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December 2016

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Volume 41 Number 12

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A Peer-Reviewed Journal for Managed Care
and Formulary Management Decision-Makers

Zika in America: The Year in Review VISIT US ONLINE AT WWW.PTCOMMUNITY.COM

C. Fellner

Systemic Thrombolysis for

Pulmonary Embolism: A Review
C. Martin, PharmD; K. Sobolewski, PharmD;
P. Bridgeman, PharmD; and D. Boutsikaris, MD

Medicare Adds New

Long-Term-Care Pharmacy Rules
Agency Passes Again on Pharmacist
Independence Requirements
S. Barlas

PHARMACOVIGILANCE FORUM
Drug-Induced Neutropenia
A Focus on Rituximab-Induced Late-Onset Neutropenia
D. C. Moore, PharmD, BCPS, BCOP

MEETING HIGHLIGHTS
European Society for Medical Oncology
2016 Congress DRUG FORECAST
W. Alexander
Daclatasvir (Daklinza)
A Treatment Option for Chronic Hepatitis C Infection
M. Montgomery, PharmD; N. Ho, PharmD;
E. Chung, PharmD; and N. Marzella, PharmD

MEDICATION ERRORS
Fatal PCA Adverse Events Continue
To Happen: Better Patient Monitoring
Is Essential to Prevent Harm
M. Grissinger, RPh, FASCP
TRESIBA (insulin degludec injection) weeks. The mean age was 58 years and 3% were older than 75 years. Fifty-eight percent
Rx Only were male, 71% were White, 7% were Black or African American and 13% were Hispanic.
BRIEF SUMMARY. Please consult package insert for full prescribing The mean BMI was 30 kg/m2. The mean duration of diabetes was 11 years and the mean
information. HbA1c at baseline was 8.3%. A history of neuropathy, ophthalmopathy, nephropathy
and cardiovascular disease at baseline was reported for 14%, 10%, 6% and 0.6% of
INDICATIONS AND USAGE: TRESIBA is indicated to improve glycemic control in participants respectively. At baseline, the mean eGFR was 83 mL/min/1.73 m 2 and 9%
adults with diabetes mellitus. Limitations of Use: TRESIBA is not recommended for had an eGFR less than 60 mL/min/1.73 m2. Common adverse reactions (excluding
the treatment of diabetic ketoacidosis. hypoglycemia) occurring in TRESIBA treated subjects during clinical trials in patients
CONTRAINDICATIONS: TRESIBA is contraindicated: During episodes of hypo- with type 1 diabetes mellitus and type 2 diabetes mellitus are listed in Table 1 and Table
glycemia; In patients with hypersensitivity to TRESIBA or one of its excipients. 2, respectively. Common adverse reactions were dened as reactions occurring in 5%
WARNINGS AND PRECAUTIONS: Never Share a TRESIBA FlexTouch Pen of the population studied. Hypoglycemia is not shown in these tables but discussed in a
Between Patients: TRESIBA FlexTouch disposable prelled pens should never dedicated subsection below.
be shared between patients, even if the needle is changed. Sharing poses a risk for Table 1: Adverse Reactions Occurring in 5% of TRESIBA-Treated
transmission of blood-borne pathogens. Hyperglycemia or Hypoglycemia with Patients with Type 1 Diabetes Mellitus
Changes in Insulin Regimen: Changes in insulin, manufacturer, type, or method
of administration may affect glycemic control and predispose to hypoglycemia or Adverse Reaction TRESIBA (n=1102)
hyperglycemia. These changes should be made cautiously and only under medical Nasopharyngitis 23.9 %
supervision and the frequency of blood glucose monitoring should be increased. For Upper respiratory tract infection 11.9 %
patients with type 2 diabetes, adjustments in concomitant oral anti-diabetic treatment Headache 11.8 %
may be needed. When converting from other insulin therapies to TRESIBA follow dosing Sinusitis 5.1 %
recommendations. Hypoglycemia: Hypoglycemia is the most common adverse
reaction of insulin, including TRESIBA. Severe hypoglycemia can cause seizures, Gastroenteritis 5.1 %
may be life-threatening or cause death. Hypoglycemia can impair concentration ability Table 2: Adverse Reactions Occurring in 5% of TRESIBA-Treated
and reaction time; this may place an individual and others at risk in situations where Patients with Type 2 Diabetes Mellitus
these abilities are important (e.g., driving or operating other machinery). TRESIBA, or
any insulin, should not be used during episodes of hypoglycemia. Hypoglycemia can Adverse Reaction TRESIBA (n=2713)
happen suddenly and symptoms may differ in each individual and change over time in Nasopharyngitis 12.9 %
the same individual. Symptomatic awareness of hypoglycemia may be less pronounced Headache 8.8 %
in patients with longstanding diabetes, in patients with diabetic nerve disease, in patients
using medications that block the sympathetic nervous system (e.g., beta-blockers), or Upper respiratory tract infection 8.4 %
in patients who experience recurrent hypoglycemia. Risk Factors for Hypoglycemia: The Diarrhea 6.3 %
risk of hypoglycemia generally increases with intensity of glycemic control. The risk of Hypoglycemia: Hypoglycemia is the most commonly observed adverse reaction in
hypoglycemia after an injection is related to the duration of action of the insulin and, in patients using insulin, including TRESIBA [see Warnings and Precautions]. The rates
general, is highest when the glucose lowering effect of the insulin is maximal. As with of reported hypoglycemia depend on the denition of hypoglycemia used, diabetes type,
all insulin preparations, the glucose lowering effect time course of TRESIBA may vary insulin dose, intensity of glucose control, background therapies, and other intrinsic
among different individuals or at different times in the same individual and depends on and extrinsic patient factors. For these reasons, comparing rates of hypoglycemia in
many conditions, including the area of injection as well as the injection site blood supply clinical trials for TRESIBA with the incidence of hypoglycemia for other products may be
and temperature. Other factors which may increase the risk of hypoglycemia include misleading and also, may not be representative of hypoglycemia rates that will occur in
changes in meal pattern (e.g., macronutrient content or timing of meals), changes in clinical practice. The percent of participants randomized to TRESIBA who experienced
level of physical activity, or changes to co-administered medication. Patients with
at least one episode of hypoglycemia in adult clinical trials of patients with type 1 and type
renal or hepatic impairment may be at higher risk of hypoglycemia. Risk Mitigation
Strategies for Hypoglycemia: Patients and caregivers must be educated to recognize and 2 diabetes respectively are shown in Table 3 and 4. No clinically important differences
manage hypoglycemia. Self-monitoring of blood glucose plays an essential role in the in risk of hypoglycemia between TRESIBA and comparators was observed in clinical
prevention and management of hypoglycemia. In patients at higher risk for hypoglycemia trials. Severe hypoglycemia was dened as an episode requiring assistance of another
and patients who have reduced symptomatic awareness of hypoglycemia, increased person to actively administer carbohydrate, glucagon, or other resuscitative actions.
frequency of blood glucose monitoring is recommended. Hypoglycemia Due to A Novo Nordisk hypoglycemia episode was dened as a severe hypoglycemia episode
Medication Errors: Accidental mix-ups between basal insulin products and other or an episode where a laboratory or a self-measured glucose calibrated to plasma was
insulins, particularly rapid-acting insulins, have been reported. To avoid medication less than 56 mg/dL or where a whole blood glucose was less than 50 mg/dL (i.e., with or
errors between TRESIBA and other insulins, instruct patients to always check the without the presence of hypoglycemic symptoms).
insulin label before each injection. Do not transfer TRESIBA from the TRESIBA pen Table 3: Percent (%) of Type 1 Diabetes Patients Experiencing at Least
to a syringe. The markings on the insulin syringe will not measure the dose correctly One Episode of Severe Hypoglycemia or Novo Nordisk Hypoglycemia on
and can result in overdosage and severe hypoglycemia [see Warnings and Precautions]. TRESIBA in Adult Clinical Trials
Hypersensitivity and Allergic Reactions: Severe, life-threatening, generalized Study A Study B Study C
allergy, including anaphylaxis, can occur with insulin products, including TRESIBA. + insulin aspart + insulin aspart + insulin aspart
If hypersensitivity reactions occur, discontinue TRESIBA ; treat per standard of care 52 weeks 26 weeks 26 weeks
and monitor until symptoms and signs resolve. TRESIBA is contraindicated in patients
who have had hypersensitivity reactions to insulin degludec or one of the excipients. TRESIBA at the TRESIBA at
Hypokalemia: All insulin products, including TRESIBA, cause a shift in potassium TRESIBA TRESIBA same time each alternating
from the extracellular to intracellular space, possibly leading to hypokalemia. Untreated (N=472) (N=301) day (N=165) times (N=164)
hypokalemia may cause respiratory paralysis, ventricular arrhythmia, and death. Severe hypoglycemia
Monitor potassium levels in patients at risk for hypokalemia if indicated (e.g., patients Percent of patients 12.3% 10.6% 12.7% 10.4%
using potassium-lowering medications, patients taking medications sensitive to serum
potassium concentrations). Fluid Retention and Congestive Heart Failure with Novo Nordisk hypoglycemia
Concomitant Use of a PPAR Gamma Agonist: Thiazolidinediones (TZDs), which Percent of patients 95.6% 93.0% 99.4% 93.9%
are peroxisome proliferator-activated receptor (PPAR)-gamma agonists can cause dose
Novo Nordisk hypoglycemia: a severe hypoglycemia episode or an episode where a laboratory or a self-
related uid retention, particularly when used in combination with insulin. Fluid retention measured glucose calibrated to plasma was less than 56 mg/dL or where a whole blood glucose was less
may lead to or exacerbate congestive heart failure. Patients treated with insulin, including than 50 mg/dL (i.e., with or without the presence of hypoglycemic symptoms).
TRESIBA and a PPAR-gamma agonist should be observed for signs and symptoms
of congestive heart failure. If congestive heart failure develops, it should be managed Table 4: Percent (%) of Patients with Type 2 Diabetes Experiencing
according to current standards of care and discontinuation or dose reduction of the at Least One Episode of Severe Hypoglycemia or Novo Nordisk
PPAR-gamma agonist must be considered. Hypoglycemia on TRESIBA in Adult Clinical Trials
ADVERSE REACTIONS: The following adverse reactions are also discussed elsewhere: Study H Study I
Hypoglycemia [see Warnings and Precautions]; Hypersensitivity and allergic reactions Study D Study E Study F T2DM T2DM
[see Warnings and Precautions]; Hypokalemia [see Warnings and Precautions]. Clinical + 1-2 + 1-2 1-3 0-2 1-2
Trial Experience: Because clinical trials are conducted under widely varying OADs* OAD*s OADs* OADs* + OADs*
conditions, adverse reaction rates observed in the clinical trials of a drug cannot be insulin insulin insulin Study G insulin insulin
directly compared to rates in the clinical trials of another drug and may not reect the nave nave nave T2DM 0-3 OADs* aspart nave
rates observed in practice. The safety of TRESIBA was evaluated in nine treat to target 52 weeks 26 weeks 26 weeks 26 weeks 26 weeks 26 weeks
trials of 6-12 months duration, conducted in subjects with type 1 diabetes or type 2
TRESIBA
diabetes. The data in Table 1 reect the exposure of 1102 patients with type 1 diabetes to TRESIBA TRESIBA TRESIBA TRESIBA (alternating TRESIBA TRESIBA
TRESIBA with a mean exposure duration to TRESIBA of 34 weeks. The mean age was (N=766) (N=228) (N=284) (N=226) time) (N=230) (N=753) (N=226)
43 years and 1% were older than 75 years. Fifty-seven percent were male, 81% were
White, 2% were Black or African American and 4% were Hispanic. The mean body mass Severe hypoglycemia
index (BMI) was 26 kg/m2. The mean duration of diabetes was 18 years and the mean Percent of 0.3% 0 0 0.9% 0.4% 4.5% 0.4%
HbA1c at baseline was 7.8%. A history of neuropathy, ophthalmopathy, nephropathy and patients
cardiovascular disease at baseline was reported in 11%, 16%, 7% and 0.5% respectively. Novo Nordisk hypoglycemia
The mean eGFR at baseline was 87 mL/min/1.73 m2 and 7% of the patients had an eGFR
less than 60 mL/min/1.73 m2. The data in Table 2 reect the exposure of 2713 patients Percent of 46.5% 28.5% 50% 43.8% 50.9% 80.9% 42.5%
with type 2 diabetes to TRESIBA with a mean exposure duration to TRESIBA of 36 patients
*OAD: oral antidiabetic agent, Novo Nordisk hypoglycemia: a severe hypoglycemia episode or an
episode where a laboratory or a self-measured glucose calibrated to plasma was less than 56 mg/dL or
where a whole blood glucose was less than 50 mg/dL (i.e., with or without the presence of hypoglycemic
symptoms).
Allergic Reactions: Severe, life-threatening, generalized allergy, including anaphylaxis,
generalized skin reactions, angioedema, bronchospasm, hypotension, and shock may
occur with any insulin, including TRESIBA and may be life threatening [see Warnings
and Precautions]. Hypersensitivity (manifested with swelling of tongue and lips,
diarrhea, nausea, tiredness, and itching) and urticaria were reported in 0.9% of patients
treated with TRESIBA. Lipodystrophy: Long-term use of insulin, including TRESIBA,
can cause lipodystrophy at the site of repeated insulin injections. Lipodystrophy
includes lipohypertrophy (thickening of adipose tissue) and lipoatrophy (thinning
of adipose tissue) and may affect insulin absorption. Rotate insulin injection sites
within the same region to reduce the risk of lipodystrophy. In the clinical program,
lipodystrophy, lipohypertrophy, or lipoatrophy was reported in 0.3% of patients treated
with TRESIBA. Injection Site Reactions: Patients taking TRESIBA may experience
injection site reactions, including injection site hematoma, pain, hemorrhage, erythema,
nodules, swelling, discoloration, pruritus, warmth, and injection site mass. In the clinical
program, injection site reactions occurred in 3.8% of patients treated with TRESIBA.
Weight Gain: Weight gain can occur with insulin therapy, including TRESIBA, and has
been attributed to the anabolic effects of insulin. In the clinical program after 52 weeks
of treatment, patients with type 1 diabetes treated with TRESIBA gained an average
of 1.8 kg and patients with type 2 diabetes treated with TRESIBA gained an average
of 3.0 kg. Peripheral Edema: Insulin, including TRESIBA, may cause sodium retention
and edema. In the clinical program, peripheral edema occurred in 0.9% of patients with
type 1 diabetes mellitus and 3.0% of patients with type 2 diabetes mellitus treated with
TRESIBA. Immunogenicity: As with all therapeutic proteins, insulin administration
may cause anti-insulin antibodies to form. The detection of antibody formation is highly
dependent on the sensitivity and specicity of the assay and may be inuenced by several
factors such as: assay methodology, sample handling, timing of sample collection,
concomitant medication, and underlying disease. For these reasons, comparison of the
incidence of antibodies to TRESIBA with the incidence of antibodies in other studies
or to other products, may be misleading. In studies of type 1 diabetes patients, 95.9%
of patients who received TRESIBA once daily were positive for anti-insulin antibodies
(AIA) at least once during the studies, including 89.7% that were positive at baseline. In
studies of type 2 diabetes patients, 31.5% of patients who received TRESIBA once daily
were positive for AIA at least once during the studies, including 14.5% that were positive
at baseline. The antibody incidence rates for type 2 diabetes may be underreported due
to potential assay interference by endogenous insulin in samples in these patients. The
presence of antibodies that affect clinical efcacy may necessitate dose adjustments
to correct for tendencies toward hyper or hypoglycemia. The incidence of anti-insulin
degludec antibodies has not been established.
DRUG INTERACTIONS: Table 5 includes clinically signicant drug interactions with
TRESIBA.
Table 5: Clinically Signicant Drug Interactions with TRESIBA
Drugs That May Increase the Risk of Hypoglycemia
Drugs: Antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents,
disopyramide, brates, uoxetine, monoamine oxidase inhibitors, pentoxifylline,
pramlintide, propoxyphene, salicylates, somatostatin analogs (e.g., octreotide),
and sulfonamide antibiotics, GLP-1 receptor agonists, DPP-4 inhibitors, SGLT-2
inhibitors.
Intervention: Dose reductions and increased frequency of glucose monitoring may be required
when TRESIBA is co-administered with these drugs.
Drugs That May Decrease the Blood Glucose Lowering Effect of TRESIBA
Drugs: Atypical antipsychotics (e.g., olanzapine and clozapine), corticosteroids,
danazol, diuretics, estrogens, glucagon, isoniazid, niacin, oral contraceptives,
phenothiazines, progestogens (e.g., in oral contraceptives), protease inhibitors,
somatropin, sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline),
and thyroid hormones.
Intervention: Dose increases and increased frequency of glucose monitoring may be required
when TRESIBA is co-administered with these drugs.
Drugs That May Increase or Decrease the Blood Glucose Lowering Effect of
TRESIBA
Drugs: Alcohol, beta-blockers, clonidine, and lithium salts. Pentamidine may cause
hypoglycemia, which may sometimes be followed by hyperglycemia.
Intervention: Dose adjustment and increased frequency of glucose monitoring may be required
when TRESIBA is co-administered with these drugs.
Drugs That May Blunt Signs and Symptoms of Hypoglycemia
Drugs: Beta-blockers, clonidine, guanethidine, and reserpine
Intervention: Increased frequency of glucose monitoring may be required when TRESIBA is
co-administered with these drugs.
USE IN SPECIFIC POPULATIONS: Pregnancy: Pregnancy Category C. There are
no well-controlled clinical studies of the use of insulin degludec in pregnant women.
Patients should be advised to discuss with their health care provider if they intend to or
if they become pregnant. Because animal reproduction studies are not always predictive
of human response, insulin degludec should be used during pregnancy only if the
potential benet justies the potential risk to the fetus. It is essential for patients with
diabetes or a history of gestational diabetes to maintain good metabolic control before
conception and throughout pregnancy. Insulin requirements may decrease during the
rst trimester, generally increase during the second and third trimesters, and rapidly
decline after delivery. Careful monitoring of glucose control is essential in these patients.
Subcutaneous reproduction and teratology studies have been performed with insulin
degludec and human insulin (NPH) as a comparator in rats and rabbits. In these studies,
insulin was given to female rats before mating throughout pregnancy until weaning, and
to rabbits during organogenesis. The effect of insulin degludec was consistent with
those observed with human insulin as both caused pre- and post-implantation losses
and visceral/skeletal abnormalities in rats at an insulin degludec dose of 21 U/kg/day
(approximately 5 times the human exposure (AUC) at a human subcutaneous dose of
0.75 U/kg/day) and in rabbits at a dose of 3.3 U/kg/day (approximately 10 times the
human exposure (AUC) at a human subcutaneous dose of 0.75 U/kg/day). The effects
are probably secondary to maternal hypoglycemia. Nursing Mothers: It is unknown
whether insulin degludec is excreted in human milk. Because many drugs, including
human insulin, are excreted in human milk, caution should be exercised when insulin
degludec is administered to a nursing mother. Women with diabetes who are lactating
may require adjustments in insulin dose, meal plan, or both. In rats, insulin degludec
was secreted in milk and the concentration in milk was lower than in plasma. Pediatric
Use: The safety and efcacy of TRESIBA in children and adolescents under the age of
18 have not been established. Geriatric Use: In controlled clinical studies a total of
77 (7%) of the 1102 TRESIBA -treated patients with type 1 diabetes were 65 years or
older and 9 (1%) were 75 years or older. A total of 670 (25%) of the 2713 TRESIBA -
treated patients with type 2 diabetes were 65 years or older and 80 (3%) were 75 years
or older. Differences in safety or effectiveness were not suggested in subgroup analyses
comparing subjects older than 65 years to younger subjects. Nevertheless, greater
caution should be exercised when TRESIBA is administered to geriatric patients since
greater sensitivity of some older individuals to the effects of TRESIBA cannot be ruled
out. The initial dosing, dose increments, and maintenance dosage should be conservative
to avoid hypoglycemia. Hypoglycemia may be more difcult to recognize in the elderly.
Renal Impairment: In clinical studies a total of 75 (7%) of the 1102 TRESIBA -treated
patients with type 1 diabetes had an eGFR less than 60 mL/min/1.73 m2 and 1 (0.1%)
had an eGFR less than 30 mL/min/1.73 m2. A total of 250 (9%) of the 2713 TRESIBA -
treated patients with type 2 diabetes had an eGFR less than 60 mL/min/1.73 m2 and no
subjects had an eGFR less than 30 mL/min/1.73 m2. No clinically relevant difference in
the pharmacokinetics of TRESIBA was identied in a study comparing healthy subjects
and subjects with renal impairment including subjects with end stage renal disease.
However, as with all insulin products, glucose monitoring should be intensied and the
TRESIBA dosage adjusted on an individual basis in patients with renal impairment.
Hepatic Impairment: No difference in the pharmacokinetics of TRESIBA was
identied in a study comparing healthy subjects and subjects with hepatic impairment
(mild, moderate, and severe hepatic impairment). However, as with all insulin products,
glucose monitoring should be intensied and the TRESIBA dosage adjusted on an
individual basis in patients with hepatic impairment.
OVERDOSAGE: An excess of insulin relative to food intake, energy expenditure, or both
may lead to severe and sometimes prolonged and life-threatening hypoglycemia and
hypokalemia [see Warnings and Precautions]. Mild episodes of hypoglycemia usually
can be treated with oral glucose. Adjustments in drug dosage, meal patterns, or exercise
may be needed. More severe episodes of hypoglycemia with coma, seizure, or neurologic
impairment may be treated with intramuscular/subcutaneous glucagon or concentrated
intravenous glucose. After apparent clinical recovery from hypoglycemia, continued
observation and additional carbohydrate intake may be necessary to avoid reoccurrence
of hypoglycemia. Hypokalemia must be corrected appropriately.
More detailed information is available upon request.
Date of Issue: 09/2015
Version: 1
Novo Nordisk, TRESIBA, FlexTouch, LEVEMIR, NOVOLOG, NovoFine and
NovoTwist are registered trademarks of Novo Nordisk A/S.
TRESIBA is covered by US Patent No. 7,615,532 and other patents pending.
FlexTouch is covered by US Patent Nos. 6,899,699, 7,686,786, 8,672,898, 8,684,969,
8,920,383, D724,721, D734,450 and other patents pending.
Manufactured by:
Novo Nordisk A/S
DK-2880 Bagsvaerd, Denmark
For information about TRESIBA contact:
Novo Nordisk Inc.
800 Scudders Mill Road
Plainsboro, NJ 08536
1-800-727-6500
www.novonordisk-us.com
2016 Novo Nordisk
USA16TSM02300 6/2016
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Vol. 41 No. 12 December 2016 P&T

731

Cover: Transmission electron micro-
scope image of negative-stained
Zika virus (green) isolated from a
microcephaly case. Since the 1950s,
the virus has been known to occur
within a narrow equatorial belt from
Africa to Asia. From 2007 to 2016,
Zika virus spread eastward to the
Americas. This month we focus on its
arrival in the U.S. and on the efforts
being made to contain it; see article
on page 778. (Credit: Science Source)
DEPARTMENTS
Medication Errors 736
Preventing fatal PCA
adverse events
Prescription: Washington 738
Medicare names plans
for Part D MTM demo
Drug and Device News 739
Approvals, new indications,
regulatory activities, and more
Pharmaceutical
Approval Update 748
Lisinopril oral solution
(Qbrelis) for the treatment of
hypertension, heart failure,
and acute myocardial
infarction; etanercept-szzs
(Erelzi) for multiple
autoimmune disorders;
and lumacaftor/ivacaftor
(Orkambi) for cystic brosis
Drug Forecast 751
Daclatasvir (Daklinza) for
chronic hepatitis C infection
Research Briefs 769
Back issues are available on
the PubMed Central archive.
Visit www.pubmedcentral.nih.gov
The digital edition does not contain some of the advertising pages that appear in the print edition.
CONTENTS
December 2016
FEATURES
Medicare Adds New Long-Term-Care Pharmacy Rules 762
Agency Passes Again on Pharmacist Independence Requirements
A nal rule from the Centers for Medicare and Medicaid Services has added
pharmacy requirements for long-term-care facilities that put more responsibility
on pharmacists but dont address conict-of-interest concerns.
Stephen Barlas
PHARMACOVIGILANCE FORUM
Drug-Induced Neutropenia:
A Focus on Rituximab-Induced Late-Onset Neutropenia 765
Rituximab can cause late-onset neutropenia that may result in serious life-
threatening complications. The author describes the pathophysiology, incidence,
and management of this adverse reaction and presents two case histories.
Donald C. Moore, PharmD, BCPS, BCOP
Systemic Thrombolysis for Pulmonary Embolism: A Review 770
The authors review the evidence behind the use of thrombolytic therapy in
patients with massive or submassive pulmonary embolism. Concurrent heparin
therapy and the management of bleeding episodes are also discussed.
Colleen Martin, PharmD; Kristine Sobolewski, PharmD; Patrick Bridgeman, PharmD;
and Daniel Boutsikaris, MD
Zika in America: The Year in Review 778
Short on funds and with no therapeutics or vaccines in sight, U.S. health officials
are scrambling to prepare for a protracted ght with Zika virus and the mosquitoes
that carry it. In this article, the author focuses on the arrival of Zika in the U.S.
Chris Fellner
MEETING HIGHLIGHTS
European Society for Medical Oncology 2016 Congress 796
We review several key sessions from the European Society for Medical Oncologys
annual congress, including those on emerging immunotherapies for melanoma and
nonsmall-cell lung cancer and on treatments for renal, ovarian, and breast cancer.
Walter Alexander
SEASONS GREETINGS
Thanks to Our Readers and Reviewers 802
Attention Readers: P&T is on Facebook, Twitter, and LinkedIn.
Search for P&T
Search for
[Pharmacy and @PTJournal780
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 For flu patients in the emergency department who may not be appropriate for oral treatment 1,2

It only takes

to be

treating the flu with

1
Rapivab (peramivir)
The first and only full course of antiviral flu therapy in a single dose1,2
Only one 15- to 30-minute IV infusion required
Treats acute uncomplicated influenza in patients 18+ who have been
symptomatic for no more than 2 days
Appropriate for many patients, including those who cannot tolerate or may
be noncompliant with oral flu treatment and those requiring IV hydration
Can be used with OTC supportive therapies

Go to www.rapivab.com to learn more and view full Prescribing Information.

Important Safety Information
Rapivab (peramivir injection) is indicated for the treatment of acute
uncomplicated influenza in patients 18 years and older who have been
symptomatic for no more than 2 days.
Efficacy of Rapivab was based on clinical trials in which the predominant
influenza virus type was influenza A; a limited number of subjects
infected with influenza B virus were enrolled.
Influenza viruses change over time. Emergence of resistance
substitutions could decrease drug effectiveness. Other factors (for
example, changes in viral virulence) might also diminish clinical benefit
of antiviral drugs. Prescribers should consider available information
on influenza drug susceptibility patterns and treatment effects when
deciding whether to use Rapivab.
Efficacy could not be established in patients with serious influenza
requiring hospitalization.
Contraindications
Rapivab is contraindicated in patients with known serious hypersensitivity
or anaphylaxis to peramivir or any component of the product. Severe
allergic reactions have included anaphylaxis, erythema multiforme, and
Stevens-Johnson syndrome.
Warnings and Precautions
Rare cases of serious skin reactions, including erythema multiforme, have been
reported with Rapivab in clinical studies and in postmarketing experience.
Cases of anaphylaxis and Stevens-Johnson syndrome have been reported
in postmarketing experience with Rapivab. Discontinue Rapivab and
institute appropriate treatment if anaphylaxis or a serious skin reaction
occurs or is suspected. The use of Rapivab is contraindicated in patients
with known serious hypersensitivity or anaphylaxis to Rapivab.
Patients with influenza may be at an increased risk of hallucinations,
delirium, and abnormal behavior early in their illness. There have
been postmarketing reports (from Japan) of delirium and abnormal
behavior leading to injury in patients with influenza who were receiving
neuraminidase inhibitors, including Rapivab. Because these events were
reported voluntarily during clinical practice, estimates of frequency
cannot be made, but they appear to be uncommon. These events were
reported primarily among pediatric patients. The contribution of Rapivab
to these events has not been established. Patients with influenza should
be closely monitored for signs of abnormal behavior.
Serious bacterial infections may begin with influenza-like symptoms
or may coexist with or occur as complications during the course of
influenza. Rapivab has not been shown to prevent such complications.
Adverse Reactions
The most common adverse reaction was diarrhea (8% Rapivab vs
7% placebo).
Lab abnormalities (incidence * 2%) occurring more commonly with Rapivab
than placebo were elevated ALT 2.5 times the upper limit of normal (3% vs
2%), elevated serum glucose greater than 160 mg/dL (5% vs 3%), elevated
CPK at least 6 times the upper limit of normal (4% vs 2%) and neutrophils less
than 1.0 x 109/L (8% vs 6%).
Concurrent use with Live Attenuated Influenza Vaccine
Antiviral drugs may inhibit viral replication of a live attenuated influenza
vaccine (LAIV). The concurrent use of Rapivab with LAIV intranasal has not
been evaluated. Because of the potential for interference between these
two products, avoid use of Rapivab within 2 weeks after or 48 hours before
administration of LAIV unless medically indicated.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088.
References: 1. Rapivab [package insert]. Durham, NC: BioCryst Pharmaceuticals, Inc; 2014. 2. Kohno S, Kida H, Mizuguchi M, Shimada J; S-021812 Clinical Study
Group. Efficacy and safety of intravenous peramivir for treatment of seasonal influenza virus infection. Antimicrob Agents Chemother. 2010;54(11):4568-4574.
doi:10.1128/AAC.00474-10.
RAPIVAB is a registered trademark of BioCryst Pharmaceuticals, Inc. All other trademarks herein are the property of their respective owners.

Seqirus USA Inc.

King of Prussia, Pennsylvania 19406 2016 Seqirus USA Inc. August 2016 US/RIV/0816/0068
RAPIVAB (peramivir injection), for intravenous use
Initial U.S. Approval: 2014
BRIEF SUMMARY OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use RAPIVAB
safely and effectively. See full prescribing information for RAPIVAB.
----------------------------------INDICATIONS AND USAGE--------------------------------
RAPIVAB is an inuenza virus neuraminidase inhibitor indicated for the treatment
of acute uncomplicated inuenza in patients 18 years and older who have been
symptomatic for no more than two days.
Limitations of Use:
Efcacy based on clinical trials in which the predominant inuenza virus type was
inuenza A; a limited number of subjects infected with inuenza B virus were
enrolled.
Consider available information on inuenza drug susceptibility patterns and
treatment effects when deciding whether to use.
Efcacy could not be established in patients with serious inuenza requiring
hospitalization.
---------------------------------DOSAGE AND ADMINISTRATION------------------------
Administer as a single dose within 2 days of onset of inuenza symptoms.
Recommended dose is 600 mg, administered by intravenous infusion for a minimum
of 15 minutes.
Renal Impairment: Recommended dose for patients with creatinine clearance 30-49
mL/min is 200 mg and the recommended dose for patients with creatinine clearance
10-29 mL/min is 100 mg.
Hemodialysis: Administer after dialysis.
RAPIVAB must be diluted prior to administration.
See the Full Prescribing Information for drug compatibility information.
Seqirus USA Inc.
King of Prussia, Pennsylvania 19406 2016 Seqirus USA Inc.
-------------------------------DOSAGE FORMS AND STRENGTHS------------------------
Injection: 200 mg in 20 mL (10 mg/mL) in a single-use vial.
------------------------------------CONTRAINDICATIONS-----------------------------------
Patients with known serious hypersensitivity or anaphylaxis to peramivir or any
component of RAPIVAB.
--------------------------------WARNINGS AND PRECAUTIONS---------------------------
Cases of anaphylaxis and serious skin/hypersensitivity reactions such as Stevens-
Johnson syndrome and erythema multiforme have occurred with RAPIVAB.
Discontinue RAPIVAB and initiate appropriate treatment if anaphylaxis or serious
skin reaction occurs or is suspected.
Neuropsychiatric events: Patients with influenza may be at an increased risk of
hallucinations, delirium and abnormal behavior early in their illness. Monitor for signs
of abnormal behavior.
---------------------------------ADVERSE REACTIONS--------------------------------------
Most common adverse reaction (incidence >2%) is diarrhea.
To report SUSPECTED ADVERSE REACTIONS, call 1-844-273-2327 or contact
FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
---------------------------------------DRUG INTERACTIONS---------------------------------
Live attenuated inuenza vaccine (LAIV), intranasal: Avoid use of LAIV within 2 weeks
before or 48 hours after administration of RAPIVAB, unless medically indicated.
--------------------------------USE IN SPECIFIC POPULATIONS---------------------------
Pregnancy: Use if benet outweighs risk.
Nursing mothers: Caution should be exercised when administered to a nursing
woman.
Revised: 8/2016
August 2016 US/RIV/0816/0068
Editor-in-Chief
David B. Nash, MD, MBA
Dr. Raymond C. and
Doris N. Grandon Professor
The Jefferson College of Population Health
Philadelphia, Pennsylvania
Richard Afable, MD, MPH
President and Chief Executive Ofcer
Hoag Memorial Hospital Presbyterian
Newport Beach, California
Robert L. Barkin, MBA, PharmD
Professor, Faculty of Anesthesiology,
Family Medicine, and Pharmacology
Rush Medical College of Rush University
Chicago, Illinois
Clinical Pharmacologist
North Shore University Health System
Pain Centers
Skokie and Evanston, Illinois
Mark J. Baumel, MD, MS
President/Chief Executive Ofcer
Colon Health Centers of America, LLC
Mendenhall, Pennsylvania
Thomas Biancaniello, MD
Clinical Professor of Pediatrics
Columbia University
College of Physicians and Surgeons
Division of Pediatric Cardiology
New York, New York
Joseph E. Biskupiak, PhD, MBA
Research Associate Professor
Department of Pharmacy Practice
Director, Pharmacotherapy Outcomes
Research Center
College of Pharmacy, University of Utah
Salt Lake City, Utah
David A. Casey, MD
Vice Chairman, Department of Psychiatry
University of Louisville
Louisville, Kentucky
Alan Caspi, PhD, PharmD, MBA
President, Caspi & Associates
New York, New York
Burke A. Cunha, MD
Professor of Medicine
State University of New York at Stony Brook
Chief, Infectious Disease Division
Winthrop-University Hospital
Mineola, New York
Joseph C. English III, MD
Professor of Dermatology
Clinical Vice Chairman
for Quality and Innovation
Founding Director of Teledermatology
University of Pittsburgh
Department of Dermatology
Pittsburgh, Pennsylvania
EDITORIAL BOARD
Marvin M. Goldenberg, PhD, RPh, MS
President, Pharmaceutical and Scientic
Services
Marvin M. Goldenberg, LLC
Westeld, New Jersey
Nancy Greengold, MD, MBA
Chief Medical Ofcer
Sharp Grossmont Hospital/Sharp
HealthCare
La Mesa, California
Matthew Grissinger, RPh, FASCP
Director, Error Reporting Programs
Institute for Safe Medication Practices
Horsham, Pennsylvania
Rusty Hailey, PharmD, DPh, MBA, FAMCP
President, Pharmaceutical Operations
Senior Vice President, HealthSpring, Inc.
Nashville, Tennessee
Steven D. Hanks, MD, MMM, FACP
Executive Vice President
and Chief Medical Ofcer
The Hospital of Central Connecticut
New Britain, Connecticut
Michele B. Kaufman, PharmD, CGP, RPh
Pharmacist, New YorkPresbyterian
Lower Manhattan Hospital, Pharmacy
Department
New York, New York
Grant D. Lawless, RPh, MD
Associate Professor of Clinical Pharmacy,
Pharmaceutical Economics and Policy
Director, Master of Science Program in
Healthcare Decision Analysis
School of Pharmacy
University of Southern California
Los Angeles, California
Burton Orland, BS, RPh
President
BioCaRe Consultants
Westport, Connecticut
Fred Joseph Pane, RPh, BS, FASHP, FABC
Senior Director, Customer Engagement
The Medicines Company
Parsippany, New Jersey
Lawrence Charles Parish, MD
Dermatologist, Editor-in-Chief
Clinics in Dermatology
Philadelphia, Pennsylvania
Associate Editor-in-Chief
Karl A. Matuszewski, MS, PharmD
Vice President
First Databank, Inc.
Clinical and Editorial
Knowledge Base Services
South San Francisco, California
Luke A. Probst, PharmD, BCPS
Director of Pharmacy Services
Upstate University Hospital/
Downtown Campus
Clinical Assistant Professor, Departments
of Pediatrics and Medicine
SUNY Upstate Medical University
Syracuse, New York
Sheldon M. Retchin, MD, MSPH
Executive Vice President of Health
Sciences, The Ohio State University
Chief Executive Ofcer, OSU Wexner
Medical Center
Columbus, Ohio
Vitalina Rozenfeld, PharmD, BCPS
Medical Affairs
AstraZeneca
Wilmington, Delaware
Fadia T. Shaya, PhD, MPH
Professor and Vice-Chair for Academic
Affairs
University of Maryland School of Pharmacy
Associate Director
Center on Drugs and Public Policy
Baltimore, Maryland
Arthur F. Shinn, PharmD, FASCP
President
Managed Pharmacy Consultants, LLC
Palm City, Florida
Brian Swift, PharmD, MBA
Vice President/Chief of Pharmacy
and Accreditation
Thomas Jefferson University Hospital
Associate Dean of Professional Affairs
Jefferson College of Pharmacy
Philadelphia, Pennsylvania
F. Randy Vogenberg, RPh, PhD
Partner
Access Market Intelligence and National
Institute of Collaborative Healthcare
Greenville, South Carolina
Scott W. Yates, MD, MBA, MS
Center for Executive Medicine
Plano, Texas
Vol. 41 No. 12 December 2016 P&T
735
MEDICATION ERRORS
Fatal PCA Adverse Events Continue
To Happen: Better Patient Monitoring
Is Essential to Prevent Harm
Matthew Grissinger, RPh, FASCP
Mr. Grissinger, an editorial
board member of P&T, is
Director of Error Reporting
Programs at the Institute for
Safe Medication Practices
(ISMP) in Horsham, Penn-
sylvania (www.ismp.org).
PROBLEM: A patient underwent surgical
repair of a heel injury. Within 15 minutes
of arrival in the postanesthesia care unit
(PACU), he received intravenous (IV)
doses of meperidine 75 mg, morphine
4 mg, and fentaNYL 25 mcg for pain. The
patients surgeon also ordered PCA per
anesthesia. A nurse anesthetist wrote
an order for morphine patient-controlled
analgesia (PCA) 1 mg/mL, 3 mg per
demand dose, lockout of 10 minutes,
and a basal rate of 1 mg/hour. Although
the patient was obese and anxious about
inadequate pain control, the prescribed
demand dosepotentially adding up to
18 mg/houralong with a basal infu-
sion were too much for the patient given
his opioid-nave status. In fact, based on
morphine prescribing information, the
dose might have been high even for an
opioid-tolerant patient.
A pharmacist reviewed the PCA order
but did not investigate the patients
current opioid usage. He did not question
the 3-mg demand dose or the basal infu-
sion, neither of which is recommended
for an opioid-nave patient. The morphine
PCA was started around 8 P.M. while the
patient was in the PACU. The patient had
not received preoperative PCA instruc-
tions, so the PACU nurse taught the
patient to self-administer the doses. No
further education was provided, and the
patients family was not warned about the
hazards of anyone other than the patient
administering a dose.
Within 30 minutes of starting the PCA,
the patient had given himself three doses
of morphine, 3 mg each. He reported
that his pain was receding, but a pain
score was not documented. Over the
next ve hours, the patient administered
736 P&T December 2016 Vol. 41 No. 12
17 more doses for a total of 20 doses
(60 mg), and the basal infusion delivered
an additional 5.5 mg of morphine. Most
of the doses were administered between
8 P.M. and midnight. It is unknown if
the patients wife, who remained at the
patients bedside until midnight, periodi-
cally awakened the patient and encour-
aged him to administer a dose or if she
administered doses for him while he
slept. Around 2 A.M., the patient was found
in respiratory arrest. Resuscitation efforts
were unsuccessful.
Since PCA initiation, nurses had been
monitoring the patient every 30 minutes
for the rst hour, every hour for the
next three hours, then every two hours.
However, monitoring was less frequent
than required by hospital policy and less
often than typically recommended for
patients receiving PCA.1 In addition, the
assessment of pain was infrequent, and
the assessment of respiratory status did
not include the depth, pattern, and effort
of respirations, or breath sounds. Pulse
oximetry was not used to measure oxygen
saturation, although policy required its
use and the oximetry equipment was
available in the patients room.
Further, a standard sedation assess-
ment scale was not utilized. Progressive
signs of impending respiratory arrest
were not recognized, particularly those
related to the patients level of seda-
tion. After the rst hour of PCA use,
the patient was assessed as awake and
alert with a pain assessment score of 4
on a 110 scale. As the evening went on,
the patient became sleepy and drowsy
but easily aroused, although no pain
assessment was documented. By mid-
night, four hours after starting the PCA,
the patient was sleeping and snoring
loudly, and no attempts were made to
arouse the patient to assess his level of
sedation and pain. Two hours later, the
patient was described as sleeping and
snoring loudly, but arousable with no
further details. Shortly thereafter, the
patient was found in respiratory arrest.
One factor that probably contributed
to the patients respiratory arrest is the
delayed transfer of morphine across
the bloodbrain barrier.2,3 The repeated
administration of relatively high doses
of morphine at short intervals and the
delayed transfer of the drug to the brain
made it possible for the fatal event to
occur almost two hours after the bulk
of self-administered doses were taken.
A patient with severe pain may tolerate
larger doses of morphine because the
pain helps counteract the respiratory-
depressant effects of opioids.2,4,5 However,
once the pain subsides, previously ade-
quate breathing can quickly become
inadequate with the onset of sedation
or sleep.4,5
Given the widespread use of PCA, most
hospitals likely have a PCA story to tell.1
Fortunately, not all of these stories have
resulted in death. However, studies have
documented the association of PCA with
harmful and fatal errors,2,6 and analyses of
voluntary reports of events have shown
a fourfold higher risk of harm with PCA
errors than with other reported medica-
tion errors.1 In most cases, characteris-
tics that place patients at higher risk for
opioid-induced respiratory depression
have not been considered, and patient
monitoring has been inadequate.7,8
SAFE PRACTICE RECOMMENDATIONS
ISMP has written about PCA errors
numerous times, describing many of the
causative factors, including prescribing
errors, failing to determine the patients
opioid status and identify risk factors
associated with respiratory depression,
lack of educating patients and families
about PCA, and inadequate monitoring.9,10
While many things went wrong in the
event described above, the remainder
of this article focuses on appropriate
monitoring of patients receiving PCA
a critical, lifesaving activity that can
provide an early warning of impending
complications, thus preventing patient
harm even in the presence of an error.

Along with a basic physical assessment
and collection of vital signs, the follow-
ing parameters are also important when
monitoring patients receiving PCA.
Pain Assessment
The patients level of pain must be con-
tinually assessed during use of PCA to
evaluate the treatments effectiveness.
Use of a standard pain scale and/or
tool (e.g., Wong-Baker Faces Scale) is
highly recommended for accuracy and
ease of eliciting a patients description
of discomfort.1 While the goal of PCA
is pain relief, remember that pain relief
can signal the loss of a compensatory
mechanism that combats the respiratory-
depressant effects of opioids. Thus, moni-
toring should be stepped up, and PCA
doses may need to be reduced if pain
relief is accompanied by oversedation.
Sedation Assessment
Sedation is an extremely useful assess-
ment parameter to observe the clinical
effects of opioids. In fact, sedation is
the most important predictor of respi-
ratory depression in patients receiv-
ing IV opioidsa fact that only 22% of
physicians, pharmacists, and nurses
knew when taking an opioid knowledge
assessment.5 Sedation generally precedes
signicant respiratory depression. While
pain can counteract opioid-induced respi-
ratory depression, sleep can intensify
the depressant effects. In addition, as
carbon dioxide levels increase with respi-
ratory depression, patients experience
a reduced level of consciousness that is
additive to the opioid sedative effects.1
Thus, for patients receiving PCA, early
recognition of excessive sedation and
intervention is essential.
A standard sedation scale should be
used when assessing patients receiv-
ing PCA. The San Diego Patient Safety
Council, which created a useful set of
PCA guidelines for opioid-nave patients,1
prefers the Richmond Agitation Sedation
Scale (RASS)11 because it is simple to use
and combines sedation and agitation into
one scale. However, some hospitals use
the Pasero, Ramsey, or Glasgow Coma
scales.
To assess sedation, health profession-
als must evaluate how much stimula-
tion is necessary to evoke the desired
response from the patient; thus, one must
rst observe the patient. If the patient is
awake, ask the patient a question and
evaluate the response to determine if the
patient is alert and oriented. If the patient
is not alert (eyes closed), assess the
patients response to verbal stimuli rst.
For example, the RASS scale suggests
stating the patients name and asking the
patient to open his or her eyes and look at
the speaker.11 The degree of movement
and length of eye contact is evaluated to
assess the sedation level. If the patient
does not respond to verbal requests, phys-
ical stimulation is used, such as lightly
shaking the patients shoulder to evaluate
the response. Practitioners should have
clear guidance regarding which levels of
the sedation scale would indicate the need
to increase the frequency of monitoring,
adjust PCA doses, stop the PCA, call the
prescriber, provide airway support and/
or oxygen, and/or administer naloxone.
Respiratory Assessment
Respiratory assessments should
include evaluation of the rate and quality
of respirations. A respiratory rate of
10 breaths per minute or less should
signal possible discontinuation of PCA.1
The depth of respirations (i.e., normal,
shallow, deep), pattern of respirations
(i.e., regular, irregular), quality of respi-
ratory effort (i.e., effortless, comfortable,
labored), and breath sounds (i.e., clear,
noisy, snoring, gurgling, stridor) are all
important parameters when assessing
respiration quality.
The Anesthesia Patient Safety Founda-
tion (APSF) also recommends routine use
of technology to continuously monitor
ventilation in patients known to be at
high risk for respiratory depression
(e.g., pre-existing respiratory impair-
ment, sleep apnea, elderly, or obese) and
consideration of its use when possible
for all patients receiving PCA.7 Continu-
ous pulse oximetry should be routine,
although practitioners should be aware
that oximetry readings may remain near
normal for minutes after a patient stops
breathing.8 Thus, the APSF suggests
using capnography whenever possible
(even if intermittent) to detect unrecog-
nized hypoventilation and carbon dioxide
retention.7 The APSF also recommends
limiting the use of supplemental oxygen
when possible for patients receiving PCA,
especially if pulse oximetry is the only
technology used to detect hypoventila-
tion. For patients receiving supplemental
MEDICATION ERRORS
oxygen, there is no evidence that moni-
toring of oxygen saturation provides an
additional measure of safety.12
Frequency of Assessments
To be effective, patient monitoring
must be conducted at the proper inter-
vals. Guidelines that can be used to assess
the adequacy of monitoring frequencies
have been developed by the San Diego
Patient Safety Council.1 Hospitals may
want to monitor patients more frequently
at night, as opioid-induced respiratory
depression is more common between
midnight and 6 A.M.4 Keep in mind that
the purpose and frequency of monitoring
should be explained to patients and their
families so they understand and expect to
be awakened and monitored frequently.
REFERENCES
1. San Diego Patient Safety Council. Patient
controlled analgesia (PCA) guidelines of
care for the opioid nave patient. Decem-
ber 2009. Available at: www.hqinstitute.
org/sites/main/les/le-attachments/
sdpsc_patient_controlled_analygesia_
pca_guidelines_of_care_toolkit_decem-
ber_2008.pdf. Accessed October 26, 2016.
2. Lotsch J, Dudziak R, Freynhagen R, et al.
Fatal respiratory depression after multiple
intravenous morphine injections. Clin
Pharmacokinet 2006;45(11):10511060.
3. Lotsch J, Skarke C, Schmidt H, et al.
The transfer half-life of morphine-6-beta-
glucuronide from plasma to effect site
assessed by pupil size measurement
in healthy volunteers. Anesthesiology
2001;95(6):13291338.
4. Borgbjerg FM, Nielsen K, Franks J.
Experimental pain stimulates respira-
tion and attenuates morphine-induced
respiratory depression: a controlled study in
human volunteers. Pain 1996;64(1):
123128.
5. Grissinger M. Results of the opioid knowl-
edge assessment from the PA Hospital
Engagement Network Adverse Drug
Event Collaboration. Pa Patient Saf Advis
2013;10(1):1926.
6. Hicks RW, Sikirica V, Nelson W, et al.
Medication errors involving patient-
controlled analgesia. Am J Health Syst
Pharm 2008;65(5):429440.
7. Stoelting RK, Weinger MB. Dangers of
postoperative opioidsis there a cure?
APSF Newsletter. Summer 2009;24:2526.
8. Weinger MB. Dangers of postoperative
opioids: APSF workshop and white paper
address prevention of postoperative respi-
ratory complications. APSF Newsletter.
Winter 2006-2007;21:6167.
9. ISMP. Safety issues with patient-
controlled analgesia. Part I. ISMP
Medication Safety Alert 2003;8(14):13.
10. ISMP. Safety issues with patient-
controlled analgesia. Part II. ISMP
Medication Safety Alert 2003;8(15):13.
continued on page 800
Vol. 41 No. 12 December 2016 P&T
737
PRESCRIPTION: WASHINGTON
Medicare Names Six Plans for Part D
MTM Demo Starting in January
Stephen Barlas
Mr. Barlas is a freelance
writer in Washington,
D.C., who covers issues
inside the Beltway. Send
ideas for topics and your
comments to sbarlas@
verizon.net.
ix Part D drug plans sail into
S uncharted waters on January 1
when they embark on experiments
with medication therapy management
(MTM) programs in the new Medicare
demonstration program.1 At a time of
seemingly rapid prescription-drug cost
increases, the ve-year demonstration
program will test the proposition that
Part D plans can target MTM programs
the way they wantnot the way Medicare
regulations insist they do. Those ex-
ible member-targeting and intervention
policies, the latter expected to include
more physicians and pharmacies, will
hopefully lead to lower Medicare Part A
and B costs for the federal government.
The six plans participating in the
demonstration are: Blue Cross and Blue
Shield Northern Plains Alliance, Blue
Cross and Blue Shield of Florida, CVS
Health, Humana, UnitedHealthcare,
and WellCare Prescription Insurance.
They will test their particular targeting
and intervention strategies in selected
regions: Region 7 (Virginia), Region 11
(Florida), Region 21 (Louisiana),
Region 25 (Iowa, Minnesota, Montana,
Nebraska, North Dakota, South Dakota,
Wyoming), and Region 28 (Arizona).2
Through this model, we are hopeful
that Part D plans will invest in medication
therapy management and identify new,
effective strategies to optimize medica-
tion use and improve care coordination
in Medicare, said Patrick Conway, MD,
Acting Principal Deputy Administrator of
the Centers for Medicare and Medicaid
Services (CMS).3
The six plans had to lay out their
strategies for the demonstration and were
chosen based on those. The idea is that
738 P&T December 2016 Vol. 41 No. 12
the CMS will pay separately, beyond its
normal payment, for each MTM demon-
stration, with those funds allowing each
plan to go beyond in spending what they
typically spend for MTM plans. They will
be allowed to target members for MTM
services in ways they have not been able
to do in the past, either because of the
presumed cost of expanding services or
the restrictions on targeting them.
There are nearly 40 million Medicare
beneciaries enrolled in a Medicare-
sponsored plan that provides prescrip-
tion drug coverage, with approximately
24 million Medicare beneciaries access-
ing their prescription drugs from a stand-
alone prescription drug plan (PDP)
operating within the Part D outpatient
benet. Those PDPs, operating in every
state, must offer MTM services to plan
members who meet three criteria: having
more than one chronic condition, taking
multiple drugs (between two and eight),
and incurring annual costs for covered
Part D drugs above a cost threshold
($3,138 in 2015). Those criteria t about
25% of Part D recipients, but only 11%
receive MTM services.
The out-of-bid annual upfront
payment is expected to allow plans
to enrich their MTM offerings. The
2% per member back-end performance
payment is an incentive for them to
reduce Part A/B costs. The CMS is
setting a minimum savings rate of 2%
in order to qualify for the performance
payment. But in guring the savings,
the agency will subtract the upfront
payments it made to the plans. That will
make it harder for the plans to reach the
2% target. The CMS explains:
Note that this approach of offsetting Parts A
and B cost savings by the aggregate amount
of prospective payments for the same period
offers plans a strong encouragement to be
judicious when determining the upfront
cost of their intervention, since this amount
will count against them when calculating
savings for purposes of determining
eligibility for performance payments.4
The CMS expects the six PDPs to
upgrade their connections, electronic
and otherwise, with both physician
ofces and pharmacies. According to the
agency, sponsors may lack information
to help assess medication-related risks,
such as claims or other descriptors of
ongoing medical care or alignment of
beneciaries with an ACO [accountable
care organization].
Again, it is unclear whether the six plans
will aggressively upgrade their MTM pro-
grams given the CMSs strong encourage-
ment to be judicious with their spending.
It seems almost contradictory to tell PDPs
to spend funds to expand their efforts, with
Medicare footing the bill, but on the other
hand, give them strong encouragement
to be judicious in those expenditures if
they want a back-end incentive payment.
The use of the word judicious, argues
Larry Kocot, a former top CMS pharmacy
ofcial now working with the Healthcare
and Life Sciences Group at KPMG LLP,
seems to be a reasonable cautionary
reminder. So maybe contradictory is
too strong a word. But no one would read
the CMS cautionary reminder as a clarion
call to action either.
REFERENCES
1. Barlas S. CMS to test enhanced medica-
tion therapy management model: Aims for
greater use of pharmacists, cost savings, and
better outcomes. P T 2016;41(7):423441.
2. Centers for Medicare and Medicaid Services.
Part D enhanced medication therapy man-
agement model. October 11, 2016. Available
at: https://innovation.cms.gov/initiatives/
enhancedmtm. Accessed November 1, 2016.
3. Centers for Medicare and Medicaid
Services. CMS announces Part D
enhanced medication therapy management
model. September 28, 2015. Available at:
www.cms.gov/Newsroom/MediaRelease-
Database/Press-releases/2015-Press-
releases-items/2015-09-28.html. Accessed
November 1, 2016.
4. Hanley S. Announcement of Part D
enhanced medication therapy manage-
ment model test. Centers for Medicare and
Medicaid Services. September 28, 2015.
Available at: https://innovation.cms.gov/
les/x/mtm-announcement.pdf. Accessed
November 1, 2016. Q
 NEW DRUG APPROVALS
Lartruvo for
Soft-Tissue Sarcoma
The FDA has granted accelerated
approval to olaratumab (Lartruvo,
Eli Lilly) in combination with doxoru-
bicin to treat adults with certain types
of soft-tissue sarcoma (STS), which are
cancers that develop in muscles, fat,
tendons, or other soft tissues. Olara-
tumab is approved for use with the FDA-
approved chemotherapy drug doxorubi-
cin for the treatment of patients with STS
who cannot be cured with radiation or
surgery and who have a type of STS for
which an anthracycline (chemotherapy)
is an appropriate treatment.
Olaratumab is a platelet-derived growth
factor (PDGF) receptor-alphablocking
antibody. When stimulated, PDGF recep-
tors cause tumor growth. Olaratumab is
the rst new therapy approved for the ini-
tial treatment of STS since doxorubicins
approval more than 40 years ago.
Source: FDA, October 19, 2016
Zinplava for
C. Difficile Infections
The FDA has approved bezlotoxumab
(Zinplava, Merck), a monoclonal anti-
body indicated to reduce the recurrence
of Clostridium difcile infection (CDI)
in patients 18 years of age or older who
are receiving antibacterial drug treat-
ment for CDI and are at high risk for
CDI recurrence. Bezlotoxumab is not
indicated for the treatment of CDI. It is
not an antibacterial drug. Bezlotoxumab
should be used only in conjunction with
antibacterial drug treatment of CDI.
As with all therapeutic proteins, there
is a potential for immunogenicity after
the administration of bezlotoxumab. After
treatment in two phase 3 studies, how-
ever, none of the 710 evaluable patients
tested positive for treatment-emergent
anti-bezlotoxumab antibodies.
Source: Merck, October 21, 2016
Flublok Quadrivalent
Flu Vaccine
A quadrivalent formulation of Flublok
influenza vaccine (Protein Sciences
Corporation) has received FDA approval.
Flublok Quadrivalent protects against
four strains of inuenzathree of the
same strains found in trivalent Flublok
plus an additional B strain. The product
is approved for adults 18 years of age and
older and will be available in prelled
syringes beginning in 2017.
Source: Protein Sciences, October 11,
2016
Generic Approvals and Launches
Olmesartan Medoxomil/
Hydrochlorothiazide and
Olmesartan Medoxomil Tablets
The FDA has approved the rst generic
versions of Daiichi Sankyos Benicar HCT
and Benicar, which together had U.S.
sales of approximately $1.8 billion for the
12 months ending with August, according
to IMS Health.
Olmesartan medoxomil and hydro-
chlorothiazide tablets, 20 mg/12.5 mg,
40 mg/12.5 mg, and 40 mg/25 mg (Beni-
car HCT), and olmesartan medoxomil
tablets, 5 mg, 20 mg, and 40 mg (Beni-
car), can be marketed by Mylan Pharma-
ceuticals. Both products are indicated for
the treatment of hypertension.
Meanwhile, Sun Pharmaceutical Indus-
tries Ltd. has announced the U.S. launch
of authorized generic versions of both
products.
Sources: FDA and Mylan, October 26,
2016; and Sun Pharmaceutical Industries,
October 27, 2016
Olmesartan Medoxomil, Amlodipine,
And Hydrochlorothiazide Tablets
Two companies have secured FDA
approval to market the first generic
olmesartan medoxomil, amlodip-
ine, and hydrochlorothiazide tablets,
sold under the brand name Tribenzor
(Daiichi Sankyo). Par Pharmaceutical,
Inc., and Torrent Pharmaceuticals Ltd.
can sell tablets in 20 mg/5 mg/12.5 mg,
40 mg/5 mg/12.5 mg, 40 mg/5 mg/
25 mg, 40 mg/10 mg/12.5 mg, and
40 mg/10 mg/25 mg. A third company,
Sun Pharmaceutical Industries Ltd.,
says it has launched authorized generic
versions. The medication is indicated for
treatment of hypertension.
Sources: FDA, October 26, 2016;
and Sun Pharmaceutical Industries,
October 27, 2016
Amlodipine and Olmesartan
Medoxomil Tablets
The FDA has authorized Macleods
Pharmaceuticals Ltd. and Teva Pharma-
ceuticals USA, Inc., to produce amlodip-
ine and olmesartan medoxomil tablets,
5 mg/20 mg, 5 mg/40 mg, 10 mg/20 mg,
and 10 mg/40 mg. These are the rst
generic versions of Azor (Daiichi
Sankyo), used for treatment of hyper-
tension. In addition, Sun Pharmaceuti-
cal Industries Ltd. says it has launched
authorized generic versions.
Sources: FDA, October 26, 2016;
and Sun Pharmaceutical Industries,
October 27, 2016
Ribavirin for Inhalation Solution
The FDA has approved ribavirin for
inhalation solution USP, 6 g per vial, to
be marketed by Navinta LLC. This is the
rst generic version of Virazole for inhala-
tion solution (Valeant Pharmaceuticals),
used for the treatment of hospitalized
infants and young children with severe
lower respiratory tract infections due to
respiratory syncytial virus.
Source: FDA, October 6, 2016
Generic Antihistamine/Decongestant
Acella Pharmaceuticals has secured
approval for a sugar-free bioequiva-
lent to the antihistamine/decon-
gestant Bromfed-DM cough syrup
Vol. 41 No. 12 December 2016 P&T
739
(brompheniramine maleate, pseudo-
ephedrine hydrochloride, and dextro-
methorphan hydrobromide syrup,
2 mg/30 mg/10 mg per 5 mL). This
combination is used to temporarily
relieve symptoms caused by the common
cold, u, allergies, and other breathing
illnesses.
Source: Acella Pharmaceuticals,
October 28, 2016
Nystatin/Triamcinolone Cream
Glenmark Pharmaceuticals has
secured nal FDA approval for nystatin
and triamcinolone acetonide cream USP,
100,000 units/g and 1 mg/g. This is a
generic version of the antifungal agent
Mycolog-II cream, 100,000 units/g, 0.1%
(Delcor Asset Corporation), which is no
longer marketed in the United States.
Source: Glenmark Pharmaceuticals,
October 25, 2016
Benztropine Mesylate Tablets
ANI Pharmaceuticals, Inc., has
announced the launch of benztropine
mesylate tablets USP 0.5 mg, 1 mg, and
2 mg. The product is indicated for use
as an adjunct to the therapy for all forms
of parkinsonism and may also be use-
ful in the control of extrapyramidal dis-
orders (except tardive dyskinesia) due to
neuroleptic drugs.
Source: ANI Pharmaceuticals, October
25, 2016
Aripiprazole Tablets
Dr. Reddys Laboratories has launched
aripiprazole USP in 2-mg, 5-mg, 10-mg,
15-mg, 20-mg, and 30-mg tablets
a generic version of the second-
generation antipsychotic agent Abilify
(Otsuka Pharmaceutical Company). Oral
Abilify has the following indications:
schizophrenia; acute treatment of manic
and mixed episodes associated with
bipolar I; adjunctive treatment of major
depressive disorder; irritability associated
740 P&T December 2016 Vol. 41 No. 12
with autistic disorder; and treatment of
Tourettes disorder.
Source: Dr. Reddys Laboratories,
October 13, 2016
NEW INDICATION
Keytruda for
Metastatic Lung Cancer
The FDA has cleared pembrolizumab
(Keytruda, Merck), an anti-programmed
death receptor-1 (PD-1) therapy, for
the rst-line treatment of patients with
metastatic nonsmall-cell lung cancer
(NSCLC) whose tumors have high
programmed death ligand-1 (PD-L1)
expression (i.e., a tumor proportion
score [TPS] of 50% or more), as deter-
mined by an FDA-approved test, with no
epidermal growth factor receptor or
anaplastic lymphoma kinase genomic
tumor aberrations. With this new indi-
cation, pembrolizumab is the only
antiPD-1 therapy to be approved in
the rst-line treatment setting for these
patients.
In addition, the FDA approved a label-
ing update to include data from the
KEYNOTE-010 trial in the second-line
or greater treatment setting for patients
with metastatic NSCLC whose tumors
express PD-L1 (TPS of 1% or more), as
determined by an FDA-approved test,
with disease progression on or after
platinum-containing chemotherapy.
Source: Merck, October 24, 2016
FDA REVIEW ACTIVITIES
Priority Review Status
Ribociclib for Breast Cancer
The FDA has accepted the new drug
application (NDA) for ribociclib (LEE011,
Novartis) and has granted the drug a
priority review for the first-line
treatment of postmenopausal women
with hormone receptor-positive, human
epidermal growth factor receptor-2-
negative advanced or metastatic breast
cancer in combination with letrozole.
The NDA was partly based on results
from a phase 3 trial that showed that
ribociclib plus letrozole reduced the
risk of disease progression or death by
44% compared with letrozole alone
(hazard ratio, 0.556; P = 0.00000329),
signicantly extending progression-free
survival.
Ribociclib is a selective cyclin-
dependent kinase (CDK) inhibitor, a
class of drugs that helps slow the progres-
sion of cancer by inhibiting two proteins,
CDK4 and CDK6. These proteins, when
overactivated in a cell, can allow cancer
cells to grow and divide too quickly.
Source: Novartis, November 1, 2016
Brigatinib for NSCLC
The FDA has accepted for review
the new drug application for brigatinib
(Ariad Pharmaceuticals), an investiga-
tional oral anaplastic lymphoma kinase
(ALK) inhibitor, for patients with
metastatic ALK-positive nonsmall-
cell lung cancer (NSCLC) who have
progressed on crizotinib. The FDA
granted a priority review and set an action
date of April 29, 2017.
An ongoing phase 3 trial is assessing
the efcacy and safety of brigatinib in
comparison with crizotinib in patients
with locally advanced or metastatic
ALK-positive NSCLC who have not
received prior treatment with an ALK
inhibitor.
Source: Ariad Pharmaceuticals,
October 31, 2016
Spinraza for Spinal Muscular Atrophy
The FDA has accepted for prior-
ity review a new drug application for
nusinersen (Spinraza, Biogen), an inves-
tigational treatment for spinal muscular
atrophy (SMA). If approved, nusinersen
would be the rst therapy for SMA, a
leading genetic cause of infant mortality.
Nusinersen is an antisense oligonucleo-
tide that is designed to alter splicing of
the SMN2 gene in order to increase the
production of fully functional SMN
proteins.
Source: Biogen, October 28, 2016
Opdivo for Bladder Cancer
The FDA has accepted a supplemental
biologics license application that seeks to
expand the use of nivolumab (Opdivo,
Bristol-Myers Squibb) to patients with
locally advanced unresectable or meta-
static urothelial carcinoma that has pro-
gressed on or after platinum-containing
therapy. The FDA granted the application
a priority review, with an action date of
March 2, 2017.
The submission was based on data
from a phase 2, single-arm study, which
evaluated the safety and efficacy of
nivolumab in 270 patients with metastatic
or unresectable urothelial carcinoma
that had progressed or recurred after
treatment with a platinum-based agent
in the metastatic setting or within
one year after neoadjuvant/adjuvant
platinum therapy. In this trial, nivolumab
achieved an objective response rate (the
primary endpoint) of 19.6%.
Source: Bristol-Myers Squibb, October
21, 2016
Ingrezza for Tardive Dyskinesia
The FDA has accepted for prior-
ity review a new drug application for
valbenazine (Ingrezza, Neurocrine Bio-
sciences) for the treatment of patients
with tardive dyskinesia. The target action
date is April 11, 2017.
Vesicular monoamine transporter 2
(VMAT2), a protein in the human brain,
is primarily responsible for repackaging
and transporting monoamines (dopa-
mine, norepinephrine, serotonin, and
histamine) in presynaptic neurons.
Valbenazine is an investigational, highly
selective VMAT2 inhibitor that modulates
dopamine release during nerve commu-
nication, showing little or no afnity for
VMAT1 or other receptors, transporters,
and ion channels.
Source: Neurocrine Biosciences,
October 11, 2016
Fast-Track Designations
OTL 38 Molecule Lights Up Cancer
The FDA has granted fast-track status
to a Purdue University scientists opti-
cal imaging technology that may signi-
cantly improve outcomes for patients with
pancreatic cancer.
Dr. Philip Low developed the OTL 38
molecule, which will move quickly to
phase 3 trials in human cancer patients.
The molecule, given to patients intra-
venously, attaches to receptors on cancer
cells and glows, identifying the cells that
should be surgically removed.
Positive results from a phase 2 study
of OTL 38 were important to gaining
fast-track status. In that study, 96% of the
tissue that was illuminated in patients
was conrmed by pathology to be can-
cerous, and 98% of the malignant lesions
identied by the surgeons uoresced
brightly because of their uptake of the
uorescent dye.
Source: Purdue University, October
26, 2016
Resolaris for Muscular Dystrophy
Resolaris (aTyr Pharma) has been
granted fast-track status by the FDA
for the treatment of patients with
facioscapulohumeral muscular dystro-
phy (FSHD), making it the rst thera-
peutic candidate for FSHD to receive
this designation. Resolaris, a designated
orphan drug in FSHD, is being studied
in a phase 1b/2 clinical program. The
treatment is derived from a naturally
occurring protein released in vitro by
human skeletal-muscle cells. FSHD, a
rare genetic myopathy affecting an esti-
mated 19,000 people in the United States,
has no approved treatments.
Source: aTyr Pharma, October 24, 2016
CC8464/ASP1807 for Neuropathic Pain
The FDA has granted a fast-track
designation to the drug candidate
CC8464/ASP1807 (Chromocell Corpo-
ration/Astellas Pharma) for the man-
agement of neuropathic pain associated
with idiopathic small-ber neuropathy.
In 2015, Chromocell and Astellas entered
into a collaboration agreement for the
development and commercialization
of CC8464/ASP1807 for the manage-
ment of neuropathic pain and other pain
indications. Chromocell recently dosed
the rst subject in a phase 1 trial designed
to evaluate the safety, tolerability, and
pharmacokinetics of an oral formulation
of CC8464/ASP1807.
Chromocells CC8464 is an oral,
highly selective, peripherally restricted
NaV1.7 inhibitor that has been shown to
be effective in animal models of human
neuropathic and inflammatory pain.
NaV1.7 is an ion channel involved in pain
transmission.
Source: Chromocell Corporation,
October 12, 2016
Breakthrough Therapy Status
NiCord Graft Modality
The FDA has granted breakthrough
therapy status to NiCord (Gamida Cell,
Ltd.), an investigational graft modality for
bone marrow transplantation in patients
with high-risk blood cancers, such as
leukemia and lymphoma. An international,
phase 3 registration study is expected to
begin before the end of the year.
Data from phase 1/2 studies of NiCord
have demonstrated clinically meaningful
improvements in the time to neutrophil
engraftment compared with cord blood
transplantation. In addition, NiCord study
data have shown fewer infections, reduced
lengths of hospitalization, quicker platelet
engraftment, and improved nonrelapse
mortality compared with unmanipulated
cord blood transplantation.
Source: Gamida Cell, October 11, 2016
Vol. 41 No. 12 December 2016 P&T
741
 Orphan Drug Designations
YS-ON-001 for Liver Cancer
The FDA has granted an orphan drug
designation for the biologic product can-
didate YS-ON-001 (Yisheng Biopharma
Co.) for the treatment of patients with
hepatocellular carcinoma. YS-ON-001 is
a multicomponent complex with immuno-
modulatory properties, such as promot-
ing Th1-biased immunity; inducing the
activation and proliferation of dendritic
cells, B cells, and natural killer cells; pro-
moting macrophage M1 polarization; and
down-regulating regulatory T cells.
Source: Yisheng Biopharma, October
24, 2016
TNT009 for Anemia
The FDA has granted orphan drug
status to TNT009 (True North Therapeu-
tics) for the treatment of patients with
autoimmune hemolytic anemia (AHA),
including cold agglutinin disease (CAD),
a form of AHA for which there are limited
treatment options. TNT009 is currently in
a phase 1b trial in patients with CAD, and
positive interim results from this study
were reported in June 2016.
TNT009 is a rst-in-class monoclonal
antibody that selectively targets C1s, a
serine protease within the C1-complex
in the immune systems complement
pathway. TNT009 prevents downstream
disease processes involving phagocytosis,
inammation, and cell lysis.
Source: True North Therapeutics,
October 13, 2016
New or Revised Applications
Subcutaneous Rituximab
For Blood Cancers
The FDA has accepted the biologics
license application for a subcutaneous
formulation of rituximab (Genentech)
for multiple blood cancer indications.
The product is a coformulation with
a proprietary recombinant human
hyaluronidase enzyme (the Enhanze
742 P&T December 2016 Vol. 41 No. 12
platform, Halozyme Therapeutics).
It is marketed under the brand name
MabThera SC in countries outside the
United States.
Source: Halozyme, November 3, 2016
Xaracoll for Postsurgical Pain
A new drug application for Xaracoll
(bupivacaine hydrochloride collagen-
matrix implants, Innocoll AG) has been
submitted to the FDA for the treatment
of postsurgical pain. The submission
was based on successful results from the
MATRIX trials, which showed statistically
signicant differences in the primary end-
point (the sum of pain intensity in both
studies), as well as statistically signi-
cant reductions in opioid use and other
secondary endpoints.
Source: Innocoll, November 3, 2016
Niraparib for Ovarian Cancer
Tesaro, Inc., has completed a roll-
ing new drug application submission to
the FDA for the use of niraparib in the
maintenance treatment of patients with
platinum-sensitive, recurrent epithe-
lial ovarian, fallopian tube, or primary
peritoneal cancer who are in response to
platinum-based chemotherapy. Niraparib
is an oral, once-daily poly (ADP-ribose)
polymerase inhibitor. The FDA granted
the drug a fast-track designation in
September 2016.
Source: Tesaro, November 1, 2016
Baxdela for Skin Infections
New drug applications have been
submitted to the FDA for the approval
of intravenous and oral formula-
tions of delaoxacin (Baxdela, Ligand
Pharmaceuticals/Melinta Therapeu-
tics) for the treatment of patients with
acute bacterial skin and skin-structure
infections. Delaoxacin is an investi-
gational anionic uoroquinolone with
a broad spectrum of antimicrobial
activity, including activity against
methicillin-resistant Staphylococcus
aureus.
The submissions were based on results
from two phase 3 studies. In both trials,
delaoxacin met the primary endpoint
of noninferiority to a combination regi-
men of vancomycin plus aztreonam in
reducing lesion size at the primary
infection site 48 to 72 hours after
treatment.
Source: Ligand Pharmaceuticals,
October 24, 2016
Shingrix Shingles Vaccine
A biologics license application has
been submitted to the FDA for a candi-
date shingles (herpes zoster) vaccine,
Shingrix (GlaxoSmithKline), seeking
approval for prevention of the disease
in people 50 years of age or older. In
phase 3 data, the nonlive recombinant
vaccine not only reduced the incidence of
shingles, but also reduced the overall inci-
dence of postherpetic neuralgia, a form
of chronic pain associated with shingles.
Regulatory approval is being sought for
the vaccine to be given intramuscularly
in two doses, with a two- to six-month
interval between doses.
Shingrix combines glycoprotein E,
a protein found on the varicella zoster
virus that causes shingles, with an adju-
vant system, AS01B, which is intended
to enhance the immunological response
to the antigen.
Source: GlaxoSmithKline, October 24,
2016
ZS-9 for Hyperkalemia
The FDA has accepted for review the
resubmission of a new drug application
for sodium zirconium cyclosilicate (ZS-9,
ZS Pharma/AstraZeneca), a potential new
medication for the treatment of patients
with hyperkalemia. Sodium zirconium
cyclosilicate is an insoluble, nonabsorbed
compound with a structure designed to
preferentially capture potassium ions.
The compound has been studied in
three double-blind, placebo-controlled
trials and in one ongoing 12-month, open-
label study in patients with hyperkalemia,
representing a treatment population of
more than 1,600 patients.
Source: AstraZeneca, October 18, 2016
Avycaz for Urinary Tract Infections
The FDA has accepted for ling a
supplemental new drug application for
Avycaz (ceftazidime/avibactam). The
manufacturer, Allergan, is seeking the
addition of new phase 3 clinical trial data
to the current product label. The new
data involve the use of Avycaz in patients
with complicated urinary tract infections,
including pyelonephritis, due to desig-
nated susceptible pathogens. The FDA
is expected to take action on the ling
during the rst quarter of 2017.
Source: Allergan, October 11, 2016
Labeling Changes
Xtandi for Prostate Cancer
The FDA has approved a supplemental
new drug application to update the prod-
uct labeling for enzalutamide capsules
(Xtandi, Astellas Pharma) to include
new clinical data versus bicalutamide
from the TERRAIN study. The updated
label includes data showing that enzalu-
tamide reduced the risk of radiographic
progression or death by 40% compared
with bicalutamide in men with metastatic
castration-resistant prostate cancer, with
median radiographic progression-free sur-
vival of 19.5 months for the enzalutamide
group compared with 13.4 months for the
bicalutamide group (hazard ratio, 0.60).
Source: Astellas Pharma, October 21,
2016
Tarceva for Lung Cancer
The FDA has modied the indication for
erlotinib (Tarceva, Astellas Pharma Global
Development, Inc.) for the treatment of
nonsmall-cell lung cancer (NSCLC)
to limit the medications use to patients
whose tumors have specic epidermal
growth factor receptor (EGFR) mutations.
The labeling change applies to patients
with NSCLC receiving maintenance or
second- or greater-line treatment. These
indications will be limited to patients
whose tumors have EGFR exon 19 dele-
tions or exon 21 L858R substitution muta-
tions, as detected by an FDA-approved
test. The rst-line indication previously
was limited to patients with EGFR exon
19 deletions or exon 21 substitution
mutations.
Source: FDA, October 18, 2016
Other Regulatory Issues
Methylphenidate ER
Lannett Company, Inc., has received
notice from the FDA that it will seek
to withdraw approval of the compa-
nys abbreviated new drug application
for methylphenidate hydrochloride
extended-release (ER) tablets. Lannett
stated that it will review the scientic
rationale for the FDAs position and
compile the scientic evidence needed
to convince the agencys Office of
Generic Products that the methyl-
phenidate ER tablets should continue
to be marketed. The company has until
December 19, 2016, to submit new data.
Source: Lannett Company, October
19, 2016
FDA Conrms Xarelto Efficacy
In July 2016, the hand-held, point-of-
care INRatio device (Alere, Inc.) was
recalled because of the potential to
generate inaccurate results. This device
was used to monitor warfarin therapy in
the control group of the pivotal ROCKET-
AF trial, which provided the primary data
to support the 2011 approval of the blood-
thinner rivaroxaban (Xarelto, Janssen).
Because of the concern about the INRatio
device, the FDAs Center for Drug Evalu-
ation and Research conducted a series
of analyses to assess the effect that
this faulty monitoring device may have
had on the ROCKET-AF study results.
The agency determined that effects of
the device on strokes or bleeding, includ-
ing intracranial bleeding, were minimal.
The FDA concluded that rivaroxaban is
a safe and effective alternative to war-
farin in patients with nonvalvular atrial
brillation.
Source: FDA, October 11, 2016
DRUG SAFETY ISSUES
Checkpoint Inhibitors
And Myocarditis Deaths
Checkpoint inhibitors are popular
treatments for cancer, but an article in
the New England Journal of Medicine
has warned that combining the check-
point inhibitors nivolumab (Opdivo) and
ipilimumab (Yervoy)both marketed
by Bristol-Myers Squibbcould lead
to death in a small number of patients.
According to the article, two melanoma
patients receiving combination treatment
with nivolumab and ipilimumab died from
fulminant myocarditis. Autopsies showed
that the immune systems of both patients
had attacked their hearts.
According to the article, myocarditis
has occurred in 0.27% of patients treated
with nivolumab and ipilimumab in
pharmacovigilance studies, suggesting
that the patients in the new report had
experienced a rare, potentially fatal,
T-celldriven drug reaction.
In addition to nivolumab and ipilim-
umab, two other checkpoint inhibitors
are on the market: pembrolizumab
(Keytruda, Merck) and atezolizumab
(Tecentriq, Genentech).
Source: BioSpace, November 3, 2016
Testosterone Warnings
The FDA has approved class-wide
labeling changes for all prescription
testosterone products, adding a new
warning and updating the abuse and
Vol. 41 No. 12 December 2016 P&T
743
dependence section to include new
safety information from published
literature and case reports regarding
the risks associated with abuse of and
dependence on testosterone and other
anabolic steroids.
The abuse of testosterone, usually at
doses higher than those typically pre-
scribed and usually in conjunction with
other anabolic steroids, is associated with
serious safety risks affecting the heart,
brain, liver, mental health, and endocrine
system. Reported serious adverse out-
comes include heart attack, heart failure,
stroke, depression, hostility, aggression,
liver toxicity, and male infertility. Individ-
uals abusing high doses of testosterone
have also reported withdrawal symptoms,
such as depression, fatigue, irritability,
loss of appetite, decreased libido, and
insomnia.
Source: FDA, October 25, 2016
Ceftriaxone/Lansoprazole
Tied to Heart Condition
Researchers at Columbia University
studied the combination of ceftriaxone
(Rocephin, Roche), an antibiotic, and
lansoprazole (Prevacid, Takeda), a
heartburn medication. Alone, these
medications carry no known heart-related
risksbut when used together, they
may increase the chance that patients
develop a heart condition known as long
QT syndrome, which can cause abnormal
heart rhythms and, in rare cases, sudden
death, according to the investigators. The
study found that patients taking ceftri-
axone and lansoprazole together were
1.4 times more likely to have a prolonged
QT interval than were patients who were
taking either drug alone.
Source: Columbia University Medical
Center, October 10, 2016
744 P&T December 2016 Vol. 41 No. 12
CLINICAL TRIAL NEWS
Bremelanotide for Hypoactive
Sexual Desire Disorder
Positive, statistically signicant results
have been reported from the phase 3
clinical trial program for bremelanotide
(Palatin Technologies), an investigational
on-demand treatment for premenopausal
women diagnosed with hypoactive sexual
desire disorder. Two studies in the clini-
cal program have met their prespecied
coprimary efcacy endpoints.
Bremelanotide, a melanocortin 4 recep-
tor agonist drug candidate, is a synthetic
peptide analogue of the naturally occur-
ring hormone alpha-MSH (melanocyte-
stimulating hormone). In clinical trials,
bremelanotide was self-administered
on an as-needed (not chronic) basis in
anticipation of sexual activity.
Source: Palatin Technologies,
November 1, 2016
Emicizumab for Hemophilia
Four patients have experienced
serious thrombotic events in a clinical
trial of the experimental hemophilia
medication emicizumab (ACE910,
Genentech/Roche), dimming hopes
for the potential blockbuster drug,
according to a Reuters report. The
patients were being treated for
breakthrough bleeding. A Roche spokes-
man told Reuters that the cases involved
patients who were treated with one of two
bypassing agents. He added that both
agentsShires FEIBA and Novos Novo-
Sevencarried thrombosis warnings.
Emicizumab is an investigational
humanized bispecic monoclonal antibody
engineered to simultaneously bind fac-
tors IXa and X. The drug is being closely
watched because it could change the way
hemophilia is treated.
Source: Reuters, November 2, 2016
Verubecestat for
Alzheimers Disease
Research leading to the discovery and
development of verubecestat (Merck)
for the potential treatment of patients
with Alzheimers disease (AD) has been
published in Science Translational
Medicine.
Verubecestat, an investigational small-
molecule inhibitor of the enzyme beta-
site amyloid precursor protein-cleaving
enzyme 1 (BACE1), emerged from
several years of detailed analysis of the
structure and function of the BACE1
protein. Subsequent phase 1 data from
both healthy volunteers and AD patients
demonstrated that once-daily doses of
verubecestat for one week provided sig-
nicant reductions of up to 80% in the
levels of amyloid-beta peptide production,
a key marker of BACE1 activity.
The efcacy and safety of verubecestat
are being evaluated in two pivotal phase 3
trials, EPOCH and APECS, for the treat-
ment of patients with mild-to-moderate
AD and prodromal AD, respectively.
Source: Merck, November 2, 2016
Lynparza for Ovarian Cancer
Results of a phase 3 study designed
to determine the efcacy of olaparib
(Lynparza, GlaxoSmithKline) as mono-
therapy for the maintenance treatment
of women with platinum-sensitive,
relapsed, BRCA-mutated ovarian cancer
demonstrated a statistically signicant
improvement in progression-free survival
among patients treated with olaparib
compared with those given placebo.
Olaparib is a rst-in-class oral poly
(ADP-ribose) polymerase inhibitor that
is believed to exploit deciencies in the
tumor DNA damage response pathway
to preferentially kill cancer cells. It is
approved by the FDA for the treatment
of women with BRCA-mutated ovarian
cancer.
Source: AstraZeneca, October 26, 2016
 Adalimumab
Biosimilar Candidate
In a pivotal phase 3 trial, BI 695501
(Boehringer Ingelheim), a biosimilar
candidate to Humira (adalimumab,
AbbVie), met the studys primary efcacy
endpoint by establishing equivalence
with Humira in patients with active rheu-
matoid arthritis. Secondary endpoints
comparing the efficacy, safety, and
immunogenicity of BI 695501 with that
of Humira were also met.
Source: Boehringer Ingelheim,
October 26, 2016
Tramiprosate for
Alzheimers Disease
Efcacy analyses have been conducted
of phase 3 data for the investigational
amyloid-targeted drug tramiprosate
(Alzheon) in patients with mild or mod-
erate Alzheimers disease (AD). These
evaluations involved patient subgroups
based on the number of epsilon-4 alleles
of apolipoprotein E (APOE4), a major
genetic risk factor in up to 65% of AD
patients. The results showed a genedose
effect at the high dosage of tramiprosate
(150 mg twice daily). Patients with two
APOE4 alleles (APOE4/4 homozygotes)
showed the largest clinical benet and
those with one APOE4 allele (APOE4
heterozygotes) showed an intermediate
benet, while APOE4 noncarriers showed
no benet from tramiprosate. The results
provided the rst evidence from a large
clinical trial to associate the efcacy of an
amyloid-targeted agent with APOE4 status
in AD patients.
Source: Alzheon, October 25, 2016
Xgeva for Bone Complications
Caused by Multiple Myeloma
A phase 3 study evaluating denosumab
(Xgeva, Amgen) versus zoledronic acid
met the primary endpoint of noninferior-
ity (hazard ratio, 0.98) in delaying the
time to the rst on-study skeletal-related
event (SRE) in patients with multiple
myeloma. The secondary endpoints of
superiority in delaying the time to the
rst SRE and superiority in delaying
the time to rst-and-subsequent SREs
were not met. The hazard ratio of Xgeva
versus zoledronic acid for overall survival
was 0.90.
Xgeva targets the RANK ligand path-
way to prevent the formation, function,
and survival of osteoclasts, which break
down bone. Xgeva is indicated for the
prevention of SREs in patients with bone
metastases from solid tumors and for the
treatment of adults and skeletally mature
adolescents with giant-cell tumors of bone
that are unresectable or where surgical
resection is likely to result in severe mor-
bidity. Xgeva is also indicated in the U.S.
for the treatment of hypercalcemia of
malignancy that is refractory to bisphos-
phonate therapy. Xgeva is not indicated
for the prevention of SREs in patients with
multiple myeloma.
Source: Amgen, October 20, 2016
Locilex for Diabetic
Foot Infections
Two phase 3 trials of pexiganan cream
0.8% (Locilex, Dipexium Pharmaceuti-
cals) in patients with mild infections of
diabetic foot ulcers did not meet the
primary clinical endpoint of superior-
ity compared with placebo cream plus
standardized wound care. The results
also did not show any meaningful differ-
ences in wound closure rates between
the pexiganan arm and the vehicle arm
in each study. Further, neither trial met
the secondary endpoint of demonstrating
a higher rate of eradication of bacteria for
the pexiganan arm.
Pexiganan cream 0.8% is a chemi-
cally synthesized, 22-amino acid peptide
isolated from the skin of the African
clawed frog.
Source: Dipexium Pharmaceuticals,
October 25, 2016
Elagolix for Pelvic Pain
Associated With Endometriosis
Positive results have been reported
from two replicate pivotal phase 3 trials
evaluating the efcacy and safety of elago-
lix (AbbVie/Neurocrine Biosciences), a
gonadotropin-releasing hormone recep-
tor antagonist, in premenopausal women
with endometriosis.
In the two studies, both dosages of
elagolix demonstrated a statistically sig-
nicant (P < 0.001) improvement com-
pared with placebo in the percentage of
dysmenorrhea (DYS) and nonmenstrual
pelvic pain (NMPP) responders. In the
first study, at three months, 46% of
patients treated with 150 mg once daily
and 76% treated with 200 mg twice daily of
elagolix were classied as DYS respond-
ers compared with 20% of patients in the
placebo group. In addition, 50% of patients
treated with 150 mg once daily and 55%
of those treated with 200 mg twice daily
of elagolix were classied as NMPP
responders compared with 36% of patients
in the placebo group. The second pivotal
study demonstrated similar results.
Source: AbbVie, October 19, 2016
Tenofovir Prodrug
For HBV Infection
Positive interim data have been
reported for CMX157 (ContraVir
Pharmaceuticals), a prodrug of tenofo-
vir, from an ongoing phase 2a multiple-
ascending-dose clinical trial. The study is
comparing CMX157 with tenofovir diso-
proxil fumarate (TDF) (Viread, Gilead
Pharmaceuticals) in patients chronically
infected with hepatitis B virus (HBV).
The interim data were obtained from
10 HBV-infected patients who completed
14 days of once-daily oral dosing of 25 mg
of CMX157, and from two HBV patients
treated for 14 days of oral dosing with
300 mg TDF. The CMX157-treated
patients showed an average 99% reduction
in the HBV viral load compared with base-
Vol. 41 No. 12 December 2016 P&T
745
line. Signicantly, the observed antiviral
activity for CMX157 was comparable with
that observed in TDF-treated patients, but
at 1/12th the dose (25 mg of CMX157
versus the standard 300 mg of TDF).
Source: ContraVir Pharmaceuticals,
October 13, 2016
AZD9412 for Asthma
AstraZeneca has decided to stop a
phase 2a trial for the inhaled interferon
(IFN)-beta product AZD9412 based on
an interim analysis in which an over-
all very low number of reported severe
exacerbations could make primary
endpoint conclusions difcult.
Synairgen, based in the United Kingdom,
licensed AZD9412 to AstraZeneca in June
2014. AZD9412 acts as an antiviral protein.
In the INEXAS study, asthma patients
were treated with AZD9412 or placebo at
the onset of common cold symptoms. Pre-
vious research has shown that common
colds can cause severe asthma exacerba-
tions and that boosting the lungs antiviral
defenses with AZD9412 during this time
could prevent exacerbations.
Source: Synairgen October 12, 2016
AB103 for Necrotizing
Soft-Tissue Infections
After reviewing the rst 50 patients
for safety, an independent data monitor-
ing committee has recommended that
the phase 3 ACCUTE trial of AB103
(Atox Bio), a candidate for the treatment
of patients with necrotizing soft-tissue
infections (NSTI; esh-eating bacteria),
continue without modication.
AB103 is a peptide that binds to the
CD28 costimulatory receptor, thereby mod-
ulating the hosts immune response. By
modulating, but not inhibiting, the immune
response, AB103 dampens the out-of-
control acute inammatory response that
leads to tissue and organ damage.
The ACCUTE trial is a randomized,
placebo-controlled study that plans to enroll
746 P&T December 2016 Vol. 41 No. 12
290 patients with NSTI at approximately
60 centers in the United States. The par-
ticipants are receiving AB103 or placebo,
administered as a single dose during or
shortly after surgical debridement, in
addition to standard-of-care treatment.
Source: Atox Bio, November 3, 2016
Nuplavid for Schizophrenia
Acadia Pharmaceuticals has announced
the initiation of a six-week phase 3 study
to evaluate pimavanserin (Nuplavid) for
the adjunctive treatment of schizophrenia
in patients with an inadequate response
to antipsychotic therapy. Antipsychotics
currently indicated for schizophrenia
primarily target the dopaminergic pathway.
As a selective serotonin inverse agonist
(SSIA), pimavanserin belongs to a new
class of antipsychotic medications with a
mechanism of action targeting serotonergic
5-HT2A receptors while avoiding activity at
dopamine and other receptors commonly
targeted by other antipsychotics.
The FDA approved pimavanserin
for the treatment of patients with
hallucinations and delusions associated
with Parkinsons disease psychosis in
April 2016. The drug is not approved for
the adjunctive treatment of patients with
schizophrenia.
Source: Acadia Pharmaceuticals,
November 3, 2016
PRX-102 for Fabry Disease
The rst patient has been dosed in
a global phase 3 study of PRX-102
(Protalix BioTherapeutics), a modi-
ed version of the recombinant human
alpha-GAL-A protein, for the treatment
of patients with Fabry disease. The
BALANCE trial is a 24-month, random-
ized, double-blind, active-control study
of PRX-102 for the treatment of Fabry
disease in patients with impaired renal
function. The trial is designed to enroll
78 patients previously treated with Fabra-
zyme (agalsidase beta, Sano/Genzyme)
with a stable dose for at least six months.
Enrolled patients will be randomly
assigned to continue treatment with
1 mg/kg of either Fabrazyme or
PRX-102, administered via intravenous
infusion every two weeks.
Source: Protalix BioTherapeutics,
October 25, 2016
DEVICE APPROVALS
BreathID Lab System
For H. Pylori Detection
The BreathID Lab System and breath-
test kits (Exalenz Bioscience), developed
for Helicobacter pylori bacterium detec-
tion, have received marketing clearance
from the FDA. The system was designed
to facilitate the diagnosis of H. pylori infec-
tion in large numbers of breath samples
at a central location. Patients at clinics
and medical centers breathe into two
designated collection bags, and the
breath samples are sent for analysis
to central laboratories, where the new
system will be installed.
Source: Exalenz Bioscience, November
1, 2016
Amplatzer PFO Occluder
Device to Limit Stroke Risk
The FDA has approved the Amplatzer
PFO Occluder device (St. Jude Medical,
Inc.) to reduce the risk of a stroke in
patients who previously experienced a
stroke believed to be caused by a blood
clot that passed through a small hole in
the heartcalled a patent foramen ovale
(PFO)and then traveled to the brain.
The Amplatzer PFO Occluder is
inserted through a catheter that is placed
in a leg vein and advanced to the heart.
It is then implanted close to the hole in
the heart between the right atrium and
the left atrium.
The device was on the market more
than a decade ago under a humanitarian
device exemption (HDE), but it was vol-
untarily withdrawn by the manufacturer in
2006 after the FDA concluded that the tar-
get population for the device was greater
than 4,000 patients and that the device no
longer qualied for HDE approval.
Source: FDA, October 28, 2016
Evarrest Fibrin Sealant Patch
The FDA has approved an expanded
indication for Evarrest brin sealant patch
(Ethicon), which leverages biologics to
stop problematic bleeding during surgery.
The expanded indication supports the use
of Evarrest as an adjunctive hemostat for a
broad range of patient types and surgical
situations. The new indication for Evarrest
was supported by a head-to-head study
that demonstrated the products superior
hemostatic efcacy compared with that
of Tachosil brin sealant patch (Baxter).
Source: Ethicon, October 25, 3016
DEVICE SAFETY ISSUES
Infection Risk With
HeaterCooler Devices
The Centers for Disease Control and
Prevention (CDC) has warned health
care providers about the potential risk
of infection from certain devices used
during open heart (open chest) surgery.
New information indicates that some
LivaNova PLC (formerly Sorin Group
Deutschland GmbH) Stckert 3T heater
cooler devices, used during many of these
surgeries, might have been contaminated
during manufacturing, which could
put patients at risk for life-threatening
infections.
Laboratory tests showed that
Mycobacterium chimaera organisms from
the heatercooler devices matched bac-
teria found in patients in several states.
These results build on previous evidence
from Europe that suggests the bacte-
ria contaminated these devices during
manufacturing in Germany.
Source: CDC, October 13, 2016
Battery Failure in
St. Jude Debrillators
The FDA and St. Jude Medical have
alerted physicians, patients, and care-
givers to respond immediately to elec-
tive replacement indicator (ERI) alerts
on implantable cardioverter debrillators
and cardiac resynchronization therapy
debrillators from St. Jude. Because of
problems with the batteries, patients do
not have the normal three-month lead
time for device replacement. Some bat-
teries have run out within 24 hours of
the patient receiving an ERI alert. The
warning applies only to St. Jude devices
manufactured before May 2015.
Source: FDA, October 11, 2016
FDA Warning:
Radiation Therapy Devices
The FDA has expressed concern
about the risks to patients from the
use of devices manufactured and sold
by Multidata Systems International
Corporation. The agency knows of at least
two Multidata medical devices manufac-
tured and distributed in the United States
for which the FDA never received nor
reviewed 510(k) pre-market notications.
These devices include accessories to
radiation therapy devices and the Dual
Channel Electrometer. In addition,
Multidata has not registered or listed
its devices with the FDA, as required by
federal law.
Source: FDA, October 20, 2016
Tracheostomy Tube Set Recalled
According to the FDA, Teleex has
recalled the Willy Rusch tracheostomy
tube set because of the possibility that
the connector may disconnect from the
tracheostomy tube during use on a ven-
tilated patient. If the connector detaches
from the tracheostomy tube shaft during
use, it can deprive the patient of adequate
ventilation and would require immedi-
ate medical intervention, including
changing the tracheostomy tube and
placing a new tube. The use of affected
products may cause serious adverse
health consequences, including oxygen
deprivation, brain damage, and death.
Source: FDA, October 20, 2016
OTHER DEVICE NEWS
Wrist-Worn Heart Rate Monitors
In a study published online in JAMA
Cardiology, researchers at the Cleve-
land Clinic assessed the accuracy of
four popular wrist-worn heart rate (HR)
monitors under conditions of varying
physical exertion. Fifty healthy adults
(average age, 37 years) wore standard
electrocardiographic limb leads and a
Polar H7 chest-strap monitor. In addition,
each subject was randomly assigned to
wear two different wrist-worn HR moni-
tors. Four monitors were assessed: Fitbit
Charge HR (Fitbit), Apple Watch (Apple),
Mio Alpha (Mio Global), and Basis Peak
(Basis).
The investigators found that the HR
monitors had variable accuracy when
compared with an electrocardiogram.
While the Basis Peak overestimated
HR during moderate exercise, the Fitbit
Charge HR underestimated HR during
more vigorous exercise. The Apple Watch
and Mio Fuse had 95% of values within
27 beats per minute (bpm) and +29 bpm
of the electrocardiogram, whereas Fitbit
Charge HR had 95% of values within 34
bpm and +39 bpm, and the corresponding
values for the Basis Peak were within 39
bpm and +33 bpm.
Because cardiac patients increasingly
rely on these monitors to stay within
physician-recommended, safe HR thresh-
olds during rehabilitation and exercise,
appropriate validation of these devices
in this group is imperative, the authors
wrote.
Source: Medical Xpress, October 12,
2016 Q
Vol. 41 No. 12 December 2016 P&T
747
 Pharmaceutical Approval Update
Michele B. Kaufman, PharmD, CGP, RPh
Lisinopril Oral Solution (Qbrelis)
Manufacturer: Silvergate Pharmaceuticals, Inc., Greenwood
Village, Colorado
Date of Approval: July 29, 2016
Indication: Lisinopril oral solution is indicated
for the treatment of hypertension (HTN) in patients
6 years of age and older. It is also approved as adjunc-
tive therapy for heart failure and to treat acute
myocardial infarction (MI).
Drug Class: Angiotensin-converting enzyme
inhibitor (ACEI)
Uniqueness of Drug: Many pediatric patients
require ACEI treatment for HTN. Until the approval
of Qbrelis, there was no commercially available Michele B. Kaufman, can be fatal. Patients at risk for excessive hypo-
ACEI preparation to treat this age group, although PharmD, CGP, RPh
a number of ACEIs were extemporaneously com-
pounded to prepare pediatric doses. Qbrelis is the rst and
only ACEI oral solution approved by the Food and Drug
Administration. It is bioequivalent to lisinopril tablets under
fasted and fed conditions.
Warnings and Precautions:
Boxed warning: fetal toxicity. Lisinopril should be dis-
continued immediately in a pregnant patient. Fetal injury and
death may occur during the second and third trimesters of
pregnancy. These drugs reduce fetal renal function and increase
fetal and neonatal morbidity and death. Potential neonatal
adverse effects include skull hypoplasia, anuria, hypotension,
renal failure, and death.
Head and neck angioedema/intestinal angioedema.
Angioedema of the face, extremities, lips, tongue, glottis,
and/or larynx, including some fatal reactions, has occurred in
ACEI-treated patients; intestinal angioedema has also occurred.
Patients with tongue, glottis, or laryngeal involvement are
likely to experience airway obstruction, especially those with
a history of airway surgery. Lisinopril should be discontinued
promptly and appropriate therapy and monitoring should be
provided until complete and sustained resolution of angioedema
has occurred. Patients with a history of angioedema unrelated
to ACEI therapy may be at increased risk while receiving an
ACEI. Coadministration of ACEIs and mammalian target of
rapamycin inhibitors (e.g., temsirolimus, sirolimus, everolimus)
may increase the risk for angioedema.
Anaphylactoid reactions. Two patients undergoing
desensitizing treatment with hymenoptera venom while receiv-
ing ACEIs had life-threatening anaphylactoid reactions. Sudden
and potentially life-threatening anaphylactoid reactions have
occurred in some patients dialyzed with high-ux membranes
while being concomitantly treated with an ACEI. Dialysis
must be immediately stopped in these patients, and aggres-
sive therapy must be initiated. Antihistamines did not relieve
the symptoms in these situations. Therefore, consideration
Michele B. Kaufman, PharmD, CGP, RPh, is a freelance medical
writer living in New York City and a Pharmacist in the NewYork
Presbyterian Lower Manhattan Hospital Pharmacy Department.
748 P&T December 2016 Vol. 41 No. 12
should be given to using a different type of dialysis membrane
or a different antihypertensive class. Anaphylactoid reactions
have also been reported in patients undergoing low-density
lipoprotein apheresis with dextran sulfate absorption.
Impaired renal function. Renal function should
be periodically monitored in patients treated with
lisinopril because acute renal failure may occur.
Consider withholding or discontinuing therapy in
patients who develop a clinically signicant decrease
in renal function.
Hypotension. Lisinopril can cause symptomatic
hypotension, sometimes complicated by oliguria,
progressive azotemia, or acute renal failure, which
tension include those with heart failure with systolic
blood pressure less than 100 mm Hg, ischemic
heart disease, cerebrovascular disease, hyponatremia, or
severe volume and/or salt depletion of any etiology, and those
undergoing high-dose diuretic therapy or renal dialysis. In
these patients, lisinopril should be started under close medical
supervision and should be followed closely during the rst
two weeks of treatment and whenever the dose is increased
and/or the diuretic dose is increased. Lisinopril should be
avoided in patients who are hemodynamically unstable after
acute MI. Symptomatic hypotension is also possible in patients
with severe aortic stenosis or hypertrophic cardiomyopathy.
Hyperkalemia. During lisinopril treatment, serum potas-
sium should be periodically monitored because ACEIs can
cause hyperkalemia. Risk factors for developing hyperkalemia
include renal insufciency, diabetes mellitus, and concomitant
use of potassium-sparing diuretics, potassium supplements,
and/or potassium-containing salt substitutes.
Hepatic failure. ACEIs have been associated with chole-
static jaundice or hepatitis progressing to fulminant hepatic
necrosis and sometimes death (mechanism unknown). Patients
receiving ACEIs who develop jaundice or marked hepatic
enzyme elevations should immediately discontinue the ACEI
and receive appropriate medical treatment.
Dosage and Administration: Qbrelis is available in a
150-mL bottle containing 1 mg/mL of lisinopril oral solution.
In adults with HTN, begin treatment with 10 mg once daily.
Adjust the dose to the blood pressure response. Doses up
to 80 mg per day have been used, but do not appear to give
greater effect. In combination with diuretics, the starting dose
is 5 mg daily.
In patients with heart failure, initiate treatment with 5 mg
once daily, and increase the dose as tolerated to 40 mg daily.
Acute MI patients should be administered 5 mg within
24 hours of the MI followed by 5 mg after 24 hours, then
10 mg once daily.
For pediatric HTN patients over the age of 6 years with a
glomerular ltration rate greater than 30 mL/min/1.73 m2,
start lisinopril oral solution at 0.07 mg per kg (up to 5 mg total)
taken once daily. The dosage should be adjusted according to
blood pressure response up to a maximum of 0.61 mg per kg
 Pharmaceutical Approval Update
(up to 40 mg) once daily. Doses above 0.61 mg per kg (or in
excess of 40 mg) have not been studied in pediatric patients.
For patients with creatinine clearance greater than or equal
to 10 mL/min and less than or equal to 30 mL/min, begin
treatment with half the usual initial dose. For patients with
creatinine clearance less than 10 mL/min or on hemodialysis,
the recommended initial dose is 2.5 mg.
Commentary: The safety and efcacy of lisinopril were
established in multiple studies treating adults with HTN, heart
failure, and MI; however, it demonstrated less antihypertensive
effect in black patients than in non-black patients.
In a clinical study of 115 hypertensive pediatric patients
6 to 16 years of age, the patients were divided into six treatment
groups: those weighing less than 50 kg received 0.625 mg,
2.5 mg, or 20 mg of lisinopril once daily and those weighing
50 kg or more received 1.25 mg, 5 mg, or 40 mg of lisinopril
once daily. Lisinopril was administered as tablets to patients
tolerant of swallowing pills or in a suspension for those children
who could not or who required a lower dose than was available
in tablet form. After two weeks, lisinopril lowered trough blood
pressure in a dose-dependent manner, with antihypertensive
efcacy demonstrated at doses greater than 1.25 mg (0.02 mg
per kg). This effect was conrmed in a randomized withdrawal
phase, where the diastolic pressure rose by about 9 mm Hg
more in patients randomized to placebo compared with patients
who remained on the middle and high doses of lisinopril. This
effect was consistent across several demographic subgroups
(e.g., age, Tanner stage, gender, and race).
Sources: Silvergate Pharmaceuticals, Qbrelis prescribing
information, Food and Drug Administration
Etanercept-szzs (Erelzi)
Manufacturer: Sandoz, Princeton, New Jersey
Date of Approval: August 30, 2016
Indication: Etanercept-szzs is indicated for the treatment of
moderately to severely active rheumatoid arthritis (RA), poly-
articular juvenile idiopathic arthritis (JIA) in patients 2 years of
age and older, psoriatic arthritis (PsA), ankylosing spondylitis
(AS), and plaque psoriasis (PsO).
Drug Class: Tumor necrosis factor-alfa (TNF-) inhibitor
biosimilar
Uniqueness of Drug: Erelzi is the rst biosimilar for the
blockbuster reference product Enbrel (etanercept, Amgen/
Immunex). It is the rst subcutaneously administered anti-TNF-
biosimilar to receive Food and Drug Administration approval.
Warnings and Precautions:
Boxed warning: malignancies.
Lymphoma. Lymphoma cases have been observed in
patients receiving TNF- inhibitors. During the controlled
portions of clinical trials in adults with RA, AS, and PsA, two
lymphomas were observed among 3,306 etanercept-treated
patients compared with none among 1,521 control patients.
In other controlled and uncontrolled portions of etanercept
clinical trials enrolling 6,543 adult patients with RA, AS,
and PsA, the observed lymphoma rate was 0.10 cases per
100 patient-years (12,845 total patient-years of therapy).
This rate was threefold higher than the rate expected in
the general U.S. population based on the Surveillance,
Epidemiology, and End Results Database (SEER).
Leukemia. Post-marketing data have reported both acute
and chronic leukemia cases associated with TNF inhibi-
tors. Compared with the general population, RA patients
may already have an approximate twofold higher risk
of developing leukemia. During controlled portions of
etanercepts trials, two cases of leukemia occurred among
5,445 etanercept-treated patients compared with zero
among 2,890 control patients (duration of treatment up
to 48 months).
Melanoma and nonmelanoma skin cancer. Melanoma
and nonmelanoma skin cancer have been reported in
TNF- inhibitor-treated patients, including etanercept
products. Periodic skin examinations should be considered
for all patients at increased skin cancer risk.
Boxed warning: serious infections. Increased risk of
serious infections leading to hospitalization or death, includ-
ing tuberculosis (TB), bacterial sepsis, invasive fungal infec-
tions (such as histoplasmosis), and infections due to other
opportunistic pathogens, have occurred.
Etanercept-szzs should not be started if a patient has an
active infection. If one develops, patients should be carefully
monitored, and etanercept-szzs should be stopped. Consider
empiric antifungal therapy for patients at risk for invasive fungal
infections who develop a severe systemic illness while receiving
etanercept-szzs. All patients should be monitored for active TB
during treatment, even if the initial latent TB test is negative.
Demyelinating disease. Etanercept and other TNF-
inhibitors have been associated with rare cases (less than
0.1%) of new-onset or exacerbated central nervous system
demyelinating disorders, some presenting with mental status
changes, permanent disability, and peripheral nervous system
demyelinating disorders. Prescribers should use caution when
considering etanercept-szzs for patients with pre-existing or
recent-onset central or peripheral nervous system demyelinating
disorders; etanercept products and TNF- inhibitors have been
associated with rare cases of new-onset multiple sclerosis,
Guillain-Barr syndrome, seizure disorders, optic neuritis,
and other related disorders.
Congestive heart failure. Worsening or new-onset
congestive heart failure may occur. Physicians should exercise
caution when using etanercept-szzs in patients who also have
heart failure.
Hematological events. Rare reports (less than 0.1%) of
pancytopenia, including very rare reports of aplastic anemia,
some with fatal outcomes, have been reported in etanercept-
treated patients. If pancytopenia or aplastic anemia symptoms
develop, patients should immediately seek medical attention
and consider stopping etanercept-szzs.
Hepatitis B reactivation. Monitor patients previously
infected with hepatitis B virus during and several months
following etanercept-szzs therapy. If reactivation of the virus
occurs, consider stopping etanercept-szzs and beginning
antiviral therapy.
Autoimmunity. Treatment with etanercept-szzs may
result in autoantibody formation. If lupus-like syndrome or
autoimmune hepatitis occurs, discontinue etanercept-szzs.
Drug interactions. Live vaccines should not be given
concurrently with etanercept-szzs. Pediatric patients should
be brought up to date with all immunizations before initiating
Vol. 41 No. 12 December 2016 P&T
749
 Pharmaceutical Approval Update
therapy. Etanercept-szzs should not be administered with
anakinra or abatacept due to an increased risk of developing
serious infections. It should not be administered with cyclophos-
phamide due to a potentially higher incidence of developing
noncutaneous solid malignancies.
Dosage and Administration: The recommended dosage
for RA, AS, and PsA patients 18 years of age or older is 50 mg
weekly. Adults with RA or PsA may also receive methotrexate
if warranted. Adult PsO patients should begin on 50 mg twice
weekly for three months, followed by maintenance doses of
50 mg once weekly. JIA patients weighing more than 63 kg
should receive a 50-mg dose weekly.
Commentary: A biosimilar is a biological product that must
demonstrate that it is highly similar to an already-approved
biological product and has no clinically meaningful differ-
ences in terms of safety and effectiveness when compared
with that reference product. The approval of Erelzi was based
on review of evidence that included structural and functional
characterization, animal study data, human pharmacokinetic
and pharmacodynamic data, clinical immunogenicity data, and
other clinical safety and effectiveness data that demonstrated
its biosimilarity to the reference product Enbrel.
Sources: Sandoz, Erelzi-szzs prescribing information
Lumacaftor 100 mg/Ivacaftor 125 mg (Orkambi)
Manufacturer: Vertex Pharmaceuticals, Inc., Boston,
Massachusetts
Date of Approval: September 30, 2016
Indication: Orkambi is indicated for the treatment of cystic
brosis (CF) in patients 6 years of age and older who are
homozygous for the F508del mutation on the CFTR gene. If the
patients genotype is unknown, a Food and Drug Administration-
cleared CF mutation test should be used to detect the presence
of the F508del mutation on both alleles of the CFTR gene.
Drug Class: Cystic brosis transmembrane conductance
regulator (CFTR) potentiator
Uniqueness of Drug: CF is a disease of exocrine gland
function that involves multiple organ systems, predominantly
the lungs, which results in chronic respiratory infections,
pancreatic enzyme insufciency, and associated complica-
tions if left untreated. Ninety percent of patients who survive
the neonatal period have pulmonary involvement. End-stage
lung disease is the principal cause of death. Previously,
Orkambi tablets (lumacaftor 200 mg/ivacaftor 125 mg) were
only approved for patients 12 years of age and older who are
homozygous for the F508del-CFTR mutation. This new approval
makes a lower-dosage tablet available (lumacaftor 100 mg/
ivacaftor 125 mg), which expands the indication to include
children 6 to 11 years of age with CF who are homozygous
for the F508del-CFTR mutation.
Warnings and Precautions:
Hepatic injury. Liver-related events, such as elevated
alanine transaminase (ALT) and aspartate transaminase (AST),
have been observed in some cases associated with elevated
bilirubin in Orkambi-treated patients. Serum transaminase and
bilirubin levels should be measured before initiating Orkambi
and should also be obtained every three months during the
rst year of treatment and annually thereafter. For patients with
a history of ALT, AST, or bilirubin elevations, more frequent
750 P&T December 2016 Vol. 41 No. 12
monitoring should be considered. Dosing should be interrupted
in patients with ALT or AST levels greater than ve times the
upper limit of normal (ULN), or ALT or AST levels greater
than three times the ULN with bilirubin levels greater than
twice the ULN. Following resolution, consider the benets
and risks of resuming treatment.
Respiratory events. Chest discomfort, dyspnea, and
abnormal respiration were observed more commonly during
initiation of Orkambi. Clinical experience in patients with a
percent-predicted forced expiratory volume in one second
of less than 40 is limited, and additional monitoring of these
patients is recommended during therapy initiation.
Blood pressure. Increased blood pressure has been
observed in some patients; therefore, blood pressure should
be periodically measured in all patients.
Cataracts. Noncongenital lens opacities/cataracts have
been reported in pediatric patients treated with Orkambi
and with ivacaftor monotherapy. Baseline ophthalmological
examinations and follow-ups are recommended for pediatric
patients.
Drug interactions. Use with sensitive cytochrome P450 3A
(CYP3A) substrates or CYP3A substrates with a narrow
therapeutic index may decrease systemic exposure of the
medicinal products, and coadministration is not recommended.
Hormonal contraceptives should not be relied upon as an
effective method of contraception. Use with strong CYP3A
inducers may diminish exposure to ivacaftor, which may
lessen its effectiveness; therefore, coadministration is not
recommended.
Adverse reactions. The most common adverse reactions
that occurred in 5% or more of patients were dyspnea,
nasopharyngitis, nausea, diarrhea, upper respiratory tract
infection, fatigue, abnormal respiration, increase in blood
creatine phosphokinase, rash, atulence, rhinorrhea, and
inuenza.
Dosage and Administration: The recommended dosage
for patients 12 years of age and older is two tablets (each
containing lumacaftor 200 mg/ivacaftor 125 mg) taken orally
every 12 hours. The recommended dosage for children
6 to 11 years old is two tablets (each containing lumacaftor
100 mg/ivacaftor 125 mg) taken orally every 12 hours. Note
that the recommended dose for this age group contains a lower
dose of lumacaftor. When commencing treatment in patients
taking strong CYP3A inhibitors, reduce the Orkambi dose for
the rst treatment week.
Commentary: The mean lumacaftor area under the curve
at steady state (AUCss) following administration of Orkambi in
6- to 11-year-old patients dosed every 12 hours was comparable
to the mean AUCss in patients 12 years of age and older. The
mean ivacaftor AUCss was also comparable to the mean AUCss
in patients 12 years of age and older. The safety prole of
Orkambi in 6- to 11-year-old patients and in patients older than
12 years is similar. The safety and efcacy of Orkambi in CF
patients younger than 6 years old have not been established.
Sources: Vertex, Orkambi prescribing information;
Medscape eMedicine Q
DRUG FORECAST
Daclatasvir (Daklinza)
A Treatment Option for Chronic Hepatitis C Infection
Maggie Montgomery, PharmD; Natalie Ho, PharmD; Elizabeth Chung, PharmD;
and Nino Marzella, PharmD
INTRODUCTION
The discovery of the hepatitis C
virus (HCV) took place 27 years ago.
Initial research was geared toward
understanding the HCV life cycle and
replication process. The Food and Drug
Administration (FDA) approved an
injectable formulation of interferon in
1997 as the initial medication active
against the virus. Although it was
considered a breakthrough in HCV
treatment, many adverse events
were reported along with a lack of
clinically sustained virological
response (SVR) that often limited the
drugs role.1
Ongoing efforts sought to develop
different means of treating HCV based
on the specic genotype of the virus.
The addition of pegylated formulations
of interferon allowed for less frequent
dosing and minimized adverse events.
The combination of peginterferon and
ribavirin then became the standard of
care for patients with chronic HCV
infection regardless of genotype. This
combination regimen resulted in an SVR
of 45% to 50% for HCV genotype 1 (GT1)
infection and rates of 70% to 80% for
At the time of writing, Drs. Montgomery and
Ho were PGY-1 Pharmacy Practice Residents
at the Department of Veterans Affairs, New
York Harbor Healthcare System, in Brooklyn,
New York. Dr. Chung is an ID Sterile Products
Specialist at the Department of Veterans
Affairs, New York Harbor Healthcare System.
Dr. Marzella is an Associate Professor of
Pharmacy Practice at LIU Pharmacy (Arnold
and Marie Schwartz College of Pharmacy) in
Brooklyn, New York, and Clinical Pharmacy
Specialist at the Department of Veterans
Affairs, New York Harbor Healthcare System.
Drug Forecast is a regular column coordinated
by Alan Caspi, PhD, PharmD, MBA, President of
Caspi and Associates in New York, New York.
Disclosure: The authors report no nancial or
commercial relationships in regard to this article.
GT2 and GT3. This regimen was also
associated with fewer adverse events
compared with earlier regimens.2
The approval of two protease inhibi-
torsboceprevir and telaprevirwas
announced as a triple-therapy combina-
tion with peginterferon plus ribavirin for
GT1 infection. The triple-therapy regi-
mens were short-lived because of their
similar response rates to standard-of-care
treatment, complicated administration
schedules, signicant adverse events,
and issues with resistance. Subsequently,
boceprevir and telaprevir were removed
from the U.S. market.3,4
More than 25 years after its initial
discovery, HCV remains a global pub-
lic health concern. According to the
Centers for Disease Control and Preven-
tion (CDC), annual U.S. HCV-related
deaths in 2013 surpassed the total com-
bined number of deaths from 60 other
infectious diseases reported to the CDC,
including human immunodeciency virus
(HIV), and CDC surveillance data from
2014 show HCV-related deaths climbed
to almost 20,000, an all-time high.5 Unlike
hepatitis A and hepatitis B, a vaccine
for hepatitis C remains unavailable. As
we continue to strive for more preven-
tive treatment options for HCV, we are
actively pursuing means to eradicate
the spread and incidence of this chronic
disease and associated complications.
Today, innovative developments for
the treatment of HCV infection have led
to the potential eradication of the virus
and a cure for infected patients. Direct-
acting antiviral agents (DAAs) that target
Figure 1 Chemical Structure of Daclatasvir8
H3CO
NH O N
O N
(S) N OCH 3
H3C N (S) H 2 HCl
CH 3
various stages of the HCV life cycle with
or without ribavirin are now available.
Combining medications that have dif-
ferent targets of action with synergistic
antiviral effects will hopefully lessen the
burden of resistance to antivirals.
In July 2015, the FDA approved
daclatasvir (Daklinza, Bristol-Myers
Squibb) for use with sofosbuvir (Sovaldi,
Gilead Sciences) as the rst 12-week,
all-oral treatment option for patients
with chronic HCV GT3.6 Daclatasvir, a
nonstructural protein 5A (NS5A) inhibi-
tor, when combined with sofosbuvir, an
NS5B inhibitor, results in higher SVR
rates, fewer adverse events, and limited
antiviral resistance.7
INDICATIONS
Daclatasvir is approved for use as
combination therapy with sofosbuvir,
with or without ribavirin, for the treat-
ment of patients with chronic HCV GT1
or GT3 infection without cirrhosis, with
compensated (ChildPugh A) or decom-
pensated (ChildPugh B or C) cirrhosis,
or post-transplant.8
PHARMACOLOGY
Daclatasvir is chemically described
as carbamic acid, N,N-[[1,1-biphenyl]-
4,4-diylbis[1H-imidazole-5,2-diyl-(2S)-2,1-
pyrrolidinediyl[(1S)-1-(1-methylethyl)-2-
oxo-2,1-ethanediyl]]] bis-, C,C-dimethyl
ester, hydrochloride (1:2). Its molecular
formula is C40H50N8O62HCl (Figure 1),
and its molecular weight is 738.88 (free
base). Daclatasvir exerts its pharma-
cological activity by the inhibition of
H 3C
N CH 3
HN (S) (S) O
O HN
Vol. 41 No. 12 December 2016 P&T
751
DRUG FORECAST
NS5A N-terminus (domain 1), causing
structural variations in HCV replication
and assembly of HCV virions.8
PHARMACODYNAMICS AND
PHARMACOKINETICS
The pharmacokinetic properties of
daclatasvir were evaluated in healthy
adults and in patients with chronic HCV.
Administration of daclatasvir tablets in
HCV-infected patients resulted in approx-
imately dose-proportional increases in
peak concentration (Cmax), area under
the curve (AUC), and minimum concen-
tration up to 60 mg once daily. Daclatasvir
is rapidly absorbed with a peak plasma
concentration within two hours of admin-
istration. Steady state is anticipated after
approximately four days of once-daily
daclatasvir administration.8
Food may affect the absorption of dacla-
tasvir. The administration of daclatasvir
60 mg after a high-fat, high-calorie meal
decreased the Cmax and AUC by 28% and
23%, respectively, compared with fasting
conditions. However, administration after
a low-fat, low-calorie meal did not result
in a signicant decrease in absorption.8
Cytochrome P450 (CYP) 3A4 is pri-
marily responsible for the metabolism of
daclatasvir, with excretion occurring pre-
dominantly in the feces. In healthy sub-
jects, 88% of the dose was excreted in the
feces (53% being unchanged drug), and
6.6% of the dose was excreted in the urine
(primarily as unchanged drug). There are
eight metabolites of daclatasvir, one of
which (BMS-805215) has some activity;
however, it is 100-fold less potent than
the parent drug. The terminal half-life of
daclatasvir is 12 to 15 hours.8
DOSAGE AND ADMINISTRATION
Daclatasvir is not recommended as
monotherapy and if, for any reason,
sofosbuvir is discontinued, discontinu-
ation of daclatasvir is recommended as
well. Another important consideration
for patients with cirrhosis is the recom-
mendation of testing for NS5A resistance-
associated polymorphisms prior to the
initiation of therapy.8
The recommended daclatasvir dose
is 60 mg once daily in combination with
sofosbuvir 400 mg once daily, with or
without food, for 12 weeks.8,9 Patients
with HCV GT1 infection with decom-
pensated cirrhosis, patients with HCV
GT3 infection with compensated or
752 P&T December 2016 Vol. 41 No. 12
decompensated cirrhosis, and post-
transplant patients with HCV GT1 or 3
infection should have ribavirin added to
their regimen. The dosage of ribavirin
varies in accordance with HCV genotype,
patient weight, and patient tolerance and
ranges from 600 mg to 1,200 mg daily. If
ribavirin is added, administration with
food is recommended.8
Because the SVR rate was just 63%
in patients with cirrhosis, an extended
treatment duration of up to 24 weeks
may be appropriate; ribavirin may also
be added to the regimen.8
Daclatasvir is available as 30-mg,
60-mg, and 90-mg tablets to allow for
dosage adjustments to circumvent drug
interactions or to ne-tune daclatasvir
concentrations. Patients with renal or
hepatic insufciencies do not require
dosage adjustments for daclatasvir.8
RESISTANCE PROFILE
As the standard of care for HCV
treatment turns toward DAAs, resis-
tance becomes a major concern due to
the selective pressure that favors HCV
variants capable of replicating in the
presence of DAAs. HCV is predisposed
to the development of resistance due to
its highly variable genome. Incorrect
nucleoside substitutions occur approxi-
mately 103 to 105 times per replication
cycle. The virus is estimated to repli-
cate 1012 times per day, resulting in a
large number of variant viral genomes
or viral quasispecies. The dominant
wild-type HCV sequence replicates the
most efciently; however, DAA-resistant
quasispecies may become the dominant
HCV sequence in the presence of DAAs.
Resistance to DAAs may be pre-existing
or may develop during or after DAA treat-
ment. Resistance to DAAs is also inu-
enced by the HCV genotype, with some
HCV genotypes having a higher barrier
to resistance than others. Overcoming
resistance with the use of more than one
DAA that target different parts of the HCV
genome has been explored. In vitro stud-
ies have demonstrated that HCV variants
that are resistant to one DAA remain fully
active against other DAAs. Despite this,
cross-resistance has been observed with
resultant HCV breakthrough.10
Several polymorphisms are associated
with daclatasvir resistance based on HCV
genotype (Table 1). In general, GT1a has
a lower barrier to resistance compared
Table 1 Most Common
Polymorphisms Associated With
Daclatasvir Resistance11
Genotype Substitution
1a M28T
L31V/M
Q30E/H/R
Y93C/H/N
1b L31V
Y93H
2 L31M
F28S
3 Y93H
4
5 L31F
6 P32L
with GT1b. The rate of daclatasvir-
resistant polymorphisms did not dif-
fer significantly between HCV/HIV
coinfected patients compared with HCV
monoinfected patients.11
CLINCIAL TRIALS
The efcacy of daclatasvir in combina-
tion with sofosbuvir and with or without
ribavirin was evaluated in three phase 3
clinical trials (Table 2). SVR, the primary
endpoint, was defined as HCV RNA
below the lower limit of quantication
(25 IU/mL) at post-treatment week 12
(SVR12).8
ALLY-3 Study8,12
ALLY-3 was a phase 3, open-label study
that evaluated the safety and efcacy of
a 12-week regimen of daclatasvir plus
sofosbuvir once daily for the treatment
of chronic HCV GT3 in adults 18 years
of age or older. Treatment-nave and
treatment-experienced patients with
HCV RNA of 10,000 IU/mL or greater at
screening were included. Patients with
compensated cirrhosis were also eligible
for the study.
Results were reported for 152 patients:
101 treatment-nave patients (66%) and
51 treatment-experienced patients (34%),
with an overall SVR12 of 89% (Table 3).
SVR12 was 90% in treatment-nave
patients, 86% in treatment-experienced
patients, 96% in patients without cirrho-
sis, 63% in patients with cirrhosis, 93%
in patients with F0F3 brosis scores,
and 70% in patients with an F4 brosis
 DRUG FORECAST

Table 2 HCV Genotype 1 and 3 Patient Populations nevirapine. Patients without cirrhosis with
GT1 HCV/HIV coinfection treated with
From Daclatasvir Clinical Trials8
daclatasvir in combination with sofosbu-
Trial Population Study Arms and Duration vir for 12 weeks achieved an SVR12 of
(Number of Patients Treated) 98%, while those with cirrhosis achieved
ALLY-3 Genotype 3, treatment-nive and Daclatasvir and sofosbuvir for 12 weeks an SVR12 of 91%. Patients with GT3
treatment-experienced, with or without (N = 152) HCV/HIV coinfection treated for 12 weeks
cirrhosis achieved an SVR12 of 100% (Table 4).
Study results revealed that eight weeks
ALLY-2 Genotypes 1 and 3, treatment-nive and Daclatasvir and sofosbuvir for 12 weeks
of therapy resulted in a lower SVR12
treatment-experienced, with or without (N = 137)
compared with 12 weeks of therapy in
cirrhosis, with HCV/HIV-1 coinfection
patients with HCV/HIV coinfection. Con-
ALLY-1 Genotypes 1 and 3, treatment-nive or Daclatasvir and sofosbuvir plus ribavirin trol of HIV infection was not negatively
treatment-experienced, with or without for 12 weeks (N = 103) impacted by HCV treatment. Overall, it
cirrhosis, including decompensated appears that HIV status does not lead to
cirrhosis and post-transplant a worse HCV treatment prognosis. Avail-
HCV = hepatitis C virus; HIV = human immunodeciency virus able data on patients with HCV GT2, 4, 5,
or 6 infection were insufcient to provide
recommendations for those genotypes.
Table 3 ALLY-3: SVR12 in Treatment-Nave and Treatment-Experienced
Patients With or Without Cirrhosis With Genotype 3 HCV Treated ALLY-1 Study8
With Daclatasvir in Combination With Sofosbuvir for 12 Weeks8 ALLY-1 was an open-label trial of
Treatment Outcomes Total (N = 152) daclatasvir, sofosbuvir, and ribavirin
that included 113 patients with chronic
SVR12
HCV infection and ChildPugh A, B, or C
All 89% (135/152)
cirrhosis (n = 60) or HCV recurrence after
No cirrhosisa 96% (115/120)
liver transplantation (n = 53). Treatment-
With cirrhosis 63% (20/32)
nave and treatment-experienced patients
Outcomes for patients without SVR12 with HCV GT1, 2, 3, 4, 5, or 6 infection
On-treatment virological failureb 0.7% (1/152) were eligible to enroll. Prior exposure to
Relapsec 11% (16/151) NS5A inhibitors was prohibited.
HCV = hepatitis C virus; SVR12 = sustained virological response at post-treatment week 12. Patients received daclatasvir 60 mg
a Includes 11 patients with missing or inconclusive cirrhosis status. once daily, sofosbuvir 400 mg once
b One patient had quantiable HCV RNA at end of treatment. daily, and ribavirin for 12 weeks and were
c Relapse rates are calculated with a denominator of patients with HCV RNA not detected at the end of monitored for 24 weeks post-treatment.
treatment. Patients received an initial ribavirin dose
of 600 mg or less daily with food; the ini-
score. One treatment-nave patient with in treatment-experienced patients with tial and on-treatment dosing of ribavirin
cirrhosis and an initial platelet count of controlled HIV infection. A total of was modied based on hemoglobin and
83 x 109 cells/L had a detectable HCV 153 HCV GT14 patients were enrolled; CrCl measurements. If tolerated, the
RNA of 53 IU/mL at the end of the study. there were no eligible patients with ribavirin dose was titrated up to 1,000 mg
Sixteen patients (nine treatment-nave, GT5 or 6. Patients with a creatinine clear- per day. A high number of reductions in
seven treatment-experienced) had a post- ance (CrCl) of less than 50 mL/min and ribavirin dosing occurred in the trial. By
treatment relapse. Eleven of these patients patients with uncontrolled diabetes mel- week 6, approximately half of the patients
had cirrhosis at baseline.The daclatasvir- litus and/or hypertension were excluded, received 400 mg per day or less of ribavi-
resistant NS5A polymorphism Y93H limiting generalizability of results to rin. In total, 16 patients (15%) completed
emerged in nine of the 16. In the other these patient populations. Many, but less than 12 weeks and 11 patients (10%)
seven relapsed patients, six had the Y93H not all, antiretroviral therapy regimens completed less than six weeks of ribavi-
polymorphism at baseline and one had were allowed concomitantly, including: rin therapy. For the cohort of patients
emergent NS5A-L31I polymorphism. Poly- atavanavir/ritonavir, darunavir/ritonavir, with cirrhosis, the median time to dis-
morphisms associated with sofosbuvir lopinavir/ritonavir, efavirenz, nevirap- continuation of ribavirin was 43 days
were not observed. ine, rilpivirine, dolutegravir, raltegravir, (range, 882 days; n = 9). For the post-
enfuviritide, maraviroc, abacavir, emtric- transplant cohort, the median time to
ALLY-2 Study8,13 itabine, lamivudine, tenofovir disoproxil discontinuation of ribavirin was 20 days
ALLY-2, a phase 3, open-label trial, fumarate, and zidovudine. (range, 357 days; n = 7).
evaluated the safety and efficacy of Daclatasvir was dose-adjusted to 30 mg The 113 treated patients in ALLY-1
daclatasvir plus sofosbuvir for eight to daily in patients receiving ritonavir- had a median age of 59 years (range,
12 weeks in treatment-nave patients with boosted protease inhibitors and to 1982 years); 67% were male; 96% were
controlled HIV infection and for 12 weeks 90 mg in patients receiving efavirenz or white, 4% were black, and 1% were Asian.

Vol. 41 No. 12 December 2016 P&T

753
DRUG FORECAST

Table 4 ALLY-2: SVR12 in Patients With Genotype 1 and 3 HCV/HIV Coinfection ADVERSE EVENTS
The most common adverse reactions
Treated With Daclatasvir in Combination With Sofosbuvir for 12 Weeks8
observed in 10% or more patients with
Treatment Outcomes Total (N = 137) daclatasvir in combination with sofosbuvir
SVR12 were headache and fatigue. The most com-
Genotype 1 97% (123/127) mon adverse reactions observed in 10% or
No cirrhosisa 98% (103/105) more patients with daclatasvir in combina-
With cirrhosis 91% (20/22) tion with sofosbuvir and ribavirin were
Genotype 3b 100% (10/10) headache, anemia, fatigue, and nausea.8
Outcomes for genotype 1 patients
CONTRAINDICATIONS
without SVR12
Medications that are strong CYP3A
On-treatment virological failurec 0.8% (1/127)
inducers, including phenytoin, carba-
Relapsed 1.6% (2/126)
mazepine, rifampin, and St. Johns wort
Missing post-treatment data 0.8% (1/126)
(Hypericum perforatum), are contra-
HCV = hepatitis C virus; HIV = human immunodeciency virus; SVR12 = sustained virological response at indicated with daclatasvir. These prod-
post-treatment week 12. ucts lower daclatasvir exposure and
a Includes ve patients with inconclusive cirrhosis status. decrease virological response.5 Medica-
b One patient with cirrhosis.
tions that are moderate CYP3A inducers,
c One patient had detectable HCV RNA at end of treatment.
such as bosentan, dexamethasone, and
d Relapse rates are calculated with a denominator of patients with HCV RNA not detected at the end of
modanil, require that the daclatasvir
treatment.
dose be increased to 90 mg. Medica-
tions that are considered strong CYP3A
Table 5 ALLY-1: SVR12 in Genotype 1 Patients with ChildPugh A, B, or C Cirrhosis inhibitors, such as clarithromycin,
Or With HCV Genotype 1 Recurrence After Liver Transplantation Treated With itraconazole, and ketoconazole, require
Daclatasvir in Combination With Sofosbuvir and Ribavirin for 12 Weeks8 a dose adjustment to 30 mg. Refer to the
full prescribing information for a list of
Treatment Outcomes ChildPugh A, B, or C Post-Liver Transplant contraindicated drugs and other potential
Cirrhosis (n = 45) (n = 41) drugdrug interactions.8
SVR12
Genotype 1 82% (37/45) 95% (39/41) WARNINGS AND PRECAUTIONS
Genotype 1a 76% (26/34) 97% (30/31) Concomitant therapy of amiodarone
Genotype 1b 100% (11/11) 90% (9/10) with daclatasvir and sofosbuvir is not
ChildPugh A 91% (10/11) recommended due to post-marketing
ChildPugh B 92% (22/24) case reports of serious symptomatic
ChildPugh C 50% (5/10) bradycardia, which presents with dizzi-
Outcomes for patients ness, malaise, weakness, shortness of
without SVR12 breath, chest pain, and/or confusion.
On-treatment virological failure 2% (1/45)a 0 Bradycardia has been observed within
Relapseb 16% (7/44) 5% (2/41) hours to two weeks after treatment ini-
tiation, with symptoms typically resolv-
HCV = hepatitis C virus; SVR12 = sustained virological response at post-treatment week 12. ing after treatment discontinuation. Risk
a One subject had detectable HCV RNA at end of treatment.
factors include underlying cardiac
b Relapse rates are calculated with a denominator of patients with HCV RNA not detected at end of
comorbidities, concomitant therapy
treatment. with beta blockers, and/or advanced
liver disease. For patients with no alter-
Most patients (59%) were treatment- score of 15 or greater. Most (55%) of the native treatment options to amiodarone,
experienced, and most (71%) had baseline 53 patients in the post-transplant cohort inpatient cardiac monitoring for the
HCV RNA levels greater than or equal had F3 or F4 brosis. rst 48 hours of coadministration and
to 800,000 IU/mL. Fifty-eight percent SVR12 and outcomes in patients outpatient self-monitoring for the rst
of patients had HCV GT1a, 19% had without SVR12 are shown for patients two weeks of therapy are recommended.8
HCV GT1b, 4% had GT2, 15% had GT3, with HCV GT1 by patient population in
4% had GT4, and 1% had GT6, while Table 5. Available data on patients with SPECIAL POPULATIONS
77% had the IL28B rs12979860 non-CC HCV GT2, 4, 5, or 6 infection were insuf- Geriatric Patients
genotype. Among the 60 patients in the cient to provide recommendations. SVR12 Clinical trials did not demonstrate any
cirrhosis cohort, 20% were ChildPugh A, rates were comparable regardless of age, trends in adverse events among the geri-
53% were ChildPugh B, and 27% were gender, IL28B allele status, or baseline atric population compared with younger
ChildPugh C, and 35% had a Baseline HCV RNA level. adults. No dosage adjustment is needed
Model for End-Stage Liver Disease for geriatric patients.8

754 P&T December 2016 Vol. 41 No. 12


Pregnancy and Lactation8,14,15
There is an approximate 3% to 10% rate
of mother-to-child transmission of HCV.
Maternal HCV infection alone is associ-
ated with cholestasis of pregnancy, neo-
natal abstinence syndrome, and neonatal
intensive care unit admission. However,
after adjusting for sociodemographic
variables, large population studies sug-
gest increased rates of preterm birth, low
birth weight, premature membrane rup-
ture, gestational diabetes, and congenital
anomalies in maternal HCV infection.
Although data in humans are lacking,
maternal and embryo-fetal toxicities were
observed in animal studies.
Daclatasvir is not recommended for
use in pregnant women or women of
childbearing potential not on highly effec-
tive contraception during therapy and for
at least ve weeks following completion
of daclatasvir treatment.
According to the manufacturer, the
decision to breastfeed during therapy
should take into account the risk of
exposure to the infant and the benets
of treatment to the mother. It is unknown
if daclatasvir is present in human breast
milk or affects human milk production. In
animal studies, daclatasvir was detected
in the milk of lactating rats.
COST
Daclatasvir is available in 30-mg,
60-mg, and 90-mg strengths at an aver-
age wholesale price (AWP) of $25,200
for a package of 28 tablets.16 Sofosbuvir, a
requirement for the combination therapy,
is distributed as a 400-mg tablet with an
AWP of $33,600 for a package of 28.16
Ribavirin, if indicated, is a generic drug
supplied as a 200-mg tablet or capsule that
can be acquired for as little as $1.37 per
pill AWP (Richmond Pharmaceuticals).16
For the recommended standard treat-
ment of 12 weeks, the patient will need
three packages of daclatasvir 60 mg at a
total AWP of $75,600 and three packages
of sofosbuvir at a total AWP of $100,800
for a total treatment cost of $176,400. The
addition of ribavirin will add another $346
to $692 AWP to the total, dependent on
the patients required dosage.
P&T COMMITTEE
CONSIDERATIONS
DDAs have transformed the treatment
of HCV infection. These highly tolerable
medications signicantly improve patient
compliance while ultimately moving
toward a cure. The major caveat associ-
ated with DAAs is the development of
resistance.17
Studies demonstrate that shorter-
duration therapies are just as effective, if
not more effective, in achieving accept-
able SVR as the longer regimens used
in the past. The trend toward interferon-
free treatment provides a more toler-
able adverse effect prole, which also
improves patient adherence.
The latest HCV guidelines developed
by the Infectious Diseases Society of
America and the American Association
for the Study of Liver Diseases include
daclatasvir in their assemblage of recom-
mended regimens for the treatment of the
disease. Because the negotiated pricing
and cost structure for pharmaceutical
products are not transparent in the U.S.,
it is difcult to estimate the true cost and
cost-effectiveness of HCV drugs.18 The
primary goal of HCV therapy remains
eliminating the virus. The secondary
goals are to decrease the progression
to liver cirrhosis and the risk of hepato-
cellular carcinoma. Drugs that meet
these goals have the potential to drasti-
cally reduce a patients future health care
expenditures.
REFERENCES
1. Manns MP, Wedemeyer H, Cornberg
M. Treating viral hepatitis C: efcacy,
side effects, and complications. Gut
2006;55(9):13501359.
2. Palumbo E. Pegylated interferon and riba-
virin treatment for hepatitis C virus infec-
tion. Ther Adv Chronic Dis 2011;2(1):3945.
3. HIVandHepatitis.com. Merck plans to
discontinue boceprevir for hepatitis C
by December 2015. January 21, 2015.
Available at: www.hivandhepatitis.com/
hcv-treatment/approved-hcv-drugs/5021-
merck-plans-to-discontinue-boceprevir-for-
hepatitis-c-by-december-2015. Accessed
November 8, 2016.
4. HIVandHepatitis.com. Vertex to discontinue
sale of telaprevir (Incivek) for hepatitis C.
August 22, 2014. Available at: www.hivand-
hepatitis.com/hcv-treatment/approved-hcv-
drugs/4808-vertex-to-discontinue-sale-of-
telaprevir-incivek-for-hepatitis-c. Accessed
November 8, 2016.
5. Centers for Disease Control and Preven-
tion. Hepatitis C kills more Americans
than any other infectious disease. May 4,
2016. Available at: www.cdc.gov/media/
releases/2016/p0504-hepc-mortality.html.
Accessed November 8, 2016.
6. Food and Drug Administration. FDA
approves new treatment for chronic hepa-
titis C genotype 3 infections. Available at:
www.fda.gov/NewsEvents/Newsroom/
DRUG FORECAST
PressAnnouncements/ucm455888.htm.
Accessed July 24, 2015.
7. Hepatitis Central. Medications to treat
hepatitis Ca timeline. Available at:
www.hepatitiscentral.com/medications-
to-treat-hepatitis-c-a-timeline. Accessed
March 2016.
8. Daklinza (daclatasvir) prescribing informa-
tion. Princeton, New Jersey: Bristol-Myers
Squibb Company; 2016.
9. Sovaldi (sofosbuvir) prescribing informa-
tion. Foster City, California: Gilead Sci-
ences; 2015.
10. Aloia AL, Locarnini S, Beard MR. Anti-
viral resistance and direct-acting antiviral
agents for HCV. Antivir Ther 2012;17
(6Pt B):11471162.
11. Plaza Z, Soriano V, Vispo E, et al.
Prevalence of natural polymorphisms at the
HCV NS5A gene associated with resistance
to daclatasvir, an NS5A inhibitor. Antivir
Ther 2012;17(5):921926.
12. Nelson DR, Cooper JN, Lalezari JP,
et al. All-oral 12-week treatment with
daclatasvir plus sofosbuvir in patients
with hepatitis C virus genotype 3 infec-
tion: ALLY-3 phase III study. Hepatology
2015;61(4):11271135.
13. Wyles DL, Ruane PJ, Sulkowski MS,
et al. Daclatasvir plus sofosbuvir for HCV
in patients coinfected with HIV-1. N Engl J
Med 2015;373(8):714725.
14. Dunkelberg JC, Berkley EMF, Thiel KW,
Leslie KK. Hepatitis B and C in pregnancy:
a review and recommendations for care.
J Perinatol 2014;34(12):882891.
15. Connell LE, Salihu HM, Salemi JL,
et al. Maternal hepatitis B and hepatitis C
carrier status and perinatal outcomes. Liver
Int 2011;31(8):11631170.
16. Red Book Online. Ann Arbor, Michi-
gan: Truven Health Analytics. Accessed
October 25, 2016.
17. McConachie SM, Wilhelm SM, Kale-
Pradhan PB. New direct-acting antivirals in
hepatitis C therapy: a review of sofosbuvir,
ledipasvir, daclatasvir, simeprevir, parita-
previr, ombitasvir and dasabuvir. Expert
Rev Clin Pharmacol 2016;9(2):287302.
18. American Association for the Study of Liver
Diseases-Infectious Diseases Society of
America. Overview of cost, reimbursement,
and cost-effectiveness considerations for
hepatitis C treatment regimens. July 6,
2016. Available at: www.hcvguidelines.
org. Accessed October 25, 2016. Q
P&T TV
P&T is accepting video clips
from readers, and we might
post yours on our website
(www.PTCommunity.com). Feel
free to send a short video about the
activities of your P&T committee.
You can contact the Editor,
J. Stephen McIver, at 267-685-3713
or smciver@medimedia.com.
Vol. 41 No. 12 December 2016 P&T
755
 Medicare Adds New Long-Term-Care Pharmacy Rules
Agency Passes Again on Pharmacist Independence Requirements
Stephen Barlas
he Medicare and Medicaid programs have added some
T pharmacy requirements for long-term-care (LTC) facilities
that put more responsibility on pharmacists. The nal rule
from the Centers for Medicare and Medicaid Services (CMS)
issued at the end of September1 keeps the requirement for a
monthly drug-regimen review (DRR) but adds a requirement
for a simultaneous review of a residents medical chart and puts
both requirements in a new pharmacy services sec-
tion of the nursing home rules, in part to emphasize
the importance of prescription drug oversight by the
pharmacist. The new pharmacy services section also
adds restrictions on the use of psychotropic medica-
tions, which have been widely described as overused
in nursing homes to keep unruly patients quiet.
The new regulation expands pharmacist ser-
vices, and in many cases will increase the costs to
provide these services, said Khristy McClelland, Stephen Barlas
President of Guardian Pharmacy in Jacksonville,
Florida. Consultant pharmacists routinely review several
sources of medical information during DRRs, including medical
charts and medical administration records. In some instances,
barriers are present and may prevent pharmacists from access-
ing all of the medical records, McClelland added. In order
to maintain compliance with the new regulations, facilities will
have to ensure that pharmacists have access to these records.
In addition, facilities must have reporting procedures for phar-
macists, which include a response timeline from prescribers
when immediate action is required based on a DRR.
The new rule, which adds numerous provisions beyond
the pharmacy section, seeks to reduce avoidable hospital
readmissions and speed quality improvement throughout
facilities.
The American Health Care Association (AHCA), which
represents the nursing home industry, tried to convince
the CMS to soften the pharmacist requirements. It argued
that mandating a pharmacists review of a residents medical
record will increase the time pharmacists spend in a facil-
ity, thus increasing facilities costs. The increased costs to
pharmacies will likely also be incorporated into the medica-
tion costs that are frequently reimbursed by Medicaid or
Medicare Part D. As such, we believe that this proposed change
represents an unfunded mandate to state Medicaid pro-
grams and Medicare Part D, which were not included in the
CMS estimates of cost implications of the proposed rule, the
AHCA argued.
The AHCA also opposed a provision requiring pharmacists
to alert the attending physician in writing of any unnecessary
Mr. Barlas is a freelance writer in Washington, D.C., who covers
issues inside the Beltway. Send ideas for topics and your comments
to sbarlas@verizon.net.
762 P&T December 2016 Vol. 41 No. 12
medications a resident may be taking. The AHCA complained
that while the pharmacists monthly DRR may have a legitimate
and clinically acceptable rationale, repeated notication of physi-
cians and repeated documenting of the rationale related to the
pharmacists ndings is not a productive use of anyones time
and may lead to inadvertent changes in medication regimens
that could be harmful. According to Mark Parkinson, President
and Chief Executive Ofcer of the AHCA:
While the agency took some steps forward in helping indi-
viduals in our centers, there were several provisions that
harm our efforts to continue the tremendous strides weve
made in quality and care delivery. Further, even CMS admits
this new wave of regulations will bring with it hundreds of
millions in additional costs without any new funding streams.
We will spend the coming days and weeks determining what
overall impact those mandates will have on our members.
CMS Punts on Pharmacist Independence
The nal rule arrived weeks before the U.S. Justice
Department announced that nursing home pharmacy service
provider Omnicare had agreed to pay $28.1 million to settle
charges it demanded kickbacks from Abbott Laboratories to
increase use of its epilepsy drug Depakote.2 Depakote (dival-
proex sodium) is used to control behavioral disturbances in
dementia patients, but the Food and Drug Administration has not
approved that use. CVS Health purchased Omnicare in 2015; the
Justice Department acknowledged that CVS halted the alleged
misconduct. In May 2012, Abbott entered its own settlement
with federal and state ofcials over the kickback scheme, paying
$1.5 billion to resolve its liability under the False Claims Act.
The scheme also involved the pharmacy company PharMerica,
which paid $9 million in 2015 for accepting kickbacks. Omnicare
and PharMerica, the two biggest players in the nursing home
pharmacy market, serve approximately half of nursing facili-
ties. The rest are served by roughly 1,200 independent LTC
pharmacies, approximately 800 of which belong to the group
purchasing organization Managed Healthcare Associates.
As the Justice Department was pursuing those cases, the
CMS, starting in 2011, was considering imposing independence
and conict-of-interest rules on nursing home pharmacy ser-
vice providers as part of a larger Medicare rule overhaul. The
AHCA and the American Society of Consultant Pharmacists
(ASCP) opposed such rules, and the CMS dropped the idea.
But when the CMS undertook this latest rulemaking in 2015
specically aimed at LTC facilitiesgroups such as the
California Advocates for Nursing Home Reform (CANHR)
pushed for pharmacy independence provisions, arguing that
any improvements on DRRs would be greatly compromised
by CMSs failure to address widespread conicts of interest
involving consultant pharmacists. Despite its legwork in 2012
 Medicare Adds Long-Term-Care Pharmacy Rules
and the subsequent Justice Department actions, the CMS omit-
ted any provisions on independence from the 2015 proposed
rule and therefore declined to address conict-of-interest
restrictions in the nal rule. However, the agency added it
would consider the issue in any future related rulemaking.1
The CMSs refusal to pursue this issue seems a bit surprising.
In October 2011, as part of broader Medicare rulemaking, the
CMS said various arrangements involving LTC facilities, LTC
pharmacies, LTC consultants, and pharmaceutical manufactur-
ers and/or distributors raised concerns about the quality of
consultant pharmacists reviews and the potential impact on
resident health and safety. We believe these concerns may be
addressed by changes we are considering that would require
LTC consultant pharmacists be independent of the LTC facility
pharmacy, pharmaceutical manufacturers or distributors, or any
afliate of these entities, the CMS said then.3 That proposed
rule stated: We are considering requiring that long-term-care
facilities employ or directly or indirectly contract the services
of a licensed pharmacist who is independent. We also are
considering including a denition of the term independence
to mean that the licensed pharmacist must not be employed,
under contract, or otherwise afliated with the facilitys phar-
macy, a pharmaceutical manufacturer or distributor, or any
afliate of these entities. Our changes would also prohibit
nursing homes from contracting for the provision of consultant
pharmacy services with entities (such as a subsidiary of an LTC
pharmacy) that have been created for the purpose of providing
reorganized consultant pharmacist services.
In February 2012, after receiving comments on the proposed
rule, the CMS said a signicant number of commenters who
identied themselves as current or former consultant pharmacists
either acknowledged that they had experienced a conict of inter-
est or conrmed that such conicts were an ongoing problem.4
The reports of conict of interest are sufcient to indicate it are not considered providers under the Social Security Act, while
continues to exist, and our concerns regarding its impact on the
quality of care in LTC facilities are well-founded. We believe that
this demonstrates that change is necessary to ensure that all LTC
consultant pharmacists are free from conicts of interest, are able
to base their professional medication recommendations on the
best interest and clinical needs of LTC facility residents, and are
able to advocate for the Medicare beneciary, the CMS said.
Despite arguing that change was necessary in 2012, the
agency decided then not to pursue it, saying that since a
requirement for independent consultant pharmacists will not
solve the entire problem, but would be signicantly disruptive
for much of the LTC industry, we are not nalizing this provision
at this time. Instead, we are soliciting additional comments to
help us determine a more comprehensive approach to eliminate
overprescribing and the use of chemical restraints in LTC.
The ASCPs position has been that the industry is taking
voluntary steps to avoid conicts of interestfor instance,
by transitioning to service agreement models for LTC facility
clients that include separate contracts for consultant pharma-
cist services and pharmacy dispensing services. However, the
ASCP agreed in 2012 that more work was needed to demon-
strate independence and to ensure transparency across the
LTC industry. It cited tools it had developed to assist consul-
tant pharmacists and LTC pharmacies with demonstrating
independence, including sample disclosure statements.
It is highly disturbing that CMS pointed to its own failure
to address this known problem in the July 2015 proposal as the
reason it could not establish an independence requirement in
the nal regulations, CANHR advocate Mike Connors said.
By continuing to punt the need to require independence
until another day, CMS is exposing hundreds of thousands
of nursing home residents to dangerous drugging practices.
Provisions That May Indirectly Affect Pharmacists
While pharmacists and nursing homes will not have to
contend with new independence rules, they will face additional
requirements beyond those in the new pharmacy services
section. For example, all LTC facilities will have to:
Develop, implement, and maintain an effective, compre-
hensive, data-driven quality assurance and performance
improvement program that focuses on systems of care,
outcomes of care, and quality of life.
Develop an infection prevention and control program that
includes an antibiotic stewardship program.
Develop and implement a baseline care plan for each resi-
dent, within 48 hours of his or her admission, that includes
the instructions needed to provide effective, person-centered
care that meets professional standards of quality care.
In some cases pharmacy groups had hoped that these new
sections would have a more direct impact. One example is the
requirement that a facility put together an interdisciplinary team
(IDT) to prepare the baseline plan cited above within 48 hours.
The rules specically add a nurses aide and a member of the food
and nutrition services staff to the required IDT membership. That
IDT would also be involved in discharge planning. The decision
to exclude pharmacists is perhaps understandable given that they
nurses aides and food and nutrition staffers are. Legislation is
pending in Congress to grant pharmacists that status, but it has
never had a hearing or vote in a House or Senate committee.
The ASCP wanted the CMS to add a pharmacist to the IDT.
Moreover, it suggested that a pharmacist ought to provide a
comprehensive medication review (CMR) both when a resident
arrives and when a resident leaves, either to go to a hospital, to
his or her home, or to a relatives home. In the nal rule, the
CMS said it considered requiring a pharmacist to participate on
the IDT and determined that it would be overly burdensome.
While pharmacist inclusion on the IDT is not required, neither
is it prohibited. The LTC can make the call. Nor did the CMS
opt to include the pharmacist in the discharge process, much
less require a CMR. The baseline plan that is required upon
admission falls short of a full medical review as well as a CMR,
which is a systematic process that includes collecting patient
information, identifying and prioritizing medication-related
problems, and creating a plan to resolve medication-related
problems with the patient, caregiver, and/or prescriber.
Pharmacists are also not included in the list of clinically
qualied personnel whom the attending physician can des-
ignate as service providers. That delegation does not include
pharmacists being able to deliver medication, which they can do
in 40 states subject to collaboration agreements with physicians.
However, pharmacists will denitely be involved in new
Vol. 41 No. 12 December 2016 P&T
763
 Medicare Adds Long-Term-Care Pharmacy Rules
infection control programs. The ASCP believes consultant
pharmacists will be called on to train the trainers on safe and
prudent antibiotic use. The association is developing products
and programs designed to give senior care pharmacotherapy
specialists the tools they will need to assist facilities.
New Pharmacy Services Section
While there were disappointments for pharmacists hoping
to gain additional statutory roles, there was also reason for
satisfaction. At the proposal stage, the requirement for a medi-
cal records review was limited to three situations: when the
resident is new to the facility; when a prior resident returns or
is transferred from a hospital or other facility; and during each
monthly DRR when the resident has been prescribed or is taking
a psychotropic drug, an antibiotic, or any drug that the quality
assessment and assurance committee has asked to be included
in the pharmacists monthly drug review. The nal rule dictates
a review of the medical chart each month for every resident.
The purpose of a DRR and the associated medical record
review is to identify any unnecessary medications a resident
may be taking. It is up to the individual facility to determine
how narrow or how broad this DRR is. But the elements must
include time frames for the different steps in the process and
actions the pharmacist must take when he or she identies an
irregularity that requires urgent action to protect the resident.
Unnecessary is dened as 1) in excessive dose (including
duplicate drug therapy); or 2) for excessive duration; or 3)
without adequate monitoring; or 4) without adequate indications
for its use. Irregularities would be any unnecessary drugs
the pharmacist believes the resident is taking. The pharmacist
must report any irregularities to the attending physician and the
facilitys medical director and director of nursing; these reports
must be acted upon. The attending physician must document
in the residents medical record that the identied irregularity
has been reviewed and what, if any, action has been taken to
address it. If there is to be no change in the medication, the
attending physician should document his or her rationale in
the residents medical record.
What happens, though, if the physician declines to change
a residents medication upon being notied by the pharmacist
of irregularities? Does the pharmacist have recourse to appeal?
Some argued the pharmacist should be able to report the
irregularities to some entity outside the purview of the LTC
and the physician. Not only did the CMS decline to provide that
outside appeal, it also declined to require a pharmacists nd-
ing of irregularities to be reported to the resident or his or her
representative. The irregularity identied by the pharmacist
may require no action, updating or modifying documentation,
or some other action that does not affect the quality of care
for the resident, the agency said. Unnecessary notications
could lead to confusion and anxiety for the resident.
New Requirements for Psychotropic Drugs
One of the more controversial aspects of this rewrite of
Medicare LTC rules is the expansion of drugs of particular con-
cern. Congressional hearings and sundry reports have focused
on the improper use of drugs to pacify unruly nursing home
residents. Formerly the CMS nursing-home rules paid enforce-
ment attention only to antipsychotics. The new rule expands
764 P&T December 2016 Vol. 41 No. 12
that to psychotropic drugs. This raised all sorts of concerns at
the proposal stage, both because of the particular drugs likely
to be included, especially opioids, and rules around PRN (pro re
nata or as needed) orders and gradual dose reduction (GDR).
The new rules say that based on a comprehensive assess-
ment of a resident, the facility must ensure that residents who
have not used psychotropic drugs are not given them unless
the medication is necessary to treat a specic condition as
diagnosed and documented in the clinical record. Residents
who use psychotropic drugs, either when entering the facility
or when having them prescribed after entering, must receive
GDR and behavioral interventions, unless clinically contra-
indicated, in an effort to discontinue these drugs. PRN orders for
psychotropic drugs are limited to 14 days unless the attending
physician or prescribing practitioner documents the rationale
in the residents medical record.
The CMS backed off a bit in the nal rule on which drugs are
considered psychotropic. The proposed denition cited any drug
that affects brain activities associated with mental processes
and behavior. Specic categories listed were antipsychotics,
antidepressants, antianxiety drugs, hypnotics, opioid analgesics,
and any other drug that results in effects similar to the drugs
listed in the categories mentioned. That last phrase prompted
a lot of opposition, as did the inclusion of opioids.
In the nal rule, the CMS admitted that the proposed deni-
tion of psychotropic drugs might include many medications for
which the additional requirements would be superuous and
unnecessary. So it removed the clause any other drug that
results in effects similar from the denition. The agency
also dropped opioids. In doing so, it stated: We are particularly
concerned about the possibility that including opioid analgesics
in the denition could result in negative consequences for pain
management, especially since they are usually given PRN and
there could be interruptions in the prescriptions due to the
proposed limitation on PRN prescriptions.
Although pharmacists will not have to tiptoe around opioid pre-
scriptions, they will have to be vigilant about the other categories.
To the extent that makes them whistleblowers of a sort, they may
sometimes be in an uncomfortable position of second-guessing
physicians treating patients with dementia and other psychiatric
afictions. Guardians McClelland says, There is concern that the
new psychotropic regulations may have the potential to impede,
rather than improve, patient health and safety.
REFERENCES
1. Centers for Medicare and Medicaid Services. Medicare and Medic-
aid programs; reform of requirements for long term care facilities.
Fed Regist 2016;81(192):6868868872.
2. U.S. Department of Justice. Nations largest nursing home
pharmacy to pay over $28 million to settle kickback allegations.
October 17, 2016. Available at: www.justice.gov/opa/pr/nation-
s-largest-nursing-home-pharmacy-pay-over-28-million-settle-kick-
back-allegations. Accessed October 28, 2016.
3. Centers for Medicare and Medicaid Services. Medicare program;
proposed changes to the Medicare Advantage and the Medicare
Prescription Drug Benet programs for contract year 2013 and other
proposed changes; considering changes to the conditions of participa-
tion for long term care facilities. Fed Regist 2011;76(196):6301863091.
4. Centers for Medicare and Medicaid Services. Medicare Program;
changes to the Medicare Advantage and the Medicare Prescription
Drug Benet programs for contract year 2013 and other changes;
nal rule. Fed Regist 2012;77(71):2207222175. Q
PHARMACOVIGILANCE FORUM
Drug-Induced Neutropenia
A Focus on Rituximab-Induced Late-Onset Neutropenia
Donald C. Moore, PharmD, BCPS, BCOP
INTRODUCTION
Drug-induced neutropenia is a poten-
tially serious and life-threatening adverse
event that may occur secondary to
therapy with a variety of agents. Cytotoxic
chemotherapy can cause a predictable
and dose-related decrease in neutrophil
count. Neutropenia secondary to other
medications tends to be an idiosyncratic
reaction either as an immune-mediated
reaction or because of direct myeloid
cell line damage. This effect has been
associated with a variety of medications
including, but not limited to, clozapine,
dapsone, methimazole, penicillin, ritux-
imab, and procainamide.1 For a compre-
hensive list of medications associated
with the development of neutropenia, see
Table 1. Neutropenia from nonchemo-
therapy drugs is much less common than
neutropenia secondary to chemotherapy.2
Rituximab is an anti-CD20 monoclonal
antibody indicated for the treatment of
a variety of B-cell lymphocytic malig-
nancies, including chronic lymphocytic
leukemia (CLL), follicular lymphoma,
and diffuse large B-cell lymphoma.3 Ritux-
imab is also used for the management
of several autoimmune disorders, such
as rheumatoid arthritis and Wegeners
granulomatosis. In the treatment of B-cell
malignancies, this monoclonal antibody
exerts its anticancer activity by depleting
malignant B cells via mechanisms such
as complement-dependent cytotoxicity,
antibody-dependent cellular cytotoxic-
ity, and by inducing apoptosis.4 In the
treatment of cancer, rituximab can be
Dr. Moore is Pharmacist Clinical Coordinator
of Oncology at the Levine Cancer Institute of
the Carolinas HealthCare System in Charlotte,
North Carolina. Michele B. Kaufman, PharmD,
CGP, RPh, editor of this column, is a freelance
medical writer living in New York City and
a Pharmacist in the NewYorkPresbyterian
Lower Manhattan Hospital Pharmacy
Department.
Disclosure: The author reports no commercial
or nancial relationships in regard to this article.
Welcome to the Pharmacovigilance Forum, Forum will discuss noteworthy topics related
where we report on interesting adverse drug to ADRs in the clinical realm. Every medication
reactions (ADRs), including drug-induced disease. has the potential to cause disease, but clinicians
All pharmaceuticals carry a are often slow to recognize drug therapy as an
risk of ADRs, whether they etiological factor. I encourage anyone with a
are new and improved, potentially interesting case to contact me, to
generic agents, older publish ADRs here or elsewhere, and to report
brand products, complex ADRs to the Food and Drug Administrations
biologics, or biosimilars. MedWatch program.
Each Pharmacovigilance Michele B. Kaufman
administered as monotherapy or in include agents such as mitomycin, carmus-
combination with chemotherapy agents, tine, and lomustine, which have a delayed
depending on the indication. nadir of about four to six weeks following
Common adverse events associated administration of each cycle. During treat-
with rituximab therapy include acute ment with these agents, neutrophil recov-
infusion reactions, lymphopenia, infec- ery will usually occur six to eight weeks
tion, and asthenia.3 Delayed and late-onset following treatment. The nadir and neutro-
serious side effects may include progres- penia associated with most types of cyto-
sive multifocal leukoencephalopathy, toxic chemotherapy are considered to be
reactivation of hepatitis B, and interstitial rather predictable in onset and occurrence.
pneumonitis. When rituximab was added In patients receiving cancer treatment
onto chemotherapy regimens, it was found regimens containing rituximab with cyto-
to be safe and tolerable without adding toxic chemotherapy (e.g., anthracyclines,
signicant hematological toxicities. Post- purine antagonists, alkylating agents,
marketing studies and case reports have etc.), the nadir of the patients neutrophil
shown that rituximab has the potential to count is expected to occur 10 to 14 days
cause delayed and late-onset neutropenia following administration of each cycle of
that may vary in severity.57 We report the treatment. Rituximab has been reported
cases of two patients who were treated for to cause neutropenia, but with a delayed
hematological malignancies with ritux-
imab that led to severe, late-onset neutro- Table 1 Medications Associated With
penia resulting in neutropenic fever, which The Development of Neutropenia1,2
required hospitalization.
Nonchemotherapy
PATHOPHYSIOLOGY Clozapine Procainamide
Neutropenia is dened as having an Dapsone Propylthiouracil
absolute neutrophil count (ANC) of less Hydroxychloroquine Quinidine/Quinine
than 500 cells/mm3 and is a common Iniximab Rituximab
Lamotrigine Sulfasalazine
adverse event associated with many
Methimazole Trimethoprim-
cytotoxic chemotherapy agents.8 During
Oxacillin sulfamethoxazole
cytotoxic chemotherapy, neutropenia
Penicillin G Vancomycin
typically occurs during the nadirthe
lowest value to which the neutrophil count
Chemotherapy
will fall following drug administration. The
Alkylating agents Hydroxyurea
nadir typically occurs 10 to 14 days follow-
Anthracyclines Mitomycin C
ing chemotherapy administration during
Antimetabolites Taxanes
each treatment cycle. Neutrophil recovery
will usually occur in three to four weeks Camptothecins Vinblastine
following treatment. Exceptions to this Epipodophyllotoxins
Vol. 41 No. 12 December 2016 P&T
765
PHARMACOVIGILANCE FORUM
and often unpredictable onset. Rituximab-
associated late-onset neutropenia has been
dened in the literature as neutropenia
developing at least three to four weeks
following the end of rituximab adminis-
tration despite a complete recovery of
ANC following chemotherapy.9 It has also
been reported that rituximab may induce
neutropenia more than 40 days after the
end of treatment.10 Neutropenia with
cytotoxic chemotherapy recovers with a
very predictable pattern and is typically
short-lived in duration; however, rituximab-
induced late-onset neutropenia may be
prolonged and result in a very unpredict-
able recovery time. Without the utilization
of granulocyte-colony stimulating factors
(GCSFs), rituximab-induced late-onset
neutropenia may last a median of six to
77 days.11
Most cases of rituximab-induced late-
onset grade 13 neutropenia are self-
limiting and resolve without any compli-
cations. However, there is the possibility
of more severe cases in grade 4 neutro-
penia.10,12 In grade 3 or 4 neutropenia,
there is a potential for prolonged and
serious life-threatening infectious com-
plications. The delayed onset, unpredict-
able occurrence, and neutrophil recov-
ery associated with rituximab-induced
late-onset neutropenia can create a clini-
cal challenge for practitioners. Diligent
patient follow-up is needed to monitor for
this adverse event, and therapeutic inter-
vention may be necessary in severe cases
that may result in neutropenic fever.
MECHANISM OF ADVERSE
DRUG REACTION
Most cytotoxic chemotherapy exerts
its pharmacological activity by causing
DNA damage in either a cell-specic or
cell-nonspecic manner. By damaging the
DNA of malignant cells, chemotherapy is
able to produce killer malignant cells.
Many chemotherapy agents cause bone
marrow suppression resulting in neutro-
penia, which leads to an increased risk of
infection. The mechanism by which ritux-
imab may induce neutropenia has yet to
be fully elucidated; however, a variety of
theories exist.
After rituximab administration, anti-
bodies against neutrophils may be
produced, resulting in neutropenia.13 It
may also develop due to aberrant B-cell
reconstitution after rituximab administra-
tion. Another theory is that homeostasis
766 P&T December 2016 Vol. 41 No. 12
of granulocytes may be disturbed by
chemokine stromal-derived factor-1 inter-
acting with B-lymphocyte recovery. One
of the most compelling theories is that
it may occur due to polymorphisms in
the immunoglobulin G (IgG) Fc receptor
(FcR). Patients harboring the FcRIIIa
158 V/F polymorphism were found to
have a higher incidence of rituximab-
induced neutropenia.14 The presence of
this polymorphism may facilitate neutro-
penia following rituximab administration
by mediating antibody-dependent cell-
mediated cytotoxicity on malignant and
nonmalignant B cells, thus increasing the
degree of B-cell depletion.
INCIDENCE AND RISK FACTORS
The reported incidence of rituximab-
induced late-onset neutropenia varies
within the literature. This adverse drug
reaction (ADR) may occur in 8% to 27% of
cancer patients treated with rituximab.15
The incidence of rituximab-induced late-
onset neutropenia has been reported to
be much lower in patients being managed
with rituximab for autoimmune disease.
These rates are as low as 1.3% to 2.3%.16
Despite the proposed high incidence
of this ADR, many of the episodes are
self-limiting and without any apparent
clinical signicance. In rare cases, severe
neutropenia has the potential to occur,
which can place patients at risk for life-
threatening infectious complications.
Severe neutropenia resulting in neutro-
penic fever and infection can lead to hos-
pitalization, the need for broad-spectrum
antibiotics, and the potential sequelae of
bacteremia, and it can be fatal.
Multiple studies have evaluated the
risk factors for developing rituximab-
induced late-onset neutropenia. Patients
with advanced stages of malignancy and
those more than 60 years of age are at
greater risk.6,9 Previous treatment with
purine analogs or methotrexate and prior
autologous peripheral blood stem cell
transplantation may also be risk factors
for developing rituximab-induced late-
onset neutropenia. In addition, patients
harboring the IgG FcRIIIa 158 V/F
polymorphism are at high risk for devel-
oping this ADR. 12,14 In patients receiving
rituximab for noncancer indications, age
and female gender have been found to
increase the risk for this adverse event.16
MANAGEMENT
Infectious complications, such as
neutro penic fever, that may occur
because of severe and prolonged neutro-
penia secondary to rituximab treatment
should be managed with antimicrobial
therapy. Antimicrobials should be
selected and modied based on guideline
recommendations.8 Empiric treatment
of neutropenic fever usually includes
an antipseudomonal beta-lactam, such
as cefepime, ceftazidime, piperacillin-
tazobactam, meropenem, or imipenem.
Treatment against methicillin-resistant
Staphylococcus aureus (MRSA) with
agents such as vancomycin should be
included in empiric antimicrobial regi-
mens when other additional clinical indi-
cators are present, such as pneumonia,
skin or soft tissue infection, or suspected
catheter-related infection, or if the patient
is hemodynamically unstable.
GCSFs can also be used in patients
with neutropenic fever with additional
risk factors for severe complications,
such as those with an ANC of less than
100 cells/mm3 and/or with pneumo-
nia, hypotension, multi-organ failure, or
invasive fungal infections.17 GCSFs, such
as Neupogen (lgrastim, Amgen), Granix
(tbo-lgrastim, Cephalon, Inc.), and Zarxio
(lgrastim-sndz, Sandoz), stimulate and
promote the maturation and activation of
neutrophils. This class of drugs can also
enhance the exodus of mature neutrophils
trapped within the bone marrow. Through
these mechanisms, GCSFs have demon-
strated proven efcacy in their ability to
reduce the incidence, magnitude, and
duration of neutropenia following che-
motherapy administration.
In severe cases of rituximab-induced
late-onset neutropenia, especially with
infectious complications, the utilization of
lgrastim or a lgrastim biosimilar may be
warranted. Filgrastim products are espe-
cially useful in managing patients treated
with rituximab because they address
the unpredictable nature of neutrophil
recovery and possible prolonged neutro-
penic duration. No specic recommenda-
tions regarding the optimal ANC target,
frequency, and duration of administration
of lgrastim products have been proposed
to manage this adverse event. The drug
is typically administered once daily until
neutrophil recovery when it is utilized
for neutropenia prophylaxis in patients
with nonmyeloid malignancies receiving
 PHARMACOVIGILANCE FORUM

myelosuppressive chemotherapy. 18 Table 2 Patient Laboratory Values

Although rituximab-induced late-onset
neutropenia has the potential to be a Tests and Vital Signs Hospitalization Day
long-lasting complication, neutro- (normal range) Day 1 Day 2 Day 3 Day 4
phil recovery with the use of a lgras-
Case 1
tim product can occur in as few as
four days.9 To keep a patients ANC WBC x 103 cells/mm3 0.8 2.6 4.6 7.1
greater than 1,000 cells/mm3, mainte- (3.511 x 103 cells/mm3)
nance strategies using the drug once ANC, cells/mm3 360 1,768 N/A 5,183
or twice weekly may be employed (> 1,500 cells/mm3)
for several months for patients with
prolonged neutropenia despite initial Hemoglobin, g/dL 10 8 7.7 7.7
neutrophil recovery.5 (13.317.7 g/dL)
Two recent cases are described below. Hematocrit, % 26.2 27.4 22.1 21.6
(40%52%)
Case 1 Platelets x 109/L 117 90 95 106
A 70-year-old man with a history of (150400 x 109/L)
stageIVA small lymphocytic lymphoma
(SLL) presented to the emergency depart- Blood pressure, mm Hg 125/48 138/76 145/60 116/52
ment (ED) with complaints of fatigue and (90149/6090 mm Hg)
fever. Forty-two days prior to presenta- Pulse, bpm (60120 bpm) 114 92 78 72
tion, his SLL was treated with bendamus-
Tmax, F (97.899) 103.2 101.8 100 99.4
tine 189 mg (90 mg/m2) on days 1 and 2
and rituximab 788 mg (375 mg/m2) on Case 2
day 1 of a 28-day cycle. Subsequently, WBC x 103 cells/mm3 0.8 1.7 2.3 3.7
his treatment was temporarily held due (3.511 x 103 cells/mm3)
to severe thrombocytopenia secondary
to bendamustine; he was scheduled to
ANC, cells/mm3 208 578 989 5,698
resume treatment with a reduced dose
(> 1,500 cells/mm3)
of bendamustine within two days of pre- Hemoglobin, g/dL 10.1 9.4 9.5 8.9
sentation to the ED. His past medical (13.317.7 g/dL)
history was also signicant for peripheral Hematocrit, % 28.7 25.9 26.8 24.7
vascular disease, coronary artery disease, (40%52%)
hypertension, and chronic kidney dis-
ease. His home medication list included Platelets x 109/L 132 74 92 108
aspirin 81mg daily, atorvastatin 40mg (150400 x 109/L)
daily, carvedilol 3.125 mg twice daily, Blood pressure, mm Hg 106/71 137/67 131/74 122/62
clopidogrel 75 mg daily, hydrochloro- (90149/6090 mm Hg)
thiazide12.5 mg daily, losartan25 mg daily,
Pulse, bpm (60120 bpm) 101 88 84 87
and a multivitamin.
Pertinent laboratory data on his initial Tmax, F (97.899.5) 103 98.4 98.3 97.8
presentation can be seen in Table2. His ANC = absolute neutrophil count; bpm = beats per minute; Tmax = maximum body temperature;
ANC was 360 cells/mcL (neutropenic). WBC = white blood cell count.
The patient had not demonstrated neutro-
penia from the time of his diagnosis until talization, and he was discharged on oral Case 2
his ED presentation. On presentation, the ciprooxacin to complete his antibiotic A 71-year-old woman with a long
patient had a maximum body tempera- course. Filgrastim was continued for a history of CLL presented to the ED with
ture (Tmax) of 103.2 F, a blood pressure of total of three doses. On hospital day2, complaints of fever and right foot pain.
125/48mmHg, and a heart rate of 114beats neutrophil recovery was evident with his Her CLL had been under observation for
per minute. He was admitted for empirical ANC rising to 1,800cells/mcL. Upon further 17years, but ve months prior to presenta-
treatment and management of neutropenic follow-up, no active antineoplastic regi- tion, she began treatment for CLL second-
fever and was initiated on cefepime 2g mens were subsequently utilized, and labo- ary to new-onset autoimmune hemolytic
intravenously (IV) every eighthours and ratory tests revealed no further episodes anemia and thrombocytopenia. She
tbo-lgrastim 480mcg subcutaneously once of neutropenia. received four cycles of bendamustine
daily. Blood cultures showed Pseudomonas 157 mg (90 mg/m2) on days1and2 and
aeruginosa that was sensitive to ciproox- rituximab 653 mg (375mg/m2) on day1
acin, cefepime, piperacillin-tazobactam, every 28 days. When she was evaluated for
and meropenem. Cefepime was contin- a fth chemotherapy cycle about a month
ued for the duration of his four-day hospi- before her ED presentation, neutropenia

Vol. 41 No. 12 December 2016 P&T 767

PHARMACOVIGILANCE FORUM
was identied, and her treatment was
discontinued. Her past medical history was
also signicant for hypertension, type-2
diabetes mellitus, and gastroesophageal
reux disease. Her home medications
included lisinopril 20mg daily, hydrochloro-
thiazide 25mg daily, and pantoprazole
40mg daily.
Pertinent laboratory data for Case 2
can be found in Table 2. Her ANC was
208 cells/mcL (neutropenic). On presenta-
tion, the patient had a Tmax of 103 F, a blood
pressure of 106/71 mm Hg, and a heart rate
of 101 beats per minute. She was admit-
ted for empirical treatment and manage-
ment of neutropenic fever. Cefepime 2g IV
piggyback (IVPB) every eighthours was
initiated, along with vancomycin 1.5 g
IVPB every 12 hours. She also received
lgrastim 480 mcg subcutaneously once
daily. Vancomycin was empirically started
because of a suspected skin and soft-tissue
infection on her right foot. Blood cultures
were negative. Podiatry was consulted
for the foot ulcer, for which an incision
and drainage were performed. Cultures
of the ulcer grew Pasteurella canis, and
antibiotics were de-escalated to oral
ciprofloxacin 500 mg twice daily for
10 days. Tbo-filgrastim 480 mcg was
administered subcutaneously daily for a
total of threedays. Neutrophil recovery to
an ANC of 1,750 cells/mcL occurred on the
nal day of administration. The patient was
discharged after a four-day hospitalization.
Follow-up laboratory tests did not reveal
any further episodes of neutropenia.
CONCLUSION
Rituximab can cause a delayed and
late-onset neutropenia that may last for
an unpredictable amount of time. Although
most cases appear to be self-limiting and
resolve without issue, rituximab-induced
late-onset neutropenia may result in seri-
ous life-threatening complications requir-
ing immediate medical intervention. When
patients with autoimmune disease or
cancer are treated with rituximab, it
is important to be aware of rituximab-
induced neutropenia, which can occur
long after therapy cessation. This adverse
event can pose a challenge for clinicians
and requires close patient follow-up during
rituximab administration as well as after
therapy has ended. Compared with what is
reported in the literature, our two patients
presented in a very similar fashion, given
the delayed onset of the neutropenia and
768 P&T December 2016 Vol. 41 No. 12
the swift ANC recovery following the
administration of a lgrastim product.
Given the unclear nature and mecha-
nism of rituximab-induced late-onset
neutropenia, it is not fully known and
understood if re-treatment with rituximab
is a viable and safe option for patients.
It has been previously reported that
rechallenging a patient with rituximab
following an episode of severe late-
onset neutropenia can lead to recurrent
episodes.19 With the possibility of recur-
rence and the unclear risks and impli-
cations of re-treatment, the decision to
administer further doses of rituximab
should be made on a case-by-case basis.
Future research is needed in this area.
REPORTING ADVERSE
DRUG REACTIONS
All ADRs should be reported to
MedWatch at 1-888-INFO-FDA,
1-888-463-6332, or online. The Food
and Drug Administration (FDA) 3500
Voluntary Adverse Event Report Form
can be accessed easily online for report-
ing ADRs at www.fda.gov/Safety/Med-
watch/HowToReport/ucm085568.htm.
The FDA is interested in serious
reports that include any of the fol-
lowing patient outcomes: death; life-
threatening condition; initial hospitaliza-
tion; prolonged hospitalization; disability
or permanent damage; congenital anoma-
lies or birth defects; and other serious
conditions for which medical or surgical
intervention is needed to prevent one
of the aforementioned outcomes. The
FDA is also interested in any unlabeled
ADRs for new drugs (e.g., usually those
approved within the previous two years).
REFERENCES
1. Andersohn F, Konzen C, Garbe E.
Systematic review: agranulocytosis
induced by nonchemotherapy drugs. Ann
Intern Med 2007;146:657665.
2. Kaufman DW, Kelly JP, Issaagrisil S,
et al. Relative incidence of agranulo-
cytosis and aplastic anemia. Am J Hematol
2006;81:6567.
3. Rituxan (rituximab) prescribing infor-
mation. South San Francisco, California:
Genentech Inc; March 2016.
4. Johnson P, Glennie M. The mechanisms
of action of rituximab in the elimina-
tion of tumor cells. Semin Oncol 2003;
30(1 suppl 2):S3S8.
5. Motl SE, Baskin RC. Delayed-onset
grade 4 neutropenia associated with
rituximab therapy in a patient with lym-
phoma: case report and literature review.
Pharmacotherapy 2005;25(8):11511155.
6. Nitta E, Izutsu K, Sato T, et al. A high
incidence of late-onset neutropenia follow-
ing rituximab-containing chemotherapy
as a primary treatment of CD20-positive
B-cell lymphoma: a single-institution
study. Ann Oncol 2007;18(2):364369.
7. Hirayama Y, Kohda K, Konuma Y, et al.
Late onset neutropenia and immuno-
globulin suppression of the patients with
malignant lymphoma following auto-
logous stem cell transplantation with
rituximab. Intern Med 2009;48(1):5760.
8. National Cancer Institute. NCI
common terminology criteria for adverse
events, v4.0 (CTCAE). May 28, 2009.
Available at: http://evs.nci.nih.gov/
ftp1/CTCAE/CTCAE_4.03_2010-06-14_
QuickReference_5x7.pdf. Accessed
May 29, 2016.
9. Frieeld AG, Bow EJ, Sepkowitz KA, et
al. Clinical practice guideline for the use
of antimicrobial agents in neutropenic
patients with cancer. Clin Infect Dis
2011;52:e56e93.
10. Arai Y, Yamashita K, Mizugishi K, et al.
Risk factors for late-onset neutropenia
after rituximab treatment of B-cell lym-
phoma. Hematology 2015;20(4):196202.
11. Fukuno K, Tsurumi H, Ando N, et al. Late-
onset neutropenia in patients treated with
rituximab for non-Hodgkins lymphoma.
Int J Hematol 2006;84:242247.
12. Tesfa D, Palblad J. Late-onset neutro-
penia following rituximab therapy;
incidence, clinical features and possible
mechanisms. Expert Rev Hematol
2011;4(6):619625.
13. Smith TJ, Khatcheressian J, Lyman GH,
et al. 2006 update of recommendations for
the use of white blood cell growth factors:
an evidence-based clinical practice guide-
line. J Clin Oncol 2006;24:119.
14. Weng WK, Negrin RS, Lavori P, Horn-
ing SJ. Immunoglobulin G Fc recep-
tor FcRIIIa 158 V/F polymorphism
correlates with rituximab-induced neutro-
penia after autologous transplantation in
patients with non-Hodgkins lymphoma.
J Clin Oncol 2010;28(2):279284.
15. Grant C, Wilson WH, Dunleavy K. Neutro-
penia associated with rituximab therapy.
Curr Opin Hematol 2011;18(1):49.
16. Salmon JH, Cacoub P, Combe B, et al.
Late-onset neutropenia after treatment
with rituximab for rheumatoid arthritis
and other autoimmune diseases: data
from the AutoImmunity and Rituximab
Registry. RMD Open 2015;1(1):e000034.
doi: 10.1136/rmdopen-2014-000034.
17. Dunleavy K, Tay K, Wilson WH.
Rituximab-associated neutropenia. Semin
Hematol 2010;47(2):180186.
18. Neupogen (filgrastim) prescribing
information. Thousand Oaks, California:
Amgen; July 2015.
19. Wolach O, Bairey O, Lahav M. Late-onset
neutropenia after rituximab treatment.
Medicine 2010;89(5):308318. Q
 RESEARCH BRIEFS
Easier Vaccination Options Boost
Coverage for Health Care Staff
Making it easier for employees to get free u vaccinations
on siteand requiring those vaccinationshas helped bump
up coverage, according to an online survey conducted for the
Centers for Disease Control and Prevention (CDC).
Of the 2,316 health care personnel who responded, 79%
reported having gotten a u shot for the 20152016 season,
up 15.5 percentage points from the 20102011 estimate but
similar to the 77.3% coverage for 20142015.
Physicians continued to be most likely to get vaccinated
(95.6%). Assistants and aides had the lowest coverage, although
it was well above half (64.1%).
Where vaccination was required, coverage was nearly total
(96.5%). But only 61% of health care personnel work in hospitals
with vaccination requirementsand thats at least 27 percent-
age points higher than the proportion in any other work setting,
the researchers said. Aides and assistants reported the lowest
prevalence of vaccination requirements (22.5%).
Next to requirements, another factor that signicantly inu-
enced vaccination response was cost. The majority of vaccinated
health care staff got the shots at their workplace. Coverage
was highest when free vaccination was available on site for a
day or more.
To boost vaccination among long-term-care staff, the CDC
and the National Vaccine Program Ofce offer a Web-based
toolkit that includes access to resources, strategies, and
educational material (www.cdc/gov/u/toolkit/long-term-
care/index.htm). Employers and health care administrators
can also check out the Guide to Community Preventive Services,
which presents evidence to support on-site vaccination at no
or low cost.
Source: Morbidity and Mortality Weekly Report, September
2016
Protein May Predict Risk for
Paclitaxel-Induced Neuropathy
A promising biomarker strategy may help identify patients
at risk for severe paclitaxel-induced peripheral neuropathy.
Paclitaxel administered weekly is more effective than
treatment once every three weeks, but it comes at the price
of more severe sensory peripheral neuropathy. As yet, treat-
ment for chemotherapy-induced peripheral neuropathy is only
symptomatic, said researchers from Singapore.
Their previous research, however, suggested that a protein
N-myc downstream regulated gene 1 (NDRG1)might be useful
in predicting paclitaxel-induced peripheral neuropathy. NDRG1
is ubiquitously expressed in human tissues and tumors, the
researchers noted, particularly in peripheral nerve tissue. It has
also been implicated in degrading myelin in Charcot-Marie-Tooth
disease, a hereditary motor and sensory neuropathy.
To expand on their earlier research, the researchers
conducted another study in 111 patients with early-stage
breast cancer. Of those patients, 41% had human epidermal
growth factor receptor 2positive breast cancer and received
adjuvant trastuzumab along with paclitaxel. Over a median
of 12 weeks, 77 patients (69%) developed all-grade periph-
eral neuropathy; in 17, the neuropathy was severe enough to
mandate reducing or delaying doses, or stopping paclitaxel.
Peripheral neuropathy occurred before cycle 6 in 48%. Not
surprisingly, patients with diabetes had more severe
neuropathy (44% versus 11%).
The mean NDRG1 score of patients without severe
neuropathy was 7.7, compared with 5.4 for patients with
severe neuropathy. Fifty-four patients had an NDRGI score of
less than 7; of those, 13 (24%) developed severe neuropathy,
compared with only four of 57 (7%) patients with a score
above 7.
The researchers are performing a larger prospective study
to explore the mechanisms of NDRG1 regulation to support
their ndings.
Source: PLOS One, October 2016
Ebola Treatment Is Promising,
But Not Denitively Better
The experimental Ebola treatment ZMapp, which is com-
posed of three monoclonal antibodies, prevents progression of
Ebola virus disease by targeting the main surface protein of the
virus. According to ndings from the clinical trial PREVAIL II,
ZMapp is safe and well tolerated. But because the Ebola epi-
demic is waning, the National Institutes of Health said, the
study enrolled too few people to determine denitively whether
it is a better treatment than the best available standard of care.
The study involved 72 men and women with conrmed
infection. However, the researchers closed the study
early because they could not enroll the target number of
200 participants due to the decline in cases. All patients
received the optimized standard of careintravenous (IV)
uids, electrolyte balance, maintaining oxygen and blood
pressure levelsand half also received three IV infusions of
ZMapp three days apart.
At 28 days, 13 of the 35 patients (37%) in the standard-care
group had died, compared with eight of 36 (22%) in the ZMapp
group. That difference, a 40% lower risk of death with ZMapp,
still did not reach statistical signicance.
The ndings are promising and provide valuable scien-
tic data, said Anthony Fauci, MD, Director of the National
Institute of Allergy and Infectious Diseases. Importantly, the
study establishes that it is feasible to conduct a randomized,
controlled trial during a major public health emergency in a
scientically and ethically sound manner.
Source: National Institutes of Health, October 2016
continued on page 801
Vol. 41 No. 12 December 2016 P&T
769
 Systemic Thrombolysis for
Pulmonary Embolism: A Review
Colleen Martin, PharmD; Kristine Sobolewski, PharmD;
Patrick Bridgeman, PharmD; and Daniel Boutsikaris, MD
INTRODUCTION
Pulmonary embolism (PE) is a common disease, occurring
in 60 to 112 of every 100,000 individuals.1 It is the third most
common cause of cardiovascular mortality and is respon-
sible for 100,000 to 180,000 deaths annually.2,3 The clinical
manifestations of acute PE are highly variable, ranging from
pulseless electrical activity to mild dyspnea, which can cloud
the diagnosis.4 PE should be a part of the differential diagno-
sis in patients who present with new or worsening dyspnea,
chest pain, or hypotension.5 Based on the physicians level of
suspicion, the diagnostic workup may include a clinical decision
rule, biomarkers (e.g., d-dimer), and/or imaging modalities,
such as computed tomography angiography or a ventilation-
perfusion scan. Additional evaluations may be performed
with troponins, B-type natriuretic peptide (BNP), Pro-BNP,
and/or echocardiography.6,7
PE is commonly classified as massive (high-risk),
submassive (intermediate-risk), and low-risk to help determine
the required treatment. Risk stratication scores are used to
determine the risk of complications and associated mortality.8
Massive PE is dened as suspected or conrmed PE in the
presence of shock, sustained hypotension, the absence of a
pulse, or persistent profound bradycardia. Submassive PE is
dened as suspected or conrmed PE with right ventricular
dysfunction in the absence of shock.1,4,8
This review focuses on the evidence behind the use of
thrombolytic therapy in patients with massive or submassive
PE. Concurrent heparin therapy and the management of
bleeding episodes are also discussed.
TREATMENT APPROACHES
Anticoagulation
The treatment of PE begins with the administration of
anticoagulants; these agents have been shown to prevent
recurrent symptoms and early death in patients with PE.4,9
The initial pharmacological treatment of acute PE may also
include intravenous (IV) unfractionated heparin (UFH),
subcutaneous low-molecular-weight heparin, or fonda-
parinux (Arixtra, GlaxoSmithKline) for the rst ve to
10 days.4,10,11 UFH is initiated at a dose of 80 units/kg followed
by 18 units/kg every hour, with dose adjustments based on the
Dr. Martin is a Clinical Pharmacy Specialist in Emergency
Medicine at Nyack Hospital in Nyack, New York. Dr. Sobolewski
is a Clinical Pharmacy Specialist in Emergency Medicine at Saint
Barnabas Medical Center in Livingston, New Jersey. Dr. Bridgeman is a
Clinical Assistant Professor in the Department of Pharmacy Practice
and Administration at the Ernest Mario School of Pharmacy at
Rutgers University in New Brunswick, New Jersey. Dr. Boutsikaris
is an Attending Physician in the Department of Emergency Medicine
at St. Peters University Hospital in New Brunswick, New Jersey.
770 P&T December 2016 Vol. 41 No. 12
activated partial thromboplastin time.4 Low-molecular-weight
heparin and fondaparinux are also dosed based on weight.
Both are administered subcutaneously once or twice daily.9
After patients with acute PE have been stabilized, parenteral
anticoagulation should be supplemented with vitamin K antago-
nists. Alternatively, a target-specic oral anticoagulant (TSOAC)
agent, such as apixaban (Eliquis, Bristol-Myers Squibb/
Pzer), rivaroxaban (Xarelto, Janssen), edoxaban (Savaysa,
Daiichi Sankyo), or dabigatran etexilate (Pradaxa, Boehringer
Ingelheim) may be initiated.4,12,13 Patients who are started on
warfarin should also receive a parenteral anticoagulant until
the international normalized ratio (INR) has been maintained
at 2.0 to 3.0 for at least two consecutive days.4 TSOACs may
be started immediately or after one to two days of parenteral
anticoagulation.4 The goal of initial anticoagulant therapy is to
inhibit the formation of additional brin clots.14 When choos-
ing between parenteral anticoagulation or TSOACs, clinicians
should consider the potential for decompensation, the need
for thrombolytic therapy or invasive intervention, the bleeding
risk, and the availability of reversal agents.14 Anticoagulants are
administered for a minimum of three months and may be contin-
ued indenitely, depending on the cause of the thrombus.9,12,13
Thrombolysis
Hemodynamically unstable PE patients are candidates for
treatment with IV thrombolysis or mechanical thrombec-
tomy.10 Thrombolytic agents convert native plasminogen to
plasmin, which in turn hydrolyzes the brin of thromboemboli,
resulting in clot lysis.10 Streptokinase, urokinase (also known
as urinary plasminogen activator), and alteplase (Activase,
Genentech) are the only agents with this indication.1519
The third-generation thrombolytics tenecteplase (TNKase,
Genentech) and reteplase (Retavase, Chiesi USA) are approved
for the treatment of acute coronary syndromes, but they have
also been evaluated in subjects with acute PE.20,21 Alteplase,
reteplase, and tenecteplase preferentially activate plasmino-
gen on the clot surface and are classied as brin specic.
The brin-specic agents have longer half-lives, which allow
bolus administration. They also alleviate the risk of allergic
reactions associated with the rst-generation thrombolytics.22
Streptokinase and urokinase, however, activate systemic plas-
minogen, which is not part of the clot matrix. Key characteristics
of the thrombolytic agents are listed in Table 1.2326
Thrombolytic therapy has been shown to improve pulmo-
nary artery pressure, arteriovenous oxygenation, pulmonary
perfusion, and echocardiographic assessment, thereby
relieving symptoms, preventing recurrent PE, and reducing
mortality.9,27 However, these benets may not outweigh an
Disclosures: The authors report no commercial or nancial interests
in regard to this article.
 Systemic Thrombolysis for Pulmonary Embolism: A Review
streptokinase. No difference in mortality or
Table 1 Key Characteristics of Thrombolytic Agents2326
reinfarction rates was noted between these
Streptokinase Urokinase Alteplase Reteplase Tenecteplase agents. However, intracranial hemorrhage
Generation First First Second Third Third occurred at a lower rate in the streptoki-
nase group. When data from the GUSTO-1
Clot-specic? No No Yes Yes Yes study, which looked at accelerated alteplase
Half-life (minutes) 12 720 410 1119 1524 administration, were removed from the
FDA-approved for PE? Yes Yes Yes No No analysis, the streptokinase group continued
to show a lower incidence of intracranial
PE = pulmonary embolism; FDA = Food and Drug Administration. hemorrhage, whereas major bleeding was
lower in the alteplase group.30
Table 2 Contraindications to Systemic Thrombolysis9,27 Another clinical consideration is the
Absolute* Relative relative merits of systemic versus catheter-
directed thrombolysis. Yoo and colleagues
Structural intracranial disease Systolic blood pressure > 180 mm Hg compared these two modalities in 72 patients
Previous intracranial hemorrhage Diastolic blood pressure > 100 mm Hg with PE.31 Forty-four patients were in the
Ischemic stroke within three months Recent bleeding systemic group, and 28 were in the catheter
Active bleeding Recent surgery or invasive procedure group. The patients mean age was 64 years.
Recent brain or spinal surgery Ischemic stroke > three months previously There was no signicant difference between
Recent head trauma with fracture or brain Anticoagulation the two groups with respect to seven-day
injury Traumatic cardiopulmonary resuscitation mortality (13.6% for systemic thrombolysis
Bleeding diathesis Pericarditis or pericardial uid versus 10.7% for catheter-directed throm-
Diabetic retinopathy bolysis), in-hospital mortality (13.6% versus
Pregnancy 14.3%), and major bleeding complications
Age > 75 years (16.7% versus 16.7%).
Low body weight (e.g., < 60 kg)
Female Thrombolytic Management
African-American of Massive PE
* Thrombolysis could cause a life-threatening situation. Massive or high-risk PE is dened as
Caution is required. Thrombolysis is acceptable if the benets outweigh the risks. sustained hypotension (i.e., systolic blood
pressure of less than 90 mm Hg for more
individual patients risk of major or clinically relevant nonmajor than 15 minutes), with the patient showing symptoms of shock
bleeding.9 Unfortunately, there is no validated tool for predict- or hemodynamic compromise in addition to other symptoms
ing the risk of bleeding in patients undergoing thrombolysis, of PE.4,8,29 Thrombolytic therapy is a key treatment option for
only identied risk factors. Standard assessment tools, such patients presenting with these clinical ndings. The European
as the Pulmonary Embolism Severity Index (PESI), can help Society of Cardiology (ESC), for example, classies thrombo-
identify patients who may benet from thrombolytic therapy.27 lytic administration in patients with acute high-risk PE as a
Conversely, clinicians may use risk stratication to identify 1B recommendation, and the 2016 updated CHEST guidelines
contraindications to thrombolysis (Table 2).9,27 list it as a grade 2B recommendation.9,23,29
A case-control study assessed 62 adults for risk factors that In the setting of massive PE, the benets of systemic
might be associated with bleeding after treatment with alteplase. thrombolysis generally outweigh the risks. Although contra-
The investigators found that patients with major bleeding more indications exist for the administration of thrombolytic agents,
often had recent major surgery (P = 0.039), an INR greater their use should be avoided only in the presence of active,
than 1.7 (P = 0.008), and one or more risk factors for bleeding uncontrollable bleeding.5,32
28
(P = 0.003) compared with those without major bleeding. Other Varying doses and infusion durations have been studied.
clinical data have shown that patients with a lower threshold for ESC guidelines recommend accelerated regimens of alteplase
bleeding during thrombolytic therapy are more likely to have 100 mg infused peripherally over two hours in place of rst-
a history of recent major surgery, trauma, pregnancy, cardio- generation thrombolytics, which require prolonged infusion.4,9
27
pulmonary resuscitation, or an invasive procedure. These Thrombolytics provide the greatest benet if they are admin-
ndings underscore the importance of considering a patients istered within 48 hours of symptom onset.4 PE patients with
bleeding potential before administering thrombolytics.29 transient, less-severe signs of hypotension or shock, but who
No head-to-head comparison trials of thrombolytic agents have later experience sudden clinical deterioration, may still be
been conducted. These drugs have been available for decades, considered for systemic thrombolytics.4,29 In patients with
however, and several meta-analyses have been performed to contraindications to thrombolytic therapy, mechanical throm-
determine their risks and benets in patients with myocardial bectomy or other procedures may be considered.29 Patients who
infarction or stroke. In one meta-analysis that looked at the com- receive systemic thrombolytic therapy and remain hypotensive
parative efcacy of thrombolytics in myocardial infarction, data with a high mortality risk before experiencing the full effect of
from 14 clinical trials involving a total of 142,907 patients were eval- the thrombolytic are candidates for catheter-assisted thrombus
uated.30 Of particular interest was a comparison of alteplase and removal or other mechanical interventions.4,29

Vol. 41 No. 12 December 2016 P&T

771
 Systemic Thrombolysis for Pulmonary Embolism: A Review
Thrombolytic Management of Submassive PE
Intermediate-risk, submassive PE is characterized by right
ventricular dysfunction (RVD) and/or myocardial necrosis, as
indicated by elevated biomarkers, in the absence of persistent
hypotension or shock.33 The use of prognostic measures, such
as the PESI model, may help clinicians with decisions on the
overall management of these patients.34
The role of thrombolysis in hemodynamically stable patients
with submassive PE continues to be an area of debate. Patients
with submassive PE require case-by-case analysis with shared
decision-making regarding the risks and benets of thrombo-
lytic therapy.35 A thorough understanding of the literature is
essential in making these determinations.
The MAPPET-3 trial, conducted in 2002, was one of the
earliest studies to evaluate the use of thrombolytic agents in
patients with submassive PE. This study compared heparin plus
alteplase 100 mg with heparin plus placebo, both administered
over a period of two hours. The primary endpoint was in-hospital
death or clinical deterioration requiring an escalation of treat-
ment. The incidence of the primary endpoint was signicantly
higher in the heparin-plus-placebo group than in the heparin-
plus-alteplase group (P = 0.006), and the probability of 30-day
event-free survival was higher in the heparin-plus-alteplase
group (P = 0.005). No difference was observed, however, in
in-hospital deaths (P = 0.71).36
In the MOPETT trial, 121 patients with moderate PE received
low-dose heparin plus alteplase 50 mg or alteplase 50 mg alone.
The coprimary endpoints were pulmonary hypertension and a
composite endpoint of pulmonary hypertension and recurrent
PE at 28 months. Pulmonary hypertension occurred in 16%
(nine of 58) of the heparin/alteplase group compared with 57%
(32 of 56) of the alteplasae group (P < 0.001). Similarly, the
composite endpoint occurred in 16% (nine of 58) of the heparin/
alteplase group compared with 63% (35 of 56) of the alteplase
group (P < 0.001). The average duration of hospitalization was
2.2 days for heparin/alteplase versus 4.9 days for alteplase
(P < 0.001). The rate of death plus recurrent PE was 1.6% for the
heparin/alteplase group compared with 10.0% for the alteplase
group (P = 0.0489). No bleeding occurred in either group.37
The randomized, double-blind PEITHO trial compared
tenecteplase plus heparin with placebo plus heparin in
1,005 patients with intermediate-risk PE. All of the patients had
RVD. The studys primary outcome was death or hemodynamic
decompensation (or collapse) within seven days after randomiza-
tion. The primary endpoint occurred in 13 of 506 patients (2.6%)
in the tenecteplase group compared with 28 of 499 patients (5.6%)
in the placebo group (P = 0.02). Extracranial bleeding occurred
in 32 patients (6.3%) in the tenecteplase group and in six patients
(1.2%) in the placebo group (P < 0.001). Stroke occurred in
12 patients (2.4%) in the tenecteplase group and was hemorrhagic
in 10 patients; one patient (0.2%) in the placebo group had a
stroke, which was hemorrhagic (P = 0.003). Thus, thrombolytic
therapy was shown to prevent hemodynamic decompensation,
but at an increased risk of major hemorrhage and stroke.21
The randomized, double-blind, placebo-controlled TIPES
trial evaluated the effect of tenecteplase on RVD in hemo-
dynamically stable patients with PE. Fifty-eight patients were
randomly assigned to receive weight-adjusted single-bolus
tenecteplase (n = 23) or placebo (n = 28) along with UFH.
772 P&T December 2016 Vol. 41 No. 12
The studys primary endpoint was the reduction in RVD
at 24 hours. The reduction of the right-to-left ventricle end-
diastolic dimension ratio at 24 hours was 0.31 in patients treated
with tenecteplase compared with 0.10 in patients given placebo
(P = 0.04). One patient treated with tenecteplase experienced
a clinical event (recurrent pulmonary embolism) compared
with three patients in the placebo group. Two nonfatal major
bleeds occurred with tenecteplase (one intracranial) and one
with placebo. The authors concluded that treatment with single-
bolus tenecteplase is feasible at the same dosages used for
acute myocardial infarction and can reduce RVD at 24 hours
in hemodynamically stable patients with PE.38
In the TOPCOAT trial, 83 normotensive patients with sub-
massive PE and right ventricular strain received low-molecular-
weight heparin followed by random assignment to either a
single weight-based bolus of tenecteplase (n = 40) or placebo
(n = 43) administered in a double-blind fashion. The authors
hypothesized that a larger proportion of patients who received
tenecteplase would have a favorable composite outcome.
Three patients treated with placebo experienced an adverse
outcome within ve days, including one who died from a cardiac
arrest that was directly attributed to PE. One patient treated
with tenecteplase died from an intracranial hemorrhage that
occurred ve hours after drug administration. No patients
died in the period between hospital discharge and 90 days. At
follow-up, 16 of the 43 patients (37%) treated with placebo and
six of the 40 patients (15%) treated with tenecteplase had at
least one adverse outcome (two-sided P = 0.017).39
Meta-analyses of thrombolytic therapies have been con-
ducted in an attempt to develop treatment recommendations
based on the current literature. In one such study, Chatterjee
and colleagues conducted a literature review to evaluate the
survival benet of thrombolysis compared with that of anti-
coagulation in patients with acute PE.19 The analysis included
16 studies, which enrolled a total of 2,115 patients. Eight of
these trials involved 1,775 patients with intermediate-risk
PE. Thrombolytic agents were found to be associated with
lower all-cause mortality compared with anticoagulants (2.17%
versus 3.89%, respectively), but they increased the risk of
major bleeding (9.24% versus 3.42%) and intracranial hem-
orrhage (1.46% versus 0.19%). Major bleeding was not sig-
nicantly increased in patients 65 years of age or younger.19
It should be noted that the results of this analysis have been chal-
lenged because of purported aws in the statistical methods.40
In another meta-analysis, Xu and colleagues analyzed
data from seven studies involving a total of 1,631 patients
with intermediate-risk PE treated with thrombolytics or
anticoagulants. The two treatment groups were not signicantly
different with regard to 30-day, all-cause mortality (P = 0.08).
The patients treated with thrombolytic agents, however, had
signicantly lower rates of clinical deterioration (P < 0.01) and
recurrent PE (P = 0.01). There was no difference in the rates
of major bleeding events between the two groups (P = 0.25).2
Meyer and colleagues recently reviewed the main advances
or recommendations in the care of patients with PE, including
recent data on the use of thrombolytic treatment. The authors
concluded that, given at the current dosage, thrombolytics are
associated with a reduction in the combined endpoint of mortality
and hemodynamic decompensation in patients with intermediate-
 Systemic Thrombolysis for Pulmonary Embolism: A Review

Table 3 Key Clinical Trials of Systemic Thrombolysis in Patients With Submassive PE

Year Design Comparators Primary Endpoint Key Results
36
MAPPET-3
2002 Prospective, Heparin + alteplase In-hospital death or clinical Rate of primary endpoint signicantly lower
randomized, (n=118) vs. heparin + deterioration requiring escalation with heparin + alteplase than with heparin +
double-blind, placebo (n = 138) of treatment at end of hospital stay placebo (11% vs. 25%, respectively; P = 0.006)
placebo-controlled or on day 30 after randomization, Rate of recurrent PE low in both groups
whichever occurred rst Bleeding incidence similar in both groups
TIPES38
2010 Randomized, Weight-adjusted, Reduction of RVD at 24 hours Reduction of right-to-left ventricle EDD ratio at
double-blind, single-bolus 24 hours was 0.31 for tenecteplase vs. 0.10 for
placebo-controlled tenecteplase (n = 23) placebo (P = 0.04)
or placebo (n = 28), Recurrent PE in one tenecteplase patient and
both with heparin in three placebo patients
Two major nonfatal bleeds with tenecteplase
vs. one with placebo
MOPETT37
2012 Prospective, Low-dose alteplase (10-mg PHTN at 28 months Rate of primary endpoint signicantly lower
randomized bolus followed by 40mg with alteplase + heparin vs. placebo + heparin
over twohours) + heparin (16% vs. 57%, respectively; P < 0.001)
vs. placebo + heparin No bleeding in either group
TOPCOAT39
2014 Randomized, Weight-adjusted, Composite outcome: 1) death, Adverse outcome rate signicantly lower with
double-blind, single-bolus circulatory shock, intubation, or tenecteplase + heparin vs. placebo + heparin
placebo-controlled tenecteplase (n = 40) major bleeding within vedays, (15% vs. 37%, respectively; P = 0.017)
or placebo (n = 43), or 2) recurrent PE, poor functional
both with heparin capacity, or SF36 PCS score of less
than30 at 90-day follow-up
PEITHO21
2014 Randomized, Tenecteplase + heparin Death or hemodynamic Six patients in the tenecteplase group died
double-blind, (n = 506) vs. placebo + decompensation (collapse) within vs. nine patients in the placebo group (1.2% vs.
placebo-controlled heparin (n = 499) seven days after randomization 1.8%, respectively; P = 0.42)
Extracranial bleeding occurred in 32 patients
in the tenecteplase group vs. six patients in
the placebo group (6.3% vs. 1.2%; P < 0.001)
Stroke occurred in 12 patients in the
tenecteplase group vs. one patient in the
placebo group (2.4% vs. 0.2%, P = 0.003)
EDD = end-diastolic dimension; PE = pulmonary embolism; PHTN = pulmonary hypertension; RVD = right ventricular dysfunction; SF36 PCS = Short Form Health
Survey (36 Items) Physical Component Summary.

risk PE, but this benet is obtained without a decrease in overall
mortality and with a signicant increase in major extracranial
and intracranial bleeding. In the authors opinion, thrombolytic
therapy should be given in cases of hemodynamic worsening
in patients with high-intermediate risk PE.32
Because of the equivocal nature of the clinical data related to
systemic thombolytic therapy in patients with submassive PE
(summarized in Table 3), the decision to treat these individuals
requires careful consideration of the risks and benets involved.
It should be noted that the 2016 CHEST guidelines recom-
mend against the administration of thrombolytics in patients
with acute PE in the absence of hypotension (grade 1B). The
European guidelines also recommend against the routine use of
thrombolysis in these patients (class III, level B).4,29 With regard
to patients with intermediate-risk PE, studies have indicated
the importance of appropriately stratifying each patient based
on his or her comorbidities and mortality risk before
administering thrombolytics.27,34
Management of Low-Risk PE
PE patients without shock, hypotension, or signs of cardiac
dysfunction are considered to have a low 30-day mortality risk.41
Thrombolytic therapy is not recommended for these patients.4
A PESI class of I or II (Table 4) should prompt clinicians to
consider outpatient treatment.30,41

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 Systemic Thrombolysis for Pulmonary Embolism: A Review
CLINICAL CONSIDERATIONS
Use of Low-Dose Thrombolytics
The bleeding complications associated with alteplase are
dose dependent and have raised questions as to whether the
standard dosage of 100 mg administered over two hours is
appropriate for all PE patients.42 As mentioned earlier, both the
PEITHO and MOPETT trials used lower doses of thrombolytics
and adjusted the doses according to weight. Specically, the
PEITHO study dosed tenecteplase as high as 50 mg in patients
weighing more than 90 kg and as low as 30 mg in patients
weighing less than 60 kg.21 In the MOPETT trial, intermediate-
risk PE patients weighing less than 50 kg received a weight-
based dosing regimen of 0.5 mg/kg (10-mg bolus administered
over one minute, with the remainder of the dose administered
over two hours).37 A meta-analysis of trials using low-dose
recombinant tissue plasminogen activator (rt-PA) in patients
with acute PE found that a low dose (50-mg infusion over
two hours) was as effective as the standard dose (100-mg
infusion over two hours), with fewer major bleeding events.43
In patients with massive PE, lower doses of thrombolytic agents
may benet patients at high risk of bleeding, such as those
weighing less than 65 kg. Lower doses of thrombolytics may
also help prevent bleeding complications in elderly, pregnant,
and surgical patients.42
Concurrent Heparin
When there is a high clinical suspicion of PE, anticoagulation
with UFH should be initiated while the diagnostic workup
is being completed. If the decision is made to administer a
thrombolytic agent, the clinician must consider how best to
handle the IV heparin infusion. According to the American Heart
Association, the decision to coadminister thrombolytic agents
Table 4 Pulmonary Embolism
Severity Index (PESI) Scoring System30,41
Parameter Points
Age Age in years
Altered mental status 60
Cancer 30
Systolic blood pressure < 100 mm Hg 30
Pulse rate 100 beats per minute 20
Respiratory rate > 30 breaths per minute 20
Temperature < 36 C 20
Arterial oxygen saturation < 90% 20
Male gender 10
with heparin anticoagulation requires a strict riskbenet assess-
ment.8 When a thrombolytic and heparin are used concomitantly,
there is a greater likelihood that the symptoms will be allevi-
ated and that the patients cardiac and respiratory parameters
will be stabilized.8 The ESC recommends withholding paren-
teral anticoagulation when rst-generation thrombolytics are
administered, but UFH may be given in conjunction with rt-PA
infusions.30 The 2016 CHEST guidelines do not go into detail
with regard to the coadministration of anticoagulants and throm-
bolytics, but they do state that patients with acute PE whose
condition worsens after parenteral anticoagulation may receive
systemic thrombolytic therapy (grade 2C recommendation).29
Management of Bleeding
If a patient shows signs or symptoms of severe bleeding, the
rst step is to discontinue both the thrombolytic and anticoagula-
tion infusions. The next step is to institute supportive therapy,
which may include the application of pressure to bleeding sites,
volume repletion with blood products and uids, and emergency
surgery.44 Protamine sulfate is an antidote to heparin overdose.
The dose required for heparin reversal is 1 mg of protamine
for every 100 units of heparin, for a maximum of 50 mg.45 It is
likely that the patient will be receiving a continuous infusion
of UFH. If so, clinicians should consider heparins half-life
(60 to 90 minutes) when calculating the protamine dose.46
Aminocaproic acid (Amicar, Xanodyne Pharmaceuticals) may
be used to enhance hemostasis when thrombolysis contributes
to bleeding. Doses of 4 g to 5 g should be injected into a 250-mL
bag of diluent and administered over one hour. A continuous
infusion of the same concentration is then given at a dosage of
1 g per hour for eight hours or until the bleeding is resolved.47
Cryoprecipitate may be indicated in patients with massive bleed-
ing to replenish brin stores, but this treatment should be
reserved for life-threatening situations.48 Intravenous tranexamic
acid has also been used in patients with post-tPA bleeding. In
a case report, a patient received 1.676 g within three hours.49
CONCLUSION
PE is a major cause of morbidity and mortality. With careful
risk stratication, clinicians should be able to perform systemic
thrombolysis safely and effectively in most of these patients.
Systemic thrombolytic agents are a viable option in patients
with hemodynamically unstable PE, as their potential benets
will almost certainly outweigh the risk of a life-threatening
bleed. Patients with submassive PE are more challenging,
and clinicians must carefully evaluate their clinical trajec-
tory, comorbidities, and bleeding risk before administering
thrombolytic therapy.

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41. Aujesky D, Obrosky DS, Stone RA, et al. Derivation and validation
of a prognostic model for pulmonary embolism. Am J Respir Crit
Care Med 2005;172:10411046.
42. Brandt K, McGinn K, Quedado J. Low-dose systemic alteplase
(tPA) for the treatment of pulmonary embolism. Ann Pharmacother
2015;49:818824.
43. Zhang Z, Zhai ZG, Liang LR, et al. Lower dosage of recombinant
tissue type plasminogen activator (rt-PA) in the treatment of acute
pulmonary embolism: a systemic review and meta-analysis. Thromb
Res 2014;133:357363.
44. Makris M, Veen JJV, Tait C, et al. Guideline on the management
of bleeding in patients on antithrombotic agents. Br J Haematol
2012;160:3536.
45. DailyMed. U.S. National Library of Medicine. Protamine sul-
fate. June 30, 2014. Available at: https://dailymed.nlm.nih.
gov/dailymed/drugInfo.cfm?setid=e1964129-33f4-4e4e-86e3-
8e6a4e65bd83. Accessed August 3, 2016.
46. Garcia DA, Baglin TP, Weitz JI, Samama MM. Parenteral anti-
coagulants: antithrombotic therapy and prevention of thrombosis,
9th ed: American College of Chest Physicians Evidence-Based
Clinical Practice Guidelines. Chest 2012;141(suppl):e24Se43S.
47. Amicar (aminocaproic acid) prescribing information.
Newport, Kentucky: Xanodyne Pharmaceuticals; September
2008. Available at: www.accessdata.fda.gov/drugsatfda_docs/
label/2009/015230s037lbl.pdf. Accessed August 3, 2016.
48. Goldstein J, Marrero M, Masrur S, et al. Management of thrombolysis-
associated symptomatic intracerebral hemorrhage. Arch Neurol
2010;67:965969.
49. French KF, White J, Hoesch RE. Treatment of intracerebral
hemorrhage with tranexamic acid after thrombolysis with tissue
plasminogen activator. Neurocrit Care 2012;17:107111. Q
Vol. 41 No. 12 December 2016 P&T
775
 NOW APPROVED
XIIDRA (litegrast ophthalmic solution) 5%
Xiidra is the rst and only prescription eye drop
FDA-approved to treat both the signs and symptoms
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and can be progressive, is associated with inammation
of the ocular surface that can be triggered by abnormal
tear composition.1-4

Diagnosing DED is complex.5

Symptoms of DED are among the most common patient
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Indication
on the assessment of both signs and symptoms, which do not
Xiidra (litegrast ophthalmic
always correlate.2,6,7
solution) 5% is indicated for
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signs and symptoms of DED. (DED).

Important Safety Information

Clinical studies demonstrated Xiidras effectiveness.1 In clinical trials, the most common
The safety and efficacy of Xiidra compared with vehicle were adverse reactions reported in
studied in 4 well-controlled, 12-week trials (N=2133). Safety was 5-25 % of patients were instillation
studied in 1 additional year-long trial (N=331).1,8 site irritation, dysgeusia and
reduced visual acuity. Other
Xiidra demonstrated a larger reduction in inferior adverse reactions reported in 1%
corneal staining score (ICSS) in 3 of the 4 studies to 5% of the patients were blurred
at Week 12.1 vision, conjunctival hyperemia,
Xiidra improved ICSS, a well-recognized sign of DED, eye irritation, headache, increased
compared with vehicle.1* lacrimation, eye discharge, eye
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ICSS was recorded at each study visit (0=no staining, 1=few/rare
sinusitis.
punctate lesions, 2=discrete and countable lesions, 3=lesions
too numerous to count but not coalescent, 4=coalescent). The To avoid the potential for eye
average baseline ICSS was ~1.8 in Studies 1 and 2 and 2.4 in injury or contamination of the
Studies 3 and 4.1 solution, patients should not touch
the tip of the single use container
Xiidra demonstrated a larger reduction in eye dryness to their eye or to any surface.
score (EDS) at Weeks 6 and 12 in all 4 studies.1
Contact lenses should be
In 2 of the 4 studies an improvement in EDS removed prior to the
favoring Xiidra was seen at Week 21 administration of Xiidra and
EDS was rated by patients using a visual analogue scale at may be reinserted 15 minutes
each study visit (0=no discomfort, 100=maximal discomfort). following administration.
The average baseline EDS was between 40 and 70.1
Safety and efficacy in pediatric
* Vehicle contains sodium chloride, sodium phosphate dibasic anhydrous, sodium thiosulfate pentahydrate, sodium hydroxide and/or hydrochloric acid (to
adjust pH), and water for injection.1 patients below the age of 17
References: 1. Xiidra [package insert]. Lexington, MA: Shire US Inc.; 2016. 2. DEWS Research Subcommittee. The denition and classication of dry eye disease: report of the Denition years have not been established.
and Classication Subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf. 2007;5(2):75-92. 3. American Academy of Ophthalmology Cornea/External Disease Panel.
Preferred Practice Pattern. Dry eye syndrome. http://www.aao.org/preferred-practice-pattern/dry-eye-syndrome-ppp--2013. Accessed May 16, 2016. 4. Baudouin C, Aragona P, Van
Setten G, et al; ODISSEY European Consensus Group members. Diagnosing the severity of dry eye: a clear and practical algorithm. Br J Ophthalmol. 2014;98(9):1168-1176. 5. Sullivan
BD, Crews LA, Messmer EM, et al. Correlations between commonly used objective signs and symptoms for the diagnosis of dry eye disease: clinical implications. Acta Ophthalmol.
Please see Brief Summary of
2014;92(2):161-166. 6. Sullivan DA, Hammitt KM, Schaumberg DA, et al. Report of the TFOS/ARVO Symposium on global treatments for dry eye disease: an unmet need. Ocul Surf. Prescribing Information on
2012;10(2):108-116. 7. Stern ME, Schaumburg CS, Pugfelder SC. Dry eye as a mucosal autoimmune disease. Int Rev Immunol. 2013;32(1):19-41. 8. Donnenfeld ED, Karpecki PM, Majmudar
PA, et al. Safety of litegrast ophthalmic solution 5.0% in patients with dry eye disease: a 1-year, multicenter, randomized, placebo-controlled study. Cornea. 2016:35(6):741-748. next page.

2016 Shire US Inc., Lexington, MA 02421 S16172 09/16

To learn more, visit xiidra.com. Marks designated and are owned by Shire or an affiliated company.

+8
Rx Only
BRIEF SUMMARY:
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INDICATIONS AND USAGE
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Discard the single use container immediately after using
KPGCEJG[G%QPVCEVNGPUGUUJQWNFDGTGOQXGFRTKQTVQ
the administration of Xiidra and may be reinserted 15
minutes following administration.
ADVERSE REACTIONS
Clinical Trials Experience
Because clinical studies are conducted under widely
varying conditions, adverse reaction rates observed in
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to rates in the clinical trials of another drug and may
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FQUGQHNKVGITCUV
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6JGOCLQTKV[QHRCVKGPVU
JCFOQPVJUQH NONCLINICAL TOXICOLOGY
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QHVJGVTGCVGFRCVKGPVUYGTGHGOCNG
6JGOQUV VQFGVGTOKPGVJGECTEKPQIGPKERQVGPVKCNQHNKVGITCUV
EQOOQPCFXGTUGTGCEVKQPUTGRQTVGFKPQHRCVKGPVU
were instillation site irritation, dysgeusia and reduced
XKUWCNCEWKV[1VJGTCFXGTUGTGCEVKQPUTGRQTVGFKP
VQQHVJGRCVKGPVUYGTGDNWTTGFXKUKQPEQPLWPEVKXCN
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and sinusitis.
+8FQUGUQHWRVQOIMIFC[
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USE IN SPECIFIC POPULATIONS
4*1&QH
Pregnancy
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women to inform any drug associated risks. Intravenous
+8CFOKPKUVTCVKQPQHNKVGITCUVVQRTGIPCPVTCVUHTQO
RTGOCVKPIVJTQWIJIGUVCVKQPFC[FKFPQVRTQFWEG
VGTCVQIGPKEKV[CVENKPKECNN[TGNGXCPVU[UVGOKEGZRQUWTGU
+PVTCXGPQWUCFOKPKUVTCVKQPQHNKVGITCUVVQRTGIPCPV
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KPEKFGPEGQHQORJCNQEGNGCVVJGNQYGUVFQUGVGUVGF
OIMIFC[
HQNFVJGJWOCPRNCUOCGZRQUWTGCV Marks designated and are owned by Shire
VJGTGEQOOGPFGFJWOCPQRJVJCNOKEFQUG=4*1&?
DCUGFQPVJGCTGCWPFGTVJGEWTXG=#7%?NGXGN5KPEG
JWOCPU[UVGOKEGZRQUWTGVQNKVGITCUVHQNNQYKPI
QEWNCTCFOKPKUVTCVKQPQH:KKFTCCVVJG4*1&KUNQYVJG
CRRNKECDKNKV[QHCPKOCNPFKPIUVQVJGTKUMQH:KKFTCWUGKP
JWOCPUFWTKPIRTGIPCPE[KUWPENGCT
Animal Data
.KVGITCUVCFOKPKUVGTGFFCKN[D[KPVTCXGPQWU
KPLGEVKQPVQTCVUHTQORTGOCVKPIVJTQWIJIGUVCVKQPFC[
ECWUGFCPKPETGCUGKPOGCPRTGKORNCPVCVKQPNQUU
and an increased incidence of several minor skeletal
CPQOCNKGUCVOIMIFC[TGRTGUGPVKPIHQNF
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on AUC. No teratogenicity was observed in the rat at
OIMIFC[
VJG4*1&DCUGFQP#7%+PVJGTCDDKVCPKPETGCUGF
KPEKFGPEGQHQORJCNQEGNGYCUQDUGTXGFCVVJGNQYGUV
FQUGVGUVGFOIMIFC[
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through 19. A fetal No Observed Adverse Effect Level
Lactation
milk, the effects on the breastfed infant, or the effects on
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HTQOQEWNCTCFOKPKUVTCVKQPKUNQY6JGFGXGNQROGPVCNCPF
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along with the mothers clinical need for Xiidra and any
RQVGPVKCNCFXGTUGGHHGEVUQPVJGDTGCUVHGFEJKNFHTQO
Xiidra.
Pediatric Use
5CHGV[CPFGHECE[KPRGFKCVTKERCVKGPVUDGNQYVJGCIGQH
17 years have not been established.
Geriatric Use
No overall differences in safety or effectiveness have been
QDUGTXGFDGVYGGPGNFGTN[CPF[QWPIGTCFWNVRCVKGPVU
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis: Animal studies have not been conducted
Mutagenesis: .KVGITCUVYCUPQVOWVCIGPKEKPVJGin vitro
#OGUCUUC[.KVGITCUVYCUPQVENCUVQIGPKEKPVJGin vivo
mouse micronucleus assay. In an in vitro chromosomal
aberration assay using mammalian cells (Chinese
JCOUVGTQXCT[EGNNUNKVGITCUVYCURQUKVKXGCVVJGJKIJGUV
concentration tested, without metabolic activation.
Impairment of fertility: .KVGITCUVCFOKPKUVGTGFCV
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NKVGITCUVQRJVJCNOKEUQNWVKQPJCFPQGHHGEVQP
HGTVKNKV[CPFTGRTQFWEVKXGRGTHQTOCPEGKPOCNGCPF
female treated rats.
Manufactured for: Shire US Inc., 300 Shire Way, Lexington, MA 02421.
For more information, go to www.Xiidra.com or call 1-800-828-2088.
QTCPCHNKCVGFEQORCP[
2016 Shire US Inc.
US Patents: 8367701; 9353088; 7314938; 7745460; 7790743;
7928122; 9216174; 8168655; 8084047; 8592450; 9085553 and
RGPFKPIRCVGPVCRRNKECVKQPU
.CUV/QFKGF5
 Zika in America: The Year in Review
Chris Fellner
INTRODUCTION
In the April 2016 P&T, we described the rapid spread of Zika
virus from East Africa, through Southeast Asia, and into South
and Central America.1 At that time, the virus had not made
signicant inroads in the United States. Unfortunately, that is
no longer the case. Short on funds and with no therapeutics or
vaccines in sight, U.S. health ofcials are scrambling to prepare
for a protracted ght with a tenacious foe. In this article, we
focus on the arrival of Zika in the U.S. and on efforts to contain it.
BACKGROUND
The virus that became known as Zika was rst identied in
1947 in rhesus monkeys inhabiting Ugandas Zika forest.2 The
rst cases of human infection were reported ve years later
in Uganda and Tanzania.3 The source of these infections was
determined to be a mosquito-borne avivirus, labeled Zika in
reference to its Ugandan origin (Figure 1). The Zika virus is
now known to be related to yellow fever virus, dengue virus, and
West Nile virus.4,5 It is transmitted to people by mosquitoes of
the Aedes species, principally Ae. aegypti (commonly known as
the yellow fever mosquito) and Ae. albopictus (the Asian tiger
mosquito) (Figures 2 and 3), which thrive in warm climates.46
By the 1980s, mosquitoes had carried the Zika virus across
equatorial Asia, from Pakistan to Indonesia.7,8 Continuing its
westward migration, the virus passed from Southeast Asia to
islands in the South Pacic, where it caused major outbreaks
in 2013 and 2014.912 On July 15, 2015, Brazil conrmed the
Figure 1 The Zika Virus
In this digitally colorized transmission electron micrograph, Zika
virus particles appear in blue; they are 40 nm in diameter, with an
outer envelope and an inner dense core. (Source: CDC)
Chris Fellner is a medical writer and the Editor of PTCommunity.com.
778 P&T December 2016 Vol. 41 No. 12
Figure 2 An Aedes Aegypti Mosquito
Source: CDC
circulation of Zika virus in that countrythe rst report of
locally acquired Zika virus infection (ZVI) in the Americas.13
Two days later, Brazilian authorities detected the neurologi-
cal disorder Guillain-Barr syndrome (GBS) in some adults
with ZVI.2,14 Then, in October, Brazilian ofcials reported an
unusual increase in microcephaly among newborns. Fifty-four
cases were recorded between August and October 30.15 By the
end of 2015, that number would explode to more than 2,900.16
Meanwhile, the virus was moving inexorably north. In
November, locally acquired ZVI cases were reported in
Colombia, El Salvador, Mexico, Venezuela, and Paraguay.1721
The following month, the disease had spread to Honduras,
Panama, and French Guiana.2224 On December 31, the Centers
for Disease Control and Prevention (CDC) announced the rst
conrmed case of locally acquired ZVI in Puerto Rico.25 Next
stop: the United States.
ZIKA COMES TO AMERICA
Given that Ae. aegypti and Ae. albopictus mosquitoes inhabit
most of the mainland U.S., the arrival of Zika virus in this
country wasnt a matter of if but of when.
Ae. aegypti mosquitoes originated in Africa but have been
in the U.S. for centuries, probably reaching the new world
on ships used for European exploration and colonization.26
Ae. aegypti occupies urban areas with or without vegetation,
and bites, rests, and lays eggs both indoors and outdoors.
It prefers taking blood meals from humans and pays less
attention to domestic mammals.6
Ae. albopictus mosquitoes, from Asia, were rst documented
in the U.S. in Texas in 1985 and near Jacksonville, Florida, in
1986. They are believed to have entered the U.S. in shipments
of used tires imported from Asia for retreading.27 Ae. albopictus
is mostly rural, inhabiting thickets and arboreal vegetation.
While it bites humans, it will just as readily feed on domestic
and wild mammals.6
In March, Brazilian scientists announced that they were able
to infect another mosquito species, Culex quinquefasciatus,
 Zika in America: The Year in Review

Figure 3 An Aedes Albopictus Mosquito man who had recently returned from Venezuela transmitted
the virus to his sexual partner.35 After this, the CDC advised
men to abstain from sex or to use condoms correctly after
traveling to areas with circulating Zika virus.36
By February 26, 116 residents in 33 states and the District
of Columbia had evidence of recent ZVI, according to CDC
gures.37
As concern about Zikas American presence grew, the
Department of Homeland Security announced that the
U.S. would not screen people entering the country for the
virus because most of those infected (an estimated 80%) are
asymptomatic.38
It wasnt long before the American Council on Science and
Health was calling Zika possibly the scariest virus since HIV. 39
Things took a turn for the worse when Florida health ofcials
Source: CDC noticed Zika cases in the Miami area.

with Zika virus in the laboratory, raising

concerns that Zika could be carried by a Figure 4 Estimated Range of Aedes Aegypti and Aedes Albopictus
species more prevalent than Ae. aegypti Mosquitoes in the United States, 201630
or Ae. albopictus. Culex mosquitoes exist
in more-temperate climes, including the
WA
southern United States, where they carry
MT ME
the West Nile virus.28 In September, ND
OR MN VT
however, scientists at Kansas State ID NH
WI
SD MA
University reported that Culex mosqui- WY MI
NY
RI
toes do not appear to transmit Zika virus, IA PA CT
NE NJ
which vanishes rather than multiplying in NV
UT IL IN OH DE
the species.29 CA CO WV
VA MD
KS MO
According to the CDC, Ae. aegypti KY
NC
and Ae. albopictus can be found as far OK
TN
AZ AR
north as Michigan, New Hampshire, and SC
NM
Washington state. The mosquitoes are MS AL GA

concentrated most heavily, however, in the TX LA

Southeast and Southwest (Figure 4).30,31 HI

FL
Ae. aegypti mosquitoes were captured at
least once in 26 states, whereas Ae. albopic- PR

tus was found in 40 states. Overall, the mos-

quitoes were observed in approximately Aedes aegypti
one-third of the 3,141 U.S. counties.31 Only
seven statesWashington, Oregon, Idaho, WA
Montana, Wyoming, North Dakota, and MT ND ME
South Dakotaare completely free of both OR MN VT
species.30 ID WI
NH
SD NY MA
In January, researchers at the University WY MI RI
of Notre Dame reported the discovery of NE
IA PA NJ
CT
NV
Ae. aegypti mosquitoes in Washington, UT IL IN OH DE

D.C. Disturbingly, the team found genetic CA CO WV MD

KS VA
MO KY
evidence that the mosquitoes had over-
NC
wintered for at least four years, meaning TN
OK
AZ AR
SC
they were adapting for persistence in a NM
MS GA
northern climate.32 AL
TX LA
At the same time, a resident in Virginia
and another in Arkansas tested positive HI
FL
for ZVI. Both had traveled to Zika-affected
PR
countries.33,34 Another Zika case occurred
in Texas a week later. This one, however,
marked the rst case of sexual transmis- Aedes albopictus
Source: CDC
sion of Zika virus in the U.S. An infected

Vol. 41 No. 12 December 2016 P&T 779

 Zika in America: The Year in Review
Zika in Florida
With its ubiquitous, almost year-round population of
Ae. aegypti and Ae. albopictus mosquitoes and a high volume
of travelers from Zika-affected countries, Florida is especially
vulnerable to Zika outbreaks.40
In February, Florida Governor Rick Scott declared a public
health emergency in four counties with travel-related cases of
ZVI and ordered state ofcials to increase mosquito-control
efforts. The counties were MiamiDade in south Florida,
Hillsborough in the Tampa Bay region, Lee in southwest
Florida, and Santa Rosa in the Florida Panhandle.41 In late July,
MiamiDade became the U.S. epicenter of Zika activity when
local health ofcials conrmed two cases of disease caused
by mosquito bites in a square-mile area of Wynwood, a trendy
neighborhood just north of downtown Miami.40,42 They were
the rst locally acquired cases of ZVI in the continental U.S.
The CDC issued a travel advisory warning pregnant women
to avoid the area.43
These cases are not unexpected, CDC Director Tom
Frieden, MD, MPH, told a press conference. At CDC, weve
been saying for months, based on experience with chikungunya
and dengue, which are viruses spread by the same mosquito
that spreads Zika, that individual cases and potentially small
clusters of Zika are possible in the U.S. As we have anticipated,
Zika is now here.44
As Dr. Frieden spoke, 1,658 cases of ZVI had been reported to
the CDC in the continental U.S. and Hawaii, but none resulted
from local mosquito bites. Fifteen cases were believed to be
related to sexual transmission, and one case in Pennsylvania
was caused by accidental laboratory exposure to the virus.42
In early August, the CDC announced that an additional
area of active Zika transmission had been identied in Miami
Beach. The Florida Department of Health also found at least
four other instances of apparently mosquito-borne Zika in
MiamiDade County.45
The CDC pointed out that detecting the local spread of Zika
virus was difcult for several reasons:45
The incubation period for ZVI is up to two weeks.
A high proportion of infected people have no symptoms.
The diagnosis and investigation of cases take weeks.
For these reasons, the CDC said, it was possible that
other MiamiDade neighborhoods could have active Zika
transmission that was not yet apparent.44
Anthony Fauci, MD, Director of the National Institute of
Allergy and Infectious Diseases (NIAID), warned that Zika
could easily continue its march into the continental U.S.46 Not
long afterward, a ZVI case was reported more than 200 miles
north of Miami in Pinellas County. The case involved a woman
with no signicant travel history, indicating that the virus was
acquired locally.47 A second nontravel-related case of ZVI was
discovered in Palm Beach County.48 In mid-August, a Texas
resident who had traveled to a Miami area with local Zika
transmission tested positive for the virus upon returning home.
It was the rst time that the virus had spread between states.49
On August 3, ofcials in MiamiDade County began the aerial
insecticide spraying recommended by the CDC in an effort to
kill Aedes mosquitoes in a 10-square-mile area.50 The program
780 P&T December 2016 Vol. 41 No. 12
used two pesticidesone that kills adult mosquitoes (naled, an
organophosphate) and another that eradicates mosquito eggs
and larvae. By the end of the month, it was obvious that the
plan wasnt working. The mosquitoes were under control in
only 20% of the target areain zones where both insecticides
were used. In the remaining 80% of the target area, where only
naled was sprayed, the Aedes mosquitoes held their own.51 On
August 29, researchers at the University of Texas Medical
Branch in Galveston reported a possible explanation: Adult
female mosquitoes can pass the Zika virus to their offspring,
making it clear that pesticide programs need to kill both adult
mosquitoes and their eggs.52
In late August, Florida health ofcials announced that they
were investigating three more Zika cases that were likely
acquired locally in MiamiDade County, including two cases
outside of the known areas of active virus transmission. That
brought the states total of nontravel-related cases to 46.53 But
people began to question the accuracy of information being
issued by state agencies. On September 10, the Miami Herald
reported that health ofcials had stopped providing detailed
information on epidemiologic investigations into local ZVI;
had refused to identify all of the locations where Zika-positive
mosquitoes were trapped in Miami Beach; and had under-
reported the number of local Zika infections in Florida by
excluding anyone who was not a state resident. Arthur Caplan,
PhD, Director of Medical Ethics at New York University
Langone Medical Center, commented: It makes no sense
unless you see it through the eyes of the impact on tourism.54
On September 17, Florida ofcials tripled the active Zika
virus transmission zone in Miami Beach from 1.5 square miles
to 4.5 square miles after ve new ZVI cases were identied in
the area. On the plus side, Governor Scott announced that he
expected the Zika zone to be lifted in neighboring Wynwood,
where aggressive mosquito control and community outreach
measures had proved effective.55
The good news didnt last. In mid-October, Governor Scott
revealed that local transmission of Zika virus was occurring in
a new Miami area, where health ofcials believed two women
and three men had been infected.56 Soon the CDC introduced
a color-coding system for MiamiDade County to distinguish
between areas of active transmission that present a signicant
risk of ZVI and areas with a possible risk of ZVI. The system
denoted the whole county as a yellow cautionary area except
for Miami Beach and the one-square-mile Little River neigh-
borhood of Miami, which were high-risk red zones. The CDC
recommended that pregnant women consider postponing
travel to the yellow areas and specically avoid the red areas.57
As of October 19, 2016, Florida remained the only state with
locally acquired ZVI, with 137 conrmed cases.58
The Government Response
As the new year began, the White House said its efforts to
ght Zika would consist mainly of sharing information about
the risks with the public. President Obama, however, acknowl-
edged the need for Zika tests, treatments, and vaccines.59
Soon afterward, he called on Congress to supply $1.9 billion
in emergency funding.60
On April 1, more than 300 local, state, and federal govern-
ment ofcials; health experts; and nongovernment partners
 Zika in America: The Year in Review
gathered at CDC headquarters in Atlanta to craft a national
plan to combat Zika.61,62 The summits aims included identifying
gaps in readiness and providing technical support to state and
local jurisdictions.62 Dr. Frieden suggested that states appoint
a Zika coordinator. Other experts urged health ofcials to
establish surveillance networks to monitor the spread of the
virus. Many called on Congress to approve the $1.9 billion in
funding requested by the White House, much of which would
be funneled to local and state agencies that couldnt afford
signicant mosquito control.63
In April, federal ofcials announced that they would transfer
$589 million originally intended to protect against Ebola for
use in the ght against Zika.64
Finally, on May 16, the Zika Response Appropriations
Act2016 was introduced in the House. The Republican-backed
bill provided $622.1 million to federal agencies to ght Zika by
repurposing leftover Ebola funding and unused Department
of Health and Human Services (HHS) administrative funding.65
President Obama immediately threatened to veto the measure,
calling the funding woefully inadequate.66 Nevertheless, the
bill passed the House by a vote of 241 to 184.67 A day later, the
Senate, on a vote of 68 to 30, passed its own bill, which called
for $1.1 billion in emergency money to ght Zika.68 Heated
bickering ensued between House and Senate negotiators
before the House grudgingly passed a $1.1 billion Zika bill on
June 23 by a vote of 239 to 171almost entirely along party
lines. Democratic leaders bristled at what they called unreason-
able spending cuts and policy changes, especially on womens
health, that Republicans had tacked onto the bill.69 On July 14,
the measure fell short of the 60 votes needed to advance in the
Senateand both sides went home for a seven-week recess.70
Dr. Frieden said simply: This is no way to ght an epidemic.71
In August, President Obama said he would divert another
$81 million from other programs to fund development of a Zika
vaccine because Congress had failed to approve funding.72
Meanwhile, Florida Governor Scott complained that the
federal government had not delivered all of the support he
had requested.48
On August 30, Dr. Frieden said that the CDC would run
out of funds to ght Zika by the end of September if nothing
was done73but his warning fell on deaf ears. The Senate
returned to Washington on September 6 and again refused to
pass a bill that would fund Zika research and prevention. The
main source of contention was a Republican effort to prevent
Planned Parenthood from receiving money to combat the
mosquito-borne disease. The vote was 52 to 46, short of the
60 votes needed to advance the bill.74
In late September, Congress nally allocated $1.1 billion to
curb Zikas spread as part of a larger spending bill designed to
keep the federal government running until December 9. Almost
$935 million was approved to ght Zika at home: $152 million
for NIAID, which is researching vaccines; $394 million for
CDC use in Zika-affected areas; and $387 million for the HHS
public health emergency fund for activities such as Zika testing
and ZVI patient care. Another $175 million was approved for
Zika efforts abroad, such as evacuating pregnant Americans
from countries where Zika is spreading and helping hard-hit
foreign nations.75 Planned Parenthood wasnt mentioned in
the September deal.75
U.S. health ofcials made it clear that the funding delay
hurt U.S. efforts to ght the Zika virus. Because weve had to
wait these seven months, Dr. Frieden said, we havent been
able to get a running start on some of the critically impor-
tant studies to understand more fully the impacts of Zika, to
establish better diagnostic tests, [and] to improve our way of
controlling mosquitoes. Vaccine development was also
delayed.76
Given how long processing and budgeting can take, public
health laboratories didnt expect a cash infusion until early
2017. Meanwhile, with local health departments shrinking,
many dont have the staff to operate laboratories at the level
needed given the volume of samples coming in.77
ZIKA HEALTH EFFECTS AND RISKS
During a Zika press conference on April 11, Anne Schuchat,
MD, the CDCs Principal Deputy Director, remarked that
everything we look at with this virus seems to be a bit scarier
than we initially thought.78 Two days later, the CDC conrmed
what many people had suspected: ZVI can cause microcephaly
and other serious fetal defects.79 The agency declined, however,
to acknowledge a link between Zika and GBS in adults, saying
it was still investigating.80
Zika: A Neurotropic Virus
Early in 2016, the World Health Organization (WHO)
announced that Zika had been detected in amniotic uid and
that the virus was able to cross the placental barrier and infect
the fetus. We can now conclude, the agency said, that Zika
virus is neurotropic, preferentially affecting tissues in the brain
and brain stem of the developing fetus.81
In July, a study at the Pasteur Institute in France found that
Zika virus could infect and impair neural stem cells in the devel-
oping neocortex of mice.82 In the U.S., similar research was
conducted at Rockefeller University in New York City, where
investigators found that Zika could attack cells in adult mice
in the hippocampus, the part of the brain involved in learning
and memoryraising disturbing questions about how the virus
might affect human adults. The researchers noted that other
studies had documented the virus ability to cause serious brain
and spinal cord infections, including encephalitis, meningitis,
and myelitis, in people with ZVI.83 Shortly afterward, scientists
in the U.S. and Venezuela described the rst case of sensory
polyneuropathy associated with acute ZVI.84
In September, American researchers found that Zika can
infect cranial neural crest cells (which give rise to bones and
cartilage in the skull) and can cause them to secrete signaling
molecules that alter their function. In the lab, the increased
levels of these molecules were enough to induce the premature
differentiation, migration, and death of human neural progenitor
cells. This may help explain why infants born to Zika-infected
mothers are at risk of microcephaly and disproportionate
facial features.85,86
Zika and Pregnancy
There is no evidence to suggest that pregnant women are
more susceptible to ZVI or experience more-severe disease
compared with women who are not pregnant, according to
the CDC.87 Infection during pregnancy, however, can result
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 Zika in America: The Year in Review
in congenital microcephaly and other severe brain defects in
the fetus.88 ZVI has also been implicated in adverse pregnancy
outcomes, including miscarriage and stillbirth.88,89
In April, researchers in Brazil reported placental inamma-
tion and the presence of Zika virus in Hofbauer cells (human
placental macrophages) in tissue samples obtained from preg-
nant women infected with the virus. The ndings suggested
that a damaged placental barrier may facilitate fetal infection
with Zika.90 Yale University investigators later reported similar
observations and theorized that Hofbauer cells, because of
their migratory characteristics, may help disseminate Zika
virus to the fetal brain.91
Because of the potential risks of ZVI during pregnancy, the
CDC has stated that its top priority in combating the virus is to
protect pregnant women and their fetuses.87 Still, the agency
acknowledges that much is not yet known about ZVI in this
setting. Uncertainties include:87,92
The incidence of ZVI among pregnant women in areas of
Zika virus transmission
The rate of vertical transmission of the virus
The rate with which infected fetuses manifest complica-
tions, such as microcephaly or death
How often the Zika virus can pass from a pregnant woman
to her fetus during pregnancy or around the time of birth
Other potential health problems that ZVI may cause during
pregnancy
Whether pregnant women are more likely to develop Zika
symptoms compared with the general population
Whether pregnant women are more likely to develop GBS.
The CDCs latest guidance recommends that all pregnant
women in the U.S. and its territories should be assessed for
possible exposure to Zika virus at each prenatal care visit. The
agency also recommends that pregnant women not travel to an
area with active Zika virus transmission. In addition, pregnant
women with a sex partner who has traveled to or lives in an
area with active Zika virus transmission should use condoms
or other barrier methods to prevent ZVI or should abstain from
sex for the duration of the pregnancy.87
In May, the CDC reported that 279 pregnant women were
infected with Zika virus in the U.S.93 By October 11, that number
had more than tripled to 899.94
Microcephaly and Other Birth Defects
Microcephaly is a rare neurological disorder in which an
infants head circumference is much smaller than normal
for the childs age and gender.9597 The deformity is typically
caused by genetic abnormalities, the mothers exposure to toxic
substances during pregnancy, or certain viral infections during
pregnancy, such as rubella or cytomegalovirus.97 Brazilian
ofcials noticed an apparent link between the birth of micro-
cephalic infants and the presence of Zika virus in pregnant
women early in that countrys Zika crisis,98100 but world health
experts were initially hesitant to conrm the connection.101103
In January, the U.S. experienced its rst microcephalic birth.
The case involved a Zika-infected woman in Hawaii who had
lived in Brazil early in her pregnancy.104 The following month,
a researcher at the Yale School of Public Health reported that,
782 P&T December 2016 Vol. 41 No. 12
in addition to microcephaly, ZVI may cause hydrops fetalis
(the abnormal accumulation of uid in fetal compartments),
hydranencephaly (the almost complete loss of brain tissue), and
stillbirth.105,106 By April, the data were sufciently compelling
to prompt the CDC to announce that ZVI in pregnant women
was denitely a cause of microcephaly and other severe brain
abnormalities in fetuses.79
In June, the CDC estimated that the potential risk for micro-
cephaly following ZVI ranged from 1% to 13%. The agency based
its estimate on statistics from a 2013 Zika outbreak in French
Polynesia and on ongoing reports of virus-related birth defects
in Brazils Bahia state. More importantly, the CDC disclosed
nine U.S. cases of ZVI-associated microcephaly. All involved
women who contracted ZVI outside the U.S. in areas with
active Zika outbreaks or were infected through unprotected
sex with an infected partner.107
Meanwhile, progress was being made on the research front.
Scientists at the University of Southern California discovered
two Zika proteins responsible for microcephaly, an important
step toward prevention. The Zika virus contains 10 proteins, but
only nonstructural protein 4A (NS4A) and NS4B matter when
it comes to microcephaly, according to the research. These
proteins stunt brain development and increase autophagy so
that the virus can spread. When they hijacked fetal neural stem
cells, the size of brain organoids was, on average, halved.108
In another August report, researchers at Harvard Medical
School and Beth Israel Deaconess Hospital in Boston described
the devastating effects that Zika has on the developing fetal
brain. The investigators used radiographs to document brain
abnormalities associated with congenital ZVI in 45 cases
from Brazil. The most common trait, observed in all subjects,
was a visible reduction in brain-tissue volume. All subjects
also showed calcication in several regions of the brain and
abnormal development of the cortex. Further, the radiolo-
gists saw enlarged uid-lled ventricles in 43 of the babies.109
Finally, in August, the CDC reported on research conducted
in Brazil that found sensorineuronal hearing loss in ve of 70
(7.1%) infants with ZVI-related microcephaly.110
That same month, ofcials in Harris County, Texas, reported
the rst known infant death linked to ZVI in the U.S. The girl
had several Zika-related birth defects, including microcephaly.
Her mother likely contracted the virus in Latin America,
ofcials said.111
Zika and Guillain-Barr Syndrome
Zikas neurotropic characteristics and high afnity for
brain tissue may also manifest as GBS in infected adults.87,112
GBS is a rare disease of the nervous system that affected an
estimated 3,000 to 6,000 people a year in the U.S. before Zika
arrived. In GBS patients, damaged nerve cells lead to muscle
weakness and sometimes paralysis. In severe cases, weak-
ness or paralysis can affect the muscles that control breath-
ing. Symptoms can last weeks or months, and most people
fully recover.87,113 Approximately 30% of those with GBS have
residual weakness after three years, while approximately 3%
may experience a relapse of muscle weakness and tingling
sensations many years after the initial attack.114 Before Zika,
GBS was linked to dengue and chikungunya infections, among
other causes.115,116
 Zika in America: The Year in Review
In March, U.S. health ofcials notied the WHO of Americas
rst two cases of Zika-related GBS. The rst case was an
elderly man who had recently traveled to Central America.
He developed an acute febrile illness shortly after returning
to the U.S. and was hospitalized in January with progressive
weakness of the extremities and diminished reexes. The
patient tested positive for ZVI by polymerase chain reaction
(PCR). He was about to be discharged when he died suddenly
from a ruptured subarachnoid aneurysm.117
The second case was an adult male resident of Haiti who
experienced the acute onset of facial weakness, difculty
swallowing, and numbness of the ngers in early January.
Days later, he travelled to the U.S. for additional medical care.
His cerebrospinal uid had elevated protein and normal white
blood cells. A physical examination showed mild weakness and
diminished reexes. The patient tested positive for ZVI by serol-
ogy. He improved after intravenous immunoglobulin therapy
(the standard treatment for GBS) and was discharged.117
In a surveillance study conducted by the Puerto Rico
Department of Health with CDC assistance, 56 suspected
cases of GBS with neurological signs were identied between
January 1 and July 31, 2016. Thirty-four (61%) of those individu-
als had evidence of ZVI or avivirus infection. The subjects
mean age was 55 years (range, 2188 years). All were treated
with intravenous immunoglobulin G.118
At the end of August, researchers at the Pan American Health
Organization compared the rates of GBS before and after Zika
arrived in seven countries and announced a strong association
between the virus and the illness. In a letter published in the
New England Journal of Medicine, Marcos Espinal, MD, PhD,
MPH, and his colleagues analyzed the rates of GBS and ZVI in
Bahia, Brazil, Colombia, the Dominican Republic, El Salvador,
Honduras, Suriname, and Venezuela. They looked at 164,237
conrmed and suspected ZVI cases and 1,474 GBS cases that
occurred between April 1, 2015, and March 31, 2016.119 The
investigators found a close association between increases in
Zika cases and increases in GBS. As Zika infections waned in
a country, they found, the incidence of GBS waned as well.119
MODES OF TRANSMISSION
Zika virus is transmitted primarily by the bite of infected
Ae. aegypti and Ae. albopictus mosquitoes, which also spread
dengue and chikungunya viruses.120 But as more is learned
about ZVI, other important modes of transmission have come
to light.
Sexual Transmission
In September 2008, an American scientist participating in
a mosquito-sampling project in Senegal became ill with ZVI
upon his return home to Colorado and infected his wifethe
rst documented case of sexual transmission of the virus in the
U.S. Both the man and his wife noticed signs of hematospermia
(redbrown uid in the mans ejaculate).121
Five years later, a patient recovering from ZVI on Tahiti
Island in French Polynesia sought treatment for bloody sperm.
Zika virus was isolated from his semen.122
Next, in February 2016, Texas reported a case of sexually
transmitted ZVI. The patient had not recently travelled outside
the U.S., but developed symptoms after sexual contact with
a traveler. This was the rst U.S. Zika case in someone who
had not traveled abroad, and the third indication that the virus
could be sexually transmitted.123,124
The CDC immediately posted interim guidelines for pre-
venting the sexual transmission of ZVI.123 In its most recent
recommendations (updated on September 30), the agency
advises that male and female condoms be used from start to
nish, every time, during vaginal, anal, and oral sex, and the
sharing of sex toys. In addition, dental dams (latex or polyure-
thane sheets) may also be used for certain types of oral sex.
According to the CDC, testing blood, semen, vaginal uids, or
urine is not recommended to determine how likely a person is
to pass Zika virus through sex. Because Zika virus can remain
in semen longer than blood, someone might have a negative
blood test but a positive semen test.126
Another important discovery took place in February, when
a man in England was found to have viable Zika virus in his
semen two months after he was infected, suggesting that the
virus may linger in semen long after ZVI symptoms fade.127
By that time, the CDC was investigating 14 new reports of
possible sexual transmission of Zika virus in the U.S. The
agency announced that sexual transmission of the virus might
be more likely than previously thought.128
In April, the CDC revealed that the case of sexual transmis-
sion in Texas involved two men, adding another dimension to
the Zika threat: The virus can be spread through unprotected
anal sex.129
More surprising news came out of New York City in
July: Health ofcials reported the rst documented case of
the sexual transmission of Zika virus from a woman to her
male sex partner. Until then, all reported cases of sexually
transmitted ZVI had been spread from men to their part-
ners.130,131 The following month, an asymptomatic man in
Maryland infected his female partner with Zika virus after
returning from the Dominican Republic, demonstrating that
the virus may be spread from a man even if he has no symp-
toms of ZVI.132 In August, Yale University investigators found
that the virus could persist in the vagina of mice for days
after infectionsuggesting that Zika may replicate
more readily in the female reproductive tract than at other
sites of infection.133
Blood Products
In February, the CDC recommended the deferral of
individuals from donating blood if they had been to areas
with active Zika virus transmission; if they potentially had
been exposed to the virus; or if they had conrmed ZVI.134
The agency revised its guidelines in August, advising that all
donated blood and blood components in the U.S. should be
tested for Zika.135
HHS announced that it was funding two pathogen-
reduction technologies to help reduce the risk of Zika
virus and other infections from being transmitted through
the blood supply. The Biomedical Advanced Research and
Development Authority, part of HHS, provided initial funding
of $30.8 million to Cerus Corporation and $17.5 million to the
U.S. division of Japans Terumo Corporation. The Food and
Drug Administration (FDA) has approved Cerus Intercept
technology to reduce pathogens in platelets and plasma. The
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 Zika in America: The Year in Review
company is conducting a trial to show that its technology can
also reduce pathogens in red blood cells. Terumo is developing
its own Mirasol system to conrm that it can reduce the risk
of infection through platelets.136
Human Cell and Tissue Products
In March, the FDA issued guidelines aimed at preventing
Zika virus transmission via human cells, tissues, and cellular
and tissue-based products (HCT/Ps). The agency noted that
there was a potential risk that Zika virus could be transmitted
by HCT/Ps used as part of a medical, surgical, or reproductive
procedure. HCT/Ps include products such as corneas, bone,
skin, heart valves, hematopoietic stem/progenitor cells, gesta-
tional tissues (such as amniotic membrane), and reproductive
tissues (such as semen and oocytes).137
According to the FDAs guidelines, living donors should be
considered ineligible if they were diagnosed with ZVI, were in
an area with active Zika virus transmission, or had sex with a
male with either of those risk factors within the past six months.
Donors of umbilical cord blood, placenta, or other gestational
tissues should be considered ineligible if they have had any of
these risk factors at any point during their pregnancy. Deceased
donors should be considered ineligible if they were diagnosed
with ZVI in the past six months.137
A Zika Mystery
Before leaving the subject of Zika virus transmission, mention
should be made of a peculiar case that occurred in Utah in
June. According to the CDC, an elderly man who died after a
bout with Zika may have infected a relative who cared for him
during his illness. The caregiver had not traveled to an area
with active Zika transmission nor had sex with a person who
had recently returned from such a place. Moreover, health
ofcials were not aware of mosquitoes in Utah that are capable
of transmitting the virus. Experts outside the CDC said the
most likely possibility was that the infected relative came into
contact with blood, urine, or other bodily uids while caring
for the man, but the infectious mechanism involved remains
a mystery. The relative recovered quickly.138,139
DIAGNOSTIC TESTS
Zika virus may be detected in infected individuals either
directly (by identifying virus RNA in tissue or bodily uids) or
indirectly (by testing for virus-specic antibodies).140 The body
uids that can be tested include whole blood, serum, EDTA
(ethylenediaminetetraacetic acid) plasma, saliva, and urine.141
The results of serological assays may be confounded by cross-
reactivity between virus genus members or by geographical
overlap with other pathogens. In those situations, pan-genus
and syndromic serum panel tests and antigens are needed and
conrmatory techniques are required, such as enzyme-linked
immunosorbent assay (ELISA), immunouorescence assay,
and virus-neutralizing testing.141
No commercially available tests for ZVI detection have been
approved or cleared by the FDA. However, the agency has
permitted applications for emergency use authorizations
(EUAs). The Zika IgM [Immunoglobulin M] Antibody Capture
Enzyme-Linked Immunosorbent Assay (Zika MAC-ELISA),
developed by the CDC, was the rst diagnostic test approved for
784 P&T December 2016 Vol. 41 No. 12
use in the U.S. for the detection of Zika virus on an emergency
basis.142,143 The test detects Zika virus indirectly by identifying
Zika-specic IgM in blood or cerebrospinal uid.144 The assay
procedure is complex, however, and the results can be difcult to
interpret, making the test unsuitable for rapid Zika diagnosis.140
In February, two Houston hospitals said they had developed
the rst U.S. hospital-based, rapid RNA test for Zika virus. The
test, created by pathologists and clinical laboratory scientists
at Texas Childrens Hospital and Houston Methodist Hospital,
was customized to each hospitals diagnostic laboratory and
provided results within hours. Assays could be performed on
blood, amniotic uid, urine, or spinal uid. The hospitals said
they were able to distinguish ZVI from dengue, West Nile, or
chikungunya infections.145
By early March, the WHO estimated that more than 30 in vitro
diagnostic assays for Zika were at various stages of development.146
Meanwhile, the FDA pressed ahead with EUAs, granting the
designation to a total of 12 Zika diagnostic tests.144 The CDC
followed its IgM assay with a test based on real-time reverse
transcriptase polymerase chain reaction (rRT-PCR), using
dual-labeled probes to detect viral RNA.140 The test, Trioplex
rRT-PCR, was awarded an EUA on March 17. It directly identi-
es ZVI by detecting Zika RNA in human sera, cerebrospinal
uid, urine, and amniotic uid.144 Two other RT-PCR assays
Zika Virus RNA Qualitative rRT-PCR (Quest Diagnostics) and
RealStar Zika Virus RT-PCR Kit (Altona Diagnostics)won
emergency approval in April and May, respectively.144 These
and other Zika assays are listed in Table 1.144
RT-PCR tests that use urine to detect ZVI have an advantage
over other assay systems in that Zika virus RNA is unlikely
to be detected in serum after the rst week of illness in most
patients.147,148 Moreover, data have shown that Zika virus stays
at higher levels or lasts longer in urine than in blood.149,150
In the spring, internal strife rocked the CDC when one of its
leading Zika experts, Robert Lanciotti, PhD, raised concerns
about the agencys decision to recommend the Trioplex test.
Dr. Lanciotti was chief of the CDC lab responsible for devel-
oping tests to diagnose viral diseases that are transmitted
by mosquitoes, ticks, and eas. According to his complaint,
Trioplex was substantially less effective than an assay he
had developed in 2007, called Singleplex, and missed nearly
40% of Zika infections. Dr. Lanciotti also said the agency with-
held information about testing differences from state and
local public health laboratories.151 In May, the CDC demoted
Dr. Lanciotti, but he was reinstated months later after ling
a whistleblower retaliation claim.151 His complaint prompted
a CDC internal investigation. In its report, the agency said it
had made improvements to boost the sensitivity of the Trioplex
test. The internal investigation also found that the agency had
acted reasonably when it withheld conicting test data from
state public health labs.151
THERAPEUTIC DRUGS
No approved treatments are available for ZVI,152 and the FDA
is unaware of any Zika therapies in advanced development.153
In searching for potential Zika therapeutics, scientists have
two options: to repurpose existing antiviral compounds or to
discover potential Zika inhibitors in compound libraries and
develop them for clinical use.154
 Zika in America: The Year in Review

Table 1 Zika Virus Tests Approved by the FDA for Temporary Emergency Use144
EUA Date Test Developer/ Description
(2016) Manufacturer
February 26 Zika MAC-ELISA CDC For detection of Zika virus-specic IgM in human sera or cerebrospinal
uid submitted with patient-matched serum specimen
March 17 Trioplex Real-Time RT-PCR CDC For detection and differentiation of RNA from Zika virus, dengue virus, and
Assay chikungunya virus in human sera or cerebrospinal uid collected with
patient-matched serum specimen; for detection of Zika virus RNA in urine
and amniotic uid, each collected with patient-matched serum specimen
April 28 Zika Virus RNA Qualitative Quest Diagnostics For detection of Zika virus RNA in human serum specimens
Real-Time RT-PCR Test
May 13 RealStar Zika Virus RT-PCR Altona Diagnostics For detection of Zika virus RNA in serum or urine collected with
Kit patient-matched serum specimen
June 17 Aptima Zika Virus Assay Hologic, Inc. For detection of Zika virus RNA in human serum and plasma specimens
July 19 Zika Virus Real-Time Viracor-IBT For detection of Zika virus RNA in human serum, plasma, or urine collected
RT-PCR Test Laboratories with patient-matched serum or plasma specimen
July 29 Versant Zika RNA 1.0 Assay Siemens Healthcare For detection of Zika virus RNA in human serum, EDTA plasma, and urine
(kPCR) Kit Diagnostics collected with patient-matched serum or plasma specimen
August 4 xMAP MultiFLEX Zika RNA Luminex For detection of Zika virus RNA in human serum, plasma, and urine
Assay Corporation collected with patient-matched serum or plasma specimen
August 17 ZIKV Detect IgM Capture InBios International For detection of Zika virus IgM antibodies in human serum
ELISA
August 26 LightMix Zika Real-Time Roche Molecular For detection of Zika virus RNA in human serum and EDTA plasma; Zika virus
RT-PCR Test Systems RNA generally detectable approximately seven days after onset of symptoms
September 23 Sentosa SA ZIKV RT-PCR Vela Diagnostics For detection of Zika virus in human serum, EDTA plasma, and urine
Test collected with patient-matched serum or EDTA plasma specimen
September 28 Zika Virus Detection by Arup Laboratories For detection of Zika virus in human serum, EDTA plasma, and urine
RT-PCR Test collected with patient-matched serum or EDTA plasma specimen
CDC = Centers for Disease Control and Prevention; EDTA = ethylenediaminetetraacetic acid; ELISA = enzyme-linked immunosorbent assay; EUA = emergency
use authorization; FDA = Food and Drug Administration; IgM = immunoglobulin M; kPCR = kappa polymerase chain reaction; MAC-ELISA = IgM antibody capture
enzyme-linked immunosorbent assay; RT-PCR = reverse transcriptase polymerase chain reaction; ZIKV = Zika virus.

NIAID used its existing antiviral drug-screening program
for other aviviruses, such as dengue, West Nile, yellow fever,
and Japanese encephalitis, to create a test that could examine
drug compounds for potential antiviral activity against Zika.
By late May, more than 60 potential anti-Zika compounds had
been tested; 15 of them were found to have moderate to high
activity and are undergoing further evaluation. The agency
hopes to develop a broad-spectrum antiviral drug that could
treat a variety of aviviruses, including Zika.155
NIAID is also working to screen a library of approved drugs
for potential activity against Zika. In addition, NIAID-supported
scientists have developed a rodent model for ZVI to evalu-
ate promising antiviral compounds. Further, NIAID is sup-
porting efforts to develop monoclonal antibodies capable of
neutralizing Zika virus.155
In August, American and Chinese scientists collaborated
on a drug-repurposing screen of more than 6,000 com-
pounds, including approved drugs and clinical trial candi-
dates. Emricasan, a pan-caspase inhibitor, was identied as
the most potent anticell-death compound. However, while
emricasan showed neuroprotective activity, it did not sup-
press Zika virus replication. The investigators also found
that 10 structurally unrelated inhibitors of cyclin-dependent
kinases inhibited Zika replication, as did the FDA-approved
anthelmintic drug niclosamide (Nicloside, Bayer Schering
Pharma). The investigators suggested that a combination
product with the ability to both inhibit Zika replication and
protect neural cells from damage might offer the best chance
at controlling the virus.156
If viable Zika inhibitors are found, the next step will be to
determine whether the concentrations required for clinical
efcacy can be achieved in humans.154
Should Zika therapeutics be successfully developed, their
use will likely be limited to specic patient subgroups, such as
congenitally infected infants and long-term carriers. Testing
therapeutic products in the primary clinical targetpregnant
womenwill require extreme caution. Prophylaxis with small-
molecule drugs or passive immunization with monoclonal
antibodies may provide a more viable approach.146,154
NIAID researchers exposed another impediment to Zika
therapeutics when they reported that the virus may be able
to hide in organs protected from the immune system, such
as the testes, eyes, placenta, and fetal brain. These sites are
safeguarded from antibodies to prevent the immune system

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 Zika in America: The Year in Review
from attacking vital tissues. But if a virus enters these protected In July, the National Institutes of Health (NIH) announced
sites, it is much harder to ght them offa serious challenge that vaccination against a single strain of Zika virus should be
for potential Zika treatments.157 sufcient to protect against genetically diverse strains of the
virusheartening news for vaccine developers. Scientists took
VACCINES serum samples from people infected by Zika virus strains circu-
Numerous organizations are involved in developing Zika lating in South America and mixed them with multiple strains
vaccines, but most products are in early preclinical studies, indi- of the virus in the laboratory to see how well serum antibodies
cating that it will be years before they are eligible for marketing neutralized the virus. The results showed that antibodies elic-
approval.140,158 Dr. Fauci, head of NIAID, remarked that the ited after infection with Zika virus strains of Asian lineage were
earliest well have a vaccine, at best if everything works, will be able to inhibit both Asian lineage and African lineage strains.
some time in 2018.159 The researchers conducted similar experiments using serum
According to WHO, females of child-bearing age (including samples from mice and found that sera from mice infected with
preadolescent and adolescent girls 9 years of age or older) and either Asian or African Zika virus strains were equally effective
males of reproductive age (9 years of age or older) comprise in neutralizing virus strains from either lineage.165
the target population for Zika vaccines. In emergency situations, In early August, the NIH initiated a phase 1 study of NIAIDs
vaccination would be prioritized to women of child-bearing DNA-based vaccine. At least 80 healthy volunteers ages
age, as this group is considered at high risk because of the 18 to 35 years at three U.S. sites were expected to participate.
causal relationships between prenatal ZVI and microcephaly, Like Inovios vaccine, the NIAID vaccine includes a plasmid that
other nervous-system malformations, and pregnancy-related scientists engineered to contain genes that code for proteins
complications.160 Mass vaccination of women of child-bearing of the Zika virus. When the vaccine is injected into the arm
age may also help prevent sexual transmission of Zika virus muscle, cells read the genes and make Zika virus proteins,
from infected men.161 which self-assemble into virus-like particles. The body mounts
The research community assumes that Zika vaccines can an immune response to these particles, including neutralizing
be developed with the same technologies that have been used antibodies and T cells. Initial safety and immunogenicity data
to create other avivirus vaccines (i.e., yellow fever, dengue, are expected by January 2017. If the data are favorable, NIAID
Japanese encephalitis, and tick-borne encephalitis).146 NIAID, plans to initiate a phase 2 study in Zika-endemic countries in
for example, is working on a DNA-based vaccine that uses a early 2017.166
strategy similar to that of an investigational
avivirus vaccine for West Nile virus infec- Table 2 Examples of Zika Virus Vaccines Under
tion. The West Nile vaccine induced an Investigation in the United States146,167174
immune response in a phase 1 study.158 In
Developer Technology
addition, NIAID is developing a live attenu-
ated investigational Zika vaccine building CaroGen Corp. VLV-based nanoparticle
on a similar approach for dengue virus. The CDC VLP expressed by DNA plasmid; live recombinant adenovirus
dengue vaccine candidate is being evaluated
GeoVax Labs, Inc. MVA-VLP technology elicits antibodies and T cells
in a phase 3 trial in Brazil.158 NIAID is also
investigating a whole-particle inactivated Hawaii Biotech Recombinant proteins produced from insect cell line, plus
Zika vaccine based on a similar approach Alhydrogel or proprietary adjuvant
used by the Walter Reed Army Institute of Inovio/GeneOne Life Science DNA (electroporation)
Research to develop vaccines against the
Japanese encephalitis and dengue viruses.158 Kansas State University DNA
In June, Inovio Pharmaceuticals and NewLink Genetics Corp. Puried inactivated virus
GeneOne Life Science, Inc., were the rst to
NIH Zika-targeted mutation, live attenuated (longer-term); DNA; live
initiate a human Zika vaccine trial. The open-
VSV recombinant
label, dose-ranging study is evaluating the
safety, tolerability, and immunogenicity of Novavax E protein (nanoparticles)
GLS-5700 in 40 healthy adults 18 to 65 years Pharos Biologicals, Inc. Nanosphere delivery
of age. GLS-5700 contains a DNA plasmid
Protein Sciences Corp. Recombinant variations of Zika virus E protein
encoding for premembrane and envelope
proteins of the Zika virus. The vaccine is Replikins, Ltd. Synthetic replilink peptides
injected intradermally with a proprietary Vaxart, Inc. Recombinant Zika vaccine in room temperature-stable tablets
DNA delivery device, which emits a brief
low-voltage electronic pulse that induces VaxInnate Corp. TLR technology; vaccine antigens are genetically fused to
cell membranes to open, making them more bacterial protein agellin
receptive, theoretically, to accepting the Xenetic Biosciences Combined Zika/dengue vaccine
vaccines genetic material. Inovio expects
CDC = Centers for Disease Control and Prevention; MVA = modied vacinnia Ankara;
to report preliminary results before the end
NIH = National Institutes of Health; TLR = toll-like receptor; VLP = virus-like particle;
of 2016. The studys estimated completion
VLV = virus-like vesicle; VSV = vesicular stomatitis virus.
date is November 2017.162164

786 P&T December 2016 Vol. 41 No. 12

 Zika in America: The Year in Review
Inovio resurfaced in the vaccine race in late August with its
second early-stage trial of GLS-5700. The vaccine was admin-
istered to 160 healthy adult volunteers in Puerto Rico, where
a Zika emergency had been declared. The studys primary
objective is to evaluate the safety, tolerability, and immuno-
genicity of GLS-5700 administered with Cellectra-3P, Inovios
proprietary intradermal DNA vaccine delivery device. The
study is also looking at differences in Zika infection rates in
participants given either vaccine or placebo.162
Table 2 lists other examples of potential Zika vaccines under
investigation in the U.S.146,167174 But developing a vaccine wont
be easy. Some key hurdles include:1,175,176
Scientists know even less about Zika than they did about
the Ebola virus.
There is no simple way to assess the right immune
response for Zika; an effective vaccine must strike a
delicate balance between provoking a response that is
strong enough to stop the virus, but not so strong that it
makes the patient ill.
In most cases, ZVI is so mild that individuals may be
unaware that they carry the virus, and they are unlikely
to see the need for immunization.
To protect the developing fetus, protective immunity
must be achieved before the time of peak vulnerability
probably during the rst and early second trimesters.
Traditionally, vaccine safety and immunogenicity are
rmly established in nonpregnant adults before the
vaccination of pregnant women is considered. Pregnant
women, however, comprise the primary target for Zika
vaccines, making vaccine testing problematic.
Developing vaccines is resource-intensive; vaccines are
made from biologic agents that require stringent lot-to-lot
consistency and stability.
CONCLUSION
2016 will be remembered as the year that Zika came to
America. Is the U.S. technologically and nancially prepared to
beat the wiliest health foe since the human immunodeciency
virus? Or will we eventually see nearly 27,000 cases of locally
acquired infections, as in Puerto Rico,58 or nearly 5,000 cases
of Zika-associated microcephaly, as in Brazil?177 Congress
protracted squabble over Zika funding got things off to a rocky
start,6875 and federal cash infusions arent expected to reach
public health laboratories until early 2017.77 As this article
goes to press, cases of locally acquired ZVI remain restricted
to Florida, but Ae. aegypti and Ae. albopictus mosquitoesthe
vectors for Zika infectioninhabit roughly half of the conti-
nental U.S. No one can predict what the future holds, but its
safe to say that America, like most of the world, faces a difcult
and costly struggle over the coming years.
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Vol. 41 No. 12 December 2016 P&T 791
 Table 1: Myelofibrosis: Adverse Reactions Occurring in Patients on Jakafi in the Double-blind,
Placebo-controlled Study During Randomized Treatment
Jakafi Placebo
(N=155) (N=151)
BRIEF SUMMARY: For Full Prescribing Information, see package insert.
All Gradesa Grade 3 Grade 4 All Grades Grade 3 Grade 4
CONTRAINDICATIONS None.
Adverse Reactions (%) (%) (%) (%) (%) (%)
WARNINGS AND PRECAUTIONS Thrombocytopenia, Anemia and Neutropenia Treatment with
Jakafi can cause thrombocytopenia, anemia and neutropenia. [see Dosage and Administration (2.1) in Full Bruisingb 23 <1 0 15 0 0
Prescribing Information]. Manage thrombocytopenia by reducing the dose or temporarily interrupting Jakafi. Dizzinessc 18 <1 0 7 0 0
Platelet transfusions may be necessary [see Dosage and Administration (2.1.1) and Adverse Reactions (6.1) in
Full Prescribing Information]. Patients developing anemia may require blood transfusions and/or dose Headache 15 0 0 5 0 0
modifications of Jakafi. Severe neutropenia (ANC less than 0.5 X 109/L) was generally reversible by withholding Urinary Tract Infectionsd 9 0 0 5 <1 <1
Jakafi until recovery [see Adverse Reactions (6.1) in Full Prescribing Information]. Perform a pre-treatment Weight Gaine 7 <1 0 1 <1 0
complete blood count (CBC) and monitor CBCs every 2 to 4 weeks until doses are stabilized, and then as clinically
indicated. [see Dosage and Administration (2.1.1) and Adverse Reactions (6.1) in Full Prescribing Information]. Flatulence 5 0 0 <1 0 0
Risk of Infection Serious bacterial, mycobacterial, fungal and viral infections have occurred. Delay starting Herpes Zosterf 2 0 0 <1 0 0
therapy with Jakafi until active serious infections have resolved. Observe patients receiving Jakafi for signs and a
National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0
symptoms of infection and manage promptly. Tuberculosis Tuberculosis infection has been reported in patients b
includes contusion, ecchymosis, hematoma, injection site hematoma, periorbital hematoma, vessel puncture site
receiving Jakafi. Observe patients receiving Jakafi for signs and symptoms of active tuberculosis and manage hematoma, increased tendency to bruise, petechiae, purpura
c
includes dizziness, postural dizziness, vertigo, balance disorder, Menieres Disease, labyrinthitis
promptly. Prior to initiating Jakafi, patients should be evaluated for tuberculosis risk factors, and those at higher d
includes urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, kidney infection, pyuria, bacteria urine,
risk should be tested for latent infection. Risk factors include, but are not limited to, prior residence in or travel to bacteria urine identified, nitrite urine present
e
countries with a high prevalence of tuberculosis, close contact with a person with active tuberculosis, and a history includes weight increased, abnormal weight gain
f
of active or latent tuberculosis where an adequate course of treatment cannot be confirmed. For patients with includes herpes zoster and post-herpetic neuralgia
evidence of active or latent tuberculosis, consult a physician with expertise in the treatment of tuberculosis before Description of Selected Adverse Drug Reactions Anemia In the two Phase 3 clinical studies, median
starting Jakafi. The decision to continue Jakafi during treatment of active tuberculosis should be based on the time to onset of first CTCAE Grade 2 or higher anemia was approximately 6 weeks. One patient (<1%)
overall risk-benefit determination. PML Progressive multifocal leukoencephalopathy (PML) has occurred with discontinued treatment because of anemia. In patients receiving Jakafi, mean decreases in hemoglobin
ruxolitinib treatment for myelofibrosis. If PML is suspected, stop Jakafi and evaluate. Herpes Zoster Advise reached a nadir of approximately 1.5 to 2.0 g/dL below baseline after 8 to 12 weeks of therapy and then
patients about early signs and symptoms of herpes zoster and to seek treatment as early as possible if suspected gradually recovered to reach a new steady state that was approximately 1.0 g/dL below baseline. This pattern
[see Adverse Reactions (6.1) in Full Prescribing Information]. Hepatitis B Hepatitis B viral load (HBV-DNA titer) was observed in patients regardless of whether they had received transfusions during therapy. In the
increases, with or without associated elevations in alanine aminotransferase and aspartate aminotransferase, randomized, placebo-controlled study, 60% of patients treated with Jakafi and 38% of patients receiving
have been reported in patients with chronic HBV infections taking Jakafi. The effect of Jakafi on viral replication in placebo received red blood cell transfusions during randomized treatment. Among transfused patients, the
patients with chronic HBV infection is unknown. Patients with chronic HBV infection should be treated and median number of units transfused per month was 1.2 in patients treated with Jakafi and 1.7 in placebo treated
monitored according to clinical guidelines. Symptom Exacerbation Following Interruption or patients. Thrombocytopenia In the two Phase 3 clinical studies, in patients who developed Grade 3 or 4
Discontinuation of Treatment with Jakafi Following discontinuation of Jakafi, symptoms from thrombocytopenia, the median time to onset was approximately 8 weeks. Thrombocytopenia was generally
myeloproliferative neoplasms may return to pretreatment levels over a period of approximately one week. Some reversible with dose reduction or dose interruption. The median time to recovery of platelet counts above 50 X
patients with myelofibrosis have experienced one or more of the following adverse events after discontinuing 109/L was 14 days. Platelet transfusions were administered to 5% of patients receiving Jakafi and to 4% of
Jakafi: fever, respiratory distress, hypotension, DIC, or multi-organ failure. If one or more of these occur after patients receiving control regimens. Discontinuation of treatment because of thrombocytopenia occurred in
discontinuation of, or while tapering the dose of Jakafi, evaluate for and treat any intercurrent illness and consider <1% of patients receiving Jakafi and <1% of patients receiving control regimens. Patients with a platelet count
restarting or increasing the dose of Jakafi. Instruct patients not to interrupt or discontinue Jakafi therapy without of 100 X 109/L to 200 X 109/L before starting Jakafi had a higher frequency of Grade 3 or 4 thrombocytopenia
consulting their physician. When discontinuing or interrupting therapy with Jakafi for reasons other than compared to patients with a platelet count greater than 200 X 109/L (17% versus 7%). Neutropenia In the two
thrombocytopenia or neutropenia [see Dosage and Administration (2.5) in Full Prescribing Information], consider Phase 3 clinical studies, 1% of patients reduced or stopped Jakafi because of neutropenia. Table 2 provides the
tapering the dose of Jakafi gradually rather than discontinuing abruptly. Non-Melanoma Skin Cancer frequency and severity of clinical hematology abnormalities reported for patients receiving treatment with Jakafi
Non-melanoma skin cancers including basal cell, squamous cell, and Merkel cell carcinoma have occurred in or placebo in the placebo-controlled study.
patients treated with Jakafi. Perform periodic skin examinations. Lipid Elevations Treatment with Jakafi has
been associated with increases in lipid parameters including total cholesterol, low-density lipoprotein (LDL) Table 2: Myelofibrosis: Worst Hematology Laboratory Abnormalities in the Placebo-Controlled Studya
cholesterol, and triglycerides. The effect of these lipid parameter elevations on cardiovascular morbidity and Jakafi Placebo
mortality has not been determined in patients treated with Jakafi. Assess lipid parameters approximately 8-12 (N=155) (N=151)
weeks following initiation of Jakafi therapy. Monitor and treat according to clinical guidelines for the management
of hyperlipidemia. Laboratory All Gradesb Grade 3 Grade 4 All Grades Grade 3 Grade 4
ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other Parameter (%) (%) (%) (%) (%) (%)
sections of the labeling: Thrombocytopenia, Anemia and Neutropenia [see Warnings and Precautions (5.1) in Thrombocytopenia 70 9 4 31 1 0
Full Prescribing Information] Risk of Infection [see Warnings and Precautions (5.2) in Full Prescribing Information] Anemia 96 34 11 87 16 3
Symptom Exacerbation Following Interruption or Discontinuation of Treatment with Jakafi [see Warnings and
Precautions (5.3) in Full Prescribing Information] Non-Melanoma Skin Cancer [see Warnings and Precautions Neutropenia 19 5 2 4 <1 1
(5.4) in Full Prescribing Information]. Because clinical trials are conducted under widely varying conditions, a
Presented values are worst Grade values regardless of baseline
b
adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0
trials of another drug and may not reflect the rates observed in practice. Clinical Trials Experience in Additional Data from the Placebo-controlled Study 25% of patients treated with Jakafi and 7% of
Myelofibrosis The safety of Jakafi was assessed in 617 patients in six clinical studies with a median duration patients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in alanine
of follow-up of 10.9 months, including 301 patients with myelofibrosis in two Phase 3 studies. In these two Phase transaminase (ALT). The incidence of greater than or equal to Grade 2 elevations was 2% for Jakafi with 1%
3 studies, patients had a median duration of exposure to Jakafi of 9.5 months (range 0.5 to 17 months), with 89% Grade 3 and no Grade 4 ALT elevations. 17% of patients treated with Jakafi and 6% of patients treated with
of patients treated for more than 6 months and 25% treated for more than 12 months. One hundred and eleven placebo developed newly occurring or worsening Grade 1 abnormalities in aspartate transaminase (AST). The
(111) patients started treatment at 15 mg twice daily and 190 patients started at 20 mg twice daily. In patients incidence of Grade 2 AST elevations was <1% for Jakafi with no Grade 3 or 4 AST elevations. 17% of patients
starting treatment with 15 mg twice daily (pretreatment platelet counts of 100 to 200 X 109/L) and 20 mg twice treated with Jakafi and <1% of patients treated with placebo developed newly occurring or worsening Grade 1
daily (pretreatment platelet counts greater than 200 X 109/L), 65% and 25% of patients, respectively, required a elevations in cholesterol. The incidence of Grade 2 cholesterol elevations was <1% for Jakafi with no Grade 3 or
dose reduction below the starting dose within the first 8 weeks of therapy. In a double-blind, randomized, placebo- 4 cholesterol elevations. Clinical Trial Experience in Polycythemia Vera In a randomized, open-label,
controlled study of Jakafi, among the 155 patients treated with Jakafi, the most frequent adverse drug reactions active-controlled study, 110 patients with polycythemia vera resistant to or intolerant of hydroxyurea received
were thrombocytopenia and anemia [see Table 2 ]. Thrombocytopenia, anemia and neutropenia are dose related Jakafi and 111 patients received best available therapy [see Clinical Studies (14.2) in Full Prescribing
effects. The three most frequent non-hematologic adverse reactions were bruising, dizziness and headache [see Information]. The most frequent adverse drug reaction was anemia. Table 3 presents the most frequent
Table 1]. Discontinuation for adverse events, regardless of causality, was observed in 11% of patients treated with non-hematologic treatment emergent adverse events occurring up to Week 32. Discontinuation for adverse
Jakafi and 11% of patients treated with placebo. Table 1 presents the most common adverse reactions occurring events, regardless of causality, was observed in 4% of patients treated with Jakafi.
in patients who received Jakafi in the double-blind, placebo-controlled study during randomized treatment.
Table 3: Polycythemia Vera: Treatment Emergent Adverse Events Occurring in 6% of Patients on with the strong CYP3A4 inducer rifampin in healthy subjects. No dose adjustment is recommended; however,
Jakafi in the Open-Label, Active-controlled Study up to Week 32 of Randomized Treatment monitor patients frequently and adjust the Jakafi dose based on safety and efficacy [see Pharmacokinetics
Jakafi Best Available Therapy (12.3) in Full Prescribing Information].
(N=110) (N=111) USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C: Risk Summary There are
no adequate and well-controlled studies of Jakafi in pregnant women. In embryofetal toxicity studies, treatment
Adverse Events All Gradesa (%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%) with ruxolitinib resulted in an increase in late resorptions and reduced fetal weights at maternally toxic doses.
Headache 16 <1 19 <1 Jakafi should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Abdominal Painb 15 <1 15 <1 Animal Data Ruxolitinib was administered orally to pregnant rats or rabbits during the period of organogenesis,
at doses of 15, 30 or 60 mg/kg/day in rats and 10, 30 or 60 mg/kg/day in rabbits. There was no evidence of
Diarrhea 15 0 7 <1 teratogenicity. However, decreases of approximately 9% in fetal weights were noted in rats at the highest and
Dizzinessc 15 0 13 0 maternally toxic dose of 60 mg/kg/day. This dose results in an exposure (AUC) that is approximately 2 times the
Fatigue 15 0 15 3 clinical exposure at the maximum recommended dose of 25 mg twice daily. In rabbits, lower fetal weights of
approximately 8% and increased late resorptions were noted at the highest and maternally toxic dose of
Pruritus 14 <1 23 4 60 mg/kg/day. This dose is approximately 7% the clinical exposure at the maximum recommended dose. In a
Dyspnead 13 3 4 0 pre- and post-natal development study in rats, pregnant animals were dosed with ruxolitinib from implantation
Muscle Spasms 12 <1 5 0 through lactation at doses up to 30 mg/kg/day. There were no drug-related adverse findings in pups for fertility
indices or for maternal or embryofetal survival, growth and development parameters at the highest dose
Nasopharyngitis 9 0 8 0 evaluated (34% the clinical exposure at the maximum recommended dose of 25 mg twice daily). Nursing
Constipation 8 0 3 0 Mothers It is not known whether ruxolitinib is excreted in human milk. Ruxolitinib and/or its metabolites were
excreted in the milk of lactating rats with a concentration that was 13-fold the maternal plasma. Because many
Cough 8 0 5 0
drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants
Edemae 8 0 7 0 from Jakafi, a decision should be made to discontinue nursing or to discontinue the drug, taking into account
Arthralgia 7 0 6 <1 the importance of the drug to the mother. Pediatric Use The safety and effectiveness of Jakafi in pediatric
patients have not been established. Geriatric Use Of the total number of patients with myelofibrosis in clinical
Asthenia 7 0 11 2
studies with Jakafi, 52% were 65years and older, while 15% were 75 years and older. No overall differences in
Epistaxis 6 0 3 0 safety or effectiveness of Jakafi were observed between these patients and younger patients. Renal
Herpes Zosterf 6 <1 0 0 Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in
healthy subjects [CrCl 72-164 mL/min (N=8)] and in subjects with mild [CrCl 53-83 mL/min (N=8)], moderate
Nausea 6 0 4 0
[CrCl 38-57 mL/min (N=8)], or severe renal impairment [CrCl 15-51 mL/min (N=8)]. Eight (8) additional
a
National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 subjects with end stage renal disease requiring hemodialysis were also enrolled. The pharmacokinetics of
b
includes abdominal pain, abdominal pain lower, and abdominal pain upper
c
includes dizziness and vertigo
ruxolitinib was similar in subjects with various degrees of renal impairment and in those with normal renal
d
includes dyspnea and dyspnea exertional function. However, plasma AUC values of ruxolitinib metabolites increased with increasing severity of renal
e
includes edema and peripheral edema impairment. This was most marked in the subjects with end stage renal disease requiring hemodialysis. The
f
includes herpes zoster and post-herpetic neuralgia change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in
Other clinically important treatment emergent adverse events observed in less than 6% of patients metabolite exposure. Ruxolitinib is not removed by dialysis; however, the removal of some active metabolites by
treated with Jakafi were: Weight gain, hypertension, and urinary tract infections. Clinically relevant dialysis cannot be ruled out. When administering Jakafi to patients with myelofibrosis and moderate
laboratory abnormalities are shown in Table 4. (CrCl 30-59 mL/min) or severe renal impairment (CrCl 15-29 mL/min) with a platelet count between 50 X
Table 4: Polycythemia Vera: Selected Laboratory Abnormalities in the Open-Label, Active-controlled 109/L and 150 X 109/L, a dose reduction is recommended. A dose reduction is also recommended for patients
Study up to Week 32 of Randomized Treatmenta with polycythemia vera and moderate (CrCl 30-59 mL/min) or severe renal impairment (CrCl 15-29 mL/min). In
all patients with end stage renal disease on dialysis, a dose reduction is recommended [see Dosage and
Jakafi Best Available Therapy
Administration (2.4) in Full Prescribing Information]. Hepatic Impairment The safety and pharmacokinetics
(N=110) (N=111)
of single dose Jakafi (25 mg) were evaluated in a study in healthy subjects (N=8) and in subjects with mild
Laboratory All Gradesb Grade 3 Grade 4 All Grades Grade 3 Grade 4 [Child-Pugh A (N=8)], moderate [Child-Pugh B (N=8)], or severe hepatic impairment [Child-Pugh C (N=8)]. The
Parameter (%) (%) (%) (%) (%) (%) mean AUC for ruxolitinib was increased by 87%, 28% and 65%, respectively, in patients with mild, moderate
and severe hepatic impairment compared to patients with normal hepatic function. The terminal elimination
Hematology
half-life was prolonged in patients with hepatic impairment compared to healthy controls (4.1-5.0 hours versus
Anemia 72 <1 <1 58 0 0 2.8 hours). The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the
Thrombocytopenia 27 5 <1 24 3 <1 corresponding increase in ruxolitinib exposure except in the severe (Child-Pugh C) hepatic impairment cohort
where the pharmacodynamic activity was more prolonged in some subjects than expected based on plasma
Neutropenia 3 0 <1 10 <1 0
concentrations of ruxolitinib. When administering Jakafi to patients with myelofibrosis and any degree of
Chemistry hepatic impairment and with a platelet count between 50 X 109/L and 150 X 109/L, a dose reduction is
Hypercholesterolemia 35 0 0 8 0 0 recommended. A dose reduction is also recommended for patients with polycythemia vera and hepatic
impairment [see Dosage and Administration (2.4) in Full Prescribing Information].
Elevated ALT 25 <1 0 16 0 0
OVERDOSAGE There is no known antidote for overdoses with Jakafi. Single doses up to 200 mg have been
Elevated AST 23 0 0 23 <1 0 given with acceptable acute tolerability. Higher than recommended repeat doses are associated with increased
Hypertriglyceridemia 15 0 0 13 0 0 myelosuppression including leukopenia, anemia and thrombocytopenia. Appropriate supportive treatment
a
Presented values are worst Grade values regardless of baseline
should be given. Hemodialysis is not expected to enhance the elimination of ruxolitinib.
b
National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0
DRUG INTERACTIONS Drugs That Inhibit or Induce Cytochrome P450 Enzymes Ruxolitinib
is metabolized by CYP3A4 and to a lesser extent by CYP2C9. CYP3A4 inhibitors: The Cmax and AUC of ruxolitinib
Jakafi is a registered trademark of Incyte. All rights reserved.
increased 33% and 91%, respectively following concomitant administration with the strong CYP3A4 inhibitor U.S. Patent Nos. 7598257; 8415362; 8722693; 8822481; 8829013; 9079912
ketoconazole in healthy subjects. Concomitant administration with mild or moderate CYP3A4 inhibitors did not 2011-2016 Incyte Corporation. All rights reserved.
result in an exposure change requiring intervention [see Pharmacokinetics (12.3) in Full Prescribing Revised: March 2016 RUX-1778
Information]. When administering Jakafi with strong CYP3A4 inhibitors, consider dose reduction [see Dosage
and Administration (2.3) in Full Prescribing Information]. Fluconazole: The AUC of ruxolitinib is predicted to
increase by approximately 100% to 300% following concomitant administration with the combined CYP3A4
and CYP2C9 inhibitor fluconazole at doses of 100 mg to 400 mg once daily, respectively [see Pharmacokinetics
(12.3) in Full Prescribing Information]. Avoid the concomitant use of Jakafi with fluconazole doses of greater
than 200 mg daily [see Dosage and Administration (2.3) in Full Prescribing Information]. CYP3A4 inducers:
The Cmax and AUC of ruxolitinib decreased 32% and 61%, respectively, following concomitant administration
 MEETING HIGHLIGHTS
European Society for Medical Oncology 2016 Congress
Walter Alexander
More than 20,000 researchers, clinicians, advocates,
and patients gathered in Copenhagen October 711 for
the European Society for Medical Oncology (ESMO)
annual congress. We review several key sessions
on emerging immunotherapies for melanoma and
nonsmall-cell lung cancer and on treatments for renal
cell carcinoma, ovarian cancer, and breast cancer.
Ipilimumab Versus Placebo After Complete
Resection of Stage 3 Melanoma: Final Overall
Survival Results From the EORTC 18071
Randomized, Double-Blind, Phase 3 Trial
Alexander M. Eggermont, MD, PhD, Institut Gustave
Roussy, Villejuif, France
Final overall survival results from the European Organization
for Research and Treatment of Cancer (EORTC) 18071 trial
of adjuvant ipilimumab versus placebo reveal a persist-
ing benet at 5.3 years of median follow-upa signicant
28% reduction in the relative risk of death. The trial
included 951 patients with completely resected stage 3
melanoma who had been randomized double-blind to
ipilimumab 10 mg/kg (induction and maintenance)
or placebo. Patients were treated for up to three years
or until disease progression, intolerable toxicity, or
withdrawal.
In a 2015 report, the trials primary endpoint of recurrence-
free survival (RFS) was 51.5% for ipilimumab compared
with 43.8% for placebo after a median of 2.3 years of
follow-up. Sixty more patients in the placebo arm relapsed
than in the ipilimumab arm (294 versus 234). The
three-year RFS rates were 46.5% for ipilimumab and
34.8% for placebo (hazard ratio [HR], 0.75; 95% condence
interval [CI], 0.640.9).
At an ESMO press brieng, Dr. Eggermont stated that
ve-year RFS was 41% in the ipilimumab arm and 30% in
the placebo arm (HR, 0.76; 95% CI, 0.640.89; P = 0.0008).
Overall survival was 65% for ipilimumab and 54% for placebo
(HR, 0.72; 95% CI, 0.580.88; P = 0.001).
Of course, this comes at a price in terms of side effects and
toxicity, Dr. Eggermont said. Immune-related events occurring
with ipilimumab fell into ve blocks: dermatological, gastro-
intestinal, endocrinological, hepatic, and neurological. The
most signicant grade 34 events that resulted when patients
stopped treatment were gastrointestinal in nature (16%), and
included colitis with fatal perforation in three patients and
hypophysitis in 4.4%. The toxicity-related death rate was 1.1%.
Overall, the immune-related grade 34 adverse event rates
were 43% for ipilimumab and 2% for placebo.
The author is a freelance writer living in New York City.
796 P&T December 2016 Vol. 41 No. 12
Ipilimumabs superiority was consistent across all survival
endpoints at ve years, and long-term safety results were also
consistent with those in the primary report.
Currently, adjuvant ipilimumab represents an important
treatment option for patients with high-risk stage 3 melanoma,
Dr. Eggermont concluded.
The results were published simultaneously in the New
England Journal of Medicine.1
Primary Analysis From OAK, a Randomized
Phase 3 Study Comparing Atezolizumab
With Docetaxel in 2L/3L NSCLC
Fabrice Barlesi, MD, Aix-Marseille University, Marseille,
France
Programmed death ligand 1 (PD-L1) inhibitors are a class
of checkpoint inhibitors that impede the binding of PD-L1 to
its receptors (PD-1 and B7.1), thereby restoring tumor-specic
T-cell immunity. OAK was the rst phase 3 study that compared
atezolizumab, a PD-L1 inhibitor, with standard chemotherapy
in patients with previously treated nonsmall-cell lung cancer
(NSCLC).
In OAK, 1,225 patients with NSCLC were randomized 1:1
to intravenous atezolizumab (1,200 mg every three weeks) or
docetaxel (75 mg/m2 every three weeks). Patients were strati-
ed according to PD-L1 status, number of prior chemotherapy
regimens, and histology. The primary endpoint was overall
survival. Dr. Barlesi presented preliminary results from the
rst 850 patients.
Overall survival after a minimum follow-up of 19 months was
improved by 27% in patients receiving atezolizumab versus
those receiving docetaxel (13.8 months versus 9.6 months,
respectively; P = 0.0003), regardless of PD-L1 expression levels.
Dr. Barlesi noted that in the patients within the highest tertile
of PD-L1 expression, overall survival was 59% greater than
among the same group receiving docetaxel (P < 0.0001). In
patients with no PD-L1 expression, the gain in overall survival
with atezolizumab was still a signicant 25%. Squamous versus
nonsquamous histology had no impact on overall survival
(hazard ratio, 0.73 for each).
Rates of treatment-related adverse events were lower in the
atezolizumab group than in the docetaxel group (64% versus
86%). The rates of treatment-related grade 34 events were also
lower in the atezolizumab group (15% versus 43%), even though
the median treatment duration was longer with atezolizumab
(3.4 months versus 2.1 months) and a higher percentage of
atezolizumab patients were treated for 12 months or more
(20.5% versus 2.4%). Treatment-related withdrawal rates were
8% and 19% in the atezolizumab and docetaxel groups,
respectively.
Martin Reck, MD, of the Grosshansdorf Lung Clinic in
Germany, who commented on the OAK study, pointed out
 MEETING HIGHLIGHTS: European Society for Medical Oncology 2016 Congress
that an improvement in overall survival, even in patients with
no PD-L1 expression, shows that we have a problem with
using PD-L1 negativity as an exclusion factor for treatment.
He suggested that PD-L1 is perhaps an imperfect surrogate
marker and that additional markers for the characterization
of patients who might benet from atezolizumab are needed.
Ceritinib Versus Chemotherapy in Patients
With Advanced Anaplastic Lymphoma Kinase-
Rearranged NonSmall-Cell Lung Cancer
Previously Treated With Chemotherapy and
Crizotinib: Results From the Conrmatory
Phase 3 ASCEND-5 Study
Giorgio Scagliotti, MD, University of Turin, Torino, Italy
Phase 2 ndings from the ASCEND-2 trial showed durable
responses in anaplastic lymphoma kinase-rearranged (ALK+)
nonsmall-cell lung cancer (NSCLC) patients receiving ceritinib
who had progressed on chemotherapy and crizotinib (including
those with brain metastases). These ndings were conrmed
in the phase 3 ASCEND-5 study conducted with patients previ-
ously treated with crizotinib. Ceritinib is a next-generation ALK
inhibitor with 20-fold greater potency than crizotinib.
Before the development of targeted therapies, chemotherapy
was the standard of care for most patients with advanced
NSCLC. While the ALK inhibitor crizotinib is effective in
patients with ALK+ NSCLC, most patients develop resistance
and progressive disease, Dr. Scagliotti said at an ESMO press
conference.
Investigators enrolled 231 patients at 99 sites in 20 countries
to the global, open-label ASCEND-5 study, randomizing them
to ceritinib 750 mg once daily or chemotherapy (pemetrexed
500 mg/m2 or docetaxel 75 mg/m2 every 21 days). Patients
were stratied according to baseline World Health Organization
performance status and presence of brain metastases. The
primary endpoint was progression-free survival (PFS), assessed
by blinded independent review.
Compared with patients receiving chemotherapy, those
receiving ceritinib had signicantly better median PFS
(5.4 versus 1.6 months) (hazard ratio [HR], 0.49; P < 0.001).
Ceritinib also had a superior overall response rate compared
with chemotherapy (39.1% versus 6.9%). Ceritinib benets
were consistent across subgroups. However, there was no
improvement in overall survival with ceritinib compared with
chemotherapy. Of the patients who discontinued chemo-
therapy due to disease progression, 75 crossed over to ceritinib.
Dr. Scagliotti attributed the lack of overall survival benet to
the high crossover rate. That probably diluted the potential
benet, he said.
The most common grade 34 adverse events with chemo-
therapy were neutropenia (15.5%), fatigue (4.4%), and nausea
(1.8%). The most common grade 34 adverse events with
ceritinib were nausea (7.8%), vomiting (7.8%), and diarrhea
(4.3%). Patient-reported outcomes, including lung-cancer
specic symptoms and overall health status, were better in the
ceritinib group (P < 0.05). The safety prole of ceritinib was
consistent with that reported in prior studies.
Ceritinib demonstrated superior efcacy compared with
standard second-line chemotherapy in crizotinib-resistant
ALK+ patients, establishing ceritinib as a preferred treatment
option in this patient population, Dr. Scagliotti concluded.
KEYNOTE-024: Pembrolizumab Versus Platinum-
Based Chemotherapy as First-Line Therapy
For Advanced NSCLC With a PD-L1 Tumor
Proportion Score of 50% or Higher
Martin Reck, MD, Chief Oncology Physician, Grosshansdorf
Lung Clinic, Grosshansdorf, Germany
In the KEYNOTE-024 trial, pembrolizumab was superior to
platinum-based chemotherapy as rst-line therapy for patients
with advanced nonsmall-cell lung cancer (NSCLC) and a
programmed death ligand 1 (PD-L1) tumor proportion score
(TPS) of 50% or higher. High PD-L1 expression, Dr. Reck said
in an ESMO press conference, is dened by PD-L1 expression
in at least 50% of tumor cells.
KEYNOTE-024 included 305 treatment-nave patients with
PD-L1 TPS of 50% or higher randomized 1:1 to intravenous
pembrolizumab 200 mg once every three weeks for two years
or standard-of-care platinum-based doublet chemotherapy
for four to six cycles. Patients with epidermal growth factor
receptor-activating mutations and anaplastic lymphoma kinase
translocations were excluded. Crossover to the pembrolizumab
regimen was allowed in the chemotherapy arm after disease
progression. The primary endpoint was progression-free
survival (PFS).
Pembrolizumab signicantly extended PFS by approxi-
mately four months compared with chemotherapy (10.3 months
versus 6.0 months) (hazard ratio [HR], 0.50; P < 0.001). The
PFS rates at six months and one year were 62% and 48% for
pembrolizumab and 50% and 15% for chemotherapy, respec-
tively. Overall survival rates, a secondary endpoint, were
higher with pembrolizumab, with 80% of patients surviving at
six months versus 72% in the chemotherapy arm (HR, 0.60;
P = 0.005). Dr. Reck pointed out that the overall survival
benet with pembrolizumab was remarkable considering
that more than 40% of patients in the control arm crossed
over to pembrolizumab. At one year, the survival rates were
70% in pembrolizumab-treated patients and 54% in those who
underwent chemotherapy.
Pembrolizumab was associated with a higher overall response
rate compared with chemotherapy (45% versus 28%), a longer
duration of response, and lower incidences of all and serious
(grade 34) adverse events. Patients in the pembrolizumab arm
tolerated treatment twice as long as those in the chemotherapy
arm (7.0 months versus 3.5 months). Discontinuation rates
for toxicity were 7% in the pembrolizumab arm and 11% in the
chemotherapy arm.
Pembrolizumab may be a new standard of care for rst-line
therapy for advanced NSCLC that expresses high levels of
PD-L1, Dr. Reck concluded.
The superior efcacy observed with pembrolizumab led
the trials data monitoring committee to recommend stopping
the trial.
Vol. 41 No. 12 December 2016 P&T
797
 MEETING HIGHLIGHTS: European Society for Medical Oncology 2016 Congress
Cabozantinib Versus Sunitinib as Initial
Targeted Therapy for Patients With
Metastatic Renal Cell Carcinoma of
Poor- and Intermediate-Risk Groups:
Results From the ALLIANCE A031203 Trial
Toni Choueiri, MD, Director, Lank Center for Genitourinary
Oncology, Dana-Farber Cancer Institute, Boston,
Massachusetts
Cabozantinib is an oral inhibitor of tyrosine kinases, includ-
ing MET and AXL, and of vascular endothelial growth factor
(VEGF) receptors. Both MET and AXL seem to be associated
with tumor progression, but more importantly, animal models
show that the development of resistance to VEGF inhibi-
tors like sunitinib can be mediated through AXL and MET,
Dr. Choueiri said at an ESMO press conference. He noted that
sunitinib has been the standard-of-care, rst-line therapy for
renal cell carcinoma (RCC) for years. Median progression-free
survival (PFS) with rst-line VEGF receptor tyrosine kinase
inhibitors has been in the eight- to 11-month range.
In the ALLIANCE clinical trial, 157 treatment-nave, poor- and
intermediate-risk RCC patients received cabozantinib (60 mg
once daily) or sunitinib (50 mg once daily) for four weeks on
and two weeks off. Overall survival was the primary outcome,
and objective response rate (investigator-assessed) and safety
were secondary outcomes. Dr. Choueiri said that outcomes
with VEGF-targeted therapy in the poor- and intermediate-risk
groups are typically inferior (median, 5.6 months) to those in
favorable-risk patients.
Cabozantinib improved PFS and the objective response rate
compared with sunitinib in this poor- and intermediate-risk
population. PFS was 8.2 months for cabozantinib and 5.6 months
for sunitinib (hazard ratio, 0.69; P = 0.012). The objective
response rate was 46% for cabozantinib and 18% for sunitinib.
Safety proles were similar, with grade 3 or higher adverse
event rates of 70.5% in the cabozantinib arm and 72.2% in
the sunitinib arm. Diarrhea, fatigue, hypertension, palmar-
plantar erythrodysesthesia, and hematological events were most
common. Toxicity led to treatment termination in 16 patients
in each treatment group.
When asked in the press conference if evidence was
sufcient to warrant a recommendation for rst-line therapy,
Dr. Choueiri replied, If approved, I think the evidence is there.
You have a drug based on a strong biological rationale that is
approved in second-line with positive primary and secondary
endpoint results. I would make the leap of faith.
A Randomized, Double-Blind, Phase 3
Trial of Maintenance Therapy With Niraparib
Versus Placebo in Patients With Platinum-
Sensitive Recurrent Ovarian Cancer
Mansoor Raza Mirza, MD, Chief Oncologist, Copenhagen
University Hospital Rigshospitalet, Copenhagen, Denmark
Cumulative toxicities and lack of subsequent benet with
platinum-based chemotherapy are limitations of the current
treatment landscape for ovarian cancer, Dr. Mirza noted in an
798 P&T December 2016 Vol. 41 No. 12
ESMO press brieng. Maintenance therapy (approved only in
the European Union) with bevacizumab can only be given once
and confers just a few months progression-free survival (PFS).
In addition, the poly (ADP-ribose) polymerase (PARP) inhibi-
tor olaparib is approved only for ovarian cancer patients with a
germline BRCA mutation (10%15% of patients).
Niraparib is an oral, highly selective inhibitor of PARP1/2.
The ENGOT-OV16/NOVA study was the rst randomized
phase 3 trial of a PARP inhibitor as maintenance therapy for use
after platinum chemotherapy in patients with platinum-sensitive
recurrent ovarian cancer.
The hypothesis of ENGOT-OV16/NOVA was that niraparib
would provide a clinical benet to all patients with platinum-
sensitive recurrent ovarian cancer regardless of BRCA muta-
tion status. The study included 553 patients randomized 2:1 to
niraparib 300 mg once daily or placebo and stratied according
to germline BRCA mutation (gBRCAmut) (n = 203) or non-
gBRCAmut status (n = 350). After four to six cycles of platinum-
based chemotherapy, patients received the study regimen until
disease progression.
Niraparib improved the primary endpoint of PFS signi-
cantly compared with placebo in both cohorts, as well as in all
subgroups. Median PFS for niraparib compared with placebo
was 21.0 months versus 5.5 months in the gBRCAmut group
(hazard ratio [HR], 0.27; 95% confidence interval [CI],
0.1730.410; P < 0.0001), 9.3 months versus 3.9 months in
the non-gBRCAmut group (HR, 0.45; 95% CI, 0.3380.607;
P < 0.0001), and 12.9 months versus 3.8 months in a sub-
group of the non-gBRCAmut cohort who had homologous
recombination DNA repair deciencies (HR, 0.38; 95% CI,
0.2430.586; P < 0.0001).
While dose adjustments generally resolved toxicity issues and
patient-reported quality of life was similar for both study arms,
grade 34 adverse events were reported in more than 10% of
patients receiving niraparib. The rates for thrombocytopenia,
anemia, and neutropenia were 28%, 25%, and 11%, respectively.
Pending approval, these landmark results could change the
way we treat this disease and warrant niraparib maintenance
treatment to the whole study population, Dr. Mirza said. He
commented further that the broad population beneting from
niraparib in this trial represents 70% of all ovarian cancer patients.
Capecitebine Monotherapy in Patients 70 Years
Of Age and Older With Metastatic Breast Cancer
David O. Okonji, MD, Royal Marsden Hospital NHS
Foundation Trust, London, United Kingdom
Chemotherapy with capecitebine has been around for about
25 years. Its registration dose of 1,250 mg/m2 twice daily is
very hefty for the elderly, however, Dr. Okonji said at a poster
session. Dose reductions and a modied schedule may work
better for patients 70 years of age and older with metastatic
breast cancer, according to his study results.
When all available endocrine therapies no longer offer
benet, capecitebine monotherapy is often prescribed. It also
may be given as a last convenient oral agent before resorting
to intravenous chemotherapy with its attendant potential side
effects of alopecia, nausea, vomiting, and fatigue.
 MEETING HIGHLIGHTS: European Society for Medical Oncology 2016 Congress
The clinical benet rate of capecitebine as a monotherapy
is 60%, and median time to progression in patients 65 years
of age or older is four months. Dose reductions due to toxic-
ity occur in 27% to 50% of patients. While the starting dose
and schedule for capecitebine at Dr. Okonjis institution is
2,000 mg/m2 on days 114 every three weeks (two weeks on/one
week off), older patients and those with poor performance status,
comorbidities, and/or moderate-to-severe renal impairment may
need dose reductions. A week on/week off (WOWO) schedule,
rst devised at Memorial Sloan Kettering Cancer Institute in New
York, is being substituted to improve tolerance in the elderly.
Dr. Okonjis single-center, retrospective, observational cohort
study assessed safety and efcacy of low-dose capecitebine
monotherapy in patients 70 years of age or older with relapsed
de novo metastatic breast cancer. Toxicity was the primary
outcome measure. Patients receiving the standard two weeks
on/one week off regimen (2,000 mg/m2) were compared with
those receiving a dose reduction or the WOWO schedule
(2,000 mg/m2). Patients on the WOWO schedule were older
(median age, 79 years versus 73 years [P < 0.001]), had impaired
renal function (P = 0.016), and had lower performance status
compared with the standard regimen group.
Complete response rates were 7% and 0% for the standard
therapy (n = 43) and WOWO (n = 34) groups, respectively, with
corresponding partial response rates of 37% and 16%. Progressive
disease was reported in 30% of those receiving the higher dose
of capecitebine and in 50% of those receiving the WOWO course
of therapy.
While clinical benet rates were higher in those receiv-
ing the higher dose, the higher rates of time to progression
(11.7 months versus 6.2 months; P = 0.111) and overall survival
(18.6 months versus 13.3 months; P = 0.288) were not signi-
cant. Patients in the WOWO cohort experienced less grade 34
toxicity with fewer subsequent dose reductions. Patients on
the WOWO schedule tolerated capecitebine better because of
less diarrhea, less hand inammation, and little or no reduced
white cell counts with their infection risk. This enabled them
to stay on their dose for a longer time, despite their poor
performance status and impaired kidney function, which is usu-
ally a contraindication for this drug, Dr. Okonji said.
Capecitebine toxicity can be managed by dose reduc-
tion and/or a switch to a WOWO schedule. Both strategies
enabled continued treatment in those deriving clinical benet,
Dr. Okonji said. With this modication of the capecitebine regi-
men, weve given this old drug a new lease on life and allowed it
to be used in patients who would not otherwise be able to tolerate
it. And, its off-patent and cheap.
First-Line Ribociclib Plus Letrozole
For Postmenopausal Women With
Hormone Receptor-Positive, HER2-
Negative Advanced Breast Cancer
Gabriel Hortobagyi, University of Texas MD Anderson
Cancer Center, Houston, Texas
Among postmenopausal women with metastatic hormone
receptor-positive breast cancer, treatment with ribociclib and
letrozole signicantly improved progression-free survival
(PFS) compared with placebo in interim results from the
MONALEESA-2 trial.
Increased cyclin-dependent kinase (CDK) 4/6 activity is
associated with endocrine therapy resistance, Dr. Hortobagyi
said in an ESMO press brieng. While endocrine therapy is
an established rst-line treatment for advanced breast can-
cer, endocrine therapy resistance and disease progression
eventually occur in most patients. CDK 4/6 inhibition is a
valid treatment strategy for hormone receptor-positive
advanced breast cancer and may help overcome or delay
endocrine therapy resistance. Ribociclib (LEE011) is an orally
bioavailable selective CDK 4/6 inhibitor.
In MONALEESA-2, a phase 3, double-blind, placebo-
controlled trial of ribociclib plus letrozole, 668 postmenopausal
women with hormone receptor-positive/HER2-negative meta-
static or locally advanced breast cancer with no prior therapy
for advanced disease were randomized to two treatment groups:
ribociclib (600 mg/day, three weeks on/one week off) plus
letrozole (2.5 mg/day, continuous) (n = 334) or letrozole plus
placebo (n = 334).
At interim analysis, median PFS was not met in the ribociclib
plus letrozole arm (95% condence interval, 19.3NR). Median
PFS was 14.7 months (range, 13.016.5 months) in the placebo
plus letrozole arm (P = 0.00000329). Differences between the
treatment arms emerged early and were sustained.
Dr. Hortobagyi said that patients with measurable disease at
baseline had a signicantly higher objective response rate to
ribociclib plus letrozole compared with letrozole plus placebo
(53% versus 37%, respectively; P = 0.00028). Ribociclib plus
letrozole also improved the clinical benet rate compared with
letrozole plus placebo (80% versus 72%, respectively; P = 0.02).
Most adverse events were grades 12 and were managed
with dose interruptions and reductions. Very few patients
discontinued treatment. Although serious adverse events
were uncommon (less than 5%) in both arms, adverse events
occurred more often in the ribociclib-treated patients. The
most common adverse events were related to uncomplicated
myelosuppression: neutropenia (59% for ribociclib/letrozole
versus 1% for letrozole/placebo), leukopenia (21% versus 1%),
and lymphopenia (7% versus 1%). Nausea, vomiting, diarrhea,
alopecia, rash, and transaminase elevations were also reported
more frequently in ribociclib-treated patients.
As a result of the interim analysis showing that the primary
endpoint had already been met, the data monitoring and safety
board recommended termination of the trial.
This is an important advance, Dr. Hortobagyi said. He
commented also that available data suggest that the three
leading approved CDK 4/6 inhibitors seem to have very similar
therapeutic value and toxicity proles. He called the results
paradigm changing and said, We have not had studies in
metastatic breast cancer before with this magnitude of benet.
Vol. 41 No. 12 December 2016 P&T
799
 MEETING HIGHLIGHTS: European Society for Medical Oncology 2016 Congress
Efficacy and Safety of Nab-Paclitaxel in Patients
With Metastatic Breast Cancer: Final Results
Of the Noninterventional NABUCCO Study
Karin Potthoff, MD, iOMEDICO, Freiburg, Germany
While several clinical trials of nab-paclitaxel have been
conducted, prospective data on real-world practice consistent
with increased use of prior taxane-containing regimens in
the neoadjuvant setting have been lacking. We wondered
if patients, in fact, were able to receive the recommended
260 mg/m2 dose or if it was too toxic, Dr. Potthoff said in an
interview at her poster.
In a pivotal phase 3 trial conducted by Gradishar et al.,
nab-paclitaxel demonstrated high efcacy (overall response
rate, 33%; time to tumor progression, 23.0 weeks; overall
survival, 60 weeks) with an acceptable toxicity prole. Peripheral
sensory polyneuropathy (grade 3) in 10% of patients was the
most critical safety issue.2
In order to test that idea, NABUCCO study investigators
collected data from approximately 100 oncology outpatient
centers across Germany on the routine treatment of 697 patients
with metastatic breast cancer in whom anthracycline therapy
was contraindicated. Data on treatment for a maximum of
six months were captured with follow-up data for a median of
17.7 months, including details on disease progression, overall
survival, and safety with a focus on neurotoxicity.
Neurotoxic adverse events at grades 3 and 4 were observed
in a low number of patients (5.2% overall: peripheral sensory
neuropathy in 4.3%; peripheral motor neuropathy in 1.1%; and
paresthesia in 0.1%). Among grade 1 and 2 events, which were
reported in 47.3% of patients, peripheral sensory neuropathy
was most common (35%).
Median age in the overall trial was 62.3 years; 58.2% of the
patients were younger than 65 years of age. Median time from
primary diagnosis was 65.2 months. Among the entire cohort,
419 patients (60.1%) had received prior taxane therapy with
treatment schemes ranging from 78260 mg/m2 every three
or four weeks. Nab-paclitaxel was received as rst-, second-,
third-, and fourth-or-greater-line therapy in 40%, 24%, 20%, and
15% of patients, respectively.
Over half of the patient population had hormone receptor-
positive/HER2-negative (HR+/HER2) disease (58.4%). The
rest of the patients had HR+/HER2+ (9.9%), HR/HER2+ (3.9%),
and triple-negative (13.8%) breast cancer, and receptor status
was unknown in 14.1%.
Overall response rates ranged from 29.0% in fourth-or-greater-
line therapy to 46.1% in rst-line therapy. Those with stable
disease ranged from 30.5% patients in third-line therapy to 37.3%
in second-line therapy. Response rates were highest among
patients who were HR/HER2+ (55.6%) and lowest in triple-
negative breast cancer (32.7%). That rate for triple-negative
disease is still quite good, Dr. Potthoff noted. The progres-
sive disease rate was highest in patients with triple-negative
breast cancer (27.1%) and lowest in those with HR/HER2+
disease (11.1%).
While overall response rates were lower in patients older than
65 years compared with patients younger than 65 years (31.6%
versus 41.1%, respectively), the progressive disease rate was
800 P&T December 2016 Vol. 41 No. 12
not higher in older patients compared with younger patients
(17.2% versus 20.0%). Patients receiving nab-paclitaxel doses
lower than 260 mg/m2 did not have lower overall response
rates. Median time to tumor progression was 5.9 months for
the overall population and similar for those younger than
age 65 years (5.7 months) and those age 65 years or older
(6.5 months). It was shortest for those with triple-
negative disease (4.9 months) and longest for those who were
HR+/HER2+ (8.6 months).
Our real-world data from NABUCCO conrm the earlier
clinical trial ndings. They conrm also that nab-paclitaxel is
an effective and safe treatment option with a favorable benet
risk prole in metastatic breast cancer patients not eligible for
anthracycline therapy, Dr. Potthoff concluded. She under-
scored that response rates were high in populations typically
difcult to treatpatients who had received multiple lines of
prior therapy, older patients, and patients with triple-negative
disease.
REFERENCES
1. Eggermont AM, Chiarion-Sileni V, Grob JJ, et al. Prolonged
survival in stage III melanoma with ipilimumab adjuvant therapy.
N Engl J Med 2016 Oct 7. [Epub ahead of print] Available at:
www.nejm.org/doi/full/10.1056/NEJMoa1611299. Accessed
November 4, 2016.
2. Gradishar WJ, Tjulandin S, Davidson N, et al. Phase III trial
of nanoparticle albumin-bound paclitaxel compared with poly-
ethylated castor oil-based paclitaxel in women with breast cancer.
J Clin Oncol 2005;23(31):77947803. Q
MEDICATION ERRORS
continued from page 737
11. Ely EW, Truman B, Shintani A, et al. Monitoring sedation status
over time in ICU patients: the reliability and validity of the Rich-
mond Agitation Sedation Scale (RASS). JAMA 2003;289(22):2983
2991.
12. McCarter T, Shaik Z, Scarfo K, Thompson LJ. Capnography
monitoring enhances safety of postoperative patient-controlled
analgesia. Am Health Drug Benets 2008;1(5):2835.
The reports described in this column were received through the
ISMP Medication Errors Reporting Program (MERP). Errors,
close calls, or hazardous conditions may be reported on the ISMP
website (www.ismp.org) or communicated directly to ISMP by
calling 1-800-FAIL-SAFE or via email at ismpinfo@ismp.org. Q
Correction
A Pipeline Plus article in Octobers P&T included out-
dated information about Intarcia Therapeutics ITCA 650
(continuous subcutaneous delivery of exenatide), which
is being developed for the treatment of patients with
type-2 diabetes. The investigational therapy employs a
subcutaneous osmotic mini-pump to provide continuous
exenatide drug therapy in a three-month initiation dose,
followed by consecutive six-month doses, as evaluated in
its phase 3 clinical trials.
 RESEARCH BRIEFS
continued from page 769
Overweight Patients Arent
Getting Needed Weight Advice
About two-thirds of overweight and obese patients are not
getting the advice they need about weight management from
their health care providers, according to a recent study.
The researchers conducted a phone survey of 1,109 over-
weight or obese adults, asking them whether a health care
provider had given them advice about their weight in the
previous 12 months. A concerning nding, the researchers
said: Only 35% of the respondents reported such advice.
As body mass index (BMI) increased, so did the likelihood
of receiving weight-loss advice: 22% of those with a BMI of
25.0 to 29.9 received advice versus 63% of those with a BMI
of 40.0 or higher. Hispanics were the most likely of the three
racial/ethnic groups to report receiving advice from a health
care provider. The researchers said other studies have sug-
gested that a higher prevalence of weight problems among
blacks and Hispanics draws more attention from health care
providers when counseling.
High-risk patients, such as the extremely obese or those with
comorbidities, are most likely to receive weight-loss advice,
the researchers said. But demographic factors also come into
play: People with high levels of education are more likely than
those with low levels to receive advice, and middle-aged people
are more likely to get advice than younger or older patients.
Patients in the lowest income groups had signicantly lower
odds of receiving weight-loss advice, compared with those in
higher income groups. Adjusting for health insurance did not
change the results. That nding is problematic, the research-
ers said, because people with the lowest incomes tend to have
poorer health outcomes than those with higher incomes.
Source: Preventing Chronic Disease, October 2016
Cutting Down on Dialysis-Related Infections
Each year about 37,000 people get potentially deadly blood-
stream infections related to dialysis. But those infections could
be cut dramatically by implementing evidence-based recom-
mendations, the Centers for Disease Control and Prevention
(CDC) says. For several years, facilities that have followed
CDC recommendations have successfully reduced bloodstream
infections in dialysis patients.
Making evidence-based safety steps a routine part of patient
care is a proven strategy to keep dialysis patients safe from blood-
stream infections, says CDC Director Tom Frieden, MD, MPH.
Now the CDC is teaming up with a coalition of health care
and patient advocacy organizations and other public health
partners in the Making Dialysis Safer for Patients Coalition, an
initiative to expand the use of the recommendations and tools
to improve dialysis patient safety.
The coalition will promote the use of the CDCs Core
Interventions and provide facilities with resources, including
patient and staff education materials with tips to prevent infec-
tion; protocols for dialysis facilities; dialysis audit tools and
checklists; and videos and DVDs on best practices.
Dialysis patients are particularly vulnerable to infections,
says Priti R. Patel, MD, MPH, Medical Director of the Coalition.
We want to get lifesaving tools into the right hands to make a
real impact on patients lives.
Source: Centers for Disease Control and Prevention,
October 2016
Patients Know About Diabetic
Retinopathy RiskBut Dont Get Screened
Patients may understand that diabetes can lead to eye disease,
and they may receive a recommendation for screening for
diabetic retinopathybut that doesnt mean theyll get screened.
Researchers from Harbor-UCLA Medical Center in Torrance,
California, surveyed 101 patients with diabetes and 44 provid-
ers and staffers at a clinic where annual screening rates for
diabetic retinopathy were low. They found that 93% of patients
understood the potential risk, but only 55% were getting
screened.
The study goal, however, wasnt to measure understand-
ing of risk, but to nd out what patients considered barriers
to screening, and whether health care providers understood
those barriers. And the researchers found quite a gap between
the two groups.
The patients were mostly low-income Hispanics and African-
Americans. The survey asked them to rate any given barrier
that would delay or prevent them from getting screened. Health
care providers and staff were asked to rate the importance of
addressing the barriers.
Most of the patients (70%) reported at least one barrier to
screening, most commonly depression (22%) and nancial
problems (26%); others reported language issues, lack of
transportation, and lack of time.
When surveying the health care providers, though, the
researchers found markedly divergent perceptions between
the two groups. For instance, only small numbers of patients
said transportation, language issues, denial, fear, or cultural
beliefs were barriersyet most providers and staff thought
those were very or extremely important.
In contrast, the barriers that the patients did think were
importantnancial burdens and depressionwere rated
as less important than other barriers by the health care
providers and staff.
The differences in opinion suggest a lack of high-quality
patientprovider communication, the researchers said. They
suggest that more effective patient education, as well as height-
ened awareness of depression and its impact, are key to getting
more patients screened.
Source: Preventing Chronic Disease, October 2016 Q
Vol. 41 No. 12 December 2016 P&T
801
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INVOKAMET XR
(canagliozin and metformin hydrochloride extended-release)
tablets, for oral use
Brief Summary of Prescribing Information.
WARNING: LACTIC ACIDOSIS
Post-marketing cases of metformin-associated lactic acidosis have
resulted in death, hypothermia, hypotension, and resistant
bradyarrhythmias. The onset of metformin-associated lactic acidosis
is often subtle, accompanied only by nonspecic symptoms such as
malaise, myalgias, respiratory distress, somnolence, and abdominal
pain. Metformin-associated lactic acidosis was characterized by
elevated blood lactate levels (> 5 mmol/Liter), anion gap acidosis
(without evidence of ketonuria or ketonemia), an increased lactate/
pyruvate ratio; and metformin plasma levels generally >5 mcg/mL
[see Warnings and Precautions].
Risk factors for metformin-associated lactic acidosis include renal
impairment, concomitant use of certain drugs (e.g., carbonic
anhydrase inhibitors such as topiramate), age 65 years old or greater,
having a radiological study with contrast, surgery and other
procedures, hypoxic states (e.g., acute congestive heart failure),
excessive alcohol intake, and hepatic impairment.
Steps to reduce the risk of and manage metformin-associated lactic
acidosis in these high risk groups are provided in the full prescribing
information [see Dosage and Administration (2.2) in full Prescribing
Information, Contraindications, Warnings and Precautions, Drug
Interactions, and Use in Specic Populations].
If metformin-associated lactic acidosis is suspected, immediately
discontinue INVOKAMET XR and institute general supportive
measures in a hospital setting. Prompt hemodialysis is recommended
[see Warnings and Precautions].
INDICATIONS AND USAGE
INVOKAMET XR (canagliozin and metformin hydrochloride extended
release) is indicated as an adjunct to diet and exercise to improve
glycemic control in adults with type 2 diabetes mellitus when treatment
with both canagliozin and metformin is appropriate.
Limitations of Use: INVOKAMETXR is not recommended in patients with
type1 diabetes or for the treatment of diabetic ketoacidosis.
CONTRAINDICATIONS
INVOKAMETXR is contraindicated in patients with:
Moderate to severe renal impairment (eGFR below 45 mL/min/1.73 m2),
end stage renal disease (ESRD) or patients on dialysis [see Warnings
and Precautions and Use in Specic Populations].
Acute or chronic metabolic acidosis, including diabetic ketoacidosis
[see Warnings and Precautions].
History of a serious hypersensitivity reaction to canagliozin or
metformin, such as anaphylaxis or angioedema [see Warnings and
Precautions and Adverse Reactions].
WARNINGS AND PRECAUTIONS
Lactic Acidosis: There have been post-marketing cases of metformin-
associated lactic acidosis, including fatal cases. These cases had a
subtle onset and were accompanied by nonspecific symptoms such as
malaise, myalgias, abdominal pain, respiratory distress, or increased
somnolence; however, hypothermia, hypotension and resistant
bradyarrhythmias have occurred with severe acidosis. Metformin-
associated lactic acidosis was characterized by elevated blood lactate
concentrations (>5 mmol/Liter), anion gap acidosis (without evidence of
ketonuria or ketonemia), and an increased lactate:pyruvate ratio;
metformin plasma levels generally >5 mcg/mL. Metformin decreases liver
uptake of lactate increasing lactate blood levels which may increase the
risk of lactic acidosis, especially in patients at risk.
If metformin-associated lactic acidosis is suspected, general supportive
measures should be instituted promptly in a hospital setting, along with
immediate discontinuation of INVOKAMETXR. In INVOKAMETXR-treated
patients with a diagnosis or strong suspicion of lactic acidosis, prompt
hemodialysis is recommended to correct the acidosis and remove
accumulated metformin (metformin hydrochloride is dialyzable, with a
clearance of up to 170 mL/minute under good hemodynamic conditions).
Hemodialysis has often resulted in reversal of symptoms and recovery.
Educate patients and their families about the symptoms of lactic acidosis
and if these symptoms occur instruct them to discontinue INVOKAMETXR
and report these symptoms to their healthcare provider.
For each of the known and possible risk factors for metformin-associated
lactic acidosis, recommendations to reduce the risk of and manage
metformin-associated lactic acidosis are provided below:
INVOKAMET XR (canagliozin and metformin hydrochloride extended-release) tablets
Renal Impairment: The postmarketing metformin-associated lactic
acidosis cases primarily occurred in patients with significant renal
impairment. The risk of metformin accumulation and metformin-associated
lactic acidosis increases with the severity of renal impairment because
metformin is substantially excreted by the kidney [see Clinical
Pharmacology (12.3) in full Prescribing Information].
Before initiating INVOKAMET XR, obtain an estimated glomerular
ltration rate (eGFR).
INVOKAMET XR is contraindicated in patients with an eGFR less than
45 mL/minute/1.73 m2.
Obtain an eGFR at least annually in all patients taking INVOKAMETXR.
In patients at increased risk for the development of renal impairment
(e.g., the elderly), renal function should be assessed more frequently.
Drug Interactions: The concomitant use of INVOKAMETXR with specific
drugs may increase the risk of metformin-associated lactic acidosis: those
that impair renal function, result in significant hemodynamic change,
interfere with acid-base balance or increase metformin accumulation
(e.g. cationic drugs) [see Drug Interactions]. Therefore, consider more
frequent monitoring of patients.
Age 65 or Greater: The risk of metformin-associated lactic acidosis
increases with the patients age because elderly patients have a greater
likelihood of having hepatic, renal, or cardiac impairment than younger
patients. Assess renal function more frequently in elderly patients [see
Use in Specific Populations].
Radiological Studies with Contrast: Administration of intravascular
iodinated contrast agents in metformin-treated patients has led to an acute
decrease in renal function and the occurrence of lactic acidosis. Stop
INVOKAMET XR at the time of, or prior to, an iodinated contrast imaging
procedure in patients with an eGFR between 45 and 60 mL/min/1.73 m2;
in patients with a history of hepatic impairment, alcoholism, or heart failure;
or in patients who will be administered intra-arterial iodinated contrast.
Re-evaluate eGFR 48 hours after the imaging procedure, and restart
INVOKAMETXR if renal function is stable.
Surgery and Other Procedures: Withholding of food and fluids during
surgical or other procedures may increase the risk for volume depletion,
hypotension and renal impairment.
INVOKAMET XR should be temporarily discontinued while patients have
restricted food and fluid intake.
Hypoxic States: Several of the postmarketing cases of metformin-
associated lactic acidosis occurred in the setting of acute congestive
heart failure (particularly when accompanied by hypoperfusion and
hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction,
sepsis, and other conditions associated with hypoxemia have been
associated with lactic acidosis and may also cause pre-renal azotemia.
When such events occur, discontinue INVOKAMETXR.
Excessive Alcohol Intake: Alcohol potentiates the effect of metformin on
lactate metabolism and this may increase the risk of metformin-associated
lactic acidosis. Warn patients against excessive alcohol intake while
receiving INVOKAMETXR.
Hepatic Impairment: Patients with hepatic impairment have developed
metformin-associated lactic acidosis. This may be due to impaired lactate
clearance resulting in higher lactate blood levels. Therefore, avoid use of
INVOKAMETXR in patients with clinical or laboratory evidence of hepatic
disease.
Hypotension: Canagliozin causes intravascular volume contraction.
Symptomatic hypotension can occur after initiating INVOKAMET XR
[see Adverse Reactions] particularly in patients with eGFR less than
60 mL/min/1.73 m2, elderly patients, patients on either diuretics or
medications that interfere with the renin-angiotensin-aldosterone system
(e.g., angiotensin-converting-enzyme [ACE] inhibitors, angiotensin
receptor blockers [ARBs]), or patients with low systolic blood pressure.
Before initiating INVOKAMET XR in patients with one or more of these
characteristics who were not already on canagliozin, volume status
should be assessed and corrected. Monitor for signs and symptoms after
initiating therapy.
Ketoacidosis: Reports of ketoacidosis, a serious life-threatening condition
requiring urgent hospitalization have been identified in postmarketing
surveillance in patients with type 1 and type 2 diabetes mellitus receiving
sodium glucose co-transporter-2 (SGLT2) inhibitors, including canagliflozin.
Fatal cases of ketoacidosis have been reported in patients taking
canagliflozin. INVOKAMET XR is not indicated for the treatment of
patients with type 1 diabetes mellitus [see Indications and Usage].
INVOKAMET XR (canagliozin and metformin hydrochloride extended-release) tablets
Patients treated with INVOKAMET XR who present with signs and
symptoms consistent with severe metabolic acidosis should be assessed
for ketoacidosis regardless of presenting blood glucose levels, as
ketoacidosis associated with INVOKAMET XR may be present even if
blood glucose levels are less than 250 mg/dL. If ketoacidosis is suspected,
INVOKAMETXR should be discontinued, patient should be evaluated, and
prompt treatment should be instituted. Treatment of ketoacidosis may
require insulin, fluid and carbohydrate replacement.
In many of the postmarketing reports, and particularly in patients with
type 1 diabetes, the presence of ketoacidosis was not immediately
recognized and institution of treatment was delayed because presenting
blood glucose levels were below those typically expected for diabetic
ketoacidosis (often less than 250 mg/dL). Signs and symptoms at
presentation were consistent with dehydration and severe metabolic
acidosis and included nausea, vomiting, abdominal pain, generalized
malaise, and shortness of breath. In some but not all cases, factors
predisposing to ketoacidosis such as insulin dose reduction, acute febrile
illness, reduced caloric intake due to illness or surgery, pancreatic
disorders suggesting insulin deficiency (e.g., type 1 diabetes, history of
pancreatitis or pancreatic surgery), and alcohol abuse were identified.
Before initiating INVOKAMET XR consider factors in the patient history
that may predispose to ketoacidosis including pancreatic insulin
deficiency from any cause, caloric restriction, and alcohol abuse. In
patients treated with INVOKAMETXR consider monitoring for ketoacidosis
and temporarily discontinuing INVOKAMETXR in clinical situations known
to predispose to ketoacidosis (e.g., prolonged fasting due to acute illness
or surgery).
Acute Kidney Injury and Impairment in Renal Function: Canagliozin
causes intravascular volume contraction [see Warnings and Precautions]
and can cause renal impairment [see Adverse Reactions]. There have
been postmarketing reports of acute kidney injury, some requiring
hospitalization and dialysis, in patients receiving canagliozin; some
reports involved patients younger than 65 years of age.
Before initiating INVOKAMET XR, consider factors that may predispose
patients to acute kidney injury including hypovolemia, chronic renal
insufciency, congestive heart failure, and concomitant medications
(diuretics, ACE inhibitors, ARBs, NSAIDs). Consider temporarily
discontinuing INVOKAMETXR in any setting of reduced oral intake (such
as acute illness or fasting) or uid losses (such as gastrointestinal illness
or excessive heat exposure); monitor patients for signs and symptoms of
acute kidney injury. If acute kidney injury occurs, discontinue
INVOKAMETXR promptly and institute treatment.
Canagliozin increases serum creatinine and decreases eGFR. Patients
with hypovolemia may be more susceptible to these changes. Renal
function abnormalities can occur after initiating INVOKAMET XR [see
Adverse Reactions]. Renal function should be evaluated prior to initiation
of INVOKAMET XR and monitored periodically thereafter. Dosage
adjustment and more frequent renal function monitoring are
recommended in patients with an eGFR below 60 mL/min/1.73 m2.
INVOKAMET XR is contraindicated in patients with an eGFR below
45 mL/min/1.73 m2 [see Dosage and Administration (2.2) in full Prescribing
Information, Contraindications, Warnings and Precautions, and Use in
Specic Populations].
Hyperkalemia: Canagliflozin can lead to hyperkalemia. Patients with
moderate renal impairment who are taking medications that interfere
with potassium excretion, such as potassium-sparing diuretics, or
medications that interfere with the renin-angiotensin-aldosterone
system are at an increased risk of developing hyperkalemia [see Dosage
and Administration (2.2) in full Prescribing Information and Adverse
Reactions].
Monitor serum potassium levels periodically after initiating
INVOKAMET XR in patients with impaired renal function and in patients
predisposed to hyperkalemia due to medications or other medical
conditions.
Urosepsis and Pyelonephritis: There have been postmarketing reports of
serious urinary tract infections including urosepsis and pyelonephritis
requiring hospitalization in patients receiving SGLT2 inhibitors, including
canagliflozin. Treatment with SGLT2 inhibitors increases the risk for
urinary tract infections. Evaluate patients for signs and symptoms of
urinary tract infections and treat promptly, if indicated [see Adverse
Reactions].
Hypoglycemia with Concomitant Use of Sulfonylurea or Insulin:
Canagliflozin: Insulin and insulin secretagogues are known to cause
hypoglycemia. Canagliozin can increase the risk of hypoglycemia when
combined with insulin or an insulin secretagogue [see Adverse
INVOKAMET XR (canagliozin and metformin hydrochloride extended-release) tablets
Reactions]. Therefore, a lower dose of insulin or insulin secretagogue
may be required to minimize the risk of hypoglycemia when used in
combination with INVOKAMETXR.
Metformin: Hypoglycemia does not occur in patients receiving metformin
alone under usual circumstances of use, but could occur when caloric
intake is decient, when strenuous exercise is not compensated by
caloric supplementation, or during concomitant use with other
glucose-lowering agents (such as sulfonylureas and insulin) or ethanol.
Elderly, debilitated, or malnourished patients, and those with adrenal or
pituitary insufciency or alcohol intoxication, are particularly susceptible
to hypoglycemic effects. Hypoglycemia may be difcult to recognize in the
elderly, and in people who are taking beta-adrenergic blocking drugs.
Monitor for a need to lower the dose of INVOKAMETXR to minimize the
risk of hypoglycemia in these patients.
Genital Mycotic Infections: Canagliozin increases the risk of genital
mycotic infections. Patients with a history of genital mycotic infections
and uncircumcised males were more likely to develop genital mycotic
infections [see Adverse Reactions]. Monitor and treat appropriately.
Hypersensitivity Reactions: Hypersensitivity reactions, including angioedema
and anaphylaxis, have been reported with canagliozin. These reactions
generally occurred within hours to days after initiating canagliozin. If
hypersensitivity reactions occur, discontinue use of INVOKAMET XR; treat
and monitor until signs and symptoms resolve [see Contraindications and
Adverse Reactions].
Bone Fracture: An increased risk of bone fracture, occurring as early as
12 weeks after treatment initiation, was observed in patients using
canagliflozin. Consider factors that contribute to fracture risk prior to
initiating INVOKAMETXR [see Adverse Reactions].
Vitamin B12 Levels: In controlled, 29-week clinical trials of metformin, a
decrease to subnormal levels of previously normal serum vitamin B12
levels, without clinical manifestations, was observed in approximately
7% of metformin-treated patients. Such decreases, possibly due to
interference with B12 absorption from the B12-intrinsic factor complex, is,
however, very rarely associated with anemia or neurologic
manifestations due to the short duration (less than1year) of the clinical
trials. This risk may be more relevant to patients receiving long-term
treatment with metformin and adverse hematologic and neurologic
reactions have been reported postmarketing. The decrease in vitamin B12
levels appears to be rapidly reversible with discontinuation of metformin
or vitamin B12 supplementation. Measure hematologic parameters on an
annual basis in patients on INVOKAMET XR and investigate and treat if
abnormalities occur. Patients with inadequate vitamin B12 or calcium
intake or absorption may be predisposed to developing subnormal
vitamin B12 levels, and routine serum vitamin B12 measurement at 2- to
3-year intervals is recommended in these patients.
Increases in Low-Density Lipoprotein (LDL-C): Dose-related increases in
LDL-C occur with canagliozin [see Adverse Reactions]. Monitor LDL-C
and treat if appropriate after initiating INVOKAMETXR.
Macrovascular Outcomes: There have been no clinical studies
establishing conclusive evidence of macrovascular risk reduction with
INVOKAMETXR or any other antidiabetic drug [see Adverse Reactions].
ADVERSE REACTIONS
The following adverse reactions are also discussed elsewhere in the
labeling:
Lactic Acidosis [see Boxed Warning and Warnings and Precautions]
Hypotension [see Warnings and Precautions]
Ketoacidosis [see Warnings and Precautions]
Acute Kidney Injury and Impairment in Renal Function [see Warnings
and Precautions]
Hyperkalemia [see Warnings and Precautions]
Urosepsis and Pyelonephritis [see Warnings and Precautions]
Hypoglycemia with Concomitant Use of Sulfonylurea or Insulin [see
Warnings and Precautions]
Genital Mycotic Infections [see Warnings and Precautions]
Hypersensitivity Reactions [see Warnings and Precautions]
Bone Fracture [see Warnings and Precautions]
Vitamin B12 Deciency [see Warnings and Precautions]
Increases in Low-Density Lipoprotein (LDL-C) [see Warnings and
Precautions]
Clinical Studies Experience: Because clinical trials are conducted under
widely varying conditions, adverse reaction rates observed in the clinical
trials of a drug cannot be directly compared to the rates in the
clinical trials of another drug and may not reect the rates observed
in clinical practice.
INVOKAMET XR (canagliozin and metformin hydrochloride extended-release) tablets INVOKAMET XR (canagliozin and metformin hydrochloride extended-release) tablets

Pool of Placebo-Controlled Trials: Canagliozin: The data in Table 1 is Pool of Placebo- and Active-Controlled Trials - Canagliozin: The occurrence
derived from four 26-week placebo-controlled trials. In one trial of adverse reactions for canagliozin was evaluated in a larger pool of
canagliozin was used as monotherapy and in three trials canagliozin patients participating in placebo- and active-controlled trials.
was used as add-on therapy with metformin (with or without other agents)
The data combined eight clinical trials and reect exposure of
[see Clinical Studies (14) in full Prescribing Information]. These data
reect exposure of 1667 patients to canagliozin and a mean duration of 6177 patients to canagliozin. The mean duration of exposure to
exposure to canagliozin of 24 weeks with 1275 patients exposed to a canagliozin was 38weeks with 1832individuals exposed to canagliozin
combination of canagliozin and metformin. Patients received for greater than 50 weeks. Patients received canagliozin 100 mg
canagliozin 100 mg (N=833), canagliozin 300 mg (N=834) or placebo (N=3092), canagliozin 300 mg (N=3085) or comparator (N=3262) once
(N=646) once daily. The mean daily dose of metformin was 2138 mg daily. The mean age of the population was 60 years and 5% were older
(SD 337.3) for the 1275 patients in the three placebo-controlled metformin than 75years of age. Fifty-eight percent (58%)of the population was male
add-on studies. The mean age of the population was 56 years and 2% and 73%were Caucasian, 16%were Asian, and 4%were Black or African
were older than 75 years of age. Fifty percent (50%) of the population was American. At baseline, the population had diabetes for an average of
male and 72% were Caucasian, 12% were Asian, and 5% were Black or 11 years, had a mean HbA1C of 8.0% and 33% had established
African American. At baseline the population had diabetes for an average microvascular complications of diabetes. Baseline renal function was
of 7.3 years, had a mean HbA1C of 8.0% and 20% had established normal or mildly impaired (mean eGFR 81mL/min/1.73m2).
microvascular complications of diabetes. Baseline renal function was
normal or mildly impaired (mean eGFR 88 mL/min/1.73 m2). The types and frequency of common adverse reactions observed in the
pool of eight clinical trials were consistent with those listed in Table 1.
Table 1 shows common adverse reactions associated with the use of
Percentages were weighted by studies. Study weights were proportional
canagliozin. These adverse reactions were not present at baseline,
occurred more commonly on canagliozin than on placebo, and occurred to the harmonic mean of the three treatment sample sizes. In this pool,
in at least 2% of patients treated with either canagliozin 100 mg or canagliflozin was also associated with the adverse reactions of fatigue
canagliozin 300 mg. (1.8% with comparator, 2.2% with canagliflozin 100 mg, and 2.0% with
canagliflozin 300 mg) and loss of strength or energy (i.e., asthenia)
Table1: Adverse Reactions From Pool of Four 26Week Placebo- (0.6% with comparator, 0.7% with canagliflozin 100 mg, and 1.1% with
Controlled Studies Reported in 2% of Canagliozin-Treated canagliflozin 300 mg).
Patients*
In the pool of eight clinical trials, the incidence rate of pancreatitis (acute
Canagliozin Canagliozin or chronic) was 0.1, 0.2, and 0.1 receiving comparator, canagliflozin
Placebo 100mg 300mg 100 mg, and canagliflozin 300 mg, respectively.
Adverse Reaction N=646 N=833 N=834
Urinary tract infections 3.8% 5.9% 4.4% In the pool of eight clinical trials, hypersensitivity-related adverse
reactions (including erythema, rash, pruritus, urticaria, and angioedema)
Increased urination 0.7% 5.1% 4.6%
occurred in 3.0%, 3.8%, and 4.2% of patients receiving comparator,
Thirst# 0.1% 2.8% 2.4% canagliozin 100mg, and canagliozin 300mg, respectively. Five patients
Constipation 0.9% 1.8% 2.4% experienced serious adverse reactions of hypersensitivity with
Nausea 1.6% 2.1% 2.3% canagliozin, which included 4 patients with urticaria and 1 patient with a
N=312 N=425 N=430 diffuse rash and urticaria occurring within hours of exposure to
Female genital canagliozin. Among these patients, 2 patients discontinued canagliozin.
mycotic infections 2.8% 10.6% 11.6% One patient with urticaria had recurrence when canagliozin was
Vulvovaginal pruritus 0.0% 1.6% 3.2% re-initiated.
N=334 N=408 N=404 Photosensitivity-related adverse reactions (including photosensitivity
Male genital reaction, polymorphic light eruption, and sunburn) occurred in 0.1%, 0.2%,
mycotic infections 0.7% 4.2% 3.8% and 0.2% of patients receiving comparator, canagliozin 100 mg, and
canagliozin 300mg, respectively.
* The four placebo-controlled trials included one monotherapy trial
and three add-on combination trials with metformin, metformin and Other adverse reactions occurring more frequently on canagliozin than
sulfonylurea, or metformin and pioglitazone. on comparator were:
Female genital mycotic infections include the following adverse
Volume Depletion-Related Adverse Reactions: Canagliozin results in an
reactions: Vulvovaginal candidiasis, Vulvovaginal mycotic infection, osmotic diuresis, which may lead to reductions in intravascular volume. In
Vulvovaginitis, Vaginal infection, Vulvitis, and Genital infection fungal. clinical studies, treatment with canagliozin was associated with a
Urinary tract infections include the following adverse reactions: Urinary
dose-dependent increase in the incidence of volume depletion-related
tract infection, Cystitis, Kidney infection, and Urosepsis.
Increased urination includes the following adverse reactions: Polyuria, adverse reactions (e.g., hypotension, postural dizziness, orthostatic
Pollakiuria, Urine output increased, Micturition urgency, and Nocturia. hypotension, syncope, and dehydration). An increased incidence was
Male genital mycotic infections include the following adverse reactions: observed in patients on the 300 mg dose. The three factors associated
Balanitis or Balanoposthitis, Balanitis candida, and Genital infection with the largest increase in volume depletion-related adverse reactions
fungal. were the use of loop diuretics, moderate renal impairment (eGFR 30 to
# Thirst includes the following adverse reactions: Thirst, Dry mouth, less than 60 mL/min/1.73 m2), and age 75 years and older (Table 2) [see
and Polydipsia. Dosage and Administration(2.2) in full Prescribing Information, Warnings
Note: Percentages were weighted by studies. Study weights were and Precautions, and Use in Specic Populations].
proportional to the harmonic mean of the three treatment sample sizes. Table2: Proportion of Patients With at Least One Volume Depletion-
Abdominal pain was also more commonly reported in patients taking Related Adverse Reaction (Pooled Results from 8 Clinical Trials)
canagliozin 100mg (1.8%), 300mg (1.7%) than in patients taking placebo Comparator Canagliozin Canagliozin
(0.8%). Group* 100mg 300mg
Canagliozin and Metformin: The incidence and type of adverse reactions Baseline Characteristic % % %
in the three 26-week placebo-controlled metformin add-on studies, Overall population 1.5% 2.3% 3.4%
representing a majority of data from the four 26-week placebo-controlled
trials, was similar to the adverse reactions described in Table 1. There 75years of age and older 2.6% 4.9% 8.7%
were no additional adverse reactions identied in the pooling of these eGFR less than
three placebo-controlled studies that included metformin relative to the 60mL/min/1.73m2 2.5% 4.7% 8.1%
four placebo-controlled studies. Use of loop diuretic 4.7% 3.2% 8.8%
In a trial with canagliflozin as initial combination therapy with metformin
* Includes placebo and active-comparator groups
[see Clinical Studies (14.1) in full Prescribing Information], an increased Patients could have more than 1 of the listed risk factors
incidence of diarrhea was observed in the canagliflozin and metformin
combination groups (4.2%) compared to canagliflozin or metformin
monotherapy groups (1.7%).
INVOKAMET XR (canagliozin and metformin hydrochloride extended-release) tablets INVOKAMET XR (canagliozin and metformin hydrochloride extended-release) tablets

Falls: In a pool of nine clinical trials with mean duration of exposure to In the pooled analysis of patients with moderate renal impairment, the
canagliozin of 85weeks, the proportion of patients who experienced falls incidence of renal-related adverse reactions was 3.7% with placebo,
was 1.3%, 1.5%, and 2.1% with comparator, canagliozin 100 mg, and 8.9% with canagliozin 100 mg, and 9.3% with canagliozin 300 mg.
canagliozin 300 mg, respectively. The higher risk of falls for patients Discontinuations due to renal-related adverse events occurred in
treated with canagliozin was observed within the rst few weeks of 1.0% with placebo, 1.2% with canagliozin 100 mg, and 1.6% with
treatment. canagliozin 300mg [see Warnings and Precautions].
Impairment in Renal Function: Canagliozin is associated with a dose- Genital Mycotic Infections: In the pool of four placebo-controlled clinical
dependent increase in serum creatinine and a concomitant fall in trials, female genital mycotic infections (e.g., vulvovaginal mycotic
infection, vulvovaginal candidiasis, and vulvovaginitis) occurred in 2.8%,
estimated GFR (Table 3). Patients with moderate renal impairment at
10.6%, and 11.6% of females treated with placebo, canagliflozin 100 mg,
baseline had larger mean changes.
and canagliflozin 300 mg, respectively. Patients with a history of genital
Table3: Changes in Serum Creatinine and eGFR Associated with mycotic infections were more likely to develop genital mycotic infections
Canagliozin in the Pool of Four Placebo-Controlled Trials and on canagliflozin. Female patients who developed genital mycotic
Moderate Renal Impairment Trial infections on canagliflozin were more likely to experience recurrence and
require treatment with oral or topical antifungal agents and anti-microbial
Canagliozin Canagliozin
agents. In females, discontinuation due to genital mycotic infections
Placebo 100mg 300mg
N=646 N=833 N=834 occurred in 0% and 0.7% of patients treated with placebo and
canagliflozin, respectively [see Warnings and Precautions].
Creatinine In the pool of four placebo-controlled clinical trials, male genital mycotic
(mg/dL) 0.84 0.82 0.82 infections (e.g., candidal balanitis, balanoposthitis) occurred in 0.7%, 4.2%,
Baseline
eGFR (mL/ and 3.8% of males treated with placebo, canagliflozin 100 mg, and
min/1.73m2) 87.0 88.3 88.8 canagliflozin 300 mg, respectively. Male genital mycotic infections
Pool occurred more commonly in uncircumcised males and in males with a
of Four Creatinine
(mg/dL) 0.01 0.03 0.05 prior history of balanitis or balanoposthitis. Male patients who developed
Placebo- Week6 genital mycotic infections on canagliflozin were more likely to experience
Controlled Change eGFR (mL/
recurrent infections (22% on canagliflozin versus none on placebo), and
Trials min/1.73m2) -1.6 -3.8 -5.0
require treatment with oral or topical antifungal agents and anti-microbial
Creatinine
End of agents than patients on comparators. In males, discontinuations due to
(mg/dL) 0.01 0.02 0.03
Treatment genital mycotic infections occurred in 0% and 0.5% of patients treated
Change* eGFR (mL/ 2 with placebo and canagliflozin, respectively. In the pooled analysis of
min/1.73m ) -1.6 -2.3 -3.4 8 controlled trials, phimosis was reported in 0.3% of uncircumcised male
Canagliozin Canagliozin patients treated with canagliflozin and 0.2% required circumcision to treat
Placebo 100mg 300mg the phimosis [see Warnings and Precautions].
N=90 N=90 N=89 Hypoglycemia: In canagliozin clinical trials, hypoglycemia was dened as
Creatinine any event regardless of symptoms, where biochemical hypoglycemia was
(mg/dL) 1.61 1.62 1.63 documented (any glucose value below or equal to 70 mg/dL). Severe
Baseline
eGFR (mL/ hypoglycemia was dened as an event consistent with hypoglycemia
min/1.73m2) 40.1 39.7 38.5 where the patient required the assistance of another person to recover,
Moderate Creatinine lost consciousness, or experienced a seizure (regardless of whether
Renal Week3 (mg/dL) 0.03 0.18 0.28 biochemical documentation of a low glucose value was obtained). In
Impairment Change eGFR (mL/ individual clinical trials [see Clinical Studies (14.6) in full Prescribing
Trial min/1.73m2) -0.7 -4.6 -6.2 Information], episodes of hypoglycemia occurred at a higher rate when
Creatinine canagliozin was co-administered with insulin or sulfonylureas (Table 4)
End of [see Warnings and Precautions].
Treatment (mg/dL) 0.07 0.16 0.18
Change* eGFR (mL/ Table4: Incidence of Hypoglycemia* in Controlled Clinical Studies
min/1.73m2) -1.5 -3.6 -4.0 Canagliozin Canagliozin
* Week26 in mITT LOCF population Monotherapy Placebo 100mg 300mg
(26weeks) (N=192) (N=195) (N=197)
In the pool of four placebo-controlled trials where patients had normal
or mildly impaired baseline renal function, the proportion of patients Overall [N (%)] 5 (2.6) 7 (3.6) 6 (3.0)
who experienced at least one event of signicant renal function decline, Canagliozin Canagliozin
dened as an eGFR below 80mL/min/1.73m2 and 30%lower than baseline, In Combination Placebo 100mg 300mg
was 2.1% with placebo, 2.0% with canagliozin 100 mg, and 4.1% with with Metformin + Metformin + Metformin + Metformin
canagliozin 300mg. At the end of treatment, 0.5%with placebo, 0.7%with (26weeks) (N=183) (N=368) (N=367)
canagliozin 100mg, and 1.4%with canagliozin 300mg had a signicant Overall [N (%)] 3 (1.6) 16 (4.3) 17 (4.6)
renal function decline.
Severe [N (%)] 0 (0) 1 (0.3) 1 (0.3)
In a trial carried out in patients with moderate renal impairment with a
In Combination Canagliozin Canagliozin
baseline eGFR of 30to less than 50mL/min/1.73m2 (mean baseline eGFR
with Metformin Placebo 100mg 300mg
39 mL/min/1.73 m2), the proportion of patients who experienced at least (18weeks) (N=93) (N=93) (N=93)
one event of signicant renal function decline, dened as an eGFR 30%
lower than baseline, was 6.9% with placebo, 18% with canagliozin Overall [N (%)] 3 (3.2) 4 (4.3) 3 (3.2)
100 mg, and 22.5% with canagliozin 300 mg. At the end of treatment, Canagliozin Canagliozin
4.6% with placebo, 3.4% with canagliozin 100 mg, and 2.2% with In Combination Placebo 100mg 300mg
canagliozin 300mg had a signicant renal function decline. with Metformin + Metformin + Metformin + Metformin
In a pooled population of patients with moderate renal impairment + Sulfonylurea + Sulfonylurea + Sulfonylurea + Sulfonylurea
(26weeks) (N=156) (N=157) (N=156)
(N=1085) with baseline eGFR of 30 to less than 60 mL/min/1.73 m2 (mean
baseline eGFR 48 mL/min/1.73 m2), the overall incidence of these events Overall [N (%)] 24 (15.4) 43 (27.4) 47 (30.1)
was lower than in the dedicated trial but a dose-dependent increase in Severe [N (%)] 1 (0.6) 1 (0.6) 0
incident episodes of signicant renal function decline compared to Canagliozin Canagliozin
placebo was still observed. In Combination Placebo 100mg 300mg
Use of canagliozin has been associated with an increased incidence of with Metformin + Metformin + Metformin + Metformin
renal-related adverse reactions (e.g., increased blood creatinine, + Pioglitazone + Pioglitazone + Pioglitazone + Pioglitazone
decreased glomerular ltration rate, renal impairment, and acute renal (26weeks) (N=115) (N=113) (N=114)
failure), particularly in patients with moderate renal impairment. Overall [N (%)] 3 (2.6) 3 (2.7) 6 (5.3)
INVOKAMET XR (canagliozin and metformin hydrochloride extended-release) tablets
Table4: Incidence of Hypoglycemia* in Controlled Clinical Studies
(continued)
In Combination Canagliozin Canagliozin
with Insulin Placebo 100mg 300mg
(18weeks) (N=565) (N=566) (N=587)
Overall [N (%)] 208 (36.8) 279 (49.3) 285 (48.6)
Severe [N (%)] 14 (2.5) 10 (1.8) 16 (2.7)
In Combination
with Insulin Canagliozin Canagliozin
and Metformin Placebo 100mg 300mg
(18weeks) (N=145) (N=139) (N=148)
Overall [N (%)] 66 (45.5) 58 (41.7) 70 (47.3)
Severe [N (%)] 4 (2.8) 1 (0.7) 3 (2.0)
* Number of patients experiencing at least one event of hypoglycemia
based on either biochemically documented episodes or severe
hypoglycemic events in the intent-to-treat population
Severe episodes of hypoglycemia were dened as those where the
patient required the assistance of another person to recover, lost
consciousness, or experienced a seizure (regardless of whether
biochemical documentation of a low glucose value was obtained)
Phase 2 clinical study with twice daily dosing (50mg or 150mg twice daily
in combination with metformin)
Subgroup of patients (N=287) from insulin substudy on canagliozin in
combination with metformin and insulin (with or without other antiglycemic
agents)
Bone Fracture: The occurrence of bone fractures was evaluated in a pool
of nine clinical trials with a mean duration of exposure to canagliozin of
85 weeks. The incidence rates of adjudicated bone fractures were 1.1, 1.4,
and 1.5 per 100patient-years of exposure in the comparator, canagliozin
100 mg, and canagliozin 300 mg groups, respectively. Fractures were
observed as early as 12 weeks after treatment initiation and were more
likely to be low trauma (e.g., fall from no more than standing height), and
affect the upper extremities [see Warnings and Precautions].
Metformin: The most common adverse reactions (5% or greater incidence)
due to initiation of metformin are diarrhea, nausea, vomiting, atulence,
asthenia, indigestion, abdominal discomfort, and headache.
Long-term treatment with metformin has been associated with a decrease
in vitamin B12, which may very rarely result in clinically signicant
vitamin B12 deciency (e.g., megaloblastic anemia) [see Warnings and
Precautions].
Laboratory and Imaging Tests: Increases in Serum Potassium: In a pooled
population of patients (N=723) with moderate renal impairment (eGFR 45 to
less than 60 mL/min/1.73 m2), increases in serum potassium to greater than
5.4 mEq/L and 15% above baseline occurred in 5.3%, 5.0%, and 8.8% of
patients treated with placebo, canagliflozin 100 mg, and canagliflozin
300 mg, respectively. Severe elevations (greater than or equal to
6.5 mEq/L) occurred in 0.4% of patients treated with placebo, no patients
treated with canagliflozin 100 mg, and 1.3% of patients treated with
canagliflozin 300 mg.
In these patients, increases in potassium were more commonly seen in
those with elevated potassium at baseline. Among patients with moderate
renal impairment, approximately 84% were taking medications that
interfere with potassium excretion, such as potassium-sparing diuretics,
angiotensin-converting-enzyme inhibitors, and angiotensin-receptor
blockers [see Warnings and Precautions and Use in Specific Populations].
Increases in Serum Magnesium: Dose-related increases in serum
magnesium were observed early after initiation of canagliozin (within
6 weeks) and remained elevated throughout treatment. In the pool of four
placebo-controlled trials, the mean percent change in serum magnesium
levels was 8.1% and 9.3% with canagliozin 100 mg and canagliozin
300 mg, respectively, compared to -0.6% with placebo. In a trial of
patients with moderate renal impairment, serum magnesium levels
increased by 0.2%, 9.2%, and 14.8% with placebo, canagliozin 100 mg,
and canagliozin 300mg, respectively.
Increases in Serum Phosphate: Dose-related increases in serum
phosphate levels were observed with canagliozin. In the pool of four
placebo-controlled trials, the mean percent change in serum phosphate
levels were 3.6% and 5.1% with canagliozin 100 mg and canagliozin
300mg, respectively, compared to 1.5%with placebo. In a trial of patients
with moderate renal impairment, the mean serum phosphate levels
increased by 1.2%, 5.0%, and 9.3% with placebo, canagliozin 100mg, and
canagliozin 300mg, respectively.
Increases in Low-Density Lipoprotein Cholesterol (LDL-C) and non-High-
Density Lipoprotein Cholesterol (non-HDL-C): In the pool of four placebo-
controlled trials, dose-related increases in LDL-C with canagliozin were
INVOKAMET XR (canagliozin and metformin hydrochloride extended-release) tablets
observed. Mean changes (percent changes) from baseline in LDL-C
relative to placebo were 4.4 mg/dL (4.5%) and 8.2 mg/dL (8.0%) with
canagliozin 100 mg and canagliozin 300 mg, respectively. The mean
baseline LDL-C levels were 104 to 110mg/dL across treatment groups [see
Warnings and Precautions].
Dose-related increases in non-HDL-C with canagliozin were observed.
Mean changes (percent changes) from baseline in non-HDL-C relative to
placebo were 2.1 mg/dL (1.5%) and 5.1 mg/dL (3.6%) with canagliozin
100 mg and 300 mg, respectively. The mean baseline non-HDL-C levels
were 140to 147mg/dL across treatment groups.
Increases in Hemoglobin: In the pool of four placebo-controlled trials,
mean changes (percent changes) from baseline in hemoglobin were
-0.18g/dL (-1.1%) with placebo, 0.47 g/dL (3.5%)with canagliozin 100mg,
and 0.51 g/dL (3.8%) with canagliozin 300 mg. The mean baseline
hemoglobin value was approximately 14.1g/dL across treatment groups.
At the end of treatment, 0.8%, 4.0%, and 2.7% of patients treated with
placebo, canagliozin 100mg, and canagliozin 300mg, respectively, had
hemoglobin levels above the upper limit of normal.
Decreases in Bone Mineral Density: Bone mineral density (BMD) was
measured by dual-energy X-ray absorptiometry in a clinical trial of 714
older adults (mean age 64 years). At 2 years, patients randomized to
canagliozin 100 mg and canagliozin 300 mg had placebo-corrected
declines in BMD at the total hip of 0.9% and 1.2%, respectively, and at the
lumbar spine of 0.3% and 0.7%, respectively. Additionally, placebo-
adjusted BMD declines were 0.1% at the femoral neck for both
canagliozin doses and 0.4% at the distal forearm for patients randomized
to canagliozin 300 mg. The placebo-adjusted change at the distal forearm
for patients randomized to canagliozin 100mg was 0%.
Postmarketing Experience: The following adverse reactions have been
identified during postapproval use of canagliflozin. Because these
reactions are reported voluntarily from a population of uncertain size, it is
not always possible to reliably estimate their frequency or establish a
causal relationship to drug exposure.
Ketoacidosis [see Warnings and Precautions]
Acute Kidney Injury and Impairment in Renal Function [see Warnings and
Precautions]
Anaphylaxis, Angioedema [see Warnings and Precautions]
Urosepsis and Pyelonephritis [see Warnings and Precautions]
DRUG INTERACTIONS
Drug Interactions with Metformin: Carbonic Anhydrase Inhibitors:
Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide,
acetazolamide or dichlorphenamide) frequently causes a decrease in
serum bicarbonate and induce non-anion gap, hyperchloremic metabolic
acidosis. Concomitant use of these drugs with INVOKAMET XR may
increase the risk for lactic acidosis. Consider more frequent monitoring of
these patients.
Drugs That Reduce Metformin Clearance: Drugs that are eliminated by
renal tubular secretion (e.g. cationic drugs such as cimetidine) have the
potential for interaction with metformin by competing for common renal
tubular transport systems, and may increase the accumulation of
metformin and the risk for lactic acidosis [see Clinical Pharmacology (12.3)
in full Prescribing Information]. Consider more frequent monitoring of
these patients.
Alcohol: Alcohol is known to potentiate the effect of metformin on lactate
metabolism. Warn patients against excessive alcohol intake while
receiving INVOKAMETXR.
Drugs Affecting Glycemic Control: Certain drugs tend to produce
hyperglycemia and may lead to loss of glycemic control. These drugs
include the thiazides and other diuretics, corticosteroids, phenothiazines,
thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid,
sympathomimetics, calcium channel blockers, and isoniazid. When such
drugs are administered to a patient receiving INVOKAMETXR, monitor for
loss of blood glucose control. When such drugs are withdrawn from a
patient receiving INVOKAMETXR, monitor for hypoglycemia.
Drug Interactions with Canagliozin: UGT Enzyme Inducers: Rifampin:
Rifampin lowered canagliozin exposure which may reduce the efcacy
of INVOKAMET XR. If an inducer of UGTs (e.g., rifampin, phenytoin,
phenobarbital, ritonavir) must be co-administered with INVOKAMET XR,
consider increasing the dose of canagliozin to a total daily dose of
300 mg once daily if patients are currently tolerating INVOKAMET XR
with 100 mg canagliozin once daily, have an eGFR greater than
60 mL/min/1.73 m2, and require additional glycemic control. Consider
other antihyperglycemic therapy in patients with an eGFR of 45 to less
than 60 mL/min/1.73 m2 receiving concurrent therapy with a UGT inducer
and require additional glycemic control [see Dosage and Administration
(2.3) and Clinical Pharmacology (12.3) in full Prescribing Information].
INVOKAMET XR (canagliozin and metformin hydrochloride extended-release) tablets
Digoxin: Canagliozin increased digoxin exposure. Digoxin, as a cationic
drug, also has the potential to compete with metformin for common
renal tubular transport systems [see Drug Interactions]. Monitor patients
taking INVOKAMETXR with concomitant digoxin for a need to adjust dose
of either drug.
Drug/Laboratory Test Interference: Positive Urine Glucose Test:
Monitoring glycemic control with urine glucose tests is not recommended
in patients taking SGLT2 inhibitors as SGLT2 inhibitors increase urinary
glucose excretion and will lead to positive urine glucose tests. Use
alternative methods to monitor glycemic control.
Interference with 1,5-anhydroglucitol (1,5-AG) Assay: Monitoring glycemic
control with 1,5-AG assay is not recommended as measurements of
1,5-AG are unreliable in assessing glycemic control in patients taking
SGLT2 inhibitors. Use alternative methods to monitor glycemic control.
USE IN SPECIFIC POPULATIONS
Pregnancy: Risk Summary: Based on animal data showing adverse renal
effects, INVOKAMETXR is not recommended during the second and third
trimesters of pregnancy.
Limited data with INVOKAMETXR or canagliflozin in pregnant women are
not sufficient to determine a drug-associated risk for major birth defects
or miscarriage. Published studies with metformin use during pregnancy
have not reported a clear association with metformin and major birth
defect or miscarriage risk [see Data]. There are risks to the mother and
fetus associated with poorly controlled diabetes in pregnancy [see Clinical
Considerations].
In animal studies, adverse renal pelvic and tubule dilatations that were not
reversible were observed in rats when canagliflozin was administered at
an exposure 0.5-times the 300 mg clinical dose, based on AUC during a
period of renal development corresponding to the late second and third
trimesters of human pregnancy. No adverse developmental effects were
observed when metformin was administered to pregnant Sprague Dawley
rats and rabbits during the period of organogenesis at doses up to 2- and
6-times, respectively, a 2000mg clinical dose, based on body surface area
[see Data].
The estimated background risk of major birth defects is 6-10% in women
with pre-gestational diabetes with an HbA1c >7 and has been reported to
be as high as 20-25% in women with a HbA1c >10. The estimated
background risk of miscarriage for the indicated population is unknown. In
the U.S. general population, the estimated background risk of major birth
defects and miscarriage in clinically recognized pregnancies is 2-4% and
15-20%, respectively.
Clinical Considerations: Disease-associated maternal and/or embryo/fetal
risk: Poorly controlled diabetes in pregnancy increases the maternal risk
for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm
delivery, stillbirth and delivery complications. Poorly controlled diabetes
increases the fetal risk for major birth defects, stillbirth, and macrosomia
related morbidity.
Data: Human Data: Published data from post-marketing studies have not
reported a clear association with metformin and major birth defects,
miscarriage, or adverse maternal or fetal outcomes when metformin was
used during pregnancy. However, these studies cannot definitely establish
the absence of any metformin-associated risk because of methodological
limitations, including small sample size and inconsistent comparator
groups.
Animal Data: Canagliflozin: Canagliflozin dosed directly to juvenile rats
from postnatal day (PND) 21 until PND 90 at doses of 4, 20, 65, or
100 mg/kg increased kidney weights and dose dependently increased the
incidence and severity of renal pelvic and tubular dilatation at all doses
tested. Exposure at the lowest dose was greater than or equal to 0.5-times
the 300 mg clinical dose, based on AUC. These outcomes occurred with
drug exposure during periods of renal development in rats that
correspond to the late second and third trimester of human renal
development. The renal pelvic dilatations observed in juvenile animals did
not fully reverse within a 1 month recovery period.
In embryo-fetal development studies in rats and rabbits, canagliflozin was
administered for intervals coinciding with the first trimester period of
organogenesis in humans. No developmental toxicities independent of
maternal toxicity were observed when canagliflozin was administered at
doses up to 100 mg/kg in pregnant rats and 160 mg/kg in pregnant rabbits
during embryonic organogenesis or during a study in which maternal rats
were dosed from gestation day (GD) 6 through PND 21, yielding exposures
up to approximately 19-times the 300 mg clinical dose, based on AUC.
Metformin Hydrochloride: Metformin hydrochloride did not cause adverse
developmental effects when administered to pregnant Sprague Dawley rats
and rabbits up to 600 mg/kg/day during the period of organogenesis. This
represents an exposure of about 2- and 6-times a 2000 mg clinical dose
based on body surface area (mg/m2) for rats and rabbits, respectively.
INVOKAMET XR (canagliozin and metformin hydrochloride extended-release) tablets
Canagliflozin and Metformin: No adverse developmental effects were
observed when canagliflozin and metformin were co-administered to
pregnant rats during the period of organogenesis at exposures up to 11
and 13 times, respectively, the 300 mg and 2000 mg clinical doses of
canagliflozin and metformin based on AUC.
Lactation: Risk Summary: There is no information regarding the presence
of INVOKAMET XR or canagliflozin in human milk, the effects on the
breastfed infant, or the effects on milk production. Limited published
studies report that metformin is present in human milk [see Data].
However, there is insufficient information on the effects of metformin on
the breastfed infant and no available information on the effects of
metformin on milk production. Canagliflozin is present in the milk of
lactating rats [see Data]. Since human kidney maturation occurs in utero
and during the first 2 years of life when lactational exposure may occur,
there may be risk to the developing human kidney.
Because of the potential for serious adverse reactions in a breastfed infant,
advise women that use of INVOKAMET XR is not recommended while
breastfeeding.
Data: Human Data: Published clinical lactation studies report that
metformin is present in human milk which resulted in infant doses
approximately 0.11% to 1% of the maternal weight-adjusted dosage and a
milk/plasma ratio ranging between 0.13 and 1. However, the studies were
not designed to definitely establish the risk of use of metformin during
lactation because of small sample size and limited adverse event data
collected in infants.
Animal Data: Radiolabeled canagliflozin administered to lactating rats on day
13 post-partum was present at a milk/plasma ratio of 1.40, indicating that
canagliflozin and its metabolites are transferred into milk at a concentration
comparable to that in plasma. Juvenile rats directly exposed to canagliflozin
showed a risk to the developing kidney (renal pelvic and tubular dilatations)
during maturation.
Females and Males of Reproductive Potential: Discuss the potential for
unintended pregnancy with premenopausal women as therapy with
metformin may result in ovulation in some anovulatory women.
Pediatric Use: Safety and effectiveness of INVOKAMET XR in pediatric
patients under 18years of age have not been established.
Geriatric Use: INVOKAMETXR: Because renal function abnormalities can
occur after initiating canagliozin, metformin is substantially excreted by
the kidney, and aging can be associated with reduced renal function,
monitor renal function more frequently after initiating INVOKAMETXR in
the elderly and then adjust dose based on renal function [see Dosage
and Administration(2.2) in full Prescribing Information and Warnings and
Precautions].
Canagliflozin: Two thousand thirty-four (2034)patients 65years and older,
and 345patients 75years and older were exposed to canagliozin in nine
clinical studies of canagliozin. Of these patients, 1334 patients 65 years
and older and 181 patients 75 years and older were exposed to the
combination of canagliozin and metformin [see Clinical Studies(14) in full
Prescribing Information]. Patients 65 years and older had a higher
incidence of adverse reactions related to reduced intravascular volume
with canagliozin (such as hypotension, postural dizziness, orthostatic
hypotension, syncope, and dehydration), particularly with the 300mg daily
dose, compared to younger patients; a more prominent increase in the
incidence was seen in patients who were 75years and older [see Dosage
and Administration (2.1) in full Prescribing Information and Adverse
Reactions]. Smaller reductions in HbA1C with canagliozin relative to
placebo were seen in older (65years and older; -0.61% with canagliozin
100 mg and -0.74% with canagliozin 300 mg relative to placebo)
compared to younger patients (-0.72% with canagliozin 100 mg and
-0.87%with canagliozin 300mg relative to placebo).
Metformin: Controlled clinical studies of metformin did not include
sufcient numbers of elderly patients to determine whether they respond
differently from younger patients, although other reported clinical
experience has not identied differences in responses between the
elderly and younger patients. The initial and maintenance dosing of
metformin should be conservative in patients with advanced age due to
the potential for decreased renal function in this population. Any dose
adjustment should be based on a careful assessment of renal function
[see Contraindications, Warnings and Precautions, and Clinical
Pharmacology(12.3) in full Prescribing Information].
Renal Impairment: Canagliflozin: The efficacy and safety of canagliflozin
were evaluated in a study that included patients with moderate renal
impairment (eGFR 30 to less than 50mL/min/1.73m2). These patients had
less overall glycemic efficacy and had a higher occurrence of adverse
reactions related to reduced intravascular volume, renal-related adverse
reactions, and decreases in eGFR compared to patients with mild renal
impairment or normal renal function (eGFR greater than or equal to
INVOKAMET XR (canagliozin and metformin hydrochloride extended-release) tablets
60 mL/min/1.73 m2). Dose-related, transient mean increases in serum
potassium were observed early after initiation of canagliflozin (i.e., within
3 weeks) in this trial. Increases in serum potassium of greater than
5.4 mEq/L and 15% above baseline occurred in 16.1%, 12.4%, and 27.0% of
patients treated with placebo, canagliflozin 100 mg, and canagliflozin
300 mg, respectively. Severe elevations (greater than or equal to
6.5 mEq/L) occurred in 1.1%, 2.2%, and 2.2% of patients treated with
placebo, canagliflozin 100 mg, and canagliflozin 300 mg, respectively [see
Dosage and Administration (2.2) in full Prescribing Information,
Contraindications, Warnings and Precautions, and Adverse Reactions].
The efcacy and safety of canagliozin have not been established in
patients with severe renal impairment (eGFR less than 30mL/min/1.73m2),
with ESRD, or receiving dialysis. Canagliozin is not expected to be
effective in these patient populations [see Contraindications and Clinical
Pharmacology (12.3) in full Prescribing Information].
Hepatic Impairment: Use of metformin in patients with hepatic
impairment has been associated with some cases of lactic acidosis.
INVOKAMETXR is not recommended in patients with hepatic impairment.
[see Warnings and Precautions]
OVERDOSAGE
In the event of an overdose with INVOKAMET XR, contact the Poison
Control Center. Employ the usual supportive measures (e.g., remove
unabsorbed material from the gastrointestinal tract, employ clinical
monitoring, and institute supportive treatment) as dictated by the patients
clinical status. Canagliozin was negligibly removed during a 4-hour
hemodialysis session. Canagliozin is not expected to be dialyzable by
peritoneal dialysis. Metformin is dialyzable with a clearance of up to
170mL/min under good hemodynamic conditions. Therefore, hemodialysis
may be useful partly for removal of accumulated metformin from patients
in whom INVOKAMETXR overdosage is suspected.
Canagliflozin: There were no reports of overdose during the clinical
development program of canagliozin.
Metformin: Overdose of metformin hydrochloride has occurred, including
ingestion of amounts greater than 50 grams. Hypoglycemia was
reported in approximately 10% of cases, but no causal association with
metformin hydrochloride has been established. Lactic acidosis has been
reported in approximately 32% of metformin overdose cases [see
Warnings and Precautions].
PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-Approved Patient Labeling (Medication
Guide).
Lactic Acidosis: Explain the risks of lactic acidosis, its symptoms, and
conditions that predispose to its development, as noted in Warnings
and Precautions. Advise patients to discontinue INVOKAMET XR
immediately and to promptly notify their healthcare provider if
unexplained hyperventilation, myalgias, malaise, unusual somnolence or
other nonspecic symptoms occur. Once a patient is stabilized on
INVOKAMETXR, gastrointestinal symptoms, which are common during
initiation of metformin, are unlikely to recur. Later occurrence of
gastrointestinal symptoms could be due to lactic acidosis or other
serious disease.
Instruct patients to keep INVOKAMETXR in the original bottle to protect
from moisture. Do not put INVOKAMETXR in pill boxes or pill organizers.
Counsel patients against excessive alcohol intake while receiving
INVOKAMETXR.
Inform patients about importance of regular testing of renal function and
hematological parameters while receiving INVOKAMETXR.
Advise patients to seek medical advice promptly during periods of stress
such as fever, trauma, infection, or surgery, as medication requirements
may change.
Instruct patients that INVOKAMET XR must be swallowed whole and
never crushed, cut, or chewed, and that the inactive ingredients may
occasionally be eliminated in the feces as a soft mass that may
resemble the original tablet.
Instruct patients to take INVOKAMET XR only as prescribed once daily
with the morning meal. If a dose is missed, advise patients to take it as
soon as it is remembered unless it is almost time for the next dose, in
which case patients should skip the missed dose and take the medicine
at the next regularly scheduled time. Advise patients not to take more
than two tablets of INVOKAMET XR at the same time.
Hypotension: Inform patients that symptomatic hypotension may occur
with INVOKAMET XR and advise them to contact their doctor if they
experience such symptoms [see Warnings and Precautions]. Inform
patients that dehydration may increase the risk for hypotension and to
have adequate uid intake.
INVOKAMET XR (canagliozin and metformin hydrochloride extended-release) tablets
Ketoacidosis: Inform patients that ketoacidosis is a serious life-
threatening condition. Cases of ketoacidosis have been reported during
use of canagliozin. Instruct patients to check ketones (when possible)
if symptoms consistent with ketoacidosis occur even if blood glucose is
not elevated. If symptoms of ketoacidosis (including nausea, vomiting,
abdominal pain, tiredness, and labored breathing) occur, instruct
patients to discontinue INVOKAMET XR and seek medical advice
immediately [see Warnings and Precautions].
Acute Kidney Injury: Inform patients that acute kidney injury has been
reported during use of canagliozin. Advise patients to seek medical
advice immediately if they have reduced oral intake (such as due to
acute illness or fasting), or increased uid losses (such as due to
vomiting, diarrhea, or excessive heat exposure), as it may be
appropriate to temporarily discontinue INVOKAMET XR use in those
settings [see Warnings and Precautions].
Serious Urinary Tract Infections: Inform patients of the potential for
urinary tract infections, which may be serious. Provide them with
information on the symptoms of urinary tract infections. Advise them to
seek medical advice if such symptoms occur [see Warnings and
Precautions].
Genital Mycotic Infections in Females: Inform female patients that
vaginal yeast infection (e.g., vulvovaginitis) may occur and provide them
with information on the signs and symptoms of a vaginal yeast infection.
Advise them of treatment options and when to seek medical advice [see
Warnings and Precautions].
Genital Mycotic Infections in Males: Inform male patients that yeast
infection of penis (e.g., balanitis or balanoposthitis) may occur,
especially in uncircumcised males and patients with prior history.
Provide them with information on the signs and symptoms of balanitis
and balanoposthitis (rash or redness of the glans or foreskin of the
penis). Advise them of treatment options and when to seek medical
advice [see Warnings and Precautions].
Hypersensitivity Reactions: Inform patients that serious hypersensitivity
reactions, such as urticaria, rash, anaphylaxis, and angioedema, have
been reported with canagliozin. Advise patients to report immediately
any signs or symptoms suggesting allergic reaction and to discontinue
drug until they have consulted prescribing physicians [see Warnings
and Precautions].
Bone Fracture: Inform patients that bone fractures have been reported
in patients taking canagliozin. Provide them with information on factors
that may contribute to fracture risk.
Laboratory Tests: Inform patients that they will test positive for glucose
in their urine while on INVOKAMETXR [see Drug Interactions].
Pregnancy: Advise pregnant women, and females of reproductive
potential of the potential risk to a fetus with treatment with
INVOKAMET XR [see use in Specic Populations]. Instruct females of
reproductive potential to report pregnancies to their physicians as soon
as possible.
Lactation: Advise women that breastfeeding is not recommended during
treatment with INVOKAMETXR [see Use in Specic Populations].
Inform females that treatment with INVOKAMET XR may result in
ovulation in some premenopausal anovulatory women which may lead to
unintended pregnancy [see Use in Specic Populations].
Inform patients that the most common adverse reactions associated
with canagliozin are genital mycotic infection, urinary tract infection,
and increased urination. Most common adverse reactions associated
with metformin are diarrhea, nausea, vomiting, atulence, asthenia,
indigestion, abdominal discomfort, and headache.
Manufactured for:
Janssen Pharmaceuticals, Inc.
Titusville, NJ 08560
Finished product manufactured by:
Janssen Ortho, LLC
Gurabo, PR 00778
Licensed from Mitsubishi Tanabe Pharma Corporation
2016 Janssen Pharmaceuticals, Inc.
Revised: 09/2016
060253-160916
 Now Approved:

Visit
INVOKAMETXRhcp.com
for more information

Please see Brief Summary of full Prescribing

Information, including Boxed WARNING,
for INVOKAMET XR on previous pages.

Janssen Pharmaceuticals, Inc.

Canagliozin is licensed from Mitsubishi Tanabe Pharma Corporation.
Janssen Pharmaceuticals, Inc. 2016 October 2016 059040-160826