathic pain, 139
painful diabetic neuropathy,
140
partial-onset seizures, 139
peripheral edema, 140
sedative effect, 139
tremor, 13940
word-nding difculties,
13940
lactulose
abdominal bloating and
distaste, 754
carpopedal spasm, 754
cirrhosis, 754
diarrhea, 754
hypocalcemia, 754
hypomagnesemia, 754
normokalemia, 754
LAM
see levacetylmethadol
lamivudine
pancreatitis, 587
pure red cell aplasia, 587
lamotrigine
see also antiepileptic drugs
affective switches, 143
alopecia and weight gain,
1434
anticonvulsant
hypersensitivity syndrome,
144
antipsychotic drugs, 142
aseptic meningitis, 143
bipolar disorder, 142
central nervous system
adverse effects, 1412
cutaneous drug reactions,
144
depression, 142
divalproex sodium, 142
DRESS, 144
drug-resistant epilepsy, 142
epilepsy, 141
facial dysmorphism, 145
facial pain, 1423
gastrointestinal adverse
effects, 1412
gingival infection, 1423
hallucinations, 143
hyperammonemic
encephalopathy, 146
hyperandrogenism or
ovulatory dysfunction,
1434
insomnia, 142
irritability, 141
levetiracetam, 142
mania, 143
monotherapy, 145
polycystic ovary syndrome,
1434
pruritus, 141
psychiatric symptoms,
1423
rashes, 141
schizophrenia or
schizoaffective disorder,
142
seizure activity, 141
Sjgren's syndrome, 144
StevensJohnson syndrome,
132
suicidal thought or tremor,
142
toxic epidermal necrolysis,
146
tremor, 141, 1434
unilateral radius aplasia, 145
urticaria, 141
valproate monotherapy, 142
vanished twin syndrome, 145
lansoprazole
acute myocardial infarction,
751
Index of drugs
acute tubulointerstitial
nephritis, 751
allergic reaction, 751
colitis, 7501
diarrhea, headache, and
abdominal pain, 7501
itching, malaise, shortness of
breath, 751
Kounis syndrome, 751
lower respiratory tract
infections, 751
nausea, 751
pallor, sweating, and
agitation, 751
rectal hemorrhage, 7501
swallowing difculty, 751
vomiting, 751
lansoprazole amoxicillin
metronidazole or
clarithromycin
abdominal pain, 749
burning sensation and
metllic taste in mouth, 749
dizziness, headache, and
rash, 749
nausea and vomiting, 749
lanthanum carbonate
abdominal pain, 451
abdominal radiography, 451
constipation, 451
diarrhea, 451
mucous membrane
inammation, 451
nausea, 451
vomiting, 451
latanoprost
chronic cough, 984
conjunctival hyperemia/
irritation, 985
difculty focusing, 985
headache, 985
iris pigmentation, 985
keratoconus progression,
985
linear erythematous facial
rash, 847
sleep disturbances, 985
latex
allergic reactions, 1018
asthma, 1018
delayed hypersensitivity
reactions, 1018
irritant dermatitis, 1018
laxatives and oral bowel
preparations
see also individual names
hypokalemia, 753
nausea, 753
serum calcium, fall in, 753
serum phosphate, rise in, 753
leunomide
cutaneous ulceration, 819
diffuse alveolar damage, 818
Index of drugs
diffuse alveolar hemorrhage,
818
interstitial lung disease, 818
interstitial pneumonitis, 818
polymyositis, 819
progressive multifocal
leukoencephalopathy, 818
rheumatoid arthritis, 818
toxic epidermal necrolysis,
8189
lenograstim
ankylosing spondylitis, 770
bone pain, 770
fatigue, 770
fever, 770
headache, 770
insomnia, 770
lung cancer, 770
nausea, 770
polyglobulia, 770
transient ischemic attack,
770
lepirudin
thrombocytopenia, 718
lercanidipine
chylous ascites, 402
letrozole
anorexia, mood
disturbances, 862
arthralgia, 862
fatigue, nausea, vomiting,
862
hot ushes, 862
musculoskeletal pain, 862
vaginal dryness, hair loss,
rashes, 862
levacetylmethadol, 214
levetiracetam
adjunctive therapy, 147
aggression, 148
aggressive behavior, 146
altered platelet function, 149
aspiration pneumonia, 150
cardiac dysrhythmias, 1467,
1501
congenital malformation,
150
depression, 148
drowsiness, 146
energy, altered, 147, 148
fatigue, 148
headache, 148
hyperactivity, 147
interstitial nephritis, 149
irritability, 147
liver failure, fulminant, 149
metabolic encephalopathy,
148
monotherapy, 146
mood instability, 147
nasopharyngitis, 148
negative behavioral effect,
148
pancytopenia, 149
pharmacokinetics, 14950
psychiatric disorder, 150
psychomotor agitation, 146
psychotropic effect, 148
reduced platelet counts, 147
renal insufciency/failure,
148, 149
restlessness, 148
seizure frequency, increased,
148
self-control, loss, 148
sleeping problem, 148
somnolence, 147, 148
thrombocytopenia, 149
tiredness, 148
vegetative symptoms, 148
vigilance, 148
visual hallucinations, 147
vomiting, 148
levodopa
hiccups, 320
Parkinson's disease, 320
levooxacin
Achilles' tendinitis, 517
Achilles' tendon rupture,
517
aminotransferase activity,
516, 517
anemia and eosinophilia, 517
benign intracranial
hypertension, 517
cutaneous vasculitis, 5178
delirium, 517
diarrhea, nausea, and
vomiting, 516, 517
gastrointestinal disorders,
516
headache, 516, 517
hypoglycemia, 517
hypokalemia, 516
leukocytosis, 516
local irritation, 516
myalgia, 517
phototoxic reaction, 517
smell sensation, altered, 637
thrombocythemia, 516
tonic-clonic seizures, 517
warfarin, interaction, 518
levonorgestrel
abdominal pain, 865
breast cancer, 865
menorrhagia, 866
menstrual disorder, 865
lian bi zhi injection
acute renal failure, 991
pneumonia, 991
lidocaine
allergic reaction, 291
bronchospasm, 388
Brugada syndrome, 2901,
388
cardiac arrest, 388
1051
chest discomfort and
profound bradycardia, 388
hallucinations, 3889
hypotension and eventual
cardiac arrest, 388
intubation and adrenaline
infusion, 388
nausea and vomiting, 3889
pain and dysalgesia, 389
reduced airway diameter,
291
somnolence and bradypnea,
388
ling yang gan mao capsule
allergic reaction, 98990
erythema, 990
ngers swollen, 990
hands itching, 990
lips itching, 990
numbness, 990
palms, pain, 990
liposomal amphotericin
(L-AmB)
Absidia corymbifera, 544
hyperkalemia, 544
nephrogenic diabetes
insipidus, 544
liraglutide
antibodies, 898
pancreatitis, 8967
renal disease, 897
thyroid tumor, 897
lisinopril
see also angiotensin
converting enzyme (ACE)
inhibitors
erythroderma, 418
lispro
see insulins
lithium
ACE inhibitors, interaction,
46
acute mania, 39
amyotrophic lateral sclerosis,
412
bipolar depression, 40
bone density, increased, 45
bone marrow neutrophil
production, 45
cardiac conduction
changes, 42
cerebral ischemia, 42
cognitive decits, 434
concentrations, 47
creatinine clearance, 47
dementia, 41
diabetes insipidus, 43, 44
Hashimoto's
encephalopathy, 43
headaches, 45
HIV infection, 42
inammatory bowel disease,
45
1052
kidney microcysts, 45
mood changes, 40, 42
mood disorders, 45
multiple sclerosis, 42
non-steroidal anti-
inammatory drugs, 46
parathyroid adenomas, 44
pseudotumor cerebri, 43
psoriasis, 45
renal dysfunction, 45
seizures, 45
syndrome of irreversible
lithium-effectuated
neurotoxicity, 43
teratogenicity, 46
thyroid carcinoma, 44
unipolar depression, 40
long-acting beta2-
adrenoceptor agonists
(LABAs)
see also individual names
asthma, 357
atrial tachycardia, 359
autism spectrum disorders,
359
bronchitis and upper
respiratory tract
infections, 359
headache, 359
hoarseness and dysphonia,
3589
lung functionand short-term
growth, 357
morbidity and mortality,
358
muscle cramps and muscle
twisting, 359
myocardial infarction, 358
oral candidiasis, 357
pneumonia, 359
psychiatric disorders, 359
salmeterol, 359
tremor frequency, 357
loop diuretics
see furosemide
loperamide
Clostridium difcile, 760
diarrhea, 760
fever, 760
lopinavir
non-fasting lipids, increased,
583
oxycodone, interaction, 595
lorazepam
Passiora incarnata,
interaction, 75
propylene glycol toxicity,
745
sexual desire, enhanced, 74
Valeriana ofcinalis,
interaction, 75
lormetazepam, 75
losartan
Index of drugs
angioedema, 419 measlesmumpsrubella
complete sinus arrest, 419 varicella (MMRV) vaccine
dysgeusia, 419 febrile convulsions, 662
hyperkalemia, 419 medroxyprogesterone
hypotension, 419 pigmented purpuric
renal impairment, 419 dermatosis, 866
sinoatrial block, third- mefenamic acid
degree, 419 bilateral transient myopia,
sinus arrest, 419 245
loxoprofen choroidal detachment,
intrahepatic cholestasis, 246 245
Lyral glaucoma, 245
contact dermatitis, 337 meoquine
anxiety, 569
M dizziness, 569
macrolide antibiotics mania, 569
see also individual names nausea, 569
breast-feeding infants, 522 Plasmodium falciparum
digoxin, interaction, 522 malaria, 569
magnesium salts psychosis, 569
abdominal hysterectomy, 452 seizures, 569
hypermagnesemia, 452 sleep disturbances, 569
kidney dysfunction, 452 megestrol acetate
muscle spasm, 452 impaired adrenal function,
maidenhair 866
see Ginkgo biloba meglitinides
manganese hypoglycemia, 897
birth weight, 4523 type 2 diabetes, 897
fetal intra uterine growth melatonin
retardation, 452 back pain, 912
lower birth weights, 452 cigarette smoking, 912
manganese concentrations, circadian rhythm sleep
4523 disorders, 912
mannitol headache, 912
asthma, 442 pharyngitis, 912
cystic brosis, 442 weakness, 912
hypocalcemia, 442 meloxicam
hyponatremia, 442 antifungal azoles,
pulmonary edema, 442 interaction, 247
maraviroc memantine
food, interaction, 600 anxiety, nausea, anorexia,
postural hypotension, 600 and arthralgia, 16
upper respiratory infections, constipation, vomiting, back
600 pain, 16
yellow fever vaccine, hallucinations, 16
interaction, 601 headache, 16
mascara inuenza-like symptoms, 16
allergic conjunctivitis, 3345 urinary incontinence, 16
blepharitis, 3345 meningococcal vaccine
contact dermatitis, 3345 injection site tenderness, 6567
corneal ulcers and meperidine
conjunctival mass, 3345 see pethidine
madarosis, 3345 mercaptopurine
pigmented conjunctival acute lymphoblastic
lesions, 3345 leukemia, 830
measlesmumpsrubella alopecia, 830
(MMR) vaccine chest pain, 830
autism/autistic spectrum Crohn's disease, 830
disorder, 661 fatigue, night sweats,
GuillainBarr syndrome, headache, 830
661 hand-foot syndrome, 830
thrombocytopenia purpura, methotrexate, interaction,
6612 830
Index of drugs
nausea and vomiting, 830
mercury and mercurial salts
attention decit disorder,
453
autism spectrum disorders,
453
blood mercury
concentration, 453
emotional disturbances, 453
tics, 453
urine mercury, 453
meropenem
bacterial meningitis, 492
clearance of autoantibody,
493
intravascular hemolysis, 493
neurotoxicity, 492
mesalazine (5-aminosalicylic
acid, mesalamine)
abdominal pain, upper
758
aplastic anemia, 758
chest pain, 757
coronary artery disease, 757
Crohn's disease, 757
diarrhea, 759
dyspnea, exertional, 757
eosinophilia, 758
exertional dyspnea, 757
fatigue, 758
fever, 757
headache, 759
hepatitis, 758
hypersensitivity
pneumonitis, 757
interstitial nephritis, 757
jaundice, 758
Kounis syndrome, 757
leukocyte count, increase,
758
myocardial infarction, 757
myocarditis, 757
nausea and vomiting, 759
nephritis, 758
pancreatitis, 759
progressive lethargy, 758
stools, blood in, 758
toxic inammatory
myopathy, 759
ulcerative colitis, 759
metamfetamine
chest pain, 3
congenital cataract, 6
intracerebroventricular
hemorrhage, 4
ischemic colitis, 45
ischemic stroke, 4
neurodevelopment
differences, 6
periventricular
leukomalacia, 4
smoking, 5
subarachnoid hemorrhage, 4
white matter maturation,
altered, 5
metamizole (dipyrone), 244
metformin
anesthesia, 484
congestive heart failure, 484
hemodialysis, 484
hemolytic anemia, 484
lactic acidosis, 483
respiratory failure, 483
methadone
antiretroviral drugs,
interaction, 216
cannabis, interaction, 216
confusion, 214
constipation, 214
drowsiness, 214
fetotoxicity, 215
HIV infection, 21516
mortality, 215
nausea, 214
necrolytic migratory
erythema, 215
nicotine, interaction, 216
pregnancy, 215
sensorineural hearing loss,
215
sweating, 214
torsade de pointes, 214
vomiting, 214
methotrexate
cytolytic hepatitis, 950
leucovorin, interactions,
951
mucositis and jaundice, 950
osteosarcoma, 950
renal damage/dysfunction,
950
renal dysfunction, 950
urinary alkalinization, 950
methoxyurane
analgesia, 258
renal toxicity, 258
methyldopa
acute hepatitis, 424
hemolytic anemia, 424
methylene blue
see methylthioninium
chloride
methylnaltrexone
abdominal pain, 227
dizziness, 227
atulence, 227
nausea, 227
methylphenidate
blood pressure and heart
rate increase, 78
cytogenetic damage, 910
enuresis, 9
uoxetine interactions, 10
Huntington's disease, 10
placebo-controlled trial, 8
psychosis, 9
1053
seizure aggravation, 9
suicide risk, 8
vasculopathy, 9
methylthioninium chloride
agitation, 1017
breast cancer, 10167
dystonia and abnormal eye
movements, 1017
intraparenchymal breast
injection, 10167
melanoma, 10167
monoamine oxidase
inhibitors, 1017
serotonin syndrome, 1017
serotonin toxicity, 1017
skin reactions, 10167
tachycardia, 1017
toxic metabolic
encephalopathy, 1017
metoclopramide
abdominal pain, 7423
agitation, 743
akathisia, 743
cardiac failure, 743
diarrhea, 7423
gastroesophageal reux, 743
gynecomastia, 743
hypertension, 743
hypotension, 7423
hypothyroidism, 743
migraine, 743
nausea, 743
QT interval prolongation,
743
respiratory depression, 742
sedation, 742
tachycardia, 743
torsade de pointes, 743
ulcer symptoms, 7423
vomiting, 7423
metoprolol
hyperadrenergic syndrome,
399
left ventricular ballooning
syndrome, 399
sleepwalking, 399
metronidazole
abdominal pain, 573
bitter taste, 573
contact dermatitis, 573
Entameba histolytica, 573
metallic taste, 573
nausea, 573
reduced appetite, 573
vomiting, 573
mexiletine
dizziness and incoordination,
389
nausea and fatigue, 389
palpitation, 389
micafungin
hepatic function tests,
abnormal, 558
1054
hepatitis, 558
immune hemolysis, 559
neonates, 559
midazolam
agitation, 75
antifungal azoles,
interaction, 76
blood pressure reduction, 75
desaturation, 75
dizziness, 75
drug overdose, 77
extrapyramidal adverse
effect, 76
herbal medicines,
interaction, 77
hiccups, 75
hyperchloremic metabolic
acidosis, 76
intranasal administration, 76
opioids, interaction, 76
protease inhibitors, 767
tidal and minute volume
reduction, 756
mifepristone
anorexia, fatigue, and mood
alterations, 867
dyspnea, 867
milrinone
atrial brillation, 3789
hypertension, 3789
mitral valve surgery, 3789
pre-operative ejection
fraction, 3789
pulmonary artery pressure,
3789
right ventricular dysfunction,
3789
minocycline
anaphylactic reaction, 500
antinuclear antibody,
positive, 499
benign intracranial
hypertension, 499
black discoloration of the
thyroid gland, 499
blue discoloration of a
palate, 500
dark discoloration, 499
diarrhea, 499
drug hypersensitivity
syndrome, 500
eosinophilic pneumonia, 499
fragile X syndrome, 499
Graves' disease, 500
hypersensitivity, 500
hyperthyroidism, 499, 500
lupus-like syndrome, 500
lymphomatoid papulosis, 500
matrix metalloproteinases
(MMPs), 499
papillary microcarcinoma,
499
skin pigmentation, 500
toxoplasmic encephalitis, 500
minoxidil
toxic epidermal necrolysis,
428
mirtazapine
see also antidepressant drugs
hyponatremia, 34
restless legs syndrome, 334
StevensJohnson syndrome,
34
misoprostol
uterine tachysystole,
increased, 8478
moclobemide
see also antidepressant drugs
carbamazepine and
valproate, interaction, 25
modanil
appetite, reduced, 11
headache, palpitation,
nausea, and dizziness, 11
psychosis exacerbation, 11
psychotic symptoms, 11
monoamine oxidase inhibitors
see moclobemide
monobactams and
monocarbams
see aztreonam
montelukast
agitation and aggression,
3667
angioedema, 367
anxiousness and dream
abnormalities, 3667
behavior and tremor, 3667
ChurgStrauss syndrome,
366
hallucinations and
depression, 3667
insomnia and irritability,
3667
pharyngitis and fever, 366
restlessness and suicidal
thinking, 3667
upper respiratory tract
infections, 366
worsening asthma, 366
Morinda citrifolia
gliobastoma, 996
phospholipidosis, 996
morphine
allergy, 216
and dexmedetomidine, 218
dizziness, 216
downbeat nystagmus, 217
and gabapentin, 218
intranasal administration,
218
itraconazole, interaction, 218
and ketamine, 218
laryngospasm, 217
and mirtazapine, 219
muscle rigidity, 217
Index of drugs
and nalbuphine, 219
and naloxone, 219
nausea, 216
and ondansetron, 219
oprelvekin, interaction, 218
postoperative nausea, 217
pruritus, 216
respiratory compromise, 217
respiratory depression, 217
reversible encephalopathy
syndrome, 217
urinary retention, 216
vomiting, 216
moxa
see Artemisia vulgaris
moxioxacin
acute generalized
exanthematous pustulosis
(AGEP), 519
aminotransferase activity, 518
Clostridium difcile-
associated disease, 518
cutaneous reactions and
allergies, 518
drug hypersensitivity
syndrome, 519
linear immunoglobulin A
bullous dermatosis, 518
tendon rupture, 518
torsade de pointes, 518
moxonidine
blood pressure, increased, 427
convulsions, 427
headache, 427
sleepiness, 427
mucolytics
epigastric pain, 369
heartburn and diarrhea, 369
nausea, 369
mugwort
see Artemisia vulgaris
mumps vaccine
LeningradZagreb strain, 662
mycophenoate mofetil
ciclosporin, interaction, 819
myrrh
gastrointestinal discomfort,
64950
N
naftidrofuryl
intermittent claudication, 408
nalmefene, 227
naloxone
cardiac arrest, 2278
cholestasis, 228
naltrexone
dry mouth, 228
gastrointestinal discomfort,
228
headache, 228
hepatotoxicity, 228
insomnia, 228
Index of drugs
nausea, 228
opioid withdrawal, 228
sertraline interaction, 228
vomiting, 228
natalizumab
anaphylactoid reactions, 791
chest pain and discomfort,
791
dyspnea and angioedema,
791
hypotension and
hypertension, 791
immune reconstitution
inammatory syndrome,
791
nervous system lymphoma,
791
progressive multifocal
leukoencephalopathy, 790
urticaria, 791
nelnavir
QT interval, 596
neomycin
allergic reaction, 513
recall dermatitis, 513
neurokinin NK1 receptor
antagonists, 748
nevirapine
toxic epidermal necrolysis,
593
niacin
carotid plaque wall area,
reduced, 928
chest pain, 928
creatine kinase activity,
increased, 929
diabetes mellitus, 929
fasting blood glucose
concentrations, 928
ushing, 928
gastrointestinal discomfort,
928
gastrointestinal symptoms,
929
hepatic transaminase
activities, increased, 929
hyperglycemia, 929
hyperuricemia, 929
nicardipine
heparin, 402
liver enzymes, raised, 402
nickel
chest pain, 453
nickel allergy, 453
pericardial effusion, 4534
skin patch testing, 453
nicorandil
ulcers of the vulva, 400
nicotine
adverse effects, 1017
bupropion, 1017
conotruncal heart defects,
1018
effects of smoking and
drinking, 1018
monoamine oxidase activity,
1017
neural tube defects, 1018
replacement therapy, 1017
result of adverse reaction,
1017
single nucleotide
polymorphisms (SNPs),
1018
smoking, 1017
smoking and alcohol
consumption, 1018
squamous cell carcinoma,
1018
suicide, 1017
nifedipine
acute graft-versus-host
disease, 402
antihypertensive therapy,
402
blood loss and septicemia,
402
blood pressure, 402
nilutamide
bilateral blindness, 874
fulminant hepatic failure, 874
prostate cancer, 874
nimesulide
xed drug eruptions, 249
liver failure, 249
premature closure, ductus
arteriosus, 249
nimodipine
hemiplegic migraine, 403
nitrates, organic
dizziness and skin irritation,
401
headache, 400, 401
neurological symptoms,
4001
vasodilatation, 400
nitric oxide
hypertension, arterial, 260
nitrofurantoin
acute toxic hepatitis, 525
bronchiolitis obliterans,
5245
granulomatous interstitial
nephritis, 525
hypersensitivity reactions,
525
nitrous oxide
agitation, 2601
gastrointestinal, 262
genotoxicity, 262
headache, 261
hypoxia, 261
megaloblastic anemia, 2612
myelopathy, 2612
nausea, 2601
nervous system, 261
1055
orthopedic, 260
postoperative nausea, 262
vomiting, 2601
non-animal stabilized
hyaluronic acid (NASHA)
granulomas and sarcoidosis,
335
hypersensitivity reactions,
335
vasculitis, 335
non-nucleoside reverse
transcriptase inhibitors
(NNRTI)
hepatotoxicity, 590
rashes, 590
O
octreotide
abdominal cramps, 914
Beau's lines/onychomadesis,
914
gallbladder abnormalities,
914
melena, 914
nocturnal bowel movement,
914
thrombocytopenia, 914
variceal bleeding, 914
ocular anesthesia
brain damage, 2878
central retinal artery
occlusion, 287
olanzapine
bradycardia, 104
breast cancer, risk, 1019
and clozapine, 1045
direct bilirubin increase, 106
and droperidol, 105
drowsiness and sedation,
104
drug withdrawal, 1078
dry mouth, 104
fasting LDL cholesterol
increase, 106
fasting total cholesterol
increase, 106
hepatic enzyme increase, 106
hypertension, 104
hypotension, 104
increased appetite and
weight gain, 106
increased prolactin, 104
and lithium, 105
orthostatic hypertension,
104
prolactin increase, 106
pulmonary
thromboembolism, 107
and quetiapine, 105
and risperidone, 106
schizophrenia, 107
sedation, 104
weight gain, 104
1056
oleic acid
blood pressure reduced,
1020
brain and adrenal glands,
1020
short bowel syndrome,
10201
olmesartan
dizziness, 419
omalizumab
allergic reaction, 791
anaphylaxis and
anaphylactic shock, 791
injection-site reactions, 791
omeprazole and esomeprazole
acute tubulointerstitial
nephritis, 751
allergic reaction, 752
anaphylactic reactions, 752
chronic hypokalemia, 751
generalized urticaria,
bronchospasm and
dizziness, 752
hypocalcemia, 751
hypomagnesemia, 751
itching of the palms and
facial angioedema, 752
microscopic colitis, 751
vomiting and diarrhea, 752
ondansetron
anaphylactic reactions,746
anesthesia, 746
bradycardia, 745
cardiac dysrhythmias, 746
consciousness, loss of, 746
coronary artery disease,
746
diabetic ketoacidosis, 746
headache, 746
hepatotoxicity, 7467
nausea and vomiting, 746
QT interval prolongation,
7467
seizures, 746
serotonin syndrome, 7467
serum aminotransferases,
rises in, 746
opioid analgesics
age factor, 208
cognitive impairment, 206
critically ill patients, 208
drug abuse, 207
narcotic bowel syndrome,
206
neonatal abstinence
syndrome, 207
obstructive, central, and
combined sleep apnea, 205
reduced cortisol
concentrations, 206
respiratory depression, 205
sexual dysfunction, 206
sexual excitation, 206
Index of drugs
opioid receptor agonists and pregabalin, 221
see also individual names pruritus, 220
opioid receptor antagonists QT interval prolongation,
see also individual names 220
oseltamivir rifampicin, interactions, 220
abnormal activity, 601 somnolence, 220
delirium, 601 vomiting, 220
hallucinations, 601 voriconazole, interactions,
nausea, 601 220
probenecid, interaction, 602 oxymorphone, 221
oxazolidinones oxytocin and analogues
see also individual names anesthesia, 913
acute interstitial nephritis, 526 hyponatremia, 913
anemia, 525, 526 mean arterial pressure fall,
auditory nerve neuropathy, 913
526 nausea, 913
creatine kinase activity, 527 stillbirth, 9123
DRESS, 526 vaginal bleeding, 913
encephalopathy, 525
hyperbilirubinemia, 526 P
lactic acidosis, 526 PA-824
linezolid, interaction, 527 Mycobacterium tuberculosis,
nephrotoxicity, 525 6367
optic disc hyperemia, 526 serum creatinine, increased,
optic neuropathy, 525 637
peripheral neuropathy, paclitaxel
5256 see also albumin-bound
petechiae and purpura, 526 paclitaxel and
reversible hypertension, 527 docosahexaenoic acid
seizures, 526 paclitaxel
serotonin syndrome, 527 abnormal microtubular
thrombocytopenia, 526 bundles, 936
oxcarbazepine anemia, 939
adjunctive therapy, 132 arthralgia and/or myalgia,
bipolar disorder, 152 941
dizziness, nausea, and atrial brillation, 938
vomiting, 151 bone-marrow suppression,
fatigue and drowsiness, 151 939
gammaglutamyl transferase bradycardia, 9412
activity, raised, 151 bronchospasm, 9412
headache, 151 cardiac ischemia, 938
hyponatremia, 132 cardiac rhythm, 9378
leukopenia, 1523 cardiac toxicity, increased,
nausea, 151 943
neuroleptic malignant convulsions, 939
syndrome, 152 cutaneous ushing, 9412
parkinsonism, 152 diabetes mellitus and alcohol
radius aplasia, 153 abuse, 939
rashes, 151 dizziness, 939
sedation, 151 dysrhythmias, 938
serum concentrations, 153 gynecological malignancies,
StevensJohnson syndrome, 942
153 hair loss, 941
oxicams headaches, 939
see meloxicam and head and neck cancers, 936
piroxicam, 247 hemopoietic stem cell
oxycodone damage, 939
constipation, 220 hepatic metabolism, 937
delusions, 220 hypersensitivity, 937
dizziness, 220 hypertension, 938
headache, 220 hypotension, 938, 9412
and naloxone, 220 interstitial pneumonia, 938
nausea, 220 leukemia, 936, 940
Index of drugs
liver dysfunction, 937
mucositis and stomatitis, 940
myocardial infarction, 938
neutropenia, 93940
numbness, burning, 939
onycholysis, 941
ototoxicity, 939
ovarian cancer, 9356, 940
peak plasma concentrations,
936
peripheral neuropathy, 9379
pharmacokinetic
interactions, 943
pneumonitis, 938
progressive disease, 938
radiation dermatitis, 941
renal function, 937
renal insufciency, 941
severe nausea, vomiting, and
diarrhea, 940
supraventricular tachycardia,
938
thrombocytopenia, 939
transient mitotic arrest, 941
urticaria, 9412
ventricular dysrhythmias, 938
visual disturbances, 939
paliperidone
atrial brillation, 109
carbamazepine, interaction,
109
palonosetron
breast cancer, 747
diarrhea, dyspepsia,
abdominal pain, 747
dizziness, somnolence, 747
drowsiness, 747
dry mouth and atulence, 747
headache and constipation,
747
insomnia, hypersomnia, and
paresthesia, 747
nausea and vomiting, 747
QT interval prolongation,
747
seizure, 747
supraventricular extra beats,
747
tachycardia, sinus
dysrhythmia, 747
Panax ginseng
anaphylactic shock, 996
limb weakness, chills, cold
sweats, and shortness of
breath, 996
Panax quinquefolius
indinavir, interactions, 996
pancreatic enzymes
abdominal pain, 761
constipation and vomiting,
761
diaper dermatitis/nappy
rash, 761
pandemic inuenza H1N1
vaccines
anaphylaxis, 659
angioedema, 659
anticoagulants, interactions,
660
autoimmune disorders, 659
fever, 660
GuillainBarr syndrome,
659
immunodeciency, 659
inuenza, 659
seizures, 660
solid organ transplants, 659
stroke, 660
urticaria, 659
vasculitis, 660
pantoprazole
abdominal pain and chest
pain, 752
belching, headache, nausea,
and rash, 752
diarrhea, dizziness, and
dyspepsia, 752
pneumonia, 752
thrombocytopenia, 752
upper respiratory tract
infection, 752
papaverine 221
paracetamol (acetaminophen)
anaphylaxis and
angioedema, 245
asthma, 2445
vulval xed drug eruption, 245
parathyroid hormone
arterial vasodilatation, 913
hypercalcemia, 913
hypercalciuria, 913
nausea, vomiting, and
dizziness, 913
parenteral nutrition
adult respiratory distress
syndrome (ARDS), 697
aluminium toxicity, 698
blood glucose
concentrations, 6978
bloodstream infections, 700
bone mineral content, 698
Candida spp, 700
cholestasis, 699
colorectal cancer, 700
death, 699
enterococcus, 700
epilepsy, 698
Fusarium oxysporum, 700
gastric carcinoma, 697
hepatic damage, 698
hepatic dysfunction, 6989
hyperglycemia, 6978
hypertriglyceridemia, 697
hypophosphatemia, 698
inammatory bowel
disease, 699
1057
intestinal failure, 698
intravenous insulin therapy,
6978
ischemic liver damage, 698
Klebsiella pneumoniae, 700
liver disease, 698
malignant lymphoma, 698
muscle cramps, 699
neonatal aluminium, 698
nosocomial infections, 700
phenylketonuria, 698
pleural effusion, 697
Pseudomonas aeruginosa,
700
pulmonary embolism, 695
serum creatinine, 698
short-bowel syndrome, 699
skin ulcer, 700
Staphylococcus aureus, 700
Staphylococcus
haemolyticus, 700
triglycerides, increased, 697
ursodeoxycholic acid, 699
paromomycin
alanine aminotransferase
activity, 513
injection site pain, 513
paroxetine
see also antidepressant drugs
ecainide, interactions, 30
personality measures, 30
partial opioid receptor agonists
see buprenorphine and
butorphanol
patupilone
diarrhea, 949
fatigue and nausea, 949
non-small-cell lung cancer,
949
ovarian cancer, 949
peripheral neuropathy, 949
renal cell cancer, 949
pegaptanib
cardiorespiratory arrest,
9778
Clostridium colitis, 9778
diabetic macular edema, 978
endophthalmitis, 9778
epiretinal membrane, 978
hypotension, 9778
iritis, 978
macular hole, 978
metastatic lung cancer,
9778
retinal and vitreous
hemorrhage, 9778
rhegmatogenous retinal
detachment, 9778
subconjunctival
hemorrhages, 978
peglgrastim
anemia, thrombocytopenia,
or chronic urticaria, 770
1058
bone pain, 770
respiratory distress, 770
penicillamine
arthralgia, 472
bullous pemphigoid, 473
elastosis perforans
serpiginosa, 472
generalized amino-aciduria,
472
goitrous hypothyroidism,
4723
hypersensitivity
pneumonitis, 472
intralobular and interlobular
septa, 472
lip elastosis, 473
neurological symptoms, 472
thyroglobulin and
thyroperoxidase, 473
Wilson's disease, 472
penicillins
see also individual names
acute inammatory
response, 495
cerebral inammation, 495
JarischHerxheimer
reaction, 495
neurosyphilis, 496
tachycardia, fever, chills,
arthralgia, and headache,
495
tertiary syphilis, 495
pentachlorophenol
hemopoietic tumors, 486
neuropsychological health
effects, 4856
non-Hodgkin's lymphoma,
486
soft tissue sarcoma, 486
pentazocine, 221
peruorocarbons
chest discomfort, 972
chest pain, 972
ushing, 972
headache, 972
hypotension, 972
left ventricular opacication,
9712
myocardial infarction, 9712
nausea, 972
peroxisome proliferator-
activated dual receptor
agonists
congestive heart failure, 902
edema, 902
hemodilution, 902
weight gain, 902
pertussis vaccine
encephalopathy, 657
fever, 657
injection site reactions, 657
sudden infant death
syndrome, 657
pethidine (meperidine), 221
phenazopyridine
sulfhemoglobinemia and
methemoglobinemia,
24950
phenobarbital and primidone
see also antiepileptic drugs
acute intermittent prophyria,
154
acute severe axonal motor
neuropathy, 154
alopecia areata universalis,
154
anticonvulsant
hypersensitivity syndrome,
154
dizziness, 154
drowsiness, 154
epilepsy, 154
erythema multiforme, 154
gastrointestinal complaints,
154
Ledderhose syndrome, 154
plantar bromatosis, 154
seizures, 1545
severe cerebrovascular
disease, 154
StevensJohnson syndrome,
154
SturgeWeber syndrome,
154
toxic epidermal necrolysis,
154
phentermine
ventricular tachycardia/
brillation, 13
phenylbutazone
DRESS, 2478
serum testosterone rise, 248
Sweet's syndrome with
sialadenitis, 248
phenylephrine
blood pressure increased,
31819
phenytoin and fosphenytoin
see also antiepileptic drugs
acute nervous system
toxicity, 1567
agranulocytosis, 156
antiepileptic drug
hypersensitivity syndrome,
156
cardiac dysrhythmias, 155
clozapine, 157
DRESS, 156
brillary glomerulonephritis,
156
granulomatous interstitial
nephritis, 156
high-ux hemodialysis, 157
hyponatremia, 155
hypothyroidism, 155
intestinal obstruction, 157
Index of drugs
junctional bradycardia, 155
motor neuron disease, 155
myopericarditis, 155
osteopenia, 156
osteoporosis, 156
pneumonitis, 155
skin necrosis, 156
urolithiasis, 156
vertigo, 155
pholcodine, 222
phosphates
abdominal bloating, 755
acute phosphate
nephropathy, 755
celiac disease, 755
chronic constipation, 755
Chvostek's sign, 755
Costello syndrome, 755
dry mouth, 755
gingival hyperplasia, 755
hyperphosphatemia, 755
hypertrophic
cardiomyopathy, 755
hypocalcemia, 755
low blood pressure, 755
nausea and cramps, 755
renal insuffciency, 7556
tachycardia, 755
phosphodiesterase type V
inhibitors
ambrisentan, interaction,
421
ushing and nasal
congestion, 409
headache, 409
intracerebral hemorrhage,
40910
respiratory distress, 410
retinal artery occlusion, 410
thrombocytopenia, 410
pimecrolimus
atopic dermatitis, 819
burning-tingling sensation,
819
eczema, 819
erythema and pruritus, 819
lymphoma, 819
pimecrolimus and tacrolimus
burning, 3378
feeling of warmth, 3378
ushing, 338
itching-burning sensation,
338
pain, 3378
smarting, 3378
soreness and rosaceiform
dermatitis, 3378
pioglitazone
bladder neoplasm, 901
edema, 900
heart failure, 900
hyperglycemia, 900
liver disorder, 900
Index of drugs
malaise and lassitude, 900
myocardial infarction, 900
nausea and vomiting, 900
weight gain, 900
piperacillin tazobactam
acute generalized
exanthematous pustulosis
(AGEP), 497
cystic brosis, 497
hemolytic anemia, 497
hypokalemia, 497
non-thrombocytopenic
petechial rash, 497
psychiatric effect, 497
thrombocytopenia, 497
piritramide
respiratory depression, 222
piroxicam
xed drug eruption, 247
plasma
transfusion-related acute
lung injury (TRALI), 675
polystyrene sulfonates
colonic necrosis, 474
ileal perforation, 474
intestinal injury, 4745
ischemic colitis, 474
polyvinyl alcohol
allergic reaction, 1021
ketoprofen, 1021
pelvic pain, 1021
uterine artery, 1021
polyvinylpyrrolidone
(povidone) and povidone
iodine
altered metabolism of
thyroid hormones, 485
hypothyroidism, 485
systemic reactions, 485
posaconazole
abdominal pain, 553
dizziness, 5534
dry mouth, 5534
headache, 5534
hepatotoxicity, 554
nausea, 553
serum creatinine increased,
553
vomiting, 553
postsynaptic a-adrenoceptor
antagonists
chest pain, 426
dizziness, 425
ejaculatory disorders, 427
ejaculatory dysfunction, 425
endophthalmitis, 426
fractures, 425
intraoperative oppy iris
syndrome (IFIS), 425
pre-syncope, 425
priapism, 4267
retinal detachment, 426
retrograde ejaculation, 426
syncope, 425
pramlintide
age, effect of, 483
pranlukast
diarrhea, 367
somnolence, 367
thirst, 367
pravastatin
colitis, 927
erythematous pigmented
rash, 927
praziquantel
abdominal discomfort, 650
allergy, 650
headache, 650
nausea, 650
Schistosoma hematobium,
650
Schistosoma japonicum, 650
stomach discomfort, 650
vomiting, 650
prazosin
chest pain, 426
pregabalin
see also antiepileptic drugs
ataxia, 158
balance worsened, 1578
blurred vision, 158
controlled-release
oxycodone monotherapy,
158
delirium and delusions, 159
diabetic polyneuropathy, 158
dizziness, 158
double vision, 158
dysautonomic crisis, 1578
fatigue, 159
u-like symptoms, 1589 propitocaine
headaches, 158
hemodialysis, 160
hyponatremia, 15960
inadequately controlled
epilepsy, 160
LennoxGastaut syndrome,
160
lethargy, 158
myoclonus, 159
nausea, 1578
neuropathic pain, 159
parkinsonium, 159
peripheral edema, 1578
postherpetic neuralgia, 158
postural instability, 1589
runamide, 160
seizures, 160
somnolence, 158
tiredness, 158
unsteadiness, 158
weight gain, 1578
prilocaine and EMLA
allergic reaction, 292
erythema and swelling, 292
methemoglobinemia, 291
1059
primaquine
see tafenoquine
primidone
see phenobarbital
pristinamycin
leukocytoclastic vasculitis,
528
procainamide
ventricular tachycardia and
brillation, 389
progestogens
allergic reaction, 865
eosinophilic pneumonia, 865
sideroblastic anemia, 865
proguanil hydrochloride and
atovaquone
bullous erythema
multiforme, 569
promethazine
anticholinergic symptoms
and signs, 349
digital necrosis, 348
erythematous, 348
ischemia and tissue necrosis,
348
left antecubital fossa, 348
neuroleptic malignant
syndrome, 349
QT interval prolongation, 348
small vessel muscular
arteries, 348
swelling and discoloration,
348
thumb and little nger, 348
propafenone
atrial tachycardia, 38990
lupus-like syndrome, 390
xed drug eruption, 293
propofol
allergic complication, 271
anaphylaxis, 275
cardiac arrest, 2701
desaturation, 270
diabetes insipidus, 274
green urine, 275
hypotension, 271
hypoxia, 270
metabolic acidosis, 274
nervous system, 273
pancreatitis, 2745
propofol infusion syndrome,
272
rhabdomyolysis, 272
secretion, 2701
prostaglandin analogues
anterior uveitis, 984
conjunctival hyperemia, 984
cystoid macular edema, 984
elongation, 984
eyelashes darkening, 984
herpes simplex keratitis,
reactivation, 984
1060 Index of drugs

iris cysts, 984 fever, 318 hyperthyroidism and thyroid

iris darkening, 984
periocular skin
pigmentation, 984
protamine
acute pulmonary
hypertension, 727
adrenaline, 727
anaphylactic reactions, 727
atrial brillation, 727
blood pressure, 727
cardiac surgery, 727
chronic smoker, 727
coronary artery bypass graft,
727
hypercholesterolemia, 727
hypotension, 727
methylthioninium chloride,
727
pulmonary vasoconstriction,
727
vasopressin, 727
protease inhibitors
see also individual names
CYP3A4, interactions, 629
efavirenz, interaction, 629
gastrointestinal intolerance,
628
liver enzymes, raised, 628
nevirapine, interaction, 629
P glycoprotein, interactions,
629
rifampicin, interaction, 6289
prothrombin complex
concentrate
deep venous thrombosis, 680
disseminated intravascular
coagulation, 680
myocardial infarction, 680
pulmonary embolism, 680
stroke, 680
proton pump inhibitors
see also individual names
abdominal pain, 749
defecation disorders, 749
atulence and anorexia,
74950
gastrointestinal motility, 749
myalgia, chest pain, 74950
nausea, anxiety, diarrhea,
749
pharyngolaryngeal pain, 749
respiratory infection, 750
sinusitis and headache, 749
prucalopride
dysrhythmias, 744
headache, abdominal pain,
743
nausea and diarrhea, 743
QT interval prolongation,
744
pseudoephedrine
facial edema, 318
malaise, 318
myocardial infarction, 318
nausea and headache, 318
psilocybin
abdominal pain, 66
altered mental status, 66
diarrhea, 66
nausea, 66
vomiting, 66
PUVA
basal cell carcinoma, 339
pyrazinamide
olfactory disorders, 637
pyrazolone derivatives
see phenylbutazone
pyrimethamine and congeners
abdominal pain, 570
dizziness, 570
fever, 570
headache, 570
nausea, 570
vomiting, 570
Q age-related macular
quetiapine
dizziness, 110
drug abuse, 111
dry mouth, 110
dyskinesias, 110
increased appetite, 110
and lithium, 11011
nausea, 110
orthostatic hypotension,
110
and risperidone, 111
sedation, 110
somnolence, 110
and valproate, 111
weight gain, 110
quinidine and derivatives
atrioventricular block, 3901
hypotension, 3901
nausea, 3901
supraventricular and
ventricular extra beats,
3901
quinine and congeners
xed drug eruptions, 571
immune thrombocytopenia,
570
thrombotic microangiopathy,
5701
ventricular brillation, 570
R rasburicase
rabies vaccine
fever, 662
headache, 662
injection site pain, 662
swelling with induration, 662
radioactive iodine
Graves' disease, 883
cancer, 883
radiaion-induced thyroiditis,
883
raloxifene
renal disease, 862
raltegravir
aminotransferase activities,
increased, 599
constipation, 599
depression, 599
etravirine, interaction, 600
atulence, 599
insomnia, 599
nausea, 599
rhabdomyolysis, 599
rifampicin, interaction, 600
tipranavir and ritonavir,
interaction, 600
ramelteon, 82
ramosetron
uvoxamine, interaction,
748
ranibizumab
degeneration, 9789
cataract, 9789
conjunctival hemorrhages,
980
endophthalmitis, 97880
oaters, 980
intraocular pressure,
transient increases, 97980
macular edema, 978
mild pain, 980
non-ocular hemorrhages, 978
ocular inammation, 9789
retinal pigment epithelial
tear, 978
rhegmatogenous retinal
detachment, 97980
stroke, 980
vitreous hemorrhage, 97980
ranitidine
anaphylactic reaction, 748
anaphylactic shock, 748
anesthesia, 748
clopidogrel and prasugrel,
interaction, 748
consciousness, loss of, 748
edema, 748
wheezing, dyspnea, and
hypotension, 748
rapamycin
see sirolimus
hemolysis and
methemoglobinemia, 250
remifentanil
bradycardia, 222
cough, 2223
drug tolerance, 223
drug withdrawal, 223
Index of drugs
hypotension, 222
intensive care, 223
mean arterial pressure,
reduced, 222
morphine interaction, 223
muscle rigidity, 223
respiratory depression, 222
repaglinide
gembrozil, interaction, 898
hypoglycemia, 897
octreotide, 898
Rhododendron spp.
BezoldJarisch reex, 996
bowel disorders, 997
bradycardia, 996
dizziness, 997
erectile dysfunction, 997
hypertension, 997
hypotension, 997
myocardial infarction, 997
nausea, 997
nodal rhythm, 997
sinus rhythm, 997
stomach pains, 997
sweating, 997
syncope, 997
systolic blood pressure, 997
vomiting, 997
weakness, 997
ribavirin
anemia, 580
azathioprine, interaction,
5812
cognitive dysfunction, 580
enterocolitis, 581
hyperpigmentation of oral
mucosa and tongue,
5801
lichenoid eruption, 581
neutropenia, 580
oral lichen planus, 581
parkinsonism, 580
pure red cell aplasia, 580
sensorineural hearing loss,
580
spermatogenesis, abnormal,
581
thrombocytopenia, 580
thyroid dysfunction, 580
rifabutin
acute generalized
exanthematous pustulosis
(AGEP), 6378
lopinavir ritonavir
interaction, 638
rifampicin
atazanavir ritonavir,
interaction, 639
atorvastatin, interaction,
639
hemolytic anemia, 639
hepatotoxicity, 638
intravascular hemolysis, 638
lopinavir ritonavir,
interaction, 639
oxycodone, interaction,
63940
protease inhibitors,
interaction, 640
ritonavir saquinavir,
interaction, 640
roumilast, interaction,
640
tuberculosis, 6238
rifaximin
IgE-mediated reactions, 640
rimonabant
atrial brillation, 14
ciclosporin, interaction, 14
depressive episode, 13
partial seizures, 14
risperidone
akathisia, 112
amenorrhea, 113
anxiety, 113
depression, 113
and divalproex, 112
dysmenorrhea, 1112
fatigue, 111
galactorrhea, 113
gynecomastia, 1113
and haloperidol, 112
headache, 113
impaired sensorimotor
function, 113
increased appetite, 111
increased prolactin
concentrations, 111
insomnia, 112, 113
menorrhagia, 113
prolactin-related adverse
events, 113
psychiatric aggravation,
1112
somnolence, 111
tardive dyskinesia, 113
tremor, 112
weight gain, 1112
weight increase, 113
ritodrine
muscle pain, 3234
rhabdomyolysis, 3234
ritonavir
adrenal suppression, 596
albendazole, interaction, 596
cat's claw, interaction, 596
mebendazole, interaction,
596
quinine, interaction, 596
rituximab
chronic graft-versus-host
disease, 791
ciclosporin-dependent
nephrotic syndrome, 791
common variable
immunodeciency, 792
1061
ushing, angioedema,
bronchospasm, 792
gastrointestinal perforation,
792
Graves' disease, 791
hyperammonemic
encephalopathy, 792
interstitial lung disease,
dyspnea, and pneumonitis,
792
progressive multifocal
leukoencephalopathy, 792
refractory myasthenia gravis,
791
Sjgren's syndrome, 791
tumor lysis syndrome, 792
vasculitic disorders, 791
vomiting, nausea, urticaria,
fatigue, 792
rivastigmine
erythema, 1617
fasciculation, 17
hepatotoxicity, 17
nausea and vomiting, 1617
pruritus, 1617
rocuronium
benet to harm balance, 301
rofecoxib
death, 247
edema, 247
embolism, 247
hemorrhage, 247
thrombosis, 247
roumilast
blood glucose and
glycosylated hemoglobin,
3689
headaches, 368
nausea and diarrhea, 368
weight loss, 368
ropivacaine
seizures, 293
tonic-clonic seizures, 293
rosiglitazone
brates, interaction, 9012
heart failure, 901
mortality, 901
myocardial infarction, 901
renal disease, 901
rosuvastatin
drug interactions, 928
enzyme induction, 928
rotavirus vaccine
intussusception, 6623
roxithromycin
abdominal pain, 524
dry mouth, 524
headache, 524
nausea, 524
rupatadine
cardiac rhythm disturbances,
349
cold symptoms, 349
1062
diabetes and dyslipidemia,
349
intermittent claudication, 349
kidney and liver impairment,
349
QT interval prolongation, 349
S impaired orgasm, 27
sagopilone
central ataxia, 949
diarrhea, 949
neuropathy, 949
neutropenia, 949
Saint John's wort
see Hypericum perforatum
salicylates
see acetylsalicylic acid
salmeterol
asthma mortality, 362
asthma treatment, 363
brain-derived neurotrophic
factor (BDNF), 362
sapropterin
see tetrahydrobiopterin
saquinavir
cat's claw, interaction, 597
sargramostim
acute myelogenous
leukemia, 771
back and bone pain, 771
Crohn's disease, 771
injection site reactions, 771
pyrexia, 771
saxagliptin
congestive heart failure, 895
edema, 895
renal or liver disease, 895
sclerosants
deep vein thrombosis,
10212
duplex ultrasonography,
1021
migraine, 10212
pelvic colicky pain, 1021
pelvic congestion syndrome,
1021
pelvic pain, 1021
post-thrombotic syndrome,
1021
pulmonary embolism,
10212
saphenous veins, 1022
septicemia, 10212
transient ischemic stroke,
10212
transthoracic
echocardiography, 1021
varicose tributaries, 1022
visual disturbances, 10212
scopolamine
see hyoscine
selective serotonin re-uptake
inhibitors (SSRIs)
see also individual names
and antidepressant drugs
carotidynia, 26
emergent suicidal ideation,
267
erectile difculties, 27
genetic predictor, 29
paroxetine, 30
photosensitivity, 27
in pregnancy, 279
reduced libido, 27
sertraline, 30
selenium
dental caries, 454
dizziness, 454
fatigue and amenorrhea, 454
fatigue and malaise, 454
glutathione peroxidase
(GPX), 454
hair loss, 454
nails, 454
superoxide dismutase
(SOD), 454
total body formula, 454
senna
abdominal pain, 7545
dizziness and headache,
7545
nausea and vomiting, 7545
serotonin and noradrenaline
re-uptake inhibitors (SNRIs)
see also antidepressant
drugs, duloxetine,
venlafaxine, and
desvenlafaxine
mania and hypomania, 301
sertindole, 114
sertraline, 30
sevourane
cardiac rhythm, 260
delirium, 25960
emergence delirium, 2589
malignant hyperthermia, 260
shen ling bai zhu san
erythema multiforme, 990
eyes swollen, 990
skin lesion, 990
shu xue ning injection
anaphylactic shock, 991
bronchospasm, 991
chest distension, 991
macular rashes, 991
nausea, 991
palpitation, 991
urticaria, 991
sibutramine
myocardial infarction, 13
obesity, 13
silicone
penile augmentation, 1022
silver salts and derivatives
sensation in limbs, 454
Index of drugs
simvastatin
acute renal insufciency, 928
bilateral leg compartment
syndrome, 928
CYP3A4 inhibition, 928
dermatomyositis, 928
muscle pain, soreness,
fatigue, or weakness, 928
myonecrosis, 928
rhabdomyolysis, 928
sirolimus (rapamycin)
bronchiolitis obliterans, 820
diabetes mellitus, 820
fever, 821
gonadal dysfunction, 8201
growth retardation, 820
infertility, 8201
interstitial pneumonitis, 820
lymphedema, 820
mouth ulser, 820
ovarian cysts, 821
proteinuria, 820
sperm count, reduced, 820
sitagliptin
anaphylaxis, 895
angioedema, 895
sitaxsentan
acenocoumarol, interaction,
423
aminotransferases, raised, 423
cough, 423
dyspnea, 423
hepatitis, 423
nasopharyngitis, 423
peripheral edema, 423
skin branding
cavernous sinus thrombosis,
10001
multiple splenic abscesses,
10001
septic shock, 10001
smallpox vaccine
myopericarditis, 663
sodium hypochlorite
allergic disease, 4845
lower respiratory tract
symptoms, 4845
pulmonary function, 484
sodium metabisulte
asthma, 1022
occupational airways
disease, 1022
vocal cord dysfunction and
underlying asthma, 1022
sodium picosulfate
hyponatremia, 756
somatostatin (growth hormone
release-inhibiting hormone)
and analogues
bradycardia, 9134
carcinoid syndrome, 914
conduction abnormalities,
9134
Index of drugs
fasting plasma glucose,
increased, 914
gallstones, 9134
parkinson-like symptoms, 914
somatropin (human growth
hormone, hGH)
abdominal pain, 911
blood pressure, increased,
910
de Quervain's tenosynovitis,
911
epiphysiolysis, 911
Hurler's syndrome, 911
impaired glucose tolerance,
911
inhaled growth hormone, 911
left ventricular mass,
increased, 910
myocardial infarction, 9101
pancreatitis, 911
sotalol
torsade de pointes, 399
spa therapy, 1001
spinal (intrathecal) anesthesia
apnea, 2845
cardiac arrest, 286
chemical meningitis, 286
heart rate, 284
hypotension, 284
microradiculopathy, 285
propriospinal myoclonus,
2856
spinal myoclonus, 285
subdural hematoma, 286
transient neurological
symptoms, 285
spironolactone
gynecomastia, 4402
hyperkalemia, 4402
polycystic ovary syndrome,
442
renal function, 4402
squirting cucumber
see Ecbalium elaterium
stavudine
distal sensory
polyneuropathy, 5878
hyperlactatemia, 583
mitochondrial dysfunction,
583
proximal renal tubular
dysfunction, 588
weight gain, 583
stem cells
abdominal cramping, 683
agitation, 683
chest pain, 683
chills, 683
cough, 683
dyspnea, 683
fever, 683
graft-versus-host disease
(GvHD), 683
1063
hiccups, 683 sulfadiazine
hypertension, 683 hemolytic anemia, 528
hypotension, 683 methemoglobinemia, 528
hypoxia, 683 urolithiasis, 528
myocardial damage, 683 sulfasalazine
nausea, 683 DRESS, 759
sore throat, 683 hypersensitivity syndrome,
stent restenosis, 682 759
tachycardia, 683 juvenile rheumatoid
vomiting, 683 arthritis, 759
stiripentol sultes
see also antiepileptic drugs amyotrophic lateral sclerosis,
adjunctive therapy, 160 1023
appetite, 1601 cysteine, 1023
ataxia, 1601 glutathione metabolism,
Dravet's syndrome, 160 1023
hyperactivity or irritability, urine sulte, 1023
1601 sulfonylureas
severe myoclonic epilepsy, gastrointestinal cancer, 898
160 sulfur hexauoride
sleep disturbance, 1601 hypotension, 972
street drugs sinus bradycardia, 972
adulteration, 53 tonic-clonic seizures, 972
clenbuterol, 53 sulprostone
contamination, 53 pulmonary edema, 848
dilution, 53 superparamagnetic iron oxide
substitution, 53 (SPIO)
streptomycin abdominal cramps, 971
tuberculosis, 623, 6278 diarrhea, 971
strontium salts headache, 971
alopecia, 455 low back pain, 971
DRESS, 455 pruritus, 971
gastrointestinal disturbances, reticuloendothelial system,
455 970, 970
green monkey kidney cells, urticaria, 971
455 suramin
hypocalcemia, 455 abdominal pain, 650
kidneys and bones receptors, conjunctivitis, 650
455 fever, 650
memory loss, 455 muscle pain, 650
minor skin complaints, 455 paresthesia, 650
StevensJohnson syndrome, rash, 650
455 renal insufciency, 650
toxic epidermal necrolysis, Trypanosoma brucei
455 gambiense, 650
venous thromboembolism, suxamethonium
455 anaphylaxis, 299300
subcutaneous immunoglobulin malignant hyperthermia, 300
fever, 6789 muscle fasciculation, 299
induration of skin, 6789 spontaneous subluxation,
malaise, 6789 temporomandibular
pain, 6789 joint, 299
palpitation, 6789 takotsubo syndrome, 299
rash, 6789
redness, 6789 T
skin induration, 6789 tacrolimus
soreness, 6789 abdominal pain, 822
swelling, 6789 abnormal glycemic control,
succinylcholine 822
see suxamethonium akinetic mutism, 821
sufentanil, 223 amlodipine, interactions, 823
sugammadex antifungal azoles,
QT interval prolongation, 302 interactions, 823
1064
appetite, 823
asymptomatic hypotension,
8234
atopic dermatitis, 822
brachial neuritis, 821
carbamazepine, interactions,
8234
cholelithiasis, 822
colitis, 822
eczema, 822
epistaxis and ecchymoses,
823
gallbladder sludge, 822
gastrointestinal symptoms,
821
infections and
hyperglycemia, 821
intermittent bloody diarrhea,
821
nausea and vomiting, 821
plasma triglyceride,
increased, 822
progressive necrotic
encephalopathy, 822
renal failure, 824
reversible
leukoencephalopathy,
8212
tachypnea, leg pains,
gingival bleeding, 823
thrombotic microangiopathy,
822
thrombotic
thrombocytopenic
purpura, 822
type 2 diabetes, 823
vomiting, diarrhea,
headache, 823
weight loss and dehydration,
822
tafenoquine and primaquine
abdominal discomfort, 569
diarrhea, 569
nausea, 569
talc
chest pain, 1023
lung cancer, 10234
ovarian cancer, 10234
respiratory distress,
1023
skin cancer, 10234
tamoxifen
breast cancer, 863
endometrial cancer, 8634
endometrial polyps, 863
fractures, 862
Goldenhar's syndrome, 864
heriditary angioedema, 863
leiomyoma, 864
oculo-auriculo-vertebral
syndrome, 864
pseudolymphoma, 863
renal disease, 8645
thromboembolism, 864
tamsulosin
ejaculatory disorders, 427
endophthalmitis, 426
priapism, 4267
retinal detachment, 426
taxanes
see also docetaxel, paclitaxel
apoptosis, 935
cell cycle arrest, 935
technetium sestamibi
angioedema, 973
difculty in speaking, 973
drooling, 973
tongue swelling, 973
tegaserod
bradycardia, dizziness, and
hypoglycemia, 744
diarrhea, 744
headache, nausea, and
abdominal pain, 744
irritable bowel syndrome,
744
ischemic events, 744
vomiting and constipation,
744
teicoplanin
osteomyelitis and prosthetic
infection, 519
pigmented eruption, 519
telavancin
nausea and vomiting, 520
telbivudine
cardiac repolarization, 582
telithromycin
hepatotoxicity, 5212
oxycodone, interaction, 522
telmisartan
mycophenolate mofetil,
interaction, 41920
temazepam, 77
temsirolimus
anemia, hyperglycemia, and
weakness, 824
creatinine, increased, 824
hypercholesterolemia, 824
hypophosphatemia, 824
hypothyroidism, 824
mucositis, 824
pneumonitis, 824
proteinuria, 824
rashes, 824
weakness/fatigue, 824
tenofovir
bone fractures, 589
Fanconi syndrome, 588
impaired glomerular
function, 5889
nephrogenic diabetes
insipidus, 588
terbinane
acenocoumarol, interaction,
5412
Index of drugs
acute generalized
exanthematous pustulosis
(AGEP), 541
anterior optic neuropathy,
541
cutaneous lupus-like
syndrome, 541
headache, 541
nasopharyngitis, 541
pyrexia, 541
terlipressin
alcoholic cirrhosis, 917
esophageal varices, 917
hepatocellular carcinoma,
917
hepatorenal syndrome, 917
interval prolongation, 916
multiple ulcers, 916
renal failure, 917
supercial dermal capillaries
thrombosis, 916
ventricular dysrhythmia, 916
tesofensine
blood pressure, increased,
1415
constipation, diarrhea, and
insomnia, 1415
dry mouth and nausea,
1415
tetrabenazine
akathisia, 306
constipation, 306
depression, 306
Huntington's disease, 306
insomnia, 306
Tourette syndrome, 305
tetracyclines
see also individual names
environment, 4978
and glycylcycline, 498
tetrahydrobiopterin and
sapropterin
plasma phenylalanine
concentrations, 694
theophylline
acute pancreatitis, 13
status epilepticus, 1213
thiazide and thiazide-like
diuretics
see also hydrochlorothiazide
hypokalemia, 4389
hyponatremia, 4389
rhabdomyolysis, 439
thiazolidinediones (glitazones)
coronary artery disease, 899
heart failure, 899, 900
macular edema, 899
mortality, 901
myocardial infection, 899,
900
thienopyridines
see also individual names
allergic, 720
Index of drugs
rash, 720
thrombocytopenic purpura,
720
thioguanine
abnormal liver function, 830
Crohn's disease, 830
nodular regenerative
hyperplasia, 830
portal hypertension, 830
thiopental sodium
electrolyte balance, 276
gastrointestinal, 275
hypotension, 275
thiopurines
arthralgia/myalgia, 825
Crohn's disease, 825
diarrhea, 825
u-like symptoms, 825
headaches, 825
hepatitis, 826
hypersensitivity reaction, 826
inammatory bowel disease,
825
malaise, 825
nausea and vomiting, 825
pancreatitis, 826
Sweet's syndrome, 826
ulcerative colitis, 825
thorn apple
see Datura stramonium
thorotrast
granuloma, 973
primary cerebral
angiosarcoma, 973
thyroid hormones
anemia, 882
antidepressants, 8812
autonomous nervous system
abnormalities, 882
depression, 882
heart rate, low, 882
hemoglobin, rise in, 882
hyponatremia, 882
increased serum ferritin, 882
increased urinary
catecholamine excretion,
882
lethargy, nausea, 882
liver failure, 8823
neonatal complications, 881
obstetric, 881
serum iron, rise in, 882
subclinical hyperthyroidism,
881
subclinical thyroid disease,
882
thyroid cancer, 881
weakness, dizziness, fainting
spells, 882
thyrotropin (thyroid-
stimulating hormone, TSH)
hyperamylasemia, 881
neutropenia, 881
non-toxic goiter, 881
sialoadenitis, 881
thrombocytopenia, 881
thyrotropin-releasing hormone
and thyrotropin, 913
tiagabine
see also antiepileptic drugs
anxiety/mood disorder, 161
gembrozil interaction, 161
headache/nausea, 161
hepatic insufciency, 161
somnolence/fatigue, 161
tibolone
breast cancer, 867
coronary heart disease, 867
endometrial hyperplasia, 867
gynecological cancers,
8678
mortality, 8678
osteoporosis, 867
stroke, 867
venous thromboembolism,
867
vertebral fractures, 867
tick-borne
meningoencephalitis vaccine
thrombocytopenic purpura,
663
ticlopidine
acute cholestatic hepatitis,
724
neutropenia, 724
tigecycline
hypobrinogenemia, 501
pancreatitis, 501
severe coagulation disorder,
501
tilidine, 2234
timolol, 983
dorzolamide, 400
tiotropium bromide
constipation, 363
dry mouth, 363
dysuria, 363
gastrointestinal obstruction,
363
urinary retention, 363
urinary symptoms, 363
tipranavir
intracranial hemorrhage,
597
ritonavir, interaction, 597
toxic epidermal necrolysis,
597
triglyceride concentrations,
raised, 597
titanium
allergic symptoms, 597
ceramic debris, 596
cytokine release, 456
dental implantation, 457
diplopia, 456
DRESS, 457
1065
endothelial cells,
hypertrophied, 457
giant cell granuloma, 457
hearing aids, 456
immunogenicity, 456
inammatory reactions, 457
lung disease, granulomatous,
4578
lymphocyte reactivity, 456
macrophage, spindle-shaped,
457
tizanidine
brain injury, 307
limb muscle, 307
spinal cord injury, 307
toad extract
intravenous injection, 999
salivary and skin glands,
secretions, 999
tobramycin
aquagenic wrinkling of the
palms, 513
loss of vestibular function,
513
toluene
balance problems, 1024
blood pressure, raised,
1024
body temperature, reduced,
1024
confusion and disorientation,
1024
coordination, loss of, 1024
horizontal nystagmus, 1024
leukoencephalopathy, 1024
metabolic acidosis, 1024
neuropsychological decits,
1024
tolvaptan
see vasopressin receptor
antagonists
topical anesthesia
allergic reactions, 289
cardiac arrest, 288
xed dilated pupils, 2889
topiramate
see also antiepileptic drugs
acute myopia, 164
angle-closure glaucoma, 164,
167
anorexia, 162
ataxia, 163
behavioral disturbances,
1667
blue pseudochromhidrosis,
165
cognitive effects, 162, 164
dizziness, 162, 162
epistaxis, 163, 165
fatigue, 162
glucocorticoids, interaction,
167
headache, 161
1066
hyperammonemic
encephalopathy, 1645
hyperesthesia, 163
hyperkinesia, 1667
hyperthermia, 165
hypesthesia, 162
hypohidrosis, 165
hypotensive therapy, 167
hypothermia, 166
maculopathy, 164
memory impairment, 161
metabolic acidosis, 165
migraine, 163
monotherapy, 162, 163
nephrolithiasis, 165
osteoporosis, 165
paresthesia, 161, 162
posaconazole, 167
pseudochromhidrosis, 165
psychiatric disorders,
1647
renal calculus, 163
renal stones, 165
restless legs syndrome, 164
sexual dysfunction, 1656
somnolence, 162
speech disorder, 1612
symptomatic epilepsy, 161
tremor and myoclonus, 164
valproate, 164
vitanin B12 deciency, 165
weight loss, 161
torcetrapib
atherosclerotic disease, 930
blood pressure, increased,
929
cardiovascular events, 930
coronary heart disease, 929
diabetes mellitus, 929
ischemic heart disease, 930
tramadol
constipation, 224
dizziness, 224
drug overdose, 225
multiorgan failure, 224
nausea, 224
paracetamol, interaction, 225
respiratory depression, 224
tremor, 224
vomiting, 224
withdrawal syndrome, 2245
transfusion
see blood transfusion
trastuzumab
abdominal pain and
bloating, 793
coronary syndrome, 793
diarrhea, vomiting, nausea,
793
febrile neutropenia, 793
heart failure, 793
interstitial lung disease, 793
travoprost, 848
blurring vision, 985
conjunctival injection, 985
eyelash thickening and
elongation, 985
eyelid skin
hyperpigmentation, 985
eyelid superior sulcus,
deepening, 985
eyelid swelling, 985
ocular irritation, 985
tretinoin (all-trans retinoic
acid, ATRA)
photoallergenicity, 341
triazolam
drug overdose, 78
sleep-dependent motor skill
memory consolidation,
778
trimethoprim and
co-trimoxazole
emtricitabine, interaction,
529
erythrodermic psoriasis, 529
xed drug eruption, 529
gait disorder, 528
liver abscesses, 5289
Pneumocystis jirovecii, 5289
Pneumocystis pneumonia,
529
StevensJohnson syndrome,
529
Sweet's syndrome, 529
toxic epidermal necrolysis,
529
triphenylmethane dyes
airways obstruction, 482
allergy, 483
anesthesia, 482
bladder injury, 483
blood cultures, 482
burning pain, 483
ceftriaxone, 482
Chagas, disease, 4812
conjunctival abrasions, 483
corneal stain, 483
cough and feeding difculty,
482
cystitis, 483
DNA damage, 484
edema, 484
edema and hematuria, 483
fever, 482
fungal tracheitis, 482
hepatocellular carcinoma, 484
hypotension, 484
HIV/AIDS, 4812
intravenous uconazole, 482
laryngotracheitis, 482
lateral neck radiographs, 482
light-fastness, 481
methemoglobinemia, 483
mononuclear cell leukemia,
484
Index of drugs
mucosal ulceration, 482
nasal congestion, 482
nasopharyngeal, 482
neutrophil inltration, 483
oral candidiasis, 482
pararosaniline pamoate, 482
Philippines, 482
respiratory syncytial virus,
482
rhinorrhea, 482
schistosomiasis, 482
sepsis, 482
skin necrosis, 483
thyroid, follicular cell
adenocarcinoma, 484
ulceration, 483
urgency and dysuria, 483
urticaria, 484
vaginal candidiasis, 481-2
viral cultures, 482
triptans
acute dystonia and
pathological laughter, 408
akathisia, 408
coronary artery disease, 408
difculty in thinking, 408
dizziness, 408
epileptic syndromes, 409
headache, 409
hemiparesis, 409
ischemic colitis, 409
migraine, 409
myocardial infarction, 408
sleepiness and tiredness,
408
symptoms of migraine, 409
Tripterygium wilfordii Hook
nephrotic syndrome, 998
rheumatoid arthritis, 998
skin pigmentation, 998
systemic autoimmune
diseases, 998
trovaoxacin
liver toxicity and acute liver
failure, 519
TSH
see thyrotropin
tumor necrosis factor alfa
(TNF-a)
aminotransferases, raised,
77980
anemia, 77980
leukopenia, 77980
myalgias, 77980
neutropenia, 77980
peripheral nerve damage,
780
thrombocytopenia, 77980
tumor necrosis factor
antagonists
alopecia areata, 780
aminotransferases, raised,
780
Index of drugs
demyelinating neuropathy,
780
discoid lupus erythematosus,
780
liches planus, 780
Nocardia farcinica, 780
psoriatic skin lesions, 780
thrombocytopenia, 780
vasculitis, 780
U hyperhomocysteinemia, 169
ultrasound contrast agents
acoustic impedance, 971
arterial circulation, 971
Uncaria tomentosa
cirrhosis, 998
hepatitis C infection, 998
urapidil
respiratory depression, 427
ursodeoxycholic acid
dyspnea, 760
hepatitis C virus infection,
760
interstitial pneumonia, 760
V neuroendocrine dysfunction,
Vaccinium macrocarpon, 998
valaciclovir
gastrointestinal disturbances,
578
headache, 578
valproate sodium and
semisodium (divalproex)
see also antiepileptic drugs
abdominal obesity, 171
alopecia, 173
appetite, increased, 168
BallerGerold syndrome,
174
bipolar disorder, 168
carbapenem, 175
cardiac dysrhythmias, 175
carotid artery intima-media
thickness, 169
chitosan, 175
cholestatic hepatitis, 172
cognitive impairment, 168
delirium, 170
dementia, 170
diarrhea, 1678
encephalopathy, 169
eosinophilic pleural effusion,
169
epilepsy refractory, 175
erythema multiforme, 172
fetal valproate syndrome,
174
brinogen concentration,
171
bular aplasia, 174
gastrointestinal disorder,
1678
glucose concentration, 171
headache, 169
hepatic failure, 172
hepatotoxicity, 176
Huntington's disease,
16970
hyperammonemia, 1701
hyperammonemic
encephalopathy, 176
hyperandrogenism, 173
hyperglycemia, 171
hyperinsulinemia, 171
hyperkeratosis, 172
hypertriglyceridemia, 171
hyponatremia, 175
lamotrigine, 1756
leukopenia, 172
lithium effect, 170
lupus-like syndrome, 173
mania, 168
menstrual irregularities, 173
mental retardation, 175
metabolic syndrome, 171
monotherapy, 1678
myopathy, 1723
173
neutropenia, 172
non-alcoholic fatty liver
disease, 172
olanzapine, 1689
onychomadesis, 172
ovulatory dysfunction, 173
oxcarbazepine, 176
pancreatitis, 172
parakeratosis, 172
parkinsonism, 169
plasma ammonia
concentration, 173
polycystic ovary syndrome,
173
psoriasiform eruption, 172
pulmonary anomalies, 174
quetiapine, 172, 176
Rowell's syndrome, 173
schizoaffective disorder,
1723
schizophrenia, 175
sinusitis, 168
Sjgren's syndrome, 169
somnolence, 1678
StevensJohnson syndrome,
172
stuttering, 170
supportive therapy, 176
thrombelastography, 171
thrombocytopenia, 171
thrombophilia, 1712
toxic epidermal necrolysis,
172, 173
tremor, 1678
upper respiratory tract
infection, 168
1067
valproate formulations, 174
valproate poisoning, 176
vertigo, 175
vomiting, 1678
weight gain, 168
von Willebrand's disease, 171
worsening, 170
valsartan
headache, 420
hypotension, 420
vancomycin
asthma, 520
DRESS, 5201
furosemide, interaction, 521
leukocytoclastic necrotizing
vasculitis, 520
lupus-like syndrome, 521
neuralgic amyotrophy, 520
red man syndrome, 521
renal insufciency, 520
thrombocytopenia, 520
varicella vaccine
interstitial keratitis, 663
vasopressin and analogues
bradycardia, 915
cardiopulmonary
resuscitation, 916
hyponatremia, 9156
placebo, 916
vasopressin receptor
antagonists
blood concentrations, 915
dry mouth, 915
heart failure, 915
hepatic cirrhosis, 915
infusion site reactions, 915
serum sodium concentration,
increased, 915
venlafaxine and desvenlafaxine
see also antidepressant drugs
and serotonin and
noradrenaline re-uptake
inhibitors (SNRIs)
constipation, 32
coronary artery disease, 31
hepatic failure, 340
nausea and insomnia, 32
verapamil
bradycardia and loss of
consciousness, 403
extreme hypotension, 403
invasive hemodynamic
monitoring, 403
levosimendan, effect of, 404
massive bowel irrigation, 403
prolonged cardiac pacing,
403
verteporn and photodynamic
therapy
accidental fall, 9812
age-related macular
degeneration, 981
cataract, 981
1068
choroidal hypoperfusion, 981
colon cancer, 9812
gastrointestinal hemorrhage,
9812
hepatic cirrhosis, 9812
hip osteoarthritis, 9812
myocardial infarction, 9812
pigment epithelial tear,
9812
renal cell carcinoma, 9812
renal failure, 9812
respiratory failure, 9812
stroke, 9812
subretinal and intraretinal
leakage, increased, 9812
transient ischemic attacks,
9812
vigabatrin
see also antiepileptic drugs
fatigue or drowsiness, 177
hypertension, 177
hypoxic brain injury, 177
induced ocular adverse
effect, 178
infantile spasms, 1767
intramyelinic edema, 1767
metamfetamine, 177
neurological or cognitive
decit, 178
ophthalmological
examination, 179
retinal function, 178
seizure, 177
somnolence, 177
tuberous sclerosis, 1767
visual abnormalities, 177
white matter vacuolation,
177
vildagliptin
headache, 895
hypoglycemia, 895
nasopharyngitis, 895
upper respiratory tract
infections, 895
vincristine
Hodgkin's lymphoma, 951
motor neuropathy, 951
neurotoxicity, 951
visilizumab
cellulitis, candidiasis, 793
chest pain, 793
Crohn's disease, 794
cytokine release, 794
facial ushing, upper limb
weakness, and low-grade
fever, 793
nasopharyngitis, rhinitis,
tonsillitis, 793
peripheral retinal
hemorrhages, 793
upper respiratory tract
infection, 793
urinary tract infection, 793
vitamin A (carotenoids)
beta-carotene, 691
body mass index, 691
bone fractures, 692
chronic hypervitaminosis A,
691
fever, 692
fractures, 692
GuineaBissau, 6912
Haemophilus inuenzae b, 692
hepatitis B, 692
hepatotoxicity, 691
hepatic failure, 692
liver transplantation, 692
lung cancer, 691
mortality rate ratio (MRR),
6912
nausea, 691
skin disoders, 691
skin irritation, 692
teratogenicity, 691
vomiting, 691
yellow-orange discoloration
of skin, 691
vitamin A (retinoids)
see also individual names
vitamin B12
see cobalamins
vitamin C (ascorbic acid)
beta-carotene, 6945
cataracts, 694
gestational hypertension,
694
oxalate crystal deposition,
694
pneumonia, risk of, 6945
tuberculosis, 6945
vitamin D analogues
calciumalkali syndrome, 695
fracture, risk of, 695
hemodialysis therapy, 695
hypercalcemia, 695
leukocytoclastic vasculitis,
695
metabolic alkalosis, 695
milk-alkali syndrome, 695
non-vertebral fractures, 695
palpable purpura, 695
vitamin E (tocopherol)
congenital heart defect, 696
diabetes mellitus, 696
heart failure, 696
hepatic metabolism, 6967
pre-existing vascular disease,
696
vitamin K metabolism, 6967
von Willebrand factor/factor
VIII concentrates
allergic symptoms, 681
chills, 681
edema, 681
pain in the limbs, 681
phlebitis, 681
Index of drugs
pseudothrombocytopenia,
681
voriconazole
auditory hallucinations,
5545
color perception altered/
blurred vision, 5545
hepatotoxicity, 554, 555
myopathy, 555
neurological toxicity, 556
periostitis, 555
phototoxicity, 555
QT interval prolongation,
554
squamous cell carcinoma,
555
W
water soluble intravascular
iodinated contrast agents
acute generalized
exanthematous pustulosis
(AGEP), 966
allergic reactions, 963, 966
bronchospasm, 967
cardiac-like symptoms, 697
chest tightness, 963
congestive heart failure, 964
contrast-induced
nephrotoxicity, 964, 965
contrast media, 963, 964
dehydration, 964
diabetes mellitus, 964
erythema or rash, 967
hypersensitivity, delayed,
967
hypertension, labile, 963
hypotension, 967
injury, 965
intra-arterial injection, 966
intracranial hemorrhage, 964
intravenous hydration, 966
iodide-induced sialadenitis,
964, 965
iodide mumps, 964, 965
laryngeal edema, 963, 967
nephrogenic systemic
brosis, 963
neurological event, 967
pruritus, 967
renal function, 966
shortness of breath, 967
sialdenitis, 964, 965
tachycardia, 967
urticaria, 963, 967
X
xing nao jing injection
allergic reactions, 991
blood pressure, raised, 991
cerebral infarction, 991
chest distension, 991
shortness of breath, 991
Index of drugs 1069

Y high blood pressure, 990 abdominal discomfort,

yellow fever vaccine liver damage, 990 180
dizziness, 664 rashes, pruritus, nausea, and anorexia, 181
dyspnea, 664 vomiting, 990 anticonvulsant
fatigue, 664 zidovudine hypersensitivity
fever, 664 adiponectin expression, syndrome, 181
headache, 664 reduction, 5834 blurred vision, 181
injection site erythema, 664 anemia, 588 diarrhea, 180
longitudinal myelitis, 664 incomplete cell dry lips, 181
nausea, 664 differentiation, emotional lability, 180
pain, 664 5834 fatigue, 180
pruritus, 664 leukopenia, 588 headache, 180
rash, 664 lipoatrophy, 584 hostility, 180
urticaria, 664 palpebral ptosis, 588 hyperammonemia, 181
pure red cell aplasia, 588 hypersensitivity syndrome,
Z zileuton 181
zaleplon headache and nausea, insomnia, 180
drug overdose, 78 369 irritability, 17980
perceptual disturbances, 78 zinc loss of appetite, 17980
zanolimumab anemia, 458 lymphocyte toxicity, 181
non-cutaneous peripheral ataxia and falls, 458 nervousness, 180
T-cell lymphomas, 794 back pain, 458 nervous system irritability,
psoriasis, 794 cold symptoms, 458 180
zedoray tumeric oil and hyperzincemia, 458 pancreatitis, 180
glucose injection hypocupremia, 458 paresthesia, 180
allergic reactions, 992 knee pain, 458 pruritus, 180
anaphylactic shock, 992 paresthesia, 458 rashes, 180
dyspnea, 992 sense of smell loss, 458 reduced sweating, 180
lead poisoning, 992 ziprasidone restless legs syndrome,
rashes, 992 insomia, 114 180
vomiting and severe nausea, 114 sedative effect, 180
abdominal pain, 992 QT interval prolongation, seizure, 180
zhi xue capsule 114 serum creatinine, increased,
anal bulge, 990 sedation, 114 181
constipation, 990 somnolence, 114 sexual dysfunction, 180
hematochezia, 990 zolpidem somnolence, 17980
liver damage, 990 sleep driving, 79 topiramate, 180
zhuang gu guan jie wan sleep walking, 789 zopiclone, 79
abdominal pain and zonisamide zotepine, 114
diarrhea, 990 see also antiepileptic drugs zuclopenthixol, 115
 Index of adverse effects
A pyrimethamine and
abdominal aortic aneurysms
carbon dioxide, 971
abdominal bloating
lactulose, 754
phosphates, 755
abdominal colic
antimony, 448
abdominal compartment
syndrome
cyanoacrylates, 1014
abdominal cramps
bisacodyl, 753
octreotide, 914
stem cells, 683
superparamagnetic iron
oxide, 971
abdominal discomfort
baclofen, 3023
praziquantel, 650
tafenoquine and primaquine,
569
zonisamide, 180
abdominal pain
balsalazide, 7567
blood substitutes, 672, 673
C1 esterase inhibitor
concentrate, 674
dexlansoprazole, 750
enteral nutrition, 700
glutaral (glutaraldehyde),
480
kadda, 992
lansoprazole, 7501
lansoprazole amoxicillin
metronidazole or
clarithromycin, 749
lanthanum carbonate, 451
levonorgestrel, 865
methylnaltrexone, 227
metoclopramide, 7423
metronidazole, 573
palonosetron, 747
pancreatic enzymes, 761
pantoprazole, 752
posaconazole, 553
proton pump inhibitors, 749
prucalopride, 743
psilocybin, 66
and reactions
congeners, 570
roxithromycin, 524
senna, 7545
somatropin, 911
suramin, 650
tacrolimus, 822
tegaserod, 744
zedoray tumeric oil and
glucose injection, 992
accidental fall
verteporn and
photodynamic therapy,
9812
Achilles' tendinitis
inhaled glucocorticoids, 355
acidosis
see metabolic acidosis
acne
hormonal contraceptives,
8589
systemic glucocorticoids, 841
acneiform eruption
dantrolene sodium, 305
acute coronary syndromes
clopidogrel, 722
acute disseminated
encephalomyelitis
human papilloma virus
(HPV) vaccine, 658
acute generalized
exanthematous pustulosis
(AGEP)
cefotaxime, 493
co-amoxiclav and clavulanic
acid, 496
moxioxacin, 519
piperacillin tazobactam,
497
rifabutin, 6378
terbinane, 541
acute intermittent porphyria
phenobarbital and
primidone, 154
acute localized exanthematous
pustulosis
ibuprofen, 246
acute macular
neuroretinopathy
adrenaline (epinephrine),
316
adenocarcinomas
dexlansoprazole, 750
adrenal function, impaired
megestrol acetate, 866
adrenal insufciency
etomidate, 2623
glucocorticoids, 983
systemic glucocorticoids, 843
adrenal suppression
etomidate, 263
inhaled glucocorticoids, 355
ritonavir, 596
adrenaline
protamine, 727
adult respiratory distress
syndrome (ARDS)
parenteral nutrition, 697
adults death
diphenhydramine, 347
adverse reactions
apraclonidine, 982
docetaxel, 946
ixabepilone, 949
paclitaxel, 936
superparamagnetic iron
oxide, 971
ultrasound contrast agents,
971
adverse risk increase
tiotropium bromide, 363364
age-related macular
degeneration
ranibizumab, 978979
verteporn and
photodynamic therapy, 981
AGEP
see acute generalized
exanthematous pustulosis
aggression
atomoxetine, 7
levetiracetam, 148
montelukast, 366367
agitation
anticholinergic drugs, 324
atomoxetine, 7
benzydamine
(benzindamine), 249
1071
1072
dextromethorphan, 210
ketamine, 264, 265266
lansoprazole, 751
methylthioninium chloride,
1019
metoclopramide, 743
midazolam, 75
montelukast, 366367
nitrous oxide, 260261
stem cells, 683
agranulocytosis
See also leukopenia;
neutropenia
antithyroid drugs, 884
azithromycin, 523
benznidazole, 649
clozapine, 103
dapsone, 630, 631
deferasirox, 467
deferiprone, 469
phenytoin and fosphenytoin,
156
airwars obstruction
triphenylmethane dyes, 482
akathisia
aripiprazole, 99100, 101
metoclopramide, 743
risperidone, 112
tetrabenazine, 306
triptans, 408
alcohol abuse
paclitaxel, 939
alkalosis
aminoglycoside antibiotics,
509
allergic conjunctivitis
mascara, 3345
allergic contact dermatitis
aciclovir, 578
diclofenac, 245
diphenhydramine, 3467
allergic disease
sodium hypochlorite, 4845
allergic rash
see rashes
allergic reaction
See also anaphylactic
reaction
Actaea racemosa, 992
acupuncture, 1000
amoxicillin, 496
aprotinin, 726
bacille Calmette-Gurin
(BCG) vaccine, 656
ci wu jia injection, 991
clopidogrel, 724
coumarin anticoagulants, 713
enteral nutrition, 701
factor IX (coagulation
proteins), 680
factor VIII (coagulation
proteins), 679680
lgrastim, 769
Index of adverse effects and reactions
uconazole, 551 aminotransferases
heparins, 716 see liver function tests
hydrochlorothiazide, 439 amyotrophic lateral sclerosis
insulin, 480 lithium, 412
ku die zi injection, 991 anal ssure
lansoprazole, 751 botulinum toxins, 304
latex, 1018 anal irritation
lidocaine, 291 bisacodyl, 7534
ling yang gan mao capsule, analgesia
98990 methoxyurane, 258
morphine, 216 anaphylactic reaction
neomycin, 513 aprotinin, 726
nickel, 453 blood transfusion, 671
omeprazole and C1 esterase inhibitor
esomeprazole, 752 concentrate, 674
polyvinyl alcohol, 1021 celecoxib, 246
praziquantel, 650 cetirizine, 345
prilocaine and EMLA, 292 clarithromycin, 524
progestogens, 865 etheried starches, 6756
propofol, 271 brin glue, 6745
thienopyridines, 720 gadolinium salts, 968
titanium, 456 glucocorticoids, systemic,
topical anesthesia, 289 845
von Willebrand factor/factor gonadotropins, 909
VIII concentrates, 681 heparins, 716
water soluble intravascular human papilloma virus
iodinated contrast agents, (HPV) vaccine, 658
966 immunoglobulin,
xing nao jing injection, 991 intravenous, 677, 678
zedoray tumeric oil and iron salts, 451
glucose injection, 992 inuenza H1N1 vaccines,
alopecia 659
albumin-bound paclitaxel, minocycline, 500
944 omeprazole and
clonazepam, 73 esomeprazole, 752
docetaxel, 947 ondansetron, 746
nasteride, 873 paracetamol
gabapentin, 138 (acetaminophen), 245
hormonal contraceptives, protamine, 727
8589 ranitidine, 748
lamotrigine, 1434 sitagliptin, 895
letrozole, 862 suxamethonium, 299300
mercaptopurine, 830 anaphylactic shock
paclitaxel, 941 aprotinin, 726
phenobarbital and cetirizine, 345
primidone, 154 gadolinium salts, 9689
selenium, 454 itraconazole, 552
strontium salts, 455 Panax ginseng, 996
valproate sodium and ranitidine, 748
semisodium (divalproex), shu xue ning injection, 991
173 zedoray tumeric oil and
aluminium toxicity glucose injection, 992
parenteral nutrition, 698 anemia
alveolar edema See also aplastic anemia,
labetalol, 399 hemolytic anemia,
alveolar hemorrhage megaloblastic anemia,
antithyroid drugs, 885 sideroblastic anemia
azithromycin, 522 aldesleukin (interleukin-2,
Alzheimer's disease IL-2), 777
aluminium, 447 alemtuzumab, 784
insulin, 483 antithyroid drugs, 884
amenorrhea azathioprine, 829
risperidone, 113 DAMB, 5423
Index of adverse effects and reactions 1073

docetaxel, 947 phenobarbital and argyria

donepezil, 15 primidone, 154 silver salts and derivatives,
ucytosine, 559 phenytoin and fosphenytoin, 4545
immunoglobulin, 156 arrhythmias
intravenous, 677 zonisamide, 181 see dysrhythmias
interferon alfa, 773 anxiety arterial occlusion
interleukin-18 (IL-18), 779 anthrax vaccine, 6556 unitrazepam, 734
levooxacin, 517 anticholinergic drugs, 324 arterial pressure
metformin, 484 aripiprazole, 99101 cobalamins (vitamin B12),
oxazolidinones, 525, 526 meoquine, 569 693
paclitaxel, 939 memantine, 16 arterial thrombosis
peglgrastim, 770 proton pump inhibitors, heparins, 7156
ribavirin, 580 749 arterial vasodilatation
temsirolimus, 824 risperidone, 113 parathyroid hormone, 913
thyroid hormones, 882 tiagabine, 161 arthralgia
tumor necrosis factor alfa, anxiousness and dream albumin-bound paclitaxel,
77980 abnormalities 944
zidovudine, 588 montelukast, 3667 anthrax vaccine, 6556
zinc, 458 aortic dissection docetaxel, 947
anesthesia cocaine, 58 exemestane, 861
5HT3 receptor antagonists, aplasia cutis huperzine, 16
744 antithyroid drugs, 885 immunoglobulin,
metformin, 484 aplasia cutis congenita intravenous, 677
ondansetron, 746 azathioprine, 828 ixabepilone, 949
oxytocin, 913 aplastic anemia letrozole, 862
ranitidine, 748 See also anemia memantine, 16
triphenylmethane dyes, 482 dapsone, 630 paclitaxel, 941
angina mesalazine (5-aminosalicylic penicillamine, 472
See also myocardial acid, mesalamine), 758 penicillins, 495
infarction apnea thiopurines, 825
alprostadil (prostaglandin alfentanil, 209 arthritis
E 1), 846 spinal (intrathecal) deferiprone, 46970
angioedema anesthesia, 284285 gold and gold salts, 451
amlodipine, 401 apoptosis leunomide, 818
angiotensin converting epothilones, 948 Tripterygium wilfordii Hook,
enzyme (ACE)inhibitors, taxanes, 935 998
417 appendicitis arthropathy
bupropion (amfebutamone), barium sulfate, 967 deferiprone, 470
33 appetite loss uoroquinolones, 514
estrogens, 852 acupuncture, 999 aseptic lymphocyte-dominated
heparins, 716 anthraquinones, 753 vasculitis-associated lesion
inuenza H1N1 vaccines, benznidazole, 649 (ALVAL)
659 ethosuximide, 136 cobalt, 450
losartan, 419 gabapentin, 1367 aseptic mediastinal cyst
montelukast, 367 immunoglobulin, albumin-derived
sitagliptin, 895 intravenous, 678 hemostatics, 670
technetium sestamibi, 973 letrozole, 862 aseptic meningitis
anion gap metabolic acidosis memantine, 16 immunoglobulin,
glycols, 1018 mifepristone, 867 intravenous, 677
anorexia proton pump inhibitors, lamotrigine, 143
see appetite loss 74950 aspergillosis
anterior optic neuropathy stiripentol, 1601 everolimus, 8178
terbinane, 541 tacrolimus, 823 glucocorticoids, systemic, 845
anterior uveitis topiramate, 162 itraconazole, 553
prostaglandin analogues, 984 valproate sodium and asterixis
anticholinergic symptoms and semisodium (divalproex), cycloserine, 630
signs 168 asthma
promethazine, 349 zonisamide, 17981 acetylsalicylic acid, 248
antiepileptic drugs appetite, reduced anticholinergic drugs,
hypersensitivity syndrome apraclonidine, 982 inhaled, 364
antiepileptic drugs, 129 metronidazole, 573 cyanoacrylates, 1015
lamotrigine, 144 modanil, 11 formoterol, 3601
1074
glimepiride, 898
glucocorticoids, inhaled, 355
glucocorticoids, systemic,
842
latex, 1018
long-acting beta2-
adrenoceptor agonists
(LABAs), 357, 358
mannitol, 442
montelukast, 366, 367
paracetamol
(acetaminophen), 2445
salmeterol, 362, 363
sodium metabisulte, 1022
vancomycin, 520
zileuton, 369
asthma, worsening
montelukast, 366
asystole
dipyridamole, 719
ataxia
pregabalin, 158
stiripentol, 1601
topiramate, 163
zinc, 458
atherosclerotic disease
alcohol, 1010
torcetrapib, 930
atopic dermatitis
pimecrolimus, 819
tacrolimus, 822
atrial brillation
adenosine and analogues,
379
adrenaline (epinephrine),
315
aprotinin, 725
gembrozil, 923
milrinone, 3789
paclitaxel, 938
paliperidone, 109
protamine, 727
rimonabant, 14
atrial tachycardia
long-acting beta2-
adrenoceptor agonists
(LABAs), 359
propafenone, 38990
atrioventricular block
cardiac glycosides, 377
dapsone, 630
attention decit disorder
mercury and mercurial salts,
453
auditory hallucinations
amantadine, 604
voriconazole, 5545
auranocyanide anion
gold and gold salts, 451
autism spectrum disorders
long-acting beta2-
adrenoceptor agonists
(LABAs), 359
Index of adverse effects and reactions
measles-mumps-rubella behavioral changes
(MMR) vaccine, 661 ethosuximide, 136
mercury and mercurial salts, lacosamide, 1401
453 topiramate, 1667
autoantibodies belching
iron chelators, combinations, pantoprazole, 752
471 benign proliferative epithelial
autoimmune disorders disorders
human papilloma virus hormone replacement
(HPV) vaccine, 658 therapy (HRT), 855
inuenza H1N1 vaccines, 659 benign intracranial
Tripterygium wilfordii Hook, hypertension
998 see intracranial
avascular osteonecrosis hypertension, benign
titanium, 457 bilateral leg compartment
axial hypotonia syndrome
deferiprone, 470 simvastatin, 928
axonal motor neuropathy bilateral temporal hemianopia
phenobarbital and ethambutol, 634
primidone, 154 biliary pseudolithiasis
azoospermia ceftriaxone, 494
nasteride, 873 binge-eating disorder
lamotrigine, 142
B bipolar disorder
back pain antiepileptic drugs, 128
agomelatine, 33 antipsychotic drugs, 95
aliskiren, 420 carbamazepine, 1334
anthrax vaccine, 6556 lamotrigine, 142
erythropoietin and oxcarbazepine, 152
derivatives, 682 valproate sodium and
immunoglobulin, semisodium (divalproex),
intravenous, 677 168
melatonin, 912 birth weight, low
memantine, 16 manganese, 4523
zinc, 458 bitter taste
bacterial cellulitis metronidazole, 573
anakinra (interleukin-1 black tongue
receptor antagonist), 779 bismuth compounds, 7523
bacterial meningitis bladder calcication
imipenem, 492 bacille Calmette-Gurin
meropenem, 492 (BCG) vaccine, 656
balance problems bladder ulceration
toluene, 1024 gentian violet, 483
BallerGerold syndrome bleeding
valproate sodium and Actaea racemosa, 992
semisodium (divalproex), acupuncture, 999
174 clopidogrel, 7201
ballismus coumarin anticoagulants, 707
umazenil, 81 drotrecogin alfa, 671
Bartter-like syndrome fondaparinux, 718
amikacin, 510 idraparinux, 7189
gentamicin, 511 blepharitis
basal cell carcinoma mascara, 3345
Artemisia vulgaris, 993 blindness
hair dyes, 336 arsenic, 449
iron chelators, 465 nilutamide, 874
PUVA, 339 blisters
basal tear secretion insulin, 890
isotretinoin, 340 bloating
Beau's lines calcium salts, 449
azathioprine, 827 dexlansoprazole, 750
behavior and tremor blood cysteine
montelukast, 3667 sultes, 1023
Index of adverse effects and reactions
blood dyscrasias
deferasirox, 467
blood loss
nifedipine, 402
blood pressure, increased. See
also hypertension
amfetamine, 12
blood substitutes, 673
ketamine, 264
methylphenidate, 78
moxonidine, 427
phenylephrine, 3189
somatropin, 910
tesofensine, 1415
toluene, 1024
torcetrapib, 929
xing nao jing injection, 991
zhuang gu guan jie wan, 990
blood pressure, reduced
see hypotension
bloodstream infection
see septicemia
bloody diarrhea
glutaral (glutaraldehyde),
480
tacrolimus, 822
blue pseudochromhidrosis
topiramate, 165
blurred vision
pregabalin, 158
voriconazole, 5545
zonisamide, 181
body temperature, reduced
toluene, 1024
bone density, increased
lithium, 45
bone dysplasia
deferoxamine, 471
bone mineral accretion
inhaled glucocorticoids, 356
bone pain
ciclosporin, 816
epoetin alfa, 682
erythropoietin and
derivatives, 682
lenograstim, 770
peglgrastim, 770
sargramostim, 771
bowel disease
etanercept, 781
iniximab, 783
glucocorticoids systemic, 844
bowel disorder
ixabepilone, 949
Rhododendron spp., 9968
bowel syndrome
balsalazide, 756
glucagon, 889
brachial neuritis
human papilloma virus
(HPV) vaccine, 658
tacrolimus, 821
bradycardia
atenolol, 397
beta-adrenoceptor
antagonists, 983
betaxolol, 3978
cyanoacrylates, 1014
endoperoxides, 571
esmolol, 398
fentanyl, 212
huperzine, 16
hydromorphone, 214
ketamine, 266
olanzapine, 104
ondansetron, 745
paclitaxel, 941942
phenytoin and fosphenytoin,
155
remifentanil, 222
Rhododendron spp., 9968
somatostatin, 9134 Brugada syndrome
tegaserod, 744
vasopressin, 915
verapamil, 403
bradydysrhythmias
cardiac glycosides, 377
bradykinesia
fentanyl, 212
bradypnea
ketamine, 266
lidocaine, 388
brain abscesses
cyanoacrylates, 1015
brain damage
insulin, 479
ocular anesthesia, 2878
tizanidine, 307
brain tumors
formaldehyde, 480
breast cancer
bevacizumab, 785
bisphosphonates, 1012
diethylstilbestrol, 853
hormone replacement
therapy (HRT), 853
insulin, 481
ixabepilone, 948
levonorgestrel, 865
methylthioninium chloride,
10189
oleic acid, 1021
palonosetron, 747
tamoxifen, 863 capillary leak syndrome
tibolone, 867
breast lump
barium sulfate, 9678 carbon monoxide poisoning
breast tenderness
Actaea racemosa, 992
breath holding
ketamine, 2645 cardiac arrest
breathing and pain
benzalkonium compounds,
481
bronchiolitis obliterans
nitrofurantoin, 5245
1075
bronchitis
memantine, 16
bronchopulmonary dysplasia
furosemide, 440
bronchospasm
See also asthma
docetaxel, 948
fentanyl, 2123
immunoglobulin,
intravenous, 677
lidocaine, 388
omeprazole and
esomeprazole, 752
paclitaxel, 9412
shu xue ning injection, 991
water soluble intravascular
iodinated contrast agents,
967
ecainide, 387
lidocaine, 2901, 388
bullous hemorrhagic
dermatosis
heparins, 715
bullous pemphigoid
furosemide, 440
penicillamine, 473
burning sensation
benzalkonium compounds,
481
lansoprazole amoxicillin
metronidazole or
clarithromycin, 749
paclitaxel, 939
pimecrolimus and
tacrolimus, 3378
burning-tingling sensation
pimecrolimus, 819
C
calcium-alkali syndrome
vitamin D analogues,
695
calvarial dysplasia
candesartan, 419
cancers
See also individual names
and organs
ezetimibe, 922
imipenem, 492
aldesleukin (interleukin-2,
IL-2), 777
chloroform, 257
carcinoid tumors
iniximab, 783
bupivacaine, 290
lacosamide, 140
lidocaine, 388
naloxone, 2278
propofol, 2701
1076
spinal (intrathecal)
anesthesia, 286
topical anesthesia, 288
cardiac dysrhythmias
see also bradydysrhythmias
adrenaline (epinephrine),
315
bupivacaine, 290
chloroform, 257
erythropoietin and
derivatives, 682
umazenil, 81
immunoglobulin,
intravenous, 677
levetiracetam, 1467
ondansetron, 746
paclitaxel, 9378
phenytoin and fosphenytoin,
155
prucalopride, 744
rupatadine, 349
sevourane, 260
valproate sodium and
semisodium (divalproex),
175
cardiac failure
metoclopramide, 743
cardiac ischemia
paclitaxel, 938
cardiac mortality
formoterol, 360
cardiac repolarization
telbivudine, 582
cardiac symptoms
balsalazide, 756
cardiac toxicity, increased
paclitaxel, 943
cardiac valvular disease
ECSTASY, 62
cardiac-like symptoms
water soluble intravascular
iodinated contrast agents,
967
cardiogenic shock
diphenhydramine, 347
cardiomyopathy
adderall, 2
anagrelide, 719
cardiorespiratory arrest
pegaptanib, 9778
cardiotoxicity
Agauria salicifolia, 997
albumin-bound paclitaxel,
943944
antimony, 448
deferiprone, 469
docetaxel, 948
indoramin, 426
cardiovascular effects
amantadine, 604
carpopedal spasm
lactulose, 754
cataract
Index of adverse effects and reactions
antipsychotic drugs, 94 aripiprazole, 1001
glucocorticoids inhaled, 355 balsalazide, 756
ranibizumab, 9789 clenbuterol, 323
verteporn and coumarin anticoagulants, 713
photodynamic therapy, 981 dobutamine, 319
vitamin C (ascorbic acid), 694 immunoglobulin,
cellulitis intravenous, 677
aripiprazole, 1001 khat, 66
gadolinium salts, 968 mercaptopurine, 830
visilizumab, 793 mesalazine (5-aminosalicylic
central blurring acid, mesalamine), 757
deferoxamine, 471 metamfetamine, 3
central nervous system effect natalizumab, 791
lacosamide, 1401 niacin, 928
lamotrigine, 1412 nickel, 453
central retinal artery occlusion pantoprazole, 752
ocular anesthesia, 287 peruorocarbons, 972
central retinal vein occlusion postsynaptic a-adrenoceptor
isotretinoin, 340 antagonists, 426
central venous catheters prazosin, 426
chlorhexidine, 4801 proton pump inhibitors,
central/centrocecal scotomas 74950
ethambutol, 634 stem cells, 683
ceramic debris talc, 1023
titanium, 456 visilizumab, 793
cerebellar syndrome chest pressure sensation
deferiprone, 470 erythropoietin and
cerebral infarction derivatives, 682
xing nao jing injection, 991 chest tightness
cerebral inammation idinated contrast agents, 963
penicillins, 495 chest trauma
cerebral ischemia amiodarone, 381
lithium, 42 chills
cerebral microbleeds amphotericin (ABCD), 542
coumarin anticoagulants, C1 esterase inhibitor
7078 concentrate, 674
cerebral venous thrombosis gadolinium salts, 970
heparins, 714 intravenous
cerebrovascular disease immunoglobulin, 677
ceftriaxone, 493 Panax ginseng, 996
phenobarbital and penicillins, 495
primidone, 154 stem cells, 683
certoparin von Willebrand factor/factor
heparins, 715 VIII concentrates, 681
chemical meningitis choanal atresia
spinal (intrathecal) antithyroid drugs, 885
anesthesia, 286 cholelithiasis
chemotherapy-induced iron chelators, 465
neuropathic pain cholestasis
gabapentin, 136 angiotensin converting
chest discomfort enzyme (ACE)inhibitors,
adenosine and analogues, 418
379 benazepril, 418
dipyridamole, 719 loxoprofen, 246
ecainide, 387 naloxone, 228
glycoprotein IIb-IIIa parenteral nutrition, 699
inhibitors, 720 cholestatic hepatitis
peruorocarbons, 972 azathioprine, 827
chest distension ciprooxacin, 515
xing nao jing injection, 991 clarithromycin, 524
chest pain exemestane, 861
adenosine receptor agonists, ucloxacillin, 497
380 ticlopidine, 724
Index of adverse effects and reactions
valproate sodium and
semisodium (divalproex),
172
cholestatic jaundice
hydralazine and
dimethylhydralazine, 428
cholestatic liver damage
clopidogrel, 721
ucloxacillin, 497
chorea and hallucinations
isourane, 258
chorioretinopathy
glucocorticosteroids, 9834
choroidal detachment
dorzolamide, 438
choroidal hypoperfusion
verteporn and
photodynamic therapy,
981
chronic obstructive pulmonary
disease (COPD)
cilomilast, 3678
glucocorticoids inhaled, 353
ChurgStrauss syndrome
montelukast, 366
chylous ascites
lercanidipine, 402
circadian rhythm sleep
disorders
melatonin, 912
circulatory disturbances
acupuncture, 999
cirrhosis
see hepatic cirrhosis
clenbuterol
dyspnea, 323
hyperglycemia, 323
hypokalemia, 323
clonic movement
ketamine, 264
clopidogrel
thienopyridines, 720
coagulopathy
coumarin anticoagulants, 713
etheried starches, 6756
brin glue, 6745
tigecycline, 501
cognitive decit
lithium, 434
vigabatrin, 178
cognitive impairment
hormone replacement
therapy (HRT), 854
ribavirin, 580
valproate sodium and
semisodium (divalproex),
168
colchicine intoxication
disulram, 1014
cold limbs
ku die zi injection, 991
cold sweats
Panax ginseng, 996
colitis
lansoprazole, 7501
pravastatin, 927
tacrolimus, 822
colon cancer
edrecolomab, 788
verteporn and
photodynamic therapy,
9812
colon ulceration
docetaxel, 947
colonic necrosis
polystyrene sulfonates, 474
colorectal cancer
parenteral nutrition, 700
coma manifestation
diphenhydramine, 347
common cold
camphor, 334
erythropoietin and
derivatives, 682
rupatadine, 349
zinc, 458
conduction abnormalities
somatostatin, 9134
confusion
anticholinergic drugs, 324
bismuth, 449
Datura stramonium, 994
eornithine, 574
gamma-hydroxybutyric acid
(GHB), 645
methadone, 214
confusion and disorientation
toluene, 1024
congenital anomalies
itraconazole, 5523
congenital heart defects
amiodarone, 380
vitamin E (tocopherol), 696
congenital malformation
uconazole, 5512
levetiracetam, 150
congestive heart failure
bevacizumab, 786
darbepoetin alfa, 682
erythropoietin and
derivatives, 682
metformin, 484
peroxisome proliferator-
activated dual receptor
agonists, 9012
rosiglitazone, 901
saxagliptin, 895
water soluble intravascular
iodinated contrast agents,
964
conjunctival abrasions
triphenylmethane dyes, 483
conjunctival hyperemia
anti-glaucoma drugs, 982
bimatoprost, 984
latanoprost, 985
1077
conjunctivitis
suramin, 650
conotruncal heart defects
nicotine, 1020
consciousness, loss of
ondansetron, 746
ranitidine, 748
constipation
5HT3 receptor antagonists,
744
agomelatine, 33
baclofen, 3023
buprenorphine, 225
calcium salts, 449
docosahexaenoic acid
(DHA) paclitaxel, 945
gabapentin, 1367
ixabepilone, 949
lanthanum carbonate, 451
memantine, 16
methadone, 214
oxycodone, 220
palonosetron, 747
pancreatic enzymes, 761
phosphates, 755
raltegravir, 599
tegaserod, 744
tesofensine, 1415
tetrabenazine, 306
tiotropium bromide, 363
tramadol, 224
venlafaxine and
desvenlafaxine, 32
zhi xue capsule, 990
contact allergy
henna, 336
contact dermatitis
angiotensin converting
enzyme (ACE) inhibitors,
418
bacille Calmette-Gurin
(BCG) vaccine, 656
benzocaine, 290
captopril, 418
chlorhexidine, 481
chlorphenamine, 346
dimethylfumarate, 336
hydrochlorothiazide, 439
Lyral, 337
mascara, 3345
metronidazole, 573
contact eczema
chelators, 474
contact leukoderma
henna, 336
convulsions
benzydamine
(benzindamine), 249
dihydrocodeine, 211
intravenous
immunoglobulin, 677
moxonidine, 427
paclitaxel, 939
1078
COPD
see chronic obstructive
pulmonary disease
cornea verticillata
amiodarone, 382
corneal endothelial
decompensation
adrenaline (epinephrine),
316
corneal steepening
isotretinoin, 340
corneal swelling
acetazolamide, 437
corneal ulcers
mascara, 3345
coronary artery calcication
coumarin anticoagulants,
707
coronary artery disease
bezabrate, 922
clopidogrel, 721
mesalazine (5-aminosalicylic
acid, mesalamine), 757
ondansetron, 746
thiazolidinediones
(glitazones), 899
triptans, 408
venlafaxine and
desvenlafaxine, 31
coronary artery spasm
dobutamine, 319
coronary heart disease
antipsychotic drugs, 93
atorvastatin, 926
ezetimibe, 921
hormone replacement
therapy (HRT), 853
tibolone, 867
torcetrapib, 929
coronary stent
adrenaline (epinephrine), 315
Costello syndrome
phosphates, 755
Cotard's syndrome
aciclovir, 57778
cough
angiotensin converting
enzyme (ACE) inhibitors,
416
fentanyl, 212
immunoglobulin,
intravenous, 677
indacaterol, 3612
latanoprost, 984
remifentanil, 2223
sitaxsentan, 423
stem cells, 683
triphenylmethane dyes, 482
cramping
intravenous
immunoglobulin, 678
cutaneous ushing
paclitaxel, 9412
Index of adverse effects and reactions
cutaneous ischemia delusions
coumarin anticoagulants, 707 bismuth, 449
cutaneous lupus-like syndrome oxycodone, 220
terbinane, 541 pregabalin, 159
cutaneous vasculitis dementia
levooxacin, 5178 Ginkgo biloba, 995
cystic brosis lithium, 41
mannitol, 442 valproate sodium and
piperacillin tazobactam, 497 semisodium (divalproex),
cystitis 170
bacille Calmette-Gurin denervation hypersensitivity
(BCG) vaccine, 656 adrenaline (epinephrine),
hematologic, 483 316
cystoid macular edema dental implantation
prostaglandin analogues, titanium, 457
984 dental plaque biolms
cytotoxicity chlorhexidine, 481
docetaxel, 9456 depression
anthrax vaccine, 6556
D aripiprazole, 99100
dark urine cannabinoids, 741
acupuncture, 999 enfuvirtide, 598
darkening hair umazenil, 80
acitretin, 339 lacosamide, 13940
de Quervain's tenosynovitis lamotrigine, 142
somatropin, 911 levetiracetam, 148
death memantine, 16
aprotinin, 725 raltegravir, 599
clopidogrel, 723 risperidone, 113
fondaparinux, 718 tetrabenazine, 306
heparins, 7145 thyroid hormones, 882
human papilloma virus dermatitis
(HPV) vaccine, 658 See also allergic contact
intravenous dermatitis; contact
immunoglobulin, 677 dermatitis; radiation
parenteral nutrition, 699 dermatitis
deep ulceration benznidazole, 649
glutaral (glutaraldehyde), dermatomyositis
480 simvastatin, 928
deep vein thrombosis desaturation
coumarin anticoagulants, anticholinergic drugs, 26970
713 ketamine, 264
erythropoietin and propofol, 270
derivatives, 682 diabetes insipidus
prothrombin complex liposomal amphotericin
concentrate, 680 (L-AmB), 544
sclerosants, 10212 lithium, 4344
defecation disorders propofol, 274
proton pump inhibitors, 749 diabetes mellitus
dehydration antipsychotic drugs, 956
tacrolimus, 822 enteral nutrition, 701
water soluble intravascular gadolinium salts, 96970
iodinated contrast agents, HMG-CoA reductase
964, 967 inhibitors, 924
delirium niacin, 929
gabapentin, 138 paclitaxel, 939
levooxacin, 517 sirolimus (rapamycin), 820
oseltamivir, 601 tacrolimus, 823
pregabalin, 159 torcetrapib, 929
sevourane, 25960 vitamin E (tocopherol), 696
valproate sodium and water soluble intravascular
semisodium (divalproex), iodinated contrast agents,
170 964
Index of adverse effects and reactions 1079

diabetic gastroparesis tegaserod, 744 febuxostat, 250

domperidone, 742 tesofensine, 1415 gabapentin, 137
diabetic ketoacidosis thiopurines, 825 gamma-hydroxybutyric acid
ondansetron, 746 valproate sodium and (GHB), 645
diabetic macular edema semisodium (divalproex), human papilloma virus
pegaptanib, 978 1678 (HPV) vaccine, 658
diabetic neuropathy zonisamide, 180 iloperidone, 104
lacosamide, 139 difculty in thinking immunoglobulin,
diabetic polyneuropathy triptans, 408 intravenous, 677
gabapentin, 136 diffuse alveolar damage ketamine, 266
diarrhea leunomide, 818 lacosamide, 13940
see also bloody diarrhea diffuse alveolar hemorrhage lansoprazole amoxicillin
acupuncture, 999 leunomide, 818 metronidazole or
albumin-bound paclitaxel, 944 digestive intolerance clarithromycin, 749
aldesleukin (interleukin-2, benznidazole, 649 meoquine, 569
IL-2), 777 digital necrosis memantine, 16
aliskiren, 420 promethazine, 348 methylnaltrexone, 227
antimony, 448 dilated hypokinetic mexiletine, 389
balsalazide, 7567 cardiomyopathy midazolam, 75
blood substitutes, 672, 673 deferiprone, 469 modanil, 11
C1 esterase inhibitor diplopia morphine, 216
concentrate, 674 carbamazepine, 132 nitrates organic, 401
clindamycin, 522 deferiprone, 470 olmesartan, 419
darunavir, 5945 uoroquinolones, 514 omeprazole and
dexlansoprazole, 750 titanium, 456 esomeprazole, 752
docetaxel, 947 discomfort oxcarbazepine, 151
docosahexaenoic acid beta-adrenoceptor oxycodone, 220
(DHA) paclitaxel, 945 antagonists, 983 paclitaxel, 939
enfuvirtide, 598 betaxolol, 3978 palonosetron, 747
erythropoietin and disorientation pantoprazole, 752
derivatives, 682 bismuth, 449 parathyroid hormone, 913
febuxostat, 250 disseminated intravascular phenobarbital and
immunoglobulin, coagulation primidone, 154
intravenous, 678 intravenous anti-D posaconazole, 5534
incretin mimetics, 896 immunoglobulin, 679 postsynaptic a-adrenoceptor
ixabepilone, 949 prothrombin complex antagonists, 425
lacosamide, 140 concentrate, 680 pregabalin, 158
lactulose, 754 distaste pyrimethamine and
lansoprazole, 7501 lactulose, 754 congeners, 570
lanthanum carbonate, 451 distension quetiapine, 110
levooxacin, 516, 517 dexlansoprazole, 750 Rhododendron spp., 9968
loperamide, 760 dizziness selenium, 454
memantine, 16 5HT3 receptor antagonists, senna, 7545
mesalazine (5-aminosalicylic 744 tegaserod, 744
acid, mesalamine), 759 acupuncture, 999 thyroid hormones, 882
metoclopramide, 7423 adenosine receptor agonists, topiramate, 161
minocycline, 499 380 tramadol, 224
omeprazole and albendazole, 647 triptans, 408
esomeprazole, 752 alpha1-antitrypsin, 674 yellow fever vaccine, 664
paclitaxel, 940 benzydamine double vision
palonosetron, 747 (benzindamine), 249 lacosamide, 13940
pantoprazole, 752 buprenorphine, 225 pregabalin, 158
patupilone, 949 buspirone, 71 downbeat nystagmus
pranlukast, 367 butorphanol, 227 morphine, 217
proton pump inhibitors, 749 C1 esterase inhibitor Dravet's syndrome
prucalopride, 743 concentrate, 674 stiripentol, 160
psilocybin, 66 cannabinoids, 55 DRESS
sagopilone, 949 deferiprone, 470 see drug rash with
superparamagnetic iron dipyridamole, 719 eosinophilia and systemic
oxide, 971 donepezil, 15 symptoms
tacrolimus, 822823 efavirenz, 590 drowsiness
tafenoquine and primaquine, erythropoietin and 5HT3 receptor antagonists,
569 derivatives, 682 745
1080
albendazole, 647
baclofen, 303
levetiracetam, 146
methadone, 214
olanzapine, 104
oxcarbazepine, 151
palonosetron, 747
phenobarbital and
primidone, 154
vigabatrin, 177
drug rash with eosinophilia
and systemic symptoms
(DRESS)
acetylsalicylic acid, 248
allopurinol, 250
carbamazepine, 134
doxycycline, 499
glycopeptides, 519
lamotrigine, 144
oxazolidinones, 526
phenylbutazone, 2478
phenytoin and fosphenytoin,
156
strontium salts, 455
sulfasalazine, 759
titanium, 457
vancomycin, 520521
drug-resistant tuberculosis
ethambutol, 627
dry eyes
anti-glaucoma drugs, 982
dry lips
zonisamide, 181
dry mouth
buspirone, 71
C1 esterase inhibitor
concentrate, 674
Datura stramonium, 994
duloxetine, 31
gabapentin, 136
huperzine, 16
naltrexone, 228
olanzapine, 104
posaconazole, 5534 dystonia
quetiapine, 110
roxithromycin, 524
tesofensine, 1415
tiotropium bromide, 363
vasopressin, 915
dry mucosa
erythropoietin and
derivatives, 682
dry skin
chlorhexidine, 4801 eczema
diphenhydramine, 347
erythropoietin and
derivatives, 682
ductal carcinoma
barium sulfate, 9678
dysgeusia
itraconazole, 553
losartan, 419
dyskinesias
Index of adverse effects and reactions
quetiapine, 110 acetazolamide, 437
dyslipidemia aldesleukin (interleukin-2,
antipsychotic drugs, 90 IL-2), 777
rupatadine, 349 basiliximab, 785
dysmenorrhea factor IX (coagulation
risperidone, 1112 proteins), 680
dyspepsia interleukin-11 (IL-11,
palonosetron, 747 oprelvekin), 778
pantoprazole, 752 natalizumab, 791
dysphagia Patent Blue Violet dye, 484
alpha1-antitrypsin, 674 peroxisome proliferator-
baclofen, 3023 activated dual receptor
bran, 754 agonists, 902
lansoprazole, 751 pioglitazone, 900
dysphoria ranitidine, 748
cannabinoids, 55, 741 rituximab, 792
dysplasia rofecoxib, 247
cidofovir, 577 saxagliptin, 895
dyspnea sulprostone, 848
adenosine and analogues, 379 von Willebrand factor/factor
adenosine receptor agonists, VIII concentrates, 681
380 ejaculatory disorder
aldesleukin (interleukin-2, postsynaptic a-adrenoceptor
IL-2), 777 antagonists, 425, 427
alpha1-antitrypsin, 674 tamsulosin, 427
bosentan, 422 electrolyte abnormality
clenbuterol, 323 amphotericin (DAMB),
folic acid, 693 5423
glycoprotein IIb-IIIa electrolyte imbalance
inhibitors, 720 angiotensin converting
immunoglobulin, enzyme (ACE) inhibitors,
intravenous, 677 416
mifepristone, 867 embolism
ranitidine, 748 cyanoacrylates, 1014
rituximab, 792 rofecoxib, 247
sitaxsentan, 423 embolism/thrombosis
stem cells, 683 darbepoetin alfa, 682
ursodeoxycholic acid, 760 erythropoietin and
yellow fever vaccine, 664 derivatives, 682
zedoray tumeric oil and emergence delirium
glucose injection, 992 ketamine, 267
dysrhythmias sevourane, 2589
see cardiac dysrhythmias emesis
see vomiting
cetirizine, 345 emotional disturbances
methylthioninium chloride, mercury and mercurial
1019 salts, 453
triptans, 408 glucocorticoids, 842843
dysuria emotionalability
emergency contraption, 859 zonisamide, 180
tiotropium bromide, 363 empty sella syndrome
uorescein, 10167
E empty ventricle syndrome
dobutamine, 31920
alogliptin, 895 encephalastrapy
danaparoid sodium, 716 duloxetine, 31
immunoglobulin, encephalitis
intravenous, 678 minocycline, 500
pimecrolimus, 819 encephalomyelitis
tacrolimus, 822 human papilloma virus
edema (HPV) vaccine, 658
See also specic forms, such encephalopathy
as peripheral edema ciclosporin, 815
Index of adverse effects and reactions
gabapentin, 137
immunoglobulin,
intravenous, 677
morphine, 217
oxazolidinones, 525
pertussis vaccine, 657
valproate sodium and
semisodium (divalproex),
169
endometrial cancer
articial sweeteners, 1011
hormone replacement
therapy (HRT), 856
tamoxifen, 8634
endometrial hyperplasia
tibolone, 867
endometrial polyps
tamoxifen, 863
endophthalmitis
pegaptanib, 9778
postsynaptic a-adrenoceptor
antagonists, 426
ranibizumab, 97880
tamsulosin, 426
endothelial cell damage
coumarin anticoagulants, 708
energy, increased
levetiracetam, 148
enterocolitis
ribavirin, 581
eosinophilia
See also drug reaction with
eosinophilia and systemic
symptoms
enfuvirtide, 598
entecavir, 579
levooxacin, 517
mesalazine (5-aminosalicylic
acid, mesalamine), 758
eosinophilic pneumonia
daptomycin, 52930
minocycline, 499
epigastric pain
anthraquinones, 753
carp gallbladder, 999
cyanoacrylates, 1014
mucolytics, 369
epilepsy
See also myoclonus, status
epilepticus
carbapenem, 492
chlorphenamine, 3456
diphenhydramine, 347
parenteral nutrition, 698
triptans, 409
epiphora
docetaxel, 946
epiphysiolysis
somatropin, 911
epistaxis
Crataegus orientalis, 993
heparins, 7156
tacrolimus, 823
topiramate, 163
erectile dysfunction
beta-adrenoceptor
antagonists, 397
Rhododendron spp., 9968
erosive pustular dermatosis
aminolevulinic acid, 3389
eryptosis
azathioprine, 827
erythema
acupuncture, 999
docetaxel, 947, 948
fentanyl, 2123
nasteride, 873
glutaral (glutaraldehyde),
480
immunoglobulin,
intravenous, 678
insulin, 890
ling yang gan mao capsule,
990
pimecrolimus, 819
prilocaine and EMLA, 292
rivastigmine, 1617
water soluble intravascular
iodinated contrast agents,
967
erythema multiforme
carbamazepine, 1345
phenobarbital and
primidone, 154
valproate sodium and
semisodium (divalproex),
172
erythroderma
angiotensin converting
enzyme (ACE) inhibitors,
418
lisinopril, 418
erythrodermic psoriasis
trimethoprim and co-
trimoxazole, 529
esophageal carcinoma
enteral nutrition, 700
esophageal obstruction
bran, 754
esophageal perforation
ibuprofen, 246
esophageal ulceration
cyanoacrylates, 1014
esophagogastric cancer
docosahexaenoic acid
(DHA) paclitaxel, 9445
euphoria
gamma-hydroxybutyric acid
(GHB), 6465
exanthematous pustulosis
ciprooxacin, 515
exertional dyspnea
mesalazine (5-aminosalicylic
acid, mesalamine), 757
extrapyramidal effects
amisulpride, 8990, 99
1081
antipsychotic drugs, 93
aripiprazole, 99
extravascular hemolysis
intravenous anti-D
immunoglobulin, 679
eye discharge
beta-adrenoceptor
antagonists, 983
eye hyperemia
beta-adrenoceptor
antagonists, 983
eye movements, abnormal
methylthioninium chloride,
1019
eye pruritus
beta-adrenoceptor
antagonists, 983
eyelid swelling
travoprost, 985
eyes swollen
shen ling bai zhu san, 990
F
facial angioedema
omeprazole and
esomeprazole, 752
facial dysmorphism
lamotrigine, 145
facial edema
pseudoephedrine, 318
facial pain
lamotrigine, 1423
facial tremor
isourane, 258
faintness
albendazole, 647
Fanconi syndrome
adefovir, 5789
deferasirox, 468
tenofovir, 588
fasting plasma glucose,
increased
somatostatin, 914
fatal disease
oleic acid, 1020
fatigue
See also malaise, weakness
acupuncture, 999
aldesleukin (interleukin-2,
IL-2), 777
aripiprazole, 1001
azathioprine, 827
benznidazole, 649
daclizumab, 788
docosahexaenoic acid
(DHA) paclitaxel, 945
erythropoietin and
derivatives, 682
exemestane, 861
lgrastim, 769
gabapentin, 137
immunoglobulin,
intravenous, 677678
1082
interferon alfa, 774
interleukin-11 (IL-11,
oprelvekin), 778
interleukin-18 (IL-18), 779
lacosamide, 13940
lenograstim, 770
letrozole, 862
levetiracetam, 148
memantine, 16
mercaptopurine, 830
mesalazine (5-aminosalicylic
acid, mesalamine), 758
mifepristone, 867
oxcarbazepine, 151
patupilone, 949
pregabalin, 159
risperidone, 111
rituximab, 792
selenium, 454
simvastatin, 928
temsirolimus, 824
tiagabine, 161
topiramate, 1612
vigabatrin, 177
yellow fever vaccine, 664
zonisamide, 180
febrile convulsions
measles-mumps-rubella-
varicella (MMRV)
vaccine, 662
fetal intrauterine growth
retardation
manganese, 452
fetal valproate syndrome
valproate sodium and
semisodium (divalproex),
174
fetotoxicity
cocaine, 601
methadone, 215
fever
aldesleukin (Interleukin-2,
IL-2), 777
amiodarone, 382
amphotericin (ABCD),
542
anthraquinones, 753
blood substitutes, 672
C1 esterase inhibitor
concentrate, 674
clonidine, 424
cyanoacrylates, 1015
edrecolomab, 788
eornithine, 574
Exilis, 9945
lgrastim, 769
formoterol, 360
furosemide, 440
gabapentin, 137
gadolinium salts, 970
gemtuzumab ozogamicin,
78990
glycopeptides, 519
Index of adverse effects and reactions
immunoglobulin, ushing
intravenous, 677678 adenosine receptor agonists,
immunoglobulin, 37980
subcutaneous, 6789 ambrisentan, 421
inuenza H1N1 vaccines, buspirone, 71
660 docetaxel, 948
interleukin-18 (IL-18), 779 gonadotropins, 910
iodine, 485 heparins, 716
labetalol, 399 immunoglobulin,
lenograstim, 770 intravenous, 677
loperamide, 760 niacin, 928
mesalazine (5-aminosalicylic peruorocarbons, 972
acid, mesalamine), 757 phosphodiesterase type V
penicillins, 495 inhibitors, 409
pertussis vaccine, 657 pimecrolimus and
pseudoephedrine, 318 tacrolimus, 338
pyrimethamine and fractures
congeners, 570 heparins, 7156
rabies vaccine, 662 inhaled glucocorticoids, 356
sargramostim, 771 postsynaptic a-adrenoceptor
sirolimus (rapamycin), 821 antagonists, 425
stem cells, 683 tamoxifen, 862
suramin, 650 tenofovir, 589
terbinane, 541 tibolone, 867
topiramate, 165 vitamin A (carotenoids),
triphenylmethane dyes, 692
482 fragile X syndrome
vitamin A (carotenoids), minocycline, 499
692 Fuchs dystrophy (corneal
yellow fever vaccine, 664 edema)
brotic heart valve disease amantadine, 6024
dopamine, 321 fungal infections, invasive
stulae See also individual organisms
bevacizumab, 786 liposomal amphotericin
xed dilated pupils (L-AmB), 5434
topical anesthesia, 2889 fungal tracheitis
xed drug eruption triphenylmethane dyes, 482
clopidogrel, 721
desloratadine, 346 G
nasteride, 873 gait disorder
ecainide, 387 donepezil, 15
gabapentin, 137138 trimethoprim and
nimesulide, 249 co-trimoxazole, 528
paracetamol galactorrhea
(acetaminophen), 245 risperidone, 113
piroxicam, 247 gallbladder abnormalities
propitocaine, 293 octreotide, 914
quinine and congeners, 571 gallbladder sludge
trimethoprim and co- tacrolimus, 822
trimoxazole, 529 gallstones
atulence somatostatin, 9134
dexlansoprazole, 750 gastric adenocarcinoma
methylnaltrexone, 227 docetaxel, 945
palonosetron, 747 gastric cancer
proton pump inhibitors, articial sweeteners, 1011
74950 parenteral nutrition, 697
raltegravir, 599 gastric pain
oaters Actaea racemosa, 992
ranibizumab, 980 gastroesophageal reux
u-like symptoms domperidone, 742
see inuenza hormone replacement
uid retention therapy (HRT), 855
docetaxel, 945 metoclopramide, 743
Index of adverse effects and reactions
gastrointestinal bleeding
clopidogrel, 721
coumarin anticoagulants, 710
cyanoacrylates, 1014
glutaral (glutaraldehyde),
480
gastrointestinal cancer
sulfonylureas, 898
gastrointestinal disorder
Actaea racemosa, 992
adenosine receptor agonists,
380
albendazole, 647
atorvastatin, 926
deferasirox, 467
dexlansoprazole, 750
erythromycin, 523
itraconazole, 553
lamotrigine, 1412
levooxacin, 516
myrrh, 64950
naltrexone, 228
niacin, 928929
nitrous oxide, 262
phenobarbital and
primidone, 154
protease inhibitors, 628
semisodium (divalproex),
1678
strontium salts, 455
tacrolimus, 821
thiopental sodium, 275
valaciclovir, 578
valproate sodium and
semisodium (divalproex),
1678
gastrointestinal hemorrhage
deferasirox, 467
diclofenac, 246
verteporn and
photodynamic therapy,
981982
gastrointestinal motility
proton pump inhibitors, 749
gastrointestinal obstruction
tiotropium bromide, 363
gastrointestinal ulceration
glutaral (glutaraldehyde),
480
genotoxicity
nitrous oxide, 262
gestational hypertension
antiepileptic drugs, 130
vitamin C (ascorbic acid),
694
gingival bleeding
tacrolimus, 823
gingival hyperplasia
calcium channel blockers,
401
phosphates, 755
gingival infection
lamotrigine, 1423
glaucoma
intravitreal injection, 985
topiramate, 164, 167
gliobastoma
Morinda citrifolia, 996
glomerular function, impaired
tenofovir, 588589
glucocorticoids
amiodarone, 383
danaparoid sodium, 716
glucose tolerance, impaired
somatropin, 911
goiter
amiodarone, 382
antithyroid drugs, 885
iodine and iodides, 883
thyrotropin (thyroid-
stimulating hormone,
TSH), 881
goitrous hypothyroidism
penicillamine, 4723
Goldenhar's syndrome
tamoxifen, 864
gonadal dysfunction
sirolimus (rapamycin),
8201
graft-versus-host disease
(GvHD)
blood transfusion, 671 hand-foot syndrome
nifedipine, 402
stem cells, 683
granulomas
non-animal stabilized
hyaluronic acid
(NASHA), 335
thorotrast, 973 Hansen's disease
granulomatous interstitial
nephritis
phenytoin and fosphenytoin,
156 head cancers
granulomatous lung disease
titanium, 4578 headache
granulomatous prostatitis
bacille Calmette-Gurin
(BCG) vaccine, 656
Graves' disease
antithyroid drugs, 884
interferon alfa, 775
minocycline, 500
radioactive iodine, 883
rituximab, 791
green monkey kidney cells
strontium salts, 455
green urine
propofol, 275
groin pain
cobalt, 450
growth retardation
sirolimus (rapamycin), 820
GuillainBarr syndrome
alemtuzumab, 784
Human papilloma virus
(HPV) vaccine, 658
1083
iniximab, 782
inuenza H1N1 vaccines,
659
measles-mumps-rubella
(MMR) vaccine, 661
gynecological malignancies
paclitaxel, 942
tibolone, 8678
gynecomastia
metoclopramide, 743
risperidone, 1113
H
hair loss
see alopecia
hallucinations
anticholinergic drugs, 324
benzydamine
(benzindamine), 249
cannabinoids, 55
diamorphine (heroin), 211
efavirenz, 590
isourane, 258
lamotrigine, 143
lidocaine, 3889
memantine, 16
montelukast, 3667
oseltamivir, 601
mercaptopurine, 830
hands itching
ling yang gan mao capsule,
990
hangover
efavirenz, 590
iniximab, 783
Hashimoto's encephalopathy
lithium, 43
paclitaxel, 936
see also migraine
5HT3 receptor antagonists,
744
adenosine receptor agonists,
380
agomelatine, 33
albendazole, 647
aliskiren, 420
alpha1-antitrypsin, 674
anthrax vaccine, 6556
aripiprazole, 101
balsalazide, 7567
benznidazole, 649
bosentan, 422
cibenzoline, 385
C1 esterase inhibitor
concentrate, 674
dipyridamole, 719
donepezil, 1516
Ecballium elaterium, 994
epoprostenol, 847
1084
erythropoietin and
derivatives, 682
gonadotropins, 909
human papilloma virus
(HPV) vaccine, 658
huperzine, 16
iloprost, 847
intravenous
immunoglobulin, 677
iodine, 485
itraconazole, 553
khat, 66
lacosamide, 140
lansoprazole, 7501
lansoprazole amoxicillin
metronidazole or
clarithromycin, 749
latanoprost, 985
levetiracetam, 148
levooxacin, 516, 517
lithium, 45
long-acting beta2-
adrenoceptor agonists
(LABAs), 359
melatonin, 912
memantine, 16
mercaptopurine, 830
mesalazine (5-aminosalicylic
acid, mesalamine), 759
modanil, 11
moxonidine, 427
naltrexone, 228
nitrates organic, 400, 401
nitrous oxide, 261
ondansetron, 746
oxycodone, 220
paclitaxel, 939
palonosetron, 747
pantoprazole, 752
penicillins, 495
peruorocarbons, 972
phosphodiesterase type V
inhibitors, 409
posaconazole, 5534
praziquantel, 650
pregabalin, 158
proton pump inhibitors, 749
prucalopride, 743
pseudoephedrine, 318
pyrimethamine and
congeners, 570
rabies vaccine, 662
risperidone, 113
roumilast, 368
roxithromycin, 524
senna, 7545
superparamagnetic iron
oxide, 971
tacrolimus, 823
tegaserod, 744
terbinane, 541
thiopurines, 825
tiagabine, 161
Index of adverse effects and reactions
topiramate, 161 hemoglobin, rise in
triptans, 409 thyroid hormones, 882
valaciclovir, 578 hemoglobinuria
valproate sodium and blood substitutes, 672
semisodium (divalproex), hemolysis
169 immunoglobulin,
valsartan, 420 intravenous, 677
vildagliptin, 895 micafungin, 559
yellow fever vaccine, 664 rasburicase, 250
zileuton, 369 hemolytic anemia
zonisamide, 17980 See also anemia
hearing loss ceftriaxone, 4934
gabapentin, 137 cephalosporins, 493
heart cimetidine, 748
See also cardi- ciprooxacin, 515
heart block dapsone, 630, 631, 632
dobutamine, 319 methyldopa, 424
umazenil, 81 piperacillin tazobactam,
heart failure 497
anticholinergic drug, rifampicin, 639
inhaled, 364 sulfadiazine, 528
bezabrate, 922 hemolytic-uremic syndrome
deferiprone, 469 ciclosporin, 816
diazoxide, 4278 hemopoietic cancers
dofetilide, 386 pentachlorophenol, 486
rosiglitazone, 899 hemorrhage
thiazolidinediones cyanoacrylates, 1014
(glitazones), 899 deferasirox, 467
trastuzumab, 793 Ginkgo biloba, 995
vasopressin, 915 rofecoxib, 247
vitamin E (tocopherol), 696 hemorrhagic cystitis
heart rate increase atorvastatin, 927
ketamine, 264 hemorrhagic pericarditis
heart rate reduction glycoprotein IIb-IIIa
blood substitutes, 673 inhibitors, 720
thyroid hormones, 882 hepatic cirrhosis
heartburn and diarrhea amiodarone, 381
mucolytics, 369 lactulose, 754
hematochezia terlipressin, 917
zhi xue capsule, 990 Uncaria tomentosa, 998
hematuria vasopressin, 915
bacille Calmette-Gurin verteporn and
(BCG) vaccine, 656 photodynamic therapy,
immunoglobulin, 9812
intravenous, 678 hepatic damage
hemifacial dystonia Actaea racemosa, 992
clebopride, 742 amiodarone, 3834
hemiparesis antiepileptic drugs, 129
gonadotropin, 851 clopidogrel, 721
triptans, 409 coumarin anticoagulants, 708
hemiplegic migraine dabigatran, 718
nimodipine, 403 ethambutol, 627
hemoglobinemia/ Exilis, 9945
hemoglobinuria Garcinia gambogia, 9945
intravenous anti-D gemtuzumab ozogamicin,
immunoglobulin, 679 78990
hemodialysis Hydroxycut, 9945
heparins, 716 isoniazid, 636
metformin, 484 parenteral nutrition, 698
pregabalin, 160 pioglitazone, 900
vitamin D analogues, 695 trovaoxacin, 519
hemoglobin, reduced zhi xue capsule, 990
bosentan, 422 zhuang gu guan jie wan, 990
Index of adverse effects and reactions 1085

hepatic dysfunction hepatocellular carcinoma horizontal nystagmus

paclitaxel, 937 cyanoacrylates, 1014 toluene, 1024
parenteral nutrition, 6989 hematologic, 484 Horner's syndrome
hepatic encephalopathy terlipressin, 917 brachial plexus anesthesia,
efavirenz, 590 hepatocellular inammation 283
hepatic failure antithyroid drugs, 885 epidural anesthesia, 2834
acitretin, 340 hepatorenal syndrome extrapleural anesthesia, 287
cyanoacrylates, 1015 terlipressin, 917 hostility
levetiracetam, 149 hepatotoxicity zonisamide, 180
nilutamide, 874 amiodarone, 3834 hot ushes
nimesulide, 249 antimony, 448 letrozole, 862
thyroid hormones, 8823 Camellia sinensis, 995 hungry bone syndrome
trovaoxacin, 519 utamide, 873 deferasirox, 468
valproate sodium and isoniazid, 628, 635 Huntington's disease
semisodium (divalproex), NNRTIs, 590 tetrabenazine, 306
172 ondansetron, 7467 valproate sodium and
venlafaxine and posaconazole, 554 semisodium (divalproex),
desvenlafaxine, 32 rifampicin, 638 16970
vitamin A (carotenoids), 692 rivastigmine, 17 Hurler's syndrome
hepatic impairment telithromycin, 5212 somatropin, 911
aripiprazole, 1012 valproate sodium and hyperactivity
rupatadine, 349 semisodium (divalproex), levetiracetam, 147
hepatic insufciency 176 stiripentol, 1601
tiagabine, 161 vitamin A (carotenoids), 691 hyperadrenergic syndrome
hepatic nodular regenerative voriconazole, 554, 555 metoprolol, 399
hyperplasia heriditary angioedema, hyperammonemic
azathioprine, 827 exacerbation encephalopathy
hepatic steatosis tamoxifen, 863 lamotrigine, 146
labetalol, 399 herpes simplex keratitis, topiramate, 1645
hepatitis reactivation valproate sodium and
See also cholestatic hepatitis, prostaglandin analogues, semisodium (divalproex),
steatohepatitis 984 176
5HT3 receptor antagonists, herpes zoster infection hyperamylasemia
745 citalopram, 29 thyrotropin (thyroid-
alcohol, 1008 hiccups stimulating hormone,
amodiaquine, 567 epidural anesthesia, 284 TSH), 881
atorvastatin, 9267 levodopa, 320 hyperandrogenism
azathioprine, 829 midazolam, 75 lamotrigine, 1434
benznidazole, 649 stem cells, 683 valproate sodium and
buprenorphine, 225 hip osteoarthritis semisodium (divalproex),
chloramphenicol, 514 verteporn and 173
chloroform, 257 photodynamic therapy, hyperarousal
doxycycline, 499 9812 ketamine, 263
famotidine, 748 hirsutism hyperbilirubinemia
halothane, 257 utamide, 8734 docosahexaenoic acid
iodine, 485 HIV infection (DHA) paclitaxel, 945
itraconazole, 552 hormone replacement ibuprofen, 246
mesalazine (5-aminosalicylic therapy (HRT), 857 oxazolidinones, 526
acid, mesalamine), 758 ibalizumab, 790 hypercalcemia
methyldopa, 424 iodine, 485 parathyroid hormone, 913
micafungin, 558 lithium, 42 vitamin D analogues, 695
sitaxsentan, 423 triphenylmethane dyes, hypercalciuria
thiopurines, 826 4812 parathyroid hormone, 913
hepatitis, autoimmune hoarseness hyperchloremic metabolic
minocycline, 500 glucocorticoids inhaled, 354 acidosis
hepatitis, cytolytic long-acting beta2- midazolam, 76
methotrexate, 950 adrenoceptor agonists hypercholesterolemia
hepatitis B virus infection (LABAs), 3589 etravirine, 592
iron chelators, combinations, Hodgkin's lymphoma protamine, 727
4712 azathioprine, 828 temsirolimus, 824
vitamin A (carotenoids), 692 vincristine, 951 hyperemia
hepatitis C virus infection Hoign syndrome betaxolol, 3978
ursodeoxycholic acid, 760 clarithromycin, 524 oxazolidinones, 526
1086 Index of adverse effects and reactions

hyperesthesia azathioprine, 829 minocycline, 499, 500

topiramate, 163 aztreonam, 495 radioactive iodine, 883
hyperglycemia bosentan, 4223 thyroid hormones, 8812
niacin, 929 caspofungin, 557 hypertrichosis
parenteral nutrition, 6978 ceftriaxone, 494t ciclosporin, 816
pioglitazone, 900 dextrans, 675 henna, 336
tacrolimus, 821 enfuvirtide, 598 hypertriglyceridemia
temsirolimus, 824 folic acid, 693 gembrozil, 923
valproate sodium and furosemide, 441t parenteral nutrition, 697
semisodium (divalproex), henna, 336 valproate sodium and
171 heparins, 715, 716 semisodium (divalproex),
hyperhomocysteinemia human papilloma virus 171
valproate sodium and (HPV) vaccine, 658 hypertrophic cardiomyopathy
semisodium (divalproex), minocycline, 500 phosphates, 755
169 nitrofurantoin, 525 hypertrophied endothelial cells
hyperinsulinemia non-animal stabilized titanium allergy, 457
valproate sodium and hyaluronic acid hyperuricemia
semisodium (divalproex), (NASHA), 335 niacin, 929
171 paclitaxel, 937 hyperviscosity
hyperkalemia thiopurines, 826 immunoglobulin,
angiotensin converting hypersensitivity syndrome intravenous, 677
enzyme (ACE) inhibitors, carbamazepine, 134 hypervitaminosis
416, 4178 minocycline, 500 vitamin A (carotenoids),
captopril, 418 moxioxacin, 519 691
cardiac glycosides, 378 sulfasalazine, 759 hyperzincemia
heparins, 713 zonisamide, 181 zinc, 458
liposomal amphotericin hypersomnia hypethesia
(L-AmB), 544 palonosetron, 747 topiramate, 162
losartan, 419 hypersomnolence hyphema
spironolactone, 4402 cycloserine, 630 coumarin anticoagulants,
hyperkeratosis hypertension 708
valproate sodium and See also blood pressure, hypoalbuminemia
semisodium (divalproex), increased factor IX (coagulation
172 alcohol, 1009 proteins), 680
hyperkinesias bevacizumab, 786 hypocalcemia
topiramate, 1667 carbamazepine, 132 chelators, 474
hyperlactatemia coumarin anticoagulants, deferasirox, 467, 468
stavudine, 583 7078 lactulose, 754
hyperlipidemia dipyridamole, 719 mannitol, 442
antipsychotic drugs, 96 epoprostenol, 847 omeprazole and
hypermagnesemia erythropoietin and esomeprazole, 751
magnesium salts, 452 derivatives, 682 phosphates, 755
hyperphosphatemia gadolinium salts, 96970 strontium salts, 455
phosphates, 755 huperzine, 16 hypocupremia
hyperpigmentation immunoglobulin, chelators, 474
ribavirin, 5801 intravenous, 677 zinc, 458
hyperplasia interleukin-11 (IL-11, hypobrinogenemia
ciclosporin, 817 oprelvekin), 778 tigecycline, 501
dexlansoprazol, 750 iodinated contrast agents, hypoglycemia
hormone replacement 963 angiotensin converting
therapy (HRT), 854 khat, 66 enzyme (ACE) inhibitors,
hyperprolactinemia metoclopramide, 743 417
antipsychotic drugs, 8990 milrinone, 3789 antihelminthic drugs, 647
domperidone, 742 olanzapine, 104 gliclazide, 898
hypersensitivity pneumonitis paclitaxel, 938 incretin mimetics, 896
mesalazine (5-aminosalicylic Rhododendron spp., 9968 insulin, 479
acid, mesalamine), 757 stem cells, 683 levooxacin, 517
penicillamine, 472 vigabatrin, 177 meglitinides, 897
hypersensitivity/ hypertension, arterial repaglinide, 897
hypersusceptibility reactions nitric oxide, 260 tegaserod, 744
See also antiepileptic drug hyperthermia vildagliptin, 895
hypersensitivity, denervation See fever hypohidrosis
hypersensitivity hyperthyroidism topiramate, 165
Index of adverse effects and reactions 1087

hypokalemia esmolol, 398 ileal perforation

5HT3 receptor antagonists, fentanyl, 2123 polystyrene sulfonates, 474
7445 hematologic, 484 imbalance
acetazolamide, 4378 heparins, 716 gabapentin, 137
aminoglycoside antibiotics, immunoglobulin, immunodeciency
509 intravenous, 677 inuenza H1N1 vaccines,
esmolol, 398 ketamine, 266 659
glucocorticoids, 842 losartan, 419 immunological sequelae
laxatives and oral bowel metoclopramide, 7423 brin glue, 6745
preparations, 753 midazolam, 75 incontinence
levooxacin, 516 natalizumab, 791 see urinary incontinence
omeprazole and olanzapine, 104 indigestion
esomeprazole, 751 paclitaxel, 938, 9412 bisacodyl, 7534
piperacillin tazobactam, 497 pegaptanib, 9778 infantile spasms
thiazide and thiazide-like peruorocarbons, 972 vigabatrin, 1767
diuretics, 4389 phosphates, 755 infections
hypomagnesemia propofol, 271 eornithine, 574
lactulose, 754 protamine, 727 tacrolimus, 821
omeprazole and quinidine and derivatives, infertility
esomeprazole, 751 3901 sirolimus (rapamycin), 8201
hyponatremia ranitidine, 748 inammation
antiepileptic drugs, 126 remifentanil, 222 hydroxyethylmethacrylate
carbamazepine, 132 Rhododendron spp., 9968 and ethylmethacrylate, 335
desmopressin, 916 spinal (intrathecal) inammation/infection of the
duloxetine, 31 anesthesia, 284 prostate
ecainide, 387 stem cells, 683 diethylstilbestrol, 852
mannitol, 442 sulfur hexauoride, 972 inammation/infection of the
mirtazapine, 34 tacrolimus, 824 testicular
oxcarbazepine, 132 thiopental sodium, 275 diethylstilbestrol, 852
oxytocin and analogues, 913 valsartan, 420 inammatory bowel disease
phenytoin and fosphenytoin, verapamil, 403 aminosalicylates, 756
155 water soluble intravascular azathioprine, 829
pregabalin, 15960 iodinated contrast agents, isotretinoin, 340
sodium picosulfate, 756 967 lithium, 45
thiazide and thiazide-like hypotension, paradoxical parenteral nutrition, 699
diuretics, 4389 adrenaline (epinephrine), thiopurines, 825
thyroid hormones, 882 316 inammatory reactions
valproate sodium and hypothermia albumin-derived
semisodium (divalproex), topiramate, 166 hemostatics, 670
175 hypothyroidism penicillins, 495
vasopressin, 9156 antiepileptic drugs, 126 titanium, 457
hypophosphatemia iodine and iodides, 883 inuenza
parenteral nutrition, 698 metoclopramide, 743 aldesleukin (interleukin-2,
temsirolimus, 824 phenytoin and fosphenytoin, IL-2), 778
hypophosphatemic 155 aripiprazole, 101
osteomalacia polyvinylpyrrolidone, 485 blood substitutes, 673
adefovir, 579 temsirolimus, 824 coumarin anticoagulants, 711
hypoplasia hypoxia immunoglobulin,
candesartan, 419