Académique Documents
Professionnel Documents
Culture Documents
Published by the Centre for Drug Administration, HSA and the Pharmacovigilance Advisory Committee
seltamivir (Tamiflu , Roche) was recently licensed for the treatment of uncomplicated illness due to influenza infections in children 1 year of age and older who have been symptomatic for no more than 2 days. It has been licensed for use in adults since October 2000. We highlight the findings of a recent preclinical study which alerts to the potential concerns pertaining to the use of Tamiflu in very young children.
the concerns to the regulatory authorities regarding the use of Tamiflu in infants.
Juvenile rats that were treated with a single dose of 1000 mg/kg oseltamivir (about 250 times the recommended total daily dose) died due to the unusually high levels of oseltamivir and its phosphate salt found in the brain of these young animals. The concentrations of oseltamivir phosphate were approximately 1,500 times those seen in adult rats given the same dose. It is likely that these high exposures are related to an immature blood brain barrier of the juvenile rats. Studies showed no death or other
significant effects in older juvenile rats given the same or higher doses of Tamiflu.
Content
Repor ting Made Easy: Online adverse drug reaction repor ting is available at http://www.hsa.gov.sg/ADR_online
Suspected drug
Suspected drug
Abnormal hepatic function / Increased hepatic enzymes / Jaundice Fatty liver Hepatic failure
Nimesulide (1) Sodium valproate (2) Phenytoin or piperacillin plus tazobactam (1) Sodium valproate (1) Allopurinol (1) Complementary medicine (1) Isoniazid or pyrazinamide or rifampicin (1) Phenobarbitone (1) Allopurinol (2) Complementary medicine (2) Complementary medicine or isoniazid or pyrazinamide or rifampicin (1) Sodium valproate (1) Chlorpromazine (1) Lovastatin (1) Simvastatin (1) Diclofenac (1) Losartan (1) Lovastatin (1) Rofecoxib (2) Teicoplanin or imipenem plus cilastin (1) Rofecoxib (1) Rituximab (1) Atovaquone plus proguanil (1) Alka-seltzer or ketoprofen (1) Allopurinol or enalapril(1) Cefazolin or diclofenac (1) Co-trimoxazole (1) Diclofenac (1) Iohexol (2) Naproxen (1) Paracetemol or tolbutamide (1) Prochlorperazine (1) Streptokinase (1) Teicloplanin or vancomycin (1) Vitamin K (1) Atracurium or propofol (1) Bromhexine or cefalexin (1) Cefazolin or diclofenac (1) Ceftriaxone (3) Ciprofloxacin (1) Ciclosporin (1) Diclofenac (4) Iohexol (1) Mepivacaine (1) Sulfasalazine (1) Hydrochlorothiazide (1) Imipenem plus cilastin or vancomycin (1) Rifampicin (1) Allopurinol (2) Amitriptyline or carbamazepine (1) Amoxicillin (1) Amoxicillin or complementary medicine or ibuprofen (1)
No. of ADRs
887 361 136 86 62 42 41 33 26 26
Hepatitis
Amoxicillin or nimesulide or spiramycin (1) Aspirin or Alka-seltzer or cotrimoxazole or diclofenac (1) Carbamazepine (3) Carbamazepine or hydrochlorothiazide (1) Cefadroxil (1) Cefalexin or chloramphenicol (1) Coamoxiclav or carbamazepine (1) Complementary medicine (2) Co-trimoxazole or phenytoin or sulfasalazine(1) Lamotrigine (1) Trimethoprim (1) Amoxicillin (2) Ampicillin or ceftriaxone or vancomycin (1) Coamoxiclav (1) Coamoxiclav or ceftriaxone (1) Co-trimoxazole (1) Co-trimoxazole or cefuroxime (1) Levofloxazin (1) Mefenamic acid (1) Nitrofurantoin (1) Rosiglitazone (1) Amifostine (1) Ampicillin or propofol (1) Bromhexine or cefalexin (1) Cefaclor (1) Ceftriaxone (1) Cisplatin (1) Complementary medicine (1) Etoposide (1) Mepivacaine (1) Ondansetron (1) Orphenadrine or paracetemol or Panadeine (1) Paclitaxel (2) Paroxetine (1) Streptokinase (1) Rosiglitazone (1) Suxamethonium or asparaginase (1) Warfarin (1) Amiloride plus hydrochlorothiazide (2) Carbamazepine (1) Citalopram (1) Hydrochlorothiazide (1) Hydrochlorothiazide plus losartan (1) Indapamide (1) Losartan (1) Rofecoxib (1)
Rhabdomyolysis
* The system-organ class refers to the adverse reaction terminology developed by the WHO. (NB: More than one ADR may be described in an ADR report)
<1
1-12
13-24
25-44
45-60
Overview of reports
From our analysis, the number of ADR reports received by the Pharmacovigilance Unit from 1997 to 2003 has been increasing steadily at an average of 20% per annum. For 2003, the unit received 1,100 reports; this represented a 38% increase over the number of reports received in 2002. The public hospitals contributed the majority of the reports (60.3%), followed by the private clinics (14.3%), public health institutions (10.3%), private hospitals/ health institutions (8.1%), pharmaceutical companies (4.2%), polyclinics (2.3%) and retail pharmacies (0.5%). Three-quarter of the reporters were doctors but reports from pharmacists have increased (197 reports for 2003 compared to 137 in 2002).
Age (years)
Amantadine or peginterferon alpha-2b or ribavirin (1) Carbamazepine (2) Carbimazole (2) Ciprofloxacin or phenytoin (1) Clopidogrel (1) Doxorubicin (1) Meropenem (1) Ranitidine or sodium valproate or vancomycin (1) Ticlopidine (1) Ticlopidine or imipenem plus cilastin (1) Vancomycin (1) Ciprofloxacin or phenytoin (1) Dapsone (1) Paroxetine (1) Carbamazepine (2) Gefitinib (1) Alka-seltzer or ketoprofen (1) Amoxicillin or diclofenac (1) Atracurium or morphine (1) Bromhexine or cefalexin (1) Cefaclor (1) Cefazolin or diclofenac (1) Ceftriaxone (1) Iohexol (1) Mepivacaine (1) Orphenadrine or paracetemol or Panadeine (1) Sultamicillin (1) Clonazepam or imipramine or risperidone (1) Chlorpromazine (1) DTP Vaccine (1) Imipenem plus cilastin (1) Infanrix IPV-HIB inj (2) Suxamethonium or asparaginase (1)
Neuroleptic malignant syndrome Psychosis Optic atrophy Brachial neuritis Motor activity retarded / Ataxia Hemiparesis Intraventricular haemorrhage Serotonin syndrome
Clonazepam or imipramine or risperidone (1) Haloperidol (1) Chloroquine (1) Hydroxychloroquine (1) Hepatitis B inj (1) Celecoxib (1) Paroxetine (1) Oxaliplatin (1) Warfarin (1) Paroxetine (1) Lovastatin (2) Complementary medicine or prednisolone (1) Complementary medicine (1) Indapamide (1) Respiratory disorders (28)
Interstitial nephritis / Proteinuria Nephropathy Pulmonary fibrosis Breathing difficulty / Shortness of breath / Stridor / Hypoxia
No. of reports
100 67 67 51 50 48 42 28 24 24 22 21 21 21 20
Anaphylactic reactions
Acute pancreatitis Adrenal insufficiency / Cushings syndrome Syndrome of inappropriate ADH secretion Diabetes mellitus
Bronchospasm / Wheezes
Olanzapine (1) Aspirin (1) Carbamazepine or hydrochlorothiazide (1) Clopidogrel (1) Co-trimoxazole or cefuroxime (1) Warfarin (1) Allopurinol (3) Complementary medicine (1) Ciclosporin (1) Moxifloxacin (1) Skin reactions (32) Exfoliative dermatitis
NB: The above data cannot be used to measure the frequency of an ADR in Singapore as ADR reporting is associated with an unknown and a variable degree of under-reporting. The submission of a suspected ADR report also does not necessarily mean that it was caused by the drug. Many factors have to be taken into account in assessing causal relationships including temporal association, the possible contribution of concomitant medication and the underlying disease.
continued from Page 1 Case report of Cushings syndrome with traditional medicine (Pil Ajaib)
On admission to the hospital for other medical conditions, the attending doctor noted that the patient was clinically cushingnoid. The patient who was not on any other medications also complained of weight gain, multiple joint pains and lethargy. Further tests conducted suggested that the Cushings syndrome may be precipitated by consumption of exogenous steroids.
labelling. The purchase of these products from unreliable sources could pose additional safety problems if they are adulterated with western medicines. As part of medical history taking, healthcare professionals are encouraged to ask if their patients are also taking complementary medicine. Healthcare professionals are encouraged to report any suspected ADRs arising from consumption of complementary medicines to the Pharmacovigilance Unit at HSA. If adulterations with western drugs are suspected, samples may be forwarded together with the report for further investigations.
HSA investigations
The analysis of the samples of Pil Ajaib revealed that it was adulterated with indomethacin 15.42 mg/capsule and dexamethasone 0.22 mg/capsule. Based on the manufacturers recommended dose of 4 capsules per day, the total intake of indomethacin and dexamethasone per day are about 60 mg and 0.88 mg respectively. These are therapeutic doses of the two drugs. The presentation of Cushings syndrome in this patient is consistent with the effects of prolonged consumption of dexamethasone.
Conclusion
Herbal medicinal products are generally perceived by the public to be safer than conventional western medicines. However the safety of some unlicensed herbal products may be compromised by lack of suitable quality control and inadequate
Doxycycline Oesophagitis
Take doxycycline with food or a large glass of water while in an upright position
&
(TGA) received 46 suspected reports of oesophagitis and 49 suspected reports of oesophageal ulceration associated with this drug 2.
oxycycline is the most commonly reported tetracycline analogue that causes oesophagitis. More than 70 drugs have been reported in the literature to induce oesophageal disorders, however antibacterials such as doxycycline, tetracycline and clindamycin account for more than 50% of cases 1.
Mechanism of action
Patients who have difficulty in swallowing solid dosage forms of medications are more susceptible to doxycycline-induced oesophagitis. When the doxycyline tablet /capsule transits down the oesophageal lumen, it dissolves to form an acidic solution. High local concentrations of the acidic solution resulting from increased transit time or when the drug gets lodged in the oesophagus can cause mucosal lesions. In addition, reflux of the medication which can occur when a patient lies down soon after taking the drug can also cause similar problems. Symptoms of reflux oesophagitis include heartburn, retrosternal pain and regurgitation.
Doxycycline-induced oesophagitis is often self-limiting upon discontinuation of the drug. However, in severe cases, symptomatic treatment may be required.
Overseas reports
The WHO ADR database (which captures the spontaneous ADR reports from more than 60 countries participating in the WHO International Drug Monitoring Program) has 352 suspected reports of doxycyclineinduced oesophagitis for the period 1969 to 2003. The New Zealand Pharmacovigilance Centre has received 46 suspected reports of oesophagitis associated with doxycycline for the period up to October 2003 and the Australia Therapeutic Goods Administration
Advice to patients
To minimise this risk, patients should be advised to take doxycycline in an upright position, with food or with a large glass of water and to also avoid taking it just before bedtime.
References 1. Jaspersen D. Drug-induced oesophageal disorders: pathogenesis, incidence, prevention and management. Drug Saf. 2000 Mar; 22(3): 237-49. 2. Medical Editorial Team. Oesophagitis with doxycycline and others. Prescriber Update 2003;24(2):30
been included. Details on the risk of patients (including pregnant women) with mechanical prosthetic valves are elaborated. Major haemorrhage cases including retroperitoneal and intracranial bleeding, some of which were fatal, have been included. 7. Epoetinum alfa (Eprex ; Johnson & Johnson) An increased incidence of thrombotic events in cancer patients has been reported. 8. Fluticasone propionate (Flixonase; GSK) New precautionary statements on interaction with ritonavir that can greatly increase fluticasone plasma levels resulting in markedly reduced serum cortisol concentrations. Postmarketing reports of this systemic corticosteroid effects including Cushings syndrome and adrenal suppression have been included in the PI. Headache has been added as a new common ADR. 9. Haemaccel Infusion Solution (Aventis Pharma) Very rare cases of air embolism have been reported. Instructions to expel air for infusion under pressure are included. 10. Ketoprofen (Fastum Gel; Pharmaforte) Under the contraindications section, hypersensitivity to other related products was elaborated. Patients are warned to avoid direct sunlight (including sunbeds) during treatment. Postmarketing experience of isolated but severe cases of erythema, burns, pruritus, dermatitis, urticaria and boil reactions have been reported. 11. Lactated Ringers Injection USP (Baxter) Frequency of allergic reactions or anaplylactoid symptoms has been reported to be higher in women during pregnancy. 12. Paroxetine (Seroxat; GSK) Statements on the lack of efficacy in children with major depressive disorder have been included. A new section on adverse events arising from paediatric clinical trials has been added. 13.Pergolide mesylate (Celance, Eli Lilly) Advice on gradual discontinuation of pergolide has been included. A complex symptom resembling the neuroleptic malignant syndrome (NMS) has been reported in association with
Adverse Drug Reaction News is produced by the Centre for Drug Administration, HSA and the Pharmacovigilance Advisory Committee
Editor-in-Chief Ms Chan Cheng Leng BSc (Pharm) Hons Editorial Board Clinical Prof. Goh Chee Leok Prof. Edmund Lee Jon Deoon A/Prof. Chia Kee Seng Clinical A/Prof. Chng Hiok Hee Dr Gilbert Lau Kwang Fatt Dr Lee Kheng Hock Enquiries, comments and suggestions to: Pharmacovigilance Unit, Centre for Drug Administration, Health Sciences Authority 2 Jalan Bukit Merah Singapore 169547 Tel: (65) 6325 5604 Fax: (65) 6325 5448 Website: http://www.hsa.gov.sg Email: HSA_drugsafety@hsa.gov.sg
Executive Editor Ms Ang Pei San BSc (Pharm) Staff Editors Ms Tan Bee Him BSc (Pharm) Dr Ting Kang Nee BPharm (Hons), PhD
Its contents are not to be reproduced in part or in whole, without prior written approval to the editor. Whilst every effort is made in compiling the content of this publication, the publishers, editors and authors accept no liability whatsoever for the consequences of any inaccurate or misleading data, opinions or statements. The mention of any product by the authors does not imply any official endorsement of the product by the Health Sciences Authority. Copyright 2004 Health Sciences Authority of Singapore. All Rights Reserved.