Pharmacy & Therapeutics (P&T) Journal-February 2016

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February 2016
Volume 41 Number 2
A Peer-Reviewed Journal for Managed Care

and Formular y Management Decision-Makers
New Directions in the

Treatment of Chronic Pain
VISIT US ONLINE AT WWW.PTCOMMUNITY.COM
National Pain Strategy Will Guide

Prevention, Management, and Research
S. L. Worley
Do SSRI Antidepressants Increase

The Risk of Extrapyramidal Side Effects
In Patients Taking Antipsychotics?
M. Allsbrook, PharmD, MS; B. E. Fries, PhD;
K. L. Szafara, PhD; and R. E. Regal, PharmD
FDA Intensies Drive to

Reduce REMS Burdens
The Key Objective Is to Ease
Workow Obstacles for Pharmacists
S. Barlas
MEETING HIGHLIGHTS
American Society of Hematology

2015 Annual Meeting
W. Alexander
DRUG FORECAST
Tiotropium Bromide/Olodaterol
(Stiolto Respimat)
Once-Daily Combination Therapy
For the Maintenance of COPD
J. F. Mosley II, PharmD, CPh, AAHIVP; L. L. Smith, PharmD,
CPh, MBA; and B. N. Dutton, PharmD Candidate
MEDICATION ERRORS
Small Effort, Big Payoff: Automated

Maximum Dose Alerts With Hard Stops
M. Grissinger, RPh, FASCP
PIPELINE PLUS
Companies Take Aim at MRSA Infections

C. Fellner
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to transform patient care.
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Learn more about our commitment to revolutionize the treatment
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ZS Pharma and the ZS Pharma logo are trademarks of ZS Pharma.
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
mission is to highlight research and data on drug utilization,
prescribing patterns, and adverse drug reactions in order to
facilitate the best possible outcomes for patients.
Subscribers include members of P&T committees across
the health care spectrum, including those in hospitals,
health systems, managed care organizations, and government agencies. This includes physicians, pharmacists, nurses, quality/risk management personnel, administrators,
and others.
Feature articles address forthcoming drugs, biologic
agents, and medical devices; guideline updates; drug utilization evaluations; medication safety; and disease management. Regular departments cover these topics as well as
drug legislation.
P&T has a circulation of approximately 59,000 readers.
EDITORIAL
Editor: J. Stephen McIver
(267) 685-3713
smciver@medimedia.com
Managing Editor: Lyn K. Chesna
(267) 685-3429
lchesna@medimedia.com
Editor, PTCommunity.com: Chris Fellner
(267) 685-3555
cfellner@medimedia.com
News Writer: Janet Dyer
ART
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
formulary management decision-makers (ISSN 1052-1372) (GST
#128741063) (IPM #0608025) and is published monthly by MMMM
Group LLC, with business ofces at 780 Township Line Road, Yardley,
PA 19067; telephone: (267) 685-3700; fax: (215) 699-6288.
Copyright: Copyright 2016 by MMMM Group LLC. All rights
reserved under the United States, International, and Pan-American
Copyright Conventions. No part of this publication may be reproduced, stored in a retrieval system, photocopied, or transmitted in
any form or by any means, mechanical, electronic, or otherwise,
without the prior written permission of MMMM Group LLC. The
copyright law of the United States governs the making of photocopies or other reproductions of copyrighted material.
Opinions: The articles in P&T are reviewed by appropriate
members of the editorial board and/or other qualied experts.
The opinions are those of the authors and are not those of the
publisher, editor, editorial board, or institutions that employ the
authors.
Clinical judgment must guide each clinician in weighing the benets of treatment against the risk of toxicity. Dosages, indications,
and methods of use for products referred to in this publication may
reect the professional literature and other clinical sources or the
clinical experience of the authors and might not be the same as indicated on the approved package insert. Please consult the complete
prescribing information for any products mentioned in this publication. MMMM Group LLC assumes no liability for the information
published herein.
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Design Director: Philip Denlinger

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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).
H^Z@^ 7ROadMah P&T
73
Cover: Coronal section of the brain,

showing areas that respond to painful
stimuli. The thalamus (center) interprets
sensory signals and relays them to the
cerebral cortex to distinguish painful
and nonpainful stimuli. The cingulate
cortex (top) coordinates sensory input
of pain with emotional responses. The
insular cortex (outermost) plays a part
in the bodys experience with pain or
emotional experiences of fear. The
hippocampus (bottom) can respond
to severe long-term traumatic stress.
See related article on page 107. (Credit:
Evan Oto / Science Source)
82
Automated dose alerts with

hard stops aid patient safety.
Prescription: Washington
83
340B guidance upsets both

hospitals and drug makers.
84
FDA approvals, drug

indications, and updates
97
Tiotropium bromide/olodaterol
(Stiolto Respimat): once-daily
combination therapy for the
maintenance of COPD
Call for Papers
FDA Intensies Drive to Reduce REMS Burdens
103
The Key Objective Is to Ease Workow Obstacles for Pharmacists

The FDA is working to solve problems with the often-confusing risk evaluation and
mitigation strategy program, which covers 74 pharmaceuticals and four drug classes.
Issues include patient access to drugs and the dominant role of specialty pharmacies.
Stephen Barlas
107
More than four years after the release of a landmark report by the Institute of Medicine
focused attention on pain in America, there are encouraging signs that the nation
may be poised to undergo the cultural transformation advocated by the report.
Susan L. Worley
Do SSRI Antidepressants Increase the Risk of Extrapyramidal

Side Effects in Patients Taking Antipsychotics?
115
In a retrospective cohort analysis of data collected at four Michigan state mental
health hospitals, the use of selective serotonin reuptake inhibitors did not appear to
potentiate the occurrence of extrapyramidal symptoms in patients on antipsychotics.
Matthew Allsbrook, PharmD, MS; Brant E. Fries, PhD; Kristina L. Szafara, PhD; and
Randolph E. Regal, PharmD
MEETING HIGHLIGHTS
95
Lesinurad (Zurampic) for

gout-related hyperuricemia;
selexipag (Uptravi) for
pulmonary arterial
hypertension; sugammadex
(Bridion) to reverse
neuromuscular blockade
after surgery; and alectinib
(Alecensa) for lung cancer
Drug Forecast
FEATURES
National Pain Strategy Will Guide Prevention, Management, and Research
Medication Errors
Pharmaceutical
Approval Update
February 2016
New Directions in the Treatment of Chronic Pain
DEPARTMENTS
New Drugs/Drug News/

New Medical Devices
CONTENTS
American Society of Hematology 2015 Annual Meeting
120
The annual meeting of the American Society of Hematology drew 25,000 attendees
for the presentation of 5,633 abstracts. We review key sessions focusing on newer
agents and their efficacy in high-risk leukemia and multiple myeloma populations.
Walter Alexander
PIPELINE PLUS
Companies Take Aim at MRSA Infections
126
Methicillin-resistant Staphylococcus aureus (MRSA) is one of the most widespread

and virulent nosocomial pathogens. The late-stage clinical pipeline includes an array
of proposed new treatments aimed at MRSA-related skin infections and pneumonia.
Chris Fellner
Attention Readers: P&T is now on Facebook, Twitter, and LinkedIn!
129
Back issues are available on

the PubMed Central archive.
Visit www.pubmedcentral.nih.gov
Search for P&T

[Pharmacy and Therapeutics]
@PTJournal780
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The digital edition does not contain some of the advertising pages that appear in the print edition.
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From innovative biotechnology to extensive experience in biologic
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Take a deeper look at our reliability and quality

visit biotechnologybyamgen.com
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MEDICATION ERRORS
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Matthew Grissinger, RPh, FASCP
Mr. Grissinger, an editorial

board member of P&T, is
Director of Error Reporting
Programs at the Institute for
Safe Medication Practices
in Horsham, Pennsylvania
(www.ismp.org).
Automated alerts can provide an effective means of communicating essential
information about a drug and patient to
clinicians who prescribe, dispense, and
administer medications. These alerts are
intended to support clinical decisions
about the safety and efcacy of the drug
therapy. Alerts are typically communicated through warning messages that pop
up on a screen. These alerts can cause
either a soft stop or a hard stop.
A soft stop provides information to the
clinician about a potential drug safety or
efcacy problem and may offer alternative suggestions for the clinician to consider. However, minimal or no action or
acknowledgment of the alert is required
on the part of the user to proceed. A hard
stop halts the progress of prescribing,
dispensing, or administering a medication that would likely be dangerous to a
patient. Further execution of the order
is blocked. A nearly hard stop may allow
continuation of the process if signicant
action is taken by the user, such as requiring a prescriber to call the pharmacy to
discuss the order.1
Studies have shown that soft stops
are often overlooked or quickly overridden without careful consideration
of the warning for a variety of reasons,
including alert fatigue and poor design
of the warning.14 Hard stops and nearly
hard stops have been shown to be much
more effective in capturing the users
attention and getting the user to change
the prescription, re-enter the drug, or
reprogram a device.1,57
As we describe errors with amphotericin B, methotrexate, and fentanyl, keep
in mind that a well-designed alert with
a hard stop could have prevented these
harmful errors.
2\_V^cRaWPW]3
In one reported event, amphotericin B
conventional was prescribed in a dose
reserved for the lipid-based product. A
patient with acute myeloblastic leukemia and a recent bone-marrow transplant
developed pulmonar y aspergilloma.
Using a computerized prescriber orderentry (CPOE) system, the patients physician entered an order for amphotericin
B conventional 375 mg intravenous (IV)
every 24 hours. Based on the patients
weight of 75 kg, the patient received
5 mg/kg of amphotericin B conventional while the maximum safe dose for
this product is 1.5 mg/kg per day. This
higher dose would have been appropriate for one of the lipid-based products,
but it was more than three times higher
than the maximum dose recommended
for conventional amphotericin B. Within
three hours of administration, the patient
suffered a cardiac arrest and died.
During prescriber order entry of the
drug, a warning had popped up on the
screen asking the prescriber to verify
that the dose did not exceed 1.5 mg/kg.
However, the CPOE system did not
require acknowledgment of the warning
or action by the prescriber. The alert
quickly disappeared after hitting the
Enter key and was bypassed without consideration. The pharmacist also missed
an opportunity to capture the dosing
error. Although the screen accessed by
the pharmacist when verifying the order
revealed that amphotericin B conventional equivalent to Fungizone had been
prescribed, the pharmacist misunderstood the order as the lipid-based product
and even obtained a required approval
from an infectious disease prescriber
to dispense AmBisome. However, the
pharmacy label that printed resulted in
preparation of the conventional amphotericin B. The nurse who administered
the drug did not notice the error, as she
was not aware of the dosing differences
between the conventional and lipid-based
forms of the drug.
Numerous risk-reduction strategies
might have helped to prevent or detect
this error, such as including brand names

when prescribing the lipid-based forms
of the drug. However, a computer alert
with a hard stop for doses of conventional
amphotericin B greater than 1.5 mg/kg
for both the CPOE and pharmacy system
is a key strategy, the importance of which
should not be minimized. While the Institute for Safe Medication Practices (ISMP)
recommends entry of patient weights in
all order-entry systems, if this does not
occur consistently at your practice site,
you may want to establish a catastrophic
dose limit for a hard-stop alert. Such an
alert would not be designed to ensure
an appropriate dose, but rather to force
a time-out and protect against a massive
overdose.
?RcV^caRgMcR
In 2004, we published a study of methotrexate errors over a four-year period
that resulted in 25 deaths and 48 serious
outcomes, many due to daily dosing.8
The latest reported event happened at a
compounding pharmacy, but the same
type of error has occurred in hospitals.
In this case, the compounding pharmacy
received a telephone order to prepare an
oral liquid preparation of methotrexate
12 mg/mL, with instructions to administer 6 mg (0.5 mL) once a week for a
19-month-old child with juvenile dermatomyositis. A pharmacist transcribed
the order incorrectly and entered it into
the pharmacy computer with a dosing
frequency of daily. The pharmacy compounded the solution using methotrexate
powder, and labeled the medication with
instructions to take 0.5 mL daily instead
of weekly. The pharmacist handling the
order was unfamiliar with methotrexate
dosing and did not recognize that a daily
dose would be toxic. Also, the pharmacy
had never lled a prescription for oral
liquid methotrexate before the event. The
child received a daily dose for seven days
before the error was noticed by the prescriber. The child was undergoing diagnostic laboratory tests to determine the
adverse effects of this overdose when the
event was reported to ISMP.
continued on page 128
82
P&T
7ROadMah H^Z@^
PRESCRIPTION: WASHINGTON
38dWQM]PRDWZRb:^b_WcMZb5adU?MYRab
FVRhBdbVW]A__^bWcRIMhb^]6ZWUWOWZWch5WbP^d]cbM]Q?âR
Stephen Barlas
Mr. Barlas is a freelance

writer in Washington,
D.C., who covers issues
inside the Beltway. Send
ideas for topics and your
comments to sbarlas@
verizon.net.
he Health Resources and Services

Administration (HRSA) may have
gotten it more right than wrong with
its new proposed guidance on the 340B
outpatient drug program.1 Hospitals and
drug manufacturers, the programs two
key constituencieslong at loggerheads
are both complaining to high heaven about
proposed changes. The program requires
drug companies to sell medicines at deep
discounts to hospitals (generally those
located in rural or poor areas with signicant indigent populations) that use those
discounts to fund medical services they
couldnt otherwise afford.
The guidance, which may be revised
based on public comments, greatly reduces
the number of patients who would qualify
to purchase 340B drugs. That has enraged
hospitals and buoyed pharmaceutical
companies. But the guidance proposed
in August does very little to crack down
on how hospitals use contract pharmacies,
to prevent duplicate discounts where drug
companies can be billed once for the 340B
discount and again for a Medicaid discount,
and to prevent private hospitals with no
local or state government contracts from
participating in the program. The HRSAs
failure to propose such restrictions is just
ne with hospitals, but drug companies
are beside themselves because of those
and other omissions.
The 340B program is controversial,
and some of its requirements are sketchy.
The HRSA, part of the Department of
Health and Human Services (HHS), has
been prohibited by federal courts from
issuing legally binding regulations in all
but a few areashence the guidance the
HRSA published in an attempt to clear up
confusion about program rules. It would
change the standard for patient eligibility, make it more difcult for patients
receiving infusion to qualify for drugs,
require hospitals to implement new billing
and tracking systems, and make other
changes. However, guidance, as opposed
to regulation, is not legally enforceable.
Upward of 2,000 covered entities
general, rural, and childrens hospitals
and AIDS and rural clinicsbuy drugs
from nearly 650 manufacturers. The drugs
are sold at discounts of around 25% to
qualied patients who receive the drugs
at outpatient pharmacies, either on the
grounds of the hospital or at satellite
locations, including nonafliated contract
pharmacies. Covered entities make money
because insured patients buy the drugs at
discounted prices and the covered entity
bills their insurance company for the full
price of the drug, pocketing the difference between that price and the lower,
discounted 340B price. Over the years, the
program rules have been abused both by
covered entities and drug manufacturers,
each side says, and the HHS inspector
general has conrmed their suspicions
hence the need for clarication.
The key change riling hospitals concerns the way the HRSA would limit the
number of patients eligible to purchase
340B drugs. The HRSA wants to substitute
a six-pronged test for the current threepronged test. The new standard would
restrict the number of physicians who
could write 340B-eligible prescriptions.
Even if they were somehow afliated with
a hospital, physicians who did their own
billing could not write a 340B-eligible
script. Physicians would have to be
employed by the hospital; having privileges would not meet the test. The
guidance would limit the covered-entity
facilities where individuals could be seen
and still t the denition of patient. For
example, outpatient facilities would have
to be listed on a reimbursable line in the
hospitals most recently led Medicare
cost report and the services provided
would have to have associated outpatient
Medicare costs and charges. An inpatient
who receives a prescription while in the

hospital, from an eligible provider, could
not go to his or her local pharmacy and
qualify for a 340B prescription.
The guidance would require every
prescription to pass at least 10 requirements to qualify for 340B discounts,
says Bruce Siegel, MD, President and
CEO of Americas Essential Hospitals,
which represents 340B hospitals. The
test must be applied to each prescription
written and depends on where an individual patient sought care for a particular
medical condition, which clinician wrote
the prescription, and what type of insurance, if any, the patient has. This would
be disastrous for patients and providers.
The Pharmaceutical Research and Manufacturers of America (PhRMA) wants
the HRSA to narrow the requirements
for hospitals to qualify as covered entities. Over the past few years, U.S. Senator
Charles Grassley (R-Iowa) has questioned
whether academic medical centers are
using 340B revenue for purposes intended
by Congress, and whether they ought to
qualify given their upscale patient mix.
So PhRMA wants the HRSA to require
private, nonprot hospitals that have a
contract with a state or local government
to provide at least a specied amount of
care to low-income people ineligible for
Medicare and Medicaid with the specied minimum threshold selected so as to
ensure that a minor contract to care for this
population cannot confer 340B eligibility.
The HRSA guidance appears to try to
split the difference between the demands
of two opposing interest groups. But
given its failure to do that successfully,
and the fact that guidance is only guidance, Congress is likely to step in. If so,
it is not clear which side of the scale Congress will put its thumb on.
D676D6@46
1.
Health Resources and Services Administration. 340B drug pricing program omnibus
guidance. Fed Regist 2015;80(167):52300
52324. Available at: www.gpo.gov/fdsys/
pkg/FR-2015-08-28/pdf/2015-21246.pdf.
Accessed December 28, 2015. Q
H^Z@^ 7ROadMah P&T
83
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2bb^PWMcRQIWcV8^dc
The FDA has approved lesinurad
(Zurampic, AstraZeneca) to treat high
levels of uric acid in the blood (hyperuricemia) associated with gout.
Lesinurad is to be used in combination
with a xanthine oxidase inhibitor (XOI), a
type of drug approved to reduce the production of uric acid in the body. Lesinurad helps the kidney excrete uric acid by
inhibiting the function of transporter proteins involved in uric acid reabsorption.
The safety and efcacy of lesinurad (in
combination with an XOI) were evaluated
in three randomized, placebo-controlled
studies involving 1,537 subjects who were
treated for up to 12 months. The subjects
treated with lesinurad and an XOI showed
reduced serum uric acid levels compared
with subjects given placebo.
Source: FDA, December 22, 2015
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The FDA has cleared uridine triacetate (Vistogard, Wellstat Therapeutics)
for the emergency treatment of adults
and children who receive an overdose
of the cancer treatment uorouracil or
capecitabine, or who develop certain
severe or life-threatening toxicities
within four days of receiving these cancer treatments.
The efcacy and safety of uridine triacetate were studied in 135 adult and pediatric
cancer patients who were treated in two
separate trials and had received an overdose of uorouracil or capecitabine, or
who had early-onset, unusually severe or
life-threatening toxicities within 96 hours
after receiving uorouracil (not due to
an overdose). Of those who were treated
with uridine for overdose, 97% were still
alive at 30 days. Of those treated with uridine for early-onset severe or life-threatening toxicity, 89% were alive at 30 days.
84
P&T
7ROadMah H^Z@^
In both studies, 33% of patients resumed

chemotherapy in fewer than 30 days.
G_caMeW Sâ B2:

Selexipag (Uptravi, Actelion Pharmaceuticals US) has been cleared for use in
adults with pulmonary arterial hypertension (PAH), a chronic, progressive lung
disease that can lead to death or the need
for transplantation.
Selexipag belongs to a class of drugs
called oral IP prostacyclin receptor agonists. The drug acts by relaxing muscles
in the walls of blood vessels to reduce the
elevated pressure in the vessels supplying
blood to the lungs.
The safety and efcacy of selexipag
were established in a long-term clinical
study of 1,156 participants with PAH.
Selexipag was shown to be effective in
reducing hospitalization for PAH and the
risks of disease progression compared
with placebo. The participants were
exposed to selexipag for a median period
of 1.4 years.
3MbMUZMa Sâ Fh_R 5WMORcRb

The FDA has approved Basaglar
(insulin glargine injection, Eli Lilly), a
long-acting human insulin analogue, to
improve glycemic control in adult and
pediatric patients with type-1 diabetes
mellitus and in adults with type-2 diabetes mellitus. Basaglar is the rst insulin
product approved through an abbreviated approval pathway under the Federal Food, Drug, and Cosmetic Act. It
received tentative approval from the FDA
in August 2014 and has now been granted
nal approval.
chloride ophthalmic solution USP, 0.1%:

USV North America, Inc.; Apotex, Inc.;
Novel Laboratories, Inc.; and Zach System, S.p.A. These are the rst generic
versions of Patanol Ophthalmic Solution
(Alcon), a relatively selective H1 receptor antagonist and inhibitor of histamine
release from the mast cell for topical
administration to the eyes. The medication is used to treat the signs and symptoms of allergic conjunctivitis.
Sources: FDA, December 7, 2015, and
Patanol prescribing information
2\WYMPW] EdZSMcR ;]XRPcW^]

The FDA has approved the application of Fresenius Kabi USA, LLC, to
market amikacin sulfate injection USP,
250 mg/mL, a generic version of Amikacin Sulfate Injection USP (Eurohealth
International SARL). Amikacin injection is a semisynthetic aminoglycoside
antibiotic that is active against a broad
spectrum of gram-negative organisms,
including Pseudomonas, and some grampositive organisms.
Sources: FDA, December 9, 2015,
and Amikacin injection prescribing
information
7Rb^cRa^QW]R 7d\MaMcR 6D
Alkem Laboratories Ltd. has secured
FDA approval to market fesoterodine
fumarate extended-release tablets, 4 mg
and 8 mg. This is the rst generic version of Toviaz Extended-Release Tablets (Pzer), a muscarinic antagonist
indicated for the treatment of overactive
bladder with symptoms of urge urinary
incontinence, urgency, and frequency.
Toviaz prescribing information
>ReRcWaMPRcM\
8R]RaWP 2__aêMZb
AZ^_McMQW]R :4Z A_VcVMZ\WP E^ZdcW^]
Four companies have received FDA
approval to market olopatadine hydro-
Generic 250-mg, 750-mg, and 1,000-mg

levetiracetam tablets can be marketed by
Secan Pharmaceuticals, Inc., the FDA has
ruled. The brand-name product, Keppra
(UCB Inc.), is indicated for adjunctive

therapy for certain types of epileptic seizures. Keppra had estimated U.S. sales
of $271 million in 2015, according to
GlobalData.
Keppra prescribing information
3dbdZSM] ;]XRPcW^]
The FDA has approved the marketing
of busulfan injection, 6 mg/mL (10 mL
single-dose vial) by Pharmaforce, Inc.
the rst generic formulation of Busulfex injection (Otsuka Pharmaceutical).
Busulfex is an alkylating drug indicated
for use in combination with cyclophosphamide as a conditioning regimen prior
to allogeneic hematopoietic progenitor
cell transplantation for chronic myelogenous leukemia.
Busulfex prescribing information
@R^bcWU\W]R ?RcVhZbdZSMcR ;]XRPcW^]

Neostigmine methylsulfate injection
USP can be marketed in 5 mg/10 mL and
10 mg/10 mL strengths by Eurohealth
International SARL. This marks the
rst generic version of Bloxiverz (Eclat
Pharmaceuticals LLC), a cholinesterase
inhibitor indicated for the reversal of the
effects of nondepolarizing neuromuscular
blocking agents after surgery.
Bloxiverz prescribing information
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IncobotulinumtoxinA (Xeomin, Merz
North America) now has FDA approval
for the treatment of upper limb spasticity (ULS) in adults. In clinical studies,
treatment with Xeomin in adults with ULS
resulted in statistically and clinically signicant improvements in muscle tone.
The FDA rst approved Xeomin in August
2010 for the treatment of adults with cervical dystonia and blepharospasm.
The approval of Xeomin for the treatment of adults with ULS was based on
results from a randomized, placebocontrolled trial that showed signicant
improvements in two coprimary outcome
endpoints: muscle tone (Ashworth Scale
score) and the Investigators Global
Impression of Change of the Primary
Target Clinical Pattern (PTCP) at week 4.
Both parameters showed statistical significance compared with placebo (P < 0.001
and P = 0.003, respectively).
Source: Merz, December 23, 2015
8MaQMbWZ GbR 6gcR]QRQ

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The FDA has approved an expanded
age indication for Gardasil 9 (human
papillomavirus [HPV] nine-valent vaccine, recombinant, Merck) to include
use in males 16 through 26 years of age
for the prevention of anal cancer caused
by HPV types 16, 18, 31, 33, 45, 52, and
58; precancerous or dysplastic lesions
caused by HPV types 6, 11, 16, 18, 31,
33, 45, 52, and 58; and genital warts
caused by HPV types 6 and 11. Gardasil
9 is already approved for use in boys 9
through 15 years of age for the prevention
of these diseases.
Gardasil 9 is also approved for use
in girls and young women 9 through
26 years of age for the prevention of cervical, vulvar, vaginal, and anal cancers
caused by HPV 16, 18, 31, 33, 45, 52, and
58; precancerous or dysplastic lesions
caused by HPV 6, 11, 16, 18, 31, 33, 45,
52, and 58; and genital warts caused by
HPV types 6 and 11.
Gardasil 9 is contraindicated in individuals with hypersensitivity, including
severe allergic reactions to yeast, or
after a previous dose of Gardasil 9 or
Gardasil (human papillomavirus quadrivalent [types 6, 11, 16, and 18] vaccine,
recombinant).
Source: Merck, December 15, 2015
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The FDA has approved docetaxel
injection, non-alcohol formula (Teikoku
Pharma USA/Eagle Pharmaceuticals)
for the treatment of breast cancer, non
small-cell lung cancer, prostate cancer,
gastric adenocarcinoma, and head and
neck cancer.
Docetaxel, a taxane product, was originally marketed by Sano-Aventis as Taxotere. Since its patent expiration in 2011,
several generic versions have become
available. Docetaxel injection is the rst
non-alcohol formulation approved in the
U.S. It is available in the following presentations: 20 mg/1 mL in single-dose
vials, and 80 mg/4 mL or 160 mg/8 mL
in multiple-dose vials.
7Wabc 6D 4VRfMOZR FMOZRc

The FDA has approved the first
extended-release (ER) chewable tablet,
developed by Tris Pharma. Prior ER tablets
and capsules typically carried the warning should not be chewed or crushed.
The ER chewable tablets are an extension of Tris Pharmas LiquiXR platform,
a particulate-based technology in which
hundreds of millions of tiny particles
(about 100 microns) deliver drug over
time. Controlled release is facilitated by
a exible particle coating.
The same particles can be used to formulate various oral ER dosage forms,
such as liquid suspensions, dispersible
tablets, and lm strips. In addition, the
chewable tablets can be scored like any
immediate-release tablets.
Source: Tris Pharma, December 16,
2015
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The FDA has granted priority review
to the new drug application (NDA) for
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85
an investigational once-daily, xed-dose

combination of the nucleotide analogue
polymerase inhibitor sofosbuvir (Sovaldi,
Gilead Sciences) and velpatasvir, an investigational pan-genotypic NS5A inhibitor,
for the treatment of chronic genotype 16
hepatitis C virus (HCV) infection.
Gilead Sciences led the NDA for
the combination in October 2015, and
the FDA set a target action date of June
28, 2016. The agency also assigned the
combination a breakthrough therapy
designation, which is granted to investigational medications that may offer
major advances in treatment over existing options.
Source: Gilead Sciences, January 4,
2016
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The FDA has awarded breakthrough
therapy status to setmelanotide (RM-493,
Rhythm), an investigational melanocortin-4 receptor (MC4R) agonist, for
the treatment of pro-opiomelanocortin
deciency obesity. Setmelanotide is in
phase 2 clinical trials for the treatment of
rare genetic disorders of obesity caused
by MC4 pathway deciencies. MC4 is a
key pathway in humans that regulates
energy expenditure, homeostasis, and
appetite.
Setmelanotide also received an orphan
drug designation for the treatment of
PraderWilli syndrome (PWS). A hallmark of PWS is severe hyperphagia, an
overriding physiological drive to eat, leading to severe obesity and other complications. Hyperphagia and obesity are the
greatest threats to PWS patients health,
and these patients are likely to die prematurely as a result of choking, stomach rupture, or complications caused by
morbid obesity. No approved treatment is
available for the obesity and hyperphagia
associated with PWS.
Source: Rhythm, January 7, 2016
86
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VTS-270 (Vtesse, Inc.), a modied
form of cyclodextrin, has received the
FDAs breakthrough therapy status for
the treatment of Niemann-Pick type
C1 disease. The agency had previously
granted an orphan drug designation to
VTS-270, which is being evaluated in a
pivotal phase 2b/3 clinical trial.
Niemann-Pick type C genes (NPC1 and
NPC2) code for proteins that are part of
the cholesterol metabolism pathway in
cells. VTS-270 targets cholesterol and
sphingolipid storage. Preliminary studies have demonstrated that VTS-270 can
help cholesterol bypass the NPC1/NPC2
pathway, promoting transport of the cholesterol that would normally accumulate
in the lysosomes of cells that have the
NPC1 or NPC2 mutation. This restores
the cells normal cholesterol metabolism
and regulation.
Source: Vtesse, Inc., January 6, 2016
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The FDA has granted a breakthrough
therapy designation to BI 1482694 (Boehringer Ingelheim), an investigational
third-generation epidermal growth factor
receptor (EGFR) mutant-specic tyrosine
kinase inhibitor (TKI). The designation
was based on results from a phase 1/2
clinical trial that evaluated the treatment
of patients with T790M mutation-positive
nonsmall-cell lung cancer whose tumors
no longer responded to currently available EGFR-directed therapies.
BI 1482694 was developed specically
to target tumors with T790M mutations,
the most common resistance mechanism
that develops in response to treatment
with EGFR TKIs. It is found in approximately 50% to 60% of patients who have
received EGFR TKI therapy.
Source: Boehringer Ingelheim, December 21, 2015
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The FDA has granted orphan drug
status to a Wilms tumor gene 1 (WT1)
cancer vaccine candidate (Sellas Life Sciences Group) for the treatment of patients
with acute myeloid leukemia (AML).
Median overall survival (OS) of approximately four years was achieved in a
phase 2 trial of the WT1 analog peptide
vaccine in adult patients with AML. Similarly, in a previous phase 1 AML study, the
WT1 vaccine resulted in median OS of
more than three years. When combined,
the results from the phase 1 and phase 2
studies demonstrated a two-year OS rate
of 79% in adult AML patients. Both trials
studied the WT1 vaccine in combination
with Montanide adjuvant plus granulocyte macrophage colony-stimulating factor in AML patients with a rst complete
response who completed any planned
post-remission therapy. A total of 31
patients were enrolled in the two studies,
which were conducted at the Memorial
Sloan Kettering Cancer Center.
Based on these ndings, Sellas plans
to initiate a pivotal phase 3 trial of its
WT1 vaccine candidate in AML patients
in early 2016.
Source: Sellas Life Sciences Group,
January 11, 2016
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The FDA has granted an orphan drug
designation to GPX-150 (Gem Pharmaceuticals), a noncardiotoxic analogue of
the anthracycline antibiotic doxorubicin,
which is being evaluated in an open-label,
phase 2 clinical trial in patients with softtissue sarcoma (STS). Final safety and
efcacy data expected to be available from
this study by the fourth quarter of 2016.
GPX-150 intercalates DNA and
impedes the activity of topoisomerase
II, inducing single- and double-stranded
breaks in DNA; inhibiting DNA replication and/or repair, transcription, and pro-
tein synthesis; and activating tumor cell

apoptosis. The drugs chemical structure
is 5-imino-13-deoxydoxoubicin.
STS includes a group of malignancies
that affect tissues such as fat, muscles,
nerves, and tendons. According to the
American Cancer Society, approximately
12,000 new cases of STS occur in the U.S.
annually, with about 5,000 deaths.
Source: Gem Pharmaceuticals, January 6, 2016
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The FDA has given orphan drug status
to Ionis-HTTRx (Ionis Pharmaceuticals)
for the treatment of patients with Huntingtons disease (HD). Ionis-HTTRx is
the rst therapy to enter clinical development that is designed to directly target the
cause of the disease by reducing the production of the huntingtin (HTT) protein.
HD is a rare genetic, progressive
neurological disease resulting in deterioration in mental abilities and physical
control. In this disease, the gene that
encodes for the HTT protein contains a
trinucleotide sequence that is repeated in
the gene more than 36 times. The resulting HTT protein is toxic and gradually
damages neurons in the brain.
Source: Ionis Pharmaceuticals, January 5, 2016
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The FDA has granted an orphan drug
designation to NRL-1 (intranasal diazepam, Neurelis, Inc.) for the treatment of
pediatric, adolescent, and adult epilepsy
patients who experience acute repetitive
seizures.
NRL-1 is a proprietary formulation
of diazepam, delivered via an alreadymarketed nasal sprayer, being developed
for the management of pediatric and adult
patients who require intermittent use of
diazepam to control bouts of acute repetitive seizure activity. NRL-1 demonstrated
high bioavailability and low variability
from dose to dose in clinical trials, and

the treatment was well tolerated.
It has been estimated that 30% to 40%
of epilepsy patients in the U.S. are uncontrolled on oral therapy and are at risk for
acute breakthrough seizures.
Source: Neurelis, Inc., December 21,
2015
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Dif ferences in dosing regimens
between the two oral formulations of the
antifungal agent posaconazole (Noxal,
Merck) have resulted in dosing errors,
according to the FDA. To help prevent
additional medication errors, the drug
labels have been revised to indicate that
the two oral formulations (an oral suspension and a delayed-release tablet) cannot
be directly substituted for each other but
require a change in dose. Direct milligram-for-milligram substitution of the two
formulations may result in drug levels
that are lower or higher than needed to
treat certain fungal infections effectively.
Since the approval of posaconazole
delayed-release tablets in November
2013, the FDA has received 11 reports
of the wrong oral formulations being prescribed and/or dispensed to patients. One
case resulted in death, and an additional
case resulted in hospitalization. According to the reports, these outcomes were
a result of health care professionals not
knowing that the two oral formulations
cannot be substituted for each other without adjusting the dose because of differences in how the medication is absorbed
and handled by the body.
Source: FDA, January 4, 2016
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The FDA has eliminated the risk evaluation and mitigation strategy (REMS)
for rosiglitazone-containing type-2 diabetes medications, which are approved as
Avandia, Avandamet, and Avandaryl (all

marketed by GlaxoSmithKline) as well as
generic products. The REMS is no longer
necessary to ensure that the benets of
rosiglitazone medications outweigh their
risks, according to the agency.
In 2013, the FDA required removal of
the prescribing and dispensing restrictions for rosiglitazone medications after
determining that data did not demonstrate an increased risk of heart attack
with rosiglitazone drugs compared with
the standard type-2 diabetes medications
metformin and sulfonylurea.
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Positive data have been reported from
subgroup analyses of a phase 3 pivotal
trial comparing cabozantinib (Cometriq,
Exelixis, Inc.) with everolimus (Anitor,
Novartis) in 658 patients with renal cell
carcinoma (RCC) who have experienced
disease progression after treatment with a
vascular endothelial growth factor (VEGF)
receptor tyrosine kinase inhibitor (TKI).
As assessed by an independent radiology committee, median progression-free
survival across all enrolled patients was
7.4 months for the cabozantinib arm compared with 3.9 months for the everolimus
arm, corresponding to a 48% reduction in
the rate of disease progression or death
for cabozantinib compared with everolimus (hazard ratio, 0.52; P < 0.001). The
objective response rate across all 658
patients was 17% for cabozantinib and
3% for everolimus. The median duration
of response for cabozantinib was not
reached compared with 7.4 months for
everolimus.
The observed benets were independent of the location and number of organ
metastases; the patients tumor burden;
the type, duration, and number of prior
VEGF receptor TKI therapies; and prior
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programmed death-1/programmed death

ligand-1 therapy.
Source: Exelixis, Inc., January 4, 2016
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A phase 3 study evaluating the
investigational compound ADS-5102
(amantadine hydrochloride, Adamas
Pharmaceuticals) for the treatment of
levodopa-induced dyskinesia (LID) associated with Parkinsons disease has met
its primary endpoint.
Results from this randomized, placebocontrolled study showed a statistically
signicant reduction (P = 0.0009) in
LID at 12 weeks in patients treated with
ADS-5102 extended-release capsules
compared with those given placebo, as
assessed by the Unied Dyskinesia Rating Scale. This represents a 23% reduction
in LID in the ADS-5102 group. The reduction in LID was maintained at 24 weeks
(P = 0.0008), a key secondary analysis.
ADS-5102 extended-release capsules
are intended for once-daily administration at bedtime.
Source: Adamas Pharmaceuticals,
December 23, 2015
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Results from the phase 2 MEASURE 1
and MEASURE 2 trials of secukinumab
(Cosentyx, Novartis), an interleukin-17A
antagonist, in patients with ankylosing
spondylitis (AS) have been published in the
New England Journal of Medicine. These
pivotal studies demonstrated signicant
clinical improvements with secukinumab
compared with placebo in reducing the
signs and symptoms of active AS.
In both studies, the primary endpoint
was the proportion of patients meeting the
Assessment of Spondyloarthritis International Society 20 (ASAS20) response
criteria at week 16 with secukinumab
150 mg. In the MEASURE 1 and MEAS-
88
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URE 2 trials, ASAS20 response rates with

secukinumab compared with placebo at
week 16 were 61% versus 29% (P < 0.001)
and 61% versus 28% (P < 0.001), respectively. Patients enrolled in these studies
were either inadequate responders to or
intolerant of medications targeting tumor
necrosis factor (TNF) or had not been previously treated with anti-TNF therapies.
Source: Novartis, December 23, 2015
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Positive results have been reported
from an ongoing phase 3 trial of binimetinib (Array BioPharma) in patients
with advanced NRAS-mutant melanoma.
The study met its primary endpoint of
improving progression-free sur vival
(PFS) compared with dacarbazine. The
median PFS in the binimetinib arm was
2.8 months, compared with 1.5 months in
the dacarbazine arm (P < 0.001).
MEK is a key protein kinase in the
RAS/RAF/MEK/ERK pathway. Research
has shown that this pathway regulates
several key cellular activities, including
proliferation, differentiation, migration,
survival, and angiogenesis. Inappropriate
activation of proteins in this pathway has
been shown to occur in many cancers,
including nonsmall-cell lung cancer,
melanoma, and colorectal, ovarian, and
thyroid cancers. Binimetinib is a smallmolecule MEK inhibitor that targets key
enzymes in this pathway.
Source: Array BioPharma, December
16, 2015
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A phase 3, double-blind, placebocontrolled trial of the drug candidate KIT302 (Kitov Pharmaceuticals) successfully
met its primary efcacy endpoint. Data
from the study showed that KIT-302 was
more effective at reducing hypertension
than the widely used hypertension treat-
ment amlodipine besylate. A new drug

application for marketing approval of KIT302 is expected to be led with the FDA
in the second half of 2016.
KIT-302 simultaneously treats the pain
caused by osteoarthritis (OA) and hypertension, which is a common adverse
effect of stand-alone drugs that treat
OA pain. KIT-302 consists of two FDAapproved drugs: celecoxib (Celebrex,
Pzer) for the pain caused by OA, and
amlodipine besylate for hypertension.
Source: Kitov Pharmaceuticals,
December 15, 2015
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Phase 3 clinical trials of STI-001, a biosimilar antibody for cetuximab (Erbitux),
and STI-002, a biosimilar antibody for
iniximab (Remicade), have been completed successfully. Both STI-001 and
STI-002 met their primary endpoints in
the conrmatory, randomized, controlled
studies. Both products are being developed by Sorrento Therapeutics and its
partner MabTech Ltd.
STI-001, a chimeric monoclonal antibody that binds to the epidermal growth
factor receptor (EGFR), was used for
treatment of EGFR-expressing metastatic
colorectal carcinoma patients in combination with irinotecan versus irinotecan
alone. The combination therapy showed
significant improvement compared
with chemotherapy alone in the overall
response rate (32.9% versus 12.8%, respectively) and progression-free survival (5.6
versus 3.2 months) as well as longer overall survival (14.1 versus 13.4 months).
STI-002, a chimeric monoclonal antibody produced in Chinese hamster ovary
cell lines, binds to soluble and transmembrane forms of tumor necrosis factor (TNF)-alpha and inhibits TNF-alpha
binding to receptors, thereby neutralizing
the biological activity of TNF-alpha. In a
phase 3 study involving 330 patients with
Patients With Metastatic Bladder Cancer

Have an Unmet Need
Bladder cancer research has seen few advancements over the past 30 years.
No new agents have been approved for metastatic bladder cancer since 1998.1-3
Metastatic Bladder Cancer4:

)Approximately 4% of new diagnoses represent metastatic disease (stage IV)
)5-year relative survival rate of patients with metastatic disease is 5.4%
)Mortality rates for metastatic disease have remained relatively constant
since 1975
Against the background of no new drug approvals for advanced bladder

cancer in decades, immunotherapy research is giving new hope to patients
and physicians.
Michael R. Harrison, MD, Duke Cancer Institute
Learn More About Immunotherapy Research

Visit http://www.researchcancerimmunotherapy.com
REFERENCES
1. Galsky MD, Domingo-Domenech J. Clin Adv Hematol Oncol. 2013;11:86-92. 2. Iyer G, Milowsky MI, Bajorin DF. Novel
strategies for treating relapsed/refractory urothelial carcinoma. Expert Rev Anticancer Ther. Dec. 10, 2010. Volume 10, Issue 12.
http://www.tandfonline.com/doi/abs/10.1586/era.10.182. 3. American Society of Clinical Oncology. Progress Against Bladder
Cancer. http://www.cancerprogress.net/sites/cancerprogress.net/les/category-downloads/progress_against_bladder_cancer_
timeline.pdf. 4. SEER Stat Fact Sheets: Bladder Cancer. National Cancer Institute website. http://seer.cancer.gov/statfacts/
html/urinb.html. Accessed November 12, 2015.
2015 Genentech, Inc., So. San Francisco, CA PDL/103015/0090 11/15
rheumatoid arthritis, STI-002 improved

pain symptoms, physical functioning,
quality of life, and inammatory markers
while inhibiting bone and joint damage.
Source: Sorrento Therapeutics, Inc.,
January 11, 2016
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CHS-0214 (Coherus BioSciences/
Baxalta Inc.), a proposed biosimilar of
etanercept (Enbrel, Amgen), met its
primary endpoint in a phase 3, doubleblind, randomized, controlled trial. This
ongoing, 52-week study is evaluating the
efcacy and safety of CHS-0214 compared
with etanercept in patients with moderateto-severe rheumatoid arthritis (RA) that
has been inadequately controlled with
methotrexate alone.
The studys primary efcacy endpoint
was the proportion of subjects achieving a 20% improvement according to the
American College of Rheumatology criteria (ACR20) at week 24. This endpoint
was within the prespecied margins for
demonstrating the equivalence of CHS0214 compared with etanercept. There
were no clinically meaningful differences
in the safety and immunogenicity proles
of the two products.
Source: Baxalta, January 11, 2016
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Researchers from Switzerlands
Geneva University Hospitals and Geneva
Faculty of Medicine performed a metaanalysis of the risks and advantages of
adjunctive therapy with corticosteroids
for patients with community-acquired
pneumonia (CAP). They reviewed 14
trials involving 2,077 patients who were
treated either with adjunctive corticotherapy or antimicrobial therapy.
Eight studies, with 1,624 patients,
reported length of stay. Researchers
90
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7ROadMah H^Z@^
found a mean of nine days for patients

treated with adjunctive corticotherapy
versus 10.6 days for those treated with
antimicrobial therapy alone. Four studies, with 1,163 patients, reported time to
clinical stability; the mean was 3.3 days
for patients on adjunctive corticotherapy,
compared with 4.3 days for antimicrobial
treatment alone.
Four studies, with 304 patients,
reported on severe complications (requiring vasopressors or mechanical ventilation); three times as many patients on
antimicrobial therapy had severe complications (37.4% versus 12.1%). In four other
studies, 3.6% of 138 patients on adjunctive corticosteroids needed vasopressors,
compared with 14.5% of 128 patients on
antimicrobial therapy. And in seven studies reporting on mechanical ventilation,
5.3% of 619 adjunctive corticosteroid
patients required ventilation, compared
with 12.1% of 580 on antimicrobials.
The researchers found no benefit
in 30-day mortality, but mortality was
signicantly reduced in a subgroup of
patients with severe CAP. Adverse events
seem to be infrequent and short-lasting,
although the risk of hyperglycemia was
higher among patients on corticosteroids.
Source: PLoS One, December 7, 2015
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Citing the rst direct real world evidence, researchers from Harvard and the
University of Southern California warn
that warfarin may potentiate the hypoglycemic action of some sulfonylureas.
In a retrospective cohort analysis
of 465,918 older adults using glipizide
and glimepiride, the researchers found
that hospital admissions or emergency
department visits for hypoglycemia and
related diagnoses were more common
among the 71,533 patients who were
also using warfarin. Concurrent use of
warfarin and glipizide or glimepiride was
also associated with other hypoglycemiarelated diagnoses, such as fractures due

to falls. The associations were strongest
for patients using warfarin for the rst
time and for those ages 65 to 74 years.
The problem seems to be a drugdrug
interaction, the researchers say. They
found no associations of hypoglycemia
rates with concurrent use of statins and
glipizide or glimepiride or between warfarin and other diabetes drugs.
Evidence suggests two possible mechanisms for the higher risk of hypoglycemia.
One is through displaced protein binding:
The warfarin displaces the sulfonylurea,
increasing its plasma drug concentration
and drug activity. A second possibility is
that because the drugs are all primarily metabolized by the CYP2C9 hepatic
metabolic pathway, the larger doses of
warfarin may interfere with metabolism
of sulfonylurea.
The potential interaction has not been
widely appreciated, the researchers say,
and health care professionals are not
routinely alerted when patients on sulfonylureas start warfarin treatment. They
suggest that, just as a lower initial dose
of warfarin is advised for older patients
to mitigate the risk of bleeding, the dose
should be lower for older patients who
start warfarin while taking glipizide or
glimepiride.
Source: BMJ, December 7, 2015
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High blood pressure and systolic
hypotension have been linked to falls,
reduced bone mineral density, and hip
fractures. But antihypertensive drugs
have, in observational studies, seemed
to increase the risk of falls and hip fractureseven though meta-analyses found
no associations between long-term treatment and falls. Indeed, research has suggested benets of thiazides, beta blockers, and angiotensin-converting enzyme
(ACE) inhibitors, such as direct stimulation of osteoblasts. University of Bergen

researchers note, however, that previous
studies of antihypertensives and hip fracture have focused on diuretics and beta
blockers; widely used combination drugs
have not been considered.
The Norwegian researchers looked
at data from 906,422 people born before
1945. Over about six years, 39,938 people
(4.4%) fractured their hips. Thiazides,
beta blockers, calcium-channel blockers, angiotensin II receptor blockers, and
certain combination products containing
ACE inhibitors/thiazides and angiotensin
II receptor blockers/thiazides reduced
the risk of hip fracture. Loop diuretics and
ACE inhibitors increased the risk of fracture in people younger than 80 years of
age but reduced risk in those older than
80. The increased risk in younger people
may be due to the more-ill-user effect,
the researchers say, because those drugs
are frequently given to relatively frail
people with heart failure.
All the drugs (except loop diuretics) were more protective for men than
women. Most antihypertensive drugs
appear to be benecial for bone health
in both sexes, the researchers say, but
risk differences were not eliminated. Sex
hormones interfere with bone metabolism, which puts postmenopausal women
at a much higher risk of hip fracture. In
this study, 72% of patients who had a hip
fracture were women.
New users of loop diuretics also had a
higher risk of hip fracture, particularly in
the rst two weeks. The numbers were relatively small, however, and the researchers
say their ndings must be interpreted with
caution. They also cite a recent study that
linked loop diuretics with hyponatremia
and a higher risk of osteoporotic fractures.
Source: BMC Geriatrics, December 1,
2015
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Herpes zoster (HZ) vaccine is mostly
effectivein clinical trials, it reduced the
risk of herpes zoster by at least 60%, the
burden of illness by 61%, and postherpetic
neuralgia (PHN) by 67%. But surveillance
studies have shown that the vaccines
effectiveness declines within ve years,
say researchers who reviewed six studies
on the vaccine.
While efficacy was 60% or higher
among younger cohorts during year 1
post-vaccination, the response was signicantly lower among patients 70 years of
age and older. Moreover, vaccine efcacy
waned considerably, the researchers say,
after the rst year of vaccination regardless of age or whether efcacy was measured by HZ incidence or burden of illness. However, some research found the
vaccines efcacy against PHN increased
in patients older than 69 years of age.
Long-term persistence of zoster vaccine efficacy hasnt been studied in
patients ages 50 to 59but those are the
patients who are most at risk of shingles
around the time the vaccine may be
declining in effectiveness. People who
reach 80 years of age have a 25% to 50%
lifetime risk of developing HZ.
The researchers say their ndings
raise the question of whether patients
will need revaccination. Until thats established, they suggest advising patients that
the vaccine loses signicant and predictable protection after ve to eight years.
Source: Clinical Therapeutics, November 2015
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Exacerbations in chronic obstructive
pulmonary disease (COPD) can impair
pulmonary function, respiration, quality
of life, and functional statusbut little is
known about their relationship to sleep.
To ll this gap, researchers assessed
sleep variables in a substudy of an observational longitudinal study.
Patients were followed for about

six months. During that time, 15 of 17
patients had 27 symptom-dened exacerbations and eight had nine clinically
reported exacerbations. Two exacerbations required hospitalization.
One-quarter of the study days were
exacerbation days.
The Stanford Sleepiness Scale score
was signicantly higher during exacerbations. Patients also had signicantly
less total sleep time and poorer sleep
efciency. Objective awakenings greatly
exceeded subjective awakenings regardless of exacerbations, but not signicantly. None of the four variablessleep
time, sleep efciency, objective awakenings, and subjective awakeningswere
strongly associated with daytime sleepiness. The study did not compare COPD
patients to people without COPD, but the
researchers found total sleep time and
sleep efciency substantially worse
than reported for people with insomnia
and older adults.
Whether the sleep disturbances can
be considered clinically meaningful or
whether the changes in sleep time and
efciency are causally related to sleepiness, the researchers say, are puzzles for
a larger study to address.
Source: Chronic Respiratory Disease,
November 2015
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Its time to harness the power of social
media to help patients with chronic diseases, say researchers, who reviewed
42 studies using a novel taxonomy that
organized results by domains of support,
education, diagnosis, disease management, and disease modication.
Their analysis revealed gaps, they say;
lling those gaps could prove valuable.
For instance, they found that the studies
focused mostly on just ve technology
platforms: Facebook, blogs, Twitter, Wiki-
H^Z@^ 7ROadMah P&T
91
pedia/wikis, and YouTubeand of those,

69% concentrated on Facebook and blogs.
By far the most attention (86%) was paid
to cancer, depression, and obesity.
Based on their study, the researchers
say contemporary social media are mostly
likely to improve chronic disease care
when used to provide social, emotional,
or experiential support. Almost half of the
studies suggested that social media offer
benets to patients with chronic disease,
such as support (via blogs) or disease
modication (via Facebook). Insights
such as those, the researchers say, could
help clinicians determine which social
media might be most useful in improving
patient care.
The studies provide valuable lessons
about the plusses of each platform, the
researchers say. For instance, one study
found that Facebook groups are useful
for weight loss and exercise because
they provide a multimodal platform to
access content, demonstrate skills, monitor progress, and organize virtual or live
groups. By the same token, blogs were
important sources of support for cancer
patients.
The researchers say few studies suggest any harm from using social media
technology in chronic disease care. On
the other hand, they found no highquality data, quantitative or qualitative,
to support the use of social media within
the domains of diagnosis or education.
Source: American Journal of Medicine,
December 2015
approved in December 2014 for use in

adults (18 years of age or older).
The Animas Vibe system allows
patients and their caregivers to view
glucose data and to administer insulin
directly from the pump, making it possible to ne-tune insulin delivery to help
manage patients diabetes. The system
includes the Dexcom G4 platinum sensor,
which is indicated for detecting trends
and tracking patterns in persons 2 years
of age and older.
Source: Animas Corporation, January
11, 2016
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Bio2 Technologies, Inc., has received
510(k) clearance from the FDA for its
Fusion implant system for interphalangeal fusion, fracture repair, and osteotomies of the toes, ngers, and other small
bones in the presence of appropriate
immobilization.
The implants are constructed with the
companys Vitrium biomaterial, which is
composed of bioactive glass, a resorbable
material with a well-studied mechanism
of action and a long track record of safe
clinical use. After years of research and
preclinical testing, Bio2 Technologies
has applied its proprietary technology to
produce a rigid, bioactive, and osteoconductive material with an interconnected
porous structure that facilitates the
ingrowth and remodeling of healthy bone.
Source: Bio2 Technologies, January
11, 2016
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The FDA has expanded the labeling

for the Animas Vibe insulin pump and
continuous glucose monitoring system
(Animas Corporation/Johnson & Johnson) to include the management of diabetes in children and adolescents 2 to
17 years of age. The system was originally
The FDA has cleared new software

designed for minimally invasive robotic
surgery. The Follow Me software, developed by Medical Surgery Technologies
(MST), allows an image-guided laparoscope to follow laparoscopic surgical tools
without manual control.
92
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Using MSTs image-analysis software,

surgeons can virtually tag the surgical
tools within the surgical cavity. The system interacts with the surgeons in vivo
movements and gestures, guiding the
robotic laparoscope positioner to follow
the surgeons tools in real time.
Source: Medical Surgery Technologies, January 6, 2016
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The FDA has approved the Fenix continence restoration system (Torax Medical, Inc.) to treat fecal incontinence in
patients who are not candidates for, or
have previously failed, medical or other
surgical options.
The system has three components: an
implant, an anal sphincter sizing tool, and
an introducer tool. The implant is a series
of titanium beads with magnetic cores
that are connected by titanium wires to
form a ring shape. The attractive force of
the magnetic beads augments the anal
sphincter to minimize involuntary opening of the anal canal, thereby reducing the
likelihood of severe fecal incontinence.
The sizing tool is used to associate the
anal sphincter size to an appropriate
implant. The introducer tool is used to
guide the sizing tool and the implant into
position.
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The FDA has granted 510(k) clearance
for the Dario blood glucose monitoring
system (LabStyle Innovations Corp.),
including its components, the Dario blood
glucose meter, Dario blood glucose test
strips, Dario glucose control solutions,
and the Dario app on the Apple iOS 6.1
platform and higher.
The Dario blood glucose monitoring
system is indicated for the quantitative
measurement of glucose in fresh capil-
lary whole-blood samples drawn from

the ngertips. The system helps people
with diabetes monitor their blood sugar
levels and to proactively manage their
diabetes using their smartphone. Dario
connects via a headphone jack to turn
a mobile device into a glucose monitor,
and it incorporates a lancing device and
test strips together with the meter in a
portable device to take blood glucose
measurements on the spot. Unlike conventional glucose monitors, there is no
carrying case or batteries.
Source: LabStyle Innovations Corp.,
December 22, 2015
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The FDA has cleared the NxTAG
respiratory pathogen panel (Luminex
Corporation), which detects 20 clinically
relevant viral and bacterial respiratory
pathogens, including the atypical bacteria
Chlamydophila pneumoniae and Mycoplasma pneumonia. The panel is the only
respiratory assay that allows laboratories
to simultaneously detect 20 respiratory
pathogens in a single closed-tube system
in a format that scales to accommodate
the changes in throughput needed to
respond to seasonal changes in demand,
especially during the u season.
Source: Luminex Corporation, December 18, 2015
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The FDA has approved a new indication for the Omnigraft dermal regeneration matrix (Integra LifeSciences Corporation) to treat certain diabetic foot
ulcers. The matrix device, which is made
of silicone, cow collagen, and shark cartilage, is placed over the ulcer and provides
an environment for new skin and tissue to
regenerate and heal the wound.
The FDA rst approved the Integra
dermal regeneration template (which the
company now also calls Omnigraft) in

1996 for the treatment of life-threatening
burn injuries when the use of a patients
own skin for a graft was not possible.
In 2002, the Integra dermal regeneration template was approved for a new
indication to treat patients undergoing
reconstructive surgery for burn scars
when they cannot have skin grafts. Now,
Omnigraft is approved to treat certain
diabetic foot ulcers that last for longer
than six weeks and do not involve exposure of the joint capsule, tendon, or bone,
when used in conjunction with standard
diabetic ulcer care.
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The FDA has approved a new indication for the LifeVest wearable cardioverter debrillator (Zoll Manufacturing Corporation). The LifeVest is now
approved for some children who are at
risk for sudden cardiac arrest but are not
candidates for an implantable debrillator
because of certain medical conditions or
lack of parental consent. The device was
rst approved in 2001 for use in adults
(18 years of age and older).
While many automated external debrillators (which require a second person
to operate them) have been cleared for
use in children, LifeVest is the only one
that is worn by the patient and that monitors the heart continuously for arrhythmias. LifeVest responds automatically
if it senses the need to deliver a shock,
restoring a life-sustaining heartbeat.
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Infuse Bone Graft (Medtronic) has
been approved for the following additional indications: 1) use in oblique lateral
interbody fusion (OLIF)-51 procedures
with certain sizes of the polyetherether-
ketone (PEEK) Perimeter implant at a

single level from L5 to S1; 2) use in OLIF25 procedures with certain sizes of the
PEEK Clydesdale implant at a single level
from L2 to L5; and 3) use in anterior lumbar interbody fusion (ALIF) procedures
with certain sizes of the PEEK Perimeter
implant at a single level from L2 to S1.
Infuse Bone Graft is used with certain
Medtronic interbody fusion devices to
treat lumbar degenerative disc disease.
The active ingredient (rhBMP-2) is a
manufactured version of an endogenous
protein that promotes new bone growth.
During surgery, the product is applied
to an absorbable collagen sponge, which
delivers the rhBMP-2 to the implant site
and acts as a scaffold for the formation
of new bone.
Source: Medtronic, December 11, 2015
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OBP Medical has announced the
availability of an improved version of
its Sure-Scope, a single-use, one-piece
laryngoscope with a built-in LED light
source. According to the company, the
design eliminates the time and expense
of reprocessing and reduces the risk of
cross-contamination in medical settings.
The device comes out of its package sterile and ready to use, with no additional
parts or assembly required. After a single
patient use, the entire devicehandle,
blade, and lightis thrown away. By
using the device, medical facilities can
cut their cost per intubation by as much
as 64%, OBP says.
Source: OBP Medical, January 11, 2016
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The Centers for Medicare and Medicaid Services (CMS) has issued a nal rule
on the ordering of durable medical equipment, prosthetics, orthotics, and supplies
H^Z@^ 7ROadMah P&T
93
(DMEPOS). The new rule establishes a

prior authorization process for DMEPOS
that are often subject to unnecessary use.
It also authorizes the creation of a master
list of DMEPOS items potentially subject
to prior authorization.
Examples of durable medical equipment include hospital beds, oxygen
tents, and wheelchairs. The CMS denes
prosthetic devices as devices (other
than dental) that replace all or part of an
internal body organ. Examples of such
devices include cochlear implants, electrical continence aids, electrical nerve
stimulators, and tracheostomy speaking
valves. Orthotics include leg, arm, back,
and neck braces; and articial legs, arms,
and eyes.
Sources: FierceHealthFinance, January
7, 2016; and Federal Register, December
30, 2015
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The first validation data for the
Decipher prostate cancer classifier
(GenomeDx Biosciences) have supported its use in the analysis of diagnostic
needle core biopsies to help guide the
management of men newly diagnosed
with prostate cancer. The test accurately predicted 10-year postoperative
metastasis from a genomic analysis of
diagnostic biopsy specimens. Decipher
scores were evaluated from primarily
low- and intermediate-risk patients with
available needle biopsy tissue who went
on to receive radical prostatectomy at
Cleveland Clinic.
The evaluation of Decipher in 57
patients yielded a c-index of 0.80 for
the prediction of metastasis at 10 years
compared with 0.75 for National Comprehensive Cancer Network (NCCN) risk
criteria alone. A combined model consisting of Decipher and NCCN risk criteria
improved the accuracy to yield a c-index
of 0.88. A multivariable analysis found
that Decipher was the only signicant

predictor of metastasis when adjusting
for age, preoperative prostate-specic
antigen (PSA), and biopsy Gleason score
(P = 0.02).
Source: GenomeDx Biosciences, January 7, 2016
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ImpediMed Ltd. has announced the
U.S. commercial launch of its L-Dex system to aid in the clinical assessment of
lymphedema. This follows a successful
pilot program involving six U.S. cancer
centers, a dedicated current procedural
terminology (CPT) category I code allowing physicians to seek reimbursement
beginning in January 2015, and a revised
FDA clearance in May 2013.
L-Dex is the rst product of its kind to
use bioimpedance spectroscopy, a noninvasive system for accurately measuring
tissue composition and uid status, to
identify lymphedema up to 10 months
before there is evidence of limb swelling.
Early detection and subsequent intervention may help prevent the progression of
the disease and, in some instances, even
reverse it, according to the company.
Through electrodes placed on the arm
and leg, L-Dex sends a small, imperceptible current using 256 frequency spectra
through tissue measuring extracellular
uid. Using a scoring system, oncologists,
breast cancer surgeons, and other health
care providers can determine in seconds
the amount of resistance from one point
to the other and thus identify the onset of
extracellular uid accumulation.
Source: ImpediMed, January 7, 2016
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The FDA has issued two nal orders
to strengthen the data requirements for
surgical mesh to repair pelvic organ prolapse (POP) transvaginally. The agency
issued one order to reclassify these medical devices from class II, which generally includes moderate-risk devices, to
class III, which generally includes highrisk devices. The second order requires
manufacturers to submit a premarket
approval (PMA) application to support
the safety and effectiveness of surgical
mesh for the transvaginal repair of POP.
The orders will require manufacturers to address safety concerns, including
severe pelvic pain and organ perforation,
through a PMA pathway to demonstrate
safety and effectiveness. The actions
apply only to mesh devices marketed
for the transvaginal repair of POP. They
do not apply to surgical mesh for other
indications, such as stress urinary incontinence or abdominal repair of POP.
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Researchers at the University of Illinois
at UrbanaChampaign have developed
a biosensor that can count blood cells
electrically using only a single drop of
blood. The gold standard routinely used
in hospitals and testing laboratories is a
hematology analyzer, which is large and
expensive.
The microuidic device electrically
counts the different types of blood cells
based on their size and membrane properties. To count leukocytes and their differentials, red blood cells are selectively
lysed, and the remaining white blood
cells are individually counted. Specic
cells, such as neutrophils, are counted
using multifrequency analysis, which
probes the cells membrane properties.
For red blood cells and platelets, 1 mcL
of whole blood is diluted with phosphate
buffered saline on the chip, and the cells
are counted electrically. The total time
for measurement is less than 20 minutes.
Source: World Scientic Publishing,
December 18, 2015
94
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7ROadMah H^Z@^
BVMa\MPRdcWPMZ2__aêMZG_QMcR
Chris Fellner
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Manufacturer: AstraZeneca, Wilmington, Delaware
Date of Approval: December 22, 2015
Indication: Zurampic is indicated in combination with a
xanthine oxidase inhibitor (XOI) for the treatment of hyperuricemia associated with gout in patients who have not achieved
target serum uric acid levels with an XOI alone.
Drug Class: Lesinurad is a uric acid transporter 1 (URAT1)
inhibitor.
Uniqueness of Drug: URAT1 is responsible for the
majority of the renal reabsorption of uric acid. By inhibiting
URAT1, lesinurad increases uric acid excretion, thereby
lowering serum uric acid. Lesinurad also inhibits organic
anion transporter (OAT) 4, a uric acid transporter involved
in diuretic-induced hyperuricemia. Lesinurad does not inhibit
OAT1 and OAT3, which are drug transporters in the kidney
associated with drugdrug interactions.
Warnings and Precautions:
Boxed warning. The labeling for Zurampic includes a
boxed warning regarding the risk for acute renal failure, which
is more common when the drug is used without an XOI or at
higher-than-approved doses.
Renal events. Treatment with Zurampic 200 mg in combination with an XOI was associated with an increased incidence
of serum creatinine elevations, most of which were reversible.
Cardiovascular events. In clinical trials, major adverse
cardiovascular events (dened as cardiovascular deaths, nonfatal myocardial infarctions, or nonfatal strokes) were observed
with Zurampic. A causal relationship with Zurampic has not
been established.
Dosage and Administration: Zurampic tablets should be
coadministered with an XOI, including allopurinol or febuxostat.
The recommended starting dosage of Zurampic is 200 mg once
daily. This is also the maximum daily dose. Zurampic should
be taken by mouth in the morning with food and water. The
drug may be added when target serum uric acid levels are not
achieved on the medically appropriate dose of the XOI alone.
The use of Zurampic is not recommended in patients taking
daily doses of allopurinol of less than 300 mg (or less than
200 mg in patients with an estimated creatinine clearance of
less than 60 mL/min).
Commentar y: In clinical trials, less than 50% of patients
treated with allopurinol 300 mg reached serum uric acid target
levels of less than 6 mg/dL. For patients who cannot reach
the target on an XOI alone, the current American College of
Rheumatology guidelines recommend adding an agent that
increases uric acid excretion (such as Zurampic).
Sources: AstraZeneca, Zurampic prescribing information
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Manufacturer: Actelion Pharmaceuticals U.S., South San
Francisco, California
Chris Fellner is a medical writer and the Editor of PTCommunity.com.
Indication: Uptravi is indicated for the treatment of pulmonary arterial hypertension (PAH, World Health Organization
[WHO] group I) to delay disease progression and to reduce
the risk of hospitalization for PAH. The drugs effectiveness
was established in a long-term study in PAH patients with
WHO functional class IIIII symptoms.
Drug Class: Selexipag is a selective nonprostanoid IP
prostacyclin receptor agonist.
Uniqueness of Drug: Selexipag is the rst medication
in its class. It acts by relaxing muscles in the walls of blood
vessels to dilate the vessels and reduce the elevated pressure
in vessels supplying blood to the lungs.
Pulmonary edema. If signs of pulmonary edema occur,
clinicians should consider the possibility of associated pulmonary veno-occlusive disease. If conrmed, Uptravi should
be discontinued.
Dosage and Administration: The recommended starting dosage of Uptravi is 200 mcg twice daily. Tolerability may
be improved when the drug is taken with food. The dosage
is increased in increments of 200 mcg twice daily, usually
at weekly intervals, to the highest tolerated dosage (up to
1,600 mcg twice daily). If a patient reaches a dose that cannot
be tolerated, the dose should be reduced to the previous
tolerated dose.
Commentary: In a pivotal phase 3 study, selexipag reduced
the risk of a morbidity/mortality event by 40% compared with
placebo (P < 0.0001). The observed efcacy was consistent
across the key subgroups: age, gender, WHO functional class,
PAH etiology, and background PAH therapy. Patients were
treated for up to 4.2 years. The tolerability prole of selexipag
was consistent with that of prostacyclin therapies.
Sources: FDA, Uptravi prescribing information
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Manufacturer: Merck, Kenilworth, New Jersey
Indication: Bridion injection is indicated for the reversal of
neuromuscular blockade induced by rocuronium bromide and
vecuronium bromide in adults undergoing surgery.
Drug Class: Sugammadex is a modied gamma cyclodextrin.
Uniqueness of Drug: The neuromuscular blocking agents
rocuronium and vecuronium cause temporary paralysis by
interfering with the transmission of nerve impulses to the
muscle and are used to paralyze the vocal cords during tracheal intubation. They can also be used to prevent patients
from moving during surgery while they are receiving general
anesthesia. Neuromuscular blocking drugs are also sometimes
used to prevent the body from breathing automatically when
a patient has to be placed on a ventilator.
Sugammadex forms a complex with rocuronium and
vecuronium, and it reduces the amount of these neuromuscular
blocking agents that is available to bind to nicotinic cholinergic
receptors in the neuromuscular junction. This results in the
H^Z@^ 7ROadMah P&T
95
BVMa\MPRdcWPMZ2__aêMZG_QMcR
reversal of neuromuscular blockade induced by rocuronium
and vecuronium.
Key Warnings and Precautions:
Anaphylaxis and hypersensitivity. Clinicians should be
prepared for the possibility of drug hypersensitivity reactions
(including anaphylactic reactions) when using Bridion and
should take the necessary precautions.
Marked bradycardia. Cases of marked bradycardia, some
of which have resulted in cardiac arrest, have been observed
within minutes after the administration of Bridion.
Monitoring of respiratory function during recovery.
Ventilatory support is mandatory for patients until adequate
spontaneous respiration is restored and the ability to maintain
a patent airway is assured.
Risk of prolonged neuromuscular blockade. In clinical
trials, a small number of patients experienced a delayed or minimal
response to the administration of sugammadex. Therefore, it is
important to monitor ventilation until recovery occurs.
Risk of coagulopathy and bleeding. In healthy volunteers,
sugammadex doses of up to 16 mg/kg were associated with
increases of up to 25% for up to one hour in two coagulation
parameters: activated partial thromboplastin time and prothrombin time/international normalized ratio.
Renal impairment. Bridion is not recommended for use
in patients with severe renal impairment, including those
requiring dialysis.
Dosage and Administration:
For rocuronium and vecuronium: A 4-mg/kg dose of
Bridion is recommended if spontaneous recovery of the twitch
response has reached one to two post-tetanic counts and there
are no twitch responses to train-of-four (TOF) stimulation following rocuronium- or vecuronium-induced neuromuscular
blockade. A Bridion dose of 2 mg/kg is recommended if spontaneous recovery has reached the reappearance of the second
twitch in response to TOF stimulation after rocuronium- or
vecuronium-induced neuromuscular blockade.
For rocuronium only: A 16-mg/kg dose of Bridion is
recommended if there is a clinical need to reverse neuromuscular blockade soon (approximately three minutes) after the
administration of a single 1.2-mg/kg dose of rocuronium. The
efcacy of the 16-mg/kg dose of Bridion after the administration of vecuronium has not been established.
Commentar y: For seven years prior to the approval of
Bridion, the FDA repeatedly declined to clear the product
largely because of concerns about potentially dangerous
allergic reactions. Doctors were also warned to monitor for
bradycardia, which could lead to cardiac arrest. Those safety
concerns spurred demands for new studies as well as periodic
regulatory delays.
Sources: Merck, Bridion prescribing information, Reuters,
FierceBiotech
2ZRPcW]WO2ZRPR]bM
Manufacturer: Genentech, South San Franscisco, California
Indication: Alecensa is indicated for the treatment of
patients with anaplastic lymphoma kinase (ALK)-positive,
metastatic nonsmall-cell lung cancer (NSCLC) who have
progressed on or are intolerant of crizotinib.
96
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7ROadMah H^Z@^
Drug Class: Alectinib is a tyrosine kinase inhibitor that

targets the ALK and RET kinase genes.
Uniqueness of Drug: In nonclinical studies, alectinib
inhibited ALK phosphorylation and ALK-mediated activation
of the downstream signaling proteins STAT3 and AKT, and
decreased tumor cell viability in multiple cell lines harboring
ALK fusions, amplications, or activating mutations. Alectinib
also demonstrated in vivo activity against multiple mutant forms
of the ALK enzyme, including some mutations identied in
NSCLC tumors in patients who had progressed on crizotinib
(Xalkori, Pzer).
Hepatotoxicity. Elevations of aspartate aminotransferase
(AST) greater than ve times the upper limit of normal (ULN)
occurred in 3.6% of patients, and elevations of alanine transaminase (ALT) greater than ve times the ULN occurred in 4.8%
of patients. Elevations of bilirubin greater than three times the
ULN occurred in 2.8% of patients.
Interstitial lung disease (ILD)/pneumonitis. Severe ILD
(grade 3) occurred in one (0.4%) of 253 patients exposed to
alectinib in clinical trials.
Bradycardia. Cases of bradycardia (7.5%) have been
reported in patients treated with alectinib. Twenty percent
of 221 patients treated with alectinib for whom serial electrocardiograms were available had heart rates of less than 50 beats
per minute.
Severe myalgia and creatine phosphokinase (CPK)
elevation. Myalgia or musculoskeletal pain occurred in 29%
of patients in clinical studies of alectinib. The incidence of
grade 3 myalgia/musculoskeletal pain was 1.2%. Elevations
of CPK occurred in 43% of 218 patients.
Embryo-fetal toxicity. Based on ndings from animal
studies and its mechanism of action, alectinib can cause fetal
harm when administered to pregnant women.
Dosage and Administration: The recommended dosage of
alectinib is 600 mg orally twice daily with food. Alectinib should
be administered until disease progression or unacceptable
toxicity occurs.
Commentar y: An ALK gene mutation can occur in several
different types of cancer cells, including lung cancer cells. ALK
gene mutations are present in approximately 5% of patients with
NSCLC. In patients with metastatic ALK-positive NSCLC, the
brain is a common target for the spread of disease.
The safety and efcacy of alectinib were studied in two
single-arm clinical trials of patients with metastatic ALK-positive
NSCLC whose disease was no longer controlled by treatment
with crizotinib. The study participants received alectinib twice
daily to measure the drugs effect on their lung cancer tumors.
In the rst study, 38% of participants experienced a partial
shrinkage of their NSCLC tumors, an effect that lasted for an
average of 7.5 months. In the second study, 44% of participants
experienced a partial shrinkage of their NSCLC tumors, lasting
for an average period of 11.2 months.
Sources: FDA, Alecensa prescribing information Q
DRUG FORECAST
FW^ca^_Wd\3a^\WQRAZ^QMcRa^Z
EcW^Zc^DRb_W\Mc
A]PR5MWZh4^\OW]McW^]FVRaM_hSâcVR?MW]cR]M]PR^S4AB5
Juan F. Mosley II, PharmD, CPh, AAHIVP; Lillian L. Smith, PharmD, CPh, MBA; and
Brittany N. Dutton, PharmD Candidate
Keywords: tiotropium bromide, olodaterol, Stiolto Respimat, COPD, anticholinergic, beta2 agonist
INTRODUCTION
Chronic obstructive pulmonary disease (COPD), a relatively common respiratory disorder in the U.S., is the third
leading cause of death in this country.1 It
has been estimated that 15 million Americans have COPD.1 Since the disorder is
so common, effective treatment regimens
are a prominent research topic in pharmacology. Still, the development of pharmacological treatments for COPD has been
a struggle. Only recently has sufcient
progress been made in understanding
the molecular and cell biology of COPD to
allow the identication of new therapeutic
targets.2 Currently, no drugs can reverse
the progression of COPD.2 Hence, the
development of new monotherapies or
combination therapies is pivotal in providing relief to these patients.
Several drug classes are used to treat
COPD, including anticholinergic agents,
short- and long-acting beta2 agonists
(LABAs), inhaled corticosteroids, and
phosphodiesterase 4 (PDE4) inhibitors.3
Since COPD is most commonly caused
by smoking and by exposure to secondhand smoke, the predominant nonpharmacological treatment is smoking cessation. Patients are also advised to avoid
Dr. Mosley and Dr. Smith are Assistant
Professors of Pharmacy Practice at the Florida
Agricultural and Mechanical University, College
of Pharmacy and Pharmaceutical Sciences, in
Crestview, Florida. Brittany Dutton is a Doctor
of Pharmacy candidate at that institution. Drug
Forecast is a regular column coordinated by
Alan Caspi, PhD, PharmD, MBA, President of
Caspi & Associates in New York, New York.
Disclosure: The authors report no commercial
or nancial interests in regard to this article.
GLOSSARY
2PcdMcW^]in an inhaler, the process by which
a single dose is released for patient use.
2PdcRZhQRcRaWâMcW]U4AB5a sustained
worsening of the patients condition, from stable
state and beyond normal day-to-day variations,
that is sudden in onset and may warrant additional treatment; also called an exacerbation.
3MjRccPâaRPcW^]b^SCFCFP3standard
formula used to correct the observed QT interval
in an electrocardiogram based on cardiac rate.
The Bazett formula is: QT = Q-Tsec/RR sec.
3a^]PV^QWZMcW^]expansion of the air passages to the lungs (bronchioles and bronchi) to
provide better air ow.
4MaQWMPRZRPca^_VhbW^ZÛhprocess that
records electrical transmissions through the
heart; used mainly to diagnose cardiac arrhythmias such as QT-interval prolongation.
4Va^]WPOa^]PVWcWbinammation of mucous
membranes leading to excess mucus production
and development of a chronic, productive cough;
associated with vulnerability to lung infections.
4Va^]WPÔbcadPcWeR_dZ\^]MahQWbRMbR
4AB5group of respiratory diseases characterized by the chronic obstruction of airow to the
lungs and not fully reversible; chronic bronchitis
and emphysema are major forms of COPD.
6\_VhbR\Mabnormal enlargement of air
sacs (alveoli) in the lungs that can progressively
damage tissue; characterized by breathlessness.
76H1forced expiratory volume in one second, the volume of air that can be forcefully
expired in that time after a full, deep inhalation.
76H17H4aMcW^percentage of the total FVC
other triggers that may worsen respiration, such as air pollution, pet dander, and
noxious chemicals.3
Because COPD is a progressive, debilitating disorder, patients commonly rely
on combination therapies for relief.2 Of
the available combination products, anticholinergic agents plus LABAs are often
used for maintenance treatment.
Anticholinergics work primarily by
that is expelled from the lungs during the rst

second of a forced exhalation.
7aRQRaWPWMPâaRPcW^]b^SCFCFP7alternative formula used to correct the observed QT
interval in an electrocardiogram based on cardiac
rate. The Fredericia formula is: QT = QT/(RR^0.33).
7H4forced vital capacity, the total volume
of air that can be forcefully expelled after a full,
deep inhalation.
?WZZWbRP^]Q\bRPone-thousandth of a
second.
BaW\W]UM]W]VMZRaspraying one or more
puffs into the air prior to using the inhaler initially
or after an extended period of disuse to ensure
proper dose delivery.
DRb_W\McE^Sc?WbcW]VMZRanew-generation,
propellant-free inhaler that allows a patient to
inhale normally and still achieve increased lung
penetration.
E_Wa^\Rcahtest of the lungs air capacity in
terms of the volumes of air inspired and expired.
Spirometric criteria are used by the COPD GOLD
guidelines to classify the severity of the illness:
mild disease, FEV1 80%; moderate disease,
FEV1 50% but < 80%; severe disease, FEV1
30% but < 50%; very severe disease, FEV1 < 30%.
Ec 8RâURb DRb_WaMcâh CdRbcW^]]MWaR
E8DC50-item survey for patients with chronic
respiratory illnesses to assess the impact of
obstructive airway diseases on overall health, daily
life, and perceived well-being. Scores range from 0
to 100; higher numbers equate to more limitations.
FVha^c^gWP^bWboverproduction of thyroid
hormones in the body; hyperthyroidism is a type
of thyrotoxicosis.
inhibiting the action of acetylcholine and

by reducing cyclic-adenosine monophosphate (cAMP) in bronchial smooth muscles, thereby triggering bronchodilation.
LABAs bind to beta-adrenergic receptors,
resulting in the relaxation of bronchial
smooth muscles.3 When drugs from these
two classes are used in combination, they
have a synergistic effect on bronchodilation and improve airow throughout
H^Z@^ 7ROadMah P&T
97
DRUG FORECAST
the respiratory system.3 Tiotropium bromide/olodaterol inhalation spray (Stiolto Respimat, Boehringer Ingelheim),
approved in May 2015 by the Food and
Drug Administration, is a new xed-dose
anticholinergic/LABA combination medication for patients with COPD.4
INDICATION AND USAGE

Tiotropium bromide/olodaterol is indicated for the long-term, once-daily maintenance therapy of airow obstruction in
patients with COPD. It is not indicated
to treat asthma or acute deterioration of
COPD.4
?64:2@;E? A7 24F;A@
As an anticholinergic agent, tiotropium bromide antagonizes the effect of
acetylcholine in the bronchioles to prevent bronchoconstriction and to trigger
bronchodilation.7 In preclinical in vitro
investigations as well as in vivo studies,
the prevention of methacholine-induced
bronchoconstriction was dose-dependent
and lasted longer than 24 hours. The
bronchodilation following inhalation of
tiotropium is predominantly a site-specic
effect.4 After topical administration by
inhalation, the LABA olodaterol binds to
beta2-adrenergic receptors in the bronchioles and triggers smooth-muscle relaxation, resulting in bronchodilation.4,8
67764F A@ 42D5;24
6>64FDAB:KE;A>A8K
In two 52-week, randomized, doubleblind trials of xed-dose tiotropium/
olodaterol, electrocardiograph (ECG)
assessments were performed after dosing on days 1, 85, 169, and 365 in a total
of 5,162 patients with COPD. In a pooled
analysis, the numbers of subjects with
changes from baseline-corrected QT
interval of greater than 30 msec, using
both the Bazett (QTcB) and Fredericia
(QTcF) corrections of QT for heart rate,
were not different for the tiotropium/olodaterol group compared with olodaterol
5 mcg alone and tiotropium 5 mcg alone
across the assessments conducted.4
FW^ca^_Wd\ 3a^\WQR
The effect of tiotropium dry powder
for inhalation on the QT interval was
evaluated in a randomized, placebo- and
positive-controlled crossover study in 53
healthy volunteers. The subjects received
tiotropium inhalation powder 18 mcg (the
98
P&T
7ROadMah H^Z@^
recommended dose), 54 mcg, or placebo

for 12 days. ECG assessments were performed at baseline and throughout the
dosing interval following the rst and last
dose of study medication. Compared with
placebo, the maximum mean changes
from baseline in the QTc interval were
3.2 msec and 0.8 msec for tiotropium
inhalation powder 18 mcg and 54 mcg,
respectively. None of the subjects had
QTc intervals of greater than 500 msec
or QTc changes from baseline of 60 msec
or more.4
Tiotropium dr y powder was also
evaluated in a multicenter, randomized,
double-blind trial involving 198 patients
with COPD. In this study, the number of
subjects with changes from the baselinecorrected QT interval of 30 to 60 msec
was higher in the tiotropium group than
in the placebo group. This betweengroup difference was established using
both QTcB (20 patients [20%] versus 12
patients [12%]) and QTcF (16 patients
[16%] versus one patient [1%]). None of
the patients in either group had either a
QTcB or QTcF of greater than 500 msec.
Other clinical studies did not detect an
effect of tiotropium on QTc intervals.4
AZ^QMcRa^Z :hQa^PVZâWQR
The effect of olodaterol on the QT/
QTc inter val was investigated in 24
healthy male and female volunteers in a
double-blind, randomized, placebo- and
active-controlled (moxioxacin) study
at single doses of 10, 20, 30, and 50 mcg.
Dose-dependent QtcI (the individual
subject-corrected QT interval) prolongation was observed. The maximum mean
(one-sided 95% upper condence bound)
differences in QTcI from placebo after
baseline corrections were 2.5 (5.6) msec,
6.1 (9.2) msec, 7.5 (10.7) msec, and
8.5 (11.6) msec after doses of 10, 20, 30,
and 50 mcg, respectively.4
The effects of 5 mcg and 10 mcg of
olodaterol on heart rate and rhythm were
assessed using continuous 24-hour ECG
recording (Holter monitoring) in 772
patients. No dose- or time-related trends
or patterns were observed for the magnitudes of mean changes in heart rate or
premature beats. Shifts from baseline to
the end of treatment in premature beats
did not indicate clinically meaningful differences among olodaterol 5 mcg, olodaterol 10 mcg, and placebo.4
B:2D?24A=;@6F;4E
When tiotropium/olodaterol was
administered by inhalation, the pharmacokinetic parameters for the two components were similar to those observed
when each substance was administered
separately.4 Some of the pharmacokinetic
data described below were obtained with
dosages that were higher than the recommended dosage of two inhalations per day.
2Obâ_cW^] M]Q 5WbcaWOdcW^]

Tiotropium
After inhalation of a tiotropium solution
by young, healthy volunteers, urinary
excretion data indicated that approximately 33% of the inhaled dose reaches
the systemic circulation. Oral solutions
of tiotropium have an absolute bioavailability of 2% to 3%. Food is not expected
to inuence the absorption of tiotropium.
Maximum tiotropium plasma concentrations are observed ve to seven minutes
after inhalation.8
Tiotropium is 72% plasma proteinbound and has a volume of distribution
of 32 L/kg. Lung concentrations are
unknown, but the mode of administration
suggests substantially higher concentrations in the lung. In rats, tiotropium did
not cross the bloodbrain barrier.4
Olodaterol
Olodaterol generally reaches maximum plasma concentrations within 10
to 20 minutes after inhalation. In healthy
volunteers, the absolute bioavailability of
olodaterol after inhalation was estimated
to be approximately 30%, whereas the
absolute bioavailability was less than 1%
when the drug was given as an oral solution. Thus, the systemic availability of
olodaterol after inhalation is primarily
determined by lung absorption.4
Olodaterol exhibits multicompartmental disposition kinetics after both
inhalation and intravenous (IV) administration. The volume of distribution is
high (1,110 L/kg), suggesting extensive
distribution into tissues. In vitro binding of [14C] olodaterol to human plasma
proteins is approximately 60% and is
independent of drug concentration.4
?RcMO^ZWb\ M]Q 6ZW\W]McW^]

Tiotropium
In vitro experiments with human liver
microsomes and human hepatocytes suggest that a fraction of the administered
DRUG FORECAST
dose of tiotropium is metabolized by cytochrome P450 (CYP450)-dependent oxidation and subsequent glutathione conjugation to a variety of phase 2 metabolites.
Tiotropium, an ester, is nonenzymatically
cleaved to the alcohol N-methylscopine
and to dithienylglycolic acid, neither of
which binds to muscarinic receptors.
This enzymatic pathway can be inhibited
by CYP2D6 and 3A4 inhibitors, such as
quinidine, ketoconazole, and gestodene.4
Olodaterol
Olodaterol is substantially metabolized by direct glucuronidation and by
O-demethylation at the methoxy moiety, followed by conjugation. Of the six
metabolites currently identied, only
the unconjugated demethylation product
binds to beta2 receptors. This metabolite,
however, is not detectable in plasma after
chronic inhalation of the recommended
therapeutic dose of tiotropium/olodaterol.
CYP2C8, 2C9, and 3A4 are involved
in the O-demethylation of olodaterol,
whereas the uridine diphosphate glycosyl transferase (UGT) isoforms UGT1A1,
1A7, 1A9, and 2B7 are involved in the
formation of olodaterol glucuronides.8
6gPaRcW^]
Tiotropium
The terminal half-life of tiotropium in
COPD patients after once-daily inhalation of 5 mcg is approximately 25 hours.
Total clearance was 880 mL/min after an
IV dose in young, healthy volunteers. IV
tiotropium bromide is mainly excreted
unchanged in urine (74%). After inhalation of the solution, urinary excretion is
19% of the dose; the remainder is mainly
nonabsorbed drug in the gut, which is
eliminated via the feces. The renal clearance of tiotropium exceeds the creatinine
clearance, indicating secretion into the
urine. After chronic once-daily inhalation by COPD patients, pharmacokinetic
steady state was reached by day 7, with
no accumulation thereafter.4
Olodaterol
Total clearance of olodaterol in healthy
volunteers is 872 mL/min, and renal clearance is 173 mL/min. The terminal half-life
after IV administration is 22 hours. In
contrast, the terminal half-life after inhalation is approximately 45 hours, indicating
that the latter is determined by absorption
rather than by elimination. The effective
half-life of olodaterol at a daily dose of

5 mcg, calculated from the Cmax in COPD
patients, is 7.5 hours.4
After IV administration of [14C]-labeled
olodaterol, 38% of the radioactive dose was
recovered in urine and 53% was recovered in feces. The amount of unchanged
olodaterol recovered in urine after IV
administration was 19%. After oral administration, only 9% of olodaterol and/or its
metabolites was recovered in urine, while
the major portion (84%) was recovered
in feces. More than 90% of the dose was
excreted within ve and six days after oral
and IV administration, respectively. After
inhalation, the excretion of unchanged
olodaterol in urine within the dosing interval in healthy volunteers at steady state
accounted for 5% to 7% of the dose.4
CLINICAL STUDIES
The efcacy of xed-dose tiotropium/
olodateral combinations is based primarily on two four-week dose-ranging trials in
a total of 592 COPD patients and on two
conrmatory, active-controlled, 52-week
trials in a total of 5,162 COPD patients.4
5^bRDM]UW]U EcdQWRb
Aalbers and colleagues conducted a
four-week, randomized, double-blind,
incomplete-crossover study to determine
the optimum once-daily dose of olodaterol
(5 and 10 mcg) and tiotropium (1.25, 2.5,
and 5 mcg) in combination when delivered via the Respimat Soft Mist inhaler in
patients with COPD. The studys primary
efcacy endpoint was the trough forced
expiratory volume in one second (FEV1)
response (the change from baseline) after
four weeks of treatment (day 29). Secondary efcacy endpoints included the
FEV1 area under the curve from zero to
six hours (AUC06 hrs) response after four
weeks of treatment; the trough forced
vital capacity (FVC) response, the FVC
AUC06 hrs response after four weeks of
treatment; and the incidence and severity
of adverse events.9
The study included male and female
patients 40 years of age and older with a
diagnosis of COPD conrmed by spirometric criteria. The patients were required
to have a post-bronchodilator FEV1 equal
to or greater than 30% and less than 80% as
well as a post-bronchodilator FEV1/FVC
ratio of less than 70%. Current and former
smokers with a smoking history of more
than 10 pack-years were also enrolled.
Concomitant respiratory medications

included inhaled corticosteroids, inhaled
short-acting beta-adrenergics, LABAs,
and short-acting anticholinergics.9
A total of 232 patients with COPD (133
men and 99 women) were enrolled and
received treatment with study medication. At day 29, the adjusted mean trough
FEV1 and FEV1 AUC06 hrs were increased
from baseline with olodaterol 5-mcg and
10-mcg monotherapy. The trough FEV1
response and FEV1 AUC06 hrs responses
were similar for olodaterol 5-mcg and
10-mcg monotherapy (0.071 L and 0.083 L,
respectively, for trough FEV1 response,
and 0.188 L and 0.198 L, respectively, for
FEV1 AUC06 hrs response).9
All of the tiotropium/olodaterol
combinations (0/5, 1.25/5, 2.5/5, 5/5,
0/10, 1.25/10, 2.5/10, and 5/10 mcg)
resulted in larger trough FEV1 and FEV1
AUC06 hrs responses and higher FVC
values compared with the respective
olodaterol monotherapies.9 The mean
differences in trough FEV1 for the tiotropium/olodaterol doses of 1.25/5, 2.5/5,
and 5/5 mcg once daily from olodaterol
5 mcg were 0.54 L, 0.065 L, and 0.084 L,
respectively.4
The authors concluded that the addition of tiotropium to olodaterol resulted
in improvements in lung function parameters compared with olodaterol monotherapy in this four-week study.9
In another dose-ranging trial, Maltais
and associates investigated the bronchodilator efcacy of a xed-dose combination
of tiotropium and olodaterol in comparison with tiotropium monotherapy, both
administered using the Respimat Soft Mist
inhaler, in 360 patients (196 men and 164
women; mean age, 63 years) with COPD.
FEV1 was measured pre-dose (trough)
and for up to six hours post-dose.10
At the end of this randomized, doubleblind, parallel-group study, the peak FEV1
response from baseline was signicantly
increased for all doses of the tiotropium/
olodaterol combination (5/2, 5/5, and
5/10 mcg) compared with tiotropium
(5 mcg) alone.10 The mean differences
in trough FEV1 for the tiotropium/olodaterol doses of 5/2, 5/5, and 5/10 mcg
once daily from olodaterol 5 mcg were
0.24 L, 0.033 L, and 0.057 L, respectively.4
4^]a\Mcâh EcdQWRb
The positive results from the doseranging studies of xed-dose tiotropium/
H^Z@^ 7ROadMah P&T
99
DRUG FORECAST
olodaterol combinations supported the
evaluation of once-daily doses of tiotropium/olodaterol 2.5/5 mcg and 5/5 mcg
in two 52-week, phase 3 conrmatory trials.4,11 These replicate, randomized, double-blind, active-controlled, parallel-group
studies evaluated a total of 5,162 COPD
patients (1,029 receiving tiotropium/
olodaterol 2.5/5 mcg or 5/5 mcg, 1,033
receiving tiotropium 2.5 mcg or 5 mcg,
and 1,038 receiving olodaterol 5 mcg). All
of the products were administered using
the Respimat inhaler.4,11 The primary endpoints of both studies were the change
from baseline in FEV1 AUC03 hrs and
trough FEV1 after 24 weeks of treatment.4
Most of the 5,162 patients were men
(73%) and were either white (71%) or
Asian (25%), with a mean age of 64 years.
The mean post-bronchodilator FEV1 was
1.37 L, and the mean beta2-agonist responsiveness was 16.6% of baseline (0.171 L).
Pulmonary medications, such as inhaled
steroids (47%) and xanthines (10%), were
allowed as concomitant therapy.4
In both studies, the two xed-dose

combinations of tiotropium/olodaterol
(2.5/5 mcg and 5/5 mcg) signicantly
improved FEV1 AUC03 hrs and trough
FEV1 compared with the individual
components.
FEV1 AUC03 hrs responses for tiotropium/olodaterol (2.5/5 mcg and 5/5 mcg),
for tiotropium (2.5 mcg and 5 mcg), and
for olodaterol (5 mcg) were 241, 256, 148,
139, and 133 mL, respectively, in the rst
study, and 256, 268, 125, 165, and 136 mL,
respectively, in the second study. In both
trials, the improvements in the adjusted
mean FEV1 AUC03 hrs with tiotropium/
olodaterol (2.5/5 mcg and 5/5 mcg) versus those with the corresponding individual components were statistically signicant (P < 0.0001) for all comparisons.11
Similarly, trough FEV1 responses
after 24 weeks for tiotropium/olodaterol
(2.5/5 mcg and 5/5 mcg), for tiotropium
(2.5 mcg and 5 mcg), and for olodaterol
(5 mcg) were 111, 136, 83, 65, and 54 mL,
respectively, in the rst study, and 125,
FMOZR5adUbIWcVMB^cR]cWMZc^;]cRaMPcIWcV7WgRQ5^bRFW^ca^_Wd\AZ^QMcRa^Z4
2UR]c
B^cR]cWMZ;]cRaMPcW^]b
Adrenergic drugs
Coadministration with tiotropium/olodaterol may potentiate

sympathetic effects of olodaterol.
Anticholinergic drugs
Coadministration with tiotropium/olodaterol may increase

anticholinergic adverse effects.
Beta-adrenergic
receptor antagonists
Beta blockers and olodaterol (a beta-adrenergic receptor agonist)

may interfere with each others effects when administered concurrently. Beta blockers inhibit therapeutic effects of beta agonists
and may produce severe bronchospasm in COPD patients.
Diuretics

hypokalemic effects of olodaterol.
Nonpotassium-sparing
diuretics
ECG changes and/or hypokalemia may result from coadministration

of nonpotassium-sparing diuretics and beta agonists, such as
olodaterol.
QTc-prolonging agents
Action of adrenergic agonists, such as olodaterol, may be

potentiated by QTc-prolonging agents, such as monoamine
oxidase inhibitors and tricyclic antidepressants. Drugs that
prolong QTc interval may increase risk of ventricular arrhythmias.
Steroids

Sympathomimetic drugs

Xanthine derivatives

COPD = chronic obstructive pulmonary disease; ECG = electrocardiogram
100 P&T
7ROadMah H^Z@^
145, 62, 96, and 57 mL, respectively, in

the second study. The improvements
with tiotropium/olodaterol 2.5/5 mcg
and 5/5 mcg over the corresponding
individual components were statistically
signicant (P < 0.05) in both studies.11
E276FK BDA7;>6
2QeRabR 6eR]cb W] 4AB5 FaWMZb

The primary safety database for tiotropium/olodaterol consists of pooled data
from the two 52-week conrmatory studies described previously. These studies
included a total of 1,029 patients who were
treated with tiotropium/olodaterol once
daily. Tiotropium 5 mcg and olodaterol
5 mcg were included as active control
arms in both studies; no placebo treatments were used.4
In these two clinical studies, 74.0% of
the patients treated with tiotropium/
olodaterol reported an adverse event,
compared with 76.6% and 73.3% of the
olodaterol and tiotropium groups, respectively. The most common adverse events
were nasopharyngitis (12.4% for tiotropium/olodaterol, 11.7% for tiotropium,
and 12.6% for olodaterol), cough (3.9%,
4.4%, and 3.0%), and back pain (3.6%, 1.8%,
and 3.4%).4 In both studies, the most common serious adverse events were COPD
exacerbation and pneumonia.
The proportions of patients who discontinued treatment because of an adverse
event were 7.4% for the tiotropium/olodaterol group, 9.9% for the olodaterol group,
and 9.0% for the tiotropium group. The
adverse event most commonly leading to
discontinuation was worsening COPD.4
5adU5adU ;]cRaMPcW^]b
Several drugs, including adrenergic
agents, sympathomimetics, and non
potassium-sparing diuretics, should be
used with caution with xed-dose tiotropium/olodaterol because of the potential for adverse drugdrug interactions.
These medications are listed in Table 1.4
4^]caMW]QWPMcW^]b
All LABAs, including olodaterol,
increase the risk of asthma-related death
and are contraindicated in patients with
asthma without the use of a long-term
asthma-control medication. Fixed-dose
tiotropium/olodaterol is not indicated for
the treatment of asthma.4 Further, xeddose tiotropium/olodaterol is contraindicated in patients with a hypersensitiv-
DRUG FORECAST
ity to tiotropium, ipratropium, olodaterol,
or any component of the product.4
Immediate hypersensitivity reactions,
including angioedema, itching, and rash,
have been reported in both clinical trials
and post-marketing experience with tiotropium monotherapy. Hypersensitivity reactions were also reported in clinical studies
of xed-dose tiotropium/olodaterol.4
=Rh IMa]W]Ub M]Q BaRPMdcW^]b

Asthma-Related Death
Data from a large placebo-controlled
study in asthma patients showed that
long-acting beta2-adrenergic agonists may
increase the risk of asthma-related death.
The increased risk of asthma-related death
is considered a class effect of these agents,
including olodaterol. No studies have been
conducted to determine whether the rate
of asthma-related death is increased in
patients treated with tiotropium/olodaterol. As noted above, tiotropium/olodaterol is contraindicated in asthma patients.4
Deterioration of COPD
and Acute Episodes
Treatment with tiotropium/olodaterol
should not be initiated in patients with
acutely deteriorating COPD because the
drug has not been studied in this population. Moreover, tiotropium/olodaterol
should not be used to relieve acute symptoms of COPD, i.e., as rescue therapy for
the treatment of acute episodes of bronchospasm. When prescribing tiotropium/
olodaterol, health care providers should
also prescribe an inhaled, short-acting
beta2 agonist in case rescue therapy is
needed, and they should instruct patients
on how and when to use it.4
Paradoxical Bronchospasm
As with other inhaled drugs containing beta2-adrenergic agents, tiotropium/
olodaterol may cause paradoxical bronchospasm, which may be life-threatening.
If paradoxical bronchospasm occurs,
tiotropium/olodaterol should be stopped
immediately and an alternative therapy
instituted.4
Cardiovascular Effects
Olodaterol, like other beta2 agonists,
can produce a clinically signicant cardiovascular effect in some patients, as
measured by increases in pulse rate, systolic or diastolic blood pressure, and/or
other cardiovascular symptoms. If such
effects occur, tiotropium/olodaterol may

need to be discontinued. In addition, beta
agonists have been reported to produce
ECG changes, such as prolongation of the
QTc interval, but the clinical signicance
of these ndings is unknown. LABAs
should be administered with caution in
patients with cardiovascular disorders,
especially coronary insufciency, cardiac
arrhythmias, hypertrophic obstructive
cardiomyopathy, and hypertension.4
Worsening of Narrow-Angle Glaucoma
Tiotropium/olodaterol should be used
with caution in patients with narrow-angle
glaucoma. Prescribers and patients
should be alert for signs and symptoms
of acute narrow-angle glaucoma. If any of
these signs or symptoms should develop,
the patient should consult a physician
immediately.4
Worsening of Urinary Retention
Tiotropium/olodaterol should be used
with caution in patients with urinary
retention. Prescribers and patients should
be alert for signs and symptoms of prostatic hyperplasia or bladder-neck obstruction, such as difculty passing urine or
painful urination. If any of these signs or
symptoms should develop, the patient
should consult a physician immediately.4
Renal Impairment
Because tiotropium is mainly excreted
via the kidneys, patients with moderateto-severe renal impairment (i.e., those
with a creatinine clearance of 60 mL/min
or less) treated with tiotropium/olodaterol should be monitored closely for anticholinergic effects.4
Hypokalemia and Hyperglycemia
Beta-adrenergic agonists may produce
signicant hypokalemia in some patients,
which can result in adverse cardiovascular effects. This decrease in serum potassium is usually transient and does not
require supplementation. The inhalation
of high doses of beta2-adrenergic agonists
may increase plasma glucose levels.4
Clinically relevant decreases in serum
potassium or changes in blood glucose
occurred infrequently during clinical trials involving the long-term administration
of olodaterol, with rates similar to those of
placebo-treated controls. Olodaterol has
not been investigated in patients whose
diabetes mellitus is not well controlled.4
5AE286 2@5 25?;@;EFD2F;A@

The recommended dose of tiotropium/
olodaterol is two inhalations once daily
at the same time of the day. Tiotropium/
olodaterol should not be used at more
than two inhalations every 24 hours.
Before the rst use, the tiotropium/
olodaterol cartridge is inserted into the
Stiolto Respimat inhaler and the unit is
primed. When using the unit for the rst
time, patients should actuate the inhaler
toward the ground until an aerosol cloud
is visible, and then repeat the process
three more times. The unit is then considered primed and ready to use. If it is not
used for more than three days, patients
should actuate the inhaler once to prepare
the inhaler for use. If it is not used for
more than 21 days, patients should actuate the inhaler until an aerosol cloud is
visible and then repeat the process three
more times to prepare the inhaler for use.4
No dosage adjustment is required for
geriatric, hepatically impaired, or renally
impaired patients. However, patients with
moderate-to-severe renal impairment treated
with tiotropium/olodaterol should be monitored closely for anticholinergic effects.4
COST
The average wholesale price (AWP)
of one tiotropium/olodaterol inhalation
device is $379. Each device supplies 60
metered inhalations of 2.5/2.5 mcg per
actuation, meaning it should last 30 days
using the recommended regimen of two
inhalations per day.12
BF 4A??;FF66
CONSIDERATIONS
Because several drug classes are
available for the treatment of COPD,
many hospital pharmacies are questioning which of these agents should be on
their institutions formularies for inpatient
use. Of the many drug classes used for
COPD, LABAs and anticholinergics are
the mainstays of current treatment protocols.3 Both of these drug classes promote
bronchodilation and improve airow in
COPD patients.
Fixed-dose tiotropium/olodaterol
offers a long-acting beta2 agonist in combination with a long-acting anticholinergic. Because of their extended activity,
the two agents have an additive effect in
maintaining airway dilation.4 Since the
approval of tiotropium bromide inhalation
powder (Spiriva HandiHaler) and olodat-
H^Z@^ 7ROadMah P&T
101
DRUG FORECAST
erol (Striverdi Respimat), both marketed
by Boehringer Ingelheim, the combined
use of anticholinergics and LABAs has
been widely incorporated into clinical
practice and has been added to treatment
guidelines for outpatient settings.3
It must be emphasized, however, that
although tiotropium and olodaterol have
been on the U.S. market for some time,
they have not been widely used as a xeddose combination, and their long-term
safety as a dual product has not yet been
established. Current treatment recommendations for COPD exacerbations call
for the use of short-acting agents, such
as albuterol or ipratropium bromide.13
Fixed-dose tiotropium/olodaterol is not
approved for the treatment of acute exacerbations of COPD and would therefore
be of limited use in acutely stressed hospitalized patients. Moreover, most COPD
patients will probably bring their maintenance therapy to the hospital from home.
While of limited use in an inpatient setting, xed-dose tiotropium/olodaterol has
the potential to become a valuable option
for outpatients. According to the Global
Initiative for Chronic Obstructive Lung
Disease (GOLD) guidelines, long-acting
anticholinergics and LABAs are the treatments of choice for GOLD classications
2 through 4.3 Therefore, tiotropium/
olodaterol, a combination of both drug
classes, is likely to provide optimal airway
dilation. In addition, the product will probably appeal to patients because of its combination of two effective drug classes, and
because it reduces the number of inhalers
required for maintenance therapy.
Fixed-dose tiotropium/olodaterol
is similar to umeclidinium/velanterol
(Anoro Ellipta, GlaxoSmithKline)
another anticholinergic/LABA combination product (approved by the FDA in
2013). Tiotropium/olodaterol requires
patients to inhale two puffs once daily,
whereas umeclidinium/velanterol
requires patients to inhale only one puff
once daily. Despite this difference, tiotropium/olodaterol comes with 60 actuations
compared with 30 actuations for umeclidinium/velanterol. Hence, the two medications are similar in terms of the length
of treatment with each inhaler device.14,15
Their costs are also the same: the AWP
of an umeclidinium/velanterol inhaler,
which should last for 30 days, is $379.12,15
One advantage that tiotropium/olodaterol
has over umeclidinium/velanterol is that
102 P&T
7ROadMah H^Z@^
it can be used in patients with an allergy

to milk. Milk proteins are used during the
manufacturing process of umeclidinium/
velanterol; therefore, this medication cannot be used in patients who are allergic to
milk. Further, umeclidinium/velanterol,
which uses a dry-powder inhaler, requires
patients to inhale with a long, steady, deep
breath, which may be difcult for elderly
patients. Tiotropium/olodaterol allows
patients to inhale normally.14,15
4A@4>GE;A@
The anticholinergic and LABA drug
classes have been shown to decrease
exacerbations and to improve respiration in patients with COPD. Tiotropium/
olodaterol (Stiolto Respimat) is the newest combination drug product indicated
for the maintenance of COPD.16 Recent
studies have demonstrated that the combination of tiotropium bromide and olodaterol hydrochloride is more effective at
improving FEV1 AUC03 hrs than either of
the two agents used alone.11 Tiotropium/
olodaterol is also one of the few combination products that includes a LABA and a
long-acting anticholinergic. Like olodaterol alone, the xed-dose combination of
tiotropium and olodaterol improves airow
within ve minutes after the rst dose.16
While the xed-dose product has been
associated with various adverse events,
including nasopharyngitis, pneumonia,
cough, and back pain, the proportions of
patients who withdrew from clinical trials
because of such events were signicantly
lower for the tiotropium/olodaterol combination than for tiotropium or olodaterol
alone.4 With these considerations in mind,
xed-dose tiotropium/olodaterol appears
to offer an attractive option for the maintenance treatment of patients with COPD.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
D676D6@46E
1.
2.
3.
4.
Centers for Disease Control and Prevention. Chronic obstructive pulmonary disease (COPD). March 12, 2015. Available
at: http://www.cdc.gov/copd/index.html.
Accessed June 10, 2015.
Barnes PJ. Chronic obstructive pulmo>ì>iU\ii>iv
COPD. Thorax 2003;58:803808.
Global Initiative for Chronic Obstructive
Lung Disease. Pocket guide to COPD
diagnosis, management, and prevention:
a guide for health care professionals. 2015.
Available at: http://www.goldcopd.org/
uploads/users/les/GOLD_Pocket_2015_
Feb18.pdf. Accessed June 10, 2015.
Stiolto Respimat (tiotropium bromide/
olodaterol inhalation spray) prescribing
15.
16.
information. Ridgeeld, Connecticut: Boehringer Ingelheim Pharmaceuticals, Inc.;

June 2015. Available at: http://docs.boehringer-ingelheim.com/Prescribing%20
Information/PIs/Stiolto%20Respimat/
stiolto.pdf. Accessed October 15, 2015.
MedLibrary. Stiolto Respimat. June 25,
2015. Available at: http://medlibrary.org/
lib/rx/meds/stiolto-respimat. Accessed
November 4, 2015.
RxList. Stiolto Respimat. 2015. Available at: http://www.rxlist.com/stioltorespimat-drug/indications-dosage.htm.
Accessed June 13, 2015.
Micromedex. Tiotropium bromide. Available at: http://www.micromedexsolutions.com. Accessed June 13, 2015.
Micromedex. Olodaterol hydrochloride.
Available at: http://www.micromedexsolutions.com. Accessed June 13, 2015.
Aalbers R, Maleki-Yazdi MR, Hamilton A,
et al. Dose-nding study for tiotropium
and olodaterol when administered in
combination via the Respimat inhaler in
patients with COPD [poster]. Presented
at the European Respirator y Society
Annual Congress; Vienna, Austria; September 15, 2012. Available at: http://
www.boehringer-ingelheim.com/content/dam/internet/opu/com_EN/document/05_clinical_trials/P2882_Aalbers_
Tiotropium_and_Olodaterol_ERS_2012_
poster.pdf. Accessed November 4, 2015.
Maltais F, Beck E, Webster D, et al.
Four weeks once daily treatment with
tiotropium+olodaterol (BI 1744) xed
dose combination compared with tiotropium in COPD patients. Eur Respir J
2010,36:1014s [abstract 5557].
Buhl R, Maltais F, Abrahams R, et al. Tiotropium and olodaterol xed-dose combination versus mono-components in COPD
(GOLD 24). Eur Respir J 2015;45:969979.
Red Book Online. Ann Arbor, Michigan: Truven Health Analytics. Accessed
December 28, 2015.
Carrera M, Sala E, Cosio BG, et al. Hospital treatment of chronic obstructive
pulmonary disease exacerbations: an
evidence-based review. Arch Bronconeumol 2005;41:220229.
Straight Healthcare. Inhaled anticholinergics. Available at: http://www.straighthealthcare.com/inhaled-anticholinergics.
html#anoro-ellipta. Accessed June 24, 2015.
Anoro Ellipta (umeclidinium/vilanterol
inhalation powder) prescribing information. Triangle Park, North Carolina:
GlaxoSmithKline; May 2014. Available at:
https://www.gsksource.com/pharma/
content/dam/GlaxoSmithKline/US/en/
Prescribing_Information/Anoro_Ellipta/
pdf/ANORO-ELLIPTA-PI-MG.PDF.
Accessed November 4, 2015.
Boehringer Ingelheim. FDA approves
Boehringer Ingelheims Stiolto Respimat as once-daily maintenance treatment for COPD. May 26, 2015. Available
at: https://www.boehringer-ingelheim.
com/news/news_releases/press_
releases/2015/26_may_2015_copd.html.
Accessed June 14, 2015. Q
752;]cR]bWRb5aWeRc^DRQdPRD6?E3daQR]b
FVR=RhAOXRPcWeR;bc^6MbRIâY^fAObcMPZRbSâBVMa\MPWbcb
Stephen Barlas
ast August, Danielle Boyce brought her young son to a
record (EHR) and independently contact an outside specialty
pharmacy that the manufacturer has designated. That leads
Pennsylvania hospital for brain surgery. The boy has catato fragmentation in the patients care and delay in getting the
strophic epilepsy and takes vigabatrin (Sabril, Lundbeck).
patient his or her medication, she explains.
Sabril is a prescription medicine used with other treatments in
Even when hospital and retail pharmacists can obtain the
adults and children 10 years of age and older with refractory
drugs, those with ETASU complicate the dispensing process,
complex partial seizures and in babies 1 month to 2 years old
with infantile spasms, if the possible benets outweigh the
forcing physicians and pharmacists to obtain certications,
possible risk of vision loss. Boyces son has infantile spasms.
make sure patients have gotten requisite tests, and complete
Because of the serious risk of vision loss associated with
numerous electronic tasks that cannot be done on their physiSabril, the FDA, when it approved the drug, required
cian and pharmacy software, much less inside the
Lundbeck to establish a risk evaluation and mitigapatients EHR. Katie Stabi, PharmD, BCPS, Clinical
tion strategy (REMS).
Coordinator of Drug Use Policy and Compliance at
University of Chicago Medicine, estimates it takes
Seventy-four pharmaceuticals have REMS
attached, as do four classes of drugs; a list is availa hospital from three weeks to three months to
able at the FDAs website.1 All of those drugs provide
implement a new REMS, including 160 hours of
major benets, but they also have potentially devaspharmacy workload.
tating side effects, which is why the FDA requires a
The FDA has been holding public workshops over
REMS as the price of approval. Some REMS require
the past few years, at Congresss insistence, and is
slowly but surely working on solutions to some of
physicians, pharmacists, and patients to do relatively
Stephen Barlas
little to obtain access, often from a specialty pharthose problems. The latest workshop took place
macy. Other REMS have elements to assure safe use (ETASU)
for a day and a half in early October 2015.2 A couple of major
attached, which require completion of such steps as certicaagency initiatives are nally emerging and were discussed there,
tion, tests, paperwork, and other tasks before access to the
though in very broad strokes. Perhaps the most signicant is a
drug is granted, often by a third-party REMS administrator
four-month pilot program that is about to end in which manuengaged by the manufacturer. In the case of Sabril, that is the
facturers with REMS have submitted the applicable documents
SHARE program.
to the agency in a format called structured product labeling
(SPL). Manufacturers already submit labeling information in
When Boyce and her son arrived at the hospital, their supply
this format, but using it for REMS will give those documents a
of Sabril was dangerously low. However, the hospital was not
allowed to dispense Sabril. So we had to order more from the
consistent format, allow them to be incorporated into EHRs, and
mail-order pharmacy, and someone had to go home, get the
greatly reduce the workow burden on physicians and pharmadrug once it was delivered, and bring it back to the hospital,
cists. Another initiative earning praise from the pharmaceutical
where we had to check it in, Boyce explains. But I wouldnt
community is the FDAs new website called REMS@FDA.
give the hospital the whole supply for fear they would lose it
and we wouldnt be able to get any more. It really added to my
D6?E:Wbcâh
stress. We hear this from families all the time.
Congress required the FDA to establish a REMS program in
The difculty some patients experience obtaining critical
2007, replacing an earlier program called RiskMap. But REMS
REMS drugs, whether at the hospital or in their homes, is
requirements can be confusing, with drug companies using
just one of the criticisms that has buffeted the program since
different terminologies and sometimes mandating different
Congress authorized it in 2007. The stranglehold specialty
requirements. The lack of standardization of elements within
pharmacies have on access is a continuing complaint from
the current REMS programs creates an unnecessary burden
hospitals and even community pharmacies.
and practical impediment to their implementation, says Melissa
JoAnn Stubbings, BS Pharm, Assistant Director of Specialty
Schulman, Senior Vice President for Government and Public
Affairs at CVS Health.
Pharmacy Services at the University of Illinois Hospital and
About half of currently approved REMS programs include
Health Sciences System, says the health care accrediting
organization URAC has accredited her specialty pharmacy
ETASU. These especially prickly demands require signicant
for its closed loop workow system. That system employs
outlays of time on the part of physicians and pharmacists. The
clinical pharmacists for all sorts of tasks. But we have been
REMS produced by Celgene for lenalidomide (Revlimid) is 100
denied access to some drugs with REMS, she says, meanpages long, for example.
ing the pharmacy has to leave the patients electronic health
The iPLEDGE program for isotretinoin, which treats severe
recalcitrant nodular acne, is frequently cited as an example
of how REMS programs should not work. There, pharmacies
Mr. Barlas, a freelance writer based in Washington, D.C., covers
topics inside the Beltway.
encounter challenges that include, but are not limited to, the
H^Z@^ 7ROadMah P&T
103
recertication and retraining requirements for participating
pharmacies; the need to access the iPLEDGE Web portal and
interactive voice response system; and matching iPLEDGE
patient identication numbers, says Michelle Cope, Director
of State Public Policy for the National Association of Chain
Drug Stores.
One REMS program is easier for pharmacists to fulll than
others: the transmucosal immediate-release fentanyl (TIRF)
shared REMS. TIRF opioid agents include brand-name drugs
Abstral (Galena Biopharma), Actiq and Fentora (Cephalon),
Lazanda (Depomed Inc.), and Onsolis (BioDelivery Sciences
International, Inc.). They are used to manage breakthrough
pain in adults with cancer who routinely take other opioid
pain medications around the clock. This was the rst class
REMS the FDA approved. In 2011, the FDA approved use of a
switch to ensure compliance, allowing pharmacies to avoid
going to a manufacturer or even the FDA website to obtain
clarication or approval of the claim.
Michele Davidson, RPh, Manager of Pharmacy Technical
Standards for Walgreens and Chairman of the Board of
Trustees of the National Council for Prescription Drug
Programs (NCPDP), says a TIRF prescription is lled via a
normal NCPDP transaction within the retail pharmacys existing software dispensing system (which, unfortunately, does
not work for hospital pharmacies, which use an X-12 standard
when submitting claims). The retail pharmacy sends the claim
to an intermediary (in the case of the TIRF REMS, a company
called Relay Health), which in this system is called the switch.
Relay acts as the REMS administrator. Relay takes the claim,
does whatever edits are necessary, approves the claim, and then
forwards the claim to the payer/processor before the claim
is transmitted back to the pharmacy. All of this transpires in
less than a second. The whole transaction is done within the
pharmacys normal dispensing system. However, if the switch
discovers that the physician didnt do what he or she needed
to do as part of his or her REMS responsibilities, the claim
will be rejected and returned to the pharmacy. The pharmacist
must then go back to the physician and correct the problem.
That is where SPL will come inif it comes in (more on that
later). With SPL, REMS approval is done within a physicians
e-prescribing system, so the prescription doesnt go to the
pharmacy until it is cleared by the REMS administrator. The
pharmacy sees what the physician has done within the patients
EHR. SPL would be an advantage over the switch process
because in the latter case, pharmacies must build their own
alerts specic to each REMS (so far only the TIRF REMS uses
a switch) into their claims system. Every pharmacy has to do
this on its own. With SPL, those alerts can be integrated into
everyones system in the same manner, Davidson explains.
ll gaps beyond the scope of the retail pharmacies, since they

already dedicate the necessary educational and administrative
time. REMS programs such as those developed by Celgene
for Revlimid, Pomalyst (pomalidomide), and Thalomid (thalidomide) are not conducive to the retail environment and
t better in the specialty environment due to burdensome,
time-consuming requirements, such as:
UProviding patient or caretaker consultation for every ll.
UObtaining and maintaining conrmation and authorization numbers.
UTracking each dispensing to adhere to quantity restrictions.
UEnsuring appropriate documentation is received.
Paul Sheehan, head of REMS for Celgene, puts it this way:
To satisfy this REMS obligation in a manner that optimizes both
patient safety and access, Celgene has adopted a limited distribution network of specialty pharmacies, hospitals, and clinics that
are authorized to dispense each of these three products. Including
additional providers into the limited distribution networks could
unnecessarily weaken the operation and effectiveness of our REMS
and could make the certication, training, auditing, and monitoring
requirements of the REMS infeasible.
7526âcbc^;\_aêRD6?E
Although Congress authorized the REMS program in 2007,
it took an additional signicant step in 2012. In exchange for
increasing user fees that drug companies pay to the agency, the
FDA agreed, among other things, to measure the effectiveness
of REMS, to continue to develop techniques to standardize
REMS, and, with stakeholder input, to seek to integrate REMS
into the existing and evolving health care system. The agency
issued a report on its ndings regarding REMS standardization
in fall 2014 that unveiled four pilot projects:3
UDevelop a report for stakeholders of ndings, counseling processes, and tools that could serve as the basis for
designing new tools and validating them in demonstration
projects.
UProvide an analysis of time and resources required
related to developing and using continuing education
(CE) programs to conduct REMS-related training and/or
communication.
UInvestigate developing SPL for REMS content, including
REMS documents, requirements, and materials.
UAllow stakeholders to compare requirements across REMS
and minimize confusion associated with complying with
multiple REMS programs.
IVÊV^dZQ5Wb_R]bR
Simplifying and injecting uniformity into REMS, which the
FDA is attempting to do with its SPL project, would not address
the access issue. Specialty pharmacies and manufacturers
believe there are good reasons to keep some REMS drugs
mostly those with ETASUout of the hands of hospital and
retail pharmacies. Schulman says the FDA should label some
REMS drugs as specialty only so they are handled appropriately. CVS Health believes that the specialty pharmacies will
104 P&T
7ROadMah H^Z@^
The completion of these projects is especially important for

pharmacists, who, the draft report acknowledged, bear most
of the burden for assuring REMS requirements are met. The
draft said:
FDA was advised that, in many organizations, primary responsibility for knowing the individual REMS requirements for prescribers,
patients, and dispensers often falls to the pharmacist. Pharmacists
noted they need to clearly understand who (prescribers, pharmacists,
nurses, etc.) is accountable for each role or activity under a REMS.
FDA heard that pharmacists often monitor individual health care
provider responsibilities for REMS with ETASU elements, especially
in inpatient health care settings. Some stakeholders expressed
concern about the administrative burden that often falls upon the
pharmacist to ensure appropriate REMS forms are completed.
Subsequent to that 2014 draft report, the FDA has made some
headway in reducing the burden on pharmacists. One perceptible advance is the new REMS@FDA website. Dr. Stabi notes
that pharmacists looking for guidance on particular aspects of
a REMS can go to ve different sources and sometimes get
ve different answers. These ve are: REMS@FDA, the REMS
document, the REMS full document, the enrollment form, and
the REMS call center. These all provide information on what
training and what level of knowledge a pharmacist must have
before he or she can participate in a given REMS. Pharmacists
can face scenarios not addressed in the REMS document, she
explains. What many pharmacists have found is that REMS
representatives at a call center are not sure how to answer these
questions and often provide answers that contradict what we
nd in the REMS document. She says the new REMS@FDA
website should be the source of truth.
While the new website is an advance and the pilot projects
are in different stages of development, the FDA knows it needs
to go further. That was the purpose of the public meeting held
at the FDA ofces in Maryland on October 5 and 6, 2015.2 The
meeting was held so the agency could obtain information on
improved strategies for evaluating and minimizing the burden
of REMS on the health care delivery system to the extent
practicable and their impact on patient access to the drugs
covered by such programs.
BVMa\MPhIâYZ^MQDRQdPcW^]
One of the key targets for the FDA is integrating more
functionality into REMS documents, particularly with regard
to integrating them with EHRs, which, for the most part, is
not possible today. SPL is a data standard used to capture and
share structured information about drug products. SPL is
maintained by Health Level Seven (HL7), a standards development organization that develops numerous standards for the
transmission of information about health care and medical
product regulation. The majority of information currently
included in SPL, including general product information, the
content of drug labeling, and registration and listing information, is entered by a sponsor and submitted to the FDA. As a
result, the FDA does currently receive some information in
the SPL format. HL7 published release 6 of the HL7 version 3
standard last February, and that allowed the FDA to start
drafting what it calls artifacts, which included a structured
prototype REMS, a controlled terminology/code set for key
REMS concepts, and an implementation guide.
Those artifacts were at the center of the four-month pilot
project started in November 2015 in which interested manufacturers submitted REMS data to the agency using SPL. For
all REMS programs in the pilot, the REMS document was captured using standardized section headings. This information is
captured in two places: a human-readable REMS summary and
associated machine-readable data elements. Both the REMS

summary and the data elements will capture four basic pieces
of information about each requirement:
UWho is required to carr y out the requirement. For
example, a requirement may be carried out by the health
care provider who prescribes the drug or dispenses it.
UWhat that individual is required to do. This could include a
clinical activity, such as counseling a patient, or an administrative one, such as completing an enrollment form.
UWhen the activity must be carried out. For example, a
REMS activity may need to be completed before a drug
is prescribed or dispensed, or before a patient is able to
receive the drug.
UReferences to REMS materials that may contain additional
information about the requirement, such as forms and
educational materials.
Adam Kroetsch, policy and information advisor at the FDA,
says that once REMS are formatted in SPL, the REMS elements
and requirements can be searched easily by a pharmacist on
his or her pharmacy system. The SPL format allows the REMS
document to be interpreted by computer and within electronic
health records, he explains. The FDA had nine spots available for the pilot, and all nine were lled. Kroetsch declines
to name the companies that participated. The nine REMS
will apparently be stored in the DailyMed repository at the
National Institutes of Health (http://dailymed.nlm.nih.gov/
dailymed). At that point it is up to drug information providers
to incorporate the REMS into pharmacy software systems.
Some insurers integrate REMS data into EHRs on their own;
Kaiser Permanente is one of the leaders. Kaiser Permanente
has its own national specialty pharmacy with a specialty pharmacy information management system (SPIMS) that provides
comprehensive functionality to link the pharmacy system to
the EHR. If a patient is receiving a drug with REMS ETASU,
SPIMS can issue system alerts to pharmacists (about required
laboratory tests, rells, etc.). It can verify prescriber compliance and has added safety measures. The integration through
the EHR provides assurance of fulllment of REMS requirements to ensure patient safetylab results, other medications
taken, clinical factors, etc. The EHR can provide additional
safeguards such as the ability to check progress notes, track
electrocardiograms or other recommended measures, or view
the REMS medication lls in the comprehensive medication
lists consulted by other prescribers, emergency department
staff, or other providers.
Jennifer M. Day, PharmD, Pharmacist Evidence Analyst and
Strategist at Kaiser Permanente Drug Information Services,
says the problem comes when Kaiser has to go to an outside
specialty pharmacy to get a REMS drug. The typical ow of
clinical information between the pharmacist and the provider
is interrupted and we lose key features of SPIMS design, such
as those that improve safety, adherence, and data collection.
While the NCPDP is working on a standard that would
set the stage for e-prescribing systems to incorporate REMS
in SPL, that standard needs to be broadened so that it can
be used by hospital pharmacies, too, which use a rival standards group for their e-prescribing systems. The NCPDP has
H^Z@^ 7ROadMah P&T
105
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@Rf5WaRPcW^]bW]cVRFaRMc\R]c^S4Va^]WPBMW]
@McW^]MZBMW]EcaMcRUhIWZZ8dWQRBaReR]cW^]?M]MUR\R]cM]QDRbRMaPV
Susan L. Worley
More than four years after the release of a landmark report
manage these complex conditions. Ultimately it will lead toward
by the Institute of Medicine (IOM) on pain in America, there
providing people who are suffering from pain the wide range
are encouraging signs that the U.S. may be poised to undergo
of services that already exist but that currently are not readily
the cultural transformation advocated by the report.
available to everyone.
Many of the services available today can be found at the
The IOMs 2011 publication, Relieving Pain in America:
A Blueprint for Transforming Prevention, Care, Education,
Stanford Pain Management Center, which has been recognized
and Research,1 succeeded in bringing attention to the longas a Center of Excellence by the American Pain Society and is
underappreciated problem of pain. The report has also served
a model for approaching pain treatment from a biopsychosocial
as an often-cited source of facts that continue to startle new
perspective. At the center, interdisciplinary teams of specialists design tailored treatment plans for patients with acute or
readersincluding the estimate that, in 2011, approximately
chronic pain to address multiple problems that contribute to
100 million U.S. adults suffered from pain at a cost of approxipain and interfere with functioning.
mately $560 billion to $635 billion a year.1 The publication
In partnership with the NIH, and in response to objectives
acknowledged that an underfunding of research was a signicant
outlined in the IOM report and the NPS, researchers at the
barrier to progress, with only about 1% of a National Institutes
of Health (NIH) budget that exceeded $30 billion devoted to
Stanford Systems Neuroscience and Pain Laboratory (SNAPL)
the study of pain; however, it envisioned a comhave established the Collaborative Health
Outcomes Information Registry (CHOIR),
prehensive solution to the problem that went
far beyond the development of new treatments.
an open-source platform that will be used to
Relabeling pain a biopsychosocial phenomcollect much-needed outcomes data on large
enon, the report urged a new recognition of its
numbers of patients suffering from chronic
complex, multidimensional nature, as well as the
pain. Researchers at the lab also are examining
wide range of individual variations in susceptibilemotional and cognitive factors that inuence
ity to pain, cultural and emotional interpretations
pain, as well as neuroplastic changes that occur
of pain, and responses to treatment.
in response to chronic pain, with a focus on the
One eagerly awaited legacy of the IOM report
use of neuroimaging3 to investigate normal
is the soon-to-be-released nal draft of the
pain processing, pain disorders, and treatment
National Pain Strategy (NPS),2 which the NIH
options. Among current projects are studies
has described as a comprehensive population
using functional magnetic resonance imaging
healthlevel strategy for pain prevention, treat(fMRI) to examine how real-time feedback
Sean Mackey, MD, PhD
ment, management, and research. It contains
might be used to improve control over pain,
recommendations for coordinating the efforts of government
and transcranial magnetic stimulation (TMS) to determine how
agencies and publicprivate partnerships to improve pain
various brain regions impact pain processing. Several studies
assessment and management programs throughout the country.
are devoted to identifying factors that lead to chronic pain after
The goal of the National Pain Strategy is to provide patientinjury or surgery, with the goal of developing interventions to
centered, interdisciplinary care that is compassionate, well
prevent the transition to chronic pain.
informed, and individualized to every patient who is experiencOne of our primary interests right now is in the development
ing pain, says Sean Mackey, MD, PhD, Chief of the Division of
of brain-based biomarkers, Dr. Mackey says. Biomarkers
Pain Medicine at Stanford University, who served as co-chair
hold a great deal of promise in helping us to better underof the Oversight Committee of the NPS as well as co-chair of
stand how to distinguish pain from not-pain. Perhaps just as
its Prevention and Care working group. The immediate past
important, they are an integral part of the developing eld of
president of the American Academy of Pain Medicine (AAPM),
neuroprognosisa eld that eventually will allow us to predict
Dr. Mackey was also on the 19-member committee that wrote
whether an individual is more likely to respond to one treatthe 2011 IOM report. He has described the NPS as a tactical
ment compared with another.
document in contrast to the IOM blueprint.
Researchers at Dr. Mackeys lab also are examining novel
pharmacological approaches4 to the treatment of pain, which
The implementation of the National Pain Strategy will
may help to provide patients and clinicians with alternatives
lead to tangible benets to people suffering from pain, says
to treatment with opioids.
Dr. Mackey. It wont happen overnight, but this strategy will
point us in a proper direction moving forward. It will help to
Its important to examine the problem of opioids as part of a
ensure, among other things, that we better educate the physicomprehensive public health issue, and to recognize that there
cians, psychologists, and physical therapists who are caring
isnt going to be a single solution, Dr. Mackey says. We need
for people with pain so that they are better prepared to help
to take a multiple-level approach to this problemto focus, for
example, on better educating our physicians in medical school
Susan Worley is a freelance medical writer who resides in Pennsylvania.
and beyond about the appropriate use of opioids, and about
H^Z@^ 7ROadMah P&T
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Carbamazepine (Tegretol, Novartis)
Trigeminal neuralgia, epilepsy
Often used off label for other chronic pain conditions
Duloxetine (Cymbalta, Eli Lilly)
Diabetic peripheral neuropathic pain,

bromyalgia, chronic musculoskeletal pain, major
depression, generalized anxiety disorder
Gabapentin (Neurontin, Pzer)
Post-herpetic neuralgia, epilepsy
Epilepsy
May be used off label for trigeminal neuralgia

and other neuropathic pain conditions
Post-herpetic neuralgia, neuropathic pain

associated with diabetic peripheral neuropathy,
spinal cord injury pain, bromyalgia, epilepsy
Spasticity
Often used off label for neuropathic pain conditions,

chronic headache, and other conditions
Depression, anxiety, and

some other psychiatric conditions
Often used off label for multiple types

of chronic pain conditions
Management of severe chronic pain in patients

for whom intrathecal therapy is warranted
Recommended reading: Practical Considerations

and Patient Selection for Intrathecal Drug Delivery
in the Management of Chronic Pain (Saulino et al.,
J Pain Res 2014;7:627638).
Lamotrigine (Lamictal,
GlaxoSmithKline)
Pregabalin (Lyrica, Pzer)
Tizanidine (Zanaex, Acorda

Therapeutics)
Tricyclic antidepressants (e.g.,
amitriptyline, nortriptyline, doxepin)
Ziconotide (Prialt, Jazz
Pharmaceuticals)
* May be used off label

Source: Charles E. Argoff, MD. For more information, see Pharmacotherapy for Neuropathic Pain in Adults: a Systematic Review and Meta-Analysis (Finnerup et
al., Lancet Neurol 2015;14:162173); American College of Rheumatology 2012 Recommendations for the Use of Nonpharmacologic and Pharmacologic Therapies in
Osteoarthritis of the Hand, Hip, and Knee (Hochberg et al., Arthritis Care Res [Hoboken] 2012;64:465474); and Medications for Acute and Chronic Low Back Pain:
a Review of the Evidence for an American Pain Society/American College of Physicians Clinical Practice Guideline (Chou et al., Ann Intern Med 2007;147:505514).
how to better recognize those individuals who are vulnerable.

Its also important to educate our patients. The solution is
not going to be simply developing new treatments. In fact,
we already have a lot of nonopioid treatments available now;
however, many physicians are not yet educated about how to
use them appropriately. A list of some currently approved
nonopioid treatments for pain appears in Table 1.
guide clinicians who receive insufcient training in prescribing

these drugs. However, since their release, some experts have
expressed a long list of concerns, ranging from the potential
legal implications of the guidelines to their potential harm to
patients. The American Cancer Society7 and a growing number
of other prominent organizations also have publicly declared
that they cannot endorse restrictions proposed by the CDC.
Lynn Webster, MD, Vice President of Scientic
FVR BMW] 6_WQR\WP HRabdb cVR A_W^WQ 4aWbWb
Affairs at PRA Health Sciences, a recent past
While the U.S. pursues new approaches to the
president of the AAPM and a leading expert
treatment of pain, problems associated with the
on the treatment of chronic pain and the use of
use of opioid analgesics persist and have led to
opioids, says he is troubled by the CDCs draft
considerable divisiveness in this country. Recent
guidelines. The inventor of a renowned opioid risk
editorials on this topic have described antagonism
tool 8 (a short, self-administered patient survey
between two principal groupsa cautious majornow used by thousands of physicians to help
ity of experts, well aware of the drawbacks of
identify individuals vulnerable to the misuse of
opioids), he is acutely aware of the risks posed
opioids but intent on taking a measured approach
to the problem, and a minority who seem intent on
by opioids but maintains that abruptly curtailing
sharply curtailing the use of these drugs despite
their use is not a responsible or humane solution.
potentially disastrous consequences. Discord
Some of the recommendations in the draft
between these groups grew more pronounced
document
are quite strong and were made with
Lynn Webster, MD
after the September 2015 release of draft guidea lack of supporting evidence, Dr. Webster says.
lines for prescribing opioids by the Centers for Disease Control
The recommendation, for example, that prescriptions not
and Prevention (CDC).5
exceed the equivalent of 90 mg of morphine is unsupportable.
A widely perceived opioid crisis, which has been traced to
There is no evidence that patients cannot be safely placed
well-documented increases in the use of opioids since the 1990s,
on more than this amount of the drug. Furthermore, there
recent increases in opioid-related deaths, and ongoing concerns
are millions of Americans who are currently taking this drug
for much-needed pain relief.
about the diversion of these drugs,6 prompted the development
of the guidelines. Their intent, according to the CDC, is to
The author of The Painful Truth (2015), a new book that docu-
108 P&T
7ROadMah H^Z@^
ments personal and physical struggles of individuals suffering
from pain, Dr. Webster says that he receives calls or emails at
least weekly from patients in chronic pain who are panicked
because their doctors are suddenly refusing to continue their
long-time treatment with opioids. With the constant stream
of negative and unbalanced information about opioids in the
media, he adds, doctors have become increasingly afraid even
to treat people in pain.
I think the consequences of these guidelines are potentially
serious, without any foundational evidence for the recommendations they contain, he says, echoing the concerns of a signicant number of his U.S. colleagues. Moreover, Dr. Webster
notes that important recommendations are missing from the
guidelines. Nowhere in the CDC guidelines are clinicians
encouraged to use abuse-deterrent formulations of opioids,
which very clearly have been demonstrated to reduce the
potential harm to patients.
Since 2014, the Food and Drug Administration (FDA) has
approved several abuse-deterrent (AD) formulations of opioids,
and more than 33 states have proposed legislation to require the
inclusion of such AD products on formularies. The development

of novel formulations and routes of administration that address
not only the potential for abuse but also the analgesic tolerance
(diminished pain relief), hyperalgesia (increased sensitivity to
pain), and other problematic side effects associated with opioids
is the focus of a great deal of current research (Table 2).9,10
Dr. Webster and colleagues at PRA Health Sciences are actively
involved in some of these efforts, as well as research aimed at
the development of new nonopioid compounds.
We are about 60 years behind cancer research when it
comes to developing new treatments for pain, Dr. Webster
says. Sixty years ago, cancer researchers were beginning
to look at novel small molecules that could be used to effect
remissions or cures, and there have been wonderful successes
in that eld. Pain researchers are just beginning their journey
on that path. We are already thinking of pain not as a symptom
but as a disease, and we are now examining a growing number
of potential targetsincluding those at sites where pain originates, along various transduction pathways, and in the brain,
where individuals experience pain.
FMOZR ERZRPcRQ@RfA_W^WQ7â\dZMcW^]bG]QRa;]eRbcWUMcW^]Sâ2PdcRM]Q4Va^]WPBMW]
2UR]c
(Manufacturer/Sponsor)
5RbPaW_cW^]?RPVM]Wb\^S2PcW^]
;]QWPMcW^]4^\\R]cb
EcMcdb
ALO-02 (Pzer)11
Small molecule; combination of oxycodone and

naltrexone, extended-release formulation
Chronic pain, abuse-deterrent formulation
NDA led
CEP-33237 (Teva)12
Small molecule; hydrocodone extended-release

formulation
NDA led
CL-108 (Charleston
Laboratories)13
Small molecule; combination of hydrocodone,

acetaminophen, promethazine
Osteoarthritis; moderate-to-severe
pain, reduced opioid-induced nausea
and vomiting
Phase 3
CR845 (Cara Therapeutics/

Enteris BioPharma)14,15
Tetrapeptide/selective kappa-opioid agonist,

peripherally acting
Acute and chronic pain; uremic pruritus

(parenteral); chronic osteoarthritis pain
(oral); anticipated low abuse liability
Phase 2/3
Egalet-001 (Egalet)16
Small molecule; morphine extended-release

formulation
Pre-NDA
MorphaBond ER (Inspirion
Delivery Technologies)17
Small molecule; morphine extended-release

formulation
NDA approved
NKTR-181 (Nektar
Therapeutics)18
Small-molecule polymer conjugate/mu-opioid

receptor agonist; peripherally acting
Chronic pain, slower brain uptake, and

anticipated lower abuse liability than
reference oxycodone
Phase 3
Small-molecule G protein-biased
mu-opioid agonist
Acute postoperative pain (parenteral);

faster onset and stronger analgesia than
morphine with lower adverse event prole,
anticipated low abuse liability
Phase 2b
Small molecule; oxycodone extended-release

formulation
NDA approved
Small molecule; sufentanil formulation
Acute postoperative pain (sublingual),

preprogrammed, patient-controlled
analgesia device; alternative to intravenous
patient-controlled analgesia opioids
Phase 3
Oliceridine, TRV130
(Trevena)19
Xtampza ER (Collegium
Pharmaceutical)20
Zalviso (AcelRx)21
NDA = new drug application

*Selected from data provided by William K. Schmidt, PhD, President, NorthStar Consulting, LLC
H^Z@^ 7ROadMah P&T
109
DRPMcRUâWjW]UBMW]IVWZR6g_ZâW]U@êRZFMaURcb
eld is moving away from categories of painsuch as those

The search for compounds that are safer than opioids and
based on a particular diagnosis, injury, or anatomic location
yet can provide signicant pain relief to fairly broad patient
that have proven to have limited utility in clinical research.
populations will require new ways of dening paina recatUnfortunately, in medical school, and even in residency and
egorization that is more in line with an individualized approach
beyond, what is still being taught are the standard categories
of pain [Table 3]. There is still a tendency to think in terms
to pain management.
of nociceptive versus neuropathic pain, for example. And this
Ultimately we want to be able to approach pain management in much the same way that we are already approaching
oversimplication ignores a great deal of what we already
treatment in other therapeutic areas, says Charles E. Argoff,
understand about the nervous system, Dr. Argoff says.
Researchers and clinicians are increasingly
MD, Professor of Neurology at Albany Medical
College and Director of the Comprehensive
turning their focus toward the identication of
Pain Center at Albany Medical Center in New
pain phenotypes,25,26 which incorporate detailed
York. To give just one example, if a patient has
descriptions of pain (e.g., burning, stabbing,
an infection, lets say a urinary tract infection
pricking, shooting) as well as specic clinical
signs and information, such as the results of
or a strep throat, the responsible agents can be
cultured, and a list of antibiotics can be tested
quantitative sensory testing.27,28 Ultimately the
as part of that process. Afterward the health
identication of pain phenotypes should enable
care provider receives a report that indicates
researchers and clinicians to better address
which antibiotics will work best and which wont
underlying neural mechanisms of pain. While
work. Nothing at all like that exists in the eld
this is an exciting area of research, it is still relaof pain management. When a clinician selects
tively new; as Dr. Argoff notes, researchers are
from the best analgesics available, whether
just beginning to learn how to assess pain pheopioid or nonopioid, there is only at best a 5050
notypes in a standard, rigorous way. Currently
Charles E. Argoff, MD
chance that a particular agent will be effective.
there is a lack of consensus on methods for
Dr. Argoff adds that even in a pivotal phase 3 clinical trial that
dening, collecting, and reporting pain phenotypes,25 and
ultimately leads to an FDA approval, less than 50% of all patients
experts have yet to establish a taxonomy, or standardized
receiving a particular treatment will experience at least 30%
language, for referring to specic phenotypes.
pain relief. This is partly because clinical trial inclusion criteria
In another compelling area of pain research, a wide range of
frequently do not produce patient populations that are ideal for
studies is more closely examining the changes that the central
meaningfully testing a particular treatment. Accordingly, the
nervous system undergoes in response to pain, and how these
changes affect both the brain and the entire body.
Pain is not just a local phenomenon, Dr. Argoff says. If an
FMOZR
ERZRPcRQBMW]FRa\W]^ZÛh2224
individual has pain, even localized painlets say an arthritic
The International Association for the Study of Pain denes pain as:
kneethat persists for any reason, that persons central nervous
system will continue to receive ongoing information about pain
An unpleasant sensory and emotional experience associated
transmission, and eventually may begin to learn to process that
with actual or potential tissue damage, or described in terms
information much more quickly and more efciently.
of such damage.
Depending upon genetic, environmental, and other unique
Standard categories of pain include:
inuences, an individuals nervous system may become primed
to have a heightened response to new painful stimuliand in
@^PWPR_cWeR_MW]pain that arises from actual or threatened
some cases, even to stimuli that are not typically regarded as
damage to nonneural tissue and is due to the activation of
painful. In patients with a condition such as mechanical allonociceptors (high-threshold sensory receptors of the peripheral
dynia,29 for example, a heightened sensitivity to pain causes
somatosensory nervous system that can transduce and encode
normally innocuous stimuli, such as a light touch, to be pernoxious stimuli). This term, designed to contrast with neuroceived as extremely painful. Researchers are examining the
pathic pain, is used to describe pain occurring with a normally
degree to which such learning by the nervous system, or
functioning somatosensory nervous system as opposed to the
strengthening of connections among nerve cells, plays a role
abnormal function seen in neuropathic pain.
in the transition from acute pain to chronic pain.30,31 In 2015,
;]M\\Mcâh_MW]pain in the presence of inammation that
the American Academy of Pain Medicine Foundation received
is increased by pressure.
funding to convene leading experts to examine this phenom 5hbSd]PcW^]MZ_MW]maladaptive pain, typically triggered
enon in a study of acute pain. Dr. Argoff, president of the foundawithout an external stimulus, which does not serve a known
tion, says the aim is to discover a method for disconnecting
protective function (e.g., pain associated with bromyalgia,
maladaptive learning, or a way to pre-emptively strike and
irritable bowel syndrome, and some types of headache).
thereby prevent chronic pain related to nerve injury.
@Rda^_McVWP_MW]pain caused by a lesion or disease of the
As knowledge of signaling mechanisms, receptors, and
somatosensory nervous system. Neuropathic pain is a clinical
pathways involved in the pathophysiology of pain deepens,
description (and not a diagnosis) that requires a demonstrable
researchers are identifying a variety of novel targets that may
lesion or a disease that satises established neurological
lead to more effective treatments for pain (Table 4). Among
diagnostic criteria.
those currently attracting intense interest are voltage-gated
110
P&T
7ROadMah H^Z@^
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2UR]c
Manufacturer/Sponsor)
5RbPaW_cW^]?RPVM]Wb\^S2PcW^]
;]QWPMcW^]4^\\R]cb
EcMcdb
Biologic, fully human monoclonal antibody,

CGRP receptor antagonist
Chronic migraine prevention

(SC monthly dosing)
Phase 3
Baricitinib (Lilly/Incyte)36
Small molecule; balanced JAK1 and JAK2 inhibitor
Rheumatoid arthritis; use as monotherapy

or in combination with methotrexate
Phase 3
CINGAL (Anika
Therapeutics)37
Biologic and small molecule; combination of sodium

hyaluronate and triamcinolone hexacetonide
Knee OA; viscosupplement plus steroid

(intra-articular injection)
Phase 3
Clazakizumab, ALD518
(Alder BioPharmaceuticals)38
Biologic; humanized IL-6 monoclonal

antibody
Rheumatoid arthritis; patients who have

experienced an inadequate response to
tissue necrosis factor inhibitors
Phase 2b
Clonidine topical gel (BDSI)39
Small molecule; topical clonidine formulation
Painful diabetic neuropathy; topical

application 3 times daily to feet
Phase 3
CNV1014802 (Convergence/
Biogen)40,41
Small-molecule sodium channel blockade

(Nav 1.7 selective)
Peripheral neuropathic pain,

trigeminal neuralgia
Phase 2
Fasinumab, REGN475
(Regeneron)4244
Biologic, fully human NGF monoclonal antibody
OA of the hip or knee (parenteral dosing)
Phase 2/3
Filgotinib, GLPG0634
(Galapagos)45
Small molecule; highly selective JAK1 inhibitor
Rheumatoid arthritis
Phase 3
Fulranumab (Janssen)46
Biologic, humanized NGF monoclonal antibody
OA of the hip or knee

(SC dosing every 4 weeks)
Phase 3
Hydros-TA (Carbylan)47
Biologic and small molecule; combination of

hyaluronic acid and triamcinolone acetonide
Knee OA; viscosupplement plus steroid

(intra-articular injection)
Phase 3
Invossa, TissueGene-C, TG-C

(Kolon Group)48
Biologic; allogeneic cell therapy (cartilage

cells plus cells with a growth factor promoting
cell differentiation)
Knee OA (intra-articular injection)
Phase 3
Ixekizumab (Lilly)49
Biologic; humanized immunoglobulin G4-type

monoclonal antibody to IL-17
Psoriatic arthritis, plaque psoriasis

(SC injection biweekly or every 4 weeks)
Phase 3
Lesinurad (Zurampic)
(AstraZeneca)50
Small molecule; selective uric acid reabsorption

inhibitor that inhibits the URAT1 transporter
Gout; used in combination with

febuxostat (xanthine oxidase inhibitor)
NDA approved
LY2951742 (Lilly)51,52
Biologic, humanized monoclonal antibody,

CGRP receptor antagonist
Episodic and chronic migraine,

cluster headache prevention
(SC monthly dosing)
Phase 3
Sarilumab (Sano/
Regeneron)53
Biologic, fully human monoclonal antibody

targeting IL-6
Rheumatoid arthritis
Phase 3
Secukinumab, Cosentyx,
AIN457 (Novartis)5457
Biologic; fully human monoclonal antibody,

selective IL-17A inhibitor
Ankylosing spondylitis, psoriatic arthritis,

plaque psoriasis (SC or IV dosing,
weekly, biweekly, or monthly dosing)
NDA approved
Biologic, humanized NGF monoclonal antibody
OA, chronic low back pain, cancer pain

Phase 3
Small molecule; cyclobenzaprine formulation
Fibromyalgia (sublingual dosing

daily at bedtime)
Phase 3
AMG 334 (Amgen/

Novartis)3235
Tanezumab (Pzer/Lilly)58,59
TNX-102 (Tonix)60
CGRP = calcitonin gene-related peptide; IL = interleukin; IV = intravenous; JAK = Janus family kinase; NDA = new drug application; NGF = nerve growth factor;
OA = osteoarthritis; SC = subcutaneous; URAT = uric acid transporter.
*Selected from data provided by William K. Schmidt, PhD, President, NorthStar Consulting, LLC
sodium channels, which have been proven to play a signicant

role in the processing of pain.61 Studies of particular isoforms
of these channelsparticularly Nav 1.7, 1.8, and 1.9,62 their
patterns of expression (especially in the peripheral nervous
system), and the effects of mutations in the genes that code

for themare expected to lead to the development of highly
selective treatments for pain, with far fewer adverse effects
than current treatments.
H^Z@^ 7ROadMah P&T
111
Among notable compounds under investigation that may lead
to similarly targeted pain relief are inhibitors of nerve growth
factor,63 calcitonin gene-related peptide (CGRP) antibodies,64
and interleukin-6 inhibitors65 (Table 4). While the list of potential targets is expanding rapidly, researchers continue to face
considerable hurdles in the translation of analgesic efcacy
from animal models to humans.
A growing trend toward personalized medicine in the eld
of pain research has intensied efforts to improve the ability
to predict whether a particular individual will respond to a
given treatment. At Albany Medical College, Dr. Argoff and
colleagues have recently completed several studies examining keratinocytes (skin cells) of patients with diabetes and
bromyalgia, to determine how they might be used to predict
responses to a number of medications.66
Keratinocytes are neurological powerhouses, Dr. Argoff
says. They contain so many different neuropeptides and
receptors and ion channels, all of which undergo changes over
time. We have been examining subtypes of sodium channels
in these cells, and exploring whether the density of these
subtypes affects the likelihood that patients will respond to
particular drugs, such as topical lidocaine.
While pain treatments with broad indications would certainly
have value, Dr. Argoff says, it is unlikely that a new compound
would effectively treat most individuals with pain. Its essential
to develop affordable and standardized processes for determining who is likely to respond to a treatment, so that patients
will suffer less by not having to experience failures. It doesnt
matter to me if 80% of patients in a study responded to a new
compound. What matters to me is whether the patient in front
of me responds.
between patients and clinicians, a lack of knowledge about

pain and its treatment on the part of both patients and providers, and stigma associated with suffering from pain and with
medications taken to treat pain.1,2
In an effort to address these factors, Dr. Payne regularly
collaborates with industry to develop educational programs
for clinicians who treat pain. These programs help clinicians
adopt better communication skills and better approaches to
assessing pain, and guide them in teaching patientsespecially
those in underserved communitiesabout pain medications
and how to navigate the medical system. Yet even with appropriate training, clinicians face signicant obstacles when it
comes to effectively treating patients with pain.
Nonpharmacologic treatments, such as behavioral
approaches to pain management, are an essential component
of any comprehensive pain program, but are simply not always
available to patients who need them, or to physicians who
wish to prescribe them, Dr. Payne says. Currently there are
not reliable means for accessing, coordinating, and getting
reimbursed for these services. This is a huge health policy
failure, because we have data to show that comprehensive
approachesthe integration of physical, behavioral, social,
and medical approachesactually do work.
New investigations of nonpharmacological approaches continue to build upon the success of earlier complementary and/or
integrative treatments; they include explorations of a range of
unique interventions, many of which recognize physical and
psychological distress as both responses to pain and factors
that contribute to the experience of pain.67,68
Multidisciplinary pain management clinics existed in the
past, says Dr. Payne, a past president of the American Pain
Society, but have largely disappeared because insurers were
2];]cRUaMcRQ2__a^MPVc^G]QRacaRMc\R]c^SBMW]
unwilling to pay for them and hospitals and health systems
While patients and clinicians await the development of more
were unwilling to sustain them. Re-establishing, promoting, and
effective drugs to treat pain, many patients
sustaining such multidisciplinary care would
help address the undertreatment of pain and
continue to receive ineffective treatments or
are unable to gain access to appropriate treatalso put a lot less pressure on physicians to
ments. The suffering experienced by these
prescribe opioids. Opioids are often the default
patients continues to result in greater medical
treatment because they are readily available
costs, in an enormous loss of productivity, and
and frequently inexpensive.
in a signicant reduction in quality of life.2 For
Dr. Payne and many of his colleagues point
to reluctance on the part of insurers to cover
these reasons, as the IOM report stated in 2011,
the costs of multidisciplinary care as an illuseffectively treating pain must be considered a
tration of short-term thinking, a position that
moral imperative.1
The undertreatment of pain is a huge
ignores the enormous costs associated with
problem, says Richard Payne, MD, Professor
the inadequate treatment of chronic pain.1,2,69
of Medicine and Divinity at Duke University,
Further research, they hope, will generate the
the John B. Francis Chair in Bioethics at the
data necessary to support the use of these treatRichard Payne, MD
Center for Practical Bioethics, and a member
ments. Data collection so far has been limited,
of the panel that produced the 2011 IOM report. Health care
partly because until recently pain was not seen as a disease in
professionals have a critically important responsibility and
its own right, but rather as a symptom of a wide range of other
obligation to address this problem. However, that does not
diseases. Consequently, pain as a therapeutic area has lacked
its own institution or home within the NIH, as well as means
mean that all undertreated pain must be addressed with medication. We have signicantly underresourced, understudied,
for centralized data collection. Although the Interagency Pain
and undernanced all of the other approaches that together
Research Coordinating Committee (IPRCC) and task forces
would contribute to the comprehensive management of pain.
convened by the NIH Pain Consortium are devoted to advancUndertreatment of pain can be traced to a wide range of
ing the eld of pain management, many experts say that the
factors, says Dr. Payne, many of which are addressed in the
lack of a bureaucratic hub has signicantly limited funding
National Pain Strategy. These include a lack of communication
and hampered the collection of data.
112
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7ROadMah H^Z@^
A member of the IPRCC, Dr. Payne says that things are
slowly beginning to improve. A major goal of the IPRCC,
for example, is to put into place a mechanism to attract and
encourage creative investigators and knowledgeable reviewers
to evaluate pain research proposals. Publicprivate partnerships also are in the process of developing new mechanisms
for data collection.
Once the National Pain Strategy is disseminated to the
public, I hope things will begin to change, says Dr. Payne. I
also look forward to reports by CMS [the Centers for Medicare
and Medicaid Services] on current demonstration projects that
are assessing the efcacy of multidisciplinary pain clinics. Data
from these reports may encourage Medicare and other payers
to begin paying for these services. The treatment of pain will
improve when patients begin to have access to a whole range
of treatments designed to improve their psychological and
physical functioning.
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Martucci KT, Ng P, Mackey S. Neuroimaging chronic pain: What
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Younger J, Noor N, McCue R, Mackey S. Low-dose naltrexone for
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Trang T, Al-Hasani R, Salvemini D, et al. Pain and poppies: the
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E670. Q
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Matthew Allsbrook, PharmD, MS; Brant E. Fries, PhD;
Kristina L. Szafara, PhD; and Randolph E. Regal, PharmD
ABSTRACT
Purpose: Among antidepressants, selective serotonin reuptake inhibitors (SSRIs) have enjoyed great popularity among
clinicians as well as generally wide acceptance and tolerance
among patients. A potentially overlooked side effect of SSRIs
is the occasional occurrence of extrapyramidal symptoms
(EPS), which could be a concern when SSRIs are used with
antipsychotics. This study was designed to explore the possible association between SSRI antidepressant use and the
incidence of EPS side effects in patients who take concomitant
antipsychotic medications.
Methods: The University of Michigan conducted a study at
the four Michigan state mental health hospitals between May
2010 and October 2010. The Michigan Public Health Institute
collected data using the InterRAI Mental Health Assessment
(InterRAI MH). The present study is a retrospective cohort
analysis of the cross-sectional data that were collected. Within
these institutions, 693 residents were using antipsychotics. We
measured the observed frequency of seven EPS recorded in
the InterRAI MH within three groups of patients: 1) those on
antipsychotic drugs who were taking an SSRI antidepressant;
2) those on antipsychotic drugs who were not taking an antidepressant; and 3) those on antipsychotic drugs who were taking
a non-SSRI antidepressant. Differences in the prevalence of
EPS were tested using one-way analysis of variance.
Results: There were no signicant differences in the observed
EPS frequencies among the three groups (F2,18 = 0.01; P < 0.9901).
Conclusion: In this study, SSRIs did not appear to potentiate the occurrence of EPS in patients using antipsychotics.
Keywords: extrapyramidal side effects, akathisia, movement
disorder, antipsychotics, neuroleptics, SSRIs, antidepressant
INTRODUCTION
Depression, a common psychiatric disorder, is the leading
cause of disability in the United States.1 Due to SSRIs apparent efcacy and lack of major side effects,2 the prescribing of
Dr. Allsbrook is a Pharmacy Resident at the University of Virginia
Health System in Charlottesville, Virginia. Dr. Fries is a Professor
of Health Management and Policy in the School of Public Health
Research and a Professor in the Geriatric Center of the School of
Medicine at the University of Michigan (UM), and Chief of Health
Systems Research at the Ann Arbor Veterans Affairs Healthcare Center, both in Ann Arbor, Michigan. Dr. Szafara is a Research Fellow
at the UM Institute of Gerontology. Dr. Regal is a Clinical Associate
Professor of Pharmacy in the UM College of Pharmacy and a Clinical
Pharmacist in Adult Internal Medicine in the UM Health System
Department of Pharmacy Services in Ann Arbor.
SSRIs is heavily favored over the older tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs).
Indeed, current guidelines suggest the use of SSRIs and/or
serotoninnorepinephrine reuptake inhibitors (SNRIs) as rstline therapy for the treatment of major depression.3
The commonly known side effects of SSRIs include transient
gastrointestinal effects, weight gain and/or weight loss, sexual
dysfunction, sleep disturbances, hypomania, the syndrome of
inappropriate antidiuretic hormone secretion (SIADH), and
movement disorders.4 New cases of movement disorders
associated with SSRIs are difcult to identify due to the low
numbers of patients involved in trials. Further, a review of the
literature for antidepressant-induced EPS indicates that EPS
can occur with various classes of antidepressants, are not
dose-related, and can occur with short-term and long-term
use.5 Prescribers are advised to monitor patients who might
be at a higher risk for developing EPS while taking SSRIs.6
However, some studies support the notion of an elevated risk
level when SSRIs are used concurrently with antipsychotics.7
The rationale for the development of SSRIs arose from the
observation that decreased brain levels of the neurotransmitter
serotonin may cause depressive symptoms, and that blockade
of a specic transporter for serotonin might therefore exert an
antidepressant effect.8 SSRIs pharmacological effect results
from inhibition of the presynaptic serotonin transporter at the
terminal ends of neurons, thereby increasing the concentration of serotonin. It is theorized that serotonin may inhibit
the brains dopaminergic system, thus causing a reduction in
dopamine activity. Reduced dopamine activity, which occurs
as a result of the antipsychotics dopamine antagonism properties, is postulated to cause EPS-like effects such as parkinsonian disorders, postural instability, and akathisia. Tardive
dyskinesia is believed to be associated with hypersensitivity of
post-synaptic dopaminergic receptors that may arise following
the chronic use of medications that decrease dopaminergic
transmission.9
An understanding of the mechanism of dopamine antagonism in regard to EPS demonstrates how SSRI use may result
in extrapyramidal side effects. With the use of conventional
antipsychotics, blockade of dopamine transmission in the
mesolimbic dopaminergic pathway provides the treatment of
the positive symptoms associated with schizophrenia. However,
this indiscriminate blockade also results in the inhibition of
dopamine transmission in the mesocortical pathway, which is
responsible for the negative symptoms and cognitive effects
associated with schizophrenia. A decrease in dopamine in the
Disclosure: The authors report no commercial or nancial interests
in regard to this article.
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nigrostriatal and tuberoinfundibular pathways gives rise to
the side effects associated with antipsychotic use. Dopamine
normally inhibits acetylcholine, but with dopamine blocked in
this pathway, acetylcholine becomes hyperactive and can lead
to effects such as EPS.9
Although all SSRIs have the class effect of potentiating
serotonin release, and thus indirectly antagonizing dopamine,
individual SSRIs may exert proles that vary somewhat. For
example, when compared with other SSRIs, sertraline causes
potent inhibition of the dopamine reuptake transporter as well
as the serotonin reuptake transporter. Therefore, sertraline
may theoretically be associated with a lower risk of movement
disorders than other SSRIs.2
In a 1997 study of depressed geriatric patients, 6% of those
receiving an SSRI for depression experienced EPS, such as
akathisia, resting tremor, cogwheel rigidity, and bradykinesia.10
In a 1995 study of 5,555 patients taking uoxetine, 15 (0.3%)
reported the emergence of EPS; of these 15, 12 improved either
partially or completely after discontinuation of uoxetine.11
The review paper by Lane showed that the administration of
a specic SSRI alone was associated with EPS; however, these
reports were also associated with known predisposing factors
to parkinsonism, such as Parkinsons disease, brain damage,
and previous use of antidopaminergic therapy.8 The frequency
of EPS with use of SSRI antidepressants is estimated to be one
in 1,000 or less.11 A review of the literature on EPS incidence
with SSRI use found that parkinsonism accounted for the
greatest percentage of SSRI-associated EPS (49%), followed
by dystonia (27%).5 It is interesting to note that this study put
akathisia frequency associated with SSRIs at 2%, far lower than
previous reports on extrapyramidal side effects.12
The University of Michigan project using the InterRAI MH
Assessment resulted in comprehensive surveillance of the adult
inpatient psychiatric population, providing data to examine
associations between SSRI use and EPS. The InterRAI MH
includes a broad assessment of the characteristics of inpatient
psychiatric hospital patients. In the University of Michigan
study, a list of currently prescribed drugs was also recorded.
From this drug list, it was possible to identify patients taking
a variety of antidepressants (Table 1). These included tricyclic
antidepressants (imipramine, clomipramine, amitriptyline,
doxepin), SSRIs (uoxetine, citalopram, paroxetine, sertraline,
uvoxamine, escitalopram), SNRIs (venlafaxine, duloxetine,
desvenlafaxine), and others (trazodone, nefazodone, mirtazapine, bupropion). Each drug class has different characteristics
regarding afnity for certain neurotransmitter transporters.
A breakdown of the incidence of EPS with respect to the use
of these agents should provide perspective regarding the
relative association of SSRIs with movement disorders. This
information could suggest pharmacotherapeutic interventions
concerning antidepressant options to maximize therapeutic
effect and minimize adverse effects. While some articles have
analyzed the incidence of EPS with antidepressant use, the body
of evidence is lacking in understanding whether concomitant
use with antipsychotics exacerbates such incidence.
METHODS
This is a retrospective cohort study of cross-sectional
data collected from the State of Michigans four adult mental
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7ROadMah H^Z@^
health hospitals. The data were collected between May 2010

and October 2010 from Caro Center, the Center for Forensic
Psychiatry, Walter Reuther Psychiatric Hospital, and Kalamazoo
Psychiatric Hospital. Every patient in each hospital on the
target dates was assessed; if the patient was discharged or died
before the assessment could be performed, the next patient
placed in the same bed was used in the study if he or she met
inclusion criteria. The Michigan Public Health Institute collected the data using the InterRAI MH.13 This comprehensive
tool provides reliable measurement of patient factors in several
areas of functional and clinical signicance. Assessors use all
available sources of data (the patient, the medical record, direct
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Chlorpromazine
Fluphenazine
Perphenazine
Triuoperazine
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Haloperidol
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Molindone
Ziprasidone
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Loxapine
Clozapine
Olanzapine
Quetiapine
Asenapine
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Risperidone
Paliperidone
Lithium
Aripiprazole
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Imipramine
Clomipramine
Amitriptyline
Doxepin
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Fluoxetine
Citalopram
Paroxetine
Sertraline
Fluvoxamine
Escitalopram
Trazodone
Nefazodone
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Venlafaxine
Duloxetine
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Bupropion
observation, staff reports, etc.) to determine the appropriate
information for each item on the instrument.
To understand the connection (or lack thereof) between
SSRIs and the incidence of EPS, we examined the data set from
three groups, a total of 693 patients. The rst cohort consisted
of all patients on antipsychotic drugs who were also taking an
SSRI antidepressant; the second cohort consisted of all patients
on antipsychotic drugs who are not taking any antidepressant;
and the third cohort consisted of all patients on antipsychotic
drugs who were taking a non-SSRI antidepressant.
We analyzed the scoring for the seven EPS included on
the InterRAI MH for each patient in one of the three cohorts.
Each extrapyramidal side effect was scored as a 0 (no) or 1
(yes). To compare the overall responses between the cohorts,
a mean EPS sum score was calculated as the total number of
EPS symptoms reported in the group divided by the number
of patients in that group. Thus, if every patient in a group
had exactly one of the seven symptoms, the score would
be 1.0.
;]PZdbW^]M]Q6gPZdbW^]4aWcRaWM
Any adult inpatient of the four state mental health institutions
named previously who was taking an antipsychotic medication
on a daily or regularly scheduled basis was eligible for inclusion. Patients were excluded if there were no data for them
regarding antipsychotic use. Patients who were listed as taking
antipsychotics as needed were also excluded.
5RbWU]
Since we compared more than two cohorts to identify a statistical difference in EPS frequency, we performed an analysis
of variance (ANOVA) statistical test with data presented in
tabular format showing the number of measurements and
the response recorded for each symptom. The F critical value
was obtained from the F Distribution Table of the University
of California at Los Angeles Department of Statistics.14 The P
value was calculated using GraphPad Software QuickCalcs.15
To calculate the statistical difference in categorical variables
(i.e., gender), the chi-square test was used.
D6EG>FE
Table 2 compares the three cohorts. The mean weights
and ages within each group were similar, but Cohort 1 had
a higher percentage of females than the other two cohorts.
The differences in the mean antipsychotic dened daily dose
(DDD) in Cohorts 1, 2, and 3 were not statistically signicant
(P = 0.837). All three cohorts had similar mean EPS sum scores
of 0.22, 0.23, and 0.21, respectively.
The most common extrapyramidal symptom observed was
tremor, which was consistently seen in 8.6% to 8.7% of patients
in each of the three cohorts. Akathisias were the second most
common EPS observed; they were higher in the Cohort 1
antipsychotic-plus-SSRI group compared with the other two
groups (7.38% versus 3.4% [Cohort 2] and 1.94% [Cohort 3]).
Dyskinesias, the third most common EPS, were highest in
Cohort 3 (5.83%) versus Cohort 2 (2.95%) and Cohort 1 (2.01%).
This was followed by dystonias and slow shifting gait, which
were seen at rates between 0 and about 2%. The nal two
symptoms, bradykinesia and rigidity, were the least frequent,
with rates between 0 and 0.68%. The overall average EPS rate
among all three cohorts ranged from 2.64% to 2.87% within
the three groups, but the differences were not signicant
(F2,18 = 0.01; P < 0.9901) (Table 3).
DISCUSSION
In a cross-sectional, single-point assessment using the
InterRAI MH in relatively young, institutionalized psychiatric
patients taking antipsychotics, the incidence of EPS in those
taking SSRIs did not appear to be greater than in those using
antipsychotics alone. Mean EPS sum scores in each of the
three cohorts were similar at 0.22, 0.23, and 0.21, respectively.
When averaging the incidence of the seven listed EPS, all three
groups had an average EPS rate of just under 3% (Table 3).
Akathisias and tremors were the most commonly reported
EPS. While the cohort using SSRIs had an appreciably higher
rate of akathisias than the other two groups (7.38% versus 3.4%
and 1.94%), tremor rates were not higher in the SSRI population; this symptom was reported in just over 8.6% of patients
in each group. The tremor rate in this study is very similar to
the tremor rate of citalopram, based on package insert data.16
Previous reports have shown that akathisia accounts for 45%
of EPS associated with SSRIs, followed by dystonia at 28%.12
However, in a review of the literature, the incidence of akathisia
has been portrayed at just 2% of adverse events.5 Some SSRI
medications have been associated with akathisia and related
symptoms of restlessness.11 Perhaps in this and earlier studies
the subjective observation of akathisias was not adequately differentiated from the motor restlessness/agitation sometimes
seen with SSRIs. This may be especially true among the most
activating agents, such as uoxetine.
Important limitations of this study could have affected the
results substantially. Most important, it was a cross-sectional
FMOZR 4VMaMPcRaWbcWPb^ScVRFVaRR4^Vâcb
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n = 149
2]cW_bhPV^cWP
n = 441
2]cW_bhPV^cWP]^]EED;
]
PeMZdR
Mean age in years (SD)
42.6 (12.8)
45.1 (13.5)
44.7 (14.7)
P = 0.149
Male, n (%)
97 (65.3)
333 (75.4)
82 (79.8)
P = 0.021
Mean weight in kilograms (SD)
91.8 (22.0)
90.2 (20.4)
91.7 (27.6)
P = 0.667
Mean antipsychotic DDD in

milligrams (SD)
12.5 (17.5)
11.3 (10.8)
8.7 (5.9)
P = 0.836
Mean EPS sum score (SD)
0.22 (0.5)
0.23 (0.52)
0.21 (0.51)
P = 0.944
DDD = dened daily dose; EPS = extrapyramidal symptoms; SD = standard deviation; SSRI = selective serotonin reuptake inhibitor
H^Z@^ 7ROadMah P&T
117
FMOZR
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2]cW_bhPV^cWPEED;
n = 149
2]cW_bhPV^cWP
n = 441
2]cW_bhPV^cWP@^]EED;
2]cWQR_aRbbM]c]
11 (7.38)
15 (3.40)
2 (1.94)
Akathisia, n (%)
Dyskinesia, n (%)
3 (2.01)
13 (2.95)
6 (5.83)
Tremor, n (%)
13 (8.72)
38 (8.62)
9 (8.74)
Bradykinesia, n (%)
1 (0.67)
3 (0.68)
0 (0)
Rigidity, n (%)
0 (0)
1 (0.23)
0 (0)
Dystonia, n (%)
0 (0)
7 (1.59)
2 (1.94)
Slow shift gait, n (%)
2 (1.34)
9 (2.04)
0 (0)
Sum of percentages
20.12
19.51
18.45
Mean
2.87
2.79
2.64
F critical value = 2.62395a

P < 0.9901; accept the null hypothesisb
a The F critical value was obtained from the F Distribution Table from the UCLA Department of Statistics.14
b The P value was calculated from GraphPad Software QuickCalcs.15
EPS = extrapyramidal symptoms; SSRI = selective serotonin reuptake inhibitor
study done at a single point in time during a patients stay at

an institution. The InterRAI MH instrument has 19 clinical
assessment protocols (CAPs) that are triggered for a patient
based on responses to certain items. The trigger may indicate
that further care and assessment are needed in a particular
area. For this study population, the most commonly triggered
CAP was medication management and adherence (67.8% of
forensic patients and 82.3% of nonforensic patients). While
the adherence rate was not captured for each patient, the
need to assess adherence may raise concerns about whether
medications were being taken appropriately. The InterRAI
MH specically asked about EPS within the last three days
from the date of assessment. Also, since EPS are related both
to cumulative time on a drug as well as daily dose, we have no
way of knowing how long the patient had been using a given
medication regimen on the day he or she was assessed. It is
well established that EPS are dose-related.
In another confounder inherent with this study, we dened
mean antipsychotic DDDs within each group and found those
numbers were very similar between Cohorts 1 and 2, but we
did not characterize the type of antipsychotic medications used
within each cohort, which could have great importance. For
instance, if the non-SSRI group happened to have a higher
incidence of use of the older, typical antipsychotics that have
a higher proclivity for EPS (such as the potent typical antipsychotic haloperidol), that could blunt the SSRI contribution
to EPS. We are also uncertain why the antipsychotic DDDs in
Cohort 3 were so much lower than those in Cohorts 1 and 2.
Possibly further obscuring differences between Cohorts
1 and 3, medications in Cohort 3 (non-SSRI antidepressants)
included venlafaxine, desvenlafaxine, and duloxetine. These
medications are classied as SNRIs. In addition to inhibiting norepinephrine reuptake from the synaptic cleft, these
drugs also inhibit the reuptake of serotonin, a pharmacological
property shared with the SSRI medications. Although these
SNRIs were not included in Cohort 1 of the analysis, it is
118
P&T
7ROadMah H^Z@^
known that these drugs are 10 to 30 times more selective for

serotonin than norepinephrine.17 Further research should be
conducted to fully elucidate the differences in efcacy and
safety of SNRI versus SSRI therapy when it comes to long-term
effects. Differences should be studied between individual
drugs rather than using pooled data about SSRIs versus SNRIs.
Future directions for assessing the correlation of EPS with
antipsychotic and SSRI use could include determining the
duration of concomitant therapy, the specic SSRIs and antipsychotics used, and the doses of the medications the patients
were taking when EPS were found to occur. A prospective study
observing similar parameters could be devised to determine
if EPS are occurring more frequently in those taking SSRIs
than those who are not.
4A@4>GE;A@
With new Food and Drug Administration labeling of certain
atypical antipsychotics as adjuvants for the treatment of bipolar
and major depressive disorders, the future may see an increase
in the concomitant use of SSRIs and antipsychotics among
younger and more ambulatory populations. This study in
mostly nongeriatric psychiatric inpatients taking antipsychotics
did not demonstrate an increased risk of extrapyramidal side
effects when SSRI antidepressants were used simultaneously.
D676D6@46E
1.
2.
3.
4.
Murray CJ, Atkinson C, Bhalla K, et al. The state of U.S. health,

1990-2010: burden of diseases, injuries, and risk factors. JAMA
2013;310(6):591608.
Gerber PE, Lynd LD. Selective serotonin-reuptake inhibitor-induced
movement disorders. Ann Pharmacother 1998;32(6):692698.
Ciechanowski P. Patient information: depression treatment options
for adults (beyond the basics). UpToDate. Available at: http://
www.uptodate.com/contents/depression-treatment-options-foradults-beyond-the-basics#. Accessed October 21, 2015.
Ferguson JM. SSRI antidepressant medications: adverse
effects and tolerability. Prim Care Companion J Clin Psychiatry
2001;3(1):2227.
EED;b6BEM]Q2]cW_bhPV^cWPb
752ERRYbc^DRQdPRD6?E3daQR]b
continued from page 105
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
Madhusoodanan S, Alexeenko L, Sanders R, et al. Extrapyramidal

symptoms associated with antidepressantsa review of the literature and an analysis of spontaneous reports. Ann Clin Psychiatry
2010;22(3):148156.
Hawthorne JM, Caley CF. Extrapyramidal reactions associated with serotonergic antidepressants. Ann Pharmacother
2015;49(10):11361152.
Schillevoort I, van Puijenbroek EP, de Boer A, et al. Extrapyramidal syndromes associated with selective serotonin reuptake
inhibitors: A case-control study using spontaneous reports. Int
Clin Psychopharmacol 2002;17(2):7579.
Lane RM. SSRI-induced extrapyramidal side-effects and akathisia:
implications for treatment. J Psychopharmacol 1998;12(2):192214.
Stahl S. Stahls essential psychopharmacology online. Available at: http://
stahlonline.cambridge.org/essential_4th_chapter.jsf?page=chapter5_
introduction.htm&name=Chapter%205&title=Conventional%20
antipsychotics#c02598-5-18. Accessed October 30, 2015.
Gormley N, Watters L, Lawlor B. Extrapyramidal side effects in elderly patients exposed to selective serotonin reuptake inhibitors. Human
Psychopharmacology: Clinical and Experimental 1997;12(2):139143.
Coulter DM, Pillans PI. Fluoxetine and extrapyramidal side effects.
Am J Psychiatry 1995;152(1):122125.
Leo RJ. Movement disorders associated with the serotonin selective reuptake inhibitors. J Clin Psychiatry 1996;57(10):449454.
Fries BE, Schmorrow A, DSouza J. Mental health assessment
project. Report to the Michigan Department of Community Health.
University of Michigan. 2011.
Statistics Online Computational Resource, University of California
at Los Angeles. F distribution tables. Available at: http://www.socr.
ucla.edu/applets.dir/f_table.html. Accessed November 13, 2013.
QuickCalcs, GraphPad Software. P value calculator. Available
at: http://graphpad.com/quickcalcs/PValue1.cfm. Accessed
November 13, 2013.
Citalopram package insert. St. Louis, Missouri: Forest Pharmaceuticals; 2014.
Bradley AJ, Lenox-Smith AJ. Does adding noradrenaline reuptake inhibition to selective serotonin reuptake inhibition improve efcacy in patients
with depression? A systematic review of meta-analyses and large randomised pragmatic trials. J Psychopharmacol 2013;27(8):740758. Q
completed work on the NCPDP ePrescribing (SCRIPT) REMS

transaction. Davidson expects it to be approved in February.
Once the standard is published, we can work with the FDA
on how to get this standard adopted, Davidson says. We may
need to tweak this standard for a broader group of stakeholders
such as hospitals as we work with the FDA on developing a
common REMS platform, a new concept recently introduced
by the FDA.
Improvements are coming to the REMS program, some of
which will make life easier for pharmacists. The question is
how fast those changes will arrive and how far-reaching they
will be. Those decisions rest with the manufacturers and then
with the health information technology vendors. It may not be
a good sign that none of the latter was at the FDAs October
2015 workshop. A representative of Epic, a leading EHR vendor
that has been active in the NCPDP, declined to comment on
the FDAs efforts. That is probably not encouraging either.
D676D6@46E
1.
2.
3.
Food and Drug Administration. Approved risk evaluation and

mitigation strategies (REMS). Available at: http://www.accessdata.
fda.gov/scripts/cder/rems/index.cfm. Accessed January 7, 2016.
Food and Drug Administration. Risk evaluation and mitigation
strategies (REMS): understanding and evaluating their impact
on the health care delivery system and patient access. December
15, 2015. Available at: http://www.fda.gov/Drugs/NewsEvents/
ucm441308.htm. Accessed January 7, 2016.
Food and Drug Administration. Standardizing and evaluating
risk evaluation and mitigation strategies (REMS). September
2014. Available at: http://www.fda.gov/downloads/ForIndustry/
UserFees/PrescriptionDrugUserFee/UCM415751.pdf. Accessed
January 7, 2016. Q
B^bWcWeRDRbdZcbDR_âcRQ
7â5ah6hR2bbMh
A prospective U.S. study has assessed
the efcacy of the TeaRx multiassay test
(BioLight Israeli Life Sciences Investments Ltd.) in evaluating the components
of tears in patients with dry eye syndrome
(DES). A total of 74 subjects were evaluated using a composite of four established
benchmark tests for the assessment of
DES. The subjects were also evaluated
using the TeaRx assays.
The study results demonstrated sensitivity of 86%, specicity of 87%, and a
positive predictive value of 87% for the
TeaRx multiassay test. The results also
indicated that the test, which incorporates
a combination of tear constituents originating from different locations in the eye,

may provide a more accurate diagnostic
output than already-marketed DES tests.
Source: BioLight, January 7, 2016
EPWR]cWbcb;\_aêRHWQR^BWZZb
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Researchers at the University of
Glasgow, Scotland, have found a way to
make cameras that can be swallowed
more effective at detecting cancers of the
throat and gut. Until now, these systems,
known as video pills, have relied on illuminating the patients innards using a small
light source, thereby restricting clinicians
to conclusions based on what they can
see in the spectrum of visible light. Using

an advanced semiconductor single-pixel
imaging technique, the Scottish team has
created uorescence imaging in a small
pill form for the rst time. In addition to
expanding the diagnostic capabilities of
video pills, the new technology could also
be used to help track antibodies used to
label cancer in the human body, creating
a new way to detect cancer, according
to research associate Dr. Mohammed
Al-Rawhani.
Source: University of Glasgow, December 18, 2015 Q
H^Z@^ 7ROadMah P&T
119
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Walter Alexander
The 57th annual meeting of the American Society of
Hematology (ASH), held from December 5 to 8, 2015,
hosted more than 25,000 attendees (about two-fths
from abroad), who traveled to Orlando for the presentation
of 5,633 abstracts. We review below key sessions, with
a focus on newer agents and their efficacy in high-risk
leukemia and multiple myeloma populations.
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The author is a freelance medical writer living in New York City.
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121
toxic, and quite expensive. Eltrombopag is a very easy-to-use
medication, and it will have a huge impact on clinical care of
patients who have this very severe illness.
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UNicola Gkbuget, MD, Department of Medicine II, Goethe
University, Frankfurt, Germany
Blinatumomab is a bispecic T-cell engager (BiTE) antibody
that directs cytotoxic T cells to CD19-positive target cells, leading to lysis in minimal residual disease (MRD)-positive acute
lymphocytic leukemia (ALL). It was tested in an open-label,
multicenter, conrmatory phase 2 study (NCT01207388) in
MRD-positive B-precursor ALL in 46 centers and 11 countries.
MRD was dened as a level of 103 or greater (molecular failure or
molecular relapse) in an assay with a minimum sensitivity of 104
in Dr. Gkbugets preplanned 18-month follow-up nal analysis.
MRD assessment, which detects the presence of leukemic
cells in bone marrow, is possible in more than 90% of ALL
patients, Dr. Gkbuget said. Patients with persistent/recurrent
MRD after rst-line induction and consolidation have a higher
risk of relapse and shorter survival than those with a complete
MRD response (no detectable MRD with minimum sensitivity
0.01%). Dr. Gkbugets prior assessment of ve trials showed
that among patients who were MRD positive before stem cell
transplantation, the relapse risk was 46% to 75%, compared
with 6% to 20% in those who were MRD negative. Nearly all
patients with persistent or recurrent MRD relapse despite
continued chemotherapy, she said, so MRD persistence
indicates resistance to conventional chemotherapy.
The usual next treatment step is allogeneic transplant.
Patients may relapse, however, during preparation for stem
cell transplant, and those with high MRD have higher posttransplant relapse rates. Achieving and maintaining molecular
CR and avoiding hematologic relapse going into transplantation
are therefore important treatment goals.
In the 18-month analysis, one-third of the included 116
patients (median age 45 years, range 1876 years) were in their
second or later remission. MRD responses were evaluated
after the rst cycle of treatment. Blinatumomab 15 mcg/m
per day was given by continuous intravenous (IV) infusion for
four weeks, followed by a two-week break (one cycle). MRD
responders in cycle 1 received up to three additional cycles or
underwent hematopoietic stem cell transplant.
Eighty percent of patients achieved a complete MRD
response. Among these, 67% were able to remain in continuous remission until transplant. OS was 36.5 months. OS was
signicantly more likely (P = 0.002) in those who achieved a
complete MRD response, and duration of complete remission
was longer (P = 0.049). Also, patients in their rst remission at
baseline had longer relapse-free survival (P = 0.004). Relapsefree survival after a median follow-up of 29.9 months was 54%.
Keeping in mind that in relapsed ALL the median survival is
around six months, and that a third had prior relapses, this is
very favorable, Dr. Gkbuget said.
122 P&T
7ROadMah H^Z@^
Twelve percent of patients discontinued blinatumomab

because of adverse events. Neurologic events, reported in
53% of patients, were grade 3 and 4 in 10% and 3%, respectively.
Dr. Gkbuget concluded, Blinatumomab may contribute
to prolonged relapse-free survival and OS in patients with
MRD-positive ALL.
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UGiovanni Martinelli, MD, Institute of Hematology, S. OrsolaMalpighi University Hospital, Bologna, Italy
Philadelphia chromosome positivity (Ph+), the most common
single cytogenetic abnormality in B-precursor ALL, occurs in
25% of adults (the frequency increases with age). This Ph+ ALL
population has a historically poor prognosis, Dr. Martinelli
said. Tyrosine kinase inhibitors (TKIs) added to rst-line
therapy have improved both response rates and the likelihood
of achieving allogeneic hematopoietic stem cell transplants
(HSCT). Allogeneic hematopoietic stem cell transplant is
probably the only curative way to long remission in these
patients, Dr. Martinelli added.
When HSCT is not an option, sequential use of chemotherapy
with second- or third-generation TKIs is the dominant approach.
Complete hematologic response rates with TKI monotherapy with nilotinib, dasatinib, or ponatinib have ranged from
33% to 41%, with one-year median OS of 3.3 to eight months.
Dr. Martinelli pointed out that a signicant proportion of TKI
resistance is attributed to emergence of single and compound
point mutations in BCR-ABL.
Blinatumomab redirects T cells to lyse the CD19-positive
malignant and nonmalignant B cells expressed in virtually all
B-lineage ALL cells. In Ph-negative relapsed and refractory
ALL, the blinatumomab monotherapy combined rate of CR and
complete remission with partial hematological recovery (CRh)
was 43%. The ALCANTARA trial was conducted to extend
this initially very positive experience to the Ph+ population,
Dr. Martinelli said.
Patients included in the ALCANTARA trial had Ph+
B-precursor ALL that had relapsed or was refractory after at
least one second- or third-generation TKI (and was intolerant
of or refractory to imatinib). Patients (n = 45) received blinatumomab by continuous IV infusion (four weeks on, two weeks
off) for up to ve cycles (9 mcg per day on days 17 in cycle
1, and 28 mcg per day thereafter). The primary endpoint was
CR/CRh during the rst two cycles.
CR and CRh rates were 31% and 4%, respectively, and the
complete MRD response rate was 88%. Four of the 16 patients
(25%) with blinatumomab-induced remission went on to HSCT.
One died within 100 days post-transplant. Response rates were
independent of mutational status, including the presence of
T315l mutations, and were equivalent in patients younger
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PIPELINE PLUS
4^\_M]WRbFMYR2W\Mc?DE2;]SRPcW^]b
Chris Fellner
ethicillin-resistant Staphylococcus aureus (MRSA) is one of

the most widespread and virulent nosocomial pathogens.1 MRSA is
categorized as either health care-associated MRSA (HA-MRSA)2 or communityassociated MRSA (CA-MRSA),3 depending on the setting where the infection
was acquired. In medical facilities, MRSA
may cause life-threatening bloodstream
infections, pneumonia, or surgical-site
infections. In the community, most MRSA
infections affect the skin.4
Although MRSA remains a major
Chris Fellner is a medical writer and the
Editor of PTCommunity.com.
patient threat, data from the Centers for

Disease Control and Prevention (CDC)
have shown that the rate of invasive
(life-threatening) MRSA infections in
health care settings is declining. Invasive
MRSA infections that began in hospitals
dropped 54% between 2005 and 2011, with
30,800 fewer severe infections. The study
showed 9,000 fewer deaths in hospital
patients in 2011 than in 2005.1
Most patients who present to U.S. hospitals with suspected MRSA infections
receive empiric antimicrobial therapy
before the causative pathogen has been
diagnosed and conrmed. Culture-based
methods are still the gold standard for
detecting MRSA.5
At least 10 marketed antibiotics have

demonstrated potent activity against
MRSA and are used to treat invasive
HA-MRSA infections in the U.S. (Table 1).
Vancomycin, a generic glycopeptide, is
the most frequently prescribed antibiotic for infections in which MRSA is
the suspected or known cause, followed
by linezolid (Zyvox, Pzer), an oxazolidinone, and daptamycin (Cubicin, Merck),
a lipopeptide.5
The late-stage clinical pipeline for
MRSA includes an array of treatments
aimed at acute bacterial skin and skinstructure infections (ABSSSIs) and/or
community-acquired bacterial pneumocontinued on page 128
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Ba^QdPc
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Cephalosporin
Ceftaroline fosamil (Tearo)
Actavis, Inc.
Glycycycline
Tigecycline (Tygacil)
Pzer
;]QWPMcW^]b
5^bMURO
4^bc^SFaRMc\R]cP
ABSSSIs, CABP
600 mg every 12 hours by IV infusion administered over

560minutes for 514 days (ABSSSIs) or 57 days (CABP) in
adults (18 years of age or older)
514 days:
$1,831$5,127
ABSSSIs, CABP, CIAIs
Initial dose: 100 mg, followed by 50 mg every 12 hours IV over

514 days:
approximately 3060 minutes for 514 days (ABSSSIs and CIAIs) $1,888$4,977
or 714 days (CABP)
Glycopeptides and Lipoglycopeptides

Dalbavancin (Dalvance)
ABSSSIs
Allergan
Oritavancin (Orbactiv)
ABSSSIs
The Medicines Company
Telavancin (Vibativ)
ABSSSIs, HABP, VABP
Theravance Biopharma US
Vancomycin
Generics
Serious or severe
infections caused by
susceptible methicillinresistant (beta-lactamresistant) staphylococci
Two-dose regimen: 1,000 mg IV followed 1 week later by

500mg IV, both administered over 30 minutes
1,200-mg single dose by IV infusion over 3 hours in adults
ABSSSIs: 10 mg/kg by IV infusion over 60 minutes every
24hours for 714 days
HABP/VABP: 10 mg/kg by IV infusion over 60 minutes every
24 hours for 721 days
Adults: 2 g IV daily, divided as 500 mg every 6 hours or 1 g
every 12 hours, administered at no more than 10 mg/min or
over a period of at least 60 minutes, whichever is longer, for
710 daysd
Pediatric patients: 10 mg/kg IV every 6 hours over a period of
at least 60 minutes for 710 daysd
$5,364
$3,480
721 days:
M, $3,523$10,568;
F: $3,002$9,007e
710 days (adults):
$101$144
Lipopeptide
Daptomycin (Cubicin)
Merck
126 P&T
ABSSSIs, S. aureus
bacteremia
7ROadMah H^Z@^
Adults with ABSSSIs (for 714 days):

CLCR 30 mL/min: 4 mg/kg once every 24 hours
CLCR < 30 mL/min: 4 mg/kg once every 48 hours
Adults with bacteremia (for 1442 days):
CLCR 30 mL/min: 6 mg/kg once every 24 hours
CLCR < 30 mL/min: 6 mg/kg once every 48 hours
4 mg/kg, 714 days:

M, $2,634$5,269;
F, $2,245$4,491
6 mg/kg, 1442
days: M, $7,903
$23,710, F, $6,736
$20,208e
PIPELINE PLUS
FMOZR2]cWOMPcRaWMZ2UR]cb?^bc4^\\^]ZhGbRQc^FaRMcGE:^b_WcMZ2P`dWaRQ?DE2;]SRPcW^]b4^]cW]dRQM
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Oxazolidinones
Linezolid (Zyvox)
Pzer
;]QWPMcW^]b
5^bMURO
ABSSSIs, CABP, HABP,

uncomplicated SSSIs,
vancomycin-resistant
Enterococcus faecium
infections
ABSSSIs, CAP, HABP in adults/adolescents: 600 mg IV or oral

every 12 hours for 1014 days
Uncomplicated SSSIs in adults: 400 mg oral every 12 hours
for 1014 days
Uncomplicated SSSIs in adolescents: 600 mg oral every
12hours for 1014 days
Vancomycin-resistant E. faecium infections in adults/adolescents: 600 mg IV or oral every 12 hours for 1428 days
200 mg once daily IV or oral over 1 hour for 6 days
Tedizolid phosphate (Sivextro) ABSSSIs

Merck
4^bc^SFaRMc\R]cP
600 mg, 1028

days: IV, $1,920
$5,376; oral,
$4,082$11,429
400 mg, oral,
1014 days:
$2,978$4,169
IV: $1,777
Oral: $2,230
a Agents are listed alphabetically, not by preferred use. This list is not all-inclusive. Additional therapies may be available.
b Based on prescribing information; doses and schedules may vary due to patient-specic requirements.
c Costs calculated using average wholesale price for regimens in prescribing information for adults with normal kidney function, rounded to the nearest dollar.
d Representative dosing for sterile vancomycin hydrochloride USP (Pzer).
e Price calculated using weights of 88 kg for men and 75 kg for women.
ABSSSIs = acute bacterial skin and skin-structure infections; CABP = community-acquired bacterial pneumonia; CIAIs = complicated intra-abdominal infections;
CLCR = creatinine clearance; F = female; HABP = hospital-acquired bacterial pneumonia; IV = intravenous; M = male; SSSIs = skin and skin-structure infections;
VABP = ventilator-associated bacterial pneumonia.
Sources: GlobalData, product prescribing information, Red Book Online
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Company
Brilacidin
Cellceutix Corp.
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Defensin-mimetic
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ABSSSIs Phase 3
Debio 1450 (Debio 1452 Fabl enzyme

prodrug)
inhibitor
Debiopharm International
Delaoxacin (RX-3341)
Fluoroquinolone
Melinta Therapeutics
ABSSSIs
KRP-AM1977X
Kyorin Pharmaceutical
Fluoroquinolone
CABP
Lefamulin (BC-3781)
Nabriva Therapeutics
Systemic
pleuromutilin
CABP
ABSSSIs
Omadacycline (PTK-0796) Aminomethylcycline ABSSSIs,

Paratek Pharmaceuticals (tetracycline
CABP
derivative)
Solithromycin
Fluoroketolide
Cempra Pharmaceuticals (macrolide
derivative)
CABP
Taksta
Fusidic acid
Cempra Pharmaceuticals (proprietary oral
formulation)
ABSSSIs
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Priced at 5% premium over average daily cost of linezolid

due to its rst-in-class status and ability to be administered
as single IV infusion; estimated cost of 7-day regimen, $2,711
Phase 2 Priced at 25% premium over average daily cost of linezolid because of its rst-in-class status and narrow spectrum of activity; estimated cost of 10-day regimen, $4,611
Phase 3 Priced at 10% premium over average daily cost of ceftaroline fosamil due to its status as novel uoroquinolone
specically indicated for MRSA and because of its oral and
IV formulations; estimated cost of 10-day regimen, $3,055
Phase 3 Priced equal to average daily cost of delaoxacin
(Japan)
(Baxdela, Melinta Therapeutics, now in phase 3 development for ABSSSIs); estimated U.S. cost undetermined
Phase 2/3 Priced at 20% premium over average daily cost of
ceftaroline fosamil because of its rst-in-class status;
estimated cost of 12-day regimen, $3,999
Phase 3 Priced at 15% premium over average daily cost of tigecycline (Tygacil, Pzer) because of more-convenient oncedaily dosing, oral and IV formulations, and improved
safety prole; estimated cost of 10-day regimen, $2,741
Phase 3 Priced at 5% premium over average daily cost of
ceftaroline fosamil because of its next-generation
macrolide status and oral and IV formulations; estimated
cost of 5-day regimen, $1,458
Phase 2/3 Priced at 5% premium over average daily cost of linezolid
because of its rst-in-class status; estimated cost of
10-day regimen, $4,058
6g_RPcRQGE
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2019
2020
2017
2018
2019
2019
2017
2018
ABSSSIs = acute bacterial skin and skin-structure infections; CABP = community-acquired bacterial pneumonia.
Sources: GlobalData (December 2015),5 company websites
H^Z@^ 7ROadMah P&T
127
PIPELINE PLUS
MEDICATION ERRORS
nia (Table 2). Three of these products

brilacidin (Cellceutix Corp.), Debio1450
(Debiopharm International), and
lefamulin (Nabriva Therapeutics)are
expected to be rst-in-class agents. The
others include a new macrolide derivative (solithromycin, Cempra Pharmaceuticals); a next-generation tetracycline
derivative (omadacycline, Paratek Pharmaceuticals); a proprietary oral formulation of fusidic acid (Taksta, Cempra
Pharmaceuticals); and two anti-MRSA
uoroquinolones (delaoxacin, Melinta
Therapeutics; and KRP-AM1977X, Kyorin
Pharmaceutical).57
While these new treatments are
expected to succeed, analysts foresee
stiff competition from generic products,
spurred by the loss of patent protection
for two leading MRSA therapies, linezolid
and daptamycin.5
Again, this is an ongoing error that

could easily be prevented by a hard
stop in the pharmacy computer for daily
dosing of oral methotrexate (or if lling
frequent oncology orders, for daily doses
without a stop date after ve days or less).
D676D6@46E
1.
2.
3.
4.
5.
6.
7.
Dantes R, Mu Y, Belflower R, et al.

National burden of invasive methicillinresistant Staphylococcus aureus infections,
United States, 2011. JAMA Intern Med
2013;173:19701978.
Stefani S, Chung DR, Lindsay JA, et
al. Methicillin-resistant Staphylococcus
aureus (MRSA): global epidemiology
and harmonisation of typing methods.
Int J Antimicrob Agents 2012;39:273282.
David MZ, Daum RS. Communityassociated methicillin-resistant Staphylococcus aureus: epidemiology and clinical
consequences of an emerging epidemic.
Clin Microbiol Rev 2010;23:616687.
Centers for Disease Control and Prevention. Methicillin-resistant Staphylococcus
aureus (MRSA) infections. August 4, 2015.
Available at: http://www.cdc.gov/mrsa.
Pace CJ, Junker M, Fu K, et al. Methicillinresistant Staphylococcus aureus (MRSA)
Global Drug Forecast and Market Analysis
to 2024. New York, New York: GlobalData; December 2015.
Kumar K, Chopra S. New drugs for
methicillin-resistant Staphylococcus
aureus: an update. J Antimicrob Chemother
2013;68:14651470.
Rodvold KA, McConeghy KW. Methicillinresistant Staphylococcus aureus therapy:
past, present, and future. Clin Infect Dis
2014;58(suppl 1):S20S27. Q
128 P&T
7ROadMah H^Z@^
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A fentanyl dosing error occurred with
a 2-month-old infant who had been admitted to the hospital for a pyeloplasty. The
anesthesia team started a fentanyl infusion (200 mcg in 20 mL of 5% dextrose)
to be delivered at 1 mcg/kg per hour
during the surgical procedure. However,
the infant received the entire 200 mcg of
fentanyl in less than an hour because the
smart infusion pump had been misprogrammed to deliver 1 mcg/kg per minute
instead of 1 mcg/kg per hour. The infant
became hypotensive for a short interval but tolerated the procedure and was
breathing spontaneously after surgery.
As with the other events, numerous
risk-reduction strategies could help
prevent infusion-pump programming
errors, but one key intervention in this
case includes a hard stop during pump
programming that would not allow the
programming of such a catastrophic dose
to continue. A hard stop in this case would
have required reprogramming of the
pump in accordance with preapproved
dosing guidelines.
are clearly not upholding their responsibility to keep patients safe from unreasonable risk. While organizations need to
address any clinicians concerns about
hard stops and to make every effort to
minimize any unintended effects, we
suggest that all organizations place the
issue of hard stops for certain drugs,
including the three described above, and
other preventable clinical situations on
the top of their safety agenda.
D676D6@46E
1.
2.
3.
4.
5.
6.
4^]PZdbW^]
The errors described above demonstrate specic situations with amphotericin B, methotrexate, and fentanyl in
which hard stops would have protected
patients from harmful medication errors.
While some clinicians may complain that
hard stops potentially delay order completion or slow the dispensing and administration process, the intent is to allow for
a brief period of investigation to ensure
safety. Clearly for drugs like amphotericin B, methotrexate, and fentanyl, the
risk of a potentially fatal dosing error
far outweighs any risk of a slight delay
in therapy. Another barrier may be that
some clinicians nd hard stops objectionable, noting that decision support should
not replace the clinicians responsibility
for patients.1,9
However, when relatively simple
actions such as thoughtfully placed hard
stops could prevent harmful events and
clinicians do not implement them, they
7.
8.
9.
Strom BL, Schinnar R, Aberra F, et al.

Unintended effects of a computerized
physician order entry nearly hard-stop
alert to prevent a drug interaction. Arch
Intern Med 2010;170(17):15781583.
Lapane KL, Waring ME, Schneider KL, et
al. A mixed method study of the merits of
e-prescribing drug alerts in primary care.
J Gen Intern Med 2008;23(4):442446.
Shah NR, Seger AC, Seger DL, et al.
Improving acceptance of computerized
prescribing alerts in ambulatory care.
J Am Med Inform Assoc 2006;13(1):511.
Miller RA, Waitman LR, Chen S, et al.
The anatomy of decision support during
inpatient care provider order entr y
(CPOE): empirical observations from a
decade of CPOE experience at Vanderbilt.
J Biomed Inform 2005;38(6):469485.
Paterno MD, Maviglia SM, Gorman PN,
et al. Tiering drug-drug interaction alerts
by severity increases compliance rates.
J Am Med Inform Assoc 2009;16(1):4046.
Shamliyan TA, Duval S, Du J, et al. Just
what the doctor ordered. Review of the
evidence of the impact of computerized
physician order entry system on medication errors. Health Serv Res 2008;43(1,
Pt 1):3253.
Eslami S, de Keizer NF, Abu-Hanna A.
The impact of computerized physician
medication order entry in hospitalized
patientsa systematic review. Int J Med
Inform 2008;77(6):365376.
Moore TJ, Walsh CS, Cohen MR.
Reported medication errors associated
with methotrexate. Am J Health Syst
Pharm 2004;61:13801384.
Van der Sijs H, Aarts J, Vulto A, et al.
Overriding of drug safety alerts in computerized physician order entry. J Am Med
Inform Assoc 2006;3(2):138147. Q
42>>7ADB2B6DE
P&T is accepting article submissions. We welcome a wide variety of manuscripts, including drug class reviews, disease state management reviews,
pharmacoeconomic analyses, strategies for coping with medication errors,
outcomes research evaluations, DUEs, P&T committee experiences, commentaries, book reviews, and letters to the editor.
While we will entertain all suggestions, readers have expressed particular
interest in these topics:
86@6D2>
U Biosimilars
U Medication reconciliation
U Clinical pharmacy and medical

staff collaborations
U Orphan drugs
U Electronic medical records
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facilities
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U Transitions of care
CLINICAL
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Please see our author guidelines at PTCommunity.com. You can contact the editor,
J. Stephen McIver, via telephone (267-685-3713) or email (smciver@medimedia.com).
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