AHDB November December 2013 Vol 6, No 9 by Dalia Buffery

The Peer-Reviewed Forum for Real-World Evidence in Benefit Design ™ November/December 2013 Volume 6, Number 9

For Payers, Purchasers, Policymakers, and Other Healthcare Stakeholders

EDITORIAL

Practicing Population Health David B. Nash, MD, MBD

The Affordable Care Act Conundrum: Facing Reality in America’s Giant Social Experiment Kip Piper, MA, FACHE CLINICAL ™

Pharmacy Staff Opinions Regarding Diabetic Retinopathy Screenings in the Community Setting: Findings from a Brief Survey Miranda G. Law, BS, PharmD Candidate; Stephanie Komura, BS, PharmD Candidate; Ann P. Murchison, MD, MPH; Laura T. Pizzi, PharmD, MPH Stakeholder Perspective by Gary M. Owens, MD BUSINESS

Modeling the Frequency and Costs Associated with Postsurgical Gastrointestinal Adverse Events for Tapentadol IR versus Oxycodone IR Andrew Paris, MBS; Chris M. Kozma, PhD; Wing Chow, PharmD, MPH; Anisha M. Patel, MS; Samir H. Mody, PharmD, MBA; Myoung S. Kim, PhD, MBA Stakeholder Perspective by Matthew Mitchell, PharmD, MBA

Insurance Companies’ Perspectives on the Orphan Drug Pipeline Robert Handfield, PhD; Josh Feldstein Stakeholder Perspective by Atheer A. Kaddis, PharmD Industry Trends

“Project IMPACT: Diabetes” Care Model Improves Health Outcomes in Underserved Populations in 25 Communities with a High Incidence of Diabetes By Benjamin M. Bluml, RPh

EST. 2008

YEAR ANNIVERSARY

Cost and Drug Utilization Patterns Associated with the Management of Rosacea Rehospitalization Is Driving Costs in Pulmonary Arterial Hypertension

Take a bite out of G-CSF acquisition costs*

*Based on wholesale acquisition cost (WAC) of all short-acting G-CSF products as of November 11, 2013. WAC represents published catalogue or list prices and may not represent actual transactional prices. Please contact your supplier for actual prices.

Indication » GRANIX (tbo-filgrastim) Injection is a leukocyte growth factor indicated for reduction TM

in the duration of severe neutropenia in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia.

Important Safety Information » Splenic rupture: Splenic rupture, including fatal cases, can occur following the administration of human granulocyte colony-stimulating factors (hG-CSFs). Discontinue GRANIX and evaluate for an enlarged spleen or splenic rupture in patients who report upper abdominal or shoulder pain after receiving GRANIX.

» Acute respiratory distress syndrome (ARDS): ARDS can occur in patients receiving hG-CSFs. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS.

» Allergic reactions: Serious allergic reactions, including anaphylaxis, can occur in patients receiving hG-CSFs. Reactions can occur on initial exposure. Permanently discontinue GRANIX in patients with serious allergic reactions. Do not administer GRANIX to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim.

NOW AVAILABLE

GRANIX is a new option in short-acting G-CSF therapy TM

» FDA approved through the rigorous BLA† process » Teva’s filgrastim, the same compound as GRANIX, was first introduced in Europe in 2008 and is available in 39 countries outside the US‡1

» GRANIX is an option for hospitals and payers to consider when determining health system budgets A unique J-code is expected for GRANIX in January 2014 † ‡

Biologics License Application. As of November 2013.

Important Safety Information (continued) » Use in patients with sickle cell disease: Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving hG-CSFs. Consider the potential risks and benefits prior to the administration of GRANIX in patients with sickle cell disease. Discontinue GRANIX in patients undergoing a sickle cell crisis.

» Potential for tumor growth stimulatory effects on malignant cells: The granulocyte colonystimulating factor (G-CSF) receptor, through which GRANIX acts, has been found on tumor cell lines. The possibility that GRANIX acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which GRANIX is not approved, cannot be excluded.

» Most common treatment-emergent adverse reaction: The most common treatment-emergent adverse reaction that occurred in patients treated with GRANIX at the recommended dose with an incidence of at least 1% or greater and two times more frequent than in the placebo group was bone pain. Please see brief summary of Full Prescribing Information on adjacent page. For more information, visit GRANIXhcp.com. Reference: 1. Data on file. Teva Pharmaceuticals: Filgrastim MA Approvals Worldwide. May 2013.

BRIEF SUMMARY OF PRESCRIBING INFORMATION FOR GRANIX™ (tbo-filgrastim) Injection, for subcutaneous use SEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE GRANIX is indicated to reduce the duration of severe neutropenia in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Splenic Rupture Splenic rupture, including fatal cases, can occur following administration of human granulocyte colony-stimulating factors. In patients who report upper abdominal or shoulder pain after receiving GRANIX, discontinue GRANIX and evaluate for an enlarged spleen or splenic rupture. 5.2 Acute Respiratory Distress Syndrome (ARDS) Acute respiratory distress syndrome (ARDS) can occur in patients receiving human granulocyte colony-stimulating factors. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS. 5.3 Allergic Reactions Serious allergic reactions including anaphylaxis can occur in patients receiving human granulocyte colony-stimulating factors. Reactions can occur on initial exposure. The administration of antihistamines‚ steroids‚ bronchodilators‚ and/or epinephrine may reduce the severity of the reactions. Permanently discontinue GRANIX in patients with serious allergic reactions. Do not administer GRANIX to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim. 5.4 Use in Patients with Sickle Cell Disease Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving human granulocyte colony-stimulating factors. Consider the potential risks and benefits prior to the administration of human granulocyte colony-stimulating factors in patients with sickle cell disease. Discontinue GRANIX in patients undergoing a sickle cell crisis. 5.5 Potential for Tumor Growth Stimulatory Effects on Malignant Cells The granulocyte colony-stimulating factor (G-CSF) receptor through which GRANIX acts has been found on tumor cell lines. The possibility that GRANIX acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which GRANIX is not approved, cannot be excluded. 6 ADVERSE REACTIONS The following potential serious adverse reactions are discussed in greater detail in other sections of the labeling: • Splenic Rupture [see Warnings and Precautions (5.1)] • Acute Respiratory Distress Syndrome [see Warnings and Precautions (5.2)] • Serious Allergic Reactions [see Warnings and Precautions (5.3)] • Use in Patients with Sickle Cell Disease [see Warnings and Precautions (5.4)] • Potential for Tumor Growth Stimulatory Effects on Malignant Cells [see Warnings and Precautions (5.5)] The most common treatment-emergent adverse reaction that occurred at an incidence of at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group was bone pain. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. GRANIX clinical trials safety data are based upon the results of three randomized clinical trials in patients receiving myeloablative chemotherapy for breast cancer (N=348), lung cancer (N=240) and non-Hodgkin’s lymphoma (N=92). In the breast cancer study, 99% of patients were female, the median age was 50 years, and 86% of patients were Caucasian. In the lung cancer study, 80% of patients were male, the median age was 58 years, and 95% of patients were Caucasian. In the non-Hodgkin’s lymphoma study, 52% of patients were male, the median age was 55 years, and 88% of patients were Caucasian. In all three studies a placebo (Cycle 1 of the breast cancer study only) or a nonUS-approved filgrastim product were used as controls. Both GRANIX and the non-US-approved filgrastim product were administered at 5 mcg/kg subcutaneously once daily beginning one day after chemotherapy for at least five days and continued to a maximum of 14 days or until an ANC of ≥10,000 x 106/L after nadir was reached. Bone pain was the most frequent treatment-emergent adverse reaction that occurred in at least 1% or greater in patients treated with GRANIX at the

recommended dose and was numerically two times more frequent than in the placebo group. The overall incidence of bone pain in Cycle 1 of treatment was 3.4% (3.4% GRANIX, 1.4% placebo, 7.5% non-US-approved filgrastim product). Leukocytosis In clinical studies, leukocytosis (WBC counts > 100,000 x 106/L) was observed in less than 1% patients with non-myeloid malignancies receiving GRANIX. No complications attributable to leukocytosis were reported in clinical studies. 6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving GRANIX has not been adequately determined. 7 DRUG INTERACTIONS No formal drug interaction studies between GRANIX and other drugs have been performed. Drugs which may potentiate the release of neutrophils‚ such as lithium‚ should be used with caution. Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone imaging changes. This should be considered when interpreting bone-imaging results. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C There are no adequate and well-controlled studies of GRANIX in pregnant women. In an embryofetal developmental study, treatment of pregnant rabbits with tbo-filgrastim resulted in adverse embryofetal findings, including increased spontaneous abortion and fetal malformations at a maternally toxic dose. GRANIX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In the embryofetal developmental study, pregnant rabbits were administered subcutaneous doses of tbo-filgrastim during the period of organogenesis at 1, 10 and 100 mcg/kg/day. Increased abortions were evident in rabbits treated with tbo-filgrastim at 100 mcg/kg/day. This dose was maternally toxic as demonstrated by reduced body weight. Other embryofetal findings at this dose level consisted of post-implantation loss‚ decrease in mean live litter size and fetal weight, and fetal malformations such as malformed hindlimbs and cleft palate. The dose of 100 mcg/kg/day corresponds to a systemic exposure (AUC0-24) of approximately 50-90 times the exposures observed in patients treated with the clinical tbo-filgrastim dose of 5 mcg/kg/day. 8.3 Nursing Mothers It is not known whether tbo-filgrastim is secreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when GRANIX is administered to a nursing woman. Other recombinant G-CSF products are poorly secreted in breast milk and G-CSF is not orally absorbed by neonates. 8.4 Pediatric Use The safety and effectiveness of GRANIX in pediatric patients have not been established. 8.5 Geriatric Use Among 677 cancer patients enrolled in clinical trials of GRANIX, a total of 111 patients were 65 years of age and older. No overall differences in safety or effectiveness were observed between patients age 65 and older and younger patients. 8.6 Renal Impairment The safety and efficacy of GRANIX have not been studied in patients with moderate or severe renal impairment. No dose adjustment is recommended for patients with mild renal impairment. 8.7 Hepatic Impairment The safety and efficacy of GRANIX have not been studied in patients with hepatic impairment. 10 OVERDOSAGE No case of overdose has been reported.

©2013 Cephalon, Inc., a wholly owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved. GRANIX is a trademark of Teva Pharmaceutical Industries Ltd. Manufactured by: Sicor Biotech UAB Vilnius, Lithuania U.S. License No. 1803 Distributed by: Teva Pharmaceuticals USA, Inc. North Wales, PA 19454 Product of Israel FIL-40045 July 2013 This brief summary is based on TBO-003 GRANIX full Prescribing Information.

editorial board Editor-in-Chief

David B. Nash, MD, MBA Dean, the Dr Raymond C. and Doris N. Grandon Professor, Jefferson School of Population Health Philadelphia, PA Deputy Editors

Joseph D. Jackson, PhD Program Director, Applied Health Economics and Outcomes Research, Jefferson University School of Population Health, Philadelphia Laura T. Pizzi, PharmD, MPH, RPh Associate Professor, Dept. of Pharmacy Practice, Jefferson School of Pharmacy, Philadelphia Aging and Wellness

Eric G. Tangalos, MD, FACP, AGSF, CMD Professor of Medicine Mayo Clinic, Rochester, MN CANCER RESEARCH

Al B. Benson, III, MD, FACP, FASCO Professor of Medicine, Associate Director for Clinical Investigations Robert H. Lurie Comprehensive Cancer Center Northwestern University, IL Past Chair, NCCN Board of Directors Samuel M. Silver, MD, PhD, FASCO Professor of Internal Medicine, Hematology/Oncology Assistant Dean for Research, Associate Director, Faculty Group Practice, University of Michigan Medical School EMPLOYERS

Arthur F. Shinn, PharmD, FASCP President, Managed Pharmacy Consultants, LLC, Lake Worth, FL F. Randy Vogenberg, RPh, PhD Principal, Institute for Integrated Healthcare Greenville, SC ENDOCRINOLOGY

James V. Felicetta, MD Chairman, Dept. of Medicine Carl T. Hayden Veterans Affairs Medical Center, Phoenix, AZ Quang Nguyen, DO, FACP, FACE Medical Director, Las Vegas Endocrinology Adjunct Associate Professor Endocrinology Touro University Nevada EPIDEMIOLOGY Research

Joshua N. Liberman, PhD Executive Director, Research, Development & Dissemination, Sutter Health, Concord, CA

Steven Miff, PhD Senior Vice President VHA, Inc., Irving, TX Terri S. Moore, PhD, RPh, MBA Senior Manager, Product Development URAC, Washington, DC Kavita V. Nair, PhD Professor and Director, Graduate Program Track in Pharmaceutical Outcomes Research Skaggs School of Pharmacy and Pharmaceutical Sciences University of Colorado, Aurora Gary M. Owens, MD President, Gary Owens Associates Ocean View, DE Andrew M. Peterson, PharmD, PhD Dean, Mayes School of Healthcare Business and Policy, Associate Professor, University of the Sciences, Philadelphia Sarah A. Priddy, PhD Director, Competitive Health Analytics Humana, Louisville, KY Timothy S. Regan, BPharm, RPh, CPh Executive Director, Strategic Accounts Xcenda, Palm Harbor, FL Vincent J. Willey, PharmD Associate Professor, School of Pharmacy, University of the Sciences, Philadelphia Paul Wilson Senior VP, Health Consumer Insights and Analytics, Blue Bell, PA David W. Wright, MPH President, Institute for Interactive Patient Care Bethesda, MD

PATIENT ADVOCACY

Russell Basser, MBBS, MD, FRACP Senior Vice President Global Clinical Research and Development CSL Behring, King of Prussia, PA Diana Brixner, RPh, PhD Professor & Chair, Dept. of Pharmacotherapy Executive Director, Outcomes Research Center, Director of Outcomes, Personalized Health Care Program, University of Utah, Salt Lake City Joseph E. Couto, PharmD, MBA Clinical Program Manager Cigna Corporation, Bloomfield, CT

Vol 6, No 9

November/December 2013

Joseph R. Antos, PhD Wilson H. Taylor Scholar in Health Care Retirement Policy, American Enterprise Institute Washington, DC Robert W. Dubois, MD, PhD Chief Science Officer National Pharmaceutical Council, Washington, DC Jack E. Fincham, PhD, RPh Professor of Pharmacy, School of Pharmacy University of Missouri, Kansas City, MO Walid F. Gellad, MD, MPH Assistant Professor of Medicine, University of Pittsburgh, Staff Physician, Pittsburgh VA Medical Center, Adjunct Scientist, RAND Health Paul Pomerantz, MBA CEO, American Society of Anesthesiologists Park Ridge, IL J. Warren Salmon, PhD Professor of Health Policy & Administration School of Public Health University of Illinois at Chicago Raymond L. Singer, MD, MMM, CPE, FACS Chief, Division of Cardiothoracic Surgery Vice Chair, Department of Surgery for Quality & Patient Safety and Outreach Lehigh Valley Health Network, PA

MANAGED MARKETS

HEALTH INFORMATION TECHNOLOGY

HEALTH OUTCOMES RESEARCH

POLICY & PUBLIC HEALTH

Craig Deligdish, MD Hematologist/Oncologist Oncology Resource Networks, Orlando, FL Thomas G. McCarter, MD, FACP Chief Clinical Officer Executive Health Resources, PA Albert Tzeel, MD, MHSA, FACPE Regional Medical Director Medicare Operations, North Florida Humana, Jacksonville

Kevin B. “Kip” Piper, MA, FACHE President, Health Results Group, LLC Washington, DC Kelly Huang, PhD President, HealthTronics, Inc. Austin, TX Victor J. Strecher, PhD, MPH Professor and Director for Innovation and Social Entrepreneurship, University of Michigan School of Public Health and Medicine

Joel V. Brill, MD, AGAF, CHCQM Chief Medical Officer, Predictive Health, Phoenix, AZ Teresa DeLuca, MD, MBA Chief Medical Officer–Pharmacy Magellan Health Services Leslie S. Fish, PharmD Vice President of Clinical Programs Fallon Community Health Plan, MA John Hornberger, MD, MS Cedar Associates, LLC CHP/PCOR Adjunct Associate, Menlo Park, CA Michael S. Jacobs, RPh MSJ Associates, Sandy Springs, GA Matthew Mitchell, PharmD, MBA Director, Pharmacy Services SelectHealth, Murray, UT Paul Anthony Polansky, BSPharm, MBA PAPRx, LLC Gulph Mills, PA Christina A. Stasiuk, DO, FACOI Senior Medical Director Cigna, Philadelphia, PA

health & value promotion

Jeffrey A. Bourret, PharmD, MS, RPh, FASHP Senior Director, North America Medical Affairs Medical Lead, Specialty Payer & Channel Customer Strategy, Pfizer Inc. Richard B. Weininger, MD Chairman, CareCore National, LLC Bluffton, SC

GOVERNMENT

PHARMACY BENEFIT DESIGN

RESEARCH & DEVELOPMENT

Amalia M. Issa, PhD, MPH Director, Program in Personalized Medicine & Targeted Therapeutics, University of the Sciences, Philadelphia

Frank Casty, MD, FACP Chief Medical Officer Senior VP, Clinical Development Medical Science Endo Pharmaceuticals, Chadds Ford, PA Christopher (Chris) P. Molineaux President, Pennsylvania BIO Malvern, PA Michael F. Murphy, MD, PhD Chief Medical Officer and Scientific Officer Worldwide Clinical Trials King of Prussia, PA

PHARMACOECONOMICs

SPECIALTY PHARMACY

Mike Pucci Sr VP, Commercial Operations and Business Development, PhytoChem Pharmaceuticals Lake Gaston, NC Personalized medicine

Josh Feldstein President & CEO, CAVA, The Center for Applied Value Analysis, Inc., Norwalk, CT Jeff Jianfei Guo, BPharm, MS, PhD Professor of Pharmacoeconomics & Pharmacoepidemiology, College of Pharmacy, Univ. of Cincinnati Medical Center, OH Grant D. Lawless, RPh, MD, FACP Assoc. Prof. and Director, Healthcare Decision Analysis, Dept. of Clinical Pharmacy Univ. of Southern California, Los Angeles

www.AHDBonline.com

Atheer A. Kaddis, PharmD Senior Vice President Sales and Business Development Diplomat Specialty Pharmacy, Flint, MI James T. Kenney, Jr, RPh, MBA Pharmacy Operations Manager, Harvard Pilgrim Health Care, Wellesley, MA Michael Kleinrock Director, Research Development IMS Institute for Healthcare Informatics

American Health & Drug Benefits

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November/December 2013

Volume 6, number 9

The Peer-Reviewed Forum for REAL-World Evidence in Benefit Design ™

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Publishing Staff

Table of Contents

Senior Vice President/Group Publisher Nicholas Englezos nenglezos@the-lynx-group.com Directors, Client Services Joe Beck jbeck@the-lynx-group.com Zach Ceretelle zceretelle@the-lynx-group.com Ron Gordon rgordon@the-lynx-group.com Editorial Director Dalia Buffery dbuffery@the-lynx-group.com Associate Editor Lara J. Lorton Editorial Assistants Jennifer Brandt Cara Guglielmon Senior Production Manager Lynn Hamilton Founding Editor-in-Chief Robert E. Henry

EDITORIAL

539 Practicing Population Health David B. Nash, MD, MBD 542 The Affordable Care Act Conundrum: Facing Reality in America’s Giant Social Experiment Kip Piper, MA, FACHE CLINICAL

548 Pharmacy Staff Opinions Regarding Diabetic Retinopathy Screenings in the Community Setting: Findings from a Brief Survey Miranda G. Law, BS, PharmD Candidate; Stephanie Komura, BS, PharmD Candidate; Ann P. Murchison, MD, MPH; Laura T. Pizzi, PharmD, MPH 552 Stakeholder Perspective: Screening for Diabetic Retinopathy in the Community Setting: Exploring the Options By Gary M. Owens, MD business

567 Modeling the Frequency and Costs Associated with Postsurgical Gastrointestinal Adverse Events for Tapentadol IR versus Oxycodone IR Andrew Paris, MBS; Chris M. Kozma, PhD; Wing Chow, PharmD, MPH; Anisha M. Patel, MS; Samir H. Mody, PharmD, MBA; Myoung S. Kim, PhD, MBA 575 Stakeholder Perspective: Can Substituting Generic Drugs with Brand-Name Agents for Acute Pain Postsurgery Help to Deliver Cost-Effective, Quality Care By Matthew Mitchell, PharmD, MBA Continued on page 536

Mission Statement American Health & Drug Benefits is founded on the concept that health and drug benefits have undergone a transformation: the econometric value of a drug is of equal importance to clinical outcomes as it is to serving as the basis for securing coverage in formularies and benefit designs. Because benefit designs are greatly affected by clinical, business, and policy conditions, this journal offers a forum for stakeholder integration and collaboration toward the improvement of healthcare. This publication further provides benefit design decision makers the integrated industry information they require to devise formularies and benefit designs that stand up to today’s special healthcare delivery and business needs. Contact Information: For subscription information and editorial queries, please contact: editorial@engagehc.com; tel: 732-992-1892; fax: 732-992-1881.

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The Lynx Group President/CEO Brian Tyburski Chief Operating Officer Pam Rattananont Ferris Vice President of Finance Andrea Kelly Director, Human Resources Blanche Marchitto Associate Editorial Director, Projects Division Terri Moore Director, Quality Control Barbara Marino Quality Control Assistant Theresa Salerno Director, Production & Manufacturing Alaina Pede Director, Creative & Design Robyn Jacobs Creative & Design Assistant Lora LaRocca Director, Digital Media Anthony Romano Web Content Managers David Maldonato Anthony Trevean Digital Programmer Michael Amundsen Senior Project Manager Andrea Boylston Project Coordinators Deanna Martinez Jackie Luma Executive Administrator Rachael Baranoski Office Coordinator Robert Sorensen Engage Healthcare Communications 1249 South River Road, Suite 202A Cranbury, NJ 08512 Phone: 732-992-1880

November/December 2013

Vol 6, No 9

Helping Patients Move Closer to Their Health Goals Care Management Solutions offers resources designed with the whole patient in mind

For healthcare professionals

For consumers

An easy-to-use, interactive, Web-based resource used by thousands of organizations to help build targeted, population-based, care management initiatives.

An easy-to-use Web site that helps empower people to take charge of their health.

• Patient education in multiple languages

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• Resources for healthcare providers, including health coaching learning modules

• Self-care tools, surveys, and trackers

CareManagementCentral.com

• More than 1,000 health-literate care management tools • Quick access to several NCQA-certified* care management programs Visit CareManagementCentral.com. First-time users, register using one-time access code: gskcares Bronze award winner in the category of “Chronic Disease Portal Website” in the Summer/Fall 2012 HIRC (Health Information Resource Center) Web Health Awards. *National Committee for Quality Assurance (NCQA) has reviewed and certified the program design capability of the Care Management Solutions Group, GlaxoSmithKline.

HealthCoach4Me.com

• Online patient health library

• Spanish language version available Gold award winner in the category of “Patient Education Portal Website” in the Winter/Spring 2012 HIRC (Health Information Resource Center) Web Health Awards. October 2012 NCQA HIP** Certification in the area of Self Management Tools. **HIP, Health Information Products

To learn more, visit CareManagementCentral.com and HealthCoach4Me.com.

November/December 2013

Volume 6, number 9

The Peer-Reviewed Forum for REAL-World Evidence in Benefit Design ™

™

Table of Contents

(Continued)

business

589 Insurance Companies’ Perspectives on the Orphan Drug Pipeline Robert Handfield, PhD; Josh Feldstein 598 Stakeholder Perspective: Breakthrough Therapy, or Breakthrough Pricing? By Atheer A. Kaddis, PharmD DEPARTMENTs

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For Payers, Purchasers, Policymakers, and Other Healthcare Stakeholders

Industry Trends

560 “Project IMPACT: Diabetes” Care Model Improves Health Outcomes in Underserved Populations in 25 Communities with a High Incidence of Diabetes By Benjamin M. Bluml, RPh 583 Cost and Drug Utilization Patterns Associated with the Management of Rosacea By Caroline Helwick 600 Rehospitalization Is Driving Costs in Pulmonary Arterial Hypertension By Neil Canavan

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American Health & Drug Benefits, ISSN 1942-2962 (print); ISSN 1942-2970 (online), is published 8 times a year by Engage Healthcare Communications, LLC, 1249 South River Rd, Suite 202A, Cranbury, NJ 08512. Copyright © 2013 by Engage Healthcare Communications, LLC. All rights reserved. American Health & Drug Benefits and The Peer-Reviewed Forum for Real-World Evidence in Benefit Design are trademarks of Engage Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the Publisher. Printed in the United States of America. Address all editorial correspondence to: editorial@engagehc.com Telephone: 732-992-1892 Fax: 732-992-1881 American Health & Drug Benefits 1249 South River Rd, Suite 202A Cranbury, NJ 08512 The ideas and opinions expressed in American Health & Drug Benefits do not necessarily reflect those of the Editorial Board, the Editors, or the Publisher. Publication of an advertisement or other product mentioned in American Health & Drug Benefits should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturers about any features or limitations of products mentioned. Neither the Editors nor the Publisher assume any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material mentioned in this publication. For permission to reuse material from American Health & Drug Benefits (ISSN 1942-2962), please access www. copyright.com <http://www.copyright. com/> or contact the Copyright Clearance Center, Inc. (CCC), 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400.

POSTMASTER: CORRESPONDENCE REGARDING SUBSCRIPTIONS OR CHANGE OF ADDRESS should be directed to CIRCULATION DIRECTOR, American Health & Drug Benefits, 1249 South River Rd, Suite 202A, Cranbury, NJ 08512. Fax: 732-992-1881. YEARLY SUBSCRIPTION RATES: One year: $99.00 USD; Two years: $149.00 USD; Three years: $199.00 USD.

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November/December 2013

Vol 6, No 9

NOW AVAILABLE

For adult patients with iron deficiency anemia (IDA) of various etiologies INDICATIONS Injectafer® (ferric carboxymaltose injection) is an iron replacement product indicated for the treatment of iron deficiency anemia in adult patients who have intolerance to oral iron or have had unsatisfactory response to oral iron, and in adult patients with non-dialysis dependent chronic kidney disease. Injectafer® is contraindicated in patients with hypersensitivity to Injectafer® or any of its inactive components.

IMPORTANT SAFETY INFORMATION Serious hypersensitivity reactions, including anaphylactic-type reactions, some of which have been life-threatening and fatal, have been reported in patients receiving Injectafer®. Patients may present with shock, clinically significant hypotension, loss of consciousness, and/or collapse. Monitor patients for signs and symptoms of hypersensitivity during and after Injectafer® administration for at least 30 minutes and until clinically stable following completion of the infusion. Only administer Injectafer® when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. In clinical trials, serious anaphylactic/ anaphylactoid reactions were reported in 0.1% (2/1775) of subjects receiving Injectafer®. Other serious or severe adverse reactions potentially associated with hypersensitivity which included, but were not limited to, pruritus, rash, urticaria, wheezing, or hypotension were reported in 1.5% (26/1775) of these subjects. In clinical studies, hypertension was reported in 3.8% (67/1775) of subjects. Transient elevations in systolic blood pressure, sometimes occurring with facial flushing, dizziness, or nausea were observed in 6% (106/1775) of subjects. These elevations generally occurred immediately after dosing and resolved within 30 minutes. Monitor patients for signs and symptoms of hypertension following each Injectafer® administration. In two randomized clinical studies, a total of 1775 patients were exposed to Injectafer®, 15 mg/kg of body weight, up to a single maximum dose of 750 mg of iron on two occasions, separated by at least 7 days, up to a cumulative dose of 1500 mg of iron. Adverse reactions reported by ≥2% of Injectafer®-treated patients were nausea (7.2%); hypertension (3.8%); flushing/hot flush (3.6%); blood phosphorus decrease (2.1%); and dizziness (2.0%). The following serious adverse reactions have been most commonly reported from the postmarketing spontaneous reports: urticaria, dyspnea, pruritus, tachycardia, erythema, pyrexia, chest discomfort, chills, angioedema, back pain, arthralgia, and syncope.

Please see Brief Summary of the Full Prescribing Information on the following page.

Injectafer® is an iron replacement product indicated for the treatment of IDA in adult patients1

• who have intolerance to oral iron or have had unsatisfactory response to oral iron

• who have non-dialysis dependent chronic kidney disease Up to 750 mg can be delivered in a single dose*1

• Give 2 doses separated by at least 7 days for a total cumulative dose of 1500 mg

• Administer intravenously by

†

– Infusion over at least 15 minutes – Slow push injection at the rate of approximately 100 mg (2 mL) per minute over at least 7.5 minutes

* For patients weighing 50 kg (110 lb) or more, give each dose as 750 mg. For patients weighing less than 50 kg (110 lb), give each dose as 15 mg/kg body weight. †

When administered via infusion, dilute up to 750 mg of iron in no more than 250 mL of sterile 0.9% sodium chloride injection, USP, such that the concentration of the infusion is not <2 mg of iron per mL and administer over at least 15 minutes. When administering as a slow intravenous push, give at the rate of approximately 100 mg (2 mL) per minute.

NDC 0517-0650-01 For more information, please call American Regent Customer Service at 800-645-1706 or visit Injectafer.com For reimbursement assistance, please call the Reimbursement Hotline at 877-4-IV-IRON REFERENCE: 1. Injectafer® [package insert]. Shirley, NY: American Regent, Inc.; 2013.

Brief Summary of Full Prescribing Information

INJECTAFER® (ferric carboxymaltose injection)

Rx Only

INDICATIONS AND USAGE: Injectafer® (ferric carboxymaltose injection) is an iron replacement product indicated for the treatment of iron deficiency anemia in adult patients: • who have intolerance to oral iron or who have had unsatisfactory response to oral iron, • who have non-dialysis dependent chronic kidney disease. DOSAGE AND ADMINISTRATION: For patients weighing 50 kg (110 lb) or more: Give Injectafer® in two doses separated by at least 7 days. Give each dose as 750 mg for a total cumulative dose not to exceed 1500 mg of iron per course. For patients weighing less than 50 kg (110 lb): Give Injectafer® in two doses separated by at least 7 days. Give each dose as 15 mg/kg body weight for a total cumulative dose not to exceed 1500 mg of iron per course. Injectafer® treatment may be repeated if iron deﬁciency anemia reoccurs. Administer Injectafer® intravenously, either as an undiluted slow intravenous push or by infusion. When administering as a slow intravenous push, give at the rate of approximately 100 mg (2 mL) per minute. When administered via infusion, dilute up to 750 mg of iron in no more than 250 mL of sterile 0.9% sodium chloride injection, USP, such that the concentration of the infusion is not less than 2 mg of iron per mL and administer over at least 15 minutes. Inspect parenteral drug products visually for the absence of particulate matter and discoloration prior to administration. The product contains no preservatives. Injectafer® is a single-use vial. Discard unused portion. Avoid extravasation of Injectafer® since brown discoloration of the extravasation site may be long lasting. Monitor for extravasation. If extravasation occurs, discontinue the Injectafer® administration at that site. DOSAGE FORMS AND STRENGTHS: Single-use vials containing 50 mg elemental iron per mL in the following presentation: 750 mg iron/15 mL CONTRAINDICATIONS: Hypersensitivity to Injectafer® or any of its inactive components. WARNINGS AND PRECAUTIONS

Hypersensitivity Reactions:

Serious hypersensitivity reactions, including anaphylactic-type reactions, some of which have been life-threatening and fatal, have been reported in patients receiving Injectafer®. Patients may present with shock, clinically significant hypotension, loss of consciousness, and/or collapse. Monitor patients for signs and symptoms of hypersensitivity during and after Injectafer® administration for at least 30 minutes and until clinically stable following completion of the infusion. Only administer Injectafer® when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. In clinical trials, serious anaphylactic/anaphylactoid reactions were reported in 0.1% (2/1775) of subjects receiving Injectafer®. Other serious or severe adverse reactions potentially associated with hypersensitivity which included, but not limited to, pruritus, rash, urticaria, wheezing, or hypotension were reported in 1.5% (26/1775) of these subjects. Hypertension: In clinical studies, hypertension was reported in 3.8% (67/1775) of subjects in clinical trials 1 and 2. Transient elevations in systolic blood pressure, sometimes occurring with facial ﬂushing, dizziness, or nausea were observed in 6% (106/1775) of subjects in these two clinical trials. These elevations generally occurred immediately after dosing and resolved within 30 minutes. Monitor patients for signs and symptoms of hypertension following each Injectafer® administration. Laboratory Test Alterations: In the 24 hours following administration of Injectafer®, laboratory assays may overestimate serum iron and transferrin bound iron by also measuring the iron in Injectafer®. ADVERSE REACTIONS Adverse Reactions in Clinical Trials: Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other clinical trials and may not reﬂect the rates observed in clinical practice. In two randomized clinical studies, a total of 1775 patients were exposed to Injectafer® 15 mg/kg body weight up to a maximum single dose of 750 mg of iron on two occasions separated by at least 7 days up to a cumulative dose of 1500 mg of iron. Adverse reactions reported by  1% of treated patients are shown in the following table. Table 1. Adverse reactions reported in  1% of Study Patients in Clinical Trials 1 and 2 Injectafer® Pooled Comparatorsa Oral iron Term (N=1775) (N=1783) (N=253) % % % 1.2 1.8 7.2 Nausea 0.4 1.9 3.8 Hypertension 0.0 0.2 3.6 Flushing/Hot Flush 0.0 0.1 2.1 Blood Phosphorus Decrease 0.0 1.2 2.0 Dizziness 0.4 0.5 1.7 Vomiting 0.0 0.3 1.4 Injection Site Discoloration 0.0 0.9 1.2 Headache 0.0 0.2 1.1 Alanine Aminotransferase Increase 0.0 2.1 1.1 Dysgeusia 0.0 1.9 1.0 Hypotension 3.2 0.9 0.5 Constipation Includes oral iron and all formulations of IV iron other than Injectafer® Transient decreases in laboratory blood phosphorus levels (< 2 mg/dL) have been observed in 27% (440/1638) of patients in clinical trials.

Adverse Reactions from Post-marketing Experience: The following serious adverse reactions have been most commonly reported from the post-marketing spontaneous reports with Injectafer®: urticaria, dyspnea, pruritus, tachycardia, erythema, pyrexia, chest discomfort, chills, angioedema, back pain, arthralgia, and syncope. One case of hypophosphatemic osteomalacia was reported in a subject who received 500 mg of Injectafer® every 2 weeks for a total of 16 weeks. Partial recovery followed discontinuation of Injectafer®. DRUG INTERACTIONS: Formal drug interaction studies have not been performed with Injectafer®. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C: Adequate and well controlled studies in pregnant women have not been conducted. Injectafer® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers: A study to determine iron concentrations in breast milk after administration of Injectafer® (n=11) or oral ferrous sulfate (n=14) was conducted in 25 lactating women with postpartum iron deficiency anemia. Mean breast milk iron levels were higher in lactating women receiving Injectafer® than in lactating women receiving oral ferrous sulfate. Pediatric Use: Safety and effectiveness has not been established in pediatric patients. Geriatric Use: Of the 1775 subjects in clinical studies of Injectafer®, 50% were 65 years and over, while 25% were 75 years and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. OVERDOSAGE: Excessive dosages of Injectafer® may lead to accumulation of iron in storage sites potentially leading to hemosiderosis. A patient who received Injectafer® 18,000 mg over 6 months developed hemosiderosis with multiple joint disorder, walking disability and asthenia. Hypophosphatemic osteomalacia was reported in a patient who received Injectafer® 4000 mg over 4 months. Partial recovery followed discontinuation of Injectafer®. DESCRIPTION: Ferric carboxymaltose, an iron replacement product, is an iron carbohydrate complex with the chemical name of polynuclear iron (III) hydroxide 4(R)-(poly-(1→4)-O-α-D-glucopyranosyl)-oxy-2(R),3(S),5(R),6-tetrahydroxy-hexanoate. It has a relative molecular weight of approximately 150,000 Da. Injectafer® (ferric carboxymaltose injection) is a dark brown, sterile, aqueous, isotonic colloidal solution for intravenous injection. Each mL contains 50 mg iron as ferric carboxymaltose in water for injection. Sodium hydroxide and/or hydrochloric acid may have been added to adjust the pH to 5.0-7.0. The vial closure is not made with natural rubber latex. CLINICAL PHARMACOLOGY Mechanism of Action: Ferric carboxymaltose is a colloidal iron (III) hydroxide in complex with carboxymaltose, a carbohydrate polymer that releases iron. Pharmacodynamics: Using positron emission tomography (PET) it was demonstrated that red cell uptake of 59Fe and 52Fe from Injectafer® ranged from 61% to 99%. In patients with iron deficiency, red cell uptake of radio-labeled iron ranged from 91% to 99% after 24 days Injectafer® dose. In patients with renal anemia red cell uptake of radio-labeled iron ranged from 61% to 84% after 24 days Injectafer® dose. Pharmacokinetics: After administration of a single dose of Injectafer® of 100 to 1000 mg of iron in iron deficient patients, maximum iron levels of 37 µg/mL to 333 µg/mL were obtained respectively after 15 minutes to 1.21 hours post dose. The volume of distribution was estimated to be 3 L. The iron injected or infused was rapidly cleared from the plasma, the terminal half life ranged from 7 to 12 hours. Renal elimination of iron was negligible. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, and Impairment of Fertility: Carcinogenicity studies have not been performed with ferric carboxymaltose. Ferric carboxymaltose was not genotoxic in the following genetic toxicology studies: in vitro microbial mutagenesis (Ames) assay, in vitro chromosome aberration test in human lymphocytes, in vitro mammalian cell mutation assay in mouse lymphoma L5178Y/TK+/- cells, in vivo mouse micronucleus test at single intravenous doses up to 500 mg/kg. In a combined male and female fertility study, ferric carboxymaltose was administered intravenously over one hour to male and female rats at iron doses of up to 30 mg/kg. Animals were dosed 3 times per week (on Days 0, 3, and 7). There was no effect on mating function, fertility or early embryonic development. The dose of 30 mg/kg in animals is approximately 40% of the human dose of 750 mg based on body surface area. CLINICAL STUDIES: The safety and efficacy of Injectafer® for treatment of iron deficiency anemia were evaluated in two randomized, open-label, controlled clinical trials (Trial 1 and Trial 2). In these two trials, Injectafer® was administered at dose of 15 mg/kg body weight up to a maximum single dose of 750 mg of iron on two occasions separated by at least 7 days up to a cumulative dose of 1500 mg of iron. PATIENT COUNSELING INFORMATION • Question patients regarding any prior history of reactions to parenteral iron products. • Advise patients of the risks associated with Injectafer®. • Advise patients to report any signs and symptoms of hypersensitivity that may develop during and following Injectafer® administration, such as rash, itching, dizziness, lightheadedness, swelling and breathing problems. Injectafer® is manufactured under license from Vifor (International) Inc, Switzerland.

IN0650BS Iss. 7/2013

Editorial

Practicing Population Health David B. Nash, MD, MBA Editor-in-Chief, American Health & Drug Benefits; Jefferson School of Population Health, Philadelphia, PA

hen nearly a score of experts get together to decipher what it means to “practice” population-based health, we ought to pay attention. That is exactly what the Advisory Board Company in Washington, DC, did this past summer. After their Population Health Leading Lights Summit, the Advisory Board Company issued a list of 8 insights that I believe are truly worth repeating.1 Insight 1 calls for engaging patients in “their 99%.” This is critical—99% of patient activity is not happening in our view. While we spend millions of dollars on electronic medical records, these electronic systems only track patients when they are “in” the health system, which may be 1% of the time. What are we doing to manage care in the context of the patient’s 99%? We ought to be reaching out to develop community partnerships with senior services, housing agencies, transportation services, medication assistance programs, and the like. Insight 2 says that we ought to elevate care management from art to science. The Leading Lights Summit participants called for a unified approach to care management, bringing together patient data, provider data, and payer data, along with predictive modeling, disease registries, and clinical guidelines. They used the analogy of an air traffic control system for managing patient care. Many other healthcare experts have tried to advocate for comparable, systemwide improvements. Insight 3 calls for consolidating care management resources for high-risk patients. Apparently, some of the Advisory Board Company integrated delivery participants have created special care centers, focusing exclusively on high-risk patients. Sometimes these are called “special care centers,” which are composed of a team of dedicated physicians and other providers who specialize in caring for high-risk patients. According to the Advisory Board Company participants, accumulating data show an increase in office visits, as well as dramatic decreases in emergency department visits, hospital admissions, and the average daily costs per inpatient stay; in other words, care management truly works when the appropriate resources are brought together for these complex, high-cost patients. Insight 4 speaks to the need for a continuum of partners to manage the costs. I was very surprised to learn

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that, on average, 50% of the total costs, especially of procedurally based cases, are associated with care received postdischarge. Obviously, this means that we have to look outside the 4 walls of the hospital to truly manage the total cost of care. Most integrated delivery systems have an incomplete view of care utilization and quality performance, especially at every postacute facility. The implications are that integrated delivery systems must now begin to measure the quality and effectiveness of care at skilled nursing facilities and related postdischarge venues.

To continue delivering appropriate high-quality care, systems will have to increase efficiency and reduce unnecessary utilization. Even in the face of a short-term lower revenue outlook, it is important for health systems to begin to have this proactive strategy. Insight 5 says that from a governance perspective, it is important to downscale growth expectations. In other words, the aim is to “use lower revenue expectations as a way to focus on maintaining margins and cutting unwarranted costs.”1 To continue delivering appropriate high-quality care, systems will have to increase efficiency and reduce unnecessary utilization. Even in the face of a short-term lower revenue outlook, it is important for health systems to begin to have this proactive strategy and help the organization to succeed in a new type of market environment. Insight 6 says that the true return on investment in population health can only be achieved under a full-risk arrangement. The Advisory Board Company said, “We did not participate in shared savings to make money, we did it to start a cultural transformation. This is a 20-mile march, and the hardest part is the first six inches—between our ears.”1 When systems migrate to a truly global payment model, they have full control over the premium cost. With that full control comes the obligation to practice based on the evidence, reduce costs per case, and realize a true return on investment. Insight 7 calls for an appeal to employers for a broad-

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er definition of value. Employers want employees to return to work sooner, and they want predictability in their total spending on healthcare. Some employers, like Intel, have the so-called 5 requirements, which include (1) “right care”—practicing based on the evidence; (2) “right time, right setting”—same-day access

I have been a proponent of full transparency for the past 25 years, so this came as no surprise to me. There is simply too much variation in quality and in the various pay-for-performance matrices we currently deploy. to care; (3) “right price”—material decreases in the cost of care; (4) “best life”—rapid return to function and productivity; and (5) “best outcome”—patient satisfaction with experience and care. Who could argue with these 5 requirements? Finally, Insight 8 calls for a push to standardization across total cost-of-care contracts. I have been a propo-

nent of full transparency for the past 25 years, so this came as no surprise to me. There is simply too much variation in quality and in the various pay-for-performance matrices we currently deploy. The Advisory Board Company members were smart to call for standardization so we could compare one provider with another. These 8 insights from successful population health managers were impressive, from my perspective. I applaud the Advisory Board Company for bringing these “leading lights” together and distilling their message for broader consumption in the healthcare industry. For additional information about this program and the Population Health Advisor, you can contact Kayleigh Hucko at huckok@advisory.com or by phone at 202266-5934. Guess what? I have already called. As always, I am interested in your views, and you can reach me at david.nash@jefferson.edu. n

Reference

1. The Advisory Board Company. Eight insights from successful population health managers. Exclusive briefing from the Population Health Leading Lights Summit. September 6, 2013. http://ns.advisory.com/Population-Health-Advisor-ResourceEight-Insights-from-Successful-Population-Health-Managers. Accessed September 18, 2013.

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Vol 6, No 9

We Offer More Than Face Time. If you haven’t heard, GSK is moving forward by aligning our actions with managed care executives’ expectations. This means we are continuously investing in the strategic expertise of our account managers to understand your needs. Difficult challenges, such as improving population outcomes, abound for managed care organizations—and that’s where the account managers at GSK can bring together experts who offer credible scientific and economic knowledge that can provide insights to inform your solutions. True collaboration is more than face time—it’s moving forward with solutions that meet your needs.

Perspective Perspective

The Affordable Care Act Conundrum: Facing Reality in

Americaâ&#x20AC;&#x2122;s Giant Social Experiment Kip Piper, MA, FACHE President, Health Results Group; CEO, Medonomics, Washington, DC

he Affordable Care Act (ACA) is the law of the land, but its implementation so far has been fraught with serious problems. The initial launch of www.healthcare.gov was a disaster. It is unclear whether the Centers for Medicare & Medicaid Services (CMS) or the office of the Department of Health and Human Services Secretary told the White House that the October 1 deadline for the launch was not doable or highly risky, or if anyone suggested a delay. It seems that everyone in the Obama Administration went into a stay-on-message-at-all-costs mode, which is understandable: it is the norm in the federal government. But it comes at the cost of poor public administration. Internally, staff within CMS always knew that the ACA implementation would be problematic. In todayâ&#x20AC;&#x2122;s Washington, optics trump honesty and transparency. It is hard to say how much this culture kept the White House from facing, or even internally admitting, the practical issues or risks involved in the launching of the website and the backroom data functions critical to actual enrollment in coverage. Where do we go from here?

A Giant Social Experiment The ACA is a giant social experiment with few precedents. It is impossible to predict precisely what will happen next with the implementation of the law, or how consumers and employers will respond in the postACA world. It is easier to predict the behavior of health insurers and providers, as well as the overall impact on them, but this is still complex. Americans and the US media have a short attention span. Change happens rapidly, and the law is so complex, that few people or organizations have the patience to understand even parts of the ACA. The enrollment numbers in the first 3 weeks of December will be critical to assessing how well the federal exchange is working, as well as the response of the public to the repaired website. The number of new Medicaid enrollees will likely remain higher than new enrollees in the subsidized exchange plans in the first 2 years. We know that this is the

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case of states that have state-run exchanges, and Medicaid enrollment increases will be especially high in the states with Medicaid expansion; but nationwide, there is every reason to believe that Medicaid enrollment will outpace the subsidized exchange enrollment. In addition to a massive jump in enrollment through expansion eligibility to millions of low-income adults in half of the states, Medicaid rolls will increase in every state from a streamlined eligibility and enrollment process mandated nationwide by the ACA. Furthermore, Medicaid enrollment is year-round, not tied to an open enrollment period, and an easier, no-cost decision-making process for consumers, unlike the enrollment process in the exchanges. The enrollment in subsidized exchange plans could outpace the rise in Medicaid rolls if and when more small and midsize employers drop their current healthcare coverage. Sign-ups during January through March 2014, the second half of the initial open enrollment period, will be important to watch, when outreach and marketing efforts are expected to restart. Under the special enrollment rules, many consumers will be able to sign up for exchange coverage after the open enrollment period, which ends on March 31, 2014, if they have a significant change in family or financial circumstances. However, that volume will not be nearly as large or as important as the exchange sign-up during the open enrollment period or the continuous, always-open Medicaid enrollment. But volume by itself is not enough information to assess the ACAâ&#x20AC;&#x2122;s success. For that we will need to know, for example, the impact on the uninsured rate, the age and the health risk characteristics of those enrolled, the benefit design choices, the number of people losing individual or employer-sponsored coverage, and the effect of Medicaid expansion and streamlined Medicaid eligibility. The law is also a moving target as a result of a series of Obama Administration decisions to delay enforcement of key ACA provisions, for a mixture of practical and political reasons. Major provisions of the ACA, in-

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Perspective

cluding the employer mandate and small employer exchanges in most states, are delayed until 2015, the start of the open enrollment period for 2015 has been shifted until after the November 2014 elections, states are encouraged to temporarily allow short-term renewal of insurance policies outlawed by the ACA, and CMS is proposing changes to how exchange plans are paid. Overall, most people have not yet experienced the effects, positive and negative, of the ACA. In terms of coverage and costs, the ACA creates a giant game of musical chairs, which has just begun. Every American will be affected by the ACA in some way. The biggest winners are the uninsured, who are or will be newly covered through Medicaid or through federally subsidized exchange coverage. Some of the losers, including people facing higher premiums, are starting to feel the pain, but the main disadvantages of the ACA are yet to be experienced. The law is all about improving equity through the use of a maze of redistributive mechanisms. It will take time before this plays out. The short experience with the ACA can only shed light on issues that should have been addressed a long time ago, but for which there was not an interested audience.

Payers’ Perspective The majority of health insurance companies know that the original strategic reasons for entering the insurance exchange market are still valid, assuming that CMS is able to get the website and the data transfers working soon. Companies that have Medicaid plans are also anxious to see how Medicaid enrollment evolves, and how soon will enrollment problems be resolved. The initial disaster with rollout of the federal exchange complicates payers’ strategy, business planning, and forecasts. Payers know that they may need to adjust their expectations and future plans to some extent, but they have little information from the federal government, which makes their job difficult. This situation is further exacerbated by the larger unknowns, such as how consumers will react to the new exchange plans, including their costs and choices. While their business dynamics are inherently complex and vary by state, health insurers specializing in the Medicaid market are naturally in a better position under the ACA, given the substantial increase in enrollees. Facing a double-edged sword of an uncertain payer marketplace and deep payment cuts—to help pay for the cost of ACA—hospitals and health systems are worried. A decrease in the number of uninsured Americans will help trim uncompensated care costs, but it will generally not offset lower reimbursement from Medicare, Medicaid, and the new exchange plans and a shift of patients from higher-paying private plans to lower-paying tax

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payer-financed health plans. Insurance companies know that they may need to reconfigure their 2014-2015 budgets to cover more Medicaid patients and fewer members with commercial plan coverage or with exchange-based coverage than was expected. Hospitals in states that are seeking Medicaid reform waivers—notably, Wisconsin, Iowa, and Pennsylvania— are generally eager to see those get approved and implemented soon, because the waivers would expand access to coverage.

The short experience with the ACA can only shed light on issues that should have been addressed a long time ago, but for which there was not an interested audience. Manufacturers’ Perspective Pharmaceutical, biotechnology, and medical device companies vary considerably in their understanding of the implications of the ACA. Some companies are fairly well-versed, but others have limited understanding of what it all means. It is harder for drug or device companies than, say, for insurance companies or for large healthcare providers, to understand the potential implications of the ACA on them, because the effects of the ACA, although significant, are indirect and nonlinear. Indirect, because the ACA and changes in the marketplace are fundamentally transforming the economics, incentives, and decision-making of coverage, payment, and care delivery. Nonlinear, because, in this time of unprecedented, polygonal change, the new policy and market spheres appear chaotic, unpredictable, or counter intuitive, and therefore defy traditional assessment. We have a tough environment for these companies to make strategic, operational, or tactical decisions. Impact on Individual Insurance It was never in doubt that the ACA would require cancellation of most policies in the individual health insurance market. It was also known that consumers would face a very different health insurance world under the ACA, with some people seeing their premiums go down and some seeing them go up, and the majority of Americans seeing higher deductibles, higher copays, and a smaller pool of providers. We also knew that the exchanges and the ACA market rules would negate the need for state high-risk pools, meaning that most of these chronically ill consumers would see their policies ending in December 2013 or early in 2014. It is puzzling why it took more than 3 years, the failed launch of the federal exchange, and the news media to

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start questioning the Obama Administration’s core approach to regulating existing health coverage. Whether you like or dislike the ACA policies, the 19.4 million Americans in various parts of the individual market deserved a heads-up.

Cost-Sharing and Premiums The ACA requires people to buy a richer benefit package. It is possible to argue that this policy is good for society, but there is no free lunch, and this does eliminate choices that were acceptable to many consumers. Some can argue that federal premium subsidies in the exchange will more than absorb the higher costs of the ACA for moderate-income Americans, but that is just another way of saying, “Don’t worry, the taxpayer will pick up the tab for the cost of government regulations.” Premiums, in and outside the exchanges, must be set using adjusted community rating, requiring the healthy, the young, and men to cross-subsidize the premiums of the unhealthy, the older, and women. Again, the foun-

Few laws are truly self-implementing, but virtually everything in the ACA, from a political, regulatory, or technical perspective, requires countless decisions and an astonishing amount of work before it is implemented. dation of the ACA is a collective redistribution intentionally creating winners and losers. You can argue the merits of this policy, but it does mean that many Americans will face vastly different premiums under the ACA. The widely anticipated higher cost-sharing many people are now seeing in the exchanges is an inevitable byproduct of the ACA insurance market rules, the brave new actuarial risks of the post-ACA marketplace, and competition based on premiums and insurer brand names.

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Medicaid Expansion Medicaid covers approximately 74 million Americans today. As a result of Medicaid expansion under the ACA, including waiver-based expansions, the crowd-out effect, the streamlined eligibility and enrollment mandated by the ACA, and the normal growth of the program, Medicaid could conceivably reach between 95 million and 100 million enrollees by the year 2020. Although it is early, state data already indicate a surge in Medicaid enrollment. Considering all the unknowns related to Medicaid expansion, including current and future economic conditions, it is safe to assume that the role of Medicaid in the US healthcare system, and the impact of Medicaid on federal and state budgets, will continue to grow. Implementation Lessons The Obama Administration, so enamored with the law and the law’s intentions and optics, grossly underestimated the push back from states and the sheer magnitude of the task. The administration’s painfully slow, opaque decision-making process hampered the state-run exchanges as well, and made life in state Medicaid agencies a nightmare. But the states, by experience and temperament, are typically far more adaptable and problem-solving oriented than the federal government. States with their own exchanges jumped in much earlier than CMS, making preliminary decisions, bringing on contractors, and pulling the pieces together as best they could. Although unprecedented in its scope and complexity, the ACA as legislation deferred most of the decisions to federal agencies, especially CMS and the Internal Revenue Service. The law was also poorly written in key areas and poorly thought-out. Few laws are truly self-implementing, but virtually everything in the ACA, from a political, regulatory, or technical perspective, requires countless decisions and an astonishing amount of work before it is implemented. n Author Disclosure Statement Mr Piper has no conflicts of interest to report.

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Vol 6, No 9

S E I G R E L L A D O O F * VE IN CHILDREN HA

INCREASED BY

18% 1

Take a closer look at who should carry an EpiPen® (epinephrine) Auto-Injector As food allergies rise, the risk of anaphylaxis may also increase.1-3 Which is why it’s important to identify patients at risk for anaphylaxis and help them create an action plan: avoid the allergen first, and always carry an EpiPen 2-Pak®.3 For more than 20 years, EpiPen has been the #1 prescribed epinephrine auto-injector,4† with over 41 million units dispensed.5‡ There is no FDA-approved therapeutic equivalent.6 Indications EpiPen® (epinephrine) 0.3 mg and EpiPen Jr® (epinephrine) 0.15 mg Auto-Injectors are indicated in the emergency treatment of type 1 allergic reactions, including anaphylaxis, to allergens, idiopathic and exercise-induced anaphylaxis, and in patients with a history or increased risk of anaphylactic reactions. Selection of the appropriate dosage strength is determined according to body weight. Important Safety Information EpiPen Auto-Injectors should only be injected into the anterolateral aspect of the thigh. DO NOT INJECT INTO BUTTOCK, OR INTRAVENOUSLY.

underlying cardiac disease or taking cardiac glycosides or diuretics. Patients with certain medical conditions or who take certain medications for allergies, depression, thyroid disorders, diabetes, and hypertension, may be at greater risk for adverse reactions. Other adverse reactions include transient moderate anxiety, apprehensiveness, restlessness, tremor, weakness, dizziness, sweating, palpitations, pallor, nausea and vomiting, headache, and/or respiratory difficulties.

EpiPen and EpiPen Jr Auto-Injectors are intended for immediate self-administration as emergency supportive Epinephrine should be used with caution in patients with therapy only and are not intended as a substitute for certain heart diseases, and in patients who are on drugs immediate medical or hospital care. that may sensitize the heart to arrhythmias, because it You are encouraged to report negative side effects may precipitate or aggravate angina pectoris and produce of prescription drugs to the FDA. Visit www.fda.gov/ ventricular arrhythmias. Arrhythmias, including fatal medwatch, or call 1-800-FDA-1088. ventricular fibrillation, have been reported in patients with Please see Brief Summary of the full Prescribing Information on the adjacent page. * Reported prevalence from 1997 through 2007. As of December 2011. Since 1990. References: 1. Branum AM, Lukacs SL. Food allergy among children in the United States. Pediatrics. 2009;124(6):1549-1555. 2. Simons FER. Anaphylaxis. J Allergy Clin Immunol. 2010;125(suppl 2):S161-S181. 3. Boyce JA, Assa’ad A, Burks AW, et al. Guidelines for the diagnosis and management of food allergy in the United States: report of the NIAID-Sponsored Expert Panel. J Allergy Clin Immunol. 2010;126(6):S1-S58. 4. Data on file. Mylan Specialty L.P. 5. Data on file. Mylan Specialty L.P. IMS data as of June 2012. 6. U.S. Department of Health and Human Services Food and Drug Administration. Approved Drug Products With Therapeutic Equivalence Evaluations. 32nd ed. Washington, DC: U.S. Department of Health and Human Services; 2012.

† ‡

epipen.com

EpiPen®, EpiPen Jr®, EpiPen 2-Pak®, and EpiPen Jr 2-Pak® are registered trademarks of Mylan Inc. licensed exclusively to its wholly-owned subsidiary, Mylan Specialty L.P. © 2012 Mylan Specialty L.P. All rights reserved. 9/12 EPI12-1046/EPI500320-01

EpiPen® 0.3 mg EPINEPHRINE AUTO-INJECTOR EpiPen Jr® 0.15 mg EPINEPHRINE AUTO-INJECTOR BRIEF SUMMARY. See package insert for full Prescribing Information. DO NOT REMOVE ACTIVATION CAP UNTIL READY FOR USE. THIS UNIT CONTAINS NO LATEX. INDICATIONS AND USAGE: EpiPen and EpiPen Jr Auto-Injectors are indicated in the emergency treatment of allergic reactions (Type I) including anaphylaxis to stinging insects (e.g., order Hymenoptera, which include bees, wasps, hornets, yellow jackets and fire ants) and biting insects (e.g., triatoma, mosquitos), allergen immunotherapy, foods, drugs, diagnostic testing substances (e.g., radiocontrast media) and other allergens, as well as idiopathic anaphylaxis or exercise-induced anaphylaxis. EpiPen and EpiPen Jr Auto-Injectors are intended for immediate administration in patients, who are determined to be at increased risk for anaphylaxis, including individuals with a history of anaphylactic reactions. Selection of the appropriate dosage strength is determined according to patient body weight (See DOSAGE AND ADMINISTRATION section of the full Prescribing Information). Such reactions may occur within minutes after exposure and consist of flushing, apprehension, syncope, tachycardia, thready or unobtainable pulse associated with a fall in blood pressure, convulsions, vomiting, diarrhea and abdominal cramps, involuntary voiding, wheezing, dyspnea due to laryngeal spasm, pruritus, rashes, urticaria or angioedema. EpiPen and EpiPen Jr Auto-Injectors are intended for immediate selfadministration as emergency supportive therapy only and are not a substitute for immediate medical care. CONTRAINDICATIONS: There are no absolute contraindications to the use of epinephrine in a life-threatening situation. WARNINGS: EpiPen and EpiPen Jr Auto-Injectors should only be injected into the anterolateral aspect of the thigh. DO NOT INJECT INTO BUTTOCK. Injection into the buttock may not provide effective treatment of anaphylaxis. Advise the patient to go immediately to the nearest emergency room for further treatment of anaphylaxis. Since epinephrine is a strong vasoconstrictor, accidental injection into the digits, hands or feet may result in loss of blood flow to the affected area. Treatment should be directed at vasodilation in addition to further treatment of anaphylaxis. (see ADVERSE REACTIONS). Advise the patient to go immediately to the nearest emergency room and to inform the healthcare provider in the emergency room of the location of the accidental injection. DO NOT INJECT INTRAVENOUSLY. Large doses or accidental intravenous injection of epinephrine may result in cerebral hemorrhage due to sharp rise in blood pressure. Rapidly acting vasodilators can counteract the marked pressor effects of epinephrine if there is such inadvertent administration. Epinephrine is the preferred treatment for serious allergic reactions or other emergency situations even though this product contains sodium metabisulfite, a sulfite that may, in other products, cause allergictype reactions including anaphylactic symptoms or life-threatening or less severe asthmatic episodes in certain susceptible persons. The alternatives to using epinephrine in a life-threatening situation may not be satisfactory. The presence of a sulfite in this product should not deter administration of the drug for treatment of serious allergic or other emergency situations even if the patient is sulfite-sensitive. Epinephrine should be administered with caution in patients who have heart disease, including patients with cardiac arrhythmias, coronary artery or organic heart disease, or hypertension. In such patients, or in

patients who are on drugs that may sensitize the heart to arrhythmias, e.g., digitalis, diuretics, or anti-arrhythmics, epinephrine may precipitate or aggravate angina pectoris as well as produce ventricular arrhythmias. It should be recognized that the presence of these conditions is not a contraindication to epinephrine administration in an acute, lifethreatening situation. Epinephrine is light sensitive and should be stored in the carrier tube provided. Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) (See USP Controlled Room Temperature). Do not refrigerate. Protect from light. Before using, check to make sure the solution in the auto-injector is not discolored. Replace the auto-injector if the solution is discolored or contains a precipitate. PRECAUTIONS: (1) General EpiPen and EpiPen Jr Auto-Injectors are not intended as a substitute for immediate medical care. In conjunction with the administration of epinephrine, the patient should seek immediate medical or hospital care. More than two sequential doses of epinephrine should only be administered under direct medical supervision. Epinephrine is essential for the treatment of anaphylaxis. Patients with a history of severe allergic reactions (anaphylaxis) to insect stings or bites, foods, drugs, and other allergens as well as idiopathic and exercise-induced anaphylaxis should be carefully instructed about the circumstances under which epinephrine should be used. It must be clearly determined that the patient is at risk of future anaphylaxis, since the following risks may be associated with epinephrine administration (see DOSAGE and ADMINISTRATION section of the full Prescribing Information). Epinephrine should be used with caution in patients who have cardiac arrhythmias, coronary artery or organic heart disease, hypertension, or in patients who are on drugs that may sensitize the heart to arrhythmias, e.g., digitalis, diuretics, quinidine, or other anti-arrhythmics. In such patients, epinephrine may precipitate or aggravate angina pectoris as well as produce ventricular arrhythmias. The effects of epinephrine may be potentiated by tricyclic antidepressants and monoamine oxidase inhibitors. Some patients may be at greater risk of developing adverse reactions after epinephrine administration. These include: hyperthyroid individuals, individuals with cardiovascular disease, hypertension, or diabetes, elderly individuals, pregnant women, pediatric patients under 30 kg (66 lbs.) body weight using EpiPen Auto-Injector, and pediatric patients under 15 kg (33 lbs.) body weight using EpiPen Jr Auto-Injector. Despite these concerns, epinephrine is essential for the treatment of anaphylaxis. Therefore, patients with these conditions, and/or any other person who might be in a position to administer EpiPen or EpiPen Jr Auto-Injector to a patient experiencing anaphylaxis should be carefully instructed in regard to the circumstances under which epinephrine should be used. (2) Information for Patients Complete patient information, including dosage, direction for proper administration and precautions can be found inside each EpiPen/ EpiPen Jr Auto-Injector carton. Epinephrine may produce symptoms and signs that include an increase in heart rate, the sensation of a more forceful heartbeat, palpitations, sweating, nausea and vomiting, difficulty breathing, pallor, dizziness, weakness or shakiness, headache, apprehension, nervousness, or anxiety. These symptoms and signs usually subside rapidly, especially

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with rest, quiet and recumbency. Patients with hypertension or hyperthyroidism may develop more severe or persistent effects, and patients with coronary artery disease could experience angina. Patients with diabetes may develop increased blood glucose levels following epinephrine administration. Patients with Parkinson’s disease may notice a temporary worsening of symptoms. In case of accidental injection, the patient should be advised to immediately go to the emergency room for treatment. Since the epinephrine in the EpiPen Auto-Injector is a strong vasoconstrictor when injected into the digits, hands or feet, treatment should be directed at vasodilation if there is such an inadvertent administration to these areas. (see ADVERSE REACTIONS). (3) Drug Interactions The carrier tube is not waterproof. The blue safety release helps prevent accidental injection and should be kept on until it will be used. Patients who receive epinephrine while concomitantly taking cardiac glycosides or diuretics should be observed carefully for the development of cardiac arrhythmias. The effects of epinephrine may be potentiated by tricyclic antidepressants, monoamine oxidase inhibitors, levothyroxine sodium, and certain antihistamines, notably chlorpheniramine, tripelennamine and diphenhydramine. The cardiostimulating and bronchodilating effects of epinephrine are antagonized by beta-adrenergic blocking drugs, such as propranolol. The vasoconstricting and hypertensive effects of epinephrine are antagonized by alpha-adrenergic blocking drugs, such as phentoloamine. Ergot alkaloids may also reverse the pressor effects of epinephrine. (4) Carcinogenesis, Mutagenesis, Impairment of Fertility Epinephrine and other catecholamines have been shown to have mutagenic potential in vitro and to be an oxidative mutagen in a WP2 bacterial reverse mutation assay. Epinephrine had a moderate degree of mutagenicity, and was positive in the DNA Repair test with B. subtilis (REC) assay, but was not mutagenic in the Salmonella bacterial reverse mutation assay. Studies of epinephrine after repeated exposure in animals to evaluate the carcinogenic and mutagenic potential or the effect on fertility have not been conducted. This should not prevent the use of epinephrine under the conditions noted under INDICATIONS AND USAGE. (5) Usage in Pregnancy Pregnancy Category C: There is no study on the acute effect of epinephrine on pregnancy. Epinephrine has been shown to have developmental effects when administered subcutaneously in rabbits at a dose of 1.2 mg/kg daily for two to three days (approximately 30 times the maximum recommended daily subcutaneous or intramuscular dose on a mg/m2 basis), in mice at a subcutaneous dose of 1 mg/kg daily for 10 days (approximately 7 times the maximum daily subcutaneous or intramuscular dose on a mg/m2 basis) and in hamsters at a subcutaneous dose of 0.5 mg/kg daily for 4 days (approximately 5 times the maximum recommended daily subcutaneous or intramuscular dose on a mg/m2 basis). These effects were not seen in mice at a subcutaneous dose of 0.5 mg/kg daily for 10 days (approximately 3 times the maximum recommended daily subcutaneous or intramuscular dose on a mg/m2 basis). Although, there are no adequate and well-controlled studies in pregnant women, epinephrine should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus. It is not known if epinephrine passes into breast milk.

ADVERSE REACTIONS: Adverse reactions to epinephrine include transient, moderate anxiety; apprehensiveness; restlessness; tremor; weakness; dizziness; sweating; palpitations; pallor; nausea and vomiting; headache; and/or respiratory difficulties. These symptoms occur in some persons receiving therapeutic doses of epinephrine, but are more likely to occur in patients with hypertension or hyperthyroidism. Arrhythmias, including fatal ventricular fibrillation, have been reported in patients with underlying cardiac disease or certain drugs [see PRECAUTIONS, Drug Interactions]. Rapid rises in blood pressure have produced cerebral hemorrhage, particularly in elderly patients with cardiovascular disease. Angina may occur in patients with coronary artery disease. The potential for epinephrine to produce these types of adverse reactions does not contraindicate its use in an acute life-threatening allergic reaction. Accidental injection into the digits, hands or feet may result in loss of blood flow to the affected area (see WARNINGS). Adverse events experienced as a result of accidental injections may include increased heart rate, local reactions including injection site pallor, coldness and hypoaesthesia or injury at the injection site resulting in bruising, bleeding, discoloration, erythema or skeletal injury. OVERDOSAGE: Epinephrine is rapidly inactivated in the body and treatment following overdose with epinephrine is primarily supportive. If necessary, pressor effects may be counteracted by rapidly acting vasodilators or alpha-adrenergic blocking drugs. If prolonged hypotension follows such measure, it may be necessary to administer another pressor drug. Overdosage of epinephrine may produce extremely elevated arterial pressure, which may result in cerebrovascular hemorrhage, particularly in elderly patients.

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Overdosage may also result in pulmonary edema because of peripheral vascular constriction together with cardiac stimulation. Treatment consists of a rapidly acting alpha-adrenergic blocking drug and/or respiratory support. Epinephrine overdosage can also cause transient bradycardia followed by tachycardia and these may be accompanied by potentially fatal cardiac arrhythmias. Premature ventricular contractions may appear within one minute after injection and may be followed by multifocal ventricular tachycardia (prefibrillation rhythm). Subsidence of the ventricular effects may be followed by atrial tachycardia and occasionally by atrioventricular block. Treatment of arrhythmias consists of administration of a beta-blocking drug such as propranolol.

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Overdosage sometimes results in extreme pallor and coldness of the skin, metabolic acidosis and kidney failure. Suitable corrective measures must be taken in such situations. Rx only. MANUFACTURED FOR Mylan Specialty L.P., Basking Ridge, NJ 07920, USA by Meridian Medical Technologies, Inc., Columbia, MD 21046, USA, a Pfizer company. EpiPen®, EpiPen Jr ®, EpiPen 2-Pak®, and EpiPen Jr 2-Pak® are registered trademarks of Mylan Inc. licensed exclusively to its wholly-owned affiliate, Mylan Specialty L.P. of Basking Ridge, NJ 07920, USA. © 2012 Mylan Specialty L.P. All rights reserved. 03-500-04C August 2012

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Case Study

Stakeholder Perspective, page 552

Am Health Drug Benefits. 2013;6(9):548-552 www.AHDBonline.com Disclosures are at end of text

Background: Diabetic retinopathy is a retinal vascular disorder that affects more than 4.1 million people in the United States. New methods of detecting and ensuring adequate follow-up of this life-altering disease are vital to improving patient outcomes. Wills Eye Hospital and the Centers for Disease Control and Prevention are conducting a collaborative study to initiate a novel diabetic retinopathy screening in the community setting. Objective: To evaluate the feasibility of a more widespread, large-scale implementation of this novel model of care for diabetic retinopathy screening in the community setting. Methods: A simple, self-administered survey was distributed to pharmacists, pharmacy technicians, student pharmacists, and Wills Eye Hospital interns. The survey consisted of open-ended questions and responders were given 1 week to respond. A total of 22 surveys were distributed and 16 were completed. The responses were culled and analyzed to assess the feasibility of implementing this novel screening model in the pharmacy. Results: The response rate to this pilot survey was 72%. The majority of the responding pharmacy staff members indicated that diabetic retinopathy screening in community pharmacies would greatly benefit patients and could improve patient care. However, they also noted barriers to implementing the screening, such as concerns about the cost of carrying out the screenings, the cost of the equipment needed to be purchased, and the lack of time and shortage of pharmacy staff. Conclusion: The potential exists for pharmacists to positively influence diabetes care by implementing retinopathy care through the early detection of the disease and reinforcement of the need for follow-up; however, real-world barriers must be addressed before widespread adoption of such a novel model of care becomes feasible.

iabetic retinopathy is a retinal vascular disorder that often presents asymptomatically in its early stages and can progress to include visual symptoms such as blurry vision, dark or floating spots, vision loss, and complete blindness in its later stages.1-3 Diabetic retinopathy affects more than 4.1 million people in the United States and can severely impact vision.2,4,5 The American Academy of Ophthalmology and the American Diabetes Association recommend that all patients affected by diabetes have fundus examinations at least Ms Law and Ms Komura are PharmD candidates, Jefferson School of Pharmacy, Thomas Jefferson University, Philadelphia, PA; Dr Murchison is Codirector, Emergency Department, and Associate Professor of Ophthalmology, Wills Eye Hospital, Philadelphia, PA; Dr Pizzi is Associate Professor, Department of Pharmacy Practice, Jefferson School of Pharmacy, Thomas Jefferson University.

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annually.6,7 Dilated fundus examinations require dilating the pupils to better see into the periphery of the eye. However, lack of time, not understanding the importance of screening for diabetic retinopathy, and lack of access to screening have resulted in 35% to 79% of patients not adhering to current recommendations.7-10 A review of the literature for any type of community pharmacyâ&#x20AC;&#x201C;based patient intervention, performed in early January of 2013, revealed no published studies on the involvement of community pharmacists in diabetic retinopathy screenings. However, community pharmacy screenings that focused on other diseases have shown promising results for this type of intervention.11-17 The Table (page 550) summarizes the findings of these previously published pharmacist community screening programs for a variety of disease states, including osteoporosis, cardiovascular disease, peripheral arterial disease, and chlamydia.

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The successful outcomes of these studies provide insight into the feasibility of implementing diabetic retinopathy screenings in community pharmacies, showing that quick interventions, such as friendly reminders and on-the-spot counseling, are effective ways to motivate patients to improve their health.

Diabetic Retinopathy Community Pharmacy Study The Wills Eye Institute Department of Research and the Centers for Disease Control and Prevention (CDC) are completing a collaborative study to test diabetic retinopathy screenings in a community pharmacy setting. The screening is performed using the Nidek fundus camera, which has a market price of $26,000 and can be completed in approximately 15 minutes. Patients do not require chemical dilation, and the process is painless. Although the Nidek fundus camera is not the gold standard for screening for diabetic retinopathy, it is an emerging practice that shows promise in identifying eye abnormalities. Of the patients screened at Wills Eye Hospital, 10% showed signs of diabetic retinopathy and 49% showed signs of other eye abnormalities, such as cataracts and hypertensive changes. Despite these promising findings, the technology can only be successfully integrated into pharmacy settings if staff members are trained and have the necessary time and tools to conduct the screenings. Pharmacies are often very busy, and additional staff may be required to operate the camera and spend time screening patients. To explore these issues, we created and conducted a brief open-ended pharmacy staff survey assessing the potential benefits and barriers of such screening. This pilot survey was an unfunded research exercise conducted outside of the formal CDC parent project. Methods Surveys were self-administered on paper by 5 pharmacists, 3 pharmacy technicians, 3 pharmacy students, and 5 research interns who were working at or who were connected to the pharmacy that participated in the diabetic retinopathy screening study. Research interns were actively running the eye screenings, while the pharmacists and pharmacy technicians referred patients with diabetes to the beneficial free screening. Each respondent was given 1 week to answer the survey, and responses were collected in person at the end of the 1-week time frame. The total study sample included 16 respondents (Figure 1, page 550) of a total of 22 surveys distributed, resulting in a 72% response rate. The survey consisted of 7 open-ended questions regarding the benefits of the eye screening, possible barriers to widespread implementation (Figure 2, page 551), and

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Key Points Diabetic retinopathy, which can severely impair vision, affects more than 4.1 million patients in the United States. ➤ Only approximately 50% to 60% of patients with diabetic retinopathy follow the recommendation for an annual fundus examination. ➤ Community pharmacy screenings for other disease states show promise for the successful screening of patients with diabetic retinopathy as well. ➤ This pilot survey is the first analysis regarding the potential role of community pharmacists in diabetic retinopathy screening. ➤ For community pharmacies to successfully screen this patient population, staff members must be trained and have the necessary time and tools to conduct the screenings. ➤ Barriers to the successful implementation of such screenings must be addressed and include lack of time, cost of the equipment needed, and a shortage of pharmacy staff. ➤ Screenings can potentially reduce the burden of diabetic retinopathy through early detection and reinforcement of the need for follow-up. ➤

personal opinions of the screening (see Appendix at www. ahdbonline.com). Because this was a pilot survey of attitudes and beliefs of the pharmacy staff, approval by an Institutional Review Board was not required.

Placing this technology at the hands of community pharmacists enables the detection not only of diabetic retinopathy but of other eye abnormalities that may remain otherwise undiagnosed. Results The responses to the survey by the pharmacy professionals revealed several potential benefits for the diabetic retinopathy screenings when done by pharmacists. First, pharmacists are convenient and accessible healthcare providers who are trained to counsel patients to improve healthy behaviors. Second, pharmacists can readily identify patients with diabetes for screening based on their medication histories. Third, placing this technology at the hands of community pharmacists enables the detection not only of diabetic retinopathy but of other eye abnormalities that may

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Table Previously Published Studies Examining Community Pharmacy Screening Programs Screening type/study Participants, (publication year) Objective Setting type (N) Results Chlamydia screening study (2010)11

Qualitative analysis of pharmacistsâ&#x20AC;&#x2122; views on chlamydia screening

Community pharmacy

Study of diabetes and CV conditions (2006)12

To assess a new screening model for diabetes, hypertension, and dyslipidemia

Community pharmacy and non-healthcare settings

Patients: high-risk elderly (888)

Pharmacists were able to identify patients with elevated glucose, cholesterol, and blood pressure

Screening for PAD (2011)13

To evaluate the feasibility of a community pharmacy pharmacist-initiated PAD screening program

Community pharmacy

Patients (39)

The screening program was effective in increasing PAD recognition and demonstrated program feasibility

COPD screening study (2012)14

To assess the ability of pharmacists in community pharmacies to accurately conduct COPD screenings

Community pharmacy

Patients (185)

Pharmacists are able to effectively conduct COPD screenings and interpret results

Screening for CV risk (2010)15

To assess the ability of community pharmacists to conduct CV risk screenings

Community pharmacy

Patients (655)

The results show the ability of a CV screening program to improve diagnoses of high-risk individuals and to help contain the burden of CV disease

Osteoporosis screening (2010)16

To assess an osteoporosis screening and patient education program in community pharmacies

Community pharmacy

Patients (262)

The osteoporosis screening program doubled the number of patients who proceeded for further testing or treatment

Osteoporosis screening study (2008)17

To develop an effective community pharmacy screening program for the detection of osteoporosis in women

Community pharmacy

Patients: women (159)

With the benefit of an effective screening program, women who were screened revealed high proportions of lifestyle or medication modifications at 3- or 6-month follow-up

Pharmacists (26)

Pharmacists appreciated the opportunity to expand their practice by providing chlamydia screenings, but were hesitant to provide screening to certain women (eg, married women or those in long-term relationships)

COPD indicates chronic obstructive pulmonary disease; CV, cardiovascular; PAD, peripheral arterial disease.

Figure 1 Participants in the Pharmacy Staff Survey, by Type (N = 16)

550

Research interns (N = 5)

Pharmacists (N = 5)

Student pharmacists (N = 3)

Pharmacy technicians (N = 3)

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remain otherwise undiagnosed. Furthermore, patients may feel comfortable approaching pharmacists, because doing so is free and does not require an appointment. However, the survey findings also suggested a number of barriers to implementing diabetic retinopathy screening in community pharmacy settings. For example, in high-volume pharmacies, respondents indicated that there would not be enough time to run diabetic retinopathy screenings in addition to completing their daily responsibilities. To do so, they would need an additional staff dedicated to run the screenings to prevent the process from interfering with the daily workflow. Another barrier relates to the cost of the Nidek fundus camera screening device. The expense associated with the purchase of this technology would only be justified if the volume of patients screened at each pharmacy resulted in reimbursements sufficient to recoup its

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urvey of Staff Opinions about Pharmacy Figure 2 S Vision Screenings 1. I am a (circle one): Pharmacist Pharmacy technician Student Staff intern Other: _______________________ 2. Have you recommended anyone to be screened for diabetic retinopathy at the TJUH pharmacy? Why or why not? _____________________________________ 3. If the pharmacy staff were asked to complete the vision screenings, do you feel that there is sufficient manpower? Why or why not? _____________________ a. If “no” to the above question, what do you think it will take for proper staffing (for example, in terms of additional employees, number of staffing hours required per week, and what training they should have)?

4. Do you feel that conducting these eye screenings is a task you would be willing to complete on a routine basis? Why or why not? _________________________ a. If “no” to the above question, what would be necessary to enable you to conduct the screenings?

5. Do you think this technology is useful to the patients at this pharmacy? Why or why not? ________________ 6. What positive and negative aspects, if any, have you noticed about offering this screening in the pharmacy?

Positive aspects of the screening in the pharmacy:

Negative aspects of the screening in the pharmacy:

7. What are your beliefs about the following?

Your beliefs about the vision screening technology:

Your beliefs about the implementation of the vision screening in the pharmacy: Your beliefs about the role a pharmacist should have with respect to implementing the screening: TJUH indicates Thomas Jefferson University Hospital.

cost. Currently, the diabetic nephropathy screening is being provided at no charge; however, the respondents noted that large-scale, sustainable implementation would require pharmacies to charge for this screening to make it financially feasible.

Conclusion The responses to our pilot survey showed that diabetic retinopathy screenings by community pharmacies are beneficial to patients, although real-world implementation barriers exist. Pharmacists are in a unique position to identify diabetic retinopathy screening candidates based on their medication histories and can utilize the screenings as a vehicle for promoting patients to seek diabetic retinopathy care from their physicians. How ever, the time and resources required to implement the screenings must be addressed. If implemented, diabetic retinopathy community pharmacy screenings have the potential to reduce the burden of diabetic retinopathy at the population level and to also positively impact the care of individual patients through detection and reinforcement of the need for follow-up. n Author Disclosure Statement Ms Law, Ms Komura, Dr Murchison, and Dr Pizzi reported no conflicts of interest.

References

1. Fraser CE, D’Amico DJ. Classification and clinical features of diabetic retinopathy. UpToDate. www.uptodate.com/contents/classification-and-clinical-features-of-diabeticretinopathy. Accessed March 4, 2012. 2. Congdon N, O’Colmain B, Klaver CC, et al; for the Eye Diseases Prevalence Research Group. Causes and prevalence of visual impairment among adults in the United States. Arch Ophthalmol. 2004;122:477-485. 3. National Eye Institute. Facts about diabetic retinopathy. Updated June 2012. www. nei.nih.gov/health/diabetic/retinopathy.asp. Accessed November 13, 2013. 4. Lee PP, Feldman ZW, Ostermann J, et al. Longitudinal prevalence of major eye diseases. Arch Ophthalmol. 2003;121:1303-1310. 5. Kempen JH, O’Colmain BJ, Leske MC, et al; for the Eye Diseases Prevalence Research Group. The prevalence of diabetic retinopathy among adults in the United States. Arch Ophthalmol. 2004;122:552-563. 6. The Foundation of the American Academy of Ophthalmology. Diabetic retinopathy summary benchmark—November 2008. www.aaofoundation.org/hoskins/ QEC-Content-Display.cfm?fuseaction=display&link=ea5c6d25-2ab9-4398-b00b 8efcb8cc5bc7&section=Summary Benchmarks. Accessed October 17, 2013. 7. American Diabetes Association. Diabetic retinopathy. Diabetes Care. 2000;23 (suppl 1):S73-S76. 8. Schoenfeld ER, Greene JM, Wu SY, Leske MC. Patterns of adherence to diabetes vision care guidelines: baseline findings from the Diabetic Retinopathy Awareness Program. Ophthalmology. 2001;108:563-571. 9. Zhang X, Saaddine JB, Lee PP, et al. Eye care in the United States: do we deliver to high-risk people who can benefit most from it? Arch Ophthalmol. 2007;125:411-418. 10. Klein R, Klein BE, Moss SE. Epidemiology of proliferative diabetic retinopathy. Diabetes Care. 1992;15:1875-1891. 11. Thomas G, Humphris G, Ozakinci G, et al. A qualitative study of pharmacists’ views on offering chlamydia screening to women requesting Emergency Hormonal Contraception. BJOG. 2010;117:109-113. 12. Snella KA, Canales AE, Irons BK, et al. Pharmacy- and community-based screenings for diabetes and cardiovascular conditions in high-risk individuals. J Am Pharm Assoc (2003). 2006;46:370-377. Erratum in: J Am Pharm Assoc (Wash DC). 2006;46:666-667.

Continued

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13. Winfrey C, Wortman S, Frede S, et al. Pharmacist-initiated peripheral arterial disease screening program in a community pharmacy setting. J Am Pharm Assoc (2003). 2011;51:373-377. 14. Fuller L, Conrad WF, Heaton PC, et al. Pharmacist-managed chronic obstructive pulmonary disease screening in a community setting. J Am Pharm Assoc (2003). 2012; 52:e59-e66. 15. Peterson GM, Fitzmaurice KD, Kruup H, et al. Cardiovascular risk screening

program in Australian community pharmacies. Pharm World Sci. 2010;32:373-380. 16. Yuksel N, Majumdar SR, Biggs C, Tsuyuki RT. Community pharmacist-initiated screening program for osteoporosis: randomized controlled trial. Osteoporos Int. 2010; 21:391-398. 17. Johnson JF, Koenigsfeld C, Hughell L, et al. Bone health screening, education, and referral project in northwest Iowa: creating a model for community pharmacies. J Am Pharm Assoc (2003). 2008;48:379-387.

Stakeholder Perspective Screening for Diabetic Retinopathy in the Community Setting: Exploring the Options By Gary M. Owens, MD President, Gary Owens Associates, Ocean View, DE

PATIENTS: Diabetes is among the most prevalent diseases in the United States today, affecting more than 8.3% of the population or almost 26 million people.1 This far exceeds earlier projections that the total number of people with diabetes would rise to 20 million by 2025 and to 29 million by 2050.2 Largely driven by the epidemic of obesity, diabetes prevalence by 2050 could impact 1 of 3 adults according to the Centers for Disease Control and Prevention.3 One major complication of diabetes is diabetic retinopathy, a leading cause of visual impairment and blindness. As Law and colleagues point out in the current article, diabetic retinopathy affects more than 4.1 million patients in the United States, yet only approximately 50% to 60% of these patients follow the recommendation for an annual fundus examination. An even smaller number of patients with diabetes have proper screening for diabetic retinopathy. With a relative shortage of primary care physicians, and larger insured populations on the horizon with the implementation of the Affordable Care Act, one can speculate that these statistics may not improve without innovative approaches to screening. PHARMACISTS/PROVIDERS: As is the case for many common chronic diseases, we can do a far better job of screening for this severely debilitating illness. In this article, the authors consider the possibility of screening for diabetic retinopathy at the community pharmacy. This is an interesting concept that bears further exploration before implementation. We know that one of the most frequently used sites of service for most patients is the pharmacy. Patients with diabetes who present to the pharmacy can readily be identified by their medication profiles, and it would be relatively easy to ask them at the

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time of encounter about the timing of their last eye examination. However, practical considerations (many of which are mentioned in the article) must be considered before moving forward with such screenings in the pharmacy. Such things as equipment cost, training, and even time needed to do the examination properly are significant considerations that need further exploration. How the results are interpreted and how continuity of care is ensured are also concerns when one entertains widescale screening in novel sites of care. In addition, we must consider whether patients would be willing to take the time to have the examination done during a pharmacy visit. These issues bear further exploration before considering implementation of this approach to diabetic retinopathy screening. What struck me as most intriguing in this article is that the authors were willing to explore the use of pharmacy resources to positively impact the care of a large and growing population of patients with a chronic illness. This potential approach to the management of a chronic illness and others like it must be considered if we are to improve access and outcomes of care in the future. Further investigation of nontraditional sites of care and perhaps integrating traditional services in alternate locations should be encouraged in the future.

References

1. US Department of Health and Human Services; National Diabetes Information Clearing House. National Diabetes Statistics, 2011. http://diabetes.niddk.nih.gov/ dm/pubs/statistics/#fast. Accessed December 8, 2013. 2. Boyle JP, Honeycutt AA, Narayan KM, et al. Projection of diabetes burden through 2050: impact of changing demography and disease prevalence in the US. Diabetes Care. 2001;24:1936-1940. 3. Centers for Disease Control and Prevention. Number of Americans with diabetes projected to double or triple by 2050. www.cdc.gov/media/pressrel/2010/r101022. html. Accessed December 9, 2013.

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Call for Papers American Health & Drug Benefits offers an open forum for all healthcare participants to exchange ideas and present their data, innovations, and initiatives to facilitate patient-centered healthcare and benefit design models that meet the needs of all stakeholders—Distributors, Employers, Manufacturers, Patients, Payers, Providers, Purchasers, Regulators, and Researchers. Readers are invited to submit articles that aim at improving the quality of patient care and patient well-being while reducing or controlling costs, enhancing the health of communities and patient populations, as well as other topics relevant to benefit design with specific implications to policymakers, payers, and employers.

Areas of High Interest: • Pharmacogenomics • Policy Issues • Prevention Initiatives • Real-World Evidence • Reimbursement Strategies • Social Media in Healthcare • Survey Results • Value-Based Healthcare

• Health Information Exchange • Health Plan Initiatives • Innovations in Healthcare • Literature Reviews • Managed Care • Medicare/Medicaid • Patient Outcomes/Advocacy • Pharmacoeconomics

• Adherence Concerns • Benefit Design • Case Studies • Comorbidities and Cost Issues • Comparative Effectiveness Research • Decision-Making Tools • Ethics in Medicine • Health Economics Research

Clinical Topics of High Interest: Aging—With the aging of the US population, there is a growing need for early implementation of outcomes-based preventive and therapeutic strategies for older people. Allergies—Allergies, such as allergic or seasonal rhinitis, affect millions of Americans daily, resulting in a significant economic burden and human cost. Undertreatment and lack of adherence are common obstacles to patient management. Arthritis—Musculoskeletal conditions are on the increase, yet many patients are undiagnosed and untreated. Comparing new and emerging therapies is a key target for improving patient outcomes and reducing costs. Cancer care—The growing focus on high-cost biologic agents dictates an enhanced study of these therapeutic options, including reimbursement policies and cost management. Cardiovascular disease—Outcomes-based research on appropriate therapies, cost comparisons, emerging prevention strategies, and best practices will enhance readers’ decision-making.

Diabetes, Obesity—The growing epidemics of these twin metabolic conditions mandate a thorough examination of best therapies, adherence issues, access, and prevention strategies. Gastrointestinal conditions—Recognizing GI conditions, such as hepatitis C, Crohn’s disease, and inflammatory bowel disorder, remains a challenge. Infectious Diseases—The spread of common and emerging pathogens within the hospital and in the community remains a major concern requiring increased vigilance. MENTAL DISORDERS—Depression, bipolar disorder, and schizophrenia exert a huge financial and human burden on individuals, employers, and payers. Topics of interest include comparative effectiveness analyses, adherence, best practices, and reimbursement.

Pain Management—Chronic pain is associated with many complicated medical disorders and an enormous economic burden, yet pain medications are still underused.

Manuscripts should follow the Manuscript Instructions for Authors available at www.AHDBonline.com. Submit articles to editorial@engagehc.com. For more information, call 732-992-1892.

554

American Health & Drug Benefits

www.AHDBonline.com

November/December 2013

Vol 6, No 9

NEW

NOW AVAILABLE FOR THE TREATMENT OF MAJOR DEPRESSIVE DISORDER (MDD) The efficacy and safety of BRINTELLIX in the treatment of MDD was established in1: 6 short-term (6- to 8-week) randomized, double-blind, placebo-controlled, fixed-dose studies (including a dedicated study in the elderly) based on mean change from baseline to endpoint in MADRS or HAM-D24 total scores  1 long-term (24- to 64-week) maintenance study in adults based on time to recurrence of depressive episodes*  In clinical studies the most common adverse reactions (incidence ≥5% and at least twice the rate of placebo in 6- to 8-week studies) were nausea, constipation, and vomiting  In pooled 6- to 8-week placebo-controlled studies, the incidence of patients who received BRINTELLIX and discontinued because of adverse reactions ranged from 5% to 8% over the 5 to 20 mg/day doses compared to 4% for placebo; nausea was the most common adverse reaction reported as a reason for discontinuation 

*Recurrence of a depressive episode is defined as MADRS total score ≥22 or lack of efficacy as judged by the investigators. Please visit BRINTELLIXHCP.com to learn more.

INDICATION

BRINTELLIX is indicated for the treatment of major depressive disorder in adults.

IMPORTANT SAFETY INFORMATION WARNING: SUICIDAL THOUGHTS AND BEHAVIORS Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-term studies. These studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in patients over age 24; there was a trend toward reduced risk with antidepressant use in patients aged 65 and older. In patients of all ages who are started on antidepressant therapy, monitor closely for worsening, and for emergence of suicidal thoughts and behaviors. Advise families and caregivers of the need for close observation and communication with the prescriber. BRINTELLIX has not been evaluated for use in pediatric patients.

Serotonin Syndrome: The development of a potentially life-threatening serotonin syndrome has been reported with serotonergic antidepressants (SNRIs, SSRIs, and others), including BRINTELLIX, when used alone but more often when used concomitantly with other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John’s Wort), and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Serotonin syndrome symptoms may include mental status changes (eg, agitation, hallucinations, delirium, and coma), autonomic instability (eg, tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (eg, tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (eg, nausea, vomiting, diarrhea). If such symptoms occur, discontinue BRINTELLIX and any concomitant serotonergic agents, and initiate supportive symptomatic treatment. If concomitant use of BRINTELLIX is clinically warranted, patients should be made aware of and monitored for potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases.

CONTRAINDICATIONS Hypersensitivity: Hypersensitivity to vortioxetine or any components of the BRINTELLIX formulation. Angioedema has been reported in patients treated with BRINTELLIX.

Abnormal Bleeding: Treatment with serotonergic antidepressants (SSRIs, SNRIs, and others) may increase the risk of abnormal bleeding. Patients should be cautioned about the increased risk of bleeding when BRINTELLIX is coadministered with NSAIDs, aspirin, or other drugs that affect coagulation.

Monoamine Oxidase Inhibitors (MAOIs): Due to an increased risk of serotonin syndrome, do not use MAOIs intended to treat psychiatric disorders with BRINTELLIX or within 21 days of stopping treatment with BRINTELLIX. Do not use BRINTELLIX within 14 days of stopping an MAOI intended to treat psychiatric disorders. Do not start BRINTELLIX in a patient who is being treated with linezolid or intravenous methylene blue.

Activation of Mania/Hypomania: Activation of mania/hypomania can occur with antidepressant treatment. Prior to initiating treatment with an antidepressant, screen patients for bipolar disorder. As with all antidepressants, use BRINTELLIX cautiously in patients with a history or family history of bipolar disorder, mania, or hypomania.

WARNINGS AND PRECAUTIONS Clinical Worsening and Suicide Risk: All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. Consideration should be given to changing the therapeutic regimen,including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality (anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, and mania), especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Families and caregivers of patients being treated with antidepressants for MDD or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients daily.

Hyponatremia: Hyponatremia has occurred as a result of serotonergic drugs and in many cases, appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Elderly patients and patients taking diuretics or who are otherwise volume-depleted can be at greater risk. More severe or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death. Discontinue BRINTELLIX in patients with symptomatic hyponatremia and initiate appropriate medical intervention. Adverse Reactions: The most commonly observed adverse reactions for BRINTELLIX in 6- to 8-week placebo-controlled studies (incidence ≥5% and at least twice the rate of placebo) were by dose (5 mg, 10 mg, 15 mg, 20 mg) vs placebo: nausea (21%, 26%, 32%, 32% vs 9%), constipation (3%, 5%, 6%, 6% vs 3%), and vomiting (3%, 5%, 6%, 6% vs 1%). Drug Interactions: Concomitant administration of BRINTELLIX and strong CYP2D6 inhibitors or strong CYP inducers may require a dose adjustment of BRINTELLIX. Reference: 1. Brintellix (vortioxetine) prescribing information. Takeda Pharmaceuticals.

Please see adjacent pages for Brief Summary of Prescribing Information and visit BRINTELLIXHCP.com for full Prescribing Information and Medication Guide.

BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION BRINTELLIX (vortioxetine) tablets, for oral use WARNING: SUICIDAL THOUGHTS AND BEHAVIORS Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-term studies. These studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in patients over age 24; there was a trend toward reduced risk with antidepressant use in patients aged 65 and older [see Warnings and Precautions]. In patients of all ages who are started on antidepressant therapy, monitor closely for worsening, and for emergence of suicidal thoughts and behaviors. Advise families and caregivers of the need for close observation and communication with the prescriber [see Warnings and Precautions]. BRINTELLIX has not been evaluated for use in pediatric patients [see Use in Specific Populations]. INDICATIONS AND USAGE Major Depressive Disorder BRINTELLIX is indicated for the treatment of major depressive disorder (MDD). The efficacy of BRINTELLIX was established in six 6 to 8 week studies (including one study in the elderly) and one maintenance study in adults. CONTRAINDICATIONS • Hypersensitivity to vortioxetine or any components of the formulation. Angioedema has been reported in patients treated with BRINTELLIX. • The use of MAOIs intended to treat psychiatric disorders with BRINTELLIX or within 21 days of stopping treatment with BRINTELLIX is contraindicated because of an increased risk of serotonin syndrome. The use of BRINTELLIX within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated [see Warnings and Precautions]. Starting BRINTELLIX in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome [see Warnings and Precautions]. WARNINGS AND PRECAUTIONS Clinical Worsening and Suicide Risk Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled studies of antidepressant drugs (selective serotonin reuptake inhibitors [SSRIs] and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with MDD and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a trend toward reduction with antidepressants compared to placebo in adults aged 65 and older. The pooled analyses of placebo-controlled studies in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term studies of nine antidepressant drugs in over 4,400 patients. The pooled analyses of placebo-controlled studies in adults with MDD or other psychiatric disorders included a total of 295 short-term studies (median duration of two months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1. The risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1 of the BRINTELLIX Full Prescribing Information, which states: 14 additional cases in patients under the age of 18, 5 additional cases in patients between 18 and 24 years of age. There was 1 fewer case in patients between 25 and 64 years of age and 6 fewer cases in patients 65 years of age and over. No suicides occurred in any of the pediatric studies. There were suicides in the adult studies, but the number was not sufficient to reach any conclusion about drug effect on suicide. It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebocontrolled maintenance studies in adults with depression that the use of antidepressants can delay the recurrence of depression.

All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. The following symptoms anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania have been reported in adult and pediatric patients being treated with antidepressants for MDD as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Families and caregivers of patients being treated with antidepressants for MDD or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers. Screening Patients for Bipolar Disorder A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled studies) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that BRINTELLIX is not approved for use in treating bipolar depression. Serotonin Syndrome The development of a potentially life-threatening serotonin syndrome has been reported with serotonergic antidepressants including BRINTELLIX, when used alone but more often when used concomitantly with other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John’s Wort), and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome. The concomitant use of BRINTELLIX with MAOIs intended to treat psychiatric disorders is contraindicated. BRINTELLIX should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with a MAOI such as linezolid or intravenous methylene blue in a patient taking BRINTELLIX. BRINTELLIX should be discontinued before initiating treatment with the MAOI [see Contraindications]. If concomitant use of BRINTELLIX with other serotonergic drugs, including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St. John’s Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases. Treatment with BRINTELLIX and any concomitant serotonergic agents should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated. Abnormal Bleeding The use of drugs that interfere with serotonin reuptake inhibition, including BRINTELLIX, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin, and other anticoagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to drugs that inhibit serotonin reuptake have ranged from ecchymosis, hematoma, epistaxis, and petechiae to life-threatening hemorrhages.

Patients should be cautioned about the increased risk of bleeding when BRINTELLIX is coadministered with NSAIDs, aspirin, or other drugs that affect coagulation or bleeding [see Drug Interactions]. Activation of Mania/Hypomania Symptoms of mania/hypomania were reported in <0.1% of patients treated with BRINTELLIX in pre-marketing clinical studies. Activation of mania/ hypomania has been reported in a small proportion of patients with major affective disorder who were treated with other antidepressants. As with all antidepressants, use BRINTELLIX cautiously in patients with a history or family history of bipolar disorder, mania, or hypomania. Hyponatremia Hyponatremia has occurred as a result of treatment with serotonergic drugs. In many cases, hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). One case with serum sodium lower than 110 mmol/L was reported in a subject treated with BRINTELLIX in a pre-marketing clinical study. Elderly patients may be at greater risk of developing hyponatremia with a serotonergic antidepressant. Also, patients taking diuretics or who are otherwise volume depleted can be at greater risk. Discontinuation of BRINTELLIX in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which can lead to falls. More severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death. ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label. • Hypersensitivity [see Contraindications] • Clinical Worsening and Suicide Risk [see Warnings and Precautions] • Serotonin Syndrome [see Warnings and Precautions] • Abnormal Bleeding [see Warnings and Precautions] • Activation of Mania/Hypomania [see Warnings and Precautions] • Hyponatremia [see Warnings and Precautions] Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice. Patient Exposure BRINTELLIX was evaluated for safety in 4746 patients (18 years to 88 years of age) diagnosed with MDD who participated in pre-marketing clinical studies; 2616 of those patients were exposed to BRINTELLIX in 6 to 8 week, placebocontrolled studies at doses ranging from 5 mg to 20 mg once daily and 204 patients were exposed to BRINTELLIX in a 24 week to 64 week placebocontrolled maintenance study at doses of 5 mg to 10 mg once daily. Patients from the 6 to 8 week studies continued into 12-month open-label studies. A total of 2586 patients were exposed to at least one dose of BRINTELLIX in open-label studies, 1727 were exposed to BRINTELLIX for six months and 885 were exposed for at least one year. Adverse Reactions Reported as Reasons for Discontinuation of Treatment In pooled 6 to 8 week placebo-controlled studies the incidence of patients who received BRINTELLIX 5 mg/day, 10 mg/day, 15 mg/day and 20 mg/day and discontinued treatment because of an adverse reaction was 5%, 6%, 8% and 8%, respectively, compared to 4% of placebo-treated patients. Nausea was the most common adverse reaction reported as a reason for discontinuation. Common Adverse Reactions in Placebo-Controlled MDD Studies The most commonly observed adverse reactions in MDD patients treated with BRINTELLIX in 6 to 8 week placebo-controlled studies (incidence ≥5% and at least twice the rate of placebo) were nausea, constipation and vomiting. Table 2 shows the incidence of common adverse reactions that occurred in ≥2% of MDD patients treated with any BRINTELLIX dose and at least 2% more frequently than in placebo-treated patients in the 6 to 8 week placebocontrolled studies. Table 2 of the BRINTELLIX Full Prescribing Information shows the incidence of common adverse reactions that occurred in ≥2% of MDD patients treated with any BRINTELLIX dose and at least 2% more frequently than in placebotreated patients in the 6- to 8-week placebo-controlled studies. The following values from Table 2 show the percentage of patients exhibiting the adverse reaction while receiving BRINTELLIX 5 mg (N=1013), 10 mg (N=699), 15 mg (N=449), 20 mg (N=455), and placebo (N=1621) respectively. Gastrointestinal Disorders: Nausea (21%, 26%, 32%, 32%, vs. 9%); Diarrhea (7%, 7%, 10%, 7%, vs. 6%); Dry Mouth (7%, 7%, 6%, 8%, vs. 6%); Constipation (3%, 5%, 6%, 6%, vs. 3%); Vomiting (3%, 5%, 6%, 6%, vs. 1%); Flatulence (1%, 3%, 2%, 1%, vs. 1%); Nervous System Disorders: Dizziness (6%, 6%, 8%, 9%, vs. 6%); Psychiatric Disorders: Abnormal Dreams (<1%, <1%, 2%, 3%, vs. 1%); Skin and Subcutaneous Tissue Disorders: Pruritus (including pruritus generalized) (1%, 2%, 3%, 3%, vs. 1%). Nausea Nausea was the most common adverse reaction and its frequency was doserelated (Table 2). It was usually considered mild or moderate in intensity and the median duration was 2 weeks. Nausea was more common in females than

males. Nausea most commonly occurred in the first week of BRINTELLIX treatment with 15 to 20% of patients experiencing nausea after 1 to 2 days of treatment. Approximately 10% of patients taking BRINTELLIX 10 mg/day to 20 mg/day had nausea at the end of the 6 to 8 week placebo-controlled studies. Sexual Dysfunction Difficulties in sexual desire, sexual performance and sexual satisfaction often occur as manifestations of psychiatric disorders, but they may also be consequences of pharmacologic treatment. In the MDD 6 to 8 week controlled trials of BRINTELLIX, voluntarily reported adverse reactions related to sexual dysfunction were captured as individual event terms. These event terms have been aggregated and the overall incidence was as follows. In male patients the overall incidence was 3%, 4%, 4%, 5% in BRINTELLIX 5 mg/day, 10 mg/day, 15 mg/day, 20 mg/day, respectively, compared to 2% in placebo. In female patients, the overall incidence was <1%, 1%, <1%, 2% in BRINTELLIX 5 mg/day, 10 mg/day, 15 mg/day, 20 mg/day, respectively, compared to <1% in placebo. Because voluntarily reported adverse sexual reactions are known to be underreported, in part because patients and physicians may be reluctant to discuss them, the Arizona Sexual Experiences Scale (ASEX), a validated measure designed to identify sexual side effects, was used prospectively in seven placebo-controlled trials. The ASEX scale includes five questions that pertain to the following aspects of sexual function: 1) sex drive, 2) ease of arousal, 3) ability to achieve erection (men) or lubrication (women), 4) ease of reaching orgasm, and 5) orgasm satisfaction. The presence or absence of sexual dysfunction among patients entering clinical studies was based on their ASEX scores. For patients without sexual dysfunction at baseline (approximately 1/3 of the population across all treatment groups in each study), Table 3 shows the incidence of patients that developed treatment-emergent sexual dysfunction when treated with BRINTELLIX or placebo in any fixed dose group. Physicians should routinely inquire about possible sexual side effects. The presence or absence of sexual dysfunction among patients entering clinical studies was based on their ASEX scores. For patients without sexual dysfunction at baseline (approximately 1/3 of the population across all treatment groups in each study), the following values from Table 3 of the BRINTELLIX Full Prescribing Information show the ASEX incidence of patients who developed treatment-emergent sexual dysfunction when treated with BRINTELLIX or placebo in any fixed-dose group. The incidence in female patients treated with BRINTELLIX 5 mg (N=65), 10 mg (N=94), 15 mg (N=57), 20 mg (N=67) or placebo (N=135), respectively was 22%, 23%, 33%, 34% vs. 20%. For male patients, the incidence of treatment-emergent sexual dysfunction when treated with BRINTELLIX 5 mg (N=67), 10 mg (N=86), 15 mg (N=67), 20 mg (N=59) or placebo (N=162), respectively was 16%, 20%, 19%, 29% vs. 14%. Incidence was based on the number of subjects with sexual dysfunction during the study / number of subjects without sexual dysfunction at baseline. Sexual dysfunction was defined as a subject scoring any of the following on the ASEX scale at two consecutive visits during the study: 1) total score ≥19; 2) any single item ≥5; 3) three or more items each with a score ≥4. The sample size for each dose group was the number of patients without sexual dysfunction at baseline. Physicians should routinely inquire about possible sexual side effects. Adverse Reactions Following Abrupt Discontinuation of BRINTELLIX Treatment Discontinuation symptoms have been prospectively evaluated in patients taking BRINTELLIX 10 mg/day, 15 mg/day, and 20 mg/day using the Discontinuation-Emergent Signs and Symptoms (DESS) scale in clinical trials. Some patients experienced discontinuation symptoms such as headache, muscle tension, mood swings, sudden outbursts of anger, dizziness, and runny nose in the first week of abrupt discontinuation of BRINTELLIX 15 mg/day and 20 mg/day. Laboratory Tests BRINTELLIX has not been associated with any clinically important changes in laboratory test parameters in serum chemistry (except sodium), hematology and urinalysis as measured in the 6 to 8 week placebo-controlled studies. Hyponatremia has been reported with the treatment of BRINTELLIX [see Warnings and Precautions]. In the 6-month, double-blind, placebocontrolled phase of a long-term study in patients who had responded to BRINTELLIX during the initial 12-week, open-label phase, there were no clinically important changes in lab test parameters between BRINTELLIX and placebo-treated patients. Weight BRINTELLIX had no significant effect on body weight as measured by the mean change from baseline in the 6 to 8 week placebo-controlled studies. In the 6-month, double-blind, placebo-controlled phase of a long-term study in patients who had responded to BRINTELLIX during the initial 12-week, open-label phase, there was no significant effect on body weight between BRINTELLIX and placebo-treated patients. Vital Signs BRINTELLIX has not been associated with any clinically significant effects on vital signs, including systolic and diastolic blood pressure and heart rate, as measured in placebo-controlled studies.

Other Adverse Reactions Observed in Clinical Studies The following listing does not include reactions: 1) already listed in previous tables or elsewhere in labeling, 2) for which a drug cause was remote, 3) which were so general as to be uninformative, 4) which were not considered to have significant clinical implications, or 5) which occurred at a rate equal to or less than placebo. Ear and labyrinth disorders — vertigo Gastrointestinal disorders — dyspepsia Nervous system disorders — dysgeusia Vascular disorders — flushing DRUG INTERACTIONS CNS Active Agents Monoamine Oxidase Inhibitors Adverse reactions, some of which are serious or fatal, can develop in patients who use MAOIs or who have recently been discontinued from an MAOI and started on a serotonergic antidepressant(s) or who have recently had SSRI or SNRI therapy discontinued prior to initiation of an MAOI [see Contraindications and Warnings and Precautions]. Serotonergic Drugs Based on the mechanism of action of BRINTELLIX and the potential for serotonin toxicity, serotonin syndrome may occur when BRINTELLIX is coadministered with other drugs that may affect the serotonergic neurotransmitter systems (e.g., SSRIs, SNRIs, triptans, buspirone, tramadol, and tryptophan products etc.). Closely monitor symptoms of serotonin syndrome if BRINTELLIX is co-administered with other serotonergic drugs. Treatment with BRINTELLIX and any concomitant serotonergic agents should be discontinued immediately if serotonin syndrome occurs [see Warnings and Precautions]. Other CNS Active Agents No clinically relevant effect was observed on steady state lithium exposure following coadministration with multiple daily doses of BRINTELLIX. Multiple doses of BRINTELLIX did not affect the pharmacokinetics or pharmacodynamics (composite cognitive score) of diazepam. A clinical study has shown that BRINTELLIX (single dose of 20 or 40 mg) did not increase the impairment of mental and motor skills caused by alcohol (single dose of 0.6 g/kg). Details on the potential pharmacokinetic interactions between BRINTELLIX and bupropion can be found in Section 7.3, Potential for Other Drugs to Affect BRINTELLIX. Drugs that Interfere with Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin) Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of case-control and cohort design have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding. These studies have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs and SNRIs are coadministered with warfarin. Following coadministration of stable doses of warfarin (1 to 10 mg/day) with multiple daily doses of BRINTELLIX, no significant effects were observed in INR, prothrombin values or total warfarin (protein bound plus free drug) pharmacokinetics for both R- and S-warfarin [see Drug Interactions]. Coadministration of aspirin 150 mg/day with multiple daily doses of BRINTELLIX had no significant inhibitory effect on platelet aggregation or pharmacokinetics of aspirin and salicylic acid [see Drug Interactions]. Patients receiving other drugs that interfere with hemostasis should be carefully monitored when BRINTELLIX is initiated or discontinued [see Warnings and Precautions]. Potential for Other Drugs to Affect BRINTELLIX Reduce BRINTELLIX dose by half when a strong CYP2D6 inhibitor (e.g., bupropion, fluoxetine, paroxetine, quinidine) is coadministered. Consider increasing the BRINTELLIX dose when a strong CYP inducer (e.g., rifampicin, carbamazepine, phenytoin) is coadministered. The maximum dose is not recommended to exceed three times the original dose (Figure 1). Figure 1. Impact of Other Drugs on Vortioxetine PK

Potential for BRINTELLIX to Affect Other Drugs No dose adjustment for the comedications is needed when BRINTELLIX is coadministered with a substrate of CYP1A2 (e.g., duloxetine), CYP2A6, CYP2B6 (e.g., bupropion), CYP2C8 (e.g., repaglinid), CYP2C9 (e.g., S-warfarin), CYP2C19 (e.g., diazepam), CYP2D6 (e.g., venlafaxine), CYP3A4/5 (e.g., budesonide), and P-gp (e.g., digoxin). In addition, no dose adjustment for lithium, aspirin, and warfarin is necessary. Vortioxetine and its metabolites are unlikely to inhibit the following CYP enzymes and transporter based on in vitro data: CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, and P-gp. As such, no clinically relevant interactions with drugs metabolized by these CYP enzymes would be expected. In addition, vortioxetine did not induce CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP3A4/5 in an in vitro study in cultured human hepatocytes. Chronic administration of BRINTELLIX is unlikely to induce the metabolism of drugs metabolized by these CYP isoforms. Furthermore, in a series of clinical drug interaction studies, coadministration of BRINTELLIX with substrates for CYP2B6 (e.g., bupropion), CYP2C9 (e.g., warfarin), and CYP2C19 (e.g., diazepam), had no clinical meaningful effect on the pharmacokinetics of these substrates (Figure 2). Because vortioxetine is highly bound to plasma protein, coadministration of BRINTELLIX with another drug that is highly protein bound may increase free concentrations of the other drug. However, in a clinical study with coadministration of BRINTELLIX (10 mg/day) and warfarin (1 mg/day to 10 mg/day), a highly protein-bound drug, no significant change in INR was observed [see Drug Interactions]. Figure 2. Impact of Vortioxetine on PK of Other Drugs

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C Risk Summary There are no adequate and well-controlled studies of BRINTELLIX in pregnant women. Vortioxetine caused developmental delays when administered during pregnancy to rats and rabbits at doses 15 and 10 times the maximum recommended human dose (MRHD) of 20 mg, respectively. Developmental delays were also seen after birth in rats at doses 20 times the MRHD of vortioxetine given during pregnancy and through lactation. There were no teratogenic effects in rats or rabbits at doses up to 77 and 58 times, the MRHD of vortioxetine, respectively, given during organogenesis. The incidence of malformations in human pregnancies has not been established for BRINTELLIX. All human pregnancies, regardless of drug exposure, have a background rate of 2 to 4% for major malformations, and 15 to 20% for pregnancy loss. BRINTELLIX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Clinical Considerations Neonates exposed to SSRIs or SNRIs, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability and constant crying. These features are consistent with either a direct toxic effect of these classes of drugs or possibly, a drug discontinuation syndrome. It should be noted that in some cases, the clinical picture is consistent with serotonin syndrome [see Warnings and Precautions]. When treating a pregnant woman with

BRINTELLIX during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. Neonates exposed to SSRIs in pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in one to two per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality. Several recent epidemiologic studies suggest a positive statistical association between SSRI use in pregnancy and PPHN. Other studies do not show a significant statistical association. A prospective longitudinal study was conducted of 201 pregnant women with a history of major depression, who were either on antidepressants or had received antidepressants less than 12 weeks prior to their last menstrual period, and were in remission. Women who discontinued antidepressant medication during pregnancy showed a significant increase in relapse of their major depression compared to those women who remained on antidepressant medication throughout pregnancy. When treating a pregnant woman with BRINTELLIX, the physician should carefully consider both the potential risks of taking a serotonergic antidepressant, along with the established benefits of treating depression with an antidepressant. Animal Data In pregnant rats and rabbits, no teratogenic effects were seen when vortioxetine was given during the period of organogenesis at oral doses up to 160 and 60 mg/kg/day, respectively. These doses are 77 and 58 times, in rats and rabbits, respectively, the maximum recommended human dose (MRHD) of 20 mg on a mg/m2 basis. Developmental delay, seen as decreased fetal body weight and delayed ossification, occurred in rats and rabbits at doses equal to and greater than 30 and 10 mg/kg (15 and 10 times the MRHD, respectively) in the presence of maternal toxicity (decreased food consumption and decreased body weight gain). When vortioxetine was administered to pregnant rats at oral doses up to 120 mg/kg (58 times the MRHD) throughout pregnancy and lactation, the number of live-born pups was decreased and early postnatal pup mortality was increased at 40 and 120 mg/kg. Additionally, pup weights were decreased at birth to weaning at 120 mg/kg and development (specifically eye opening) was slightly delayed at 40 and 120 mg/kg. These effects were not seen at 10 mg/kg (5 times the MRHD). Nursing Mothers It is not known whether vortioxetine is present in human milk. Vortioxetine is present in the milk of lactating rats. Because many drugs are present in human milk and because of the potential for serious adverse reactions in nursing infants from BRINTELLIX, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Clinical studies on the use of BRINTELLIX in pediatric patients have not been conducted; therefore, the safety and effectiveness of BRINTELLIX in the pediatric population have not been established. Geriatric Use No dose adjustment is recommended on the basis of age (Figure 3). Results from a single-dose pharmacokinetic study in elderly (>65 years old) vs. young (24 to 45 years old) subjects demonstrated that the pharmacokinetics were generally similar between the two age groups. Of the 2616 subjects in clinical studies of BRINTELLIX, 11% (286) were 65 and over, which included subjects from a placebo-controlled study specifically in elderly patients. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients. Serotonergic antidepressants have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event [see Warnings and Precautions]. Use in Other Patient Populations No dose adjustment of BRINTELLIX on the basis of race, gender, ethnicity, or renal function (from mild renal impairment to end-stage renal disease) is necessary. In addition, the same dose can be administered in patients with mild to moderate hepatic impairment (Figure 3). BRINTELLIX has not been studied in patients with severe hepatic impairment. Therefore, BRINTELLIX is not recommended in patients with severe hepatic impairment.

Figure 3. Impact of Intrinsic Factors on Vortioxetine PK

DRUG ABUSE AND DEPENDENCE BRINTELLIX is not a controlled substance. OVERDOSAGE Human Experience There is limited clinical trial experience regarding human overdosage with BRINTELLIX. In pre-marketing clinical studies, cases of overdose were limited to patients who accidentally or intentionally consumed up to a maximum dose of 40 mg of BRINTELLIX. The maximum single dose tested was 75 mg in men. Ingestion of BRINTELLIX in the dose range of 40 to 75 mg was associated with increased rates of nausea, dizziness, diarrhea, abdominal discomfort, generalized pruritus, somnolence, and flushing. Management of Overdose No specific antidotes for BRINTELLIX are known. In managing over dosage, consider the possibility of multiple drug involvement. In case of overdose, call Poison Control Center at 1-800-222-1222 for latest recommendations. Distributed and marketed by: Takeda Pharmaceuticals America, Inc. Deerfield, IL 60015 Marketed by: Lundbeck Deerfield, IL 60015 BRINTELLIX is a trademark of H. Lundbeck A/S and is used under license by Takeda Pharmaceuticals America, Inc. ÂŠ2013 Takeda Pharmaceuticals America, Inc. LUN205P R1_Brf. September 2013 90243 L-LUN-0913-2

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“Project IMPACT: Diabetes” Care Model Improves Health Outcomes in Underserved Populations in 25 Communities with a High Incidence of Diabetes Benjamin M. Bluml, RPh Senior Vice President for Research and Innovation American Pharmacists Association Foundation Washington, DC

hronic disease is responsible for 7 of 10 deaths in the United States and 75% of the nation’s $2.2trillion healthcare bill.1,2 According to the American Diabetes Association, nearly 26 million Americans have diabetes, and more than 200,000 die of this chronic disease annually. Patients with diabetes are at increased risk for diabetes-related complications, includ ing heart disease, stroke, kidney failure, blindness, and lower-limb amputations.3 In 2010, the Bristol-Myers Squibb (BMS) Foundation announced the establishment of Together on Diabetes—a 5-year, $100-million initiative designed to improve the health outcomes of underserved patients with type 2 diabetes in the United States, China, and India. One of the first 4 organizations in the BMS Foundation’s Together on Diabetes, the American Pharmacists Association (APhA) Foundation received a grant from the BMS Foundation to launch “Project IMPACT: Diabetes,” to bring quality care to underserved people in 25 US communities with a high incidence of diabetes.

Project IMPACT: Diabetes The objectives of Project IMPACT: Diabetes are to expand the proven community-based model of care to patients who need it the most in communities across the United States, to improve key indicators of diabetes care in these selected communities, and to strengthen local models of care by establishing community peer-to-peer networking and mentoring relationships. Organizations selected to participate in Project IMPACT: Diabetes include community and university- affiliated pharmacies, self-insured employers, federally qualified health centers, free health clinics, and others that have the opportunity to leverage unique stakeholders, existing programs, creative ideas, and additional resources to effectively adapt and implement similar models of care. The APhA Foundation also provides

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communities with tools, resources, guidance, and support to facilitate local success. The APhA Foundation educates each community about this care model that places the patient with diabetes on the healthcare team, and inserts the pharmacist as a valued health coach. The Foundation also provides training and access to the Patient Self-Management Credential for Diabetes and a clinical data management tool, which are core components of the project. The clinical data management tool standardized the data set that all 25 communities are collecting throughout the project. The APhA Foundation’s Patient Self-Management Credential for diabetes helps pharmacists identify the patient’s knowledge strengths and areas for improvement, allowing providers to customize the patient’s education and to address the biggest knowledge gaps first. Pharmacists are also able to use each patient’s credential level to recognize achievements in diabetes self-management knowledge, skills, and performance. Through Project IMPACT: Diabetes, more than 2000 underserved patients, including those who are uninsured, underinsured, homeless, and/or living below the poverty line are currently receiving care from community-based interdisciplinary teams that include pharmacists, physicians, diabetes educators, and other healthcare professionals. The cornerstone of local implementations is one-onone patient consultations with pharmacists trained in diabetes care who monitor the patients’ A1c level, blood pressure, cholesterol, and body mass index, and help patients to manage their disease through appropriate medication use, exercise, nutrition, and other lifestyle changes. Pharmacists collaborate with and refer patients to physicians and other healthcare providers to ensure that patients receive comprehensive care. In addition, the communities are encouraged to incentivize patients to stay motivated about diabetes self-management. Some incentives include bus passes,

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Table Interim Results from 25 Underserved Communities Clinical indicators (recognized standards Participants, for diabetes care) N

Mean baseline Mean interim measure measure

Mean change

A1c (American Diabetes Association goal: <7.0%) LDL cholesterol level (NCEP goal: <100 mg/dL)

1580

9.0%

8.3%

–0.7%a

966

99.5 mg/dL

92.2 mg/dL

–7.3 mg/dLa

Systolic blood pressure (JNC VII goal: <130 mm Hg) Body mass index (World Health Organization normal: 18.5-24.9 kg/m2) Participant demographics Sex

1702

131.8 mm Hg

129.9 mm Hg

–1.9 mm Hga

1699

35.1 kg/m2

34.9 kg/m2

–0.2 kg/m2a

Women, 58.3% Men, 41.7% Age (average, 53.8 yrs) ≥50 yrs, 67.6% ≥62 yrs, 23.4% Ethnicity Caucasian, 41.2% African American, 24.2% Hispanic, 21.3% Other, including not specified, 13.4% Statistically significant change. National Institutes of Health Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. December 2003. A1c indicates glycosylated hemoglobin; JNC VII, The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; LDL, low-density lipoprotein; NCEP, National Cholesterol Education Program. Copyright © 2013 APhA Foundation. Used with permission.

food store gift cards, discounted or free healthy lunches at employer worksites, discounted copayments, or simply the ability to continue to have a healthcare provider focus on helping the patient.

Interim Results Project IMPACT: Diabetes has scaled previous APhA Foundation collaborative care programs for the selected 25 communities. Over a mean duration of 6 months, healthcare teams saw statistically significant improvements in the diabetes-related clinical outcomes of their patients (Table), including an overall reduction in A1c levels from 9.0% to 8.3%; a 7.3-mg/dL reduction in low-density lipoprotein cholesterol; and a 1.9-mm Hg reduction in systolic blood pressure.4 Dramatic improvements were also seen in patients’ ability to manage their diabetes, in large part as a result of the adaptability of the care model to fit local needs. Conclusion Every patient with diabetes faces challenges, such as adhering to prescribed medications, monitoring blood glucose levels, staying current with vaccines and foot and

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eye examinations, and maintaining a healthy diet and lifestyle. This initiative shows that all types of patients with diabetes, including the poor and uninsured, by working together with pharmacists and other members of the healthcare team, can be empowered to take the steps they need to understand and manage their diabetes. The interim results of Project IMPACT: Diabetes demonstrate that when patients are supported and empowered to make the lifestyle changes that are necessary to manage a chronic disease such as diabetes, significant improvements are possible. It is an idea whose time has come. n Author Disclosure Statement Mr Bluml is an employee of the APhA Foundation.

References

1. Centers for Disease Control and Prevention. Chronic diseases and health promotion. Updated August 13, 2012. Reviewed August 13, 2012. www.cdc.gov/chronic disease/overview/index.htm. Accessed November 26, 2013. 2. Centers for Disease Control and Prevention. Chronic diseases: the power to prevent, the call to control: at a glance 2009. www.cdc.gov/chronicdisease/resources/ publications/aag/pdf/chronic.pdf. Accessed November 26, 2013. 3. American Diabetes Association. Diabetes statistics. Reviewed June 6, 2013. www. diabetes.org/diabetes-basics/diabetes-statistics/. Accessed November 26, 2013. 4. American Pharmacists Association Foundation. Project IMPACT: Diabetes: the results. www.aphafoundation.org/project-impact-diabetes/results. Accessed November 26, 2013.

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For your members with COPD (chronic obstructive pulmonary disease)

The only once-daily ICS/LABA (inhaled corticosteroid/long-acting beta2-agonist) for the maintenance treatment of COPD. Contact your GlaxoSmithKline Account Manager to schedule a presentation. Indications • BREO ELLIPTA is a combination inhaled corticosteroid/long-acting beta2 -adrenergic agonist (ICS/LABA) indicated for the longterm, once-daily, maintenance treatment of airﬂow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema. BREO ELLIPTA is also indicated to reduce exacerbations of COPD in patients with a history of exacerbations. • BREO ELLIPTA is NOT indicated for the relief of acute bronchospasm or for the treatment of asthma.

Important Safety Information for BREO ELLIPTA WARNING: ASTHMA-RELATED DEATH • Long-acting beta2-adrenergic agonists (LABAs), such as vilanterol, one of the active ingredients in BREO ELLIPTA, increase the risk of asthma-related death. A placebo-controlled trial with another LABA (salmeterol) showed an increase in asthma-related deaths in subjects receiving salmeterol. This finding with salmeterol is considered a class effect of all LABAs, including vilanterol. • The safety and efficacy of BREO ELLIPTA in patients with asthma have not been established. BREO ELLIPTA is not indicated for the treatment of asthma. CONTRAINDICATIONS • BREO ELLIPTA is contraindicated in patients with severe hypersensitivity to milk proteins or who have demonstrated hypersensitivity to either fluticasone furoate, vilanterol, or any of the excipients. WARNINGS AND PRECAUTIONS • BREO ELLIPTA should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of COPD. • BREO ELLIPTA should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. Acute symptoms should be treated with an inhaled, short-acting beta2 -agonist. • BREO ELLIPTA should not be used more often than recommended, at higher doses than recommended, or in conjunction with other medications containing LABAs, as an overdose may result. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Patients using BREO ELLIPTA should not use another medicine containing a LABA (e.g., salmeterol, formoterol fumarate, arformoterol tartrate, indacaterol) for any reason. • Oropharyngeal candidiasis has occurred in patients treated with BREO ELLIPTA. Advise patients to rinse the mouth without swallowing following inhalation to help reduce the risk of oropharyngeal candidiasis. • An increase in the incidence of pneumonia has been observed in subjects with COPD receiving BREO ELLIPTA. There was also an increased incidence of pneumonias resulting in hospitalization. In some incidences these pneumonia events were fatal. – In replicate 12-month studies of 3255 subjects with COPD who had experienced a COPD exacerbation in the previous year, there was a higher incidence of pneumonia reported in subjects receiving BREO ELLIPTA 100/25 mcg (6% [51 of 806 subjects]), fluticasone furoate (FF)/vilanterol (VI) 50/25 mcg (6% [48 of 820 subjects]), and FF/VI 200/25 mcg (7% [55 of 811 subjects]) than in subjects receiving VI 25 mcg (3% [27 of 818 subjects]). There was no fatal pneumonia in subjects receiving VI or FF/VI 50/25 mcg. There was fatal pneumonia in 1 subject receiving BREO ELLIPTA at the approved strength (100/25 mcg) and in 7 subjects receiving FF/VI 200/25 mcg (<1% for each treatment group). • Physicians should remain vigilant for the possible development of pneumonia in patients with COPD, as the clinical features of such infections overlap with the symptoms of COPD exacerbations. • Patients who use corticosteroids are at risk for potential worsening of existing tuberculosis; fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex. A more serious or even fatal course of chickenpox or measles may occur in susceptible patients. Use caution in patients with the above because of the potential for worsening of these infections. • Particular care is needed for patients who have been transferred from systemically active corticosteroids to inhaled corticosteroids because deaths due to adrenal insufficiency have occurred in patients with asthma during and after transfer from systemic corticosteroids to less systemically available inhaled corticosteroids. Taper patients slowly from systemic corticosteroids if transferring to BREO ELLIPTA. • Hypercorticism and adrenal suppression may occur with very high dosages or at the regular dosage of inhaled corticosteroids in susceptible individuals. If such changes occur, discontinue BREO ELLIPTA slowly.

Important Safety Information for BREO ELLIPTA (cont’d) WARNINGS AND PRECAUTIONS (cont’d) • Caution should be exercised when considering the coadministration of BREO ELLIPTA with long-term ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir, clarithromycin, conivaptan, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, saquinavir, telithromycin, troleandomycin, voriconazole) because increased systemic corticosteroid and cardiovascular adverse effects may occur. • If paradoxical bronchospasm occurs, discontinue BREO ELLIPTA and institute alternative therapy. • Vilanterol can produce clinically significant cardiovascular effects in some patients as measured by increases in pulse rate, systolic or diastolic blood pressure, and also cardiac arrhythmias, such as supraventricular tachycardia and extrasystoles. If such effects occur, BREO ELLIPTA may need to be discontinued. BREO ELLIPTA should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension. • Decreases in bone mineral density (BMD) have been observed with long-term administration of products containing inhaled corticosteroids. Patients with major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis, postmenopausal status, tobacco use, advanced age, poor nutrition, or chronic use of drugs that can reduce bone mass (e.g., anticonvulsants, oral corticosteroids) should be monitored and treated with established standards of care. Since patients with COPD often have multiple risk factors for reduced BMD, assessment of BMD is recommended prior to initiating BREO ELLIPTA and periodically thereafter. • Glaucoma, increased intraocular pressure, and cataracts have been reported in patients with COPD following the long-term administration of inhaled corticosteroids. Therefore, close monitoring is warranted in patients with a change in vision or with a history of increased intraocular pressure, glaucoma, and/or cataracts. • Use with caution in patients with convulsive disorders, thyrotoxicosis, diabetes mellitus, ketoacidosis, and in patients who are unusually responsive to sympathomimetic amines. • Be alert to hypokalemia and hyperglycemia. ADVERSE REACTIONS • The most common adverse reactions (≥3% and more common than placebo) reported in two 6-month clinical trials with BREO ELLIPTA (and placebo) were nasopharyngitis, 9% (8%); upper respiratory tract infection, 7% (3%); headache, 7% (5%); and oral candidiasis, 5% (2%). • In addition to the events reported in the 6-month studies, adverse reactions occurring in ≥3% of the subjects treated with BREO ELLIPTA in two 1-year studies included COPD, back pain, pneumonia, bronchitis, sinusitis, cough, oropharyngeal pain, arthralgia, hypertension, influenza, pharyngitis, diarrhea, peripheral edema, and pyrexia. DRUG INTERACTIONS • Caution should be exercised when considering the coadministration of BREO ELLIPTA with long-term ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir, clarithromycin, conivaptan, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, saquinavir, telithromycin, troleandomycin, voriconazole) because increased systemic corticosteroid and cardiovascular adverse effects may occur. • BREO ELLIPTA should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors, tricyclic antidepressants, or drugs known to prolong the QTc interval, or within 2 weeks of discontinuation of such agents, because the effect of adrenergic agonists, such as vilanterol, on the cardiovascular system may be potentiated by these agents. • Use beta-blockers with caution as they not only block the pulmonary effect of beta-agonists, such as vilanterol, but may produce severe bronchospasm in patients with reversible obstructive airways disease. • Use with caution in patients taking non–potassium-sparing diuretics, as electrocardiographic changes and/or hypokalemia associated with non–potassium-sparing diuretics may worsen with concomitant beta-agonists. USE IN SPECIFIC POPULATIONS • Use BREO ELLIPTA with caution in patients with moderate or severe hepatic impairment. Fluticasone furoate exposure may increase in these patients. Monitor for systemic corticosteroid effects. Please see Brief Summary of Prescribing Information, including Boxed Warning, for BREO ELLIPTA on the following pages. BREO ELLIPTA was developed in collaboration with

BRIEF SUMMARY BREOTM ELLIPTATM (fluticasone furoate and vilanterol inhalation powder) FOR ORAL INHALATION USE The following is a brief summary only; see full prescribing information for complete product information WARNING: ASTHMA-RELATED DEATH Long-acting beta2-adrenergic agonists (LABA) increase the risk of asthma-related death. Data from a large placebo-controlled US trial that compared the safety of another LABA (salmeterol) with placebo added to usual asthma therapy showed an increase in asthma-related deaths in subjects receiving salmeterol. This finding with salmeterol is considered a class effect of LABA, including vilanterol, an active ingredient in BREO ELLIPTA [see Warnings and Precautions (5.1)]. The safety and efficacy of BREO ELLIPTA in patients with asthma have not been established. BREO ELLIPTA is not indicated for the treatment of asthma. 1 INDICATIONS AND USAGE BREO ELLIPTA is a combination inhaled corticosteroid/long-acting beta2-adrenergic agonist (ICS/LABA) indicated for the long-term, once-daily, maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema. BREO ELLIPTA is also indicated to reduce exacerbations of COPD in patients with a history of exacerbations. Important Limitations of Use: BREO ELLIPTA is NOT indicated for the relief of acute bronchospasm or for the treatment of asthma. 4 CONTRAINDICATIONS The use of BREO ELLIPTA is contraindicated in patients with severe hypersensitivity to milk proteins or who have demonstrated hypersensitivity to either fluticasone furoate, vilanterol, or any of the excipients [see Warnings and Precautions (5.11), Description (11) of full prescribing information]. 5 WARNINGS AND PRECAUTIONS 5.1 Asthma-Related Death Data from a large placebo-controlled trial in subjects with asthma showed that LABA may increase the risk of asthma-related death. Data are not available to determine whether the rate of death in patients with COPD is increased by LABA. A 28-week, placebo-controlled, US trial comparing the safety of another LABA (salmeterol) with placebo, each added to usual asthma therapy, showed an increase in asthma-related deaths in subjects receiving salmeterol (13/13,176 in subjects treated with salmeterol vs 3/13,179 in subjects treated with placebo; relative risk: 4.37 [95% CI: 1.25, 15.34]). The increased risk of asthmarelated death is considered a class effect of LABA, including vilanterol, one of the active ingredients in BREO ELLIPTA. No study adequate to determine whether the rate of asthma-related death is increased in subjects treated with BREO ELLIPTA has been conducted. The safety and efficacy of BREO ELLIPTA in patients with asthma have not been established. BREO ELLIPTA is not indicated for the treatment of asthma. 5.2 Deterioration of Disease and Acute Episodes BREO ELLIPTA should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of COPD. BREO ELLIPTA has not been studied in patients with acutely deteriorating COPD. The initiation of BREO ELLIPTA in this setting is not appropriate. BREO ELLIPTA should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. BREO ELLIPTA has not been studied in the relief of acute symptoms and extra doses should not be used for that purpose. Acute symptoms should be treated with an inhaled, short-acting beta2-agonist. When beginning treatment with BREO ELLIPTA, patients who have been taking oral or inhaled, short-acting beta2-agonists on a regular basis (e.g., 4 times a day) should be instructed to discontinue the regular use of these drugs and to use them only for symptomatic relief of acute respiratory symptoms. When prescribing BREO ELLIPTA, the healthcare provider should also prescribe an inhaled, short-acting beta2-agonist and instruct the patient on how it should be used. Increasing inhaled, short-acting beta2-agonist use is a signal of deteriorating disease for which prompt medical attention is indicated. COPD may deteriorate acutely over a period of hours or chronically over several days or longer. If BREO ELLIPTA no longer controls symptoms of bronchoconstriction; the patientâ&#x20AC;&#x2122;s inhaled, shortacting, beta2-agonist becomes less effective; or the patient needs more short-acting beta2-agonist than usual, these may be markers of deterioration of disease. In this setting a re-evaluation of the patient and the COPD treatment regimen should be undertaken at once. Increasing the daily dose of BREO ELLIPTA beyond the recommended dose is not appropriate in this situation. 5.3 Excessive Use of BREO ELLIPTA and Use With Other Long-Acting Beta2Agonists BREO ELLIPTA should not be used more often than recommended, at higher doses than recommended, or in conjunction with other medicines containing LABA, as an overdose may result. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Patients using BREO ELLIPTA should not use another medicine containing a LABA (e.g., salmeterol, formoterol fumarate, arformoterol tartrate, indacaterol) for any reason. 5.4 Local Effects of Inhaled Corticosteroids In clinical trials, the development of localized infections of the mouth and pharynx with Candida albicans has occurred in subjects treated with BREO ELLIPTA. When such an infection develops, it should be treated with appropriate local or systemic (i.e., oral) antifungal therapy while treatment with BREO ELLIPTA continues, but at times therapy with BREO ELLIPTA may need to be interrupted. Advise the patient to rinse his/her mouth without swallowing following inhalation to help reduce the risk of oropharyngeal candidiasis. 5.5 Pneumonia An increase in the incidence of pneumonia has been observed in subjects with COPD receiving the fluticasone furoate/vilanterol combination, including BREO ELLIPTA 100 mcg/25 mcg, in clinical trials. There was also an increased incidence of pneumonias resulting in hospitalization. In some incidences

these pneumonia events were fatal. Physicians should remain vigilant for the possible development of pneumonia in patients with COPD as the clinical features of such infections overlap with the symptoms of COPD exacerbations. In replicate 12-month trials in 3,255 subjects with COPD who had experienced a COPD exacerbation in the previous year, there was a higher incidence of pneumonia reported in subjects receiving the fluticasone furoate/vilanterol combination (50 mcg/25 mcg: 6% [48 of 820 subjects]; 100 mcg/25 mcg: 6% [51 of 806 subjects]; or 200 mcg/25 mcg: 7% [55 of 811 subjects]) than in subjects receiving vilanterol 25 mcg (3% [27 of 818 subjects]). There was no fatal pneumonia in subjects receiving vilanterol or fluticasone furoate/vilanterol 50 mcg/25 mcg. There was fatal pneumonia in 1 subject receiving fluticasone furoate/vilanterol 100 mcg/25 mcg and in 7 subjects receiving fluticasone furoate/vilanterol 200 mcg/25 mcg (less than 1% for each treatment group). 5.6 Immunosuppression Persons who are using drugs that suppress the immune system are more susceptible to infections than healthy individuals. Chickenpox and measles, for example, can have a more serious or even fatal course in susceptible children or adults using corticosteroids. In such children or adults who have not had these diseases or been properly immunized, particular care should be taken to avoid exposure. How the dose, route, and duration of corticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If a patient is exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If a patient is exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See the respective package inserts for complete VZIG and IG prescribing information.) If chickenpox develops, treatment with antiviral agents may be considered. Inhaled corticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculosis infections of the respiratory tract; systemic fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex. 5.7 Transferring Patients From Systemic Corticosteroid Therapy Particular care is needed for patients who have been transferred from systemically active corticosteroids to inhaled corticosteroids because deaths due to adrenal insufficiency have occurred in patients with asthma during and after transfer from systemic corticosteroids to less systemically available inhaled corticosteroids. After withdrawal from systemic corticosteroids, a number of months are required for recovery of hypothalamic-pituitary-adrenal (HPA) function. Patients who have been previously maintained on 20 mg or more of prednisone (or its equivalent) may be most susceptible, particularly when their systemic corticosteroids have been almost completely withdrawn. During this period of HPA suppression, patients may exhibit signs and symptoms of adrenal insufficiency when exposed to trauma, surgery, or infection (particularly gastroenteritis) or other conditions associated with severe electrolyte loss. Although BREO ELLIPTA may control COPD symptoms during these episodes, in recommended doses it supplies less than normal physiological amount of glucocorticoid systemically and does NOT provide the mineralocorticoid activity that is necessary for coping with these emergencies. During periods of stress or a severe COPD exacerbation, patients who have been withdrawn from systemic corticosteroids should be instructed to resume oral corticosteroids (in large doses) immediately and to contact their physicians for further instruction. These patients should also be instructed to carry a warning card indicating that they may need supplementary systemic corticosteroids during periods of stress or severe COPD exacerbation. Patients requiring oral corticosteroids should be weaned slowly from systemic corticosteroid use after transferring to BREO ELLIPTA. Prednisone reduction can be accomplished by reducing the daily prednisone dose by 2.5 mg on a weekly basis during therapy with BREO ELLIPTA. Lung function (mean forced expiratory volume in 1 second [FEV1]), beta-agonist use, and COPD symptoms should be carefully monitored during withdrawal of oral corticosteroids. In addition, patients should be observed for signs and symptoms of adrenal insufficiency, such as fatigue, lassitude, weakness, nausea and vomiting, and hypotension. Transfer of patients from systemic corticosteroid therapy to BREO ELLIPTA may unmask allergic conditions previously suppressed by the systemic corticosteroid therapy (e.g., rhinitis, conjunctivitis, eczema, arthritis, eosinophilic conditions). During withdrawal from oral corticosteroids, some patients may experience symptoms of systemically active corticosteroid withdrawal (e.g., joint and/or muscular pain, lassitude, and depression) despite maintenance or even improvement of respiratory function. 5.8 Hypercorticism and Adrenal Suppression Inhaled fluticasone furoate is absorbed into the circulation and can be systemically active. Effects of fluticasone furoate on the HPA axis are not observed with the therapeutic dose of BREO ELLIPTA. However, exceeding the recommended dosage or coadministration with a strong cytochrome P450 3A4 (CYP3A4) inhibitor may result in HPA dysfunction [see Warnings and Precautions (5.9), Drug Interactions (7.1)]. Because of the possibility of significant systemic absorption of inhaled corticosteroids in sensitive patients, patients treated with BREO ELLIPTA should be observed carefully for any evidence of systemic corticosteroid effects. Particular care should be taken in observing patients postoperatively or during periods of stress for evidence of inadequate adrenal response. It is possible that systemic corticosteroid effects such as hypercorticism and adrenal suppression (including adrenal crisis) may appear in a small number of patients who are sensitive to these effects. If such effects occur, BREO ELLIPTA should be reduced slowly, consistent with accepted procedures for reducing systemic corticosteroids, and other treatments for management of COPD symptoms should be considered. 5.9 Drug Interactions With Strong Cytochrome P450 3A4 Inhibitors Caution should be exercised when considering the coadministration of BREO ELLIPTA with long-term ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir, clarithromycin, conivaptan, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, saquinavir, telithromycin, troleandomycin, voriconazole) because increased systemic corticosteroid and increased cardiovascular adverse effects may occur [see Drug Interactions (7.1), Clinical Pharmacology (12.3) of full prescribing information]. 5.10 Paradoxical Bronchospasm As with other inhaled medicines, BREO ELLIPTA

can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs following dosing with BREO ELLIPTA, it should be treated immediately with an inhaled, short-acting bronchodilator; BREO ELLIPTA should be discontinued immediately; and alternative therapy should be instituted. 5.11 Hypersensitivity Reactions Hypersensitivity reactions may occur after administration of BREO ELLIPTA. There have been reports of anaphylactic reactions in patients with severe milk protein allergy after inhalation of other powder products containing lactose; therefore, patients with severe milk protein allergy should not take BREO ELLIPTA [see Contraindications (4)]. 5.12 Cardiovascular Effects Vilanterol, like other beta2-agonists, can produce a clinically significant cardiovascular effect in some patients as measured by increases in pulse rate, systolic or diastolic blood pressure, and also cardiac arrhythmias, such as supraventricular tachycardia and extrasystoles. If such effects occur, BREO ELLIPTA may need to be discontinued. In addition, beta-agonists have been reported to produce electrocardiographic changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment depression, although the clinical significance of these findings is unknown. In healthy subjects, large doses of inhaled fluticasone furoate/vilanterol (4 times the recommended dose of vilanterol, representing a 12-fold higher systemic exposure than seen in patients with COPD) have been associated with clinically significant prolongation of the QTc interval, which has the potential for producing ventricular arrhythmias. Therefore, BREO ELLIPTA, like other sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension. 5.13 Reduction in Bone Mineral Density Decreases in bone mineral density (BMD) have been observed with long-term administration of products containing inhaled corticosteroids. The clinical significance of small changes in BMD with regard to long-term consequences such as fracture is unknown. Patients with major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis, postmenopausal status, tobacco use, advanced age, poor nutrition, or chronic use of drugs that can reduce bone mass (e.g., anticonvulsants, oral corticosteroids) should be monitored and treated with established standards of care. Since patients with COPD often have multiple risk factors for reduced BMD, assessment of BMD is recommended prior to initiating BREO ELLIPTA and periodically thereafter. If significant reductions in BMD are seen and BREO ELLIPTA is still considered medically important for that patient’s COPD therapy, use of medicine to treat or prevent osteoporosis should be strongly considered. In replicate 12-month trials in 3,255 subjects with COPD, bone fractures were reported by 2% of subjects receiving the fluticasone furoate/vilanterol combination (50 mcg/25 mcg: 2% [14 of 820 subjects]; 100 mcg/25 mcg: 2% [19 of 806 subjects]; or 200 mcg/25 mcg: 2% [14 of 811 subjects]) than in subjects receiving vilanterol 25 mcg alone (less than 1% [8 of 818 subjects]). 5.14 Glaucoma and Cataracts Glaucoma, increased intraocular pressure, and cataracts have been reported in patients with COPD following the long-term administration of inhaled corticosteroids. Therefore, close monitoring is warranted in patients with a change in vision or with a history of increased intraocular pressure, glaucoma, and/or cataracts. In replicate 12-month trials in 3,255 subjects with COPD, similar incidences of ocular effects (including glaucoma and cataracts) were reported in subjects receiving the fluticasone furoate/vilanterol combination (50 mcg/25 mcg: less than 1% [7 of 820 subjects]; 100 mcg/25 mcg: 1% [12 of 806 subjects]; 200 mcg/25 mcg: less than 1% [7 of 811 subjects]) as those receiving vilanterol 25 mcg alone (1% [9 of 818 subjects]). 5.15 Coexisting Conditions BREO ELLIPTA, like all medicines containing sympathomimetic amines, should be used with caution in patients with convulsive disorders or thyrotoxicosis and in those who are unusually responsive to sympathomimetic amines. Doses of the related beta2-adrenoceptor agonist albuterol, when administered intravenously, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis. 5.16 Hypokalemia and Hyperglycemia Beta-adrenergic agonist medicines may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects. The decrease in serum potassium is usually transient, not requiring supplementation. Beta-agonist medications may produce transient hyperglycemia in some patients. In 4 clinical trials of 6- and 12-month duration evaluating BREO ELLIPTA in subjects with COPD, there was no evidence of a treatment effect on serum glucose or potassium. 6 ADVERSE REACTIONS LABA, such as vilanterol, one of the active ingredients in BREO ELLIPTA, increase the risk of asthma-related death. BREO ELLIPTA is not indicated for the treatment of asthma. [See Boxed Warnings and Warnings and Precautions (5.1).] Systemic and local corticosteroid use may result in the following: Increased risk of pneumonia in COPD [see Warnings and Precautions (5.5)]; Increased risk for decrease in bone mineral density [see Warnings and Precautions (5.13)]. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. The clinical program for BREO ELLIPTA included 7,700 subjects with COPD in two 6-month lung function trials, two 12-month exacerbation trials, and 6 other trials of shorter duration. A total of 2,034 subjects have received at least 1 dose of BREO ELLIPTA 100 mcg/25 mcg, and 1,087 subjects have received higher doses of fluticasone furoate/vilanterol. The safety data described below are based on the confirmatory 6-month and 12-month trials. Adverse reactions observed in the other trials were similar to those observed in the confirmatory trials. 6-Month Trials: The incidence of adverse reactions associated with BREO ELLIPTA in Table 1 is based on 2 placebo-controlled, 6-month clinical trials (Trials 1 and 2; n = 1,224 and n = 1,030, respectively). Of the 2,254 subjects, 70% were male and 84% were Caucasian. They had a mean age of 62 years and an average smoking

history of 44 pack years, with 54% identified as current smokers. At screening, the mean postbronchodilator percent predicted FEV1 was 48% (range: 14% to 87%), the mean postbronchodilator FEV1/forced vital capacity (FVC) ratio was 47% (range: 17% to 88%), and the mean percent reversibility was 14% (range: -41% to 152%). Subjects received 1 inhalation once daily of the following: BREO ELLIPTA 100 mcg/25 mcg, fluticasone furoate/vilanterol 50 mcg/25 mcg, fluticasone furoate/ vilanterol 200 mcg/25 mcg, fluticasone furoate 100 mcg, fluticasone furoate 200 mcg, vilanterol 25 mcg, or placebo. Table 1. Adverse Reactions With ≥3% Incidence and More Common Than Placebo With BREO ELLIPTA in Subjects With Chronic Obstructive Pulmonary Disease

Adverse Event

BREO ELLIPTA 100 mcg/25 mcg (n = 410) %

Vilanterol 25 mcg (n = 408) %

Fluticasone Furoate 100 mcg (n = 410) %

Placebo (n = 412) %

Infections and infestations Nasopharyngitis Upper respiratory tract infection Oropharyngeal candidiasisa

Nervous system disorders Headache

Includes terms oral candidiasis, oropharyngeal candidiasis, candidiasis, and oropharyngitis fungal.

12-Month Trials: Long-term safety data is based on two 12-month trials (Trials 3 and 4; n = 1,633 and n = 1,622, respectively). Trials 3 and 4 included 3,255 subjects, of which 57% were male and 85% were Caucasian. They had a mean age of 64 years and an average smoking history of 46 pack years, with 44% identified as current smokers. At screening, the mean postbronchodilator percent predicted FEV1 was 45% (range: 12% to 91%), and the mean postbronchodilator FEV1/FVC ratio was 46% (range: 17% to 81%), indicating that the subject population had moderate to very severely impaired airflow obstruction. Subjects received 1 inhalation once daily of the following: BREO ELLIPTA 100 mcg/25 mcg, fluticasone furoate/vilanterol 50 mcg/25 mcg, fluticasone furoate/vilanterol 200 mcg/25 mcg, or vilanterol 25 mcg. In addition to the events shown in Table 1, adverse reactions occurring in greater than or equal to 3% of the subjects treated with BREO ELLIPTA (N = 806) for 12 months included COPD, back pain, pneumonia [see Warnings and Precautions (5.5)], bronchitis, sinusitis, cough, oropharyngeal pain, arthralgia, hypertension, influenza, pharyngitis, diarrhea, peripheral edema, and pyrexia. 7 DRUG INTERACTIONS 7.1 Inhibitors of Cytochrome P450 3A4 Fluticasone furoate and vilanterol, the individual components of BREO ELLIPTA, are both substrates of CYP3A4. Concomitant administration of the potent CYP3A4 inhibitor ketoconazole increases the systemic exposure to fluticasone furoate and vilanterol. Caution should be exercised when considering the coadministration of BREO ELLIPTA with longterm ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir, clarithromycin, conivaptan, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, saquinavir, telithromycin, troleandomycin, voriconazole) [see Warnings and Precautions (5.9) and Clinical Pharmacology (12.3) of full prescribing information]. 7.2 Monoamine Oxidase Inhibitors and Tricyclic Antidepressants Vilanterol, like other beta2-agonists, should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors, tricyclic antidepressants, or drugs known to prolong the QTc interval or within 2 weeks of discontinuation of such agents, because the effect of adrenergic agonists on the cardiovascular system may be potentiated by these agents. Drugs that are known to prolong the QTc interval have an increased risk of ventricular arrhythmias. 7.3 Beta Adrenergic Receptor Blocking Agents Beta-blockers not only block the pulmonary effect of beta-agonists, such as vilanterol, a component of BREO ELLIPTA, but may produce severe bronchospasm in patients with reversible obstructive airways disease. Therefore, patients with COPD should not normally be treated with beta-blockers. However, under certain circumstances, there may be no acceptable alternatives to the use of beta-adrenergic blocking agents for these patients; cardioselective beta-blockers could be considered, although they should be administered with caution. 7.4 Non–Potassium-Sparing Diuretics The electrocardiographic changes and/ or hypokalemia that may result from the administration of non-potassium-sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by betaagonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is not known, caution is advised in the coadministration of beta-agonists with non–potassium-sparing diuretics. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Teratogenic Effects: Pregnancy Category C. There are no adequate and well-controlled trials with BREO ELLIPTA in pregnant women. Corticosteroids and beta2-agonists have been shown to be teratogenic in laboratory animals when administered systemically at relatively low dosage levels. Because animal studies are not always predictive of human response, BREO ELLIPTA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Women should be advised to contact their physicians if they become pregnant while

taking BREO ELLIPTA. Fluticasone Furoate and Vilanterol: There was no evidence of teratogenic interactions between fluticasone furoate and vilanterol in rats at approximately 9 and 40 times, respectively, the maximum recommended human daily inhalation dose (MRHDID) in adults (on a mcg/m2 basis at maternal inhaled doses of fluticasone furoate and vilanterol, alone or in combination, up to approximately 95 mcg/kg/day). Fluticasone Furoate: There were no teratogenic effects in rats and rabbits at approximately 9 and 2 times, respectively, the MRHDID in adults (on a mcg/ m2 basis at maternal inhaled doses up to 91 and 8 mcg/kg/day in rats and rabbits, respectively). There were no effects on perinatal and postnatal development in rats at approximately 3 times the MRHDID in adults (on a mcg/m2 basis at maternal doses up to 27 mcg/kg/day). Vilanterol: There were no teratogenic effects in rats and rabbits at approximately 13,000 and 160 times, respectively, the MRHDID in adults (on a mcg/m2 basis at maternal inhaled doses up to 33,700 mcg/kg/day in rats and on an AUC basis at maternal inhaled doses up to 591 mcg/kg/day in rabbits). However, fetal skeletal variations were observed in rabbits at approximately 1,000 times the MRHDID in adults (on an AUC basis at maternal inhaled or subcutaneous doses of 5,740 or 300 mcg/kg/ day, respectively). The skeletal variations included decreased or absent ossification in cervical vertebral centrum and metacarpals. There were no effects on perinatal and postnatal development in rats at approximately 3,900 times the MRHDID in adults (on a mcg/m2 basis at maternal oral doses up to 10,000 mcg/kg/day). Nonteratogenic Effects: Hypoadrenalism may occur in infants born of mothers receiving corticosteroids during pregnancy. Such infants should be carefully monitored. 8.2 Labor and Delivery There are no adequate and well-controlled human trials that have investigated the effects of BREO ELLIPTA during labor and delivery. Because beta-agonists may potentially interfere with uterine contractility, BREO ELLIPTA should be used during labor only if the potential benefit justifies the potential risk. 8.3 Nursing Mothers It is not known whether fluticasone furoate or vilanterol are excreted in human breast milk. However, other corticosteroids and beta2-agonists have been detected in human milk. Since there are no data from controlled trials on the use of BREO ELLIPTA by nursing mothers, caution should be exercised when it is administered to a nursing woman. 8.5 Geriatric Use Based on available data, no adjustment of the dosage of BREO ELLIPTA in geriatric patients is necessary, but greater sensitivity in some older individuals cannot be ruled out. Clinical trials of BREO ELLIPTA for COPD included 2,508 subjects aged 65 and older and 564 subjects aged 75 and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger subjects. 8.6 Hepatic Impairment Fluticasone furoate systemic exposure increased by up to 3-fold in subjects with hepatic impairment compared with healthy subjects. Hepatic impairment had no effect on vilanterol systemic exposure. Use BREO ELLIPTA with caution in patients with moderate or severe hepatic impairment. Monitor patients for corticosteroid-related side effects [see Clinical Pharmacology (12.3) of full prescribing information]. 8.7 Renal Impairment There were no significant increases in either fluticasone furoate or vilanterol exposure in subjects with severe renal impairment (CrCl<30 mL/min) compared with healthy subjects. No dosage adjustment is required in patients with renal impairment [see Clinical Pharmacology (12.3) of full prescribing information]. 10 OVERDOSAGE No human overdosage data has been reported for BREO ELLIPTA. BREO ELLIPTA contains both fluticasone furoate and vilanterol; therefore, the risks associated with overdosage for the individual components described below apply to BREO ELLIPTA. 10.1 Fluticasone Furoate Because of low systemic bioavailability (15.2%) and an absence of acute drug-related systemic findings in clinical trials, overdosage of fluticasone furoate is unlikely to require any treatment other than observation. If used at excessive doses for prolonged periods, systemic effects such as hypercorticism may occur [see Warnings and Precautions (5.8)]. Single- and repeat-dose trials of fluticasone furoate at doses of 50 to 4,000 mcg have been studied in human subjects. Decreases in mean serum cortisol were observed at dosages of 500 mcg or higher given once daily for 14 days. 10.2 Vilanterol The expected signs and symptoms with overdosage of vilanterol are those of excessive beta-adrenergic stimulation and/or occurrence or exaggeration of any of the signs and symptoms of beta-adrenergic stimulation (e.g., angina, hypertension or hypotension, tachycardia with rates up to 200 beats/ min, arrhythmias, nervousness, headache, tremor, seizures, muscle cramps, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, insomnia, hyperglycemia, hypokalemia, metabolic acidosis). As with all inhaled sympathomimetic medicines, cardiac arrest and even death may be associated with an overdose of vilanterol. Treatment of overdosage consists of discontinuation of BREO ELLIPTA together with institution of appropriate symptomatic and/or supportive therapy. The judicious use of a cardioselective beta-receptor blocker may be considered, bearing in mind that such medicine can produce bronchospasm. Cardiac monitoring is recommended in cases of overdosage. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility BREO ELLIPTA: No studies of carcinogenicity, mutagenicity, or impairment of fertility were conducted with BREO ELLIPTA; however, studies are available for the individual components, fluticasone furoate and vilanterol, as described below. Fluticasone Furoate: Fluticasone furoate produced no treatment-related increases in the incidence of tumors in 2-year inhalation studies in rats and mice at inhaled doses up to 9 and 19 mcg/kg/day, respectively (approximately equal to the MRHDID in adults on a mcg/m2 basis). Fluticasone furoate did not induce gene mutation in bacteria or chromosomal damage in a mammalian cell mutation test in mouse lymphoma L5178Y cells in vitro. There was also no evidence of genotoxicity in the in vivo micronucleus test in rats. No evidence of impairment of fertility was observed

in male and female rats at inhaled fluticasone furoate doses up to 29 and 91 mcg/kg/ day, respectively (approximately 3 and 9 times, respectively, the MRHDID in adults on a mcg/m2 basis). Vilanterol: In a 2-year carcinogenicity study in mice, vilanterol caused a statistically significant increase in ovarian tubulostromal adenomas in females at an inhalation dose of 29,500 mcg/kg/day (approximately 8,750 times the MRHDID in adults on an AUC basis). No increase in tumors was seen at an inhalation dose of 615 mcg/kg/ day (approximately 530 times the MRHDID in adults on an AUC basis). In a 2-year carcinogenicity study in rats, vilanterol caused statistically significant increases in mesovarian leiomyomas in females and shortening of the latency of pituitary tumors at inhalation doses greater than or equal to 84.4 mcg/kg/day (greater than or equal to approximately 45 times the MRHDID in adults on an AUC basis). No tumors were seen at an inhalation dose of 10.5 mcg/kg/day (approximately 2 times the MRHDID in adults on an AUC basis). These tumor findings in rodents are similar to those reported previously for other beta-adrenergic agonist drugs. The relevance of these findings to human use is unknown. Vilanterol tested negative in the following genotoxicity assays: the in vitro Ames assay, in vivo rat bone marrow micronucleus assay, in vivo rat unscheduled DNA synthesis (UDS) assay, and in vitro Syrian hamster embryo (SHE) cell assay. Vilanterol tested equivocal in the in vitro mouse lymphoma assay. No evidence of impairment of fertility was observed in reproductive studies conducted in male and female rats at inhaled vilanterol doses up to 31,500 and 37,100 mcg/kg/day, respectively (approximately 12,000 and 14,000 times, respectively, the MRHDID in adults on a mcg/m2 basis). 17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Medication Guide and Instructions for Use) 17.1 Asthma-Related Death Patients should be informed that LABA, such as vilanterol, one of the active ingredients in BREO ELLIPTA, increase the risk of asthmarelated death. BREO ELLIPTA is not indicated for the treatment of asthma. 17.2 Not for Acute Symptoms BREO ELLIPTA is not meant to relieve acute symptoms of COPD and extra doses should not be used for that purpose. Acute symptoms should be treated with a rescue inhaler such as albuterol. The physician should provide the patient with such medicine and instruct the patient in how it should be used. Patients should be instructed to notify their physicians immediately if they experience any of the following: Symptoms get worse; Need for more inhalations than usual of their rescue inhaler; Significant decrease in lung function as outlined by the physician. Patients should not stop therapy with BREO ELLIPTA without physician/provider guidance since symptoms may recur after discontinuation. 17.3 Do Not Use Additional Long-Acting Beta2-Agonists When patients are prescribed BREO ELLIPTA, other medicines containing a LABA should not be used. 17.4 Risks Associated With Corticosteroid Therapy Local Effects: Patients should be advised that localized infections with Candida albicans occurred in the mouth and pharynx in some patients. If oropharyngeal candidiasis develops, it should be treated with appropriate local or systemic (i.e., oral) antifungal therapy while still continuing therapy with BREO ELLIPTA, but at times therapy with BREO ELLIPTA may need to be temporarily interrupted under close medical supervision. Rinsing the mouth without swallowing after inhalation is advised to help reduce the risk of thrush. Pneumonia: Patients with COPD who have received BREO ELLIPTA have a higher risk of pneumonia and should be instructed to contact their healthcare providers if they develop symptoms of pneumonia (e.g., fever, chills, change in sputum color, increase in breathing problems). Immunosuppression: Patients who are on immunosuppressant doses of corticosteroids should be warned to avoid exposure to chickenpox or measles and, if exposed, to consult their physicians without delay. Patients should be informed of potential worsening of existing tuberculosis, fungal, bacterial, viral, or parasitic infections, or ocular herpes simplex. Hypercorticism and Adrenal Suppression: Patients should be advised that BREO ELLIPTA may cause systemic corticosteroid effects of hypercorticism and adrenal suppression. Additionally, patients should be instructed that deaths due to adrenal insufficiency have occurred during and after transfer from systemic corticosteroids. Reduction in Bone Mineral Density: Patients who are at an increased risk for decreased BMD should be advised that the use of corticosteroids may pose an additional risk. Ocular Effects: Long-term use of inhaled corticosteroids may increase the risk of some eye problems (cataracts or glaucoma); regular eye examinations should be considered. 17.5 Risks Associated With Beta-Agonist Therapy Patients should be informed of adverse effects associated with beta2-agonists, such as palpitations, chest pain, rapid heart rate, tremor, or nervousness. BREO and ELLIPTA are trademarks of GlaxoSmithKline. BREO ELLIPTA was developed in collaboration with

BRE:1BRS

Modeling the Frequency and Costs Associated with Postsurgical Gastrointestinal Adverse Events for Tapentadol IR versus Oxycodone IR Andrew Paris, MBA; Chris M. Kozma, PhD; Wing Chow, PharmD, MPH; Anisha M. Patel, MS; Samir H. Mody, PharmD, MBA; Myoung S. Kim, PhD, MBA Background: Few studies have estimated the economic effect of using an opioid that is associated with lower rates of gastrointestinal (GI) adverse events (AEs) than another opioid for postsurgical pain. Objective: To estimate the number of postsurgical GI events and incremental hospital costs, including potential savings, associated with lower GI AE rates, for tapentadol immediate release (IR) versus oxycodone IR, using a literature-based calculator. Methods: An electronic spreadsheet–based cost calculator was developed to estimate the total number of GI AEs (ie, nausea, vomiting, or constipation) and incremental costs to a hospital when using tapentadol IR 100 mg versus oxycodone IR 15 mg, in a hypothetical cohort of 1500 hospitalized patients requiring short-acting opioids for postsurgical pain. Data inputs were chosen from recently published, well-designed studies, including GI AE rates from a previously published phase 3 clinical trial of postsurgical patients who received these 2 opioids; GI event–related incremental length of stay from a large US hospital database; drug costs using wholesale acquisition costs in 2011 US dollars; and average hospitalization cost from the 2009 Healthcare Cost and Utilization Project database. The base case assumed that 5% (chosen as a conservative estimate) of patients admitted to the hospital would shift from oxycodone IR to tapentadol IR. Results: In this hypothetical cohort of 1500 hospitalized patients, replacing 5% of oxycodone IR 15-mg use with tapentadol IR 100-mg use predicted reductions in the total number of GI events from 1095 to 1085, and in the total cost of GI AEs from $2,978,400 to $2,949,840. This cost reduction translates to a net savings of $22,922 after factoring in drug cost. For individual GI events, the net savings were $26,491 for nausea; $12,212 for vomiting; and $7187 for constipation. Conclusion: Using tapentadol IR in place of a traditional μ-opioid shows the potential for reduced GI events and subsequent cost-savings in the postsurgical hospital setting. In the absence of sufficient real-world data, this literature-based cost calculator may assist hospital Pharmacy & Therapeutics committees in their evaluation of the costs of opioid-related GI events.

ain is a global health problem that affects 1 of 5 adults in the community1 and occurs in 43% to 77%2-4 of the approximate 35.1 million patients who are hospitalized annually in the United States.5 Pain is ubiquitous among the nearly 30.2 million people who undergo inpatient surgery annually in the United States.5 Opioid analgesics are a mainstay of postsurgical pain

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Am Health Drug Benefits. 2013;6(9):567-575 www.AHDBonline.com Disclosures are at end of text

management,6 but are often associated with treatment-limiting gastrointestinal (GI), central nervous system, and respiratory adverse events (AEs).7 Of these, opioid-related GI AEs are the most common,8-10 with an incidence rate of 10% to 32% for nausea and/or vomiting and 15% to 41% for constipation.7,11-14 These GI AEs are particularly troublesome after surgery, because they can

Mr Paris is an Independent Research Consultant, Vigilytics LLC, Victor, NY; Dr Kozma is an Independent Research Consultant, Ck Consulting Associates, LLC, St Helena Island, SC; Dr Chow is Associate Director, Health Economics and Outcomes Research, Janssen Scientific Affairs, LLC; Ms Patel is formerly a contractor with Health Economics and Outcomes Research, Janssen Scientific Affairs, LLC; Dr Mody is Director, Translational Science Team, Health Economics and Outcomes Research, Janssen Scientific Affairs, LLC, Raritan, NJ; Dr Kim is Executive Director, Epidemiology, Medical Affairs, Johnson & Johnson, New Brunswick, NJ.

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Key Points Opioid analgesics, a key to postsurgical pain management, are associated with lower gastrointestinal (GI) and other adverse event rates. ➤ Unlike traditional opioids, such as oxycodone IR, that exert analgesic activity by binding to μ-opioid receptors, tapentadol IR has a second mechanism involving norepinephrine reuptake inhibition, which may help to minimize GI events. ➤ Previous studies have shown that tapentadol IR causes fewer GI events than oxycodone IR in the postsurgical setting. ➤ This new study compared the total GI events and associated incremental costs for tapentadol IR versus oxycodone IR in the postsurgical setting from a hospital perspective, using a cost calculator and a hypothetical cohort of 1500 hospitalized patients requiring short-acting opioids. ➤ Replacing 5% of oxycodone IR 15-mg use with tapentadol IR 100 mg reduced the total number of postsurgical GI events from 1095 to 1085, which was associated with a cost reduction from $2,978,400 to $2,949,840. ➤ Individual GI event net savings for the 5% use of tapentadol IR instead of oxycodone IR were $26,491 for nausea, $12,212 for vomiting, and $7187 for constipation. ➤ The potential cost-savings associated with reduced GI events seen with tapentadol IR versus oxycodone IR in the postsurgical setting may suggest the need to look beyond drug-acquisition cost to consider the effect on net costs of care when making formulary decisions. ➤

exacerbate anesthesia-induced nausea and decreased GI motility, sometimes resulting in ileus.7 Furthermore, GI AEs are associated with increased healthcare resource utilization because of additional medications used to manage the GI AEs and an increase in hospital length of stay (LOS).7,10,15-17 The guidelines for managing surgery-related pain advocate a multimodal, opioid-sparing approach to improve analgesic activity and to minimize the risk for opioid-related AEs.6,18 Most traditional opioids exert analgesic activity by binding to μ-opioid receptors in the brain; these receptors are also present in the GI tract. Tapentadol is a centrally acting analgesic with 2 mechanisms of action—μ-opioid receptor agonism and norepinephrine reuptake inhibition.19,20 These 2 mechanisms of action may account for the significant analgesia, along with the lower incidence and intensity of AEs that are

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normally associated with traditional μ-opioid receptor agonists, such as oxycodone.21 In 2 phase 3 studies of patients with acute pain, including postoperative pain, the incidence of GI AEs was lower with tapentadol immediate release (IR) than with oxycodone IR at equianalgesic doses, including dose strengths other than tapentadol IR 100 mg.22,23 We chose oxycodone IR as the traditional opioid because of its inclusion in guidelines for surgery-related pain,6 the availability of pivotal clinical studies comparing oxycodone IR with tapentadol IR,23,24 and its spectrum of AEs that is similar to that of tapentadol IR.23,24 Although the clinical benefits of using opioids with different mechanisms of action are well documented, few studies have examined the potential economic effect of this strategy in postsurgical populations. The objective of this study was to estimate the number of potential reductions in postsurgical GI AEs and incremental hospital costs for GI event rates associated with tapentadol IR versus oxycodone IR, using a literature-based calculator. The analysis focused on data related to postsurgical GI AE rates, because of their availability in the published literature.

Methods Study Design We developed a cost calculator using literature-based data to estimate the number of postsurgical GI AEs and the costs associated with incremental hospital LOS for tapentadol IR versus oxycodone IR. Studies were chosen on the basis of their recent publication date, the relevance of AE end points evaluated in the study, the clinical setting, and the quality of the study design. The model estimated the GI AEs for a hypothetical cohort of 1500 hospitalized patients using Schedule II short-acting opioids for the management of moderate-to-severe acute postsurgical pain. The model assumed that tapentadol IR 100 mg could be substituted for oxycodone IR 15 mg (each given every 4 to 6 hours), because of the availability of published trial results suggesting that these dosages were equianalgesic for postsurgical pain.24 The GI AEs were considered collectively and individually, and included composite GI AEs (ie, nausea, vomiting, and/or constipation); nausea and/or vomiting; nausea; vomiting; and constipation. Data Sources for GI AE Rates and Length of Stay We obtained the GI AE rates from 2 randomized, double-blind, multicenter phase 3 trials conducted by Johnson & Johnson Pharmaceutical Research & Development between 2006 and 2007 (Table 1).24,25 For the base-case analysis, we used data from a trial of 603 pa-

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Table 1 Model Input Estimates and Sources Input variable Cohort size and hospital admissions, N

Point estimate

Range tested

Source(s) for point estimate and range tested

1500

1000 and 2000

Modeled numbers Daniels et al24; Hale et al25

AE rate for tapentadol IR vs oxycodone IR Gastrointestinal AEs,a %

59 vs 73

44.2 vs 63.5

Nausea/vomiting, %

53 vs 70

Nausea, %

49 vs 67

18.4 vs 29.4

Mean incremental LOS, days

Suh et al15; assumption

Nausea/vomiting/constipation medications (vs no nausea/vomiting/constipation medications)

1.36b

1.02-1.70 (±25%)

Nausea/vomiting medications (vs no nausea/ vomiting/constipation medications)

1.19b

10 and 2

Current model; assumption

Cost of tapentadol IR per hospital stay, $

75.18c

±25%

Kwong et al27; assumption

Cost per day of hospital stay, $

2000

HCUP 2009 estimate28

Shift rate from oxycodone IR to tapentadol IR, %

Gastrointestinal AEs as a system organ class may include AEs beyond nausea, vomiting, and constipation. Incremental LOS was calculated as the difference between LOS for nausea/vomiting/constipation (6.48 – 5.12 = 1.36) or nausea/vomiting (6.31 – 5.12 = 1.19), and no nausea/vomiting/constipation (5.12), which was used as the reference value. c Wholesale acquisition cost per tablet ($3.23) multiplied by number of daily doses (5.06) and mean LOS (4.6 days).27 AE indicates adverse event; HCUP, Healthcare Cost and Utilization Project; IR, immediate release; LOS, length of stay; NR, not reported.

tients with moderate-to-severe acute postsurgical pain evaluated over 72 hours who were randomized to receive tapentadol IR, oxycodone IR, or placebo.24 For the base-case analysis, LOS data for patients who experienced AEs were obtained from a retrospective cohort study of an inpatient database of 450 hospitals used in the study by Suh and colleagues (Table 1).15 In this study, the total treatment costs and hospital LOS were compared for 2 cohorts who received analgesics— patients who received medications for nausea, vomiting, and/or constipation and patients who did not. The use of medication for nausea, vomiting, and/or constipation was a proxy for a nausea, vomiting, and/or constipation event. The proxy, however, was defined to minimize the risk of including prophylactic use by excluding patients who received nausea, vomiting, and/or constipation medications during the 6-month period before the initiation of analgesics; patients who received a medication for nausea, vomiting, and/or constipation on the first day of treatment with analgesics were also excluded.15 A generalized linear model with log link function and gamma distribution was used to estimate the LOS for the 2 cohorts, adjusting for potential confounders (eg, type of analgesics received, age, sex, comorbidities, surgical procedures, number of prescription drugs received during hospital stay). More

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than 50% of the patients receiving analgesics subsequently received medications for the management of GI AEs, which are associated with longer hospital LOS and higher treatment costs.15 To simulate the target population for our model, we focused on patients who received oral analgesics rather than the overall population of patients who received injectable and/or oral analgesics, including nonopioids. The hospital LOS for the base case was the difference between the predicted, covariate-adjusted LOS with and without GI medication (Table 1). For the sensitivity analysis, we applied GI AE rates from an outpatient 90-day trial of 878 patients with moderate-to-severe lower back pain or osteoarthritis of the hip or knee for ≥3 months who were randomized to receive tapentadol IR or oxycodone IR.25 The hospital LOS data from a retrospective chart and an electronic medical records review of a random sample of 402 patients who underwent orthopedic surgery were used for an additional sensitivity analysis.26 In this study, the effect of opioid-related AEs, including GI AEs, on the hospital LOS was examined. Bivariate and multivariate analyses were performed to identify potential predictors of postsurgical LOS. Vomiting and constipation were associated with longer postsurgical LOS after adjusting for other variables.26

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a Figure 1 E stimated Total Number of GI AEs and Related Costs, Before and After Use of Tapentadol IR

Before tapentadol IR After tapentadol IR After tapentadol IR (with drug costs) 1100

2.99

1095

2.98

}

2.97

1090

2.96

1085

$22,922

2.95

1080

2.94

1075

2.93

AEs, N

Total cost of AEs in $ millions

GI refers to composite GI events, including nausea, vomiting, and/ or constipation. AE indicates adverse event; GI, gastrointestinal; IR, immediate release.

Calculator Structure and Analysis Three types of calculations were performed using the spreadsheet model. These calculations were repeated under the assumption of no tapentadol use, followed by a shift to tapentadol. First, we calculated the number of GI AEs as the cohort size multiplied by the rate of AEs of interest. Second, we calculated the cost of GI AEs as the number of GI AEs multiplied by the incremental hospital LOS (in days) resulting from GI AEs, multiplied by the daily cost of the hospital stay. Third, we calculated the net costs as the cost of GI AEs minus the incremental cost of using tapentadol IR instead of oxycodone IR. Mathematical calculations were performed using Excel 2007 (Microsoft Corporation; Redmond, WA). The model required several inputs, including cohort size; GI AE rates for tapentadol IR and oxycodone IR24,25; incremental hospital LOS resulting from GI AEs15; percent allocation of the oxycodone IR and tapentadol IR treatments; tapentadol IR cost27 using wholesale acquisition cost in 2011 US dollars; and daily cost of hospital stay (Table 1).28 The cohort size was chosen arbitrarily. The cost of oxycodone IR was excluded (ie, conservatively set at $0.00) because of the availability of inexpensive generic formulations. All other treatment costs (eg, nursing time, drug treatments) were assumed to be reflected in the LOS cost, because it was based on average hospitalization costs. In the base-case analysis, tapentadol IR was assumed to represent 5% of the use of short-acting opioids to

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control acute postsurgical pain in the hypothetical hospital setting; the use of oxycodone IR was set at 95%. Two separate data points were used for the hospital LOS—incremental LOS of patients who used nausea, vomiting, and/or constipation medication versus patients who did not, and incremental LOS of patients who used nausea and/or vomiting medication versus patients who did not use nausea, vomiting, and/or constipation medication.15 Because both data points reflected differences in LOS compared with patients who did not use nausea, vomiting, and/or constipation medication, no adjustment was made. We performed several sensitivity analyses (Table 1). In the first sensitivity analysis, the shift rate for tapentadol IR was changed from 5% to 10% and 2%. In the second analysis, the cohort size was changed from 1500 patients to 1000 and 2000 patients. Third, the hospital LOS was varied by ±25%. Fourth, the cost of tapentadol IR was varied by ±25%. Fifth, we applied a different set of GI AE rates using data from a randomized trial of patients with lower back pain or osteoarthritis.25 In this 90-day safety trial, the AE rates for tapentadol IR versus oxycodone IR were 44.2% versus 63.5% for GI, and 18.4% versus 29.4% for nausea.25 Finally, we explored the impact of increasing incremental LOS while adjusting the cost of tapentadol IR per hospital stay, using data from the chart review study.26 Relative to the base-case analysis, the LOS was increased by 7%, 15%, and 40%, and the cost of tapentadol IR was adjusted using a mean LOS of 3.2 days (vs 4.6 days in the base-case analysis15), resulting in a drug cost of $52.30 per hospital stay.

Results In the base-case analysis of composite GI AEs in the 1500-patient hypothetical cohort, replacing 5% of oxycodone IR 15-mg use with tapentadol IR 100 mg was associated with decreases in the number of GI AEs, from 1095 to 1085, and in the overall cost, from $2,978,400 to $2,949,840 (Figure 1). The cost was reduced by $28,560, resulting in a net savings of $22,922 after factoring in drug cost, or approximately $2300 per event avoided. For nausea and/or vomiting, replacing 5% of oxycodone IR 15 mg was associated with a decrease in the number of nausea and/or vomiting AEs from 1050 to 1037, and a total cost reduction from $2,499,000 to $2,468,655. The cost was reduced by $30,345, resulting in a net savings of $24,707 after factoring in drug cost. In the base-case analysis of individual GI AEs, replacing 5% of oxycodone IR 15-mg use with tapentadol IR 100 mg was associated with findings similar to those for the composite GI AEs. For nausea, the cost was reduced by $32,130, resulting in a net savings of $26,491 after factoring in drug cost. The corresponding cost reductions

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and net savings after factoring in drug cost were $17,850 and $12,212, respectively, for vomiting and $12,825 and $7187, respectively, for constipation. In the sensitivity analyses, replacing 10% of oxycodone IR 15-mg use with tapentadol IR 100 mg was associated with a net savings of $45,843, whereas replacing 2% use was associated with a net savings of $9169 (Figure 2). Increasing the cohort size to 2000 patients was associated with a net savings of $30,562, whereas decreasing the size to 1000 patients was associated with a net savings of $15,281. The effects of varying the incremental hospital LOS and drug cost are shown in Figure 2; the effect of varying the GI AE rate is shown in Table 2. Increasing the incremental hospital LOS by 7% was associated with a net savings of $26,637, whereas increasing the LOS by 40% was associated with a net savings of $36,061 (Table 2). A final sensitivity analysis was conducted to establish the worst-case and break-even scenarios for the LOS. For the worst-case scenario, the assumption was made that the incremental LOS for the composite GI AEs was zero days when replacing 5% of oxycodone in the base-case analysis with tapentadol IR while using the other parameters from the base case. The result yielded a net cost increase of $5639, which accounts for the difference in the acquisition cost of tapentadol IR 100 mg. The breakeven analysis was done to determine the minimum incremental LOS for the composite GI AEs required for the base-case analysis (5%) to yield a cost-neutral result. An incremental LOS of a little more than 25% of 1 day (ie, 0.27 days) yielded a neutral net cost. These analyses demonstrated the relatively small change necessary to achieve cost benefits with tapentadol IR.

Discussion Our analyses demonstrate the potential cost-savings associated with replacing oxycodone IR with tapentadol IR in hospitalized patients who are experiencing acute postsurgical pain under the assumption (based on published data) that treatment-related GI AEs result in a longer hospital LOS. The difference in the acquisition cost of tapentadol IR 100 mg compared with that of oxycodone IR 15 mg (set at $0.00) was offset by the savings associated with a reduction in the incidence of GI AEs, avoiding the costs of increased hospital LOS.10,15-17 For example, replacing 5% of oxycodone IR 15-mg use with tapentadol IR 100-mg use in the base-case analysis of a hypothetical set of 1500 hospitalized patients was associated with 10 fewer GI AEs, resulting in a net savings of $22,922, or approximately $2300 per event avoided. These savings are likely as a result of improving patient health status. As recommended by the Panel on Cost-Effectiveness

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Figure 2 Potential Hospital Savings Parameter (AEs eliminated, N)

$10,000 $20,000 $30,000 $40,000 $50,000

Shift ratea to tapentadol IR: 2% (4 AEs) 10% (21 AEs) Incremental LOS: ±25% (10 AEs) Tapentadol cost: ±25% (10 AEs) Base-case analysis, $22,922

NOTE: The vertical line represents the net savings in the base-case scenario. The horizontal bars represent the range in the net savings associated with varying each input between the upper and lower limits, while holding other parameters constant. a Replacing oxycodone IR. AEs indicates adverse events; LOS, length of stay.

ensitivity Analysis of Effect of Replacing Oxycodone Table 2 S IR 15 mg with Tapentadol IR 100 mg GI AEs Change in hospital cost eliminated, Variance N Cost, $ Net,a $ AE rateb Nausea/vomiting/ constipation: 44.2% vs 63.5%

–39,372

33,734

Nausea: 18.4% vs 29.4%

–22,400

16,802

7% increase; 55.38

–30,559

26,637

15% increase; 59.59

–32,844

28,921

40% increase; 72.54

–39,984

36,061

LOS; cost of tapentadol IR per hospital stay, $c

Savings after factoring in the drug cost of tapentadol IR. AE rates for tapentadol IR versus oxycodone IR.25 c The cost of tapentadol IR per hospital stay was changed to $52.30, based on wholesale acquisition cost per tablet ($3.23) multiplied by number of daily doses (5.06) and mean LOS (3.2 days), and adjusted for increased LOS.26 AE indicates adverse event; GI, gastrointestinal; IR, immediate release; LOS, length of stay; NA, not applicable. a

in Health and Medicine,29 we varied the model inputs to provide estimates for alternative scenarios. For example, we considered the GI AE rates from a 90-day randomized, double-blind safety trial.25 This was done to simulate clinical practice in an outpatient setting, because the GI AE rate may differ from that in the hospital. In

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the safety trial, nausea was reported in 29.4% of patients who received oxycodone IR,25 which is within the range reported for patients receiving opioid analgesics in systematic reviews11,12 and in a large cohort study of hospitalized patients.13 We performed sensitivity testing to assess the uncertainty of the model’s inputs. Over the ranges tested, the cost-calculator model was the most sensitive to the change in the percentage of tapentadol IR use (ie, shift rate; Figure 2). The model provides linear estimates for net costs based on market share: a market share that is twice as large will yield a cost-savings that is twice as large. Comparing selected model inputs with worst-case and break-even scenarios provides a perspective on the size of the change needed to result in an overall cost-savings. As long as there is a modest increase in the hospital LOS (ie, 0.27 days) that is associated with GI AEs, the model will predict savings. The model was least sensitive to the acquisition cost of tapentadol IR. The model used data from published studies for inputs, such as the hospital LOS for the base-case analysis. Specifically, we chose a retrospective cohort study of the Premier Perspective database, the largest inpatient drug utilization database in the United States.15 We also used a published study that was based on patients undergoing orthopedic surgery, and examined the effect of opioid- related AEs (including GI AEs) on inpatient LOS using medical records from 2007, to provide a relevant perspective for the effect of an increased number of GI AEs on hospital LOS.26 Our model focused on GI AEs because they are most frequently associated with opioids,6,8-10 are particularly bothersome in postsurgical patients,7 and can interfere with pain relief.9,14 Specifically, in the clinical trial used for our model inputs, tapentadol IR 100 mg was associated with lower incidences of GI AEs versus oxycodone IR 15 mg, including nausea (49% vs 67%, respectively), vomiting (32% vs 42%), and constipation (10% vs 15%).24 In the second study used in our model, the use of tapentadol IR 50 mg or 100 mg versus oxycodone IR was associated with lower incidences of any GI AE (44.2% vs 63.5%, respectively), nausea (18.4% vs 29.4%, respectively; P <.001), vomiting (16.9% vs 30.0%, respectively; P <.001), and constipation (12.8% vs 27.1%, respectively; P <.001), but not diarrhea (6.6% vs 5.9%, respectively) and dry mouth (5.3% vs 2.9%, respectively).25 In addition, studies documenting the economic burden associated with GI AEs are available,7,10,15-17 which allowed us to develop the economic calculator for this study. The cost-saving drivers were primarily from event avoidance (ie, decreased hospital LOS), with some savings offset by a higher cost for tapentadol IR. In other words, the costs of AEs are incremental inpatient LOS

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costs. We assumed no additional costs for medications used to treat these AEs, and simply multiplied the average cost of a daily hospital stay by the percentage LOS increase to estimate the cost of an AE. The estimated decreased LOS for the avoidance of AEs is modeled on the rate of AEs from the 2 clinical trials mentioned earlier,24,25 as well as for a database study that assessed the impact of AEs on LOS, in which patients who were not receiving a medication for nausea, vomiting, and/or constipation had a 1.36-day decreased LOS.15 The model assumed a hospital cost of $2000 daily, using the Healthcare Cost and Utilization Project (HCUP) 2009 national estimate.28 After incorporating higher drug cost, the model estimated a net savings of approximately $2300 for a GI event avoided. The approximate $2300 net savings per nausea, vomiting, and/or constipation event avoided as predicted by the cost calculator was similar to the savings reported in one study,15 but was higher than in 2 other studies,16,17 which may be a result of the differences in methods, timing, or study population. Our drug costs were calculated in 2011 US dollars, and hospital costs were based on 2009 costs.28 Similar to our findings, Suh and colleagues estimated that the additional cost associated with the treatment of nausea, vomiting, and/or constipation in hospitalized patients who received opioid analgesics was $2223; data for this retrospective cohort study were collected between 2005 and 2007.15 By contrast, Kwong and colleagues estimated that inpatient service costs within 3 months after the initiation of an index opioid prescription in the outpatient setting were approximately $1900 higher for patients with prescription claims for antiemetics or laxatives than for patients with no GI events or therapies; data for this retrospective database study with multivariate regression analysis were collected between 2002 and 2005.17 Oderda and colleagues estimated that the additional cost associated with opioid-related AEs—including GI and non-GI AEs—was $840 in surgical patients at a university hospital; data for this retrospective matched cohort study were collected in the 1990s.16 Our findings have clinical and economic implications. From a clinical perspective, the burden of acute pain comprises inadequate analgesia and treatment-related GI AEs; although cause and effect have not been demonstrated, the evidence suggests that these 2 components are related.6,8,9 In a recent survey of more than 50,000 patients with moderate-to-severe acute pain, including postsurgical pain, 44% of patients received potentially inadequate analgesia and 28% had at least 1 GI AE.9 Patients who received inadequate analgesia were more likely to take their opioid medication in smaller

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doses or less frequently because of GI AEs than patients who received adequate analgesia.9 Inadequate treatment of postsurgical pain can lead to needless suffering, impairment of health-related quality of life, readmission for further pain treatment, and the development of chronic pain.18 Of note, fewer recipients of tapentadol IR stopped treatment because of any AEs than recipients of oxycodone IR in the 90-day safety trial.25 From a hospital perspective, the economic burden of acute pain comprises direct costs associated with drug acquisition, pharmacologic interventions, extended LOS,10,15-17,26 and intangible costs (ie, burden on hospital personnel resulting from the time required to relieve pain and to manage treatment-related AEs, as well as the emotional toll of caring for patients suffering from inadequate pain relief). Collectively, these findings suggest that the use of an opioid with a dual mechanism of action and an improved tolerability profile may offer an attractive alternative for managing the clinical and economic burden of postsurgical pain. This may be of relevance to hospital Pharmacy & Therapeutics (P&T) committees, especially when the Centers for Medicare & Medicaid Services implements value-based purchasing and considers patient response (eg, pain-management domain) on the Hospital Consumer Assessment of Healthcare Providers and Systems Survey as a determinant of hospital reimbursement and performance.

Limitations Our study has several limitations that may affect its generalizability. The cost calculator was designed to estimate potentially lower costs associated with replacing oxycodone IR with tapentadol IR, as long as the rate of GI AEs associated with tapentadol IR was lower. Clinical trials comparing the 2 analgesics consistently demonstrated lower nausea, vomiting, and/or constipation rates for the patients receiving tapentadol IR than for patients receiving oxycodone IR.22-25 Therefore, the model estimates only lower potential event costs, because the number of nausea, vomiting, and/or constipation events for switching to tapentadol IR would be lower. In addition, the calculator did not include other oral opioid agents, because comparative data were not available. Our analysis included data from a previously published clinical trial,24 a study using an administrative claims database,15 and national hospital discharge data.28 Clinical trials provide input parameters that demonstrate outcomes under ideal clinical circumstances (ie, efficacy), and may not reflect real-world utilization and outcomes (ie, effectiveness). Although the use of an administrative claims database provides for a generalizable insured population, and the study design allows for the inclusion of a more diverse patient population compared

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with patients studied within the confine of clinical trials, residual methodologic bias and coding or documentation errors are possible. Confounders were adjusted in the administrative claims-based study, and the results revealed the potential effect on LOS while patients were using opioids. The hypothetical cohort of 1500 surgeries requiring postoperative opioid therapy was chosen arbitrarily, given the marked variability among hospitals in the number of surgeries performed depending on the patientâ&#x20AC;&#x201C;physician mix. Therefore, we performed sensitivity analysis with cohorts of 1000 and 2000 surgeries to demonstrate the effect of varying this input. We might have underestimated the overall cost, because HCUP had only made available its 2009 costs in US dollars at the time of this project.

These findings suggest that the use of an opioid with a dual mechanism of action and an improved tolerability profile may offer an attractive alternative for managing the clinical and economic burden of postsurgical pain. We did not include AEs involving the central nervous system, respiratory system, or other non-GI systems. The overall rate of any AE was similar for tapentadol IR 100 mg and oxycodone IR 15 mg (85% vs 87%, respectively) in one of the model input studies,24 suggesting the potential for different outcomes if all AEs had been considered. P values were not provided for these comparisons but are included below whenever available. In a post hoc analysis, tapentadol IR was associated with less nausea or vomiting (53% vs 70%, respectively; P = .007) and numerically lower incidences of headache (12% vs 14%, respectively), generalized pruritus (7% vs 10%, respectively), hyperhidrosis (4% vs 6%, respectively), and pyrexia (0% vs 2%, respectively) versus oxycodone IR 15 mg.24 The only AEs with numerically higher incidences for tapentadol IR versus for oxycodone IR 15 mg were dizziness (31% vs 30%, respectively), somnolence (21% vs 10%, respectively), and pruritus (17% vs 12%, respectively).24 In the second model input study, the non-GI AEs associated with tapentadol IR 50 mg or 100 mg versus oxycodone IR were dizziness (18.1% vs 17.1%, respectively; P >.05), headache (11.5% vs 10.0%, respectively), somnolence (10.2% vs 9.4%, respectively; P >.05), fatigue (5.6% vs 2.4%, respectively), and pruritus (4.3% vs 11.8%, respectively).25 Therefore, the lack of significant differences in non-GI AEs supports our decision to model GI AEs only.

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Conclusions The results of this cost calculator using previously published data demonstrate the potential GI AE–related cost-savings for a hospital by using tapentadol IR in place of a traditional μ-opioid. Studies are needed to determine the clinical value of these findings and to validate their economic implications in the real-world setting. In the absence of sufficient real-world data, a literature-based modeling approach using a cost calculator may assist hospital P&T committees to assess the cost impact of opioid-related GI AEs on their inpatient populations. This study reaffirms the need to look beyond drug acquisition cost and to consider the effect on net costs of care when making formulary decisions related to opioid use in the postsurgical inpatient setting. n Acknowledgments The authors would like to thank Cindy W. Hamilton, PharmD, ELS, of Hamilton House (Virginia Beach, VA) for assisting with manuscript preparation. Hamilton House received compensation from Janssen Scientific Affairs, LLC, for its contributions. Funding Source This study, including manuscript preparation, was supported by funding from Janssen Scientific Affairs, LLC (formerly Ortho-McNeil Janssen Scientific Affairs, LLC). Author Disclosure Statement Mr Paris and Dr Kozma received research funding and writing support from Janssen Scientific Affairs, LLC; Dr Chow is an employee and stockholder of Janssen Scientific Affairs, LLC; Ms Patel was formerly a contractor for Janssen Scientific Affairs, LLC; Dr Mody is an employee of Janssen Scientific Affairs, LLC, and a shareholder of Johnson & Johnson; Dr Kim is an employee of Johnson & Johnson and a stockholder of Janssen Scientific Affairs, LLC.

References

1. Goldberg DS, McGee SJ. Pain as a global public health priority. BMC Public Health. 2011;11:770. 2. Desbiens NA, Wu AW, Broste SK, et al. Pain and satisfaction with pain control in seriously ill hospitalized adults: findings from the SUPPORT research investigations. For the SUPPORT Investigators. Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatment. Crit Care Med. 1996;24:1953-1961. 3. van den Beuken-van Everdingen MH, de Rijke JM, Kessels AG, et al. Prevalence of pain in patients with cancer: a systematic review of the past 40 years. Ann Oncol. 2007;18:1437-1449. 4. Whelan CT, Jin L, Meltzer D. Pain and satisfaction with pain control in hospitalized medical patients: no such thing as low risk. Arch Intern Med. 2004;164:175-180. 5. Centers for Disease Control and Prevention. National Hospital Discharge Survey. Number, rate, and average length of stay for discharges from short-stay hospitals, by age,

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region, and sex: United States, 2010. Updated August 28, 2012. www.cdc.gov/nchs/ data/nhds/4procedures/2010pro4_numberrate.pdf. Accessed November 18, 2013. 6. Savoia G, Alampi D, Amantea B, et al; for the SIAARTI Study Group. Postoperative pain treatment SIAARTI Recommendations 2010. Short version. Minerva Anestesiol. 2010;76:657-667. 7. Boswell K, Kwong WJ, Kavanagh S. Burden of opioid-associated gastrointestinal side effects from clinical and economic perspectives: a systematic literature review. J Opioid Manag. 2010;6:269-289. 8. Anastassopoulos KP, Chow W, Ackerman SJ, et al. Oxycodone-related side effects: impact on degree of bother, adherence, pain relief, satisfaction, and quality of life. J Opioid Manag. 2011;7:203-215. 9. Moskovitz BL, Benson CJ, Patel AA, et al. Analgesic treatment for moderate-to-severe acute pain in the United States: patients’ perspectives in the Physicians Partnering Against Pain (P3) survey. J Opioid Manag. 2011;7:277-286. 10. Oderda GM, Said Q, Evans RS, et al. Opioid-related adverse drug events in surgical hospitalizations: impact on costs and length of stay. Ann Pharmacother. 2007; 41:400-406. 11. Kalso E, Edwards JE, Moore RA, McQuay HJ. Opioids in chronic non-cancer pain: systematic review of efficacy and safety. Pain. 2004;112:372-380. 12. Moore RA, McQuay HJ. Prevalence of opioid adverse events in chronic non-malignant pain: systematic review of randomised trials of oral opioids. Arthritis Res Ther. 2005;7:R1046-R1051. 13. Cepeda MS, Farrar JT, Baumgarten M, et al. Side effects of opioids during short-term administration: effect of age, gender, and race. Clin Pharmacol Ther. 2003;74:102-112. 14. Camilleri M. Opioid-induced constipation: challenges and therapeutic opportunities. Am J Gastroenterol. 2011;106:835-842; quiz 843. 15. Suh DC, Kim MS, Chow W, Jang EJ. Use of medications and resources for treatment of nausea, vomiting, or constipation in hospitalized patients treated with analgesics. Clin J Pain. 2011;27:508-517. 16. Oderda GM, Evans RS, Lloyd J, et al. Cost of opioid-related adverse drug events in surgical patients. J Pain Symptom Manage. 2003;25:276-283. 17. Kwong WJ, Diels J, Kavanagh S. Costs of gastrointestinal events after outpatient opioid treatment for non-cancer pain. Ann Pharmacother. 2010;44:630-640. 18. American Society of Anesthesiologists Task Force on Acute Pain Management. Practice guidelines for acute pain management in the perioperative setting: an updated report by the American Society of Anesthesiologists Task Force on Acute Pain Management. Anesthesiology. 2004;100:1573-1581. 19. Tzschentke TM, Christoph T, Kögel B, et al. (-)-(1R,2R)-3-(3-dimethylamino1-ethyl-2-methyl-propyl)-phenol hydrochloride (tapentadol HCl): a novel mu-opioid receptor agonist/norepinephrine reuptake inhibitor with broad-spectrum analgesic properties. J Pharmacol Exp Ther. 2007;323:265-276. 20. Tzschentke TM, de Vry J, Terlinden R, et al. Tapentadol hydrochloride. Analgesic, mu-opioid receptor agonist, noradrenaline reuptake inhibitor. Drugs Future. 2006; 31:1053-1061. 21. Kress HG. Tapentadol and its two mechanisms of action: is there a new pharmacological class of centrally-acting analgesics on the horizon? Eur J Pain. 2010;14:781-783. 22. Daniels S, Casson E, Stegmann JU, et al. A randomized, double-blind, placebo-controlled phase 3 study of the relative efficacy and tolerability of tapentadol IR and oxycodone IR for acute pain. Curr Med Res Opin. 2009;25:1551-1561. Erratum in: Curr Med Res Opin. 2009;25:1561. 23. Hartrick C, Van Hove I, Stegmann JU, et al. Efficacy and tolerability of tapentadol immediate release and oxycodone HCl immediate release in patients awaiting primary joint replacement surgery for end-stage joint disease: a 10-day, phase III, randomized, double-blind, active- and placebo-controlled study. Clin Ther. 2009;31:260-271. 24. Daniels SE, Upmalis D, Okamoto A, et al. A randomized, double-blind, phase III study comparing multiple doses of tapentadol IR, oxycodone IR, and placebo for postoperative (bunionectomy) pain. Curr Med Res Opin. 2009;25:765-776. 25. Hale M, Upmalis D, Okamoto A, et al. Tolerability of tapentadol immediate release in patients with lower back pain or osteoarthritis of the hip or knee over 90 days: a randomized, double-blind study. Curr Med Res Opin. 2009;25:1095-1104. 26. Pizzi LT, Toner R, Foley K, et al. Relationship between potential opioid-related adverse effects and hospital length of stay in patients receiving opioids after orthopedic surgery. Pharmacotherapy. 2012;32:502-514. 27. Kwong WJ, Ozer-Stillman I, Miller JD, et al. Cost-effectiveness analysis of tapentadol immediate release for the treatment of acute pain. Clin Ther. 2010;32:1768-1781. 28. Healthcare Cost and Utilization Project. HCUP facts and figures: statistics on hospital-based care in the United States, 2009. October 2011. Modified October 19, 2011. www.hcup-us.ahrq.gov/reports/factsandfigures/2009/exhibit1_1.jsp. Accessed January 3, 2012. 29. Weinstein MC, Siegel JE, Gold MR, et al. Recommendations of the Panel on Cost-effectiveness in Health and Medicine. JAMA. 1996;276:1253-1258.

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November/December 2013

Vol 6, No 9

Net Hospital Cost Associated with Tapentadol IR versus Oxycodone IR

Stakeholder Perspective Can Substituting Generic Drugs with Brand-Name Agents for Acute Pain Postsurgery Help to Deliver Cost-Effective, Quality Care? By Matthew Mitchell, PharmD, MBA Director, Pharmacy Services SelectHealth, Salt Lake City, UT

PAYERS/HOSPITALS: The use of brand-name drugs in the place of generic therapeutic alternatives always gets the attention of payers. Justifying the replacement of a generic, standard-of-care medication requires the demonstration of better efficacy, safety, and/or superior cost-effectiveness. Paris and colleagues created a model to demonstrate potential cost offsets with a hypothetical replacement of a portion of oxycodone immediate release (IR) with tapentadol IR in a postsurgical setting. A lower incidence of gastrointestinal (GI) adverse events was extrapolated from an active comparator study with oxycodone after bunionectomy. Cost-savings resulting from a lower rate of GI adverse events in the outpatient setting are difficult to ascertain, particularly if a visit to an urgent care facility or an emergency department is not required. Outside of the possible use of antiemetics, of which several inexpensive generics are available, the majority of intervention-based costs are for over-the-counter medications used for constipation, as well as agents for adequate hydration. The majority of other expenditures are indirect costs. The model created by the authors suggests a substantial cost-savings when replacing oxycodone IR with tapentadol IR for use after surgery in the hospital setting. The majority of the cost-savings, according to this model, results from a lower required hospital length of stay if oxycodone IR is replaced by tapentadol IR. The cost of tapentadol IR was modeled at $52.30 daily com-

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November/December 2013

pared with no cost for oxycodone; however, this is inconsequential, because of the increased length of stay by almost 2 days for the group using oxycodone IR compared with the group using tapentadol IR. Many health plans cover hospital stays based on a diagnosis-related group payment. Hospitals may be incentivized to deliver the most efficient care possible, including eliminating extended stays resulting from medication-induced adverse events. These data may generate interest in evaluating realworld data with the use of observational analyses. If the data are in line with these published cost-savings, hospitals may be wise to evaluate standing orders for acute pain control and determine if, or when, a substitution, such as tapentadol IR, should be used. In implementing accountable care models of risk and reimbursement, these types of analyses will become even more important for delivering cost-effective, quality care. PATIENTS: A lower rate of GI adverse events has been shown with tapentadol IR compared with oxycodone IR, which can clearly be beneficial for patients undergoing surgery, in addition to the reduced number of days at the hospital. If these numbers are borne out by real-world data, the advantage of switching from a generic medication to a brand-name drug in the context of postsurgical acute pain may become evident for patients as well.

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POMALYST® (pomalidomide) is indicated for patients with multiple myeloma who have received at least two prior therapies including lenalidomide and bortezomib and have demonstrated disease progression on or within 60 days of completion of the last therapy. Approval is based on response rate. Clinical benefit, such as improvement in survival or symptoms, has not been verified.

Help give your patients a chance for response Overall response rate (ORR) of 29.2% was achieved with all-oral POMALYST + low-dose dex ORR (≥PR) 100%

Patients, %

80%

95% CI for ORR: POMALYST: 3.3% to 14.1% POMALYST + low-dose dex: 21.0% to 38.5%

60% 40% 20%

ORR 7.4% (n=8)

PR 7.4% (n=8) CR 0% (n=0)

ORR 29.2% (n=33)

PR 28.3% (n=32) CR 0.9% (n=1)

POMALYST (N=108)

POMALYST + low-dose dex (N=113)

Study design: A Phase II, Stud multicenter, randomized open-label study in patients who were refractory to their last myeloma therapy and had received lenalidomide and bortezomib. The safety and efficacy of POMALYST 4 mg 21/28 days until disease progression was evaluated alone and in combination with low-dose dex: 40 mg per day (patients ≤75 years) or 20 mg per day (patients >75 years) only on Days 1, 8, 15, and 22 for each 28-day cycle. Patients in the POMALYST alone arm were allowed to add low-dose dex upon disease progression.

CI, confidence interval; CR, complete response; Dex, dexamethasone; PR, partial response. Endpoint based on responses assessed by IRAC, based on EBMT criteria.

7.4-month median duration of response (n=33; 95% CI, 5.1 to 9.2) vs NE for POMALYST + low-dose dex and POMALYST, respectively NE, not established (the median has not yet been reached).

ORR did not differ based on type of prior anti-myeloma therapy

For more information visit www.pomalyst.com or use your smartphone to scan this code.

WARNING: EMBRYO-FETAL TOXICITY and VENOUS THROMBOEMBOLISM See full prescribing information for complete boxed warning EMBRYO-FETAL TOXICITY • POMALYST is contraindicated in pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a known human teratogen that causes severe life-threatening birth defects • For females of reproductive potential: Exclude pregnancy before start of treatment. Prevent pregnancy during treatment by the use of two reliable methods of contraception POMALYST is available only through a restricted program called the POMALYST REMS program. VENOUS THROMBOEMBOLISM • Deep Venous Thrombosis (DVT) and Pulmonary Embolism (PE) occur in patients with multiple myeloma treated with POMALYST

CONTRAINDICATIONS Pregnancy POMALYST can cause fetal harm when administered to a pregnant female. POMALYST is contraindicated in females who are pregnant. Pomalidomide is a thalidomide analogue, and is teratogenic in both rats and rabbits when administered during the period of organogenesis. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. POMALYST is only available under a restricted distribution program, POMALYST REMS™. Please see brief summary of full Prescribing Information, including Boxed WARNINGS, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS, and Important Safety Information on following pages.

Important Safety Information WARNING: EMBRYO-FETAL TOXICITY and VENOUS THROMBOEMBOLISM Embryo-Fetal Toxicity • POMALYST is contraindicated in pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting POMALYST treatment • Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after stopping POMALYST treatment POMALYST is only available through a restricted distribution program called POMALYST REMS™. Venous Thromboembolism • Deep Venous Thrombosis (DVT) and Pulmonary Embolism (PE) occur in patients with multiple myeloma treated with POMALYST. Prophylactic anti-thrombotic measures were employed in the clinical trial. Consider prophylactic measures after assessing an individual patient’s underlying risk factors

CONTRAINDICATIONS: Pregnancy

• POMALYST can cause fetal harm and is contraindicated in females who are pregnant. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus • Pomalidomide is a thalidomide analogue and is teratogenic in both rats and rabbits when administered during the period of organogenesis

WARNINGS AND PRECAUTIONS Embryo-Fetal Toxicity

• Females of Reproductive Potential: Must avoid pregnancy while taking POMALYST and for at least 4 weeks after completing therapy. Must commit either to abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control, beginning 4 weeks prior to initiating treatment with POMALYST, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of POMALYST therapy. Must obtain 2 negative pregnancy tests prior to initiating therapy • Males: Pomalidomide is present in the semen of patients receiving the drug. Males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy. Males must not donate sperm • Blood Donation: Patients must not donate blood during treatment with POMALYST and for 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to POMALYST

POMALYST REMS Program

Because of the embryo-fetal risk, POMALYST is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called “POMALYST REMS.” Prescribers and pharmacists must be certified with the program; patients must sign an agreement form and comply with the requirements. Further information about the POMALYST REMS program is available at [celgeneriskmanagement.com] or by telephone at 1-888-423-5436.

Venous Thromboembolism: Patients receiving POMALYST have developed venous thromboembolic events reported as serious adverse reactions. In the trial, all patients were required to receive prophylaxis or antithrombotic treatment. The rate of DVT or PE was 3%. Consider anticoagulation prophylaxis after an assessment of each patient’s underlying risk factors. Hematologic Toxicity: Neutropenia of any grade was reported in 50% of patients and was the most frequently reported Grade 3/4 adverse event, followed by anemia and thrombocytopenia. Monitor patients for hematologic toxicities, especially neutropenia, with complete blood counts weekly for the first 8 weeks and monthly thereafter. Treatment is continued or modified for Grade 3 or 4 hematologic toxicities based upon clinical and laboratory findings. Dosing interruptions and/or modifications are recommended to manage neutropenia and thrombocytopenia. Hypersensitivity Reactions: Patients with a prior history of serious hypersensitivity associated with thalidomide or lenalidomide were excluded from studies and may be at higher risk of hypersensitivity.

WARNINGS AND PRECAUTIONS (continued) Dizziness and Confusional State: 18% of patients experienced dizziness and 12% of patients experienced a confusional state;

1% of patients experienced grade 3/4 dizziness, and 3% of patients experienced grade 3/4 confusional state. Instruct patients to avoid situations where dizziness or confusion may be a problem and not to take other medications that may cause dizziness or confusion without adequate medical advice. Neuropathy: 18% of patients experienced neuropathy (approximately 9% peripheral neuropathy). There were no cases of grade 3 or higher neuropathy adverse reactions reported. Risk of Second Primary Malignancies: Cases of acute myelogenous leukemia have been reported in patients receiving POMALYST as an investigational therapy outside of multiple myeloma.

ADVERSE REACTIONS

In the clinical trial of 219 patients who received POMALYST alone (n=107) or POMALYST + low-dose dexamethasone (low-dose dex) (n=112), all patients had at least one treatment-emergent adverse reaction. • In the POMALYST alone versus POMALYST + low dose dexamethasone arms, respectively, most common adverse reactions (≥30%) included fatigue and asthenia (55%, 63%), neutropenia (52%, 47%), anemia (38%, 39%), constipation (36%, 35%), nausea (36%, 22%), diarrhea (34%, 33%), dyspnea (34%, 45%), upper respiratory tract infection (32%, 25%), back pain (32%, 30%), and pyrexia (19%, 30%) • 90% of patients treated with POMALYST alone and 88% of patients treated with POMALYST + low-dose dex had at least one treatment-emergent NCI CTC Grade 3 or 4 adverse reaction • In the POMALYST alone versus POMALYST + low dose dexamethasone arms, respectively, most common Grade 3/4 adverse reactions (≥15%) included neutropenia (47%, 38%), anemia (22%, 21%), thrombocytopenia (22%, 19%), and pneumonia (16%, 23%). For other Grade 3 or 4 toxicities besides neutropenia and thrombocytopenia, hold treatment and restart treatment at 1 mg less than the previous dose when toxicity has resolved to less than or equal to Grade 2 at the physician’s discretion • 67% of patients treated with POMALYST and 62% of patients treated with POMALYST + low-dose dex had at least one treatment-emergent serious adverse reaction • In the POMALYST alone versus POMALYST + low dose dexamethasone arms, respectively, most common serious adverse reactions (≥5%) were pneumonia (14%, 19%), renal failure (8%, 6%), dyspnea (5%, 6%), sepsis (6%, 3%), pyrexia (3%, 5%) dehydration (5%, 3%), hypercalcemia (5%, 2%), urinary tract infection (0%, 5%), and febrile neutropenia (5%, 1%)

DRUG INTERACTIONS

No formal drug interaction studies have been conducted with POMALYST. Pomalidomide is primarily metabolized by CYP1A2 and CYP3A. Pomalidomide is also a substrate for P-glycoprotein (P-gp). Coadministration of POMALYST with drugs that are strong inhibitors or inducers of CYP1A2, CYP3A, or P-gp should be avoided. Cigarette smoking may reduce pomalidomide exposure due to CYP1A2 induction. Patients should be advised that smoking may reduce the efficacy of pomalidomide.

USE IN SPECIFIC POPULATIONS

Pregnancy: If pregnancy does occur during treatment, immediately discontinue the drug and refer patient to an obstetrician/

gynecologist experienced in reproductive toxicity for further evaluation and counseling. Report any suspected fetal exposure to POMALYST to the FDA via the MedWatch program at 1-800-332-1088 and also to Celgene Corporation at 1-888-423-5436. Nursing Mothers: It is not known if pomalidomide is excreted in human milk. Pomalidomide was excreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from POMALYST, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use: Safety and effectiveness of POMALYST in patients under the age of 18 have not been established. Geriatric Use: No dosage adjustment is required for POMALYST based on age. Patients greater than or equal to 65 years of age were more likely than patients less than or equal to 65 years of age to experience pneumonia. Renal and Hepatic Impairment: Pomalidomide is metabolized in the liver. Pomalidomide and its metabolites are primarily excreted by the kidneys. The influence of renal and hepatic impairment on the safety, efficacy, and pharmacokinetics of pomalidomide has not been evaluated. Avoid POMALYST in patients with a serum creatinine >3.0 mg/dL. Avoid POMALYST in patients with serum bilirubin >2.0 mg/dL and AST/ALT >3.0 x ULN.

Please see full Prescribing Information, including Boxed WARNINGS, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS. POMALYST® is a registered trademark of Celgene Corporation. POMALYST REMS™ is a trademark of Celgene Corporation. © 2013 Celgene Corporation 04/13 US-POM120033

This brief summary does not include all the information needed to use POMALYST® (pomalidomide) safely and effectively. See full prescribing information for POMALYST. WARNING: EMBRYO-FETAL TOXICITY and VENOUS THROMBOEMBOLISM Embryo-Fetal Toxicity • POMALYST is contraindicated in pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting POMALYST treatment. • Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after stopping POMALYST treatment [see Contraindications (4), Warnings and Precautions (5.1), and Use in Specific Populations (8.1, 8.6)]. POMALYST is only available through a restricted distribution program called POMALYST REMS [see Warnings and Precautions (5.2)]. Venous Thromboembolism • Deep Venous Thrombosis (DVT) and Pulmonary Embolism (PE) occur in patients with multiple myeloma treated with POMALYST. Prophylactic anti-thrombotic measures were employed in the clinical trial. Consider prophylactic measures after assessing an individual patient’s underlying risk factors [see Warnings and Precautions (5.3)]. 1 INDICATIONS AND USAGE 1.1 Multiple Myeloma POMALYST is indicated for patients with multiple myeloma who have received at least two prior therapies including lenalidomide and bortezomib and have demonstrated disease progression on or within 60 days of completion of the last therapy. Approval is based on response rate [see Clinical Studies (14.1)]. Clinical benefit, such as improvement in survival or symptoms, has not been verified. 2 DOSAGE AND ADMINISTRATION 2.1 Multiple Myeloma Females of reproductive potential must have negative pregnancy testing and use contraception methods before initiating POMALYST [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)]. The recommended starting dose of POMALYST is 4 mg once daily orally on Days 1-21 of repeated 28-day cycles until disease progression. POMALYST may be given in combination with dexamethasone [see Clinical Studies (14.1)]. POMALYST may be taken with water. Inform patients not to break, chew or open the capsules. POMALYST should be taken without food (at least 2 hours before or 2 hours after a meal). 2.2 Dose Adjustments for Toxicity Table 1: Dose Modification Instructions for POMALYST for Hematologic Toxicities Toxicity

Dose Modification

Neutropenia • ANC* < 500 per mcL Interrupt POMALYST or Febrile neutropenia treatment, follow CBC (fever more than or weekly. equal to 38.5°C and ANC < 1,000 per mcL) • ANC return to more than or equal to 500 per mcL

Resume POMALYST at 3 mg daily.

• For each subsequent drop < 500 per mcL

Interrupt POMALYST treatment

• Return to more than or equal to 500 per mcL

Resume POMALYST at 1 mg less than the previous dose

Toxicity

Dose Modification

Thrombocytopenia • Platelets < 25,000 per Interrupt POMALYST mcL treatment, follow CBC weekly • Platelets return to > 50,000 per mcL

Resume POMALYST treatment at 3 mg daily

• For each subsequent drop < 25,000 per mcL

Interrupt POMALYST treatment

• Return to more than Resume POMALYST at or equal to 50,000 per 1 mg less than previous mcL dose. *Note: ANC = Absolute Neutrophil Count For other Grade 3 or 4 toxicities hold treatment and restart treatment at 1 mg less than the previous dose when toxicity has resolved to less than or equal to Grade 2 at the physician’s discretion. To initiate a new cycle of POMALYST, the neutrophil count must be at least 500 per mcL, the platelet count must be at least 50,000 per mcL. If toxicities occur after dose reductions to 1 mg, then discontinue POMALYST. 4 CONTRAINDICATIONS Pregnancy POMALYST can cause fetal harm when administered to a pregnant female [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)]. POMALYST is contraindicated in females who are pregnant. Pomalidomide is a thalidomide analogue, and is teratogenic in both rats and rabbits when administered during the period of organogenesis. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. 5 WARNINGS AND PRECAUTIONS 5.1 Embryo-Fetal Toxicity POMALYST is a thalidomide analogue and is contraindicated for use during pregnancy. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death [see Use in Specific Populations (8.1)]. POMALYST is only available through the POMALYST REMS program [see Warnings and Precautions (5.2)].Females of Reproductive Potential Females of reproductive potential must avoid pregnancy while taking POMALYST and for at least 4 weeks after completing therapy. Females must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control, beginning 4 weeks prior to initiating treatment with POMALYST, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of POMALYST therapy. Two negative pregnancy tests must be obtained prior to initiating therapy. The first test should be performed within 10-14 days and the second test within 24 hours prior to prescribing POMALYST therapy and then weekly during the first month, then monthly thereafter in women with regular menstrual cycles or every 2 weeks in women with irregular menstrual cycles [see Use in Specific Populations (8.6)].Males Pomalidomide is present in the semen of patients receiving the drug. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy. Male patients taking POMALYST must not donate sperm [see Use in Specific Populations (8.6)]. Blood Donation Patients must not donate blood during treatment with POMALYST and for 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to POMALYST. 5.2 POMALYST REMS ™ Program Because of the embryo-fetal risk [see Warnings and Precautions

(5.1)], POMALYST is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called “POMALYST REMS.” Required components of the POMALYST REMS program include the following: • Prescribers must be certified with the POMALYST REMS program by enrolling and complying with the REMS requirements. • Patients must sign a Patient-Prescriber agreement form and comply with the REMS requirements. In particular, female patients of reproductive potential who are not pregnant must comply with the pregnancy testing and contraception requirements [see Use in Specific Populations (8.6)] and males must comply with contraception requirements [see Use in Specific Populations (8.6)]. • Pharmacies must be certified with the POMALYST REMS program, must only dispense to patients who are authorized to receive POMALYST and comply with REMS requirements. Further information about the POMALYST REMS program is available at [celgeneriskmanagement.com] or by telephone at 1-888-423-5436. 5.3 Venous Thromboembolism Patients receiving POMALYST have developed venous thromboembolic events (Venous Thromboembolism [VTEs]) reported as serious adverse reactions. In the trial, all patients were required to receive prophylaxis or anti-thrombotic treatment; 81% used aspirin, 16% warfarin, 21% heparin, and 3% clopidogrel. The rate of deep vein thrombosis or pulmonary embolism was 3%. Consider anti-coagulation prophylaxis after an assessment of each patient’s underlying risk factors. 5.4 Hematologic Toxicity Neutropenia was the most frequently reported Grade 3/4 adverse event (AE), followed by anemia and thrombocytopenia. Neutropenia of any grade was reported in 50% of patients in the trial. The rate of Grade 3/4 neutropenia was 43%. The rate of febrile neutropenia was 3%. Monitor patients for hematologic toxicities, especially neutropenia. Monitor complete blood counts weekly for the first 8 weeks and monthly thereafter. Patients may require dose interruption and/or modification [see Dosage and Administration (2.2)]. 5.5 Hypersensitivity Reactions. Patients with a prior history of serious hypersensitivity associated with thalidomide or lenalidomide were excluded from studies and may be at higher risk of hypersensitivity. 5.6 Dizziness and Confusional State. In the trial, 18% of patients experienced dizziness and 12% of patients experienced a confusional state; 1% of patients experienced grade 3/4 dizziness, and 3% of patients experienced grade 3/4 confusional state. Instruct patients to avoid situations where dizziness or confusion may be a problem and not to take other medications that may cause dizziness or confusion without adequate medical advice. 5.7 Neuropathy In the trial, 18% of patients experienced neuropathy, with approximately 9% of the patients experiencing peripheral neuropathy. There were no cases of grade 3 or higher neuropathy adverse reactions reported. 5.8 Risk of Second Primary Malignancies Cases of acute myelogenous leukemia have been reported in patients receiving POMALYST as an investigational therapy outside of multiple myeloma. 6 ADVERSE REACTIONS The following adverse reactions are described in detail in other labeling sections: • Fetal Risk [see Boxed Warnings, Warnings and Precautions (5.1, 5.2)] • Venous Thromboembolism [see Boxed Warnings, Warnings and Precautions (5.3)] • Hematologic Toxicity [see Warnings and Precautions (5.4)] • Hypersensitivity Reactions [see Warnings and Precautions (5.5)]

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• Dizziness and Confusional State [see Warnings and Precautions (5.6)] • Neuropathy [see Warnings and Precautions (5.7)] • Risk of Second Primary Malignancies [see Warnings and Precautions (5.8)] 6.1 Clinical Trials Experience in Multiple Myeloma Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In clinical trial 1, data were evaluated from 219 patients (safety population) who received treatment with POMALYST + Low Dose Dexamethasone (Low dose Dex) (112 patients) or POMALYST alone (107 patients). Median number of treatment cycles was 5. Sixty three percent of patients in the study had a dose interruption of either drug due to adverse reactions. Thirty seven percent of patients in the study had a dose reduction of either drug due to adverse reactions. The discontinuation rate due to treatment-related adverse reaction was 3%. Tables 2, 3 and 4 summarize all treatment-emergent adverse reactions reported for POMALYST + Low dose Dex and POMALYST alone groups regardless of attribution of relatedness to pomalidomide. In the absence of a randomized comparator arm, it is often not possible to distinguish adverse events that are drug-related and those that reflect the patient’s underlying disease. In the clinical trial of 219 patients who received POMALYST alonea (n=107) or POMALYST + Lowdose Dex (n=112), all patients had at least one treatment-emergent adverse reaction. Adverse reactions ≥10% in either arm, respectively, included: General disorders and administration site conditions: Fatigue and asthenia (55%, 63%), Pyrexia (19%, 30%), Edema peripheral (23%, 16%), Chills (9%, 11%), Pain (6%, 5%); Blood and lymphatic system disorders: Neutropenia (52%, 47%), Anemia (38%, 39%), Thrombocytopenia (25%, 23%), Leukopenia (11%, 18%), Lymphopenia (4%, 15%); Gastrointestinal disorders: Constipation (36%, 35%), Diarrhea (34%, 33%), Nausea (36%, 22%), Vomiting (14%, 13%); Infections and infestations: Pneumonia (23%, 29%), Upper respiratory tract infection (32%, 25%), Urinary tract infection (8%, 16%); Musculoskeletal and connective tissue disorders: Back pain (32%, 30%), Musculoskeletal chest pain (22%, 20%), Muscle spasms (19%, 19%), Arthralgia (16%, 15%), Musculoskeletal pain (11%, 15%), Pain in extremity (5%, 14%), Muscular weakness (12%, 12%), Bone pain (12%, 5%); Respiratory, thoracic and mediastinal disorders: Dyspnea (34%, 45%), Cough (14%, 21%), Epistaxis (15%, 11%); Metabolism and nutritional disorders: Decreased appetite (22%, 18%), Hyperglycemia (12%, 15%), Hyponatremia (10%, 13%), Hypercalcemia (21%, 12%), Hypocalcemia (6%, 12%), Hypokalemia (10%, 11%); Skin and subcutaneous tissue disorders: Hyperhidrosis (6%, 16%), Rash (22%, 16%), Night sweats (5%, 13%), Dry skin (9%, 11%), Pruritus (15%, 11%); Nervous system disorders: Dizziness (20%, 17%), Tremor (9%, 13%), Headache (13%, 8%), Neuropathy peripheral (10%, 7%); Investigations: Blood creatinine increased (15%, 11%), Weight increased (1%, 11%), Weight decreased (14%, 8%); Psychiatric disorders: Insomnia (7%, 14%), Confusional state (10%, 13%), Anxiety (11%, 7%); Renal and urinary disorders: Renal failure (15%, 10%). Grade 3/4 adverse reactions reported in 90% of patients treated with POMALYSTa alone (96/107) and 88% with POMALYST + Low dose Dex (99/112). Grade 3/4 Adverse Reactions ≥ 5% in either arm, respectively, included: Blood and lymphatic system disorders: Neutropenia (47%, 38%), Anemia (22%, 21%), Thrombocytopenia (22%, 19%), Leukopenia

(6%, 10%), Lymphopenia (2%, 7%); Infections and infestations: Pneumonia (16%, 23%), Urinary tract infection (2%, 8%), Sepsis (6%, 3%); Metabolism and nutritional disorders: Hypercalcemia (9%, 1%); General disorders and administration site conditions: Fatigue and asthenia (11%, 13%); Investigations: Blood creatinine increased (6%, 3%); Respiratory, thoracic and mediastinal disorders: Dyspnea (7%, 13%); Musculoskeletal and connective tissue disorders: Back pain (12%, 9%), Muscular weakness (6%, 4%); Renal and urinary disorders: Renal failure (9%, 6%). Serious adverse events were reported in 67% of patients treated with POMALYSTa (72/107) and 62% with POMALYST + Low dose Dex (69/112). Serious Adverse Reactions in 2 or more patients in either arm, respectively, included: Infections and infestations: Pneumonia (14%, 19%), Urinary tract infection (0%, 5%), Sepsis (6%, 3%); Respiratory, Thoracic and mediastinal disorders: Dyspnea (5%, 6%); General disorders and administration site conditions: Pyrexia (3%, 5%); General physical health deterioration (0%, 2%); Cardiac Disorders: Atrial fibrillation (2%, 3%), Cardiac failure congestive (0%, 3%); Renal and urinary disorders: Renal failure (8%, 6%), Gastrointestinal disorders: constipation (1%, 3%); Blood and Lymphatic system disorders: Febrile neutropenia (5%, 1%); Metabolism and nutrition disorders: Dehydration (5%, 3%), Hypercalcemia (5%, 2%); Musculoskeletal and connective tissue disorders: Back pain (4%, 2%) aPOMALYST alone arm includes all patients randomized to the POMALYST alone arm who took study drug; 61 of the 107 patients had dexamethasone added during the treatment period. Other Adverse Reactions Other adverse reactions of POMALYST in patients with multiple myeloma, not described above, and considered important: Ear and Labyrinth Disorders: Vertigo; Hepatobiliary Disorders: Hyperbilirubinemia; Infections and Infestations: Pneumocystis jiroveci pneumonia, Respiratory syncytial virus infection, Neutropenic sepsis; Investigations: Alanine aminotransferase increased; Metabolism and Nutritional Disorders: Hyperkalemia; Renal and Urinary Disorders: Urinary retention; Reproductive System and Breast Disorders: Pelvic Pain; Respiratory, Thoracic and Mediastinal Disorders: Interstitial Lung Disease 7 DRUG INTERACTIONS No formal drug interaction studies have been conducted with POMALYST. Pomalidomide is primarily metabolized by CYP1A2 and CYP3A. Pomalidomide is also a substrate for P-glycoprotein (P-gp). 7.1 Drugs That May Increase Pomalidomide Plasma Concentrations CYP3A, CYP1A2 or P-gp inhibitors: Co-administration of POMALYST with drugs that are strong inhibitors of CYP1A2, CYP3A (e.g. ketoconazole) or P-gp could increase exposure and should be avoided. 7.2 Drugs That May Decrease Pomalidomide Plasma Concentrations CYP3A, CYP1A2 or P-gp inducers: Co-administration of POMALYST with drugs that are strong inducers of CYP1A2, CYP3A (e.g. rifampin) or P-gp could decrease exposure and should be avoided. Smoking: Cigarette smoking may reduce pomalidomide exposure due to CYP1A2 induction. Patients should be advised that smoking may reduce the efficacy of pomalidomide. Dexamethasone: Co-administration of multiple doses of 4 mg POMALYST with 20 mg to 40 mg dexamethasone (a weak inducer of CYP3A) to patients with multiple myeloma had no effect on the pharmacokinetics of pomalidomide compared with pomalidomide administered alone. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category X [see Boxed Warnings and Contraindications (4)]

Risk Summary POMALYST can cause embryo-fetal harm when administered to a pregnant female and is contraindicated during pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a human teratogen, inducing a high frequency of severe and life-threatening birth defects such as amelia (absence of limbs), phocomelia (short limbs), hypoplasticity of the bones, absence of bones, external ear abnormalities (including anotia, micropinna, small or absent external auditory canals), facial palsy, eye abnormalities (anophthalmos, microphthalmos), and congenital heart defects. Alimentary tract, urinary tract, and genital malformations have also been documented and mortality at or shortly after birth has been reported in about 40% of infants. Pomalidomide was teratogenic in both rats and rabbits when administered during the period of organogenesis. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. If pregnancy does occur during treatment, immediately discontinue the drug. Under these conditions, refer patient to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling. Report any suspected fetal exposure to POMALYST to the FDA via the MedWatch program at 1-800-332-1088 and also to Celgene Corporation at 1-888-423-5436. Animal Data Pomalidomide was teratogenic in both rats and rabbits in the embryofetal developmental studies, when administered during the period of organogenesis. In rats, pomalidomide was administered orally to pregnant animals at doses of 25 to 1000 mg per kg per day. Malformations of absence of urinary bladder, absence of thyroid gland, and fusion and misalignment of lumbar and thoracic vertebral elements (vertebral, central and/or neural arches) were observed at all dose levels. There was no maternal toxicity observed in this study. The lowest dose in rats resulted in an exposure (AUC) approximately 85-fold of the human exposure at the recommended dose of 4 mg per day. Other embryofetal toxicities included increased resorptions leading to decreased number of viable fetuses. In rabbits, pomalidomide was administered orally to pregnant animals at doses of 10 to 250 mg per kg per day. Increased cardiac malformations such as interventricular septal defect were seen at all doses with significant increases at 250 mg per kg per day. Additional malformations observed at 250 mg per kg per day included anomalies in limbs (flexed and/or rotated fore- and/or hindlimbs, unattached or absent digit) and associated skeletal malformations (not ossified metacarpal, misaligned phalanx and metacarpal, absent digit, not ossified phalanx, and short not ossified or bent tibia), moderate dilation of the lateral ventricle in the brain, abnormal placement of the right subclavian artery, absent intermediate lobe in the lungs, low-set kidney, altered liver morphology, incompletely or not ossified pelvis, an increased average for supernumerary thoracic ribs and a reduced average for ossified tarsals. No maternal toxicity was observed at the low dose (10 mg per kg per day) that resulted in cardiac anomalies in fetuses; this dose resulted in an exposure (AUC) approximately equal to that reported in humans at the recommended dose of 4 mg per day. Additional embryofetal toxicity included increased resorption. 8.3 Nursing mothers It is not known if pomalidomide is excreted in human milk. Pomalidomide was excreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from POMALYST, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric use Safety and effectiveness of POMALYST in patients below the age of 18 have not been established.

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8.5 Geriatric use No dosage adjustment is required for POMALYST based on age. Of the total number of patients in clinical studies of POMALYST, 41 percent were 65 and over, while 12 percent were 75 and over. No overall differences in effectiveness were observed between these patients and younger patients. In this study, patients greater than or equal to 65 years of age were more likely than patients less than or equal to 65 years of age to experience pneumonia. 8.6 Females of Reproductive Potential and Males POMALYST can cause fetal harm when administered during pregnancy [see Use in Specific Populations (8.1)]. Females of reproductive potential must avoid pregnancy while taking POMALYST and for at least 4 weeks after completing therapy. Females Females of reproductive potential must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control simultaneously (one highly effective form of contraception – tubal ligation, IUD, hormonal (birth control pills, injections, hormonal patches, vaginal rings or implants) or partner’s vasectomy and one additional effective contraceptive method – male latex or synthetic condom, diaphragm or cervical cap. Contraception must begin 4 weeks prior to initiating treatment with POMALYST, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of POMALYST therapy. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy. Females of reproductive potential should be referred to a qualified provider of contraceptive methods, if needed. Females of reproductive potential must have 2 negative pregnancy tests before initiating POMALYST. The first test should be performed within 10-14 days, and the second test within 24 hours prior to prescribing POMALYST. Once treatment has started and during dose interruptions, pregnancy testing for females of reproductive potential should occur weekly during the first 4 weeks of use, then pregnancy testing should be repeated every 4 weeks in females with regular menstrual cycles. If menstrual cycles are irregular, the pregnancy testing should occur every 2 weeks. Pregnancy testing and counseling should be performed if a patient misses her period or if there is any abnormality in her menstrual bleeding. POMALYST treatment must be discontinued during this evaluation. Males Pomalidomide is present in the semen of males who take POMALYST. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy. Male patients taking POMALYST must not donate sperm. 8.7 Renal Impairment Pomalidomide and its metabolites are primarily excreted by the kidneys [see Clinical Pharmacology (12.3)]. The influence of renal impairment on the safety, efficacy, and pharmacokinetics of pomalidomide has not been evaluated. Patients with serum creatinine greater than 3.0 mg/dL were excluded in clinical studies. Avoid POMALYST in patients with a serum creatinine greater than 3.0 mg/dL. 8.8 Hepatic Impairment Pomalidomide is metabolized in the liver [see Clinical Pharmacology (12.3)]. The influence of hepatic impairment on the safety, efficacy, and pharmacokinetics of pomalidomide has not been evaluated. Patients with serum bilirubin greater than 2.0 mg/dL and AST/ALT greater than 3.0 x upper limit normal (ULN) were excluded in clinical studies. Avoid POMALYST in patients with serum bilirubin greater than 2.0 mg/dL and AST/ALT greater than 3.0 x ULN. 10 OVERDOSAGE No specific information is available on the treatment of overdose with pomalidomide, and it is unknown whether pomalidomide or its metabolites are dialyzable.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Studies examining the carcinogenic potential of pomalidomide have not been conducted. One of twelve monkeys dosed with 1 mg/kg of pomalidomide (an exposure approximately 15-fold of the exposure in patients at the recommended dose of 4 mg/per day) developed acute myeloid leukemia in a 9-month repeat-dose toxicology study. Pomalidomide was not mutagenic or clastogenic in a battery of tests, including the bacteria reverse mutation assay (Ames test), the in vitro assay using human peripheral blood lymphocytes and the micronucleus test in orally treated rats administered doses up to 2000 mg/kg/day. In a fertility and early embryonic development study in rats, drug-treated males were mated with untreated or treated females. Pomalidomide was administered to males and females at doses of 25 to 1000 mg/kg/day. When treated males were mated with treated females, there was an increase in post-implantation loss and a decrease in mean number of viable embryos at all dose levels. There were no other effects on reproductive functions or the number of pregnancies. The lowest dose tested in animals resulted in an exposure (AUC) approximately 100-fold of the exposure in patients at the recommended dose of 4 mg/day. When treated males on this study were mated with untreated females, all uterine parameters were comparable to the controls. Based on these results, the observed effects were attributed to the treatment of females. 17 PATIENT COUNSELING INFORMATION See FDA- approved Patient labeling (Medication Guide). Embryo-Fetal Toxicity Advise patients that POMALYST is contraindicated in pregnancy [see Contraindicatons (4)]. POMALYST is a thalidomide analog and may cause serious birth defects or death to a developing baby. [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)]. • Advise females of reproductive potential that they must avoid pregnancy while taking POMALYST and for at least 4 weeks after completing therapy. • Initiate POMALYST treatment in females of reproductive potential only following a negative pregnancy test. • Advise females of reproductive potential of the importance of monthly pregnancy tests and the need to use two different forms of contraception including at least one highly effective form simultaneously during POMALYST therapy, during therapy interruption and for 4 weeks after she has completely finished taking POMALYST. Highly effective forms of contraception other than tubal ligation include IUD and hormonal (birth control pills, injections, patch or implants) and a partner’s vasectomy. Additional effective contraceptive methods include latex or synthetic condom, diaphragm and cervical cap. • Instruct patient to immediately stop taking POMALYST and contact her doctor if she becomes pregnant while taking this drug, if she misses her menstrual period, or experiences unusual menstrual bleeding, if she stops taking birth control, or if she thinks FOR ANY REASON that she may be pregnant. • Advise patient that if her doctor is not available, she can call 1-888-668-2528 for information on emergency contraception [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)]. • Advise males to always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy. • Advise male patients taking POMALYST that they must not donate sperm [see Warnings and

Precautions (5.1) and Use in Specific Populations (8.6)]. • All patients must be instructed to not donate blood while taking POMALYST and for 1 month following discontinuation of POMALYST [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)]. POMALYST REMS Program Because of the risk of embryo-fetal toxicity, POMALYST is only available through a restricted program call POMALYST REMS [see Warnings and Precautions (5.2)]. • Patients must sign a Patient-Prescriber agreement form and comply with the requirements to receive POMALYST. In particular, females of reproductive potential must comply with the pregnancy testing, contraception requirements and participate in monthly telephone surveys. Males must comply with the contraception requirements [see Use in Specific Populations (8.6)]. • POMALYST is available only from pharmacies that are certified in POMALYST REMS program. Provide patients with the telephone number and website for information on how to obtain the product. Venous Thromboembolism Inform patients of the potential risk of developing venous thromboembolic events and discuss the need for appropriate prophylactic treatment. Hematologic Toxicities Inform patients on the risks of developing neutropenia, thrombocytopenia and anemia and the need to report signs and symptoms associated with these events to their health care provider for further evaluation. Hypersensitivity Inform patients of the potential for a severe hypersensitivity reaction to POMALYST if they have had such a reaction in the past to either THALOMID® or REVLIMID®. Dizziness and Confusional State Inform patients of the potential risk of dizziness and confusion with the drug and to avoid situations where dizziness or confusion may be a problem and not to take other medications that may cause dizziness or confusion without adequate medical advice. Neuropathy Inform patients of the risk of neuropathy and report the signs and symptoms associated with these events to their health care provider for further evaluation. Second Primary Malignancies Inform the patient that the potential risk of developing acute myelogenous leukemia during treatment with POMALYST is unknown. Dosing Instructions Inform patients on how to take POMALYST [see Dosage and Administration (2.1)] • POMALYST should be taken once daily at about the same time each day • POMALYST should be taken without food (at least 2 hours before or 2 hours after a meal). • The capsules should not be opened, broken, or chewed. POMALYST should be swallowed whole with water. • Instruct patients that if they miss a dose of POMALYST, they may still take it up to 12 hours after the time they would normally take it. If more than 12 hours have elapsed, they should be instructed to skip the dose for that day. The next day, they should take POMALYST at the usual time. Warn patients not to take 2 doses to make up for the one that they missed. Other Information Advise patients who smoke to stop because smoking may reduce the efficacy of pomalidomide [see Drug Interactions (7.2)]. Manufactured for: Celgene Corporation Summit, NJ 07901 POMALYST®, REVLIMID® and THALOMID® are registered trademarks of Celgene Corporation. POMALYST REMS™ is a trademark of Celgene Corporation. U.S. Pat. Nos. 5,635,517; 6,045,501; 6,315,720; 6,316,471; 6,476,052; 6,561,976; 6,561,977; 6,755,784; 6,908,432; 8,158,653; 8,198,262; 8,204,763; 8,315,886 ©2005-2013Celgene Corporation, All Rights Reserved. POMBSv.001a 02/13

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Cost and Drug Utilization Patterns Associated with the Management of Rosacea By Caroline Helwick, Medical Writer

osacea is a chronic skin disease that often requires continuous treatment, but data about healthcare utilization and the costs associated with its management have been lacking, especially for relatively newer therapies. James D. Kendall, PharmD, and Norman J. Preston, PhD, of Galderma Laboratories, LP, recently addressed this information gap in a poster presentation at the 2013 Academy of Managed Care Pharmacy Nexus meeting.1 This retrospective analysis was based on claims data from the IMS LifeLink Health Plan Claims Database between July 1, 2006, and June 30, 2011. This database contains 79 managed care health plans encompassing more than 70 million members who are primarily commercially insured. Patients with rosacea were identified if they received any prescription drug for the treatment of rosacea. Patients were aged ≥30 years and had at least 1 diagnosis of rosacea. The index date was the time of first prescription for rosacea. A 1-year period after the index date was used to capture pharmacy and medical claims to assess utilization patterns and associated costs. Dr Kendall and Dr Preston documented the medication possession ratio (MPR), which measures the percentage of time the patient has access to the medication (patients with only 1 prescription had an MPR of zero); therapy changes; and prescribing trends for rosacea and costs associated with the specialty of the prescribing physician (ie, dermatologist or nondermatologist).

Database of Nearly 100,000 Patients A total of 99,894 patients met the inclusion criteria for the analysis. The majority (73.2%) of the patients were women (mean age, 52.4 years). Overall, 81.7% of the patients were treated with a single agent—57.3% received a topical agent and 24.6% received an oral antibiotic. Combination therapy with ≥2 medications was prescribed for 18.3% of patients. The topical medications included metronidazole, azelaic acid, and sulfacetamide sulfur. The oral antibiotics included doxycycline, minocycline, and tetracycline. Among the patients who received a topical medica-

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tion, 70% had only 1 prescription filled. “The high onetime fill of topical medication suggests that patients self-dose based on self-diagnosis of rosacea flares,” the researchers commented. Another reason for the high one-time fill of topical medications is that patients may have erythematotelangiectatic rosacea, for which none of the topical therapies has shown a significant effect. The MPR for monotherapy was higher for oral medications (37.8%) than for topical agents (18.2%). A higher proportion (27%) of patients who were prescribed oral drugs changed therapy than those prescribed a topical agent (17.5%; P <.001).

Costs Associated with Rosacea Treatment The treatment of rosacea incurred primarily pharmacy rather than medical costs. The median annual pharmacy costs, by type of therapy, were: • $285 for combination therapy • $142 for a topical medication • $63 for an oral antibiotic agent. The median annual rosacea-related medical costs were $0. Of note, prescribing patterns varied according to the medical specialty of the treating physician. Dermatologists were more likely to prescribe oral antibiotics and combination therapies, whereas nondermatologists were more likely to prescribe topical therapies. Treatment by a dermatologist also was associated with higher costs overall. The median annual pharmacy-related costs per patient were $154 for dermatologists and $137 for nondermatologists; the median rosacea-related medical costs were $37 for dermatologists and $0 for nondermatologists. When considered by type of drug prescribed, the median annual cost per drug type was significantly different, based on the type of prescriber: • Oral antibiotic: $83 when prescribed by a dermatologist versus $46 (P <.001) by a nondermatologist • Topical medications: $143 versus $137 (P <.001), respectively • Combination therapy: $302 versus $256 (P <.001), respectively. The various cost and utilization analyses in this study

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show that “specialist care was associated with more complex treatments, higher costs, and additional physician visits,” Dr Kendall and Dr Preston concluded.

The various cost and utilization analyses in this study show that “specialist care was associated with more complex treatments, higher costs, and additional physician visits.” Skin Conditions Top Reason for Medical Visits Dermatologic conditions are often not on a payer’s radar, because the management of skin conditions has not been perceived as a major driver of healthcare utilization and costs. However, the results of a new study may require payers to revise their approach to skin conditions, in light of this new study, which indicates that the general public’s concern about skin conditions is the most common reason to visit a physician in the United States. Researchers from the Mayo Clinic conducted an extensive review of a large database of 142,377 residents of Olmsted County, MN, in 2009. The study captured adult residents in 2009 and reached a rather unpredictable conclusion—more patients seek medical help for skin disorders than for back pain, colds, arthritis, and other common ailments.2 The researchers were surprised to find that the most prevalent nonacute conditions are not age-related chronic conditions, such as diabetes or heart disease, but are instead conditions that affect men and women equally at all age-groups. These disorders include, in this order, skin disorders, osteoarthritis and joint disorders, back problems, lipid disorders, and upper respiratory tract disease (excluding

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asthma).2 “Unexpectedly, almost half of the Olmsted County population of all ages received a diagnosis of skin disorders within approximately 5 years,”2 Sauver and colleagues observed. “Skin disorders are not typically major drivers of disability or death but may be important determinants of healthcare utilization and cost.”2 They also noted that many dermatologic conditions require continued follow-up and treatment. When grouped according to age, skin disorders were the most prevalent (32.9%) for the youngest age-group (ie, newborn-18 years) in both sexes. This frequency steadily rose across the life span; resulting in 38.2% for the 19- to 29-year age-group, 41.3% for the 30- to 49-year age-group, 50.4% for the group aged 50 to 64 years, and 65.7% for patients aged ≥65 years.2 According to the investigators, the “finding that skin and back problems are major drivers of healthcare utilization affirms the importance of moving beyond the commonly recognized health care priorities....Our findings highlight opportunities to improve healthcare and decrease costs related to common nonacute conditions as we move forward through the changing healthcare landscape.”2 This study sheds new light on the potential role of dermatologic conditions in healthcare utilization and costs and may suggest that payers reexamine their approach to skin conditions, including rosacea, as an increasing and significant driver of healthcare utilization and costs, especially in light of the introduction of new therapies for a variety of skin conditions. n

Reference

1. Kendall JD, Preston NJ. Treatment patterns and costs associated with rosacea in the United States. Poster presented at the Academy of Managed Care Pharmacy Nexus meeting; San Antonio, TX; October 15-18, 2013. 2. St Sauver JL, Jacobson DJ, McGree ME, et al. Why patients visit their doctors: assessing the most prevalent conditions in a defined American population. Mayo Clin Proc. 2013;88:56-67.

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November/December 2013

Vol 6, No 9

In the fight against active, autoantibody-positive systemic lupus erythematosus (SLE) in adult patients receiving standard therapy

Add BENLYSTA to Help Make SLE More Manageable When added to standard therapy, BENLYSTA significantly reduced disease activity vs standard therapy alone at Week 521

•

BENLYSTA 10 mg/kg + standard therapy demonstrated superior efficacy vs placebo + standard therapy in reducing disease activity at Week 52 in 2 Phase III trials (Total N=1684)1-3

•

The primary endpoint was the percentage of patients meeting the SLE Responder Index (SRI) at Week 52. The SRI components measure reduction in disease activity defined as clinical improvement (SELENA-SLEDAI*) with no significant worsening in any organ system (BILAG†) and no worsening in overall patient condition (PGA‡)1

– •

A Phase II trial (Total N=449) did not meet the prespecified co-primary endpoints of percent change in SELENA-SLEDAI at Week 24 and time to first flare over 52 weeks. The Phase II trial led to the selection of a targeted autoantibody-positive population in the Phase III trials (28% of the Phase II trial population was autoantibody negative at baseline)4

In Phase II and III clinical trials, 1458 patients with SLE have been exposed to BENLYSTA for a total of 1516 patient-years2-5

* SELENA-SLEDAI (Safety of Estrogens in Lupus Erythematosus: National Assessment Version of the Systemic Lupus Erythematosus Disease Activity Index). † BILAG (British Isles Lupus Assessment Group). ‡ PGA (Physician’s Global Assessment).

Indication BENLYSTA is indicated for the treatment of adult patients with active, autoantibody-positive, systemic lupus erythematosus (SLE) who are receiving standard therapy. Limitations of Use: The efficacy of BENLYSTA has not been evaluated in patients with severe active lupus nephritis or severe active central nervous system lupus. BENLYSTA has not been studied in combination with other biologics or intravenous cyclophosphamide. Use of BENLYSTA is not recommended in these situations. How supplied: BENLYSTA is available as 120 mg in a 5-mL single-use vial and 400 mg in a 20-mL single-use vial for injection, for intravenous use only.

Important Safety Information for BENLYSTA CONTRAINDICATION BENLYSTA is contraindicated in patients who have had anaphylaxis with belimumab.

WARNINGS AND PRECAUTIONS MORTALITY There were more deaths reported with BENLYSTA than with placebo during the controlled period of the clinical trials. Out of 2133 patients in 3 clinical trials, a total of 14 deaths occurred in the following groups: 3/675 in placebo, 5/673 in BENLYSTA 1 mg/kg, 0/111 in BENLYSTA 4 mg/kg, and 6/674 in BENLYSTA 10 mg/kg. No single cause of death predominated. Etiologies included infection, cardiovascular disease, and suicide. SERIOUS INFECTIONS Serious and sometimes fatal infections have been reported in patients receiving immunosuppressive agents, including BENLYSTA. Caution should be exercised when considering use in patients with a history of chronic infections. Patients receiving therapy for a chronic infection should not receive BENLYSTA. Consider interrupting BENLYSTA therapy in patients who develop a new infection while receiving BENLYSTA. The most frequent serious infections included pneumonia, urinary tract infection, cellulitis, and bronchitis.

Please see additional Important Safety Information for BENLYSTA on following page. Please see Brief Summary of Prescribing Information for BENLYSTA on adjacent pages.

www.GSKSource.com

Important Safety Information for BENLYSTA (cont’d) WARNINGS AND PRECAUTIONS (cont’d) MALIGNANCY The impact of treatment with BENLYSTA on the development of malignancies is not known. As with other immunomodulating agents, the mechanism of action of BENLYSTA could increase the risk of malignancies. HYPERSENSITIVITY REACTIONS (INCLUDING ANAPHYLAXIS) AND INFUSION REACTIONS Hypersensitivity reactions, including anaphylaxis and death, have been reported with BENLYSTA. Delay in the onset of acute hypersensitivity reactions has been observed. Patients with a history of multiple drug allergies or significant hypersensitivity may be at increased risk. Some patients received premedication; however, there is insufficient evidence to determine whether premedication diminishes the frequency or severity of these reactions. Healthcare providers should be aware of the risk of hypersensitivity reactions, which may present as infusion reactions, and monitor patients closely. Manifestations of hypersensitivity included hypotension, angioedema, urticaria or other rash, pruritus, and dyspnea. In the event of a serious hypersensitivity reaction, discontinue BENLYSTA immediately and administer appropriate medical therapy. Infusion-associated adverse events were also reported. Serious infusion reactions included bradycardia, myalgia, headache, rash, urticaria, and hypotension. In the event of an infusion reaction, the infusion rate may be slowed or interrupted. Patients should be informed of the signs and symptoms of a hypersensitivity reaction and instructed to seek immediate medical care should a reaction occur. DEPRESSION In clinical trials, psychiatric events (primarily depression, insomnia, and anxiety) were reported more frequently with BENLYSTA than with placebo. Serious psychiatric events, serious depression, and two suicides were also reported. It is unknown if BENLYSTA treatment is associated with increased risk for these events. Instruct patients to contact their healthcare provider if they experience new or worsening depression, suicidal thoughts, or other mood changes. IMMUNIZATION Live vaccines should not be given for 30 days before or concurrently with BENLYSTA. BENLYSTA may interfere with the response to immunizations. USE WITH BIOLOGIC THERAPIES OR IV CYCLOPHOSPHAMIDE BENLYSTA has not been studied in combination with other biologic therapies, including B-cell targeted therapies, or IV cyclophosphamide. Therefore, use of BENLYSTA is not recommended in combination with these therapies.

ADVERSE REACTIONS The most commonly reported adverse reactions (≥5%) were nausea, diarrhea, pyrexia, nasopharyngitis, bronchitis, insomnia, pain in extremity, depression, migraine, and pharyngitis.

Other Important Information for BENLYSTA USE IN SPECIFIC POPULATIONS Pregnancy: Category C. BENLYSTA should be used during pregnancy only if the potential benefit outweighs the risk. Women of childbearing potential should use adequate contraception during BENLYSTA treatment and for at least 4 months after the last dose. Pregnancy Registry: Healthcare professionals are encouraged to register patients and pregnant women are encouraged to enroll themselves by calling 1-877-681-6296. Effect in black/African American patients: In exploratory analyses of 2 Phase III trials, response rates were lower for black patients (N=148) in the BENLYSTA group relative to black patients in the placebo group. In the Phase II trial, black patients (N=106) in the BENLYSTA group did not appear to have a different response than the rest of the study population. Although no definitive conclusions can be drawn from these analyses, caution should be used when considering BENLYSTA for black/African American patients. References: 1. BENLYSTA [package insert]. Rockville, MD: Human Genome Sciences, Inc; 2012. 2. Navarra SV, Guzmán RM, Gallacher AE, et al. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial. Lancet. 2011;377(9767):721-731. 3. Furie R, Petri M, Zamani O, et al. A phase III, randomized, placebo-controlled study of belimumab, a monoclonal antibody that inhibits B lymphocyte stimulator, in patients with systemic lupus erythematosus. Arthritis Rheum. 2011;63(12):3918-3930. 4. Wallace DJ, Stohl W, Furie RA, et al. A phase II, randomized, double-blind, placebo-controlled, dose-ranging study of belimumab in patients with active systemic lupus erythematosus. Arthritis Rheum. 2009;61(9):1168-1178. 5. Data on file, Human Genome Sciences, Inc.

Please see Brief Summary of Prescribing Information for BENLYSTA on adjacent pages.

BRIEF SUMMARY BENLYSTA® (belimumab) for injection, for intravenous use only. The following is a brief summary only; see full Prescribing Information for complete product information. INDICATIONS AND USAGE BENLYSTA® (belimumab) is indicated for the treatment of adult patients with active, autoantibody-positive, systemic lupus erythematosus (SLE) who are receiving standard therapy. Limitations of Use The efficacy of BENLYSTA has not been evaluated in patients with severe active lupus nephritis or severe active central nervous system lupus. BENLYSTA has not been studied in combination with other biologics or intravenous cyclophosphamide. Use of BENLYSTA is not recommended in these situations. CONTRAINDICATIONS BENLYSTA is contraindicated in patients who have had anaphylaxis with belimumab. WARNINGS AND PRECAUTIONS Mortality There were more deaths reported with BENLYSTA than with placebo during the controlled period of the clinical trials. Out of 2133 patients in 3 clinical trials, a total of 14 deaths occurred during the placebo-controlled, double-blind treatment periods: 3/675 (0.4%), 5/673 (0.7%), 0/111 (0%), and 6/674 (0.9%) deaths in the placebo, BENLYSTA 1 mg/kg, BENLYSTA 4 mg/kg, and BENLYSTA 10 mg/kg groups, respectively. No single cause of death predominated. Etiologies included infection, cardiovascular disease and suicide. Serious Infections Serious and sometimes fatal infections have been reported in patients receiving immunosuppressive agents, including BENLYSTA. Physicians should exercise caution when considering the use of BENLYSTA in patients with chronic infections. Patients receiving any therapy for chronic infection should not begin therapy with BENLYSTA. Consider interrupting BENLYSTA therapy in patients who develop a new infection while undergoing treatment with BENLYSTA and monitor these patients closely. In the controlled clinical trials, the overall incidence of infections was 71% in patients treated with BENLYSTA compared with 67% in patients who received placebo. The most frequent infections (>5% of patients receiving BENLYSTA) were upper respiratory tract infection, urinary tract infection, nasopharyngitis, sinusitis, bronchitis, and influenza. Serious infections occurred in 6.0% of patients treated with BENLYSTA and in 5.2% of patients who received placebo. The most frequent serious infections included pneumonia, urinary tract infection, cellulitis, and bronchitis. Infections leading to discontinuation of treatment occurred in 0.7% of patients receiving BENLYSTA and 1.0% of patients receiving placebo. Infections resulting in death occurred in 0.3% (4/1458) of patients treated with BENLYSTA and in 0.1% (1/675) of patients receiving placebo. Malignancy The impact of treatment with BENLYSTA on the development of malignancies is not known. In the controlled clinical trials, malignancies (including non-melanoma skin cancers) were reported in 0.4% of patients receiving BENLYSTA and 0.4% of patients receiving placebo. In the controlled clinical trials, malignancies, excluding non-melanoma skin cancers, were observed in 0.2% (3/1458) and 0.3% (2/675) of patients receiving BENLYSTA and placebo, respectively. As with other immunomodulating agents, the mechanism of action of BENLYSTA could increase the risk for the development of malignancies. Hypersensitivity Reactions, Including Anaphylaxis Hypersensitivity reactions, including anaphylaxis and death, have been reported in association with BENLYSTA. Delay in the onset of acute hypersensitivity reactions has been observed. Limited data suggest that patients with a history of multiple drug allergies or significant hypersensitivity may be at increased risk. In the controlled clinical trials, hypersensitivity reactions (occurring on the same day of infusion) were reported in 13% (191/1458) of patients receiving BENLYSTA and 11% (76/675) of patients receiving placebo. Anaphylaxis was observed in 0.6% (9/1458) of patients receiving BENLYSTA and 0.4% (3/675) of patients receiving placebo. Manifestations included hypotension, angioedema, urticaria or other rash, pruritus, and dyspnea. Due to overlap in signs and symptoms, it was not possible to distinguish between hypersensitivity reactions and infusion reactions in all cases [see Warnings and Precautions]. Some patients (13%) received premedication, which may have mitigated or masked a hypersensitivity response; however, there is insufficient evidence to determine whether premedication diminishes the frequency or severity of hypersensitivity reactions. BENLYSTA should be administered by healthcare providers prepared to manage anaphylaxis. In the event of a serious reaction, administration of BENLYSTA must be discontinued immediately and appropriate medical therapy administered. Patients should be monitored during and for an appropriate period of time after administration of BENLYSTA. Patients should be informed of the signs and symptoms of a hypersensitivity reaction and instructed to seek immediate medical care should a reaction occur. Infusion Reactions In the controlled clinical trials, adverse events associated with the infusion (occurring on the same day of the infusion) were reported in 17% (251/1458) of patients receiving BENLYSTA and 15% (99/675) of patients receiving placebo. Serious infusion reactions (excluding hypersensitivity

reactions) were reported in 0.5% of patients receiving BENLYSTA and 0.4% of patients receiving placebo and included bradycardia, myalgia, headache, rash, urticaria, and hypotension. The most common infusion reactions (≥ 3% of patients receiving BENLYSTA) were headache, nausea, and skin reactions. Due to overlap in signs and symptoms, it was not possible to distinguish between hypersensitivity reactions and infusion reactions in all cases [see Warnings and Precautions]. Some patients (13%) received premedication, which may have mitigated or masked an infusion reaction; however there is insufficient evidence to determine whether premedication diminishes the frequency or severity of infusion reactions [see Adverse Reactions]. BENLYSTA should be administered by healthcare providers prepared to manage infusion reactions. The infusion rate may be slowed or interrupted if the patient develops an infusion reaction. Healthcare providers should be aware of the risk of hypersensitivity reactions, which may present as infusion reactions, and monitor patients closely. Depression In the controlled clinical trials, psychiatric events were reported more frequently with BENLYSTA (16%) than with placebo (12%), related primarily to depression-related events (6.3% BENLYSTA and 4.7% placebo), insomnia (6.0% BENLYSTA and 5.3% placebo), and anxiety (3.9% BENLYSTA and 2.8% placebo). Serious psychiatric events were reported in 0.8% of patients receiving BENLYSTA (0.6% and 1.2% with 1 and 10 mg/kg, respectively) and 0.4% of patients receiving placebo. Serious depression was reported in 0.4% (6/1458) of patients receiving BENLYSTA and 0.1% (1/675) of patients receiving placebo. Two suicides (0.1%) were reported in patients receiving BENLYSTA. The majority of patients who reported serious depression or suicidal behavior had a history of depression or other serious psychiatric disorders and most were receiving psychoactive medications. It is unknown if BENLYSTA treatment is associated with increased risk for these events. Patients receiving BENLYSTA should be instructed to contact their healthcare provider if they experience new or worsening depression, suicidal thoughts, or other mood changes. Immunization Live vaccines should not be given for 30 days before or concurrently with BENLYSTA as clinical safety has not been established. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving BENLYSTA or the effect of BENLYSTA on new immunizations. Because of its mechanism of action, BENLYSTA may interfere with the response to immunizations. Concomitant Use with Other Biologic Therapies or Intravenous Cyclophosphamide BENLYSTA has not been studied in combination with other biologic therapies, including B-cell targeted therapies, or intravenous cyclophosphamide. Therefore, use of BENLYSTA is not recommended in combination with biologic therapies or intravenous cyclophosphamide. ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. Clinical Trials Experience The data described below reflect exposure to BENLYSTA plus standard of care compared with placebo plus standard of care in 2133 patients in 3 controlled studies. Patients received BENLYSTA at doses of 1 mg/kg (N=673), 4 mg/kg (N=111; Trial 1 only), or 10 mg/kg (N=674) or placebo (N=675) intravenously over a 1-hour period on Days 0, 14, 28, and then every 28 days. In two of the studies (Trial 1 and Trial 3), treatment was given for 48 weeks, while in the other study (Trial 2) treatment was given for 72 weeks [see Clinical Studies]. Because there was no apparent dose-related increase in the majority of adverse events observed with BENLYSTA, the safety data summarized below are presented for the 3 doses pooled, unless otherwise indicated; the adverse reaction table displays the results for the recommended dose of 10 mg/kg compared with placebo. The population had a mean age of 39 (range 18-75), 94% were female, and 52% were Caucasian. In these trials, 93% of patients treated with BENLYSTA reported an adverse reaction compared with 92% treated with placebo. The most common serious adverse reactions were serious infections (6.0% and 5.2% in the groups receiving BENLYSTA and placebo, respectively) [see Warnings and Precautions]. The most commonly-reported adverse reactions, occurring in ≥5% of patients in clinical trials were nausea, diarrhea, pyrexia, nasopharyngitis, bronchitis, insomnia, pain in extremity, depression, migraine, and pharyngitis. The proportion of patients who discontinued treatment due to any adverse reaction during the controlled clinical trials was 6.2% for patients receiving BENLYSTA and 7.1% for patients receiving placebo. The most common adverse reactions resulting in discontinuation of treatment (≥1% of patients receiving BENLYSTA or placebo) were infusion reactions (1.6% BENLYSTA and 0.9% placebo), lupus nephritis (0.7% BENLYSTA and 1.2% placebo), and infections (0.7% BENLYSTA and 1.0% placebo). Brief summary of Prescribing Information continued on reverse.

Table 1 lists adverse reactions, regardless of causality, occurring in at least 3% of patients with SLE who received BENLYSTA 10 mg/kg and at an incidence at least 1% greater than that observed with placebo in the 3 controlled studies.

Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women exposed to BENLYSTA, a pregnancy registry has been established. Healthcare professionals are encouraged to register patients and pregnant women are encouraged to enroll themselves by calling 1-877-681-6296.

Table 1. Incidence of Adverse Reactions Occurring in at Least 3% of Patients Treated With BENLYSTA 10 mg/kg Plus Standard of Care and at Least 1% More Frequently Than in Patients Receiving Placebo plus Standard of Care in 3 Controlled SLE Studies

Nursing Mothers It is not known whether BENLYSTA is excreted in human milk or absorbed systemically after ingestion. However, belimumab was excreted into the milk of cynomolgus monkeys. Because maternal antibodies are excreted in human breast milk, a decision should be made whether to discontinue breastfeeding or to discontinue the drug, taking into account the importance of breastfeeding to the infant and the importance of the drug to the mother.

Preferred Term Nausea Diarrhea Pyrexia Nasopharyngitis Bronchitis Insomnia Pain in extremity Depression Migraine Pharyngitis Cystitis Leukopenia Gastroenteritis viral

BENLYSTA 10 mg/kg + Standard of Care (n = 674) %

Placebo + Standard of Care (n = 675) %

15 12 10 9 9 7 6 5 5 5 4 4 3

12 9 8 7 5 5 4 4 4 3 3 2 1

Immunogenicity In Trials 2 and 3, anti-belimumab antibodies were detected in 4 of 563 (0.7%) patients receiving BENLYSTA 10 mg/kg and in 27 of 559 (4.8%) patients receiving BENLYSTA 1 mg/kg. The reported frequency for the group receiving 10 mg/kg may underestimate the actual frequency due to lower assay sensitivity in the presence of high drug concentrations. Neutralizing antibodies were detected in 3 patients receiving BENLYSTA 1 mg/kg. Three patients with anti-belimumab antibodies experienced mild infusion reactions of nausea, erythematous rash, pruritus, eyelid edema, headache, and dyspnea; none of the reactions was life-threatening. The clinical relevance of the presence of anti-belimumab antibodies is not known. The data reflect the percentage of patients whose test results were positive for antibodies to belimumab in specific assays. The observed incidence of antibody positivity in an assay is highly dependent on several factors, including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to belimumab with the incidence of antibodies to other products may be misleading. DRUG INTERACTIONS Formal drug interaction studies have not been performed with BENLYSTA. In clinical trials of patients with SLE, BENLYSTA was administered concomitantly with other drugs, including corticosteroids, antimalarials, immunomodulatory and immunosuppressive agents (including azathioprine, methotrexate, and mycophenolate), angiotensin pathway antihypertensives, HMG-CoA reductase inhibitors (statins), and NSAIDs without evidence of a clinically meaningful effect of these concomitant medications on belimumab pharmacokinetics. The effect of belimumab on the pharmacokinetics of other drugs has not been evaluated [see Pharmacokinetics]. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C. There are no adequate and well-controlled clinical studies using BENLYSTA in pregnant women. Immunoglobulin G (IgG) antibodies, including BENLYSTA, can cross the placenta. Because animal reproduction studies are not always predictive of human response, BENLYSTA should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. Women of childbearing potential should use adequate contraception during treatment with BENLYSTA and for at least 4 months after the final treatment. Nonclinical reproductive studies have been performed in pregnant cynomolgus monkeys receiving belimumab at doses of 0, 5 and 150 mg/kg by intravenous infusion (the high dose was approximately 9 times the anticipated maximum human exposure) every 2 weeks from gestation day 20 to 150. Belimumab was shown to cross the placenta. Belimumab was not associated with direct or indirect teratogenicity under the conditions tested. Fetal deaths were observed in 14%, 24% and 15% of pregnant females in the 0, 5 and 150 mg/kg groups, respectively. Infant deaths occurred with an incidence of 0%, 8% and 5%. The cause of fetal and infant deaths is not known. The relevance of these findings to humans is not known. Other treatment-related findings were limited to the expected reversible reduction of B cells in both dams and infants and reversible reduction of IgM in infant monkeys. B-cell numbers recovered after the cessation of belimumab treatment by about 1 year post-partum in adult monkeys and by 3 months of age in infant monkeys. IgM levels in infants exposed to belimumab in utero recovered by 6 months of age.

Pediatric Use Safety and effectiveness of BENLYSTA have not been established in children. Geriatric Use Clinical studies of BENLYSTA did not include sufficient numbers of subjects aged 65 or over to determine whether they respond differently from younger subjects. Use with caution in elderly patients. Race In Trial 2 and Trial 3, response rates for the primary endpoint were lower for black subjects in the BENLYSTA group relative to black subjects in the placebo group [see Clinical Studies]. Use with caution in black/AfricanAmerican patients. OVERDOSAGE There is no clinical experience with overdosage of BENLYSTA. Two doses of up to 20 mg/kg have been given by intravenous infusion to humans with no increase in incidence or severity of adverse reactions compared with doses of 1, 4, or 10 mg/kg. PATIENT COUNSELING INFORMATION See Medication Guide. Advice for the Patient Patients should be given the Medication Guide for BENLYSTA and provided an opportunity to read it prior to each treatment session. It is important that the patient’s overall health be assessed at each infusion visit and any questions resulting from the patient’s reading of the Medication Guide be discussed. Mortality: Patients should be advised that more patients receiving BENLYSTA in the main clinical trials died than did patients receiving placebo treatment [see Warnings and Precautions]. Serious Infections: Patients should be advised that BENLYSTA may decrease their ability to fight infections. Patients should be asked if they have a history of chronic infections and if they are currently on any therapy for an infection [see Warnings and Precautions]. Patients should be instructed to tell their healthcare provider if they develop signs or symptoms of an infection. Hypersensitivity/Anaphylactic and Infusion Reactions: Educate patients on the signs and symptoms of anaphylaxis, including wheezing, difficulty breathing, peri-oral or lingual edema, and rash. Patients should be instructed to immediately tell their healthcare provider if they experience symptoms of an allergic reaction during or after the administration of BENLYSTA [see Warnings and Precautions]. Depression: Patients should be instructed to contact their healthcare provider if they experience new or worsening depression, suicidal thoughts or other mood changes. [see Warnings and Precautions]. Immunizations: Patients should be informed that they should not receive live vaccines while taking BENLYSTA. Response to vaccinations could be impaired by BENLYSTA [see Warnings and Precautions]. Pregnancy and Nursing Mothers: Patients should be informed that BENLYSTA has not been studied in pregnant women or nursing mothers so the effects of BENLYSTA on pregnant women or nursing infants are not known. Patients should be instructed to tell their healthcare provider if they are pregnant, become pregnant, or are thinking about becoming pregnant [see Use in Specific Populations]. Patients should be instructed to tell their healthcare provider if they plan to breastfeed their infant [see Use in Specific Populations]. BENLYSTA is a registered trademark of Human Genome Sciences, Inc., used under license by GlaxoSmithKline. Manufactured by: Human Genome Sciences, Inc. Rockville, Maryland 20850 U.S. License No. 1820 Marketed by:

Human Genome Sciences, Inc. Rockville, MD 20850

GlaxoSmithKline Research Triangle Park, NC 27709

BUSINESS

Original Article

Insurance Companies’ Perspectives on the Orphan Drug Pipeline Robert Handfield, PhD; Josh Feldstein Background: Rare diseases are of increasing concern to private and public healthcare insurance plans. Largely neglected by manufacturers before the 1983 passing of the Orphan Drug Act (ODA), orphan drugs have become a commercialization target of steadily increasing importance to the healthcare industry. The ODA mandates the coverage of rare diseases, which are defined in research communities as diseases that are so infrequent that there is no reasonable expectation of a drugmaker recovering the cost of developing that drug. Objectives: To determine the views of leading commercial US payers regarding providing access to and coverage for orphan drugs; to assess whether and to what degree cost-effectiveness analysis (CEA) is viewed by payers as relevant to rare disease coverage. Methods: The study sample was identified through a call for action sent by America’s Health Insurance Plans to its members, resulting in 4 interviews conducted and 3 completed surveys from a total of 7 companies. These 7 US health insurance companies represent approximately 75% of the US private insurance market by revenue and include approximately 157 million covered lives (using self-reported data from insurance companies). Representatives of 3 companies responded to the survey, and representatives of 4 companies were interviewed via the phone. The interviews were conducted with subject matter experts at each company and included 2 senior vice presidents of a pharmacy program, 1 chief medical director, and 1 head of pharmacoeconomics. The surveys were completed by 1 vice president of clinical pharmacy strategy, 1 chief pharmacy director, and 1 medical director. Results: Based on the responses in this study, approximately 67% of US private insurance companies are concerned about orphan drugs, but only approximately 17% have developed meaningful strategies for addressing the cost of orphan drugs. Of the companies who do have such a strategy, 100% are unsure how to determine the best economic assessment tools to control orphan drug costs, and two thirds are relying on prior authorization as a means to control costs. More than 80% of the companies are not using cost-effectiveness methodologies with regard to rare diseases, generally because of a lack of the availability of medicines to facilitate such comparisons. CEA is used by less than 20% of our study sample of payers in dealing with orphan drug policies. Conclusions: Evaluating cost-effectiveness is a valuable strategy for payers seeking to facilitate appropriate access and coverage decision-making related to orphan drugs, but it is not well understood or adapted by private insurance companies. Health economists, along with providers and payers, must work together to design rational methodologies to evaluate the value of orphan drugs, perhaps by adopting cost-effectiveness methodologies to consider a compound’s total research and development and commercialization demands relative to its cost-effectiveness.

are diseases have recently been identified as a major source of concern for health insurance companies, with some states seeking to shift a

Dr Handfield is Bank of America University Distinguished Professor of Supply Chain Management, and Codirector, Supply Chain Resource Cooperative, Poole College of Management, North Carolina State University, Raleigh; and Mr Feldstein is Chief Executive Officer, Center for Applied Value Analysis, New York, NY.

Vol 6, No 9

November/December 2013

Stakeholder Perspective, page 598

Am Health Drug Benefits. 2013;6(9):589-598 www.AHDBonline.com Disclosures are at end of text

portion of the fiscal burden of orphan drugs to patients, much to patients’ concern.1 Rare diseases and orphan drugs, which have also been referred to as “orphan medicine,” “high-cost drugs,” and “rare medicine,” are subjects of increasing and intense study in pharmacoeconomics and cost-effectiveness analysis (CEA).2-4 By current estimates, between 25 million and 30 million Americans (8%-10% of the US population) have 1 of the more than 6800 diseases deemed rare, because they

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Key Points

Figure 1 Orphan Drugs in Development 0 20 40 60 80 100

Autoimmune disorders

Blood disorders

Cancer

107

Cancer, blood

Cancer, skin Cancer-related conditions

31 10

Cardiovascular diseases 6 Eye disorders

Gastrointestinal disorders

Genetic disorders

Growth disorders 5 31

Infectious diseases

Neurological disorders Respiratory disorders Transplantation Other

14 20 37

Reprinted from PhRMA. Orphan drugs in development for rare diseases. Report. February 2011. www.phrma.org/sites/default/files/pdf/ rarediseases2011.pdf. Accessed November 11, 2012.

affect less than 200,000 people, which is the threshold used to define a “rare disease.”5 In some diseases, defined by the UK’s National Institute for Clinical Excellence as “ultra-orphan diseases,” only a few hundred patients are identified as having that disease.6 More than 350 orphan drugs have been approved by the US Food and Drug Administration (FDA) since the Orphan Drug Act (ODA) was introduced in 1983 (as opposed to <10 approvals in the 1970s).3 Today, many new orphan drugs are in the pharmaceutical pipeline, which is good news for patients and for their physicians, with 193 new orphan drug designation reviews performed by the FDA in the first 6 months of 2013 alone.6,7 Diseases with the highest number of orphan drug designations include AIDS (57), melanoma (51), cystic fibrosis (46), acute myeloid leukemia (34), ovarian cancer (34), and pancreatic cancer (33).8 An overview of the orphan drugs that are currently in development is shown in Figure 1. In 1983, the founding of the National Organization for Rare Disorders led to the passing of the ODA by President Ronald Reagan, which provided significant incentives for manufacturers to develop drugs for orphan diseases.4 Incentives included a longer period of market-

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Rare diseases were largely ignored by the pharmaceutical industry before the 1983 passing of the Orphan Drug Act. ➤ Rare diseases and the drugs developed to treat them are costly for patients, providers, and payers, and their costs continue to rise. ➤ This study is based on responses from 7 large health insurance companies representing approximately 75% of the US private insurance market. ➤ The analysis shows that few health insurance companies have a meaningful strategy to address the rising costs of orphan drugs. ➤ Payers are unsure how to assess the cost of these drugs and rely on prior authorization as the costcontainment strategy, similar to specialty drugs. ➤ Cost-effectiveness is a valuable strategy to guide access and coverage decision-making for orphan drugs but is used by less than 20% of the study payers for dealing with orphan drug policies. ➤ Cost-effectiveness methodologies should be adopted to consider an orphan drug’s commercial demands relative to its cost and clinical effectiveness. ➤ Healthcare stakeholders, including economists, providers, and payers must work together to design rational methodologies for considering the value of orphan drugs. ➤

ing exclusivity for these drugs to recoup development targeted at orphan diseases.4 The FDA has designated at least 2313 medicines as orphan drugs since 1983.3 Although this is good news for countless patients, the issue of orphan drugs is of growing concern for payers, who are faced with covering the high costs of drugs for rare diseases.9 Much of the orphan drug research has occurred through research partnerships with academic institutions.10

US and Global Payer Policies for Orphan Drugs Health insurance companies, whether public or private, are facing a pivotal point with regard to rare diseases, leading to a paradigm shift on how to best determine the comparative cost and effectiveness of orphan drugs to treat these conditions. For example, the cost of imiglucerase (Cerezyme), a treatment for Gaucher disease, can cost up to $300,000 annually, according to an interview with a pharmaceutical executive. In the European Union (EU), for example, alipogene tiparvovec (Glybera), a new breed of gene therapy drug for a rare metabolic disease, is a 1-time injection that could cost in the range of $1.6 million and has recently

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been approved by EU authorities.11 However, the approval of this drug by the FDA is not yet pending, because of multiple approval failures in other countries over the past 20 years.11 Payers in the United States and around the world are questioning these potentially exorbitant annual outlays,11 turning to cost-effectiveness studies to provide insight and a firmer rationale for coverage decision-making. To drive greater insight into the effectiveness of orphan drugs versus their high cost, there is a need to adopt CEA approaches that go beyond the elementary budgetary impact models that have historically been used to assess the economic dimension of more prevalent medical therapies. Nevertheless, when applied to rare diseases, CEA has been seen by some individuals to limit appropriate access to care and to lead to care rationing; there is also a concern that CEA will be used by payers for cost-containment.12 This is even more challenging because high-quality evidence about the clinical (and certainly economic) added value of orphan drugs is almost never available at the time of orphan drug marketing authorization by the FDA, as a result of the low number of relevant patients.9 Even after market launch of the drug, the challenges to gather the cost-effectiveness data needed to conduct meaningful CEA in rare diseases can often be daunting. The FDA does not take into consideration the payer’s perspective, but simply ensures that the drug is safe and is clinically better than doing nothing. This challenge is becoming a growing concern to payers. A 2010 study of orphan drug pricing and payer management strategies emphasizes the nature of the gap between the methods that payers are using and the rising tide of orphan drug use.9 Payers not only expect orphan drug costs to rise, they also see the number of orphan drugs being introduced by large pharmaceutical com panies increasing as well.13 Yet no new management cost-effectiveness assessment approaches appear to be in development. Clinical data (ie, FDA-approved indications) remain the primary basis for prior authorization and for continued use of a specific orphan drug.13 The United States is not alone in facing the payer challenge to orphan drugs; other countries with government-regulated payment structures have adopted various stances toward orphan drugs.9 Based on our study, US private insurers are looking to other countries’ national policies on orphan drugs as potential models for new orphan disease policy development, and are closely watching the outcomes from these various approaches. A summary of how global government agencies differ in their payment policies on orphan drugs is summarized in Table 1,9 which has potential implications to the US healthcare system. As shown in Table 1, the approaches

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Table 1 Orphan Drug Policies by International Payers Country: program

Policy

Belgium: National Institute for Health and Disability Insurance

Restricts reimbursement of some orphan drugs to prescribers belonging to specialized centers, but no policy or research incentives exist

France: National Plan for Rare Diseases

Temporary use authorization; a committee negotiates the price of an orphan drug with the pharmaceutical company, taking into account the improvement in clinical added value of the drug, with prices based on those that serve the same therapeutic purposes in other European countries

The Netherlands

Majority of orphan drugs incorporated in List 1B of the Medicine Reimbursement system; price is considered together with reimbursement decisions, and a maximum price is set based on therapeutically equivalent drugs

Italy: National Health Service Plan/ National Network for Rare Diseases

Price negotiation takes into account the efficacy of the drug and price comparison with other countries

Sweden

Reimbursement considers cost-effectiveness, the human value principle (ie, equality of all people), and the need and solidarity principle (ie, products that treat those with the greatest health need take precedence), but not budget impact

United Kingdom

Prices are set by the pharmaceutical company but need to meet profit control criteria, as stated in the Pharmaceutical Price Regulation Scheme; reimbursement considers budget impact and costeffectiveness; the UK’s NICE has stated that many orphan drugs had incremental costeffectiveness ratios at the high end of what the appraisal committee deemed to be costeffective14; in addition, NICE has defined a category of “ultra-orphan disease” for conditions affecting <1000 patients6

NICE indicates National Institute for Health and Care Excellence.

vary from tougher negotiations with drug companies to limits on profitability to cost-effectiveness studies based on the “human value principle,” but no single measure seems to be emerging across the board.9 In the United States, no specific coverage of orphan drugs is addressed in the Affordable Care Act (ACA). To some extent, payment policies are still in motion, because this legislation is composed of many provisions that become effective at various times, starting with its signing into law in March 2010. However, 2 elements related to orphan drugs are clear in the ACA: • Medicare does not have special or different coverage rules for orphan drugs: Medicare largely covers drugs, regardless of whether they are “reasonable and necessary,” and based on delivery mechanism • The ACA specifically excludes Medicare and Medicaid

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Figure 2 US Medically Insured Population, % of Total

15.4% (47,951,000)

Medicare Medicaid Military Commercial Uninsured

15.7% (48,884,000)

16.4% (50,903,000)

63.9% (198,812,000)

4.4% (13,702,000)

Medicaid enrollment is net of Medicare/Medicaid dualeligibles. Source: DeNavas-Walt C, Proctor BD, Smith JC; for the US Census Bureau. Income, poverty, and health insurance coverage in the United States: 2012. Current population reports. September 2013. www.census.gov/prod/2013pubs/ p60-245.pdf. Accessed November 14, 2013.

from making coverage decisions for any drug (not just orphan products) based solely on its cost-effectiveness. To the extent that they are discussed, orphan drugs are addressed in the ACA under provisions dealing with biosimilars, annual tax on pharmaceutical sales, and on the 340B drug pricing program. Orphan drugs are not granted special coverage rules by the ACA that would distinguish them from other drugs. However, numerous states are creating laws to limit out-of-pocket (OOP) payments for patients, including yearly caps (eg, in Hawaii, New York, Maine, Connecticut, and Rhode Island).1 The laws being passed are for limitations on OOP payments for plans in the exchange, but most commercial health plans already have an OOP maximum. Pharmaceutical companies are generally supportive of such bills, because high copayments discourage patient adherence.1 Cost is only 1 factor that drives nonadherence. Our study sought to describe the current posture of private healthcare insurers in the United States relative to orphan drugâ&#x20AC;&#x201C;specific coverage issues, and their approaches to CEA for this class of drugs, and to investigate the application of cost-effectiveness analytic methods as a potential means to generate insights into the cost of orphan drug delivery and patient care for payers. This study is intended as an exploratory investigation, in that cost-effectiveness methods are relatively nascent

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Table 2 Respondents to Interviews and/or Surveys Medical lives Insurance covered, in Data company millions Position collection A

Senior Vice Interviewed President, Pharmacy Programs

Staff Vice President, Clinical Pharmacy Strategy

Survey

Chief Pharmacy Director

Survey

18.3

Head, Interviewed Pharmacoeconomic Comparative Effectiveness Research

4.4

Medical Director

Survey

3.8

Medical Director

Interviewed

Total Total private lives covered

Senior Vice Interviewed President, National Pharmacy Programs

157.5 210

in the health benefits environment, especially as they apply to rare diseases. Given the unprecedented nature of cost escalations in this category, our research explored the potential application of these methods to the impending wave of orphan drug costs facing the US healthcare industry. The US healthcare population consists of approximately 311 million lives, of which approximately 60% are covered by commercial insurance, approximately 31% are covered by Medicare or Medicaid, approximately 15% are uninsured, and approximately 4% are covered by military insurance (Figure 2).15 Given the changes resulting from the ACA, Medicare policy for orphan drugs is not yet fully developed and remains a work in progress. Consequently, the research summarized in this article focuses on the views of private insurance carriers, covering approximately 161 million individuals in a managed care environment.

Methods This study involved 4 in-depth, qualitative interviews with a representative sample of vice presidents of pharmacy programs, pharmacy strategy, and pharmacoeconomic think tanks, and chief medical directors from a sample of the largest private US health insurance com-

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panies. These were complemented by 3 completed online surveys from other major insurers as well, including 1 vice president of clinical pharmacy strategy, 1 chief pharmacy director, and 1 medical director. All contacts were made through America’s Health Insurance Plans, a trade organization that represents the combined majority of private medical insurance carriers in the United States. As shown in Table 2, the majority of the data were collected through interviews, with a small number of responses collected through surveys. Because of the exploratory nature of the study, we sought to clarify insights into the current state of cost-effectiveness measures being applied by private insurance companies to the case of rare diseases. All respondents were guaranteed confidentiality of their responses, and have therefore not been attributed to any specific insurance company. The total number sampled included 7 major private US health insurance companies representing approximately 157 million medical covered lives. The interviews were conducted with 1 medical director, 2 senior vice presidents of pharmacy programs, and 1 head of pharmacoeconomics via telephone. Although this is a small number of data points, the sample represents a large proportion of health plan member lives (based on data obtained from each company’s website). The representative nature of our sample is shown in Figure 3, which demonstrates how the US health insurance market is relatively fragmented, with no commercial provider having a majority market share. This is because of the regional positioning of many commercial US insurers. Our sample covers the smaller number of health insurance companies that represent the largest share of privately insured individuals, and provides a representative indicator of current practices relative to orphan drug coverage. The questions in the interviews and survey were: • How do US health insurance companies view orphan drugs? • What are US payers’ strategies to better manage drug access and coverage claims for patients with rare diseases who need orphan drugs? • What steps, if any, are private insurance companies taking to reduce the coverage of rare diseases? • What impact will such payer initiatives have on healthcare providers when treating patients with rare diseases? • What tools or strategies are currently in use among US payers to assess the cost-effectiveness of orphan drugs? • What measurable clinical and economic benefit are they concluding? • What data are required or available to support the CEA of orphan drugs?

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Figure 3 Breakdown of Private Insurer Market UnitedHealthcare BlueCross BlueShield (all over the United States) WellPoint Kaiser Foundation Humana Aetna Health Care Service Corporation Highmark Cigna Coventry Health Care Amerigroup Others Medicare/Medicaid

Source: Data were collected from each company’s site at America’s Health Insurance Plans. 2012. www.ahip.org/AHIPResearch/. Accessed November 11, 2012.

Figure 4 I nsurance Company Concern toward Orphan Drugs Q: How would you describe your company’s posture toward the coming wave of orphan drugs? Unimportant Aware but passive Concerned Regularly discussed at meetings Of strategic importance to the company

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0.0%

8.3% 16.7%

8.3%

66.7%

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Figure 5 I nsurance Company Plans to Manage Orphan Drugs Q: Does your company have a plan in place to deal with the coming wave of orphan drugs? No, it is not on our corporate agenda at this time No, we think it is important, but are unsure what to do No, but we are in dialogue with providers and physicians now about this Yes, strategic plans are in process but have not yet been rolled out Yes, we have a plan that is being actively rolled out at the current time 0.0%

8.3% 8.3% 33.4%

50.0%

The responses were reviewed, coded, analyzed, and summarized based on these questions.

Results The US health insurance companies studied in this analysis view the ODA as well-intentioned and designed with sympathetic intent, and appropriately written into law to assist the patients with greatest need to address critical medical challenges. Although almost 67% of the payers in this study are concerned with the growing impact of orphan drugs, almost 17% of payers do not even have orphan drugs on their radar or are passive toward them (Figure 4, page 593). In their view, however, the ODA has been adopted as a source for revenue growth and is protected under the shield of the ODA’s original incentives, with payers generally unclear on what steps to take to better manage the impending FDA approval of many new orphan drugs (Figure 4). One insurance company noted that some medical conditions are now being labeled as rare diseases that never used to be classified as such, in part because of the improvements in research and DNA coding. Consequently, pharmaceutical and biotechnology companies

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can have conditions named as rare diseases with an International Classification of Diseases, Ninth Revision code, but no such label existed in the past. This gap in regulatory governance is only one of the key issues within the debate concerning the ODA.13 None of the payers who were interviewed provided evidence of a definitive orphan drug management plan (Figure 5). Even in the survey, responses to questions in the “open-ended” section were answered with “we don’t have a strategy for orphan drugs.” Based on our study, 3 insurance companies simply approach orphan drugs as any other specialty drug, and have no special provisions or policies for them. Approximately 33% of the respondents believe that rare diseases are an important policy issue, but they noted that they do not know what to do. At least 50% of the insurance companies in this study are in dialogues with physicians and other healthcare providers about rare diseases (Figure 5), but only 1 leading payer (Company A) claimed to be actively developing a strategic plan, which has not yet launched, to manage the growing number of orphan drugs. That particular payer stated, “There is no data pool, no pharmacoeconomics analysis, and it is becoming more and more of an issue. We are on the alert for alarming new drugs with outrageous list prices on a daily basis. We already have a tier-3 status, and it is very likely that there will be a tier-4 status developed with a substantial coinsurance. But we will be bumping up against health reform, and we will be compelled to make these highcost drugs available. We know that we need to begin doing our own modeling, but if it is a life-threatening disease, the last thing we want to do is make it less accessible. This always trumps the affordability issue.” This comment underscores the key challenge that faces insurance companies regarding orphan drugs—being required to provide access and coverage for pharmacotherapies that treat severe or life-threatening rare diseases, even in cases when the value of the therapy cannot be ascertained. Although this is true of many of the specialty drugs that are currently approved, the sheer number of pending orphan drugs is raising growing concern. Approximately 85% of the payers in this study observed that some action must be taken (although 20% noted that “doing nothing” is part of the risk-pooling process). For many insurance companies, a risk pool is a function of the types of members the plan has, and doing nothing is a perfectly appropriate plan of action given the level of risk involved. As shown in Figure 6, 67% of the payers believe that with no comparative clinical or cost data available on orphan drugs, it is unlikely that any meaningful action can occur. All of the payers who responded to this question

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Figure 6 Actions Taken for Orphan Drugs Q: If you have no plans in place, what actions are you taking? 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0%

Orphan drugs are an insignificant budget concern

There is nothing we can do about orphan drugs

We believe our current approach to orphan drugs is sufficient

expressed uncertainty regarding what constitutes the right tools to be used for such a CEA. One company (Company F), however, deferred policy decisions to its specialty pharmacy partner to address the issue, stating, “Unequivocally across the many companies I’ve worked with, there are not a lot of [effective] methods being used. Approaches vary from sophisticated prior authorizations, to manual review of prior authorizations (providing they can pull them out of their spend analysis), to simply paying the bill. There is somewhat of a shift, however. Five years ago, 80% were just paying the bill, and 20% were on some continuum of prior authorizations. Today that has flipped, with about 80% now realizing they have operational challenges with orphan diseases on their radar, but have no clue what to do beyond placing prior authorizations on them. To be perfectly blunt, they are not looking at this in a sophisticated manner.” Every insurance company we interviewed is struggling to identify evidence to assess comparative drug efficacy (Figure 6). This is even more of an issue in the realm of data access and analytic methodologies to evaluate the cost-effectiveness of a drug, which becomes still more complex when rare diseases are involved. As shown in Figure 7, the primary approach used to render decisions on orphan disease budget exposure was prior authorizations (for high-prevalence medications), which involve determining if a drug will save “outpatient days,” or the number of days that a patient will miss work; however, assessing quality-of-life changes is typically avoided because of the subjective nature of the assessment. Furthermore, based on our interviews, 100% of insurance companies that have a plan for orphan drugs are

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There is no cost or We are unsure We rely on our comparative clinical how to determine specialty pharmacy data on orphan the most appropriate partner/group to drugs, and it is economic assessment handle this directly unlikely that there tools to address will be for many cost-effectiveness years to come in orphan drugs

Figure 7 Cost-Containment Strategies Used Q: What cost-containment strategies are you using to reduce orphan drug budget exposure? Prior authorization programs Ongoing clinical review for all renewals Genetic testing and other diagnostic screening Step therapy Tier 4 or specialty drug pricing and copays Maximum annual or lifetime benefit policies Per-member per-month premium increases to offset budget impact 0% 9% 9% 9% 64%

relying on prior authorizations as a cost-containment strategy to screen patients for the drug coverage. Approximately 27% of the respondents are experimenting with approaches that rely on the ongoing monitoring of an insured’s clinical progress, step therapy, and diagnostic and genetic screening—which are all approached in

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Figure 8 Strategies for Cost-Effectiveness for Orphan Drugs Q: Which of the following strategies is currently being used to assess the cost-effectiveness of orphan drugs? 45% 40% 35% 30% 25% 20% 15% 10% 5% 0%

Apply qualitative models (eg, data envelopment analysis) to measure relative benefits of orphan drugs compared with other treatments

Apply predictive comparative cost-effectiveness models for orphan drugs using a variety of publicly available and other data sources (eg, literature reviews, expert opinions, third-party data, etc) to consider the total cost of treatment relative to other forms of treatment

an ad hoc manner and not as an organized strategy aimed at data collection and CEA (Figure 7). As shown in Figure 8, approximately 40% of the payers are using some form of analytical tool to measure the clinical effectiveness of orphan drugs. One carrier cited the use of data envelopment analysis, a qualitative assessment that essentially examines comparative efficiency between drugs. Data envelopment analysis techniques have been used to benchmark other treatments, such as medical ventilation treatments16 and physician practice behavior.17 Other payers cited the use of expert opinion in their analyses. Another more promising comparative approach that payers are beginning to explore is cost-effectiveness modeling, which aggregates a variety of clinical and economic data sources on comparative drugs as a means of gaining insight into the head-to-head comparative value of a drug.

Discussion One health insurance company in the study cited reliance on its specialty pharmacy department, whereas another cited pushing decision-making to its pharmacy benefits organization. Two companies rely on a Pharmacy & Therapeutics committee, and another relies on a combination of medical affairs and its pharmacy department. Based on this small sample size, no common denominator emerged regarding how US insurance companies best handle decisions regarding medications for rare diseases. A large percentage of Medicaid state plans do not treat the coverage of orphan drugs differently from that of drugs for prevalent diseases.18 States often have little or no basis on which to make cost-effectiveness decisions, because they are required to cover drugs for which

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Employ outside health economists to address these issues

Apply total cost models to weigh off the cost of treatment compared with missed employment days for employers

they receive a rebate. The Medicaid Drug Rebate Program requires a drug manufacturer to provide a rebate of at least 13% of the drug’s cost for it to be covered by a state Medicaid program.18 Therefore, any manufacturer that provides a rebate has a drug that Medicaid providers must cover, automatically putting the medication onto the state formulary list. This drug access and coverage policy is in turn pushed onto managed care organizations (MCOs), requiring the MCOs to cover any drug that a given state covers. Like state Medicaid plans, several private insurers in this study pointed out that they do not have resources for conducting cost-benefit or cost-effectiveness analyses, citing thin margins and insufficient budgets for studies. Consequently, payers often rely on what is published and on what is preferred by healthcare providers, together with assessments based on drug monographs, and, at times, input from external consulting firms and market intelligence. Company G’s representative noted, “We know that some manufacturers are labeling more and more medicines as having unique indications that allow them to price drugs at 20 times what they should be.” Because the pharmaceutical industry has sharpened its commercial focus on rare diseases in the “postblockbuster” era, the fair balance of the US ODA among patients, providers, and healthcare insurance companies has been eclipsed, moving beyond the ODA’s original intent of 3 decades ago. Aligning the ODA more closely with orphan drug incentivization and market access policies of other global markets will help the ODA to more appropriately meet the needs of the entire US healthcare system. Like all pharmaceuticals, orphan drugs have specific

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indications. Physicians are responsible for verifying the needs of patients with a rare disease and for correctly directing them to novel therapies for rare diseases. Then insurance companies screen the claims and can refuse payment unless the screening criteria are met. This critical element—evidence of substantiation—is the leverage point on which the decision is made. The FDA neither calls into question the cost nor the appropriate level of cost associated with a drug, only whether it is effective or better than nothing.

Limitations There are several limitations to this study. The primary limitation is the small sample size of insurance companies identified in this study. Even so, the small number of companies represents a sizable proportion of the private insurance industry. Within this sample, there is a possibility of selection bias, and it is possible that a broader representation of organizations would reveal some isolated strategies that have not been captured here. There is also a possibility of respondent bias, in that we interviewed a single individual within each company. However, we sought to identify the highest-level executive responsible for strategic planning on orphan drug policy development, and we have assumed that this individual was willing to provide a clear picture based on the guaranteed anonymity of the study. There is also a possibility of misrepresentation of the results through the survey data collection, although most of the statements are self-evident in nature. Conclusions Although the ODA has shown tremendous success in advancing the development and commercialization of life-saving and life-enhancing medications for patients with rare diseases, there remains a singular lack of cost-effectiveness measures. Measures that take into consideration a far more comprehensive array of issues, data, and CEA, as well as a sliding scale of orphan drug pricing policies, standards, and commercial incentives for industry, are needed to provide a more equitable set of guidelines for payers and for patients. The results of this study suggest little in the way of cost-effectiveness methods that align with pricing policies. We believe that work is needed to construct the design of a sliding scale of orphan drug pricing policies subject not only to a compound’s total research and development and commercialization demand, but also whether and to what degree its cost-effectiveness can be ascertained through the application of new cost-effectiveness methodologies. Current research provides limited accurate data on the prices, sales, and profit margins.13 Health economists, together with providers and payers,

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must work together to design rational methodologies for considering the value of orphan drugs, vis-à-vis other interventions when available (which is uncommon, given the nature of rare diseases) or in relation to the cost in overall medical utilization and quality of life versus the natural progression of rare diseases. A new series of rare disease–specific incremental cost-effectiveness ratio (ICER) modeling may help to provide greater clarity into the true costs versus benefits of a drug. Although the expectation should not be perfection for any such novel orphan disease–specific ICER, intellectual resources need to be deployed in this direction to address the orphan disease comparative effectiveness research gap, given the considerable number of orphan drugs now under FDA review, as well as the payer and commercial challenges. n Author Disclosure Statement Dr Handfield is a consultant to Caterpillar, Thomson Reuters, and Enbridge Gas Distribution. Mr Feldstein is a consultant to QLT, Inc.

References

1. Pollack A. States seek curb on patient bills for costly drugs. New York Times. April 12, 2012. www.nytimes.com/2012/04/13/health/states-seek-to-curb-exorbitant-drugcosts-incurred-by-patients.html?pagewanted=all&_r=0. Accessed November 11, 2012. 2. Denis A, Mergaert L, Foster C, et al. Orphan diseases and orphan medicines: a Belgian and European study. J Pharm Belg. 2009;(4):131-137. 3. Pharmaceutical Research and Manufacturers of America. Orphan drugs in development for rare diseases. Report. February 2011. www.phrma.org/sites/default/files/ pdf/rarediseases2011.pdf. Accessed November 11, 2012. 4. Brewer GJ. Drug development for orphan diseases in the context of personalized medicine. Transl Res. 2009;154:314-322. 5. National Institutes of Health; National Center for Advancing Translational Sciences. FAQ about rare diseases. www.ncats.nih.gov/about/faq/rare/rare-faq.html. Accessed November 11, 2013. 6. National Institute for Clinical Excellence. Ultra orphan drugs. NICE Citizens Council Report. November 2004. www.nice.org.uk/media/065/85/Citizens_Council_ Ultraorphan.pdf. Accessed November 11, 2013. 7. US Food and Drug Administration. Total number of orphan drug designation reviews completed in the month. Fiscal year 2013. Current as of June 30, 2013. www.accessdata. fda.gov/FDATrack/track?program=osmp&id=OSMP-OOPD-Total-number-orphandrug-designation-reviews-completed&fy=2013. Accessed November 11, 2013. 8. Braun MM, Faraq-El-Massah S, Xu K, Coté TR. Emergence of orphan drugs in the United States: a quantitative assessment of the first 25 years. Nat Rev Drug Discov. 2010; 9:519-522. 9. Denis A, Mergaert L, Fostier C, et al. A comparative study of European rare disease and orphan drug markets. Health Policy. 2010;97:173-179. 10. Brewer GJ. Fundamental problems lie ahead in the drug discovery and commercialization process: restructuring of the pharmaceutical industry and an improved partnership with academia are required. J Investig Med. 2006;54:291-302. 11. Whalen J. Gene-therapy approval marks major milestone. Wall Street Journal. Updated November 2, 2012. http://online.wsj.com/article/SB1000142405297020370 7604578095091940871524.html. Accessed November 11, 2012. 12. Hughes D. Rationing of drugs for rare diseases. Pharmacoeconomics. 2006;24:315-316. 13. Hyde R, Dobrovolny D. Orphan drug pricing and payer management in the United States: are we approaching the tipping point? Am Health Drug Benefits. 2010; 3(1):15-23. 14. National Institute for Health and Clinical Excellence. Appraising orphan drugs. Draft v3. March 16, 2006. www.nice.org.uk/niceMedia/pdf/smt/120705item4. pdf. Accessed November 11, 2012. 15. DeNavas-Walt C, Proctor BD, Smith JC; for the US Census Bureau. Income, poverty, and health insurance coverage in the United States: 2012. Current population reports. September 2013. www.census.gov/prod/2013pubs/p60-245.pdf. Accessed November 14, 2013. 16. O’Neal PV, Ozcan YA, Ma Y. Benchmarking mechanical ventilation services in teaching hospitals. J Med Syst. 2002;26:227-240.

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17. Ozcan YA. Physician benchmarking: measuring variation in practice behavior in treatment of otitis media. Health Care Manag Sci. 1998;1:5-17. 18. Centers for Medicare & Medicaid Services. Medicaid Drug Rebate Program.

November 5, 2013. www.medicaid.gov/Medicaid-CHIP-Program-Information/ByTopics/Benefits/Prescription-Drugs/Medicaid-Drug-Rebate-Program.html. Accessed November 14, 2013.

Stakeholder Perspective Breakthrough Therapy, or Breakthrough Pricing? By Atheer A. Kaddis, PharmD Senior Vice President, Sales and Business Development, Diplomat Specialty Pharmacy, Flint, MI

PAYERS: The struggle continues for payers trying to solve the puzzle of rising specialty drug cost trends. Annual cost trends for specialty drugs of up to 15% to 20% are not uncommon in the market today, and it is expected that these trends will continue into the next 10 years.1 We are well aware of the contributing factors to the rising cost trends, such as the pipeline of new drugs, expanded indications for currently marketed drugs, the drug mix, and price increases. We are becoming more aware of another phenomenon leading to increasing cost trends, that of new orphan drugs coming to market and the price tags that are associated with them. In their article, Handfield and Feldstein provide an overview of the orphan drug market, and they describe how some of the largest insurance companies in the United States are (or are not) addressing the cost concerns associated with orphan drugs. Very few of us can deny the need for more potentially life-saving medicines, especially for patients with rare, devastating diseases that lead to significantly shortened life spans and considerable morbidity, not to mention the emotional, mental, and physical impact that these rare diseases have on families and caregivers. The average lifespan of a patient diagnosed with cystic fibrosis is approximately 37 years; however, some patients live much longer.2 The challenge that payers are facing is being driven by the cost of orphan drugs, primarily â&#x20AC;&#x153;ultra-orphanâ&#x20AC;? drugs, as termed in the United Kingdom. Costs in the hundreds of thousands of dollars per patient annually may become unsustainable, given the number of orphan drugs in the pipeline. This is becoming one of the contributing factors to overall increases in drug cost trends for specialty pharmacy for most payers. MANUFACTURERS/PHARMACIES: What can we do about this? I am not one to preach price controls; however, if pharmaceutical manufacturers are receiving incentives from taxpayers to develop drugs for rare diseases, there should be some form of responsibility placed

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on the manufacturer to address some of the exorbitant costs we have seen with some of the orphan drugs. The idea of cost-effectiveness analysis is absolutely appropriate for orphan drugs, as it is for specialty drugs in general. Prior authorization to ensure the appropriate use of a drug is also a proven and effective way to ensure that it is prescribed according to its approved labeling. It is also important to ensure that patients are utilizing the prescribed therapy appropriately, including optimal adherence to therapy, addressing potential adverse effects proactively, ensuring appropriate administration and storage of the prescribed therapy, and also minimizing waste of the drug. These are all activities that can be supported by specialty pharmacies. PATIENTS: Another strategy we will be sure to experience is cost shifting to the patient. We are already familiar with the specialty tier within most Medicare Part D formularies and 5-tier benefit designs used by commercial health plans. We have also experienced an increase in out-of-pocket costs for patients, with some coinsurance designs set as high as 33% of the cost of the prescription.3 This can be very difficult for patients with rare diseases, given that the cost of their orphan drug therapy can be up to $25,000 monthly. Although there are charitable organizations and some pharmaceutical manufacturers that can help cover a portion of the costs of orphan drugs, this can be a significant hardship for patients and their families. We must find workable solutions to the rising drug cost trends. Increases in the number and the cost of orphan drugs on the market, as well as an increase in the number of orphan drugs in the pipeline, are starting to put this issue in the spotlight for all stakeholders. 1. Specialty drug trend across the pharmacy and medical benefit. Artemetrx. 2013. www.artemetrx.com/docs/ARTEMETRX_Specialty_Trend_Rpt.pdf. Accessed December 9, 2013. 2. Simmonds, NJ, Cullinan P, Hodson ME. Growing old with cystic fibrosisâ&#x20AC;&#x201D;the characteristics of long-term survivors of cystic fibrosis. Respir Med. 2008;103:629-635. 3. Dieguez G, Pyenson B, Johnson R. Specialty tiers: benefit design considerations for Medicare Part D. Milliman. June 25, 2013. www.milliman.com/uploadedFiles/insight/ 2013/specialty-tiers.pdf. Accessed December 9, 2013.

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November/December 2013

Vol 6, No 9

GE Healthcare Clarient Diagnostic Services

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JB15955US

Industry Trends

Rehospitalization Is Driving Costs in Pulmonary Arterial Hypertension By Neil Canavan, Medical Writer

ulmonary arterial hypertension (PAH) is a chronic, debilitating, and life-threatening disease of the pulmonary vasculature characterized by remodeling of the small pulmonary arteries. The estimated prevalence of PAH in the United States is 12.4 cases per 1 million people, with an annual incidence of 2.3 cases per 1 million.1 Although these figures suggest that the disease is relatively rare, the societal impact is significant; morbidity and mortality rates for patients with PAH are high, and high-cost hospital stays are common. Michael Lacey, MSc, of OptumInsight, Eden Prairie, MN, and colleagues set out to investigate the rates and costs of rehospitalization of patients with PAH within 1 year of their initial hospitalization, based on the knowledge that patients with PAH are frequently rehospitalized, leading to a high burden to the US healthcare system, as well as to patients and payers. They presented their findings at the 2013 Academy of Managed Care Pharmacy (AMCP) Nexus meeting.2 According to this analysis by Lacey and colleagues, more than 75% of patients with PAH are indeed readmitted to the hospital within 1 year of an initial PAHrelated hospitalization, and of those who are readmitted, more than 20% are back in the hospital within 30 days of their initial discharge, which translates to a significant clinical and economic burden.

The average LOS also differed by insurance type, with a higher LOS—28.5 days—seen in patients with Medicare Advantage coverage compared with 21.7 days in patients with commercial insurance coverage. Study Scope The effort by Lacey and colleagues to establish the scope of the financial burden of PAH was in part motivated by recent efforts by Medicare to reduce rehospitalization rates through reimbursement adjustments. To explore this issue, the investigators used the Optum Research Database (which is affiliated with OptumInsight), using a managed care database that included approximately 30 million members during the study period, from January 2007 through December

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2011. The investigators generated the study cohort of patients with PAH who have had medical and pharmacy claims using a commercial plan and a Medicare Advantage health insurance plan. Initial hospitalization was defined as the admission that followed the first PAH-related claim (including medications, diagnostics, and other types of claims). Of the 4009 patients who were identified with PAH, 2275 (56.7%) experienced at least 1 PAH-related hospitalization during the study period. Of these patients, 1203 (52.9%) were rehospitalized at least once during the study period. Of this latter group, approximately 255 (21.2%) patients were readmitted for the second time within the first 30 days of the initial hospitalization, and 954 (79.1%) were readmitted at least once within the first year after initial hospital discharge. Overall, of all the patients with PAH who were hospitalized during the study period from January 2007 through December 2011, 39.2% were rehospitalized more than once.

Hospitalization Costs, Length of Stay The results showed that the cost of the initial hospitalization for a patient with PAH was $30,286, and the average length of stay (LOS) was 11 days. The average cumulative cost per a rehospitalized patient with PAH was $71,622, with an average LOS of 24.5 days. As shown in the Table, the cumulative cost of rehospitalization in the first year after discharge, excluding the initial discharge, was $95,254 per hospitalization for a patient a with commercial insurance plan compared with $36,543 for a member with Medicare Advantage coverage. When including the initial hospitalization, the total average cost of both types of insurance coverage was $101,908; the total hospitalization, including the initial hospitalization, was $134,830 for commercially insured patients and $53,039 for patients with Medicare Advantage (Table). The average LOS also differed by insurance type, with a higher LOS—28.5 days—seen in patients with Medicare Advantage coverage compared with 21.7 days in patients with commercial insurance coverage. Based on these results, Lacey and colleagues conclud-

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Vol 6, No 9

Industry Trends

Table P H-Related Hospitalization and Rehospitalization Costs and Lengths of Stay within 1 Year of Discharge, by Insurance Type Mean 1-year Mean Mean 1-year total Mean cumulative PH-related rehospitalization PH-related hospitalization rehospitalization costs, LOS per patient, hospitalization costs LOS per patient, Insurance type per patient, $a days per patient, $b daysc Total population (average)

71,622

24.5

101,908

Commercially insured

95,254

21.7

134,830

Medicare Advantage

36,543

28.5

53,039

Excludes initial hospitalization. Includes initial hospitalization. c Days have been approximated. LOS indicates length of stay; PH, pulmonary hypertension. a

ed that, “PAH is characterized by frequent re-hospitalizations with subsequent substantial costs and LOS. This highlights the high morbidity of PAH and the need for more effective therapies [for] reducing the morbidity burden and associated hospitalizations.”

New Medications Approved for PAH As luck would have it, in October 2013, the US Food and Drug Administration (FDA) approved 2 new therapies for the treatment of patients with PAH. Riociguat (Adempas; Bayer Healthcare Pharmaceuticals) was approved by the FDA on October 8, 2013, for the treatment of patients with pulmonary hypertension, as well as those with PAH. Riociguat is a first-in-class drug of the soluble guanylate cyclase stimulators and has a boxed warning about the potential harm this medication has on a fetus. A few days later, on October 18, 2013, on the heels of the AMCP meeting, the second agent, macitentan (Opsumit; Actelion Pharmaceuticals), was approved by the FDA for the treatment of patients with PAH. Macitentan is an oral dual endothelin receptor antagonist, and it, too, carries a boxed warning about the potential harm to a fetus.

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These 2 new drugs are the first medications in 5 years to be approved by the FDA for the treatment of PAH. Commenting on the FDA approval of these 2 newest medications for patients with PAH, Rino Aldreghetti, President of the Pulmonary Hypertension Association, a patient advocacy group, said, “Of the 7,000 rare diseases, only three have as many or more treatments available.” He added, “We are fortunate to have a strong and growing research community with great communication and cooperation. That has helped foster industry interest in exploring new options for our patients.”3 New treatment options, yes. But will they bring down costs? Potentially, if they can reduce the clinical burden of PAH and prevent rehospitalization in this patient population. Time will tell. n

References

1. Frost AE, Badesch DB, Barst RJ, et al. The changing picture of patients with pulmonary arterial hypertension in the United States: how REVEAL differs from historic and non-US Contemporary Registries. Chest. 2011;139:128-137. 2. Lacey M, Buzinec P, Hunsche E, et al. Pulmonary hypertension-related rehospitalization among Medicare Advantage or commercially insured patients with pulmonary arterial hypertension in the US. Poster presented at the Academy of Managed Care Pharmacy Nexus Meeting; San Antonio, TX; October 15-18, 2013. 3. Pulmonary Hypertension Association. Eleventh PH drug approved, the second in just ten days. PH Research news; October 18, 2013. www.phassociation.org/ ResearchNews. Accessed December 8, 2013.

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Brief Summary of Prescribing Information for IMBRUVICATM (ibrutinib) IMBRUVICATM (ibrutinib) capsules, for oral use See package insert for Full Prescribing Information INDICATIONS AND USAGE IMBRUVICA is indicated for the treatment of patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. This indication is based on overall response rate. An improvement in survival or disease-related symptoms has not been established [see Clinical Studies (14.1) in full Prescribing Information]. CONTRAINDICATIONS None WARNINGS AND PRECAUTIONS Hemorrhage: Five percent of patients with MCL had Grade 3 or higher bleeding events (subdural hematoma, gastrointestinal bleeding, and hematuria). Overall, bleeding events including bruising of any grade occurred in 48% of patients with MCL treated with 560 mg daily. The mechanism for the bleeding events is not well understood. Consider the benefit-risk of ibrutinib in patients requiring antiplatelet or anticoagulant therapies. Consider the benefit-risk of withholding ibrutinib for at least 3 to 7 days pre and post-surgery depending upon the type of surgery and the risk of bleeding [see Clinical Studies (14.1) in full Prescribing Information]. Infections: Fatal and non-fatal infections have occurred with IMBRUVICA therapy. At least 25% of patients with MCL had infections Grade 3 or greater NCI Common Terminology Criteria for Adverse Events (CTCAE) [See Adverse Reactions]. Monitor patients for fever and infections and evaluate promptly. Myelosuppression: Treatment-emergent Grade 3 or 4 cytopenias were reported in 41% of patients. These included neutropenia (29%), thrombocytopenia (17%) and anemia (9%). Monitor complete blood counts monthly. Renal Toxicity: Fatal and serious cases of renal failure have occurred with IMBRUVICA therapy. Treatment-emergent increases in creatinine levels up to 1.5 times the upper limit of normal occurred in 67% of patients and from 1.5 to 3 times the upper limit of normal in 9% of patients. Periodically monitor creatinine levels. Maintain hydration. Second Primary Malignancies: Other malignancies (5%) have occurred in patients with MCL who have been treated with IMBRUVICA, including skin cancers (4%), and other carcinomas (1%). Embryo-Fetal Toxicity: Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman. Ibrutinib caused malformations in rats at exposures 14 times those reported in patients with MCL receiving the ibrutinib dose of 560 mg per day. Reduced fetal weights were observed at lower exposures. Advise women to avoid becoming pregnant while taking IMBRUVICA. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations]. ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling: • Hemorrhage [see Warnings and Precautions] • Infections [see Warnings and Precautions] • Myelosuppression [see Warnings and Precautions] • Renal Toxicity [see Warnings and Precautions] • Second Primary Malignancies [see Warnings and Precautions] Because clinical trials are conducted under widely variable conditions, adverse event rates observed in clinical trials of a drug cannot be directly compared with rates of clinical trials of another drug and may not reflect the rates observed in practice. The data described below reflect exposure to IMBRUVICA in a clinical trial that included 111 patients with previously treated MCL treated with 560 mg daily with a median treatment duration of 8.3 months. The most commonly occurring adverse reactions (≥ 20%) were thrombocytopenia, diarrhea, neutropenia, anemia, fatigue, musculoskeletal pain, peripheral edema, upper respiratory tract infection, nausea, bruising, dyspnea, constipation, rash, abdominal pain, vomiting and decreased appetite (See TableTables 1 and 2). The most common Grade 3 or 4 non-hematological adverse reactions (≥ 5%) were pneumonia, abdominal pain, atrial fibrillation, diarrhea, fatigue, and skin infections. Adverse reactions from the MCL trial (N=111) using single agent IMBRUVICA 560 mg daily occurring at a rate of ≥ 10% are presented in Table 1.

IMBRUVICATM (ibrutinib) capsules Table 1: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with Mantle Cell Lymphoma (N=111) System Organ Class

Preferred Term

Diarrhea Nausea Constipation Abdominal pain Vomiting Stomatitis Dyspepsia Infections and Upper respiratory tract infestations infection Urinary tract infection Pneumonia Skin infections Sinusitis General disorders and Fatigue Peripheral edema administrative site Pyrexia conditions Asthenia Bruising Skin and subcutaneous tissue Rash Petechiae disorders Musculoskeletal and Musculoskeletal pain Muscle spasms connective tissue Arthralgia disorders Respiratory, thoracic Dyspnea Cough and mediastinal Epistaxis disorders Metabolism and Decreased appetite nutritional disorders Dehydration Nervous system Dizziness disorders Headache

Gastrointestinal disorders

All Grades Grade 3 or 4 (%) (%) 5 51 0 31 0 25 5 24 0 23 1 17 0 11 34 14 14 14 13 41 35 18 14 30 25 11 37 14 11 27 19 11 21 12 14 13

0 3 7 5 1 5 3 1 3 0 3 0 1 0 0 4 0 0 2 4 0 0

Table 2: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils in Patients with MCL (N=111)

Platelets Decreased Neutrophils Decreased Hemoglobin Decreased

Percent of Patients (N=111) All Grades (%) Grade 3 or 4 (%) 57 17 47 29 41 9

* Based on laboratory measurements and adverse reactions Ten patients (9%) discontinued treatment due to adverse reactions in the trial (N=111). The most frequent adverse reaction leading to treatment discontinuation was subdural hematoma (1.8%). Adverse reactions leading to dose reduction occurred in 14% of patients. Patients with MCL who develop lymphocytosis greater than 400,000/mcL have developed intracranial hemorrhage, lethargy, gait instability, and headache. However, some of these cases were in the setting of disease progression. Forty percent of patients had elevated uric acid levels on study including 13% with values above 10 mg/dL. Adverse reaction of hyperuricemia was reported for 15% of patients. DRUG INTERACTIONS Ibrutinib is primarily metabolized by cytochrome P450 enzyme 3A. CYP3A Inhibitors: In healthy volunteers, co-administration of ketoconazole, a strong CYP3A inhibitor, increased Cmax and AUC of ibrutinib by 29- and 24-fold, respectively. The highest ibrutinib dose evaluated in clinical trials was 12.5 mg/kg (actual doses of 840 – 1400 mg) given for 28 days with single dose AUC values of 1445 ± 869 ng • hr/mL which is approximately 50% greater than steady state exposures seen at the highest indicated dose (560 mg). Avoid concomitant administration of IMBRUVICA with strong or moderate inhibitors of CYP3A. For strong CYP3A inhibitors used short-term (e.g., antifungals and antibiotics for 7 days or less, e.g., ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin) consider interrupting IMBRUVICA therapy during the duration of inhibitor use. Avoid strong CYP3A inhibitors that are needed chronically. If a moderate CYP3A inhibitor must be used, reduce the IMBRUVICA dose.

IMBRUVICATM (ibrutinib) capsules

Patients taking concomitant strong or moderate CYP3A4 inhibitors should be monitored more closely for signs of IMBRUVICA toxicity [see Dosage and Administration (2.4) in full Prescribing Information]. Avoid grapefruit and Seville oranges during IMBRUVICA treatment, as these contain moderate inhibitors of CYP3A [see Dosage and Administration (2.4), and Clinical Pharmacology (12.3) in full Prescribing Information]. CYP3A Inducers: Administration of IMBRUVICA with strong inducers of CYP3A decrease ibrutinib plasma concentrations by approximately 10-fold. Avoid concomitant use of strong CYP3A inducers (e.g., carbamazepine, rifampin, phenytoin and St. John’s Wort). Consider alternative agents with less CYP3A induction [see Clinical Pharmacology (12.3) in full Prescribing Information]. USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category D [see Warnings and Precautions]. Risk Summary: Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman. If IMBRUVICA is used during pregnancy or if the patient becomes pregnant while taking IMBRUVICA, the patient should be apprised of the potential hazard to the fetus. Animal Data: Ibrutinib was administered orally to pregnant rats during the period of organogenesis at oral doses of 10, 40 and 80 mg/kg/day. Ibrutinib at a dose of 80 mg/kg/day was associated with visceral malformations (heart and major vessels) and increased post-implantation loss. The dose of 80 mg/kg/day in animals is approximately 14 times the exposure (AUC) in patients with MCL administered the dose of 560 mg daily. Ibrutinib at doses of 40 mg/kg/day or greater was associated with decreased fetal weights. The dose of 40 mg/kg/day in animals is approximately 6 times the exposure (AUC) in patients with MCL administered the dose of 560 mg daily. Nursing Mothers: It is not known whether ibrutinib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from IMBRUVICA, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use: The safety and effectiveness of IMBRUVICA in pediatric patients has not been established. Geriatric Use: Of the 111 patients treated for MCL, 63% were 65 years of age or older. No overall differences in effectiveness were observed between these patients and younger patients. Cardiac adverse events (atrial fibrillation and hypertension), infections (pneumonia and cellulitis) and gastrointestinal events (diarrhea and dehydration) occurred more frequently among elderly patients. Renal Impairment: Less than 1% of ibrutinib is excreted renally. Ibrutinib exposure is not altered in patients with Creatinine clearance (CLcr) > 25 mL/min. There are no data in patients with severe renal impairment (CLcr < 25 mL/min) or patients on dialysis [see Clinical Pharmacology (12.3) in full Prescribing Information]. Hepatic Impairment: Ibrutinib is metabolized in the liver and significant increases in exposure of ibrutinib are expected in patients with hepatic impairment. Patients with serum aspartate transaminase (AST/SGOT) or alanine transaminase (ALT/SGPT) ≥ 3.0 x upper limit of normal (ULN) were excluded from IMBRUVICA clinical trials. There is insufficient data to recommend a dose of IMBRUVICA in patients with baseline hepatic impairment [see Clinical Pharmacology (12.3) in full Prescribing Information]. Females and Males of Reproductive Potential: Advise women to avoid becoming pregnant while taking IMBRUVICA because IMBRUVICA can cause fetal harm [see Use in Specific Populations]. PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information) • Hemorrhage: Inform patients of the possibility of bleeding, and to report any signs or symptoms (blood in stools or urine, prolonged or uncontrolled bleeding). Inform the patient that IMBRUVICA may need to be interrupted for medical or dental procedures [see Warnings and Precautions]. • Infections: Inform patients of the possibility of serious infection, and to report any signs or symptoms (fever, chills) suggestive of infection [see Warnings and Precautions]. • Renal toxicity: Inform patients of the possibility of renal toxicity. Advise patients to maintain adequate hydration [see Warnings and Precautions]. • Second primary malignancies: Inform patients that other malignancies have occurred in patients with MCL who have been treated with IMBRUVICA, including skin cancers and other carcinomas [see Warnings and Precautions].

• Embryo-fetal toxicity: Advise women of the potential hazard to a fetus and to avoid becoming pregnant [see Warnings and Precautions]. • Inform patients to take IMBRUVICA orally once daily according to their physician’s instructions and that the capsules should be swallowed whole with a glass of water without being opened, broken, or chewed at approximately the same time each day [see Dosage and Administration (2.1) in full Prescribing Information]. • Advise patients that in the event of a missed daily dose of IMBRUVICA, it should be taken as soon as possible on the same day with a return to the normal schedule the following day. Patients should not take extra capsules to make up the missed dose [see Dosage and Administration (2.5) in full Prescribing Information]. • Advise patients of the common side effects associated with IMBRUVICA [see Adverse Reactions]. Direct the patient to a complete list of adverse drug reactions in PATIENT INFORMATION. • Advise patients to inform their health care providers of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products [see Drug Interactions]. • Advise patients that they may experience loose stools or diarrhea, and should contact their doctor if their diarrhea persists. Active ingredient made in China. Distributed and Marketed by: Pharmacyclics, Inc. Sunnyvale, CA USA 94085 and Marketed by: Janssen Biotech, Inc. Horsham, PA USA 19044 Patent http://www.imbruvica.com IMBRUVICA™ is a trademark owned by Pharmacyclics, Inc. ©Pharmacyclics, Inc. 2013 K08BR13131B

Issued: November 2013

NOW APPROVED FOR PREVIOUSLY TREATED MCL

INDICATION - IMBRUVICA™ (ibrutinib) is indicated for the treatment of patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. This indication is based on overall response rate. An improvement in survival or disease-related symptoms has not been established.

Learn more at www.IMBRUVICA.com IMPORTANT SAFETY INFORMATION WARNINGS AND PRECAUTIONS Hemorrhage - 5% of patients with MCL had ≥ Grade 3 bleeding events (subdural hematoma, gastrointestinal bleeding, and hematuria). Bleeding events including bruising of any grade occurred in 48% of patients with MCL treated with 560 mg daily. The mechanism for the bleeding events is not well understood. Consider the benefit-risk of ibrutinib in patients requiring antiplatelet or anticoagulant therapies and the benefit-risk of withholding ibrutinib for at least 3 to 7 days pre and post-surgery depending upon the type of surgery and the risk of bleeding. Infections - Fatal and non-fatal infections have occurred. At least 25% of patients with MCL had infections ≥ Grade 3, according to NCI Common Terminology Criteria for Adverse Events (CTCAE). Monitor patients for fever and infections and evaluate promptly. Myelosuppression - Treatment-emergent Grade 3 or 4 cytopenias were reported in 41% of patients. These included neutropenia (29%), thrombocytopenia (17%) and anemia (9%). Monitor complete blood counts monthly. Renal Toxicity - Fatal and serious cases of renal failure have occurred. Treatmentemergent increases in creatinine levels up to Please review the Brief Summary of full Prescribing Information on the following page. © Pharmacyclics, Inc. 2013 © Janssen Biotech, Inc. 2013 11/13

K08BR13037D

1.5 times the upper limit of normal occurred in 67% of patients and from 1.5 to 3 times the upper limit of normal in 9% of patients. Periodically monitor creatinine levels. Maintain hydration. Second Primary Malignancies - Other malignancies (5%) have occurred in patients with MCL who have been treated with IMBRUVICA™, including skin cancers (4%) and other carcinomas (1%). Embryo-Fetal Toxicity - Based on findings in animals, IMBRUVICA™ can cause fetal harm when administered to a pregnant woman. Advise women to avoid becoming pregnant while taking IMBRUVICA™. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. ADVERSE REACTIONS - The most commonly occurring adverse reactions (≥ 20%) in the clinical trial were thrombocytopenia*, diarrhea (51%), neutropenia*, anemia*, fatigue (41%), musculoskeletal pain (37%), peripheral edema (35%), upper respiratory tract infection (34%), nausea (31%), bruising (30%), dyspnea (27%), constipation (25%), rash (25%), abdominal pain (24%), vomiting (23%) and decreased appetite (21%).

*Treatment-emergent decreases (all grades) of platelets (57%), neutrophils (47%) and hemoglobin (41%) were based on laboratory measurements and adverse reactions. The most common Grade 3 or 4 nonhematological adverse reactions (≥ 5%) were pneumonia (7%), abdominal pain (5%), atrial fibrillation, diarrhea (5%), fatigue (5%), and skin infections (5%). Treatment-emergent Grade 3 or 4 cytopenias were reported in 41% of patients. Ten patients (9%) discontinued treatment due to adverse reactions in the trial (N=111). The most frequent adverse reaction leading to treatment discontinuation was subdural hematoma (1.8%). Adverse reactions leading to dose reduction occurred in 14% of patients. DRUG INTERACTIONS CYP3A Inhibitors - Avoid concomitant administration with strong or moderate inhibitors of CYP3A. If a moderate CYP3A inhibitor must be used, reduce the IMBRUVICA™ dose. CYP3A Inducers - Avoid co-administration with strong CYP3A inducers. SPECIAL POPULATIONS - Hepatic Impairment - Avoid use in patients with baseline hepatic impairment.