Vi F ct F

December 2016

Fo

sit or o
rP
Volume 41 Number 12

A
an mk rmu
t
ro

d it. la
du

Re co ry
gi m D
st
er at
a
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 decline after delivery. Careful monitoring of glucose control is essential in these patients.
episode where a laboratory or a self-measured glucose calibrated to plasma was less than 56 mg/dL or Subcutaneous reproduction and teratology studies have been performed with insulin
where a whole blood glucose was less than 50 mg/dL (i.e., with or without the presence of hypoglycemic degludec and human insulin (NPH) as a comparator in rats and rabbits. In these studies,
symptoms). 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
Allergic Reactions: Severe, life-threatening, generalized allergy, including anaphylaxis, those observed with human insulin as both caused pre- and post-implantation losses
generalized skin reactions, angioedema, bronchospasm, hypotension, and shock may and visceral/skeletal abnormalities in rats at an insulin degludec dose of 21 U/kg/day
occur with any insulin, including TRESIBA and may be life threatening [see Warnings (approximately 5 times the human exposure (AUC) at a human subcutaneous dose of
and Precautions]. Hypersensitivity (manifested with swelling of tongue and lips, 0.75 U/kg/day) and in rabbits at a dose of 3.3 U/kg/day (approximately 10 times the
diarrhea, nausea, tiredness, and itching) and urticaria were reported in 0.9% of patients human exposure (AUC) at a human subcutaneous dose of 0.75 U/kg/day). The effects
treated with TRESIBA. Lipodystrophy: Long-term use of insulin, including TRESIBA, are probably secondary to maternal hypoglycemia. Nursing Mothers: It is unknown
can cause lipodystrophy at the site of repeated insulin injections. Lipodystrophy whether insulin degludec is excreted in human milk. Because many drugs, including
includes lipohypertrophy (thickening of adipose tissue) and lipoatrophy (thinning human insulin, are excreted in human milk, caution should be exercised when insulin
of adipose tissue) and may affect insulin absorption. Rotate insulin injection sites degludec is administered to a nursing mother. Women with diabetes who are lactating
within the same region to reduce the risk of lipodystrophy. In the clinical program, may require adjustments in insulin dose, meal plan, or both. In rats, insulin degludec
lipodystrophy, lipohypertrophy, or lipoatrophy was reported in 0.3% of patients treated was secreted in milk and the concentration in milk was lower than in plasma. Pediatric
with TRESIBA. Injection Site Reactions: Patients taking TRESIBA may experience Use: The safety and efcacy of TRESIBA in children and adolescents under the age of
injection site reactions, including injection site hematoma, pain, hemorrhage, erythema, 18 have not been established. Geriatric Use: In controlled clinical studies a total of
nodules, swelling, discoloration, pruritus, warmth, and injection site mass. In the clinical 77 (7%) of the 1102 TRESIBA -treated patients with type 1 diabetes were 65 years or
program, injection site reactions occurred in 3.8% of patients treated with TRESIBA. older and 9 (1%) were 75 years or older. A total of 670 (25%) of the 2713 TRESIBA -
Weight Gain: Weight gain can occur with insulin therapy, including TRESIBA, and has treated patients with type 2 diabetes were 65 years or older and 80 (3%) were 75 years
been attributed to the anabolic effects of insulin. In the clinical program after 52 weeks or older. Differences in safety or effectiveness were not suggested in subgroup analyses
of treatment, patients with type 1 diabetes treated with TRESIBA gained an average comparing subjects older than 65 years to younger subjects. Nevertheless, greater
of 1.8 kg and patients with type 2 diabetes treated with TRESIBA gained an average caution should be exercised when TRESIBA is administered to geriatric patients since
of 3.0 kg. Peripheral Edema: Insulin, including TRESIBA, may cause sodium retention greater sensitivity of some older individuals to the effects of TRESIBA cannot be ruled
and edema. In the clinical program, peripheral edema occurred in 0.9% of patients with out. The initial dosing, dose increments, and maintenance dosage should be conservative
type 1 diabetes mellitus and 3.0% of patients with type 2 diabetes mellitus treated with to avoid hypoglycemia. Hypoglycemia may be more difcult to recognize in the elderly.
TRESIBA. Immunogenicity: As with all therapeutic proteins, insulin administration Renal Impairment: In clinical studies a total of 75 (7%) of the 1102 TRESIBA -treated
may cause anti-insulin antibodies to form. The detection of antibody formation is highly patients with type 1 diabetes had an eGFR less than 60 mL/min/1.73 m2 and 1 (0.1%)
dependent on the sensitivity and specicity of the assay and may be inuenced by several had an eGFR less than 30 mL/min/1.73 m2. A total of 250 (9%) of the 2713 TRESIBA -
factors such as: assay methodology, sample handling, timing of sample collection, treated patients with type 2 diabetes had an eGFR less than 60 mL/min/1.73 m2 and no
concomitant medication, and underlying disease. For these reasons, comparison of the subjects had an eGFR less than 30 mL/min/1.73 m2. No clinically relevant difference in
incidence of antibodies to TRESIBA with the incidence of antibodies in other studies the pharmacokinetics of TRESIBA was identied in a study comparing healthy subjects
or to other products, may be misleading. In studies of type 1 diabetes patients, 95.9% and subjects with renal impairment including subjects with end stage renal disease.
of patients who received TRESIBA once daily were positive for anti-insulin antibodies However, as with all insulin products, glucose monitoring should be intensied and the
(AIA) at least once during the studies, including 89.7% that were positive at baseline. In TRESIBA dosage adjusted on an individual basis in patients with renal impairment.
studies of type 2 diabetes patients, 31.5% of patients who received TRESIBA once daily Hepatic Impairment: No difference in the pharmacokinetics of TRESIBA was
were positive for AIA at least once during the studies, including 14.5% that were positive identied in a study comparing healthy subjects and subjects with hepatic impairment
at baseline. The antibody incidence rates for type 2 diabetes may be underreported due (mild, moderate, and severe hepatic impairment). However, as with all insulin products,
to potential assay interference by endogenous insulin in samples in these patients. The glucose monitoring should be intensied and the TRESIBA dosage adjusted on an
presence of antibodies that affect clinical efcacy may necessitate dose adjustments individual basis in patients with hepatic impairment.
to correct for tendencies toward hyper or hypoglycemia. The incidence of anti-insulin OVERDOSAGE: An excess of insulin relative to food intake, energy expenditure, or both
degludec antibodies has not been established. may lead to severe and sometimes prolonged and life-threatening hypoglycemia and
DRUG INTERACTIONS: Table 5 includes clinically signicant drug interactions with hypokalemia [see Warnings and Precautions]. Mild episodes of hypoglycemia usually
TRESIBA. 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
Table 5: Clinically Signicant Drug Interactions with TRESIBA impairment may be treated with intramuscular/subcutaneous glucagon or concentrated
Drugs That May Increase the Risk of Hypoglycemia intravenous glucose. After apparent clinical recovery from hypoglycemia, continued
observation and additional carbohydrate intake may be necessary to avoid reoccurrence
Drugs: Antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, of hypoglycemia. Hypokalemia must be corrected appropriately.
disopyramide, brates, uoxetine, monoamine oxidase inhibitors, pentoxifylline, More detailed information is available upon request.
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. Date of Issue: 09/2015
Version: 1
Drugs That May Increase or Decrease the Blood Glucose Lowering Effect of Novo Nordisk, TRESIBA, FlexTouch, LEVEMIR, NOVOLOG, NovoFine and
TRESIBA NovoTwist are registered trademarks of Novo Nordisk A/S.
Drugs: Alcohol, beta-blockers, clonidine, and lithium salts. Pentamidine may cause TRESIBA is covered by US Patent No. 7,615,532 and other patents pending.
hypoglycemia, which may sometimes be followed by hyperglycemia. FlexTouch is covered by US Patent Nos. 6,899,699, 7,686,786, 8,672,898, 8,684,969,
Intervention: Dose adjustment and increased frequency of glucose monitoring may be required 8,920,383, D724,721, D734,450 and other patents pending.
when TRESIBA is co-administered with these drugs. Manufactured by:
Novo Nordisk A/S
Drugs That May Blunt Signs and Symptoms of Hypoglycemia DK-2880 Bagsvaerd, Denmark
Drugs: Beta-blockers, clonidine, guanethidine, and reserpine For information about TRESIBA contact:
Intervention: Increased frequency of glucose monitoring may be required when TRESIBA is Novo Nordisk Inc.
co-administered with these drugs. 800 Scudders Mill Road
Plainsboro, NJ 08536
USE IN SPECIFIC POPULATIONS: Pregnancy: Pregnancy Category C. There are 1-800-727-6500
no well-controlled clinical studies of the use of insulin degludec in pregnant women. www.novonordisk-us.com
Patients should be advised to discuss with their health care provider if they intend to or 2016 Novo Nordisk
if they become pregnant. Because animal reproduction studies are not always predictive USA16TSM02300 6/2016
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
 STATEMENT OF PURPOSE
P&T provides managed care and formulary management
decision-makers with the latest information to help them
manage their formularies and establish medication-related
policies. Clinical feature articles are written by experts in
the eld and undergo a thorough peer review. The journals
EDITORIAL
mission is to highlight research and data on drug utilization, Editor: J. Stephen McIver
prescribing patterns, and adverse drug reactions in order to (267) 685-3713
facilitate the best possible outcomes for patients. smciver@medimedia.com
Subscribers include members of P&T committees across Managing Editor: Lyn K. Chesna
the health care spectrum, including those in hospitals, (267) 685-3429
health systems, managed care organizations, and govern- lchesna@medimedia.com
ment agencies. This includes physicians, pharmacists, nurs-
es, quality/risk management personnel, administrators, Editor, PTCommunity.com: Chris Fellner
and others. (267) 685-3555
Feature articles address forthcoming drugs, biologic cfellner@medimedia.com
agents, and medical devices; guideline updates; drug utili-
zation evaluations; medication safety; and disease manage- News Writer: Janet Dyer
ment. Regular departments cover these topics as well as
drug legislation. ART
P&T has a circulation of approximately 59,000 readers.
Design Director: Philip Denlinger

Designer: Kevin Riley

Trademark: P&T is a registered trademark of MMMM Group LLC,
an ICON Plc Company.
Publisher: P&T is a peer-reviewed journal for managed care and PUBLISHING
formulary management decision-makers (ISSN 1052-1372) (GST President:
#128741063) (IPM #0608025) and is published monthly by MMMM Lee Termini
Group LLC, with business ofces at 780 Township Line Road, Yardley, (267) 685-3682
PA 19067; telephone: (267) 685-3700; fax: (215) 699-6288. ltermini@medimedia.com
Copyright: Copyright 2016 by MMMM Group LLC. All rights
reserved under the United States, International, and Pan-American Vice President, Group Publisher:
Copyright Conventions. No part of this publication may be repro- Maureen Dwyer Liberti
duced, stored in a retrieval system, photocopied, or transmitted in (267) 685-3603
any form or by any means, mechanical, electronic, or otherwise,
mliberti@medimedia.com
without the prior written permission of MMMM Group LLC. The
copyright law of the United States governs the making of photo- Circulation Manager:
copies or other reproductions of copyrighted material. Jacquelyn Ott
Opinions: The articles in P&T are reviewed by appropriate
(267) 685-3712
members of the editorial board and/or other qualied experts.
The opinions are those of the authors and are not those of the
jott@medimedia.com
publisher, editor, editorial board, or institutions that employ the
authors. Director of Production Services:
Clinical judgment must guide each clinician in weighing the ben- Dawn Flook
ets of treatment against the risk of toxicity. Dosages, indications, (267) 685-3422
and methods of use for products referred to in this publication may dook@medimedia.com
reect the professional literature and other clinical sources or the
clinical experience of the authors and might not be the same as indi- Ofce fax: (215) 699-6288
cated on the approved package insert. Please consult the complete
prescribing information for any products mentioned in this publica- ADVERTISING
tion. MMMM Group LLC assumes no liability for the information
published herein.
Director of Sales:
Reprints: Contact Dawn Flook; telephone: (267) 685-3422; John Loughran
email: dook@medimedia.com. (215) 292-4112
jloughran@americanmedicalcomm.com
POSTMASTER: Send address changes to P&T Journal,
P.O. Box 2019, Morrisville, PA 19067. Periodicals postage paid at
Morrisville, PA, and at additional mailing ofces.

P&T is abstracted or indexed in the following reference sources:

CINAHL (electronic database and Cumulative Index to Nursing
and Allied Health Literature print index), EMBASE (in print and
online), International Pharmaceutical Abstracts, and Scopus. The
full contents of each issue are included in the National Institutes of
Healths PubMed Central archive (www. pubmedcentral.nih.gov).

Vol. 41 No. 12 December 2016 P&T

731
 CONTENTS
December 2016

Cover: Transmission electron micro- FEATURES

scope image of negative-stained
Zika virus (green) isolated from a
microcephaly case. Since the 1950s, Medicare Adds New Long-Term-Care Pharmacy Rules 762
the virus has been known to occur Agency Passes Again on Pharmacist Independence Requirements
within a narrow equatorial belt from A nal rule from the Centers for Medicare and Medicaid Services has added
Africa to Asia. From 2007 to 2016,
Zika virus spread eastward to the
pharmacy requirements for long-term-care facilities that put more responsibility
Americas. This month we focus on its on pharmacists but dont address conict-of-interest concerns.
arrival in the U.S. and on the efforts Stephen Barlas
being made to contain it; see article
on page 778. (Credit: Science Source) PHARMACOVIGILANCE FORUM
Drug-Induced Neutropenia:
DEPARTMENTS 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,
Medication Errors 736
and management of this adverse reaction and presents two case histories.
Preventing fatal PCA
adverse events Donald C. Moore, PharmD, BCPS, BCOP

Prescription: Washington 738 Systemic Thrombolysis for Pulmonary Embolism: A Review 770
Medicare names plans The authors review the evidence behind the use of thrombolytic therapy in
for Part D MTM demo patients with massive or submassive pulmonary embolism. Concurrent heparin
therapy and the management of bleeding episodes are also discussed.
Drug and Device News 739 Colleen Martin, PharmD; Kristine Sobolewski, PharmD; Patrick Bridgeman, PharmD;
Approvals, new indications, and Daniel Boutsikaris, MD
regulatory activities, and more
Zika in America: The Year in Review 778
Pharmaceutical Short on funds and with no therapeutics or vaccines in sight, U.S. health officials
Approval Update 748 are scrambling to prepare for a protracted ght with Zika virus and the mosquitoes
Lisinopril oral solution that carry it. In this article, the author focuses on the arrival of Zika in the U.S.
(Qbrelis) for the treatment of Chris Fellner
hypertension, heart failure,
and acute myocardial MEETING HIGHLIGHTS
infarction; etanercept-szzs
(Erelzi) for multiple
European Society for Medical Oncology 2016 Congress 796
We review several key sessions from the European Society for Medical Oncologys
autoimmune disorders;
annual congress, including those on emerging immunotherapies for melanoma and
and lumacaftor/ivacaftor
nonsmall-cell lung cancer and on treatments for renal, ovarian, and breast cancer.
(Orkambi) for cystic brosis
Walter Alexander
Drug Forecast 751
Daclatasvir (Daklinza) for SEASONS GREETINGS
chronic hepatitis C infection Thanks to Our Readers and Reviewers 802
Research Briefs 769
Attention Readers: P&T is on Facebook, Twitter, and LinkedIn.
Back issues are available on Search for P&T
the PubMed Central archive. Search for
[Pharmacy and @PTJournal780
P&T in Groups
Visit www.pubmedcentral.nih.gov Therapeutics]

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

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 -------------------------------DOSAGE FORMS AND STRENGTHS------------------------
Injection: 200 mg in 20 mL (10 mg/mL) in a single-use vial.
BRIEF SUMMARY OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use RAPIVAB ------------------------------------CONTRAINDICATIONS-----------------------------------
safely and effectively. See full prescribing information for RAPIVAB. Patients with known serious hypersensitivity or anaphylaxis to peramivir or any
component of RAPIVAB.

----------------------------------INDICATIONS AND USAGE-------------------------------- --------------------------------WARNINGS AND PRECAUTIONS---------------------------

RAPIVAB is an inuenza virus neuraminidase inhibitor indicated for the treatment Cases of anaphylaxis and serious skin/hypersensitivity reactions such as Stevens-
of acute uncomplicated inuenza in patients 18 years and older who have been Johnson syndrome and erythema multiforme have occurred with RAPIVAB.
symptomatic for no more than two days. Discontinue RAPIVAB and initiate appropriate treatment if anaphylaxis or serious
skin reaction occurs or is suspected.
Limitations of Use: Neuropsychiatric events: Patients with influenza may be at an increased risk of
Efcacy based on clinical trials in which the predominant inuenza virus type was hallucinations, delirium and abnormal behavior early in their illness. Monitor for signs
inuenza A; a limited number of subjects infected with inuenza B virus were of abnormal behavior.
enrolled.
Consider available information on inuenza drug susceptibility patterns and ---------------------------------ADVERSE REACTIONS--------------------------------------
treatment effects when deciding whether to use. Most common adverse reaction (incidence >2%) is diarrhea.
Efcacy could not be established in patients with serious inuenza requiring
hospitalization. To report SUSPECTED ADVERSE REACTIONS, call 1-844-273-2327 or contact
FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
---------------------------------DOSAGE AND ADMINISTRATION------------------------
Administer as a single dose within 2 days of onset of inuenza symptoms. ---------------------------------------DRUG INTERACTIONS---------------------------------
Recommended dose is 600 mg, administered by intravenous infusion for a minimum Live attenuated inuenza vaccine (LAIV), intranasal: Avoid use of LAIV within 2 weeks
of 15 minutes. before or 48 hours after administration of RAPIVAB, unless medically indicated.
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 --------------------------------USE IN SPECIFIC POPULATIONS---------------------------
10-29 mL/min is 100 mg. Pregnancy: Use if benet outweighs risk.
Hemodialysis: Administer after dialysis. Nursing mothers: Caution should be exercised when administered to a nursing
RAPIVAB must be diluted prior to administration. woman.
See the Full Prescribing Information for drug compatibility information. Revised: 8/2016

Seqirus USA Inc.

King of Prussia, Pennsylvania 19406 2016 Seqirus USA Inc. August 2016 US/RIV/0816/0068
Editor-in-Chief Associate Editor-in-Chief
David B. Nash, MD, MBA Karl A. Matuszewski, MS, PharmD
Dr. Raymond C. and Vice President
Doris N. Grandon Professor First Databank, Inc.
The Jefferson College of Population Health Clinical and Editorial
Philadelphia, Pennsylvania Knowledge Base Services
South San Francisco, California
EDITORIAL BOARD
Richard Afable, MD, MPH Marvin M. Goldenberg, PhD, RPh, MS Luke A. Probst, PharmD, BCPS
President and Chief Executive Ofcer President, Pharmaceutical and Scientic Director of Pharmacy Services
Hoag Memorial Hospital Presbyterian Services Upstate University Hospital/
Newport Beach, California Marvin M. Goldenberg, LLC Downtown Campus
Westeld, New Jersey Clinical Assistant Professor, Departments
Robert L. Barkin, MBA, PharmD of Pediatrics and Medicine
Professor, Faculty of Anesthesiology, Nancy Greengold, MD, MBA SUNY Upstate Medical University
Family Medicine, and Pharmacology Chief Medical Ofcer Syracuse, New York
Rush Medical College of Rush University Sharp Grossmont Hospital/Sharp
Chicago, Illinois HealthCare Sheldon M. Retchin, MD, MSPH
Clinical Pharmacologist La Mesa, California Executive Vice President of Health
North Shore University Health System
Sciences, The Ohio State University
Pain Centers
Matthew Grissinger, RPh, FASCP Chief Executive Ofcer, OSU Wexner
Skokie and Evanston, Illinois
Director, Error Reporting Programs Medical Center
Institute for Safe Medication Practices Columbus, Ohio
Mark J. Baumel, MD, MS Horsham, Pennsylvania
President/Chief Executive Ofcer
Colon Health Centers of America, LLC Vitalina Rozenfeld, PharmD, BCPS
Mendenhall, Pennsylvania Rusty Hailey, PharmD, DPh, MBA, FAMCP Medical Affairs
President, Pharmaceutical Operations AstraZeneca
Thomas Biancaniello, MD Senior Vice President, HealthSpring, Inc. Wilmington, Delaware
Clinical Professor of Pediatrics Nashville, Tennessee
Columbia University Fadia T. Shaya, PhD, MPH
College of Physicians and Surgeons Steven D. Hanks, MD, MMM, FACP Professor and Vice-Chair for Academic
Division of Pediatric Cardiology Executive Vice President Affairs
New York, New York and Chief Medical Ofcer University of Maryland School of Pharmacy
The Hospital of Central Connecticut Associate Director
Joseph E. Biskupiak, PhD, MBA New Britain, Connecticut Center on Drugs and Public Policy
Research Associate Professor Baltimore, Maryland
Department of Pharmacy Practice Michele B. Kaufman, PharmD, CGP, RPh
Director, Pharmacotherapy Outcomes Pharmacist, New YorkPresbyterian
Research Center Arthur F. Shinn, PharmD, FASCP
Lower Manhattan Hospital, Pharmacy
College of Pharmacy, University of Utah President
Department
Salt Lake City, Utah Managed Pharmacy Consultants, LLC
New York, New York
Palm City, Florida
David A. Casey, MD Grant D. Lawless, RPh, MD
Vice Chairman, Department of Psychiatry Associate Professor of Clinical Pharmacy, Brian Swift, PharmD, MBA
University of Louisville Pharmaceutical Economics and Policy Vice President/Chief of Pharmacy
Louisville, Kentucky Director, Master of Science Program in and Accreditation
Healthcare Decision Analysis Thomas Jefferson University Hospital
Alan Caspi, PhD, PharmD, MBA School of Pharmacy Associate Dean of Professional Affairs
President, Caspi & Associates University of Southern California Jefferson College of Pharmacy
New York, New York Los Angeles, California Philadelphia, Pennsylvania

Burke A. Cunha, MD Burton Orland, BS, RPh F. Randy Vogenberg, RPh, PhD
Professor of Medicine President Partner
State University of New York at Stony Brook BioCaRe Consultants Access Market Intelligence and National
Chief, Infectious Disease Division Westport, Connecticut Institute of Collaborative Healthcare
Winthrop-University Hospital Greenville, South Carolina
Mineola, New York
Fred Joseph Pane, RPh, BS, FASHP, FABC
Joseph C. English III, MD Senior Director, Customer Engagement Scott W. Yates, MD, MBA, MS
Professor of Dermatology The Medicines Company Center for Executive Medicine
Clinical Vice Chairman Parsippany, New Jersey Plano, Texas
for Quality and Innovation
Founding Director of Teledermatology Lawrence Charles Parish, MD
University of Pittsburgh Dermatologist, Editor-in-Chief
Department of Dermatology Clinics in Dermatology
Pittsburgh, Pennsylvania Philadelphia, Pennsylvania

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 17 more doses for a total of 20 doses One factor that probably contributed
board member of P&T, is (60 mg), and the basal infusion delivered to the patients respiratory arrest is the
Director of Error Reporting an additional 5.5 mg of morphine. Most delayed transfer of morphine across
Programs at the Institute for of the doses were administered between the bloodbrain barrier.2,3 The repeated
Safe Medication Practices 8 P.M. and midnight. It is unknown if administration of relatively high doses
(ISMP) in Horsham, Penn- the patients wife, who remained at the of morphine at short intervals and the
sylvania (www.ismp.org). patients bedside until midnight, periodi- delayed transfer of the drug to the brain
cally awakened the patient and encour- made it possible for the fatal event to
PROBLEM: A patient underwent surgical aged him to administer a dose or if she occur almost two hours after the bulk
repair of a heel injury. Within 15 minutes administered doses for him while he of self-administered doses were taken.
of arrival in the postanesthesia care unit slept. Around 2 A.M., the patient was found A patient with severe pain may tolerate
(PACU), he received intravenous (IV) in respiratory arrest. Resuscitation efforts larger doses of morphine because the
doses of meperidine 75 mg, morphine were unsuccessful. pain helps counteract the respiratory-
4 mg, and fentaNYL 25 mcg for pain. The Since PCA initiation, nurses had been depressant effects of opioids.2,4,5 However,
patients surgeon also ordered PCA per monitoring the patient every 30 minutes once the pain subsides, previously ade-
anesthesia. A nurse anesthetist wrote for the rst hour, every hour for the quate breathing can quickly become
an order for morphine patient-controlled next three hours, then every two hours. inadequate with the onset of sedation
analgesia (PCA) 1 mg/mL, 3 mg per However, monitoring was less frequent or sleep.4,5
demand dose, lockout of 10 minutes, than required by hospital policy and less Given the widespread use of PCA, most
and a basal rate of 1 mg/hour. Although often than typically recommended for hospitals likely have a PCA story to tell.1
the patient was obese and anxious about patients receiving PCA.1 In addition, the Fortunately, not all of these stories have
inadequate pain control, the prescribed assessment of pain was infrequent, and resulted in death. However, studies have
demand dosepotentially adding up to the assessment of respiratory status did documented the association of PCA with
18 mg/houralong with a basal infu- not include the depth, pattern, and effort harmful and fatal errors,2,6 and analyses of
sion were too much for the patient given of respirations, or breath sounds. Pulse voluntary reports of events have shown
his opioid-nave status. In fact, based on oximetry was not used to measure oxygen a fourfold higher risk of harm with PCA
morphine prescribing information, the saturation, although policy required its errors than with other reported medica-
dose might have been high even for an use and the oximetry equipment was tion errors.1 In most cases, characteris-
opioid-tolerant patient. available in the patients room. tics that place patients at higher risk for
A pharmacist reviewed the PCA order Further, a standard sedation assess- opioid-induced respiratory depression
but did not investigate the patients ment scale was not utilized. Progressive have not been considered, and patient
current opioid usage. He did not question signs of impending respiratory arrest monitoring has been inadequate.7,8
the 3-mg demand dose or the basal infu- were not recognized, particularly those
sion, neither of which is recommended related to the patients level of seda- SAFE PRACTICE RECOMMENDATIONS
for an opioid-nave patient. The morphine tion. After the rst hour of PCA use, ISMP has written about PCA errors
PCA was started around 8 P.M. while the the patient was assessed as awake and numerous times, describing many of the
patient was in the PACU. The patient had alert with a pain assessment score of 4 causative factors, including prescribing
not received preoperative PCA instruc- on a 110 scale. As the evening went on, errors, failing to determine the patients
tions, so the PACU nurse taught the the patient became sleepy and drowsy opioid status and identify risk factors
patient to self-administer the doses. No but easily aroused, although no pain associated with respiratory depression,
further education was provided, and the assessment was documented. By mid- lack of educating patients and families
patients family was not warned about the night, four hours after starting the PCA, about PCA, and inadequate monitoring.9,10
hazards of anyone other than the patient the patient was sleeping and snoring While many things went wrong in the
administering a dose. loudly, and no attempts were made to event described above, the remainder
Within 30 minutes of starting the PCA, arouse the patient to assess his level of of this article focuses on appropriate
the patient had given himself three doses sedation and pain. Two hours later, the monitoring of patients receiving PCA
of morphine, 3 mg each. He reported patient was described as sleeping and a critical, lifesaving activity that can
that his pain was receding, but a pain snoring loudly, but arousable with no provide an early warning of impending
score was not documented. Over the further details. Shortly thereafter, the complications, thus preventing patient
next ve hours, the patient administered patient was found in respiratory arrest. harm even in the presence of an error.

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

 MEDICATION ERRORS

Along with a basic physical assessment awake, ask the patient a question and oxygen, there is no evidence that moni-
and collection of vital signs, the follow- evaluate the response to determine if the toring of oxygen saturation provides an
ing parameters are also important when patient is alert and oriented. If the patient additional measure of safety.12
monitoring patients receiving PCA. is not alert (eyes closed), assess the
patients response to verbal stimuli rst. Frequency of Assessments
Pain Assessment For example, the RASS scale suggests To be effective, patient monitoring
The patients level of pain must be con- stating the patients name and asking the must be conducted at the proper inter-
tinually assessed during use of PCA to patient to open his or her eyes and look at vals. Guidelines that can be used to assess
evaluate the treatments effectiveness. the speaker.11 The degree of movement the adequacy of monitoring frequencies
Use of a standard pain scale and/or and length of eye contact is evaluated to have been developed by the San Diego
tool (e.g., Wong-Baker Faces Scale) is assess the sedation level. If the patient Patient Safety Council.1 Hospitals may
highly recommended for accuracy and does not respond to verbal requests, phys- want to monitor patients more frequently
ease of eliciting a patients description ical stimulation is used, such as lightly at night, as opioid-induced respiratory
of discomfort.1 While the goal of PCA shaking the patients shoulder to evaluate depression is more common between
is pain relief, remember that pain relief the response. Practitioners should have midnight and 6 A.M.4 Keep in mind that
can signal the loss of a compensatory clear guidance regarding which levels of the purpose and frequency of monitoring
mechanism that combats the respiratory- the sedation scale would indicate the need should be explained to patients and their
depressant effects of opioids. Thus, moni- to increase the frequency of monitoring, families so they understand and expect to
toring should be stepped up, and PCA adjust PCA doses, stop the PCA, call the be awakened and monitored frequently.
doses may need to be reduced if pain prescriber, provide airway support and/
relief is accompanied by oversedation. or oxygen, and/or administer naloxone. REFERENCES
1. San Diego Patient Safety Council. Patient
controlled analgesia (PCA) guidelines of
Sedation Assessment Respiratory Assessment care for the opioid nave patient. Decem-
Sedation is an extremely useful assess- Respiratory assessments should ber 2009. Available at: www.hqinstitute.
ment parameter to observe the clinical include evaluation of the rate and quality org/sites/main/les/le-attachments/
effects of opioids. In fact, sedation is of respirations. A respiratory rate of sdpsc_patient_controlled_analygesia_
pca_guidelines_of_care_toolkit_decem-
the most important predictor of respi- 10 breaths per minute or less should ber_2008.pdf. Accessed October 26, 2016.
ratory depression in patients receiv- signal possible discontinuation of PCA.1 2. Lotsch J, Dudziak R, Freynhagen R, et al.
ing IV opioidsa fact that only 22% of The depth of respirations (i.e., normal, Fatal respiratory depression after multiple
physicians, pharmacists, and nurses shallow, deep), pattern of respirations intravenous morphine injections. Clin
Pharmacokinet 2006;45(11):10511060.
knew when taking an opioid knowledge (i.e., regular, irregular), quality of respi-
3. Lotsch J, Skarke C, Schmidt H, et al.
assessment.5 Sedation generally precedes ratory effort (i.e., effortless, comfortable, The transfer half-life of morphine-6-beta-
signicant respiratory depression. While labored), and breath sounds (i.e., clear, glucuronide from plasma to effect site
pain can counteract opioid-induced respi- noisy, snoring, gurgling, stridor) are all assessed by pupil size measurement
ratory depression, sleep can intensify important parameters when assessing in healthy volunteers. Anesthesiology
2001;95(6):13291338.
the depressant effects. In addition, as respiration quality. 4. Borgbjerg FM, Nielsen K, Franks J.
carbon dioxide levels increase with respi- The Anesthesia Patient Safety Founda- Experimental pain stimulates respira-
ratory depression, patients experience tion (APSF) also recommends routine use tion and attenuates morphine-induced
a reduced level of consciousness that is of technology to continuously monitor respiratory depression: a controlled study in
human volunteers. Pain 1996;64(1):
additive to the opioid sedative effects.1 ventilation in patients known to be at
123128.
Thus, for patients receiving PCA, early high risk for respiratory depression 5. Grissinger M. Results of the opioid knowl-
recognition of excessive sedation and (e.g., pre-existing respiratory impair- edge assessment from the PA Hospital
intervention is essential. ment, sleep apnea, elderly, or obese) and Engagement Network Adverse Drug
A standard sedation scale should be consideration of its use when possible Event Collaboration. Pa Patient Saf Advis
2013;10(1):1926.
used when assessing patients receiv- for all patients receiving PCA.7 Continu- 6. Hicks RW, Sikirica V, Nelson W, et al.
ing PCA. The San Diego Patient Safety ous pulse oximetry should be routine, Medication errors involving patient-
Council, which created a useful set of although practitioners should be aware controlled analgesia. Am J Health Syst
PCA guidelines for opioid-nave patients,1 that oximetry readings may remain near Pharm 2008;65(5):429440.
7. Stoelting RK, Weinger MB. Dangers of
prefers the Richmond Agitation Sedation normal for minutes after a patient stops
postoperative opioidsis there a cure?
Scale (RASS)11 because it is simple to use breathing.8 Thus, the APSF suggests APSF Newsletter. Summer 2009;24:2526.
and combines sedation and agitation into using capnography whenever possible 8. Weinger MB. Dangers of postoperative
one scale. However, some hospitals use (even if intermittent) to detect unrecog- opioids: APSF workshop and white paper
the Pasero, Ramsey, or Glasgow Coma nized hypoventilation and carbon dioxide address prevention of postoperative respi-
ratory complications. APSF Newsletter.
scales. retention.7 The APSF also recommends Winter 2006-2007;21:6167.
To assess sedation, health profession- limiting the use of supplemental oxygen 9. ISMP. Safety issues with patient-
als must evaluate how much stimula- when possible for patients receiving PCA, controlled analgesia. Part I. ISMP
tion is necessary to evoke the desired especially if pulse oximetry is the only Medication Safety Alert 2003;8(14):13.
10. ISMP. Safety issues with patient-
response from the patient; thus, one must technology used to detect hypoventila-
controlled analgesia. Part II. ISMP
rst observe the patient. If the patient is tion. For patients receiving supplemental 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 the CMS will pay separately, beyond its The CMS expects the six PDPs to
writer in Washington, normal payment, for each MTM demon- upgrade their connections, electronic
D.C., who covers issues stration, with those funds allowing each and otherwise, with both physician
inside the Beltway. Send plan to go beyond in spending what they ofces and pharmacies. According to the
ideas for topics and your typically spend for MTM plans. They will agency, sponsors may lack information
comments to sbarlas@ be allowed to target members for MTM to help assess medication-related risks,
verizon.net. services in ways they have not been able such as claims or other descriptors of
to do in the past, either because of the ongoing medical care or alignment of
presumed cost of expanding services or beneciaries with an ACO [accountable
ix Part D drug plans sail into the restrictions on targeting them. care organization].

S uncharted waters on January 1

when they embark on experiments
with medication therapy management
There are nearly 40 million Medicare
beneciaries enrolled in a Medicare-
sponsored plan that provides prescrip-
Again, it is unclear whether the six plans
will aggressively upgrade their MTM pro-
grams given the CMSs strong encourage-
(MTM) programs in the new Medicare tion drug coverage, with approximately ment to be judicious with their spending.
demonstration program.1 At a time of 24 million Medicare beneciaries access- It seems almost contradictory to tell PDPs
seemingly rapid prescription-drug cost ing their prescription drugs from a stand- to spend funds to expand their efforts, with
increases, the ve-year demonstration alone prescription drug plan (PDP) Medicare footing the bill, but on the other
program will test the proposition that operating within the Part D outpatient hand, give them strong encouragement
Part D plans can target MTM programs benet. Those PDPs, operating in every to be judicious in those expenditures if
the way they wantnot the way Medicare state, must offer MTM services to plan they want a back-end incentive payment.
regulations insist they do. Those ex- members who meet three criteria: having The use of the word judicious, argues
ible member-targeting and intervention more than one chronic condition, taking Larry Kocot, a former top CMS pharmacy
policies, the latter expected to include multiple drugs (between two and eight), ofcial now working with the Healthcare
more physicians and pharmacies, will and incurring annual costs for covered and Life Sciences Group at KPMG LLP,
hopefully lead to lower Medicare Part A Part D drugs above a cost threshold seems to be a reasonable cautionary
and B costs for the federal government. ($3,138 in 2015). Those criteria t about reminder. So maybe contradictory is
The six plans participating in the 25% of Part D recipients, but only 11% too strong a word. But no one would read
demonstration are: Blue Cross and Blue receive MTM services. the CMS cautionary reminder as a clarion
Shield Northern Plains Alliance, Blue The out-of-bid annual upfront call to action either.
Cross and Blue Shield of Florida, CVS payment is expected to allow plans
Health, Humana, UnitedHealthcare, to enrich their MTM offerings. The REFERENCES
and WellCare Prescription Insurance. 2% per member back-end performance 1. Barlas S. CMS to test enhanced medica-
They will test their particular targeting payment is an incentive for them to tion therapy management model: Aims for
and intervention strategies in selected reduce Part A/B costs. The CMS is greater use of pharmacists, cost savings, and
better outcomes. P T 2016;41(7):423441.
regions: Region 7 (Virginia), Region 11 setting a minimum savings rate of 2% 2. Centers for Medicare and Medicaid Services.
(Florida), Region 21 (Louisiana), in order to qualify for the performance Part D enhanced medication therapy man-
Region 25 (Iowa, Minnesota, Montana, payment. But in guring the savings, agement model. October 11, 2016. Available
Nebraska, North Dakota, South Dakota, the agency will subtract the upfront at: https://innovation.cms.gov/initiatives/
enhancedmtm. Accessed November 1, 2016.
Wyoming), and Region 28 (Arizona).2 payments it made to the plans. That will
3. Centers for Medicare and Medicaid
Through this model, we are hopeful make it harder for the plans to reach the Services. CMS announces Part D
that Part D plans will invest in medication 2% target. The CMS explains: enhanced medication therapy management
therapy management and identify new, model. September 28, 2015. Available at:
effective strategies to optimize medica- Note that this approach of offsetting Parts A www.cms.gov/Newsroom/MediaRelease-
Database/Press-releases/2015-Press-
tion use and improve care coordination and B cost savings by the aggregate amount releases-items/2015-09-28.html. Accessed
in Medicare, said Patrick Conway, MD, of prospective payments for the same period November 1, 2016.
Acting Principal Deputy Administrator of offers plans a strong encouragement to be 4. Hanley S. Announcement of Part D
the Centers for Medicare and Medicaid judicious when determining the upfront enhanced medication therapy manage-
Services (CMS).3 ment model test. Centers for Medicare and
cost of their intervention, since this amount
Medicaid Services. September 28, 2015.
The six plans had to lay out their will count against them when calculating Available at: https://innovation.cms.gov/
strategies for the demonstration and were savings for purposes of determining les/x/mtm-announcement.pdf. Accessed
chosen based on those. The idea is that eligibility for performance payments.4 November 1, 2016. Q

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

 NEW DRUG APPROVALS Flublok Quadrivalent (Daiichi Sankyo). Par Pharmaceutical,
Lartruvo for Flu Vaccine Inc., and Torrent Pharmaceuticals Ltd.
Soft-Tissue Sarcoma A quadrivalent formulation of Flublok can sell tablets in 20 mg/5 mg/12.5 mg,
The FDA has granted accelerated influenza vaccine (Protein Sciences 40 mg/5 mg/12.5 mg, 40 mg/5 mg/
approval to olaratumab (Lartruvo, Corporation) has received FDA approval. 25 mg, 40 mg/10 mg/12.5 mg, and
Eli Lilly) in combination with doxoru- Flublok Quadrivalent protects against 40 mg/10 mg/25 mg. A third company,
bicin to treat adults with certain types four strains of inuenzathree of the Sun Pharmaceutical Industries Ltd.,
of soft-tissue sarcoma (STS), which are same strains found in trivalent Flublok says it has launched authorized generic
cancers that develop in muscles, fat, plus an additional B strain. The product versions. The medication is indicated for
tendons, or other soft tissues. Olara- is approved for adults 18 years of age and treatment of hypertension.
tumab is approved for use with the FDA- older and will be available in prelled Sources: FDA, October 26, 2016;
approved chemotherapy drug doxorubi- syringes beginning in 2017. and Sun Pharmaceutical Industries,
cin for the treatment of patients with STS Source: Protein Sciences, October 11, October 27, 2016
who cannot be cured with radiation or 2016
surgery and who have a type of STS for Amlodipine and Olmesartan
which an anthracycline (chemotherapy) Generic Approvals and Launches Medoxomil Tablets
is an appropriate treatment. Olmesartan Medoxomil/ The FDA has authorized Macleods
Olaratumab is a platelet-derived growth Hydrochlorothiazide and Pharmaceuticals Ltd. and Teva Pharma-
factor (PDGF) receptor-alphablocking Olmesartan Medoxomil Tablets ceuticals USA, Inc., to produce amlodip-
antibody. When stimulated, PDGF recep- The FDA has approved the rst generic ine and olmesartan medoxomil tablets,
tors cause tumor growth. Olaratumab is versions of Daiichi Sankyos Benicar HCT 5 mg/20 mg, 5 mg/40 mg, 10 mg/20 mg,
the rst new therapy approved for the ini- and Benicar, which together had U.S. and 10 mg/40 mg. These are the rst
tial treatment of STS since doxorubicins sales of approximately $1.8 billion for the generic versions of Azor (Daiichi
approval more than 40 years ago. 12 months ending with August, according Sankyo), used for treatment of hyper-
Source: FDA, October 19, 2016 to IMS Health. tension. In addition, Sun Pharmaceuti-
Olmesartan medoxomil and hydro- cal Industries Ltd. says it has launched
Zinplava for chlorothiazide tablets, 20 mg/12.5 mg, authorized generic versions.
C. Difficile Infections 40 mg/12.5 mg, and 40 mg/25 mg (Beni- Sources: FDA, October 26, 2016;
The FDA has approved bezlotoxumab car HCT), and olmesartan medoxomil and Sun Pharmaceutical Industries,
(Zinplava, Merck), a monoclonal anti- tablets, 5 mg, 20 mg, and 40 mg (Beni- October 27, 2016
body indicated to reduce the recurrence car), can be marketed by Mylan Pharma-
of Clostridium difcile infection (CDI) ceuticals. Both products are indicated for Ribavirin for Inhalation Solution
in patients 18 years of age or older who the treatment of hypertension. The FDA has approved ribavirin for
are receiving antibacterial drug treat- Meanwhile, Sun Pharmaceutical Indus- inhalation solution USP, 6 g per vial, to
ment for CDI and are at high risk for tries Ltd. has announced the U.S. launch be marketed by Navinta LLC. This is the
CDI recurrence. Bezlotoxumab is not of authorized generic versions of both rst generic version of Virazole for inhala-
indicated for the treatment of CDI. It is products. tion solution (Valeant Pharmaceuticals),
not an antibacterial drug. Bezlotoxumab Sources: FDA and Mylan, October 26, used for the treatment of hospitalized
should be used only in conjunction with 2016; and Sun Pharmaceutical Industries, infants and young children with severe
antibacterial drug treatment of CDI. October 27, 2016 lower respiratory tract infections due to
As with all therapeutic proteins, there respiratory syncytial virus.
is a potential for immunogenicity after Olmesartan Medoxomil, Amlodipine, Source: FDA, October 6, 2016
the administration of bezlotoxumab. After And Hydrochlorothiazide Tablets
treatment in two phase 3 studies, how- Two companies have secured FDA Generic Antihistamine/Decongestant
ever, none of the 710 evaluable patients approval to market the first generic Acella Pharmaceuticals has secured
tested positive for treatment-emergent olmesartan medoxomil, amlodip- approval for a sugar-free bioequiva-
anti-bezlotoxumab antibodies. ine, and hydrochlorothiazide tablets, lent to the antihistamine/decon-
Source: Merck, October 21, 2016 sold under the brand name Tribenzor gestant Bromfed-DM cough syrup

Vol. 41 No. 12 December 2016 P&T

739
(brompheniramine maleate, pseudo- with autistic disorder; and treatment of The NDA was partly based on results
ephedrine hydrochloride, and dextro- Tourettes disorder. from a phase 3 trial that showed that
methorphan hydrobromide syrup, Source: Dr. Reddys Laboratories, ribociclib plus letrozole reduced the
2 mg/30 mg/10 mg per 5 mL). This October 13, 2016 risk of disease progression or death by
combination is used to temporarily 44% compared with letrozole alone
relieve symptoms caused by the common NEW INDICATION (hazard ratio, 0.556; P = 0.00000329),
cold, u, allergies, and other breathing Keytruda for signicantly extending progression-free
illnesses. Metastatic Lung Cancer survival.
Source: Acella Pharmaceuticals, The FDA has cleared pembrolizumab Ribociclib is a selective cyclin-
October 28, 2016 (Keytruda, Merck), an anti-programmed dependent kinase (CDK) inhibitor, a
death receptor-1 (PD-1) therapy, for class of drugs that helps slow the progres-
Nystatin/Triamcinolone Cream the rst-line treatment of patients with sion of cancer by inhibiting two proteins,
Glenmark Pharmaceuticals has metastatic nonsmall-cell lung cancer CDK4 and CDK6. These proteins, when
secured nal FDA approval for nystatin (NSCLC) whose tumors have high overactivated in a cell, can allow cancer
and triamcinolone acetonide cream USP, programmed death ligand-1 (PD-L1) cells to grow and divide too quickly.
100,000 units/g and 1 mg/g. This is a expression (i.e., a tumor proportion Source: Novartis, November 1, 2016
generic version of the antifungal agent score [TPS] of 50% or more), as deter-
Mycolog-II cream, 100,000 units/g, 0.1% mined by an FDA-approved test, with no Brigatinib for NSCLC
(Delcor Asset Corporation), which is no epidermal growth factor receptor or The FDA has accepted for review
longer marketed in the United States. anaplastic lymphoma kinase genomic the new drug application for brigatinib
Source: Glenmark Pharmaceuticals, tumor aberrations. With this new indi- (Ariad Pharmaceuticals), an investiga-
October 25, 2016 cation, pembrolizumab is the only tional oral anaplastic lymphoma kinase
antiPD-1 therapy to be approved in (ALK) inhibitor, for patients with
Benztropine Mesylate Tablets the rst-line treatment setting for these metastatic ALK-positive nonsmall-
ANI Pharmaceuticals, Inc., has patients. cell lung cancer (NSCLC) who have
announced the launch of benztropine In addition, the FDA approved a label- progressed on crizotinib. The FDA
mesylate tablets USP 0.5 mg, 1 mg, and ing update to include data from the granted a priority review and set an action
2 mg. The product is indicated for use KEYNOTE-010 trial in the second-line date of April 29, 2017.
as an adjunct to the therapy for all forms or greater treatment setting for patients An ongoing phase 3 trial is assessing
of parkinsonism and may also be use- with metastatic NSCLC whose tumors the efcacy and safety of brigatinib in
ful in the control of extrapyramidal dis- express PD-L1 (TPS of 1% or more), as comparison with crizotinib in patients
orders (except tardive dyskinesia) due to determined by an FDA-approved test, with locally advanced or metastatic
neuroleptic drugs. with disease progression on or after ALK-positive NSCLC who have not
Source: ANI Pharmaceuticals, October platinum-containing chemotherapy. received prior treatment with an ALK
25, 2016 Source: Merck, October 24, 2016 inhibitor.
Source: Ariad Pharmaceuticals,
Aripiprazole Tablets FDA REVIEW ACTIVITIES October 31, 2016
Dr. Reddys Laboratories has launched Priority Review Status
aripiprazole USP in 2-mg, 5-mg, 10-mg, Ribociclib for Breast Cancer Spinraza for Spinal Muscular Atrophy
15-mg, 20-mg, and 30-mg tablets The FDA has accepted the new drug The FDA has accepted for prior-
a generic version of the second- application (NDA) for ribociclib (LEE011, ity review a new drug application for
generation antipsychotic agent Abilify Novartis) and has granted the drug a nusinersen (Spinraza, Biogen), an inves-
(Otsuka Pharmaceutical Company). Oral priority review for the first-line tigational treatment for spinal muscular
Abilify has the following indications: treatment of postmenopausal women atrophy (SMA). If approved, nusinersen
schizophrenia; acute treatment of manic with hormone receptor-positive, human would be the rst therapy for SMA, a
and mixed episodes associated with epidermal growth factor receptor-2- leading genetic cause of infant mortality.
bipolar I; adjunctive treatment of major negative advanced or metastatic breast Nusinersen is an antisense oligonucleo-
depressive disorder; irritability associated cancer in combination with letrozole. tide that is designed to alter splicing of

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

the SMN2 gene in order to increase the VMAT1 or other receptors, transporters, CC8464/ASP1807 for Neuropathic Pain
production of fully functional SMN and ion channels. The FDA has granted a fast-track
proteins. Source: Neurocrine Biosciences, designation to the drug candidate
Source: Biogen, October 28, 2016 October 11, 2016 CC8464/ASP1807 (Chromocell Corpo-
ration/Astellas Pharma) for the man-
Opdivo for Bladder Cancer Fast-Track Designations agement of neuropathic pain associated
The FDA has accepted a supplemental OTL 38 Molecule Lights Up Cancer with idiopathic small-ber neuropathy.
biologics license application that seeks to The FDA has granted fast-track status In 2015, Chromocell and Astellas entered
expand the use of nivolumab (Opdivo, to a Purdue University scientists opti- into a collaboration agreement for the
Bristol-Myers Squibb) to patients with cal imaging technology that may signi- development and commercialization
locally advanced unresectable or meta- cantly improve outcomes for patients with of CC8464/ASP1807 for the manage-
static urothelial carcinoma that has pro- pancreatic cancer. ment of neuropathic pain and other pain
gressed on or after platinum-containing Dr. Philip Low developed the OTL 38 indications. Chromocell recently dosed
therapy. The FDA granted the application molecule, which will move quickly to the rst subject in a phase 1 trial designed
a priority review, with an action date of phase 3 trials in human cancer patients. to evaluate the safety, tolerability, and
March 2, 2017. The molecule, given to patients intra- pharmacokinetics of an oral formulation
The submission was based on data venously, attaches to receptors on cancer of CC8464/ASP1807.
from a phase 2, single-arm study, which cells and glows, identifying the cells that Chromocells CC8464 is an oral,
evaluated the safety and efficacy of should be surgically removed. highly selective, peripherally restricted
nivolumab in 270 patients with metastatic Positive results from a phase 2 study NaV1.7 inhibitor that has been shown to
or unresectable urothelial carcinoma of OTL 38 were important to gaining be effective in animal models of human
that had progressed or recurred after fast-track status. In that study, 96% of the neuropathic and inflammatory pain.
treatment with a platinum-based agent tissue that was illuminated in patients NaV1.7 is an ion channel involved in pain
in the metastatic setting or within was conrmed by pathology to be can- transmission.
one year after neoadjuvant/adjuvant cerous, and 98% of the malignant lesions Source: Chromocell Corporation,
platinum therapy. In this trial, nivolumab identied by the surgeons uoresced October 12, 2016
achieved an objective response rate (the brightly because of their uptake of the
primary endpoint) of 19.6%. uorescent dye. Breakthrough Therapy Status
Source: Bristol-Myers Squibb, October Source: Purdue University, October NiCord Graft Modality
21, 2016 26, 2016 The FDA has granted breakthrough
therapy status to NiCord (Gamida Cell,
Ingrezza for Tardive Dyskinesia Resolaris for Muscular Dystrophy Ltd.), an investigational graft modality for
The FDA has accepted for prior- Resolaris (aTyr Pharma) has been bone marrow transplantation in patients
ity review a new drug application for granted fast-track status by the FDA with high-risk blood cancers, such as
valbenazine (Ingrezza, Neurocrine Bio- for the treatment of patients with leukemia and lymphoma. An international,
sciences) for the treatment of patients facioscapulohumeral muscular dystro- phase 3 registration study is expected to
with tardive dyskinesia. The target action phy (FSHD), making it the rst thera- begin before the end of the year.
date is April 11, 2017. peutic candidate for FSHD to receive Data from phase 1/2 studies of NiCord
Vesicular monoamine transporter 2 this designation. Resolaris, a designated have demonstrated clinically meaningful
(VMAT2), a protein in the human brain, orphan drug in FSHD, is being studied improvements in the time to neutrophil
is primarily responsible for repackaging in a phase 1b/2 clinical program. The engraftment compared with cord blood
and transporting monoamines (dopa- treatment is derived from a naturally transplantation. In addition, NiCord study
mine, norepinephrine, serotonin, and occurring protein released in vitro by data have shown fewer infections, reduced
histamine) in presynaptic neurons. human skeletal-muscle cells. FSHD, a lengths of hospitalization, quicker platelet
Valbenazine is an investigational, highly rare genetic myopathy affecting an esti- engraftment, and improved nonrelapse
selective VMAT2 inhibitor that modulates mated 19,000 people in the United States, mortality compared with unmanipulated
dopamine release during nerve commu- has no approved treatments. cord blood transplantation.
nication, showing little or no afnity for Source: aTyr Pharma, October 24, 2016 Source: Gamida Cell, October 11, 2016

Vol. 41 No. 12 December 2016 P&T

741
 Orphan Drug Designations platform, Halozyme Therapeutics). methicillin-resistant Staphylococcus
YS-ON-001 for Liver Cancer It is marketed under the brand name aureus.
The FDA has granted an orphan drug MabThera SC in countries outside the The submissions were based on results
designation for the biologic product can- United States. from two phase 3 studies. In both trials,
didate YS-ON-001 (Yisheng Biopharma Source: Halozyme, November 3, 2016 delaoxacin met the primary endpoint
Co.) for the treatment of patients with of noninferiority to a combination regi-
hepatocellular carcinoma. YS-ON-001 is Xaracoll for Postsurgical Pain men of vancomycin plus aztreonam in
a multicomponent complex with immuno- A new drug application for Xaracoll reducing lesion size at the primary
modulatory properties, such as promot- (bupivacaine hydrochloride collagen- infection site 48 to 72 hours after
ing Th1-biased immunity; inducing the matrix implants, Innocoll AG) has been treatment.
activation and proliferation of dendritic submitted to the FDA for the treatment Source: Ligand Pharmaceuticals,
cells, B cells, and natural killer cells; pro- of postsurgical pain. The submission October 24, 2016
moting macrophage M1 polarization; and was based on successful results from the
down-regulating regulatory T cells. MATRIX trials, which showed statistically Shingrix Shingles Vaccine
Source: Yisheng Biopharma, October signicant differences in the primary end- A biologics license application has
24, 2016 point (the sum of pain intensity in both been submitted to the FDA for a candi-
studies), as well as statistically signi- date shingles (herpes zoster) vaccine,
TNT009 for Anemia cant reductions in opioid use and other Shingrix (GlaxoSmithKline), seeking
The FDA has granted orphan drug secondary endpoints. approval for prevention of the disease
status to TNT009 (True North Therapeu- Source: Innocoll, November 3, 2016 in people 50 years of age or older. In
tics) for the treatment of patients with phase 3 data, the nonlive recombinant
autoimmune hemolytic anemia (AHA), Niraparib for Ovarian Cancer vaccine not only reduced the incidence of
including cold agglutinin disease (CAD), Tesaro, Inc., has completed a roll- shingles, but also reduced the overall inci-
a form of AHA for which there are limited ing new drug application submission to dence of postherpetic neuralgia, a form
treatment options. TNT009 is currently in the FDA for the use of niraparib in the of chronic pain associated with shingles.
a phase 1b trial in patients with CAD, and maintenance treatment of patients with Regulatory approval is being sought for
positive interim results from this study platinum-sensitive, recurrent epithe- the vaccine to be given intramuscularly
were reported in June 2016. lial ovarian, fallopian tube, or primary in two doses, with a two- to six-month
TNT009 is a rst-in-class monoclonal peritoneal cancer who are in response to interval between doses.
antibody that selectively targets C1s, a platinum-based chemotherapy. Niraparib Shingrix combines glycoprotein E,
serine protease within the C1-complex is an oral, once-daily poly (ADP-ribose) a protein found on the varicella zoster
in the immune systems complement polymerase inhibitor. The FDA granted virus that causes shingles, with an adju-
pathway. TNT009 prevents downstream the drug a fast-track designation in vant system, AS01B, which is intended
disease processes involving phagocytosis, September 2016. to enhance the immunological response
inammation, and cell lysis. Source: Tesaro, November 1, 2016 to the antigen.
Source: True North Therapeutics, Source: GlaxoSmithKline, October 24,
October 13, 2016 Baxdela for Skin Infections 2016
New drug applications have been
New or Revised Applications submitted to the FDA for the approval ZS-9 for Hyperkalemia
Subcutaneous Rituximab of intravenous and oral formula- The FDA has accepted for review the
For Blood Cancers tions of delaoxacin (Baxdela, Ligand resubmission of a new drug application
The FDA has accepted the biologics Pharmaceuticals/Melinta Therapeu- for sodium zirconium cyclosilicate (ZS-9,
license application for a subcutaneous tics) for the treatment of patients with ZS Pharma/AstraZeneca), a potential new
formulation of rituximab (Genentech) acute bacterial skin and skin-structure medication for the treatment of patients
for multiple blood cancer indications. infections. Delaoxacin is an investi- with hyperkalemia. Sodium zirconium
The product is a coformulation with gational anionic uoroquinolone with cyclosilicate is an insoluble, nonabsorbed
a proprietary recombinant human a broad spectrum of antimicrobial compound with a structure designed to
hyaluronidase enzyme (the Enhanze activity, including activity against preferentially capture potassium ions.

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

The compound has been studied in to limit the medications use to patients of analyses to assess the effect that
three double-blind, placebo-controlled whose tumors have specic epidermal this faulty monitoring device may have
trials and in one ongoing 12-month, open- growth factor receptor (EGFR) mutations. had on the ROCKET-AF study results.
label study in patients with hyperkalemia, The labeling change applies to patients The agency determined that effects of
representing a treatment population of with NSCLC receiving maintenance or the device on strokes or bleeding, includ-
more than 1,600 patients. second- or greater-line treatment. These ing intracranial bleeding, were minimal.
Source: AstraZeneca, October 18, 2016 indications will be limited to patients The FDA concluded that rivaroxaban is
whose tumors have EGFR exon 19 dele- a safe and effective alternative to war-
Avycaz for Urinary Tract Infections tions or exon 21 L858R substitution muta- farin in patients with nonvalvular atrial
The FDA has accepted for ling a tions, as detected by an FDA-approved brillation.
supplemental new drug application for test. The rst-line indication previously Source: FDA, October 11, 2016
Avycaz (ceftazidime/avibactam). The was limited to patients with EGFR exon
manufacturer, Allergan, is seeking the 19 deletions or exon 21 substitution DRUG SAFETY ISSUES
addition of new phase 3 clinical trial data mutations. Checkpoint Inhibitors
to the current product label. The new Source: FDA, October 18, 2016 And Myocarditis Deaths
data involve the use of Avycaz in patients Checkpoint inhibitors are popular
with complicated urinary tract infections, Other Regulatory Issues treatments for cancer, but an article in
including pyelonephritis, due to desig- Methylphenidate ER the New England Journal of Medicine
nated susceptible pathogens. The FDA Lannett Company, Inc., has received has warned that combining the check-
is expected to take action on the ling notice from the FDA that it will seek point inhibitors nivolumab (Opdivo) and
during the rst quarter of 2017. to withdraw approval of the compa- ipilimumab (Yervoy)both marketed
Source: Allergan, October 11, 2016 nys abbreviated new drug application by Bristol-Myers Squibbcould lead
for methylphenidate hydrochloride to death in a small number of patients.
Labeling Changes extended-release (ER) tablets. Lannett According to the article, two melanoma
Xtandi for Prostate Cancer stated that it will review the scientic patients receiving combination treatment
The FDA has approved a supplemental rationale for the FDAs position and with nivolumab and ipilimumab died from
new drug application to update the prod- compile the scientic evidence needed fulminant myocarditis. Autopsies showed
uct labeling for enzalutamide capsules to convince the agencys Office of that the immune systems of both patients
(Xtandi, Astellas Pharma) to include Generic Products that the methyl- had attacked their hearts.
new clinical data versus bicalutamide phenidate ER tablets should continue According to the article, myocarditis
from the TERRAIN study. The updated to be marketed. The company has until has occurred in 0.27% of patients treated
label includes data showing that enzalu- December 19, 2016, to submit new data. with nivolumab and ipilimumab in
tamide reduced the risk of radiographic Source: Lannett Company, October pharmacovigilance studies, suggesting
progression or death by 40% compared 19, 2016 that the patients in the new report had
with bicalutamide in men with metastatic experienced a rare, potentially fatal,
castration-resistant prostate cancer, with FDA Conrms Xarelto Efficacy T-celldriven drug reaction.
median radiographic progression-free sur- In July 2016, the hand-held, point-of- In addition to nivolumab and ipilim-
vival of 19.5 months for the enzalutamide care INRatio device (Alere, Inc.) was umab, two other checkpoint inhibitors
group compared with 13.4 months for the recalled because of the potential to are on the market: pembrolizumab
bicalutamide group (hazard ratio, 0.60). generate inaccurate results. This device (Keytruda, Merck) and atezolizumab
Source: Astellas Pharma, October 21, was used to monitor warfarin therapy in (Tecentriq, Genentech).
2016 the control group of the pivotal ROCKET- Source: BioSpace, November 3, 2016
AF trial, which provided the primary data
Tarceva for Lung Cancer to support the 2011 approval of the blood- Testosterone Warnings
The FDA has modied the indication for thinner rivaroxaban (Xarelto, Janssen). The FDA has approved class-wide
erlotinib (Tarceva, Astellas Pharma Global Because of the concern about the INRatio labeling changes for all prescription
Development, Inc.) for the treatment of device, the FDAs Center for Drug Evalu- testosterone products, adding a new
nonsmall-cell lung cancer (NSCLC) ation and Research conducted a series warning and updating the abuse and

Vol. 41 No. 12 December 2016 P&T

743
dependence section to include new CLINICAL TRIAL NEWS Verubecestat for
safety information from published Bremelanotide for Hypoactive Alzheimers Disease
literature and case reports regarding Sexual Desire Disorder Research leading to the discovery and
the risks associated with abuse of and Positive, statistically signicant results development of verubecestat (Merck)
dependence on testosterone and other have been reported from the phase 3 for the potential treatment of patients
anabolic steroids. clinical trial program for bremelanotide with Alzheimers disease (AD) has been
The abuse of testosterone, usually at (Palatin Technologies), an investigational published in Science Translational
doses higher than those typically pre- on-demand treatment for premenopausal Medicine.
scribed and usually in conjunction with women diagnosed with hypoactive sexual Verubecestat, an investigational small-
other anabolic steroids, is associated with desire disorder. Two studies in the clini- molecule inhibitor of the enzyme beta-
serious safety risks affecting the heart, cal program have met their prespecied site amyloid precursor protein-cleaving
brain, liver, mental health, and endocrine coprimary efcacy endpoints. enzyme 1 (BACE1), emerged from
system. Reported serious adverse out- Bremelanotide, a melanocortin 4 recep- several years of detailed analysis of the
comes include heart attack, heart failure, tor agonist drug candidate, is a synthetic structure and function of the BACE1
stroke, depression, hostility, aggression, peptide analogue of the naturally occur- protein. Subsequent phase 1 data from
liver toxicity, and male infertility. Individ- ring hormone alpha-MSH (melanocyte- both healthy volunteers and AD patients
uals abusing high doses of testosterone stimulating hormone). In clinical trials, demonstrated that once-daily doses of
have also reported withdrawal symptoms, bremelanotide was self-administered verubecestat for one week provided sig-
such as depression, fatigue, irritability, on an as-needed (not chronic) basis in nicant reductions of up to 80% in the
loss of appetite, decreased libido, and anticipation of sexual activity. levels of amyloid-beta peptide production,
insomnia. Source: Palatin Technologies, a key marker of BACE1 activity.
Source: FDA, October 25, 2016 November 1, 2016 The efcacy and safety of verubecestat
are being evaluated in two pivotal phase 3
Ceftriaxone/Lansoprazole Emicizumab for Hemophilia trials, EPOCH and APECS, for the treat-
Tied to Heart Condition Four patients have experienced ment of patients with mild-to-moderate
Researchers at Columbia University serious thrombotic events in a clinical AD and prodromal AD, respectively.
studied the combination of ceftriaxone trial of the experimental hemophilia Source: Merck, November 2, 2016
(Rocephin, Roche), an antibiotic, and medication emicizumab (ACE910,
lansoprazole (Prevacid, Takeda), a Genentech/Roche), dimming hopes Lynparza for Ovarian Cancer
heartburn medication. Alone, these for the potential blockbuster drug, Results of a phase 3 study designed
medications carry no known heart-related according to a Reuters report. The to determine the efcacy of olaparib
risksbut when used together, they patients were being treated for (Lynparza, GlaxoSmithKline) as mono-
may increase the chance that patients breakthrough bleeding. A Roche spokes- therapy for the maintenance treatment
develop a heart condition known as long man told Reuters that the cases involved of women with platinum-sensitive,
QT syndrome, which can cause abnormal patients who were treated with one of two relapsed, BRCA-mutated ovarian cancer
heart rhythms and, in rare cases, sudden bypassing agents. He added that both demonstrated a statistically signicant
death, according to the investigators. The agentsShires FEIBA and Novos Novo- improvement in progression-free survival
study found that patients taking ceftri- Sevencarried thrombosis warnings. among patients treated with olaparib
axone and lansoprazole together were Emicizumab is an investigational compared with those given placebo.
1.4 times more likely to have a prolonged humanized bispecic monoclonal antibody Olaparib is a rst-in-class oral poly
QT interval than were patients who were engineered to simultaneously bind fac- (ADP-ribose) polymerase inhibitor that
taking either drug alone. tors IXa and X. The drug is being closely is believed to exploit deciencies in the
Source: Columbia University Medical watched because it could change the way tumor DNA damage response pathway
Center, October 10, 2016 hemophilia is treated. to preferentially kill cancer cells. It is
Source: Reuters, November 2, 2016 approved by the FDA for the treatment
of women with BRCA-mutated ovarian
cancer.
Source: AstraZeneca, October 26, 2016

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

 Adalimumab event (SRE) in patients with multiple Elagolix for Pelvic Pain
Biosimilar Candidate myeloma. The secondary endpoints of Associated With Endometriosis
In a pivotal phase 3 trial, BI 695501 superiority in delaying the time to the Positive results have been reported
(Boehringer Ingelheim), a biosimilar rst SRE and superiority in delaying from two replicate pivotal phase 3 trials
candidate to Humira (adalimumab, the time to rst-and-subsequent SREs evaluating the efcacy and safety of elago-
AbbVie), met the studys primary efcacy were not met. The hazard ratio of Xgeva lix (AbbVie/Neurocrine Biosciences), a
endpoint by establishing equivalence versus zoledronic acid for overall survival gonadotropin-releasing hormone recep-
with Humira in patients with active rheu- was 0.90. tor antagonist, in premenopausal women
matoid arthritis. Secondary endpoints Xgeva targets the RANK ligand path- with endometriosis.
comparing the efficacy, safety, and way to prevent the formation, function, In the two studies, both dosages of
immunogenicity of BI 695501 with that and survival of osteoclasts, which break elagolix demonstrated a statistically sig-
of Humira were also met. down bone. Xgeva is indicated for the nicant (P < 0.001) improvement com-
Source: Boehringer Ingelheim, prevention of SREs in patients with bone pared with placebo in the percentage of
October 26, 2016 metastases from solid tumors and for the dysmenorrhea (DYS) and nonmenstrual
treatment of adults and skeletally mature pelvic pain (NMPP) responders. In the
Tramiprosate for adolescents with giant-cell tumors of bone first study, at three months, 46% of
Alzheimers Disease that are unresectable or where surgical patients treated with 150 mg once daily
Efcacy analyses have been conducted resection is likely to result in severe mor- and 76% treated with 200 mg twice daily of
of phase 3 data for the investigational bidity. Xgeva is also indicated in the U.S. elagolix were classied as DYS respond-
amyloid-targeted drug tramiprosate for the treatment of hypercalcemia of ers compared with 20% of patients in the
(Alzheon) in patients with mild or mod- malignancy that is refractory to bisphos- placebo group. In addition, 50% of patients
erate Alzheimers disease (AD). These phonate therapy. Xgeva is not indicated treated with 150 mg once daily and 55%
evaluations involved patient subgroups for the prevention of SREs in patients with of those treated with 200 mg twice daily
based on the number of epsilon-4 alleles multiple myeloma. of elagolix were classied as NMPP
of apolipoprotein E (APOE4), a major Source: Amgen, October 20, 2016 responders compared with 36% of patients
genetic risk factor in up to 65% of AD in the placebo group. The second pivotal
patients. The results showed a genedose Locilex for Diabetic study demonstrated similar results.
effect at the high dosage of tramiprosate Foot Infections Source: AbbVie, October 19, 2016
(150 mg twice daily). Patients with two Two phase 3 trials of pexiganan cream
APOE4 alleles (APOE4/4 homozygotes) 0.8% (Locilex, Dipexium Pharmaceuti- Tenofovir Prodrug
showed the largest clinical benet and cals) in patients with mild infections of For HBV Infection
those with one APOE4 allele (APOE4 diabetic foot ulcers did not meet the Positive interim data have been
heterozygotes) showed an intermediate primary clinical endpoint of superior- reported for CMX157 (ContraVir
benet, while APOE4 noncarriers showed ity compared with placebo cream plus Pharmaceuticals), a prodrug of tenofo-
no benet from tramiprosate. The results standardized wound care. The results vir, from an ongoing phase 2a multiple-
provided the rst evidence from a large also did not show any meaningful differ- ascending-dose clinical trial. The study is
clinical trial to associate the efcacy of an ences in wound closure rates between comparing CMX157 with tenofovir diso-
amyloid-targeted agent with APOE4 status the pexiganan arm and the vehicle arm proxil fumarate (TDF) (Viread, Gilead
in AD patients. in each study. Further, neither trial met Pharmaceuticals) in patients chronically
Source: Alzheon, October 25, 2016 the secondary endpoint of demonstrating infected with hepatitis B virus (HBV).
a higher rate of eradication of bacteria for The interim data were obtained from
Xgeva for Bone Complications the pexiganan arm. 10 HBV-infected patients who completed
Caused by Multiple Myeloma Pexiganan cream 0.8% is a chemi- 14 days of once-daily oral dosing of 25 mg
A phase 3 study evaluating denosumab cally synthesized, 22-amino acid peptide of CMX157, and from two HBV patients
(Xgeva, Amgen) versus zoledronic acid isolated from the skin of the African treated for 14 days of oral dosing with
met the primary endpoint of noninferior- clawed frog. 300 mg TDF. The CMX157-treated
ity (hazard ratio, 0.98) in delaying the Source: Dipexium Pharmaceuticals, patients showed an average 99% reduction
time to the rst on-study skeletal-related October 25, 2016 in the HBV viral load compared with base-

Vol. 41 No. 12 December 2016 P&T

745
line. Signicantly, the observed antiviral 290 patients with NSTI at approximately with a stable dose for at least six months.
activity for CMX157 was comparable with 60 centers in the United States. The par- Enrolled patients will be randomly
that observed in TDF-treated patients, but ticipants are receiving AB103 or placebo, assigned to continue treatment with
at 1/12th the dose (25 mg of CMX157 administered as a single dose during or 1 mg/kg of either Fabrazyme or
versus the standard 300 mg of TDF). shortly after surgical debridement, in PRX-102, administered via intravenous
Source: ContraVir Pharmaceuticals, addition to standard-of-care treatment. infusion every two weeks.
October 13, 2016 Source: Atox Bio, November 3, 2016 Source: Protalix BioTherapeutics,
October 25, 2016
AZD9412 for Asthma Nuplavid for Schizophrenia
AstraZeneca has decided to stop a Acadia Pharmaceuticals has announced DEVICE APPROVALS
phase 2a trial for the inhaled interferon the initiation of a six-week phase 3 study BreathID Lab System
(IFN)-beta product AZD9412 based on to evaluate pimavanserin (Nuplavid) for For H. Pylori Detection
an interim analysis in which an over- the adjunctive treatment of schizophrenia The BreathID Lab System and breath-
all very low number of reported severe in patients with an inadequate response test kits (Exalenz Bioscience), developed
exacerbations could make primary to antipsychotic therapy. Antipsychotics for Helicobacter pylori bacterium detec-
endpoint conclusions difcult. currently indicated for schizophrenia tion, have received marketing clearance
Synairgen, based in the United Kingdom, primarily target the dopaminergic pathway. from the FDA. The system was designed
licensed AZD9412 to AstraZeneca in June As a selective serotonin inverse agonist to facilitate the diagnosis of H. pylori infec-
2014. AZD9412 acts as an antiviral protein. (SSIA), pimavanserin belongs to a new tion in large numbers of breath samples
In the INEXAS study, asthma patients class of antipsychotic medications with a at a central location. Patients at clinics
were treated with AZD9412 or placebo at mechanism of action targeting serotonergic and medical centers breathe into two
the onset of common cold symptoms. Pre- 5-HT2A receptors while avoiding activity at designated collection bags, and the
vious research has shown that common dopamine and other receptors commonly breath samples are sent for analysis
colds can cause severe asthma exacerba- targeted by other antipsychotics. to central laboratories, where the new
tions and that boosting the lungs antiviral The FDA approved pimavanserin system will be installed.
defenses with AZD9412 during this time for the treatment of patients with Source: Exalenz Bioscience, November
could prevent exacerbations. hallucinations and delusions associated 1, 2016
Source: Synairgen October 12, 2016 with Parkinsons disease psychosis in
April 2016. The drug is not approved for Amplatzer PFO Occluder
AB103 for Necrotizing the adjunctive treatment of patients with Device to Limit Stroke Risk
Soft-Tissue Infections schizophrenia. The FDA has approved the Amplatzer
After reviewing the rst 50 patients Source: Acadia Pharmaceuticals, PFO Occluder device (St. Jude Medical,
for safety, an independent data monitor- November 3, 2016 Inc.) to reduce the risk of a stroke in
ing committee has recommended that patients who previously experienced a
the phase 3 ACCUTE trial of AB103 PRX-102 for Fabry Disease stroke believed to be caused by a blood
(Atox Bio), a candidate for the treatment The rst patient has been dosed in clot that passed through a small hole in
of patients with necrotizing soft-tissue a global phase 3 study of PRX-102 the heartcalled a patent foramen ovale
infections (NSTI; esh-eating bacteria), (Protalix BioTherapeutics), a modi- (PFO)and then traveled to the brain.
continue without modication. ed version of the recombinant human The Amplatzer PFO Occluder is
AB103 is a peptide that binds to the alpha-GAL-A protein, for the treatment inserted through a catheter that is placed
CD28 costimulatory receptor, thereby mod- of patients with Fabry disease. The in a leg vein and advanced to the heart.
ulating the hosts immune response. By BALANCE trial is a 24-month, random- It is then implanted close to the hole in
modulating, but not inhibiting, the immune ized, double-blind, active-control study the heart between the right atrium and
response, AB103 dampens the out-of- of PRX-102 for the treatment of Fabry the left atrium.
control acute inammatory response that disease in patients with impaired renal The device was on the market more
leads to tissue and organ damage. function. The trial is designed to enroll than a decade ago under a humanitarian
The ACCUTE trial is a randomized, 78 patients previously treated with Fabra- device exemption (HDE), but it was vol-
placebo-controlled study that plans to enroll zyme (agalsidase beta, Sano/Genzyme) untarily withdrawn by the manufacturer in

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

2006 after the FDA concluded that the tar- Battery Failure in changing the tracheostomy tube and
get population for the device was greater St. Jude Debrillators placing a new tube. The use of affected
than 4,000 patients and that the device no The FDA and St. Jude Medical have products may cause serious adverse
longer qualied for HDE approval. alerted physicians, patients, and care- health consequences, including oxygen
Source: FDA, October 28, 2016 givers to respond immediately to elec- deprivation, brain damage, and death.
tive replacement indicator (ERI) alerts Source: FDA, October 20, 2016
Evarrest Fibrin Sealant Patch on implantable cardioverter debrillators
The FDA has approved an expanded and cardiac resynchronization therapy OTHER DEVICE NEWS
indication for Evarrest brin sealant patch debrillators from St. Jude. Because of Wrist-Worn Heart Rate Monitors
(Ethicon), which leverages biologics to problems with the batteries, patients do In a study published online in JAMA
stop problematic bleeding during surgery. not have the normal three-month lead Cardiology, researchers at the Cleve-
The expanded indication supports the use time for device replacement. Some bat- land Clinic assessed the accuracy of
of Evarrest as an adjunctive hemostat for a teries have run out within 24 hours of four popular wrist-worn heart rate (HR)
broad range of patient types and surgical the patient receiving an ERI alert. The monitors under conditions of varying
situations. The new indication for Evarrest warning applies only to St. Jude devices physical exertion. Fifty healthy adults
was supported by a head-to-head study manufactured before May 2015. (average age, 37 years) wore standard
that demonstrated the products superior Source: FDA, October 11, 2016 electrocardiographic limb leads and a
hemostatic efcacy compared with that Polar H7 chest-strap monitor. In addition,
of Tachosil brin sealant patch (Baxter). FDA Warning: each subject was randomly assigned to
Source: Ethicon, October 25, 3016 Radiation Therapy Devices wear two different wrist-worn HR moni-
The FDA has expressed concern tors. Four monitors were assessed: Fitbit
DEVICE SAFETY ISSUES about the risks to patients from the Charge HR (Fitbit), Apple Watch (Apple),
Infection Risk With use of devices manufactured and sold Mio Alpha (Mio Global), and Basis Peak
HeaterCooler Devices by Multidata Systems International (Basis).
The Centers for Disease Control and Corporation. The agency knows of at least The investigators found that the HR
Prevention (CDC) has warned health two Multidata medical devices manufac- monitors had variable accuracy when
care providers about the potential risk tured and distributed in the United States compared with an electrocardiogram.
of infection from certain devices used for which the FDA never received nor While the Basis Peak overestimated
during open heart (open chest) surgery. reviewed 510(k) pre-market notications. HR during moderate exercise, the Fitbit
New information indicates that some These devices include accessories to Charge HR underestimated HR during
LivaNova PLC (formerly Sorin Group radiation therapy devices and the Dual more vigorous exercise. The Apple Watch
Deutschland GmbH) Stckert 3T heater Channel Electrometer. In addition, and Mio Fuse had 95% of values within
cooler devices, used during many of these Multidata has not registered or listed 27 beats per minute (bpm) and +29 bpm
surgeries, might have been contaminated its devices with the FDA, as required by of the electrocardiogram, whereas Fitbit
during manufacturing, which could federal law. Charge HR had 95% of values within 34
put patients at risk for life-threatening Source: FDA, October 20, 2016 bpm and +39 bpm, and the corresponding
infections. values for the Basis Peak were within 39
Laboratory tests showed that Tracheostomy Tube Set Recalled bpm and +33 bpm.
Mycobacterium chimaera organisms from According to the FDA, Teleex has Because cardiac patients increasingly
the heatercooler devices matched bac- recalled the Willy Rusch tracheostomy rely on these monitors to stay within
teria found in patients in several states. tube set because of the possibility that physician-recommended, safe HR thresh-
These results build on previous evidence the connector may disconnect from the olds during rehabilitation and exercise,
from Europe that suggests the bacte- tracheostomy tube during use on a ven- appropriate validation of these devices
ria contaminated these devices during tilated patient. If the connector detaches in this group is imperative, the authors
manufacturing in Germany. from the tracheostomy tube shaft during wrote.
Source: CDC, October 13, 2016 use, it can deprive the patient of adequate Source: Medical Xpress, October 12,
ventilation and would require immedi- 2016 Q
ate medical intervention, including

Vol. 41 No. 12 December 2016 P&T

747
 Pharmaceutical Approval Update
Michele B. Kaufman, PharmD, CGP, RPh

Lisinopril Oral Solution (Qbrelis) should be given to using a different type of dialysis membrane
Manufacturer: Silvergate Pharmaceuticals, Inc., Greenwood or a different antihypertensive class. Anaphylactoid reactions
Village, Colorado have also been reported in patients undergoing low-density
Date of Approval: July 29, 2016 lipoprotein apheresis with dextran sulfate absorption.
Indication: Lisinopril oral solution is indicated Impaired renal function. Renal function should
for the treatment of hypertension (HTN) in patients be periodically monitored in patients treated with
6 years of age and older. It is also approved as adjunc- lisinopril because acute renal failure may occur.
tive therapy for heart failure and to treat acute Consider withholding or discontinuing therapy in
myocardial infarction (MI). patients who develop a clinically signicant decrease
Drug Class: Angiotensin-converting enzyme in renal function.
inhibitor (ACEI) Hypotension. Lisinopril can cause symptomatic
Uniqueness of Drug: Many pediatric patients hypotension, sometimes complicated by oliguria,
require ACEI treatment for HTN. Until the approval progressive azotemia, or acute renal failure, which
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 tension include those with heart failure with systolic
a number of ACEIs were extemporaneously com- blood pressure less than 100 mm Hg, ischemic
pounded to prepare pediatric doses. Qbrelis is the rst and heart disease, cerebrovascular disease, hyponatremia, or
only ACEI oral solution approved by the Food and Drug severe volume and/or salt depletion of any etiology, and those
Administration. It is bioequivalent to lisinopril tablets under undergoing high-dose diuretic therapy or renal dialysis. In
fasted and fed conditions. these patients, lisinopril should be started under close medical
Warnings and Precautions: supervision and should be followed closely during the rst
Boxed warning: fetal toxicity. Lisinopril should be dis- two weeks of treatment and whenever the dose is increased
continued immediately in a pregnant patient. Fetal injury and and/or the diuretic dose is increased. Lisinopril should be
death may occur during the second and third trimesters of avoided in patients who are hemodynamically unstable after
pregnancy. These drugs reduce fetal renal function and increase acute MI. Symptomatic hypotension is also possible in patients
fetal and neonatal morbidity and death. Potential neonatal with severe aortic stenosis or hypertrophic cardiomyopathy.
adverse effects include skull hypoplasia, anuria, hypotension, Hyperkalemia. During lisinopril treatment, serum potas-
renal failure, and death. sium should be periodically monitored because ACEIs can
Head and neck angioedema/intestinal angioedema. cause hyperkalemia. Risk factors for developing hyperkalemia
Angioedema of the face, extremities, lips, tongue, glottis, include renal insufciency, diabetes mellitus, and concomitant
and/or larynx, including some fatal reactions, has occurred in use of potassium-sparing diuretics, potassium supplements,
ACEI-treated patients; intestinal angioedema has also occurred. and/or potassium-containing salt substitutes.
Patients with tongue, glottis, or laryngeal involvement are Hepatic failure. ACEIs have been associated with chole-
likely to experience airway obstruction, especially those with static jaundice or hepatitis progressing to fulminant hepatic
a history of airway surgery. Lisinopril should be discontinued necrosis and sometimes death (mechanism unknown). Patients
promptly and appropriate therapy and monitoring should be receiving ACEIs who develop jaundice or marked hepatic
provided until complete and sustained resolution of angioedema enzyme elevations should immediately discontinue the ACEI
has occurred. Patients with a history of angioedema unrelated and receive appropriate medical treatment.
to ACEI therapy may be at increased risk while receiving an Dosage and Administration: Qbrelis is available in a
ACEI. Coadministration of ACEIs and mammalian target of 150-mL bottle containing 1 mg/mL of lisinopril oral solution.
rapamycin inhibitors (e.g., temsirolimus, sirolimus, everolimus) In adults with HTN, begin treatment with 10 mg once daily.
may increase the risk for angioedema. Adjust the dose to the blood pressure response. Doses up
Anaphylactoid reactions. Two patients undergoing to 80 mg per day have been used, but do not appear to give
desensitizing treatment with hymenoptera venom while receiv- greater effect. In combination with diuretics, the starting dose
ing ACEIs had life-threatening anaphylactoid reactions. Sudden is 5 mg daily.
and potentially life-threatening anaphylactoid reactions have In patients with heart failure, initiate treatment with 5 mg
occurred in some patients dialyzed with high-ux membranes once daily, and increase the dose as tolerated to 40 mg daily.
while being concomitantly treated with an ACEI. Dialysis Acute MI patients should be administered 5 mg within
must be immediately stopped in these patients, and aggres- 24 hours of the MI followed by 5 mg after 24 hours, then
sive therapy must be initiated. Antihistamines did not relieve 10 mg once daily.
the symptoms in these situations. Therefore, consideration For pediatric HTN patients over the age of 6 years with a
glomerular ltration rate greater than 30 mL/min/1.73 m2,
Michele B. Kaufman, PharmD, CGP, RPh, is a freelance medical start lisinopril oral solution at 0.07 mg per kg (up to 5 mg total)
writer living in New York City and a Pharmacist in the NewYork taken once daily. The dosage should be adjusted according to
Presbyterian Lower Manhattan Hospital Pharmacy Department. blood pressure response up to a maximum of 0.61 mg per kg

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

 Pharmaceutical Approval Update

(up to 40 mg) once daily. Doses above 0.61 mg per kg (or in Leukemia. Post-marketing data have reported both acute
excess of 40 mg) have not been studied in pediatric patients. and chronic leukemia cases associated with TNF inhibi-
For patients with creatinine clearance greater than or equal tors. Compared with the general population, RA patients
to 10 mL/min and less than or equal to 30 mL/min, begin may already have an approximate twofold higher risk
treatment with half the usual initial dose. For patients with of developing leukemia. During controlled portions of
creatinine clearance less than 10 mL/min or on hemodialysis, etanercepts trials, two cases of leukemia occurred among
the recommended initial dose is 2.5 mg. 5,445 etanercept-treated patients compared with zero
Commentary: The safety and efcacy of lisinopril were among 2,890 control patients (duration of treatment up
established in multiple studies treating adults with HTN, heart to 48 months).
failure, and MI; however, it demonstrated less antihypertensive Melanoma and nonmelanoma skin cancer. Melanoma
effect in black patients than in non-black patients. and nonmelanoma skin cancer have been reported in
In a clinical study of 115 hypertensive pediatric patients TNF- inhibitor-treated patients, including etanercept
6 to 16 years of age, the patients were divided into six treatment products. Periodic skin examinations should be considered
groups: those weighing less than 50 kg received 0.625 mg, for all patients at increased skin cancer risk.
2.5 mg, or 20 mg of lisinopril once daily and those weighing Boxed warning: serious infections. Increased risk of
50 kg or more received 1.25 mg, 5 mg, or 40 mg of lisinopril serious infections leading to hospitalization or death, includ-
once daily. Lisinopril was administered as tablets to patients ing tuberculosis (TB), bacterial sepsis, invasive fungal infec-
tolerant of swallowing pills or in a suspension for those children tions (such as histoplasmosis), and infections due to other
who could not or who required a lower dose than was available opportunistic pathogens, have occurred.
in tablet form. After two weeks, lisinopril lowered trough blood Etanercept-szzs should not be started if a patient has an
pressure in a dose-dependent manner, with antihypertensive active infection. If one develops, patients should be carefully
efcacy demonstrated at doses greater than 1.25 mg (0.02 mg monitored, and etanercept-szzs should be stopped. Consider
per kg). This effect was conrmed in a randomized withdrawal empiric antifungal therapy for patients at risk for invasive fungal
phase, where the diastolic pressure rose by about 9 mm Hg infections who develop a severe systemic illness while receiving
more in patients randomized to placebo compared with patients etanercept-szzs. All patients should be monitored for active TB
who remained on the middle and high doses of lisinopril. This during treatment, even if the initial latent TB test is negative.
effect was consistent across several demographic subgroups Demyelinating disease. Etanercept and other TNF-
(e.g., age, Tanner stage, gender, and race). inhibitors have been associated with rare cases (less than
Sources: Silvergate Pharmaceuticals, Qbrelis prescribing 0.1%) of new-onset or exacerbated central nervous system
information, Food and Drug Administration demyelinating disorders, some presenting with mental status
changes, permanent disability, and peripheral nervous system
Etanercept-szzs (Erelzi) demyelinating disorders. Prescribers should use caution when
Manufacturer: Sandoz, Princeton, New Jersey considering etanercept-szzs for patients with pre-existing or
Date of Approval: August 30, 2016 recent-onset central or peripheral nervous system demyelinating
Indication: Etanercept-szzs is indicated for the treatment of disorders; etanercept products and TNF- inhibitors have been
moderately to severely active rheumatoid arthritis (RA), poly- associated with rare cases of new-onset multiple sclerosis,
articular juvenile idiopathic arthritis (JIA) in patients 2 years of Guillain-Barr syndrome, seizure disorders, optic neuritis,
age and older, psoriatic arthritis (PsA), ankylosing spondylitis and other related disorders.
(AS), and plaque psoriasis (PsO). Congestive heart failure. Worsening or new-onset
Drug Class: Tumor necrosis factor-alfa (TNF-) inhibitor congestive heart failure may occur. Physicians should exercise
biosimilar caution when using etanercept-szzs in patients who also have
Uniqueness of Drug: Erelzi is the rst biosimilar for the heart failure.
blockbuster reference product Enbrel (etanercept, Amgen/ Hematological events. Rare reports (less than 0.1%) of
Immunex). It is the rst subcutaneously administered anti-TNF- pancytopenia, including very rare reports of aplastic anemia,
biosimilar to receive Food and Drug Administration approval. some with fatal outcomes, have been reported in etanercept-
Warnings and Precautions: treated patients. If pancytopenia or aplastic anemia symptoms
Boxed warning: malignancies. develop, patients should immediately seek medical attention
Lymphoma. Lymphoma cases have been observed in and consider stopping etanercept-szzs.
patients receiving TNF- inhibitors. During the controlled Hepatitis B reactivation. Monitor patients previously
portions of clinical trials in adults with RA, AS, and PsA, two infected with hepatitis B virus during and several months
lymphomas were observed among 3,306 etanercept-treated following etanercept-szzs therapy. If reactivation of the virus
patients compared with none among 1,521 control patients. occurs, consider stopping etanercept-szzs and beginning
In other controlled and uncontrolled portions of etanercept antiviral therapy.
clinical trials enrolling 6,543 adult patients with RA, AS, Autoimmunity. Treatment with etanercept-szzs may
and PsA, the observed lymphoma rate was 0.10 cases per result in autoantibody formation. If lupus-like syndrome or
100 patient-years (12,845 total patient-years of therapy). autoimmune hepatitis occurs, discontinue etanercept-szzs.
This rate was threefold higher than the rate expected in Drug interactions. Live vaccines should not be given
the general U.S. population based on the Surveillance, concurrently with etanercept-szzs. Pediatric patients should
Epidemiology, and End Results Database (SEER). 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 monitoring should be considered. Dosing should be interrupted
anakinra or abatacept due to an increased risk of developing in patients with ALT or AST levels greater than ve times the
serious infections. It should not be administered with cyclophos- upper limit of normal (ULN), or ALT or AST levels greater
phamide due to a potentially higher incidence of developing than three times the ULN with bilirubin levels greater than
noncutaneous solid malignancies. twice the ULN. Following resolution, consider the benets
Dosage and Administration: The recommended dosage and risks of resuming treatment.
for RA, AS, and PsA patients 18 years of age or older is 50 mg Respiratory events. Chest discomfort, dyspnea, and
weekly. Adults with RA or PsA may also receive methotrexate abnormal respiration were observed more commonly during
if warranted. Adult PsO patients should begin on 50 mg twice initiation of Orkambi. Clinical experience in patients with a
weekly for three months, followed by maintenance doses of percent-predicted forced expiratory volume in one second
50 mg once weekly. JIA patients weighing more than 63 kg of less than 40 is limited, and additional monitoring of these
should receive a 50-mg dose weekly. patients is recommended during therapy initiation.
Commentary: A biosimilar is a biological product that must Blood pressure. Increased blood pressure has been
demonstrate that it is highly similar to an already-approved observed in some patients; therefore, blood pressure should
biological product and has no clinically meaningful differ- be periodically measured in all patients.
ences in terms of safety and effectiveness when compared Cataracts. Noncongenital lens opacities/cataracts have
with that reference product. The approval of Erelzi was based been reported in pediatric patients treated with Orkambi
on review of evidence that included structural and functional and with ivacaftor monotherapy. Baseline ophthalmological
characterization, animal study data, human pharmacokinetic examinations and follow-ups are recommended for pediatric
and pharmacodynamic data, clinical immunogenicity data, and patients.
other clinical safety and effectiveness data that demonstrated Drug interactions. Use with sensitive cytochrome P450 3A
its biosimilarity to the reference product Enbrel. (CYP3A) substrates or CYP3A substrates with a narrow
Sources: Sandoz, Erelzi-szzs prescribing information therapeutic index may decrease systemic exposure of the
medicinal products, and coadministration is not recommended.
Lumacaftor 100 mg/Ivacaftor 125 mg (Orkambi) Hormonal contraceptives should not be relied upon as an
Manufacturer: Vertex Pharmaceuticals, Inc., Boston, effective method of contraception. Use with strong CYP3A
Massachusetts inducers may diminish exposure to ivacaftor, which may
Date of Approval: September 30, 2016 lessen its effectiveness; therefore, coadministration is not
Indication: Orkambi is indicated for the treatment of cystic recommended.
brosis (CF) in patients 6 years of age and older who are Adverse reactions. The most common adverse reactions
homozygous for the F508del mutation on the CFTR gene. If the that occurred in 5% or more of patients were dyspnea,
patients genotype is unknown, a Food and Drug Administration- nasopharyngitis, nausea, diarrhea, upper respiratory tract
cleared CF mutation test should be used to detect the presence infection, fatigue, abnormal respiration, increase in blood
of the F508del mutation on both alleles of the CFTR gene. creatine phosphokinase, rash, atulence, rhinorrhea, and
Drug Class: Cystic brosis transmembrane conductance inuenza.
regulator (CFTR) potentiator Dosage and Administration: The recommended dosage
Uniqueness of Drug: CF is a disease of exocrine gland for patients 12 years of age and older is two tablets (each
function that involves multiple organ systems, predominantly containing lumacaftor 200 mg/ivacaftor 125 mg) taken orally
the lungs, which results in chronic respiratory infections, every 12 hours. The recommended dosage for children
pancreatic enzyme insufciency, and associated complica- 6 to 11 years old is two tablets (each containing lumacaftor
tions if left untreated. Ninety percent of patients who survive 100 mg/ivacaftor 125 mg) taken orally every 12 hours. Note
the neonatal period have pulmonary involvement. End-stage that the recommended dose for this age group contains a lower
lung disease is the principal cause of death. Previously, dose of lumacaftor. When commencing treatment in patients
Orkambi tablets (lumacaftor 200 mg/ivacaftor 125 mg) were taking strong CYP3A inhibitors, reduce the Orkambi dose for
only approved for patients 12 years of age and older who are the rst treatment week.
homozygous for the F508del-CFTR mutation. This new approval Commentary: The mean lumacaftor area under the curve
makes a lower-dosage tablet available (lumacaftor 100 mg/ at steady state (AUCss) following administration of Orkambi in
ivacaftor 125 mg), which expands the indication to include 6- to 11-year-old patients dosed every 12 hours was comparable
children 6 to 11 years of age with CF who are homozygous to the mean AUCss in patients 12 years of age and older. The
for the F508del-CFTR mutation. mean ivacaftor AUCss was also comparable to the mean AUCss
Warnings and Precautions: in patients 12 years of age and older. The safety prole of
Hepatic injury. Liver-related events, such as elevated Orkambi in 6- to 11-year-old patients and in patients older than
alanine transaminase (ALT) and aspartate transaminase (AST), 12 years is similar. The safety and efcacy of Orkambi in CF
have been observed in some cases associated with elevated patients younger than 6 years old have not been established.
bilirubin in Orkambi-treated patients. Serum transaminase and Sources: Vertex, Orkambi prescribing information;
bilirubin levels should be measured before initiating Orkambi Medscape eMedicine Q
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

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 GT2 and GT3. This regimen was also various stages of the HCV life cycle with
The discovery of the hepatitis C associated with fewer adverse events or without ribavirin are now available.
virus (HCV) took place 27 years ago. compared with earlier regimens.2 Combining medications that have dif-
Initial research was geared toward The approval of two protease inhibi- ferent targets of action with synergistic
understanding the HCV life cycle and torsboceprevir and telaprevirwas antiviral effects will hopefully lessen the
replication process. The Food and Drug announced as a triple-therapy combina- burden of resistance to antivirals.
Administration (FDA) approved an tion with peginterferon plus ribavirin for In July 2015, the FDA approved
injectable formulation of interferon in GT1 infection. The triple-therapy regi- daclatasvir (Daklinza, Bristol-Myers
1997 as the initial medication active mens were short-lived because of their Squibb) for use with sofosbuvir (Sovaldi,
against the virus. Although it was similar response rates to standard-of-care Gilead Sciences) as the rst 12-week,
considered a breakthrough in HCV treatment, complicated administration all-oral treatment option for patients
treatment, many adverse events schedules, signicant adverse events, with chronic HCV GT3.6 Daclatasvir, a
were reported along with a lack of and issues with resistance. Subsequently, nonstructural protein 5A (NS5A) inhibi-
clinically sustained virological boceprevir and telaprevir were removed tor, when combined with sofosbuvir, an
response (SVR) that often limited the from the U.S. market.3,4 NS5B inhibitor, results in higher SVR
drugs role.1 More than 25 years after its initial rates, fewer adverse events, and limited
Ongoing efforts sought to develop discovery, HCV remains a global pub- antiviral resistance.7
different means of treating HCV based lic health concern. According to the
on the specic genotype of the virus. Centers for Disease Control and Preven- INDICATIONS
The addition of pegylated formulations tion (CDC), annual U.S. HCV-related Daclatasvir is approved for use as
of interferon allowed for less frequent deaths in 2013 surpassed the total com- combination therapy with sofosbuvir,
dosing and minimized adverse events. bined number of deaths from 60 other with or without ribavirin, for the treat-
The combination of peginterferon and infectious diseases reported to the CDC, ment of patients with chronic HCV GT1
ribavirin then became the standard of including human immunodeciency virus or GT3 infection without cirrhosis, with
care for patients with chronic HCV (HIV), and CDC surveillance data from compensated (ChildPugh A) or decom-
infection regardless of genotype. This 2014 show HCV-related deaths climbed pensated (ChildPugh B or C) cirrhosis,
combination regimen resulted in an SVR to almost 20,000, an all-time high.5 Unlike or post-transplant.8
of 45% to 50% for HCV genotype 1 (GT1) hepatitis A and hepatitis B, a vaccine
infection and rates of 70% to 80% for for hepatitis C remains unavailable. As PHARMACOLOGY
we continue to strive for more preven- Daclatasvir is chemically described
At the time of writing, Drs. Montgomery and tive treatment options for HCV, we are as carbamic acid, N,N-[[1,1-biphenyl]-
Ho were PGY-1 Pharmacy Practice Residents actively pursuing means to eradicate 4,4-diylbis[1H-imidazole-5,2-diyl-(2S)-2,1-
at the Department of Veterans Affairs, New the spread and incidence of this chronic pyrrolidinediyl[(1S)-1-(1-methylethyl)-2-
York Harbor Healthcare System, in Brooklyn, disease and associated complications. oxo-2,1-ethanediyl]]] bis-, C,C-dimethyl
New York. Dr. Chung is an ID Sterile Products Today, innovative developments for ester, hydrochloride (1:2). Its molecular
Specialist at the Department of Veterans the treatment of HCV infection have led formula is C40H50N8O62HCl (Figure 1),
Affairs, New York Harbor Healthcare System. to the potential eradication of the virus and its molecular weight is 738.88 (free
Dr. Marzella is an Associate Professor of and a cure for infected patients. Direct- base). Daclatasvir exerts its pharma-
Pharmacy Practice at LIU Pharmacy (Arnold acting antiviral agents (DAAs) that target cological activity by the inhibition of
and Marie Schwartz College of Pharmacy) in
Brooklyn, New York, and Clinical Pharmacy
Figure 1 Chemical Structure of Daclatasvir8
Specialist at the Department of Veterans
Affairs, New York Harbor Healthcare System. H 3C
Drug Forecast is a regular column coordinated
H3CO N CH 3
by Alan Caspi, PhD, PharmD, MBA, President of HN (S) (S) O
NH O N
Caspi and Associates in New York, New York. O N O HN
(S) N OCH 3
H3C N (S) H 2 HCl
Disclosure: The authors report no nancial or CH 3
commercial relationships in regard to this article.

Vol. 41 No. 12 December 2016 P&T

751
DRUG FORECAST

NS5A N-terminus (domain 1), causing decompensated cirrhosis, and post-

Table 1 Most Common
structural variations in HCV replication transplant patients with HCV GT1 or 3
and assembly of HCV virions.8 infection should have ribavirin added to
Polymorphisms Associated With
their regimen. The dosage of ribavirin Daclatasvir Resistance11
PHARMACODYNAMICS AND varies in accordance with HCV genotype, Genotype Substitution
PHARMACOKINETICS patient weight, and patient tolerance and 1a M28T
The pharmacokinetic properties of ranges from 600 mg to 1,200 mg daily. If L31V/M
daclatasvir were evaluated in healthy ribavirin is added, administration with Q30E/H/R
adults and in patients with chronic HCV. food is recommended.8 Y93C/H/N
Administration of daclatasvir tablets in Because the SVR rate was just 63%
HCV-infected patients resulted in approx- in patients with cirrhosis, an extended 1b L31V
imately dose-proportional increases in treatment duration of up to 24 weeks Y93H
peak concentration (Cmax), area under may be appropriate; ribavirin may also 2 L31M
the curve (AUC), and minimum concen- be added to the regimen.8 F28S
tration up to 60 mg once daily. Daclatasvir Daclatasvir is available as 30-mg,
3 Y93H
is rapidly absorbed with a peak plasma 60-mg, and 90-mg tablets to allow for
concentration within two hours of admin- dosage adjustments to circumvent drug 4
istration. Steady state is anticipated after interactions or to ne-tune daclatasvir 5 L31F
approximately four days of once-daily concentrations. Patients with renal or
daclatasvir administration.8 hepatic insufciencies do not require 6 P32L
Food may affect the absorption of dacla- dosage adjustments for daclatasvir.8
tasvir. The administration of daclatasvir with GT1b. The rate of daclatasvir-
60 mg after a high-fat, high-calorie meal RESISTANCE PROFILE resistant polymorphisms did not dif-
decreased the Cmax and AUC by 28% and As the standard of care for HCV fer significantly between HCV/HIV
23%, respectively, compared with fasting treatment turns toward DAAs, resis- coinfected patients compared with HCV
conditions. However, administration after tance becomes a major concern due to monoinfected patients.11
a low-fat, low-calorie meal did not result the selective pressure that favors HCV
in a signicant decrease in absorption.8 variants capable of replicating in the CLINCIAL TRIALS
Cytochrome P450 (CYP) 3A4 is pri- presence of DAAs. HCV is predisposed The efcacy of daclatasvir in combina-
marily responsible for the metabolism of to the development of resistance due to tion with sofosbuvir and with or without
daclatasvir, with excretion occurring pre- its highly variable genome. Incorrect ribavirin was evaluated in three phase 3
dominantly in the feces. In healthy sub- nucleoside substitutions occur approxi- clinical trials (Table 2). SVR, the primary
jects, 88% of the dose was excreted in the mately 103 to 105 times per replication endpoint, was defined as HCV RNA
feces (53% being unchanged drug), and cycle. The virus is estimated to repli- below the lower limit of quantication
6.6% of the dose was excreted in the urine cate 1012 times per day, resulting in a (25 IU/mL) at post-treatment week 12
(primarily as unchanged drug). There are large number of variant viral genomes (SVR12).8
eight metabolites of daclatasvir, one of or viral quasispecies. The dominant
which (BMS-805215) has some activity; wild-type HCV sequence replicates the ALLY-3 Study8,12
however, it is 100-fold less potent than most efciently; however, DAA-resistant ALLY-3 was a phase 3, open-label study
the parent drug. The terminal half-life of quasispecies may become the dominant that evaluated the safety and efcacy of
daclatasvir is 12 to 15 hours.8 HCV sequence in the presence of DAAs. a 12-week regimen of daclatasvir plus
Resistance to DAAs may be pre-existing sofosbuvir once daily for the treatment
DOSAGE AND ADMINISTRATION or may develop during or after DAA treat- of chronic HCV GT3 in adults 18 years
Daclatasvir is not recommended as ment. Resistance to DAAs is also inu- of age or older. Treatment-nave and
monotherapy and if, for any reason, enced by the HCV genotype, with some treatment-experienced patients with
sofosbuvir is discontinued, discontinu- HCV genotypes having a higher barrier HCV RNA of 10,000 IU/mL or greater at
ation of daclatasvir is recommended as to resistance than others. Overcoming screening were included. Patients with
well. Another important consideration resistance with the use of more than one compensated cirrhosis were also eligible
for patients with cirrhosis is the recom- DAA that target different parts of the HCV for the study.
mendation of testing for NS5A resistance- genome has been explored. In vitro stud- Results were reported for 152 patients:
associated polymorphisms prior to the ies have demonstrated that HCV variants 101 treatment-nave patients (66%) and
initiation of therapy.8 that are resistant to one DAA remain fully 51 treatment-experienced patients (34%),
The recommended daclatasvir dose active against other DAAs. Despite this, with an overall SVR12 of 89% (Table 3).
is 60 mg once daily in combination with cross-resistance has been observed with SVR12 was 90% in treatment-nave
sofosbuvir 400 mg once daily, with or resultant HCV breakthrough.10 patients, 86% in treatment-experienced
without food, for 12 weeks.8,9 Patients Several polymorphisms are associated patients, 96% in patients without cirrho-
with HCV GT1 infection with decom- with daclatasvir resistance based on HCV sis, 63% in patients with cirrhosis, 93%
pensated cirrhosis, patients with HCV genotype (Table 1). In general, GT1a has in patients with F0F3 brosis scores,
GT3 infection with compensated or a lower barrier to resistance compared and 70% in patients with an F4 brosis

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

 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

 DRUG FORECAST

Pregnancy and Lactation8,14,15 compliance while ultimately moving PressAnnouncements/ucm455888.htm.

There is an approximate 3% to 10% rate toward a cure. The major caveat associ- Accessed July 24, 2015.
7. Hepatitis Central. Medications to treat
of mother-to-child transmission of HCV. ated with DAAs is the development of hepatitis Ca timeline. Available at:
Maternal HCV infection alone is associ- resistance.17 www.hepatitiscentral.com/medications-
ated with cholestasis of pregnancy, neo- Studies demonstrate that shorter- to-treat-hepatitis-c-a-timeline. Accessed
natal abstinence syndrome, and neonatal duration therapies are just as effective, if March 2016.
8. Daklinza (daclatasvir) prescribing informa-
intensive care unit admission. However, not more effective, in achieving accept-
tion. Princeton, New Jersey: Bristol-Myers
after adjusting for sociodemographic able SVR as the longer regimens used Squibb Company; 2016.
variables, large population studies sug- in the past. The trend toward interferon- 9. Sovaldi (sofosbuvir) prescribing informa-
gest increased rates of preterm birth, low free treatment provides a more toler- tion. Foster City, California: Gilead Sci-
birth weight, premature membrane rup- able adverse effect prole, which also ences; 2015.
10. Aloia AL, Locarnini S, Beard MR. Anti-
ture, gestational diabetes, and congenital improves patient adherence. viral resistance and direct-acting antiviral
anomalies in maternal HCV infection. The latest HCV guidelines developed agents for HCV. Antivir Ther 2012;17
Although data in humans are lacking, by the Infectious Diseases Society of (6Pt B):11471162.
maternal and embryo-fetal toxicities were America and the American Association 11. Plaza Z, Soriano V, Vispo E, et al.
Prevalence of natural polymorphisms at the
observed in animal studies. for the Study of Liver Diseases include
HCV NS5A gene associated with resistance
Daclatasvir is not recommended for daclatasvir in their assemblage of recom- to daclatasvir, an NS5A inhibitor. Antivir
use in pregnant women or women of mended regimens for the treatment of the Ther 2012;17(5):921926.
childbearing potential not on highly effec- disease. Because the negotiated pricing 12. Nelson DR, Cooper JN, Lalezari JP,
tive contraception during therapy and for and cost structure for pharmaceutical et al. All-oral 12-week treatment with
daclatasvir plus sofosbuvir in patients
at least ve weeks following completion products are not transparent in the U.S., with hepatitis C virus genotype 3 infec-
of daclatasvir treatment. it is difcult to estimate the true cost and tion: ALLY-3 phase III study. Hepatology
According to the manufacturer, the cost-effectiveness of HCV drugs.18 The 2015;61(4):11271135.
decision to breastfeed during therapy primary goal of HCV therapy remains 13. Wyles DL, Ruane PJ, Sulkowski MS,
et al. Daclatasvir plus sofosbuvir for HCV
should take into account the risk of eliminating the virus. The secondary
in patients coinfected with HIV-1. N Engl J
exposure to the infant and the benets goals are to decrease the progression Med 2015;373(8):714725.
of treatment to the mother. It is unknown to liver cirrhosis and the risk of hepato- 14. Dunkelberg JC, Berkley EMF, Thiel KW,
if daclatasvir is present in human breast cellular carcinoma. Drugs that meet Leslie KK. Hepatitis B and C in pregnancy:
milk or affects human milk production. In these goals have the potential to drasti- a review and recommendations for care.
J Perinatol 2014;34(12):882891.
animal studies, daclatasvir was detected cally reduce a patients future health care 15. Connell LE, Salihu HM, Salemi JL,
in the milk of lactating rats. expenditures. et al. Maternal hepatitis B and hepatitis C
carrier status and perinatal outcomes. Liver
COST REFERENCES Int 2011;31(8):11631170.
16. Red Book Online. Ann Arbor, Michi-
Daclatasvir is available in 30-mg, 1. Manns MP, Wedemeyer H, Cornberg gan: Truven Health Analytics. Accessed
60-mg, and 90-mg strengths at an aver- M. Treating viral hepatitis C: efcacy, October 25, 2016.
age wholesale price (AWP) of $25,200 side effects, and complications. Gut 17. McConachie SM, Wilhelm SM, Kale-
2006;55(9):13501359. Pradhan PB. New direct-acting antivirals in
for a package of 28 tablets.16 Sofosbuvir, a 2. Palumbo E. Pegylated interferon and riba-
requirement for the combination therapy, hepatitis C therapy: a review of sofosbuvir,
virin treatment for hepatitis C virus infec- ledipasvir, daclatasvir, simeprevir, parita-
is distributed as a 400-mg tablet with an tion. Ther Adv Chronic Dis 2011;2(1):3945. previr, ombitasvir and dasabuvir. Expert
AWP of $33,600 for a package of 28.16 3. HIVandHepatitis.com. Merck plans to Rev Clin Pharmacol 2016;9(2):287302.
discontinue boceprevir for hepatitis C
Ribavirin, if indicated, is a generic drug 18. American Association for the Study of Liver
by December 2015. January 21, 2015. Diseases-Infectious Diseases Society of
supplied as a 200-mg tablet or capsule that Available at: www.hivandhepatitis.com/ America. Overview of cost, reimbursement,
can be acquired for as little as $1.37 per hcv-treatment/approved-hcv-drugs/5021- and cost-effectiveness considerations for
pill AWP (Richmond Pharmaceuticals).16 merck-plans-to-discontinue-boceprevir-for- hepatitis C treatment regimens. July 6,
For the recommended standard treat- hepatitis-c-by-december-2015. Accessed 2016. Available at: www.hcvguidelines.
November 8, 2016. org. Accessed October 25, 2016. Q
ment of 12 weeks, the patient will need 4. HIVandHepatitis.com. Vertex to discontinue
three packages of daclatasvir 60 mg at a sale of telaprevir (Incivek) for hepatitis C.
total AWP of $75,600 and three packages August 22, 2014. Available at: www.hivand-
of sofosbuvir at a total AWP of $100,800 hepatitis.com/hcv-treatment/approved-hcv- P&T TV
drugs/4808-vertex-to-discontinue-sale-of- P&T is accepting video clips
for a total treatment cost of $176,400. The
telaprevir-incivek-for-hepatitis-c. Accessed
addition of ribavirin will add another $346 November 8, 2016. from readers, and we might
to $692 AWP to the total, dependent on 5. Centers for Disease Control and Preven- post yours on our website
the patients required dosage. tion. Hepatitis C kills more Americans (www.PTCommunity.com). Feel
than any other infectious disease. May 4, free to send a short video about the
P&T COMMITTEE 2016. Available at: www.cdc.gov/media/
activities of your P&T committee.
releases/2016/p0504-hepc-mortality.html.
CONSIDERATIONS Accessed November 8, 2016. You can contact the Editor,
DDAs have transformed the treatment 6. Food and Drug Administration. FDA J. Stephen McIver, at 267-685-3713
of HCV infection. These highly tolerable approves new treatment for chronic hepa- or smciver@medimedia.com.
titis C genotype 3 infections. Available at:
medications signicantly improve patient
www.fda.gov/NewsEvents/Newsroom/

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 medications a resident may be taking. The AHCA complained

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)
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
issued at the end of September1 keeps the requirement for a pharmacists ndings is not a productive use of anyones time
monthly drug-regimen review (DRR) but adds a requirement and may lead to inadvertent changes in medication regimens
for a simultaneous review of a residents medical chart and puts that could be harmful. According to Mark Parkinson, President
both requirements in a new pharmacy services sec- and Chief Executive Ofcer of the AHCA:
tion of the nursing home rules, in part to emphasize
the importance of prescription drug oversight by the While the agency took some steps forward in helping indi-
pharmacist. The new pharmacy services section also viduals in our centers, there were several provisions that
adds restrictions on the use of psychotropic medica- harm our efforts to continue the tremendous strides weve
tions, which have been widely described as overused made in quality and care delivery. Further, even CMS admits
in nursing homes to keep unruly patients quiet. this new wave of regulations will bring with it hundreds of
The new regulation expands pharmacist ser- millions in additional costs without any new funding streams.
vices, and in many cases will increase the costs to We will spend the coming days and weeks determining what
provide these services, said Khristy McClelland, Stephen Barlas
overall impact those mandates will have on our members.
President of Guardian Pharmacy in Jacksonville,
Florida. Consultant pharmacists routinely review several CMS Punts on Pharmacist Independence
sources of medical information during DRRs, including medical The nal rule arrived weeks before the U.S. Justice
charts and medical administration records. In some instances, Department announced that nursing home pharmacy service
barriers are present and may prevent pharmacists from access- provider Omnicare had agreed to pay $28.1 million to settle
ing all of the medical records, McClelland added. In order charges it demanded kickbacks from Abbott Laboratories to
to maintain compliance with the new regulations, facilities will increase use of its epilepsy drug Depakote.2 Depakote (dival-
have to ensure that pharmacists have access to these records. proex sodium) is used to control behavioral disturbances in
In addition, facilities must have reporting procedures for phar- dementia patients, but the Food and Drug Administration has not
macists, which include a response timeline from prescribers approved that use. CVS Health purchased Omnicare in 2015; the
when immediate action is required based on a DRR. Justice Department acknowledged that CVS halted the alleged
The new rule, which adds numerous provisions beyond misconduct. In May 2012, Abbott entered its own settlement
the pharmacy section, seeks to reduce avoidable hospital with federal and state ofcials over the kickback scheme, paying
readmissions and speed quality improvement throughout $1.5 billion to resolve its liability under the False Claims Act.
facilities. The scheme also involved the pharmacy company PharMerica,
The American Health Care Association (AHCA), which which paid $9 million in 2015 for accepting kickbacks. Omnicare
represents the nursing home industry, tried to convince and PharMerica, the two biggest players in the nursing home
the CMS to soften the pharmacist requirements. It argued pharmacy market, serve approximately half of nursing facili-
that mandating a pharmacists review of a residents medical ties. The rest are served by roughly 1,200 independent LTC
record will increase the time pharmacists spend in a facil- pharmacies, approximately 800 of which belong to the group
ity, thus increasing facilities costs. The increased costs to purchasing organization Managed Healthcare Associates.
pharmacies will likely also be incorporated into the medica- As the Justice Department was pursuing those cases, the
tion costs that are frequently reimbursed by Medicaid or CMS, starting in 2011, was considering imposing independence
Medicare Part D. As such, we believe that this proposed change and conict-of-interest rules on nursing home pharmacy ser-
represents an unfunded mandate to state Medicaid pro- vice providers as part of a larger Medicare rule overhaul. The
grams and Medicare Part D, which were not included in the AHCA and the American Society of Consultant Pharmacists
CMS estimates of cost implications of the proposed rule, the (ASCP) opposed such rules, and the CMS dropped the idea.
AHCA argued. But when the CMS undertook this latest rulemaking in 2015
The AHCA also opposed a provision requiring pharmacists specically aimed at LTC facilitiesgroups such as the
to alert the attending physician in writing of any unnecessary California Advocates for Nursing Home Reform (CANHR)
pushed for pharmacy independence provisions, arguing that
Mr. Barlas is a freelance writer in Washington, D.C., who covers any improvements on DRRs would be greatly compromised
issues inside the Beltway. Send ideas for topics and your comments by CMSs failure to address widespread conicts of interest
to sbarlas@verizon.net. involving consultant pharmacists. Despite its legwork in 2012

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

 Medicare Adds Long-Term-Care Pharmacy Rules
and the subsequent Justice Department actions, the CMS omit- It is highly disturbing that CMS pointed to its own failure
ted any provisions on independence from the 2015 proposed to address this known problem in the July 2015 proposal as the
rule and therefore declined to address conict-of-interest reason it could not establish an independence requirement in
restrictions in the nal rule. However, the agency added it the nal regulations, CANHR advocate Mike Connors said.
would consider the issue in any future related rulemaking.1 By continuing to punt the need to require independence
The CMSs refusal to pursue this issue seems a bit surprising. until another day, CMS is exposing hundreds of thousands
In October 2011, as part of broader Medicare rulemaking, the of nursing home residents to dangerous drugging practices.
CMS said various arrangements involving LTC facilities, LTC
pharmacies, LTC consultants, and pharmaceutical manufactur- Provisions That May Indirectly Affect Pharmacists
ers and/or distributors raised concerns about the quality of While pharmacists and nursing homes will not have to
consultant pharmacists reviews and the potential impact on contend with new independence rules, they will face additional
resident health and safety. We believe these concerns may be requirements beyond those in the new pharmacy services
addressed by changes we are considering that would require section. For example, all LTC facilities will have to:
LTC consultant pharmacists be independent of the LTC facility
pharmacy, pharmaceutical manufacturers or distributors, or any Develop, implement, and maintain an effective, compre-
afliate of these entities, the CMS said then.3 That proposed hensive, data-driven quality assurance and performance
rule stated: We are considering requiring that long-term-care improvement program that focuses on systems of care,
facilities employ or directly or indirectly contract the services outcomes of care, and quality of life.
of a licensed pharmacist who is independent. We also are Develop an infection prevention and control program that
considering including a denition of the term independence includes an antibiotic stewardship program.
to mean that the licensed pharmacist must not be employed, Develop and implement a baseline care plan for each resi-
under contract, or otherwise afliated with the facilitys phar- dent, within 48 hours of his or her admission, that includes
macy, a pharmaceutical manufacturer or distributor, or any the instructions needed to provide effective, person-centered
afliate of these entities. Our changes would also prohibit care that meets professional standards of quality care.
nursing homes from contracting for the provision of consultant
pharmacy services with entities (such as a subsidiary of an LTC In some cases pharmacy groups had hoped that these new
pharmacy) that have been created for the purpose of providing sections would have a more direct impact. One example is the
reorganized consultant pharmacist services. requirement that a facility put together an interdisciplinary team
In February 2012, after receiving comments on the proposed (IDT) to prepare the baseline plan cited above within 48 hours.
rule, the CMS said a signicant number of commenters who The rules specically add a nurses aide and a member of the food
identied themselves as current or former consultant pharmacists and nutrition services staff to the required IDT membership. That
either acknowledged that they had experienced a conict of inter- IDT would also be involved in discharge planning. The decision
est or conrmed that such conicts were an ongoing problem.4 to exclude pharmacists is perhaps understandable given that they
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 nurses aides and food and nutrition staffers are. Legislation is
quality of care in LTC facilities are well-founded. We believe that pending in Congress to grant pharmacists that status, but it has
this demonstrates that change is necessary to ensure that all LTC never had a hearing or vote in a House or Senate committee.
consultant pharmacists are free from conicts of interest, are able The ASCP wanted the CMS to add a pharmacist to the IDT.
to base their professional medication recommendations on the Moreover, it suggested that a pharmacist ought to provide a
best interest and clinical needs of LTC facility residents, and are comprehensive medication review (CMR) both when a resident
able to advocate for the Medicare beneciary, the CMS said. arrives and when a resident leaves, either to go to a hospital, to
Despite arguing that change was necessary in 2012, the his or her home, or to a relatives home. In the nal rule, the
agency decided then not to pursue it, saying that since a CMS said it considered requiring a pharmacist to participate on
requirement for independent consultant pharmacists will not the IDT and determined that it would be overly burdensome.
solve the entire problem, but would be signicantly disruptive While pharmacist inclusion on the IDT is not required, neither
for much of the LTC industry, we are not nalizing this provision is it prohibited. The LTC can make the call. Nor did the CMS
at this time. Instead, we are soliciting additional comments to opt to include the pharmacist in the discharge process, much
help us determine a more comprehensive approach to eliminate less require a CMR. The baseline plan that is required upon
overprescribing and the use of chemical restraints in LTC. admission falls short of a full medical review as well as a CMR,
The ASCPs position has been that the industry is taking which is a systematic process that includes collecting patient
voluntary steps to avoid conicts of interestfor instance, information, identifying and prioritizing medication-related
by transitioning to service agreement models for LTC facility problems, and creating a plan to resolve medication-related
clients that include separate contracts for consultant pharma- problems with the patient, caregiver, and/or prescriber.
cist services and pharmacy dispensing services. However, the Pharmacists are also not included in the list of clinically
ASCP agreed in 2012 that more work was needed to demon- qualied personnel whom the attending physician can des-
strate independence and to ensure transparency across the ignate as service providers. That delegation does not include
LTC industry. It cited tools it had developed to assist consul- pharmacists being able to deliver medication, which they can do
tant pharmacists and LTC pharmacies with demonstrating in 40 states subject to collaboration agreements with physicians.
independence, including sample disclosure statements. 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 that to psychotropic drugs. This raised all sorts of concerns at
pharmacists will be called on to train the trainers on safe and the proposal stage, both because of the particular drugs likely
prudent antibiotic use. The association is developing products to be included, especially opioids, and rules around PRN (pro re
and programs designed to give senior care pharmacotherapy nata or as needed) orders and gradual dose reduction (GDR).
specialists the tools they will need to assist facilities. The new rules say that based on a comprehensive assess-
ment of a resident, the facility must ensure that residents who
New Pharmacy Services Section have not used psychotropic drugs are not given them unless
While there were disappointments for pharmacists hoping the medication is necessary to treat a specic condition as
to gain additional statutory roles, there was also reason for diagnosed and documented in the clinical record. Residents
satisfaction. At the proposal stage, the requirement for a medi- who use psychotropic drugs, either when entering the facility
cal records review was limited to three situations: when the or when having them prescribed after entering, must receive
resident is new to the facility; when a prior resident returns or GDR and behavioral interventions, unless clinically contra-
is transferred from a hospital or other facility; and during each indicated, in an effort to discontinue these drugs. PRN orders for
monthly DRR when the resident has been prescribed or is taking psychotropic drugs are limited to 14 days unless the attending
a psychotropic drug, an antibiotic, or any drug that the quality physician or prescribing practitioner documents the rationale
assessment and assurance committee has asked to be included in the residents medical record.
in the pharmacists monthly drug review. The nal rule dictates The CMS backed off a bit in the nal rule on which drugs are
a review of the medical chart each month for every resident. considered psychotropic. The proposed denition cited any drug
The purpose of a DRR and the associated medical record that affects brain activities associated with mental processes
review is to identify any unnecessary medications a resident and behavior. Specic categories listed were antipsychotics,
may be taking. It is up to the individual facility to determine antidepressants, antianxiety drugs, hypnotics, opioid analgesics,
how narrow or how broad this DRR is. But the elements must and any other drug that results in effects similar to the drugs
include time frames for the different steps in the process and listed in the categories mentioned. That last phrase prompted
actions the pharmacist must take when he or she identies an a lot of opposition, as did the inclusion of opioids.
irregularity that requires urgent action to protect the resident. In the nal rule, the CMS admitted that the proposed deni-
Unnecessary is dened as 1) in excessive dose (including tion of psychotropic drugs might include many medications for
duplicate drug therapy); or 2) for excessive duration; or 3) which the additional requirements would be superuous and
without adequate monitoring; or 4) without adequate indications unnecessary. So it removed the clause any other drug that
for its use. Irregularities would be any unnecessary drugs results in effects similar from the denition. The agency
the pharmacist believes the resident is taking. The pharmacist also dropped opioids. In doing so, it stated: We are particularly
must report any irregularities to the attending physician and the concerned about the possibility that including opioid analgesics
facilitys medical director and director of nursing; these reports in the denition could result in negative consequences for pain
must be acted upon. The attending physician must document management, especially since they are usually given PRN and
in the residents medical record that the identied irregularity there could be interruptions in the prescriptions due to the
has been reviewed and what, if any, action has been taken to proposed limitation on PRN prescriptions.
address it. If there is to be no change in the medication, the Although pharmacists will not have to tiptoe around opioid pre-
attending physician should document his or her rationale in scriptions, they will have to be vigilant about the other categories.
the residents medical record. To the extent that makes them whistleblowers of a sort, they may
What happens, though, if the physician declines to change sometimes be in an uncomfortable position of second-guessing
a residents medication upon being notied by the pharmacist physicians treating patients with dementia and other psychiatric
of irregularities? Does the pharmacist have recourse to appeal? afictions. Guardians McClelland says, There is concern that the
Some argued the pharmacist should be able to report the new psychotropic regulations may have the potential to impede,
irregularities to some entity outside the purview of the LTC rather than improve, patient health and safety.
and the physician. Not only did the CMS decline to provide that
outside appeal, it also declined to require a pharmacists nd- REFERENCES
ing of irregularities to be reported to the resident or his or her 1. Centers for Medicare and Medicaid Services. Medicare and Medic-
representative. The irregularity identied by the pharmacist aid programs; reform of requirements for long term care facilities.
may require no action, updating or modifying documentation, Fed Regist 2016;81(192):6868868872.
2. U.S. Department of Justice. Nations largest nursing home
or some other action that does not affect the quality of care pharmacy to pay over $28 million to settle kickback allegations.
for the resident, the agency said. Unnecessary notications October 17, 2016. Available at: www.justice.gov/opa/pr/nation-
could lead to confusion and anxiety for the resident. 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;
New Requirements for Psychotropic Drugs proposed changes to the Medicare Advantage and the Medicare
One of the more controversial aspects of this rewrite of Prescription Drug Benet programs for contract year 2013 and other
Medicare LTC rules is the expansion of drugs of particular con- proposed changes; considering changes to the conditions of participa-
cern. Congressional hearings and sundry reports have focused tion for long term care facilities. Fed Regist 2011;76(196):6301863091.
on the improper use of drugs to pacify unruly nursing home 4. Centers for Medicare and Medicaid Services. Medicare Program;
changes to the Medicare Advantage and the Medicare Prescription
residents. Formerly the CMS nursing-home rules paid enforce- Drug Benet programs for contract year 2013 and other changes;
ment attention only to antipsychotics. The new rule expands nal rule. Fed Regist 2012;77(71):2207222175. Q

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

PHARMACOVIGILANCE FORUM

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

INTRODUCTION Welcome to the Pharmacovigilance Forum, Forum will discuss noteworthy topics related
Drug-induced neutropenia is a poten- where we report on interesting adverse drug to ADRs in the clinical realm. Every medication
tially serious and life-threatening adverse reactions (ADRs), including drug-induced disease. has the potential to cause disease, but clinicians
event that may occur secondary to All pharmaceuticals carry a are often slow to recognize drug therapy as an
therapy with a variety of agents. Cytotoxic risk of ADRs, whether they etiological factor. I encourage anyone with a
chemotherapy can cause a predictable are new and improved, potentially interesting case to contact me, to
and dose-related decrease in neutrophil generic agents, older publish ADRs here or elsewhere, and to report
count. Neutropenia secondary to other brand products, complex ADRs to the Food and Drug Administrations
medications tends to be an idiosyncratic biologics, or biosimilars. MedWatch program.
reaction either as an immune-mediated Each Pharmacovigilance Michele B. Kaufman
reaction or because of direct myeloid
cell line damage. This effect has been administered as monotherapy or in include agents such as mitomycin, carmus-
associated with a variety of medications combination with chemotherapy agents, tine, and lomustine, which have a delayed
including, but not limited to, clozapine, depending on the indication. nadir of about four to six weeks following
dapsone, methimazole, penicillin, ritux- Common adverse events associated administration of each cycle. During treat-
imab, and procainamide.1 For a compre- with rituximab therapy include acute ment with these agents, neutrophil recov-
hensive list of medications associated infusion reactions, lymphopenia, infec- ery will usually occur six to eight weeks
with the development of neutropenia, see tion, and asthenia.3 Delayed and late-onset following treatment. The nadir and neutro-
Table 1. Neutropenia from nonchemo- serious side effects may include progres- penia associated with most types of cyto-
therapy drugs is much less common than sive multifocal leukoencephalopathy, toxic chemotherapy are considered to be
neutropenia secondary to chemotherapy.2 reactivation of hepatitis B, and interstitial rather predictable in onset and occurrence.
Rituximab is an anti-CD20 monoclonal pneumonitis. When rituximab was added In patients receiving cancer treatment
antibody indicated for the treatment of onto chemotherapy regimens, it was found regimens containing rituximab with cyto-
a variety of B-cell lymphocytic malig- to be safe and tolerable without adding toxic chemotherapy (e.g., anthracyclines,
nancies, including chronic lymphocytic signicant hematological toxicities. Post- purine antagonists, alkylating agents,
leukemia (CLL), follicular lymphoma, marketing studies and case reports have etc.), the nadir of the patients neutrophil
and diffuse large B-cell lymphoma.3 Ritux- shown that rituximab has the potential to count is expected to occur 10 to 14 days
imab is also used for the management cause delayed and late-onset neutropenia following administration of each cycle of
of several autoimmune disorders, such that may vary in severity.57 We report the treatment. Rituximab has been reported
as rheumatoid arthritis and Wegeners cases of two patients who were treated for to cause neutropenia, but with a delayed
granulomatosis. In the treatment of B-cell hematological malignancies with ritux-
malignancies, this monoclonal antibody imab that led to severe, late-onset neutro- Table 1 Medications Associated With
exerts its anticancer activity by depleting penia resulting in neutropenic fever, which The Development of Neutropenia1,2
malignant B cells via mechanisms such required hospitalization.
Nonchemotherapy
as complement-dependent cytotoxicity,
antibody-dependent cellular cytotoxic- PATHOPHYSIOLOGY Clozapine Procainamide
ity, and by inducing apoptosis.4 In the Neutropenia is dened as having an Dapsone Propylthiouracil
treatment of cancer, rituximab can be absolute neutrophil count (ANC) of less Hydroxychloroquine Quinidine/Quinine
than 500 cells/mm3 and is a common Iniximab Rituximab
Dr. Moore is Pharmacist Clinical Coordinator Lamotrigine Sulfasalazine
adverse event associated with many
of Oncology at the Levine Cancer Institute of Methimazole Trimethoprim-
cytotoxic chemotherapy agents.8 During
the Carolinas HealthCare System in Charlotte, Oxacillin sulfamethoxazole
cytotoxic chemotherapy, neutropenia
North Carolina. Michele B. Kaufman, PharmD, Penicillin G Vancomycin
typically occurs during the nadirthe
CGP, RPh, editor of this column, is a freelance
lowest value to which the neutrophil count
medical writer living in New York City and Chemotherapy
will fall following drug administration. The
a Pharmacist in the NewYorkPresbyterian Alkylating agents Hydroxyurea
nadir typically occurs 10 to 14 days follow-
Lower Manhattan Hospital Pharmacy Anthracyclines Mitomycin C
ing chemotherapy administration during
Department. Antimetabolites Taxanes
each treatment cycle. Neutrophil recovery
Disclosure: The author reports no commercial will usually occur in three to four weeks Camptothecins Vinblastine
or nancial relationships in regard to this article. following treatment. Exceptions to this Epipodophyllotoxins

Vol. 41 No. 12 December 2016 P&T

765
PHARMACOVIGILANCE FORUM

and often unpredictable onset. Rituximab- of granulocytes may be disturbed by MANAGEMENT

associated late-onset neutropenia has been chemokine stromal-derived factor-1 inter- Infectious complications, such as
dened in the literature as neutropenia acting with B-lymphocyte recovery. One neutro penic fever, that may occur
developing at least three to four weeks of the most compelling theories is that because of severe and prolonged neutro-
following the end of rituximab adminis- it may occur due to polymorphisms in penia secondary to rituximab treatment
tration despite a complete recovery of the immunoglobulin G (IgG) Fc receptor should be managed with antimicrobial
ANC following chemotherapy.9 It has also (FcR). Patients harboring the FcRIIIa therapy. Antimicrobials should be
been reported that rituximab may induce 158 V/F polymorphism were found to selected and modied based on guideline
neutropenia more than 40 days after the have a higher incidence of rituximab- recommendations.8 Empiric treatment
end of treatment.10 Neutropenia with induced neutropenia.14 The presence of of neutropenic fever usually includes
cytotoxic chemotherapy recovers with a this polymorphism may facilitate neutro- an antipseudomonal beta-lactam, such
very predictable pattern and is typically penia following rituximab administration as cefepime, ceftazidime, piperacillin-
short-lived in duration; however, rituximab- by mediating antibody-dependent cell- tazobactam, meropenem, or imipenem.
induced late-onset neutropenia may be mediated cytotoxicity on malignant and Treatment against methicillin-resistant
prolonged and result in a very unpredict- nonmalignant B cells, thus increasing the Staphylococcus aureus (MRSA) with
able recovery time. Without the utilization degree of B-cell depletion. agents such as vancomycin should be
of granulocyte-colony stimulating factors included in empiric antimicrobial regi-
(GCSFs), rituximab-induced late-onset INCIDENCE AND RISK FACTORS mens when other additional clinical indi-
neutropenia may last a median of six to The reported incidence of rituximab- cators are present, such as pneumonia,
77 days.11 induced late-onset neutropenia varies skin or soft tissue infection, or suspected
Most cases of rituximab-induced late- within the literature. This adverse drug catheter-related infection, or if the patient
onset grade 13 neutropenia are self- reaction (ADR) may occur in 8% to 27% of is hemodynamically unstable.
limiting and resolve without any compli- cancer patients treated with rituximab.15 GCSFs can also be used in patients
cations. However, there is the possibility The incidence of rituximab-induced late- with neutropenic fever with additional
of more severe cases in grade 4 neutro- onset neutropenia has been reported to risk factors for severe complications,
penia.10,12 In grade 3 or 4 neutropenia, be much lower in patients being managed such as those with an ANC of less than
there is a potential for prolonged and with rituximab for autoimmune disease. 100 cells/mm3 and/or with pneumo-
serious life-threatening infectious com- These rates are as low as 1.3% to 2.3%.16 nia, hypotension, multi-organ failure, or
plications. The delayed onset, unpredict- Despite the proposed high incidence invasive fungal infections.17 GCSFs, such
able occurrence, and neutrophil recov- of this ADR, many of the episodes are as Neupogen (lgrastim, Amgen), Granix
ery associated with rituximab-induced self-limiting and without any apparent (tbo-lgrastim, Cephalon, Inc.), and Zarxio
late-onset neutropenia can create a clini- clinical signicance. In rare cases, severe (lgrastim-sndz, Sandoz), stimulate and
cal challenge for practitioners. Diligent neutropenia has the potential to occur, promote the maturation and activation of
patient follow-up is needed to monitor for which can place patients at risk for life- neutrophils. This class of drugs can also
this adverse event, and therapeutic inter- threatening infectious complications. enhance the exodus of mature neutrophils
vention may be necessary in severe cases Severe neutropenia resulting in neutro- trapped within the bone marrow. Through
that may result in neutropenic fever. penic fever and infection can lead to hos- these mechanisms, GCSFs have demon-
pitalization, the need for broad-spectrum strated proven efcacy in their ability to
MECHANISM OF ADVERSE antibiotics, and the potential sequelae of reduce the incidence, magnitude, and
DRUG REACTION bacteremia, and it can be fatal. duration of neutropenia following che-
Most cytotoxic chemotherapy exerts Multiple studies have evaluated the motherapy administration.
its pharmacological activity by causing risk factors for developing rituximab- In severe cases of rituximab-induced
DNA damage in either a cell-specic or induced late-onset neutropenia. Patients late-onset neutropenia, especially with
cell-nonspecic manner. By damaging the with advanced stages of malignancy and infectious complications, the utilization of
DNA of malignant cells, chemotherapy is those more than 60 years of age are at lgrastim or a lgrastim biosimilar may be
able to produce killer malignant cells. greater risk.6,9 Previous treatment with warranted. Filgrastim products are espe-
Many chemotherapy agents cause bone purine analogs or methotrexate and prior cially useful in managing patients treated
marrow suppression resulting in neutro- autologous peripheral blood stem cell with rituximab because they address
penia, which leads to an increased risk of transplantation may also be risk factors the unpredictable nature of neutrophil
infection. The mechanism by which ritux- for developing rituximab-induced late- recovery and possible prolonged neutro-
imab may induce neutropenia has yet to onset neutropenia. In addition, patients penic duration. No specic recommenda-
be fully elucidated; however, a variety of harboring the IgG FcRIIIa 158 V/F tions regarding the optimal ANC target,
theories exist. polymorphism are at high risk for devel- frequency, and duration of administration
After rituximab administration, anti- oping this ADR. 12,14 In patients receiving of lgrastim products have been proposed
bodies against neutrophils may be rituximab for noncancer indications, age to manage this adverse event. The drug
produced, resulting in neutropenia.13 It and female gender have been found to is typically administered once daily until
may also develop due to aberrant B-cell increase the risk for this adverse event.16 neutrophil recovery when it is utilized
reconstitution after rituximab administra- for neutropenia prophylaxis in patients
tion. Another theory is that homeostasis with nonmyeloid malignancies receiving

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

 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 the swift ANC recovery following the 6. Nitta E, Izutsu K, Sato T, et al. A high
discontinued. Her past medical history was administration of a lgrastim product. incidence of late-onset neutropenia follow-
ing rituximab-containing chemotherapy
also signicant for hypertension, type-2 Given the unclear nature and mecha- as a primary treatment of CD20-positive
diabetes mellitus, and gastroesophageal nism of rituximab-induced late-onset B-cell lymphoma: a single-institution
reux disease. Her home medications neutropenia, it is not fully known and study. Ann Oncol 2007;18(2):364369.
included lisinopril 20mg daily, hydrochloro- understood if re-treatment with rituximab 7. Hirayama Y, Kohda K, Konuma Y, et al.
Late onset neutropenia and immuno-
thiazide 25mg daily, and pantoprazole is a viable and safe option for patients.
globulin suppression of the patients with
40mg daily. It has been previously reported that malignant lymphoma following auto-
Pertinent laboratory data for Case 2 rechallenging a patient with rituximab logous stem cell transplantation with
can be found in Table 2. Her ANC was following an episode of severe late- rituximab. Intern Med 2009;48(1):5760.
208 cells/mcL (neutropenic). On presenta- onset neutropenia can lead to recurrent 8. National Cancer Institute. NCI
common terminology criteria for adverse
tion, the patient had a Tmax of 103 F, a blood episodes.19 With the possibility of recur- events, v4.0 (CTCAE). May 28, 2009.
pressure of 106/71 mm Hg, and a heart rate rence and the unclear risks and impli- Available at: http://evs.nci.nih.gov/
of 101 beats per minute. She was admit- cations of re-treatment, the decision to ftp1/CTCAE/CTCAE_4.03_2010-06-14_
ted for empirical treatment and manage- administer further doses of rituximab QuickReference_5x7.pdf. Accessed
May 29, 2016.
ment of neutropenic fever. Cefepime 2g IV should be made on a case-by-case basis.
9. Frieeld AG, Bow EJ, Sepkowitz KA, et
piggyback (IVPB) every eighthours was Future research is needed in this area. al. Clinical practice guideline for the use
initiated, along with vancomycin 1.5 g of antimicrobial agents in neutropenic
IVPB every 12 hours. She also received REPORTING ADVERSE patients with cancer. Clin Infect Dis
lgrastim 480 mcg subcutaneously once DRUG REACTIONS 2011;52:e56e93.
10. Arai Y, Yamashita K, Mizugishi K, et al.
daily. Vancomycin was empirically started All ADRs should be reported to Risk factors for late-onset neutropenia
because of a suspected skin and soft-tissue MedWatch at 1-888-INFO-FDA, after rituximab treatment of B-cell lym-
infection on her right foot. Blood cultures 1-888-463-6332, or online. The Food phoma. Hematology 2015;20(4):196202.
were negative. Podiatry was consulted and Drug Administration (FDA) 3500 11. Fukuno K, Tsurumi H, Ando N, et al. Late-
onset neutropenia in patients treated with
for the foot ulcer, for which an incision Voluntary Adverse Event Report Form
rituximab for non-Hodgkins lymphoma.
and drainage were performed. Cultures can be accessed easily online for report- Int J Hematol 2006;84:242247.
of the ulcer grew Pasteurella canis, and ing ADRs at www.fda.gov/Safety/Med- 12. Tesfa D, Palblad J. Late-onset neutro-
antibiotics were de-escalated to oral watch/HowToReport/ucm085568.htm. penia following rituximab therapy;
ciprofloxacin 500 mg twice daily for The FDA is interested in serious incidence, clinical features and possible
mechanisms. Expert Rev Hematol
10 days. Tbo-filgrastim 480 mcg was reports that include any of the fol- 2011;4(6):619625.
administered subcutaneously daily for a lowing patient outcomes: death; life- 13. Smith TJ, Khatcheressian J, Lyman GH,
total of threedays. Neutrophil recovery to threatening condition; initial hospitaliza- et al. 2006 update of recommendations for
an ANC of 1,750 cells/mcL occurred on the tion; prolonged hospitalization; disability the use of white blood cell growth factors:
an evidence-based clinical practice guide-
nal day of administration. The patient was or permanent damage; congenital anoma-
line. J Clin Oncol 2006;24:119.
discharged after a four-day hospitalization. lies or birth defects; and other serious 14. Weng WK, Negrin RS, Lavori P, Horn-
Follow-up laboratory tests did not reveal conditions for which medical or surgical ing SJ. Immunoglobulin G Fc recep-
any further episodes of neutropenia. intervention is needed to prevent one tor FcRIIIa 158 V/F polymorphism
of the aforementioned outcomes. The correlates with rituximab-induced neutro-
penia after autologous transplantation in
CONCLUSION FDA is also interested in any unlabeled patients with non-Hodgkins lymphoma.
Rituximab can cause a delayed and ADRs for new drugs (e.g., usually those J Clin Oncol 2010;28(2):279284.
late-onset neutropenia that may last for approved within the previous two years). 15. Grant C, Wilson WH, Dunleavy K. Neutro-
an unpredictable amount of time. Although penia associated with rituximab therapy.
Curr Opin Hematol 2011;18(1):49.
most cases appear to be self-limiting and REFERENCES 16. Salmon JH, Cacoub P, Combe B, et al.
resolve without issue, rituximab-induced 1. Andersohn F, Konzen C, Garbe E. Late-onset neutropenia after treatment
late-onset neutropenia may result in seri- Systematic review: agranulocytosis with rituximab for rheumatoid arthritis
ous life-threatening complications requir- induced by nonchemotherapy drugs. Ann and other autoimmune diseases: data
Intern Med 2007;146:657665. from the AutoImmunity and Rituximab
ing immediate medical intervention. When 2. Kaufman DW, Kelly JP, Issaagrisil S, Registry. RMD Open 2015;1(1):e000034.
patients with autoimmune disease or et al. Relative incidence of agranulo- doi: 10.1136/rmdopen-2014-000034.
cancer are treated with rituximab, it cytosis and aplastic anemia. Am J Hematol 17. Dunleavy K, Tay K, Wilson WH.
is important to be aware of rituximab- 2006;81:6567. Rituximab-associated neutropenia. Semin
induced neutropenia, which can occur 3. Rituxan (rituximab) prescribing infor- Hematol 2010;47(2):180186.
mation. South San Francisco, California: 18. Neupogen (filgrastim) prescribing
long after therapy cessation. This adverse Genentech Inc; March 2016. information. Thousand Oaks, California:
event can pose a challenge for clinicians 4. Johnson P, Glennie M. The mechanisms Amgen; July 2015.
and requires close patient follow-up during of action of rituximab in the elimina- 19. Wolach O, Bairey O, Lahav M. Late-onset
rituximab administration as well as after tion of tumor cells. Semin Oncol 2003; neutropenia after rituximab treatment.
30(1 suppl 2):S3S8. Medicine 2010;89(5):308318. Q
therapy has ended. Compared with what is 5. Motl SE, Baskin RC. Delayed-onset
reported in the literature, our two patients grade 4 neutropenia associated with
presented in a very similar fashion, given rituximab therapy in a patient with lym-
the delayed onset of the neutropenia and phoma: case report and literature review.
Pharmacotherapy 2005;25(8):11511155.

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

 RESEARCH BRIEFS

Easier Vaccination Options Boost To expand on their earlier research, the researchers
Coverage for Health Care Staff conducted another study in 111 patients with early-stage
Making it easier for employees to get free u vaccinations breast cancer. Of those patients, 41% had human epidermal
on siteand requiring those vaccinationshas helped bump growth factor receptor 2positive breast cancer and received
up coverage, according to an online survey conducted for the adjuvant trastuzumab along with paclitaxel. Over a median
Centers for Disease Control and Prevention (CDC). of 12 weeks, 77 patients (69%) developed all-grade periph-
Of the 2,316 health care personnel who responded, 79% eral neuropathy; in 17, the neuropathy was severe enough to
reported having gotten a u shot for the 20152016 season, mandate reducing or delaying doses, or stopping paclitaxel.
up 15.5 percentage points from the 20102011 estimate but Peripheral neuropathy occurred before cycle 6 in 48%. Not
similar to the 77.3% coverage for 20142015. surprisingly, patients with diabetes had more severe
Physicians continued to be most likely to get vaccinated neuropathy (44% versus 11%).
(95.6%). Assistants and aides had the lowest coverage, although The mean NDRG1 score of patients without severe
it was well above half (64.1%). neuropathy was 7.7, compared with 5.4 for patients with
Where vaccination was required, coverage was nearly total severe neuropathy. Fifty-four patients had an NDRGI score of
(96.5%). But only 61% of health care personnel work in hospitals less than 7; of those, 13 (24%) developed severe neuropathy,
with vaccination requirementsand thats at least 27 percent- compared with only four of 57 (7%) patients with a score
age points higher than the proportion in any other work setting, above 7.
the researchers said. Aides and assistants reported the lowest The researchers are performing a larger prospective study
prevalence of vaccination requirements (22.5%). to explore the mechanisms of NDRG1 regulation to support
Next to requirements, another factor that signicantly inu- their ndings.
enced vaccination response was cost. The majority of vaccinated Source: PLOS One, October 2016
health care staff got the shots at their workplace. Coverage
was highest when free vaccination was available on site for a Ebola Treatment Is Promising,
day or more. But Not Denitively Better
To boost vaccination among long-term-care staff, the CDC The experimental Ebola treatment ZMapp, which is com-
and the National Vaccine Program Ofce offer a Web-based posed of three monoclonal antibodies, prevents progression of
toolkit that includes access to resources, strategies, and Ebola virus disease by targeting the main surface protein of the
educational material (www.cdc/gov/u/toolkit/long-term- virus. According to ndings from the clinical trial PREVAIL II,
care/index.htm). Employers and health care administrators ZMapp is safe and well tolerated. But because the Ebola epi-
can also check out the Guide to Community Preventive Services, demic is waning, the National Institutes of Health said, the
which presents evidence to support on-site vaccination at no study enrolled too few people to determine denitively whether
or low cost. it is a better treatment than the best available standard of care.
Source: Morbidity and Mortality Weekly Report, September The study involved 72 men and women with conrmed
2016 infection. However, the researchers closed the study
early because they could not enroll the target number of
Protein May Predict Risk for 200 participants due to the decline in cases. All patients
Paclitaxel-Induced Neuropathy received the optimized standard of careintravenous (IV)
A promising biomarker strategy may help identify patients uids, electrolyte balance, maintaining oxygen and blood
at risk for severe paclitaxel-induced peripheral neuropathy. pressure levelsand half also received three IV infusions of
Paclitaxel administered weekly is more effective than ZMapp three days apart.
treatment once every three weeks, but it comes at the price At 28 days, 13 of the 35 patients (37%) in the standard-care
of more severe sensory peripheral neuropathy. As yet, treat- group had died, compared with eight of 36 (22%) in the ZMapp
ment for chemotherapy-induced peripheral neuropathy is only group. That difference, a 40% lower risk of death with ZMapp,
symptomatic, said researchers from Singapore. still did not reach statistical signicance.
Their previous research, however, suggested that a protein The ndings are promising and provide valuable scien-
N-myc downstream regulated gene 1 (NDRG1)might be useful tic data, said Anthony Fauci, MD, Director of the National
in predicting paclitaxel-induced peripheral neuropathy. NDRG1 Institute of Allergy and Infectious Diseases. Importantly, the
is ubiquitously expressed in human tissues and tumors, the study establishes that it is feasible to conduct a randomized,
researchers noted, particularly in peripheral nerve tissue. It has controlled trial during a major public health emergency in a
also been implicated in degrading myelin in Charcot-Marie-Tooth scientically and ethically sound manner.
disease, a hereditary motor and sensory neuropathy. 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 activated partial thromboplastin time.4 Low-molecular-weight

Pulmonary embolism (PE) is a common disease, occurring heparin and fondaparinux are also dosed based on weight.
in 60 to 112 of every 100,000 individuals.1 It is the third most Both are administered subcutaneously once or twice daily.9
common cause of cardiovascular mortality and is respon- After patients with acute PE have been stabilized, parenteral
sible for 100,000 to 180,000 deaths annually.2,3 The clinical anticoagulation should be supplemented with vitamin K antago-
manifestations of acute PE are highly variable, ranging from nists. Alternatively, a target-specic oral anticoagulant (TSOAC)
pulseless electrical activity to mild dyspnea, which can cloud agent, such as apixaban (Eliquis, Bristol-Myers Squibb/
the diagnosis.4 PE should be a part of the differential diagno- Pzer), rivaroxaban (Xarelto, Janssen), edoxaban (Savaysa,
sis in patients who present with new or worsening dyspnea, Daiichi Sankyo), or dabigatran etexilate (Pradaxa, Boehringer
chest pain, or hypotension.5 Based on the physicians level of Ingelheim) may be initiated.4,12,13 Patients who are started on
suspicion, the diagnostic workup may include a clinical decision warfarin should also receive a parenteral anticoagulant until
rule, biomarkers (e.g., d-dimer), and/or imaging modalities, the international normalized ratio (INR) has been maintained
such as computed tomography angiography or a ventilation- at 2.0 to 3.0 for at least two consecutive days.4 TSOACs may
perfusion scan. Additional evaluations may be performed be started immediately or after one to two days of parenteral
with troponins, B-type natriuretic peptide (BNP), Pro-BNP, anticoagulation.4 The goal of initial anticoagulant therapy is to
and/or echocardiography.6,7 inhibit the formation of additional brin clots.14 When choos-
PE is commonly classified as massive (high-risk), ing between parenteral anticoagulation or TSOACs, clinicians
submassive (intermediate-risk), and low-risk to help determine should consider the potential for decompensation, the need
the required treatment. Risk stratication scores are used to for thrombolytic therapy or invasive intervention, the bleeding
determine the risk of complications and associated mortality.8 risk, and the availability of reversal agents.14 Anticoagulants are
Massive PE is dened as suspected or conrmed PE in the administered for a minimum of three months and may be contin-
presence of shock, sustained hypotension, the absence of a ued indenitely, depending on the cause of the thrombus.9,12,13
pulse, or persistent profound bradycardia. Submassive PE is
dened as suspected or conrmed PE with right ventricular Thrombolysis
dysfunction in the absence of shock.1,4,8 Hemodynamically unstable PE patients are candidates for
This review focuses on the evidence behind the use of treatment with IV thrombolysis or mechanical thrombec-
thrombolytic therapy in patients with massive or submassive tomy.10 Thrombolytic agents convert native plasminogen to
PE. Concurrent heparin therapy and the management of plasmin, which in turn hydrolyzes the brin of thromboemboli,
bleeding episodes are also discussed. resulting in clot lysis.10 Streptokinase, urokinase (also known
as urinary plasminogen activator), and alteplase (Activase,
TREATMENT APPROACHES Genentech) are the only agents with this indication.1519
Anticoagulation The third-generation thrombolytics tenecteplase (TNKase,
The treatment of PE begins with the administration of Genentech) and reteplase (Retavase, Chiesi USA) are approved
anticoagulants; these agents have been shown to prevent for the treatment of acute coronary syndromes, but they have
recurrent symptoms and early death in patients with PE.4,9 also been evaluated in subjects with acute PE.20,21 Alteplase,
The initial pharmacological treatment of acute PE may also reteplase, and tenecteplase preferentially activate plasmino-
include intravenous (IV) unfractionated heparin (UFH), gen on the clot surface and are classied as brin specic.
subcutaneous low-molecular-weight heparin, or fonda- The brin-specic agents have longer half-lives, which allow
parinux (Arixtra, GlaxoSmithKline) for the rst ve to bolus administration. They also alleviate the risk of allergic
10 days.4,10,11 UFH is initiated at a dose of 80 units/kg followed reactions associated with the rst-generation thrombolytics.22
by 18 units/kg every hour, with dose adjustments based on the Streptokinase and urokinase, however, activate systemic plas-
minogen, which is not part of the clot matrix. Key characteristics
Dr. Martin is a Clinical Pharmacy Specialist in Emergency of the thrombolytic agents are listed in Table 1.2326
Medicine at Nyack Hospital in Nyack, New York. Dr. Sobolewski Thrombolytic therapy has been shown to improve pulmo-
is a Clinical Pharmacy Specialist in Emergency Medicine at Saint nary artery pressure, arteriovenous oxygenation, pulmonary
Barnabas Medical Center in Livingston, New Jersey. Dr. Bridgeman is a perfusion, and echocardiographic assessment, thereby
Clinical Assistant Professor in the Department of Pharmacy Practice relieving symptoms, preventing recurrent PE, and reducing
and Administration at the Ernest Mario School of Pharmacy at mortality.9,27 However, these benets may not outweigh an
Rutgers University in New Brunswick, New Jersey. Dr. Boutsikaris
is an Attending Physician in the Department of Emergency Medicine Disclosures: The authors report no commercial or nancial interests
at St. Peters University Hospital in New Brunswick, New Jersey. in regard to this article.

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

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

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

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

Vol. 41 No. 12 December 2016 P&T 773

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

Chronic heart failure 10 REFERENCES

Chronic pulmonary disease 10 1. Marti C, John G, Konstantinides S, et al. Systemic thrombolytic
therapy for acute pulmonary embolism: a systematic review and
PESI Class Score meta-analysis. Eur Heart J 2015;36:605614.
Class I (very low 30-day mortality risk) 65 points 2. Xu Q, Huang K, Zhai Z, et al. Initial thrombolysis treatment
compared with anticoagulation for acute intermediate-risk
Class II (low mortality risk) 6685 points pulmonary embolism: a meta-analysis. J Thorac Dis 2015;7:810821.
3. Goldhaber SZ. Venous thromboembolism: epidemiology and magni-
Class III (moderate mortality risk) 86105 points tude of the problem. Best Pract Res Clin Haematol 2012; 25:235242.
Class IV (high mortality risk) 106125 points 4. Konstantinides SV, Torbicki A, Agnelli G, et al. 2014 ESC
guidelines on the diagnosis and management of acute pulmonary
Class V (very high mortality risk) > 125 points embolism. Eur Heart J 2014;35:30333073.

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

 Systemic Thrombolysis for Pulmonary Embolism: A Review
5. Righini M, Le Gal G, Aujesky D, et al. Diagnosis of pulmonary 28. Cutis GM, Lam SW, Reddy AJ, Bauer SR. Risk factors associ-
embolism by multidetector CT alone or combined with venous ated with bleeding after alteplase administration for pulmonary
ultrasonography of the leg: a randomised non-inferiority trial. embolism: a case-control study. Pharmacotherapy 2014;34:818825.
Lancet 2008;371:13431352. 29. Kearon C, Akl EA, Ornelas J, et al. Antithrombotic therapy for
6. Wells PS, Ginsberg JS, Anderson DR, et al. Use of a clinical VTE disease: CHEST guideline and expert panel report. Chest
model for safe management of patients with suspected pulmonary 2016;149:315352.
embolism. Ann Intern Med 1998;129:9971005. 30. Dundar Y, Hill R, Dickson R, Walley T. Comparative efcacy of
7. Le Gal G, Righini M, Roy PM, et al. Prediction of pulmonary thrombolytics in acute myocardial infarction: a systematic review.
embolism in the emergency department: the revised Geneva Q J Med 2013;96:103113.
score. Ann Intern Med 2006;144:165171. 31. Yoo JW, Choi HC, Lee SJ, et al. Comparison between systemic
8. Jaff MR, McMurtry MS, Archer SL, et al. Management of and catheter thrombolysis in patients with pulmonary embolism.
massive and submassive pulmonary embolism, iliofemoral Am J Emerg Med 2016;34:985988.
deep vein thrombosis, and chronic thromboembolic pulmonary 32. Meyer G, Viellard-Baron A, Planquette B. Recent advances in
hypertension: a scientic statement from the American Heart management of pulmonary embolism: focus on the critically ill
Association. Circulation 2011;123:17881830. patients. Ann Intensive Care 2016;6:19. doi: 10.1186/s13613-016-
9. Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for 0122-z. Epub 2016 Mar 3.
VTE disease: antithrombotic therapy and prevention of thrombosis, 33. Konstantinides S. Thrombolysis in submassive pulmonary
9th ed: American College of Chest Physicians Evidence-Based embolism? Yes. J Thromb Haemost 2003;1:11271129.
Clinical Practice Guidelines. Chest 2012;141(suppl):e419Se494S. 34. Vanni S, Nazerian P, Pepe G, et al. Comparison of two prognostic
10. Weinberg I, Jaff MR. Accelerated thrombolysis for pulmo- models for acute pulmonary embolism: clinical vs right ventricular
nary embolism: Will clinical benet be ULTIMAtely realized? dysfunction-guided approach. J Thromb Haemost 2011;9:19161923.
Circulation 2014;129:420421. 35. Long B, Koyfman A. Current controversies in thrombolytic use in
11. Sanchez O, Trinquart L, Colombet I, et al. Prognostic value of right ven- acute pulmonary embolism. J Emerg Med 2016;51:3744.
tricular dysfunction in patients with haemodynamically stable pulmo- 36. Konstantinides S, Geibel A, Heusel G, et al. Heparin plus alteplase
nary embolism: a systematic review. Eur Heart J 2008; 29:15691577. compared with heparin alone in patients with submassive
12. Xarelto (rivaroxaban) prescribing information. Titusville, New pulmonary embolism. N Engl J Med 2002;347:11431150.
Jersey: Janssen Pharmaceuticals, Inc.; May 2015. Available at: 37. Shari M, Bay C, Skrocki L, et al. Moderate pulmonary embolism
www.xareltohcp.com/shared/product/xarelto/prescribing- treated with thrombolysis (from the MOPETT trial). Am J Cardiol
information.pdf. Accessed August 3, 2016. 2013;11:273277.
13. Eliquis (apixaban) prescribing information. Princeton, New Jersey: 38. Becattini C, Agnelli G, Salvi A, et al. Bolus tenecteplase for right
Bristol-Myers Squibb; July 2016. Available at: http://packagein- ventricle dysfunction in hemodynamically stable patients with
serts.bms.com/pi/pi_eliquis.pdf. Accessed August 3, 2016. pulmonary embolism. Thromb Res 2010;125:e82e86.
14. Streiff MB, Agnelli G, Connors JM, et al. Guidance for the 39. Kline JA, Nordenholz KE, Courtney DM, et al. Treatment of submas-
treatment of deep vein thrombosis and pulmonary embolism. sive pulmonary embolism with tenecteplase or placebo: cardiopul-
J Thromb Thrombolysis 2016;41:3267. monary outcomes at 3 months: multicenter double-blind, placebo-
15. Thabut G, Thabut D, Myers RP, et al. Thrombolytic therapy of pulmo- controlled randomized trial. J Thromb Haemost 2014;12:459468.
nary embolism: a meta-analysis. J Am Coll Cardiol 2002;40:16601667. 40. Bradford MA, Adhikari NK, Friedrich JO. Benets and risks
16. Dong B, Jirong Y, Liu G, et al. Thrombolytic therapy for pulmonary associated with thrombolysis for pulmonary embolism. JAMA
embolism. Cochrane Database Syst Rev 2006 Apr 19;(2):CD004437. 2014;312:15881589.
17. Dong BR, Hao Q, Yue J, et al. Thrombolytic therapy for pulmonary 41. Aujesky D, Obrosky DS, Stone RA, et al. Derivation and validation
embolism. Cochrane Database Syst Rev 2009 Jul 8;(3):CD004437. of a prognostic model for pulmonary embolism. Am J Respir Crit
18. Wan S, Quinlan DJ, Agnelli G, Eikelboom JW. Thrombolysis Care Med 2005;172:10411046.
compared with heparin for the initial treatment of pulmonary 42. Brandt K, McGinn K, Quedado J. Low-dose systemic alteplase
embolism: a meta-analysis of the randomized controlled trials. (tPA) for the treatment of pulmonary embolism. Ann Pharmacother
Circulation 2004;110:744749. 2015;49:818824.
19. Chatterjee S, Chakraborty A, Weinberg I, et al. Thrombolysis 43. Zhang Z, Zhai ZG, Liang LR, et al. Lower dosage of recombinant
for pulmonary embolism and risk of all-cause mortality, major tissue type plasminogen activator (rt-PA) in the treatment of acute
bleeding, and intracranial hemorrhage: a meta-analysis. JAMA pulmonary embolism: a systemic review and meta-analysis. Thromb
2014;311:24142421. Res 2014;133:357363.
20. Becattini C, Agnelli G, Salvi A, et al. Bolus tenecteplase for right 44. Makris M, Veen JJV, Tait C, et al. Guideline on the management
ventricle dysfunction in hemodynamically stable patients with of bleeding in patients on antithrombotic agents. Br J Haematol
pulmonary embolism. Thromb Res 2010;125:e82e86. 2012;160:3536.
21. Meyer G, Vicaut E, Danays T, et al. Fibrinolysis for patients with inter- 45. DailyMed. U.S. National Library of Medicine. Protamine sul-
mediate-risk pulmonary embolism. N Engl J Med 2014;370:14021411. fate. June 30, 2014. Available at: https://dailymed.nlm.nih.
22. Wander GS, Chhabra ST. Critical analysis of various drugs used for gov/dailymed/drugInfo.cfm?setid=e1964129-33f4-4e4e-86e3-
thrombolytic therapy in acute myocardial infarction. In: Medicine 8e6a4e65bd83. Accessed August 3, 2016.
Update: Volume 23, 2013. Mumbai, India: Association of Physicians 46. Garcia DA, Baglin TP, Weitz JI, Samama MM. Parenteral anti-
of India; 2013:109116. Available at: www.apiindia.org/medicine_ coagulants: antithrombotic therapy and prevention of thrombosis,
update_2013/chap24.pdf. Accessed August 3, 2016. 9th ed: American College of Chest Physicians Evidence-Based
23. Collen D. Molecular mechanisms of fibrinolysis and their Clinical Practice Guidelines. Chest 2012;141(suppl):e24Se43S.
application to brin-specic thrombolytic therapy. J Cell Biochem 47. Amicar (aminocaproic acid) prescribing information.
1987;33:7786. Newport, Kentucky: Xanodyne Pharmaceuticals; September
24. Lexicomp Online, Lexi-Drugs. Hudson, Ohio: Lexi-Comp, Inc.; 2008. Available at: www.accessdata.fda.gov/drugsatfda_docs/
January 29, 2015. label/2009/015230s037lbl.pdf. Accessed August 3, 2016.
25. Logan JK, Pantle H, Huiras P, et al. Evidence-based diagnosis 48. Goldstein J, Marrero M, Masrur S, et al. Management of thrombolysis-
and thrombolytic treatment of cardiac arrest or periarrest due to associated symptomatic intracerebral hemorrhage. Arch Neurol
suspected pulmonary embolism. Am J Emerg Med 2014;32:789796. 2010;67:965969.
26. Becker RC, Fintel DJ, Green D. Antithrombotic Therapy, 5th ed. 49. French KF, White J, Hoesch RE. Treatment of intracerebral
Caddo, Oklahoma: Professional Communications; 2011. hemorrhage with tranexamic acid after thrombolysis with tissue
27. Vedantham S, Piazza G, Sista A, Goldenberg N. Guidance for the plasminogen activator. Neurocrit Care 2012;17:107111. Q
use of thrombolytic therapy for the treatment of venous thrombo-
embolism. J Thromb Thrombolysis 2016;41:6880.

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
of dry eye disease (DED), a multifactorial disease of the
tears and ocular surface. DED, which is often chronic
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
complaints to eye care professionals. DED diagnosis is based
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
the treatment of the signs and
Only Xiidra is indicated to treat both the symptoms of dry eye disease
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
discomfort, eye pruritus and
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.
 Animal Data
.KVGITCUVCFOKPKUVGTGFFCKN[D[KPVTCXGPQWU
+8
KPLGEVKQPVQTCVUHTQORTGOCVKPIVJTQWIJIGUVCVKQPFC[
ECWUGFCPKPETGCUGKPOGCPRTGKORNCPVCVKQPNQUU
and an increased incidence of several minor skeletal
CPQOCNKGUCVOIMIFC[TGRTGUGPVKPIHQNF
Rx Only VJGJWOCPRNCUOCGZRQUWTGCVVJG4*1&QH:KKFTCDCUGF
BRIEF SUMMARY: on AUC. No teratogenicity was observed in the rat at
%QPUWNVVJG(WNN2TGUETKDKPI+PHQTOCVKQPHQTEQORNGVG OIMIFC[
HQNFVJGJWOCPRNCUOCGZRQUWTGCV
RTQFWEVKPHQTOCVKQP VJG4*1&DCUGFQP#7%+PVJGTCDDKVCPKPETGCUGF
KPEKFGPEGQHQORJCNQEGNGYCUQDUGTXGFCVVJGNQYGUV
FQUGVGUVGFOIMIFC[
HQNFVJGJWOCP
INDICATIONS AND USAGE RNCUOCGZRQUWTGCVVJG4*1&DCUGFQP#7%YJGP
:KKFTCv
NKVGITCUVQRJVJCNOKEUQNWVKQPKUKPFKECVGF CFOKPKUVGTGFD[+8KPLGEVKQPFCKN[HTQOIGUVCVKQPFC[U
HQTVJGVTGCVOGPVQHVJGUKIPUCPFU[ORVQOUQHFT[G[G through 19. A fetal No Observed Adverse Effect Level
FKUGCUG
&'&
01#'.YCUPQVKFGPVKGFKPVJGTCDDKV

DOSAGE AND ADMINISTRATION Lactation

+PUVKNNQPGFTQRQH:KKFTCVYKEGFCKN[
CRRTQZKOCVGN[ 6JGTGCTGPQFCVCQPVJGRTGUGPEGQHNKVGITCUVKPJWOCP
JQWTUCRCTVKPVQGCEJG[GWUKPICUKPINGWUGEQPVCKPGT milk, the effects on the breastfed infant, or the effects on
Discard the single use container immediately after using OKNMRTQFWEVKQP*QYGXGTU[UVGOKEGZRQUWTGVQNKVGITCUV
KPGCEJG[G%QPVCEVNGPUGUUJQWNFDGTGOQXGFRTKQTVQ HTQOQEWNCTCFOKPKUVTCVKQPKUNQY6JGFGXGNQROGPVCNCPF
the administration of Xiidra and may be reinserted 15 JGCNVJDGPGVUQHDTGCUVHGGFKPIUJQWNFDGEQPUKFGTGF
minutes following administration. along with the mothers clinical need for Xiidra and any
RQVGPVKCNCFXGTUGGHHGEVUQPVJGDTGCUVHGFEJKNFHTQO
ADVERSE REACTIONS Xiidra.
Clinical Trials Experience
Pediatric Use
Because clinical studies are conducted under widely
5CHGV[CPFGHECE[KPRGFKCVTKERCVKGPVUDGNQYVJGCIGQH
varying conditions, adverse reaction rates observed in
17 years have not been established.
ENKPKECNUVWFKGUQHCFTWIECPPQVDGFKTGEVN[EQORCTGF
to rates in the clinical trials of another drug and may Geriatric Use
PQVTGGEVVJGTCVGUQDUGTXGFKPRTCEVKEG+PXGENKPKECN No overall differences in safety or effectiveness have been
UVWFKGUQHFT[G[GFKUGCUGEQPFWEVGFYKVJNKVGITCUV QDUGTXGFDGVYGGPGNFGTN[CPF[QWPIGTCFWNVRCVKGPVU
QRJVJCNOKEUQNWVKQPRCVKGPVUTGEGKXGFCVNGCUV
FQUGQHNKVGITCUV
QHYJKEJTGEGKXGFNKVGITCUV
6JGOCLQTKV[QHRCVKGPVU
JCFOQPVJUQH NONCLINICAL TOXICOLOGY
VTGCVOGPVGZRQUWTGRCVKGPVUYGTGGZRQUGFVQ Carcinogenesis, Mutagenesis, Impairment of Fertility
NKVGITCUVHQTCRRTQZKOCVGN[OQPVJU6JGOCLQTKV[ Carcinogenesis: Animal studies have not been conducted
QHVJGVTGCVGFRCVKGPVUYGTGHGOCNG
6JGOQUV VQFGVGTOKPGVJGECTEKPQIGPKERQVGPVKCNQHNKVGITCUV
EQOOQPCFXGTUGTGCEVKQPUTGRQTVGFKPQHRCVKGPVU Mutagenesis: .KVGITCUVYCUPQVOWVCIGPKEKPVJGin vitro
were instillation site irritation, dysgeusia and reduced #OGUCUUC[.KVGITCUVYCUPQVENCUVQIGPKEKPVJGin vivo
XKUWCNCEWKV[1VJGTCFXGTUGTGCEVKQPUTGRQTVGFKP mouse micronucleus assay. In an in vitro chromosomal
VQQHVJGRCVKGPVUYGTGDNWTTGFXKUKQPEQPLWPEVKXCN aberration assay using mammalian cells (Chinese
J[RGTGOKCG[GKTTKVCVKQPJGCFCEJGKPETGCUGF JCOUVGTQXCT[EGNNUNKVGITCUVYCURQUKVKXGCVVJGJKIJGUV
NCETKOCVKQPG[GFKUEJCTIGG[GFKUEQOHQTVG[GRTWTKVWU concentration tested, without metabolic activation.
and sinusitis. Impairment of fertility: .KVGITCUVCFOKPKUVGTGFCV
KPVTCXGPQWU
+8FQUGUQHWRVQOIMIFC[

HQNFVJGJWOCPRNCUOCGZRQUWTGCVVJG
USE IN SPECIFIC POPULATIONS TGEQOOGPFGFJWOCPQRJVJCNOKEFQUG
4*1&QH
Pregnancy NKVGITCUVQRJVJCNOKEUQNWVKQPJCFPQGHHGEVQP
6JGTGCTGPQCXCKNCDNGFCVCQP:KKFTCWUGKPRTGIPCPV HGTVKNKV[CPFTGRTQFWEVKXGRGTHQTOCPEGKPOCNGCPF
women to inform any drug associated risks. Intravenous female treated rats.

+8CFOKPKUVTCVKQPQHNKVGITCUVVQRTGIPCPVTCVUHTQO
RTGOCVKPIVJTQWIJIGUVCVKQPFC[FKFPQVRTQFWEG
VGTCVQIGPKEKV[CVENKPKECNN[TGNGXCPVU[UVGOKEGZRQUWTGU
+PVTCXGPQWUCFOKPKUVTCVKQPQHNKVGITCUVVQRTGIPCPV Manufactured for: Shire US Inc., 300 Shire Way, Lexington, MA 02421.
TCDDKVUFWTKPIQTICPQIGPGUKURTQFWEGFCPKPETGCUGF
For more information, go to www.Xiidra.com or call 1-800-828-2088.
KPEKFGPEGQHQORJCNQEGNGCVVJGNQYGUVFQUGVGUVGF
OIMIFC[
HQNFVJGJWOCPRNCUOCGZRQUWTGCV Marks designated and are owned by Shire
VJGTGEQOOGPFGFJWOCPQRJVJCNOKEFQUG=4*1&? QTCPCHNKCVGFEQORCP[
DCUGFQPVJGCTGCWPFGTVJGEWTXG=#7%?NGXGN5KPEG 2016 Shire US Inc.
JWOCPU[UVGOKEGZRQUWTGVQNKVGITCUVHQNNQYKPI US Patents: 8367701; 9353088; 7314938; 7745460; 7790743;
QEWNCTCFOKPKUVTCVKQPQH:KKFTCCVVJG4*1&KUNQYVJG 7928122; 9216174; 8168655; 8084047; 8592450; 9085553 and
CRRNKECDKNKV[QHCPKOCNPFKPIUVQVJGTKUMQH:KKFTCWUGKP RGPFKPIRCVGPVCRRNKECVKQPU
JWOCPUFWTKPIRTGIPCPE[KUWPENGCT .CUV/QFKGF5
 Zika in America: The Year in Review
Chris Fellner

INTRODUCTION Figure 2 An Aedes Aegypti Mosquito

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
Source: CDC
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 circulation of Zika virus in that countrythe rst report of
West Nile virus.4,5 It is transmitted to people by mosquitoes of locally acquired Zika virus infection (ZVI) in the Americas.13
the Aedes species, principally Ae. aegypti (commonly known as Two days later, Brazilian authorities detected the neurologi-
the yellow fever mosquito) and Ae. albopictus (the Asian tiger cal disorder Guillain-Barr syndrome (GBS) in some adults
mosquito) (Figures 2 and 3), which thrive in warm climates.46 with ZVI.2,14 Then, in October, Brazilian ofcials reported an
By the 1980s, mosquitoes had carried the Zika virus across unusual increase in microcephaly among newborns. Fifty-four
equatorial Asia, from Pakistan to Indonesia.7,8 Continuing its cases were recorded between August and October 30.15 By the
westward migration, the virus passed from Southeast Asia to end of 2015, that number would explode to more than 2,900.16
islands in the South Pacic, where it caused major outbreaks Meanwhile, the virus was moving inexorably north. In
in 2013 and 2014.912 On July 15, 2015, Brazil conrmed the November, locally acquired ZVI cases were reported in
Colombia, El Salvador, Mexico, Venezuela, and Paraguay.1721
Figure 1 The Zika Virus 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
In this digitally colorized transmission electron micrograph, Zika is mostly rural, inhabiting thickets and arboreal vegetation.
virus particles appear in blue; they are 40 nm in diameter, with an While it bites humans, it will just as readily feed on domestic
outer envelope and an inner dense core. (Source: CDC) and wild mammals.6
In March, Brazilian scientists announced that they were able
Chris Fellner is a medical writer and the Editor of PTCommunity.com. to infect another mosquito species, Culex quinquefasciatus,

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

 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 used two pesticidesone that kills adult mosquitoes (naled, an
With its ubiquitous, almost year-round population of organophosphate) and another that eradicates mosquito eggs
Ae. aegypti and Ae. albopictus mosquitoes and a high volume and larvae. By the end of the month, it was obvious that the
of travelers from Zika-affected countries, Florida is especially plan wasnt working. The mosquitoes were under control in
vulnerable to Zika outbreaks.40 only 20% of the target areain zones where both insecticides
In February, Florida Governor Rick Scott declared a public were used. In the remaining 80% of the target area, where only
health emergency in four counties with travel-related cases of naled was sprayed, the Aedes mosquitoes held their own.51 On
ZVI and ordered state ofcials to increase mosquito-control August 29, researchers at the University of Texas Medical
efforts. The counties were MiamiDade in south Florida, Branch in Galveston reported a possible explanation: Adult
Hillsborough in the Tampa Bay region, Lee in southwest female mosquitoes can pass the Zika virus to their offspring,
Florida, and Santa Rosa in the Florida Panhandle.41 In late July, making it clear that pesticide programs need to kill both adult
MiamiDade became the U.S. epicenter of Zika activity when mosquitoes and their eggs.52
local health ofcials conrmed two cases of disease caused In late August, Florida health ofcials announced that they
by mosquito bites in a square-mile area of Wynwood, a trendy were investigating three more Zika cases that were likely
neighborhood just north of downtown Miami.40,42 They were acquired locally in MiamiDade County, including two cases
the rst locally acquired cases of ZVI in the continental U.S. outside of the known areas of active virus transmission. That
The CDC issued a travel advisory warning pregnant women brought the states total of nontravel-related cases to 46.53 But
to avoid the area.43 people began to question the accuracy of information being
These cases are not unexpected, CDC Director Tom issued by state agencies. On September 10, the Miami Herald
Frieden, MD, MPH, told a press conference. At CDC, weve reported that health ofcials had stopped providing detailed
been saying for months, based on experience with chikungunya information on epidemiologic investigations into local ZVI;
and dengue, which are viruses spread by the same mosquito had refused to identify all of the locations where Zika-positive
that spreads Zika, that individual cases and potentially small mosquitoes were trapped in Miami Beach; and had under-
clusters of Zika are possible in the U.S. As we have anticipated, reported the number of local Zika infections in Florida by
Zika is now here.44 excluding anyone who was not a state resident. Arthur Caplan,
As Dr. Frieden spoke, 1,658 cases of ZVI had been reported to PhD, Director of Medical Ethics at New York University
the CDC in the continental U.S. and Hawaii, but none resulted Langone Medical Center, commented: It makes no sense
from local mosquito bites. Fifteen cases were believed to be unless you see it through the eyes of the impact on tourism.54
related to sexual transmission, and one case in Pennsylvania On September 17, Florida ofcials tripled the active Zika
was caused by accidental laboratory exposure to the virus.42 virus transmission zone in Miami Beach from 1.5 square miles
In early August, the CDC announced that an additional to 4.5 square miles after ve new ZVI cases were identied in
area of active Zika transmission had been identied in Miami the area. On the plus side, Governor Scott announced that he
Beach. The Florida Department of Health also found at least expected the Zika zone to be lifted in neighboring Wynwood,
four other instances of apparently mosquito-borne Zika in where aggressive mosquito control and community outreach
MiamiDade County.45 measures had proved effective.55
The CDC pointed out that detecting the local spread of Zika The good news didnt last. In mid-October, Governor Scott
virus was difcult for several reasons:45 revealed that local transmission of Zika virus was occurring in
a new Miami area, where health ofcials believed two women
The incubation period for ZVI is up to two weeks. and three men had been infected.56 Soon the CDC introduced
A high proportion of infected people have no symptoms. a color-coding system for MiamiDade County to distinguish
The diagnosis and investigation of cases take weeks. between areas of active transmission that present a signicant
risk of ZVI and areas with a possible risk of ZVI. The system
For these reasons, the CDC said, it was possible that denoted the whole county as a yellow cautionary area except
other MiamiDade neighborhoods could have active Zika for Miami Beach and the one-square-mile Little River neigh-
transmission that was not yet apparent.44 borhood of Miami, which were high-risk red zones. The CDC
Anthony Fauci, MD, Director of the National Institute of recommended that pregnant women consider postponing
Allergy and Infectious Diseases (NIAID), warned that Zika travel to the yellow areas and specically avoid the red areas.57
could easily continue its march into the continental U.S.46 Not As of October 19, 2016, Florida remained the only state with
long afterward, a ZVI case was reported more than 200 miles locally acquired ZVI, with 137 conrmed cases.58
north of Miami in Pinellas County. The case involved a woman
with no signicant travel history, indicating that the virus was The Government Response
acquired locally.47 A second nontravel-related case of ZVI was As the new year began, the White House said its efforts to
discovered in Palm Beach County.48 In mid-August, a Texas ght Zika would consist mainly of sharing information about
resident who had traveled to a Miami area with local Zika the risks with the public. President Obama, however, acknowl-
transmission tested positive for the virus upon returning home. edged the need for Zika tests, treatments, and vaccines.59
It was the rst time that the virus had spread between states.49 Soon afterward, he called on Congress to supply $1.9 billion
On August 3, ofcials in MiamiDade County began the aerial in emergency funding.60
insecticide spraying recommended by the CDC in an effort to On April 1, more than 300 local, state, and federal govern-
kill Aedes mosquitoes in a 10-square-mile area.50 The program ment ofcials; health experts; and nongovernment partners

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

 Zika in America: The Year in Review
gathered at CDC headquarters in Atlanta to craft a national U.S. health ofcials made it clear that the funding delay
plan to combat Zika.61,62 The summits aims included identifying hurt U.S. efforts to ght the Zika virus. Because weve had to
gaps in readiness and providing technical support to state and wait these seven months, Dr. Frieden said, we havent been
local jurisdictions.62 Dr. Frieden suggested that states appoint able to get a running start on some of the critically impor-
a Zika coordinator. Other experts urged health ofcials to tant studies to understand more fully the impacts of Zika, to
establish surveillance networks to monitor the spread of the establish better diagnostic tests, [and] to improve our way of
virus. Many called on Congress to approve the $1.9 billion in controlling mosquitoes. Vaccine development was also
funding requested by the White House, much of which would delayed.76
be funneled to local and state agencies that couldnt afford Given how long processing and budgeting can take, public
signicant mosquito control.63 health laboratories didnt expect a cash infusion until early
In April, federal ofcials announced that they would transfer 2017. Meanwhile, with local health departments shrinking,
$589 million originally intended to protect against Ebola for many dont have the staff to operate laboratories at the level
use in the ght against Zika.64 needed given the volume of samples coming in.77
Finally, on May 16, the Zika Response Appropriations
Act2016 was introduced in the House. The Republican-backed ZIKA HEALTH EFFECTS AND RISKS
bill provided $622.1 million to federal agencies to ght Zika by During a Zika press conference on April 11, Anne Schuchat,
repurposing leftover Ebola funding and unused Department MD, the CDCs Principal Deputy Director, remarked that
of Health and Human Services (HHS) administrative funding.65 everything we look at with this virus seems to be a bit scarier
President Obama immediately threatened to veto the measure, than we initially thought.78 Two days later, the CDC conrmed
calling the funding woefully inadequate.66 Nevertheless, the what many people had suspected: ZVI can cause microcephaly
bill passed the House by a vote of 241 to 184.67 A day later, the and other serious fetal defects.79 The agency declined, however,
Senate, on a vote of 68 to 30, passed its own bill, which called to acknowledge a link between Zika and GBS in adults, saying
for $1.1 billion in emergency money to ght Zika.68 Heated it was still investigating.80
bickering ensued between House and Senate negotiators
before the House grudgingly passed a $1.1 billion Zika bill on Zika: A Neurotropic Virus
June 23 by a vote of 239 to 171almost entirely along party Early in 2016, the World Health Organization (WHO)
lines. Democratic leaders bristled at what they called unreason- announced that Zika had been detected in amniotic uid and
able spending cuts and policy changes, especially on womens that the virus was able to cross the placental barrier and infect
health, that Republicans had tacked onto the bill.69 On July 14, the fetus. We can now conclude, the agency said, that Zika
the measure fell short of the 60 votes needed to advance in the virus is neurotropic, preferentially affecting tissues in the brain
Senateand both sides went home for a seven-week recess.70 and brain stem of the developing fetus.81
Dr. Frieden said simply: This is no way to ght an epidemic.71 In July, a study at the Pasteur Institute in France found that
In August, President Obama said he would divert another Zika virus could infect and impair neural stem cells in the devel-
$81 million from other programs to fund development of a Zika oping neocortex of mice.82 In the U.S., similar research was
vaccine because Congress had failed to approve funding.72 conducted at Rockefeller University in New York City, where
Meanwhile, Florida Governor Scott complained that the investigators found that Zika could attack cells in adult mice
federal government had not delivered all of the support he in the hippocampus, the part of the brain involved in learning
had requested.48 and memoryraising disturbing questions about how the virus
On August 30, Dr. Frieden said that the CDC would run might affect human adults. The researchers noted that other
out of funds to ght Zika by the end of September if nothing studies had documented the virus ability to cause serious brain
was done73but his warning fell on deaf ears. The Senate and spinal cord infections, including encephalitis, meningitis,
returned to Washington on September 6 and again refused to and myelitis, in people with ZVI.83 Shortly afterward, scientists
pass a bill that would fund Zika research and prevention. The in the U.S. and Venezuela described the rst case of sensory
main source of contention was a Republican effort to prevent polyneuropathy associated with acute ZVI.84
Planned Parenthood from receiving money to combat the In September, American researchers found that Zika can
mosquito-borne disease. The vote was 52 to 46, short of the infect cranial neural crest cells (which give rise to bones and
60 votes needed to advance the bill.74 cartilage in the skull) and can cause them to secrete signaling
In late September, Congress nally allocated $1.1 billion to molecules that alter their function. In the lab, the increased
curb Zikas spread as part of a larger spending bill designed to levels of these molecules were enough to induce the premature
keep the federal government running until December 9. Almost differentiation, migration, and death of human neural progenitor
$935 million was approved to ght Zika at home: $152 million cells. This may help explain why infants born to Zika-infected
for NIAID, which is researching vaccines; $394 million for mothers are at risk of microcephaly and disproportionate
CDC use in Zika-affected areas; and $387 million for the HHS facial features.85,86
public health emergency fund for activities such as Zika testing
and ZVI patient care. Another $175 million was approved for Zika and Pregnancy
Zika efforts abroad, such as evacuating pregnant Americans There is no evidence to suggest that pregnant women are
from countries where Zika is spreading and helping hard-hit more susceptible to ZVI or experience more-severe disease
foreign nations.75 Planned Parenthood wasnt mentioned in compared with women who are not pregnant, according to
the September deal.75 the CDC.87 Infection during pregnancy, however, can result

Vol. 41 No. 12 December 2016 P&T

781
 Zika in America: The Year in Review
in congenital microcephaly and other severe brain defects in in addition to microcephaly, ZVI may cause hydrops fetalis
the fetus.88 ZVI has also been implicated in adverse pregnancy (the abnormal accumulation of uid in fetal compartments),
outcomes, including miscarriage and stillbirth.88,89 hydranencephaly (the almost complete loss of brain tissue), and
In April, researchers in Brazil reported placental inamma- stillbirth.105,106 By April, the data were sufciently compelling
tion and the presence of Zika virus in Hofbauer cells (human to prompt the CDC to announce that ZVI in pregnant women
placental macrophages) in tissue samples obtained from preg- was denitely a cause of microcephaly and other severe brain
nant women infected with the virus. The ndings suggested abnormalities in fetuses.79
that a damaged placental barrier may facilitate fetal infection In June, the CDC estimated that the potential risk for micro-
with Zika.90 Yale University investigators later reported similar cephaly following ZVI ranged from 1% to 13%. The agency based
observations and theorized that Hofbauer cells, because of its estimate on statistics from a 2013 Zika outbreak in French
their migratory characteristics, may help disseminate Zika Polynesia and on ongoing reports of virus-related birth defects
virus to the fetal brain.91 in Brazils Bahia state. More importantly, the CDC disclosed
Because of the potential risks of ZVI during pregnancy, the nine U.S. cases of ZVI-associated microcephaly. All involved
CDC has stated that its top priority in combating the virus is to women who contracted ZVI outside the U.S. in areas with
protect pregnant women and their fetuses.87 Still, the agency active Zika outbreaks or were infected through unprotected
acknowledges that much is not yet known about ZVI in this sex with an infected partner.107
setting. Uncertainties include:87,92 Meanwhile, progress was being made on the research front.
Scientists at the University of Southern California discovered
The incidence of ZVI among pregnant women in areas of two Zika proteins responsible for microcephaly, an important
Zika virus transmission step toward prevention. The Zika virus contains 10 proteins, but
The rate of vertical transmission of the virus only nonstructural protein 4A (NS4A) and NS4B matter when
The rate with which infected fetuses manifest complica- it comes to microcephaly, according to the research. These
tions, such as microcephaly or death proteins stunt brain development and increase autophagy so
How often the Zika virus can pass from a pregnant woman that the virus can spread. When they hijacked fetal neural stem
to her fetus during pregnancy or around the time of birth cells, the size of brain organoids was, on average, halved.108
Other potential health problems that ZVI may cause during In another August report, researchers at Harvard Medical
pregnancy School and Beth Israel Deaconess Hospital in Boston described
Whether pregnant women are more likely to develop Zika the devastating effects that Zika has on the developing fetal
symptoms compared with the general population brain. The investigators used radiographs to document brain
Whether pregnant women are more likely to develop GBS. abnormalities associated with congenital ZVI in 45 cases
from Brazil. The most common trait, observed in all subjects,
The CDCs latest guidance recommends that all pregnant was a visible reduction in brain-tissue volume. All subjects
women in the U.S. and its territories should be assessed for also showed calcication in several regions of the brain and
possible exposure to Zika virus at each prenatal care visit. The abnormal development of the cortex. Further, the radiolo-
agency also recommends that pregnant women not travel to an gists saw enlarged uid-lled ventricles in 43 of the babies.109
area with active Zika virus transmission. In addition, pregnant Finally, in August, the CDC reported on research conducted
women with a sex partner who has traveled to or lives in an in Brazil that found sensorineuronal hearing loss in ve of 70
area with active Zika virus transmission should use condoms (7.1%) infants with ZVI-related microcephaly.110
or other barrier methods to prevent ZVI or should abstain from That same month, ofcials in Harris County, Texas, reported
sex for the duration of the pregnancy.87 the rst known infant death linked to ZVI in the U.S. The girl
In May, the CDC reported that 279 pregnant women were had several Zika-related birth defects, including microcephaly.
infected with Zika virus in the U.S.93 By October 11, that number Her mother likely contracted the virus in Latin America,
had more than tripled to 899.94 ofcials said.111

Microcephaly and Other Birth Defects Zika and Guillain-Barr Syndrome

Microcephaly is a rare neurological disorder in which an Zikas neurotropic characteristics and high afnity for
infants head circumference is much smaller than normal brain tissue may also manifest as GBS in infected adults.87,112
for the childs age and gender.9597 The deformity is typically GBS is a rare disease of the nervous system that affected an
caused by genetic abnormalities, the mothers exposure to toxic estimated 3,000 to 6,000 people a year in the U.S. before Zika
substances during pregnancy, or certain viral infections during arrived. In GBS patients, damaged nerve cells lead to muscle
pregnancy, such as rubella or cytomegalovirus.97 Brazilian weakness and sometimes paralysis. In severe cases, weak-
ofcials noticed an apparent link between the birth of micro- ness or paralysis can affect the muscles that control breath-
cephalic infants and the presence of Zika virus in pregnant ing. Symptoms can last weeks or months, and most people
women early in that countrys Zika crisis,98100 but world health fully recover.87,113 Approximately 30% of those with GBS have
experts were initially hesitant to conrm the connection.101103 residual weakness after three years, while approximately 3%
In January, the U.S. experienced its rst microcephalic birth. may experience a relapse of muscle weakness and tingling
The case involved a Zika-infected woman in Hawaii who had sensations many years after the initial attack.114 Before Zika,
lived in Brazil early in her pregnancy.104 The following month, GBS was linked to dengue and chikungunya infections, among
a researcher at the Yale School of Public Health reported that, other causes.115,116

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

 Zika in America: The Year in Review
In March, U.S. health ofcials notied the WHO of Americas a traveler. This was the rst U.S. Zika case in someone who
rst two cases of Zika-related GBS. The rst case was an had not traveled abroad, and the third indication that the virus
elderly man who had recently traveled to Central America. could be sexually transmitted.123,124
He developed an acute febrile illness shortly after returning The CDC immediately posted interim guidelines for pre-
to the U.S. and was hospitalized in January with progressive venting the sexual transmission of ZVI.123 In its most recent
weakness of the extremities and diminished reexes. The recommendations (updated on September 30), the agency
patient tested positive for ZVI by polymerase chain reaction advises that male and female condoms be used from start to
(PCR). He was about to be discharged when he died suddenly nish, every time, during vaginal, anal, and oral sex, and the
from a ruptured subarachnoid aneurysm.117 sharing of sex toys. In addition, dental dams (latex or polyure-
The second case was an adult male resident of Haiti who thane sheets) may also be used for certain types of oral sex.
experienced the acute onset of facial weakness, difculty According to the CDC, testing blood, semen, vaginal uids, or
swallowing, and numbness of the ngers in early January. urine is not recommended to determine how likely a person is
Days later, he travelled to the U.S. for additional medical care. to pass Zika virus through sex. Because Zika virus can remain
His cerebrospinal uid had elevated protein and normal white in semen longer than blood, someone might have a negative
blood cells. A physical examination showed mild weakness and blood test but a positive semen test.126
diminished reexes. The patient tested positive for ZVI by serol- Another important discovery took place in February, when
ogy. He improved after intravenous immunoglobulin therapy a man in England was found to have viable Zika virus in his
(the standard treatment for GBS) and was discharged.117 semen two months after he was infected, suggesting that the
In a surveillance study conducted by the Puerto Rico virus may linger in semen long after ZVI symptoms fade.127
Department of Health with CDC assistance, 56 suspected By that time, the CDC was investigating 14 new reports of
cases of GBS with neurological signs were identied between possible sexual transmission of Zika virus in the U.S. The
January 1 and July 31, 2016. Thirty-four (61%) of those individu- agency announced that sexual transmission of the virus might
als had evidence of ZVI or avivirus infection. The subjects be more likely than previously thought.128
mean age was 55 years (range, 2188 years). All were treated In April, the CDC revealed that the case of sexual transmis-
with intravenous immunoglobulin G.118 sion in Texas involved two men, adding another dimension to
At the end of August, researchers at the Pan American Health the Zika threat: The virus can be spread through unprotected
Organization compared the rates of GBS before and after Zika anal sex.129
arrived in seven countries and announced a strong association More surprising news came out of New York City in
between the virus and the illness. In a letter published in the July: Health ofcials reported the rst documented case of
New England Journal of Medicine, Marcos Espinal, MD, PhD, the sexual transmission of Zika virus from a woman to her
MPH, and his colleagues analyzed the rates of GBS and ZVI in male sex partner. Until then, all reported cases of sexually
Bahia, Brazil, Colombia, the Dominican Republic, El Salvador, transmitted ZVI had been spread from men to their part-
Honduras, Suriname, and Venezuela. They looked at 164,237 ners.130,131 The following month, an asymptomatic man in
conrmed and suspected ZVI cases and 1,474 GBS cases that Maryland infected his female partner with Zika virus after
occurred between April 1, 2015, and March 31, 2016.119 The returning from the Dominican Republic, demonstrating that
investigators found a close association between increases in the virus may be spread from a man even if he has no symp-
Zika cases and increases in GBS. As Zika infections waned in toms of ZVI.132 In August, Yale University investigators found
a country, they found, the incidence of GBS waned as well.119 that the virus could persist in the vagina of mice for days
after infectionsuggesting that Zika may replicate
MODES OF TRANSMISSION more readily in the female reproductive tract than at other
Zika virus is transmitted primarily by the bite of infected sites of infection.133
Ae. aegypti and Ae. albopictus mosquitoes, which also spread
dengue and chikungunya viruses.120 But as more is learned Blood Products
about ZVI, other important modes of transmission have come In February, the CDC recommended the deferral of
to light. individuals from donating blood if they had been to areas
with active Zika virus transmission; if they potentially had
Sexual Transmission been exposed to the virus; or if they had conrmed ZVI.134
In September 2008, an American scientist participating in The agency revised its guidelines in August, advising that all
a mosquito-sampling project in Senegal became ill with ZVI donated blood and blood components in the U.S. should be
upon his return home to Colorado and infected his wifethe tested for Zika.135
rst documented case of sexual transmission of the virus in the HHS announced that it was funding two pathogen-
U.S. Both the man and his wife noticed signs of hematospermia reduction technologies to help reduce the risk of Zika
(redbrown uid in the mans ejaculate).121 virus and other infections from being transmitted through
Five years later, a patient recovering from ZVI on Tahiti the blood supply. The Biomedical Advanced Research and
Island in French Polynesia sought treatment for bloody sperm. Development Authority, part of HHS, provided initial funding
Zika virus was isolated from his semen.122 of $30.8 million to Cerus Corporation and $17.5 million to the
Next, in February 2016, Texas reported a case of sexually U.S. division of Japans Terumo Corporation. The Food and
transmitted ZVI. The patient had not recently travelled outside Drug Administration (FDA) has approved Cerus Intercept
the U.S., but developed symptoms after sexual contact with technology to reduce pathogens in platelets and plasma. The

Vol. 41 No. 12 December 2016 P&T

783
 Zika in America: The Year in Review
company is conducting a trial to show that its technology can use in the U.S. for the detection of Zika virus on an emergency
also reduce pathogens in red blood cells. Terumo is developing basis.142,143 The test detects Zika virus indirectly by identifying
its own Mirasol system to conrm that it can reduce the risk Zika-specic IgM in blood or cerebrospinal uid.144 The assay
of infection through platelets.136 procedure is complex, however, and the results can be difcult to
interpret, making the test unsuitable for rapid Zika diagnosis.140
Human Cell and Tissue Products In February, two Houston hospitals said they had developed
In March, the FDA issued guidelines aimed at preventing the rst U.S. hospital-based, rapid RNA test for Zika virus. The
Zika virus transmission via human cells, tissues, and cellular test, created by pathologists and clinical laboratory scientists
and tissue-based products (HCT/Ps). The agency noted that at Texas Childrens Hospital and Houston Methodist Hospital,
there was a potential risk that Zika virus could be transmitted was customized to each hospitals diagnostic laboratory and
by HCT/Ps used as part of a medical, surgical, or reproductive provided results within hours. Assays could be performed on
procedure. HCT/Ps include products such as corneas, bone, blood, amniotic uid, urine, or spinal uid. The hospitals said
skin, heart valves, hematopoietic stem/progenitor cells, gesta- they were able to distinguish ZVI from dengue, West Nile, or
tional tissues (such as amniotic membrane), and reproductive chikungunya infections.145
tissues (such as semen and oocytes).137 By early March, the WHO estimated that more than 30 in vitro
According to the FDAs guidelines, living donors should be diagnostic assays for Zika were at various stages of development.146
considered ineligible if they were diagnosed with ZVI, were in Meanwhile, the FDA pressed ahead with EUAs, granting the
an area with active Zika virus transmission, or had sex with a designation to a total of 12 Zika diagnostic tests.144 The CDC
male with either of those risk factors within the past six months. followed its IgM assay with a test based on real-time reverse
Donors of umbilical cord blood, placenta, or other gestational transcriptase polymerase chain reaction (rRT-PCR), using
tissues should be considered ineligible if they have had any of dual-labeled probes to detect viral RNA.140 The test, Trioplex
these risk factors at any point during their pregnancy. Deceased rRT-PCR, was awarded an EUA on March 17. It directly identi-
donors should be considered ineligible if they were diagnosed es ZVI by detecting Zika RNA in human sera, cerebrospinal
with ZVI in the past six months.137 uid, urine, and amniotic uid.144 Two other RT-PCR assays
Zika Virus RNA Qualitative rRT-PCR (Quest Diagnostics) and
A Zika Mystery RealStar Zika Virus RT-PCR Kit (Altona Diagnostics)won
Before leaving the subject of Zika virus transmission, mention emergency approval in April and May, respectively.144 These
should be made of a peculiar case that occurred in Utah in and other Zika assays are listed in Table 1.144
June. According to the CDC, an elderly man who died after a RT-PCR tests that use urine to detect ZVI have an advantage
bout with Zika may have infected a relative who cared for him over other assay systems in that Zika virus RNA is unlikely
during his illness. The caregiver had not traveled to an area to be detected in serum after the rst week of illness in most
with active Zika transmission nor had sex with a person who patients.147,148 Moreover, data have shown that Zika virus stays
had recently returned from such a place. Moreover, health at higher levels or lasts longer in urine than in blood.149,150
ofcials were not aware of mosquitoes in Utah that are capable In the spring, internal strife rocked the CDC when one of its
of transmitting the virus. Experts outside the CDC said the leading Zika experts, Robert Lanciotti, PhD, raised concerns
most likely possibility was that the infected relative came into about the agencys decision to recommend the Trioplex test.
contact with blood, urine, or other bodily uids while caring Dr. Lanciotti was chief of the CDC lab responsible for devel-
for the man, but the infectious mechanism involved remains oping tests to diagnose viral diseases that are transmitted
a mystery. The relative recovered quickly.138,139 by mosquitoes, ticks, and eas. According to his complaint,
Trioplex was substantially less effective than an assay he
DIAGNOSTIC TESTS had developed in 2007, called Singleplex, and missed nearly
Zika virus may be detected in infected individuals either 40% of Zika infections. Dr. Lanciotti also said the agency with-
directly (by identifying virus RNA in tissue or bodily uids) or held information about testing differences from state and
indirectly (by testing for virus-specic antibodies).140 The body local public health laboratories.151 In May, the CDC demoted
uids that can be tested include whole blood, serum, EDTA Dr. Lanciotti, but he was reinstated months later after ling
(ethylenediaminetetraacetic acid) plasma, saliva, and urine.141 a whistleblower retaliation claim.151 His complaint prompted
The results of serological assays may be confounded by cross- a CDC internal investigation. In its report, the agency said it
reactivity between virus genus members or by geographical had made improvements to boost the sensitivity of the Trioplex
overlap with other pathogens. In those situations, pan-genus test. The internal investigation also found that the agency had
and syndromic serum panel tests and antigens are needed and acted reasonably when it withheld conicting test data from
conrmatory techniques are required, such as enzyme-linked state public health labs.151
immunosorbent assay (ELISA), immunouorescence assay,
and virus-neutralizing testing.141 THERAPEUTIC DRUGS
No commercially available tests for ZVI detection have been No approved treatments are available for ZVI,152 and the FDA
approved or cleared by the FDA. However, the agency has is unaware of any Zika therapies in advanced development.153
permitted applications for emergency use authorizations In searching for potential Zika therapeutics, scientists have
(EUAs). The Zika IgM [Immunoglobulin M] Antibody Capture two options: to repurpose existing antiviral compounds or to
Enzyme-Linked Immunosorbent Assay (Zika MAC-ELISA), discover potential Zika inhibitors in compound libraries and
developed by the CDC, was the rst diagnostic test approved for develop them for clinical use.154

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

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

Vol. 41 No. 12 December 2016 P&T 785

 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 4. Campos S, Bandeira AC, Sardi SI. Zika virus outbreak, Bahia,
second early-stage trial of GLS-5700. The vaccine was admin- Brazil [letter]. Emerg Infect Dis 2015;21:18851886.
5. Kindhauser MK, Allen T, Frank V, et al. Zika: the origin and
istered to 160 healthy adult volunteers in Puerto Rico, where spread of a mosquito-borne virus. Bull World Health Organ E-pub:
a Zika emergency had been declared. The studys primary 9 Feb 2016. doi: http://dx.doi.org/10.2471/BLT.16.171082.
objective is to evaluate the safety, tolerability, and immuno- 6. Centers for Disease Control and Prevention. Aedes aegypti, Aedes
genicity of GLS-5700 administered with Cellectra-3P, Inovios albopictus. January 30, 2012. Available at: www.cdc.gov/dengue/
resources/30jan2012/comparisondenguevectors.pdf. Accessed
proprietary intradermal DNA vaccine delivery device. The
August 18, 2016.
study is also looking at differences in Zika infection rates in 7. Darwish MA, Hoogstraal H, Roberts TJ, et al. A sero-
participants given either vaccine or placebo.162 epidemiological survey for certain arboviruses (Togaviridae) in
Table 2 lists other examples of potential Zika vaccines under Pakistan. Trans R Soc Trop Med Hyg 1983;77:442445.
investigation in the U.S.146,167174 But developing a vaccine wont 8. Olson JG, Ksiazek TG, Suhandiman, Triwibowo. Zika virus, a
cause of fever in Central Java, Indonesia. Trans R Soc Trop Med
be easy. Some key hurdles include:1,175,176 Hyg 1981;75:389393.
9. Duffy MR, Chen T-H, Hancock WT, Powers AM. Zika virus
Scientists know even less about Zika than they did about outbreak on Yap Island, Federated States of Micronesia. N Engl
the Ebola virus. J Med 2009;360:25362543.
10. Cao-Lormeau VM, Roche C, Teissier A, et al. Zika virus, French
There is no simple way to assess the right immune
Polynesia, South Pacic, 2013. Emerg Infect Dis 2014;20:10851086.
response for Zika; an effective vaccine must strike a 11. Roth A, Mercier A, Lepers C, et al. Concurrent outbreaks of
delicate balance between provoking a response that is dengue, chikungunya, and Zika virus infections: an unprecedented
strong enough to stop the virus, but not so strong that it epidemic wave of mosquito-borne viruses in the Pacic 20122014.
makes the patient ill. Euro Surveill 2014;19:20929.
12. Dupont-Rouzeyrol M, OConnor O, Calvez E, et al. Co-infection
In most cases, ZVI is so mild that individuals may be with zika and dengue viruses in 2 patients, New Caledonia, 2014.
unaware that they carry the virus, and they are unlikely Emerg Infect Dis 2015;21:381382.
to see the need for immunization. 13. International Society for Infectious Diseases. Zika virusBrazil:
To protect the developing fetus, protective immunity conrmed. May 15, 2015. Available at: www.promedmail.org/
direct.php?id=3370768. Accessed August 15, 2016.
must be achieved before the time of peak vulnerability
14. World Health Organization. Zika situation report: neuro-
probably during the rst and early second trimesters. logic syndrome and congenital anomalies. February 5, 2016.
Traditionally, vaccine safety and immunogenicity are Available at: http://apps.who.int/iris/bitstream/10665/204348/1/
rmly established in nonpregnant adults before the zikasitrep_5Feb2016_eng.pdf. Accessed August 15, 2016.
vaccination of pregnant women is considered. Pregnant 15. Brazilian Ministry of Health. Informative Note No. 01/2015: COES
microcephaly [in Portuguese]. November 17, 2015. Available at:
women, however, comprise the primary target for Zika www.saude.rs.gov.br/upload/1448404998_microcefalia_nota_
vaccines, making vaccine testing problematic. informativa_17nov2015_MINISTERIO%20DA%20SAUDE.pdf.
Developing vaccines is resource-intensive; vaccines are Accessed August 15, 2016.
made from biologic agents that require stringent lot-to-lot 16. Avian Flu Diary. Brazil: MOH updates microcephalic birth
numbers. December 29, 2015. Available at: http://audiary.
consistency and stability.
blogspot.com/2015/12/brazil-moh-updates-microcephalic-birth.
html. Accessed August 15, 2016.
CONCLUSION 17. European Center for Disease Prevention and Control.
2016 will be remembered as the year that Zika came to Communicable Disease Threats Report. Week 47, 1521
America. Is the U.S. technologically and nancially prepared to November 2015. Available at: http://ecdc.europa.eu/en/pub-
lications/Publications/communicable-disease-threats-report-
beat the wiliest health foe since the human immunodeciency 21-nov-2015.pdf. Accessed August 17, 2016.
virus? Or will we eventually see nearly 27,000 cases of locally 18. World Health Organization. Zika virus infectionEl Salvador.
acquired infections, as in Puerto Rico,58 or nearly 5,000 cases November 27, 2015. Available at: www.who.int/csr/don/27-
of Zika-associated microcephaly, as in Brazil?177 Congress november-2015-zika-el-salvador/en. Accessed February 24, 2016.
19. World Health Organization. Zika virus infectionMexico.
protracted squabble over Zika funding got things off to a rocky
December 3, 2015. Available at: www.who.int/csr/don/03-decem-
start,6875 and federal cash infusions arent expected to reach ber-2015-zika-mexico/en. Accessed August 17, 2016.
public health laboratories until early 2017.77 As this article 20. World Health Organization. Zika virus infectionVenezuela.
goes to press, cases of locally acquired ZVI remain restricted December 3, 2015. Available at: www.who.int/csr/don/03-decem-
to Florida, but Ae. aegypti and Ae. albopictus mosquitoesthe ber-2015-zika-venezuela/en. Accessed August 17, 2016.
21. World Health Organization. Zika virus infectionParaguay.
vectors for Zika infectioninhabit roughly half of the conti- December 3, 2015. Available at: www.who.int/csr/don/03-decem-
nental U.S. No one can predict what the future holds, but its ber-2015-zika-paraguay/en. Accessed August 17, 2016.
safe to say that America, like most of the world, faces a difcult 22. World Health Organization. Zika virus infectionHonduras.
and costly struggle over the coming years. December 21, 2015. Available at: www.who.int/csr/don/21-
december-2015-zika-honduras/en. Accessed August 17, 2016.
23. World Health Organization. Zika virus infectionPanama.
REFERENCES December 22, 2015. Available at: www.who.int/csr/don/22-decem-
1. Fellner C. Zika virus: anatomy of a global health crisis. P T ber-2015-zika-panama/en. Accessed August 17, 2016.
2016;41:242253. 24. World Health Organization. Zika virus infectionFrance
2. Dick GW, Kitchen SF, Haddow AJ. Zika virus. I. Isolations and French Guiana and Martinique. January 8, 2016. Available at:
serological specicity. Trans R Soc Trop Med Hyg 1952;46:509520. www.who.int/csr/don/8-january-2016-zika-france/en. Accessed
3. Smithburn KC. Neutralizing antibodies against certain recently August 17, 2016.
isolated viruses in the sera of human beings residing in East Africa. 25. Centers for Disease Control and Prevention. First case of Zika
J Immunol 1952;69:223234. virus reported in Puerto Rico. December 31, 2015. Available at:

Vol. 41 No. 12 December 2016 P&T

787
 Zika in America: The Year in Review
www.cdc.gov/media/releases/2015/s1231-zika.html. Accessed at: www.cdc.gov/media/releases/2016/t0729-zika-update.html.
February 25, 2016. Accessed September 16, 2016.
26. University of Florida, Department of Entomology and Nematology. 45. Centers for Disease Control and Prevention. Additional area of
Aedes aegypti. April 2016. Available at: http://entnemdept.u.edu/ active Zika transmission identied in Miami Beach. August 19,
creatures/aquatic/aedes_aegypti.htm. Accessed August 19, 2016. 2016. Available at: www.cdc.gov/media/releases/2016/p0819-
27. University of Florida, Department of Entomology and Nematology. zika-miami-beach.html. Accessed September 16, 2016.
Aedes albopictus. July 2014. Available at: http://entnemdept.u. 46. Reuters. Health ofcial warns Zika could spread across U.S.
edu/creatures/aquatic/asian_tiger.htm. Accessed August 19, 2016. Gulf. August 21, 2016. Available at: www.reuters.com/article/us-
28. Reuters. Research indicates another common mosquito may health-zika-miami-idUSKCN10W0SM. Accessed September 16, 2016.
be able to carry Zika. March 3, 2016. Available at: www.reuters. 47. Reuters. Florida announces Zika case hundreds of miles from
com/article/us-health-zika-brazil-idUSKCN0W52AW. Accessed Miami. August 23, 2016. Available at: www.reuters.com/article/us-
August 19, 2016. health-zika-orida-idUSKCN10Y1OO. Accessed September 16, 2016.
29. Kansas State University. Culex mosquitoes do not transmit Zika 48. Reuters. Florida governor complains U.S. not doing enough to ght
virus, Kansas State University study nds. September 22, 2016. Zika. August 24, 2016. Available at: www.reuters.com/article/us-
Available at: www.k-state.edu/media/newsreleases/2016-09/ health-zika-orida-idUSKCN10Z2SF. Accessed September 16, 2016.
culex92216.html. Accessed October 4, 2016. 49. TIME. Texas traveler gets Zika in Florida. August 15, 2016.
30. Centers for Disease Control and Prevention. Zika virus: potential Available at: http://time.com/4453371/texas-florida-zika.
range in US. August 2, 2016. Available at: www.cdc.gov/zika/ Accessed September 16, 2016.
vector/range.html. Accessed August 19, 2016. 50. Reuters. Florida to begin aerial spraying of insecticides to
31. Reuters. Ofcial map nds Zika-transmitting mosquitoes in control Zika. August 3, 2016. Available at: www.reuters.com/
much of U.S. June 10, 2016. Available at: http://news.trust.org/ article/us-health-zika-insecticide-idUSKCN10E06Q. Accessed
item/20160610203744-li7a1. Accessed August 19, 2016. September 16, 2016.
32. University of Notre Dame. Mosquitoes capable of carrying Zika 51. Staletovich J. Air attacks against Zika hit and miss in Miami, CDC
virus found in Washington, D.C. January 26, 2016. Available at: reports. Miami Herald. August 15, 2016. Available at: www.miami-
http://news.nd.edu/news/64004-mosquitoes-capable-of-carry- herald.com/news/health-care/article95838697.html. Accessed
ing-zika-virus-found-in-washington-dc. Accessed August 19, 2016. September 16, 2016.
33. Virginia Department of Health. Virginia resident tests positive 52. Reuters. Adult mosquitoes can pass Zika to their offspring:
for Zika virus after travel in Zika-affected country. January 26, U.S. study. August 29, 2016. Available at: www.reuters.com/
2016. Available at: www.vdh.virginia.gov/news/public-relations- article/us-health-zika-mosquitoes-idUSKCN1142CD. Accessed
contacts/news-releases/2016-statewide-news-releases/virginia- September 16, 2016.
resident-tests-positive-for-zika-virus-after-travel-in-zika-affected- 53. Reuters. Three new cases of local Zika transmission in Florida:
country. Accessed August 19, 2016. ofcials. August 30, 2016. Available at: www.reuters.com/article/us-
34. Arkansas Times. Dept. of Health: Case of Zika virus conrmed health-zika-orida-idUSKCN11605O. Accessed September 16, 2016.
in Arkansas. January 26, 2016. Available at: www.arktimes.com/ 54. Chang D. Floridas Zika undercount hides extent of virus spread,
ArkansasBlog/archives/2016/01/26/dept-of-health-case-of-zika- experts say. Miami Herald September 10, 2016. Available at:
virus-conrmed-in-arkansas. Accessed August 19, 2016. www.miamiherald.com/news/health-care/article100939277.html.
35. Reuters. First U.S. Zika virus transmission reported, attributed Accessed September 16, 2016.
to sex. February 3, 2016. Available at: www.reuters.com/article/ 55. Reuters. Florida expands Zika zone in Miami Beach after ve
us-health-zika-idUSKCN0VB145. Accessed August 19, 2016. new cases. September 17, 2016. Available at: www.reuters.com/
36. Oster AM, Brooks JT, Stryker JE, et al. Interim guidelines for article/us-health-zika-miamibeach-idUSKCN11N03K. Accessed
prevention of sexual transmission of Zika virusUnited States, September 19, 2016.
2016. MMWR Morb Mortal Wkly Rep 2016;65:120121. 56. Reuters. Florida declares new area of Zika transmission in Miami.
37. Armstrong P, Hennessey M, Adams M, et al. Travel-associated October 13, 2016. Available at: www.reuters.com/article/us-
Zika virus disease cases among U.S. residentsUnited States, health-zika-orida-idUSKCN12D2X6. Accessed October 14, 2016.
January 2015February 2016. MMWR Morb Mortal Wkly Rep 57. Reuters. U.S. health ofcials create color-coded Zika zones in
2016;65:286289. Available at: www.cdc.gov/mmwr/volumes/65/ Florida. October 19, 2016. Available at: www.reuters.com/article/
wr/mm6511e1.htm. Accessed September 15, 2016. us-health-zika-orida-idUSKCN12J2R3. Accessed October 20, 2016.
38. Department of Homeland Security. Zika virus: DHS response plan. 58. Centers for Disease Control and Prevention. Zika virus: case counts
January 11, 2016. Available at: www.dhs.gov/news/2016/02/11/ in the U.S. October 6, 2016. Available at: www.cdc.gov/zika/geo/
zika-virus-dhs-response-plan. Accessed September 15, 2016. united-states.html. Accessed October 11, 2016.
39. American Council on Science and Health. Zika is possibly 59. Reuters. Most U.S. efforts to ght Zika virus to be informational:
the scariest virus since HIV. February 19, 2016. Available at: White House. January 27, 2016. Available at: www.reuters.
http://acsh.org/news/2016/02/19/zika-maybe-the-scariest-virus- com/article/us-health-zika-usa-white-house-idUSKCN0V52FG.
since-hiv. Accessed September 15, 2016. Accessed August 22, 2016.
40. Dapena K, Alcantara C, Franco D. Florida particularly at risk. Miami 60. Associated Press. Obama asking Congress for emergency funding to
Herald. No date. Available at: www.miamiherald.com/news/health- combat Zika. February 8, 2016. Available at: http://bigstory.ap.org/
care/article66790817.html. Accessed September 16, 2016. article/49c5f168ff214eb2b01ff42730789e44/obama-asking-congress-
41. Reuters. Florida governor declares health emergency in four emergency-funding-combat-zika. Accessed August 22, 2016.
counties over Zika. February 3, 2016. Available at: www.reuters. 61. Reuters. White House and states to craft Zika attack plan at summit.
com/article/us-health-zika-orida-idUSKCN0VC2S9. Accessed March 4, 2016. Available at: www.reuters.com/article/us-health-zika-
September 16, 2016. whitehouse-idUSKCN0W60XM. Accessed August 23, 2016.
42. Centers for Disease Control and Prevention. Florida investiga- 62. Centers for Disease Control and Prevention. National Zika summit
tion links four recent Zika cases to local mosquito-borne virus focused on coordinated U.S. response. April 1, 2016. Available at:
transmission. July 29, 2016. Available at: www.cdc.gov/media/ www.cdc.gov/media/releases/2016/p0401-zika-summit.html.
releases/2016/p0729-florida-zika-cases.html. Accessed Accessed September 21, 2016.
September 16, 2016. 63. Joseph A. At Zika summit, ofcials stress need for funding and
43. Centers for Disease Control and Prevention. Advice for people action now to avoid crisis later. STAT. April 1, 2016. Available
living in or traveling to South Florida. September 1, 2016. at: www.statnews.com/2016/04/01/zika-action-plan-summit.
Available at: www.cdc.gov/zika/intheus/orida-update.html. Accessed September 21, 2016.
Accessed September 16, 2016. 64. McNeil Jr DG. Obama administration to transfer Ebola funds to Zika
44. Centers for Disease Control and Prevention. Transcript for CDC ght. New York Times. April 6, 2016. Available at: www.nytimes.
telebrieng: Zika virus updateJuly 29. July 29, 2016. Available com/2016/04/07/health/zika-virus-budget-ebola.html?rref=collect

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

 Zika in America: The Year in Review
ion%2Ftimestopic%2FEbola&action=click&contentCollection=times research.pasteur.fr/en/project/neural-stem-cells-infection-by-zika-
topics&region=stream&module=stream_unit&version=latest&cont virus-in-the-mouse-developing-neocortex. Accessed October 4, 2016.
entPlacement=8&pgtype=collection. Accessed September 21, 2016. 83. Rockefeller University. Zika infection may affect adult brain cells,
65. U.S. House of Representatives, Committee on Appropriations. suggesting risk may not be limited to pregnant women. August 18,
Rogers introduces funding bill to ght the Zika virus. May 16, 2016. 2016. Available at: http://newswire.rockefeller.edu/2016/08/18/
Available at: http://appropriations.house.gov/news/documents- zika-infection-may-affect-adult-brain-cells-suggesting-risk-may-not-
ingle.aspx?DocumentID=394533. Accessed September 21, 2016. be-limited-to-pregnant-women. Accessed October 4, 2016.
66. Reuters. White House opposes House Zika bill, calls funding 84. World Federation of Neurology. Zika experts: acute virus
inadequate. May 17, 2016. Available at: www.reuters.com/ infection associated with sensory polyneuropathy. August 26, 2016.
article/us-usa-zika-white-house-idUSKCN0Y826Z. Accessed Available at: www.wfneurology.org/zika-experts-acute-virus-
September 21, 2016. infection. Accessed October 4, 2016.
67. Reuters. House approves $622 million to combat Zika virus. 85. Reuters. Study nds Zika infects neural cells related to skull
May 18, 2016. Available at: www.reuters.com/article/us-health-zika- formation. September 29, 2016. Available at: www.reuters.com/arti-
house-idUSKCN0YA02O. Accessed September 21, 2016. cle/us-health-zika-skull-idUSKCN11Z2CN. Accessed October 4, 2016.
68. Reuters. Senate approves $1.1 billion to fight Zika virus. 86. Bayless NL, Greenberg RS, Swigut T, et al. Zika virus infection
May 19, 2016. Available at: www.reuters.com/article/us-health-zika- induces cranial neural crest cells to produce cytokines at levels
congress-idUSKCN0YA28Z. Accessed September 21, 2016. detrimental to neurogenesis. Cell Host Microbe 2016;20(4):423428.
69. Scott D. House passes Zika bill in early morning vote over doi: 10.1016/j.chom.2016.09.006. Epub 2016 Sep 29.
Democratic opposition. STAT. June 22, 2016. Available at: 87. Centers for Disease Control and Prevention. Key messages: Zika
www.statnews.com/2016/06/22/congress-reach-1-1-billion-zika- virus disease. October 18, 2016. Available at: www.cdc.gov/zika/
deal. Accessed September 21, 2016. pdfs/zika-key-messages.pdf. Accessed October 20, 2016.
70. Drabold W. Zika funding bill fails as Congress is unable to reach 88. Rasmussen SA, Jamieson DJ, Honein MA, et al. Zika virus and
compromise. TIME. July 14, 2016. Available at: http://time. birth defects: reviewing the evidence for causality. N Engl J Med
com/4406114/zika-funding-bill-fails-as-congress-is-unable-to- 2016;374;19811987.
reach-compromise. Accessed October 4, 2016. 89. Meaney-Delman D, Rasmussen SA, Staples JE, et al. Zika virus
71. McKenna M. CDC director: This is no way to ght an epidemic. and pregnancy: what obstetric health care providers need to know.
National Geographic. July 19, 2016. Available at: http://news. Obstet Gynecol 2016;127:642648.
nationalgeographic.com/2016/07/cdc-warns-zika-epidemic-birth- 90. de Noronha L, Zanluca C, Azevedo MLV, et al. Zika virus
defects. Accessed October 4, 2016. damages the human placental barrier and presents marked
72. Davis JH. With Congress deadlocked, White House diverts funds fetal neurotropism. Mem Inst Oswaldo Cruz 2016;111:287293.
to ght Zika. New York Times. August 11, 2016. Available at: doi: 10.1590/0074-02760160085. Epub 2016 Apr 29.
www.nytimes.com/2016/08/12/us/politics/with-congress-dead- 91. Jurado KA, Simoni MK, Tang Z, et al. Zika virus productively
locked-white-house-diverts-funds-to-ght-zika.html?_r=0. Accessed infects primary human placenta-specic macrophages. JCI Insight
October 4, 2016. 2016 Aug 18;1(13). pii: e88461.
73. Sun LH. Centers for Disease Control will run out of money to 92. American Congress of Obstetricians and Gynecologists. Practice
ght Zika in U.S. next month. August 30, 2016. Washington Post. advisory on Zika virus. August 3, 2016. Available at: www.acog.
Available at: www.washingtonpost.com/news/to-your-health/ org/About-ACOG/News-Room/Practice-Advisories/Practice-
wp/2016/08/30/cdc-will-run-out-of-money-to-ght-zika-in-u-s- Advisory-Interim-Guidance-for-Care-of-Obstetric-Patients-During-
next-month. Accessed October 4, 2016. a-Zika-Virus-Outbreak. Accessed October 5, 2016.
74. Huetteman E, Tavernise S. Senate Democrats block Zika bill 93. Reuters. U.S. reports 279 Zika cases in pregnant women,
over Planned Parenthood provisions. New York Times. Obama pushes Congress on funds. May 20, 2016. Available at:
September 6, 2016. Available at: www.nytimes.com/2016/09/07/us/ www.reuters.com/article/us-health-zika-usa-idUSKCN0YB1QN.
politics/zika-senate-congress.html?_r=0. Accessed October 4, 2016. Accessed October 5, 2016.
75. Luthra S. Congress nally approves funding to ght Zikabut 94. Centers for Disease Control and Prevention. Pregnant women with
what does this mean? Kaiser Health News. September 29, 2016. any laboratory evidence of possible Zika virus infection in the United
Available at: http://khn.org/news/congress-nally-approves-fund- States and territories, 2016. October 6, 2016. Available at: www.cdc.
ing-to-ght-zika-but-what-does-this-mean. Accessed October 4, 2016. gov/zika/geo/pregwomen-uscases.html. Accessed October 12, 2016.
76. Reuters. Zika funding delay hurt effort to ght virus: U.S. health 95. Opitz JM, Holt MC. Microcephaly: general considerations and
ofcials. October 3, 2016. Available at: www.reuters.com/article/ aids to nosology. J Craniofac Genet Dev Biol 1990;10:175204.
us-health-zika-usa-idUSKCN12327R?utm_medium=referral&utm_ 96. Woods CG. Human microcephaly. Curr Opin Neurobiol
source=morefromreuters. Accessed October 4, 2016. 2004;14:112117.
77. Luthra S. Got Zika? For pregnant women, lab constraints mean 97. Centers for Disease Control and Prevention. Facts about micro-
its often hard to know. Kaiser Health News. October 7, 2016. cephaly. July 25, 2016. Available at: www.cdc.gov/ncbddd/birth-
Available at: http://khn.org/news/got-zika-for-pregnant-women-lab- defects/microcephaly.html. Accessed October 5, 2016.
constraints-mean-its-often-hard-to-know. Accessed October 7, 2016. 98. Brazilian Ministry of Health. Informative Note No. 01/2015: COES
78. Reuters. U.S. ofcials warn Zika scarier than initially thought. microcephaly [in Portuguese]. November 17, 2015. Available at:
April 11, 2016. Available at: www.reuters.com/article/us-health-zika- www.saude.rs.gov.br/upload/1448404998_microcefalia_nota_
whitehouse-idUSKCN0X825A. Accessed October 4, 2016. informativa_17nov2015_MINISTERIO%20DA%20SAUDE.pdf.
79. Centers for Disease Control and Prevention. CDC concludes Accessed October 5, 2016.
Zika causes microcephaly and other birth defects. April 13, 2016. 99. European Center for Disease Prevention and Control. Microcephaly
Available at: www.cdc.gov/media/releases/2016/s0413-zika- in Brazil potentially linked to the Zika virus epidemic, ECDC
microcephaly.html. Accessed October 4, 2016. assesses the risk. November 25, 2015. Available at: http://ecdc.
80. Centers for Disease Control and Prevention. Zika and Guillain- europa.eu/en/press/news/_layouts/forms/News_DispForm.
Barr syndrome. August 9, 2016. Available at: www.cdc.gov/zika/ aspx?ID=1329&List=8db7286c-fe2d-476c-9133-18ff4cb1b568&So
healtheffects/gbs-qa.html. Accessed October 4, 2016. urce=http%3A%2F%2Fecdc.europa.eu%2Fen%2FPages%2Fhome.
81. World Health Organization. WHO Director-General addresses aspx. Accessed October 5, 2016.
media after Zika emergency committee. March 8, 2016. Available 100. Pan American Health Organization, World Health Organiza-
at: www.who.int/mediacentre/news/statements/2016/zika-ec/en. tion. Epidemiological alert: increase of microcephaly in the
Accessed October 4, 2016. northeast of Brazil. November 17, 2015. Available at: www.paho.
82. Pasteur Institute. Neural stem cells infection by Zika virus in the org/hq/index.php?option=com_docman&task=doc_view&Ite-
mouse developing cortex. July 16, 2016. Available at: https:// mid=270&gid=32285 =en. Accessed October 5, 2016.

Vol. 41 No. 12 December 2016 P&T 789

 Zika in America: The Year in Review
101. Petersen LR, Jamieson DJ, Powers AM, Honein MA. Zika virus. 121. Foy BD, Kobylinski KC, Chilson Foy JL, et al. Probable nonvector-
N Engl J Med 2016;374:15521563. borne transmission of Zika virus, Colorado, USA. Emerg Infect Dis
102. Science Daily. New doubts on Zika as cause of micro- 2011;17:880882.
cephaly. June 24, 2016. Available at: www.sciencedaily.com/ 122. Musso D, Roche C, Robin E, et al. Potential sexual transmission
releases/2016/06/160624150813.htm. Accessed October 5, 2016. of Zika virus. Emerg Infect Dis 2015;21:359361.
103. World Health Organization. WHO Director-General summarizes the 123. Dallas County Health and Human Services. DCHHS reports rst Zika
outcome of the emergency committee regarding clusters of micro- virus case in Dallas County acquired through sexual transmission.
cephaly and Guillain-Barr syndrome. February 1, 2016. Available February 2, 2016. Available at: www.dallascounty.org/department/
at: www.who.int/mediacentre/news/statements/2016/emergency- hhs/press/documents/PR2-2-16DCHHSReportsFirstCaseofZika-
committee-zika-microcephaly/en. Accessed October 5, 2016. VirusThroughSexualTransmission.pdf. Accessed October 5, 2016.
104. Pan American Health Organization, World Health Organization. 124. Reuters. First U.S. Zika virus transmission reported, attributed
Epidemiological update: neurological syndrome, congenital to sex. February 3, 2016. Available at: www.reuters.com/article/
anomalies, and Zika virus infection. January 17, 2016. Available at: us-health-zika-idUSKCN0VB145. Accessed October 5, 2016.
www.paho.org/hq/index.php?option=com_docman&task=doc_vie 125. Centers for Disease Control and Prevention. Interim guidelines
w&Itemid=270&gid=32879&lang=en. Accessed October 5, 2016. for prevention of sexual transmission of Zika virusUnited States,
105. Greenwood M. Zika virus linked to stillbirth, other symptoms in 2016. MMWR Morb Mortal Wkly Rep 2016;65:120121. Available at:
Brazil. Yale News February 25, 2016. Available at: http://news. www.cdc.gov/mmwr/volumes/65/wr/mm6505e1.htm. Accessed
yale.edu/2016/02/25/zika-virus-linked-stillbirth-other-symptoms- October 5, 2016.
brazil. Accessed October 5, 2016. 126. Centers for Disease Control and Prevention. Zika and sexual
106. Samo M, Sacramento GA, Khouri R, et al. Zika virus infection and transmission. September 30, 2016. Available at: www.cdc.gov/zika/
stillbirths: a case of hydrops fetalis, hydranencephaly, and fetal transmission/sexual-transmission.html. Accessed October 5, 2016.
demise. PloS Negl Trop Dis February 25, 2016. doi: 10.1371/jour- 127. Reuters. Zika may linger in semen long after symptoms fade: doctors
nal.pntd.0004517. Available at: http://journals.plos.org/plosntds/ report. February 12, 2016. Available at: www.reuters.com/article/
article?id=10.1371/journal.pntd.0004517. Accessed October 5, 2016. us-health-zika-semen-idUSKCN0VL1N5. Accessed October 5, 2016.
107. Reuters. Health agency reports U.S. babies with Zika-related birth 128. Centers for Disease Control and Prevention. CDC encourages
defects. June 16, 2016. Available at: www.reuters.com/article/ following guidance to prevent sexual transmission of Zika virus.
us-health-zika-usa-idUSKCN0Z22DL. Accessed October 5, 2016. February 23, 2016. Available at: www.cdc.gov/media/releases/2016/
108. Keck School of Medicine of USC. Zika proteins responsible for s0223-zika-guidance.html. Accessed October 5, 2016.
microcephaly identied. August 11, 2016. Available at: http://keck. 129. Branswell H. Sexual transmission of Zika seen between gay men
usc.edu/zika-proteins-responsible-for-microcephaly-identied. for rst time. STAT April 14, 2016. Available at: www.statnews.
Accessed October 5, 2016. com/2016/04/14/zika-men-sexual-transmission/?trendmd-
109. Beth Israel Deaconess Hospital. Special report documents Zika shared=0. Accessed October 5, 2016.
virus impact on the fetal brain. August 24, 2016. Available at: 130. Centers for Disease Control and Prevention. First female-to-male
www.bidmc.org/News/PRLandingPage/2016/August/ sexual transmission of Zika virus infection reported in New York
Levine-Zika-RadiologyStudy.aspx. Accessed October 5, 2016. City. July 15, 2016. Available at: www.cdc.gov/media/releases/2016/
110. Leal MC, Muniz LF, Ferreira TSA, et al. Hearing loss in infants s0715-zika-female-to-male.html. Accessed October 5, 2016.
with microcephaly and evidence of congenital Zika virus 131. Santora M. Twist in Zika outbreak: New York case shows women
infectionBrazil, November 2015May 2016. MMWR Morb Mortal can spread it to men. New York Times. July 15, 2016. Available at:
Wkly Rep 2016;65:917919. Available at: www.cdc.gov/mmwr/ www.nytimes.com/2016/07/16/nyregion/zika-virus-female-to-
volumes/65/wr/mm6534e3.htm. Accessed October 5, 2016. male-sexual-transmission.html?_r=0. Accessed October 5, 2016.
111. Phippen JW. The rst-known Zika infant death in the U.S. 132. Reuters. Zika likely to spread sexually from asymptomatic man
The Atlantic. August 9, 2016. Available at: www.theatlantic.com/ to woman: study. August 26, 2016. Available at: www.reuters.
news/archive/2016/08/texas-zika-infant-death/495059. Accessed com/article/us-health-zika-research-idUSKCN111224. Accessed
October 5, 2016. October 5, 2016.
112. Del Carpio-Orantes L. Zika, a neurotropic virus? [in Spanish] 133. Kashef Z. Zika virus may persist in the vagina days after
Rev Med Inst Mex Seguro Soc 2016;54:540543. infection. Yales News. August 25, 2016. Available at: http://news.
113. Van den Berg B, Walgaard C, Drenthen J, et al. Guillain-Barr yale.edu/2016/08/25/zika-virus-may-persist-vagina-days-after-
syndrome: pathogenesis, diagnosis, treatment and prognosis. infection. Accessed October 5, 2016.
Nat Rev Neurol 2014;10:469482. 134. Food and Drug Administration. FDA issues recommendations to
114. National Institute of Neurological Disorders and Stroke, National reduce the risk for Zika virus blood transmission in the United
Institutes of Health. NINDS Guillain-Barr information page. States. February 16, 2016. Available at: www.fda.gov/NewsEvents/
June 1, 2016. Available at: www.ninds.nih.gov/disorders/gbs/ Newsroom/PressAnnouncements/ucm486359.htm. Accessed
gbs.htm. Accessed October 7, 2016. October 5, 2016.
115. Solomon T, Dung NM, Vaughn DW, et al. Neurological 135. Food and Drug Administration. FDA advises testing for Zika virus
manifestations of dengue infection. Lancet 2000;355:10531059. in all donated blood and blood components in the U.S. August 26,
116. Wielanek AC, Monredon JD, Amrani ME, et al. Guillain-Barr 2016. Available at: www.fda.gov/NewsEvents/Newsroom/Pres-
syndrome complicating a Chikungunya virus infection. Neurology sAnnouncements/ucm518218.htm. Accessed October 5, 2016.
2007;69:21052107. 136. Reuters. U.S. to help fund technology to eliminate Zika in blood
117. World Health Organization. Guillain-Barr syndromeUnited supply. June 20, 2016. Available at: www.reuters.com/article/us-
States of America. March 21, 2016. Available at: www.who.int/ health-zika-cerus-corp-idUSKCN0Z61Y3. Accessed October 5, 2016.
csr/don/21-march-2016-gbs-usa/en. Accessed October 7, 2016. 137. Food and Drug Administration. FDA issues recommendations to
118. Dirlikov M, Major CG, Mayshack M, et al. Guillain-Barr syndrome reduce the risk of Zika virus transmission by human cell and tissue
during ongoing Zika virus transmissionPuerto Rico, January 1 products. March 1, 2016. Available at: www.fda.gov/NewsEvents/
July 31, 2016. MMWR Morb Mortal Wkly Rep 2016;65:910914. Newsroom/PressAnnouncements/ucm488612.htm. Accessed
Available at: www.cdc.gov/mmwr/volumes/65/wr/mm6534e1. October 5, 2016.
htm. Accessed October 7, 2016. 138. Reuters. Zika mystery widens as Utah caregiver contracts virus.
119. Reuters. Study nds strong link between Zika and Guillain-Barr. July 18, 2016. Available at: www.reuters.com/article/us-health-zika-
August 31, 2016. Available at: www.reuters.com/article/us- infection-idUSKCN0ZY22S. Accessed October 5, 2016.
health-zika-guillainbarre-idUSKCN1162X8. Accessed October 7, 2016. 139. Maron DF. Zika mystery case raises questions about new trans-
120. Centers for Disease Control and Prevention. Zika virus: mission route. Scientic American. July 18, 2016. Available at:
transmission and risks. August 27, 2016. Available at: www.cdc. www.scienticamerican.com/article/zika-mystery-case-raises-
gov/zika/transmission. Accessed October 7, 2016. questions-about-new-transmission-route. Accessed October 5, 2016.

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

 Zika in America: The Year in Review
140. Junker M. The Zika virus: an update on the outbreak and the ght 159. PR Newswire. Broad-spectrum antiviral drug HSRx 431 tests
against it. GlobalData. June 2016. Available at: https://healthcare.glo- effective against Zika virus. September 6, 2016. Available at:
baldata.com/resources/white-papers/the-zika-virus-an-update-on- www.prnewswire.com/news-releases/broad-spectrum-antiviral-
the-outbreak-and-the-ght-against-it. Accessed September 12, 2016. drug-hsrx-431-tests-effective-against-zika-virus-300322646.html.
141. Charrel RN, Leparc-Goffart I, Pas S, et al. Background review for Accessed October 11, 2016.
diagnostic test development for Zika virus detection. Bull World 160. World Health Organization. WHO Zika virus vaccine target product
Health Organ 2016;94:574D584D. Available at: www.who.int/ prole: vaccine to protect against congenital Zika virus syndrome
bulletin/volumes/94/8/16-171207/en. Accessed October 5, 2016. for use during an emergency. July 2016. Available at: www.who.
142. Centers for Disease Control and Prevention. New CDC int/csr/research-and-development/who_zika_vaccine_tpp.pdf.
laboratory test for Zika virus authorized for emergency use by FDA. Accessed October 11, 2016.
February 26, 2016. Available at: www.cdc.gov/media/ 161. DOrtenzio E, Matheron S, Yazdanpanah Y, et al. Evidence
releases/2016/s0226-laboratory-test-for-zika-virus.html. Accessed of sexual transmission of Zika virus. N Engl J Med 2016;374:
October 5, 2016. 21952198. doi: 10.1056/NEJMc1604449. Epub 2016 Apr 13.
143. Food and Drug Administration. Zika MAC-ELISA authorization 162. Inovio Pharmaceuticals. Inovio launches Zika vaccine trial in
letter. June 29, 2016. Available at: www.fda.gov/downloads/ midst of Puerto Rico epidemic to explore early signals of vaccine
MedicalDevices/Safety/EmergencySituations/UCM488040.pdf. efcacy. August 29, 2016. Available at: http://ir.inovio.com/news/
Accessed October 5, 2016. news-releases/news-releases-details/2016/Inovio-Launches-Zika-
144. Food and Drug Administration. Emergency use authorizations. Vaccine-Trial-in-Midst-of-Puerto-Rico-Epidemic-to-Explore-Early-Sig-
October 11, 2016. Available at: www.fda.gov/MedicalDevices/Safety/ nals-of-Vaccine-Efcacy/default.aspx. Accessed October 11, 2016.
EmergencySituations/ucm161496.htm. Accessed October 11, 2016. 163. National Institutes of Health. Study of GLS-5700 in healthy
145. Texas Childrens Hospital. First rapid detection Zika test now volunteers. August 29, 2016. Available at: https://clinicaltrials.gov/
available through collaboration with Texas Childrens Hospital ct2/show/NCT02809443. Accessed October 11, 2016.
and Houston Methodist Hospital. February 23, 2016. Available 164. Reuters. Zika vaccine race spurred by crisis and prot potential.
at: www.texaschildrens.org/about-us/news/releases/rst-rapid- October 4, 2016. Available at: www.reuters.com/article/us-health-zika-
detection-zika-test-now-available-through-collaboration-texas- vaccines-analysis-idUSKCN12409V. Accessed October 4, 2016.
children%E2%80%99s-hospital-and. Accessed October 7, 2016. 165. National Institute of Allergy and Infectious Diseases, National
146. World Health Organization. Current Zika Product Pipeline. Institutes of Health. Zika infection is caused by one virus serotype,
March 3, 2016. Available at: www.who.int/csr/research-and- NIH study nds. July 29, 2016. Available at: www.niaid.nih.gov/
development/zika-rd-pipeline.pdf. Accessed September 12, 2016. news-events/zika-infection-caused-one-virus-serotype-nih-study-
147. Lanciotti RS, Kosoy OL, Laven JJ, et al. Genetic and serologic nds. Accessed October 4, 2016.
properties of Zika virus associated with an epidemic, Yap State, 166. National Institutes of Health. NIH begins testing investigational
Micronesia, 2007. Emerg Infect Dis 2008;14:12321239. Zika vaccine in humans. August 3, 2016. Available at: www.nih.
148. Bingham AM, Cone M, Mock V, et al. Comparison of Zika virus gov/news-events/news-releases/nih-begins-testing-investiga-
testing in serum, urine, and saliva specimens from travel-associated tional-zika-vaccine-humans. Accessed October 11, 2016.
Zika virus disease casesFlorida, 2016. MMWR Morb Mortal Wkly 167. GeoVax Labs, Inc. GeoVax discusses Zika vaccine development at
Rep 2016;65(18). Epub May 10, 2016. Available at: www.cdc.gov/ American Society for Virologys 35th annual meeting. June 21, 2016.
mmwr/volumes/65/wr/mm6518e2.htm. Accessed October 7, 2016. Available at: www.geovax.com/news-events/entry/2016/06/21/
149. de M, Campos R, Cirne-Santos C, et al. Prolonged detection of geovax-discusses-zika-vaccine-development-at-american-society-for-
Zika virus RNA in urine samples during the ongoing Zika virus virology-s-35th-annual-meeting.html. Accessed October 11, 2016.
epidemic in Brazil. J Clin Virol 2016;77:6970. 168. Pipeline Review. Xenetic Biosciences announces collaboration with
150. Gourinat AC, OConnor O, Calvez E, et al. Detection of Zika virus Excivion Ltd., U.K., to develop a novel combined Zika and dengue
in urine. Emerg Infect Dis 2015;21:8486. vaccine. August 18, 2016. Available at: www.pipelinereview.com/index.
151. Sun LH. CDC whistleblower claims agency has been using wrong php/2016081862101/Vaccines/Xenetic-Biosciences-Announces-Col-
Zika test. Washington Post. September 27, 2016. Available at: laboration-with-Excivion-Ltd.-UK-to-Develop-a-Novel-Combined-Zika-
www.washingtonpost.com/news/to-your-health/wp/2016/09/27/ and-Dengue-Vaccine.html. Accessed October 11, 2016.
cdc-whistleblower-claims-agency-has-been-using-wrong-zika-test. 169. Protein Sciences Corporation. Vaccines. 2016. Available at: www.
Accessed September 28, 2016. proteinsciences.com/VAC.htm. Accessed October 11, 2016.
152. Centers for Disease Control and Prevention. Zika virus: treatment. 170. Vaxart. Vaxart begins preclinical testing of an oral Zika virus
June 28, 2016. Available at: www.cdc.gov/zika/symptoms/treat- vaccine. March 3, 2016. Available at: www.vaxart.com/NRles/
ment.html. Accessed October 7, 2016. VaxartZikaTabletVaccine030316.pdf. Accessed October 11, 2016.
153. Food and Drug Administration. Zika virus response updates from 171. Pharos Biologicals. Pharos: a completely unique approach to DNA
FDA. September 9, 2016. Available at: www.fda.gov/%20Emergen- vaccines. 2016. Available at: www.pharosbiologicals.com/pharos.
cyPreparedness/Counterterrorism/MedicalCountermeasures/ html. Accessed October 12, 2016.
MCMIssues/ucm485199.htm. Accessed September 22, 2016. 172. VaxInnate Corporation. Message from the CEO. 2015. Available at:
154. Shan S, Xie X, Barrett ADT, et al. Zika virus: diagnosis, http://vaxinnate.com/about-us/message-from-the-ceo. Accessed
therapeutics, and vaccine. ACS Infect Dis 2016;2:170172. October 12, 2016.
155. National Institute of Allergy and Infectious Diseases, National 173. CaroGen Corporation. Technology. 2013. Available at: www.caro-
Institutes of Health. Zika virus treatment. May 24, 2016. gencorp.com/technology.html. Accessed October 12, 2016.
Available at: www.niaid.nih.gov/diseases-conditions/zika-treat- 174. Kansas State University. Kansas State University contributes to
ment. Accessed September 22, 2016. potential Zika virus vaccine development. September 29, 2016.
156. Xu M, Lee EM, Wen Z, et al. Identication of small-molecule Available at: www.k-state.edu/media/newsreleases/2016-09/
inhibitors of Zika virus infection and induced neural cell death zika92916.html. Accessed October 12, 2016.
via a drug repurposing screen. Nat Med 2016;22:11011107. doi: 175. Reuters. Scientists path to usable Zika vaccine strewn with
10.1038/nm.4184. Epub 2016 Aug 29. hurdles. February 3, 2016. Available at: www.reuters.com/article/
157. Reuters. CorrectedZika virus may hide in organs protected from us-health-zika-vaccine-idUSKCN0VB21X. Accessed October 4, 2016.
the immune system. February 16, 2016. Available at: www.reuters. 176. Marston HD, Lurie N, Borio LL, Fauci AS. Considerations for
com/article/health-zika-immune-idUSL2N15V1C9. Accessed developing a Zika virus vaccine. N Engl J Med 2016;375:12091212.
February 26, 2016. 177. Reuters. Brazil says Zika-linked microcephaly cases stable at
158. National Institute of Allergy and Infectious Diseases, National 4,908. April 26, 2016. Available at: www.reuters.com/article/us-
Institutes of Health. Zika virus vaccines. August 18, 2016. health-zika-brazil-idUSKCN0XN2NP. Accessed October 24,2016. Q
Available at: www.niaid.nih.gov/diseases-conditions/zika-vaccines.
Accessed October 11, 2016.

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

Ipilimumabs superiority was consistent across all survival

More than 20,000 researchers, clinicians, advocates, endpoints at ve years, and long-term safety results were also
and patients gathered in Copenhagen October 711 for consistent with those in the primary report.
the European Society for Medical Oncology (ESMO) Currently, adjuvant ipilimumab represents an important
annual congress. We review several key sessions treatment option for patients with high-risk stage 3 melanoma,
on emerging immunotherapies for melanoma and Dr. Eggermont concluded.
nonsmall-cell lung cancer and on treatments for renal The results were published simultaneously in the New
cell carcinoma, ovarian cancer, and breast cancer. England Journal of Medicine.1

Ipilimumab Versus Placebo After Complete Primary Analysis From OAK, a Randomized
Resection of Stage 3 Melanoma: Final Overall Phase 3 Study Comparing Atezolizumab
Survival Results From the EORTC 18071 With Docetaxel in 2L/3L NSCLC
Randomized, Double-Blind, Phase 3 Trial Fabrice Barlesi, MD, Aix-Marseille University, Marseille,
Alexander M. Eggermont, MD, PhD, Institut Gustave France
Roussy, Villejuif, France
Programmed death ligand 1 (PD-L1) inhibitors are a class
Final overall survival results from the European Organization of checkpoint inhibitors that impede the binding of PD-L1 to
for Research and Treatment of Cancer (EORTC) 18071 trial its receptors (PD-1 and B7.1), thereby restoring tumor-specic
of adjuvant ipilimumab versus placebo reveal a persist- T-cell immunity. OAK was the rst phase 3 study that compared
ing benet at 5.3 years of median follow-upa signicant atezolizumab, a PD-L1 inhibitor, with standard chemotherapy
28% reduction in the relative risk of death. The trial in patients with previously treated nonsmall-cell lung cancer
included 951 patients with completely resected stage 3 (NSCLC).
melanoma who had been randomized double-blind to In OAK, 1,225 patients with NSCLC were randomized 1:1
ipilimumab 10 mg/kg (induction and maintenance) to intravenous atezolizumab (1,200 mg every three weeks) or
or placebo. Patients were treated for up to three years docetaxel (75 mg/m2 every three weeks). Patients were strati-
or until disease progression, intolerable toxicity, or ed according to PD-L1 status, number of prior chemotherapy
withdrawal. regimens, and histology. The primary endpoint was overall
In a 2015 report, the trials primary endpoint of recurrence- survival. Dr. Barlesi presented preliminary results from the
free survival (RFS) was 51.5% for ipilimumab compared rst 850 patients.
with 43.8% for placebo after a median of 2.3 years of Overall survival after a minimum follow-up of 19 months was
follow-up. Sixty more patients in the placebo arm relapsed improved by 27% in patients receiving atezolizumab versus
than in the ipilimumab arm (294 versus 234). The those receiving docetaxel (13.8 months versus 9.6 months,
three-year RFS rates were 46.5% for ipilimumab and respectively; P = 0.0003), regardless of PD-L1 expression levels.
34.8% for placebo (hazard ratio [HR], 0.75; 95% condence Dr. Barlesi noted that in the patients within the highest tertile
interval [CI], 0.640.9). of PD-L1 expression, overall survival was 59% greater than
At an ESMO press brieng, Dr. Eggermont stated that among the same group receiving docetaxel (P < 0.0001). In
ve-year RFS was 41% in the ipilimumab arm and 30% in patients with no PD-L1 expression, the gain in overall survival
the placebo arm (HR, 0.76; 95% CI, 0.640.89; P = 0.0008). with atezolizumab was still a signicant 25%. Squamous versus
Overall survival was 65% for ipilimumab and 54% for placebo nonsquamous histology had no impact on overall survival
(HR, 0.72; 95% CI, 0.580.88; P = 0.001). (hazard ratio, 0.73 for each).
Of course, this comes at a price in terms of side effects and Rates of treatment-related adverse events were lower in the
toxicity, Dr. Eggermont said. Immune-related events occurring atezolizumab group than in the docetaxel group (64% versus
with ipilimumab fell into ve blocks: dermatological, gastro- 86%). The rates of treatment-related grade 34 events were also
intestinal, endocrinological, hepatic, and neurological. The lower in the atezolizumab group (15% versus 43%), even though
most signicant grade 34 events that resulted when patients the median treatment duration was longer with atezolizumab
stopped treatment were gastrointestinal in nature (16%), and (3.4 months versus 2.1 months) and a higher percentage of
included colitis with fatal perforation in three patients and atezolizumab patients were treated for 12 months or more
hypophysitis in 4.4%. The toxicity-related death rate was 1.1%. (20.5% versus 2.4%). Treatment-related withdrawal rates were
Overall, the immune-related grade 34 adverse event rates 8% and 19% in the atezolizumab and docetaxel groups,
were 43% for ipilimumab and 2% for placebo. respectively.
Martin Reck, MD, of the Grosshansdorf Lung Clinic in
The author is a freelance writer living in New York City. Germany, who commented on the OAK study, pointed out

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

 MEETING HIGHLIGHTS: European Society for Medical Oncology 2016 Congress

that an improvement in overall survival, even in patients with Ceritinib demonstrated superior efcacy compared with
no PD-L1 expression, shows that we have a problem with standard second-line chemotherapy in crizotinib-resistant
using PD-L1 negativity as an exclusion factor for treatment. ALK+ patients, establishing ceritinib as a preferred treatment
He suggested that PD-L1 is perhaps an imperfect surrogate option in this patient population, Dr. Scagliotti concluded.
marker and that additional markers for the characterization
of patients who might benet from atezolizumab are needed. KEYNOTE-024: Pembrolizumab Versus Platinum-
Based Chemotherapy as First-Line Therapy
Ceritinib Versus Chemotherapy in Patients For Advanced NSCLC With a PD-L1 Tumor
With Advanced Anaplastic Lymphoma Kinase- Proportion Score of 50% or Higher
Rearranged NonSmall-Cell Lung Cancer Martin Reck, MD, Chief Oncology Physician, Grosshansdorf
Previously Treated With Chemotherapy and Lung Clinic, Grosshansdorf, Germany
Crizotinib: Results From the Conrmatory
In the KEYNOTE-024 trial, pembrolizumab was superior to
Phase 3 ASCEND-5 Study platinum-based chemotherapy as rst-line therapy for patients
Giorgio Scagliotti, MD, University of Turin, Torino, Italy with advanced nonsmall-cell lung cancer (NSCLC) and a
programmed death ligand 1 (PD-L1) tumor proportion score
Phase 2 ndings from the ASCEND-2 trial showed durable (TPS) of 50% or higher. High PD-L1 expression, Dr. Reck said
responses in anaplastic lymphoma kinase-rearranged (ALK+) in an ESMO press conference, is dened by PD-L1 expression
nonsmall-cell lung cancer (NSCLC) patients receiving ceritinib in at least 50% of tumor cells.
who had progressed on chemotherapy and crizotinib (including KEYNOTE-024 included 305 treatment-nave patients with
those with brain metastases). These ndings were conrmed PD-L1 TPS of 50% or higher randomized 1:1 to intravenous
in the phase 3 ASCEND-5 study conducted with patients previ- pembrolizumab 200 mg once every three weeks for two years
ously treated with crizotinib. Ceritinib is a next-generation ALK or standard-of-care platinum-based doublet chemotherapy
inhibitor with 20-fold greater potency than crizotinib. for four to six cycles. Patients with epidermal growth factor
Before the development of targeted therapies, chemotherapy receptor-activating mutations and anaplastic lymphoma kinase
was the standard of care for most patients with advanced translocations were excluded. Crossover to the pembrolizumab
NSCLC. While the ALK inhibitor crizotinib is effective in regimen was allowed in the chemotherapy arm after disease
patients with ALK+ NSCLC, most patients develop resistance progression. The primary endpoint was progression-free
and progressive disease, Dr. Scagliotti said at an ESMO press survival (PFS).
conference. Pembrolizumab signicantly extended PFS by approxi-
Investigators enrolled 231 patients at 99 sites in 20 countries mately four months compared with chemotherapy (10.3 months
to the global, open-label ASCEND-5 study, randomizing them versus 6.0 months) (hazard ratio [HR], 0.50; P < 0.001). The
to ceritinib 750 mg once daily or chemotherapy (pemetrexed PFS rates at six months and one year were 62% and 48% for
500 mg/m2 or docetaxel 75 mg/m2 every 21 days). Patients pembrolizumab and 50% and 15% for chemotherapy, respec-
were stratied according to baseline World Health Organization tively. Overall survival rates, a secondary endpoint, were
performance status and presence of brain metastases. The higher with pembrolizumab, with 80% of patients surviving at
primary endpoint was progression-free survival (PFS), assessed six months versus 72% in the chemotherapy arm (HR, 0.60;
by blinded independent review. P = 0.005). Dr. Reck pointed out that the overall survival
Compared with patients receiving chemotherapy, those benet with pembrolizumab was remarkable considering
receiving ceritinib had signicantly better median PFS that more than 40% of patients in the control arm crossed
(5.4 versus 1.6 months) (hazard ratio [HR], 0.49; P < 0.001). over to pembrolizumab. At one year, the survival rates were
Ceritinib also had a superior overall response rate compared 70% in pembrolizumab-treated patients and 54% in those who
with chemotherapy (39.1% versus 6.9%). Ceritinib benets underwent chemotherapy.
were consistent across subgroups. However, there was no Pembrolizumab was associated with a higher overall response
improvement in overall survival with ceritinib compared with rate compared with chemotherapy (45% versus 28%), a longer
chemotherapy. Of the patients who discontinued chemo- duration of response, and lower incidences of all and serious
therapy due to disease progression, 75 crossed over to ceritinib. (grade 34) adverse events. Patients in the pembrolizumab arm
Dr. Scagliotti attributed the lack of overall survival benet to tolerated treatment twice as long as those in the chemotherapy
the high crossover rate. That probably diluted the potential arm (7.0 months versus 3.5 months). Discontinuation rates
benet, he said. for toxicity were 7% in the pembrolizumab arm and 11% in the
The most common grade 34 adverse events with chemo- chemotherapy arm.
therapy were neutropenia (15.5%), fatigue (4.4%), and nausea Pembrolizumab may be a new standard of care for rst-line
(1.8%). The most common grade 34 adverse events with therapy for advanced NSCLC that expresses high levels of
ceritinib were nausea (7.8%), vomiting (7.8%), and diarrhea PD-L1, Dr. Reck concluded.
(4.3%). Patient-reported outcomes, including lung-cancer The superior efcacy observed with pembrolizumab led
specic symptoms and overall health status, were better in the the trials data monitoring committee to recommend stopping
ceritinib group (P < 0.05). The safety prole of ceritinib was the trial.
consistent with that reported in prior studies.

Vol. 41 No. 12 December 2016 P&T

797
 MEETING HIGHLIGHTS: European Society for Medical Oncology 2016 Congress

Cabozantinib Versus Sunitinib as Initial ESMO press brieng. Maintenance therapy (approved only in
Targeted Therapy for Patients With the European Union) with bevacizumab can only be given once
and confers just a few months progression-free survival (PFS).
Metastatic Renal Cell Carcinoma of In addition, the poly (ADP-ribose) polymerase (PARP) inhibi-
Poor- and Intermediate-Risk Groups: tor olaparib is approved only for ovarian cancer patients with a
Results From the ALLIANCE A031203 Trial germline BRCA mutation (10%15% of patients).
Toni Choueiri, MD, Director, Lank Center for Genitourinary Niraparib is an oral, highly selective inhibitor of PARP1/2.
Oncology, Dana-Farber Cancer Institute, Boston, The ENGOT-OV16/NOVA study was the rst randomized
Massachusetts phase 3 trial of a PARP inhibitor as maintenance therapy for use
after platinum chemotherapy in patients with platinum-sensitive
Cabozantinib is an oral inhibitor of tyrosine kinases, includ- recurrent ovarian cancer.
ing MET and AXL, and of vascular endothelial growth factor The hypothesis of ENGOT-OV16/NOVA was that niraparib
(VEGF) receptors. Both MET and AXL seem to be associated would provide a clinical benet to all patients with platinum-
with tumor progression, but more importantly, animal models sensitive recurrent ovarian cancer regardless of BRCA muta-
show that the development of resistance to VEGF inhibi- tion status. The study included 553 patients randomized 2:1 to
tors like sunitinib can be mediated through AXL and MET, niraparib 300 mg once daily or placebo and stratied according
Dr. Choueiri said at an ESMO press conference. He noted that to germline BRCA mutation (gBRCAmut) (n = 203) or non-
sunitinib has been the standard-of-care, rst-line therapy for gBRCAmut status (n = 350). After four to six cycles of platinum-
renal cell carcinoma (RCC) for years. Median progression-free based chemotherapy, patients received the study regimen until
survival (PFS) with rst-line VEGF receptor tyrosine kinase disease progression.
inhibitors has been in the eight- to 11-month range. Niraparib improved the primary endpoint of PFS signi-
In the ALLIANCE clinical trial, 157 treatment-nave, poor- and cantly compared with placebo in both cohorts, as well as in all
intermediate-risk RCC patients received cabozantinib (60 mg subgroups. Median PFS for niraparib compared with placebo
once daily) or sunitinib (50 mg once daily) for four weeks on was 21.0 months versus 5.5 months in the gBRCAmut group
and two weeks off. Overall survival was the primary outcome, (hazard ratio [HR], 0.27; 95% confidence interval [CI],
and objective response rate (investigator-assessed) and safety 0.1730.410; P < 0.0001), 9.3 months versus 3.9 months in
were secondary outcomes. Dr. Choueiri said that outcomes the non-gBRCAmut group (HR, 0.45; 95% CI, 0.3380.607;
with VEGF-targeted therapy in the poor- and intermediate-risk P < 0.0001), and 12.9 months versus 3.8 months in a sub-
groups are typically inferior (median, 5.6 months) to those in group of the non-gBRCAmut cohort who had homologous
favorable-risk patients. recombination DNA repair deciencies (HR, 0.38; 95% CI,
Cabozantinib improved PFS and the objective response rate 0.2430.586; P < 0.0001).
compared with sunitinib in this poor- and intermediate-risk While dose adjustments generally resolved toxicity issues and
population. PFS was 8.2 months for cabozantinib and 5.6 months patient-reported quality of life was similar for both study arms,
for sunitinib (hazard ratio, 0.69; P = 0.012). The objective grade 34 adverse events were reported in more than 10% of
response rate was 46% for cabozantinib and 18% for sunitinib. patients receiving niraparib. The rates for thrombocytopenia,
Safety proles were similar, with grade 3 or higher adverse anemia, and neutropenia were 28%, 25%, and 11%, respectively.
event rates of 70.5% in the cabozantinib arm and 72.2% in Pending approval, these landmark results could change the
the sunitinib arm. Diarrhea, fatigue, hypertension, palmar- way we treat this disease and warrant niraparib maintenance
plantar erythrodysesthesia, and hematological events were most treatment to the whole study population, Dr. Mirza said. He
common. Toxicity led to treatment termination in 16 patients commented further that the broad population beneting from
in each treatment group. niraparib in this trial represents 70% of all ovarian cancer patients.
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. Capecitebine Monotherapy in Patients 70 Years
You have a drug based on a strong biological rationale that is Of Age and Older With Metastatic Breast Cancer
approved in second-line with positive primary and secondary David O. Okonji, MD, Royal Marsden Hospital NHS
endpoint results. I would make the leap of faith. Foundation Trust, London, United Kingdom

A Randomized, Double-Blind, Phase 3 Chemotherapy with capecitebine has been around for about
25 years. Its registration dose of 1,250 mg/m2 twice daily is
Trial of Maintenance Therapy With Niraparib very hefty for the elderly, however, Dr. Okonji said at a poster
Versus Placebo in Patients With Platinum- session. Dose reductions and a modied schedule may work
Sensitive Recurrent Ovarian Cancer better for patients 70 years of age and older with metastatic
Mansoor Raza Mirza, MD, Chief Oncologist, Copenhagen breast cancer, according to his study results.
University Hospital Rigshospitalet, Copenhagen, Denmark When all available endocrine therapies no longer offer
benet, capecitebine monotherapy is often prescribed. It also
Cumulative toxicities and lack of subsequent benet with may be given as a last convenient oral agent before resorting
platinum-based chemotherapy are limitations of the current to intravenous chemotherapy with its attendant potential side
treatment landscape for ovarian cancer, Dr. Mirza noted in an effects of alopecia, nausea, vomiting, and fatigue.

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

 MEETING HIGHLIGHTS: European Society for Medical Oncology 2016 Congress

The clinical benet rate of capecitebine as a monotherapy (PFS) compared with placebo in interim results from the
is 60%, and median time to progression in patients 65 years MONALEESA-2 trial.
of age or older is four months. Dose reductions due to toxic- Increased cyclin-dependent kinase (CDK) 4/6 activity is
ity occur in 27% to 50% of patients. While the starting dose associated with endocrine therapy resistance, Dr. Hortobagyi
and schedule for capecitebine at Dr. Okonjis institution is said in an ESMO press brieng. While endocrine therapy is
2,000 mg/m2 on days 114 every three weeks (two weeks on/one an established rst-line treatment for advanced breast can-
week off), older patients and those with poor performance status, cer, endocrine therapy resistance and disease progression
comorbidities, and/or moderate-to-severe renal impairment may eventually occur in most patients. CDK 4/6 inhibition is a
need dose reductions. A week on/week off (WOWO) schedule, valid treatment strategy for hormone receptor-positive
rst devised at Memorial Sloan Kettering Cancer Institute in New advanced breast cancer and may help overcome or delay
York, is being substituted to improve tolerance in the elderly. endocrine therapy resistance. Ribociclib (LEE011) is an orally
Dr. Okonjis single-center, retrospective, observational cohort bioavailable selective CDK 4/6 inhibitor.
study assessed safety and efcacy of low-dose capecitebine In MONALEESA-2, a phase 3, double-blind, placebo-
monotherapy in patients 70 years of age or older with relapsed controlled trial of ribociclib plus letrozole, 668 postmenopausal
de novo metastatic breast cancer. Toxicity was the primary women with hormone receptor-positive/HER2-negative meta-
outcome measure. Patients receiving the standard two weeks static or locally advanced breast cancer with no prior therapy
on/one week off regimen (2,000 mg/m2) were compared with for advanced disease were randomized to two treatment groups:
those receiving a dose reduction or the WOWO schedule ribociclib (600 mg/day, three weeks on/one week off) plus
(2,000 mg/m2). Patients on the WOWO schedule were older letrozole (2.5 mg/day, continuous) (n = 334) or letrozole plus
(median age, 79 years versus 73 years [P < 0.001]), had impaired placebo (n = 334).
renal function (P = 0.016), and had lower performance status At interim analysis, median PFS was not met in the ribociclib
compared with the standard regimen group. plus letrozole arm (95% condence interval, 19.3NR). Median
Complete response rates were 7% and 0% for the standard PFS was 14.7 months (range, 13.016.5 months) in the placebo
therapy (n = 43) and WOWO (n = 34) groups, respectively, with plus letrozole arm (P = 0.00000329). Differences between the
corresponding partial response rates of 37% and 16%. Progressive treatment arms emerged early and were sustained.
disease was reported in 30% of those receiving the higher dose Dr. Hortobagyi said that patients with measurable disease at
of capecitebine and in 50% of those receiving the WOWO course baseline had a signicantly higher objective response rate to
of therapy. ribociclib plus letrozole compared with letrozole plus placebo
While clinical benet rates were higher in those receiv- (53% versus 37%, respectively; P = 0.00028). Ribociclib plus
ing the higher dose, the higher rates of time to progression letrozole also improved the clinical benet rate compared with
(11.7 months versus 6.2 months; P = 0.111) and overall survival letrozole plus placebo (80% versus 72%, respectively; P = 0.02).
(18.6 months versus 13.3 months; P = 0.288) were not signi- Most adverse events were grades 12 and were managed
cant. Patients in the WOWO cohort experienced less grade 34 with dose interruptions and reductions. Very few patients
toxicity with fewer subsequent dose reductions. Patients on discontinued treatment. Although serious adverse events
the WOWO schedule tolerated capecitebine better because of were uncommon (less than 5%) in both arms, adverse events
less diarrhea, less hand inammation, and little or no reduced occurred more often in the ribociclib-treated patients. The
white cell counts with their infection risk. This enabled them most common adverse events were related to uncomplicated
to stay on their dose for a longer time, despite their poor myelosuppression: neutropenia (59% for ribociclib/letrozole
performance status and impaired kidney function, which is usu- versus 1% for letrozole/placebo), leukopenia (21% versus 1%),
ally a contraindication for this drug, Dr. Okonji said. and lymphopenia (7% versus 1%). Nausea, vomiting, diarrhea,
Capecitebine toxicity can be managed by dose reduc- alopecia, rash, and transaminase elevations were also reported
tion and/or a switch to a WOWO schedule. Both strategies more frequently in ribociclib-treated patients.
enabled continued treatment in those deriving clinical benet, As a result of the interim analysis showing that the primary
Dr. Okonji said. With this modication of the capecitebine regi- endpoint had already been met, the data monitoring and safety
men, weve given this old drug a new lease on life and allowed it board recommended termination of the trial.
to be used in patients who would not otherwise be able to tolerate This is an important advance, Dr. Hortobagyi said. He
it. And, its off-patent and cheap. commented also that available data suggest that the three
leading approved CDK 4/6 inhibitors seem to have very similar
First-Line Ribociclib Plus Letrozole therapeutic value and toxicity proles. He called the results
paradigm changing and said, We have not had studies in
For Postmenopausal Women With metastatic breast cancer before with this magnitude of benet.
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

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 not higher in older patients compared with younger patients
With Metastatic Breast Cancer: Final Results (17.2% versus 20.0%). Patients receiving nab-paclitaxel doses
lower than 260 mg/m2 did not have lower overall response
Of the Noninterventional NABUCCO Study rates. Median time to tumor progression was 5.9 months for
Karin Potthoff, MD, iOMEDICO, Freiburg, Germany the overall population and similar for those younger than
age 65 years (5.7 months) and those age 65 years or older
While several clinical trials of nab-paclitaxel have been (6.5 months). It was shortest for those with triple-
conducted, prospective data on real-world practice consistent negative disease (4.9 months) and longest for those who were
with increased use of prior taxane-containing regimens in HR+/HER2+ (8.6 months).
the neoadjuvant setting have been lacking. We wondered Our real-world data from NABUCCO conrm the earlier
if patients, in fact, were able to receive the recommended clinical trial ndings. They conrm also that nab-paclitaxel is
260 mg/m2 dose or if it was too toxic, Dr. Potthoff said in an an effective and safe treatment option with a favorable benet
interview at her poster. risk prole in metastatic breast cancer patients not eligible for
In a pivotal phase 3 trial conducted by Gradishar et al., anthracycline therapy, Dr. Potthoff concluded. She under-
nab-paclitaxel demonstrated high efcacy (overall response scored that response rates were high in populations typically
rate, 33%; time to tumor progression, 23.0 weeks; overall difcult to treatpatients who had received multiple lines of
survival, 60 weeks) with an acceptable toxicity prole. Peripheral prior therapy, older patients, and patients with triple-negative
sensory polyneuropathy (grade 3) in 10% of patients was the disease.
most critical safety issue.2
In order to test that idea, NABUCCO study investigators REFERENCES
collected data from approximately 100 oncology outpatient 1. Eggermont AM, Chiarion-Sileni V, Grob JJ, et al. Prolonged
centers across Germany on the routine treatment of 697 patients survival in stage III melanoma with ipilimumab adjuvant therapy.
with metastatic breast cancer in whom anthracycline therapy N Engl J Med 2016 Oct 7. [Epub ahead of print] Available at:
www.nejm.org/doi/full/10.1056/NEJMoa1611299. Accessed
was contraindicated. Data on treatment for a maximum of November 4, 2016.
six months were captured with follow-up data for a median of 2. Gradishar WJ, Tjulandin S, Davidson N, et al. Phase III trial
17.7 months, including details on disease progression, overall of nanoparticle albumin-bound paclitaxel compared with poly-
survival, and safety with a focus on neurotoxicity. ethylated castor oil-based paclitaxel in women with breast cancer.
J Clin Oncol 2005;23(31):77947803. Q
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 MEDICATION ERRORS
reported in 47.3% of patients, peripheral sensory neuropathy
was most common (35%). continued from page 737
Median age in the overall trial was 62.3 years; 58.2% of the 11. Ely EW, Truman B, Shintani A, et al. Monitoring sedation status
patients were younger than 65 years of age. Median time from over time in ICU patients: the reliability and validity of the Rich-
primary diagnosis was 65.2 months. Among the entire cohort, mond Agitation Sedation Scale (RASS). JAMA 2003;289(22):2983
2991.
419 patients (60.1%) had received prior taxane therapy with 12. McCarter T, Shaik Z, Scarfo K, Thompson LJ. Capnography
treatment schemes ranging from 78260 mg/m2 every three monitoring enhances safety of postoperative patient-controlled
or four weeks. Nab-paclitaxel was received as rst-, second-, analgesia. Am Health Drug Benets 2008;1(5):2835.
third-, and fourth-or-greater-line therapy in 40%, 24%, 20%, and
15% of patients, respectively. The reports described in this column were received through the
Over half of the patient population had hormone receptor- ISMP Medication Errors Reporting Program (MERP). Errors,
positive/HER2-negative (HR+/HER2) disease (58.4%). The close calls, or hazardous conditions may be reported on the ISMP
rest of the patients had HR+/HER2+ (9.9%), HR/HER2+ (3.9%), website (www.ismp.org) or communicated directly to ISMP by
and triple-negative (13.8%) breast cancer, and receptor status calling 1-800-FAIL-SAFE or via email at ismpinfo@ismp.org. Q
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%
Correction
in second-line therapy. Response rates were highest among A Pipeline Plus article in Octobers P&T included out-
patients who were HR/HER2+ (55.6%) and lowest in triple- dated information about Intarcia Therapeutics ITCA 650
negative breast cancer (32.7%). That rate for triple-negative (continuous subcutaneous delivery of exenatide), which
disease is still quite good, Dr. Potthoff noted. The progres- is being developed for the treatment of patients with
sive disease rate was highest in patients with triple-negative type-2 diabetes. The investigational therapy employs a
breast cancer (27.1%) and lowest in those with HR/HER2+ subcutaneous osmotic mini-pump to provide continuous
disease (11.1%). exenatide drug therapy in a three-month initiation dose,
While overall response rates were lower in patients older than followed by consecutive six-month doses, as evaluated in
65 years compared with patients younger than 65 years (31.6% its phase 3 clinical trials.
versus 41.1%, respectively), the progressive disease rate was

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

 RESEARCH BRIEFS
continued from page 769
Overweight Patients Arent patient and staff education materials with tips to prevent infec-
Getting Needed Weight Advice tion; protocols for dialysis facilities; dialysis audit tools and
About two-thirds of overweight and obese patients are not checklists; and videos and DVDs on best practices.
getting the advice they need about weight management from Dialysis patients are particularly vulnerable to infections,
their health care providers, according to a recent study. says Priti R. Patel, MD, MPH, Medical Director of the Coalition.
The researchers conducted a phone survey of 1,109 over- We want to get lifesaving tools into the right hands to make a
weight or obese adults, asking them whether a health care real impact on patients lives.
provider had given them advice about their weight in the Source: Centers for Disease Control and Prevention,
previous 12 months. A concerning nding, the researchers October 2016
said: Only 35% of the respondents reported such advice.
As body mass index (BMI) increased, so did the likelihood Patients Know About Diabetic
of receiving weight-loss advice: 22% of those with a BMI of Retinopathy RiskBut Dont Get Screened
25.0 to 29.9 received advice versus 63% of those with a BMI Patients may understand that diabetes can lead to eye disease,
of 40.0 or higher. Hispanics were the most likely of the three and they may receive a recommendation for screening for
racial/ethnic groups to report receiving advice from a health diabetic retinopathybut that doesnt mean theyll get screened.
care provider. The researchers said other studies have sug- Researchers from Harbor-UCLA Medical Center in Torrance,
gested that a higher prevalence of weight problems among California, surveyed 101 patients with diabetes and 44 provid-
blacks and Hispanics draws more attention from health care ers and staffers at a clinic where annual screening rates for
providers when counseling. diabetic retinopathy were low. They found that 93% of patients
High-risk patients, such as the extremely obese or those with understood the potential risk, but only 55% were getting
comorbidities, are most likely to receive weight-loss advice, screened.
the researchers said. But demographic factors also come into The study goal, however, wasnt to measure understand-
play: People with high levels of education are more likely than ing of risk, but to nd out what patients considered barriers
those with low levels to receive advice, and middle-aged people to screening, and whether health care providers understood
are more likely to get advice than younger or older patients. those barriers. And the researchers found quite a gap between
Patients in the lowest income groups had signicantly lower the two groups.
odds of receiving weight-loss advice, compared with those in The patients were mostly low-income Hispanics and African-
higher income groups. Adjusting for health insurance did not Americans. The survey asked them to rate any given barrier
change the results. That nding is problematic, the research- that would delay or prevent them from getting screened. Health
ers said, because people with the lowest incomes tend to have care providers and staff were asked to rate the importance of
poorer health outcomes than those with higher incomes. addressing the barriers.
Source: Preventing Chronic Disease, October 2016 Most of the patients (70%) reported at least one barrier to
screening, most commonly depression (22%) and nancial
Cutting Down on Dialysis-Related Infections problems (26%); others reported language issues, lack of
Each year about 37,000 people get potentially deadly blood- transportation, and lack of time.
stream infections related to dialysis. But those infections could When surveying the health care providers, though, the
be cut dramatically by implementing evidence-based recom- researchers found markedly divergent perceptions between
mendations, the Centers for Disease Control and Prevention the two groups. For instance, only small numbers of patients
(CDC) says. For several years, facilities that have followed said transportation, language issues, denial, fear, or cultural
CDC recommendations have successfully reduced bloodstream beliefs were barriersyet most providers and staff thought
infections in dialysis patients. those were very or extremely important.
Making evidence-based safety steps a routine part of patient In contrast, the barriers that the patients did think were
care is a proven strategy to keep dialysis patients safe from blood- importantnancial burdens and depressionwere rated
stream infections, says CDC Director Tom Frieden, MD, MPH. as less important than other barriers by the health care
Now the CDC is teaming up with a coalition of health care providers and staff.
and patient advocacy organizations and other public health The differences in opinion suggest a lack of high-quality
partners in the Making Dialysis Safer for Patients Coalition, an patientprovider communication, the researchers said. They
initiative to expand the use of the recommendations and tools suggest that more effective patient education, as well as height-
to improve dialysis patient safety. ened awareness of depression and its impact, are key to getting
The coalition will promote the use of the CDCs Core more patients screened.
Interventions and provide facilities with resources, including Source: Preventing Chronic Disease, October 2016 Q

Vol. 41 No. 12 December 2016 P&T

801
 THANK YOU TO OUR 2016 REVIEWERS
Uche Anadu Ndefo, PharmD, BCPS Robert J. McCarthy, PharmD
Jacquelyn Bainbridge, PharmD Lina Meng, PharmD
Judith L. Belzer, PharmD Heather Minger, PharmD, BCPS
Jessica Biggs, PharmD Juan F. Mosley, PharmD, CPH, AAHIVP
Kathryn Blake, PharmD Scott W. Mueller, PharmD, BCCCP
Mitchell S. Buckley, PharmD, FASHP, FCCM, FCCP, BCPS Megan Musselman, PharmD, MS, BCPS, BCCCP
Dustin Carr, PharmD, BCPS Charles Oo, PharmD, PhD, FACCP
Alan Caspi, PhD, PharmD, MBA Ronny M. Otero, MD
Zlatan Coralic, PharmD, BCPS Samit Patel, PharmD, BCOP
Ericka L. Crouse, PharmD, BCPP, CGP, FASCP, FASHP Nima Patel-Shori, PharmD
Amanda F. Dempsey, MD, PhD, MPH Roy A. Pleasants, PharmD
Marcia S. Driscoll, MD, PharmD William A. Prescott, Jr., PharmD
Gladys El-Chaar, PharmD Theresa R. Prosser, PharmD
Rachel W. Flurie, PharmD, BCPS Zara Risoldi, PharmD, MS, FASCP
Kelly Gable, PharmD, BCPP Kiri M. Rolek, PharmD
Ronald G. Hall, PharmD, MSCS Barbara O. Rothbaum, PhD, ABPP
Coleen Hart, PharmD, BCPS Tracy L. Skaer, PharmD
Julie Harting, PharmD Tyler Sledge, PharmD
Darrell Hulisz, RPh, PharmD Jennifer Splawski, PharmD, BCPS
Michele B. Kaufman, PharmD, CGP, RPh Steven C. Stoner, PharmD, BCPP
Julie A. Kreyenbuhl, PharmD, PhD David C. Swinney, PhD
Jason Lancaster, PharmD, MEd Michael C. Thomas, PharmD, BCPS, FCCP
Tristan Lindfelt, PharmD, BCPS, BCACP Omar Viswanath, MD
Erin M. Lingenfelter, PharmD F. Randy Vogenberg, RPh, PhD
Robert MacLaren, PharmD, FCCM, FCCP C. Dustin Waters, PharmD, BCPS
Tyler C. Madere, PharmD, BCPS Craig Whitman, PharmD, BCPS

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

INVOKAMET XR INVOKAMET XR (canagliozin and metformin hydrochloride extended-release) tablets
(canagliozin and metformin hydrochloride extended-release)
Renal Impairment: The postmarketing metformin-associated lactic
tablets, for oral use
acidosis cases primarily occurred in patients with significant renal
Brief Summary of Prescribing Information. impairment. The risk of metformin accumulation and metformin-associated
lactic acidosis increases with the severity of renal impairment because
WARNING: LACTIC ACIDOSIS metformin is substantially excreted by the kidney [see Clinical
Post-marketing cases of metformin-associated lactic acidosis have Pharmacology (12.3) in full Prescribing Information].
resulted in death, hypothermia, hypotension, and resistant Before initiating INVOKAMET XR, obtain an estimated glomerular
bradyarrhythmias. The onset of metformin-associated lactic acidosis ltration rate (eGFR).
is often subtle, accompanied only by nonspecic symptoms such as
malaise, myalgias, respiratory distress, somnolence, and abdominal INVOKAMET XR is contraindicated in patients with an eGFR less than
pain. Metformin-associated lactic acidosis was characterized by 45 mL/minute/1.73 m2.
elevated blood lactate levels (> 5 mmol/Liter), anion gap acidosis Obtain an eGFR at least annually in all patients taking INVOKAMETXR.
(without evidence of ketonuria or ketonemia), an increased lactate/ In patients at increased risk for the development of renal impairment
pyruvate ratio; and metformin plasma levels generally >5 mcg/mL (e.g., the elderly), renal function should be assessed more frequently.
[see Warnings and Precautions]. Drug Interactions: The concomitant use of INVOKAMETXR with specific
Risk factors for metformin-associated lactic acidosis include renal drugs may increase the risk of metformin-associated lactic acidosis: those
impairment, concomitant use of certain drugs (e.g., carbonic that impair renal function, result in significant hemodynamic change,
anhydrase inhibitors such as topiramate), age 65 years old or greater, interfere with acid-base balance or increase metformin accumulation
having a radiological study with contrast, surgery and other (e.g. cationic drugs) [see Drug Interactions]. Therefore, consider more
procedures, hypoxic states (e.g., acute congestive heart failure), frequent monitoring of patients.
excessive alcohol intake, and hepatic impairment. Age 65 or Greater: The risk of metformin-associated lactic acidosis
Steps to reduce the risk of and manage metformin-associated lactic increases with the patients age because elderly patients have a greater
acidosis in these high risk groups are provided in the full prescribing likelihood of having hepatic, renal, or cardiac impairment than younger
information [see Dosage and Administration (2.2) in full Prescribing patients. Assess renal function more frequently in elderly patients [see
Information, Contraindications, Warnings and Precautions, Drug Use in Specific Populations].
Interactions, and Use in Specic Populations].
Radiological Studies with Contrast: Administration of intravascular
If metformin-associated lactic acidosis is suspected, immediately iodinated contrast agents in metformin-treated patients has led to an acute
discontinue INVOKAMET XR and institute general supportive decrease in renal function and the occurrence of lactic acidosis. Stop
measures in a hospital setting. Prompt hemodialysis is recommended
INVOKAMET XR at the time of, or prior to, an iodinated contrast imaging
[see Warnings and Precautions].
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;
INDICATIONS AND USAGE
or in patients who will be administered intra-arterial iodinated contrast.
INVOKAMET XR (canagliozin and metformin hydrochloride extended Re-evaluate eGFR 48 hours after the imaging procedure, and restart
release) is indicated as an adjunct to diet and exercise to improve INVOKAMETXR if renal function is stable.
glycemic control in adults with type 2 diabetes mellitus when treatment
with both canagliozin and metformin is appropriate. Surgery and Other Procedures: Withholding of food and fluids during
surgical or other procedures may increase the risk for volume depletion,
Limitations of Use: INVOKAMETXR is not recommended in patients with
type1 diabetes or for the treatment of diabetic ketoacidosis. hypotension and renal impairment.
INVOKAMET XR should be temporarily discontinued while patients have
CONTRAINDICATIONS restricted food and fluid intake.
INVOKAMETXR is contraindicated in patients with:
Hypoxic States: Several of the postmarketing cases of metformin-
Moderate to severe renal impairment (eGFR below 45 mL/min/1.73 m2), associated lactic acidosis occurred in the setting of acute congestive
end stage renal disease (ESRD) or patients on dialysis [see Warnings heart failure (particularly when accompanied by hypoperfusion and
and Precautions and Use in Specic Populations].
hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction,
Acute or chronic metabolic acidosis, including diabetic ketoacidosis sepsis, and other conditions associated with hypoxemia have been
[see Warnings and Precautions]. associated with lactic acidosis and may also cause pre-renal azotemia.
History of a serious hypersensitivity reaction to canagliozin or When such events occur, discontinue INVOKAMETXR.
metformin, such as anaphylaxis or angioedema [see Warnings and
Precautions and Adverse Reactions]. Excessive Alcohol Intake: Alcohol potentiates the effect of metformin on
lactate metabolism and this may increase the risk of metformin-associated
WARNINGS AND PRECAUTIONS lactic acidosis. Warn patients against excessive alcohol intake while
Lactic Acidosis: There have been post-marketing cases of metformin- receiving INVOKAMETXR.
associated lactic acidosis, including fatal cases. These cases had a Hepatic Impairment: Patients with hepatic impairment have developed
subtle onset and were accompanied by nonspecific symptoms such as metformin-associated lactic acidosis. This may be due to impaired lactate
malaise, myalgias, abdominal pain, respiratory distress, or increased
clearance resulting in higher lactate blood levels. Therefore, avoid use of
somnolence; however, hypothermia, hypotension and resistant
INVOKAMETXR in patients with clinical or laboratory evidence of hepatic
bradyarrhythmias have occurred with severe acidosis. Metformin-
associated lactic acidosis was characterized by elevated blood lactate disease.
concentrations (>5 mmol/Liter), anion gap acidosis (without evidence of Hypotension: Canagliozin causes intravascular volume contraction.
ketonuria or ketonemia), and an increased lactate:pyruvate ratio; Symptomatic hypotension can occur after initiating INVOKAMET XR
metformin plasma levels generally >5 mcg/mL. Metformin decreases liver [see Adverse Reactions] particularly in patients with eGFR less than
uptake of lactate increasing lactate blood levels which may increase the 60 mL/min/1.73 m2, elderly patients, patients on either diuretics or
risk of lactic acidosis, especially in patients at risk. medications that interfere with the renin-angiotensin-aldosterone system
If metformin-associated lactic acidosis is suspected, general supportive (e.g., angiotensin-converting-enzyme [ACE] inhibitors, angiotensin
measures should be instituted promptly in a hospital setting, along with receptor blockers [ARBs]), or patients with low systolic blood pressure.
immediate discontinuation of INVOKAMETXR. In INVOKAMETXR-treated Before initiating INVOKAMET XR in patients with one or more of these
patients with a diagnosis or strong suspicion of lactic acidosis, prompt characteristics who were not already on canagliozin, volume status
hemodialysis is recommended to correct the acidosis and remove should be assessed and corrected. Monitor for signs and symptoms after
accumulated metformin (metformin hydrochloride is dialyzable, with a initiating therapy.
clearance of up to 170 mL/minute under good hemodynamic conditions). Ketoacidosis: Reports of ketoacidosis, a serious life-threatening condition
Hemodialysis has often resulted in reversal of symptoms and recovery. requiring urgent hospitalization have been identified in postmarketing
Educate patients and their families about the symptoms of lactic acidosis surveillance in patients with type 1 and type 2 diabetes mellitus receiving
and if these symptoms occur instruct them to discontinue INVOKAMETXR sodium glucose co-transporter-2 (SGLT2) inhibitors, including canagliflozin.
and report these symptoms to their healthcare provider. Fatal cases of ketoacidosis have been reported in patients taking
For each of the known and possible risk factors for metformin-associated canagliflozin. INVOKAMET XR is not indicated for the treatment of
lactic acidosis, recommendations to reduce the risk of and manage patients with type 1 diabetes mellitus [see Indications and Usage].
metformin-associated lactic acidosis are provided below:
INVOKAMET XR (canagliozin and metformin hydrochloride extended-release) tablets INVOKAMET XR (canagliozin and metformin hydrochloride extended-release) tablets

Patients treated with INVOKAMET XR who present with signs and Reactions]. Therefore, a lower dose of insulin or insulin secretagogue
symptoms consistent with severe metabolic acidosis should be assessed may be required to minimize the risk of hypoglycemia when used in
for ketoacidosis regardless of presenting blood glucose levels, as combination with INVOKAMETXR.
ketoacidosis associated with INVOKAMET XR may be present even if Metformin: Hypoglycemia does not occur in patients receiving metformin
blood glucose levels are less than 250 mg/dL. If ketoacidosis is suspected, alone under usual circumstances of use, but could occur when caloric
INVOKAMETXR should be discontinued, patient should be evaluated, and intake is decient, when strenuous exercise is not compensated by
prompt treatment should be instituted. Treatment of ketoacidosis may caloric supplementation, or during concomitant use with other
require insulin, fluid and carbohydrate replacement. glucose-lowering agents (such as sulfonylureas and insulin) or ethanol.
In many of the postmarketing reports, and particularly in patients with Elderly, debilitated, or malnourished patients, and those with adrenal or
type 1 diabetes, the presence of ketoacidosis was not immediately pituitary insufciency or alcohol intoxication, are particularly susceptible
recognized and institution of treatment was delayed because presenting to hypoglycemic effects. Hypoglycemia may be difcult to recognize in the
blood glucose levels were below those typically expected for diabetic elderly, and in people who are taking beta-adrenergic blocking drugs.
ketoacidosis (often less than 250 mg/dL). Signs and symptoms at Monitor for a need to lower the dose of INVOKAMETXR to minimize the
presentation were consistent with dehydration and severe metabolic risk of hypoglycemia in these patients.
acidosis and included nausea, vomiting, abdominal pain, generalized Genital Mycotic Infections: Canagliozin increases the risk of genital
malaise, and shortness of breath. In some but not all cases, factors mycotic infections. Patients with a history of genital mycotic infections
predisposing to ketoacidosis such as insulin dose reduction, acute febrile and uncircumcised males were more likely to develop genital mycotic
illness, reduced caloric intake due to illness or surgery, pancreatic infections [see Adverse Reactions]. Monitor and treat appropriately.
disorders suggesting insulin deficiency (e.g., type 1 diabetes, history of Hypersensitivity Reactions: Hypersensitivity reactions, including angioedema
pancreatitis or pancreatic surgery), and alcohol abuse were identified. and anaphylaxis, have been reported with canagliozin. These reactions
Before initiating INVOKAMET XR consider factors in the patient history generally occurred within hours to days after initiating canagliozin. If
that may predispose to ketoacidosis including pancreatic insulin hypersensitivity reactions occur, discontinue use of INVOKAMET XR; treat
deficiency from any cause, caloric restriction, and alcohol abuse. In and monitor until signs and symptoms resolve [see Contraindications and
patients treated with INVOKAMETXR consider monitoring for ketoacidosis Adverse Reactions].
and temporarily discontinuing INVOKAMETXR in clinical situations known Bone Fracture: An increased risk of bone fracture, occurring as early as
to predispose to ketoacidosis (e.g., prolonged fasting due to acute illness 12 weeks after treatment initiation, was observed in patients using
or surgery). canagliflozin. Consider factors that contribute to fracture risk prior to
Acute Kidney Injury and Impairment in Renal Function: Canagliozin initiating INVOKAMETXR [see Adverse Reactions].
causes intravascular volume contraction [see Warnings and Precautions] Vitamin B12 Levels: In controlled, 29-week clinical trials of metformin, a
and can cause renal impairment [see Adverse Reactions]. There have decrease to subnormal levels of previously normal serum vitamin B12
been postmarketing reports of acute kidney injury, some requiring levels, without clinical manifestations, was observed in approximately
hospitalization and dialysis, in patients receiving canagliozin; some 7% of metformin-treated patients. Such decreases, possibly due to
reports involved patients younger than 65 years of age. interference with B12 absorption from the B12-intrinsic factor complex, is,
Before initiating INVOKAMET XR, consider factors that may predispose however, very rarely associated with anemia or neurologic
patients to acute kidney injury including hypovolemia, chronic renal manifestations due to the short duration (less than1year) of the clinical
insufciency, congestive heart failure, and concomitant medications trials. This risk may be more relevant to patients receiving long-term
(diuretics, ACE inhibitors, ARBs, NSAIDs). Consider temporarily treatment with metformin and adverse hematologic and neurologic
discontinuing INVOKAMETXR in any setting of reduced oral intake (such reactions have been reported postmarketing. The decrease in vitamin B12
as acute illness or fasting) or uid losses (such as gastrointestinal illness levels appears to be rapidly reversible with discontinuation of metformin
or excessive heat exposure); monitor patients for signs and symptoms of or vitamin B12 supplementation. Measure hematologic parameters on an
acute kidney injury. If acute kidney injury occurs, discontinue annual basis in patients on INVOKAMET XR and investigate and treat if
INVOKAMETXR promptly and institute treatment. abnormalities occur. Patients with inadequate vitamin B12 or calcium
intake or absorption may be predisposed to developing subnormal
Canagliozin increases serum creatinine and decreases eGFR. Patients
vitamin B12 levels, and routine serum vitamin B12 measurement at 2- to
with hypovolemia may be more susceptible to these changes. Renal
3-year intervals is recommended in these patients.
function abnormalities can occur after initiating INVOKAMET XR [see
Adverse Reactions]. Renal function should be evaluated prior to initiation Increases in Low-Density Lipoprotein (LDL-C): Dose-related increases in
of INVOKAMET XR and monitored periodically thereafter. Dosage LDL-C occur with canagliozin [see Adverse Reactions]. Monitor LDL-C
adjustment and more frequent renal function monitoring are and treat if appropriate after initiating INVOKAMETXR.
recommended in patients with an eGFR below 60 mL/min/1.73 m2. Macrovascular Outcomes: There have been no clinical studies
INVOKAMET XR is contraindicated in patients with an eGFR below establishing conclusive evidence of macrovascular risk reduction with
45 mL/min/1.73 m2 [see Dosage and Administration (2.2) in full Prescribing INVOKAMETXR or any other antidiabetic drug [see Adverse Reactions].
Information, Contraindications, Warnings and Precautions, and Use in ADVERSE REACTIONS
Specic Populations]. The following adverse reactions are also discussed elsewhere in the
Hyperkalemia: Canagliflozin can lead to hyperkalemia. Patients with labeling:
moderate renal impairment who are taking medications that interfere Lactic Acidosis [see Boxed Warning and Warnings and Precautions]
with potassium excretion, such as potassium-sparing diuretics, or Hypotension [see Warnings and Precautions]
medications that interfere with the renin-angiotensin-aldosterone
Ketoacidosis [see Warnings and Precautions]
system are at an increased risk of developing hyperkalemia [see Dosage
and Administration (2.2) in full Prescribing Information and Adverse Acute Kidney Injury and Impairment in Renal Function [see Warnings
Reactions]. and Precautions]
Hyperkalemia [see Warnings and Precautions]
Monitor serum potassium levels periodically after initiating
INVOKAMET XR in patients with impaired renal function and in patients Urosepsis and Pyelonephritis [see Warnings and Precautions]
predisposed to hyperkalemia due to medications or other medical Hypoglycemia with Concomitant Use of Sulfonylurea or Insulin [see
conditions. Warnings and Precautions]
Urosepsis and Pyelonephritis: There have been postmarketing reports of Genital Mycotic Infections [see Warnings and Precautions]
serious urinary tract infections including urosepsis and pyelonephritis Hypersensitivity Reactions [see Warnings and Precautions]
requiring hospitalization in patients receiving SGLT2 inhibitors, including Bone Fracture [see Warnings and Precautions]
canagliflozin. Treatment with SGLT2 inhibitors increases the risk for Vitamin B12 Deciency [see Warnings and Precautions]
urinary tract infections. Evaluate patients for signs and symptoms of Increases in Low-Density Lipoprotein (LDL-C) [see Warnings and
urinary tract infections and treat promptly, if indicated [see Adverse Precautions]
Reactions]. Clinical Studies Experience: Because clinical trials are conducted under
Hypoglycemia with Concomitant Use of Sulfonylurea or Insulin: widely varying conditions, adverse reaction rates observed in the clinical
Canagliflozin: Insulin and insulin secretagogues are known to cause trials of a drug cannot be directly compared to the rates in the
hypoglycemia. Canagliozin can increase the risk of hypoglycemia when clinical trials of another drug and may not reect the rates observed
combined with insulin or an insulin secretagogue [see Adverse 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 INVOKAMET XR (canagliozin and metformin hydrochloride extended-release) tablets

Table4: Incidence of Hypoglycemia* in Controlled Clinical Studies observed. Mean changes (percent changes) from baseline in LDL-C
(continued) relative to placebo were 4.4 mg/dL (4.5%) and 8.2 mg/dL (8.0%) with
In Combination Canagliozin Canagliozin canagliozin 100 mg and canagliozin 300 mg, respectively. The mean
with Insulin Placebo 100mg 300mg baseline LDL-C levels were 104 to 110mg/dL across treatment groups [see
(18weeks) (N=565) (N=566) (N=587) Warnings and Precautions].
Dose-related increases in non-HDL-C with canagliozin were observed.
Overall [N (%)] 208 (36.8) 279 (49.3) 285 (48.6) Mean changes (percent changes) from baseline in non-HDL-C relative to
Severe [N (%)] 14 (2.5) 10 (1.8) 16 (2.7) placebo were 2.1 mg/dL (1.5%) and 5.1 mg/dL (3.6%) with canagliozin
In Combination 100 mg and 300 mg, respectively. The mean baseline non-HDL-C levels
with Insulin Canagliozin Canagliozin were 140to 147mg/dL across treatment groups.
and Metformin Placebo 100mg 300mg Increases in Hemoglobin: In the pool of four placebo-controlled trials,
(18weeks) (N=145) (N=139) (N=148) 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,
Overall [N (%)] 66 (45.5) 58 (41.7) 70 (47.3) and 0.51 g/dL (3.8%) with canagliozin 300 mg. The mean baseline
Severe [N (%)] 4 (2.8) 1 (0.7) 3 (2.0) hemoglobin value was approximately 14.1g/dL across treatment groups.
* Number of patients experiencing at least one event of hypoglycemia At the end of treatment, 0.8%, 4.0%, and 2.7% of patients treated with
based on either biochemically documented episodes or severe placebo, canagliozin 100mg, and canagliozin 300mg, respectively, had
hypoglycemic events in the intent-to-treat population hemoglobin levels above the upper limit of normal.
Severe episodes of hypoglycemia were dened as those where the Decreases in Bone Mineral Density: Bone mineral density (BMD) was
patient required the assistance of another person to recover, lost measured by dual-energy X-ray absorptiometry in a clinical trial of 714
consciousness, or experienced a seizure (regardless of whether older adults (mean age 64 years). At 2 years, patients randomized to
biochemical documentation of a low glucose value was obtained) canagliozin 100 mg and canagliozin 300 mg had placebo-corrected
Phase 2 clinical study with twice daily dosing (50mg or 150mg twice daily declines in BMD at the total hip of 0.9% and 1.2%, respectively, and at the
in combination with metformin) lumbar spine of 0.3% and 0.7%, respectively. Additionally, placebo-
Subgroup of patients (N=287) from insulin substudy on canagliozin in adjusted BMD declines were 0.1% at the femoral neck for both
combination with metformin and insulin (with or without other antiglycemic canagliozin doses and 0.4% at the distal forearm for patients randomized
agents) to canagliozin 300 mg. The placebo-adjusted change at the distal forearm
for patients randomized to canagliozin 100mg was 0%.
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 Postmarketing Experience: The following adverse reactions have been
85 weeks. The incidence rates of adjudicated bone fractures were 1.1, 1.4, identified during postapproval use of canagliflozin. Because these
and 1.5 per 100patient-years of exposure in the comparator, canagliozin reactions are reported voluntarily from a population of uncertain size, it is
100 mg, and canagliozin 300 mg groups, respectively. Fractures were not always possible to reliably estimate their frequency or establish a
observed as early as 12 weeks after treatment initiation and were more causal relationship to drug exposure.
likely to be low trauma (e.g., fall from no more than standing height), and Ketoacidosis [see Warnings and Precautions]
affect the upper extremities [see Warnings and Precautions]. Acute Kidney Injury and Impairment in Renal Function [see Warnings and
Metformin: The most common adverse reactions (5% or greater incidence) Precautions]
due to initiation of metformin are diarrhea, nausea, vomiting, atulence, Anaphylaxis, Angioedema [see Warnings and Precautions]
asthenia, indigestion, abdominal discomfort, and headache.
Urosepsis and Pyelonephritis [see Warnings and Precautions]
Long-term treatment with metformin has been associated with a decrease
in vitamin B12, which may very rarely result in clinically signicant DRUG INTERACTIONS
vitamin B12 deciency (e.g., megaloblastic anemia) [see Warnings and Drug Interactions with Metformin: Carbonic Anhydrase Inhibitors:
Precautions]. Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide,
Laboratory and Imaging Tests: Increases in Serum Potassium: In a pooled acetazolamide or dichlorphenamide) frequently causes a decrease in
population of patients (N=723) with moderate renal impairment (eGFR 45 to serum bicarbonate and induce non-anion gap, hyperchloremic metabolic
less than 60 mL/min/1.73 m2), increases in serum potassium to greater than acidosis. Concomitant use of these drugs with INVOKAMET XR may
5.4 mEq/L and 15% above baseline occurred in 5.3%, 5.0%, and 8.8% of increase the risk for lactic acidosis. Consider more frequent monitoring of
patients treated with placebo, canagliflozin 100 mg, and canagliflozin these patients.
300 mg, respectively. Severe elevations (greater than or equal to Drugs That Reduce Metformin Clearance: Drugs that are eliminated by
6.5 mEq/L) occurred in 0.4% of patients treated with placebo, no patients renal tubular secretion (e.g. cationic drugs such as cimetidine) have the
treated with canagliflozin 100 mg, and 1.3% of patients treated with potential for interaction with metformin by competing for common renal
canagliflozin 300 mg. tubular transport systems, and may increase the accumulation of
In these patients, increases in potassium were more commonly seen in metformin and the risk for lactic acidosis [see Clinical Pharmacology (12.3)
those with elevated potassium at baseline. Among patients with moderate in full Prescribing Information]. Consider more frequent monitoring of
renal impairment, approximately 84% were taking medications that these patients.
interfere with potassium excretion, such as potassium-sparing diuretics, Alcohol: Alcohol is known to potentiate the effect of metformin on lactate
angiotensin-converting-enzyme inhibitors, and angiotensin-receptor metabolism. Warn patients against excessive alcohol intake while
blockers [see Warnings and Precautions and Use in Specific Populations]. receiving INVOKAMETXR.
Increases in Serum Magnesium: Dose-related increases in serum Drugs Affecting Glycemic Control: Certain drugs tend to produce
magnesium were observed early after initiation of canagliozin (within hyperglycemia and may lead to loss of glycemic control. These drugs
6 weeks) and remained elevated throughout treatment. In the pool of four include the thiazides and other diuretics, corticosteroids, phenothiazines,
placebo-controlled trials, the mean percent change in serum magnesium thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid,
levels was 8.1% and 9.3% with canagliozin 100 mg and canagliozin sympathomimetics, calcium channel blockers, and isoniazid. When such
300 mg, respectively, compared to -0.6% with placebo. In a trial of drugs are administered to a patient receiving INVOKAMETXR, monitor for
patients with moderate renal impairment, serum magnesium levels loss of blood glucose control. When such drugs are withdrawn from a
increased by 0.2%, 9.2%, and 14.8% with placebo, canagliozin 100 mg, patient receiving INVOKAMETXR, monitor for hypoglycemia.
and canagliozin 300mg, respectively. Drug Interactions with Canagliozin: UGT Enzyme Inducers: Rifampin:
Increases in Serum Phosphate: Dose-related increases in serum Rifampin lowered canagliozin exposure which may reduce the efcacy
phosphate levels were observed with canagliozin. In the pool of four of INVOKAMET XR. If an inducer of UGTs (e.g., rifampin, phenytoin,
placebo-controlled trials, the mean percent change in serum phosphate phenobarbital, ritonavir) must be co-administered with INVOKAMET XR,
levels were 3.6% and 5.1% with canagliozin 100 mg and canagliozin consider increasing the dose of canagliozin to a total daily dose of
300mg, respectively, compared to 1.5%with placebo. In a trial of patients 300 mg once daily if patients are currently tolerating INVOKAMET XR
with moderate renal impairment, the mean serum phosphate levels with 100 mg canagliozin once daily, have an eGFR greater than
increased by 1.2%, 5.0%, and 9.3% with placebo, canagliozin 100mg, and 60 mL/min/1.73 m2, and require additional glycemic control. Consider
canagliozin 300mg, respectively. other antihyperglycemic therapy in patients with an eGFR of 45 to less
Increases in Low-Density Lipoprotein Cholesterol (LDL-C) and non-High- than 60 mL/min/1.73 m2 receiving concurrent therapy with a UGT inducer
Density Lipoprotein Cholesterol (non-HDL-C): In the pool of four placebo- and require additional glycemic control [see Dosage and Administration
controlled trials, dose-related increases in LDL-C with canagliozin were (2.3) and Clinical Pharmacology (12.3) in full Prescribing Information].
INVOKAMET XR (canagliozin and metformin hydrochloride extended-release) tablets INVOKAMET XR (canagliozin and metformin hydrochloride extended-release) tablets

Digoxin: Canagliozin increased digoxin exposure. Digoxin, as a cationic Canagliflozin and Metformin: No adverse developmental effects were
drug, also has the potential to compete with metformin for common observed when canagliflozin and metformin were co-administered to
renal tubular transport systems [see Drug Interactions]. Monitor patients pregnant rats during the period of organogenesis at exposures up to 11
taking INVOKAMETXR with concomitant digoxin for a need to adjust dose and 13 times, respectively, the 300 mg and 2000 mg clinical doses of
of either drug. canagliflozin and metformin based on AUC.
Drug/Laboratory Test Interference: Positive Urine Glucose Test: Lactation: Risk Summary: There is no information regarding the presence
Monitoring glycemic control with urine glucose tests is not recommended of INVOKAMET XR or canagliflozin in human milk, the effects on the
in patients taking SGLT2 inhibitors as SGLT2 inhibitors increase urinary breastfed infant, or the effects on milk production. Limited published
glucose excretion and will lead to positive urine glucose tests. Use studies report that metformin is present in human milk [see Data].
alternative methods to monitor glycemic control. However, there is insufficient information on the effects of metformin on
Interference with 1,5-anhydroglucitol (1,5-AG) Assay: Monitoring glycemic the breastfed infant and no available information on the effects of
control with 1,5-AG assay is not recommended as measurements of metformin on milk production. Canagliflozin is present in the milk of
1,5-AG are unreliable in assessing glycemic control in patients taking lactating rats [see Data]. Since human kidney maturation occurs in utero
SGLT2 inhibitors. Use alternative methods to monitor glycemic control. and during the first 2 years of life when lactational exposure may occur,
there may be risk to the developing human kidney.
USE IN SPECIFIC POPULATIONS
Because of the potential for serious adverse reactions in a breastfed infant,
Pregnancy: Risk Summary: Based on animal data showing adverse renal
advise women that use of INVOKAMET XR is not recommended while
effects, INVOKAMETXR is not recommended during the second and third
breastfeeding.
trimesters of pregnancy.
Data: Human Data: Published clinical lactation studies report that
Limited data with INVOKAMETXR or canagliflozin in pregnant women are
metformin is present in human milk which resulted in infant doses
not sufficient to determine a drug-associated risk for major birth defects
approximately 0.11% to 1% of the maternal weight-adjusted dosage and a
or miscarriage. Published studies with metformin use during pregnancy
milk/plasma ratio ranging between 0.13 and 1. However, the studies were
have not reported a clear association with metformin and major birth
not designed to definitely establish the risk of use of metformin during
defect or miscarriage risk [see Data]. There are risks to the mother and
lactation because of small sample size and limited adverse event data
fetus associated with poorly controlled diabetes in pregnancy [see Clinical
collected in infants.
Considerations].
Animal Data: Radiolabeled canagliflozin administered to lactating rats on day
In animal studies, adverse renal pelvic and tubule dilatations that were not
13 post-partum was present at a milk/plasma ratio of 1.40, indicating that
reversible were observed in rats when canagliflozin was administered at
canagliflozin and its metabolites are transferred into milk at a concentration
an exposure 0.5-times the 300 mg clinical dose, based on AUC during a
comparable to that in plasma. Juvenile rats directly exposed to canagliflozin
period of renal development corresponding to the late second and third
showed a risk to the developing kidney (renal pelvic and tubular dilatations)
trimesters of human pregnancy. No adverse developmental effects were
during maturation.
observed when metformin was administered to pregnant Sprague Dawley
rats and rabbits during the period of organogenesis at doses up to 2- and Females and Males of Reproductive Potential: Discuss the potential for
6-times, respectively, a 2000mg clinical dose, based on body surface area unintended pregnancy with premenopausal women as therapy with
[see Data]. metformin may result in ovulation in some anovulatory women.
The estimated background risk of major birth defects is 6-10% in women Pediatric Use: Safety and effectiveness of INVOKAMET XR in pediatric
with pre-gestational diabetes with an HbA1c >7 and has been reported to patients under 18years of age have not been established.
be as high as 20-25% in women with a HbA1c >10. The estimated Geriatric Use: INVOKAMETXR: Because renal function abnormalities can
background risk of miscarriage for the indicated population is unknown. In occur after initiating canagliozin, metformin is substantially excreted by
the U.S. general population, the estimated background risk of major birth the kidney, and aging can be associated with reduced renal function,
defects and miscarriage in clinically recognized pregnancies is 2-4% and monitor renal function more frequently after initiating INVOKAMETXR in
15-20%, respectively. the elderly and then adjust dose based on renal function [see Dosage
Clinical Considerations: Disease-associated maternal and/or embryo/fetal and Administration(2.2) in full Prescribing Information and Warnings and
risk: Poorly controlled diabetes in pregnancy increases the maternal risk Precautions].
for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm Canagliflozin: Two thousand thirty-four (2034)patients 65years and older,
delivery, stillbirth and delivery complications. Poorly controlled diabetes and 345patients 75years and older were exposed to canagliozin in nine
increases the fetal risk for major birth defects, stillbirth, and macrosomia clinical studies of canagliozin. Of these patients, 1334 patients 65 years
related morbidity. and older and 181 patients 75 years and older were exposed to the
Data: Human Data: Published data from post-marketing studies have not combination of canagliozin and metformin [see Clinical Studies(14) in full
reported a clear association with metformin and major birth defects, Prescribing Information]. Patients 65 years and older had a higher
miscarriage, or adverse maternal or fetal outcomes when metformin was incidence of adverse reactions related to reduced intravascular volume
used during pregnancy. However, these studies cannot definitely establish with canagliozin (such as hypotension, postural dizziness, orthostatic
the absence of any metformin-associated risk because of methodological hypotension, syncope, and dehydration), particularly with the 300mg daily
limitations, including small sample size and inconsistent comparator dose, compared to younger patients; a more prominent increase in the
groups. incidence was seen in patients who were 75years and older [see Dosage
Animal Data: Canagliflozin: Canagliflozin dosed directly to juvenile rats and Administration (2.1) in full Prescribing Information and Adverse
from postnatal day (PND) 21 until PND 90 at doses of 4, 20, 65, or Reactions]. Smaller reductions in HbA1C with canagliozin relative to
100 mg/kg increased kidney weights and dose dependently increased the placebo were seen in older (65years and older; -0.61% with canagliozin
incidence and severity of renal pelvic and tubular dilatation at all doses 100 mg and -0.74% with canagliozin 300 mg relative to placebo)
tested. Exposure at the lowest dose was greater than or equal to 0.5-times compared to younger patients (-0.72% with canagliozin 100 mg and
the 300 mg clinical dose, based on AUC. These outcomes occurred with -0.87%with canagliozin 300mg relative to placebo).
drug exposure during periods of renal development in rats that Metformin: Controlled clinical studies of metformin did not include
correspond to the late second and third trimester of human renal sufcient numbers of elderly patients to determine whether they respond
development. The renal pelvic dilatations observed in juvenile animals did differently from younger patients, although other reported clinical
not fully reverse within a 1 month recovery period. experience has not identied differences in responses between the
In embryo-fetal development studies in rats and rabbits, canagliflozin was elderly and younger patients. The initial and maintenance dosing of
administered for intervals coinciding with the first trimester period of metformin should be conservative in patients with advanced age due to
organogenesis in humans. No developmental toxicities independent of the potential for decreased renal function in this population. Any dose
maternal toxicity were observed when canagliflozin was administered at adjustment should be based on a careful assessment of renal function
doses up to 100 mg/kg in pregnant rats and 160 mg/kg in pregnant rabbits [see Contraindications, Warnings and Precautions, and Clinical
during embryonic organogenesis or during a study in which maternal rats Pharmacology(12.3) in full Prescribing Information].
were dosed from gestation day (GD) 6 through PND 21, yielding exposures Renal Impairment: Canagliflozin: The efficacy and safety of canagliflozin
up to approximately 19-times the 300 mg clinical dose, based on AUC. were evaluated in a study that included patients with moderate renal
Metformin Hydrochloride: Metformin hydrochloride did not cause adverse impairment (eGFR 30 to less than 50mL/min/1.73m2). These patients had
developmental effects when administered to pregnant Sprague Dawley rats less overall glycemic efficacy and had a higher occurrence of adverse
and rabbits up to 600 mg/kg/day during the period of organogenesis. This reactions related to reduced intravascular volume, renal-related adverse
represents an exposure of about 2- and 6-times a 2000 mg clinical dose reactions, and decreases in eGFR compared to patients with mild renal
based on body surface area (mg/m2) for rats and rabbits, respectively. impairment or normal renal function (eGFR greater than or equal to
INVOKAMET XR (canagliozin and metformin hydrochloride extended-release) tablets INVOKAMET XR (canagliozin and metformin hydrochloride extended-release) tablets

60 mL/min/1.73 m2). Dose-related, transient mean increases in serum Ketoacidosis: Inform patients that ketoacidosis is a serious life-
potassium were observed early after initiation of canagliflozin (i.e., within threatening condition. Cases of ketoacidosis have been reported during
3 weeks) in this trial. Increases in serum potassium of greater than use of canagliozin. Instruct patients to check ketones (when possible)
5.4 mEq/L and 15% above baseline occurred in 16.1%, 12.4%, and 27.0% of if symptoms consistent with ketoacidosis occur even if blood glucose is
patients treated with placebo, canagliflozin 100 mg, and canagliflozin not elevated. If symptoms of ketoacidosis (including nausea, vomiting,
300 mg, respectively. Severe elevations (greater than or equal to abdominal pain, tiredness, and labored breathing) occur, instruct
6.5 mEq/L) occurred in 1.1%, 2.2%, and 2.2% of patients treated with patients to discontinue INVOKAMET XR and seek medical advice
placebo, canagliflozin 100 mg, and canagliflozin 300 mg, respectively [see immediately [see Warnings and Precautions].
Dosage and Administration (2.2) in full Prescribing Information, Acute Kidney Injury: Inform patients that acute kidney injury has been
Contraindications, Warnings and Precautions, and Adverse Reactions]. reported during use of canagliozin. Advise patients to seek medical
The efcacy and safety of canagliozin have not been established in advice immediately if they have reduced oral intake (such as due to
patients with severe renal impairment (eGFR less than 30mL/min/1.73m2), acute illness or fasting), or increased uid losses (such as due to
with ESRD, or receiving dialysis. Canagliozin is not expected to be vomiting, diarrhea, or excessive heat exposure), as it may be
effective in these patient populations [see Contraindications and Clinical appropriate to temporarily discontinue INVOKAMET XR use in those
Pharmacology (12.3) in full Prescribing Information]. settings [see Warnings and Precautions].
Hepatic Impairment: Use of metformin in patients with hepatic Serious Urinary Tract Infections: Inform patients of the potential for
impairment has been associated with some cases of lactic acidosis. urinary tract infections, which may be serious. Provide them with
INVOKAMETXR is not recommended in patients with hepatic impairment. information on the symptoms of urinary tract infections. Advise them to
[see Warnings and Precautions] seek medical advice if such symptoms occur [see Warnings and
Precautions].
OVERDOSAGE Genital Mycotic Infections in Females: Inform female patients that
In the event of an overdose with INVOKAMET XR, contact the Poison vaginal yeast infection (e.g., vulvovaginitis) may occur and provide them
Control Center. Employ the usual supportive measures (e.g., remove with information on the signs and symptoms of a vaginal yeast infection.
unabsorbed material from the gastrointestinal tract, employ clinical Advise them of treatment options and when to seek medical advice [see
monitoring, and institute supportive treatment) as dictated by the patients Warnings and Precautions].
clinical status. Canagliozin was negligibly removed during a 4-hour Genital Mycotic Infections in Males: Inform male patients that yeast
hemodialysis session. Canagliozin is not expected to be dialyzable by infection of penis (e.g., balanitis or balanoposthitis) may occur,
peritoneal dialysis. Metformin is dialyzable with a clearance of up to especially in uncircumcised males and patients with prior history.
170mL/min under good hemodynamic conditions. Therefore, hemodialysis Provide them with information on the signs and symptoms of balanitis
may be useful partly for removal of accumulated metformin from patients and balanoposthitis (rash or redness of the glans or foreskin of the
in whom INVOKAMETXR overdosage is suspected. penis). Advise them of treatment options and when to seek medical
Canagliflozin: There were no reports of overdose during the clinical advice [see Warnings and Precautions].
development program of canagliozin. Hypersensitivity Reactions: Inform patients that serious hypersensitivity
Metformin: Overdose of metformin hydrochloride has occurred, including reactions, such as urticaria, rash, anaphylaxis, and angioedema, have
ingestion of amounts greater than 50 grams. Hypoglycemia was been reported with canagliozin. Advise patients to report immediately
reported in approximately 10% of cases, but no causal association with any signs or symptoms suggesting allergic reaction and to discontinue
metformin hydrochloride has been established. Lactic acidosis has been drug until they have consulted prescribing physicians [see Warnings
reported in approximately 32% of metformin overdose cases [see and Precautions].
Warnings and Precautions]. Bone Fracture: Inform patients that bone fractures have been reported
in patients taking canagliozin. Provide them with information on factors
PATIENT COUNSELING INFORMATION that may contribute to fracture risk.
Advise the patient to read the FDA-Approved Patient Labeling (Medication Laboratory Tests: Inform patients that they will test positive for glucose
Guide). in their urine while on INVOKAMETXR [see Drug Interactions].
Lactic Acidosis: Explain the risks of lactic acidosis, its symptoms, and Pregnancy: Advise pregnant women, and females of reproductive
conditions that predispose to its development, as noted in Warnings potential of the potential risk to a fetus with treatment with
and Precautions. Advise patients to discontinue INVOKAMET XR INVOKAMET XR [see use in Specic Populations]. Instruct females of
immediately and to promptly notify their healthcare provider if reproductive potential to report pregnancies to their physicians as soon
unexplained hyperventilation, myalgias, malaise, unusual somnolence or as possible.
other nonspecic symptoms occur. Once a patient is stabilized on Lactation: Advise women that breastfeeding is not recommended during
INVOKAMETXR, gastrointestinal symptoms, which are common during treatment with INVOKAMETXR [see Use in Specic Populations].
initiation of metformin, are unlikely to recur. Later occurrence of Inform females that treatment with INVOKAMET XR may result in
gastrointestinal symptoms could be due to lactic acidosis or other ovulation in some premenopausal anovulatory women which may lead to
serious disease. unintended pregnancy [see Use in Specic Populations].
Instruct patients to keep INVOKAMETXR in the original bottle to protect Inform patients that the most common adverse reactions associated
from moisture. Do not put INVOKAMETXR in pill boxes or pill organizers. with canagliozin are genital mycotic infection, urinary tract infection,
Counsel patients against excessive alcohol intake while receiving and increased urination. Most common adverse reactions associated
INVOKAMETXR. with metformin are diarrhea, nausea, vomiting, atulence, asthenia,
Inform patients about importance of regular testing of renal function and indigestion, abdominal discomfort, and headache.
hematological parameters while receiving INVOKAMETXR.
Advise patients to seek medical advice promptly during periods of stress Manufactured for:
such as fever, trauma, infection, or surgery, as medication requirements Janssen Pharmaceuticals, Inc.
may change. Titusville, NJ 08560
Instruct patients that INVOKAMET XR must be swallowed whole and
never crushed, cut, or chewed, and that the inactive ingredients may Finished product manufactured by:
occasionally be eliminated in the feces as a soft mass that may Janssen Ortho, LLC
resemble the original tablet. Gurabo, PR 00778
Instruct patients to take INVOKAMET XR only as prescribed once daily Licensed from Mitsubishi Tanabe Pharma Corporation
with the morning meal. If a dose is missed, advise patients to take it as 2016 Janssen Pharmaceuticals, Inc.
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 Revised: 09/2016
at the next regularly scheduled time. Advise patients not to take more
060253-160916
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.
 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