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Volume 41 Number 11

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

Pharmacological Management VISIT US ONLINE AT WWW.PTCOMMUNITY.COM

And Prevention of Exacerbations of Chronic bronchitis Emphysema
Chronic Obstructive Pulmonary Disease
In Hospitalized Patients
D. Dixit, PharmD, BCPS; M. Barna Bridgeman, PharmD,
BCPS, CGP; R. Patel Madduri, PharmD, BCPS, AAHIVP;
S. T. Kumar, MD Candidate; and M. J. Cawley, PharmD,
RRT, CPFT, FCCM

Minnesota Pharmacists and Medical

Cannabis: A Survey of Knowledge, Concerns,
And Interest Prior to Program Launch
J. Hwang, PharmD, MPH; T. Arneson, MD, MPH; and
W. St. Peter, PharmD

The Missing Link: Evolving Accessibility

To Formulary-Related Information
A. Van Rossum, PharmD, BCPS; M. Holsopple, PharmD,
BCPS; J. Karpinski, PharmD, BCPS; and J. Dow, PharmD,
FACHE
Chronic obstructive pulmonary disease
Prescription Drug Data
Might Help Protect Obamacare The New Pregnancy and
Medication Use Will Be Integrated Lactation Labeling Rule
Into Marketplace Plan Risk Adjustments
S. Pernia, PharmD; and G. DeMaagd, PharmD, BCPS
S. Barlas

DRUG FORECAST
Perampanel (Fycompa)
A Review of Clinical Efficacy and Safety in Epilepsy
J. Greenwood, MS, PharmD Candidate; and J. Valdes,
PharmD, BCPP
 For flu patients in the emergency department who may not be appropriate for oral treatment 1,2

It only takes

to be

treating the flu with

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

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

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

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

Seqirus USA Inc.

King of Prussia, Pennsylvania 19406 2016 Seqirus USA Inc. August 2016 US/RIV/0816/0068
RAPIVAB (peramivir injection), for intravenous use
Initial U.S. Approval: 2014
BRIEF SUMMARY OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use RAPIVAB
safely and effectively. See full prescribing information for RAPIVAB.
----------------------------------INDICATIONS AND USAGE--------------------------------
RAPIVAB is an inuenza virus neuraminidase inhibitor indicated for the treatment
of acute uncomplicated inuenza in patients 18 years and older who have been
symptomatic for no more than two days.
Limitations of Use:
Efcacy based on clinical trials in which the predominant inuenza virus type was
inuenza A; a limited number of subjects infected with inuenza B virus were
enrolled.
Consider available information on inuenza drug susceptibility patterns and
treatment effects when deciding whether to use.
Efcacy could not be established in patients with serious inuenza requiring
hospitalization.
---------------------------------DOSAGE AND ADMINISTRATION------------------------
Administer as a single dose within 2 days of onset of inuenza symptoms.
Recommended dose is 600 mg, administered by intravenous infusion for a minimum
of 15 minutes.
Renal Impairment: Recommended dose for patients with creatinine clearance 30-49
mL/min is 200 mg and the recommended dose for patients with creatinine clearance
10-29 mL/min is 100 mg.
Hemodialysis: Administer after dialysis.
RAPIVAB must be diluted prior to administration.
See the Full Prescribing Information for drug compatibility information.
Seqirus USA Inc.
King of Prussia, Pennsylvania 19406 2016 Seqirus USA Inc.
-------------------------------DOSAGE FORMS AND STRENGTHS------------------------
Injection: 200 mg in 20 mL (10 mg/mL) in a single-use vial.
------------------------------------CONTRAINDICATIONS-----------------------------------
Patients with known serious hypersensitivity or anaphylaxis to peramivir or any
component of RAPIVAB.
--------------------------------WARNINGS AND PRECAUTIONS---------------------------
Cases of anaphylaxis and serious skin/hypersensitivity reactions such as Stevens-
Johnson syndrome and erythema multiforme have occurred with RAPIVAB.
Discontinue RAPIVAB and initiate appropriate treatment if anaphylaxis or serious
skin reaction occurs or is suspected.
Neuropsychiatric events: Patients with influenza may be at an increased risk of
hallucinations, delirium and abnormal behavior early in their illness. Monitor for signs
of abnormal behavior.
---------------------------------ADVERSE REACTIONS--------------------------------------
Most common adverse reaction (incidence >2%) is diarrhea.
To report SUSPECTED ADVERSE REACTIONS, call 1-844-273-2327 or contact
FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
---------------------------------------DRUG INTERACTIONS---------------------------------
Live attenuated inuenza vaccine (LAIV), intranasal: Avoid use of LAIV within 2 weeks
before or 48 hours after administration of RAPIVAB, unless medically indicated.
--------------------------------USE IN SPECIFIC POPULATIONS---------------------------
Pregnancy: Use if benet outweighs risk.
Nursing mothers: Caution should be exercised when administered to a nursing
woman.
Revised: 8/2016
August 2016 US/RIV/0816/0068
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662 P&T November 2016 Vol. 41 No. 11

 Chronic bronchitis Emphysema
Cover: Illustration of chronic
obstructive pulmonary disease,
a common lung disease with two
main forms: chronic bronchitis and
emphysema. Pharmacological
interventions and preventive strategies
play a large role in inhibiting
exacerbations of the disease. See
related story on page 703. (Credit:
Monica Schroeder / Science Source)
DEPARTMENTS
Medication Errors 665
Using a saline ush site
unseen could lead to a
wrong-route error
Prescription: Washington 667
Can the FDA do more to
encourage orphan drug
development?
Drug and Device News 668
Approvals, new indications,
regulatory activities, and more
Pharmaceutical
Approval Update 677
Calcifediol (Rayaldee) for
secondary hyperparathyroidism
in adults with chronic kidney
disease; dasabuvir/ombitasvir/
paritaprevir/ritonavir (Viekira
XR) for hepatitis C virus
infection; and lixisenatide
(Adlyxin) for type-2 diabetes
Drug Forecast 683
Perampanel (Fycompa):
a review of clinical efficacy
and safety in epilepsy
Research Briefs 723
Back issues are available on
the PubMed Central archive.
Visit www.pubmedcentral.nih.gov
The digital edition does not contain some of the advertising pages that appear in the print edition.
CONTENTS
November 2016
FEATURES
Prescription Drug Data Might Help Protect Obamacare 689
Medication Use Will Be Integrated Into Marketplace Plan Risk Adjustments
The Centers for Medicare and Medicaid Services addition of drug utilization
categories to the risk-assessment process aims to make scores more sensitive and
accurate, which may help stem the exodus of companies from the marketplace.
Stephen Barlas
The Missing Link: Evolving Accessibility
To Formulary-Related Information 698
After incorporating system formulary-related information and related resources
into a single commercial formulary management tool, one health system increased
pharmacist end-user satisfaction and overall use of formulary-related information.
Alison Van Rossum, PharmD, BCPS; Megan Holsopple, PharmD, BCPS; Julie Karpinski,
PharmD, BCPS; and Jordan Dow, PharmD, FACHE
Pharmacological Management and Prevention of
Exacerbations of Chronic Obstructive Pulmonary
Disease in Hospitalized Patients 703
Rapid-acting bronchodilators, systemic corticosteroids, and antibiotics are among
the keys to managing exacerbations of chronic obstructive pulmonary disease.
Preventing exacerbations should also be a component of therapy for the disease.
Deepali Dixit, PharmD, BCPS; Mary Barna Bridgeman, PharmD, BCPS, CGP;
Rani Patel Madduri, PharmD, BCPS, AAHIVP; Samir T. Kumar, MD Candidate;
and Michael J. Cawley, PharmD, RRT, CPFT, FCCM
The New Pregnancy and Lactation Labeling Rule 713
To address the need for updated pregnancy risk categories, the Food and Drug
Administration published a nal rule in 2014. The authors review the changes the
rule makes, its implementation schedule, and its potential clinical impact.
Sonia Pernia, PharmD; and George DeMaagd, PharmD, BCPS
Minnesota Pharmacists and Medical Cannabis:
A Survey of Knowledge, Concerns, and
Interest Prior to Program Launch 716
Researchers surveyed pharmacists preparedness for the states medical cannabis
program and found that more training and education on the regulatory and clinical
aspects of cannabis were needed in preparation for their work with patients.
Joy Hwang, PharmD, MPH; Tom Arneson, MD, MPH; and Wendy St. Peter, PharmD
Attention Readers: P&T is on Facebook, Twitter, and LinkedIn.
Search for P&T
Search for
[Pharmacy and @PTJournal780
P&T in Groups
Therapeutics]
Editor-in-Chief
David B. Nash, MD, MBA
Dr. Raymond C. and
Doris N. Grandon Professor
The Jefferson College of Population Health
Philadelphia, Pennsylvania
Richard Afable, MD, MPH
President and Chief Executive Ofcer
Hoag Memorial Hospital Presbyterian
Newport Beach, California
Robert L. Barkin, MBA, PharmD
Professor, Faculty of Anesthesiology,
Family Medicine, and Pharmacology
Rush Medical College of Rush University
Chicago, Illinois
Clinical Pharmacologist
North Shore University Health System
Pain Centers
Skokie and Evanston, Illinois
Mark J. Baumel, MD, MS
President/Chief Executive Ofcer
Colon Health Centers of America, LLC
Mendenhall, Pennsylvania
Thomas Biancaniello, MD
Clinical Professor of Pediatrics
Columbia University
College of Physicians and Surgeons
Division of Pediatric Cardiology
New York, New York
Joseph E. Biskupiak, PhD, MBA
Research Associate Professor
Department of Pharmacy Practice
Director, Pharmacotherapy Outcomes
Research Center
College of Pharmacy, University of Utah
Salt Lake City, Utah
David A. Casey, MD
Vice Chairman, Department of Psychiatry
University of Louisville
Louisville, Kentucky
Alan Caspi, PhD, PharmD, MBA
President, Caspi & Associates
New York, New York
Burke A. Cunha, MD
Professor of Medicine
State University of New York at Stony Brook
Chief, Infectious Disease Division
Winthrop-University Hospital
Mineola, New York
Joseph C. English III, MD
Professor of Dermatology
Clinical Vice Chairman
for Quality and Innovation
Founding Director of Teledermatology
University of Pittsburgh
Department of Dermatology
Pittsburgh, Pennsylvania
664 P&T November 2016 Vol. 41 No. 11
EDITORIAL BOARD
Marvin M. Goldenberg, PhD, RPh, MS
President, Pharmaceutical and Scientic
Services
Marvin M. Goldenberg, LLC
Westeld, New Jersey
Nancy Greengold, MD, MBA
Chief Medical Ofcer
Sharp Grossmont Hospital/Sharp
HealthCare
La Mesa, California
Matthew Grissinger, RPh, FASCP
Director, Error Reporting Programs
Institute for Safe Medication Practices
Horsham, Pennsylvania
Rusty Hailey, PharmD, DPh, MBA, FAMCP
President, Pharmaceutical Operations
Senior Vice President, HealthSpring, Inc.
Nashville, Tennessee
Steven D. Hanks, MD, MMM, FACP
Executive Vice President
and Chief Medical Ofcer
The Hospital of Central Connecticut
New Britain, Connecticut
Michele B. Kaufman, PharmD, CGP, RPh
Pharmacist, New YorkPresbyterian
Lower Manhattan Hospital, Pharmacy
Department
New York, New York
Grant D. Lawless, RPh, MD
Associate Professor of Clinical Pharmacy,
Pharmaceutical Economics and Policy
Director, Master of Science Program in
Healthcare Decision Analysis
School of Pharmacy
University of Southern California
Los Angeles, California
Burton Orland, BS, RPh
President
BioCaRe Consultants
Westport, Connecticut
Fred Joseph Pane, RPh, BS, FASHP, FABC
Senior Director, Customer Engagement
The Medicines Company
Parsippany, New Jersey
Lawrence Charles Parish, MD
Dermatologist, Editor-in-Chief
Clinics in Dermatology
Philadelphia, Pennsylvania
Associate Editor-in-Chief
Karl A. Matuszewski, MS, PharmD
Vice President
First Databank, Inc.
Clinical and Editorial
Knowledge Base Services
South San Francisco, California
Luke A. Probst, PharmD, BCPS
Director of Pharmacy Services
Upstate University Hospital/
Downtown Campus
Clinical Assistant Professor, Departments
of Pediatrics and Medicine
SUNY Upstate Medical University
Syracuse, New York
Sheldon M. Retchin, MD, MSPH
Executive Vice President of Health
Sciences, The Ohio State University
Chief Executive Ofcer, OSU Wexner
Medical Center
Columbus, Ohio
Vitalina Rozenfeld, PharmD, BCPS
Medical Affairs
AstraZeneca
Wilmington, Delaware
Fadia T. Shaya, PhD, MPH
Professor and Vice-Chair for Academic
Affairs
University of Maryland School of Pharmacy
Associate Director
Center on Drugs and Public Policy
Baltimore, Maryland
Arthur F. Shinn, PharmD, FASCP
President
Managed Pharmacy Consultants, LLC
Palm City, Florida
Brian Swift, PharmD, MBA
Vice President/Chief of Pharmacy
and Accreditation
Thomas Jefferson University Hospital
Associate Dean of Professional Affairs
Jefferson College of Pharmacy
Philadelphia, Pennsylvania
F. Randy Vogenberg, RPh, PhD
Partner
Access Market Intelligence and National
Institute of Collaborative Healthcare
Greenville, South Carolina
Scott W. Yates, MD, MBA, MS
Center for Executive Medicine
Plano, Texas
MEDICATION ERRORS
Using a Saline Flush Site Unseen
Could Lead to a Wrong-Route Error
Matthew Grissinger, RPh, FASCP
Mr. Grissinger, an editorial
board member of P&T, is
Director of Error Reporting
Programs at the Institute for
Safe Medication Practices
(ISMP) in Horsham, Penn-
sylvania (www.ismp.org).
PROBLEM: The Institute for Safe Medi-
cation Practices (ISMP) learned about an
event that resulted in the administration
of a saline ush solution by the wrong
route. In an unusual twist, the saline ush
was administered by a laboratory techni-
cian who was attempting to collect blood
samples from what she thought was a
central venous access device (CVAD).
The saline ush was instead administered
via extension tubing that was connected
to a continuous peripheral nerve-block
infusion.
Prior to the event, an anesthesia
practitioner had placed an ON-Q C-bloc
continuous peripheral nerve-block
system (Halyard Health) in the patients
thoracic paravertebral region to help
control pain. The ON-Q system catheter
(Figure 1, green arrow) that bathed the
thoracic region with a local anesthetic was
anchored at the patients right shoulder
using a large white stabilization device
(Figure 1, red arrow). Typically, anes-
thesia staff places the stabilization device
on the back of a patients shoulder. In
this case, placing the stabilization device
on the front of the shoulder, presum-
ably to promote comfort, contributed
to mistaking the ON-Q system tubing
as the CVAD catheter, which was also
located near the patients right shoulder
(Figure 1, blue arrow).
When placing the ON-Q system in
the patients paravertebral region, anes-
thesia staff decided to attach a short
extension set with yellow-striped tubing
(Figure 1, yellow arrow) to warn staff
that the infusion was not being admin-
istered intravenously but rather into
the paravertebral region. Before this
instance, yellow-striped tubing had been
reserved for epidural infusions only.
Because the extension set had been
added, a MicroClave connector (Figure 1,
purple arrow) had to be used to connect
the yellow-striped tubing to the main
tubing of the ON-Q system. This type of
connector is commonly used with CVADs
(Figure 1, orange arrow).
When the technician went to withdraw
blood from the patient, the upper part of
the patients gown obscured the ON-Q
C-bloc system afxed to the upper right
shoulder; only the CVAD insertion site
was visible (Figure 1, blue arrow). The
yellow-striped tubing and the connector
(Figure 1, purple arrow) associated with
the ON-Q system were also visible, giving
the appearance that they were actually
attached to the CVAD. The technician
was familiar with the connector because
these were frequently used with CVADs.
The technician had difculty disconnect-
ing the connector from the tubing so she
could withdraw the blood specimens.
She left the patients room and asked a
busy nurse for help. The nurse did not
remember that the patients CVAD was
capped and did not need to be discon-
nected from an infusion. She gave the
Figure 1 The ON-Q C-bloc continuous
peripheral nerve-block system (red,
green, yellow, and purple arrows) was
confused with the central venous
catheter (blue and orange arrows),
leading to a wrong-route error.
technician a hemostat, which helped
remove the tubing from the connector.
The technician attempted to conrm
placement of the CVAD but could not
obtain a blood return. She then ushed
the line with normal saline, which infused
into the paravertebral region. Fortunately,
the patient was not injured. The inability
to collect the blood specimens led the
technician to seek additional help from
the nursing staff, which then led to the
discovery of the error.
SAFE PRACTICE RECOMMENDATIONS
According to the Association for the
Advancement of Medical Instrumen-
tation, hospitals will likely start to see
newly designed connectors on medical
tubing on the marketthe end result of
a joint working group that is developing
standards that will make misconnections
virtually impossible because the design
of the connectors will no longer be uni-
versal as it is now with Luer connectors.1
Instead, the design of each connector will
be specic to its application. The rst
Provisional American National Standards
that were released in 2014 are associated
with connectors for enteral applications.
But there isnt anything on the horizon
that would prevent a Luer connector on
a syringe used to withdraw blood from
being connected to tubing used for the
delivery of regional anesthetics via the
ON-Q systems.
Considering all the elements that con-
tributed to this particular event, please
take the following precautions to prevent
a similar error in your organization.
Limit access. Limit access to CVAD
lines for any purpose, including
blood collection, to those with pro-
fessional health care training and
demonstrated competencies; these
staff are more likely to know and
follow safety measures associated
with these devices and are more
likely to be knowledgeable about
the serious ramications of mis-
connections, infections, occlusions,
or misadministration of medications.
Vol. 41 No. 11 November 2016 P&T
665
MEDICATION ERRORS
For example, given the risk of occlu-
sion and infection alone, most hospi-
tals do not allow laboratory techni-
cians to draw blood from CVADs.
Some hospitals prohibit technician
access to these catheters in certain
settings, such as critical care units,
or for certain patient groups, such
as bone marrow transplant patients
(as did the hospital where the error
occurred).
Trace access lines. Promote a
consistent process for tracing all
catheters/lines from the access site
into the patients body all the way
to the end source of an infusion or
capped access port before drawing
blood, connecting or reconnecting
tubing, and/or administering drugs,
solutions, ushes, or other products.
Remind staff that, for patients with
multiple tubes and catheters, situ-
ational awareness of each tubes loca-
tion and insertion site can be lost,
especially if tubing is obscured by
clothes and bed sheets. It is also
important to fully uncover the inser-
tion site before access is attempted;
otherwise mix-ups between look-
alike tubing and devices can lead to
serious wrong-route errors.
Communicate practice changes.
Changes in dressing locations, types
of tubing and connectors, and other
altered practices should be readily
communicated with all members
of the health care team who are
providing care to the patient.
Provide training. Educate all staff
who might use or encounter ON-Q
C-bloc, ON-Q PainBuster, or other
new tubes, catheters, connectors,
or drug-delivery systems regard-
ing proper use or access. Include
discussions about possible sources
of errors and steps to avoid these
errors. When possible, include
tubing misconnections in simula-
tion training during orientation and
annual safety competencies.
Label lines. Afx labels on lines if
the patient has more than one poten-
tial connection to a port of entry
into the body (e.g., intravenous,
arterial, umbilical, enteral, bladder,
drainage tubes). For ON-Q C-bloc
infusions, afx labels indicating
CONTINUOUS NERVE BLOCK
to alert staff, particularly given that,
666 P&T November 2016 Vol. 41 No. 11
in many hospitals, only anesthesia
staff can manipulate these catheters
or dressings. COMING
Use epidural tubing appropri-
ately. Avoid use of yellow-striped SOON
tubing for anything other than its
intended purpose: administration Zika in America:
of epidural infusions. Its use in The Year in Review
other circumstances could result in
unintended negative consequences,
Chris Fellner
as it did in this case. When possible,
avoid use of any extension sets with Systemic Thrombolysis
the ON-Q C-bloc infusions or tubing for Pulmonary Embolism:
connectors that may resemble those A Review
used with CVAD catheters and
Colleen Martin, PharmD;
tubing.
Additional strategies. For address- Kristine Sobolewski, PharmD;
ing the wide-ranging potential for Patrick Bridgeman, PharmD;
tubing misconnections, hospitals and Daniel Boutsikaris, MD
might also want to conduct a self-
assessment to identify all products PHARMACOVIGILANCE FORUM
and practices that pose a risk of
inadvertent tubing misconnections, Drug-Induced
with the goal of mitigating identi- Neutropenia: A Focus
ed risks. A tool created in 2012 by on Rituximab-Induced
Baxter in cooperation with ISMP Late-Onset Neutropenia
guides users through a modied Donald C. Moore, PharmD,
risk assessment that evaluates BCPS, BCOP
current delivery systems and mating
devices, rating ease of connection
and potential for patient harm, and DRUG FORECAST
assigning a risk priority score.2 Daclatasvir (Daklinza):
A Treatment Option
REFERENCES for Chronic Hepatitis C
1. Association for the Advancement of
Medical Instrumentation. Ambitious Infection
standards initiative on small-bore Maggie Montgomery, PharmD;
connectors moves forward. April 24, 2013.
Available at: www.aami.org/newsviews/
Natalie Ho, PharmD; Elizabeth
newsdetail.aspx?ItemNumber=1025. Chung, PharmD; and Nino
Accessed October 4, 2016. Marzella, PharmD
2. Institute for Safe Medication Practices.
Tubing misconnections self assessment
for healthcare facilities. Available at: www. HEALTH CARE & LAW
ismp.org/selfassessments/tubingMis-
connections. Accessed October 4, 2016. Systemic Market and
Organizational Changes:
The reports described in this column were Impact on P&T Committees
received through the ISMP Medication F. Randy Vogenberg, RPh, PhD;
Errors Reporting Program (MERP).
Rita Marcoux, RPh, MBA; and
Errors, close calls, or hazardous condi-
tions may be reported on the ISMP website
Martha M. Rumore, PharmD,
(www.ismp.org) or communicated directly JD, MS, LLM, FAPhA
to ISMP by calling 1-800-FAIL-SAFE or
via email at ismpinfo@ismp.org. Q MEETING HIGHLIGHTS
European Society
for Medical Oncology
2016 Congress
Walter Alexander
PRESCRIPTION: WASHINGTON
The Push for Additional Orphan Drugs
Can the FDA Do More to Encourage Their Development?
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.
straZenecas failed attempts to
A convince the Food and Drug Admin-
istration (FDA) and a federal court
to require extra labeling on the slew of
generic versions of Crestor that became
available this summer illustrate the lengths
to which brand-drug companies will go to
protect orphan drug prices and prots. In
May, the FDA approved AstraZenecas
Crestor (rosuvastatin calcium) as a treat-
ment for a rare condition called homo-
zygous familial hypercholesterolemia
(HoFH). As a result, AstraZeneca gained
seven-year orphan market exclusivity for
Crestor for that indication. Its broader
patent expired in July.
Then AstraZeneca tried to force the FDA
and a U.S. District Court to require the
agency to mandate that the new Crestor
generics include pediatric HoFH label-
ing that would prevent safety problems if
physicians prescribed generic Crestor off-
label for pediatric HoFH. The agency and
a judge rejected AstraZenecas demand.1
Other brand-drug companies have tried
unsuccessfully to use the same tactic.
The global orphan drug market is
estimated at $170 billion a year and is
growing at 12% annually, according to con-
sultant EvaluatePharma.2 Patient advocacy
groups, such as Global Genes and the
National Organization for Rare Disorders
(NORD), say there are 7,000 rare diseases,
and only 326 drugs have been approved
for them since the Orphan Drug Act was
passed in 1983.3 Given the prots that
orphan drugs generate, one might wonder
why more arent on the market. Still, 80%
of all rare-disease patients are affected
by approximately 350 rare diseases.3 If
each of the 326 drugs had been approved
for one of those 350 rare diseases, one
might assume that many people with rare
diseases already have a drug treatment.
So whats the problem?
Patient advocacy groups would like to
see an effective drug made available at a
reasonable price for every rare disease,
dened by the FDA as one affecting fewer
than 200,000 people in the United States.
Congress is sensitive to those desires.
The House included a provision in its 21st
Century Cures Act, passed in July 2015, that
would add six months of market exclusivity
to the seven years already granted to an
orphan drug when the company added a
second orphan indication.4 The Senate has
not passed a 21st Century Cures bill, and
none of the disparate Senate bills that could
be packaged into a 21st Century Cures
companion act contains a similar provision.
The Senate did pass a bill in late
September to extend an orphan-drug
development voucher program to the
end of 2016. In March, the Government
Accountability Ofce (GAO) published
a report questioning the effectiveness
of the vouchers, which Congress estab-
lished in 2012. The program awards a
pediatric orphan voucher to companies
that market a new pediatric orphan drug.
The voucher authorization expired at the
end of September, and the FDA opposed
extending it because they have seen no
evidence that the program is effective,
according to the GAO.5
The FDA approved 21 orphan drugs in
2015almost half of all its approvals. We
believe the FDA is using a historic amount
of exibility in reviewing orphan therapies,
something we are very thankful for, says
Paul Melmeyer, Associate Director of Public
Policy at NORD. While the FDA is doing
quite well overall, we are still aware of situ-
ations in which the FDA will request extra
conrmatory trials, particular endpoints,
limited inclusion criteria, or other clinical
trial structures or requests that our patient
organization members that participate in
such trials deem inappropriate.
The FDA has included potentially
signicant orphan-drug enhancements in
its commitment letter laying out what
the agency will do in conjunction with
Congress expected approval of the next
version of the Prescription Drug User
Fee Act (PDUFA) when the current law
expires in September 2017. The PDUFA
species the fees companies pay the FDA
to support the drug approval process, and
the commitment letter outlines improve-
ments the FDA plans in the approval
process, in part to justify higher fees.
One proposed initiative would expand
the Rare Diseases Program by integrating
rare disease specialists in each review
division. I think the addition of the rare
disease specialists into the review teams
is helpful from an overall understanding
of clinical development programs in the
context of a rare disease; however, the
scientic expertise will still lie with the
clinical review personnel, says Lisa N.
Pitt, PharmD, Vice President of Global
Regulatory Affairs at Premier Research.
One thing seems certain. If Congress
allowed companies such as AstraZeneca to
tack an extra six months of market exclusiv-
ity onto goldmines like Crestor, there would
be an explosion of private sector research
and development on orphan drugs. But
Congress may not pass even the much more
anemic incentive in the House bill.
REFERENCES
1. AstraZeneca Pharms. LP v. Burwell. Civil
Action No. 16-cv-1336. (D.D.C. 2016).
Available at: https://casetext.com/case/
astrazeneca-pharms-lp-v-burwell. Accessed
September 27, 2016.
2. EvaluatePharma. Orphan Drug Report 2015.
October 2015. Available at: http://info.evalu-
ategroup.com/rs/607-YGS-364/images/
EPOD15.pdf. Accessed September 27, 2016.
3. Global Genes. Rare diseases: facts and sta-
tistics. Available at: https://globalgenes.
org/rare-diseases-facts-statistics. Accessed
September 28, 2016.
4. Upton F. H.R.6: 21st Century Cures Act. July
10, 2015. Available at: www.congress.gov/
bill/114th-congress/house-bill/6. Accessed
September 28, 2016.
5. Government Accountability Ofce. Rare
diseases: too early to gauge effectiveness
of FDAs pediatric voucher program.
March 2016. Available at: www.gao.gov/
assets/680/675544.pdf. Accessed Septem-
ber 28, 2016. Q
Vol. 41 No. 11 November 2016 P&T 667
 NEW DRUG APPROVALS
Amjevita, the First
Humira Biosimilar
The FDA has approved Amjevita
(adalimumab-atto, Amgen) as a biosimilar
to Humira (adalimumab, AbbVie) for
the treatment of multiple inammatory
diseases. Amjevita is approved for the
following indications in adults: mod-
erately to severely active rheumatoid
arthritis; active psoriatic arthritis; active
ankylosing spondylitis; moderately to
severely active Crohns disease; moder-
ately to severely active ulcerative colitis;
and moderate-to-severe plaque psoriasis.
Amjevita is also indicated for moderately
to severely active polyarticular juvenile
idiopathic arthritis in patients 4 years of
age and older.
Source: Amgen, September 23, 2016
Exondys 51 for Duchenne MD
Exondys 51 (eteplirsen injection,
Sarepta Therapeutics) has received
FDA approval as the rst drug indicated
to treat patients with Duchenne muscu-
lar dystrophy (DMD). The treatment is
approved for DMD patients who have
a conrmed mutation of the dystrophin
gene amenable to exon 51 skipping,
which is found in approximately 13% of
this population.
Exondys 51 was approved under the
accelerated approval pathway. The FDA
is requiring Sarepta to conduct a study
to conrm the drugs clinical benet. If
that trial fails to verify a benet, the FDA
may initiate proceedings to withdraw its
approval of the drug.
Source: Sarepta Therapeutics,
September 19, 2016
Cuvitru for Primary
Immunodeciencies
The FDA has approved the use of
Cuvitru (immune globulin subcutaneous
[human], 20% solution, Shire) in adult
and pediatric patients 2 years of age and
668 P&T November 2016 Vol. 41 No. 11
older with primary immunodeciencies, a
group of more than 300 genetic disorders
in which part of the bodys immune
system is missing or functions improperly.
According to Shire, Cuvitru is the only
20% subcutaneous immunoglobulin (IG)
treatment option without proline and with
the ability to infuse up to 60 mL (12 g)
per site and 60 mL per hour per site, as
tolerated, resulting in fewer infusion sites
and shorter infusion durations compared
with other conventional subcutaneous
IG treatments. Regardless of the infu-
sion rate or volume per site, Cuvitru was
generally associated with a low incidence
of local adverse and systemic reactions
(0.022 per infusion and 0.042 per infusion,
respectively) in a North American study.
Source: Shire, September 14, 2016
Yosprala to Prevent Cardio-
And Cerebrovascular Events
The FDA has approved once-daily
Yosprala (Aralez Pharmaceuticals), a
xed-dose combination of enteric-coated
aspirin, an antiplatelet agent, and omepra-
zole, a proton pump inhibitor. The prod-
uct is indicated for patients who require
aspirin for secondary prevention of
cardiovascular and cerebrovascular
events and who are at risk of developing
aspirin-associated gastric ulcers.
Yosprala was designed to support both
cardiac and gastric protection for at-risk
patients through the proprietary Intelli-
COAT system, which is formulated to
sequentially deliver immediate-release
omeprazole (40 mg) followed by a delayed-
release, enteric-coated aspirin core in
either 81-mg or 325-mg strengths. The
immediate-release omeprazole in Yosprala
is designed to elevate the gastric pH into
a gastroprotective zone. The enteric-
coated aspirin dissolves after the pH has
been elevated to 5.5 or greater, thereby
reducing the risk of stomach ulcers.
Source: Aralez Pharmaceuticals,
September 15, 2016
Generic Approvals and Launches
Memantine ER Capsules
The FDA has approved the rst generic
versions of memantine hydrochloride
extended-release capsules by three compa-
nies. Lupin, Ltd., Mylan Pharmaceuticals,
Inc., and Sun Pharma Global FZE can sell
7-mg, 14-mg, 21-mg, and 28-mg generic
versions of Namenda (Allergan), which is
indicated for the treatment of moderate-to-
severe dementia of the Alzheimers type.
Source: FDA, September 28, 2016
Acetaminophen, Caffeine, and
Dihydrocodeine Bitartrate Tablets
The FDA has approved the sale of
acetaminophen, caffeine, and dihydro-
codeine bitartrate tablets, 325 mg, 30 mg,
and 16 mg, by Larken Laboratories, Inc.
The product is indicated for the relief of
moderate to moderately severe pain.
Source: FDA, September 30, 2016
Abacavir Oral Solution
Hetero Labs, Ltd., has secured FDA
approval to market abacavir oral solu-
tion USP, 20 mg/mL. The FDA describes
this as the rst generic version of Ziagen
oral solution (ViiV Healthcare), which is
used in combination with other antiretro-
viral agents for the treatment of human
immunodeciency virus-1 infection.
Source: FDA, September 26, 2016
Fenobric Acid DR Capsules
The first generic formulation of
fenofibric acid delayed-release (DR)
capsules (Trilipix, AbbVie) has secured
FDA approval. Impax Laboratories, Inc.,
can produce 45-mg and 135-mg capsules
of the peroxisome proliferator-activated
receptor alpha agonist, which is indicated
as adjunctive therapy to diet to reduce
triglycerides in patients with severe
hypertriglyceridemia and to reduce
elevated low-density lipoprotein-cholesterol,
total cholesterol, triglycerides, and apo-
lipoprotein B and to increase high-density
lipoprotein-cholesterol in patients with
primary hypercholesterolemia or mixed
dyslipidemia.
Source: FDA, September 7, 2016
Abacavir/Lamivudine Tablets
Teva Pharmaceutical Industries has
announced the U.S. launch of a generic
equivalent of Epzicom (abacavir and
lamivudine, ViiV Healthcare/GlaxoSmith-
Kline) tablets, 600 mg/300 mg. Abacavir/
lamivudine tablets are indicated in com-
bination with other antiretroviral agents
for the treatment of patients with human
immunodeciency virus-1 infection.
Source: Teva, September 29, 2016
Buprenorphine/Naloxone
Sublingual Tablets
The FDA has approved buprenor-
phine and naloxone sublingual tablets,
2 mg/0.5 mg and 8 mg/2 mg (Lannett
Company)the therapeutic equivalent to
Suboxone sublingual tablets, 2 mg/0.5 mg
and 8 mg/2 mg (Indivior, Inc.). Suboxone
is used to treat adults who are dependent
on opioid drugs.
Source: Lannett Company, September
20, 2016
NEW INDICATION
Orkambi for Cystic Fibrosis
The FDA has approved Orkambi
(lumacaftor/ivacaftor, Vertex Pharma-
ceuticals) for use in children 6 through
11 years of age with cystic brosis (CF)
who have two copies of the F508del
mutation. People with this mutation
represent the largest subset of CF
patients.
Orkambi is the only medication that
treats the underlying cause of CF for
people with this mutation. The treat-
ment was previously approved by the
FDA for use in people 12 years of age
and older with two copies of the F508del
mutation. With the new approval,
approximately 11,000 people with CF are
eligible for treatment with Orkambi in the
United States.
Orkambi combines lumacaftor, which is
designed to increase the amount of mature
protein at the cell surface by targeting
the processing and trafcking defect of
the F508del CFTR protein, and ivacaftor,
which is designed to enhance the function
of the CFTR protein once it reaches the
cell surface.
Source: Vertex Pharmaceuticals,
September 28, 2016
NEW FORMULATIONS
Invokamet XR for Diabetes
Invokamet XR (Janssen Pharmaceuti-
cals), a combination of canagliozin and
extended-release (XR) metformin, has
obtained FDA approval for rst-line use as
an adjunct to diet and exercise to improve
blood glucose control in adults with type-2
diabetes (T2D) when treatment with the
two medications is appropriate.
Invokamet XR is a once-daily, xed-
dose combination of canagliflozin
(Invokana), the most-prescribed sodium-
glucose cotransporter-2 (SGLT2)
inhibitor, and XR metformin, which is
commonly prescribed as an initial therapy
for the treatment of patients with T2D.
Canagliozin works with the kidneys to
help adults with T2D lose some sugar
through the process of urination, and
metformin decreases the production of
glucose in the liver and improves the
bodys response to insulin.
Invokamet, the rst combination of
an SGLT2 inhibitor and an immediate-
release metformin formulation available
in the United States, was approved by the
FDA in August 2014 as an adjunct to diet
and exercise to improve glycemic con-
trol in adults with T2D not adequately
controlled with metformin or canagliozin,
or who are being treated with both medi-
cations separately. In May 2016, the FDA
expanded the Invokamet indication to
include adults with T2D who are not being
treated with canagliozin or metformin
and may benet from dual therapy.
Source: Janssen, September 21, 2016
Carnexiv Injection for Seizures
The FDA has approved carbamazepine
injection (Carnexiv, Lundbeck) as a short-
term (seven-day) replacement therapy
for oral carbamazepine formulations in
adults with certain seizure types when
oral administration is temporarily not
feasible. Carnexiv received an orphan
drug designation from the FDA for this
indication and will be the rst available
intravenous formulation of the anti-
epileptic drug carbamazepine. Lundbeck
plans to make Carnexiv commercially
available in the U.S. in early 2017.
Source: Lundbeck, October 8, 2016
Lomaira for Weight Loss
The FDA has approved phenter-
mine hydrochloride USP 8-mg tablets
CIV (Lomaira, KVK Tech, Inc.), a low-
dose prescription medication used for
a short period (a few weeks) for weight
reduction in adults with an initial body
mass index of 30 or more (obese) or
27 or more (overweight) with at least
one weight-related condition, such as
controlled hypertension, diabetes, or
hypercholesterolemia. The product
should be used with regular exercise
and a reduced-calorie diet.
Phentermine, an appetite suppressant,
is the most commonly prescribed drug
for weight loss. The limited usefulness of
agents in this class (anorectics), includ-
ing phentermine, should be measured
against possible risk factors inherent in
their use. Phentermine has been associ-
ated with pulmonary hypertension, valvu-
lar heart disease, palpitations, increased
heart rate or blood pressure, insom-
nia, restlessness, dry mouth, diarrhea,
constipation, and changes in sexual drive.
Source: KVK Tech, Inc., September
20, 2016
Vol. 41 No. 11 November 2016 P&T
669
 FDA REVIEW ACTIVITIES
Priority Review Status
Dupilumab for Dermatitis
The FDA has accepted for priority
review a biologics license application for
dupilumab (Regeneron Pharmaceuticals/
Sano) for the treatment of adults with
inadequately controlled moderate-to-
severe atopic dermatitis. The applica-
tion was given a target action date of
March 29, 2017. Dupilumab, an anti-
body therapy, inhibits the signaling of
interleukin (IL)-4 and IL-13, two key cyto-
kines required for the type-2 (including
Th2) immune response, which is believed
to be a major driver in the pathogenesis
of atopic dermatitis.
Source: Regeneron Pharmaceuticals,
September 26, 2016
Fast-Track Designations
Galinpepimut-S for Mesothelioma
The FDA has granted fast-track status
to the immunotherapy galinpepimut-S
(Sellas Life Sciences Group) for the treat-
ment of patients with malignant pleural
mesothelioma (MPM). Galinpepimut-S,
a WT1 peptide cancer vaccine, is being
developed to target hematological cancers
and solid tumors, including MPM, acute
myeloid leukemia, multiple myeloma, and
ovarian cancer. A pivotal phase 3 trial is
expected to begin in patients with MPM
during the second half of 2017.
Source: Sellas, September 19, 2016
NYX-2925 for Neuropathic Pain
Aptinyx, Inc., is developing NYX-2925,
an N-methyl-D-aspartate receptor modu-
lator, for the treatment of pain associated
with diabetic peripheral neuropathy. The
FDA has designated the investigation of
NYX-2925 in this indication as a fast-track
program. The safety and tolerability of
NYX-2925 are being evaluated in a phase 1,
randomized, double-blind, placebo-
controlled study in healthy volunteers.
Source: Aptinyx, September 13, 2016
670 P&T November 2016 Vol. 41 No. 11
Breakthrough Therapy Status
Tocilizumab for Giant Cell Arteritis
The FDA has granted breakthrough
therapy status to tocilizumab (Actemra/
RoActemra, Roche), an antiinterleukin-6
receptor biologic, for the treatment of
patients with giant cell arteritis, a poten-
tially life-threatening autoimmune condi-
tion. The disease is caused by inamma-
tion of large- and medium-sized arteries,
most often in the head, but also in the aorta
and its branches. Tocilizumab is currently
indicated for the treatment of adults with
moderately to severely active rheumatoid
arthritis.
Source: Roche, October 5, 2016
Glecaprevir/Pibrentasvir for HCV
The FDA has granted breakthrough
therapy status to the investigational,
pan-genotypic regimen of glecaprevir/
pibrentasvir (AbbVie) for the treatment
of patients with chronic hepatitis C virus
(HCV) infection who failed previous
therapy with direct-acting antivirals
(DAAs) in genotype 1 (GT1), including
therapy with a nonstructural protein 5A
inhibitor and/or a protease inhibitor.
Ninety-one percent (20 of 22) of GT1
chronic HCV-infected patients who failed
previous therapy with DAAs achieved
a sustained viral response at 12 weeks
(SVR12) with glecaprevir and pibrentas-
vir with ribavirin in the primary intent-to-
treat analysis. In addition, 86% (19 of 22)
of GT1 patients who received glecaprevir
and pibrentasvir without ribavirin achieved
SVR12. This endpoint was also achieved by
95% of patients with and without ribavirin
(20 of 21 and 19 of 20, respectively) in a
modied intent-to-treat analysis, which
excluded patients who did not achieve SVR
for reasons other than virological failure.
Source: AbbVie, September 30, 2016
Orphan Drug Designations
SOR-C13 for Pancreatic Cancer
The FDA has granted orphan drug
status to SOR-C13 (Soricimed Bio-
pharma) for the treatment of patients
with pancreatic cancer.
SOR-C13 (which previously received
orphan drug status for ovarian cancer)
is a rst-in-class peptide that binds with
high selectivity and afnity to TRPV6, a
calcium channel that is highly elevated in
prostate, breast, lung, and ovarian cancer
and is correlated with poor outcomes.
By binding to the TRPV6 channel, SOR-
C13 starves cancer cells of the calcium
that is needed for cell growth and division.
Source: Soricimed Biopharma,
September 27, 2016
N-Methanocarbathymidine for
Neonatal Herpes Simplex
N-Methanocarbathymidine (N&N
Pharmaceuticals) has received an orphan
drug designation for the treatment of
neonatal herpes simplex. Most neonates
(85%) infected with herpes simplex virus-2
(HSV-2) die within one year even after
aggressive treatment. Of those who
survive, 67% have long-term neuro-
developmental problems. Approximately
25% of pregnant women are seropositive
for HSV-2 infection, and 1% with a history
of recurrent genital HSV-2 infection pass
the infection to their newborns. Central
nervous system and disseminated neo-
natal HSV-2 infections are associated with
substantial morbidity and mortality result-
ing from virus-related encephalitis and
neutropenia.
Source: N&N Pharmaceuticals,
September 27, 2016
Nintedanib for Systemic Sclerosis
The FDA has granted orphan drug
status to the kinase inhibitor nintedanib
(Ofev, Boehringer Ingelheim) for the
treatment of patients with systemic
sclerosis (also known as scleroderma),
including associated interstitial lung
disease (SSc-ILD). The SENSCIS trial,
the largest study to date in this disease
area, is evaluating nintedanib to under-
stand the disease process and the poten-
tial benet of the compound in patients
with SSc-ILD.
The FDA approved nintedanib for
the treatment of idiopathic pulmonary
brosis in October 2014.
Source: Boehringer Ingelheim,
September 9, 2016
THN102 for Narcolepsy
THN102 (ecainide acetate/modanil,
Theranexus) has received an orphan drug
designation from the FDA for the treat-
ment of patients with narcolepsy, a rare
and debilitating sleep/wake disorder.
A phase 2 study has been initiated to
determine the efcacy of THN102 in this
setting.
Source: Theranexus, October 4, 2016
Complete Response Letters
AC-170 for Itchy Eyes
The FDA has issued a complete
response letter (CRL) regarding the new
drug application for AC-170 (Nicox S.A.),
a cetirizine eye-drop formulation for the
treatment of ocular itching associated
with allergic conjunctivitis. The FDAs
stated reason for the CRL pertained to an
inspection at a third-party facility produc-
ing the active pharmaceutical ingredient
cetirizine and supplying it to Nicox. The
FDA did not request additional clinical
or nonclinical testing for further review
of the AC-170 application.
Source: Nicox, October 10, 2016
Remoxy ER for Pain
Pain Therapeutics has received a
complete response letter from the FDA
regarding its new drug application for
Remoxy ER (oxycodone) extended-
release capsules CII. Based on its review,
the FDA determined additional actions
and data were needed for approval that
may take approximately one year to
conduct, according to the drugs developer.
Source: Pain Therapeutics, September
26, 2016
New Applications
Peglgrastim Biosimilar Candidate
The FDA has accepted a biologics
license application for CHS-1701 (Coherus
BioSciences, Inc.), a biosimilar candidate
for peglgrastim (Neulasta, Amgen). The
application is supported by similarity
data from analytical, pharmacokinetic,
pharmacodynamic, and immunogenic-
ity studies that compared CHS-1701 and
Neulasta. An approval decision is expected
in June 2017.
Source: Coherus BioSciences,
October 6, 2016
Romosozumab for Osteoporosis
The FDA has accepted for review the
biologics license application for romoso-
zumab (Amgen/UCB), an investigational
monoclonal antibody for the treatment of
osteoporosis in postmenopausal women at
increased risk of fracture. Romosozumab
works by binding to and inhibiting the
activity of sclerostin, a protein present in
bone, thereby increasing bone formation
and decreasing bone resorption. The FDA
set a target action date of July 19, 2017.
Source: Amgen, September 26, 2016
Cantrixil for Ovarian Cancer
Novogen, Ltd., has received conrma-
tion from the FDA that its investigational
new drug application for cantrixil had
been opened and that a phase 1 study of
the drug in patients with ovarian cancer
may proceed.
Cantrixil is a cyclodextrin-based
formulation of TRX-E-002-1, which has
shown in vitro and in vivo anticancer
activity in a range of tumor types.
Novogen anticipates that, if approved, the
drug would be used as an intraperitoneal
chemotherapy, either alone or in combina-
tion with other agents, in one or more can-
cers of the abdominal or pelvic cavity (e.g.,
ovarian, uterine, colorectal, or gastric
carcinomas). A rst-in-human clinical
study is planned to start in the fourth
quarter of 2016.
Source: Novogen, September 12, 2016
DRUG SAFETY ISSUES
Direct-Acting Antivirals for HCV
The FDA warns that hepatitis B
virus (HBV) could become an active
infection again in patients who have a
current or previous infection with HBV
and are treated with certain direct-
acting antivirals (DAAs) for hepatitis C
virus. In a few cases, HBV reactivation
in patients treated with DAAs resulted
in serious liver problems or death. HBV
reactivation usually occurred within
four to eight weeks.
As a result, the FDA is requiring a
boxed warning about the risk of HBV
reactivation to be added to the drug labels
of these DAAs, directing health care
professionals to screen and monitor
for HBV in all patients receiving DAA
treatment. This warning will also be
included in the patient information
leaets or medication guides for these
medications.
Source: FDA, October 4, 2016
I.V. Flush Syringes
Nurse Assist has recalled all
unexpired lots of I.V. Flush syringes
because of a potential link to
Burkholderia cepacia bloodstream
infections. According to the Centers for
Disease Control and Prevention, the
effects of B. cepacia vary widely, rang-
ing from no symptoms at all to serious
respiratory infections, especially in
patients with cystic fibrosis. Nurse
Assist voluntarily recalled its I.V. Flush
syringes after becoming aware of patients
who developed B. cepacia bloodstream
Vol. 41 No. 11 November 2016 P&T
671
infections while receiving intravenous
care using prepackaged saline ushes
from the company.
Source: FDA, October 5, 2016
CLINICAL TRIAL NEWS
Cabozantinib Outperforms
Sunitinib in Renal Cancer
Cabozantinib (Cabometyx, Exelixis,
Inc.) demonstrated a 31% reduction
in the rate of disease progression or
death compared with sunitinib (Sutent,
Pzer) among patients with advanced
renal cell carcinoma (RCC) in the CABO-
SUN trial (P = 0.012). The phase 2 trial
compared cabozantinib with sunitinib in
157 patients with previously untreated
advanced RCC with intermediate- or
poor-risk disease.
Median progression-free survival for
cabozantinib was 8.2 months compared
with 5.6 months for sunitinib, correspond-
ing to a 2.6-month (46%) improvement
favoring cabozantinib. With a median
follow-up of 22.8 months, median overall
survival was 30.3 months for cabozantinib
compared with 21.8 months for sunitinib
(hazard ratio, 0.80).
Source: Exelisis, October 10, 2016
Pembrolizumab for Lung Cancer
Positive results from two major studies
of pembrolizumab (Keytruda, Merck), an
anti-programmed death therapy, in the
rst-line treatment of patients with meta-
static nonsmall-cell lung cancer (NSCLC)
were presented at the European Society for
Medical Oncology 2016 Congress.
The phase 3, randomized KEYNOTE-024
study evaluated pembrolizumab as
monotherapy compared with standard-of-
care platinum-based chemotherapy in the
treatment of 305 patients with squamous
and nonsquamous metastatic NSCLC.
Pembrolizumab reduced the risk of
disease progression or death by 50%
compared with chemotherapy (hazard
ratio, 0.50; P < 0.001).
672 P&T November 2016 Vol. 41 No. 11
The phase 1/2, open-label KEYNOTE-021
trial evaluated the efcacy and safety of
pembrolizumab in combination with
pemetrexed and carboplatin compared
with pemetrexed and carboplatin in a
cohort of patients with metastatic, non-
squamous, EGFR- and ALK-negative
NSCLC in the rst-line treatment set-
ting. Pembrolizumab plus chemotherapy
(carboplatin plus pemetrexed) achieved a
55% objective response rate compared with
29% for chemotherapy alone (the standard
of care) and reduced the risk of disease
progression or death by 47%.
Source: Merck, October 9, 2016
Fulvestrant for Breast Cancer
Fulvestrant (Faslodex) 500 mg dem-
onstrated superior median progression-
free survival (PFS) compared with
anastrozole (Arimidex) 1 mg in the
phase 3 FALCON trial, according to
AstraZeneca, which makes both products.
The data relate to the first-line
treatment of 462 postmenopausal women
with locally advanced or metastatic breast
cancer who have not received hormonal
treatment for hormone receptor-positive
(HR+) breast cancer. Median PFS was
2.8 months longer with fulvestrant than
with anastrozole (P = 0.0486). The median
PFS was 16.6 months in the fulvestrant
arm compared with 13.8 months in the
anastrozole arm. Aromatase inhibitors,
such as anastrozole, are the current stan-
dard of care in the rst-line treatment
of postmenopausal women with HR+
advanced breast cancer.
Source: AstraZeneca, October 8, 2016
Ataluren for Duchenne MD
PTC Therapeutics has announced
data supporting the potential benet of
ataluren, a protein-restoration therapy,
in preserving lung function in patients
with nonambulatory nonsense mutation
Duchenne muscular dystrophy (DMD).
The results were based on analyses
of lung function data from one of the
companys ongoing open-label extension
studies compared with natural history
data from a comparable nonambulatory
cohort.
In the untreated natural history cohort,
forced vital capacity (FVC) peaked at a
mean age of 12.5 years and declined
thereafter. In comparison, ataluren-
treated patients achieved peak FVC at
a mean age of 16.5 years. In addition,
the absolute FVC was 13.8% higher in
ataluren-treated patients compared with
untreated patients (P = 0.005), which sug-
gested a slower progression in the loss
of lung function in the ataluren group.
Source: PTC Therapeutics, October 6,
2016
Allob for Spinal Fusion
Positive efficacy data have been
reported from a phase 2a study of Allob
(Bone Therapeutics), a first-in-class
allogeneic osteoblastic cell-therapy
product, for lumbar spinal fusion. Allob
was developed for the treatment of ortho-
pedic conditions and bone diseases. Allo-
geneic cell therapy involves the harvest-
ing of cells from a healthy donor, rather
than from the treated patient.
In the new study, dynamic x-rays
showed fusion (i.e., the absence of
motion) of the vertebral bodies in six of
eight patients at six months and in all
patients at nine and 12 months. Fusion
was further evidenced by computed
tomography scans, which showed the
presence of bone bridges in 75% of
evaluable patients.
Source: Bone Therapeutics, October 5,
2016
Tildrakizumab for Psoriasis
Tildrakizumab (Sun Pharma), an
investigational interleukin (IL)-23p19
inhibitor, has achieved the primary
endpoint in two pivotal phase 3 studies
involving patients with moderate-to-
severe plaque psoriasis. An average of
63% of patients showed 75% skin clearance
(Psoriasis Area Sensitivity Index
[PASI] 75) by week 12 after two injec-
tions of tildrakizumab 100 mg, and 77%
showed PASI 75 after 28 weeks and
three injections.
Similarly, an average of 57% and 66% of
patients had a Physicians Global Assess-
ment (PGA) score of clear or minimal pointthe change from baseline on the
with the 100-mg dose at weeks 12 and 28,
respectively. In addition, 64% and 78% of
patients treated with a 200-mg dose of
tildrakizumab achieved PASI 75 at
weeks 12 and 28 respectively, and 59%
and 69% had PGA scores of clear or
minimal at those time points.
Tildrakizumab is an investigational
humanized, antiIL-23p19 monoclonal
antibody designed to selectively block
the cytokine IL-23.
Source: Sun Pharma, October 1, 2016
Voclosporin for Lupus Nephritis
Low-dose voclosporin (23.7 mg twice
daily) achieved its primary endpoint of
complete remission (CR) at 24 weeks
in the AURA-LV trial in patients with
lupus nephritis, Aurinia Pharmaceuticals
announced. In addition, both low-dose
and high-dose (39.5 mg twice daily) voclo-
sporin, when added to the current stan-
dard of care of mycophenolate mofetil and
a forced oral corticosteroid taper, met all
24-week secondary endpoints compared
with the control group. Among these end-
points, the time to CR was 19.7 weeks
for low-dose voclosporin and 23.4 weeks
for high-dose voclosporin compared with
not achieved for the control group
(P < 0.001 and P = 0.001 for the two
voclosporin doses versus control).
Partial remission was achieved by 70%
of the low-dose group (P = 0.007) and by
66% of the high-dose group (P = 0.024)
compared with 49% of the control group.
Source: Aurinia Pharmaceuticals,
September 29, 2016
ITI-007 for Schizophrenia
Disappointing results were reported
from the second phase 3 trial of
ITI-007 (Intra-Cellular Therapies, Inc.),
an oral, first-in-class investigational
medication for the treatment of patients
with schizophrenia. Neither dose of
ITI-007 was signicantly different from
placebo on the studys primary end-
protein that promotes the develop-
Positive and Negative Syndrome Scale
(PANSS) total score.
ITI-007 20 mg and 60 mg demonstrated
reductions from baseline on the PANSS
total score of 15.0 points and14.6 points,
respectively, compared with a reduc-
tion of 15.1 points with placebo. In con-
trast, the active control, risperidone,
demonstrated a 20.5-point reduction from
baseline.
Source: Intra-Cellular Therapies,
September 28, 2016
Erenumab for Migraine
A phase 3 study of the investigational
migraine treatment erenumab (Amgen/
Novartis) has met its primary endpoint,
demonstrating a statistically signicant
reduction from baseline in monthly
migraine days in patients with episodic
migraine compared with placebo at
12 weeks (2.9 days versus 1.8 days,
respectively). Erenumab, a fully human
monoclonal antibody, was designed to tar-
get and block the calcitonin gene-related
peptide receptor, which is believed to have
a critical role in mediating migraine pain.
Source: Amgen, September 28, 2016
Zykadia for Lung Cancer
Positive results have been reported
from a phase 3 study of ceritinib
(Zykadia, Novartis) in patients with
advanced anaplastic lymphoma kinase-
positive (ALK+) nonsmall-cell lung
cancer (NSCLC). The multicenter,
randomized trial, which assessed
the efcacy and safety of ceritinib in
previously untreated adults, met its
primary endpoint, demonstrating a
clinically signicant improvement in
progression-free survival compared
with standard chemotherapy, including
maintenance.
Ceritinib is an oral, selective inhibi-
tor of ALK, a gene that can fuse with
others to form an abnormal fusion
ment and growth of certain tumors in
cancers, including NSCLC. In the U.S.,
ceritinib was granted accelerated
approval for the treatment of patients
with ALK+ metastatic NSCLC who have
progressed on or are intolerant of
crizotinib.
Source: Novartis, September 23, 2016
Dasotraline for ADHD
A pivotal study evaluating dasotraline
(Sunovion Pharmaceuticals), a dopamine
and norepinephrine reuptake inhibitor,
in children with attention-decit/hyper-
activity disorder (ADHD) has met its
primary efcacy endpoint.
The six-week SEP360-202 trial was a
phase 2/3, randomized, double-blind,
multicenter, placebo-controlled, parallel-
group, fixed-dose safety and efficacy
study that evaluated once-daily dasotraline
(2 mg or 4 mg per day) in 342 children
6 to 12 years of age with ADHD. The
studys primary efcacy endpoint was
the change from baseline to week 6 in
the ADHD Rating Scale-IV: Home Ver-
sion total score. The 4-mg dosage arm
demonstrated a statistically signicant and
clinically relevant difference compared
with placebo. The 2-mg dosage arm was
not signicantly different from placebo.
Source: Sunovion, September 20, 2016
Vepoloxamer for
Sickle Cell Disease
Disappointing results have been
reported from a phase 3 study of vepo-
loxamer (Mast Therapeutics) for the
Vol. 41 No. 11 November 2016 P&T
673
treatment of individuals with sickle cell
disease experiencing vaso-occlusive
crisis (VOC). The study did not meet its
primary efcacy endpoint of demonstrat-
ing a statistically signicant reduction
in the mean duration of VOC (82 hours
in the vepoloxamer group versus
78 hours in the placebo group; P = 0.09).
Moreover, there were no statistically
significant differences between the
two treatment groups in the rate of
rehospitalization for VOC and the
occurrence of acute chest syndrome
(secondary efcacy endpoints).
Vepoloxamer is puried poloxamer
188a nonionic block copolymer.
Its hydrophobic polyoxypropylene
core is believed to adhere to hydro-
phobic domains exposed on damaged
cell membranes, thereby restoring
membrane integrity and reducing
surface tensions that otherwise
promote pathologic adhesive inter-
actions. As the damaged area of the cell
membrane repairs, vepoloxamer is
removed from the cell surface and
excreted from the body, unchanged,
primarily in the urine.
Source: Mast Therapeutics, September
20, 2016
Romosozumab for Osteoporosis
Findings from a phase 3 study
have shown that the investigational
agent romosozumab (Amgen/UCB)
significantly reduced the incidence
of new vertebral fractures in post-
menopausal women with osteoporosis
through 12 and 24 months, meeting
the studys coprimary endpoints. The
results from this study, the first to
evaluate fracture risk reduction as early
as one year as a primary endpoint,
were published in the New England
Journal of Medicine.
Romosozumab works by binding to
and inhibiting the activity of the protein
sclerostin. As a result, the treatment has
674 P&T November 2016 Vol. 41 No. 11
a dual effect on bone, both increasing
bone formation and decreasing bone
breakdown.
Source: Amgen, September 18, 2016
Siponimod for Progressive MS
Positive results have been reported from
a phase 3 study of oral once-daily siponi-
mod (Novartis), a selective sphingosine-
1-phosphate receptor modulator, in
patients with secondary progressive
multiple sclerosis (MS). Treatment
with siponimod reduced the risk of
three-month confirmed disability
progression by 21% compared with
placebo (P = 0.013). Moreover, a sig-
nicant difference in favor of siponimod
was observed in the annualized relapse
rate; the percent change in brain volume;
and the change from baseline in the
volume of T2 lesions (i.e., brain lesions
identied by a T2-weighted magnetic
resonance imaging scan).
Source: Novartis, September 17, 2016
Lasmiditan for Migraine
The pivotal phase 3 SAMURAI trial
evaluating lasmiditan (CoLucid Phar-
maceuticals) has achieved its secondary
endpoints with statistical signicance.
SAMURAI was a randomized, double-
blind, placebo-controlled, parallel-group
study designed to evaluate the efcacy
and safety of lasmiditan (100 mg and
200 mg) in comparison with placebo in
patients with migraine. Both lasmiditan
doses were efcacious in terms of free-
dom from headache pain and freedom
from the most bothersome symptom at
two hours (P < 0.001), the studys primary
and key secondary endpoints. Lasmidi-
tan selectively targets 5-HT1F receptors
expressed in the trigeminal pathway.
Source: CoLucid Pharmaceuticals,
September 17, 2016
Semaglutide for
Diabetes Cardiac Risk
Semaglutide (Novo Nordisk) signi-
cantly reduced the risk of the primary
composite endpointtime to rst occur-
rence of cardiovascular (CV) death, non-
fatal myocardial infarction, or nonfatal
strokeby 26% compared with placebo
when added to standard of care among
3,297 adults with type-2 diabetes at high
CV risk in the SUSTAIN 6 trial.
Semaglutide is an investigational
glucagon-like peptide-1 analogue.
SUSTAIN 6 was an international,
randomized, double-blind, placebo-
controlled premarketing CV outcomes
trial investigating the long-term effects
of semaglutide (0.5 mg and 1.0 mg)
administered once weekly compared
with placebo. Standard of care included
lifestyle modications, glucose-lowering
treatments, and CV medications.
Source: Novo Nordisk, September 16,
2016
Sublingual Sufentanil for Pain
In an open-label phase 3 trial, the inves-
tigational product ARX-04 (sufentanil
sublingual tablets 30 mcg, AcelRx Phar-
maceuticals) was well tolerated in the
management of moderate-to-severe acute
pain in postoperative patients, including
elderly patients and those with organ
impairment. Regardless of age and organ
function, 63% of the patients experienced
no adverse events during the study. In a
global assessment of ARX-04 as a method
of pain control, 90% of health care profes-
sionals and 87% of patients responded
that the treatment was good or excel-
lent. ARX-04 tablets are delivered sub-
lingually by a health care professional
using a disposable, prelled, single-dose
applicator.
Source: AcelRx Pharmaceuticals,
September 15, 2016
 Shingrix Vaccine for Shingles
Results from a phase 3 study of
the investigational shingles vaccine
Shingrix (GlaxoSmithKline) have shown
90% efcacy in adults 70 years of age
and older, which was maintained for at
least four years. Shingrix is a nonlive,
adjuvanted, subunit candidate vaccine
to help prevent herpes zoster and its
complications. The vaccine combines
glycoprotein E, a protein found on the
varicella zoster virus that causes shingles,
with an adjuvant system, AS01B, which is
intended to enhance the immunological
response to the antigen.
Source: GlaxoSmithKline, September
14, 2016
Raxone for Muscular Dystrophy
Data from a pivotal phase 3 study
demonstrate the positive effect of
idebenone (Raxone, Santhera Phar-
maceuticals) on inspiratory function
in patients with Duchenne muscular
dystrophy (DMD).
The DELOS trial evaluated the effect of
idebenone on the maximum inspiratory
ow (VI,max) generated during a forced
vital capacity (FVC) maneuver. Patients
in the studys two treatment groups
idebenone (n = 31) and placebo (n = 33)
had comparable and abnormally
low VI,max(FVC) at baseline. During
the study period, VI,max(FVC) further
declined by 0.29 L per second (L/s)
in patients receiving placebo at week 52
(P = 0.008) but remained stable in
patients treated with idebenone (change
from baseline to week 52: 0.01 L/s;
P = 0.950). The between-group difference
demonstrated a positive treatment effect
for idebenone of 0.27 L/s (P = 0.043)
at week 26 and 0.30 L/s (P = 0.061) at
week 52.
Source: Santhera Pharmaceuticals,
September 13, 2016
Sotagliozin for Type-1 Diabetes
A pivotal phase 3 study of oral sota-
gliflozin (Lexicon Pharmaceuticals)
showed a statistically signicant reduc-
tion in hemoglobin A1c (HbA1c) at
24 weeks in patients with type-1 diabetes
on a background of optimized insulin.
Patients treated with sotagliozin had
a mean HbA1c reduction from baseline
of 0.43% on a 200-mg once-daily dosage
(P < 0.001) and a reduction of 0.49% on
a 400-mg once-daily dosage (P < 0.001)
compared with a reduction of 0.08% with
placebo after 24 weeks of treatment,
meeting the studys primary endpoint.
Sotagliozin is a rst-in-class, oral dual
inhibitor of sodium-glucose cotransporter
types 1 and 2 (SGLT1 and SGLT2). SGLT1
is responsible for glucose absorption in
the gastrointestinal tract, and SGLT2 is
responsible for glucose reabsorption by
the kidneys.
Source: Lexicon Pharmaceuticals,
September 9, 2016
DEVICE APPROVALS
Automated Insulin Delivery
Device for Type-1 Diabetes
The FDA has approved the MiniMed
670G hybrid closed-looped system
(Medtronic), the rst agency-approved
device that is intended to automatically
monitor glucose and provide appropriate
basal insulin doses in people 14 years of
age and older with type-1 diabetes.
The MiniMed system, often referred
to as an articial pancreas, is intended
to adjust insulin levels with little or no
input from the user. It works by measur-
ing glucose levels every ve minutes and
automatically administering or withhold-
ing insulin. The system includes a sen-
sor that attaches to the body to measure
glucose levels under the skin; an insulin
pump strapped to the body; and an infu-
sion patch connected to the pump with
a catheter that delivers insulin. While
the device automatically adjusts insulin
levels, users must manually request
insulin doses to counter carbohydrate
(meal) consumption.
Source: FDA, September 28, 2016
Diabetes Sensing System
The FDA has approved the FreeStyle
Libre Pro system (Abbott), a continuous
glucose monitoring system for diabetes
patients. A clinician applies a small, round
sensor to the back of the patients upper
arm. The water-resistant, disposable sen-
sor is held in place with a self-adhesive pad
and remains on the back of the arm for up
to 14 days, requiring no patient interaction
with the device or the need for the patient
to draw blood via a nger stick to calibrate
the sensor.
The sensor continuously measures
glucose in interstitial uid through a
small (5-mm by 0.4-mm) lament that
is inserted under the skin. This lament
records glucose levels every 15 minutes,
capturing up to 1,340 glucose results for
up to 14 days, giving treating doctors
comprehensive data for complete glyce-
mic proles of their patients. After 14 days,
the patient returns to his or her doctors
ofce, where the doctor uses a FreeStyle
Libre Pro reader to scan the sensor and
to download the 14-days worth of glucose
results, which are stored in the sensor.
The process takes as little as ve seconds.
Source: Abbott, September 28, 2016
Obalon for Weight Loss
The FDA has given the green light to
the Obalon Balloon System (Obalon Ther-
apeutics), a nonsurgical, fully reversible
device for weight loss. The intragastric
balloon system is indicated for temporary
use to facilitate weight loss in adults with
obesity (i.e., a body mass index of 30 to
40 kg/m2) who have failed to lose weight
through diet and exercise. The system
is intended to be used as an adjunct to
a moderate-intensity diet and behavior-
modication program.
Vol. 41 No. 11 November 2016 P&T
675
 The system consists of a balloon folded
inside a capsule that is swallowed by the
patient, with no sedation or anesthesia
required. Once the balloon reaches the
stomach, it is remotely inated with
gas via a microcatheter, which is then
removed, leaving a lightweight, buoyant
balloon in the stomach. During the next
three months of treatment, two additional
balloons are swallowed and inated.
At the end of the six-month treatment
period, all three balloons are removed
via outpatient endoscopy under conscious
sedation.
Source: Obalon Therapeutics,
September 12, 2016
Mi-eye 2 Lets Doctors
Visualize Joint Injuries
The FDA has cleared mi-eye 2
(Trice Medical), a disposable needle
with a fully integrated camera and light
source that allows physicians to use diag-
nostic imaging to visualize joint injuries
in their clinics. The device is designed
for use in diagnostic and operative
arthroscopic and endoscopic procedures
to provide illumination and visualization
through either a natural or surgical
opening. The mi-eye 2 also gives
physicians the ability to inject or
aspirate under direct visualization.
Source: Trice Medical, October 6, 2016
Disposable Colonoscope
The FDA has granted 510(k) clear-
ance for the Aer-O-Scope (GI View Ltd.),
a disposable, self-propelled, joystick-
controlled colonoscope system. The
new device allows therapeutic access
using standard tools, such as snares
and forceps, to obtain biopsies or to
perform polypectomies. According to
the manufacturer, the Aer-O-Scope is the
rst colonoscope to provide 360-degree
visualization of the colon to detect polyps
behind folds. In addition, there is no risk
of contamination or disease transmission
676 P&T November 2016 Vol. 41 No. 11
between patients from the device because
it is used only once and then discarded.
Source: GI View, September 20, 2016
Kyleena Contraceptive Device
The FDA has approved Kyleena
(levonorgestrel-releasing intrauterine
system, Bayer), a progestin-containing
intrauterine system, for the prevention of
pregnancy for up to ve years. Kyleena is
a small, exible, plastic T-shaped device
containing 19.5 mg of the progestin
hormone levonorgestrel. The device is
placed by a health care provider during
an ofce visit and may be removed by a
health care provider at any time.
Source: Bayer, September 19, 2016
Aera for Dysfunction
Of the Eustachian Tube
The FDA has permitted marketing
of the Aera system (Acclarent, Inc.),
which uses a small balloon to treat
persistent eustachian tube dysfunction,
a condition in which pressure, pain,
or clogged or mufed sensations occur
in the ear. With the Aera system, a
doctor uses a catheter to insert a
small balloon through the patients
nose and into the eustachian tube.
Once inated, the balloon opens a path-
way for mucus and air to ow through
the eustachian tube, which may help
restore proper function. After the
eustachian tube is dilated, a doctor
deates and removes the balloon.
Source: FDA, September 16, 2016
OTHER DEVICE NEWS
Rezm System for BPH
NxThera has launched the Rezu m not been approved for wide use in the
system for the treatment of men with
benign prostatic hyperplasia (BPH).
Administered by urologists in an ofce-
based procedure, the system uses stored
thermal energy in water vapor (steam)
created with a radiofrequency current to
treat enlarged prostate tissue, which can
cause bothersome symptoms, such as
urinary frequency and urgency; irregular
or weak urinary ow; straining during
urination; and getting up frequently at
night to urinate.
The Rezu m procedure is performed
using oral sedation and/or local anes-
thesia. Studies have reported clinically
signicant improvements in BPH symp-
toms within two weeks, with continued
improvement for three months, after
which the improvements were consis-
tent and durable, with no impairment of
sexual function.
Source: NxThera, October 3, 2016
Hemoperfusion for Sepsis
Disappointing results have been
reported from a pivotal phase 3 trial of the
Toraymyxin therapeutic hemoperfusion
device (Spectral Medical Inc.), which
removes sepsis-causing endotoxin from
the bloodstream. A total of 450 patients
were treated with either two Toraymyxin
columns or two shams. The study did not
achieve its primary endpoint of an abso-
lute reduction in mortality at four weeks.
Spectral Medical intends to meet with
the FDA to discuss the next step on the
regulatory pathway.
The Toraymyxin technology was devel-
oped in Japan to restore blood pressure
and to correct organ dysfunction by using
an antibiotic to detoxify the blood. Once
the patients blood has been extracted,
it is passed through a column to remove
endotoxins, which are believed to be a
major trigger for sepsis.
The device has been used in Japan
and parts of Europe for years but has
U.S. because, in the FDAs opinion, it has
never been tested in trials large enough
to prove its effectiveness and safety. The
agency did, however, clear the system for
compassionate use in select hospitals.
Source: Spectral Medical, October 3,
2016 Q
 Pharmaceutical Approval Update
Mary Choy, PharmD, CGP, FASHP
Calcifediol (Rayaldee)
Manufacturer: OPKO Health, Inc., Miami, Florida
Date of Approval: June 17, 2016
Indication: Calcifediol is indicated for the treatment
of secondary hyperparathyroidism (SHPT) in adults with
stage 3 or 4 chronic kidney disease (CKD) and
serum total 25-hydroxyvitamin D levels less than
30 ng/mL. Calcifediol is not intended for use in
patients with stage 5 CKD or with end-stage renal
disease receiving dialysis.
Drug Class: Vitamin D analogue
Uniqueness of Drug: Stage 3 and 4 CKD patients
are treated with high-dose vitamin D supplements
with arguable efcacy. Calcifediol is the rst drug
approved to treat SHPT in predialysis patients. It is
Mary Choy, PharmD,
a prohormone formulated as an extended-release CGP, FASHP
capsule containing 30 mcg of the medication.
Calcifediol raises serum total 25-hydroxyvitamin D levels and
lowers elevated intact parathyroid hormone (iPTH) levels.
Warnings and Precautions:
Hypercalcemia. Excessive administration of vitamin D
compounds, including calcifediol, can cause hypercalcemia
and hypercalciuria. Acute hypercalcemia may increase the
risk of cardiac arrhythmias and seizures and may potentiate
the effect of digitalis on the heart. Chronic hypercalcemia can
lead to generalized vascular calcication and other soft-tissue
calcication. Severe hypercalcemia may require emergency
attention. Patients should be informed about the symptoms
of elevated serum calcium, which include feeling tired, dif-
culty thinking clearly, loss of appetite, nausea, vomiting,
constipation, increased thirst, increased urination, and
weight loss.
Digitalis toxicity. Hypercalcemia increases the risk of
digitalis toxicity. In patients using calcifediol concomitantly
with digitalis compounds, monitor both the serum calcium
level and the patient for signs and symptoms of digitalis toxic-
ity and increase the frequency of monitoring when initiating
or adjusting the calcifediol dose.
Adynamic bone disease. Adynamic bone disease with
subsequent increased risk of fractures may develop if iPTH
levels are suppressed by calcifediol to abnormally low levels.
Monitor iPTH levels and adjust dose if needed.
Dosage and Administration: The initial dose of calcifediol is
30 mcg administered orally once daily at bedtime. Ensure serum
calcium is lower than 9.8 mg/dL before initiating treatment.
The maintenance dose should target serum total 25-hydroxy-
vitamin D levels between 30 and 100 ng/mL, iPTH levels within
the desired therapeutic range, serum calcium (corrected for
low albumin) within the normal range, and serum phosphorus
lower than 5.5 mg/dL. Monitor serum calcium, phosphorus,
25-hydroxyvitamin D, and iPTH levels three months after
Dr. Choy is an Associate Professor at Touro College of Pharmacy
and a Clinical Pharmacist at Metropolitan Hospital in New York,
New York.
starting therapy or changing dose. Increase the dose to 60 mcg
once daily after three months if iPTH is greater than the treat-
ment goal. Ensure serum calcium is lower than 9.8 mg/dL,
phosphorus is lower than 5.5 mg/dL, and 25-hydroxyvitamin D
is lower than 100 ng/mL before increasing the dose. Suspend
dosing if iPTH is persistently abnormally low, serum
calcium is consistently above the normal range, or
serum 25-hydroxyvitamin D is consistently greater
than 100 ng/mL.
Commentary: Two double-blind, randomized,
dose-ranging, placebo-controlled clinical trials have
met all primary efcacy and safety endpoints. At
26 weeks, treatment with calcifediol achieved at
least a 30% reduction in plasma iPTH in patients
with stage 3 or 4 CKD with SHPT and vitamin D
insufciency, compared with those treated with
placebo. More than 80% of patients treated with
calcifediol saw their vitamin D insufciency corrected com-
pared with fewer than 7% of patients treated with the placebo.
Sources: OPKO Health, Inc., Rayaldee prescribing information
Dasabuvir/Ombitasvir/Paritaprevir/Ritonavir (Viekira XR)
Manufacturer: AbbVie, Inc., North Chicago, Illinois
Date of Approval: July 22, 2016
Indication: Viekira XR is indicated for the treatment of
adult patients with chronic hepatitis C virus (HCV) infection
of two specic genotypes: 1) genotype 1b without cirrhosis
or with compensated cirrhosis and 2) genotype 1a without
cirrhosis or with compensated cirrhosis for use in combination
with ribavirin.
Drug Class: HCV non-nucleoside nonstructural protein (NS)
5B palm polymerase inhibitor (dasabuvir), HCV NS5A inhibitor
(ombitasvir), HCV NS3/4A protease inhibitor (paritaprevir),
and cytochrome P450 (CYP) 3A inhibitor (ritonavir)
Uniqueness of Drug: Viekira XR is the rst coformulated
treatment combining three direct-acting HCV antiviral agents
with distinct mechanisms of action for adult patients with
genotype 1 HCV. Although ritonavir is not active against HCV,
it is a potent CYP3A inhibitor that increases peak and trough
plasma drug concentrations of paritaprevir and overall drug
exposure (i.e., area under the curve). Of the six major HCV
genotypes, genotype 1 is the most prevalent form of HCV in
the U.S., accounting for approximately 74% of all cases.
Warnings and Precautions:
Hepatic decompensation and hepatic failure in patients
with cirrhosis. Hepatic decompensation and hepatic failure,
including liver transplantation or fatal outcomes, have been
reported mostly in patients with advanced cirrhosis. Viekira XR
is contraindicated in patients with moderate-to-severe hepatic
impairment (ChildPugh B and C).
For patients with cirrhosis:
Monitor for clinical signs and symptoms of hepatic
decompensation (such as ascites, hepatic encephalopathy,
or variceal hemorrhage).
continued on page 682
Vol. 41 No. 11 November 2016 P&T
677
Indications and Usage
Jakafi is indicated for treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis,
postpolycythemia vera myelofibrosis and postessential thrombocythemia myelofibrosis.

Overall survival was a prespecified secondary end point

in COMFORT-I and COMFORT-II 1
COMFORT-I: At 3 years, survival probability was 70% for patients COMFORTII: At 3 years, survival probability was 79% for patients
originally randomized to Jakafi and 61% for those originally originally randomized to Jakafi and 59% for those originally
randomized to placebo1 randomized to best available therapy1

COMFORT-I Overall Survival: Kaplan-Meier Curves COMFORT-II Overall Survival: Kaplan-Meier Curves
by Treatment Group1 by Treatment Group1

1.0 Jakafi 1.0 Jakafi

0.9 Placebo 0.9 BATBAT
Survival Probability

Survival Probability
0.8 0.8

0.7 0.7

0.6 0.6 Median crossover:

Median crossover: 0.5 17 months
0.5
9 months Jakafi BAT
Jakafi Placebo
0.4 0.4
(n = 155) (n = 154) (n = 146) (n = 73)
0.3 0.3 % 1-year survival 96% 94%
% 1-year survival 91% 84%
0.2 0.2 % 2-year survival 86% 81%
% 2-year survival 80% 69%
0.1 % 3-year survival 70% 61% 0.1 % 3-year survival 79% 59%

0.0 0.0
0 6 12 18 24 30 36 42 0 6 12 18 24 30 36 42

Time (Months) Time (Months)

Number of patients at risk Number of patients at risk
Jakafi 155 145 134 122 111 102 29 0 Jakafi 146 135 126 115 107 104 33 0
Placebo 154 142 117 101 92 82 32 0 BAT 73 58 50 47 42 33 9 0

BAT, best available therapy.

Because of progression-driven events or at the physicians discretion, patients randomized to placebo (COMFORT-I) or best available
therapy (COMFORT-II) who crossed over to receive Jakafi continued to be grouped within their original randomized assignment for
analysis purposes4

When discontinuing Jakafi, myeloproliferative neoplasm-related
symptoms may return within one week. After discontinuation, some
patients with myelofibrosis have experienced fever, respiratory
distress, hypotension, DIC, or multi-organ failure. If any of these
occur after discontinuation or while tapering Jakafi, evaluate and
treat any intercurrent illness and consider restarting or increasing the
dose of Jakafi. Instruct patients not to interrupt or discontinue Jakafi
without consulting their physician. When discontinuing or interrupting
Jakafi for reasons other than thrombocytopenia or neutropenia,
consider gradual tapering rather than abrupt discontinuation
Non-melanoma skin cancers including basal cell, squamous cell,
and Merkel cell carcinoma have occurred. Perform periodic
skin examinations
Treatment with Jakafi has been associated with increases in total
cholesterol, low-density lipoprotein cholesterol, and triglycerides.
Assess lipid parameters 8-12 weeks after initiating Jakafi. Monitor
and treat according to clinical guidelines for the management
of hyperlipidemia
The three most frequent non-hematologic adverse reactions
(incidence >10%) were bruising, dizziness and headache
A dose modification is recommended when administering Jakafi
with strong CYP3A4 inhibitors or fluconazole or in patients with
renal or hepatic impairment. Patients should be closely monitored
and the dose titrated based on safety and efficacy
Use of Jakafi during pregnancy is not recommended and should
only be used if the potential benefit justifies the potential risk to
the fetus. Women taking Jakafi should not breast-feed
Please see Brief Summary of Full Prescribing
Information for Jakafi on the following pages.
To learn more about Jakafi, visit Jakafi.com/HCP
References: 1. Jakafi Prescribing Information. Wilmington, DE: Incyte Corporation.
2. Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of
ruxolitinib for myelofibrosis. N Engl J Med. 2012;366(9):799-807. 3. Harrison C, Kiladjian
J-J, Al-Ali HK, et al. JAK inhibition with ruxolitinib versus best available therapy for
myelofibrosis. N Engl J Med. 2012;366(9):787-798. 4. Data on file. Incyte Corporation.
Wilmington, DE.
 Table 1: Myelofibrosis: Adverse Reactions Occurring in Patients on Jakafi in the Double-blind,
Placebo-controlled Study During Randomized Treatment
Jakafi Placebo
(N=155) (N=151)
BRIEF SUMMARY: For Full Prescribing Information, see package insert.
All Gradesa Grade 3 Grade 4 All Grades Grade 3 Grade 4
CONTRAINDICATIONS None.
Adverse Reactions (%) (%) (%) (%) (%) (%)
WARNINGS AND PRECAUTIONS Thrombocytopenia, Anemia and Neutropenia Treatment with
Jakafi can cause thrombocytopenia, anemia and neutropenia. [see Dosage and Administration (2.1) in Full Bruisingb 23 <1 0 15 0 0
Prescribing Information]. Manage thrombocytopenia by reducing the dose or temporarily interrupting Jakafi. Dizzinessc 18 <1 0 7 0 0
Platelet transfusions may be necessary [see Dosage and Administration (2.1.1) and Adverse Reactions (6.1) in
Full Prescribing Information]. Patients developing anemia may require blood transfusions and/or dose Headache 15 0 0 5 0 0
modifications of Jakafi. Severe neutropenia (ANC less than 0.5 X 109/L) was generally reversible by withholding Urinary Tract Infectionsd 9 0 0 5 <1 <1
Jakafi until recovery [see Adverse Reactions (6.1) in Full Prescribing Information]. Perform a pre-treatment Weight Gaine 7 <1 0 1 <1 0
complete blood count (CBC) and monitor CBCs every 2 to 4 weeks until doses are stabilized, and then as clinically
indicated. [see Dosage and Administration (2.1.1) and Adverse Reactions (6.1) in Full Prescribing Information]. Flatulence 5 0 0 <1 0 0
Risk of Infection Serious bacterial, mycobacterial, fungal and viral infections have occurred. Delay starting Herpes Zosterf 2 0 0 <1 0 0
therapy with Jakafi until active serious infections have resolved. Observe patients receiving Jakafi for signs and a
National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0
symptoms of infection and manage promptly. Tuberculosis Tuberculosis infection has been reported in patients b
includes contusion, ecchymosis, hematoma, injection site hematoma, periorbital hematoma, vessel puncture site
receiving Jakafi. Observe patients receiving Jakafi for signs and symptoms of active tuberculosis and manage hematoma, increased tendency to bruise, petechiae, purpura
c
includes dizziness, postural dizziness, vertigo, balance disorder, Menieres Disease, labyrinthitis
promptly. Prior to initiating Jakafi, patients should be evaluated for tuberculosis risk factors, and those at higher d
includes urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, kidney infection, pyuria, bacteria urine,
risk should be tested for latent infection. Risk factors include, but are not limited to, prior residence in or travel to bacteria urine identified, nitrite urine present
e
countries with a high prevalence of tuberculosis, close contact with a person with active tuberculosis, and a history includes weight increased, abnormal weight gain
f
of active or latent tuberculosis where an adequate course of treatment cannot be confirmed. For patients with includes herpes zoster and post-herpetic neuralgia
evidence of active or latent tuberculosis, consult a physician with expertise in the treatment of tuberculosis before Description of Selected Adverse Drug Reactions Anemia In the two Phase 3 clinical studies, median
starting Jakafi. The decision to continue Jakafi during treatment of active tuberculosis should be based on the time to onset of first CTCAE Grade 2 or higher anemia was approximately 6 weeks. One patient (<1%)
overall risk-benefit determination. PML Progressive multifocal leukoencephalopathy (PML) has occurred with discontinued treatment because of anemia. In patients receiving Jakafi, mean decreases in hemoglobin
ruxolitinib treatment for myelofibrosis. If PML is suspected, stop Jakafi and evaluate. Herpes Zoster Advise reached a nadir of approximately 1.5 to 2.0 g/dL below baseline after 8 to 12 weeks of therapy and then
patients about early signs and symptoms of herpes zoster and to seek treatment as early as possible if suspected gradually recovered to reach a new steady state that was approximately 1.0 g/dL below baseline. This pattern
[see Adverse Reactions (6.1) in Full Prescribing Information]. Hepatitis B Hepatitis B viral load (HBV-DNA titer) was observed in patients regardless of whether they had received transfusions during therapy. In the
increases, with or without associated elevations in alanine aminotransferase and aspartate aminotransferase, randomized, placebo-controlled study, 60% of patients treated with Jakafi and 38% of patients receiving
have been reported in patients with chronic HBV infections taking Jakafi. The effect of Jakafi on viral replication in placebo received red blood cell transfusions during randomized treatment. Among transfused patients, the
patients with chronic HBV infection is unknown. Patients with chronic HBV infection should be treated and median number of units transfused per month was 1.2 in patients treated with Jakafi and 1.7 in placebo treated
monitored according to clinical guidelines. Symptom Exacerbation Following Interruption or patients. Thrombocytopenia In the two Phase 3 clinical studies, in patients who developed Grade 3 or 4
Discontinuation of Treatment with Jakafi Following discontinuation of Jakafi, symptoms from thrombocytopenia, the median time to onset was approximately 8 weeks. Thrombocytopenia was generally
myeloproliferative neoplasms may return to pretreatment levels over a period of approximately one week. Some reversible with dose reduction or dose interruption. The median time to recovery of platelet counts above 50 X
patients with myelofibrosis have experienced one or more of the following adverse events after discontinuing 109/L was 14 days. Platelet transfusions were administered to 5% of patients receiving Jakafi and to 4% of
Jakafi: fever, respiratory distress, hypotension, DIC, or multi-organ failure. If one or more of these occur after patients receiving control regimens. Discontinuation of treatment because of thrombocytopenia occurred in
discontinuation of, or while tapering the dose of Jakafi, evaluate for and treat any intercurrent illness and consider <1% of patients receiving Jakafi and <1% of patients receiving control regimens. Patients with a platelet count
restarting or increasing the dose of Jakafi. Instruct patients not to interrupt or discontinue Jakafi therapy without of 100 X 109/L to 200 X 109/L before starting Jakafi had a higher frequency of Grade 3 or 4 thrombocytopenia
consulting their physician. When discontinuing or interrupting therapy with Jakafi for reasons other than compared to patients with a platelet count greater than 200 X 109/L (17% versus 7%). Neutropenia In the two
thrombocytopenia or neutropenia [see Dosage and Administration (2.5) in Full Prescribing Information], consider Phase 3 clinical studies, 1% of patients reduced or stopped Jakafi because of neutropenia. Table 2 provides the
tapering the dose of Jakafi gradually rather than discontinuing abruptly. Non-Melanoma Skin Cancer frequency and severity of clinical hematology abnormalities reported for patients receiving treatment with Jakafi
Non-melanoma skin cancers including basal cell, squamous cell, and Merkel cell carcinoma have occurred in or placebo in the placebo-controlled study.
patients treated with Jakafi. Perform periodic skin examinations. Lipid Elevations Treatment with Jakafi has
been associated with increases in lipid parameters including total cholesterol, low-density lipoprotein (LDL) Table 2: Myelofibrosis: Worst Hematology Laboratory Abnormalities in the Placebo-Controlled Studya
cholesterol, and triglycerides. The effect of these lipid parameter elevations on cardiovascular morbidity and Jakafi Placebo
mortality has not been determined in patients treated with Jakafi. Assess lipid parameters approximately 8-12 (N=155) (N=151)
weeks following initiation of Jakafi therapy. Monitor and treat according to clinical guidelines for the management
of hyperlipidemia. Laboratory All Gradesb Grade 3 Grade 4 All Grades Grade 3 Grade 4
ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other Parameter (%) (%) (%) (%) (%) (%)
sections of the labeling: Thrombocytopenia, Anemia and Neutropenia [see Warnings and Precautions (5.1) in Thrombocytopenia 70 9 4 31 1 0
Full Prescribing Information] Risk of Infection [see Warnings and Precautions (5.2) in Full Prescribing Information] Anemia 96 34 11 87 16 3
Symptom Exacerbation Following Interruption or Discontinuation of Treatment with Jakafi [see Warnings and
Precautions (5.3) in Full Prescribing Information] Non-Melanoma Skin Cancer [see Warnings and Precautions Neutropenia 19 5 2 4 <1 1
(5.4) in Full Prescribing Information]. Because clinical trials are conducted under widely varying conditions, a
Presented values are worst Grade values regardless of baseline
b
adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0
trials of another drug and may not reflect the rates observed in practice. Clinical Trials Experience in Additional Data from the Placebo-controlled Study 25% of patients treated with Jakafi and 7% of
Myelofibrosis The safety of Jakafi was assessed in 617 patients in six clinical studies with a median duration patients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in alanine
of follow-up of 10.9 months, including 301 patients with myelofibrosis in two Phase 3 studies. In these two Phase transaminase (ALT). The incidence of greater than or equal to Grade 2 elevations was 2% for Jakafi with 1%
3 studies, patients had a median duration of exposure to Jakafi of 9.5 months (range 0.5 to 17 months), with 89% Grade 3 and no Grade 4 ALT elevations. 17% of patients treated with Jakafi and 6% of patients treated with
of patients treated for more than 6 months and 25% treated for more than 12 months. One hundred and eleven placebo developed newly occurring or worsening Grade 1 abnormalities in aspartate transaminase (AST). The
(111) patients started treatment at 15 mg twice daily and 190 patients started at 20 mg twice daily. In patients incidence of Grade 2 AST elevations was <1% for Jakafi with no Grade 3 or 4 AST elevations. 17% of patients
starting treatment with 15 mg twice daily (pretreatment platelet counts of 100 to 200 X 109/L) and 20 mg twice treated with Jakafi and <1% of patients treated with placebo developed newly occurring or worsening Grade 1
daily (pretreatment platelet counts greater than 200 X 109/L), 65% and 25% of patients, respectively, required a elevations in cholesterol. The incidence of Grade 2 cholesterol elevations was <1% for Jakafi with no Grade 3 or
dose reduction below the starting dose within the first 8 weeks of therapy. In a double-blind, randomized, placebo- 4 cholesterol elevations. Clinical Trial Experience in Polycythemia Vera In a randomized, open-label,
controlled study of Jakafi, among the 155 patients treated with Jakafi, the most frequent adverse drug reactions active-controlled study, 110 patients with polycythemia vera resistant to or intolerant of hydroxyurea received
were thrombocytopenia and anemia [see Table 2 ]. Thrombocytopenia, anemia and neutropenia are dose related Jakafi and 111 patients received best available therapy [see Clinical Studies (14.2) in Full Prescribing
effects. The three most frequent non-hematologic adverse reactions were bruising, dizziness and headache [see Information]. The most frequent adverse drug reaction was anemia. Table 3 presents the most frequent
Table 1]. Discontinuation for adverse events, regardless of causality, was observed in 11% of patients treated with non-hematologic treatment emergent adverse events occurring up to Week 32. Discontinuation for adverse
Jakafi and 11% of patients treated with placebo. Table 1 presents the most common adverse reactions occurring events, regardless of causality, was observed in 4% of patients treated with Jakafi.
in patients who received Jakafi in the double-blind, placebo-controlled study during randomized treatment.
Table 3: Polycythemia Vera: Treatment Emergent Adverse Events Occurring in 6% of Patients on with the strong CYP3A4 inducer rifampin in healthy subjects. No dose adjustment is recommended; however,
Jakafi in the Open-Label, Active-controlled Study up to Week 32 of Randomized Treatment monitor patients frequently and adjust the Jakafi dose based on safety and efficacy [see Pharmacokinetics
Jakafi Best Available Therapy (12.3) in Full Prescribing Information].
(N=110) (N=111) USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C: Risk Summary There are
no adequate and well-controlled studies of Jakafi in pregnant women. In embryofetal toxicity studies, treatment
Adverse Events All Gradesa (%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%) with ruxolitinib resulted in an increase in late resorptions and reduced fetal weights at maternally toxic doses.
Headache 16 <1 19 <1 Jakafi should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Abdominal Painb 15 <1 15 <1 Animal Data Ruxolitinib was administered orally to pregnant rats or rabbits during the period of organogenesis,
at doses of 15, 30 or 60 mg/kg/day in rats and 10, 30 or 60 mg/kg/day in rabbits. There was no evidence of
Diarrhea 15 0 7 <1 teratogenicity. However, decreases of approximately 9% in fetal weights were noted in rats at the highest and
Dizzinessc 15 0 13 0 maternally toxic dose of 60 mg/kg/day. This dose results in an exposure (AUC) that is approximately 2 times the
Fatigue 15 0 15 3 clinical exposure at the maximum recommended dose of 25 mg twice daily. In rabbits, lower fetal weights of
approximately 8% and increased late resorptions were noted at the highest and maternally toxic dose of
Pruritus 14 <1 23 4 60 mg/kg/day. This dose is approximately 7% the clinical exposure at the maximum recommended dose. In a
Dyspnead 13 3 4 0 pre- and post-natal development study in rats, pregnant animals were dosed with ruxolitinib from implantation
Muscle Spasms 12 <1 5 0 through lactation at doses up to 30 mg/kg/day. There were no drug-related adverse findings in pups for fertility
indices or for maternal or embryofetal survival, growth and development parameters at the highest dose
Nasopharyngitis 9 0 8 0 evaluated (34% the clinical exposure at the maximum recommended dose of 25 mg twice daily). Nursing
Constipation 8 0 3 0 Mothers It is not known whether ruxolitinib is excreted in human milk. Ruxolitinib and/or its metabolites were
excreted in the milk of lactating rats with a concentration that was 13-fold the maternal plasma. Because many
Cough 8 0 5 0
drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants
Edemae 8 0 7 0 from Jakafi, a decision should be made to discontinue nursing or to discontinue the drug, taking into account
Arthralgia 7 0 6 <1 the importance of the drug to the mother. Pediatric Use The safety and effectiveness of Jakafi in pediatric
patients have not been established. Geriatric Use Of the total number of patients with myelofibrosis in clinical
Asthenia 7 0 11 2
studies with Jakafi, 52% were 65years and older, while 15% were 75 years and older. No overall differences in
Epistaxis 6 0 3 0 safety or effectiveness of Jakafi were observed between these patients and younger patients. Renal
Herpes Zosterf 6 <1 0 0 Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in
healthy subjects [CrCl 72-164 mL/min (N=8)] and in subjects with mild [CrCl 53-83 mL/min (N=8)], moderate
Nausea 6 0 4 0
[CrCl 38-57 mL/min (N=8)], or severe renal impairment [CrCl 15-51 mL/min (N=8)]. Eight (8) additional
a
National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 subjects with end stage renal disease requiring hemodialysis were also enrolled. The pharmacokinetics of
b
includes abdominal pain, abdominal pain lower, and abdominal pain upper
c
includes dizziness and vertigo
ruxolitinib was similar in subjects with various degrees of renal impairment and in those with normal renal
d
includes dyspnea and dyspnea exertional function. However, plasma AUC values of ruxolitinib metabolites increased with increasing severity of renal
e
includes edema and peripheral edema impairment. This was most marked in the subjects with end stage renal disease requiring hemodialysis. The
f
includes herpes zoster and post-herpetic neuralgia change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in
Other clinically important treatment emergent adverse events observed in less than 6% of patients metabolite exposure. Ruxolitinib is not removed by dialysis; however, the removal of some active metabolites by
treated with Jakafi were: Weight gain, hypertension, and urinary tract infections. Clinically relevant dialysis cannot be ruled out. When administering Jakafi to patients with myelofibrosis and moderate
laboratory abnormalities are shown in Table 4. (CrCl 30-59 mL/min) or severe renal impairment (CrCl 15-29 mL/min) with a platelet count between 50 X
Table 4: Polycythemia Vera: Selected Laboratory Abnormalities in the Open-Label, Active-controlled 109/L and 150 X 109/L, a dose reduction is recommended. A dose reduction is also recommended for patients
Study up to Week 32 of Randomized Treatmenta with polycythemia vera and moderate (CrCl 30-59 mL/min) or severe renal impairment (CrCl 15-29 mL/min). In
all patients with end stage renal disease on dialysis, a dose reduction is recommended [see Dosage and
Jakafi Best Available Therapy
Administration (2.4) in Full Prescribing Information]. Hepatic Impairment The safety and pharmacokinetics
(N=110) (N=111)
of single dose Jakafi (25 mg) were evaluated in a study in healthy subjects (N=8) and in subjects with mild
Laboratory All Gradesb Grade 3 Grade 4 All Grades Grade 3 Grade 4 [Child-Pugh A (N=8)], moderate [Child-Pugh B (N=8)], or severe hepatic impairment [Child-Pugh C (N=8)]. The
Parameter (%) (%) (%) (%) (%) (%) mean AUC for ruxolitinib was increased by 87%, 28% and 65%, respectively, in patients with mild, moderate
and severe hepatic impairment compared to patients with normal hepatic function. The terminal elimination
Hematology
half-life was prolonged in patients with hepatic impairment compared to healthy controls (4.1-5.0 hours versus
Anemia 72 <1 <1 58 0 0 2.8 hours). The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the
Thrombocytopenia 27 5 <1 24 3 <1 corresponding increase in ruxolitinib exposure except in the severe (Child-Pugh C) hepatic impairment cohort
where the pharmacodynamic activity was more prolonged in some subjects than expected based on plasma
Neutropenia 3 0 <1 10 <1 0
concentrations of ruxolitinib. When administering Jakafi to patients with myelofibrosis and any degree of
Chemistry hepatic impairment and with a platelet count between 50 X 109/L and 150 X 109/L, a dose reduction is
Hypercholesterolemia 35 0 0 8 0 0 recommended. A dose reduction is also recommended for patients with polycythemia vera and hepatic
impairment [see Dosage and Administration (2.4) in Full Prescribing Information].
Elevated ALT 25 <1 0 16 0 0
OVERDOSAGE There is no known antidote for overdoses with Jakafi. Single doses up to 200 mg have been
Elevated AST 23 0 0 23 <1 0 given with acceptable acute tolerability. Higher than recommended repeat doses are associated with increased
Hypertriglyceridemia 15 0 0 13 0 0 myelosuppression including leukopenia, anemia and thrombocytopenia. Appropriate supportive treatment
a
Presented values are worst Grade values regardless of baseline
should be given. Hemodialysis is not expected to enhance the elimination of ruxolitinib.
b
National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0
DRUG INTERACTIONS Drugs That Inhibit or Induce Cytochrome P450 Enzymes Ruxolitinib
is metabolized by CYP3A4 and to a lesser extent by CYP2C9. CYP3A4 inhibitors: The Cmax and AUC of ruxolitinib
Jakafi is a registered trademark of Incyte. All rights reserved.
increased 33% and 91%, respectively following concomitant administration with the strong CYP3A4 inhibitor U.S. Patent Nos. 7598257; 8415362; 8722693; 8822481; 8829013; 9079912
ketoconazole in healthy subjects. Concomitant administration with mild or moderate CYP3A4 inhibitors did not 2011-2016 Incyte Corporation. All rights reserved.
result in an exposure change requiring intervention [see Pharmacokinetics (12.3) in Full Prescribing Revised: March 2016 RUX-1778
Information]. When administering Jakafi with strong CYP3A4 inhibitors, consider dose reduction [see Dosage
and Administration (2.3) in Full Prescribing Information]. Fluconazole: The AUC of ruxolitinib is predicted to
increase by approximately 100% to 300% following concomitant administration with the combined CYP3A4
and CYP2C9 inhibitor fluconazole at doses of 100 mg to 400 mg once daily, respectively [see Pharmacokinetics
(12.3) in Full Prescribing Information]. Avoid the concomitant use of Jakafi with fluconazole doses of greater
than 200 mg daily [see Dosage and Administration (2.3) in Full Prescribing Information]. CYP3A4 inducers:
The Cmax and AUC of ruxolitinib decreased 32% and 61%, respectively, following concomitant administration
 Pharmaceutical Approval Update
continued from page 677
Hepatic laboratory testing, including direct bilirubin
levels, should be performed at baseline and during the rst
four weeks of treatment and as clinically indicated.
Discontinue Viekira XR in patients who develop evidence
of hepatic decompensation.
Alanine aminotransferase (ALT) elevations. Discontinue
ethinyl estradiol-containing medications prior to starting Viekira
XR (alternative contraceptive methods are recommended).
Perform hepatic laboratory testing on all patients during the
rst four weeks of treatment and as clinically indicated there-
after. If ALT is found to be elevated above baseline levels,
testing should be repeated and monitored closely. Consider
discontinuing Viekira XR if ALT levels remain persistently
greater than 10 times the upper limit of normal. Discontinue
treatment if ALT elevation is accompanied by signs or symp-
toms of liver inammation or increasing direct bilirubin, alkaline
phosphatase, or international normalized ratio.
Risks associated with ribavirin combination treatment.
If Viekira XR is administered with ribavirin, the warnings and
precautions for ribavirin also apply to this combination regimen.
Drug interactions. The concomitant use of Viekira XR
and certain other drugs may result in known or potentially
signicant drug interactions, some of which may lead to loss
of therapeutic effect of Viekira XR. Consult the full prescribing
information for the complete list.
Dosage and Administration: Prior to initiation of therapy,
assess for laboratory and clinical evidence of hepatic decom-
pensation. The recommended dosage is three tablets taken
once daily with a meal for the duration of treatment (Table 1).
Administration under fasting conditions may result in reduced
virological response and possible development of resistance.
Follow the genotype 1a dosing recommendations for patients
with an unknown genotype 1 subtype or with mixed genotype 1
infection. Patients with HCV/human immunodeciency virus
(HIV)-1 coinfection should be treated as indicated in Table 1,
but also must be prescribed a suppressive antiretroviral drug
regimen to reduce the risk of HIV-1 protease inhibitor drug
resistance. In liver transplant recipients with normal hepatic
function and mild brosis (Metavir brosis score of 2 or less),
the recommended duration of Viekira XR with ribavirin is
24 weeks.
Table 1 Viekira XR Treatment Regimen and
Duration by Patient Population
Patient Population Treatment Duration
Genotype 1a, Viekira XR + ribavirin 12 weeks
without cirrhosis
Genotype 1a, Viekira XR + ribavirin 24 weeks*
with compensated
cirrhosis
Genotype 1b, Viekira XR 12 weeks
with or without
compensated
cirrhosis
* Viekira XR + ribavirin for 12 weeks may be considered for some patients
based on prior treatment history.
682 P&T November 2016 Vol. 41 No. 11
Commentary: The components of Viekira XR were studied
in seven phase 3 clinical trials in which more than 2,000 patients
received the components of Viekira XR with or without
ribavirin for 12 or 24 weeks. A sustained viral response
12 or more weeks past the end of treatment was achieved
in 95% to 100% of patients, meaning the virus was no longer
detectable in their blood. Cure rates depended on the subtype
of HCV and whether the person had cirrhosis.
Sources: AbbVie, Inc., Viekira XR prescribing information
Lixisenatide (Adlyxin)
Manufacturer: Sano-Aventis, Bridgewater, New Jersey
Date of Approval: July 27, 2016
Indication: Lixisenatide is indicated as an adjunct to diet
and exercise to improve glycemic control in adults with type-2
diabetes mellitus. It has not been studied in patients with
chronic pancreatitis or a history of unexplained pancreati-
tis. It is not approved for the treatment of type-1 diabetes or
diabetic ketoacidosis and has not been studied in combination
with short-acting insulin. Lixisenatide has not been studied in
patients with gastroparesis.
Drug Class: Glucagon-like peptide-1 (GLP-1) receptor
agonist
Uniqueness of Drug: GLP-1 is a peptide hormone that
is released within minutes of eating a meal. It is known to
suppress glucagon secretion from pancreatic alpha cells and
stimulate glucose-dependent insulin secretion by pancreatic
beta cells. Lixisenatide increases glucose-dependent insulin
release, decreases glucagon secretion, and slows gastric empty-
ing. Lixisenatide is already approved in more than 60 countries
worldwide and marketed in over 40 under a different brand
name.
Warnings and Precautions:
Anaphylaxis and serious hypersensitivity reactions.
Closely monitor patients with a history of anaphylaxis or angio-
edema with other GLP-1 receptor agonists for allergic reactions
to lixisenatide; it is unknown whether these patients will be
predisposed to anaphylaxis with this agent. If a hypersensitivity
reaction occurs, the patient should discontinue the medication
and promptly seek medical attention.
Pancreatitis. Acute pancreatitis, including fatal and nonfatal
hemorrhagic or necrotizing pancreatitis, has been reported
post-marketing in patients treated with GLP-1 receptor ago-
nists. If pancreatitis is suspected, promptly discontinue the
medication and initiate appropriate management. If pancreatitis
is conrmed, do not restart therapy. Consider other antidiabetic
therapies in patients with a history of pancreatitis.
Never share lixisenatide pens between patients. Lixisen-
atide pens should never be shared between patients, even if the
needle is changed. Pen sharing poses a risk for transmission
of blood-borne pathogens.
Hypoglycemia and concomitant use of sulfonylurea or
basal insulin. When lixisenatide is used with a sulfonylurea
or basal insulin, consider lowering the dose of the sulfonylurea
or basal insulin to reduce the risk of hypoglycemia.
Acute kidney injury. Monitor renal function in patients with
renal impairment who report severe adverse gastrointestinal
reactions. Lixisenatide is not recommended in patients with
end-stage renal disease.
continued on page 712
DRUG FORECAST
Perampanel (Fycompa)
A Review of Clinical Efficacy and Safety in Epilepsy
Jessica Greenwood, MS, PharmD Candidate; and Jose Valdes, PharmD, BCPP
INTRODUCTION
Epilepsy is a serious neurological
condition that affects more than 50 million
individuals globally, 80% of whom live in
developing countries.1,2 An estimated 1.7%
of U.S. adults have been diagnosed with
the condition.3 From prominent historical
gures, such as Julius Caesar and Vladimir
Lenin, to friends or family members, most
people probably know someone affected
by epilepsy.2
Epileptic seizures (dened by two or
more unprovoked seizures separated by
more than 24 hours, or one unprovoked
seizure with high probability of an addi-
tional seizure in the next 10 years, or as
better dened by an epileptic syndrome)
are separated into two broad categories:
partial-onset seizures (POS) and gen-
eralized seizures, which affect one or
both hemispheres of the brain, respec-
tively.1 While many risk factors (e.g.,
infection, genetics, prenatal injury, or
structural or metabolic abnormalities)
have been elucidated, more than half of
all cases of epilepsy are due to unknown
causes.4 Regardless of the causative
factor, epileptic seizures result from a
persistent and uncontrolled increase in
hypersynchronous neuronal excitability
implicating various receptors (e.g.,
sodium, calcium, potassium, gamma-
aminobutyric acid, or glutamate)
involved in normal neurotransmission.5
Antiepileptic drugs (AEDs) target the
Ms. Greenwood (the primary author) is a Doctor
of Pharmacy Candidate, Class of 2018, at Nova
Southeastern University College of Pharmacy
in Palm Beach Gardens, Florida. Dr. Valdes
(the secondary and corresponding author) is
an Assistant Professor at Nova Southeastern
University College of Pharmacy specializing in
neurology and neuropsychiatry. Drug Forecast
is a regular column coordinated by Alan Caspi,
PhD, PharmD, MBA, President of Caspi and
Associates in New York, New York.
Disclosure: The authors report no nancial or
commercial relationships in regard to this article.
various receptors to reduce neuronal
excitability and control seizures, thus
reducing the risk of seizure-related
injuries and death.5 Although monotherapy
is ideal for treating epileptic seizures, only
about 49% of patients achieve seizure free-
dom while using their rst appropriately
selected AED. Subsequently, 62% to 66%
of patients might only be able to achieve
seizure freedom with a second or third
appropriately selected AED, respectively,
leaving up to one-third of patients with
inadequate control of their seizures.6 In
addition, patients may have a higher risk of
toxicity if AEDs with similar mechanisms
of action are used concomitantly.7 In the
last two decades, the number of agents
commercially available in the armamen-
tarium against epilepsy has risen fourfold,
few with a novel mechanism of action.1
The Food and Drug Administration
approved perampanel (Fycompa, Eisai,
Inc.) in October 2012 as an adjunctive
agent for the treatment of POS with or
without secondary generalization in
patients with epilepsy at least 12 years of
age. In June 2015, the agency approved a
second indication for primary generalized
tonic-clonic (PGTC) seizures in patients
with epilepsy who are at least 12 years
of age.8
MECHANISM OF ACTION
Perampanel (2-[2-oxo-1-phenyl-
5-pyridin-2-yl-1,2 dihydropyridin-3-yl]
benzonitrile hydrate) is a novel non-
competitive selective antagonist at the
postsynaptic ionotropic alpha-amino-3-
hydroxy-5-methyl-4-isoxazolepropionic
acid (AMPA) glutamate receptor.1,8,9 In
the nervous system, glutamate is known
to be a major excitatory neurotransmit-
ter, but the exact antiepileptic mechanism
of perampanel in humans is unknown.8
Studies suggest that AMPA receptor
antagonism can lead to reduced overstimu-
lation and anticonvulsant effects, as well as
inhibiting seizure generation and spread.
In addition, AMPA receptor antagonists
may prevent neuronal death.10
PHARMACOKINETICS
Absorption
Administration of perampanel results
in rapid and complete absorption with
negligible rst-pass metabolism. The
median time to reach peak concentra-
tion varies between 0.5 to 2.5 hours fast-
ing (delayed by two to three hours when
taken with food). Peak plasma concentra-
tion is reached in approximately one hour
(decreased by 40% when taken with
food). It is worth noting that the extent
of absorption is not affected by food.8,10
Distribution
Fycompa is approximately 95% to 96%
protein-bound in the concentration range
of 20 ng/mL to 2,000 ng/mL.8
Metabolism
Mediated by cytochrome P450 (CYP)
3A4/5, CYP1A2, and CYP2B6, peram-
panel is metabolized extensively through
oxidation followed by glucuronidation
based on in vitro results.8 Radiolabeled
perampanel administration resulted in
approximately 30% and 70% of oxidative
and conjugated metabolites being found
in urine and feces, respectively.10
Elimination
The half-life of perampanel is approxi-
mately 105 hours in patients who are
not concomitantly taking an enzyme-
inducing AED, allowing for steady state
to be reached in two to three weeks.8
Clearance rates for adult males (0.730 L
per hour) and females (0.605 L per hour)
were similar to those of patients less than
18 years of age (0.787 L per hour).10
CLINICAL TRIALS
Clinical trials of perampanel have been
conducted with patients diagnosed with
PGTC seizures, and with those under-
going uncontrolled, drug-resistant, or
refractory POS. These trials are summa-
rized in Table 1. In all studies, the pri-
mary efcacy endpoint was the percent
change in seizure frequency per 28 days,
Vol. 41 No. 11 November 2016 P&T
683
DRUG FORECAST

Table 1 Summary of Clinical Trials of Perampanel

French et al.11 French et al. Study 30412 French et al. Study 30513 Krauss et al. Study 30614

Locations 78 sites in Australia, Austria,
and dates China, Czech Republic, France,
Germany, Greece, India, Israel,
Japan, Latvia, Lithuania,
Poland, Serbia, South Korea,
and the U.S.
September 2011May 2014
Study 163 patients with PGTC and
subjectsa idiopathic generalized epilepsy
Primary Assess efficacy of adjunctive
objective PER in patients with drug-
resistant PGTC associated with
idiopathic generalized epilepsy
Study Randomized, multicenter,
design double-blind, PBO-controlled,
parallel- group study comparing
8mg or highest tolerated dose
of oral PER with oral PBO
Primary Percent change in seizure frequency per 28 days
efficacy
endpoint
Primary Statistically signicant median
endpoint percent change for seizure
results frequency with PER vs. PBO
(76.5% vs. 38.4%; P < 0.0001)
68 centers across Argentina, Canada, 78 sites in Australia, Austria, 116 centers in Germany, Bulgaria,
Chile, Mexico, and the U.S. Belgium, Germany, Finland, France, Portugal, Lithuania, India, and China
April 2008November 2010 United Kingdom, Greece, India, August 2008May 2010
Israel, Italy, The Netherlands, Russia,
Sweden, South Africa, and the U.S.
May 2008January 2011
388 patients with POS with or 386 patients with simple or complex 706 patients with simple or complex
without secondary generalization POS with or without secondary POS with or without secondary
who had failed 2 AEDs, had generalization who failed 2 AEDs, generalization who had uncontrolled
5 partial seizures during had 5 partial seizures during POS despite treatment with at least
baseline, and were taking stable baseline without a 25-day seizure- 2 different AEDs in prior 2 years
doses of up to 3 approved AEDs free period, and were taking stable
doses of up to 3 approved AEDs
Assess efficacy and safety of once- Assess the efficacy and safety of Assess efficacy and safety of once-
daily 8mg or 12mg PER when added once-daily 8mg and 12mg PER when daily 2mg, 4mg, and 8mg PER added
to concomitant AEDs in the treatment added to 13 concomitant AEDs in to 13 concomitant AEDs in patients
of POS patients with uncontrolled POS with uncontrolled POS
Randomized, multicenter, double-blind, PBO-controlled, parallel-group study Randomized, multicenter, double-
comparing once-daily 8mg or 12mg oral PER with oral PBO blind, PBO-controlled study
comparing once-daily 2mg, 4mg,
and 8mg oral PER with oral PBO
Statistically signicant median Statistically signicant median Statistically signicant percent
percent change for seizure percent change for seizure change for seizure frequency with
frequency with PER 8mg and 12mg frequency with PER 8mg and PER 4mg and 8mg vs. PBO (23.3%
vs. PBO (26.3% and 34.5%, 12mg vs. PBO (30.5% and 17.6%, and 30.8%, respectively, vs. 10.7%;
respectively, vs. 21%; P=0.0261 and respectively, vs. 9.7%; P < 0.001 P=0.003 and P < 0.001). Statistically
P=0.0158) and P=0.011) insignicant for 2mg (13.6%,
P=0.420)

Secondary 50% responder rate 50% responder rate 50% responder rate
efficacy Percent change in 28-day complex partial plus secondarily generalized Percent change in 28-day complex
endpoint(s) seizure frequency partial plus secondary generalized
seizure frequency
Secondary Statistically signicant 50% Statistically insignicant 50% Statistically signicant 50% responder Statistically signicant 50% responder
efficacy PGTC responder rate for PER responder rate for 8mg and 12mg PER rate for 8mg and 12mg PER vs. PBO rate for 4mg and 8mg PER vs. PBO
endpoint vs. PBO (64.2% vs. 39.5%; vs. PBO (37.6% and 36.1%, respectively, (33.3% and 33.9%, respectively, (28.5% and 34.9%, respectively,
results P=0.0019) vs. 26.4%; P=0.0760 and P=0.0914). vs. 14.7%; P=0.002 and P < 0.001). vs. 17.9%; P=0.013 and P < 0.001).
Statistically signicant percent change Statistically signicant percent Statistically insignicant for 2mg
in the 28-day complex partial plus change for frequency of complex (20.6%; P value NP). Statistically
secondarily generalized seizure partial plus secondarily signicant percent change in 4mg and
frequency for 8mg and 12mg PER vs. generalized seizures with 8mg and 8mg PER vs. PBO (31.2% and 38.7%,
PBO (33% and 33.1%, respectively, 12mg PER vs. PBO (32.7% and respectively, vs. 17.6%; P=0.007 and
vs. 17.9%) 21.9%, respectively, vs. 8.1%; P < 0.001). Statistically insignicant for
P<0.001 and P=0.005) 2mg (20.5%; P valueNP)
Adverse Dizziness (32.1%), fatigue Dizziness (8mg, 37.6%; 12mg, 38.1%), Dizziness (8mg, 32.6%; 12mg, Dizziness (2mg, 10%; 4mg, 16.3%;
eventsb (14.8%), headache (12.3%), somnolence (18%; 17.2%), irritability 47.9%), somnolence (12.4%; 18.2%), 8mg, 26.6%), somnolence (12.2%;
somnolence (11.1%), and (7.5%; 14.2%), headache (15%; 13.4%), fatigue (13.2%; 16.5%), and 9.3%; 16%), and headache (8.9%; 11%;
irritability (11.1%) falls (9.8%; 12.7%), and ataxia (6%; 11.9%) headache (8.5%; 13.2%) 10.7%)
AED = antiepileptic drug; ILEA = International League Against Epilepsy; NP = not published; PBO = placebo; PER = perampanel; PGTC = primary generalized
tonic-clonic seizures; POS = partial-onset seizures.
a All patients were 12 years of age or older and were diagnosed using ILEA criteria.
b Most frequently reported in 10% or more of patients

684 P&T November 2016 Vol. 41 No. 11

 DRUG FORECAST

Table 1 Summary of Clinical Trials of Perampanel (continued)

Krauss et al. Study 30715 Steinhoff et al. Pooled Analysis Vazquez et al. Pooled Subanalysis
of 304, 305, and 30616 of 304, 305, and 30617
Locations 249 centers in 39 countries (including Australia, More than 40 countries on ve continents
and dates Bulgaria, Czech Republic, Estonia, Germany, Hong April 2008January 2011
Kong, Hungary, India, Italy, South Korea, Latvia,
Lithuania, Malaysia, Philippines, Poland, Portugal,
Romania, Russia, Serbia, Spain, Taiwan, and Thailand)
October 2008December 2010

Study 1,218 patients (from those who completed the
subjectsa double-blind phase of studies 304, 305, and 306)
with uncontrolled simple or POS with or without
secondary generalization despite treatment with
13 approved AEDs
1,478 patients with refractory POS despite 1,478 patients (719 males, 759 nonpregnant
treatment with 13 approved AEDs females) with drug-resistant POS with or
without secondary generalization despite
treatment with 13 AEDs in prior 2 years

Primary Assess safety, tolerability, and seizure outcome Assess efficacy and safety of adjunctive PER Assess efficacy and tolerability of adjunctive
objective data for long-term treatment with adjunctive PER PER by gender
for refractory POS

Study Multicenter, randomized, double-blind, Randomized, multicenter, double-blind, Randomized, multicenter, double-blind,
design PBO-controlled, parallel-group study comparing PBO-controlled study comparing once-daily PBO-controlled, parallel-group study
12mg or highest tolerated dose of oral PER with 4mg, 8mg, and 12mg oral PER with oral PBO comparing once-daily 2mg, 4mg, 8mg,
oral PBO or 12mg oral PER with oral PBO

Primary Percent change in seizure frequency per 28 days Percent change in seizure frequency per 28 days
efficacy over 2 years
endpoint
Primary Percent change in seizure frequency per 28 days Statistically signicant percent change for seizure Statistically insignicant percent change for
endpoint over 2 years (in weeks): frequency with PER 4mg, 8mg, and 12mg seizure frequency greater in females than
results 113: 29.1% (n = 1,207) vs. PBO (23.3%, 28.8%, and 27.2%, males with PER 4mg and 12mg vs. PBO;
1426: 39.2% (n = 1,114) respectively, vs. 12.8%; P < 0.01, each dose statically signicant median percent change
2739: 44% (n = 979) vs. PBO). for seizure frequency greater in females
4052: 46.5% (n = 731) than males with PER 8mg (female, 35%;
5365: 51.2% (n = 495) male, 22%; P < 0.05)
6678: 52.3% (n = 323)
7991: 51.2% (n = 176)
92104: 58.1% (n = 59)
Secondary 50% responder rate over 2 years 50% responder rate 50% responder rate
efficacy Percent change in the 28-day complex partial
endpoint(s) plus secondary generalized seizure frequency

Secondary 50% responder rate for PER over 2 years Statistically signicant 50% responder rate for Statistically insignicant 50% responder rate
efficacy (in weeks): 4mg, 8mg, and 12mg PER vs. PBO (28.5%, greater for females than males for 412mg
endpoint 113: 31.1% (n = 1,207) 35.3%, and 35%, respectively, vs. 19.3%; PER
results 1426: 41.4% (n = 1,114) P < 0.05, each dose vs. PBO). Statistically
2739: 45.3% (n = 979) signicant percent change for frequency of
4052: 46.9% (n = 731) complex partial plus secondarily generalized
5365: 50.7% (n = 495) seizures for 4mg, 8mg, and 12mg PER vs. PBO
6678: 51.1% (n = 323) (31.2%, 35.6%, and 28.6%, respectively,
7991: 51.7% (n = 176) vs. 13.9%; P < 0.001 )
92104: 62.7% (n = 59)

Adverse Dizziness (43.9%), somnolence (20.2%), Dizziness (4mg, 16.3%; 8mg, 31.8%; 12mg, Dizziness (female, 31.5%; male, 24.4%),
eventsb headache (16.7%), and fatigue (12.1%) 42.7%), somnolence (9.3%;15.5%; 17.6%), somnolence (14.3%; 14.6%), and headache
headache (11%; 11.4%; 13.3%), fatigue (13.2%; 9.4%)
(7.6%; 8.4%; 12.2%), and falls (1.7%; 5.1%; 10.2%)
AED = antiepileptic drug; ILEA = International League Against Epilepsy; NP = not published; PBO = placebo; PER = perampanel; PGTC = primary generalized
tonic-clonic seizures; POS = partial-onset seizures.
a All patients were 12 years of age or older and were diagnosed using ILEA criteria.
b Most frequently reported in 10% or more of patients

Vol. 41 No. 11 November 2016 P&T 685

DRUG FORECAST
and a common secondary efcacy end-
point was the 50% responder rate. In the
2015 clinical trial conducted by French
et al., patients with PGTC seizures who
were taking 8 mg or the highest tolerated
dose of perampanel showed a statistically
signicant reduction in the frequency of
seizures compared with placebo (76.5%
versus 38.4%; P < 0.0001).11 The study
also demonstrated that the number
of patients achieving a 50% or more
reduction in PGTC seizure frequency
(50% responder rate) was statistically
signicant for patients taking perampanel
(64.2% versus 39.5%; P = 0.0019).11
In Study 304, the efcacy and safety of
once-daily 8-mg and 12-mg perampanel
were assessed for patients with POS with
or without secondary generalization who
did not respond to at least two AEDs,
had at least ve partial seizures at base-
line, and were on stable doses of up to
three approved AEDs. Results showed
a statistically signicant reduction in
the frequency of seizures for patients
on 8-mg and 12-mg perampanel com-
pared with placebo (26.3% and 34.5%,
respectively, versus 21%; P = 0.0261 and
P = 0.0158).12 The studys secondary ef-
cacy endpoint was patients achieving at
least a 50% reduction in POS frequency
(50% responder rate).12 Results for the
50% responder rate were not statistically
signicant for patients taking peram-
panel (37.6% and 36.1%, respectively,
versus 39.5%; P = 0.0760 and P = 0.0914).12
Study 304 had an additional secondary
efcacy endpoint: the percent change in
the 28-day frequency of complex partial
plus secondarily generalized seizures.
Those results showed a statistically sig-
nicant percent change for 8 mg and
12 mg versus placebo (33% and 33.1%,
respectively, versus 17.9%).12
In Study 305, the efcacy and safety of
once-daily 8-mg and 12-mg perampanel
were assessed for patients with simple or
complex POS with or without secondary
generalization who did not respond to at
least two AEDs, had at least ve partial
seizures at baseline, and were on stable
doses of up to three approved AEDs.
Results showed a statistically signicant
reduction in the frequency of seizures
for patients on 8-mg and 12-mg peram-
panel compared with placebo (30.5%
and 17.6%, respectively, versus 9.7%;
P < 0.001 and P = 0.011).13 The study
also demonstrated that the number of
686 P&T November 2016 Vol. 41 No. 11
patients achieving at least a 50% reduction
in POS frequency (50% responder rate)
was statistically signicant for patients
on 8 mg and 12 mg of perampanel (33.3%
and 33.9%, respectively, versus 14.7%;
P = 0.002 and P < 0.001).13 Study 305 also
had a secondary efcacy endpoint of
percent change in the 28-day frequency
of complex partial plus secondarily gen-
eralized seizures. Those results showed
a statistically signicant percent change
with perampanel 8 mg and 12 mg versus
placebo (32.7% and 21.9%, respectively,
versus 8.1%; P < 0.001 and P = 0.005).13
Study 306 was modeled after Study 305
except that the objective was to assess
the efcacy and safety of once-daily 2-mg,
4-mg, and 8-mg perampanel in patients
with simple or complex POS with or with-
out secondary generalization who did not
respond to at least two AEDs, had at least
ve partial seizures at baseline, and were
on stable doses of up to three approved
AEDs. Results showed a statistically
signicant percent change for seizure
frequency with perampanel 4 mg and
8 mg versus placebo (23.3% and 30.8%,
respectively, versus 10.7%; P = 0.003
and P < 0.001), but the change was not
statistically signicant for 2 mg (13.6%;
P = 0.420).14 The study also demonstrated
that the number of patients achieving
a 50% or greater reduction in POS fre-
quency (50% responder rate) was statisti-
cally signicant for 4 mg and 8 mg versus
placebo (28.5% and 34.9%, respectively,
versus 17.9%; P = 0.013 and P < 0.001),
but was statistically insignicant for 2 mg
(20.6%; P value not published).14 As an
additional secondary efcacy endpoint,
Study 306 evaluated the percent change
in the 28-day frequency of complex par-
tial plus secondarily generalized seizures
and found a statistically signicant per-
cent change with perampanel 4 mg and
8 mg versus placebo (31.2% and 38.7%,
respectively, versus 17.6%; P = 0.007 and
P < 0.001), but the change was not statisti-
cally signicant for 2 mg (20.5%; P value
not published).14
Study 307 extended Studies 304, 305,
and 306 to assess the safety, tolerability,
and seizure outcome data for long-term
treatment with adjunctive perampanel
for refractory POS.15 The primary ef-
cacy endpoint was percent change in
seizure frequency per 28 days over a
two-year period.15 Results showed a sus-
tained reduction in seizure frequency
for patients who had at least 26 weeks,
39 weeks, one year, and two years of expo-
sure to perampanel.15 The percent change
in seizure frequency was recorded for
every 13-week interval (Table 1).
Steinhoff et al. conducted a pooled anal-
ysis of Studies 304, 305, and 306 to assess
the efcacy and safety of adjunctive 4-mg,
8-mg, and 12-mg perampanel.16 Results
showed a statistically signicant percent
change for seizure frequency with per-
ampanel 4 mg, 8 mg, and 12 mg versus
placebo (23.3%, 28.8%, and 27.2%,
respectively, versus 12.8%; P < 0.01 for
each dose versus placebo).16 The study
also demonstrated that the rate of patients
achieving at least a 50% reduction in POS
frequency (50% responder rate) was
statistically signicant for patients tak-
ing perampanel 4 mg, 8 mg, and 12 mg
versus placebo (28.5%, 35.3%, and 35%,
respectively, versus 19.3%; P < 0.05 for
each dose versus placebo).16 The pooled
analysis had an additional secondary
efcacy endpoint: percent change in
the 28-day frequency of complex partial
plus secondarily generalized seizures.
Results showed a statistically signicant
percent change for the frequency of such
seizures with perampanel 4 mg, 8 mg, and
12 mg versus placebo (31.2%, 35.6%,
and 28.6%, respectively, versus 13.9%;
P < 0.001 for all doses).16
Vazquez et al. conducted a pooled
analysis of Studies 304, 305, and 306
to assess the efcacy and tolerability
of adjunctive perampanel by gender.17
The primary efcacy endpoint was the
percent change in seizure frequency per
28 days, and results showed a statistically
signicant difference in gender only at
8 mg, with female efcacy greater than
male efcacy (female, 35%; male, 22%;
P < 0.05).17 The 50% responder rate was a
secondary efcacy endpoint, and results
showed the difference between genders
to be statistically insignicant.17
INDICATIONS AND DOSING
Perampanel is indicated in patients
with epilepsy who are 12 years of age
and older for the treatment of POS with
or without secondary generalization and
for the treatment of PGTC seizures, in
both cases as an adjunctive agent.8
The recommended starting dose of
perampanel for POS and PGTC seizures
in patients not concomitantly taking
an enzyme-inducing AED is 2 mg by
 DRUG FORECAST

mouth at bedtime. Titrate by 2 mg daily 422 patients taking a pla- Table 2 Most Common Adverse Reactions in Clinical
at weekly intervals. The recommended cebo, the most common Trials in Patients With Partial-Onset Seizures8*
dosage range for patients with POS in adverse reactions (at least
Perampanel
the absence of enzyme-inducing AEDs 5%) were dizziness, som- Placebo
is 8 mg to 12 mg at bedtime, while in nolence, headache, irrita- n = 442 4mg 8mg 12mg
patients with PGTC seizures the recom- bility, fatigue, falls, ataxia, % n = 172 n = 431 n = 255
mended maintenance dose is 8 mg at bed- nausea, vertigo, and back % % %
time. Dosing should be individualized and pain (Table 2).8,9 Dizziness 9 16 32 43
based on the patients clinical response In a study population Somnolence 7 9 16 18
and tolerability.8 of patients with PGTC Headache 11 11 11 13
For patients with POS and PGTC seizures (n = 163), the
Irritability 3 4 7 12
seizures concomitantly taking an enzyme- most common adverse
inducing AED (including but not lim- effects seen in patients Fatigue 5 8 8 12
ited to phenytoin, carbamazepine, and taking perampanel 8 mg Falls 3 2 5 10
oxcarbazepine), the recommended initial versus placebo were Ataxia 0 1 3 8
dose is 4 mg of perampanel once a day at dizziness, fatigue, head- Nausea 5 3 6 8
bedtime. Titrate by 2 mg daily at weekly ache, somnolence, irrita-
Vertigo 1 4 3 5
intervals. The maximum dose in the pres- bility, vertigo, vomiting,
ence or absence of concomitant enzyme- weight gain, contusion, Back pain 2 2 2 5
inducing AEDs is 12 mg at bedtime.8 nausea, abdominal pain, * Reactions in at least 5% of patients at highest dose in
In patients with hepatic impairment, and anxiety (Table 3).8,9 Studies 1, 2, and 3
perampanel should be initiated at 2 mg
WARNINGS AND Table 3 Most Common Adverse Reactions in Patients
once a day at bedtime and titrated by
With Primary Generalized Tonic-Clonic Seizures8*
no more than 2 mg every two weeks. PRECAUTIONS
The maximum recommended doses for Patients should be Placebo Perampanel 8mg
patients with mild and moderate hepatic monitored for serious n = 82 n = 81
impairment are 6 mg and 4 mg, respec- psychiatric and behav- % %
tively. In patients with moderate renal ioral reactions. In the POS Dizziness 6 32
impairment, close monitoring and slower clinical trials, dose-related Fatigue 6 15
titration is recommended. Perampanel is adverse reactions related Headache 10 12
not recommended in the setting of severe to hostility and aggression
hepatic or severe renal impairment or in were reported in 20%, 12%, Somnolence 4 11
patients undergoing hemodialysis.8 and 6% of patients taking Irritability 2 11
In the event of a single missed dose, perampanel 12 mg, peram- Vertigo 2 9
patients may wait to take their next dose as panel 8 mg, and placebo, Vomiting 2 9
regularly scheduled. Perampanel may be respectively (Table 4).
Weight gain 4 7
restarted at the last given dose for patients Homicidal ideation and/or
who have missed more than one dose threat was seen in 0.1% of Contusion 4 6
continuously for less than three weeks 4,368 patients in controlled Nausea 5 6
(one week for patients concomitantly tak- or open-label trials for epi- Abdominal pain 1 5
ing enzyme-inducing AEDs). For patients lepsy and other conditions. Anxiety 4 5
who have discontinued the use of peram- Belligerence, affect labil- * Reactions in at least 5% of patients in Study 4
panel for more than three weeks, initial ity, agitation, and physical
dosing recommendations should be fol- assault were more com- Table 4 Hostility and Aggression in Partial-Onset
lowed. Perampanel should be reduced mon with perampanel, Seizure Trials8
gradually when considering discontinu- although percentages Perampanel
ation because of a potential increase in were not reported in clini- Placebo
4mg 8mg 12mg
seizure frequency, but abrupt cessation cal trials. These events %
% % %
may be attempted if needed due to its long can occur with or without
half-life. In the event of a perampanel over- prior psychiatric histories, Irritability 3 4 7 12
dose, supportive care is indicated. Forced aggressive behavior, or Aggression 1 1 2 3
diuresis, dialysis, or hemoperfusion may use of other medications Anger <1 0 1 3
not be of value due to the medications associated with hostility Anxiety 1 2 3 4
poor renal clearance.9 or aggression. Patients
with pre-existing psychiatric conditions significantly worsened mood and
ADVERSE DRUG REACTIONS may experience a worsening of their increased anger. Additionally, AEDs as
Based on pooled analysis of three psychiatric condition while taking peram- a class may increase the risk of suicidal
placebo-controlled trials with 858 patients panel. Concomitant use of perampanel ideation or behavior for any indication,
with POS taking perampanel versus with alcohol should be avoided, as it and patients taking them should be

Vol. 41 No. 11 November 2016 P&T

687
DRUG FORECAST
monitored for unusual changes in mood
or behavior. 8
No contraindications are listed for the
medication.
Pregnancy and Lactation
This medication is classied as preg-
nancy category C, indicating it may cause
fetal harm based on animal studies; how-
ever, due to the lack of well-controlled
studies in pregnant women, the risk is
uncertain. Administration of perampanel
during organogenesis in rats and rabbits
resulted in diverticulum of the intestine,
reduced fetal body weight, and embryo
lethality. In addition, perampanel and/or
its metabolites can be found in rat milk
in concentrations higher than serum;
however, it is unknown if perampanel
is excreted in human milk. Caution is
advised when considering the use of
perampanel in women who are of child-
bearing age or who may be pregnant or
nursing.8,9
DRUG INTERACTIONS
The concomitant use of central ner-
vous system depressants such as alcohol,
benzodiazepines, narcotics, barbiturates,
and sedating antihistamines may cause
additive central nervous system depres-
sion. Patients are advised not to drive or
operate machinery until they have gained
experience with perampanel. At doses of
12 mg per day, perampanel can reduce
levonorgestrel serum levels by 40%,
thus rendering contraceptives contain-
ing levonorgestrel less effective. CYP3A4
enzyme inducers (e.g., carbamazepine,
phenytoin, oxcarbazepine) can decrease
serum levels of perampanel by up to 67%.
Following an appropriate dosing strategy
is recommended when using perampanel
concomitantly with a CYP3A4 enzyme-
inducing agent.8,9
P&T COMMITTEE
CONSIDERATIONS
Perampanel joins the market as one
of more than 20 AEDs in the armamen-
tarium to treat epilepsy. Although peram-
panel shares a mechanism of action with
topiramate and both take approximately
one month to titrate to the recommended
dose, perampanel may be preferred in
patients who have a history of closed-
angle glaucoma, kidney stones, or meta-
bolic acidosis.18 In addition, perampanel
is indicated as an adjunctive AED for POS
688 P&T November 2016 Vol. 41 No. 11
and PGTC seizures, whereas topiramate
may be used as monotherapy.
Perampanel has an average wholesale
price of $450 for a package of 30 2-mg tab-
lets, $891 for a package of 30 4-mg, 6-mg,
8-mg, 10-mg, or 12-mg tablets, and $1,149
for a 340-mL bottle of the oral suspension
(0.5 mg/1 mL).19 Formulary inclusion for
restricted uses may be prudent to ensure
appropriate initiation and titration.
CONCLUSION
Perampanel is a safe and effective
adjunctive treatment option for patients
with POS and PGTC seizures. Additional
evidence suggests perampanel may also
be useful in refractory POS, but less
useful for drug-resistant POS. Careful
monitoring of the patients clinical status,
concomitant medications, and comorbid
conditions is essential when initiating
and titrating perampanel. Patients and
caregivers should be educated on the
common adverse effects and precautions
of using perampanel and should report
any changes in mood or behavior to their
prescriber.
REFERENCES
1. Frampton JE. Perampanel: a review
in drug-resistant epilepsy. Drugs
2015;75(14):16571668. doi 10.1007/
s40265-015-0465-z.
2. Ali R, Connolly ID, Feroze AH, et al.
Epilepsy: a disruptive force in history.
World Neurosurg 2016;90:685690. doi:
10.1016/j.wneu.2015.11.060.
3. Bush MA, Franco S. QuickStats:
age-adjusted percentages of adults aged
18 years who have epilepsy, by epilepsy
status and race/ethnicityNational
Health Interview Survey, United States,
2010 and 2013 combined. MMWR Morb
Mortal Wkly Rep 2016;65:611. doi: http://
dx.doi.org/10.15585/mmwr.mm6523a8.
4. Walsh S, Donnan J, Fortin Y, et al.
A systematic review of the risks factors
associated with the onset and natural
progression of epilepsy. Neurotoxicology
2016 Mar 19. pii: S0161-813X(16)30030-4.
doi: 10.1016/j.neuro.2016.03.011. [Epub
ahead of print.]
5. Engelborghs S, DHooge R, De Deyn PP.
Pathophysiology of epilepsy. Acta Neurol
Belg 2000;100(4):201213.
6. Brodie MJ, Barry SJ, Bamagous GA,
et al. Patterns of treatment response in
newly diagnosed epilepsy. Neurology
2012;78(20):15481554.
7. Trinka E, Steinhoff BJ, Nikanorova M,
Brodie MJ. Perampanel for focal epilepsy:
insights from early clinical experience.
Acta Neurol Scand 2016;133(3):160172.
doi: 10.1111/ane.12529. Epub 2015 Oct
28.
8. Fycompa (perampanel) prescribing
information. Woodcliff Lake, New Jersey:
Eisai R&D Management (Eisai Ltd.); 2016.
9. Fycompa (perampanel) product mono-
graph. Mississauga, Ontario: Eisai Ltd.;
2013.
10. Franco V, Crema F, Iudice A, et al.
Novel treatment options for epilepsy:
focus on perampanel. Pharmacol
Res 2013;70(1):3540. doi: 10.1016/j.
phrs.2012.12.006. Epub 2013 Jan 1.
11. French JA, Krauss MD, Bibbiani MD,
et al. Perampanel for tonic-clonic
seizures in idiopathic generalized epilepsy.
Neurology 2015;85(11):950957.
12. French JA, Krauss GL, Biton V, et al.
Adjunctive perampanel for refractory
partial-onset seizures: randomized phase III
study 304. Neurology 2012;79(6):589596.
13. French JA, Krauss GL, Steinhoff BJ, et al.
Evaluation of adjunctive perampanel in
patients with refractory-onset seizures:
results of randomized global phase III
study 305. Epilepsia 2013;54(1):117125.
14. Krauss GL, Serratosa JM, Villaneuva
V, et al. Randomized phase III study
306: adjunctive perampanel for refrac-
tory partial-onset seizures. Neurology
2012;78(18):14081415.
15. Krauss GL, Perucca E, Ben-Menachem
E, et al. Perampanel, a selective, non-
competitive -amino-3-hydroxyl-5-methyl-
4-isoxazolepropionic acid receptor antago-
nist, as adjunctive therapy for refractory
partial-onset seizures: interim results from
phase III, extension study 307. Epilepsia
2013;54(1):117125.
16. Steinhoff BJ, Ben-Menachem E, Ryvlin
P, et al. Efcacy and safety of adjunctive
perampanel for the treatment of refrac-
tory partial seizures: a pooled analysis
of three phase III studies. Epilepsia
2013;54(8):14811489.
17. Vazquez B, Yang H, Williams B, et al.
Perampanel efcacy and safety by gen-
der: subanalysis of phase III randomized
clinical studies in subjects with partial
seizures. Epilepsia 2015;56(7):e90e94.
18. Topamax (topiramate) prescribing
information. Titusville, New Jersey:
Janssen Pharmaceuticals, Inc.; 2014.
19. Red Book Online. Ann Arbor, Michigan:
Truven Health Analytics. Accessed
October 17, 2016. Q
P&T TV
P&T is accepting video clips
from readers, and we might
post yours on our website
(www.PTCommunity.com). Feel
free to send a short video about the
activities of your P&T committee.
You can contact the Editor,
J. Stephen McIver, at 267-685-3713
or smciver@medimedia.com.
 Prescription Drug Data Might Help Protect Obamacare
Medication Use Will Be Integrated Into Marketplace Plan Risk Adjustments
Stephen Barlas
ill prescription drugs be the savior of the insurance
W exchanges in the Patient Protection and Affordable
Care Act (PPACA)? Thats probably too much to ask.
But a decision by the Obama administration to incorporate drug
utilization data into the risk assessment used to determine the
size of revenue transfers between marketplace insurers1 is
meant to stem the exodus of companies from that marketplace.
The Centers for Medicare and Medicaid Services (CMS)
wants to create 12 drug utilization categories (RXCs) to supple-
ment what are called hierarchical condition catego-
ries (HCCs), essentially medical codes for each
patient that the CMS uses to calculate risk scores for
each plan. The CMS hopes that by testing a handful
of combined categories, using prescription data for
the rst time, the risk scores will be more accurate.
Those risk scores are important because they dictate
whether a plan with less-healthy members receives
additional revenue from plans with healthier-than-
average members.
Stephen Barlas
Qualied health plans (QHPs) offer insurance on
the state and federal marketplace exchanges. Risk adjustment
is suppose to keep QHPs honest, ostensibly making it more
difcult to design plans that mostly appeal to healthy (read:
less costly, so more protable) patients. The ip side is that
struggling plans, some of which are now leaving the state and
federal marketplaces, will be better compensated for making
broader formularies available.
All parties interested in this proposal agree it will improve
accuracy of plan payments, says Caroline Pearson, Senior
Vice President at Avalere Health. But there are still a lot of
details left out, including which drugs go into each RXC, and
the way you do that matters a lot. For example, one RXC is
composed of immune suppressants and immunomodulators.
It is paired with HCCs that include rheumatoid arthritis and
specied autoimmune disorders. Pearson notes, for example,
that if both the brand-name biologic products and generic
methotrexate are in that RXC, that would reduce the payment
accuracy of the model changes.
Patient advocacy groups believe that adding RXCs to HCCs
will force QHPs to broaden their formularies. Some QHPs
do not cover all of the single-tablet regimens and curative
hepatitis C medications that are commonly prescribed and
recommended in clinical treatment guidelines, says Michael
Ruppal, Executive Director of The AIDS Institute. To the
extent that a risk-adjustment model incorporates prescription
drug utilization, it will compensate plans that cover high-cost
medications for its enrollees.
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.
The change will go into effect in 2018, and the technical
details are still being worked out. But the CMS proposal to
make an initial foray into adding drug utilization data to medi-
cal data to formulate risk scores for plans is meant to stabilize
the leakage of insurance co-ops out of the marketplace and to
better protect new plans and smaller plans with less clinical
data. However, larger companies such as Aetna, Humana, and
United Healthcare, which are dropping plans in some states,
also approve of the addition of drug utilization data to the risk-
assessment model of the Department of Health and
Human Services (HHS).
Criticism of Current Risk-Adjustment Model
A number of groups have criticized the current
risk-assessment methodology. Last February, Al
Redmer Jr., the Maryland Insurance Commissioner,
told a congressional subcommittee that CareFirst
BlueCross BlueShields share of the marketplace
in his state had plummeted from 91% to 57% as new
carriers started offering plans. These carriers have
the potential to continue, but their ability to do so is severely
jeopardized by the adverse and perhaps fatal nancial impact
caused by the technical shortcoming of the current risk-
adjustment and risk-corridor programs, he told the House
Oversight and Government Reform Subcommittee on Health
Care, Benets, and Administrative Rules. The risk-corridor
program (which limits losses and gains beyond an allowable
range) expires at the end of this year. Redmer explained:
The risk-adjustment formula is of concern to state regulators because
it has proven to place newer carriers at a distinct disadvantage.
For example, the risk-adjustment formula quanties an enrollees
health status based on age, sex, and diagnoses recorded during
the course of the year. New carriers have very limited information
on the health status or previous claims history of the applicants.
Therefore, the carriers population may appear healthier than it
actually is if some diagnoses are not captured, which may result in
improper risk-adjustment payments.
According to the CMS, the 2014 risk-adjustment transfer
amounts were especially volatile for small insurers, with many
having to pay out amounts in excess of 10% of their aggregate
premium revenues. The Choices Coalition, made up of relatively
small insurers, states: A payment that is both very large and
very unpredictable is a signicant problem for any health plan
but particularly difcult to manage for smaller plans.
Insurers, too, have been critical of the current risk-
assessment model. Anthem argues: Our primary and over-
arching comment is that the existing risk-adjustment program
threatens to destabilize the market by creating incentives that
subject each issuers risk pool to continued deterioration. The
Vol. 41 No. 11 November 2016 P&T
689
 Prescription Drug Data Might Help Protect Obamacare
current program, on average, overcharges issuers for young
and/or healthy individuals and generally overcompensates
issuers for higher-risk members. This imbalance is not in the
long-term interest of the program because the incentive creates a
worse risk pool that results in higher premiums for consumers.
Broad Support for Adding Prescription Data
There is near unanimity among players in the market-
place exchanges that the addition of prescription information
will make the risk-assessment model more sensitive. We
support a pharmacy model that would both augment or impute
missing diagnoses and also use pharmacy data to predict the
severity of conditions, says UnitedHealthcare. Even though
CMS already captures information about illness severity from
diagnosis, prescription drug data could help to rene the sever-
ity of the illness within a single HCC. We believe that both of
these markers foster the programs goal to reduce issuers
incentives to avoid high-cost enrollees.
The fact that the HCCs do not account for prescriptions
makes them a skewed measure on which to base risk scores,
given the expense of some specialty drugs and the way they
affect a QHPs nances. Part of the concern is that some plans
decline to make expensive drugs available as a way of warding
off the membership of high-cost individuals with serious chronic
diseases. Those QHPs that do offer those same expensive
drugs may have high risk scores, leading to an outow of
risk payments, even though their formularies are broad and
inclusive. They therefore may have to subsidize another plan
in the state with a very narrow, restrictive formulary with a
similar HCC-based risk score.
When Andy Slavitt, Acting Administrator of the CMS,
appeared before a House committee in mid-April, Republicans
battered him with questions about the perceived weaknesses
of the QHPs operating in the PPACA marketplaces. Slavitt
went to great lengths to underline the perceived successes
of the plansmore people with insurance and relatively high
satisfaction ratesbefore explaining some of the changes the
Obama administration has recently made and is in the process
of making, all with the hopes of making the marketplaces more
attractive to both consumers and eeing insurance companies.
Slavitts list of improvements was topped by changes to the
risk-assessment methodology. The addition of drug utilization
data on a test basis will be one of the big changes.
The HHS Proposal1
The CMS proposes to base the RXCs on United States
Pharmacopeia (USP) classications, instead of its original plan
to base them on the American Hospital Formulary Service
Pharmacologic-Therapeutic Classication, which is pub-
lished by the Board of the American Society of Health-System
Pharmacists (ASHP). The problem with the ASHP classication
is that its mappings from National Drug Codes (NDCs) are
proprietary, so the CMS decided to use the USP classications.
NDC codes are classied into 153 USP therapeutic classes. The
HHS selected the 12 RXC-HCC pairs based on seven principles,
such as that each pair had to be clinically meaningful, should
predict total medical and drug expenditures, and should have
adequate sample sizes to permit accurate and stable estimates
of expenditures.
690 P&T November 2016 Vol. 41 No. 11
Based on these considerations, the HHS came up with
two types of RXC-HCC pairs to integrate into the adult risk-
adjustment model. Ten will be used to impute a diagnosis
and calibrate the severity of the condition and two only as an
indication of severity (Table 1). The 10 RXCs with imputation
potential have three levels of incremental predicted costs
(diagnosis only, prescription drug only, both diagnosis and
prescription drug). So, for example, if a plan member is diag-
nosed with disease X one year and is prescribed drug Y, he or
she would get a certain risk score, which would be aggregated
with the other individual risk scores of plan members. But the
next year, maybe that same plan member will not get an X
diagnosis but will still be taking drug Y. He or she would get
the same risk score as the prior year.
The drug-diagnosis pairs can include more than one HCC.
For example, the list in the proposed rule includes one of the 12
HCC labels devoted to potential diabetes drug-diagnosis rela-
tionships that includes three HCCs (diabetes with acute com-
plications, diabetes with chronic complications, and diabetes
without complications) that are grouped together in the model
estimation. Their HCCs are 019, 020, and 021, respectively. They
are paired with RXC 6a, in which the drugs include antidiabetic
agents, except insulin and metformin only. RXC 6a can be
interpreted as an indication that the individual should have a
diagnosis of one of these three diabetes HCCs. That particu-
lar RXC is labeled imputation/severity, as are nine others,
while two are labeled severity only. The severity possibility
allows the plan to give two members with the same diagnosis
i.e., 019different risk scores if one is taking a more advanced
drug in category 6a, meaning he or she is more advanced in
his or her sickness, and thus is more costly.
In addition, an RXC can be linked in the model to more
than one HCC, and vice versa. For example, RXC 8 (immune
suppressants and immunomodulators) has an imputation/
severity relationship with HCC 056 (rheumatoid arthritis and
specied autoimmune disorders), and also has a severity-only
relationship with HCC 048 (inammatory bowel disease).
When the CMS rst broached its plans last March in a white
paper,2 it suggested it could use one of four different modeling
approaches to integrate prescription drug data with HCCs. This
gets mind-bogglingly technical. One option was to impute risk
regardless of how a disease condition is identied, that is, by
either diagnosis or by drug utilization. A second was modeling
by severity, meaning that only if a drug class and a specic
diagnosis are present would the model predict incremental
costs beyond the diagnosis alone. A third approach would be
drug-dominant, meaning that when a drug is utilized a diagnosis
is imputed, so the predicted expenditures should be the same
irrespective of whether the diagnosis is reported. A fourth
method, which the CMS terms exible/generalized, is a hybrid
approach that allows for different predictions for diagnosis
only, drug only, and diagnosis and drug combination groups.
Many insurance companies supported the imputation model.
Anthem says, The imputation-only model allows issuers to ll
in those gaps where diagnoses may be missing in the medical
claims data. Additional benets of the imputation-only model
include that the factors under this model tend to be more stable,
it is less susceptible to gaming of discretionary prescribing,
and it is the simplest of the four proposed approaches, which
 Prescription Drug Data Might Help Protect Obamacare

Table 1 Drug-Diagnosis Pairs Chosen for Hybrid Risk-Adjustment Models1

RXC RXC Label HCC HCC Label
Imputation/Severity
1 Hepatitis C antivirals 037C, 036, 035, 034 Chronic hepatitis C, cirrhosis of liver, end-stage liver disease, and liver transplant
status/complications
2 HIV/AIDS antivirals 001 HIV/AIDS
3 Antiarrhythmics 142 Specied heart arrhythmias
4 End-stage renal disease 184, 183, 187, 188 End-stage renal disease; kidney transplant status; chronic kidney disease,
phosphate binders stage5; chronic kidney disease, severe (stage 4)
5 Anti-inammatories for 048, 041 Inammatory bowel disease, intestine transplant status/complications
inammatory bowel disease
6a Antidiabetic agents, except 019, 020, 021, 018 Diabetes with acute complications, diabetes with chronic complications,
insulin and metformin only diabetes without complications, pancreas transplant status/complications
6b Insulin 019, 020, 021, 018 Diabetes with acute complications, diabetes with chronic complications,
diabetes without complications, pancreas transplant status/complications
7 Multiple sclerosis agents 118 Multiple sclerosis
8 Immune suppressants and 056, 057, 048, 041 Rheumatoid arthritis and specied autoimmune disorders, systemic lupus
immunomodulators erythematosus and other autoimmune disorders, inammatory bowel disease,
intestine transplant status/complications
9 Cystic brosis agents 159, 158 Cystic brosis, lung transplant status/complications
Severity Only
10 Ammonia detoxicants 036, 035, 034 Cirrhosis of liver, end-stage liver disease, liver transplant status/complications
11 Diuretics, loop and select 130, 129, 128 Congestive heart failure, heart transplant, heart assistive device/articial heart
potassium-sparing
AIDS = acquired immunodeciency syndrome; HCC = hierarchical condition category; HIV = human immunodeciency virus; RXC = drug utilization category.

has value as CMS rst introduces drug utilization into the
model. What Anthem meant was that some members come to
a health plan without any diagnoses and dont see a physician
right awayin some cases not for a long time.
However, that view was not unanimous. For example,
CareSource believes that the exible hybrid model would
be best. The CMS blessed the exible hybrid model in the
proposed rule.
Risk Adjustment in Health Insurance Is Not New
When the marketplaces went into operation in 2014, they
did so with three risk programs meant to prevent adverse
selection. Two of those (risk corridors and risk reinsurance)
expire at the end of 2016. Only the risk-adjustment program
will remain. The agency currently assigns risk scores for all
marketplace plans based on HCCs. Those scores are basically
a cumulative look at the health of a plans members, based on
medical claims data. That basically yields a statistic telling the
CMS how healthy, on average, a plans members are compared
to a baseline for other plans in the state. Healthy plans are
dunned, with that revenue distributed to less-healthy plans.
But the risk-adjustment methodology has been criticized.
Risk adjustment has been used in public programsnotably
Medicare and Medicaidsince 2004 and 1997, respectively.
The methodology the CMS uses for Medicare Advantage
is similar to the one it uses for the marketplace plans. But
there are signicant differences. For example, the Medicare
Advantage risk-adjustment model uses diagnoses from 2016
to predict 2017 costs. The HHS-HCC model uses diagnoses
from 2017 to predict 2017 costs. In Medicare Advantage, the
government uses risk adjustment to increase or decrease
the per-member payments to each plan. Payments are not
reduced or increased compared to other plans risk scores.
It is a little difcult for plans in the PPACA marketplace to
predict whether they will be making payments or receiving
payments, because that determination is based on how their
costs compare to other plans in the same state. That in turn
makes it difcult to set premiums that recoup costs and earn
the QHP a reasonable prot.
How Current Risk Assessments Work
The current PPACA risk-assessment program was estab-
lished as a means of discouraging plans from formulating
benets in a way that discouraged the less-healthy members
of the pool from joining a particular plan. That is called
adverse selection.
Diagnoses are grouped into HCCs and assigned a numeric
value that represents the relative expenditures a plan is likely to
incur for an enrollee with a given category of medical diagnosis.
If an enrollee has multiple, unrelated diagnoses (such as prostate
cancer and arthritis), both HCC values are used in calculating
the individual risk score. In addition, if an adult enrollee has
certain combinations of illnesses (such as a severe illness and
an opportunistic infection), an interaction factor is added to the
continued on page 725

Vol. 41 No. 11 November 2016 P&T 691

 The Missing Link: Evolving Accessibility
To Formulary-Related Information
Alison Van Rossum, PharmD, BCPS; Megan Holsopple, PharmD, BCPS;
Julie Karpinski, PharmD, BCPS; and Jordan Dow, PharmD, FACHE
ABSTRACT
Background: Formulary management is a key compo-
nent to ensuring the safe, effective, and scally responsible
use of medications for health systems. One challenge in the
formulary management process is making the most rele-
vant formulary information easily accessible to practitioners
involved in medication therapy decisions at the point of care.
In September 2014, Froedtert and the Medical College of
Wisconsin (F&MCW) implemented a commercial formulary
management tool (CFMT) to improve accessibility to the
recently aligned health-system formulary. The CFMT replaced
an internally developed formulary management tool.
Objectives: The primary objective was to determine
pharmacist end-user satisfaction with accessibility to system
formulary and formulary-related information through a new
CMFT compared with the historical formulary management
tool (HFMT). The secondary objective was to measure the
use of formulary-related information in the CFMT and HFMT.
Methods: The primary objective was measured through
pharmacist end-user satisfaction surveys before and after
integration of formulary-related information into the CFMT.
The secondary objective was measured by comparing monthly
usage reports for the CFMT with monthly usage reports for
the HFMT.
Results: Survey respondents reported being satised (52.5%)
or very satised (18.8%) more frequently with the CFMT
compared with the HFMT (31.7% satised and 2.5% very satis-
ed). Between October 2014 and January 2015 the frequency
of access to formulary-related information increased from
92 to 104 requests per day through the CFMT and decreased
from 47 to 33 requests per day through the HFMT.
Conclusions: Initial data suggest incorporating system
formulary-related information and related resources into a
single platform increases pharmacist end-user satisfaction and
overall use of formulary-related information.
INTRODUCTION
Hospitals and health systems have used formularies since the
1940s. Over the last seven decades, formularies have evolved
from simple medication lists into comprehensive systems of
Dr. Van Rossum, principal investigator of this project, is a
Drug Information Specialist at University of Florida Health
Jacksonville in Jacksonville, Florida. Co-investigators were
Dr. Holsopple, Pharmacist at the Center for Medication
Utilization at Froedtert and the Medical College of Wisconsin in
Milwaukee, Wisconsin; Dr. Karpinski, Coordinator of the Center
for Medication Utilization and PGY2 Drug Information Residency
Director at Froedtert and the Medical College of Wisconsin; and
Dr. Dow, Regional Director of Pharmacy at the Mayo Clinic Health
System in Eau Claire, Wisconsin.
698 P&T November 2016 Vol. 41 No. 11
medication policies that help to ensure safe, effective, and
cost-effective use of medications.1 In that time, formulary
use not only became standard practice, but a requirement for
reimbursement by the Centers for Medicare and Medicaid
Services (CMS) and accreditation by The Joint Commission.
The Joint Commission has specic requirements for manag-
ing formularies, which include making the formulary readily
available to those involved in medication management and com-
municating formulary changes to independent practitioners.2
Various methods have been used to ensure that formulary-
related information is readily accessible to health care
practitioners. Other health systems that integrated formulary-
related information into an online commercial medication
information database reported an increase in end-users accessing
formulary-related information, a decrease in formulary-related
phone calls to the pharmacy, and improved formulary manage-
ment.3 In addition, commercial databases used to centralize for-
mulary-related information, as with other online formulary man-
agement systems, allow for clear communication of changes after
each P&T committee meeting. According to physician surveys,
availability of current information is an important determinant
of physician use of online formulary-related information on a
consistent basis.4 In addition, clinical staff surveys have shown
increased satisfaction with the formulary when formulary-related
information was integrated into an online system.5,6 While
Froedtert and the Medical College of Wisconsin (F&MCW)
already utilized an online formulary management system, there
were concerns with accessibility, navigability, and general
end-user satisfaction.
F&MCW is a three-hospital health system that aligned
formularies from each site into a single, standardized system
formulary consisting of approximately 890 medications.
The health system formulary is also utilized by 28 primary
care locations and four infusion clinics across the integrated
health network. To help guide appropriate medication use,
the system formulary and related documents were stored on a
shared, homegrown intranet website (the historical formulary
management tool [HFMT]) available to health care practitio-
ners across the system. However, this intranet website was
difcult to navigate and often required end-users to look in
several places to nd relevant formulary-related information.
In addition, the HFMT was not accessible across all computer
platforms, specically at the afliated medical college, limit-
ing the information end-users could access at different health
system locations. These factors created barriers to adherence
with system guidelines, restrictions, therapeutic interchanges,
and other decision-support resources. Finally, maintaining the
system formulary and formulary-related documents using the
Disclosures: The authors report no commercial or nancial interests
in regard to this article.
 The Missing Link: Evolving Accessibility to Formulary-Related Information
GLOSSARY OF FORMULARY TERMS
End-userAny individual who uses the medication
information database and the associated tools within it.
Formulary management toolA system, generally
electronic, used to store and organize formulary-related
information.
Formulary-related informationGuidelines, policies,
and other resources approved by the P&T committee used
to guide medication use at all hospitals, clinics, pharmacies,
and associated entities across the health system.
Formulary-related resourceA single piece of formulary-
related information (e.g., guideline, policy, restriction,
therapeutic interchange).
Commercial formulary management tool (CFMT)
An online electronic formulary service within a commercial
medication information database (MID) allowing for the
integration of formulary-related information.
HFMT was labor intensive, and interoperability between the
formulary management tool and the electronic medical record
(EMR) was limited.
In September 2014, F&MCW implemented a new
commercial medication information database (MID) to assist in
formulary management and address the aforementioned issues.
The selected MID, Lexicomp, was chosen because it provided
general medication information, access to CMS-recognized
drug compendia information, represented cost savings over
the previously used MID, and had functionality to manage the
hospital formulary and formulary-related information.
Formulink, the commercial formulary management tool
(CFMT) within the MID, was anticipated to be easier to access,
navigate, and maintain than the HFMT; it also allowed end-users
to search a single online database for both formulary-related
information and general medication information. F&MCW
integrated guidelines, restrictions, therapeutic interchanges,
and other formulary-related information along with general
medication information into the CFMT based on a pharma-
cist workgroup survey. In addition, the MID met CMS inter-
operability criteria for meaningful use.7 Meeting these criteria
indicates the software is able to exchange data with the system
EMR in a way that both systems understand the structure and
content of the exchanged information. MID interoperability
can be used to enhance accessibility to formulary-related
information and general medication information from the EMR.8
The primary objective of this project was to determine
pharmacist end-user satisfaction with accessibility to system
formulary and formulary-related information through integra-
tion of formulary-related information into a single-platform
CFMT. The secondary objective was to measure how frequently
formulary-related information was accessed in the database
compared with the HFMT.
METHODS
No patients were enrolled and patient data was not used in
this descriptive project focused on formulary management
optimization. Data collection, analysis, and reporting occurred
from September 1, 2014, to January 31, 2015. Both the CFMT
and HFMT were simultaneously updated and available to
Health system formularyA single comprehensive list
of P&T committee-approved formulary medications, available
formulations, and associated restricted use criteria for use
at all hospitals, clinics, pharmacies, and associated entities
across the health system.
Information management systemThe editing tool
within the CFMT allowing for customization of hospital
and health system formulary-related information. Allows
content facilitators to easily incorporate information
from the database, add relevant Web links, and build
customized headers for convenient access to formulary-
related information.
Medication information database (MID)A
resource that contains general medication information
(e.g., indications, dosing, adverse effects, pharmacokinetics).
Pharmacist end-userAny pharmacist who uses the
MID and the associated tools within it.
end-users during this time period, allowing the authors to
compare frequency of use for each formulary management
tool when end-users could choose between systems. The
primary objective of this project was measured through pre- and
post-CFMT implementation surveys of pharmacist end-users.
The secondary objective was measured using monthly action
reports of both the CFMT and HFMT. Monthly reports included
the number of times per month F&MCW formulary-related
information was accessed.
Prior to conversion to the new MID and CFMT in
September 2014, end-users were notied of the upcoming
change and were encouraged to attend staff meetings in
which F&MCW faculty demonstrated how to navigate the
new systems. Similar demonstrations for navigating the HFMT
had been given to end-users in the past. With the new MID and
CFMT, staff were also provided with temporary trial access
prior to full integration to become more familiar with the tools
in their daily workows. Links to both the CFMT and HFMT
were available in the EMR at the point of order entry and on
the medication administration record to enhance accessibility
to formulary-related information. This allowed end-users to
review formulary-related information through either system
at the point of order entry or medication administration. The
CFMT provided advanced linking in the EMR by allowing direct
access to a specic formulary medication while the HFMT
could only link to the formulary, not a specic medication. The
HFMT link in the EMR had been available prior to conversion
to the new MID and CFMT and remained available until the
HFMT was formally discontinued at the end of January 2015.
In September 2014, the new MID and CFMT became
available to all health care professionals across the F&MCW
system. Initially, formulary-related information available in
the CFMT was limited to a formulary list, available dosage
forms, medication restrictions, and limited hyperlinks to other
F&MCW online resources. During the course of this project,
other key formulary-related resources were integrated into
the CFMT.
The initial survey was distributed to pharmacist end-users
in September 2014 to assess satisfaction with the HFMT with
a follow-up survey distributed in February 2015 to assess
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 The Missing Link: Evolving Accessibility to Formulary-Related Information
satisfaction with the CFMT. Both surveys were voluntary, asked how long it took to locate formulary-related information
electronically distributed, and remained open for two weeks. using each tool, 20.3% reported an estimated formulary-related
Information collected through the surveys included overall information search time of less than one minute using the
satisfaction with accessibility to the formulary, self-perceived HFMT, while 42.5% of survey respondents reported a search
time to search for formulary-related information, and the time of less than one minute using the new CFMT. However,
frequency of accessing formulary-related information. In addi- for both formulary management tools, the most commonly
tion, all information provided in the surveys was anonymous, reported range of time to locate formulary-related information
and feedback was used to prioritize integration of key formulary- was one to two minutes. See Figure 1 and Figure 2 for further
related information into the CFMT. Monthly usage reports details on survey responses.
were collected for both the HFMT and the CFMT between All end-users accessed formulary-related informa-
September 1, 2014, and January 31, 2015. tion more frequently through the CFMT than the HFMT.
Formulary denitions can be ambiguous, vary among Between September 1, 2014, and January 31, 2015, end-users
accrediting and national organizations, and may be applied dif- accessed the formulary-related information using the HFMT
ferently depending on clinical practice models.2,8 A summary 6,493 times and the CFMT 16,319 times (P < 0.0001). See
of denitions used in this project is provided in the Glossary Figure 3 for additional details on how often formulary-related
of Formulary Terms. information was accessed. Survey responses also contained
self-reported increases in frequency of access to formulary-related
DATA ANALYSIS information through the new CFMT when compared with the
Descriptive statistics were used to report end-user satisfac- HFMT. Survey results indicated 39.2% of respondents accessed
tion and monthly usage of the CFMT and HFMT. A chi-square formulary-related information at least weekly through the
test was used to compare the frequency with which formulary- HFMT while 62.5% accessed formulary-related information at
related information was accessed in each formulary manage- least weekly through the CFMT. In addition, survey respon-
ment tool between September 1, 2014, and January 31, 2015. dents reported daily access to formulary-related information
Other outcomes were reported using descriptive statistics. more frequently using the new CFMT (27.5%) compared with
the HFMT (11.4%).
RESULTS
The initial satisfaction survey of pharmacist end-users at DISCUSSION
F&MCW had 79 responses, and the follow-up survey had When F&MCW transitioned to the new CFMT, it created a
80 responses. The majority of survey responders in both the more accessible, user-friendly platform for accessing formulary-
pre- and post-implementation surveys were inpatient decentral- related information. The results of this project indicate that
ized pharmacists (49.4% and 51.3%) and outpatient ambulatory end-users were more satised with accessibility of information
care pharmacists (29.1% and 21.3%). Additional characteristics through the new CFMT compared with the HFMT. The results
of the survey respondents are detailed in Table 1. also show that formulary-related information was accessed
Survey respondents reported being satised (52.5%) or very more frequently through the new CFMT. The increased
satised (18.8%) more frequently with the new CFMT compared satisfaction with accessibility and increased frequency of access
with the HFMT (31.7% satised and 2.5% very satised). When to formulary-related information demonstrate the benets
of using a single location to house key formulary-related
Table 1 Survey Respondent Characteristics information. Similar results were reported at another tertiary
medical center that used the same MID and CFMT system
Characteristic Initial Survey Follow-Up Survey and historically used a similar intranet page to communicate
(N = 79) (N = 80) formulary information.5 At the tertiary medical center, the
n (%) n (%) formulary was available through the CFMT, and institutional
Primary Area of Pharmacy Practice policies and guidelines were available only on the intranet.5
Following integration of three key formulary policies into
Outpatient retail 4 (5.1) 5 (6.2)
the CFMT, 20% of pharmacy staff reported medication man-
Outpatient ambulatory 23 (29.1) 17 (21.3) agement information was much easier to access, and 50%
Inpatient central 7 (8.8) 8 (10.0) reported access as somewhat easier.5 In addition, 50% of phar-
macy staff respondents reported increased satisfaction with
Inpatient decentral 39 (49.4) 41 (51.3)
the online formulary after policy integration.5 A ve-hospital
Administration 6 (7.6) 9 (11.2) health system also found improved satisfaction from staff after
Years at Froedtert and the Medical College of Wisconsin integrating formulary informationincluding therapeutic
interchanges, drug policies, shortages, and clinical informa-
Less than 1 year 15 (19.0) 15 (18.8) tion pertaining to the system formularyinto a single online
1 to 3 years 26 (32.9) 22 (27.5) location using a commercial formulary management system.6
4 to 6 years 10 (12.7) 14 (17.5) However, that study did not indicate whether staff included
all clinical staff or pharmacy staff only.6
7 to 10 years 11 (13.9) 12 (15.0) There was improved satisfaction and more frequent use
11 years or more 17 (21.5) 17 (21.2) of the new formulary management tool at F&MCW through-
out the course of the project, despite a transitional period

700 P&T November 2016 Vol. 41 No. 11

 The Missing Link: Evolving Accessibility to Formulary-Related Information
interchanges, were incorporated
Figure 1 Pharmacist End-User Satisfaction With New and Historical Formulary Management Tool into the new CFMT either upon
implementation or soon after
45 implementation, it was not pos-
42
sible to incorporate all pieces of
40
formulary-related information
35 immediately. Ongoing system
alignment projects, such as medi-
30 cation treatment guidelines and
Number of responses

28
collaborative practice agreements,
25
25 will result in a continued need
to incorporate formulary-related
20 resources into the CFMT. With
16 16 15 these updates and as end-users
15 become more familiar with the
CFMT, continued satisfaction
10 8 with access to formulary-related
4
information is expected.
5 3
2 When selecting groups to survey
0 regarding satisfaction with access to
Never use it Not satised Neutral Satised Very satised formulary-related information, only
pharmacists were chosen rather
than all end-users (e.g., physicians,
Historical formulary management tool (N = 79) Commercial formulary management tool (N = 80)
nurses). It was determined that
pharmacists would be the most fre-
quent users of the formulary man-
Figure 2 Pharmacist End-User Time to Complete A Single Formulary-Related Information Search agement tool and that surveying
40
other end-users would not provide
38 as much benecial information.
35
35 When considering how to
34
present information through the
30
new CFMT, there were two primary
28 options. One option was to create
Number of responses

25
formulary-related resources in
the new CFMT. These resources
20
would be developed directly in the
information management system of
16
15
the MID. The second option was to
incorporate direct links to formulary-
10
related resources into the new
8 CFMT. Both options enable end-
5
users to connect quickly to formulary-
related resources utilizing the
0
CFMT.
Less than 1 minute 1 to 2 minutes 3 minutes or greater The advantages and disadvan-
tages of each option were evalu-
ated. Developing all content directly
Historical formulary management tool (N = 79) Commercial formulary management tool (N = 80)
in the CFMT using the informa-
tion management system allows
for information to be located and
that required end-users to access both tools. There were updated in a single location. However, creating and maintain-
reports of dissatisfaction and difculty locating necessary ing these resources could only be done by super-users with
information following implementation of the CFMT. editing access. In addition, this method would have required
However, it is unknown if dissatisfaction was related to all existing formulary-related resources to be recreated in the
the CFMT itself, certain formulary-related information CFMT. Using the Web links function in the CFMT to interface
still being located on the HFMT and other intranet sites, with an intranet site allowed use of existing documents and
or staff member lack of participation in pre- and post- allowed content experts to develop and update documents
implementation education. Although key formulary-related that super-users could then link to specic medications in
information, such as formulary restrictions and therapeutic the CFMT. However, this method required formulary-related

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 The Missing Link: Evolving Accessibility to Formulary-Related Information
contained the desired information.
Figure 3 Frequency of Access to New and Historical Formulary Management Tools This increased awareness may
account for the decrease in fre-
4,500 quency of access to the CFMT in
subsequent months. In addition, the
4,000
4,186 number of end-users could theoreti-
cally have increased after the con-
Number of times accessed per month

3,500
3,000
2,860 2,906
2,500
2,000
1,500
1,656
1,401
1,326
1,000
500
0 basis, the individuals accessing the
September 1, 2014 October 1, 2014 November 1, 2014 December 1, 2014
Commercial formulary management tool
information to be located on the intranet site that was then
linked in the CFMT, thus making the information available in
two locations. A mix of both options was utilized when inte-
grating information into the CFMT; however, the majority of
content is supported by the Web links option. A process for
updating the CFMT and intranet sites is in place to ensure
consistency of content and hyperlinks between both locations.
LIMITATIONS
A potential limitation of the project was the lack of historical
information on how frequently formulary-related information was
accessed when only the HFMT was available. The authors were
unable to obtain this baseline data due to software limitations in
the historical tool, and as a result could not compare how fre-
quently formulary-related information was accessed before and
after the new CFMT was implemented. However, the frequency of
access to each tool when both tools were available was evaluated
to determine which resource end-users would select when given
an option. End-users accessed the CFMT more frequently than
the HFMT when both were available and linked in the EMR. This
suggests the new tool was more user-friendly and had a greater
potential for making important information available to front-line
staff. However, the frequency of access to the new CFMT may
have been increased due to searches within the MID. When a
medication is searched in the MID and the medication is on the
F&MCW formulary, the link at the top of the list leads to the
CFMT containing F&MCW formulary-related information for
that particular medication. This may be specically reected in
the higher frequency of access to the CFMT in the rst month
it was available. However, each link indicates whether it leads
to the CFMT containing F&MCW information or to the MID
general medication monograph. As end-users learned which links
led to the F&MCW formulary-related information and which to
the monographs, they were presumably conscious of which link
version because the HFMT was not
3,280 accessible in all locations associated
3,087
with F&MCW. However, it appears
more likely that there were the same
number of total users before and
after the conversion with expanded
accessibility at the afliated medical
college after the conversion. An
incidental nding during this project
1,085 1,025 showed that, while the historical tool
was being accessed on a regular
January 1, 2015 HFMT most frequently were those
updating the resources located there.
Historical formulary management tool In another potential limitation
of this project, compliance was not
measured with system formulary,
policies, and guidelines before and
after the new formulary management tool was implemented. This
analysis was not completed because conversion to the new CFMT
impacted all formulary medication, policies, and guidelines, and it
was not feasible to measure compliance with all resources before
and after the conversion. Potential metrics for compliance could
include frequency of nonformulary medication use or frequency
with which criteria for medication use were met; however, these
metrics were not formally tracked prior to conversion. In addition,
concurrent updates in other systems could confound compliance
data. For example, therapeutic interchanges were standardized
and integrated into the new CFMT and, at the same time, updated
in the EMR. Assessing compliance with therapeutic interchanges
before and after use of the CFMT would be confounded by the
fact that the same information was made available in the EMR.
In addition, therapeutic interchanges were updated to align
across the system, which added some therapeutic interchanges
and removed others at each sitemaking a before-and-after
comparison unreliable. There was also lack of initial data on
compliance with existing formulary-related resources prior to
the formulary management tool conversion. However, data from
previous studies indicate that provider accessibility to formulary-
related information increases compliance with use of formulary
medications and guidelines.4,9,10 Using these data, it is likely
that as more resources are incorporated into a single formulary
management tool, compliance with system restrictions, policies,
and guidelines may improve.
CONCLUSION
Incorporating system formulary-related information and
related resources into a single accessible platform increased
pharmacist end-user satisfaction with accessibility and overall
access to formulary-related information.
continued on page 725

702 P&T November 2016 Vol. 41 No. 11

 Pharmacological Management and Prevention
Of Exacerbations of Chronic Obstructive
Pulmonary Disease in Hospitalized Patients
Deepali Dixit, PharmD, BCPS; Mary Barna Bridgeman, PharmD, BCPS, CGP;
Rani Patel Madduri, PharmD, BCPS, AAHIVP; Samir T. Kumar, MD Candidate; and
Michael J. Cawley, PharmD, RRT, CPFT, FCCM
Keywords: chronic obstructive pulmonary disease (COPD),
acute exacerbations, bronchodilators, systemic steroids
INTRODUCTION
Chronic obstructive pulmonary disease (COPD) is
characterized by chronic airow limitation and airway inam-
mation that is not fully reversible and is progressive in nature.1
COPD is the third-leading cause of death and a considerable
cause of disability in the United States.2 In 2011, an estimated
13.7 million Americans had been diagnosed with COPD.2
The disease led to 10.3 million ofce visits, 1.5 million emer-
gency department (ED) visits, and 699,000 hospitalizations in
2010.2 The economic burden continues to rise; approximately
$50 billion was spent in 2010, including $20 billion in indirect
costs and $30 billion in direct health care costs.3 A signicant
portion (50% to 70%) of the direct health care costs related
to COPD are attributed to exacerbations.1,3 A recent report
indicated an increase in cost with each COPD readmission,
ranging from $8,400 to $11,100 based on principal diagnosis
and all-cause COPD readmissions, respectively.3
The overall goals of COPD management are to optimize
pulmonary function, to prevent progression, to improve quality
of life, and to prevent and reduce the frequency and severity
of exacerbations.1
An exacerbation of COPD is dened as an event in the
natural course of the disease characterized by a change in
the patients baseline dyspnea, cough, and/or sputum that is
beyond normal day-to-day variations; is acute in onset; and may
require a change in medication regimen.1 The most common
etiologies of COPD exacerbations are bacterial and viral infec-
tions. Air pollutants, cigarette smoke, and noncompliance
with medication can also result in exacerbations, although the
cause is never identied in about one-third of exacerbations. At
Dr. Dixit is a Clinical Assistant Professor at the Ernest Mario School
of Pharmacy at Rutgers University in Piscataway, New Jersey, and
a Critical Care Specialist at Robert Wood Johnson University
Hospital in New Brunswick, New Jersey. Dr. Bridgeman is a Clinical
Associate Professor at the Ernest Mario School of Pharmacy at
Rutgers University and an Internal Medicine Clinical Pharmacist at
Robert Wood Johnson University Hospital. Dr. Madduri is Clinical
Coordinator of Pharmacotherapy and Infectious Diseases at
Hunterdon Medical Center in Flemington, New Jersey.
Mr. Kumar is an MD Candidate at the American University of
Antigua in New York, New York. Dr. Cawley is a Professor of Clinical
Pharmacy and Vice-Chair of the Department of Pharmacy Practice and
Administration at the Philadelphia College of Pharmacy at the
University of the Sciences in Philadelphia, Pennsylvania.
present, exacerbations are diagnosed based upon the patients
clinical presentation.
The three cardinal symptoms of COPD exacerbation are
increased dyspnea, cough, and purulent sputum production.1
The frequency and severity of exacerbations are among
the factors that determine the prognosis of COPD. Exacerbations
become more frequent and severe as COPD severity
increases (Table 1).1 It is estimated that patients with
moderate COPD experience an average of 1.3 exacerbations
per year; those with severe COPD experience an average of
two exacerbations per year.4 The risk of exacerbations varies
greatly among patients. Recent trials have identied several
risk factors for exacerbations (Table 2).5,6 It is critical to iden-
tify patients at risk for frequent exacerbations and to prevent
associated hospital readmissions; this has implications for
targeting of exacerbation-prevention strategies across the
spectrum of disease severity.57
Pharmacological management of an acute exacerbation
of COPD (AECOPD) includes rapid-acting bronchodilators;
systemic corticosteroids; and, in select patients, antimicrobials.
The goals of therapy are prevention of hospitalization or reduc-
tion in length of hospital stay, prevention of acute respiratory
failure and mortality, resolution of exacerbation symptoms,
and resumption of baseline clinical status and quality of life.
Recommended strategies for preventing AECOPD include
selection of and adherence to optimal pharmacological therapy,
smoking cessation, pulmonary rehabilitation, and inuenza
and pneumococcal vaccination.1
As part of its Hospital Readmissions Reduction Program, the
Centers for Medicare and Medicaid Services in 2015 began
measuring all-cause readmissions for patients hospitalized
for AECOPD, in addition to heart failure, acute myocardial
infarction, and pneumonia; hospitals are penalized for excess
unplanned 30-day readmissions for exacerbations of COPD.8
However, according to the 2015 American College of Chest
Physicians (ACCP) and Canadian Thoracic Society (CTS)
guidelines, hospitals currently have little guidance on how to
reduce readmissions related to COPD. The 30-day readmission
rate may be reduced by pharmacist involvement in transitions
of care, medication reconciliation, patient counseling, tracking
outpatient adherence, and postdischarge outpatient follow-up.7
This review highlights ndings from the recent body of
evidence on pharmacological interventions, including broncho-
dilators, corticosteroids, antibiotics, and preventive strategies
for AECOPD.
Disclosures: The authors report no commercial or nancial interests
in regard to this article.
Vol. 41 No. 11 November 2016 P&T
703
 Management and Prevention of Exacerbations of COPD in Hospitalized Patients
Table 1 Model of Symptom/Risk Evaluation of COPD1
When assessing risk, choose the highest risk according to GOLD grade or exacerbation history. One or more hospitalizations for COPD
exacerbations should be considered high risk.

2 or
4 1 leading to
hospital admission

(exacerbation history)
(C) (D)
of airow limitation)
(GOLD classication

Risk
Risk

1 not leading to
2 hospital admission
(A) (B)
1

CAT < 10 CAT 10

Symptoms
mMRC 01 mMRC 2
Breathlessness

Patient Characteristic Spirometric Exacerbations CAT mMRC

Category Classication Per year Score Score
A Low risk, less symptoms GOLD 12 1 < 10 01
B Low risk, more symptoms GOLD 12 1 10 2
C High risk, less symptoms GOLD 34 2 < 10 01
D High risk, more symptoms GOLD 34 2 10 2
CAT = COPD Assessment Test; COPD = chronic obstructive pulmonary disease; GOLD = Global Initiative for Chronic Obstructive Lung Disease;
mMRC = Modied Medical Research Council Dyspnea Scale

PHARMACOLOGICAL TREATMENT Delivery of bronchodilators during AECOPD via metered-

Bronchodilators
Bronchodilator therapy is considered to be one of the corner-
stones of treating COPD exacerbation. In stable COPD, inhaled
antimuscarinic agents and beta2 agonists are often used in
combination on either a scheduled and/or as-needed basis for
symptom management. Long-acting inhaled bronchodilators,
such as tiotropium and salmeterol, offer minimal advantages
in AECOPD, with limited published data to support their use;
frequently dosed short-acting inhaled bronchodilators are
generally used instead. Beta agonists onset of action is faster
than antimuscarinics with a marginally shorter duration of
action. To date, studies have not demonstrated a difference in
efcacy between these two classes of drugs; treatment is usually
initiated with beta agonists because of their faster onset, with
antimuscarinics added if beta agonist monotherapy results in
an inadequate response.1,9 Furthermore, trials have shown
that beta2 agonists provide benets similar to antimuscarinic
agents with regard to change in forced expiratory volume of
air in one second (FEV1); however, optimal doses for AECOPD
have yet to be established.9 Bronchodilator dosing during
AECOPD includes increasing the dose and/or frequency
(every two to four hours) and utilizing combination therapy
to optimize symptomatic relief (Table 3).10,11
dose inhalers with a spacer/holding chamber is considered
equivalent to nebulization. Several factors, such as patient
preference, disease severity, and ability and willingness to
comply with instructions and technique, usually guide the
choice of delivery method. According to the recent guide-
lines, methylxanthines are considered second-line therapy
for AECOPD management due to signicant side effects
and a narrow therapeutic window. Methylxanthines may be
considered in patients with insufcient response to inhaled
short-acting bronchodilators.1
Corticosteroids
Systemic corticosteroids (sCS) have been shown to improve
symptoms and lung function (FEV1), reduce risk of treatment
failure and relapse, and reduce the length of hospitalization,1,12,13
although there is a lack of benet in reduction of mortality rate
related to COPD exacerbation.1,12,13 To date, studies suggest
that lower-dose corticosteroids and shorter treatment duration
are associated with a lower incidence of treatment failures and
a lower rate of side effects.1214 The Global Initiative for Chronic
Obstructive Lung Disease (GOLD) guidelines recommend oral
prednisone 40 mg daily for ve days, based on the ndings
from an observational analysis and the Reduction in the Use
of Corticosteroids in Exacerbated COPD (REDUCE) trial.1,12,13

704 P&T November 2016 Vol. 41 No. 11

 Management and Prevention of Exacerbations of COPD in Hospitalized Patients
in hospitalized patients for AECOPD,14,15 a recent retrospective
Table 2 Risk Factors for Exacerbations5,6
cohort study suggests that patients admitted to the ICU for
Frequent exacerbator phenotype (this group of patients is AECOPD are managed with higher doses of sCS than inpatient
susceptible to exacerbations, irrespective of disease severity) non-ICU patients, predisposing them to potential side effects
Older age without a clear benet. Side effects associated with cumula-
Poor health status tive high-dose sCS include muscle weakness, myopathy, sleep
disturbances, immune suppression, tremors, susceptibility to
Past history of hospitalized exacerbation infections, hyperglycemia, and other metabolic disorders.16
Severe airow limitation Clinicians should consider the risks and benets of prescribing
More severe depression and poorer cognition high doses of sCS in ICU patients with AECOPD.
Only a few randomized clinical trials have evaluated the
Greater inammation
efcacy of sCS in patients with AECOPD requiring venti-
Bacterial colonization of lower airways lator support.17,18 A prospective, randomized controlled trial
Presence of system disease/comorbidities was conducted that included 217 patients with severe COPD
Radiological evidence of emphysema exacerbations requiring ventilator support.18 Study investigators
compared open-label use of prednisone 1 mg/kg per day (oral or via
Increased pulmonary artery diameter
enteral tube) for a maximum of 10 days or usual care. The primary
Prior history of asthma endpoint was ICU mortality, and secondary endpoints were days
on ventilator support and ICU length of stay
Table 3 Bronchodilator Dosing10,11 (LOS). The results showed no signicant
differences between the prednisone versus
Agent Metered-Dose Inhaler Nebulizer
the usual care groups in ICU mortality
Albuterol 48 puffs every 30 minutes up to 2.55 mg every 20 minutes for (15% versus 14%; P = 0.81), median
4 hours, then every 14 hours as 3doses, then 2.510 mg every duration of ventilation (six days versus
needed 14hours as needed, or 1015mg six days; P = 0.87), noninvasive ventila-
per hour continuously tion failure (16% versus 13%; P = 0.59), or
Terbutaline Same as albuterol N/A ICU LOS (nine days versus eight days;
P = 0.88). Insulin treatment for manag-
Levalbuterol 48 puffs every 20 minutes up to 0.631.25 mg at the same dosing ing hyperglycemia was significantly
4 hours, then every 14 hours as frequency as albuterol higher in patients receiving prednisone
needed (50% versus 33%; P = 0.01). The results
Ipratropium 48 puffs as needed 0.5 mg every 30 minutes for 3 doses, suggest that prednisone did not exhibit a
then every 24 hours as needed reduction in ICU mortality rate or patient-
centered outcomes.
The REDUCE trial was a prospective, randomized, non- Although the studies above offer insight into efcacy and
inferiority, multicenter study that included 314 patients with a treatment regimens for critically ill patients with AECOPD,
mean age of 69 years; more than 50% of the participants in both immediate change in clinical practice seems unlikely based on
groups (prednisone 40 mg daily for ve days or for 14 days) these ndings due to the small, retrospective, observational
had moderate-severity disease (GOLD stage IV), and many nature of the studies.
of the patients had experienced prior exacerbations.14 The Recently a multicenter, retrospective, observational cohort
primary endpoint was time to next COPD exacerbation within study evaluated the efcacy and safety of lower versus higher
six months. The investigators found that a ve-day course of doses of corticosteroids in critically ill patients with AECOPD.15
prednisone 40 mg daily was noninferior to a 14-day course The trial included 17,239 patients (77% of them more than
with respect to re-exacerbation within six months. In light 60 years of age) using a quality and health care utilization
of the recent robust body of evidence, it appears that the database from 400 U.S. hospitals between 2003 and 2008.
optimal corticosteroid regimen in hospitalized patients may Patients were included if they were admitted with a diagnosis
be a low-dose, short course of oral prednisone 40 mg per day of AECOPD and received oral or intravenous (IV) sCS within
for ve days, concurrently reducing the risks associated with the rst two days of admission. The study subjects were split
steroid exposure. into two groups according to the dosing regimen: high dose
In contrast, the body of evidence supporting the efcacy (more than 240 mg per day methylprednisolone equivalent) and
and safety of sCS among critically ill patients with AECOPD low dose (240 mg per day or less methylprednisolone equiva-
on mechanical ventilation is scant. Nearly all studies have lent). The primary endpoint was hospital mortality; secondary
excluded patients requiring mechanical ventilation or intensive endpoints were ICU LOS, hospital LOS, and total hospital costs.
care unit (ICU) admission for AECOPD, leading to uncertainty Patients were matched by propensity scoring. The analysis
as to whether the results from the aforementioned studies are included 11,083 (64%) in the high-dose group and 6,156 (36%)
applicable to patients on mechanical ventilators. However, in the low-dose group. Though there was only a trend toward
extrapolation of data from non-ICU AECOPD has led to sCS reduction in hospital mortality in the low-dose group (P = 0.06),
use in critically ill patients with AECOPD. Despite evidence the lower dose was associated with a decrease in hospital LOS
demonstrating that higher doses are not superior to lower doses (P < 0.01), ICU LOS (P < 0.01), hospital costs (P = 0.01), length

Vol. 41 No. 11 November 2016 P&T

705
 Management and Prevention of Exacerbations of COPD in Hospitalized Patients
of invasive ventilation (P = 0.01), insulin therapy (22.7% in the
low-dose group versus 25.1% in the high-dose group; P < 0.01),
and fungal infections (3.3% in the low-dose group versus 4.4%
in the high-dose group; P < 0.01). Even though this study did
not ascertain the optimal dose, route of administration, or
duration of sCS therapy in critically ill patients, study ndings
suggest that lower doses of steroids (no more than 240 mg
per day methylprednisolone equivalent) should be promoted
for patients in the ICU for AECOPD until future clinical trials
delineate the optimal dosing regimen.
Despite study limitations, the results from these trials are
noteworthy and offer some insight into steroid treatment for
critically ill patients, especially because none of the guidelines
or systematic reviews provide guidance on dosing and dura-
tion of sCS therapy in patients with exacerbations requiring
ventilator support. In light of recent publications, it appears
that the evidence weighs against the practice of using high
doses of sCS in patients with AECOPD requiring mechanical
ventilation. Large randomized clinical trials comparing the
safety and efcacy of high-dose versus low-dose steroids are
required to determine the most effective dosing regimen to
manage patients with severe AECOPD. Owing to sCSs excel-
lent bioavailability, ease of administration, lower costs, and
similar efcacy in head-to-head equivalence trials of oral versus
IV sCS, oral sCS should be used in the inpatient management
of AECOPD when oral or enteral feeding tube administration
is feasible.19,20
As an alternative to sCS, nebulized corticosteroids have
minimal bioavailability, absorption, and systemic adverse
effects. The GOLD guidelines recommend nebulized
budesonide as an alternative to oral corticosteroids for the
treatment of AECOPD.1 Only a few nonblinded studies have
examined nebulized corticosteroids in AECOPD. Investigators
compared 4 mg to 8 mg of nebulized budesonide with various
doses of oral or IV prednisolone.21,22 The results showed no
difference between the groups, and interpretation was hin-
dered by small sample sizes, heterogeneous populations, and
exclusion of severe exacerbation. Larger studies are needed
to conrm the long-term impact of clinical outcomes, optimal
agent, and dosage of nebulized corticosteroids for AECOPD.
Antibiotics
Utilization of antibiotics in COPD exacerbations remains
a part of management, despite overestimation of bacteria
in older studies and newer evidence of viruses as causative
pathogens. More recent studies with improved study design
and methodology estimate that only 50% of exacerbations
have a bacterial source.23 At least a third of cases are caused
by viruses, including inuenza, parainuenza, respiratory
syncytial virus, human metapneumonia virus, picomaviruses,
and coronavirus.2325
Nevertheless, COPD guidelines recommend empiric anti-
biotic treatment in certain patient populations, particularly in
patients with moderate-to-severe exacerbations.1 This determi-
nation is characterized by presence of the Anthonisen criteria
of increased sputum purulence and at least one of the follow-
ing: increased dyspnea and increased sputum volume.1,26
Employment of this classication to initiate therapy in patients
with moderate-to-severe exacerbations is largely based on a
706 P&T November 2016 Vol. 41 No. 11
systematic review by Ram et al.27 In this evaluation, antibiotics
showed a decrease in short-term mortality by 77%, treatment
failure by 53%, and sputum purulence by 44%.
Production of purulent versus mucoid sputum is indicative
of patients who will benet from antibiotics as determined by
Stockley et al. In their study, purulent sputum resulted in posi-
tive bacterial cultures in 84% of patients, compared with 38%
of those producing mucoid sputum (P < 0.0001). The former
was found to be 94.4% sensitive and 77% specic for the yield
of high bacterial load. When evaluating resolution, all patients
with mucoid sputum improved without antibiotic treatment.28
Utilization of sputum purulence as a cornerstone in the deci-
sion to initiate antibiotics is not entirely reliable. Patients may
not routinely assess expectorated sputum, and the appearance
may change quickly. In a study by Daniels et al., sputum colors
reported by patients were compared to those assessed using
a validated color chart as markers for bacterial load and sys-
temic inammation. The sensitivity and specicity for reported
sputum color were 73% and 39% respectively, compared to 90%
and 52% in assessed sputum, indicating that patient-reported
color was unreliable.29
Biomarkers have been identied as a means of determining
etiology of COPD exacerbations in addition to playing a role
in diagnosing and assessing severity.30 Most recently, the
COPD Biomarker Qualication Consortium received Food
and Drug Administration approval for plasma brinogen as a
COPD biomarker.31 Pertaining to infection-related biomarkers,
procalcitonin is utilized as a marker of sepsis due to bacteria.
As it is an indicator of systemic bacterial infection, it can there-
fore be employed to identify exacerbations caused by such
pathogens to determine if antibiotics should be administered.
This was evaluated by Stolz et al., who randomized patients
into standard-care or procalcitonin-guided treatment groups.32
Antibiotic use in patients with procalcitonin levels up to
0.1 mcg/L was discouraged. Levels between 0.1 and 0.25 mcg/L
indicated a possible bacterial infection, and antibiotic treat-
ment was to be based upon clinical condition. In patients with
procalcitonin levels greater than 0.25 mcg/L, antibiotic use
was strongly supported. The study indicated no difference in
clinical success, hospital LOS, and ICU LOS despite decreased
use of antibiotics in patients with low procalcitonin levels.
Furthermore, when patients were evaluated at six months,
there were no statistically signicant differences in exacerbation
rates, rehospitalization rates, and time to next exacerbation.
Procalcitonin has also been studied in assessing treatment
response. In a systematic review of 14 trials, Schuetz et al.
evaluated the effect of using a procalcitonin algorithm to guide
initiation and discontinuation of antibiotics in acute respiratory
tract infections.33 In this analysis, there was no statistically sig-
nicant difference in treatment failure or mortality at 30 days
when procalcitonin was used to guide initiation and duration of
antibiotic treatment. Furthermore, mean duration of antibiotic
exposure was 34.8% lower in the procalcitonin group com-
pared with the standard-care group (95% condence interval
[CI], 40.3 to 28.7).
If antibiotics are initiated in patients with COPD exacer-
bations, the regimen should be based upon severity, likely
pathogens, and local susceptibility patterns.1 While cultures
may be drawn, therapy is generally empiric. Common bacterial
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tear composition.1-4

Diagnosing DED is complex.5

Symptoms of DED are among the most common patient
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Indication
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Xiidra (litegrast ophthalmic
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Important Safety Information

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

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

To learn more, visit xiidra.com. Marks designated and are owned by Shire or an affiliated company.

+8
Rx Only
BRIEF SUMMARY:
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HQNFVJGJWOCPRNCUOCGZRQUWTGCV
RTQFWEVKPHQTOCVKQP
HQNFVJGJWOCP
INDICATIONS AND USAGE
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HQTVJGVTGCVOGPVQHVJGUKIPUCPFU[ORVQOUQHFT[G[G
FKUGCUG
&'&
01#'.YCUPQVKFGPVKGFKPVJGTCDDKV
DOSAGE AND ADMINISTRATION
+PUVKNNQPGFTQRQH:KKFTCVYKEGFCKN[
CRRTQZKOCVGN[ 6JGTGCTGPQFCVCQPVJGRTGUGPEGQHNKVGITCUVKPJWOCP
JQWTUCRCTVKPVQGCEJG[GWUKPICUKPINGWUGEQPVCKPGT
Discard the single use container immediately after using
KPGCEJG[G%QPVCEVNGPUGUUJQWNFDGTGOQXGFRTKQTVQ
the administration of Xiidra and may be reinserted 15
minutes following administration.
ADVERSE REACTIONS
Clinical Trials Experience
Because clinical studies are conducted under widely
varying conditions, adverse reaction rates observed in
ENKPKECNUVWFKGUQHCFTWIECPPQVDGFKTGEVN[EQORCTGF
to rates in the clinical trials of another drug and may
PQVTGGEVVJGTCVGUQDUGTXGFKPRTCEVKEG+PXGENKPKECN
UVWFKGUQHFT[G[GFKUGCUGEQPFWEVGFYKVJNKVGITCUV
QRJVJCNOKEUQNWVKQPRCVKGPVUTGEGKXGFCVNGCUV
FQUGQHNKVGITCUV
QHYJKEJTGEGKXGFNKVGITCUV
6JGOCLQTKV[QHRCVKGPVU
JCFOQPVJUQH NONCLINICAL TOXICOLOGY
VTGCVOGPVGZRQUWTGRCVKGPVUYGTGGZRQUGFVQ
NKVGITCUVHQTCRRTQZKOCVGN[OQPVJU6JGOCLQTKV[
QHVJGVTGCVGFRCVKGPVUYGTGHGOCNG
6JGOQUV VQFGVGTOKPGVJGECTEKPQIGPKERQVGPVKCNQHNKVGITCUV
EQOOQPCFXGTUGTGCEVKQPUTGRQTVGFKPQHRCVKGPVU
were instillation site irritation, dysgeusia and reduced
XKUWCNCEWKV[1VJGTCFXGTUGTGCEVKQPUTGRQTVGFKP
VQQHVJGRCVKGPVUYGTGDNWTTGFXKUKQPEQPLWPEVKXCN
J[RGTGOKCG[GKTTKVCVKQPJGCFCEJGKPETGCUGF
NCETKOCVKQPG[GFKUEJCTIGG[GFKUEQOHQTVG[GRTWTKVWU
and sinusitis.
+8FQUGUQHWRVQOIMIFC[
HQNFVJGJWOCPRNCUOCGZRQUWTGCVVJG
USE IN SPECIFIC POPULATIONS
4*1&QH
Pregnancy
6JGTGCTGPQCXCKNCDNGFCVCQP:KKFTCWUGKPRTGIPCPV
women to inform any drug associated risks. Intravenous
+8CFOKPKUVTCVKQPQHNKVGITCUVVQRTGIPCPVTCVUHTQO
RTGOCVKPIVJTQWIJIGUVCVKQPFC[FKFPQVRTQFWEG
VGTCVQIGPKEKV[CVENKPKECNN[TGNGXCPVU[UVGOKEGZRQUWTGU
+PVTCXGPQWUCFOKPKUVTCVKQPQHNKVGITCUVVQRTGIPCPV
TCDDKVUFWTKPIQTICPQIGPGUKURTQFWEGFCPKPETGCUGF
KPEKFGPEGQHQORJCNQEGNGCVVJGNQYGUVFQUGVGUVGF
OIMIFC[
HQNFVJGJWOCPRNCUOCGZRQUWTGCV Marks designated and are owned by Shire
VJGTGEQOOGPFGFJWOCPQRJVJCNOKEFQUG=4*1&?
DCUGFQPVJGCTGCWPFGTVJGEWTXG=#7%?NGXGN5KPEG
JWOCPU[UVGOKEGZRQUWTGVQNKVGITCUVHQNNQYKPI
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CRRNKECDKNKV[QHCPKOCNPFKPIUVQVJGTKUMQH:KKFTCWUGKP
JWOCPUFWTKPIRTGIPCPE[KUWPENGCT
Animal Data
.KVGITCUVCFOKPKUVGTGFFCKN[D[KPVTCXGPQWU
KPLGEVKQPVQTCVUHTQORTGOCVKPIVJTQWIJIGUVCVKQPFC[
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and an increased incidence of several minor skeletal
CPQOCNKGUCVOIMIFC[TGRTGUGPVKPIHQNF
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on AUC. No teratogenicity was observed in the rat at
OIMIFC[
VJG4*1&DCUGFQP#7%+PVJGTCDDKVCPKPETGCUGF
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through 19. A fetal No Observed Adverse Effect Level
Lactation
milk, the effects on the breastfed infant, or the effects on
OKNMRTQFWEVKQP*QYGXGTU[UVGOKEGZRQUWTGVQNKVGITCUV
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JGCNVJDGPGVUQHDTGCUVHGGFKPIUJQWNFDGEQPUKFGTGF
along with the mothers clinical need for Xiidra and any
RQVGPVKCNCFXGTUGGHHGEVUQPVJGDTGCUVHGFEJKNFHTQO
Xiidra.
Pediatric Use
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17 years have not been established.
Geriatric Use
No overall differences in safety or effectiveness have been
QDUGTXGFDGVYGGPGNFGTN[CPF[QWPIGTCFWNVRCVKGPVU
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis: Animal studies have not been conducted
Mutagenesis: .KVGITCUVYCUPQVOWVCIGPKEKPVJGin vitro
#OGUCUUC[.KVGITCUVYCUPQVENCUVQIGPKEKPVJGin vivo
mouse micronucleus assay. In an in vitro chromosomal
aberration assay using mammalian cells (Chinese
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concentration tested, without metabolic activation.
Impairment of fertility: .KVGITCUVCFOKPKUVGTGFCV
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female treated rats.
Manufactured for: Shire US Inc., 300 Shire Way, Lexington, MA 02421.
For more information, go to www.Xiidra.com or call 1-800-828-2088.
QTCPCHNKCVGFEQORCP[
2016 Shire US Inc.
US Patents: 8367701; 9353088; 7314938; 7745460; 7790743;
7928122; 9216174; 8168655; 8084047; 8592450; 9085553 and
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.CUV/QFKGF5
 Management and Prevention of Exacerbations of COPD in Hospitalized Patients
pathogens include Haemophilus inuenzae, Moraxella catarrhalis, who received antibiotics for the rst or second exacerbation
Streptococcus pneumoniae, and Staphylococcus aureus.24 Although had a longer median time to subsequent exacerbations by
uncommon, atypical pathogens, including Chlamydophila 97 and 113 days, respectively (P < 0.001).37 In addition, early
pneumoniae and Mycoplasma pneumoniae, can also be infectious antibiotic administration has been associated with improved
causes of exacerbations.24 Moderately to severely ill patients may outcomes in hospitalized patients. An observational study of
be divided into uncomplicated and complicated exacerbations 84,621 patients by Rothberg et al. identied a decrease in treat-
based on certain parameters to help guide therapy. Generally, ment failure, inpatient mortality, and late mechanical ventilation
patients with uncomplicated exacerbations include those younger in patients started on antibiotics by day 2 of hospitalization.38
than 65 years of age with FEV1 more than 50% of predicted who Regardless of the empiric regimen and severity of exacerba-
experience fewer than three exacerbations per year.23,24 These tion, patients should be reassessed in 48 to 72 hours. If the
patients may be treated with an advanced macrolide or a second- patient exhibits signs of clinical improvement, conversion to
or third-generation cephalosporin. While amoxicillin was once oral therapy may occur or the regimen may be de-escalated
considered an option for rst-line therapy, it should no longer be based on sputum culture and susceptibility results.39 Duration
used due to the incidence of beta-lactamase production among of treatment can range from ve to 10 days.1
H. inuenzae and M. catarrhalis. Similarly, resistance to
doxycycline and trimethoprim/sulfamethoxazole has emerged, STRATEGIES FOR PREVENTING AECOPD
and therefore, these medications may not be considered rst Medications available for the treatment of COPD have not
line.34 Complicated exacerbations should be treated with a been shown consistently to modify the underlying pulmonary
respiratory fluoroquinolone or amoxicillin/clavulanate architecture or reverse airway destruction; thus, the goals
(Table 4).23,24 of comprehensive disease management include alleviating
Among various agents, the literature does not strongly acute symptoms and reducing the severity and frequency of
support the utilization of one antibiotic over another. In the exacerbations, as well as improving quality of life and exercise
MAESTRAL study, moxioxacin administered for ve days was tolerance.1,40,41 Nonpharmacological interventions, such as pre-
compared with amoxicillin/clavulanate given over seven days. vention of inuenza or pneumococcal disease via immunization,
Clinical failure at eight weeks post-therapy was found to be smoking cessation, pulmonary rehabilitation, and education,
20.6% and 22% (95% CI, 5.89 to 3.83) for moxioxacin and along with specic pharmacological approaches, including
amoxicillin/clavulanate, respectively, indicating noninferior- antibiotics, bronchodilators, and corticosteroids, may reduce
ity.35 Similarly, in a study conducted by Yoon et al., levooxacin or prevent exacerbations of disease.1,7
was compared with cefuroxime in AECOPD, stratied by sever-
ity. Clinical efcacy was found to be comparable between the IMMUNIZATION RECOMMENDATIONS
two agents (90.4% in the levooxacin group compared to 90.6% AND NONPHARMACOLOGICAL STRATEGIES
in the cefuroxime group; 95% CI, 9.40 to 10.91).36 Vaccination
In patients with severe exacerbations or in those with fre- According to current recommendations from the Centers
quent antibiotic usage or recent hospitalization, Pseudomonas for Disease Control and Prevention, all individuals 6 months
aeruginosa and other gram-negative bacilli must also be consid- of age or older should receive the inuenza vaccine annually.
ered, particularly if such pathogens were previously isolated.34 Pooled results of randomized clinical trials suggest immuniza-
In this subset of patients, depending on local susceptibilities, tion against inuenza may be associated with a reduction in
ciprooxacin, levooxacin, pipercillin/tazobactam, ceftazidime, exacerbations of COPD.42 Adults 19 to 64 years of age who have
or cefepime should be initiated empirically and sputum cul- chronic lung diseases, including COPD, should also receive a
tures should be obtained.24,34 Patients with recent exposure to one-time dose of the 23-valent pneumococcal polysaccharide
antibiotics should be initiated on an agent of a different class vaccine (PPSV23), followed by a single dose of the 13-valent
for the treatment of exacerbation (Table 4).34 pneumococcal conjugate vaccine (PCV13) at age 65 years or
Once patients are deemed eligible, treatment should be older, with a single subsequent dose of PPSV23 administered
initiated in a timely manner, because antibiotics have been at least one year after PCV13 and at least ve years after the
associated with a longer median time to the next exacerba- last dose of PPSV23.43 The most recent ACCP/CTS guidelines
tion. In a study conducted in 49,599 Dutch patients, those suggest that PPSV23 be administered to all COPD patients as
part of disease management, although evi-
Table 4 Antibiotics for Treatment of Exacerbations23,24,34 * dence from clinical trials does not suggest
Moderate-to-Severe Exacerbations vaccination to reduce exacerbations of
Severe Exacerbations disease.44
Uncomplicated Complicated
Azithromycin Moxioxacin Ciprooxacin Smoking Cessation
Clarithromycin Levooxacin Levooxacin Smoking cessation is the single most
Cefuroxime Amoxicillin/clavulanate Pipercillin/tazobactam effective intervention for altering the
Cefpodoxime Ceftazidime progressive decline in lung function that
Doxycycline Cefepime is characteristic of this disease.1 Every
Cefotaxime encounter with a clinician, regardless of
* This list is not all-inclusive. care setting, represents an opportunity
Covers Pseudomonas depending on local suceptiblities to evaluate the patients readiness to

Vol. 41 No. 11 November 2016 P&T

709
 Management and Prevention of Exacerbations of COPD in Hospitalized Patients
quit and provide education on strategies to reduce nicotine
cravings. Various pharmacological and behavioral strategies
exist to support quitting attempts, including a variety of nico-
tine replacement therapies (gum, lozenge, patch, inhaler, or
nasal spray), varenicline or sustained-release bupropion, and
behavioral approaches, including support through counseling
and motivational interviewing, print-based self-help materials,
or computer-based interventions.1,45,46 Specically regard-
ing efforts to reduce COPD exacerbations, there is low-level
evidence to suggest that smoking cessation has a direct effect
on reducing exacerbations of pulmonary disease; regardless,
most recent clinical guidelines emphasize that multimodal
smoking cessation should be offered as part of a comprehensive
strategy to reduce exacerbations of disease.7
Pulmonary Rehabilitation
The effects of pulmonary rehabilitationa comprehensive
and multidisciplinary intervention that includes provision of
exercise, education, and behavioral approaches to improve
physical and psychological function of patients living with
COPDhave been evaluated in clinical trials and are well
established.1,7,47 Although not completely elucidated, the effects
of pulmonary rehabilitation include improvement in exercise
tolerance, improved health-related quality of life, and reduced
number and duration of hospitalizations for exacerbations, as
well as improved recovery after hospitalization for COPD exac-
erbation.1 Current guidelines suggest that pulmonary rehabilita-
tion may have particular benet for individuals with moderate,
severe, or very severe COPD who have had an exacerbation of
disease requiring hospitalization within the previous four weeks
to prevent subsequent exacerbations and hospitalizations.7
The frequency with which this therapy should be provided
is not specied in current clinical guidelines, and there may
be heterogeneity among rehabilitation programs and centers.
Most programs meet three times a week for at least six weeks
after the acute-care hospitalization and typically include two to
three hours of both education and exercise at each session.48
Education, Case Management, and Telemonitoring
Recent clinical guidelines underscore the importance of the
general principles of chronic disease management, including
patient empowerment and education regarding the chronic
disease as well as a coordinated team-based effort to meet the
patients comprehensive health care needs.7 Evidence exists
to support the position that a comprehensive disease self-
management strategy, including monthly access to a health care
specialist to prevent disease exacerbations, may inuence and
reduce exacerbations of COPD.7 In addition, the need to reduce
readmissions after COPD hospitalizations under the Centers
for Medicare and Medicaid Services Hospital Readmission
Reduction Program has mandated that hospitals increasingly
focus on ensuring that patients receive optimal medical treat-
ment and therapy based on evidence-based guidelines and on
medication reconciliation at the time of hospital admission
and discharge.49 Although telemedicine and telemonitoring
of disease are a rapidly developing area of clinical medicine
services, evidence at this time does not suggest telemonitoring
to be associated with a reduced incidence of exacerbations of
disease compared with usual care.7
710 P&T November 2016 Vol. 41 No. 11
PHARMACOLOGICAL STRATEGIES
Bronchodilators
As previously described, long-acting bronchodilators are
generally preferred for management of chronic broncho-
constriction in COPD; both long-acting beta agonists (LABAs)
and long-acting muscarinic antagonists (LAMAs), when com-
pared with placebo, are likely to reduce moderate-to-severe
acute exacerbations of disease.7 A systematic review encom-
passing seven clinical trials and 12,223 participants with COPD
designed to compare the effects of tiotropium to LABAs (salme-
terol, formoterol, and indacaterol) concluded there is equivocal
evidence regarding the effects of LABAs and tiotropium on
patients quality of life. Tiotropium use was associated with a
reduction in the number of participants experiencing one or
more exacerbations compared with use of a LABA (odds ratio
[OR], 0.86; 95% CI, 0.790.93), with no differences observed
among the different types of LABAs. No statistical difference
in mortality was observed between the treatment groups. As a
secondary outcome, tiotropium was associated with a reduction
in the number of COPD exacerbations leading to hospitalization
compared with LABA treatment (OR, 0.87; 95% CI, 0.770.99),
but not in the overall rate of all-cause hospitalizations; thus, in
moderate-to-severe COPD, use of tiotropium may be associated
with a lower rate of exacerbation and hospitalization compared
with LABAs.50 More recent trials suggest that combination
LABA/LAMA therapy (indacaterol/glycopyrronium) is more
effective than a LABA with an inhaled corticosteroid (ICS)
(salmeterol/uticasone) at preventing COPD exacerbations
in patients with a history of exacerbation in the previous year
and that withdrawal of use of an ICS in patients receiving
LABA/LAMA combination therapy (tiotropium plus salmeterol)
is not associated with exacerbation of disease.51,52
Corticosteroids
Although COPD is characterized by chronic broncho-
constriction, the anti-inammatory effects of systemically
administered corticosteroids may be benecial not only in
alleviating acute shortness of breath and reversing broncho-
constriction when an asthmatic component exists, but may
also reduce exacerbations of disease in a 30-day window
following an initial exacerbation, as well as having a preventive
effect on hospitalization.7 There are numerous well-established
risks associated with chronic systemic corticosteroid therapy,
including hyperglycemia, hypertension, weight gain, mood
disturbances, skeletal adverse effects, and insomnia, and long-
term use (beyond 30 days) has not been demonstrated to have
a greater effect on exacerbation reduction.7
While associated with fewer systemic adverse effects,
ICS should only be used in conjunction with long-acting
bronchodilator therapy to reduce exacerbations of disease and
may be utilized in individuals with moderate to very severe
disease.7 The availability of newer classes and types of inhaled
bronchodilators, including LABAs and LAMAs; emerging data
on comparative efcacy of various bronchodilator regimens
versus ICS combinations; and data suggesting that stepwise and
gradual withdrawal of ICS therapy will not worsen exacerba-
tions of disease, have prompted reconsideration of the role of
ICS therapy to prevent exacerbations of disease.52
 Management and Prevention of Exacerbations of COPD in Hospitalized Patients
Antibiotics
There has been much interest regarding long-term anti-
microbial use to reduce exacerbations of pulmonary disease.
Specically, the macrolide antibiotic azithromycin is not only
thought to have antimicrobial effects but may also reduce
inammation and modulate the immune response in the upper
airways. Several clinical trials have evaluated different dosing
and administration strategies for azithromycin in reducing
exacerbations of disease, including azithromycin 250 mg admin-
istered orally once daily for one year versus placebo for patients
with moderate-to-severe COPD who either experienced an
exacerbation within the year prior to study enrollment or
required long-term oxygen therapy.53 Investigators found
azithromycin use to be associated with a signicant reduction
in exacerbations of COPD, from 1.83 to 1.48 acute exacerba-
tions per patient-year (relative risk, 0.83; 95% CI, 0.720.95;
P = 0.01).53 Based on this data, current guidelines suggest use
of long-term macrolide therapy for patients with one or more
moderate-to-severe exacerbations of disease in the previous
year despite optimization of inhaler use, although clinicians
must weigh the risks of QTc prolongation (including history of
cardiovascular disease or dysrhythmia, concomitant medication
use, and presence of electrolyte disturbances), emergence of
bacterial resistance, and patient cost when considering this
type of treatment.7
Other Pharmacological Treatment Options
Other therapies, including theophylline, the phospho-
diesterase-4 inhibitor roumilast, oral N-acetylcysteine, and
mucolyticsas well as emerging treatment options for COPD
may have effects on reducing exacerbations of COPD, but they
are beyond the scope of this article. The reader is encouraged
to evaluate clinical guideline evidence to gain additional insight
into the role of these complementary therapies in modulating
the course of disease.7
CONCLUSION
Acute exacerbations of COPD are associated with substantial
negative impact on pulmonary function, morbidity, mortal-
ity, and increased health care costs. Rapid-acting broncho-
dilators, systemic corticosteroids, and antibiotics are considered
cornerstones of therapy for managing COPD exacerbations.
Prevention of COPD exacerbations should be a key component
of management. Recent guidelines emphasize several preven-
tive pharmacological and nonpharmacological strategies to
reduce or prevent exacerbations of COPD.
REFERENCES
1. Global Initiative for Chronic Obstructive Lung Disease. Global
strategy for the diagnosis, management, and prevention of chronic
obstructive pulmonary disease. 2016. Available at: http://goldcopd.
org/global-strategy-diagnosis-management-prevention-copd-2016.
Accessed March 27, 2016.
2. Ford ES, Croft JB, Mannino DM, et al. COPD surveillanceUnited
States, 19992011. Chest 2013;144(1):284305.
3. Guarascio AJ, Ray SM, Finch CK, Self TH. The clinical and
economic burden of chronic obstructive pulmonary disease in the
USA. Clinicoecon Outcomes Res 2013;5:235245.
4. Johnston AK, Mannino DM. Epidemiology of COPD exacerba-
tions. In: Wedzicha JA, Martinez FJ, eds. Exacerbations of Chronic
Obstructive Pulmonary Disease. London, England: Informa
Healthcare; 2008:1526.
5. Hurst JR, Vestbo J, Anzueto A, et al. Susceptibility to exacerba-
tion in chronic obstructive pulmonary disease. N Engl J Med
2010;363(12):11281138.
6. Wells JM, Washko GR, Han MK, et al. Pulmonary arterial
enlargement and acute exacerbations of COPD. N Engl J Med
2012;367(10):913921.
7. Criner GJ, Bourbeau J, Diekemper RL, et al. Prevention of acute
exacerbations of COPD: American College of Chest Physicians
and Canadian Thoracic Society Guideline. Chest 2015;147:894942.
8. Centers for Medicare and Medicaid Services. Readmissions
reduction program. April 20, 2013. Available at: www.cms.gov/
medicare/medicare-fee-for-service-payment/acuteinpatientpps/
readmissions-reduction-program.html. Accessed July 20, 2016.
9. Celli BR, MacNee W, ATS/ERS Task Force. Standards for the
diagnosis and treatment of patients with COPD: a summary of the
ATS/ERS position paper. Eur Respir J 2004;23:932946.
10. Standards for the diagnosis and care of patients with chronic
obstructive pulmonary disease. American Thoracic Society.
Am J Respir Crit Care Med 1995;152(5 Pt 2):S77S121.
11. Schatz M, Kazzi A, Brenner B, et al. Introduction. Proc Am Thorac
Soc 2009;6:353356.
12. Walters JA, Tan DJ, White CJ, et al. Systemic corticosteroids for
acute exacerbations of chronic obstructive pulmonary disease.
Cochrane Database Syst Rev 2014;9:CD001288.
13. Lindenauer PK, Pekow PS, Lahti MC, et al. Association of
corticosteroid dose and route of administration with risk of
treatment failure in acute exacerbation of chronic obstructive
pulmonary disease. JAMA 2010;303:23592367.
14. Leuppi JD, Schuetz P, Bingisser R, et al. Short-term vs. conven-
tional glucocorticoid therapy in acute exacerbations of chronic
obstructive pulmonary disease: the REDUCE randomized clinical
trial. JAMA 2013;309:22232231.
15. Kiser TH, Allen RR, Valuck RJ, et al. Outcomes associated with
corticosteroid dosage in critically ill patients with acute exacerba-
tions of chronic obstructive pulmonary disease. Am J Respir Crit
Care Med 2014;189:10521064.
16. Amaya-Villar R, Garnacho-Montero J, Garcia-Garmenda JL, et al.
Steroid-induced myopathy in patients intubated due to exacerba-
tion of chronic obstructive pulmonary disease. Intensive Care Med
2005;31:157161.
17. Ala I, de la Cal MA, Esteban A, et al. Efcacy of corticosteroid
therapy in patients with an acute exacerbation of chronic obstruc-
tive pulmonary disease receiving ventilatory support. Arch Intern
Med 2011;171:19391946.
18. Abroug F, Ouanes-Besbes L, Fkih-Hassen M, et al. Prednisone in
COPD exacerbation requiring ventilatory support: an open label
randomized evaluation. Eur Respir J 2014;43:717724.
19. Al-Habet S, Rogers HJ. Pharmacokinetics of intravenous and oral
prednisolone. Br J Clin Pharmacol 1980;10(5):503508.
20. de Jong YP, Uil SM, Grotjohan HP, et al. Oral or IV prednisolone
in the treatment of COPD exacerbations: a randomized, controlled,
double-blind study. Chest 2007;132(6):17411747.
21. Yilmazel Ucar E, Araz O, Meral M, et al. Two different dosages of
nebulized steroid versus parenteral steroid in the management of
COPD exacerbations: A randomized control trial. Med Sci Monit
2014;20:513520. doi: 10.12659/MSM.890210.
22. Gaude GS, Nadagouda S. Nebulized corticosteroids in the manage-
ment of acute exacerbation of COPD. Lung India 2009;26:S11S12.
23. Sethi S, Murphy TM. Infection in the pathogenesis and course
of chronic obstructive pulmonary disease. N Engl J Med
2008;359(22):23552365.
24. Sykes A, Mallia P, Johnston SL. Diagnosis of pathogens of chronic
obstructive pulmonary disease. Proc Am Thorac Soc 2007;4(8):642646.
25. Rohde G, Wiethege A, Borg I, et al. Respiratory viruses in exac-
erbations of chronic obstructive pulmonary disease requiring
hospitalization: a case-control study. Thorax 2003;58:3742.
26. Anthonisen NR, Manfreda J, Warren CP, et al. Antibiotic ther-
apy in exacerbations of chronic obstructive pulmonary disease.
Ann Intern Med 1987;106:196204.
27. Ram FS, Rodriguez-Roisin R, Granados-Navarrete A, et al. Anti-
biotics for exacerbations of chronic obstructive pulmonary disease.
Cochrane Database Syst Rev 2006;(2):CD004403.
Vol. 41 No. 11 November 2016 P&T
711
 Management and Prevention of Exacerbations of COPD in Hospitalized Patients
28. Stockley RA, OBrien C, Pye A, et al. Relationship of sputum color
to nature and outpatient management of acute exacerbations of
COPD. Chest 2000;117(6):16381645.
29. Daniels JM, de Graaf CS, Vlaspolder F, et al. Sputum colour
reported by patients is not a reliable marker of the presence of
bacteria in acute exacerbations of chronic obstructive pulmonary
disease. Clin Microbiol Infect 2010;16:583588.
30. Lacoma A, Prat C, Andreo F, et al. Biomarkers in the management
of COPD. Eur Respir Rev 2009;18(112):96104.
31. Miller BE, Tal-Singer R, Rennard SI, et al. Plasma brinogen
qualication as a drug development tool in chronic obstructive
pulmonary disease. Perspective of the Chronic Obstructive
Pulmonary Disease Biomarker Qualification Consortium.
Am J Respir Crit Care Med 2016;193(6):607613.
32. Stoltz D, Christ-Crain M, Bingisser R, et al. Antibiotic treatment
of exacerbations of COPD. Chest 2007;131(1):919.
33. Schuetz P, Mller B, Christ-Crain M, et al. Procalcitonin to
initiate or discontinue antibiotics in acute respiratory tract
infections. Cochrane Database Syst Rev 2012;12(9):CD007498.
34. Sponsler KC, Markley JD, LaBrin J. What is the appropriate use
of antibiotics in acute exacerbations of COPD? The Hospitalist.
January 26, 2012. Available at: www.the-hospitalist.org/article/
what-is-the-appropriate-use-of-antibiotics-in-acute-exacerbations-
of-copd. Accessed July 20, 2016.
35. Wilson R, Anzuelo A, Miravitlles M, et al. Moxioxacin versus
amoxicillin/clavulanate in outpatient acute exacerbations of COPD:
MAESTRAL results. Eur Respir J 2012;40(1):1727.
36. Yoon HI, Lee CH, Kim DK, et al. Efcacy of levooxacin ver-
sus cefuroxime in treating exacerbations of chronic obstructive
pulmonary disease. Int J Chron Obstruct Pulmon Dis 2013;8:329334.
37. Roede BM, Bresser P, Bindels PJ, et al. Antibiotic treatment
is associated with reduced risk of subsequent exacerbation in
obstructive lung disease: a historical population-based cohort
study. Thorax 2008;63(11):968973.
38. Rothberg MB, Pekow PS, Lahti M, et al. Antibiotic therapy and treat-
ment failure in patients hospitalized for acute exacerbations of chronic
obstructive pulmonary disease. JAMA 2010;303(20):20352042.
39. Siddiqi A, Sethi S. Optimizing antibiotic selection in treating COPD
exacerbations. Int J Chron Obstruct Pulm Dis 2008;3(1):3144.
40. Celli BR, Thomas NE, Anderson JA, et al. Effect of pharmaco-
therapy on rate of decline of lung function in chronic obstructive
pulmonary disease: results from the TORCH study. Am J Respir
Crit Care Med 2008;178:332338.
41. Decramer M, Celli B, Kesten S, et al. Effect of tiotropium on
outcomes in patients with moderate chronic obstructive pulmo-
nary disease (UPLIFT): a prespecied subgroup analysis of a
randomised controlled trial. Lancet 2009;374:11711178.
42. Centers for Disease Control and Prevention. Updated recommen-
dations for prevention of invasive pneumococcal disease among
adults using the 23-valent pneumococcal polysaccharide vaccine
(PPSV23). MMWR Morb Mortal Wkly Rep 2010;59(34):11021106.
43. Centers for Disease Control and Prevention. Adult immunization
scheduleUnited States2016. Available at: www.cdc.gov/vac-
cines/schedules/downloads/adult/adult-schedule.pdf. Accessed
July 19, 2016.
44. Walters JS, Smith S, Poole P, et al. Injectable vaccine for preventing
pneumococcal infection in patients with chronic obstructive pul-
monary disease. Cochrane Database Syst Rev 2010;(11):CD001390.
45. Patnode CD, Henderson JT, Thompson JH, et al. Behavioral coun-
seling and pharmacotherapy interventions for tobacco cessation in
adults, including pregnant women: a review of reviews for the U.S.
Preventive Services Task Force. Ann Intern Med 2015;163:608621.
46. Siu AL. Behavioral and pharmacotherapy interventions for
tobacco smoking cessation in adults, including pregnant women:
U.S. Preventive Services Task Force Recommendation Statement.
Ann Intern Med 2015;163:622634.
47. Spruit MA, Singh SJ, Garvey C, et al. ATS/ERS Task Force
on Pulmonary Rehabilitation. An ofcial American Thoracic
Society/European Respiratory Society statement: key concepts
and advances in pulmonary rehabilitation. Am J Respir Crit Care
Med 2013;188:e13e64.
712 P&T November 2016 Vol. 41 No. 11
48. Corhay J-L, Dang DN, Van Cauwenberge H, et al. Pulmonary
rehabilitation and COPD: providing patients a good environ-
ment for optimizing therapy. Int J Chron Obstruct Pulmon Dis
2014;9:2739.
49. Krishnan JA, Gussin HA, Prieto-Centurion V, et al. Integrating
COPD into patient-centered hospital readmissions reduction
programs. Chronic Obstr Pulm Dis 2015;2:7080.
50. Chong J, Karner C, Poole P. Tiotropium versus long-acting
beta-agonists for stable chronic obstructive pulmonary disease.
Cochrane Database Syst Rev 2012;(9):CD009157.
51. Wedzicha JA, Banerji D, Chapman KR, et al. Indacaterol-glyco-
pyrronium versus salmeterol-uticasone for COPD. N Engl J Med
2016;374:22222234.
52. Magnussen H, Disse B, Rodriguez-Roisin R, et al. Withdrawal
of inhaled glucocorticoids and exacerbations of COPD. N Engl J
Med 2014;371:12851294.
53. Albert RK, Connett J, Bailey WC, et al.; COPD Clinical Research
Network. Azithromycin for prevention of exacerbations of COPD.
N Engl J Med 2011;365:689698. Q
Pharmaceutical Approval Update
continued from page 682
Immunogenicity. Patients may develop antibodies to
lixisenatide. If there is worsening glycemic control or failure
to achieve targeted glycemic control, signicant injection-site
reactions or allergic reactions, alternative antidiabetic therapy
should be considered
Macrovascular outcomes. Clinical studies have not shown
macrovascular risk reduction with lixisenatide or any other
antidiabetic drug.
Dosage and Administration: The starting dose of lixisena-
tide is 10 mcg subcutaneously once daily for 14 days. Increase
the dose to the maintenance dose of 20 mcg once daily starting
on day 15. Instruct patients and caregivers on the preparation
and use of the pen prior to rst use of lixisenatide. Training
should include a practice injection. Administer lixisenatide
by subcutaneous injection in the abdomen, thigh, or upper
arm once daily. Rotate injection sites with each dose. Instruct
patients to administer an injection of lixisenatide one hour
before the rst meal of the day, preferably the same meal each
day. If a dose is missed, administer within one hour prior to
the next meal. Instruct patients to protect the pen from light
by keeping it in its original packaging and to discard it 14 days
after its rst use.
Commentary: The Food and Drug Administration (FDA)
approval of lixisenatide was based on the review of results
from the GetGoal clinical program and ndings from the
ELIXA trial, which successfully addressed the FDAs request
to demonstrate cardiovascular safety. The GetGoal clinical
program, which included 13 clinical trials involving more than
5,000 adults with type-2 diabetes worldwide, evaluated the safety
and efcacy of lixisenatide. All studies of the GetGoal program
successfully met the primary efcacy endpoint of hemoglobin
A1c reduction. The most common adverse events reported for
lixisenatide included nausea, hypoglycemia, and vomiting.
Sources: Sano-Aventis, Adlyxin prescribing information Q
 The New Pregnancy and Lactation Labeling Rule
Sonia Pernia, PharmD; and George DeMaagd, PharmD, BCPS
INTRODUCTION
The use of medications in pregnancy and lactation presents
a challenge to all health care providers. This is especially true
with the long-standing pregnancy risk categories A, B, C, D,
and X (Table 1), which make riskbenet ratio assessment
difcult. Numerous medications have been used safely and
effectively in pregnancy with minimal risk to the fetus and
mother, although the decision to use them is not without
apprehension. The availability of more detailed information
related to the safety and efcacy of medications in pregnancy
and lactation may assist providers and patients in making more
evidence-based decisions.1
To address the need for updated risk categories, the Food
and Drug Administration (FDA) published a nal rule entitled
Content and Format of Labeling for Human Prescription Drug and
Biological Products: Requirements for Pregnancy and Lactation
Labeling, which is also known simply as the Pregnancy and
Lactation Labeling Rule (PLLR), in December 2014.2,3 Along
with the PLLR, the FDA issued a draft document entitled
Pregnancy, Lactation, and Reproductive Potential: Labeling for
Human Prescription Drug and Biological ProductsContent and
Format to serve as a guidance to industry in preparing PLLR-
compliant drug applications.3 The PLLR represents a signicant
departure from the previously established pregnancy categories,
initially implemented in the FDAs 1979 Labeling for Prescription
Drugs Used in Man regulations.2,5 These regulations required
the assignation of a pregnancy letter category (A, B, C, D, or X)
to medications (Table 1).4 Under the PLLR, these categories are
being phased out, which will be discussed later in this article.
DEVELOPING THE PLLR
During the development of the PLLR, the FDA received input
from public hearings, focus groups, and advisory committees.
Input from these sessions and groups included concerns that
the existing pregnancy categories may be misinterpreted or
misused and that pregnancy drug labeling lacked clarity. In
addition, the groups reported that the categories failed to
provide meaningful clinical information about drug exposure
during pregnancy and lactation and did not address the potential
maternal and fetal consequences of discontinuing needed drug
therapy during pregnancy.2 In the new PLLR, drugs may be
placed in the same category but have varying degrees of risk
that a single letter category oversimplies. For example, 60% of
all medications assigned a pregnancy category fall into category
C. This category includes medications with data supporting
adverse effects in animals, as well as medications with no data
from animal studies; the older pregnancy category system allows
drugs with evidence of risk and those without evidence of risk
to be assigned the same category.5 These previous pregnancy
Dr. Pernia is a Pharmacy Practice Resident at Jackson Madison County
General Hospital in Jackson, Tennessee. Dr. DeMaagd is the Associate
Dean of Academic Administration and a Professor of Pharmacy Prac-
tice at the Union University School of Pharmacy in Jackson, Tennessee.
Table 1 Pregnancy Categories Prior to
New Pregnancy and Lactation Labeling Rule2
Category Risk Examples
A Adequate and well-controlled studies Doxylamine
in pregnant women have failed to Folic acid
demonstrate a risk to the fetus in the Levothyroxine
rst trimester of pregnancy.
B Animal reproduction studies have failed Amoxicillin
to demonstrate a risk to the fetus, and Loratadine
there are no adequate and well- Ondansetron
controlled studies in pregnant women,
or animal reproduction studies have
shown adverse effects, but well-
controlled studies in pregnant women have
shown no adverse effects to the fetus.
C Animal reproduction studies have shown Fluconazole
an adverse effect on the fetus, Metoprolol
or there are no animal reproduction Sertraline
studies and no well-controlled studies
in humans.
D Positive evidence of fetal risk, but Lisinopril
benets may outweigh risks. Lithium
Phenytoin
X Positive evidence of fetal risk, and risks Methotrexate
clearly outweigh any possible benet. Simvastatin
Warfarin
categories are dened not by severity or incidence of risk, but
rather by the amount and quality of available data.2
The FDA also conducted a mental-models research study
in 2009 to understand the treatment decisions of health care
professionals prescribing medications to pregnant and lactat-
ing women.6 This mental-modeling approach compared the
decision-making process of study participants to what was
considered an expert model. A total of 54 health care providers
were involved in this study. The prescribers were asked by tele-
phone to describe factors that inuence their decisions when
treating pregnant and nursing women with chronic conditions.7
The study found that health care providers relied heavily upon
pregnancy categories, more so than on additional information
found in the product labeling. In addition, prescribers reported
they relied on sources other than the labeling to determine the
pregnancy category. The study participants suggested ways
to improve drug pregnancy labeling, including simplifying the
information presented, centralizing the relevant information,
and making the information more clinically relevant.5
WHAT THE PLLR CHANGES
The PLLR seeks to address the criticisms of the previous
labeling system and reform pregnancy labeling with a number
Disclosures: The authors report no commercial or nancial interests
in regard to this article.
Vol. 41 No. 11 November 2016 P&T
713
 The New Pregnancy and Lactation Labeling Rule
of changes to all prescribing information.3 The PLLR will
remove the pregnancy letter categories, change and combine
sections pertaining to pregnancy and lactation, and add one
new section (Table 2).
The previous sections 8.1 Pregnancy and 8.2 Labor
and Delivery are now combined to form one section, 8.1
Pregnancy. This section will include the following subsections:
Pregnancy Exposure Registry, Risk Summary, Clinical
Considerations, and Data. The Pregnancy Exposure
Registry subsection is required only if such a registry exists
for the product and should include information about how
to enroll in the registry. The Risk Summary subsection
should be presented as a narrative and summarize any human,
animal, and pharmacological risk data available. It should also
include background information regarding the risk of major
birth defects and miscarriage in the U.S. general population.3
The Clinical Considerations subsection details disease-
associated maternal and fetal risk, relevant dose adjustments,
maternal and fetal adverse reactions, and labor and delivery
information. The Data subsection describes the information
used for the Risk Summary and Clinical Considerations
subsections.3
The previous section 8.3 Nursing Mothers now becomes
8.2 Lactation. Similar to the pregnancy section above,
8.2 Lactation also contains the subheadings Risk Summary,
Clinical Considerations, and Data. The Risk Summary
describes the presence of the drug in human milk and the
Table 2 Comparison of Pregnancy and
Lactation Labeling Rules: 1979 versus 20152,3
Rule in Phase-Out New PLLR
Pregnancy risk letter categories Pregnancy risk letter categories
(A, B, C, D, X) assigned. eliminated.
Section 8.1 Pregnancy Combined to form one section:
Section 8.2 Labor and Delivery 8.1 Pregnancy
Pregnancy Exposure Registry
Risk Summary
Clinical Considerations
Data
Section 8.3 Nursing Mothers Becomes Section 8.2 Lactation
Risk Summary
Clinical Considerations
Data
Requirement to update the label Requirement to update the label
as information becomes outdated as information becomes outdated
New section added:
8.3 Females and Males of
Reproductive Potential *
Pregnancy Testing
Contraception
Infertility
PLLR = Pregnancy and Lactation Labeling Rule.
* Only included when there are recommendations or requirements for
pregnancy testing and/or contraception before, during, or after drug therapy,
and/or there are human and/or animal data suggesting drug-associated
effects on fertility and/or preimplantation loss effects.
714 P&T November 2016 Vol. 41 No. 11
effects on milk production and the breastfed child, and
contains a statement on the riskbenet ratio related to use.
The Clinical Considerations section will include information
on minimizing exposure and monitoring for adverse reactions.3
The new section incorporated into the PLLR is 8.3 Females
and Males of Reproductive Potential. This section should be
utilized in the following situations: 1) if there are recommenda-
tions or requirements for pregnancy testing and/or contraception
before, during, or after drug therapy, and 2) if there are human
and/or animal data suggesting drug-associated effects on fertility
and/or preimplantation loss effects.3 Subheadings in this section
include Pregnancy Testing, Contraception, and Infertility.
Finally, the PLLR requires manufacturers to update all labels
as new information or data become available.
IMPLEMENTATION OF THE PLLR
The PLLR became effective on June 30, 2015, and
implementation of this rule will occur in several stages over
three to ve years from that date. Compliance will be
determined by drug application and approval dates (Table 3).
The new rule has several potential limitations. Older
medications and over-the-counter products approved prior
to June 30, 2001, will have neither a pregnancy category
nor a narrative summary readily available to providers. The
requirement of close collaboration between the FDA and
manufacturers to ensure timely updates also may be problematic.8
In addition, consumers need to cooperate with the pregnancy
registry process and share their health information in order to
accumulate a meaningful quantity of data.9
LABELING SAMPLES
Since the effective date of the PLLR, a total of 48 new novel
drugs have been approved by the FDA.10,11 Only three of these
(insulin degludec injection [Tresiba, Novo Nordisk], brivarace-
tam [Briviact, UCB, Inc.], and obiltoxaximab [Anthim, Elusys
Therapeutics, Inc.]) have not yet conformed to the new rule.1214
Elbasvir/grazoprevir (Zepatier, Merck), approved on
January 28, 2016, is a good example of compliance with the
PLLR.15 Its section 8.1 Pregnancy provides a narrative risk
summary and detailed animal data, a background risk state-
ment, and the estimated background risk for major birth defects
and miscarriage. Section 8.2 Lactation similarly summarizes
risk and provides available animal data. Because there are no
human pregnancy or lactation data for elbasvir/grazoprevir,
only the animal data are summarized. Finally, per labeling
guidelines, no pregnancy category is provided.
If the previous pregnancy category guidelines were to be
applied to elbasvir/grazoprevir, a category of B may have
been appropriate. However, this category would be overly
simplistic and would not detail the animal data available for
this agent. Therefore, in this case, a narrative as required for
PLLR compliance presents useful information rather than a
broad category or recommendation.
Trabectedin (Yondelis, Janssen Biotech), approved on
October 23, 2015, also provides labeling that conforms to the
PLLR and includes the new section 8.3 Females and Males
of Reproductive Potential. The Contraception subheading
provides specic contraception guidelines for women and men,
while the Infertility subheading informs prescribers and
 The New Pregnancy and Lactation Labeling Rule
Table 3 Implementation Schedule of the New PLLR2
Applications for Drug Compliance
or Biological Product Requirements
Approved prior to Remove pregnancy category within
June 30, 2001 3years of the effective date of PLLR.
No other compliance requirements.
Approved June 30, 2001 3 years after the effective
June 29, 2002 date of PLLR.
Approved June 30, 2002 5 years after the effective
June 29, 2005 date of PLLR.
Approved June 30, 2005 3 years after the effective
June 29, 2007 date of PLLR.
Approved June 30, 2007 4 years after the effective
June 30, 2015 date of PLLR.
Pending approval on 4 years after the effective date of PLLR
June 30, 2015 or at time of approval, whichever is later.
Submitted on or after Time of submission.
June 30, 2015
PLLR = Pregnancy and Lactation Labeling Rule.
patients that Yondelis has the potential to decrease fertility in
both genders.16 The labeling information produced under the
new rule allows the provider and patient to review and discuss
the risks in order to make an informed treatment decision.
CLINICAL IMPACT
Although the PLLR requires a concise, standardized summary
of available evidence, the departure from pregnancy categories
may prove to be a challenging transition. The FDA received
16 comments regarding the proposed rule that supported the
old category system. Those comments stated that the old
system was simple and effective and expressed concern that
a narrative summary may prove confusing and could lead to
inconsistent decision-making.2 The transition to a narrative
summary style is not without risk and requires that providers
review the available evidence instead of relying on category
designations.17 Such evidence review will require more time
and may involve some complex decision-making. Risk arises if
an incomplete assessment is made or if the evidence is unclear.
The lack of a standardized schema may also make it difcult
to make blanket formulary decisions because each medication
will need a more individualized review.
CONCLUSION
In announcing the nal PLLR, Sandra Kweder, MD, Deputy
Director of the Ofce of New Drugs in the FDAs Center for
Drug Evaluation and Research, stated, Prescribing decisions
during pregnancy and lactation are individualized and involve
complex maternal, fetal, and infant riskbenet considerations.
The letter category system was overly simplistic and was
misinterpreted as a grading system, which gave an oversimplied
view of the product risk. 18 The PLLR remedies the perception
of pregnancy categories as a grading system by doing away with
them altogether. In place of pregnancy categories, the PLLR
requires narrative explanations of risk and supporting data.
REFERENCES
1. Ramoz LL, Patel-Shori NM. Recent changes in pregnancy and
lactation labeling: retirement of risk categories. Pharmacotherapy
2014;34(4):389395.
2. Food and Drug Administration. Content and format of labeling for
human prescription drug and biological products: requirements
for pregnancy and lactation labeling. Fed Regist 2014;79(233):
7206472103. Available at: www.gpo.gov/fdsys/pkg/FR-2014-12-
04/pdf/2014-28241.pdf. Accessed February 13, 2016.
3. Food and Drug Administration. Pregnancy, lactation, and
reproductive potential: labeling for human prescription drug and
biological productscontent and format: guidance for industry.
December 2014. Available at: www.fda.gov/downloads/Drugs/
GuidanceComplianceRegulatoryInformation/Guidances/
UCM425398.pdf. Accessed February 27, 2016.
4. Moseley JF 2nd, Smith LL, Dezan MD. An overview of upcoming
changes in pregnancy and lactation labeling information.
Pharm Pract (Granada) 2015;13(2):605.
5. Food and Drug Administration. Content and format of labeling for
human prescription drug and biological products; requirements
for pregnancy and lactation labelingproposed rule. Fed Regist
2008:73(104):3083130868. Available at: www.regulations.gov/
contentStreamer?documentId=FDA-2006-N-0515-0001&disposit
ion=attachment&contentType=pdf. Accessed February 13, 2016.
6. Decision Partners, LLC. Evaluation of how best to communi-
cate to healthcare providers about the risks and benets of
prescription drug use for pregnant and nursing women: a mental
models research report. September 2009. Available at: www.fda.
gov/AboutFDA/ReportsManualsForms/Reports/EconomicAnaly-
ses/default.htm. Accessed March 19, 2016.
7. Food and Drug Administration. Agency information collec-
tion activities; submission for Office of Management and
Budget review; comment request; mental models study of
communicating with health care providers about the risks and ben-
ets of prescription drug use for pregnant and nursing women with
chronic conditions. August 25, 2008. Available at: www.fda.gov/
ohrms/dockets/98fr/E8-19653.htm. Accessed March 19, 2016.
8. Greene MF. FDA drug labeling for pregnancy and lactation drug
safety monitoring systems. Semin Perinatol 2015;39(7):520523.
9. Gruber MF. The U.S. FDA pregnancy lactation and labeling ruleImpli-
cations for maternal immunization. Vaccine 2015;33(47):64996500.
10. Food and Drug Administration. Novel drugs 2015. January 2016. Avail-
able at: www.fda.gov/downloads/Drugs/DevelopmentApprovalPro-
cess/DrugInnovation/UCM485053.pdf. Accessed February 13, 2016.
11. Food and Drug Administration. Novel drug approvals for 2016. Septem-
ber 21, 2016. Available at: www.fda.gov/Drugs/DevelopmentApproval-
Process/DrugInnovation/ucm483775.htm. Accessed March 23, 2016.
12. Tresiba (insulin degludec injection) prescribing informa-
tion. Bagsvaerd, Denmark: Novo Nordisk; 2015. Available at:
www.tresibapro.com/about-Tresiba.html. Accessed April 5, 2016.
13. Briviact (brivaracetam) prescribing information. Smyrna, Georgia:
UCB, Inc.; 2016. Available at: www.briviact.com/briviact-PI.pdf.
Accessed April 5, 2016.
14. Anthim (obiltoxaximab) prescribing information. Pine Brook,
New Jersey: Elusys Therapeutics, Inc.; 2016. Available at:
www.anthim.com/download/pdf/ANTHIM-prescribing-infor-
mation.pdf. Accessed October 4, 2016.
15. Zepatier (elbasvir/grazoprevir) prescribing information.
Whitehouse Station, New Jersey: Merck; 2016. Available at:
www.merck.com/product/usa/pi_circulars/z/zepatier/
zepatier_pi.pdf. Accessed February 13, 2016.
16. Yondelis (trabectedin) prescribing information. Horsham,
Pennsylvania: Janssen Biotech; 2015. Available at: www.yondelis.
com/prescribing-information.pdf. Accessed February 13, 2016.
17. Beroukhim K, Abrouk M, Farahnik B. Impact of the Pregnancy
and Lactation Labeling Rule (PLLR) on practicing dermatologists.
Dermatol Online J 2015;21(11). pii: 13030/qt46c4m2tw.
18. Food and Drug Administration. FDA issues nal rule on changes
to pregnancy and lactation labeling information for prescription
drug and biological products. December 3, 2014. Available at:
www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/
ucm425317.htm. Accessed February 13, 2016. Q
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 Minnesota Pharmacists and Medical Cannabis:
A Survey of Knowledge, Concerns, and
Interest Prior to Program Launch
Joy Hwang, PharmD, MPH; Tom Arneson, MD, MPH; and Wendy St. Peter, PharmD
ABSTRACT
Objectives: To assess Minnesota pharmacists prepared-
ness for the states medical cannabis program in terms of
professional competency in policies and regulations and in
pharmacotherapy, as well as their concerns and perceptions
about the impact on their practice. The secondary objective
was to identify pharmacists perceptions about ways to reduce
potential gaps in knowledge.
Methods: A Web-based 14-item questionnaire was
distributed to all pharmacists whose email addresses were
registered with the Minnesota Board of Pharmacy.
Results: Pharmacists reported limited knowledge of
Minnesota state-level cannabis policies and regulations and
felt that they were inadequately trained in cannabis pharmaco-
therapy. Most pharmacists were unprepared to counsel patients
on medical cannabis and had many concerns regarding its
availability and usage. Only a small proportion felt that the
medical cannabis program would impact their practice.
Pharmacists leading topics of interest for more education
included Minnesotas regulations on the medical cannabis
program, cannabis pharmacotherapy, and the types and forms
of cannabis products available for commercialization. Preferred
modes of receiving information were electronic-based, including
email and online continuing education credit. Since the surveys
completion, educational presentations have been provided to
pharmacists and health professionals in Minnesota.
Conclusion: Pharmacists need more training and education
on the regulatory and clinical aspects of cannabis in preparation
for their work with patients in the medical cannabis program.
Keywords: medical marijuana, cannabis, pharmacists,
surveys, questionnaires, clinical competence, professional
practice
INTRODUCTION
The use of cannabis for medical purposes has garnered
much polarized attention in the United States since the imple-
mentation of the rst state-specic medical marijuana pro-
grams. As of September 2016, cannabis had been legalized
for medical use in 25 states, the District of Columbia, Guam,
and Puerto Rico.1 Seventeen other states permit limited access
to marijuana products with restrictive concentrations of its
key active components: delta-9-tetrahydrocannabinol and
Dr. Hwang is a recent graduate from the College of Pharmacy
at the University of Minnesota in Minneapolis, Minnesota.
Dr. Arneson is Research Manager in the Ofce of Medical Cannabis
of the Minnesota Department of Health in St. Paul, Minnesota.
Dr. St. Peter is a Professor in the College of Pharmacy at the University
of Minnesota in Minneapolis.
716 P&T November 2016 Vol. 41 No. 11
cannabidiol.1 Five jurisdictions with medical marijuana pro-
grams also have legalized recreational marijuana use: Colorado,
Washington, Oregon, Alaska, and the District of Columbia.1
Because cannabis is a federally classied Schedule I substance,
its legalization at the state level offers no protection for health
care professionals against consequences of conicting federal
regulations. Health care professionals who provide access to
marijuana, either medically or recreationally, can be subject
to federal prosecution and their licenses can be revoked by
the U.S. Drug Enforcement Administration.2
Pharmacists are positioned to play an important role in under-
standing and communicating the impact of medical cannabis
use. In some states, pharmacists are vital to the operation of
the medical cannabis program. In 2014, Minnesota became the
22nd state with a medical cannabis program (see Minnesota
Medical Cannabis Program at right). Minnesota, Connecticut,
and New York share a similar inclusion of pharmacists in
their state-specic programs. In these three states, pharma-
cists provide registered patients with consultations at one of
the state-approved cannabis distribution centers. Moreover,
they are the only health care professionals who are permit-
ted to dispense cannabis products. This distinguishes these
states from most other legalization states, where cannabis
productsboth medical and recreationalcan be purchased
from retail dispensaries that operate under the guidance of
certied personnel known as budtenders. To date, no research
has assessed pharmacists readiness to manage patients or
legal consequences for dispensing cannabis products follow-
ing implementation of medical cannabis programseither as
potential employees at the distribution centers or as providers
in other settings.
OBJECTIVES
We conducted this study to determine potential gaps in
knowledge and concerns among Minnesota pharmacists regard-
ing the states cannabis program regulations and pharmaco-
therapy of cannabis products, as well as pharmacists comfort
level in counseling patients receiving these products. Our
goal was to provide insight into Minnesota pharmacists self-
assessed competency and understanding that could indicate
their preparedness for program implementation. A secondary
objective was to assess pharmacists preferences on ways to
improve their knowledge on the medical cannabis program.
Disclosures: The authors report no financial or commercial
relationships in regard to this article. No funding was required for
this study. The use of the Qualtrics online survey platform was made
possible through the University of Minnesotas campus-wide survey
connection access. This study was the subject of a Student Poster
Session at the American Society of Health-System Pharmacists Midyear
Clinical Meeting in New Orleans, Louisiana, on December 5, 2015.
 Minnesota Pharmacists and Medical Cannabis: A Preparedness Survey
Minnesota Medical Cannabis Program
In May 2014, Minnesota became the 22nd state in which
medical cannabis is legal for use by patients. Initially, one
or more of nine qualifying medical conditions was required:
cancer, glaucoma, human immunodeciency virus/acquired
immunodeciency syndrome, Tourettes syndrome, amyo-
trophic lateral sclerosis, seizures, severe and persistent
muscle spasms, Crohns disease, or terminal illness with
less than one year of life expectancy.3 As of August 2016,
patients with intractable pain also became eligible to
receive medical cannabis in Minnesota.4 Only nonsmoked
forms of medical cannabis are permitted. These include
oral liquids (including oils), tablets, capsules, and vaporized
cannabis extracts (liquid or oils). In July 2015, two state-
approved medical cannabis manufacturers began distribut-
ing products through four distribution centers apiece. All
manufactured products contain labeled amounts of delta-
9-tetrahydrocannabinol and cannabidiol in their packaged
forms. Both manufacturers must conduct quality testing of
their products through state-approved laboratories.
Patients who are interested in using medical cannabis
must be certied as having at least one of the qualify-
ing medical conditions by a state-registered health care
METHODS
Study Design, Settings, and Subjects
We conducted this cross-sectional study through an online
survey platform, Qualtrics, two months before the implemen-
tation of the statewide medical cannabis program. An email
containing a link to the questionnaire was disseminated to
all pharmacists whose email addresses were registered with
the Minnesota Board of Pharmacys database at the end of
March 2015 (N = 7,332). A follow-up email was sent weekly
reminding nonrespondents to take the survey. We provided
participants with information on the studys purpose, proce-
dures, condentiality, and voluntary nature, and explained
that only pharmacists holding an active Minnesota pharmacy
practice license should participate. Only those consenting to
the study had access to the survey. The questionnaire was
deactivated at midnight on May 1, 2015.
Questionnaire
A 14-item questionnaire was assessed for content validity
by four pharmacists and a staff member of the Minnesota
Department of Healths Ofce of Medical Cannabis. The initial
draft was modied based on their evaluation. The wording of
questions and answer choices was revised to strengthen the
questionnaires validity and reliability as an assessment tool of
respondents knowledge and opinions about medical cannabis.
The nal draft of the questionnaire, informed consent form,
and methodology were approved by the Institutional Review
Board of the University of Minnesota at Minneapolis. The
questionnaire assessed the following areas: 1) pharmacists
demographic information; 2) pharmacists knowledge of the
Minnesota medical cannabis program and federal regulations;
3) pharmacists concerns about the Minnesota medical cannabis
professional: a medical doctor, an advanced practice
registered nurse, or a physician assistant. Then they submit
an application through the state Department of Health.
Once approved for registration, patients may receive up to
a 30-day supply of the medical cannabis product at a time.
The states strict prohibition against the use of smoked
marijuana makes it one of only two legalization states (the
other being New York) where only nonsmokable forms
of cannabis are permitted. Another distinctive feature of
the Minnesota medical cannabis program is pharmacists
involvement in the patient registry model. Registered
patients are required to meet with a pharmacist at the
distribution center for a consultation on their treatment
goals and selection guidance for their medical cannabis
dosage and dosage form.2 For assessment of side effects
and effectiveness, patients will meet with their cannabis-
dispensing pharmacist during follow-up visits and obtain
rells as necessary. This model closely follows the process
that is implemented in only two other states, Connecticut
and New York. For more information on this program, visit
the Minnesota Department of Health Office of Cannabis
website at www.health.state.mn.us/topics/cannabis.
program or issues related to medical cannabis products; and
4) pharmacists rating and preference on medical cannabis-
related topics and resources for future education. See Appendix
for a copy of the questionnaire.
RESULTS
Response Rate
Out of the 7,332 pharmacists recruited for this study,
738 responses were collected (10%); 607 of these 738 question-
naires (81%) were fully completed. Twenty questionnaires were
excluded due to invalid email addresses (n = 14) or because
the pharmacists had retired or practiced out of state (n = 6).
Demographic and Practice Characteristics
Compared with all licensed Minnesota pharmacists, the
respondents were younger and more likely to practice in
urban/suburban regions and in hospital and clinical pharmacy
practice settings. Responding pharmacists mean age was about
49 years. Most were from nonrural areas (75%), and the major-
ity practiced in either community settings (39%) or hospital
settings (37%). Respondent characteristics were compared with
licensed pharmacist characteristics from the Minnesota Board
of Pharmacy. Age and practice-setting categories were not
identical for the survey and the Board of Pharmacy statistics,
but rough comparisons were possible (Figure 1).
Knowledge Assessment
The rst four questions in the knowledge assessment section
evaluated pharmacists familiarity with the Minnesota medical
cannabis program. Respondents had variable knowledge about
dosage forms eligible for distribution under the state program.
Eighty-seven percent knew that cannabis extracts in oral pill
Vol. 41 No. 11 November 2016 P&T
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 Minnesota Pharmacists and Medical Cannabis: A Preparedness Survey
form were eligible, but only 46% knew that inhaled marijuana
from cannabis extract was an eligible dosage form. In addition,
25% and 17%, respectively, incorrectly indicated that topical
cannabis lotion or ointment and smoked marijuana leaves
were eligible dosage forms.
Pharmacists knowledge of qualifying medical conditions
was also mixed. Most correctly identied cancer-related pain
(90%), seizures or epilepsy (73%), and terminal illness with less
than one year of life expectancy (69%), but less than half cor-
rectly identied glaucoma (46%), amyotrophic lateral sclerosis
(43%), acquired immune deciency syndrome (40%), Tourettes
syndrome (24%), and Crohns disease (24%). Smaller propor-
tions incorrectly identied rheumatoid arthritis (13%), hydro-
cephalus (9%), migraine (15%), and hepatitis C (7%) as qualifying
conditions. The majority correctly understood that patients
needed to enroll in the states patient registry in order to obtain
medical cannabis (88%). However, 77% incorrectly thought that a
prescription was required to obtain medical cannabis.
Most pharmacists knew that physicians can certify patients
as having a qualifying condition (77%), but the majority was
unaware that advanced practice registered nurses (nurse
practitioners) also have this authority (71%). A small propor-
tion of respondents incorrectly believed pharmacists had this
authority (17%). Forty-six percent and 29% of respondents,
respectively, correctly understood the pharmacists roles in
consulting with patients about their treatment goals for medical
cannabis and guiding patient selection of medical cannabis
products at distribution centers. More than half of the phar-
macists were aware that cannabis was federally classied as
a Schedule I drug (62%). Approximately one-third thought
cannabis was a Schedule II substance, and a handful thought
it was a Schedule IIIIV drug.
Assessment of Medical Cannabis Concerns
Most pharmacists rated themselves on the lower end of
the Likert scale for self-perceived knowledge about medical
cannabis and readiness to counsel patients on medical canna-
bis use (1 = poor; 7 = excellent) and concerns about medical
cannabis use under the Minnesota program (1 = no concern;
7 = most concern) (Tables 1 and 2). Respondents were also

Figure 1 Comparison of Respondent Characteristics and Characteristics of All Licensed Minnesota Pharmacists

Survey respondents/total emails registered Total Minnesota pharmacists with active license:
with Minnesota Board of Pharmacy: N = 738/7,332 N = 8,057
Respondent pools Minnesota pharmacists
age distribution age distribution
1% 3%
5% < 34 years 2030 years
13% 15%
3544 years 3140 years
19% 35%
4554 years 4150 years
20%
5564 years 28% 5160 years
14%
6574 years 6170 years
26% 21%
75+ years 71+ years

Respondent pools Minnesota pharmacists

distribution by practice setting distribution by practice setting

6% 2% 3% 4%
4% 2%
Community Retail
Hospital 8% Hospital
12% 39% Clinical pharmacy
Clinic
Academics 25% 58% Teaching/government
37% Managed care Pharmacy benet manager
Hospice/assisted living facility Long-term care

Respondent pools Minnesota pharmacists

distribution by region of practice distribution by region of practice

25%
Rural 41% Greater Minnesota
75% Urban/suburban 59% 7-county metro area

718 P&T November 2016 Vol. 41 No. 11

 Minnesota Pharmacists and Medical Cannabis: A Preparedness Survey
encouraged to report other concerns on the questionnaire
Table 1 Pharmacists Responses to Questions on
(see Appendix), and some indicated concern about diversion
and abuse (n = 17), psychoactive effects (n = 12), and man-
Competency in Cannabis Clinical Knowledge Related to
agement of medical cannabis in the hospital setting (n = 9). Its Usage
Eighty-eight percent of participants responded that they were Question 6: On the scale of 17, please rate your competency level
less than moderately prepared to provide counseling services in medical cannabis pharmacotherapy knowledge in the following
to patients using cannabis products. areas (1 = poor; 7 = excellent)
As for the pharmacists rating on the anticipated impact of 13 4 57 Mean SD
the program, only 21% indicated concern about the programs
potential impact on their current professional practice; about Pharmacology 75.7% 14.4% 9.9% 2.4 1.4
one-third of the respondents were unsure (32%) (Figure 2). Pharmacokinetics 85.7% 9.3% 5.0% 2.1 1.3
The most frequent concerns were related to care transitions
Pharmacodynamics 84.3% 10.9% 4.8% 2.1 1.3
associated with hospital admissions (n = 42), knowledge limita-
tion on the topic (n = 27), and the regulatory-related aspects of SD = standard deviation
medical cannabis practice (n = 10).
Table 2 Pharmacists Responses to Questions on
Preferences for Future Education Concerns Regarding Minnesota Medical Cannabis Program
Respondents were very interested in
Question 7: On the scale of 17, how concerned are you about the following factors regarding
learning more about medical cannabis
the use of medical cannabis? (1 = no concern; 7 = most concern)
in the following areas: state-specic
rules and regulation (87%), pharmaco- 13 4 57 Mean SD
therapy (88%), and available types and Federal regulation related to 34.6% 13.1% 52.3% 4.4 2.0
forms of products on the market (82%). cannabis
Fifty-three percent were interested in
learning more about federal laws related Consistency in quality of 29.5% 15.9% 54.5% 4.5 1.8
to marijuana. Only 7% indicated no interest medical cannabis products
in learning more about any of these topics. Limited evidence of therapeutic 43.4% 16.4% 40.2% 3.9 2.0
The survey included questions about the benets from cannabis use
preferred source and delivery method for
Safety concerns of cannabis 28.3% 16.9% 54.8% 4.5 1.9
information on the Minnesota medical
use (i.e., drug interactions,
cannabis program. The Minnesota
contraindications, and adverse
Board of Pharmacy was ranked as the
reactions)
most preferred source (62%), followed
by the Minnesota Department of Health Psychoactive effect and potential 36.4% 15.0% 48.7% 4.3 2.0
(23%) and the Minnesota Pharmacists addiction from cannabis use
Association (11%). The preferred routes SD = standard deviation
of delivery were email (56%) and online
courses (48%). Few identied mail (12%) and conferences (11%) cannabis and a state-specic medical cannabis program. We
as most preferred, and approximately 50% indicated they did surveyed Minnesota pharmacists two months prior to the states
not prefer these routes of delivery. implementation of its medical cannabis program. Pharmacists
appeared to have an incomplete understanding about their role
DISCUSSION in the imminent medical cannabis program, medical cannabis
To the best of our knowledge, this is the rst survey of pharmacotherapy, and state-specic regulations. The majority
U.S. pharmacists knowledge and opinions regarding medical had low self-perceived preparedness to provide counseling on
medical cannabis products. The majority also reported a lack
of concern about the medical cannabis programs potential
Figure 2 Pharmacists Concern About How the impact on their practice, but most pharmacists were highly
Minnesota Medical Cannabis Program Would interested in lling their knowledge gaps about the program
Impact Their Current Practice and cannabis as a medication.
In 2011, Mueller and colleagues evaluated pharmacy stu-
dents knowledge and attitudes regarding medical marijuana.
21% Although the perceptions of students are not directly compa-
32% Concerned about impact rable with those of licensed pharmacists, it is interesting that
Not concerned about impact both groups commonly reported being unprepared to counsel
Unsure of impact patients with information about medical cannabis products.5
47% Both groups also reported interest in having more education
on the topic.5
Less than a quarter of Minnesota pharmacists expressed
concern regarding the impact medical cannabis would

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 Minnesota Pharmacists and Medical Cannabis: A Preparedness Survey
potentially have on their practice. Many concerns focused
on how the implementation of the medical cannabis program
would affect the process of care transition for patients who use
the product. Because medical cannabis is a Schedule I drug at
the federal level, many pharmacists cited the need for more
guidance on the management of product storage and adminis-
tration during the patients hospitalization. Some commented
on the difculty in verifying the products integrity and safety
as their patients home medication per their institutional policy.
Other concerns included worries about medical cannabis
psychoactive side effects, potentials for diversion and abuse,
public and professional stigma, and the discrepancy between
state and federal classications.
The state legalization of a once-illicit substance as a thera-
peutic agent calls for pharmacists in all health care settings,
as medication experts, to understand all aspects of cannabis
products, including pharmacology, dosage forms, new evidence
on efcacy and safety, and regulatory parameters regarding
cannabis. Pharmacists must also become procient in provid-
ing counseling about cannabis products to current or future
patients whose medical conditions may benet from its use.
Comparable to the medication counseling that pharmacists
already provide for federally recognized prescriptions, proper
patient counseling can help to minimize misuse and safety
concerns. The increasing number of states where medicinal
use of cannabis has been legalized also means that many prac-
ticing pharmacists will encounter patients who use medical
cannabis as part of their medication regimen. Pharmacists
providing medication reconciliation, medication review, and/or
comprehensive medication management need to be prepared
to inquire about medical cannabis use and to feel comfortable
counseling and monitoring medicinal cannabis patients. They
could also aid in their states research process by gathering
information on medical cannabis efcacy and safety based on
their patients medical cannabis utilization experience. Thus,
pharmacists general view that the medical cannabis program
will have a low impact on their practice may underestimate
the signicance of this program on pharmacy practice. This is
particularly true now that intractable pain has been added as a
qualifying condition in Minnesotas medical cannabis program.4
It is anticipated that this will greatly increase the number of
registered patients in the program.
Most pharmacists had low self-rated competency in both regu-
latory and clinical aspects of medical cannabis and possessed
only a partial understanding of the patient registry program.
They lacked in-depth knowledge about the patient certication
process and requirements. Most pharmacists did not know
that advanced practice registered nurses, like physicians, can
certify patients medical cannabis eligibility. An overwhelming
number of pharmacists also thought that prescriptions must
be obtained in order for patients to purchase medical canna-
bis. This confusion may stem from the conict presented by
federal regulations that prohibit Schedule I substances (such
as cannabis) from being legally prescribed. States have been
required to develop alternative systems and terminology to allow
for medical cannabis use. The common terms that are used in
place of prescription in these states include recommendation
(i.e., Arizona, California, and Colorado) and certication (i.e.,
Delaware, Hawaii, and Minnesota).610 However, limitations on
720 P&T November 2016 Vol. 41 No. 11
form, strength, and amount of cannabis for possession or cultiva-
tion are typically determined by state-specic regulation rather
than direction by the health care practitioner who provides the
recommendation or certication.
Most pharmacists are interested in learning more about
cannabis as a medicine and its state-level regulation. Findings
from this study indicated that most pharmacists preferred to
obtain their educational resources from the states Board of
Pharmacy and Department of Health. They also preferred
asynchronous learning methods through email and Web-based
continuing education (CE) rather than by attending a confer-
ence. Recognized as the most accessible health care profes-
sional by patients, pharmacists play a vital part in safeguarding
public health through ensuring proper medication usage. With
Connecticut as the rst state model with pharmacists integrated
into the medical cannabis program, the collective members of
the profession in corresponding states with legalized medical
cannabis should become more engaged in encouraging legisla-
tive support for similar programs in their home states.1113 In
Minnesota, the states Department of Health collects informa-
tion from registered medicinal cannabis patients to facilitate a
better understanding of potential clinical benets and harms
from cannabis usage. Mirroring this registry in afliated states
will help bolster the collection of medical cannabis data that are
valuable for determination of indications, dosing, efcacy, and
safety; therefore, the pharmacy community should advocate for
the creation of such registries.1114
Since the time of the survey, Minnesotas Ofce of Medical
Cannabis staff has provided educational presentations to many
hospitals, clinics, and hospital-clinic organizations in Minnesota
with pharmacists as part of the audience. In addition, presenta-
tions have been provided to numerous professional organiza-
tions, including statewide pharmacist groups. The University of
Minnesota College of Pharmacy, as well as the Medical School
and School of Nursing, worked with the Ofce of Medical
Cannabis to produce a well-attended, in-person, CE-granting, full-
day educational symposium on medical cannabis in April 2016.
Professional organizations, such as the Minnesota Pharmacists
Association (MPhA) and the Minnesota College of Clinical
Pharmacists, have also delivered educational presentations to
pharmacists at statewide conferences, including the 2015 MPhA
Legislative Day and the 2015 Annual Learning Networking
Event, as well as a CE event titled Arriving at a Precipice:
Medical Cannabis in Minnesota. The University of Minnesota
College of Pharmacy is currently in the planning stage for a
Web-based educational program that will grant CE credit on
medical cannabis and the Minnesota medical cannabis program.
Strengths of This Study
Among the strengths of our study is that the study population
was made up of practicing pharmacists who were registered
with the Minnesota State Board of Pharmacy shortly before
the medical cannabis program went into effect. Information
about the program was widely disseminated in the media at
the time, so it is likely that most of the pharmacy community
in Minnesota was aware of program, but because it had not
been implemented, they had not yet experienced the programs
effect on their practice. Our results reinforce that pharmacists
perceive the need for targeted education regarding medicinal
 Minnesota Pharmacists and Medical Cannabis: A Preparedness Survey
cannabis before the initiation of their state-specic program 6.
education that is likely also lacking in health care professions
without a pharmacological focus.
Limitations of This Study
Our study was conducted in the state of Minnesota. Thus,
the results may not be representative of pharmacists percep-
tions in other states. Selection bias may have been introduced
by participants self-selected participation. In comparison with
Minnesotas statistics on the states pharmacists, survey respon-
dents were younger, more likely to be from nonrural areas, and
more likely to practice in clinical and hospital settings rather
than in community dispensing pharmacies. The low response
rate of 10% may also indicate low generalizability of the results
to the entire targeted population. Regarding the knowledge
assessment section of the questionnaire, some respondents
may be unaware of the difference in federal scheduling between
cannabis and cannabinoid products, such as dronabinol and
nabilone. This may have led to the incorrect selection of the
response as a result.
CONCLUSION
This study suggests that Minnesota pharmacists were not
sufciently prepared to work with patients in the medical can-
nabis program. Of those who provided survey responses, an
overwhelming majority felt incompetent in medical cannabis
clinical knowledge; however, almost half were unconcerned
about the potential impact the programs implementation would
have on their practice. Nonetheless, pharmacists were inter-
ested in learning about medical cannabis and its state-specic
regulation. Targeted education regarding cannabis pharmaco-
therapy, product availability and variability, and state-specic
regulations should be available for health care professionals
practicing in states with medical cannabis programs prior to
program implementation and patient access.
ACKNOWLEDGEMENTS
We would like to thank the following individuals:
Sean T. Lasota, PharmD, Christine Jolowsky, MS, RPh, FASHP,
and Jon Schommer, PhD, RPh, for providing resources and
technical assistance on the drafting of the survey; Cody Wiberg,
PharmD, for providing the email database of registered
pharmacists for this research; and Lowell Anderson,
DSc, FAPhA, and Todd Sorensen, PharmD, for providing
instrumental contacts.
REFERENCES
1. National Conference of State Legislatures. State medical marijuana
laws. July 7, 2016. Available at: www.ncsl.org/research/health/
state-medical-marijuana-laws.aspx. Accessed September 2, 2016.
2. Rannazzisi J, Caverly M. Practitioners manual: an information
outline of the Controlled Substances Act. Drug Enforcement
Administration. 2006. Available at: www.deadiversion.usdoj.gov/
pubs/manuals/pract. Accessed July 3, 2015.
3. Minnesota Department of Health. Medical cannabis qualifying
conditions. Available at: www.health.state.mn.us/topics/cannabis/
patients/conditions.html. Accessed July 5, 2015.
4. Minnesota Department of Health. Intractable pain. Available at:
www.health.state.mn.us/topics/cannabis/intractable/index.html.
Accessed December 3, 2015.
5. Moeller KE, Woods B. Pharmacy students knowledge and attitudes
regarding medical marijuana. Am J Pharm Educ 2015;79(6):85.
Arizona Department of Health Services. Medical marijuana.
Available at: http://azdhs.gov/licensing/medical-marijuana/
index.php. Accessed July 5, 2015.
7. The Medical Board of California. Marijuana for medical purposes.
Available at: www.mbc.ca.gov/Licensees/Prescribing/Medi-
cal_Marijuana.aspx. Accessed July 5, 2015.
8. Colorado Department of Public Health and Environment.
Medical marijuana statutes, regulations, and policies. Available at:
www.colorado.gov/pacic/cdphe/medicalmarijuana. Accessed
July 5, 2015.
9. State of Delaware Department of Health and Social Services,
Division of Public Health. Medical marijuana program.
Available at: http://dhss.delaware.gov/dph/hsp/medmarhome.
html. Accessed July 5, 2015.
10. State of Hawaii Department of Public Safety, Narcotics Enforce-
ment Division. Hawaii medical use of marijuana. Available at:
http://dps.hawaii.gov/wp-content/uploads/2012/09/Physian-
Information-Med-Marijuana-rev113011.pdf. Accessed July 5, 2015.
11. Seamon MJ, Fass JA, Maniscalco-Feichtl M, Abu-Shraie NA.
Medical marijuana and the developing role of the pharmacist.
Am J Health Syst Pharm 2007;64:10371044.
12. American Pharmacists Association. Role of the pharmacist in the
care of patients using cannabis. Available at: www.pharmacist.
com/2015policytopic-cannabis. Accessed December 3, 2015.
13. Report of the 2015 APhA House of Delegates. J Am Pharm Assoc (2003)
2015;55(4):364375. doi: 10.1331/JAPhA.2015.15529.
14. Daigle L. ASHP policy analysis: medical marijuana. Available
at: www.ashp.org/DocLibrary/Advocacy/AnalysisPaper/
ASHP-Medical-Marijuana-Policy-Analysis.aspx. Accessed
December 3, 2015. Q
APPENDIX
Survey on Pharmacists Knowledge of and Concerns
About Medical Cannabis Use and Regulations by the
Minnesota Medical Cannabis Program
Demographic Information
1. Please select your age range:
 Less than 34
 3544
 4554
 5564
 6574
 75+
2. What is your primary pharmacy practice setting? (Select one.)
 Academics
 Community
 Clinic
 Managed care
 Hospital
 Hospice/Assisted living facility
3. Which of the following areas do you practice in?
 Rural
 Urban/Suburban
Knowledge Assessment
4. In May 2014, the medical cannabis legislation was signed into law in
Minnesota. Which of the following dosage forms are permitted for use?
(Select all that apply.)
 Smoked marijuana leaves
 Inhaled marijuana from cannabis extract
 Topical cannabis lotion or ointment
 Cannabis extracts in oral pill form
appendix continues

Vol. 41 No. 11 November 2016 P&T 721

 Minnesota Pharmacists and Medical Cannabis: A Preparedness Survey
5. Which of the following medical conditions are eligible for medical 11. In continuation with the previous question, if you have other concern(s)
cannabis use in Minnesota? (Select all that apply.) regarding the use of medical cannabis that did not appear on the list,
 Cancer-related pain please explain in the provided space below:
 Rheumatoid arthritis
 Terminal illness with less than one year of life expectancy _________________________________________________________________
 Seizures/epilepsy 12. Do you have any concerns about how the Minnesota Medical Cannabis
 Hydrocephalus Program will impact your current practice?
 Tourette syndrome  Yes (please explain below)
 Migraine
 ALS _________________________________________________________________
 Crohns disease  No
 Hepatitis C  Unsure
 Glaucoma
 HIV/AIDS 13. On the scale of 17, how prepared are you to provide medication
 Severe and persistent muscle spasms counseling to patients who use medical cannabis as part of their
medication regimen? (Select one.)
6. Which of the following statement(s) is/are true? (Select all true (1 = not at all prepared; 7 = very much prepared)
statement[s].)
1 2 3 4 5 6 7
 Prescriptions are needed to purchase medical cannabis products in
Minnesota Future Education and Information
 Enrollment in the Minnesota States patient registry is required to obtain
medical cannabis products 14. To provide you with more education and information, please select the
 Pharmacists can certify patients eligibility for Minnesotas Medical topics about Minnesotas Medical Cannabis Program you would like to
Cannabis Program learn more about. (Select all that apply.)
 Advanced practice registered nurses (nurse practitioners) can certify  State rules and regulations governing the Minnesota Medical Cannabis
patients eligibility for Minnesotas Medical Cannabis Program Program
 Medical doctors can certify patients eligibility for Minnesotas Medical  Federal laws related to marijuana
Cannabis Program  Medical cannabis pharmacotherapy
 None of the above statements is true  Available types and forms of medical cannabis products on the market
 I am not interested in learning about Minnesotas Medical Cannabis
7. What is the role of pharmacists who are employed in Minnesotas Program (do not proceed beyond this question)
Medical Cannabis Program? (Select all true statement[s].)  Other (please specify below):
 Pharmacists guide patients selection of medical cannabis products
 Pharmacists provide assistance for patients at the distribution centers _______________________________________________________________
 Pharmacists determine patients eligibility for medical cannabis use
 Pharmacists dispense medical cannabis products at eligible pharmacies 15. Based on your selection(s) from the previous question, which is the top
 None of the above statements is true topic youre most interested in? (Select one.)
 State rules and regulations governing the Minnesota Medical Cannabis
8. Under the Controlled Substances Act (CSA), how is medical cannabis Program
classied? (Select one.)  Federal laws related to marijuana
 Schedule I  Medical cannabis pharmacotherapy
 Schedule II  Available types and forms of medical cannabis products on the market
 Schedule III  Other (please specify below):
 Schedule IV
 Schedule V ________________________________________________________________
Concerns Assessment 16. Please rank the top three choices of the following as your primary
resource of information related to the Minnesota Medical Cannabis
9. On the scale of 17, please rate your competency level in medical
Program? (1 = top choice; 3 = less preferred choice)
cannabis pharmacotherapy knowledge in the following areas
 Minnesota Board of Pharmacy
(1 = poor; 7 = excellent):
 Minnesota Department of Health
Pharmacology:  Minnesota Pharmacist Association
1 2 3 4 5 6 7  None; I have no interest in the topic
Pharmacokinetics:  Other (please specify below):
1 2 3 4 5 6 7
Pharmacodynamics: _______________________________________________________________
1 2 3 4 5 6 7 17. What is/are your preferred method(s) to receive information and
10. On the scale of 17, how concerned are you about the following factors education about the Minnesota Medical Cannabis Program?
regarding the use of medical cannabis? Not Preferred Preferred Most Preferred
(1 = no concern; 7 = most concern) E-mail:   
Safety concerns of cannabis use (i.e., drug interactions, contraindications, Mail:   
and adverse reactions) Conference:   
1 2 3 4 5 6 7 Online Course:   
Consistency in quality of medical cannabis products Other (please specify below):
1 2 3 4 5 6 7
Federal regulation related to cannabis ________________________________________________________________
1 2 3 4 5 6 7
Psychoactive effect and potential addiction from cannabis use
1 2 3 4 5 6 7
Limited evidence of therapeutic benets from cannabis use
1 2 3 4 5 6 7

722 P&T November 2016 Vol. 41 No. 11

 RESEARCH BRIEFS
Doxazosin Versus Prazosin in PTSD
Prazosin, used to treat symptoms of post-traumatic stress
disorder (PTSD), has some drawbacks, say clinicians from Xavier
University and George Washington University. They performed
a comparecontrast review and concluded that prazosins me-too
version, doxazosin, may be a better choice for several reasons.
For one, prazosins short half-life (two to three hours)
and duration of action (six to 10 hours) mean patients need
multiple daytime doses. Patients also need to take varying
doses, a complication that can make it more difcult for them to
stick to the regimen. In addition, the benecial effects wear off
within three hours, which can lead to nightmares in the latter
half of regular sleep.
In contrast, doxazosin offers distinct advantages. One of the
major benets is a long half-life (16 to 30 hours), meaning it
can be taken much less often than prazosineven once daily.
That pared-down regimen can help with medication adherence.
Research has shown doxazosin is safe and effective in patients
with PTSD. The authors cite, for instance, a case report about
a combat veteran who took 4 mg daily for eight weeks and
had improved sleep quality, suffered fewer and less intense
trauma-related nightmares, and was able to function better in
the daytime.
Studies, although small, have found doxazosin signicantly
improved PTSD symptoms. One 12-week study of 51 patients
found a signicant drop in nightmares. Approximately 25% of
the patients experienced full remission. Those researchers also
found sleep recuperation improved within the rst four weeks
of treatment with doxazosin.
While prazosin compares well on certain adverse effects,
such as dizziness and headache, doxazosin scores better on
drowsiness, palpitations, anxiety, depression, and hallucina-
tions. It also has an improved absorption prole, reducing the
risk of hypotension.
Source: Psychiatric Annals, September 2016
Global Polio Vaccine Switch a Success
Type-2 circulating vaccine-derived polioviruses (cVDPV2s)
have caused hundreds of cases of paralytic poliomyelitis since
2006. The type-2 component of oral poliovirus (OPV) vaccine
was therefore scheduled for global withdrawal, and a synchro-
nized switch was planned: from trivalent oral poliovirus vaccine
(tOPV) to bivalent oral poliovirus vaccine (bOPV).
The 155 countries and territories that use OPV in their
immunization programs have reported that they had com-
pletely stopped using tOPV by May 2016. (All manufacturers
of OPV ended production of tOPV before the switch.) All
countries not already using inactivated polio vaccine (IPV) have
committed to introducing it. As of August 2016, 173 of 194
World Health Organization countries had introduced IPV into
their programsdespite a global shortage of IPV.
The global cooperation in stopping tOPV use has gone
smoothly and is unprecedented, according to the Centers
for Disease Control and Prevention (CDC). But while its
a milestone in the effort to eradicate polio, vigilance is still
needed: Any tOPV found in a vaccine storage refrigerator
or freezer should be destroyed. All remaining type-2 polio-
viruses, including type-2 wild poliovirus, VDPV2s, and the type-2
Sabin polioviruses used in tOPV and monovalent OPV type-2
(mOPV2) should be destroyed or appropriately contained in
certied poliovirus-essential facilities.
If type-2 poliovirus outbreaks do occur, the United Nations
Childrens Fund has a global stockpile of approximately
36 million doses of mOPV2, with 100 million more to become
available soon. Hundreds of millions of doses stored in bulk
form are also available for conversion, the CDC says.
Ultimately, we wont know how well the process went until
we know the number of polio cases caused by cVDPV2s that
arise after the tOPV withdrawal, the CDC says, with fewer
cases indicating a greater success. As of August 31, 2016, no
new circulating VDPV outbreaks had been identied in 2016.
Source: Morbidity and Mortality Weekly Report, September
2016
New Program Offers Medication Therapy
Management Services to PCPs
Primary care physicians (PCPs) often dont have the time
to manage the complex medication needs of patients with
chronic conditions, and PCPs working in federally qualied
health centers (FQHCs) who care for low-income, at-risk
patients face particularly large barriers, according to the
Agency for Healthcare Research and Quality (AHRQ). But
that lack of time can contribute to low patient adherence to
medication regimens.
While clinical pharmacists can help, they may not be available
to FQHCs, PCP ofces, and other primary care settingsso
innovators in Ohio established a statewide consortium or
shared learning community that provides the resources for
FQHCs to offer pharmacist-led medication therapy management
(MTM) services to patients with diabetes or hypertension.
The collaborating organizations include the Ohio Association
for Community Health Centers, the Health Services Advisory
Group, and six Ohio-based colleges of pharmacy.
The programs developers, Jennifer Rodis, PharmD, BCPS,
FAPhA, Assistant Dean for Outreach and Engagement at the
Ohio State University (OSU) College of Pharmacy, and Barbara
Pryor, MS, RD, LD, Manager of the Chronic Disease Section
in the Ohio Department of Health (ODH), reported on the
consortiums program and successes in AHRQs Health Care
Innovations Exchange.
Program leaders meet with participating pharmacists to
orient them; those pharmacists then introduce the program
Vol. 41 No. 11 November 2016 P&T
723
 RESEARCH BRIEFS
to clinicians and staff at their respective practice sites. Every
month, they check in with program leaders from the ODH, the
OSU College of Pharmacy, and Ohio Association of Community
Health Centers to give status updates and get guidance and
troubleshooting advice.
The consortium has markedly increased the number of
FQHCs offering pharmacist-led MTM services, as well as boost-
ing awareness and interest in MTM. When the program began
in 2013, very few of the 41 FQCHs in Ohio had pharmacist-led
MTM programs, the AHRQ report says. Nine FQHCs now
participate in the consortium.
During the rst year, the three participating sites enrolled
nearly 400 eligible patients with out-of-control hypertension
or diabetes. By the end of that year, 68% of the hypertensive
patients had controlled their blood pressure, and 45% of patients
with diabetes were controlling their hemoglobin A1c. The
pharmacists providing MTM addressed 75 adverse drug events
and remedied 145 potential events.
Source: AHRQ, September 2016
Nurses Health Study Points to Risk Factors,
Biomarkers for Some Cancers
Certain lifestyle, dietary, environmental, serological, and
genetic factors may raise the risk of non-Hodgkins lymphoma
(NHL), according to researchers who reviewed 40 years of
follow-up data from the Nurses Health Study (NHS).
The researchers from Brigham and Womens Hospital,
Harvard University, and Boston University aimed to highlight
the NHSs contributions to epidemiologic knowledge of endo-
metrial, ovarian, pancreatic, and hematological cancers. Among
other things, they focused on ndings that identied novel risk
factors and markers of early detection, or helped clarify discrep-
ant literature.
Because severe immune compromise is the strongest, best-
established risk factor for NHL, the researchers say, they studied
factors that might lead to subclinical immune dysregulation, such
as diet, body mass index (BMI), and supplement use. They found
a number of risk factors and biomarkers for NHL and the more
than 35 distinct tumors in that category, including chronic lym-
phocytic leukemia (CLL). Trans fats and red meat, for instance,
doubled the risk of NHL. The researchers also found a higher risk
for women who reported long-term multivitamin use. However,
they found no risk associated with diet or sugar-sweetened soda
or aspartame, or with dietary intake of vitamin D.
Greater adiposity during childhood and adolescence was
signicantly associated with NHL. The researchers also observed
a 19% increased risk of all NHL per 5-kg/m2 increase in BMI in
young adulthood. Interestingly, taller women also had a higher
risk of NHL.
The researchers conducted one of the rst prospective studies
to evaluate a putative inverse association of NHL risk with
724 P&T November 2016 Vol. 41 No. 11
exposure to ambient ultraviolet radiation. They found, contrary
to expectation, a 10% to 20% increased risk of NHL among
women with the highest (versus lowest) ultraviolet-B exposure
at baseline and birth, 5 years, and 30 years.
In investigating biomarkers, the researchers noted a
suggestive increase in CLL risk associated with an Epstein-Barr
virus antibody prole indicative of poor host immune control
of the virus.
The researchers have established several working groups
to study cancers such as NHL and multiple myeloma. They
are also collecting archival tissue specimens for NHL,
multiple myeloma, and Hodgkins lymphoma for better eval-
uation of factors related to the unique molecular subsets of
hematological tumors.
Source: American Journal of Public Health, September 2016
Predicting Flu Epidemics
Its easy to see there might be a seasonal link between
epidemic waves of respiratory syncytial virus (RSV)
infections and inuenza. But forecasting seasonal patterns
with accuracy isnt so easy, due to the many varieties of u
and environmental factors.
Researchers from the Public Health Center of Valencia and
University of Valencia in Spain say they have a way to predict
an inuenza epidemic three to four weeks in advance. And
that could allow for more effective vaccination programs and
inuenza prophylaxis.
They used two epidemiologic surveillance systems: One
(AVE), in use in Eastern Spain since 2004, collects real-time
data from notiable disease outbreaks and alerts. The second,
RedMIVA, collects cases of RSV.
The researchers conducted a study that lasted from week 40
of 2010 to week 8 of 2014. During that time, 239,321 people
reported cases of u, and 19,676 cases of RSV were recorded,
with 5,112 laboratory conrmed. Most (85%) of the RSV cases
were children 1 year of age and younger.
Using the data from the surveillance systems, the researchers
found that the peak of maximum activity of the inuenza virus
appears at least three weeks after the RSV peak.
They also found evidence suggesting that RSV infection has
a short-term protective effect against type A (H1N1) inuenza
infection. The seasons with the highest number of recorded
cases of RSV coincided with the lowest number of inuenza
cases. In both seasons, the predominant inuenza virus was
type A (H1N1).
Source: Epidemiology and Infection, September 2016 Q
 Prescription Drug Data Might Help Protect Obamacare
continued from page 691
persons individual risk score. Finally, if the enrollee is receiv-
ing subsidies to reduce his or her cost-sharing, an induced
utilization factor is applied to account for induced demand.
Plans with enrollees who receive cost-sharing reductions under
the PPACA receive an adjustment because cost-sharing reduc-
tions may induce demand for health care and are not otherwise
accounted for in the other premium stabilization programs.
The HCC-based methodology has weaknesses, however.
It doesnt always uncover the full range of a patients issues.
Some physicians might be hesitant to record conditions with
stigmas. Clinical diagnostic reporting systems may focus on
the diagnosis under current treatment, and not record the full
set of a patients underlying conditions. A signicant percent-
age of marketplace plan-holders it in and out of the market,
sometimes changing plans, sometimes dropping insurance
temporarily. When they exit the marketplace, data on their
treatment do not exist. So when they return to the marketplace,
the full extent of their health situation is not clear. One benet
of drug utilization data is that they are much easier to tap into
and can be found for patients even when they are outside
the marketplace. Those prescription data provide clues about
previously unknown health conditions.
In addition, HCCs do not measure the progression of a dis-
ease. Normally, the sicker someone gets, the more expensive
his or her treatment becomes. Drug utilization may provide
insights into the progression of an illness as a patient moves
from rst-line to second-line treatments and so on.
Potential Flaws of Adding Drug Utilization Data
Including drug utilization in risk assessment opens the
door to potential problems. It may encourage companies to
prescribe inexpensive drugs included in therapeutic classes
that are statistically linked to high total medical expenditures.
In that way, a small cost to the insurance plan could bring a
relatively large increase in revenue. A corollary here is that
physicians, ostensibly encouraged directly or indirectly by the
plan, could prescribe a drug for a patient for whom that drug
may be called foror may not bebecause the patient is at
the outer edge of the clinical indication.
Then, of course, there is the possibility that plans might
decide it is in their best nancial interests to avoid managing
drug utilization, or to look less kindly on nondrug treatments,
or to lean toward use of the specic drug therapeutic classes
linked to getting them payments in risk adjustment.
Another potential issue is that prescription data are avail-
able only for outpatient use, not for inpatient hospitalization.
Hospitalized patients may appear to be less severely ill as a
result. Moreover, some QHPs have lower prescribing rates than
others. That is especially true for plans covering individuals in
rural areas with low access to pharmacies. Those plans would
incorrectly appear to have healthier populations, and they
would pay higher risk charges or receive lower risk payments.
Then there is the formulary variability within plans of dif-
ferent colors. The most expensive plans at the platinum and
gold levels might appear to have much higher drug utilization
because their formularies are much more complete, and their
copays and deductibles are low. They may be much less likely
than a plan at the bronze level to use utilization management
tools, such as prior authorization and step therapy, which help
keep costs in line. So members of a gold plan might appear to
be much sicker, based on the drug data, than those in a bronze
plan. But that is not necessarily so.
To the layman, this 12 RXC model appears incredibly com-
plex and seems to leave plenty of room for interpretation. You
have to be an actuary to understand this, one pharmaceutical
ofcial says. However, it is unusual for a CMS rulemaking to
attract the kind of unanimous support this one has. Everyone
thinks it is a good idea to add prescription drug data to the
risk-adjustment model. I love that CMS is taking this rst set
of RXCs for a test drive, says one industry ofcial. They are
not implying their model is perfect but acknowledging there
is room for further renement.
REFERENCES
1. Centers for Medicare and Medicaid Services. Patient Protection
and Affordable Care Act; HHS notice of benet and payment
parameters for 2018. Fed Regist 2016;81(72):6145661536.
2. Centers for Medicare and Medicaid Services. March 31, 2016,
HHS-operated risk adjustment methodology meeting. Discus-
sion paper. March 24, 2016. Available at: www.cms.gov/CCIIO/
Resources/Forms-Reports-and-Other-Resources/Downloads/RA-
March-31-White-Paper-032416.pdf. Accessed September 29, 2016. Q
Accessibility of Formulary Information
continued from page 702
ACKNOWLEDGEMENT
The surviving authors dedicate this publication to the late
Julie Karpinski, PharmD, BCPS, whose drive and dedication to
this project and the profession of pharmacy were an inspiration.
REFERENCES
1. Tyler LS, Cole SW, May JR, et al. ASHP guidelines on the
pharmacy and therapeutics committee and the formulary system.
Am J Health Syst Pharm 2008;65(13):12721283.
2. The Joint Commission. Elements of performanceMM.02.01.01.
In: Hospital Accreditation Standards. Oakbrook, Illinois: Joint
Commission Resources; 2011.
3. Leonard MC. Cleveland Clinic Foundation multi-platform
formulary. U.S. Pharmacist 2004:29.
4. Grossman JM, Boukus ER, Cross DA, Cohen GR. Physician
practices, e-prescribing, and accessing information to improve
prescribing decisions. Res Brief 2011;(20):110.
5. Johnston KS, Fox ER, Beckwith MC. Integrating medication
management information into the online formulary at a tertiary
academic medical center. Am J Health Syst Pharm 2014;71(12):
981, 986.
6. Albarana T, Cecere D. A multi-hospital formulary and drug
information website. Pharmacy Purchasing and Products 2012;
9(2):44.
7. Meaningful use. Hudson, Ohio: Lexicomp, Inc.: 2014. Accessed
August 2014.
8. McManus R, Nemec EC, Ferer DS, et al. Suggested denitions for
informatics terms: interfacing, integration, and interoperability.
Am J Health Syst Pharm 2012;69:11631165.
9. Fischer MA, Choudhry NK, Brill G, et al. Trouble getting start-
ed: predictors of primary medication nonadherence. Am J Med
2011;124(11):1081.e922. doi: 10.1016/j.amjmed.2011.05.028.
10. Michelis KC, Choi BG. Getting started: the benefit of
formulary decision support. Am J Med 2012;125(9):e7.
doi: 10.1016/j.amjmed.2011.11.031. Q
Vol. 41 No. 11 November 2016 P&T
725
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