AHDB_may_june_2013

The Peer-Reviewed Forum for Evidence in Benefit Design ™ May/June 2013

Volume 6, Number 4

For Payers, Purchasers, Policymakers, and Other Healthcare Stakeholders

EDITORIAL

Reflections on Japan’s Complex Medical Culture David B. Nash, MD, MBA BUSINESS

Optimizing the Economic Impact of rtPA Use in a Stroke Belt State: The Case of South Carolina ™

Abby Swanson Kazley, PhD; Kit N. Simpson, DrPH; Annie Simpson, PhD; Edward Jauch, MD; Robert J. Adams, MD Stakeholder Perspective by Albert Tzeel, MD, MHSA, FACPE REGULATORY

US Propofol Drug Shortages: Review of the Problem and Stakeholder Analysis Christopher Hvisdas, PharmD Candidate; Andrea Lordan, PharmD Candidate; Laura T. Pizzi, PharmD, MPH; Brandi N. Thoma, PharmD Stakeholder Perspective by Jack E. Fincham, PhD, RPh CLINICAL

Opioid Utilization Patterns among Medicare Patients with Diabetic Peripheral Neuropathy Jacqueline Pesa, MSEd, PhD, MPH; Roxanne Meyer, PharmD; Tiffany P. Quock, PhD, MS; Stacy K. Rattana, RN, BSN; Samir H. Mody, PharmD, MBA Stakeholder Perspective by Curtis Wander, PharmD

Industry Trends The Race to Open Enrollment: Critical Success Factors for Exchanges AMCP Highlights

6

EST. 2008

YEAR ANNIVERSARY

Payer’s Trends An Inside Look at Managed Care Executive Conversations within the Health Payer Council: What Is Evidence?

www.AHDBonline.com ©2013 Engage Healthcare Communications, LLC

The median age of patients in the VISTA† trial was 71 years (range: 48-91).

Indication and Important safety Information for VELCADE® (bortezomib) InDICAtIon VELCADE (bortezomib) is indicated for the treatment of patients with multiple myeloma.

ContrAInDICAtIons VELCADE is contraindicated in patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol, including anaphylactic reactions. VELCADE is contraindicated for intrathecal administration.

WArnIngs, prECAutIons, AnD Drug IntErACtIons ▼ Peripheral neuropathy: Manage with dose modification or discontinuation. Patients with preexisting severe neuropathy should be treated with VELCADE only after careful risk-benefit assessment. ▼ Hypotension: Use caution when treating patients taking antihypertensives, with a history of syncope, or with dehydration.

▼ Cardiac toxicity: Worsening of and development of cardiac failure have occurred. Closely monitor patients with existing heart disease or risk factors for heart disease. ▼ Pulmonary toxicity: Acute respiratory syndromes have occurred. Monitor closely for new or worsening symptoms. ▼ Posterior reversible encephalopathy syndrome: Consider MRI imaging for onset of visual or neurological symptoms; discontinue VELCADE if suspected. ▼ Gastrointestinal toxicity: Nausea, diarrhea, constipation, and vomiting may require use of antiemetic and antidiarrheal medications or fluid replacement. ▼ Thrombocytopenia or Neutropenia: Monitor complete blood counts regularly throughout treatment. ▼ Tumor lysis syndrome: Closely monitor patients with high tumor burden. ▼ Hepatic toxicity: Monitor hepatic enzymes during treatment.

In treating multiple myeloma

What is the value of ® VELCADE (bortezomib)? ▼ Overall survival advantage ▼ Defined length of therapy ▼ Medication cost If you DEfInE VALuE As An oVErALL surVIVAL ADVAntAgE: VELCADE (bortezomib) combination delivered a >13-month overall survival advantage At 5-year median follow-up, VELCADE+MP* provided a median overall survival of 56.4 months vs 43.1 months with MP alone (HR=0.695 [95% CI, 0.57-0.85]; p<0.05)† At 3-year median follow-up, VELCADE+MP provided an overall survival advantage over MP that was not regained with subsequent therapies

If you DEfInE VALuE As DEfInED LEngth of thErApy: Results achieved using VELCADE twice-weekly followed by weekly dosing for a median of 50 weeks (54 planned)1

If you DEfInE VALuE As MEDICAtIon Cost: Medication cost is an important factor when considering overall drug spend. The Wholesale Acquisition Cost for VELCADE is $1,540 per 3.5-mg vial as of January 2013 When determining the value of a prescription drug regimen, it may be worth considering medication cost, length of therapy, and dosing regimens. This list is not all-inclusive; there are additional factors to consider when determining value for a given regimen

▼ Embryo-fetal risk: Women should avoid becoming pregnant while being treated with VELCADE. Advise pregnant women of potential embryo-fetal harm. ▼ Closely monitor patients receiving VELCADE in combination with strong CYP3A4 inhibitors. Avoid concomitant use of strong CYP3A4 inducers.

ADVErsE rEACtIons Most commonly reported adverse reactions (incidence ≥20%) in clinical studies include nausea, diarrhea, thrombocytopenia, neutropenia, peripheral neuropathy, fatigue, neuralgia, anemia, leukopenia, constipation, vomiting, lymphopenia, rash, pyrexia, and anorexia.

Please see Brief Summary for VELCADE on the next page of this advertisement.

For Reimbursement Assistance, call 1-866-VELCADE (835-2233), Option 2, or visit VELCADEHCP.com.

Reference: 1. Mateos M-V, Richardson PG, Schlag R, et al. Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: updated follow-up and impact of subsequent therapy in the phase III VISTA trial.

J Clin Oncol. 2010;28(13):2259-2266. *Melphalan+prednisone. † VISTA TRIAL: a randomized, open-label, international phase 3 trial (N=682) evaluating the efficacy and safety of VELCADE administered intravenously in combination with MP vs MP in previously untreated multiple myeloma. The primary endpoint was TTP. Secondary endpoints were CR, ORR, PFS, and overall survival. At a prespecified interim analysis (median follow-up 16.3 months), VELCADE+MP resulted in significantly superior results for TTP (median 20.7 months with VELCADE+MP vs 15.0 months with MP [p=0.000002]), PFS, overall survival, and ORR. Further enrollment was halted and patients receiving MP were offered VELCADE in addition. Updated analysis was performed.

Brief Summary INDICATIONS: VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma.

VELCADE for Injection is indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy.

CONTRAINDICATIONS: VELCADE is contraindicated in patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol, including anaphylactic reactions. VELCADE is contraindicated for intrathecal administration.

WARNINGS AND PRECAUTIONS: Peripheral Neuropathy: VELCADE treatment causes a peripheral neuropathy that is predominantly sensory; however, cases of severe sensory and motor peripheral neuropathy have been reported.

Patients with pre-existing symptoms (numbness, pain, or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including ≥Grade 3) during treatment with VELCADE. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. In the Phase 3 relapsed multiple myeloma trial comparing VELCADE subcutaneous vs intravenous, the incidence of Grade ≥2 peripheral neuropathy events was 24% for subcutaneous and 39% for intravenous. Grade ≥3 peripheral neuropathy occurred in 6% of patients in the subcutaneous treatment group, compared with 15% in the intravenous treatment group. Starting VELCADE subcutaneously may be considered for patients with pre-existing or at high risk of peripheral neuropathy.

Patients experiencing new or worsening peripheral neuropathy during VELCADE therapy may require a decrease in the dose and/or a less dose-intense schedule. In the VELCADE vs dexamethasone phase 3 relapsed multiple myeloma study, improvement in or resolution of peripheral neuropathy was reported in 48% of patients with ≥Grade 2 peripheral neuropathy following dose adjustment or interruption. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had ≥Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma.

Hypotension: The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 8%.

These events are observed throughout therapy. Caution should be used when treating patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids and/or sympathomimetics.

Cardiac Toxicity: Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have occurred during VELCADE therapy, including reports in patients with no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing, heart disease should be closely monitored. In the relapsed multiple myeloma study of VELCADE vs dexamethasone, the incidence of any treatment-related cardiac disorder was 8% and 5% in the VELCADE and dexamethasone groups, respectively. The incidence of adverse reactions suggestive of heart failure (acute pulmonary edema, pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock) was ≤1% for each individual reaction in the VELCADE group. In the dexamethasone group, the incidence was ≤1% for cardiac failure and congestive cardiac failure; there were no reported reactions of acute pulmonary edema, pulmonary edema, or cardiogenic shock. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established.

Pulmonary Toxicity: Acute Respiratory Distress Syndrome (ARDS) and acute diffuse infiltrative pulmonary disease of unknown etiology, such as pneumonitis, interstitial pneumonia, and lung infiltration have occurred in patients receiving VELCADE. Some of these events have been fatal.

In a clinical trial, the first two patients given high-dose cytarabine (2 g/m2 per day) by continuous infusion with daunorubicin and VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy. There have been reports of pulmonary hypertension associated with VELCADE administration in the absence of left heart failure or significant pulmonary disease. In the event of new or worsening cardiopulmonary symptoms, consider interrupting VELCADE until a prompt, comprehensive, diagnostic evaluation is conducted.

Posterior Reversible Encephalopathy Syndrome (PRES): Posterior Reversible Encephalopathy Syndrome (PRES; formerly termed Reversible Posterior Leukoencephalopathy Syndrome (RPLS)) has occurred in patients receiving VELCADE. PRES is a rare, reversible, neurological disorder, which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances. Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing PRES, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previously experiencing PRES is not known.

Gastrointestinal Toxicity: VELCADE treatment can cause nausea, diarrhea, constipation, and vomiting, sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur.

Fluid and electrolyte replacement should be administered to prevent dehydration. Interrupt VELCADE for severe symptoms.

Thrombocytopenia/Neutropenia: VELCADE is associated with thrombocytopenia and neutropenia that follow a cyclical pattern, with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and recovery remained consistent over the 8 cycles of twice-weekly dosing, and there was no evidence of cumulative thrombocytopenia or neutropenia. The mean platelet count nadir measured was approximately 40% of baseline.

The severity of thrombocytopenia was related to pretreatment platelet count. In the relapsed multiple myeloma study of VELCADE vs dexamethasone, the incidence of bleeding (≥Grade 3) was 2% on the VELCADE arm and <1% on the dexamethasone arm. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE. Platelet counts should be monitored prior to each dose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and schedule of VELCADE. Gastrointestinal and intracerebral hemorrhage has been reported in association with VELCADE. Transfusions may be considered.

Tumor Lysis Syndrome: Tumor lysis syndrome has been reported with VELCADE therapy.

Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment.

Monitor patients closely and take appropriate precautions.

Hepatic Toxicity: Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic reactions include hepatitis, increases in liver enzymes, and hyperbilirubinemia. Interrupt VELCADE therapy to assess reversibility. There is limited re-challenge information in these patients.

Embryo-fetal: Pregnancy Category D. Women of reproductive potential should avoid becoming pregnant while being treated with VELCADE. Bortezomib administered to rabbits during organogenesis at a dose approximately 0.5 times the clinical dose of 1.3 mg/m2 based on body surface area caused post-implantation loss and a decreased number of live fetuses.

ADVERSE EVENT DATA: Safety data from phase 2 and 3 studies of single-agent VELCADE 1.3 mg/m2/dose administered intravenously twice weekly for 2 weeks followed by a 10-day rest period in 1163 patients with previously-treated multiple myeloma (N=1008) and previously-treated mantle cell lymphoma (N=155) were integrated and tabulated. In these studies, the safety profile of VELCADE was similar in patients with multiple myeloma and mantle cell lymphoma.

In the integrated analysis, the most commonly reported (≥10%) adverse reactions were nausea (49%), diarrhea NOS (46%), fatigue (41%), peripheral neuropathies NEC (38%), thrombocytopenia (32%), vomiting NOS (28%), constipation (25%), pyrexia (21%), anorexia (20%), anemia NOS (18%), headache NOS (15%), neutropenia (15%), rash NOS (13%), paresthesia (13%), dizziness (excl vertigo 11%), and weakness (11%). Eleven percent (11%) of patients experienced at least 1 episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (4%) and neutropenia (2%).

A total of 26% of patients experienced a serious adverse reaction during the studies. The most commonly reported serious adverse reactions included diarrhea, vomiting, and pyrexia (3% each), nausea, dehydration, and thrombocytopenia (2% each), and pneumonia, dyspnea, peripheral neuropathies NEC, and herpes zoster (1% each).

In the phase 3 VELCADE+melphalan and prednisone study in previously untreated multiple myeloma, the safety profile of VELCADE administered intravenously in combination with melphalan/prednisone is consistent with the known safety profiles of both VELCADE and melphalan/prednisone. The most commonly reported adverse reactions in this study (VELCADE+melphalan/prednisone vs melphalan/prednisone) were thrombocytopenia (48% vs 42%), neutropenia (47% vs 42%), peripheral neuropathy (46% vs 1%), nausea (39% vs 21%), diarrhea (35% vs 6%), neuralgia (34% vs <1%), anemia (32% vs 46%), leukopenia (32% vs 28%), vomiting (26% vs 12%), fatigue (25% vs 14%), lymphopenia (23% vs 15%), constipation (23% vs 4%), anorexia (19% vs 6%), asthenia (16% vs 7%), pyrexia (16% vs 6%), paresthesia (12% vs 1%), herpes zoster (11% vs 3%), rash (11% vs 2%), abdominal pain upper (10% vs 6%), and insomnia (10% vs 6%).

In the phase 3 VELCADE subcutaneous vs intravenous study in relapsed multiple myeloma, safety data were similar between the two treatment groups. The most commonly reported adverse reactions in this study were peripheral neuropathy NEC (37% vs 50%), thrombocytopenia (30% vs 34%), neutropenia (23% vs 27%), neuralgia (23% vs 23%), anemia (19% vs 23%), diarrhea (19% vs 28%), leukopenia (18% vs 20%), nausea (16% vs 14%), pyrexia (12% vs 8%), vomiting (9% vs 11%), asthenia (7% vs 16%), and fatigue (7% vs 15%). The incidence of serious adverse reactions was similar for the subcutaneous treatment group (20%) and the intravenous treatment group (19%). The most commonly reported SARs were pneumonia and pyrexia (2% each) in the subcutaneous treatment group and pneumonia, diarrhea, and peripheral sensory neuropathy (3% each) in the intravenous treatment group.

DRUG INTERACTIONS: Bortezomib is a substrate of cytochrome P450 enzyme 3A4, 2C19 and 1A2. Co-administration of ketoconazole, a strong CYP3A4 inhibitor, increased the exposure of bortezomib by 35% in 12 patients. Monitor patients for signs of bortezomib toxicity and consider a bortezomib dose reduction if bortezomib must be given in combination with strong CYP3A4 inhibitors (eg, ketoconazole, ritonavir). Co-administration of omeprazole, a strong inhibitor of CYP2C19, had no effect on the exposure of bortezomib in 17 patients. Co-administration of rifampin, a strong CYP3A4 inducer, is expected to decrease the exposure of bortezomib by at least 45%.

Because the drug interaction study (n=6) was not designed to exert the maximum effect of rifampin on bortezomib PK, decreases greater than 45% may occur. Efficacy may be reduced when VELCADE is used in combination with strong CYP3A4 inducers; therefore, concomitant use of strong CYP3A4 inducers is not recommended in patients receiving VELCADE. St. John’s wort (Hypericum perforatum) may decrease bortezomib exposure unpredictably and should be avoided. Co-administration of dexamethasone, a weak CYP3A4 inducer, had no effect on the exposure of bortezomib in 7 patients. Co-administration of melphalan-prednisone increased the exposure of bortezomib by 17% in 21 patients. However, this increase is unlikely to be clinically relevant.

USE IN SPECIFIC POPULATIONS: Nursing Mothers: It is not known whether bortezomib 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 VELCADE, 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 VELCADE in children has not been established.

Geriatric Use: No overall differences in safety or effectiveness were observed between patients ≥age 65 and younger patients receiving VELCADE; but greater sensitivity of some older individuals cannot be ruled out.

Patients with Renal Impairment: The pharmacokinetics of VELCADE are not influenced by the degree of renal impairment. Therefore, dosing adjustments of VELCADE are not necessary for patients with renal insufficiency. Since dialysis may reduce VELCADE concentrations, VELCADE should be administered after the dialysis procedure. For information concerning dosing of melphalan in patients with renal impairment, see manufacturer’s prescribing information.

Patients with Hepatic Impairment: The exposure of bortezomib is increased in patients with moderate and severe hepatic impairment. Starting dose should be reduced in those patients.

Patients with Diabetes: During clinical trials, hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving VELCADE treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetic medication.

Please see full Prescribing Information for VELCADE at VELCADEHCP.com.

VELCADE, MILLENNIUM and are registered trademarks of Millennium Pharmaceuticals, Inc. Other trademarks are property of their respective owners.

Millennium Pharmaceuticals, Inc., Cambridge, MA 02139 Copyright © 2013, Millennium Pharmaceuticals, Inc. All rights reserved.

Printed in USA

V-12-0306

11/12

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 and Bentteligence, Sharon, MA 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 GOVERNMENT

Kevin B. “Kip” Piper, MA, FACHE President, Health Results Group, LLC Washington, DC HEALTH INFORMATION TECHNOLOGY

Kelly Huang, PhD President, HealthTronics, Inc. Austin, TX J. B. Jones, PhD, MBA Research Investigator, Geisinger Health System, Danville, PA Victor J. Strecher, PhD, MPH Professor and Director for Innovation and Social Entrepreneurship, University of Michigan School of Public Health and Medicine HEALTH OUTCOMES RESEARCH

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 Couto, PharmD, MBA Clinical Program Manager Cigna Corporation, Bloomfield, CT Steve Miff, PhD Senior Vice President VHA, Inc., Irving, TX

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Christopher (Chris) P. Molineaux President, Pennsylvania BIO Malvern, PA Terri S. Moore, PhD, RPh, MBA Senior Manager, Product Development URAC, Washington, DC Kavita V. Nair, PhD Associate Professor, School of Pharmacy University of Colorado at Denver, CO Gary M. Owens, MD President, Gary Owens Associates Glen Mills, PA Andrew M. Peterson, PharmD, PhD Dean, Mayes School of Healthcare Business and Policy, Associate Professor, University of the Sciences, Philadelphia, PA 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, PA Paul Wilson Senior VP, Health Consumer Insights and Analytics, Blue Bell, PA David W. Wright, MPH President, Institute for Interactive Patient Care Bethesda, MD health & value promotion

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 National Medical Director HumanaOne, Waukesha, WI MANAGED MARKETS

Jeffrey A. Bourret, RPh, MS, FASHP Senior Director, Medical Lead, Payer and Specialty Channel Strategy, Medical Affairs Pfizer Specialty Care Business Unit, PA Richard B. Weininger, MD Chairman, CareCore National, LLC Bluffton, SC PATIENT ADVOCACY

William E. Fassett, BSPharm, MBA, PhD, FAPhA Professor of Pharmacy Law & Ethics Dept. of Pharmacotherapy, College of Pharmacy Washington State University, Spokane, WA Mike Pucci Sr VP Commercial Operations and Business Development, PhytoChem Pharmaceuticals Lake Gaston, NC Personalized medicine

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

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 PHARMACY BENEFIT DESIGN

Joel V. Brill, MD, AGAF, CHCQM Chief Medical Officer, Predictive Health, Phoenix, AZ

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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 Vice President, National Accounts Truveris, Inc., New York, NY Matthew Mitchell, PharmD, MBA Manager, Pharmacy Services SelectHealth, Salt Lake City, UT Paul Anthony Polansky, BSPharm, MBA Senior Field Scientist, Health Outcomes and PharmacoEconomics (HOPE) Endo Health Solutions, Chadds Ford, PA Christina A. Stasiuk, DO, FACOI Senior Medical Director Cigna, Philadelphia, PA Scott R. Taylor, BSPharm, MBA Executive Director, Industry Relations Geisinger Health System, Danville, PA POLICY & PUBLIC HEALTH

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, Practice and Administration 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 Executive Director Drug Information Association, Horsham, PA 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 RESEARCH & DEVELOPMENT

Frank Casty, MD, FACP Chief Medical Officer Senior VP, Clinical Development Medical Science Endo Pharmaceuticals, Chadds Ford, PA Michael F. Murphy, MD, PhD Chief Medical Officer and Scientific Officer Worldwide Clinical Trials King of Prussia, PA SPECIALTY PHARMACY

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 Collegeville, PA

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Vol 6, No 4

May/june 2013

Volume 6, number 4 The Peer-Reviewed Forum for Evidence in Benefit Design ™

™

™

For Payers, Purchasers, Policymakers, and Other Healthcare Stakeholders

Table of Contents

Publishing Staff

155 O ptimizing the Economic Impact of rtPA Use in a Stroke Belt State: The Case of South Carolina Abby Swanson Kazley, PhD; Kit N. Simpson, DrPH; Annie Simpson, PhD; Edward Jauch, MD; Robert J. Adams, MD

Senior Vice President/Group Publisher Nicholas Englezos nick@engagehc.com Editorial Director Dalia Buffery dalia@engagehc.com Associate Editor Lara J. Lorton Editorial Assistants Jennifer Brandt Cara Guglielmon Director, Client Services Joesph Beck Projects Manager John Welz Senior Production Manager Lynn Hamilton

163 Stakeholder Perspective by Albert Tzeel, MD, MHSA, FACPE

The Lynx Group

EDITORIAL

153 Reflections on Japan’s Complex Medical Culture

David B. Nash, MD, MBA business

REGULATORY

171 US Propofol Drug Shortages: Review of the Problem and Stakeholder Analysis Christopher Hvisdas, PharmD Candidate; Andrea Lordan, PharmD Candidate; Laura T. Pizzi, PharmD, MPH; Brandi N. Thoma, PharmD 175 Stakeholder Perspective by Jack E. Fincham, PhD, RPh CLINICAL

188 O pioid Utilization Patterns among Medicare Patients with Diabetic Peripheral Neuropathy Jacqueline Pesa, MSEd, PhD, MPH; Roxanne Meyer, PharmD; Tiffany P. Quock, PhD, MS; Stacy K. Rattana, RN, BSN; Samir H. Mody, PharmD, MBA 195 Stakeholder Perspective by Curtis Wander, PharmD Continued on page 149

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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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

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Vol 6, No 4

NEW

For the treatment of elevated IOP

UNLOCK NEW TREATMENT POSSIBILITIES

SIMBRINZA™ Suspension provided additional 1-3 mm Hg IOP lowering compared to the individual components1 ■ IOP measured at 8 AM, 10 AM, 3 PM, and 5 PM was reduced by 21-35% at Month 32-4 ■ Efficacy proven in two pivotal Phase 3 randomized, multicenter, double-masked, parallel-group, 3-month, 3-arm, contribution-of-elements studies2,3 ■ The most frequently reported adverse reactions (3-5%) were blurred vision, eye irritation, dysgeusia (bad taste), dry mouth, and eye allergy1 ■ Only available beta-blocker-free fixed combination2,3 INDICATIONS AND USAGE SIMBRINZA™ (brinzolamide/brimonidine tartrate ophthalmic suspension) 1%/0.2% is a fixed combination indicated in the reduction of elevated intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension.

Dosage and Administration The recommended dose is one drop of SIMBRINZA™ Suspension in the affected eye(s) three times daily. Shake well before use.

SIMBRINZA™ Suspension may be used concomitantly with other topical ophthalmic drug products to lower intraocular pressure. If more than one topical ophthalmic drug is being used, the drugs should be administered at least five (5) minutes apart.

IMPORTANT SAFETY INFORMATION Contraindications SIMBRINZA™ Suspension is contraindicated in patients who are hypersensitive to any component of this product and neonates and infants under the age of 2 years.

Warnings and Precautions Sulfonamide Hypersensitivity Reactions—Brinzolamide is a sulfonamide, and although administered topically, is absorbed systemically. Sulfonamide attributable adverse reactions may occur. Fatalities have occurred due to severe reactions to sulfonamides. Sensitization may recur when a sulfonamide is readministered irrespective of the route of administration.

If signs of serious reactions or hypersensitivity occur, discontinue the use of this preparation.

Corneal Endothelium—There is an increased potential for developing corneal edema in patients with low endothelial cell counts.

References: 1. SIMBRINZA™ Suspension Package Insert. 2. Katz G, DuBiner H, Samples J, et al. Three-month randomized trial of fixed-combination brinzolamide, 1%, and brimonidine, 0.2% [published online ahead of print April 11, 2013]. JAMA Ophthalmol. doi:10.1001/jamaophthalmol.2013.188. 3. Nguyen QH, McMenemy MG, Realini T, et al.

Phase 3 randomized 3-month trial with an ongoing 3-month safety extension of fixedcombination brinzolamide 1%/brimonidine 0.2%. J Ocul Pharmacol Ther. 2013;29(3): 290-297. 4. Data on file, 2013.

© 2013 Novartis 4/13

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Severe Hepatic or Renal Impairment (CrCl <30 mL/min)—SIMBRINZA™ Suspension has not been specifically studied in these patients and is not recommended.

Adverse Reactions In two clinical trials of 3 months’ duration with SIMBRINZA™ Suspension, the most frequent reactions associated with its use occurring in approximately 3-5% of patients in descending order of incidence included: blurred vision, eye irritation, dysgeusia (bad taste), dry mouth, and eye allergy. Adverse reaction rates with SIMBRINZA™ Suspension were comparable to those of the individual components. Treatment discontinuation, mainly due to adverse reactions, was reported in 11% of SIMBRINZA™ Suspension patients.

Drug Interactions—Consider the following when prescribing SIMBRINZA™ Suspension: Concomitant administration with oral carbonic anhydrase inhibitors is not recommended due to the potential additive effect. Use with high-dose salicylate may result in acid-base and electrolyte alterations. Use with CNS depressants may result in an additive or potentiating effect. Use with antihypertensives/cardiac glycosides may result in additive or potentiating effect on lowering blood pressure. Use with tricyclic antidepressants may blunt the hypotensive effect of systemic clonidine and it is unknown if use with this class of drugs interferes with IOP lowering. Use with monoamine oxidase inhibitors may result in increased hypotension.

For additional information about SIMBRINZA™ Suspension, please see Brief Summary of full Prescribing Information on adjacent page.

B:6.875” T:6.875” S:6.875” BRIEF SUMMARY OF PRESCRIBING INFORMATION INDICATIONS AND USAGE SIMBRINZA™ (brinzolamide/brimonidine tartrate ophthalmic suspension) 1%/0.2% is a fixed combination of a carbonic anhydrase inhibitor and an alpha 2 adrenergic receptor agonist indicated for the reduction of elevated intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension.

DOSAGE AND ADMINISTRATION The recommended dose is one drop of SIMBRINZA™ Suspension in the affected eye(s) three times daily. Shake well before use. SIMBRINZA™ Suspension may be used concomitantly with other topical ophthalmic drug products to lower intraocular pressure. If more than one topical ophthalmic drug is being used, the drugs should be administered at least five (5) minutes apart.

DOSAGE FORMS AND STRENGTHS Suspension containing 10 mg/mL brinzolamide and 2 mg/mL brimonidine tartrate.

CONTRAINDICATIONS Hypersensitivity - SIMBRINZA™ Suspension is contraindicated in patients who are hypersensitive to any component of this product.

Neonates and Infants (under the age of 2 years) - SIMBRINZA™ Suspension is contraindicated in neonates and infants (under the age of 2 years) see Use in Specific Populations WARNINGS AND PRECAUTIONS Sulfonamide Hypersensitivity Reactions - SIMBRINZA™ Suspension contains brinzolamide, a sulfonamide, and although administered topically is absorbed systemically. Therefore, the same types of adverse reactions that are attributable to sulfonamides may occur with topical administration of SIMBRINZA™ Suspension.

Fatalities have occurred due to severe reactions to sulfonamides including Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias. Sensitization may recur when a sulfonamide is re-administered irrespective of the route of administration. If signs of serious reactions or hypersensitivity occur, discontinue the use of this preparation [see Patient Counseling Information] Corneal Endothelium - Carbonic anhydrase activity has been observed in both the cytoplasm and around the plasma membranes of the corneal endothelium. There is an increased potential for developing corneal edema in patients with low endothelial cell counts.

Caution should be used when prescribing SIMBRINZA™ Suspension to this group of patients.

Severe Cardiovascular Disease - Brimonidine tartrate, a component of SIMBRINZATM Suspension, has a less than 5% mean decrease in blood pressure 2 hours after dosing in clinical studies; caution should be exercised in treating patients with severe cardiovascular disease.

Severe Hepatic Impairment - Because brimonidine tartrate, a component of SIMBRINZA™ Suspension, has not been studied in patients with hepatic impairment, caution should be exercised in such patients.

Potentiation of Vascular Insufficiency - Brimonidine tartrate, a component of SIMBRINZATM Suspension, may potentiate syndromes associated with vascular insufficiency. SIMBRINZA™ Suspension should be used with caution in patients with depression, cerebral or coronary insufficiency, Raynaud’s phenomenon, orthostatic hypotension, or thromboangitis obliterans.

Contamination of Topical Ophthalmic Products After Use - There have been reports of bacterial keratitis associated with the use of multiple-dose containers of topical ophthalmic products. These containers have been inadvertently contaminated by patients who, in most cases, had a concurrent corneal disease or a disruption of the ocular epithelial surface [see Patient Counseling Information].

ADVERSE REACTIONS Clinical Studies Experience - Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to the rates in the clinical studies of another drug and may not reflect the rates observed in practice.

SIMBRINZA™ Suspension - In two clinical trials of 3 months duration 435 patients were treated with SIMBRINZA™ Suspension, and 915 were treated with the two individual components. The most frequently reported adverse reactions in patients treated with SIMBRINZA™ Suspension occurring in approximately 3 to 5% of patients in descending order of incidence were blurred vision, eye irritation, dysgeusia (bad taste), dry mouth, and eye allergy. Rates of adverse reactions reported with the individual components were comparable.

Treatment discontinuation, mainly due to adverse reactions, was reported in 11% of SIMBRINZA™ Suspension patients.

Other adverse reactions that have been reported with the individual components during clinical trials are listed below.

Reactions occurring in approximately 3 to 9% of the subjects, in descending order included corneal staining/erosion, photophobia, eyelid erythema, ocular ache/pain, ocular dryness, tearing, upper respiratory symptoms, eyelid edema, conjunctival edema, dizziness, blepharitis, ocular irritation, gastrointestinal symptoms, asthenia, conjunctival blanching, abnormal vision and muscular pain.

The following adverse reactions were reported in less than 3% of the patients: lid crusting, conjunctival hemorrhage, abnormal taste, insomnia, conjunctival discharge, depression, hypertension, anxiety, palpitations/arrhythmias, nasal dryness and syncope.

Postmarketing Experience - The following reactions have been identified during postmarketing use of brimonidine tartrate ophthalmic solutions in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. The reactions, which have been chosen for inclusion due to either their seriousness, frequency of reporting, possible causal connection to brimonidine tartrate ophthalmic solutions, or a combination of these factors, include: bradycardia, hypersensitivity, iritis, keratoconjunctivitis sicca, miosis, nausea, skin reactions (including erythema, eyelid pruritus, rash, and vasodilation), and tachycardia.

Apnea, bradycardia, coma, hypotension, hypothermia, hypotonia, lethargy, pallor, respiratory depression, and somnolence have been reported in infants receiving brimonidine tartrate ophthalmic solutions [see Contraindications].

DRUG INTERACTIONS Oral Carbonic Anhydrase Inhibitors - There is a potential for an additive effect on the known systemic effects of carbonic anhydrase inhibition in patients receiving an oral carbonic anhydrase inhibitor and brinzolamide ophthalmic suspension 1%, a component of SIMBRINZA™ Suspension. The concomitant administration of SIMBRINZA™ Suspension and oral carbonic anhydrase inhibitors is not recommended.

High-Dose Salicylate Therapy - Carbonic anhydrase inhibitors may produce acid-base and electrolyte alterations. These alterations were not reported in the clinical trials with brinzolamide ophthalmic suspension 1%. However, in patients treated with oral carbonic anhydrase inhibitors, rare instances of acid-base alterations have occurred with high-dose salicylate therapy. Therefore, the potential for such drug interactions should be considered in patients receiving SIMBRINZA™ Suspension.

CNS Depressants - Although specific drug interaction studies have not been conducted with SIMBRINZA™, the possibility of an additive or potentiating effect with CNS depressants (alcohol, opiates, barbiturates, sedatives, or anesthetics) should be considered.

Antihypertensives/Cardiac Glycosides - Because brimonidine tartrate, a component of SIMBRINZA™ Suspension, may reduce blood pressure, caution in using drugs such as antihypertensives and/or cardiac glycosides with SIMBRINZA™ Suspension is advised.

Tricyclic Antidepressants - Tricyclic antidepressants have been reported to blunt the hypotensive effect of systemic clonidine. It is not known whether the concurrent use of these agents with SIMBRINZA™ Suspension in humans can lead to resulting interference with the IOP lowering effect. Caution is advised in patients taking tricyclic antidepressants which can affect the metabolism and uptake of circulating amines.

Monoamine Oxidase Inhibitors - Monoamine oxidase (MAO) inhibitors may theoretically interfere with the metabolism of brimonidine tartrate and potentially result in an increased systemic side-effect such as hypotension. Caution is advised in patients taking MAO inhibitors which can affect the metabolism and uptake of circulating amines.

USE IN SPECIFIC POPULATIONS Pregnancy - Pregnancy Category C: Developmental toxicity studies with brinzolamide in rabbits at oral doses of 1, 3, and 6 mg/ kg/day (20, 60, and 120 times the recommended human ophthalmic dose) produced maternal toxicity at 6 mg/kg/day and a significant increase in the number of fetal variations, such as accessory skull bones, which was only slightly higher than the historic value at 1 and 6 mg/kg. In rats, statistically decreased body weights of fetuses from dams receiving oral doses of 18 mg/kg/day (180 times the recommended human ophthalmic dose) during gestation were proportional to the reduced maternal weight gain, with no statistically significant effects on organ or tissue development. Increases in unossified sternebrae, reduced ossification of the skull, and unossified hyoid that occurred at 6 and 18 mg/kg were not statistically significant. No treatment-related malformations were seen. Following oral adminis-

AMCM3M0054_SIMBRINZA_JournalAd_PI_ASize_r5.indd 1

There are no adequate and well-controlled studies in pregnant women. SIMBRINZA™ Suspension should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers - In a study of brinzolamide in lactating rats, decreases in body weight gain in offspring at an oral dose of 15 mg/ kg/day (150 times the recommended human ophthalmic dose) were observed during lactation. No other effects were observed. However, following oral administration of 14C-brinzolamide to lactating rats, radioactivity was found in milk at concentrations below those in the blood and plasma. In animal studies, brimonidine was excreted in breast milk.

It is not known whether brinzolamide and brimonidine tartrate are excreted in human milk following topical ocular administration.

Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from SIMBRINZA™ (brinzolamide/brimonidine tartrate ophthalmic suspension) 1%/0.2%, 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 individual component, brinzolamide, has been studied in pediatric glaucoma patients 4 weeks to 5 years of age. The individual component, brimonidine tartrate, has been studied in pediatric patients 2 to 7 years old. Somnolence (50-83%) and decreased alertness was seen in patients 2 to 6 years old. SIMBRINZA™ Suspension is contraindicated in children under the age of 2 years [see Contraindications].

Geriatric Use - No overall differences in safety or effectiveness have been observed between elderly and adult patients.

OVERDOSAGE Although no human data are available, electrolyte imbalance, development of an acidotic state, and possible nervous system effects may occur following an oral overdose of brinzolamide. Serum electrolyte levels (particularly potassium) and blood pH levels should be monitored.

Very limited information exists on accidental ingestion of brimonidine in adults; the only adverse event reported to date has been hypotension. Symptoms of brimonidine overdose have been reported in neonates, infants, and children receiving brimonidine as part of medical treatment of congenital glaucoma or by accidental oral ingestion.

Treatment of an oral overdose includes supportive and symptomatic therapy; a patent airway should be maintained.

PATIENT COUNSELING INFORMATION Sulfonamide Reactions - Advise patients that if serious or unusual ocular or systemic reactions or signs of hypersensitivity occur, they should discontinue the use of the product and consult their physician.

Temporary Blurred Vision - Vision may be temporarily blurred following dosing with SIMBRINZA™ Suspension. Care should be exercised in operating machinery or driving a motor vehicle.

Effect on Ability to Drive and Use Machinery - As with other drugs in this class, SIMBRINZA™ Suspension may cause fatigue and/or drowsiness in some patients. Caution patients who engage in hazardous activities of the potential for a decrease in mental alertness.

Avoiding Contamination of the Product - Instruct patients that ocular solutions, if handled improperly or if the tip of the dispensing container contacts the eye or surrounding structures, can become contaminated by common bacteria known to cause ocular infections.

Serious damage to the eye and subsequent loss of vision may result from using contaminated solutions [see Warnings and Precautions ]. Always replace the cap after using. If solution changes color or becomes cloudy, do not use. Do not use the product after the expiration date marked on the bottle.

Intercurrent Ocular Conditions - Advise patients that if they have ocular surgery or develop an intercurrent ocular condition (e.g., trauma or infection), they should immediately seek their physician’s advice concerning the continued use of the present multidose container.

Concomitant Topical Ocular Therapy - If more than one topical ophthalmic drug is being used, the drugs should be administered at least five minutes apart.

Contact Lens Wear - The preservative in SIMBRINZA™, benzalkonium chloride, may be absorbed by soft contact lenses. Contact lenses should be removed during instillation of SIMBRINZA™ Suspension, but may be reinserted 15 minutes after instillation. ©2013 Novartis U.S. Patent No: 6,316,441 ALCON LABORATORIES, INC. Fort Worth, Texas 76134 USA 1-800-757-9195 alcon.medinfo@alcon.com

© 2013 Novartis 4/13

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Contact Lens Wear - The preservative in SIMBRINZA™, benzalkonium chloride, may be absorbed by soft contact lenses. Contact lenses should be removed during instillation of SIMBRINZA™ Suspension but may be reinserted 15 minutes after instillation [see Patient Counseling Information].

Brimonidine Tartrate 0.2% - In clinical studies of brimonidine tartrate 0.2%, adverse reactions occurring in approximately 10 to 30% of the subjects, in descending order of incidence, included oral dryness, ocular hyperemia, burning and stinging, headache, blurring, foreign body sensation, fatigue/drowsiness, conjunctival follicles, ocular allergic reactions, and ocular pruritus.

Developmental toxicity studies performed in rats with oral doses of 0.66 mg brimonidine base/kg revealed no evidence of harm to the fetus. Dosing at this level resulted in a plasma drug concentration approximately 100 times higher than that seen in humans at the recommended human ophthalmic dose. In animal studies, brimonidine crossed the placenta and entered into the fetal circulation to a limited extent.

T:9.875”

Acute Angle-Closure Glaucoma - The management of patients with acute angle-closure glaucoma requires therapeutic interventions in addition to ocular hypotensive agents. SIMBRINZA™ Suspension has not been studied in patients with acute angle-closure glaucoma.

The following adverse reactions were reported at an incidence below 1%: allergic reactions, alopecia, chest pain, conjunctivitis, diarrhea, diplopia, dizziness, dry mouth, dyspnea, dyspepsia, eye fatigue, hypertonia, keratoconjunctivitis, keratopathy, kidney pain, lid margin crusting or sticky sensation, nausea, pharyngitis, tearing and urticaria.

tration of 14C-brinzolamide to pregnant rats, radioactivity was found to cross the placenta and was present in the fetal tissues and blood.

S:9.875”

Severe Renal Impairment - SIMBRINZA™ Suspension has not been specifically studied in patients with severe renal impairment (CrCl < 30 mL/min). Since brinzolamide and its metabolite are excreted predominantly by the kidney, SIMBRINZA™ Suspension is not recommended in such patients.

Brinzolamide 1% - In clinical studies of brinzolamide ophthalmic suspension 1%, the most frequently reported adverse reactions reported in 5 to 10% of patients were blurred vision and bitter, sour or unusual taste. Adverse reactions occurring in 1 to 5% of patients were blepharitis, dermatitis, dry eye, foreign body sensation, headache, hyperemia, ocular discharge, ocular discomfort, ocular keratitis, ocular pain, ocular pruritus and rhinitis.

May/June 2013

Volume 6, number 4 The Peer-Reviewed Forum for Evidence in Benefit Design ™

™

™

For Payers, Purchasers, Policymakers, and Other Healthcare Stakeholders

Table of Contents

(Continued) 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.

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DEPARTMENTs

INDUSTRY TRENDS 168 The Race to Open Enrollment: Critical Success Factors for Exchanges

By Caroline F. Pearson 184 S tep-Up Therapy Program for Anti-Inflammatory Biologic Agents Does Not Increase Cost Nor Adversely Affect Patient Outcomes

By Wayne Kuznar 202 AMCP Highlights

By Charles Bankhead 209 Payer’s Trends

An Inside Look at Managed Care Executive Conversations within the Health Payer Council: What Is Evidence?

By Enid W. McDonough, JD; Roger Green, MBA

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

Correction In the April 2013 Payers’ Guide to New FDA Approvals, a Special Feature of American Health & Drug Benefits, the name of the drug Xeljanz (tofacitinib), which was approved in 2012, was misspelled on page 99. The correct spelling is Xeljanz. We regret the error.

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Vol 6, No 4

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May/June 2013

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FOR ADULT PATIENTS WITH TYPE 2 DIABETES TRADJENTAÂŽ (LINAGLIPTIN) TABLETS: THE ONLY SINGLE-STRENGTH DPP-4 INHIBITOR

Focusing on what matters Improving glycemic control for adult patients with type 2 diabetes Indication and Important Limitations of Use TRADJENTA is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

in a clinical trial. Therefore, a lower dose of the insulin secretagogue or insulin may be required to reduce the risk of hypoglycemia when used in combination with TRADJENTA.

TRADJENTA should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.

Macrovascular Outcomes There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with TRADJENTA or any other antidiabetic drug.

Important Safety Information

ADVERSE REACTIONS

CONTRAINDICATIONS TRADJENTA is contraindicated in patients with a history of hypersensitivity reaction to linagliptin, such as urticaria, angioedema or bronchial hyperreactivity.

WARNINGS AND PRECAUTIONS Use with Medications Known to Cause Hypoglycemia Insulin secretagogues and insulin are known to cause hypoglycemia. The use of TRADJENTA in combination with an insulin secretagogue (e.g., sulfonylurea) was associated with a higher rate of hypoglycemia compared with placebo

Adverse reactions reported in â&#x2030;Ľ5% of patients treated with TRADJENTA and more commonly than in patients treated with placebo included nasopharyngitis.

Hypoglycemia was more commonly reported in patients treated with the combination of TRADJENTA and sulfonylurea compared with those treated with the combination of placebo and sulfonylurea. When TRADJENTA was administered in combination with metformin and a sulfonylurea, 181 of 792 (22.9%) patients reported hypoglycemia compared with 39 of 263 (14.8%) patients administered placebo in combination with metformin and a sulfonylurea. In patients receiving

TRADJENTA delivers proven glycemic control Placebo-adjusted difference in A1C with oral monoand dual therapy at 24 weeks (%) TRADJENTA monotherapy1,2* Baseline A1C 8.0%

*A randomized, multicenter, double-blind, placebo-controlled study of

adult patients with type 2 diabetes (aged 18-80) who were randomized to TRADJENTA 5 mg/day (n=336; mean baseline A1C=8.0%) or placebo (n=167; mean baseline A1C=8.0%) for 24 weeks. Primary endpoint was change from baseline in A1C at 24 weeks. 20.9% of patients in the placebo group required rescue therapy vs 10.2% of patients in the TRADJENTA group. Full analysis population using last observation on study.

TRADJENTA add-on to metformin2,3† Baseline A1C 8.1%

–0.7%

‡

(n=333) P<0.0001

†

A randomized, double-blind, placebo-controlled, parallel-group study of adult patients with type 2 diabetes (aged 18-80) with insufficient glycemic control despite metformin therapy who were randomized to TRADJENTA 5 mg/day (n=524; mean baseline A1C=8.1%) or placebo (n=177; mean baseline A1C=8.0%) in combination with metformin ≥1500 mg/day for 24 weeks. Primary endpoint was change from baseline in A1C at 24 weeks.

18.9% of patients in the placebo group required rescue therapy vs 7.8% of patients in the TRADJENTA group. Full analysis population using last observation on study.

‡

0.3% adjusted mean increase from baseline A1C 8.0% with placebo (n=163).2

§

0.15% adjusted mean increase from baseline A1C 8.0% with placebo plus metformin (n=175).2

–0.6%§ (n=513) P<0.0001

TRADJENTA: A single-strength DPP-4 inhibitor No dose adjustment required regardless of declining renal function or hepatic impairment TRADJENTA is primarily nonrenally excreted with 80% eliminated via the bile and gut and 5% eliminated via the kidney within 4 days of dosing

T:10.5”

TRADJENTA has a demonstrated safety profile evaluated in more than 6000 patients

TRADJENTA as add-on therapy to a stable dose of insulin, severe hypoglycemic events were reported in 11 (1.7%) patients compared with 7 (1.1%) for placebo.

In the clinical trial program, pancreatitis was reported in 15.2 cases per 10,000 patient-years of exposure while being treated with TRADJENTA compared with 3.7 cases per 10,000 patient-years of exposure while being treated with comparator (placebo and active comparator, sulfonylurea).

Three additional cases of pancreatitis were reported following the last administered dose of linagliptin.

DRUG INTERACTIONS The efficacy of TRADJENTA may be reduced when administered in combination with a strong P-glycoprotein or CYP3A4 inducer (e.g., rifampin). Therefore, use of alternative treatments to TRADJENTA is strongly recommended.

USE IN SPECIFIC POPULATIONS

should be exercised when TRADJENTA is administered to a nursing woman.

The safety and effectiveness of TRADJENTA in patients below the age of 18 have not been established.

TJ PROF ISI Sept 28 2012

References: 1. Del Prato S, Barnett AH, Huisman H, et al. Effect of linagliptin monotherapy on glycaemic control and markers of β-cell function in patients with inadequately controlled type 2 diabetes: a randomized controlled trial. Diabetes Obes Metab. 2011;13:258-267. 2. Data on file. Boehringer Ingelheim Pharmaceuticals, Inc. 3. Taskinen M-R, Rosenstock J, Tamminen I, et al. Safety and efficacy of linagliptin as add-on therapy to metformin in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled study. Diabetes Obes Metab. 2011;13:65-74.

Please see brief summary of full Prescribing Information on adjacent page.

There are no adequate and well-controlled studies in pregnant women. Therefore, TRADJENTA should be used during pregnancy only if clearly needed.

It is not known whether linagliptin is excreted in human milk.

Because many drugs are excreted in human milk, caution

Find out more about TRADJENTA and the Savings Card program at www.tradjenta.com Copyright © 2012 Boehringer Ingelheim Pharmaceuticals, Inc. All rights reserved.

ENTA TRADJ 30 5 MG # O QD Sig: i P ILLS x2 REF

(11/12) TJ527600PROFA

Tradjenta® (linagliptin) tablets BRIEF SUMMARY OF PRESCRIBING INFORMATION Please see package insert for full Prescribing Information.

INDICATIONS AND USAGE Monotherapy and Combination Therapy: TRADJENTA tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Important Limitations of Use: TRADJENTA should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings.

CONTRAINDICATIONS TRADJENTA is contraindicated in patients with a history of a hypersensitivity reaction to linagliptin, such as urticaria, angioedema, or bronchial hyperreactivity.

WARNINGS AND PRECAUTIONS Use with Medications Known to Cause Hypoglycemia: Insulin secretagogues and insulin are known to cause hypoglycemia. The use of TRADJENTA in combination with an insulin secretagogue (e.g., sulfonylurea) was associated with a higher rate of hypoglycemia compared with placebo in a clinical trial. The use of TRADJENTA in combination with insulin in subjects with severe renal impairment was associated with a higher rate of hypoglycemia. Therefore, a lower dose of the insulin secretagogue or insulin may be required to reduce the risk of hypoglycemia when used in combination with TRADJENTA. Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with TRADJENTA tablets or any other antidiabetic drug.

ADVERSE REACTIONS 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 practice. The safety evaluation of TRADJENTA 5 mg once daily in patients with type 2 diabetes is based on 14 placebo-controlled trials, 1 activecontrolled study, and one study in patients with severe renal impairment. In the 14 placebo-controlled studies, a total of 3625 patients were randomized and treated with TRADJENTA 5 mg daily and 2176 with placebo. The mean exposure in patients treated with TRADJENTA across studies was 29.6 weeks. The maximum follow-up was 78 weeks. TRADJENTA 5 mg once daily was studied as monotherapy in three placebo-controlled trials of 18 and 24 weeks’ duration and in five additional placebocontrolled studies lasting ≤18 weeks. The use of TRADJENTA in combination with other antihyperglycemic agents was studied in six placebo-controlled trials: two with metformin (12 and 24 weeks’ treatment duration); one with a sulfonylurea (18 weeks’ treatment duration); one with metformin and sulfonylurea (24 weeks’ treatment duration); one with pioglitazone (24 weeks’ treatment duration); and one with insulin (primary endpoint at 24 weeks). In a pooled dataset of 14 placebo-controlled clinical trials, adverse reactions that occurred in ≥2% of patients receiving TRADJENTA (n = 3625) and more commonly than in patients given placebo (n = 2176), are shown in Table 1. The overall incidence of adverse events with TRADJENTA were similar to placebo.

Table 1 Adverse Reactions Reported in ≥2% of Patients Treated with TRADJENTA and Greater than Placebo in Placebo-Controlled Clinical Studies of TRADJENTA Monotherapy or Combination Therapy

Nasopharyngitis Diarrhea Cough

Number (%) of Patients TRADJENTA 5 mg Placebo n = 3625 n = 2176 254 (7.0) 132 (6.1) 119 (3.3) 65 (3.0) 76 (2.1) 30 (1.4)

Rates for other adverse reactions for TRADJENTA 5 mg versus placebo when TRADJENTA was used in combination with specific anti-diabetic agents were: urinary tract infection (3.1% vs 0%) and hypertriglyceridemia (2.4% vs 0%) when TRADJENTA was used as add-on to sulfonylurea; hyperlipidemia (2.7% vs 0.8%) and weight increased (2.3% vs 0.8%) when TRADJENTA was used as add-on to pioglitazone; and constipation (2.1% vs 1%) when TRADJENTA was used as add-on to basal insulin therapy. Following 104 weeks’ treatment in a controlled study comparing TRADJENTA with glimepiride in which all patients were also receiving metformin, adverse reactions reported in ≥5% of patients treated with TRADJENTA (n = 776) and more frequently than in patients treated with a sulfonylurea (n = 775) were back pain (9.1% vs 8.4%), arthralgia (8.1% vs 6.1%), upper respiratory tract infection (8.0% vs 7.6%), headache (6.4% vs 5.2%), cough (6.1% vs 4.9%), and pain in extremity (5.3% vs 3.9%). Other adverse reactions reported in clinical studies with treatment of TRADJENTA were hypersensitivity (e.g., urticaria, angioedema, localized skin exfoliation, or bronchial hyperreactivity), and myalgia. In the clinical trial program, pancreatitis was reported in 15.2 cases per 10,000 patient year exposure while being treated with TRADJENTA compared with 3.7 cases per 10,000 patient year exposure while being treated with comparator (placebo and active comparator, sulfonylurea). Three additional cases of pancreatitis were reported following the last administered dose of linagliptin. Hypoglycemia: In the placebo-controlled studies, 199 (6.6%) of the total 2994 patients treated with TRADJENTA 5 mg reported hypoglycemia compared to 56 patients (3.6%) of 1546 placebo-treated patients. The incidence of hypoglycemia was similar to placebo when TRADJENTA was administered as monotherapy or in combination with metformin, or with pioglitazone. When TRADJENTA was administered in combination with metformin and a sulfonylurea, 181 of 792 (22.9%) patients reported hypoglycemia compared with 39 of 263 (14.8%) patients administered placebo in combination with metformin and a sulfonylurea.

Adverse reactions of hypoglycemia were based on all reports of hypoglycemia. A concurrent glucose measurement was not required or was normal in some patients.

Therefore, it is not possible to conclusively determine that all these reports reflect true hypoglycemia. In the study of patients receiving TRADJENTA as add-on therapy to a stable dose of insulin for up to 52 weeks (n=1261), no significant difference in

the incidence of investigator reported hypoglycemia, defined as all symptomatic or asymptomatic episodes with a self measured blood glucose ≤70 mg/dL, was noted between the TRADJENTA (31.4%) and placebo (32.9%) treated groups. During the same time period, severe hypoglycemic events, defined as requiring the assistance of another person to actively administer carbohydrate, glucagon or other resuscitative actions, were reported in 11 (1.7%) of TRADJENTA treated patients and 7 (1.1%) of placebo treated patients. Events that were considered life-threatening or required hospitalization were reported in 3 (0.5%) patients on TRADJENTA and 1 (0.2%) on placebo. Use in Renal Impairment: TRADJENTA was compared to placebo as add-on to pre-existing antidiabetic therapy over 52 weeks in 133 patients with severe renal impairment (estimated GFR <30 mL/min). For the initial 12 weeks of the study, background antidiabetic therapy was kept stable and included insulin, sulfonylurea, glinides, and pioglitazone. For the remainder of the trial, dose adjustments in antidiabetic background therapy were allowed. In general, the incidence of adverse events including severe hypoglycemia was similar to those reported in other TRADJENTA trials.

The observed incidence of hypoglycemia was higher (TRADJENTA, 63% compared to placebo, 49%) due to an increase in asymptomatic hypoglycemic events especially during the first 12 weeks when background glycemic therapies were kept stable. Ten TRADJENTA treated patients (15%) and 11 placebo-treated patients (17%) reported at least one episode of confirmed symptomatic hypoglycemia (accompanying finger stick glucose ≤54 mg/dL). During the same time period, severe hypoglycemic events, defined as an event requiring the assistance of another person to actively administer carbohydrate, glucagon or other resuscitative actions, were reported in 3 (4.4%) TRADJENTA treated patients and 3 (4.6%) placebo treated patients. Events that were considered life-threatening or required hospitalization were reported in 2 (2.9%) patients on TRADJENTA and 1 (1.5%) on placebo. Renal function as measured by mean eGFR and creatinine clearance did not change over 52 weeks treatment compared to placebo. Laboratory Tests: Changes in laboratory findings were similar in patients treated with TRADJENTA 5 mg compared to patients treated with placebo. Changes in laboratory values that occurred more frequently in the TRADJENTA group and ≥1% more than in the placebo group were increases in uric acid (1.3% in the placebo group, 2.7% in the TRADJENTA group). No clinically meaningful changes in vital signs were observed in patients treated with TRADJENTA. DRUG INTERACTIONS Inducers of P-glycoprotein or CYP3A4 Enzymes: Rifampin decreased linagliptin exposure suggesting that the efficacy of TRADJENTA may be reduced when administered in combination with a strong P-gp or CYP3A4 inducer. Therefore, use of alternative treatments is strongly recommended when linagliptin is to be administered with a strong P-gp or CYP3A4 inducer.

USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category B. Reproduction studies have been performed in rats and rabbits. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Linagliptin administered during the period of organogenesis was not teratogenic at doses up to 30 mg/kg in the rat and 150 mg/kg in the rabbit, or approximately 49 and 1943 times the clinical dose based on AUC exposure. Doses of linagliptin causing maternal toxicity in the rat and the rabbit also caused developmental delays in skeletal ossification and slightly increased embryofetal loss in rat (1000 times the clinical dose) and increased fetal resorptions and visceral and skeletal variations in the rabbit (1943 times the clinical dose). Linagliptin administered to female rats from gestation day 6 to lactation day 21 resulted in decreased body weight and delays in physical and behavioral development in male and female offspring at maternally toxic doses (exposures >1000 times the clinical dose). No functional, behavioral, or reproductive toxicity was observed in offspring of rats exposed to 49 times the clinical dose.

Linagliptin crossed the placenta into the fetus following oral dosing in pregnant rats and rabbits. Nursing Mothers: Available animal data have shown excretion of linagliptin in milk at a milk-to-plasma ratio of 4:1. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when TRADJENTA is administered to a nursing woman. Pediatric Use: Safety and effectiveness of TRADJENTA in pediatric patients have not been established. Geriatric Use: There were 4040 type 2 diabetes patients treated with linagliptin 5 mg from 15 clinical trials of TRADJENTA; 1085 (27%) were 65 years and over, while 131 (3%) were 75 years and over. Of these patients, 2566 were enrolled in 12 doubleblind placebo-controlled studies; 591 (23%) were 65 years and over, while 82 (3%) were 75 years and over. No overall differences in safety or effectiveness were observed between patients 65 years and over and younger patients. Therefore, no dose adjustment is recommended in the elderly population. While clinical studies of linagliptin have not identified differences in response between the elderly and younger patients, greater sensitivity of some older individuals cannot be ruled out. Renal Impairment: No dose adjustment is recommended for patients with renal impairment. Hepatic Impairment: No dose adjustment is recommended for patients with hepatic impairment.

OVERDOSAGE In the event of an overdose with TRADJENTA, contact the Poison Control Center. Employ the usual supportive measures (e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive treatment) as dictated by the patient’s clinical status. Removal of linagliptin by hemodialysis or peritoneal dialysis is unlikely. During controlled clinical trials in healthy subjects, with single doses of up to 600 mg of TRADJENTA (equivalent to 120 times the recommended daily dose) there were no dose-related clinical adverse drug reactions. There is no experience with doses above 600 mg in humans.

Copyright © 2012 Boehringer Ingelheim International GmbH Revised: September 2012

TJ-BS (9-12)

TJ481100PROF-A

Editorial

Reflections on Japan’s Complex Medical Culture David B. Nash, MD, MBA Editor-in-Chief, American Health & Drug Benefits Jefferson School of Population Health, Philadelphia, PA

I

had the recent privilege of carrying the “flags” of our school and of American Health & Drug Benefits to the enchanting island of Japan as a plenary speaker at the 113th Annual Congress of the Japanese Surgical Society.

I would like to share some of my reflections on this incredibly complicated, and sometimes even paradoxical, medical culture during my 1-week whirlwind visit.

The theme of the 113th Annual Congress was designated as “soushi” and “keiji,” which mean “the creation and succession of will.” Each major medical conference in Japan has a theme, and this conference was no exception. Hence, my first observation is of the great respect Japanese have for their ancestors, juxtaposed with a modern, vibrant, and futuristic society. Soushi and keiji, as articulated by Yoshihiko Maehara, MD, PhD, the Congress president, mean that by developing various revolutionary diagnostic techniques, creative surgical methods, and robust perioperative management methods, the subsequent achievements accompanied by the strong will that made them possible have been continuously passed down to us as keiji. In the past 25 years I have never attended a medical meeting in the United States that had a theme explicitly recognizing the contribution of our elders and the notion of a collective will to succeed.

In Tokyo, the hyperkinetic movement of one of the world’s mega cities is in stark contrast to the ancient city center with the Emperor’s palace, reflecting the long­estlived dynasty in the world. The palace is surrounded by unbelievable traffic and skyscrapers, including the world’s tallest observation tower.

While in Tokyo, I had the opportunity to meet Takashi Fukuda, PhD, and Shunya Ikeda, MD, MS, DrMedSci, who are members of the Japanese National Committee that is charged with establishing individual drug pricing. Let me put this into context. Japanese universal healthcare insurance is composed of essentially 3 categories: employee health insurance, district health insurance, and elderly health insurance. Employers are mandated to provide health insurance coverage to employees and their dependents, although premiums are shared by both the employer and employees. This is a

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hybrid model: the government pays 25% of the healthcare costs, and the remainder is paid by employers and workers. In a nutshell, it is a single-payer system that is used by multiple payers.

In my meeting with Dr Fukuda and Dr Ikeda, it became clear that Japan’s cost-containment strategy is primarily attributed to its payment system; that is, through supply-side cost control provided by the nationally uniform fee schedule, the central government annually revisits all reimbursement decisions. In other words, a multidisciplinary team of experts, including my dinner guests, thoroughly review every single drug sold in Japan and establish a uniform price for its use. In addition to drug price review, all procedures in Japan are similarly assessed. This means that throughout the nation there is an almost completely uniform reimbursement rate.

The multidisciplinary groups make a recommendation to the central government, and the cabinet then decides on the global revised rate of all services and drug prices based on the prime minister’s evaluation of the nation’s political and economic situation.

In a way, one can draw a straight line from Japan’s overall economic condition to the cabinet to these multidisciplinary assessment committees to the price of an individual pharmaceutical agent.

A multidisciplinary team of experts, including my dinner guests, thoroughly review every single drug sold in Japan and establish a uniform price for its use. In addition to drug price review, all procedures in Japan are similarly assessed. This means that throughout the nation there is an almost completely uniform reimbursement rate.

As a result of this national drug review process, the science of health economics and outcomes research (HEOR) becomes paramount. Japanese pharmaceutical companies have continued to invest resources in skilled

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scientific teams that are capable of conducting advanced HEOR. These teams then promote their work, both in Japan and globally, in the peer-reviewed literature in an attempt to influence the decision-making of the multispecialty review boards that are charged with individual drug assessments.

During my visit, I had the opportunity to meet with a team of HEOR experts from Bayer Pharmaceuticals. The team, led by Edward C.Y. Wang, PharmD, MBA, Head of Health Economics and Outcomes Research at Bayer Yakuhin, Ltd, was truly representative of a global company in that most of the individuals were multicultural and multilingual. They had been trained in various leading academic organizations in the United States and abroad.

They were an impressive lot, and they helped me to further understand how important HEOR data have become in Japan. If a nation is going to build a national formulary, it is best to have the most current available information about the cost-benefit and cost-effectiveness of each product.

Although the price of every drug and service is revised on an item-by-item basis, it is fascinating to note that these decisions are supported by a national claims data survey. With a centralized system, the Japanese government is able to collect claims data on virtually every rendered service. Once this level of data is collected, it can be adjusted for severity. The Japanese severity (or case mix classification) system is called the diagnosis procedure combination (DPC). This is a methodology used to level the playing field across Japan, and it enables the government to more accurately predict next year’s utilization level. The DPC is made up of 3 core elements: the diagnosis, the procedures, and a combination of the comorbidities and the complications. Hospitals have a mandatory reporting system, whereby they submit clinical information from medical records and claims data.

Then, by linking information about severity, resource use, and outcome, the Minister of Health, Labour, and Welfare can apply these data to their per-diem and perdrug pricing schemes.

Japan’s centralized delivery system helps to promote greater uniformity in pricing. Because 80% of major surgeries and cancer treatments are conducted in only 200 hospitals nationwide, the central government has a tight rein on overall costs. During my trip, I had an opportunity to briefly visit one of these 200 major hospitals, namely, Kyushu University Hospital in Fukuoka. Kyushu University Hospital has nearly 1300 beds and would rival any major academic medical center with which I am familiar in our country. Three blocks from Kyushu Univer-

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sity Hospital is a Shinto shrine, Hakozakigu, that dates back more than 9 centuries and was rebuilt after a fire in 1594. The juxtaposition of a 1200-bed, ultramodern, 5-year-old major academic medical center within walking distance from a historically important shrine built in the 16th century was truly a unique sight.

My trip culminated with my plenary presentation at the Japanese Surgical Society meeting in Fukuoka. I had the opportunity to describe the “volume-to-value” movement in the United States, with a special emphasis on the Affordable Care Act. The 8 presentations that followed my opening address were also quite fascinating.

Although I cannot describe each in detail here, 2 are worth noting.

I was particularly impressed by Gen Shimada, MD, the Director of Medical Information in the Department of General Surgery at St Luke’s International Hospital, Tokyo. Dr Shimada reviewed St Luke’s experience with the American-based National Surgical Quality Improvement Program (NSQIP) and related national measures. It was clear to me that St Luke’s was making very enviable progress in keeping pace with most major American medical centers regarding their excellent NSQIP scores.

The other presentation that I found memorable was

by Kenji Takenaka, MD, PhD, Director of Fukuoka City Hospital. Dr Takenaka described his journey in creating surgeon-specific measures of quality and outcomes. Although some aspects were clearly lost in translation, the gist of his presentation was how difficult it is to implement cultural change, especially in a society that has such deep respect for hierarchy, and a comparable level of respect for experience and age.

With business meetings in Tokyo, Kyoto, and the Surgical Congress in Fukuoka, it made for a whirlwind week of travel on the Shinkansen, better known as the “Bullet Train.” After my Fukuoka-based plenary presentation at the surgical society, I was fortunate to be able to travel by Shinkansen to Hiroshima with my physician wife for one deeply moving afternoon. My heartfelt wish is that every physician would have an opportunity to visit Hiroshima and thereby rededicate ourselves to a world focused on peace and on friendship.

Soushi and keiji—creation and the will to succeed.

We have much to learn from our Japanese colleagues about drug pricing, utilization of resources, establishing a national budget for healthcare, and related concepts. I hope to return to Japan in the near future, and I look forward to providing you with additional reflections at that time. n

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original research

Optimizing the Economic Impact of rtPA Use in a Stroke Belt State: The Case of South Carolina

Abby Swanson Kazley, PhD; Kit N. Simpson, DrPH; Annie Simpson, PhD; Edward Jauch, MD; Robert J. Adams, MD Background: Stroke is the fourth leading cause of death in the United States, and its incidence is especially high in South Carolina. Recombinant tissue plasminogen activator (rtPA) has been given to patients with acute ischemic stroke since 1996 and has shown overall improved outcomes relative to patients who are not treated with rtPA. Objective: A 1998 study by Fagan and colleagues reported the economic impact of the use of rtPA. The purpose of this current article is to present an updated economic analysis of the impact of rtPA. Methods: In the current analysis, an updated estimate of the economic and health benefits of treatment with rtPA in South Carolina was provided using estimates of cost, incidence, and course of treatment from several data sources. The Markov model in the 1998 study was used as a guide in this current study; we sought to replicate the methodology, while providing updated economic figures and applying it to the state of South Carolina. We estimated the costs per 1000 patients who are eligible for treatment with rtPA compared with 1000 untreated patients, as well as routine medical practice and outcomes of quality-adjusted life-years (QALYs) and economic costs based on whether a patient was treated with rtPA or not. We calculated the number of stroke cases that would be treated with rtPA if the rate were to increase from 3% to 20%, using the most recent number of strokes in South Carolina and prorating for 5 years to estimate the total expected cost-savings with increased rtPA use.

Results: The results indicate that the use of rtPA in South Carolina accounts for a cost-savings of $3454 per treated patient over a 6-year period. The model estimates an increase of 0.425 QALYs (or 5.1 quality-adjusted months) of survival per patient treated with rtPA. Over the lifetime of a treated patient, the estimated cost-savings are $4084, with an accrued health benefit of 0.692 QALYs (or 8.3 quality-adjusted months). For every 100 patients treated with rtPA, there is a gain of 69.17 QALYs and of $408,419 over the lifetime of 100 treated patients with acute ischemic stroke. We calculated that the cost-savings gained by increasing the rtPA treatment rate in a state with a high incidence of stroke from the current 3% rate to an achievable 20% rate over a 5-year period would be $16,615,723.

Conclusions: This new analysis demonstrates a significant savings associated with the use of rtPA for patients with stroke and provides great support for the increased systematic use of rtPA in the state of South Carolina for patients with acute ischemic stroke. For every additional 100 patients who are treated with rtPA in South Carolina, a robust savings supports the wider economic benefit that would be gained with an increased use of rtPA.

S

troke remains a leading cause of disability and is the fourth leading cause of death in the United States.1,2 Approximately 780,000 strokes occur in the Unit-

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2013;6(4):155-163 www.AHDBonline.com Disclosures are at end of text

ed States annually; in 2004, stroke accounted for 1 of every 16 deaths.3 The burden of stroke is especially high in South Carolina, which is central within the so-called

Dr Kazley is Program Director, Master of Health Administration Program, and Associate Professor, Department of Health Care Management and Leadership; Dr K Simpson is Professor, Department of Health Care Management and Leadership; Dr A Simpson is Assistant Professor, Department of Health Care Management and Leadership; Dr Jauch is Professor, Department of Neurosciences; Dr Adams is a Distinguished Professor and Co-Director, Comprehensive Stroke and Cerebrovascular Center, all at the Medical University of South Carolina.

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Key Points Stroke is a leading cause of disability and death in the United States and is most prevalent in the so-called Stroke Belt. ➤ Recombinant tissue plasminogen activator (rtPA) has been shown to improve outcomes in patients with stroke, but currently less than 5% of patients with acute ischemic stroke receive rtPA. ➤ Using data for patients with stroke in South Carolina, this study analyzes the economic and health benefits of treating acute ischemic stroke with rtPA. ➤ The results show a cost-savings of $3454 and an increase of 0.425 quality-adjusted life-years per treated patient over a 6-year period. ➤ By increasing the rtPA treatment rate in South Carolina from the current 3% to an achievable rate of 20% over 5 years, the potential increased costsavings would be $16,615,723. ➤ Each percentage increase of rtPA use is associated with an estimated increased cost-savings of nearly $1 million. ➤ For these outcomes to be fully realized, systems and policies must be in place to allow for the timely care of patients with acute ischemic stroke. ➤

Stroke Belt.4-7 The Stroke Belt is an 11-state region in the southeastern United States that has been characterized as having a particularly high incidence of stroke.

Recombinant tissue plasminogen activator (rtPA) has been approved by the US Food and Drug Administration (FDA) for the treatment of stroke.8 There have been few analyses on the economic impact of rtPA9-13; however, no study has focused on 1 single state. Stroke is a costly disease to the US healthcare system and to patients, and it can have a significant impact on a patient’s quality of life.

The direct costs of stroke treatment include initial hospitalization and treatment, rehabilitation, nursing home care, physician care, home healthcare, rehabilitation, drugs, and medical equipment.9 The indirect costs include reduced or loss of productivity as a result of disability or mortality from stroke.9 In 2008, the American Heart Association estimated the total direct and indirect costs of stroke at $65.5 billion and the mean lifetime cost at $140,048 per patient.3 Others have projected that this cost would reach $2.2 trillion between 2005 and 2050, suggesting that the economic impact on the healthcare system remains significant.10 Much of these high costs are the result of the need for skilled nursing and rehabilitation care after a stroke.

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Previous research has suggested that these costs may be reduced through increased treatment with rtPA, which was approved by the FDA in 1996 for patients with acute ischemic stroke, and has been shown to significantly reduce disability.11-13 Fagan and colleagues analyzed the use of rtPA in 1000 hypothetical patients using a Markov model14; this present analysis is an update of that earlier study. Such an update is needed, because of the time that has passed since the last analysis, the updated costs of rtPA, and the changes in routine care and clinical outcomes for patients with acute ischemic stroke. Furthermore, we examined the specified estimates of the use of rtPA in a very specific statewide basis in a state of high stroke incidence and mortality, South Carolina, which is the buckle of the Stroke Belt. Although recent analyses have shown that hospitalization costs for patients with acute ischemic stroke who are treated with rtPA are higher than diagnosis-related group reimbursement from Medicare, there may be long-term cost-savings associated with the use of rtPA.15 The purpose of this new study is to examine the potential cost-savings of treating patients with acute ischemic stroke with rtPA in South Carolina. To provide an updated and state-specific prediction of the health and economic outcomes of the use of rtPA for this patient population, a Markov model was used, which was similar to previous research.11,14 In the model used in the study

by Fagan and colleagues, healthcare provided for patients with acute ischemic stroke was assumed to be consistent with routine medical practice for 2 groups: one group that received rtPA and a placebo group that did not receive rtPA.14 That analysis estimated cost-savings of $600,000 in the first year of care and an increase in quality-­adjusted life-years (QALYs) of 751 per 1000 patients by using one-way sensitivity analysis of assumptions and a Monte Carlo multiway sensitivity analysis for validation.14 Similarly, a Markov model estimated the costs of each component of treatment and the quality-­ adjusted survival expected based on patient age, the distribution of health outcomes at the time of hospital discharge, and on the likelihood of having a recurring stroke for patients over a 5-year period.14 The current study provides an updated economic analysis to a single Stroke Belt state, South Carolina, from a societal perspective. In addition to estimating the economic impact of the use of rtPA for patients with stroke, we also sought to measure the impact of increased rtPA use on a patient’s quality of life.

Methods Markov Model by Fagan and Colleagues The Markov model by Fagan and colleagues was used

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as a guide in this present study, and we sought to replicate the methodology, while providing updated economic figures and applying it to the state of South Carolina. Fagan’s original study developed a Markov model to measure the potential benefit of the use of rtPA in patients with acute ischemic stroke against the cost of the drug, increased time in the intensive care unit, and the risk of intracerebral hemorrhage. Fagan and colleagues then estimated the costs per 1000 patients who are eligible for treatment with rtPA compared with 1000 untreated patients. The model assumed routine medical practice and considered outcomes of QALYs and economic costs.14 The model had 7 poststroke disability states based on the modified Rankin scale (mRS), and all patients were assumed to be age 67 years at the time of stroke.14 Fagan and colleagues used a sensitivity analysis to address the concern that patients in the National Institute of Neurological Disorders and Stroke (NINDS) trial were healthier than patients in the general population.

Applying a societal perspective, Fagan and colleagues used previous data to make assumptions of economic cost, patient value and preference, and epidemiologic factors. The data sources included a local survey, NINDS data, and related literature. The model examined patient states at 10 days, 3 months, 6 months, and 1 year.14

The Updated Model In building the model in the current analysis, NINDS data from previous research in the study by Fagan and colleagues were used to verify the structure of our model and to assess its predictive validity in replicating their results. We used an approach similar to that used by Fagan and colleagues, in which patients could move between 7 poststroke states based on the mRS: no symptoms (mRS 0), no significant disability (mRS 1), minimal disability (mRS 2), moderate disability (mRS 3), moderate-to-severe disability (mRS 4), severe disability (mRS 5), and death (mRS 6). The health outcomes were measured using QALYs, and the economic outcomes were based on the estimated cost to treat a patient based on whether that patient received rtPA. The model held most of the previous assumptions, including the rate of recurrent stroke (0.052), the rate of symptomatic hemorrhage after treatment with rtPA (6.45%), the inclusion of a charge for a 2-hour visit to a specialist during the initial evaluation, patients being discharged to a nursing home and remaining there until death, and patients who did not receive rtPA having subsequent strokes. Other assumptions included patients being discharged from rehabilitation and going to a nursing home, and all patients were aged 67 years (the reported mean age of patients in the NINDS rtPA stroke trial) at the time of the stroke.

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Table 1 The Model’s Assumptions Variables

rtPA

Placebo

Source

rtPA cost, $

2750

—

Hospital billing

Consult physician cost, $

467

—

Hospital billing

ICU cost, $

1206

—

Hospital billing

Intracranial hemorrhage rate, %

0.0645

0.01

NINDS

Died in hospital, %

0.074

0.101

NINDS

Discharged home, %

0.46

0.36

NINDS

Rehabilitation to nursing home, %

0.18

0.18

NINDS

Death multiplier

1.65

1.65

NINDS

Annual restroke, %

0.052

0.052

NINDS

Recurrent stroke death, %

0.18

0.18

NINDS

Hospital days, N

10.9

12.4

NINDS

Daily hospital cost, $

2984

2984

HCUP

20

20

NINDS

1652

1652

HCUP

Home health days, N

10

10

NINDS

Daily home health cost, $

349

349

HCUP

ICH added cost, $

7002

7002

HCUP

Annual nursing home cost, $

62,218

62,218

HCUP

Subsequent stroke cost, $

64,096

64,096

HCUP

Utilities R0

0.9

0.9

Fagan model

Utilities R1

0.8

0.8

Fagan model

Utilities R2

0.46

0.46

Fagan model

Utilities R3

0.34

0.34

Fagan model

Utilities R4

0.3

0.3

Fagan model

Utilities R5

0.01

0.01

Reflective of national policy

Rehabilitation days, N Daily rehabilitation cost, $

HCUP indicates Healthcare Cost and Utilization Project; ICH, intracerebral hemorrhage; ICU, intensive care unit; NINDS, National Institute of Neurological Disorders and Stroke; rtPA, recombinant tissue plasminogen activator.

Sources: South Carolina Universal Billing 92 Form discharge data; HCUP nationwide inpatient sample 2010. www.hcup-us.ahrq. gov/db/nation/nis/nisdbdocumentation.jsp; 2009 and 2010 HCUP state inpatient data for South Carolina, State Inpatient Databases. www.hcup-us.ahrq.gov/db/state/siddbdocumentation.jsp; NINDS. Clinical research tool kit. www.ninds.nih.gov/research/clinical_ research/toolkit/common_data_elements.htm.

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Figure Illustration of Patient Movement in the Model

Receive rtPA

R0 R1 R2 R3 R4 R5 Dead

No intracerebral hemorrhage

Stroke

Intracerebral hemorrhage

No rtPA

Home

Stroke recurrence

Rehabilitation Nursing home

Nonstroke death

NOTE: Patients enter the model when they are seen in the hospital for stroke and receive or do not receive rtPA. Then, they experience or do not experience an intracerebral hemorrhage and either enter into varying states of disability, based on Rankin score (R0-R5), or die. On discharge from the hospital, and based on the patient’s state of disability, the patient is then discharged home, to rehabilitation, or to a nursing home, and subsequently has a stroke recurrence or a nonstroke death in varying time intervals. rtPA indicates recombinant tissue plasminogen activator.

Several assumptions in our study were updated. First, the mRS of 5 was assigned to a utility of 0.01 instead of –0.02, because this is consistent with euthanasia, which is illegal in the United States. Other utility values remained the same as the previous model in the Fagan and colleagues study. First, a score of 1.0 was used for perfect health (with mRS of 1-4 corresponding to scores of 0.80, 0.46, 0.34, and 0.30, respectively). Second, a Centers for Disease Control and Prevention– specific death rate was used instead of an actuarial death rate for the patients with stroke.16 Third, a 9-month follow-up period was added to the model to account for a patient’s movement between outcome states at another designated time interval. Fourth, the cost of rtPA was updated based on average hospital billing in South Carolina ($2750 for 100 mg), and hospitalization rates were provided by the Uniform Billing form (UB-92) discharge data.

Finally, unlike previous models, for our model we first considered only 6 years poststroke, to be able to predict the short-term quality of life and economic outcomes.

The lifetime costs predicted by the same model and a sensitivity analysis of the lifetime model were also considered. The sensitivity analysis was conducted using Crystal Ball software (Oracle; Redwood Shores, CA).

The assumptions of our model are provided in Table 1, and the stages of the model are shown in the Figure.

The following variables were included based on NINDS trials: (1) patients treated with rtPA experienced an intracerebral hemorrhage rate of 0.0645% compared with a rate of 0.010% in the group that received a placebo, (2) 46% of patients treated with rtPA were discharged home compared with 36% of those

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who received a placebo, and (3) the average number of inpatient hospital days for patients treated with rtPA was 10.9 compared with 12.4 days for patients who received a placebo.

Updated cost information using Healthcare Cost and Utilization Project (HCUP) data from South Carolina and Maryland was included to account for the cost of patients with acute ischemic stroke who were treated with rtPA and patients who did not receive rtPA. Although the focus of the analysis was on South Carolina, we also examined HCUP data from Maryland to ensure that the cost was nationally representative, and then applied the cost to South Carolina–specific incidence.

South Carolina Medicare data from 1996 to 1997 and 2004 to 2005 were used to calculate the frequency of time in the sequence of care for patients in each of the health states and treatment types. Data from these 2 different decades were used to ensure that the included estimates are reflective of the episodes of care in South Carolina. A transition matrix is provided in the Appendix (page 162).

The use of these data sets allowed for the estimation of the impact of rtPA use for a specific population, to inform policymakers and payer groups of the potential budget and impact on health benefits of increasing access to rtPA treatment. The HCUP data were inflated using the medical care Consumer Price Index for 2011 from the US Bureau of Labor and Statistics.17 Future costs and QALYs were discounted by 3%, which was consistent with requirements of economic analyses exceeding a 1-year time horizon.

After calculating the cost and quality-of-life gains that are associated with rtPA use for individual patients, we estimated (based on our model) outcomes for

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Table 2 Short-Term Cost-Savings with rtPA Treatment

Table 3 Lifetime Cost-Savings with rtPA Treatment

Outputs

rtPA

Placebo

Outputs

rtPA

Placebo

Intracerebral hemorrhage events, N

6.45

1.00

Intracerebral hemorrhage events, N

6.45

1

225.16

179.85

392.02

310.8

8,872,933

9,225,364

11,778,377

12,215,019

Total QALYs, N Total cost, $

Total QALYs, N Total cost, $

Additional intracerebral hemorrhage events, N

5.45

Additional intracerebral hemorrhage events, N

5.45

QALYs gained, N

45.31

QALYs gained, N

81.22

Cost-Savings, $

Cost-savings, $

352,430

Discounted outcomes

Discounted outcomesa Total discounted QALYs, N Total discounted cost, $ QALYs gained, N Cost-savings, $

210.97

168.59

8,651,313

8,996,752

Total discounted QALYs, N Total discounted cost, $ QALYs gained, N

42.38

Cost-savings, $

345,438

335.7

266.54

10,806,268

11,214,687

69.17 408,419

Per patient

Per patient Quality-adjusted months gained, N Cost-savings, $

Quality-adjusted months gained, N

5.1

Cost-savings, $

3454

Discounts were made using the US Bureau of Labor Statistics. Consumer Price Index, Medical Care. Series ID, CUUR0000SAM2; not seasonally adjusted; area, US city average; item, medical care services; base period, 1982-1984 = 100. www.data.bls.gov/.

QALYs indicates quality-adjusted life-years; rtPA, recombinant tissue plasminogen activator.

a

an achievable rate (ie, 20%) of rtPA use. Specifically, we calculated the number of stroke cases that would be treated with rtPA if the rate were to increase from 3% to 20%, using the most recent number of strokes in South Carolina and prorating this number for 5 years to estimate the total cost-savings that are expected for increased rtPA use in the state.

The number of strokes in South Carolina was provided by the UB-92 hospital discharge data, and the rate of ideal use was estimated to increase from 3% to 20% for the years 2012 to 2016. In 2009, the most recent year available, 9299 cases of acute ischemic stroke were reported in South Carolina for patients aged >45 years.

This number was used as a baseline estimate for the number of strokes in 2012, with small increases of strokes estimated annually, based on recent trends in South Carolina, according to the UB-04 data. Patients aged <45 years were not included in this study, because these strokes are often associated with conditions such as sickle-足cell disease or with cocaine use.

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8.3 4084

QALYs indicates quality-adjusted life-years; rtPA, recombinant tissue plasminogen activator.

tatewide Cost-Savings of Increased rtPA Use Table 4 S in South Carolina Patients receiving rtPA, % Cost-savings 3

$2,498,166,586

20

$2,514,782,309

rtPA indicates recombinant tissue plasminogen activator.

Results Based on our model, the use of rtPA to treat 100 patients with acute ischemic stroke was estimated to result in an increased QALYs of 225.16 Our analysis predicted cost-savings for South Carolina of $352,430 for 100 patients over a 6-year period. At an individual patient level, this amounted to 5.1 quality-adjusted months gained per patient and a cost-savings of $3454 per patient (Table 2).

Consistent with previously published studies, our model also examined the lifetime costs associated with rtPA treatment. The estimated overall lifetime cost-savings for 100 patients was $408,419, with 69.17 QALYs gained.

These estimates indicate a $4084 cost-savings per patient over a lifetime of treatment with rtPA, and 8.3 quality-adjusted months gained per patient over a life-

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Table 5 Sensitivity Analysis of Lifetime Model Months Cost-savings Months Cost-savings gained, N (increase), $ gained, N (increase), $ Base model

8.3

4084

Increase

Increase

Decrease

Decrease

Double or halve intracranial hemorrhage rate

8.3

3703

8.3

4275

Died in hospital: up 20%, down 20%

8.3

4087

8.3

4084

Died at home: up 20%, down 20%

8.3

6278

8.3

1891

Rehabilitation at nursing home: up 20%, down 20%

8.3

4747

8.3

3421

Death multiplier: up 20%, down 20%

7.6

3930

9.2

4279

Annual restroke: up 20%, down 20%

8.2

3861

8.4

4312

Recurring stroke death: up 20%, down 20%

8.2

4065

8.4

4104

Hospital days: up 20%, down 20%

8.3

–2421

8.3

10,589

Hospital cost: up 20%, down 20%

8.3

4979

8.3

3189

Rehabilitation days: up 20%, down 20%

8.3

4582

8.3

3586

Rehabilitation cost: up 20%, down 20%

8.3

4582

8.3

3586

Home health days: up 20%, down 20%

8.3

4013

8.3

4156

Home health cost: up 20%, down 20%

8.3

4013

8.3

4156

Intracerebral hemorrhage added cost: up 20%, down 20%

8.3

4008

8.3

4161

Annual nursing home cost: up 20%, down 20%

8.3

4747

8.3

3421

Subsequent stroke cost: up 20%, down 20%

8.3

3878

8.3

4291

QALY weights: up 10%, down 10%

9.1

4084

7.5

4084

QALY indicates quality-adjusted life-year.

time of treatment with rtPA. The results of the model for a lifetime savings are presented in Table 3 and are similar to the findings of Fagan and colleagues.

Given the magnitude and frequency of stroke in South Carolina, if the rate of rtPA treatment would increase from 3% of all strokes to 20% of all strokes, the estimated total cost-savings for South Carolina would increase by $16,615,723, to $2,514,782,309 (Table 4). The cost-­ savings for treating 3% of patients with stroke with rtPA between 2012 and 2016 would be $2,531,398,032. This indicates an increased cost-savings of nearly $1 million for each percentage increase of rtPA use.

The sensitivity analysis of the lifetime model was conducted using the Crystal Ball software and is presented in Table 5. Examining the sensitivity of a 20% change in either direction for each factor in the model (except for intracerebral hemorrhage rate, which was halved and doubled) and the QALYs weight estimated a change of 10%. The QALYs gained ranged from 0.625 years to 0.767 years (7.5 months-9.2 months) per patient. A

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doubling of the intracerebral hemorrhage rate decreased the cost-savings to $3703, whereas a halving of the intracerebral hemorrhage rate increased the cost-savings to $4275. A 20% change in the hospital costs led to a per-patient cost-savings from $3189 to $4979.

Discussion In 1998, Fagan and colleagues used a Markov model to predict the economic and health outcomes of acute ischemic stroke based on the use of rtPA versus placebo on a national level.14 That analysis predicted significant economic savings throughout a patient’s lifetime with the use of rtPA, along with an increase in QALYs.14 This current analysis was repeated for South Carolina, using updated economic estimates for cost and outcomes, revealing similar cost-savings as seen in the previous study.

As part of the Stroke Belt, South Carolina has a high rate of stroke, strokes in young people, and stroke mortality.4-7,18 In fact, previous research has shown that Stroke Belt residents are more likely to die from stroke

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The Economic Impact of rtPA Use in a Stroke Belt State

while in their home county, and that visitors to the area are more likely to die from stroke while visiting there than in their own region, but Stroke Belt residents are less likely to die from stroke while away from the region.5 The reasons for this are unclear and complex, but the economic case for increased access to treatment with rtPA is neither unclear nor complex.

The findings of the current analysis show that the patient outcomes and cost benefits of increased rtPA utilization are real, even when estimated only over a 6-year period; however, to be fully realized, systems and policies must be in place to allow for the timely care of acute ischemic stroke.

Because South Carolina has a higher rate of mortality from stroke in young people aged <70 years than in other areas, the findings of this model are important to the state. The care and treatment of younger patients with stroke have been shown to be more expensive than that for patients with stroke overall, providing additional potential cost-savings opportunities through the use of rtPA.18 The savings predicted by our model will save money for the US healthcare system overall, particularly for public and private insurance payers.

Although rtPA was the first FDA-approved treatment for acute ischemic stroke, the use of rtPA has not become widespread, in part because it must be administered within 3 hours of the onset of stroke symptoms.19-21 In fact, Capampangan and colleagues report that more than a decade after its FDA approval, fewer than 5% of patients with acute ischemic stroke receive rtPA.22 As Fagan and colleagues pointed out, rtPA is a relatively expensive drug,14 which has continued to increase in price since their 1998 analysis. Yet, treatment with rtPA has been shown to improve the short- and long-term health outcomes of patients with acute ischemic stroke. Although the decision to treat a patient with rtPA should be based solely on clinical eligibility, the financial case should be considered in designing stroke systems of care and statewide policies to optimize treatment opportunities with rtPA. When comparing the early cost-savings with the lifetime cost-savings of treatment with rtPA for patients with acute ischemic stroke, the marginal savings decrease over time. Although the lifetime cost-savings ($4084) for patients treated with rtPA may seem only slightly greater than the savings over the first 6 years ($3454), the quality-adjusted months (8.3 lifetime vs 5.1, respectively) should be considered. Our analysis suggests that much of the cost-savings of the use of rtPA occur in the early years after treatment. This is likely a function of the aging process, with individuals being more likely to suffer from other expensive medical conditions as their age increases.

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Limitations Our study has several limitations. First, we examined only a single state, which may limit the generalizability of our findings.

Second, differences in clinical practice and the NINDS study in the area of intracerebral hemorrhage and entry-patient severity have been noted, and the QALY assumptions applied to each state may not fit the modeled population.

Third, although the data are the most recent available, they do not represent the current year. In addition, advances in stroke treatment could be developed and could improve patientsâ&#x20AC;&#x2122; quality of life in future years, thus complicating the study.

Furthermore, because we have conservatively estimated our model and have built it based on a previously validated model, we believe that we may be underestimating the benefits. Finally, although a recent study reported that rtPA may be effective up to 4.5 hours after treatment, we only considered treatment within 3 hours, to be conservative.15 Conclusions When looking at a short-term period of time after hospitalization, the treatment of acute ischemic stroke with rtPA is a cost-saving approach that provides increased quality of life for patients. However, challenges to such a treatment exist. Providers and administrators should be aware of the challenges of timely treatment of acute ischemic stroke, and they should work with policymakers to improve the systems of care to allow patients appropriate access to high-quality care. Funding sources, such as Medicare, Medicaid, and private insurers, will also want to offer reasonable motivation and reimbursement for treatment with rtPA to be given to appropriate patients, considering that the costs for treatment during hospitalization may be higher than current payments for providers.19 The patient outcomes and cost benefits with the use of rtPA described in this article are real, even when estimated only over a 6-year period. However, for these benefits to be fully realized, systems and policies must be in place to allow for the timely care of patients with acute ischemic stroke. n Source of Funding This research and development project was conducted by the Medical University of South Carolina and is made possible by a cooperative agreement that was awarded and administered by the US Army Medical Research and Materiel Command (USAMRMC) and the Telemedicine and Advanced Technology Research Center (TATRC), Fort Detrick, MD, under contract number W81XWH-10-2-0057.

Continued

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Appendix A. Transition Matrix for a 67-Year-Old Patient with Stroke Receiving rtPA Start Hospital Mos 3 Mos 6 Mos 9 Mos 12

Ran 0

Ran 1

Ran 2

Ran 3

Ran 4

Ran 5

15.8

16.8

18.4

24.0

19.5 20.0 20.5

Died of stroke Summary

8.4

9.4

21.9

20.3

7.4

100.00

7.4

12.9

13.6

6.2

17.5

100.00

22.4

8.2

13.9

9.9

4.6

21.5

100.00

22.2

8.0

13.4

8.3

4.6

23.5

100.00

22.1

7.7

13.1

6.4

4.7

25.5

100.00

B. Transition Matrix for a 67-Year-Old Comparison Group Patient Start Hospital Mos 3 Mos 6 Mos 9 Mos 12

Ran 0

Ran 1

Ran 2

Ran 3

Ran 4

Ran 5

Died of stroke Summary

7.5

10.1

9.5

9.4

28.3

25.1

10.1

100.00

10.8

16.3

11.7

14.3

19.5

6.5

20.9

100.00

10.9

18.5

10.5

16.5

13.9

5.9

23.8

100.00

10.9

17.8

11.4

14.7

12.8

5.8

26.6

100.00

10.9

17.0

12.2

12.9

11.6

5.8

29.6

100.00

Mos indicates months; Ran, ranking scale; rtPA, recombinant tissue plasminogen activator.

Author Disclosure Statement Dr Adams is on the Speaker’s Bureau for Genentech and is a stockholder of REACH Health, Inc. Dr Kazley, Dr K Simpson, Dr A Simpson, and Dr Jauch have reported no conflicts of interest.

References

1. Lloyd-Jones D, Adams RJ, Brown TM, et al, for the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics—2010 update: a report from the American Heart Association. Circulation.

2010;121:e46-e215. Errata in Circulation. 2010;121:e260; Circulation. 2011;124:e425.

2. Hoody D, Hanson S, Carter D, Zink T. Implementing a stroke system of care in a rural hospital: a case report from Granite Falls. Minn Med. 2008;91:37-40.

3. Rosamond W, Flegal K, Furie K, et al, for the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics—2008 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2008;117:e25-e146.

4. Glymour MM, Kosheleva A, Boden-Albala B. Birth and adult residence in the Stroke Belt independently predict stroke mortality. Neurology. 2009;73:1858-1865.

5. Feng W, Nietert PJ, Adams RJ. Influence of age on racial disparities in stroke admission rates, hospital charges, and outcomes in South Carolina. Stroke. 2009;40: 3096-3101.

6. Shrira I, Christenfeld N, Howard G. Exposure to the US Stroke Buckle as a risk factor for cerebrovascular mortality. Neuroepidemiology. 2008;30:229-233.

7. Lackland DT, Bachman DL, Carter TD, et al. The geographic variation in stroke incidence in two areas of Southeastern stroke belt: the Anderson and Pee Dee Stroke Study. Stroke. 1998;29:2061-2068.

8. Gross H, Hall C, Switzer JA, et al. Using tPA for acute stroke in a rural setting.

Neurology. 2007;68:1957-1958.

9. Taylor TN, Davis PH, Torner JC, et al. Lifetime cost of stroke in the United

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States. Stroke. 1996;27:1459-1466.

10. Brown DL, Boden-Albala B, Langa KM, et al. Projected costs of ischemic stroke in the United States. Neurology. 2006;67:1390-1395.

11. Demaerschalk BM, Hwang HM, Leung G. US cost burden of ischemic stroke: a systematic literature review. Am J Manag Care. 2010;16:525-533.

12. O’Fallon WM, Asplund K, Goldfrank LR, et al. Report of the t-PA Review Committee. National Institute of Neurological Disorders and Stroke; 2004. www. ninds.nih.gov/funding/review_committees/t-pa_review_committee/t-pa_committee_ report.pdf. Accessed May 2, 2013.

13. Brinjikji W, Rabinstein AA, Cloft HJ. Hospitalization costs for acute ischemic stroke patients treated with intravenous thrombolysis in the United States are substantially higher than Medicare payments. Stroke. 2012;43:1131-1133.

14. Fagan SC, Morgenstern LB, Petitta A, et al, for the NINDS rtPA Stroke Study Group. Cost-effectiveness of tissue plasminogen activator for acute ischemic stroke.

Neurology. 1998;50:883-890.

15. Demaerschalk BM, Hwang HM, Leung G. Cost analysis review of stroke centers, telestroke, and rtPA. Am J Manag Care. 2010;16:537-544.

16. Mortality Data. Centers for Disease Control and Prevention. Updated April 17, 2013. www.cdc.gov/nchs/deaths.htm. Accessed March 25, 2013.

17. US Bureau of Labor Statistics. Consumer Price Index, Medical Care. Series ID, CUUR0000SAM2; not seasonally adjusted; area, US city average; item, medical care services; base period, 1982-84=100. www.data.bls.gov/. Accessed May 8, 2011.

18. Ellis C. Stroke in young adults. Disabil Health J. 2010;3:222-224.

19. Kleindorfer D, Kissela B, Schneider A, et al, for the Neuroscience Institute. Eligibility for recombinant tissue plasminogen activator in acute ischemic stroke: a population-based study. Stroke. 2004;35:e27-e29.

20. Kleindorfer D, Xu Y, Moomaw CJ, et al. US geographic distribution of rtPA utilization by hospital for acute ischemic stroke. Stroke. 2009;40:3580-3584.

21. Hacke W, Kaste M, Bluhmki E, et al, for the ECASS Investigators. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med. 2008;359: 1317-1329.

22. Capampangan DJ, Wellik KE, Bobrow BJ, et al. Telemedicine versus telephone for remote emergency stroke consultations: a critically appraised topic. Neurologist.

2009;15:163-166.

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The Economic Impact of rtPA Use in a Stroke Belt State

Stakeholder Perspective Stroking This South Carolina Model: Will It Play in Peoria?

By Albert Tzeel, MD, MHSA, FACPE National Medical Director, HumanaOne, Waukesha, WI

A

phrase once uttered by US Supreme Court Associate Justice Louis D. Brandeis can often be heard within the realm of political science. In opining on one case, Brandeis described each of the states as the “laboratories of democracy.”1 In doing so, he stated, “it is one of the happy accidents of the federal system that a single courageous state may, if its citizens choose, serve as a laboratory, and try novel social and economic experiments without risk to the rest of the country.”1 Within the political arena, Brandeis’ comment has spawned much discussion; outside of the political arena, it has served as an analogy for looking at how a positive result obtained in one state should be expanded to others.

POLICYMAKERS: And so it is with the article by Kazley and colleagues appearing in this issue of the journal. In their study, Kazley and colleagues use the methodology of the 1998 study by Fagan and colleagues, which looked at the economic impact of the potential widespread use of recombinant tissue plasminogen activator, and applies updated cost figures to a key state residing within the so-called 11-state Stroke Belt, South Carolina. Their results reiterate several encouraging findings from the study by Fagan and colleagues, including cost-savings and improved quality of life. In fact, Kazley and colleagues acknowledge that “the savings predicted by our model will save money for the US healthcare system overall,” assuming that appropriate systems of care are in place.

However, as noted by the Centers for Disease Control and Prevention, several medical consequences of lifestyle, including diabetes, hypertension, hypercholesterolemia, overweight, and obesity, are key risk factors for stroke.2 Translating the Joseph Juran model for the “cost of poor quality” to our example, the cost of preventing a stroke (by addressing stroke risk factors) will always be less than the cost of “appraising” a stroke (also known as a “rule-out stroke” workup).3 Both of those will still cost less than addressing “an internal failure” (defined as treating a stroke acutely) or the yet more expensive “ex-

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ternal failure” (defined as treating the rehabilitation needs of the sequelae of stroke or, worse yet, the lost productivity of a stroke death). It should not, then, be a surprise to anyone that public health policy focuses more on prevention and early identification of strokes and, given the promotion and coverage of preventive health services through the Affordable Care Act, will continue to do so for the foreseeable future.

PAYERS/PROVIDERS: That being said, we are still aware of the need for treating acute ischemic stroke early and effectively, and the study by Kazley and colleagues provides some key points that health plans and providers must address. First, given that many of the country’s largest payers are involved in providing services to older adults through Medicare Advantage plans, the fact that the results noted in the study were geared toward a population aged ≥67 years should not be discounted. If health plans can serve as an impetus for providers to arrange for appropriate systems of care, then health plans should, in the short-term, experience decreased costs for their members’ care and an improved member experience through decreased member morbidity (as defined by improved quality-adjusted life-years).

More important, as accountable care organizations accept both responsibility and risk for the populations they serve, providers will further drive the development of the appropriate, and necessary, systems of care to treat stroke as well as its underlying risk factors. Such changes yield the longer-term results that Kazley and colleagues allude to in their analysis. Should these happen, will we actually see such results in South Carolina or, beyond its borders, in other states comprising the Stroke Belt? Maybe. Or, to paraphrase another US Supreme Court Associate Justice, Potter Stewart, we’ll know it when we see it. n 1. New State Ice Company v. Liebmann, 285 U.S. 262, 311 (1932).

2. Centers for Disease Control and Prevention. Stroke conditions. www.cdc.gov/ stroke/conditions.htm. Accessed June 5, 2013.

3. The Juran Institute. Cost of poor quality. www.juran.com/elifeline/elifefiles/ 2009/09/Cost-of-Poor-Quality.ppt. Accessed June 5, 2013.

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Indication Qsymiaâ&#x201E;˘ (phentermine and topiramate extended-release) capsules CIV is a combination of phentermine, a sympathomimetic amine anorectic, and topiramate extended-release, an antiepileptic drug, indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m2 or greater (obese) or 27 kg/m2 or greater (overweight) in the presence of at least one weight-related comorbidity such as hypertension, type 2 diabetes mellitus, or dyslipidemia Limitations of Use: The effect of Qsymia on cardiovascular morbidity and mortality has not been established The safety and effectiveness of Qsymia in combination with other products intended for weight loss, including prescription and over-the-counter drugs, and herbal preparations, have not been established

Important Safety Information Qsymia (phentermine and topiramate extended-release) capsules CIV is contraindicated in pregnancy; in patients with glaucoma; in hyperthyroidism; in patients receiving treatment or within 14 days following treatment with monoamine oxidase inhibitors (MAOIs); or in patients with hypersensitivity to sympathomimetic amines, topiramate, or any of the inactive ingredients in Qsymia.

Qsymia can cause fetal harm. A fetus exposed to topiramate, a component of Qsymia, in the first trimester of pregnancy has an increased risk of oral clefts (cleft lip with or without cleft palate).

Females of reproductive potential should have a negative pregnancy test before treatment and monthly thereafter and use effective contraception consistently during Qsymia therapy.

If a patient becomes pregnant while taking Qsymia, treatment should be discontinued immediately, and the patient should be informed of the potential hazard to the fetus.

Achieve and maintain weight loss that is clinically meaningful for 1 year1 In Study 2, the CONQUER Trial, 2,487 overweight or obese patients (BMI* 27 or greater and less than or equal to 45) with 2 or more weight-related comorbidities were evaluated for 1 year 1 5% weight loss or greater† was achieved by 70% of patients who took the Qsymia™ 15 mg/92 mg dose and 62% who took the 7.5 mg/46 mg dose, compared with 21% in the placebo group (P<0.0001)1 • In CONQUER, patients randomized to Qsymia 7.5 mg/46 mg or 15 mg/92 mg achieved, on average, at least 5% weight loss within 8 weeks1,2 In CONQUER, 84% of patients randomized to Qsymia 7.5 mg/46 mg responded to treatment. Responders were defined as patients who achieved at least 3% weight loss at 12 weeks1,2 In CONQUER, Qsymia provided clinically meaningful weight loss, even in obese patients taking SSRIs, SNRIs, or bupropion1,2

QSYMIA (phentermine and topiramate extended-release) capsules CIV VS PLACEBO FOR 1 YEAR OF TREATMENT (P<0.0001) 1,2‡ COMPLETERS

Percent Weight Loss (LS mean)

0

1.6%

ITT-LOCF†

1.2%

Placebo (n=564) Qsymia 7.5 mg/ 46 mg (n=344)

4

7.8%

8

9.6% 9.8%

Qsymia 15 mg/ 92 mg (n=634)

12.4%

12

16 8

12

24

36

48

56

56

Time (Weeks) At the beginning of the study, the average weight and BMI of patients were 227 pounds and 36.6, respectively.1 Eligible comorbidities included hypertension with an elevated blood pressure (greater than or equal to 140/90 mmHg, or greater than or equal to 130/85 mmHg for diabetics) or requirement for greater than or equal to 2 antihypertensive medications; high cholesterol with triglycerides greater than 200-400 mg/dL or were receiving treatment with 2 or more lipid-lowering agents; diabetes with an elevated fasting blood glucose (greater than 100 mg/dL) or diabetes; waist circumference of 102 cm or greater in men, 88 cm or greater in women.1 For all patients, a well-balanced, reduced-calorie diet (decrease of 500 kcal/day) was recommended, and nutritional and lifestyle modification counseling was also offered.1 66% of patients in the Qsymia groups completed 1 year of treatment vs 57% in the placebo group.2

Qsymia is not indicated for the treatment of hypertension, type 2 diabetes mellitus, or dyslipidemia1

Safety profile evaluated for 1 year1 Most common adverse reactions (incidence 5% or greater and at least 1.5 times placebo) are: paraesthesia,§ dizziness, dysgeusia, insomnia, constipation, and dry mouth1 *BMI is measured in kg/m2. †Primary endpoint. Intent-to-treat, last observation carried forward.1 ‡Completers data (from subjects who had a 1-year evaluation within 7 days of their last dose). 2 § Reports of paraesthesia were typically characterized as tingling in the hands, feet, or face.1

Please see brief summary of Qsymia Prescribing Information on the following pages and Qsymia Full Prescribing Information available at www.Qsymia.com.

© 2012-2013 VIVUS, Inc. All rights reserved. 100009.01-USP

LEARN MORE AT WWW.QSYMIA.COM

QSYMIA™ (phentermine and topiramate extended-release) capsules CIV BRIEF SUMMARY: Consult package insert or www.Qsymia.com for Full Prescribing Information. For more information about Qsymia, please call VIVUS Medical Information at 1-888-998-4887 or visit our Web site at www.Qsymia.com.

INDICATIONS AND USAGE: Qsymia is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adult patients with an initial body mass index (BMI) of 30 kg/m2 or greater (obese), or 27 kg/m2 or greater (overweight) in the presence of at least one weight related comorbidity such as hypertension, type 2 diabetes mellitus, or dyslipidemia. The indication includes the following limitations of use: The effect of Qsymia on cardiovascular morbidity and mortality has not been established, and the safety and effectiveness of Qsymia in combination with other products intended for weight loss, including prescription and over-the-counter drugs and herbal preparations have not been established.

CONTRAINDICATIONS: Qsymia is contraindicated in the following conditions: Pregnancy, glaucoma, hyperthyroidism, during or within 14 days following the administration of monoamine oxidase inhibitors, and known hypersensitivity or idiosyncrasy to the sympathomimetic amines.

DOSAGE AND ADMINISTRATION: In adults with an initial BMI of 30 kg/m2 or greater or 27 kg/m2 or greater when accompanied by weight-related co-morbidities such as hypertension, type 2 diabetes mellitus, or dyslipidemia prescribe Qsymia as follows: 1) Take Qsymia once daily in the morning with or without food. Avoid dosing with Qsymia in the evening due to the possibility of insomnia. 2) Start treatment with Qsymia 3.75 mg/23 mg (phentermine 3.75 mg/topiramate 23 mg extended-release) daily for 14 days; after 14 days increase to the recommended dose of Qsymia 7.5 mg/46 mg (phentermine 7.5 mg/topiramate 46 mg extended-release) once daily. 3) Evaluate weight loss after 12 weeks of treatment with Qsymia 7.5 mg/46 mg. If a patient has not lost at least 3% of baseline body weight on Qsymia 7.5 mg/46 mg, discontinue Qsymia or escalate the dose, as it is unlikely that the patient will achieve and sustain clinically meaningful weight loss at the Qsymia 7.5 mg/ 46 mg dose. To escalate the dose: Increase to Qsymia 11.25 mg/69 mg (phentermine 11.25 mg/ topiramate 69 mg extended-release) daily for 14 days; followed by dosing Qsymia 15 mg/ 92 mg (phentermine 15 mg/topiramate 92 mg extended-release) daily. 4) Evaluate weight loss following dose escalation to Qsymia 15 mg/92 mg after an additional 12 weeks of treatment. If a patient has not lost at least 5% of baseline body weight on Qsymia 15 mg/ 92 mg, discontinue Qsymia as directed, as it is unlikely that the patient will achieve and sustain clinically meaningful weight loss with continued treatment. 5) Qsymia 3.75 mg/23 mg and Qsymia 11.25 mg/69 mg are for titration purposes only. 6) Discontinuing Qsymia: Discontinue Qsymia 15 mg/92 mg gradually by taking a dose every other day for at least 1 week prior to stopping treatment altogether, due to the possibility of precipitating a seizure (see WARNINGS AND PRECAUTIONS). Dosing in Patients with Renal Impairment: In patients with moderate (creatinine clearance [CrCl] greater than or equal to 30 and less than 50 mL/min) or severe (CrCl less than 30 mL/min) renal impairment dosing should not exceed Qsymia 7.5 mg/46 mg once daily. Renal impairment is determined by calculating CrCl using the Cockcroft-Gault equation with actual body weight (see WARNINGS AND PRECAUTIONS).

Dosing in Patients with Hepatic Impairment: In patients with moderate hepatic impairment (Child-Pugh score 7-9), dosing should not exceed Qsymia 7.5 mg/46 mg once daily (see WARNINGS AND PRECAUTIONS).

DOSAGE FORMS AND STRENGTHS: Qsymia capsules are formulated in the following four strength combinations (phentermine mg/topiramate mg extended-release): • 3.75 mg/23 mg [Purple cap imprinted with VIVUS, Purple body imprinted with 3.75/23] • 7.5 mg/46 mg [Purple cap imprinted with VIVUS, Yellow body imprinted with 7.5/46] • 11.25 mg/69 mg [Yellow cap imprinted with VIVUS, Yellow body imprinted with 11.25/69] • 15 mg/92 mg [Yellow cap imprinted with VIVUS, White body imprinted with 15/92] QSYMIA RISK EVALUATION AND MITIGATION STRATEGY (REMS): Because of the teratogenic risk associated with Qsymia therapy, Qsymia is available through a limited program under the REMS. Under the Qsymia REMS, only certified pharmacies may distribute Qsymia. Further information is available at www.QsymiaREMS.com or by telephone at 1-888-998-4887.

WARNINGS AND PRECAUTIONS: Fetal Toxicity: Qsymia can cause fetal harm. Data from pregnancy registries and epidemiology studies indicate that a fetus exposed to topiramate, a component of Qsymia, in the first trimester of pregnancy has an increased risk of oral clefts (cleft lip with or without cleft palate). If Qsymia is used during pregnancy or if a patient becomes pregnant while taking Qsymia, treatment should be discontinued immediately, and the patient should be apprised of the potential hazard to a fetus. Females of reproductive potential should have a negative pregnancy test before starting Qsymia and monthly thereafter during Qsymia therapy. Females of reproductive potential should use effective contraception during Qsymia therapy. Increase in Heart Rate: Qsymia can cause an increase in resting heart rate. A higher percentage of Qsymia-treated overweight and obese adults experienced heart rate increases from baseline of more than 5, 10, 15, and 20 beats per minute (bpm) compared to placebo-treated overweight and obese adults. The clinical significance of a heart rate elevation with Qsymia treatment is unclear, especially for patients with cardiac and cerebrovascular disease (such as patients with a history of myocardial infarction or stroke in the previous 6 months, life-threatening arrhythmias, or congestive heart failure). Regular measurement of resting heart rate is recommended for all patients taking Qsymia, especially patients with cardiac or cerebrovascular disease or when initiating or increasing the dose of Qsymia.

Qsymia has not been studied in patients with recent or unstable cardiac or cerebrovascular disease and therefore use is not recommended. Patients should inform healthcare providers of palpitations

or feelings of a racing heartbeat while at rest during Qsymia™ (phentermine and topiramate extended-release) capsules CIV treatment. For patients who experience a sustained increase in resting heart rate while taking Qsymia, the dose should be reduced or Qsymia discontinued. Suicidal Behavior and Ideation: Antiepileptic drugs (AEDs), including topiramate, a component of Qsymia, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication.

Patients treated with Qsymia should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Discontinue Qsymia in patients who experience suicidal thoughts or behaviors. Avoid Qsymia in patients with a history of suicidal attempts or active suicidal ideation. Acute Myopia and Secondary Angle Closure Glaucoma: A syndrome consisting of acute myopia associated with secondary angle closure glaucoma has been reported in patients treated with topiramate, a component of Qsymia.

Symptoms include acute onset of decreased visual acuity and/or ocular pain. Ophthalmologic findings can include myopia, anterior chamber shallowing, ocular hyperemia (redness), and increased intraocular pressure. Mydriasis may or may not be present. This syndrome may be associated with supraciliary effusion resulting in anterior displacement of the lens and iris, with secondary angle closure glaucoma. Symptoms typically occur within 1 month of initiating treatment with topiramate but may occur at any time during therapy. The primary treatment to reverse symptoms is immediate discontinuation of Qsymia. Elevated intraocular pressure of any etiology, if left untreated, can lead to serious adverse events including permanent loss of vision. Mood and Sleep Disorders: Qsymia can cause mood disorders, including depression, and anxiety, as well as insomnia. Patients with a history of depression may be at increased risk of recurrent depression or other mood disorders while taking Qsymia. The majority of these mood and sleep disorders resolved spontaneously, or resolved upon discontinuation of dosing (see ADVERSE REACTIONS). For clinically significant or persistent symptoms consider dose reduction or withdrawal of Qsymia. If patients have symptoms of suicidal ideation or behavior, discontinue Qsymia. Cognitive Impairment: Qsymia can cause cognitive dysfunction (e.g., impairment of concentration/attention, difficulty with memory, and speech or language problems, particularly word-finding difficulties). Rapid titration or high initial doses of Qsymia may be associated with higher rates of cognitive events such as attention, memory, and language/word-finding difficulties (see ADVERSE REACTIONS). Since Qsymia has the potential to impair cognitive function, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain Qsymia therapy does not affect them adversely. If cognitive dysfunction persists consider dose reduction or withdrawal of Qsymia for symptoms that are moderate to severe, bothersome, or those which fail to resolve with dose reduction. Metabolic Acidosis: Hyperchloremic, non-anion gap, metabolic acidosis (decreased serum bicarbonate below the normal reference range in the absence of chronic respiratory alkalosis) has been reported in patients treated with Qsymia (see ADVERSE REACTIONS). Conditions or therapies that predispose to acidosis (i.e., renal disease, severe respiratory disorders, status epilepticus, diarrhea, surgery or ketogenic diet) may be additive to the bicarbonate lowering effects of topiramate. Concomitant use of Qsymia and a carbonic anhydrase inhibitor (e.g., zonisamide, acetazolamide, or dichlorphenamide) may increase the severity of metabolic acidosis and may also increase the risk of kidney stone formation. Therefore, if Qsymia is given concomitantly with another carbonic anhydrase inhibitor to a patient with a predisposing condition for metabolic acidosis the patient should be monitored for the appearance or worsening of metabolic acidosis. Some manifestations of acute or chronic metabolic acidosis may include hyperventilation, nonspecific symptoms such as fatigue and anorexia, or more severe sequelae including cardiac arrhythmias or stupor. Chronic, untreated metabolic acidosis may increase the risk for nephrolithiasis or nephrocalcinosis, and may also result in osteomalacia (referred to as rickets in pediatric patients) and/or osteoporosis with an increased risk for fractures. The effect of Qsymia on growth and bonerelated sequelae has not been systematically investigated in long-term, placebo-controlled trials.

Measurement of electrolytes including serum bicarbonate prior to starting Qsymia and during Qsymia treatment is recommended. In Qsymia clinical trials, the peak reduction in serum bicarbonate occurred by week 4, and in most subjects there was a correction of bicarbonate by week 56, without any change to study drug. However, if persistent metabolic acidosis develops while taking Qsymia, reduce the dose or discontinue Qsymia. Elevation in Creatinine: Qsymia can cause an increase in serum creatinine. Peak increases in serum creatinine were observed after 4 to 8 weeks of treatment.

On average, serum creatinine gradually declined but remained elevated over baseline creatinine values. Elevations in serum creatinine often signify a decrease in renal function, but the cause for Qsymia-associated changes in serum creatinine has not been definitively established. Therefore, measurement of serum creatinine prior to starting Qsymia and during Qsymia treatment is recommended. If persistent elevations in creatinine occur while taking Qsymia, reduce the dose or discontinue Qsymia (see ADVERSE REACTIONS). Potential Risk of Hypoglycemia in Patients with Type 2 Diabetes Mellitus on Anti-Diabetic Therapy: Weight loss may increase the risk of hypoglycemia in patients with type 2 diabetes mellitus treated with insulin and/or insulin secretagogues (e.g., sulfonylureas). Qsymia has not been studied in combination with insulin.

Measurement of blood glucose levels prior to starting Qsymia and during Qsymia treatment is recommended in patients with type 2 diabetes. Decreases in medication doses for antidiabetic medications which are non-glucose-dependent should be considered to mitigate the risk of hypoglycemia. If a patient develops hypoglycemia after starting Qsymia, appropriate changes should be made to the antidiabetic drug regimen. Potential Risk of Hypotension in Patients Treated with Antihypertensive Medications: In hypertensive patients being treated with antihypertensive medications, weight loss may increase the risk of hypotension, and associated symptoms including dizziness, lightheadedness, and syncope. Measurement of blood pressure prior to starting Qsymia and during Qsymia treatment is recommended in patients being treated for hypertension. If a patient develops symptoms associated with low blood pressure after starting Qsymia, appropriate changes should be made to the antihypertensive drug regimen. CNS Depression with Concomitant CNS Depressants Including Alcohol: The concomitant use of alcohol or central nervous system (CNS) depressant drugs (e.g., barbiturates, benzodiazepines, and sleep medications) with phentermine or topiramate may potentiate CNS depression or other centrally mediated effects of these agents, such

as dizziness, cognitive adverse reactions, drowsiness, light-headedness, impaired coordination and somnolence. Therefore, avoid concomitant use of alcohol with Qsymia™ (phentermine and topiramate extended-release) capsules CIV. Potential Seizures with Abrupt Withdrawal of Qsymia: Abrupt withdrawal of topiramate, a component of Qsymia, has been associated with seizures in individuals without a history of seizures or epilepsy. In situations where immediate termination of Qsymia is medically required, appropriate monitoring is recommended. Patients discontinuing Qsymia 15 mg/92 mg should be gradually tapered as recommended to reduce the possibility of precipitating a seizure (see DOSAGE AND ADMINISTRATION). Patients with Renal Impairment: Phentermine and topiramate, the components of Qsymia, are cleared by renal excretion. Therefore, exposure to phentermine and topiramate is higher in patients with moderate (creatinine clearance [CrCl] greater than or equal to 30 and less than 50 mL/min) or severe (CrCl less than 30 mL/min) renal impairment. Adjust dose of Qsymia for both patient populations. Qsymia has not been studied in patients with end-stage renal disease on dialysis. Avoid use of Qsymia in this patient population (see DOSAGE AND ADMINISTRATION). Patients with Hepatic Impairment: In patients with mild (Child-Pugh score 5-6) or moderate (Child-Pugh score 7-9) hepatic impairment, exposure to phentermine was higher compared to healthy volunteers. Adjust dose of Qsymia for patients with moderate hepatic impairment. Qsymia has not been studied in patients with severe hepatic impairment (Child-Pugh score 10-15). Avoid use of Qsymia in this patient population (see DOSAGE AND ADMINISTRATION). Kidney Stones: Use of Qsymia has been associated with kidney stone formation. Topiramate, a component of Qsymia, inhibits carbonic anhydrase activity and promotes kidney stone formation by reducing urinary citrate excretion and increasing urine pH. Avoid the use of Qsymia with other drugs that inhibit carbonic anhydrase (e.g., zonisamide, acetazolamide or methazolamide). Use of topiramate by patients on a ketogenic diet may also result in a physiological environment that increases the likelihood of kidney stone formation. Increase fluid intake to increase urinary output which can decrease the concentration of substances involved in kidney stone formation (see ADVERSE REACTIONS). Oligohidrosis and Hyperthermia: Oligohidrosis (decreased sweating), infrequently resulting in hospitalization, has been reported in association with the use of topiramate, a component of Qsymia. Decreased sweating and an elevation in body temperature above normal characterized these cases. Some of the cases have been reported with topiramate after exposure to elevated environmental temperatures. Patients treated with Qsymia should be advised to monitor for decreased sweating and increased body temperature during physical activity, especially in hot weather. Caution should be used when Qsymia is prescribed with other drugs that predispose patients to heat-related disorders; these drugs include, but are not limited to, other carbonic anhydrase inhibitors and drugs with anticholinergic activity. Hypokalemia: Qsymia can increase the risk of hypokalemia through its inhibition of carbonic anhydrase activity. In addition, when Qsymia is used in conjunction with non-potassium sparing diuretics such as furosemide (loop diuretic) or hydrochlorothiazide (thiazide-like diuretic) this may further potentiate potassiumwasting. When prescribing Qsymia, patients should be monitored for hypokalemia (see ADVERSE REACTIONS). Monitoring: Laboratory Tests: Qsymia was associated with changes in several clinical laboratory analytes in randomized, double-blind, placebo-controlled studies. Obtain a blood chemistry profile that includes bicarbonate, creatinine, potassium, and glucose at baseline and periodically during treatment (see WARNINGS AND PRECAUTIONS).

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 to rates in the clinical studies of another drug and may not reflect the rates observed in practice. Common Adverse Reactions: Adverse reactions occurring at a rate of greater than or equal to 5% and at a rate at least 1.5 times placebo include paraesthesia, dizziness, dysgeusia, insomnia, constipation, and dry mouth.

Incidence in Controlled Trials: Adverse reactions reported in greater than or equal to 2% of Qsymiatreated patients and more frequently than in the placebo group are listed below. Consult Full Prescribing Information on adverse reactions. Nervous System Disorders: Paraesthesia, headache, dizziness, dysgeusia, hypoesthesia, disturbance in attention. Psychiatric Disorders: Insomnia, depression, anxiety. Gastrointestinal Disorders: Constipation, dry mouth, nausea, diarrhea, dyspepsia, gastroesophageal reflux disease, paraesthesia oral. General Disorders and Administration Site Conditions: Fatigue, irritability, thirst, chest discomfort. Eye Disorders: Vision blurred, eye pain, dry eye. Cardiac Disorders: Palpitations. Skin and Subcutaneous Tissue Disorders: Rash, alopecia. Metabolism and Nutrition Disorders: Hypokalemia, decreased appetite. Reproductive System and Breast Disorders: Dysmenorrhea. Infections and Infestations: Upper respiratory tract infection, nasopharyngitis, sinusitis, bronchitis, influenza, urinary tract infection, gastroenteritis. Musculoskeletal and Connective Tissue Disorders: Back pain, pain in extremity, muscle spasms, musculoskeletal pain, neck pain. Respiratory, Thoracic, and Mediastinal Disorders: Cough, sinus congestion, pharyngolaryngeal pain, nasal congestion. Injury, Poisoning, and Procedural Complications: Procedural pain. Paraesthesias/ Dysgeusia: Reports of Paraesthesia, characterized as tingling in hands, feet, or face, occurred in 4.2%, 13.7%, and 19.9% of patients treated with Qsymia 3.75 mg/23 mg, 7.5 mg/46 mg, and 15 mg/ 92 mg, respectively, compared to 1.9% of patients treated with placebo. Dysgeusia was characterized as a metallic taste, and occurred in 1.3%, 7.4%, and 9.4% of patients treated with Qsymia 3.75 mg/23 mg, 7.5 mg/46 mg, and 15 mg/92 mg, respectively, compared to 1.1% of patients treated with placebo. Mood and Sleep Disorders: The proportion of patients in 1-year controlled trials of Qsymia reporting one or more adverse reactions related to mood and sleep disorders was 15.8%, 14.5%, and 20.6% with Qsymia 3.75 mg/23 mg, 7.5 mg/46 mg, and 15 mg/92 mg, respectively, compared to 10.3% with placebo. These events were further categorized into sleep disorders, anxiety, and depression. Reports of sleep disorders were typically characterized as insomnia, and occurred in 6.7%, 8.1%, and 11.1% of patients treated with Qsymia 3.75 mg/23 mg, 7.5 mg/46 mg, and 15 mg/92 mg, respectively, compared to 5.8% of patients treated with placebo. Reports of anxiety occurred in 4.6%, 4.8%, and 7.9% of patients treated with Qsymia 3.75 mg/23 mg, 7.5 mg/46 mg, and 15 mg/92 mg, respectively, compared to 2.6% of patients treated with placebo.

Reports of depression/mood problems occurred in 5.0%, 3.8%, and 7.6% of patients treated with

Qsymia™ (phentermine and topiramate extended-release) capsules CIV 3.75 mg/23 mg, 7.5 mg/46 mg, and 15 mg/92 mg, respectively, compared to 3.4% of patients treated with placebo. The majority of these events first occurred within the initial 12 weeks of drug therapy; however, in some patients, events were reported later in the course of treatments. Cognitive Disorders: In the 1-year controlled trials of Qsymia, the proportion of patients who experienced one or more cognitive-related adverse reactions was 2.1% for Qsymia 3.75 mg/ 23 mg, 5.0% for Qsymia 7.5 mg/46 mg, and 7.6% for Qsymia 15 mg/92 mg, compared to 1.5% for placebo. These adverse reactions were comprised primarily of reports of problems with attention/ concentration, memory, and language (word finding). These events typically began within the first 4 weeks of treatment, had a median duration of approximately 28 days or less, and were reversible upon discontinuation of treatment; however, individual patients did experience events later in treatment, and events of longer duration. Drug Discontinuation Due to Adverse Reactions: In the 1-year placebo-controlled clinical studies, 11.6% of Qsymia 3.75 mg/23 mg, 11.6% of Qsymia 7.5 mg/46 mg, 17.4% of Qsymia 15 mg/92 mg, and 8.4% of placebo-treated patients discontinued treatment due to reported adverse reactions. The most common adverse reactions (greater than or equal to 1% in any treatment group) that led to discontinuation of treatment are: Vision blurred, headache, irritability, dizziness, paraesthesia, insomnia, depression, anxiety.

DRUG ABUSE AND DEPENDENCE: Controlled Substance: Qsymia is controlled in Schedule IV of the Controlled Substances Act because it contains phentermine, a Schedule IV drug. Any material, compound, mixture, or preparation that contains any quantity of phentermine is controlled as a Schedule IV drug. Topiramate is not controlled in the Controlled Substances Act. Abuse: Phentermine, a component of Qsymia, has a known potential for abuse.

Phentermine, a component of Qsymia, is related chemically and pharmacologically to the amphetamines. Amphetamines and other stimulant drugs have been extensively abused and the possibility of abuse of phentermine should be kept in mind when evaluating the desirability of including Qsymia as part of a weight reduction program. Abuse of amphetamines and related drugs (e.g., phentermine) may be associated with impaired control over drug use and severe social dysfunction. There are reports of patients who have increased the dosage of these drugs to many times that recommended. Dependence: Qsymia has not been systematically studied for its potential to produce physical dependence. Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use. Physical dependence manifests by drug-class-specific withdrawal symptoms after abrupt discontinuation or a significant dose reduction of a drug.

OVERDOSAGE: In the event of a significant overdose with Qsymia, if the ingestion is recent, the stomach should be emptied immediately by gastric lavage or by induction of emesis.

Appropriate supportive treatment should be provided according to the patient’s clinical signs and symptoms. Management of acute phentermine intoxication is largely symptomatic and includes lavage and sedation with a barbiturate. Acidification of the urine increases phentermine excretion. Intravenous phentolamine has been suggested for possible acute, severe hypertension, if this complicates phentermine overdosage. Activated charcoal has been shown to adsorb topiramate in vitro. Hemodialysis is an effective means of removing topiramate from the body.

Brief summary of Qsymia Full Prescribing Information, revised July 2012.

Manufactured for: VIVUS, Inc. For more information about Qsymia, please call VIVUS Medical Information at 1-888-998-4887 or visit our Web site at www.Qsymia.com.

References: 1. Qsymia [package insert]. Mountain View, CA: VIVUS, Inc; 2012. 2. Data on file. VIVUS, Inc.

© 2012-2013 VIVUS, Inc. All rights reserved. 100162.01-USP

Industry Trends

The Race to Open Enrollment:

Critical Success Factors for Exchanges

By Caroline F. Pearson, Vice President, Avalere Health, Washington, DC

W

ith less than 4 months until the start of open enrollment for health insurance exchanges, health plans, policymakers, and consumer groups are rushing to finalize plans for these new marketplaces. The stakes are high for the centerpiece of the Affordable Care Act’s (ACA) coverage expansion.

Avalere Health estimates that exchanges will enroll 8 million individuals and families in 2014, growing to 26 million in the next decade. Millions of chronically ill individuals who to date have had limited access to insurance, wait anxiously for coverage to begin on January 1.

But, to create a successful market for the long-term, exchanges will need to attract healthier individuals with a range of plan options that are sold at competitive prices.

Key Factors to Achieving Success Over the next few months, the viability of exchange markets will hinge on 3 critical success factors: • Choice—the selection of health plans in each market • Cost—competitive premiums for price-sensitive purchasers • Consumer response—widespread awareness yielding robust and diverse exchange enrollment.

1. Choice: Selection of Health Plans in Each Market We are already beginning to get a picture of health plan participation in exchange markets. A successful exchange will offer consumers a choice of health plans and product offerings across metal levels (ie, bronze, silver, gold). Blues plans and other regional carriers, which dominate the individual market today, will be prominent participants in almost all exchanges. These plans have the brand equity to gain new enrollment, but they must also work to keep their current customers who will newly qualify for exchange subsidies in 2014. States have a choice of operating model options with varying degrees of state responsibility for exchange functions (Figure 1).

The growth opportunity of exchange coverage is also expected to draw new plans into the market, although some carriers are making these investments cautiously.

CIGNA, which today controls only 1% of the individual insurance market, plans to participate in 5 state exchanges—an effort to grow the business line in pursuit of new customers. Conversely, Aetna and UnitedHealthcare have both been selective about choosing which ex-

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change markets to enter, and have been carefully considering the competitive landscapes, network designs, and the marketing challenges in each state. Early indications suggest that most exchanges will include relatively strong plan participation, including regional and national carriers and nonprofit or provider-sponsored plans.

Of the 15 states and the District of Columbia that have so far released details about insurer participation, almost all have a range of plan choices for consumers (Figure 2).

Some small states in New England, such as Vermont, have fewer carriers participating. In Vermont, the BlueCross BlueShield of Vermont and MVP Health Care plans, which already dominate the individual market, will be the only carriers to sell in the exchange.

So, although concerns persist about the potential lack of products in some rural regions of the country, thus far, participation appears strong enough to guarantee most consumers meaningful choice among several plan options, with more competition occurring in large, urban markets.

2. Cost: Competitive Premiums for Price-Sensitive Purchasers The consumers in exchanges will most likely be sensitive to price. Without the benefit of employer contributions to offset their premiums, enrollees will be driven to the lowest-cost plans, especially plans in the bronze and silver metal levels. Although most enrollees will receive premium subsidies, these subsidies will be tied to the second-lowest-cost silver plan, and consumers will still be motivated to reduce their portion of the cost. As such, keeping premiums as low as possible in this market will be essential for health plans to drive enrollment.

Health plans face a difficult proposition in pricing products for this new market. The age and health status of likely enrollees in the exchanges remain uncertain, and individuals with the greatest health needs are the most motivated to enroll in the early years of the program. Relative to prices in today’s individual market, the exchange premiums will be higher as a result of a range of new benefit requirements, rating rules, and higher-risk enrollees entering the market. Health plans need to strike a careful balance between fiscally responsible pricing that accounts for the risk profile of the anticipated exchange enrollees and competitive premiums that drive enrollment.

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Figure 1 State Operating Model Options for Exchange Functions Decision deadlines have passed for the 2014 plan year. Next opportunity for states to change models is the 2015 plan year—state plans or blueprint due November 2013.

Marketplace Plan Management

State Partnership Exchange

State-Based Exchange

Federally Facilitated Exchange

Plan management Although HHS will perform all key exchange functions, states continue to perform traditional regulatory role for health plans

Plan management

Consumer assistance

Rely on FFE, but take on increased plan certification responsibility

Eligibility Enrollment

Consumer assistance

Financial management

FFE indicates federally facilitated exchange; HHS, Department of Health and Human Services.

Copyright © Avalere Health, LLC. Used with permission.

Figure 2 Insurance Exchange Operational Model

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As of May 21, 2013, 16 states and Washington, DC, will run exchanges in 2014, 6 states are pursuing partnership, and others are relying on the FFE.

In addition to the marketplace plan management model for its individual exchange, Utah will rely on its existing small group exchange as its SHOP. b Although New Mexico will operate a partnership for its individual exchange, the state will run its own SHOP. FFE indicates federally facilitated exchange; SHOP, small business health option program.

Source: Avalere State Reform Insights, May 21, 2013. Copyright © Avalere Health, LLC. Used with permission. a

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One of the ways that plans will keep premiums down is by relying on narrow networks of providers with whom they can negotiate lower payment rates. Although most health plans enforce physician networks today, exchanges may feature a greater use of limited hospital and pharmacy networks to drive enrollees toward lower-cost providers. Such strategies have been a major thrust of the Massachusetts exchange efforts used to limit premium increases in its market.

Over the next several months, the government will launch a marketing campaign about the exchanges and will rely on navigators. Health plans, consumer advocates, providers, and other healthcare stakeholders will play a crucial role in raising awareness about exchanges, particularly for people with low healthcare needs.

A second strategy that plans are expected to use to manage costs is to control access to prescription drugs.

Minimum formulary coverage will vary greatly by state, based on the essential health benefit (EHB) rules. Although plans in 21 states are required to include more than 95% of drugs on their formularies, plans in Colorado and Utah must cover only 55% of drugs. Furthermore, the EHB rules give broad plan flexibility to manage access to drugs using prior authorization, formulary tiers, and increased cost-sharing for nonpreferred and specialty drugs. Given the limits on benefit design included in the ACA, plans will be aggressive in using narrow networks, formulary management, and other tools at their disposal to be price competitive in exchange markets.

3. Consumer Response: Widespread Awareness Yielding Diverse Exchange Enrollment In the early years of exchanges, the highest-risk consumers will enroll faster than lower-risk individuals.

Reinsurance and risk corridor programs will temporarily help insulate plans from some of the adverse selection that is sure to occur. However, long-term market stability will depend on drawing younger and healthier enrollees into exchanges via premium subsidies, the individual mandate, and the availability of catastrophic plans for young adults. The faster these healthy individ-

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uals enroll, the more functional exchanges will become.

Nonetheless, in a March 2013 poll by the Kaiser Family Foundation, 77% of the respondents reported that they had heard little or nothing at all about their stateâ&#x20AC;&#x2122;s exchange, and 57% of the respondents stated that they did not have enough information about how the ACA would impact them personally.1 Furthermore, although individual mandate penalties will raise awareness of the requirement to maintain health insurance coverage, the initial penalties are low, and taxpayers may not realize that they are subject to the penalty until April 2015 (after the end of the 2014 open enrollment period). Clearly, state and federal governments and private stakeholders face a daunting challenge to educate the public about their new coverage options and about how exchanges will impact them.

Exchange Navigators Over the next several months, the government will launch a marketing campaign about the exchanges and will rely on navigators. Navigators will be hired to educate individuals about exchanges and to facilitate their subsidy application and plan selection process. But, limited fundingâ&#x20AC;&#x201D;the federal government has awarded $54 million in grants for navigators and has awarded an $8 million contract for marketingâ&#x20AC;&#x201D;could stymie widespread outreach efforts. Instead, health plans, consumer advocates, providers, and other healthcare stakeholders will play a crucial role in raising awareness about exchanges, particularly for people with low healthcare needs.

Conclusion Exchanges are positioned to be the most important tool for achieving the insurance coverage goals set forth in the ACA, and success of the law depends on the viability of these new markets. Exchanges have the potential to extend coverage to millions of people who today cannot access health insurance in the dysfunctional individual market. As we anticipate the impact of exchanges in 2014 and beyond, success will depend on plan choice, competitive cost, and diverse consumers. n Author Disclosure Statement Ms Pearson has no conflicts of interest to report.

Reference

1. Kaiser Health Tracking Poll: March 2013. March 20, 2013. http://kff.org/healthreform/poll-finding/march-2013-tracking-poll/. Accessed May 23, 2013.

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Review Article

US Propofol Drug Shortages: A Review of the Problem and Stakeholder Analysis

Christopher Hvisdas, PharmD Candidate; Andrea Lordan, PharmD Candidate; Laura T. Pizzi, PharmD, MPH; Brandi N. Thoma, PharmD Background: Drug shortages have increased in recent years in the United States, with a majority involving sterile injectable drugs. Propofol, a sterile injectable drug, is frequently used as a sedative, thanks to its rapid onset of action and a short recovery period. However, propofol is complicated and expensive to manufacture, and recent events involving major manufacturers have led to shortages of the drug in the United States.

Objectives: To review the events leading to the shortage of propofol and to discuss how the shortage is affecting various healthcare stakeholders, as an example of the systemwide problem of drug shortages in the United States.

Discussion: Manufacturers currently have little economic incentive to produce propofol, a generic drug whose production is costly and carries a high liability. The enforcement of good manufacturing practices by the US Food and Drug Administration is beneficial for the safety of US citizens, but it can inherently lead to a sudden halt in the manufacturers’ production of drugs. Hospitals are affected because they must develop a plan to address current and potential shortages, including restricting the use of medications that have a shortage and shifting to alternative agents.

Conclusion: The shortage of propofol significantly impacted the delivery of care in the United States in 2009, and various stakeholders are working to increase the existing supply of propofol and to investigate the use of alternative medications when the supply runs short. The case of propofol presented in this article is used to illustrate a systemwide view of the impact of drug shortages on the US healthcare system.

I

n recent years, drug shortages have become a common occurrence in hospital and retail settings, with a record high of 267 drug shortages reported in 2011.1 Julie A. Golembiewski, PharmD, Clinical Associate Professor, Departments of Pharmacy Practice and Anesthesiology, University of Illinois at Chicago, defines a drug shortage as “a situation in which the total supply of all clinically interchangeable versions of an FDA [US Food and Drug Administration]-regulated drug is inadequate to meet the current or projected demand at the user level.”1 The impact and prevalence of such drug short­ ages were illustrated by a 2011 American Hospital Association survey of community hospitals.2 Nearly 50% of the responding hospitals reported ≥21 drug shortages within the first 6 months of 2011, and more than 99% of hospitals reported at least 1 drug shortage.2 Mr Hvisdas and Ms Lordan are Doctor of Pharmacy students and Dr Pizzi is Associate Professor, Department of Pharmacy Practice, Jefferson School of Pharmacy, Philadelphia, PA; Dr Thoma is Clinical Pharmacy Specialist, Surgical Cardiac Care Unit, Thomas Jefferson University Hospital, Philadelphia, PA.

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2013;6(4):171-175 www.AHDBonline.com Disclosures are at end of text

Approximately 80% of drug shortages involve sterile injectable drugs, such as anesthesia agents and chemotherapy drugs.1 These drugs can be difficult and expensive to manufacture, thereby forcing companies to operate on slim profit margins and leading to other companies exiting the market altogether.3 Currently, 3 pharmaceutical companies account for 70% of the sterile injectable products manufactured in the United States.1 The FDA maintains a useful website on drugs (www.fda.gov/Drugs/DrugSafety/ DrugShortages) that provides notifications regarding drug shortages, guidelines on shortage management, and the agency’s actions to address specific shortages.

Propofol, one of the sterile injectable drugs that is currently experiencing a shortage, is a phenolic derivative with sedative and hypnotic properties that is frequently used in intensive care units.4 It is formulated as an oil-in-water emulsion for intravenous use, which makes it highly lipophilic and allows it to rapidly cross the blood–brain barrier.4 Propofol is also quickly redistributed into peripheral tissues and is metabolized, resulting in a rapid onset of action, as well as a rapid emergence from sedation, making it the preferred choice for many anesthetists.4

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Key Points Drug shortages are common in hospitals and retail settings across the United States with serious impact to all healthcare stakeholders. ➤ The majority of drug shortages involve sterile injectable agents. ➤ Propofol is often used as a sedative and is undersupplied for the demand in the United States; manufacturers of this drug need greater financial incentives to produce it. ➤ The FDA can help to resolve drug shortages by enforcing good manufacturing practices and by designating alternate suppliers. ➤ Hospitals must develop plans to address shortages, including restrictions on drug use and using alternate agents. ➤ The propofol shortage had implications for various stakeholders, including patients, providers, payers, and drug manufacturers. This case is a good example of the impact of drug shortages overall on the US healthcare delivery system as a whole. ➤

Two major problems led to a recent shortage of propofol in 2010. After an outbreak of hepatitis C resulting from the inappropriate, unsanitary use of propofol, a verdict was issued against Teva Pharmaceuticals, which held 40% of the US market share at the time.3 As part of this ruling, Teva was ordered to pay $356 million to 1 man who developed hepatitis C, and their partner, Baxter International, was ordered to pay $144 million.3 The precedent set by this ruling discourages companies from making drugs with a high liability risk, especially when the court system unfairly holds pharmaceutical manufacturers responsible for the misuse of their products.3 It should be noted that the manufacturers’ marketing of oversized vials may have contributed to a hepatitis C outbreak, because the practice of reusing such vials inherently poses a risk of infectious contamination.

The second major problem deals with noncompliance with the FDA’s good manufacturing practices. In 2010, Hospira, Inc, voluntarily closed its manufacturing plant in North Carolina to address quality assurance and regulatory issues that had been identified during inspections by the FDA.1 This plant has remained closed for most of the past 2 years, focusing its efforts on becoming FDA compliant.1 An additional factor that has affected propofol availability was a voluntary recall of select lots of propofol that were manufactured by Hospira.5 The recall was issued as a result of possible contamination with particulate matter on March 31, 2010, and was extended nationwide on May 27, 2010, resulting in a shortage of

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propofol between April 1, 2010, and June 30, 2010.5 As manufacturers continue to merge, fewer companies provide a larger portion of a drug’s supply. Problems with one of these companies, such as the recall by Hospira, can lead to a sudden shortage of a drug.

In critical care, drugs are chosen for a certain condition based on their efficacy, pharmacodynamics, pharmacokinetics, bioavailability, or actions on distinct receptors.6 However, in recent years, with the epidemic of drug shortages, medications are sometimes chosen simply because they are the only ones available.6 Drug short­ ages, including that of propofol, can alter how the pharmacy dispenses or prepares medications, as well as affect government regulation of pharmaceutical manufacturers and patient care, especially when alternative medications must be used in place of the preferred drug.

Stakeholder Analysis Government The government, the FDA in particular, has a responsibility to resolve issues that adversely affect the safety and well-being of US citizens. Drug shortages, which can affect the treatment of life-threatening diseases, are an important issue that the FDA needs to address. One contributing factor to the propofol shortage was the FDA’s increased enforcement of compliance.7 Drug manufacturers now only have 15 days to respond to issues found in good manufacturing practices during inspection before the FDA issues a warning or takes corrective action.7 Of the 5 major generic companies producing injectable drugs, 4 underwent remediation simultaneously to comply with this new policy, causing a sudden halt in the production of many drugs.7 Manufacturers are now required to notify the FDA if a drug has the potential to be in short supply, along with reasons and expected unavailability, whereas the previous law only required this in cases where there was only 1 manufacturer of a given drug.8 On receipt of notice of potential shortages, the FDA then works to resolve any underlying causes, such as manufacturing or quality issues.8 In the meantime, the FDA reaches out to other suppliers of the drug to help increase the overall production of the product and expedites processes needed to increase production, such as the approval of new production lines.8 In cases where US drug companies are unable to resolve manufacturing issues in a timely manner, such as with propofol, the FDA searches abroad for companies that are willing and able to import similar products of adequate quality that pose little to no risk to US patients.8 Currently, according to the American Society of Anesthesiologists, propofol should be treated as “deep sedation,” and therefore should only be administered by people who are trained in general anesthesia administra-

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tion and who are not directly involved in the medical procedure being done.9 Because of this, propofol is usually administered by an anesthesiologist or a certified nurse anesthetist in a process called monitored anesthesia care (MAC). This procedure is not very cost-effective, especially in healthy persons who are undergoing routine procedures. Adding MAC to a procedure creates an additional fee; the Centers for Medicare & Medicaid Services pays an average of $155 for the addition of MAC to an endoscopy, whereas private insurers pay an average of $437 for the same procedure.9 However, alternatives to propofol may be even more costly.

Dexmedetomidine, one of the major proposed alternatives to propofol, is currently much more expensive than propofol or midazolam (another proposed alternative). Dexmedetomidine has a median per-patient drug acquisition cost of $1166 compared with only $60 for midazolam.10 Because dexmedetomidine will lose its patent in 2013, its acquisition price is expected to decrease dramatically, which may make it a viable alternative in the future.10

Pharmaceutical Suppliers: Manufacturers and Purchasing Organizations The current propofol shortage is a result of the supply being unable to meet the demand. As the source for all drugs, drug manufacturers are directly responsible for the supply of propofol in the market. In 2009, only 3 drug manufacturing companies were producing propofol for the US market.11 One of these companies, Hospira, temporarily stopped producing propofol, whereas Teva decided to stop its production of this agent completely.11 It was clearly impossible for the remain­ing manufacturer, APP Pharmaceuticals, to produce enough propofol to meet the demand of the entire US market.11 Although there is a great demand for this drug, most manufacturers are unwilling or are unable to produce propofol, which has been a major roadblock to alleviating the shortage.

One of the major reasons for the limited production of propofol is that there is very little economic incentive for manufacturers to produce the drug. Propofol, a sterile injectable drug, is both complex and time-consuming to produce. Some manufacturing companies simply do not have the capacity to produce such a drug, whereas many companies that do have the capacity are unwilling to invest the extra money and time that are necessary to manufacture it.11 Furthermore, because propofol is a generic drug, it commands a much lower price in the market than a patent drug, and any profits that could be earned from its production are minor. In addition, the ruling against Teva in 2010 has made manufacturing companies more wary of producing drugs with high liability.3 Therefore, from the perspective of the manufac-

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turers, the benefits of supplying propofol are outweighed by the costs and the risks, and it is much more logical to produce drugs that are easier to manufacture and that can be sold for a higher price.11 Group purchasing organizations also contribute to the issue. Group purchasing organizations generally select a preferred manufacturer, which guarantees demand for a particular product for that manufacturer.7 Because of this, there is constant competition between drug companies to make a product in large quantities to win group purchasing organization contracts, which drives product prices down and ultimately lowers profit margins.7 If a company is unable to win a group purchasing organization contract for a drug, it has much less financial incentive to continue producing the drug.7 In addition, this â&#x20AC;&#x153;exclusivityâ&#x20AC;? decreases incentive for other companies to enter the market, which keeps the market small.7 If there is an issue with production at a preferred manufacturing company, there are little to no other suppliers of the drug, thus causing a shortage when demand cannot be met.7 Although high demand for a drug on shortage can increase its price and can create an incentive for more manufacturers to enter the market, this is only a temporary situation. As soon as more supply enters the market, the price will drop, creating a disincentive for new drug manufacturers to enter the market. Because manufacturing companies are not increasing the supply to fill the gap left by the recall of large amounts of propofol or the withdrawal of major propofol manufacturers from the market, the shortage with propofol persists.

Hospitals Hospital administrators typically step in to regulate the dispensation of medications during drug shortages.

This requires significant effort on the part of hospital administrators, who must analyze and determine how best to address the shortage based on the volume and the types of medical procedures. Ultimately, however, all hospital employees are affected by a drug shortage: they need to be apprised as to which drugs are approved for procedures, ensure that appropriate alternatives are available, and they must quantify all medications on shortage to regulate their distribution. Given the number of recent drug shortages, this is no simple task.1 A major challenge for hospitals is to quickly develop a clear plan for addressing the shortage and to ensure that this plan is communicated to its clinicians, its staff, and when necessary, to its patients. A study conducted in 2012 presented specific drug shortage management approaches to be used by hospitals, advocating a reliable process that developed a hierarchy of clinical need.12 The study promoted the distribution of medications on shortage to patients who needed them the most.12

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Hospital administrations can develop such a hier­ archy through their Pharmacy & Therapeutics (P&T) committees. For example, in response to the recent propofol shortage, in October 2012 our hospital’s P&T committee limited the use of propofol to traumatic brain injury, bedside invasive intracranial procedures, spinal cord injuries, nontraumatic subarachnoid hemorrhage, ventilated acute liver failure, refractory status epilepticus, and ventilated stroke. In addition, the availability of propofol within Pyxis units was restricted to a select number of intensive care units.

Restricting the use of a drug on shortage to patients and procedures that rely on it most heavily is a sensible and ethical solution; however, it is not a long-term solution, and it only provides temporary relief. Also, limiting the use of medications that are on shortage can lead to an important drug being unavailable during an emergency, a situation that is both frustrating for hospital staff and potentially dangerous for patients.

In rare cases, a restricted drug may lead to improved outcomes as a result of using an alternative agent. After the propofol shortage at our institution, cardiac surgery intensivists began using dexmedetomidine for sedation immediately postoperatively. In a comparative analysis, more patients sedated with dexmedetomidine were extubated within a goal of 6 hours compared with patients sedated with propofol (P = .001). This contributed to a significant decrease in overall length of stay in the patients receiving dexmedetomidine (P = .012).13

The Search for Cost-Effective Alternatives Propofol is favored as a sedative because it is potent and has a rapid onset of action with a relatively short recovery period.4 As a result, it is the sedative of choice amongst physicians for many procedures. In practice, certain medications—dexmedetomidine and midazolam­­ —may effectively replace propofol in certain clinical settings. A 2012 study conducted by Jakob and colleagues analyzed the differences between dexmedetomidine, midazolam, and propofol in prolonged mechanical ventilation.14 The results demonstrated that dexmedetomidine was as effective at sedating patients who are on mechanical ventilation in an intensive care unit setting as midazolam and propofol.14 In this particular study, patients given dexmedetomidine were better able to communicate their pain levels and were more easily aroused compared with patients sedated with propofol or with midazolam.14 This is an important advantage, because it allows clinicians to communicate with sedated patients, which permits the clinicians to better perform procedures. However, more adverse events were observed with dexmedetomidine, and it had a longer onset of action than that of propofol.14

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From an economic standpoint, there is a significant difference in price-per-patient drug costs between dexmedetomidine and propofol. One study showed that patients who were sedated with dexmedetomidine during coronary artery bypass graft (CABG) surgery or with valvular surgery had $50 more in sedation-related costs per patient.15 However, emerging evidence suggests that these additional sedation costs can be offset by reduced intubation time and by reduced intensive care unit length of stay with dexmedetomidine. At our hospital, we examined data for patients undergoing CABG surgery and reported an estimated $4246 cost-savings per case for the use of dexmedetomidine versus propofol.13 This estimate reflects the positive financial impact that the transition to dexmedetomidine can have on patient and hospital expenses.

Conclusion Overall, the propofol drug shortage has impacted various stakeholders with differing perspectives in ways that immediately affect the US healthcare system. Drug manufacturers need financial incentives to undertake the risks that are associated with the production of propofol, and they should promote single-use packaging to reduce the likelihood of contamination. Hospitals are stressed by their efforts to distribute their remaining propofol and to acquire more propofol from the limited supply. Physicians are concerned with providing efficacious sedation to patients. It is evident that the propofol shortage has significantly impacted healthcare delivery and that it serves as an interesting case study to inform stakeholders’ efforts to proactively identify and manage future drug shortages. This case of propofol shortage is one example of the impact of drug shortages overall on the US healthcare system as a whole and why it is urgently necessary to address such shortages. n Author Disclosure Statement Mr Hvisdas, Ms Lordan, Dr Pizzi, and Dr Thoma have reported no conflicts of interest.

References

1. Golembiewski J. Drug shortages in the perioperative setting: causes, impact, and strategies. J Perianesth Nurs. 2012;27:286-292.

2. Schulman RDW, Sweet G. Impact of drug shortages: results of two independent national surveys. September 26, 2011. www.fda.gov/downloads/Drugs/NewsEvents/ UCM274568.pdf. Accessed May 17, 2013.

3. Weaver JM. Why are there so many drug shortages? Anesth Prog. 2010;57:89-90.

4. McKeage K, Perry CM. Propofol: a review of its use in intensive care sedation of adults. CNS Drugs. 2003;17:235-272.

5. US Food and Drug Administration. Hospira announces an expansion of a nationwide voluntary recall of certain lots of Liposyn and propofol that may contain particulate matter. May 27, 2010. www.fda.gov/Safety/Recalls/ucm213880.htm. Accessed May 17, 2013.

6. Popovich MJ. Bioavailability or just availability? How the national propofol shortage example may transform tenets of critical care management. Crit Care Med. 2012; 40:661-662.

7. Committee on Oversight and Government Reform. FDA’s Contribution to the Drug Shortage Crisis. Washington, DC: US House of Representatives; 2012. http://

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oversight.house.gov/wp-content/uploads/2012/06/6-15-2012-Report-FDAs-­ Contribution-to-the-Drug-Shortage-Crisis.pdf. Accessed May 14, 2013.

8. Frequently asked questions about drug shortages. US Food and Drug Administration. Updated August 24, 2012. www.fda.gov/Drugs/DrugSafety/DrugShortages/ucm­­ 050796.htm. Accessed November 21, 2012.

9. Rex DK. Effect of the Centers for Medicare & Medicaid Services policy about deep sedation on use of propofol. Ann Intern Med. 2011;154:622-626.

10. Wunsch H. Weighing the costs and benefits of a sedative. JAMA. 2012;307: 1195-1197.

11. Jensen V, Rappaport BA. The reality of drug shortages—the case of the injectable agent propofol. N Engl J Med. 2010;363:806-807.

12. Rosoff PM, Patel KR, Scates A, et al. Coping with critical drug shortages: an

ethical approach for allocating scarce resources in hospitals. Arch Intern Med. 2012; 172:1494-1499.

13. Thoma B, Pizzi LT, McDaniel C, et al. Dexmedetomidine versus propofol and midazolam in patients undergoing coronary artery bypass grafting surgery. Crit Care Med. 2012;40(suppl 1):Abstract 1120.

14. Jakob SM, Ruokonen E, Grounds RM, et al, for the Dexmedetomidine for LongTerm Sedation Investigators. Dexmedetomidine vs midazolam or propofol for sedation during prolonged mechanical ventilation: two randomized controlled trials.

JAMA. 2012;307:1151-1160.

15. Barletta JF, Miedema SL, Wiseman D, et al. Impact of dexmedetomidine on analgesic requirements in patients after cardiac surgery in a fast-track recovery room setting. Pharmacotherapy. 2009;29:1427-1432.

Stakeholder Perspective Drug Shortages in the United States Continue to Undermine Patient Care

By Jack E. Fincham, PhD, RPh Professor of Pharmacy Practice and Administration, University of Missouri-Kansas City School of Pharmacy

POLICYMAKERS: Mr Hvisdas and colleagues’ exceptionally well-written analysis of the incidence, impact, and outcomes of drug shortages in the United States is timely. Their discussion provides an excellent example of how the shortage of one drug, in this case propofol, can impact so many stakeholders in differing aspects of healthcare delivery in the United States.

And although as of May 31, 2013, the US Food and Drug Administration (FDA) classifies the drug shortage of propofol as “resolved: no supply issue anticipated,”1 many other drugs have experienced drug shortages. The article by Mr Hvisdas and colleagues gives providers, governmental policymakers, manufacturers, patients, and regulatory entities a comprehensive overview of the significant, negative outcomes that occur with the understated problem of drug shortages in the United States.

To further focus attention on the importance of the topic of drug shortages in the United States, it is impor­ tant to note that as of June 6, 2013, the FDA lists 130 drugs in the Current Drug Shortages Index.2 Therefore, the suggestions outlined in this article by Mr Hvisdas and colleagues provide a sound base for future situations that may result from drug shortages.

As early as 2010, Jensen and Rappaport noted that sterile injectable drugs, such as propofol, are susceptible to problematic drug shortage issues.3 The authors discussed the serious issues that are affecting all those involved when these types of crucial drugs are in short supply.3 Referring specifically to drugs required for anesthesia, De Oliveira and colleagues suggest that patient safety is at risk by an increased probability for medication errors occurring more frequently as a result of the environment becoming conducive to confusion

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and subsequent errors from drug shortages.4 Rider and colleagues propose the use of an expanded-phase approach to dealing with drug shortages.5 This approach involves several phases, including a preparation phase that is focused on multidisciplinary risk management, followed by a contingency phase that incorporates a drug shortage task force, as well as an assessment phase that examines the outcomes of the systemwide approach to analyzing drug shortages.5 Furthermore, drug shortages and their critical nature have had an international reach and reaction as well. In Canada, similar assessments and calls for action have been deemed crucial for the Canadian anesthesia milieus.6,7 PROVIDERS/PATIENTS: A more focused approach to dealing with drug shortages at the outset of any potential occurrences needs to be incorporated into academic and clinical settings—in the institutional setting and the community setting—to a much greater extent than is presently in place. Patient safety should be the driving force to making these changes a real outcome of the dangerous situation that puts patients at risk and has undermined, and continues to undermine, patient care.

1. US Food and Drug Administration. Resolved drug shortages. www.fda.gov/Drugs/ DrugSafety/DrugShortages/ucm050793.htm. Accessed June 6, 2013.

2. US Food and Drug Administration. Current Drug Shortages Index. www.fda.gov/ Drugs/DrugSafety/DrugShortages/ucm050792.htm. Accessed June 6, 2013.

3. Jensen V, Rappaport BA. The reality of drug shortages—the case of the injectable agent propofol. N Engl J Med. 2010;363:806-807.

4. De Oliveira GS Jr, Theilken LS, McCarthy RJ. Shortage of perioperative drugs: implications for anesthesia practice and patient safety. Anesth Analg. 2011;113:1429-1435.

5. Rider AE, Templet DJ, Daley MJ, et al. Clinical dilemmas and a review of strategies to manage drug shortages. J Pharm Pract. 2013;26:183-191.

6. Hall R, Bryson GL, Flowerdew G, et al. Drug shortages in Canadian anesthesia: a national survey. Can J Anesth. 2013;60:539-551.

7. Houston P, Chisholm R. Water, water everywhere, but not a drop in sight: the impact of drug shortages on Canadian anesthesia care. Can J Anesth. 2013;60:519-522.

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Call for Papers Cardiometabolic Health Special Issue American Health & Drug Benefits will be publishing a Special Issue on Cardiometabolic Health in 2013 Readers are invited to submit articles for publication in this special issue on topics relevant to the clinical, business, and policy aspects of cardiometabolic health and wellness. Original research, comparative effectiveness analyses, white papers, evidence-based comprehensive reviews, and case studies are of particular interest. All articles will undergo the journal’s rigorous peer-review process and acceptance is contingent on that review.

Topics of high interest include: • Benefit designs to improve cardiometabolic patient outcomes • Best practices in insulin control, lipid management, or blood pressure control • Comparative effectiveness analyses of best therapies for cardiovascular health • Cost-effectiveness comparisons of current therapies for diabetes • Current recommendations for optimizing A1c target outcomes • Diabetes management and prevention • Employers’ strategies to enhance employees’ cardiometabolic wellness • Emerging therapies for diabetes, heart disease, and/or obesity • Health plan initiatives for cardiometabolic health and prevention • Hot topics in diabetes management

• Insulin resistance and type 2 diabetes • Lifestyle strategies and cardiometabolic health and wellness • Lipid management in patients with diabetes • Medication adherence • New biomarkers for assessing cardiometabolic risk • New therapies for diabetes, cardiovascular disease, or obesity • Optimal therapies for cardiovascular disease, diabetes, and/or obesity • Pharmacoeconomic analyses • Prevention strategies for diabetes risk reduction • Wellness programs for patients with heart disease, diabetes, or obesity

Submission deadline: July 15, 2013 Articles must follow the Manuscript Instructions for Authors at www.AHDBonline.com.

Submit articles to editorial@engagehc.com. For more information, call 732-992-1889.

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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.

NOW APPROVED Introducing an oral medication for patients with refractory multiple myeloma who have received at least two prior therapies, including lenalidomide and bortezomib

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 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.

To find out more information about POMALYST, go to www.pomalyst.com or use your smartphone to scan this code.

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.

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 02/13 US-POM120044

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This brief summary does not include all the information needed to use POMALYST® 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.

Neutropenia • ANC* < 500 per mcL or Febrile neutropenia (fever more than or equal to 38.5°C and ANC < 1,000 per mcL)

Interrupt POMALYST treatment, follow CBC weekly.

• ANC return to more than or equal to Resume POMALYST at 3 mg daily.

500 per mcL • For each subsequent drop < 500 per Interrupt POMALYST treatment mcL • Return to more than or equal to 500 Resume POMALYST at 1 mg less per mcL than the previous dose Thrombocytopenia • Platelets < 25,000 per mcL

Interrupt POMALYST treatment, follow CBC weekly

• Platelets return to > 50,000 per mcL Resume POMALYST treatment at 3 mg daily • For each subsequent drop < 25,000 Interrupt POMALYST treatment per mcL • Return to more than or equal to 50,000 per mcL

Resume POMALYST at 1 mg less than previous 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

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.

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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

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.

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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)] • 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.

Table 2: Adverse Reactions Reported in 10% of Patients in Any Treatment Arm Trial 1 POMALYSTa

System Organ Class/Preferred Term Number(%) of Patients With at Least One Treatment Emergent Adverse Reaction

(N = 107)

POMALYST + Low dose Dex (N=112)

n (%)

n (%)

107 (100)

112 (100)

59 (55)

70 (63)

Pyrexia

20 (19)

34 (30)

Edema peripheral

25 (23)

18 (16)

Chills

10 (9)

12 (11)

Pain

6 (6)

5 (5)

Blood and lymphatic system disorders Neutropenia

56 (52)

53 (47)

Anemia

41 (38)

44 (39)

Thrombocytopenia

27 (25)

26 (23)

Leukopenia

12 (11)

20 (18)

4 (4)

17 (15)

38 (36)

39 (35)

Gastrointestinal disorders Constipation Diarrhea

36 (34)

37 (33)

Nausea

38 (36)

25 (22)

Vomiting

15 (14)

15 (13)

Infections and infestations Pneumonia

25 (23)

32 (29)

Upper respiratory tract infection

34 (32)

28 (25)

8 (8)

18 (16)

Urinary tract infection

(N = 107)

POMALYST + Low dose Dex (N=112)

n (%)

n (%)

Back pain

34 (32)

34 (30)

Musculoskeletal chest pain

23 (22)

22 (20)

Muscle spasms

20 (19)

21 (19)

System Organ Class/Preferred Term Musculoskeletal and connective tissue disorders

Arthralgia

17 (16)

17 (15)

Musculoskeletal pain

12 (11)

17 (15)

Pain in extremity

5 (5)

16 (14)

Muscular weakness

13 (12)

13 (12)

Bone pain

13 (12)

5 (5)

Dyspnea

36 (34)

50 (45)

Cough

15 (14)

23 (21)

Epistaxis

16 (15)

12 (11)

Respiratory, thoracic and mediastinal disorders

Metabolism and nutritional disorders Decreased appetite

23 (22)

20 ( 18)

Hyperglycemia

13 ( 12)

17 ( 15)

Hyponatremia

11 ( 10)

14 ( 13)

Hypercalcemia

22 ( 21)

13 (12)

Hypocalcemia

6 (6)

13 ( 12)

Hypokalemia

11 ( 10)

12 ( 11)

6 ( 6)

18 ( 16)

23 ( 22)

18 ( 16)

Skin and subcutaneous tissue disorders Hyperhidrosis

Fatigue and asthenia

Lymphopenia

Trial 1 POMALYSTa

(continued)

Rash Night sweats

5 ( 5)

14 ( 13)

Dry skin

10 ( 9)

12 ( 11)

Pruritus

16 ( 15)

12 ( 11)

Dizziness

21 ( 20)

19 ( 17)

Tremor

10 ( 9)

14 ( 13)

Headache

14 ( 13)

9 ( 8)

Neuropathy peripheral

11 ( 10)

8 ( 7)

Nervous system disorders

Investigations Blood creatinine increased

16 ( 15)

12 ( 11)

Weight increased

1 ( 1)

12 ( 11)

Weight decreased

15 ( 14)

9 ( 8)

Psychiatric disorders Insomnia

7 ( 7)

16 ( 14)

Confusional state

11 ( 10)

15 ( 13)

Anxiety

12 ( 11)

8 ( 7)

16 ( 15)

11 ( 10)

Renal and urinary disorders Renal failure aPOMALYST

alone arm includes all patients randomized to the pomalidomide alone arm who took study drug; 61 of the 107 patients had dexamethasone added during the treatment period

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General disorders and administration site conditions

Table 2: Adverse Reactions Reported in 10% of Patients in Any Treatment Arm

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Table 3: Grade 3/4 Adverse Reactions Reported in ≥5% of Patients in Any Treatment Arm

Table 4: Serious Adverse Reactions Reported in 2 or more Patients Trial 1

Trial 1 POMALYSTa

System Organ Class/Preferred Term [a] Number(%) of Patients With at Least One Treatment Emergent NCI CTC Grade 3 or 4 Adverse Reaction

(N = 107)

POMALYST + Low dose Dex (N=112)

n (%)

n (%)

96 ( 90)

99 ( 88)

Neutropenia

50 ( 47)

43 ( 38)

Anemia

24 ( 22)

23 ( 21)

Thrombocytopenia

24 ( 22)

21 ( 19)

Leukopenia

6 ( 6)

11 ( 10)

Lymphopenia

2 ( 2)

8 ( 7)

Infections and infestations 26 (23)

2 ( 2)

9 ( 8)

Sepsis

6 ( 6)

3 ( 3)

10 ( 9)

1 ( 1)

12 ( 11)

14 ( 13)

6 ( 6)

3 ( 3)

7 ( 7)

14 ( 13)

13 ( 12)

10 ( 9)

6 ( 6)

4 ( 4)

10 ( 9)

7 ( 6)

Metabolism and nutritional disorders General disorders and administration site conditions Fatigue and asthenia Investigations Blood creatinine increased Respiratory, thoracic and mediastinal disorders Dyspnea Musculoskeletal and connective tissue disorders Back pain Muscular weakness Renal and urinary disorders Renal failure a

POMALYST alone arm includes all patients randomized to the pomalidomide alone arm who took study drug; 61 of the 107 patients had dexamethasone added during the treatment period.

Table 4: Serious Adverse Reactions Reported in 2 or more Patients Trial 1 POMALYSTa (N = 107)

POMALYST + Low dose Dex (N=112)

System Organ Class/Preferred Term

n (%)

n (%)

Number(%) of Patients With at Least One Treatment Emergent Serious Adverse Reaction

72 ( 67)

69 ( 62)

Pneumonia

15 (14)

21 (19)

Urinary tract infection

0 ( 0)

6 ( 5)

Sepsis

6 ( 6)

3 ( 3)

5 (5)

7 (6)

Pyrexia

3 (3)

5 (5)

General physical health deterioration

0 (0)

2 (2)

Atrial fibrillation

2 (2)

3 (3)

Cardiac failure congestive

0 (0)

3 (3)

Infections and infestations

Respiratory, Thoracic and mediastinal disorders Dyspnea

n (%)

n (%)

9 (8)

7 (6)

1 (1)

3 (3)

5 (5)

1 (1)

Dehydration

5 (5)

3 (3)

Hypercalcemia

5 (5)

2 (2)

4 (4)

2 (2)

System Organ Class/Preferred Term Renal and urinary disorders Renal failure Gastrointestinal disorders

General disorders and administration site conditions

Cardiac Disorders

(continued)

Blood and Lymphatic system disorders Febrile neutropenia Metabolism and nutrition disorders

Musculoskeletal and connective tissue disorders Back pain

[a] POMALYST 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 Cosmos Communications

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17 ( 16)

Urinary tract infection

Hypercalcemia

POMALYST + Low dose Dex (N=112)

constipation

Blood and lymphatic system disorders

Pneumonia

POMALYSTa (N = 107)

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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. 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.

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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. 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,

industry Trends

Step-Up Therapy Program for Anti-Inflammatory Biologic Agents Does Not Increase Cost Nor Adversely Affect Patient Outcomes

By Wayne Kuznar, Medical Writer

www.AHDBonline.com

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1. Burcher K, Kavety J, Rogers N, et al. Impact of adalimumab step therapy on health and economic outcomes. Poster presented at the Academy of Managed Care Pharmacy, April 3-5, 2013; San Diego, CA.

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Dr Burcher and colleagues compared the health and cost utilization outcomes of 149 members in the intervention group who were affected by the step therapy program and 317 members in the control group who were not affected by the program.

The intervention group had a step therapy edit for

Economic and Health Impact In the 180 days before the index claim, no significant difference was evident between the 2 groups in mean medical cost, but the mean pharmacy cost was significantly higher in the intervention group compared with the control group—$1343.32 versus $847.76 (P = .005).

The mean medical costs during the 180 days after the index claim were $3233.18 in the intervention group versus $2874.99 in the control group, a nonsignificant difference.

All secondary end points were also not significantly different between the 2 groups. In the intervention group, the mean number of pharmacy claims for nonbiologic disease-related therapies (ie, nonsteroidal anti-inflammatory drugs, corticosteroids, and immunosuppressants) was 3.38 compared with 2.98 in the control group (P = .821); the mean number of ambulatory visits was 9.35 versus 8.50, respectively (P = .276); and the percentage of members with an emergency department or inpatient visit was 16.8% versus 16.2%, respectively (P = .889).

“Outcomes studies like this are necessary to show that the resultant pharmacy savings do not lead to unintended increases in medical utilization and cost,” suggested Dr Burcher and colleagues. n

M08

The mean medical costs during the 180 days after the index claim were $3233.18 in the intervention group versus $2874.99 in the control group, a nonsignificant difference.

All secondary end points were also not significantly different between the 2 groups.

adalimumab in the first quarter of 2012, followed by a paid claim for a step-1 agent within 30 days. The members in the control group (who were not affected by the program) had a paid claim for adalimumab during the same time. Members in the 95th to 100th percentile by total cost were removed from the analysis to mitigate the impact of outliers.

Psoriasis was the most frequent (26%) diagnosis in the study sample, followed by rheumatoid arthritis (22%). Approximately 25% of the sample members had multiple diagnoses. The mean Charlson comorbidity indices were 0.50 in the intervention group and 0.52 in the control group.

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he step therapy requirement for adalimumab coverage does not lead to increased cost to the health plan or increased utilization, according to a retrospective claims-based study by Kyle Burcher, PharmD, UnitedHealthcare Pharmacy, Minnetonka, MN, and colleagues from UnitedHealthcare and OptumInsight.

They presented their data at the 2013 annual meeting of the Academy of Managed Care Pharmacy.1 Biologic agents have been a top driver of pharmacy costs over the past decade, a trend that is likely to continue in the future, according to Dr Burcher and colleagues. The lack of head-to-head trials showing superiority of one biologic agent over another in terms of outcomes has created opportunities for health plans to implement utilization management programs to control cost while maintaining access to current therapies.

UnitedHealthcare introduced a step therapy program in 2012 for the treatment of rheumatoid arthritis, psoriatic arthritis, psoriasis, ankylosing spondylitis, and Crohn’s disease. The program requires that member prescribers first try 1 or more of the step-1 self-administered biologic anti-inflammatory agents included in the program—certolizumab, etanercept, golimumab, and ustekinumab—before UnitedHealthcare would provide coverage for the use of adalimumab.

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S E I G R E L L A D FOO * IN CHILDREN HAVE

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

(Epinephrine) Auto-Injectors

(Epinephrine) Auto-Injectors

(Epinephrine) Auto-Injectors

(Epinephrine) Auto-Injectors 0.3/0.15mg

(Epinephrine) Auto-Injectors 0.3 mg

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.

(Epinephrine) Auto-Injectors 0

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.

(Epinephrine) Auto-Injectors

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

(Epinephrine) Auto-Injectors

(Epinephrine) Auto-Injectors 0.3/0.15mg

(Epinephrine) Auto-Injectors 0.3 mg

CLINICAL

Original research

Opioid Utilization Patterns Among Medicare Patients with Diabetic Peripheral Neuropathy Jacqueline Pesa, MSEd, PhD, MPH; Roxanne Meyer, PharmD; Tiffany P. Quock, PhD, MS; Stacy K. Rattana, RN, BSN; Samir H. Mody, PharmD, MBA

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2013;6(4):188-196 www.AHDBonline.com Disclosures are at end of text

Background: Diabetic peripheral neuropathy (DPN) affects a large percentage of patients with type 2 diabetes and is associated with moderate-to-severe pain. Patients with DPN bear a substantial economic burden as a result of increased overall healthcare utilization. The reported costs of treating DPN are nearly $11 billion, with elderly (aged ≥65 years) patients with type 2 diabetes accounting for 93.1% ($10.2 billion) of the total costs.

Objectives: To describe the real-world utilization patterns of long-acting opioids (LAOs) and chronic short-acting opioids (SAOs) use in a sample of Medicare enrollees (aged ≥65 years) with painful DPN, and to identify potential areas for improvement in the management of elderly patients with painful DPN who are treated with opioids.

Methods: In this retrospective pharmacy claims analysis, the Chronic Opioid Medication Use Evaluation (MUE) software was used to import and analyze individual plan, retrospective pharmacy utilization claims data from the MarketScan claims databases. Patients aged ≥65 years who had painful DPN as identified by ≥2 International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes for painful DPN (250.6X or 357.2) in at least 2 quarters in 2009, and who had ≥1 claims for LAO and/or chronic use of SAO (≥60 days of continuous therapy), were selected for analysis. Pharmacy claim data were extracted for 12 months, and various opioid utilization measures were reported.

Results: A total of 1448 unique Medicare patients with painful DPN were identified who had 11,740 claims for an LAO and/or chronic use of an SAO. Of the 1448 patients, 62% had chronic use of an SAO, and of these, 89% had no concurrent claim for LAO (minimum, 60day overlap). The most frequently filled LAOs were fentanyl transdermal (38%), oxycodone controlled release (CR; 26%), and morphine CR/extended release (ER)/sustained release (SR; 20%). The daily average consumptions for fentanyl transdermal, oxycodone CR, and morphine CR/ER/SR were 0.3, 2.5, and 2.4, respectively. Among the study population, 15.2% of the patients filled an LAO or SAO prescription at ≥2 pharmacies. Furthermore, these elderly patients with painful DPN used greater doses of LAOs than what is recommended in the package insert, and 1.6% of patients used high doses of acetaminophen and 15.2% utilized multiple pharmacies to obtain their opioid prescriptions. Moreover, this population had prevalent concomitant use of opioids and prescribed gastrointestinal (GI) medications.

Conclusion: Results from our retrospective pharmacy claims analysis demonstrated that elderly patients with painful DPN use doses of LAOs above those recommended in the package insert, with some patients using high doses of acetaminophen and utilizing multiple pharmacies to obtain their opioid prescriptions. In addition, this population had prevalent concomitant use of opioids and prescription GI medications. The use of software, such as the Opioid MUE, to monitor opioid drug utilization trends and examine other utilization measures can assist healthcare decision makers and payers in their utilization reviews to appropriately manage this population.

Dr Pesa is Associate Director, Translational Science, Health Economics and Outcomes Research, Janssen Scientific Affairs, LLC, Superior, CO; Dr Meyer is Manager, Janssen Scientific Affairs, Raritan, NJ; Dr Quock is Senior Health Economist, Oxford Outcomes, San Francisco, CA; Ms Rattana is Manager, InVentiv Health Clinical, Deerfield, IL; Dr Mody is Director, Health Economics and Outcomes Research, Janssen Scientific Affairs, Raritan, NJ.

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Opioid Utilization in Medicare Patients with DPN

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iabetic peripheral neuropathy (DPN) is one of the most common complications associated with diabetes, occurring in 30% to 50% of patients with type 2 diabetes and affecting approximately 1 million Americans annually.1,2 DPN manifests as spontaneous painful, burning, electric, or shooting sensations in the extremities, with 10% to 20% of patients with DPN experiencing moderate-to-severe pain.3-6 Of these patients, 11% to 26% develop chronic pain, which is defined as pain that continues for an extended period of time that may be associated with a recognizable disease process.7,8 The American Chronic Pain Association has defined chronic pain as “lasting beyond the usual course of acute illness or injury or more than 3 to 6 months, and which adversely affects the individual’s well-being.”9 The majority of patients with DPN experience pain on a daily and ongoing basis, which significantly and negatively impacts their quality of life and daily functioning.3-6,10-12 Patients with DPN endure a substantial economic burden as a result of increased healthcare utilization (eg, medication use, hospitalizations, and health services visits).13-15 The reported costs of treating DPN are nearly $11 billion, with patients with type 2 diabetes comprising 92.5% of the study population and accounting for 93.1% ($10.2 billion) of the total costs.16 In another study, the total annual direct and indirect costs for patients with painful DPN during the 2006 to 2008 study period ranged from $8435 to $10,120.17 In contrast, the total costs during this period for diabetic patients without painful DPN ranged from $5536 to $6308.17 Opioids have been frequently used in the management of painful DPN, particularly as an adjunct treatment for diabetic patients suffering from chronic pain.18,19 The various practice guidelines recommend the use of long-acting opioids (LAOs) for continuous pain as part of a multimodal treatment plan if first-line agents that are approved for DPN are inadequate in providing analgesia.8,20-22 However, opioid use in the elderly pre­ sents several challenges because of the rapidly increasing population of older Americans, higher incidence of pain, and greater susceptibility to the adverse effects of pain medication.23 Opioids are frequently started at doses that are too low for pain relief, and concerns about adverse effects from or addiction to pain medication may further contribute to a high incidence of undertreated pain.24,25 The high risks of abuse and misuse related to opioids can also lead to frequent physician office visits and to increased emergency care. Therefore, opioid users must be closely monitored, and dosing adjustments or treatment terminations should be considered when appropriate, to ensure that opioids are administered properly.26,27 Our analysis describes the real-world utilization of

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Key Points Diabetic peripheral neuropathy (DPN) affects 30% to 50% of patients with type 2 diabetes. ➤ DPN manifests as spontaneous painful, burning, electric, or shooting sensations in the extremities, with 10% to 20% of patients with DPN experiencing moderate-to-severe pain. ➤ The reported costs of treating DPN are nearly $11 billion, with patients aged ≥65 years accounting for 93.1% of the total costs. ➤ This study describes the real-world utilization patterns of long-acting opioids (LAOs) and chronic use of short-acting opioids (SAOs) in Medicare enrollees. ➤ Patients with painful DPN used greater doses of LAOs than indicated in the drug’s package insert, and some patients used multiple pharmacies to fill their prescriptions. ➤ Furthermore, patients were concomitantly using several opioids and high doses of acetaminophen. ➤ Approximately 33% of patients with an LAO prescription and 42% of patients with chronic use of an SAO prescription were concomitantly using a prescription gastrointestinal (GI) medication for drug-related GI side effects. ➤ Medication use evaluation software can help monitor opioid drug utilization trends. ➤

LAOs and chronic use of short-acting opioids (SAOs) in a sample of Medicare enrollees (aged ≥65 years) with painful DPN, and identifies areas for potential improvement in the management of elderly patients with painful DPN who are treated with opioids to enhance clinical outcomes and reduce the cost of care for this patient population.

Methods Study Design and Tool The Chronic Opioid Medication Use Evaluation (MUE) software (Janssen Pharmaceuticals) was developed to import and to analyze individual health plan retrospective pharmacy utilization claims data to help in assessing chronic use of opioid therapy among plan members. The MUE software provides a cross-sectional perspective of opioid utilization patterns that is based on retrospective pharmacy claims data.

In this current analysis, the Opioid MUE software was used to import and to analyze data from the MarketScan databases. In addition, a reference sample of opioid-treated patients independent of diagnosis was used to com-

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pare study measure results for the study population with painful DPN. The reference group consisted of a 10% random sample of an aggregate IMS LifeLink Health Plan Claims Database from July 2008 to June 2009. The full IMS LifeLink Health Plan Claims Database consists of integrated medical and pharmaceutical claims data from 101 different managed healthcare plans encompassing 65.8 million lives between 1997 and March 2010. In 2008, 37 healthcare plans covering 24.1 million lives contributed to this database. These commercial default reference data provide 1 set of real-world benchmarks based on pharmacy claims between July 1, 2008, and June 30, 2009, for patients who were continuously enrolled in their health plan throughout 2009.

Study Inclusion Criteria DPN sample. Patients were included in this analysis if they met the following inclusion criteria: • Aged ≥65 years with DPN as identified by ≥2 Interna­ tional Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes for DPN (250.6X or 357.2) in at least 2 quarters in 2009 • Had ≥1 claims for LAO and/or chronic use (≥60 days of continuous therapy) of SAO. Reference sample. A 10% (N = 31,511) random sample of patients from commercial health plans was included in the analysis as our reference population. The patients in the reference sample had ≥1 claims for an LAO and/or chronic use (as evidenced by ≥60 days of continuous therapy) of an SAO. The reference sample did not exclude patients based on age or on DPN status.

The IMS LifeLink Health Plan Claims Database was selected as the data set for the reference sample, because it is nationally representative, including more than 65 million lives and more than 100 health plans. Furthermore, this reference data set was selected for inclusion into the Opioid MUE software to provide a relevant and applicable benchmark for commercial plans when comparing their data.

Where comparisons to the reference group were made, the intent was to provide some context for the descriptive data for the analysis cohort. Although it would have been interesting to define a reference sample that was more similar to the analysis cohort, the reference data set is built into the Opioid MUE software and cannot be manipulated.

Data Source In this descriptive retrospective analysis, data on patients with painful DPN were obtained from 2 Truven Health Analytics MarketScan Research databases, the Commercial Claims and Encounters Database and the Medicare Supplemental and Coordination of Benefits

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Table 1 Chronic SAO and LAO Use Among Elderly Patients with DPN Parameter N (%) Total patients

1448

Patients with LAO therapy

727 (50)

Patients with chronic (≥60 days of continuous therapy) use of SAO therapy

902 (62)

SAO with concomitant LAO claims

97 (11)

SAO without concomitant LAO claims

805 (89)

DPN indicates diabetic peripheral neuropathy; LAO, long-acting opioid; SAO, short-acting opioid.

Database. The MarketScan databases provide service­level claims data for inpatient and outpatient services and for outpatient prescription drugs that are collected from employers, health plans, Medicare, and state Medicaid agencies.

The MarketScan Commercial Claims and Encounters Database contains medical and drug data for more than 45 million individuals who are covered by employer-­ sponsored private health insurance. Healthcare for these individuals is provided under a variety of health plans, including fee-for-service, fully capitated, and partially capitated health plans.

The MarketScan Medicare Supplemental Database is the first in the United States to provide data on the healthcare experience of retirees with Medicare supplemental insurance paid for by employers. The database provides detailed cost, use, and outcomes data for healthcare services that are performed in the inpatient and the outpatient settings. The database includes the Medicare-covered and employer-paid portions of payment, as well as any out-of-pocket patient expenses. In addition, Medicare beneficiaries in this database have drug coverage, and these drug data offer valuable insight into the drug use and spending patterns of older Americans.28

Data Measures Data were extracted for 12 months from January 1, 2010, to December 31, 2010. The following opioid utilization measures were analyzed: LAO use and the chronic use (ie, evidence of ≥60 days of continuous therapy) of SAOs; the concomitant use of LAOs and the chronic use of SAOs (minimum, 60-day overlap), the most frequently utilized opioids; the average day’s supply; the average daily dose; daily average consumption; opioid rotation (defined as change in therapy within the same formulation group, such as one LAO to another LAO); opioid switching (defined as switching from one opioid molecule and/or formulation to another

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ost Frequently Prescribed Opioids Among Figure 1 M Elderly Patients with DPN 40%

Daily Acetaminophen Dose Distribution Figure 2 Among Elderly (≥65 Years) Patients with DPN Using SAOs

38% 30%

35%

25%

30%

26%

25%

20%

20%

20%

15%

15% 10%

10%

5%

5%

0%

Study population Reference population

26.7% 26.2%

5.2%

3.6% 1.6% 1.0%

Fentanyl Oxycodone CR transdermal

0%

Morphine CR/ER/SR

CR indicates controlled release; DPN, diabetic peripheral neuropathy; ER, extended release; SR, sustained release.

ACON and Average Day’s Supply of Opioids Table 2 D Among Elderly Patients with DPN Average day’s supply per Opioids DACON prescription Fentanyl transdermal

0.3

29.2

Oxycodone CR

2.5

30.0

Morphine CR/ER/SR

2.4

33.2

CR indicates controlled release; DACON, daily average consumption; DPN, diabetic peripheral neuropathy; ER, extended release; SR, sustained release.

[eg, from chronic use of an SAO to an LAO]); acetaminophen use; unique prescribers and unique pharmacies per patient; the concomitant use of opioids and gastrointestinal (GI) medications, with a minimum overlap of 45 days; and safety and tolerability indicators, including the percentage (1.6%) of patients with evidence of >3.1-g daily acetaminophen use.

Results The reference group population consisted of 31,511 patients (mean age, 53.5 years). In the elderly painful DPN study population, a total of 1448 unique patients with 11,740 claims for an LAO and/or the chronic use of an SAO were identified (Table 1). The mean age across the overall study sample was 76 years. The chronic use of an SAO was found in 62% of patients; of these, 89% had no concurrent LAO claim (minimum, 60-day overlap; Table 1).

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2.0-3.0 g/day 3.1-4.0 g/day ≥4.1 g/day

acetaminophen acetaminophen acetaminophen

DPN indicates diabetic peripheral neuropathy; SAO, short-acting opioid.

The most frequently filled LAOs were fentanyl transdermal (38%), oxycodone controlled release (CR; 26%), and morphine CR/extended release (ER)/sustained release (SR; 20%), with average day’s supplies of 29.2 (reference sample mean, 27.9), 30.0 (reference sample mean, 27.2), and 33.2 (reference sample mean, 28.4) days, respectively.

Among patients who were prescribed a new LAO, 45% were started on a fentanyl transdermal patch (reference sample mean, 23%). Oxycodone CR was the most frequently used in combination with a chronic SAO (18%) among LAO users and chronic SAO users.

The daily average consumptions for fentanyl transdermal, oxycodone CR, and morphine CR/ER/SR were 0.3 (reference sample mean, 0.4), 2.5 (reference sample mean, 2.8), and 2.4 (reference sample mean, 2.4), respectively (Figure 1, Table 2). In addition, 5.2% of patients in this sample had an average daily dose between 3.1 g and 4.0 g compared with 3.6% of the patients in the reference sample. For acetaminophen, 1.6% of patients in this sample compared with 0% of the reference sample mean had an average daily dose of ≥4.1 g (Figure 2).

Among the total study population, 24% of patients switched opioid therapy over the study period; opioid rotation (defined as change in therapy within the same formulation group, such as one LAO to another LAO) was observed more frequently in chronic SAO users (20%) than in the LAO users (5%). Approximately 33% of patients with an LAO prescription (reference sample mean, 18%) and 42% of patients with a chronic SAO prescription (reference sample mean, 25%) had evidence

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P ercent of Elderly Patients with DPN with Figure 3 Evidence of Concomitant GI Medication Use (Minimum, 45-Day Overlap) 45%

Number of Pharmacies Used to Fill LAO or Figure 4 SAO Prescriptions in Elderly Patients with Painful DPN

42%

1.9%

40% 35%

0.9%

33%

1 pharmacy 2 pharmacies 3 pharmacies ≥4 pharmacies

30% 25%

12.4%

20% 15% 10% 5% 0%

LAO prescription

Chronic SAO prescription

84.8%

DPN indicates diabetic peripheral neuropathy; GI, gastrointestinal; LAO, long-acting opioid; SAO, short-­acting opioid.

of concomitant use of a prescription GI medication (minimum, 45-day overlap; Figure 3).

Of the patients taking both LAO and SAO medications concomitantly, 20% of LAO users and 23% of chronic SAO users had claims for a prescription GI medication that started with or after the concomitant opioid claim.

Among the population with DPN, 15.2% of the patients filled their LAO or SAO prescription at ≥2 pharmacies. Of these patients, 12.4% filled their LAO or SAO prescription at 2 pharmacies, 1.9% filled their LAO or SAO prescription at 3 pharmacies (Figure 4), and 0.9% had evidence of filling their prescription at ≥4 unique pharmacies.

The majority of elderly patients with DPN use SAOs chronically (62%) without a concurrent LAO (89%). The treatment guidelines for chronic pain recommend that patients start with an SAO and rapidly switch to a CR formulation.

Although the current data used in this study do not provide information on overutilization, health plans can assess utilization and overutilization based on their respective benchmarks.

Discussion The results of this analysis provide insight into the real-world utilization of LAOs and chronic SAOs in a

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DPN indicates diabetic peripheral neuropathy; LAO, long-acting opioid; SAO, short-acting opioid.

sample of elderly patients with painful DPN, a population that has not been previously investigated by researchers.

Opioid Utilization This analysis demonstrates increased opioid use by Medicare patients with painful DPN compared with patients in commercial health plans. Cost implications are also associated with higher opioid utilization patterns, and the excess costs related to painful DPN have been estimated to be nearly $6000 for the calendar year compared with patients without DPN.29 In the study examining patients with DPN in a managed care setting, the cost difference was largely attributed to an increase in healthcare utilization. The likelihood of any hospital admission for patients with painful DPN was more than 2.5 times higher than that of patients without painful DPN.29 Chronic Use of SAOs without LAOs Results from this retrospective descriptive analysis suggest that the majority of elderly patients with DPN use SAOs chronically (62%) without a concurrent LAO (89%). The treatment guidelines for chronic pain recommend that patients start with an SAO and rapidly switch to a CR formulation.24 In general, SAOs are considered appropriate for transient pain (eg, acute, breakthrough, or chronic intermittent pain) that does not require long-lasting analgesia.30-32 Although LAOs may be associated with

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improved treatment adherence, patients may prefer SAOs because these agents confer analgesic benefit, improve functioning and quality of life, and may have fewer adverse effects.33 As such, treating chronic pain with SAOs or LAOs needs to be customized to the individual patientâ&#x20AC;&#x2122;s response for the selected treatment regimen.33

Daily Average Consumption The use of SAOs and LAOs for moderate-to-severe chronic pain continues to increase, representing a significant cost for payers.34 To assess the utilization of SAOs and LAOs, daily average consumptions are frequently used to describe the average number of dosage units dispensed daily based on claims data. Our daily average consumption findings of 2.5 tablets for oxycodone CR are more than the package insert recommendation of every-12-hour dosing.35 These findings were consistent with previous studies, as well as with those observed in the reference population.34,36 In a study by Rubino and colleagues, the unadjusted daily average consumption mean value for the highest strength of oxycodone CR 80 mg was 3.9, and for all strengths was 3.1.34 Similarly, in a study by Malkin and colleagues, the daily average consumption for all strengths of oxycodone CR was 3.4, with higher strengths associated with daily average consumption values ranging from 2.9 for the 10-mg tablets to 5.2 for the 80-mg tablets.37 In another study by Berner and colleagues, the reported daily average consumption value was 3.9 for the oxycodone CR 80-mg tablet.36 Furthermore, Berner and colleagues calculated the costs for daily average consumption differences for equipotent doses of oxycodone CR and oxymorphone ER using wholesale average costs, and they estimated an average daily additional cost of $10.56 per patient for oxycodone CR 80 mg.36 Our findings, combined with the findings of these previous studies, suggest the potential for newer and higher dosing options.

Unique Pharmacies Most patients in this study utilized 1 pharmacy to fill their opioid prescriptions. However, 12.4% of patients filled their LAO or SAO prescriptions at â&#x2030;Ľ2 unique pharmacies. Although this may result from a variety of reasons, the utilization of multiple pharmacies may potentially be associated with opioid misuse. The observation of this behavior warrants further research to more definitively conclude the relationship between a number of unique pharmacies and the potential for and impact of opioid abuse.

Adverse Effects Higher doses of opioids are associated with an increased risk of side effects. Specifically, GI adverse effects

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are common with opioid use, incurring significant costs to patients, as well as negatively affecting function and productivity.38-40 In a study examining the costs associated with GI events after outpatient SAO treatment, the investigators found that patients with GI event claims had substantially more hospitalizations (adjusted mean, 0.20-0.97 vs 0.17, respectively; P <.001), hospitalization days (1.12-12.05 vs 1.00; P <.001), emergency department visits (0.36-1.44 vs 0.25; P <.001), outpatient office visits (5.68-11.81 vs 4.11; P <.001), and prescription claims (7.46-8.21 vs 6.06; P <.001) than patients who did not have any GI claims in the 3 months after the index opioid prescription.41 In addition, the incremental adjusted mean total healthcare costs for patients with any GI claims ranged from $4880 to $36,152 (P <.001) compared with patients without any GI claims.41

Our study found that 28.4% of patients with an LAO prescription and 42% of patients with a chronic SAO prescription took concomitant GI medications after starting opioids. Recent data have suggested that novel opioids with multiple mechanisms of action have similar efficacy with lower GI adverse effects.

Our study found that 28.4% of patients with an LAO prescription and 42% of patients with a chronic SAO prescription took concomitant GI medications after starting opioids. Recent data have suggested that novel opioids with multiple mechanisms of action have similar efficacy with lower GI adverse effects.42 As such, additional research should be conducted to identify all of the conditions and patient populations that would benefit from the use of these new opioids.

Acetaminophen Use Although our findings show that a relatively low proportion (1.6%) of patients use high doses of acetaminophen, nonopioids (eg, acetaminophen) are often the first line of therapy for mild-to-moderate pain because of their relatively safe profile in elderly patients.24 In our analysis, we only captured prescription acetaminophen and did not account for over-the-counter medication; thus, we are most likely underreporting the problem of acetaminophen use.

Because acetaminophen is used in many combination products, and acetaminophen-related hepatic disease and deaths are found more often in older patients,43 the treatment guidelines recommend vigilance when pre-

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scribing prescription and nonprescription medications containing acetaminophen, because there is a risk of hepatotoxicity with the overuse of acetaminophen.24 In particular, with patients who potentially abuse alcohol, it is important to exercise caution in using medications with large amounts of acetaminophen.44,45 Nonetheless, acetaminophen is well tolerated in older patients compared with nonsteroidal anti-inflammatory drugs, which frequently have a worse GI side-effect profile and can be more problematic in older patients.46-49

The use of software, such as the MUE, to monitor drug utilization trends and to examine other utilization measures can assist healthcare decision makers in managing this population and in identifying areas for patient- or physician-directed quality improvement efforts.

Limitations There are several limitations to this study. First, opioid utilization was based on prescription claims data, which may differ from actual use. As with all claims analysis, there is the potential that prescription claims data used may not be entirely complete, and it is possible that patients may be misclassified and may have missing data. In addition, claims data are primarily used for administrative purposes rather than for research objectives. Therefore, the data may not capture certain clinical characteristics and may not accurately represent treatment diagnostics.

Another limitation is our inclusion of LAOs and SAOs only, which did not encompass all of the available opioids in the United States. However, the vast majority of opioids are included in this analysis, because “a small proportion of use” was our exclusion criterion for opioids.

In addition, our study did not account for over-thecounter medications.

Finally, the analysis did not include all of the patients’ diagnoses or account for differences in disease severity because of the lack of data. As such, this analysis only considered patients for whom there were available data, and this may only be representative of a proportion of the elderly patients with DPN. Conclusion Pain management and opioid therapy can be complicated in patients with chronic pain, particularly in elderly patients with painful DPN, because of comorbid conditions.50 This retrospective pharmacy claims analysis

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provides a snapshot of real-world opioid use among elderly patients with painful DPN. Our results demonstrated that these patients frequently use SAOs without LAOs, and they use doses of LAOs that are higher than the dose recommended in the package insert, with a proportion of this population using high doses of acetaminophen and utilizing multiple pharmacies to obtain their opioid prescriptions. In addition, the concomitant use of opioids and prescription GI medications was prevalent in the examined population. The use of software, such as the MUE, to monitor drug utilization trends and to examine other utilization measures can assist healthcare decision makers in managing this population and in identifying areas for patient- or physician-directed quality improvement efforts.

Further research on opioid utilization is needed to better understand the association of the demographic and clinical profiles of elderly patients using opioids for painful DPN. Additional research is also warranted to study the chronic use of an SAO without concomitant LAO use, for higher-than-indicated daily average consumptions for frequently used LAOs, and for the number of prescriptions obtained from multiple pharmacies, to evaluate the association between patient profiles and their opioid utilization pattern. n Study Funding Funding for this study was provided by Janssen Scien­ tific Affairs.

Author Disclosure Statement Dr Pesa and Dr Meyer are employees of Janssen Scientif­ ic Affairs and stockholders of Johnson & Johnson; Dr Quock and Ms Rattana are consultants to Janssen; and Dr Mody is an employee of Janssen Scientific Affairs and a stockholder of Johnson & Johnson.

References

1. Lindsay TJ, Rodgers BC, Savath V, Hettinger K. Treating diabetic peripheral neuropathic pain. Am Fam Physician. 2010;82:151-158.

2. Cole BE. Diabetic peripheral neuropathic pain: recognition and management. Pain Med. 2007;8(suppl 2):S27-S32.

3. Galer BS, Gianas A, Jensen MP. Painful diabetic polyneuropathy: epidemiology, pain description, and quality of life. Diabetes Res Clin Pract. 2000;47:123-128.

4. Argoff CE, Cole BE, Fishbain DA, Irving GA. Diabetic peripheral neuropathic pain: clinical and quality-of-life issues. Mayo Clin Proc. 2006;81(4 suppl):S3-S11.

5. Boulton AJ, Malik RA, Arezzo JC, Sosenko JM. Diabetic somatic neuropathies.

Diabetes Care. 2004;27:1458-1486.

6. Boulton AJ. Management of diabetic peripheral neuropathy. Clin Diabetes.

2005;23:9-15.

7. Possidente CJ, Tandan R. A survey of treatment practices in diabetic peripheral neuropathy. Prim Care Diabetes. 2009;3:253-257.

8. AGS Panel on Persistent Pain in Older Persons. The management of persistent pain in older persons. J Am Geriatr Soc. 2002;50(suppl):S205-S224.

9. American Chronic Pain Association. Conditions A to Z: chronic pain. www. theacpa.org/condition/Chronic-Pain. Accessed May 6, 2013.

10. Benbow SJ, Wallymahmed ME, MacFarlane IA. Diabetic peripheral neuropathy and quality of life. QJM. 1998;91:733-737.

11. Gore M, Brandenburg NA, Dukes E, et al. Pain severity in diabetic peripheral neuropathy is associated with patient functioning, symptom levels of anxiety and depression, and sleep. J Pain Symptom Manage. 2005;30:374-385.

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12. Jensen MP, Chodroff MJ, Dworkin RH. The impact of neuropathic pain on health-related quality of life: review and implications. Neurology. 2007;68:1178-1182.

13. Boulanger L, Zhao Y, Bao Y, Russell MW. A retrospective study on the impact of comorbid depression or anxiety on healthcare resource use and costs among diabetic neuropathy patients. BMD Health Serv Res. 2009;9:111.

14. Candrilli SD, Davis KL, Kan HJ, et al. Prevalence and the associated burden of illness of symptoms of diabetic peripheral neuropathy and diabetic retinopathy. J Dia­ betes Complications. 2007;21:306-314.

15. Gore M, Brandenburg NA, Hoffman DL, et al. Burden of illness in painful diabetic peripheral neuropathy: the patients’ perspectives. J Pain. 2006;7:892-900.

16. Gordois A, Scuffham P, Shearer A, et al. The health care costs of diabetic peripheral neuropathy in the US. Diabetes Care. 2003;26:1790-1795.

17. daCosta DiBonaventura M, Cappelleri JC, Joshi AV. A longitudinal assessment of painful diabetic peripheral neuropathy on health status, productivity, and health care utilization and cost. Pain Med. 2011;12:118-126.

18. Wu N, Chen S, Boulanger L, et al. Duloxetine compliance and its association with healthcare costs among patients with diabetic peripheral neuropathic pain. J Med Econ.

2009;12:192-202.

19. Jensen TS, Backonja MM, Hernández Jiménez S, et al. New perspectives on the management of diabetic peripheral neuropathic pain. Diab Vasc Dis Res. 2006;3:108-119.

20. O’Connor AB. Neuropathic pain: quality-of-life impact, costs and cost effectiveness of therapy. Pharmacoeconomics. 2009;27:95-112.

21. Argoff CE, Backonja MM, Belgrade MJ. Consensus guidelines: treatment planning and options: diabetic peripheral neuropathic pain. Mayo Clin Proc. 2006;81(suppl):S12-S25. Erratum in: Mayo Clin Proc. 2006;81:854.

22. American Society of Anesthesiologists Task Force on Chronic Pain Management, American Society of Regional Anesthesia and Pain Medicine. Practice guidelines for chronic pain management: an updated report by the American Society of Anesthesiologists Task Force on Chronic Pain Management and the American Society of Regional Anesthesia and Pain Medicine. Anesthesiology. 2010;112:810-833.

23. Wilder-Smith OH. Opioid use in the elderly. Eur J Pain. 2005;9:137-140.

24. Gloth FM 3rd. Pain management in older adults: prevention and treatment. J Am Geriatr Soc. 2001;49:188-199.

25. 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.

26. Robinson-Papp J, Simpson DM. Safety profile of treatment in diabetic peripheral neuropathic pain. Pain Med. 2007;8(suppl 2):S43-S49.

27. Wu N, Chen SY, Hallett LA, et al. Opioid utilization and health-care costs among patients with diabetic peripheral neuropathic pain treated with duloxetine vs. other therapies. Pain Pract. 2011;11:48-56.

28. Hansen LG, Chang S. Health Research Data for the Real World: The MarketScan Databases. White paper. July 2012. www.truvenhealth.com/assets/2012_Truven_ MarketScan_white_paper.pdf. Accessed May 6, 2013.

29. Ritzwoller DP, Ellis JL, Korner EJ, et al. Comorbidities, healthcare service utilization and costs for patients identified with painful DPN in a managed-care setting.

Curr Med Res Opin. 2009;25:1319-1328.

30. McCarberg BH, Barkin RL. Long-acting opioids for chronic pain: pharmacotherapeutic opportunities to enhance compliance, quality of life, and analgesia. Am J Ther.

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31. Bennett D, Burton AW, Fishman S, et al. Consensus panel recommendations for the assessment and management of breakthrough pain: part 2: management. Pharm Ther. 2005;30:354-361.

32. Gimbel J, Ahdieh H. The efficacy and safety of oral immediate-release oxymorphone for postsurgical pain. Anesth Analg. 2004;99:1472-1477.

33. Argoff CE, Silvershein DI. A comparison of long- and short-acting opioids for the treatment of chronic noncancer pain: tailoring therapy to meet patient needs. Mayo Clin Proc. 2009;84:602-612.

34. Rubino M, Summers KH, Puenpatom A, et al. A comparison of daily average consumption (DACON) of oxycodone and oxymorphone long-acting oral tablets.

J Manag Care Pharm. 2011;17:367-376.

35. Nucynta ER [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc; August 2012.

36. Berner T, Thomson H, Hartry A, et al. A comparison of daily average consumption of oxycodone controlled release (OxyContin CR) and oxymorphone extended release (Opana ER) in patients with low back pain. Pharm Ther. 2011;36:139-144.

37. Malkin JD, Ackerman SJ, Schein J, et al. Cost and utilization patterns of fentanyl transdermal system and oxycodone hydrochloride controlled-release in a California Medicaid population. J Manag Care Pharm. 2002;8:132-140.

38. Bell T, Annunziata K, Freedman D, et al. Opioid-induced constipation increases healthcare resource use and impairs productivity: comparison with other patient groups with and without constipation (abstract). J Pain. 2007;8(suppl):Abstract 897.

39. Carroll NV, Miederhoff P, Cox FM, Hirsch JD. Postoperative nausea and vomiting after discharge from outpatient surgery centers. Anesth Analg. 1995;80:903-909.

40. Aparasu R, McCoy RA, Weber C, et al. Opioid-induced emesis among hospitalized nonsurgical patients: effect on pain and quality of life. J Pain Symptom Manage.

1999;18:280-288.

41. Kwong WJ, Diels J, Kavanagh S. Costs of gastrointestinal events after outpatient opioid treatment for non-cancer pain. Ann Pharmacother. 2010;44:630-640.

42. Biondi D, Xiang J, Etropolski M, et al. A post hoc pooled data analysis to evaluate the gastrointestinal tolerability profile of Tapentadol extended release versus Oxycodone controlled release in patients ≥75 years of age. J Pain. 2011;12(suppl 4):P56.

Abstract 320.

43. Schmidt LE. Age and paracetamol self-poisoning. Gut. 2005;54:686-690.

44. Kumar S, Rex DK. Failure of physicians to recognize acetaminophen hepatotoxicity in chronic alcoholics. Arch Intern Med. 1991;151:1189-1191.

45. Whitecomb DC, Block GD. Association of acetaminophen hepatotoxicity with fasting and ethanol use. JAMA. 1994;272:1845-1850.

46. Brooks PM, Day RO. Nonsteroidal antiinflammatory drugs—differences and similarities. N Engl J Med. 1991;324:1716-1725.

47. Griffin MR, Piper JM, Daugherty JR, et al. Nonsteroidal anti-inflammatory drug use and increased risk for peptic ulcer disease in elderly persons. Ann Intern Med. 1991;114:257-263.

48. Bradley JD, Brandt KD, Katz BP, et al. Comparison of an antiinflammatory dose of ibuprofen, an analgesic dose of ibuprofen, and acetaminophen in the treatment of patients with osteoarthritis of the knee. N Engl J Med. 1991;325:87-91.

49. Wolfe MM, Lichtenstein DR, Singh G. Gastrointestinal toxicity of nonsteroidal antiinflammatory drugs. N Engl J Med. 1999;340:1888-1899.

50. Smith H, Bruckenthal P. Implications of opioid analgesia for medically complicated patients. Drugs Aging. 2010;27:417-433.

Stakeholder Perspective Monitoring for Aberrant Opioid Utilization Patterns a Growing Need in Managed Care

By Curtis Wander, PharmD Clinical Pharmacy Coordinator, SelectHealth, Murray, UT

PAYERS: Appropriate opioid utilization is often a priority to managed care organizations, especially in recent years, as opioid diversion (for recreational use) has increased. With opioid use, there is often a fine line between appropriately controlling pain and overutilizing these medications. Herein lies the challenge for managed care—the need to set meaningful utilization manage-

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ment into place to allow for adequate pain control for its members while limiting the potential for diversion and overutilization.

In their article on opioid utilization in patients with diabetic peripheral neuropathy, Pesa and colleagues found that within the study population, the average daily consumption of oxycodone controlled release (CR) was Continued

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Stakeholder Perspective Continued The potential for tolerance to the dose of the medication, as well as to the opioid, in particular, needs to be communicated. When tolerance to an opioid arises, it can often be discouraging to patients who feel that their pain is becoming worse when an opioid rotation may be necessary.

Opioids are not benign medications, and they carry a host of adverse events, particularly impaired motor function, gastrointestinal (GI) side effects, and respiratory depression. All patients using opioids for the long-term should be aware of the side effects of these medications and should report them to their providers. As noted by Pesa and colleagues, 33% of patients using a long-acting opioid and 42% of patients using a chronic short-acting opioid were receiving concomitant prescriptions for the GI-related side effects.

The proper disposal of opioid medications is very important to the safety of both the patients and the public.

According to the US Food and Drug Administration, opioids should be disposed of by either taking them to a Medication Take-Back program or by flushing them down the toilet or sink to keep them away from children and pets.

2.5 tablets. This finding conflicts with the labeled dosing of oxycodone CR, which calls for a once-every-12-hour medication use, especially in the population of patients with diabetic peripheral neuropathy, where the quantities of this medication would not be expected to be as large as in other populations with pain.

Payers also must be vigilant in monitoring aberrant behaviors of health plan members who are utilizing opioids. Trends in utilization that need to be monitored include using multiple pharmacies to fill opioid prescriptions, multiple providers writing opioid prescriptions, and the total number of opioid prescriptions that a member is filling.

Opioid abusers have been found to cost health plans $14,054 more per member than nonopioid abusers in medical and pharmacy costs.1 Utilizing pharmacy limitations to only allow 1 provider to write prescriptions for opioids and 1 pharmacy to dispense opioids for any member showing aberrant behavior should be strongly considered.

PATIENTS/PROVIDERS: The management of pain can often be frustrating and challenging for patients. There are several issues that patients need to be aware of while taking opioids.

1. Strassels SA. Economic burden of prescription opioid misuse and abuse. J Manag Care Pharm. 2009;15:556-562.

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IN THE TREATMENT OF ACUTE CORONARY SYNDROME

DECISIONS TODAY CAN IMPACT A LIFE

IN THE TREATMENT OF ACUTE CORONARY SYNDROME

HELP MAKE AN IMPACT WITH BRILINTA BEYOND 30 DAYS, BEYOND THE HOSPITAL, BETTER EFFICACY THAN CLOPIDOGREL

AT 30 DAYS, BRILINTA plus aspirin reduced the primary composite end point of cardiovascular (CV) death, myocardial infarction (MI),* or stroke by 12% RRR† (ARR‡ 0.6%) vs clopidogrel plus aspirin.§1,2

AT 12 MONTHS, BRILINTA plus aspirin significantly reduced the primary composite end point by 16% RRR (ARR 1.9%) vs clopidogrel plus aspirin. The difference between treatments was driven by CV death and MI with no difference in stroke.§1

IMPORTANT SAFETY INFORMATION ABOUT BRILINTA WARNING: BLEEDING RISK • BRILINTA, like other antiplatelet agents, can cause significant, sometimes fatal, bleeding • Do not use BRILINTA in patients with active pathological bleeding or a history of intracranial hemorrhage • Do not start BRILINTA in patients planned to undergo urgent coronary artery bypass graft surgery (CABG). When possible, discontinue BRILINTA at least 5 days prior to any surgery • Suspect bleeding in any patient who is hypotensive and has recently undergone coronary angiography, percutaneous coronary intervention (PCI), CABG, or other surgical procedures in the setting of BRILINTA • If possible, manage bleeding without discontinuing BRILINTA. Stopping BRILINTA increases the risk of subsequent cardiovascular events

WARNING: ASPIRIN DOSE AND BRILINTA EFFECTIVENESS • Maintenance doses of aspirin above 100 mg reduce the effectiveness of BRILINTA and should be avoided. After any initial dose, use with aspirin 75 mg–100 mg per day CONTRAINDICATIONS BRILINTA is contraindicated in patients with: • History of intracranial hemorrhage • Active pathological bleeding such as peptic ulcer or intracranial hemorrhage • Severe hepatic impairment because of a probable increase in exposure; it has not been studied in these patients.

Severe hepatic impairment increases the risk of bleeding because of reduced synthesis of coagulation proteins • Hypersensitivity (e.g. angioedema) to ticagrelor or any component of the product

PROVEN SUPERIOR TO CLOPIDOGREL IN REDUCING CV DEATH AT 12 MONTHS CV death secondary end point: RRR with BRILINTA plus aspirin was 21% (ARR 1.1%) vs clopidogrel plus aspirin.§1 INDICATIONS BRILINTA is indicated to reduce the rate of thrombotic CV events in patients with acute coronary syndrome (ACS) (unstable angina [UA], non–ST-elevation MI [NSTEMI], or ST-elevation MI [STEMI]). BRILINTA has been shown to reduce the rate of a combined end point of CV death, MI, or stroke compared to clopidogrel. The difference between treatments was driven by CV death and MI with no difference in stroke. In patients treated with PCI, it also reduces the rate of stent thrombosis.

BRILINTA has been studied in ACS in combination with aspirin.

Maintenance doses of aspirin >100 mg decreased the effectiveness of BRILINTA. Avoid maintenance doses of aspirin >100 mg daily.

BLEEDING AT 12 MONTHS, there was no significant difference in Total Major Bleeding (which includes Fatal and Life-threatening bleeding) for BRILINTA plus aspirin vs clopidogrel plus aspirin (11.6% vs 11.2%).

There was a somewhat greater risk of Non–CABG-related Major plus Minor Bleeding for BRILINTA plus aspirin vs clopidogrel plus aspirin (8.7% vs 7.0%) and Non–CABGrelated Major Bleeding (4.5% vs 3.8%), respectively.

PLATO trial did not show an advantage for BRILINTA compared with clopidogrel for CABG-related Bleeding (Total Major 85.8% vs 86.9% and Fatal/Life-threatening 48.1% vs 47.9%, respectively). 1

*Excluding silent MI. †RRR=relative risk reduction. ‡ARR=absolute risk reduction. § The PLATO study compared BRILINTA (180-mg loading dose, 90 mg twice daily thereafter) and clopidogrel (300-mg to 600-mg loading dose, 75 mg daily thereafter) for the prevention of CV events in 18,624 patients with ACS (UA, NSTEMI, STEMI).

Patients were treated for at least 6 months and up to 12 months. BRILINTA and clopidogrel were studied with aspirin and other standard therapies.

WARNINGS AND PRECAUTIONS • Moderate Hepatic Impairment: Consider the risks and benefits of treatment, noting the probable increase in exposure to ticagrelor • Premature discontinuation increases the risk of MI, stent thrombosis, and death • Dyspnea was reported in 14% of patients treated with BRILINTA and in 8% of patients taking clopidogrel.

Dyspnea resulting from BRILINTA is self-limiting.

Rule out other causes • BRILINTA is metabolized by CYP3A4/5. Avoid use with strong CYP3A inhibitors and potent CYP3A inducers.

Avoid simvastatin and lovastatin doses >40 mg • Monitor digoxin levels with initiation of, or any change in, BRILINTA therapy

ADVERSE REACTIONS • The most commonly observed adverse reactions associated with the use of BRILINTA vs clopidogrel were Total Major Bleeding (11.6% vs 11.2%) and dyspnea (14% vs 8%) • In clinical studies, BRILINTA has been shown to increase the occurrence of Holter-detected bradyarrhythmias.

PLATO excluded patients at increased risk of bradycardic events. Consider the risks and benefits of treatment

PLATO used the following bleeding severity categorization: Major Bleed–Fatal/ Life threatening. Any one of the following: fatal; intracranial; intrapericardial bleed with cardiac tamponade; hypovolemic shock or severe hypotension due to bleeding and requiring pressors or surgery; clinically overt or apparent bleeding associated with a decrease in hemoglobin (Hb) of more than 5 g/dL; transfusion of 4 or more units (whole blood or packed red blood cells [PRBCs]) for bleeding. Major Bleed–Other. Any one of the following: significantly disabling (eg, intraocular with permanent vision loss); clinically overt or apparent bleeding associated with a decrease in Hb of 3 g/dL; transfusion of 2 to 3 units (whole blood or PRBCs) for bleeding. Minor Bleed. Requires medical intervention to stop or treat bleeding (eg, epistaxis requiring visit to medical facility for packing).

Please see Brief Summary of Prescribing Information, including Boxed WARNINGS, on the adjacent pages.

References: 1. Data on file, 1755503, AstraZeneca.

2. BRILINTA Prescribing Information, AstraZeneca.

BRILINTA is a trademark of the AstraZeneca group of companies. ©2013 AstraZeneca. 2575001 4/13

BRILINTA® (ticagrelor) Tablets WARNING: BLEEDING RISK • BRILINTA, like other antiplatelet agents, can cause significant, sometimes fatal bleeding [see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS].

• Do not use BRILINTA in patients with active pathological bleeding or a history of intracranial hemorrhage [see CONTRAINDICATIONS].

• Do not start BRILINTA in patients planned to undergo urgent coronary artery bypass graft surgery (CABG). When possible, discontinue BRILINTA at least 5 days prior to any surgery [see WARNINGS AND PRECAUTIONS].

• Suspect bleeding in any patient who is hypotensive and has recently undergone coronary angiography, percutaneous coronary intervention (PCI), CABG, or other surgical procedures in the setting of BRILINTA [see WARNINGS AND PRECAUTIONS].

• If possible, manage bleeding without discontinuing BRILINTA. Stopping BRILINTA increases the risk of subsequent cardiovascular events [see WARNINGS AND PRECAUTIONS].

WARNING: ASPIRIN DOSE AND BRILINTA EFFECTIVENESS • Maintenance doses of aspirin above 100 mg reduce the effectiveness of BRILINTA and should be avoided. After any initial dose, use with aspirin 75-100 mg per day [see WARNINGS AND PRECAUTIONS and CLINICAL STUDIES (14) in full Prescribing Information].

BRIEF SUMMARY of PRESCRIBING INFORMATION: For full Prescribing Information, see package insert.

INDICATIONS AND USAGE Acute Coronary Syndromes BRILINTA is a P2Y12 platelet inhibitor indicated to reduce the rate of thrombotic cardiovascular events in patients with acute coronary syndrome (ACS) (unstable angina, non-ST elevation myocardial infarction, or ST elevation myocardial infarction). BRILINTA has been shown to reduce the rate of a combined endpoint of cardiovascular death, myocardial infarction or stroke compared to clopidogrel. The difference between treatments was driven by CV death and MI with no difference in stroke. In patients treated with PCI, it also reduces the rate of stent thrombosis [see Clinical Studies (14) in full Prescribing Information]. BRILINTA has been studied in ACS in combination with aspirin. Maintenance doses of aspirin above 100 mg decreased the effectiveness of BRILINTA. Avoid maintenance doses of aspirin above 100 mg daily [see Warnings and Precautions and Clinical Studies (14) in full Prescribing Information].

DOSAGE AND ADMINISTRATION Initiate BRILINTA treatment with a 180 mg (two 90 mg tablets) loading dose and continue treatment with 90 mg twice daily. After the initial loading dose of aspirin (usually 325 mg), use BRILINTA with a daily maintenance dose of aspirin of 75-100 mg. ACS patients who have received a loading dose of clopidogrel may be started on BRILINTA. BRILINTA can be administered with or without food. A patient who misses a dose of BRILINTA should take one 90 mg tablet (their next dose) at its scheduled time.

CONTRAINDICATIONS History of Intracranial Hemorrhage BRILINTA is contraindicated in patients with a history of intracranial hemorrhage (ICH) because of a high risk of recurrent ICH in this population [see Clinical Studies (14) in full Prescribing Information].

Active Bleeding BRILINTA is contraindicated in patients with active pathological bleeding such as peptic ulcer or intracranial hemorrhage [see Warnings and Precautions (5.1) and Adverse Reactions (6.1) in full Prescribing Information].

Severe Hepatic Impairment BRILINTA is contraindicated in patients with severe hepatic impairment because of a probable increase in exposure, and it has not been studied in these patients. Severe hepatic impairment increases the risk of bleeding because of reduced synthesis of coagulation proteins [see Clinical Pharmacology (12.3) in full Prescribing Information].

Hypersensitivity BRILINTA is contraindicated in patients with hypersensitivity (e.g. angioedema) to ticagrelor or any component of the product [see Adverse Reactions (6.1) in full Prescribing Information].

WARNINGS AND PRECAUTIONS General Risk of Bleeding Drugs that inhibit platelet function including BRILINTA increase the risk of bleeding. BRILINTA increased the overall risk of bleeding (Major + Minor) to a somewhat greater extent than did clopidogrel. The increase was seen for non-CABG-related bleeding, but not for CABG-related bleeding.

Fatal and life-threatening bleeding rates were not increased [see Adverse Reactions (6.1) in full Prescribing Information]. In general, risk factors for bleeding include older age, a history of bleeding disorders, performance of percutaneous invasive procedures and concomitant use of medications that increase the risk of bleeding (e.g., anticoagulant and fibrinolytic therapy, higher doses of aspirin, and chronic nonsteroidal anti-inflammatory drugs [NSAIDS]). When possible, discontinue BRILINTA five days prior to surgery. Suspect bleeding in any patient who is hypotensive and has recently undergone coronary angiography, PCI, CABG, or other surgical procedures, even if the patient does not have any signs of bleeding. If possible, manage bleeding without discontinuing BRILINTA. Stopping BRILINTA increases the risk of subsequent cardiovascular events [see Warnings and Precautions (5.5) and Adverse Reactions (6.1) in full Prescribing Information].

Concomitant Aspirin Maintenance Dose In PLATO, use of BRILINTA with maintenance doses of aspirin above 100 mg decreased the effectiveness of BRILINTA. Therefore, after the initial loading dose of aspirin (usually 325 mg), use BRILINTA with a maintenance dose of aspirin of 75-100 mg [see Dosage and Administration and Clinical Studies (14) in full Prescribing Information].

Moderate Hepatic Impairment BRILINTA has not been studied in patients with moderate hepatic impairment. Consider the risks and benefits of treatment, noting the probable increase in exposure to ticagrelor.

Dyspnea In PLATO, dyspnea was reported in 14% of patients treated with BRILINTA and in 8% of patients taking clopidogrel. Dyspnea was usually mild to moderate in intensity and often resolved during continued treatment, but occasionally required discontinuation (0.9% of patients taking BRILINTA versus 0.1% of patients taking clopidogrel). If a patient develops new, prolonged, or worsened dyspnea during treatment with BRILINTA, exclude underlying diseases that may require treatment. If dyspnea is determined to be related to BRILINTA, no specific treatment is required; continue BRILINTA without interruption. In the case of intolerable dyspnea requiring discontinuation of BRILINTA, consider prescribing another antiplatelet agent. In a substudy, 199 patients from PLATO underwent pulmonary function testing irrespective of whether they reported dyspnea. There was no significant difference between treatment groups for FEV1. There was no indication of an adverse effect on pulmonary function assessed after one month or after at least 6 months of chronic treatment.

Discontinuation of BRILINTA Avoid interruption of BRILINTA treatment. If BRILINTA must be temporarily discontinued (e.g., to treat bleeding or for elective surgery), restart it as soon as possible. Discontinuation of BRILINTA will increase the risk of myocardial infarction, stent thrombosis, and death.

Strong Inhibitors of Cytochrome CYP3A Ticagrelor is metabolized by CYP3A4/5. Avoid use with strong CYP3A inhibitors, such as atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin and voriconazole [see Drug Interactions (7.1) and Clinical Pharmacology (12.3) in full Prescribing Information].

Cytochrome CYP3A Potent Inducers Avoid use with potent CYP3A inducers, such as rifampin, dexamethasone, phenytoin, carbamazepine, and phenobarbital [see Drug Interactions (7.2) and Clinical Pharmacology (12.3) in full Prescribing Information].

ADVERSE REACTIONS Clinical Trials Experience The following adverse reactions are also discussed elsewhere in the labeling: • Dyspnea [see Warnings and Precautions (5.4) in full Prescribing Information] 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. BRILINTA has been evaluated for safety in more than 10000 patients, including more than 3000 patients treated for more than 1 year.

Bleeding PLATO used the following bleeding severity categorization: • Major bleed – fatal/life-threatening. Any one of the following: fatal; intracranial; intrapericardial bleed with cardiac tamponade; hypovolemic shock or severe hypotension due to bleeding and requiring pressors or surgery; clinically overt or apparent bleeding associated with a decrease in hemoglobin (Hb) of more than 5 g/dL; transfusion of 4 or more units (whole blood or packed red blood cells (PRBCs)) for bleeding.

• Major bleed – other. Any one of the following: significantly disabling (e.g., intraocular with permanent vision loss); clinically overt or apparent bleeding associated with a decrease in Hb of 3 g/dL; transfusion of 2-3 units (whole blood or PRBCs) for bleeding.

• Minor bleed. Requires medical intervention to stop or treat bleeding (e.g., epistaxis requiring visit to medical facility for packing).

• Minimal bleed. All others (e.g., bruising, bleeding gums, oozing from injection sites, etc.) not requiring intervention or treatment.

Figure 1 shows major bleeding events over time. Many events are early, at a time of coronary angiography, PCI, CABG, and other procedures, but the risk persists during later use of antiplatelet therapy.

Figure 1 Kaplan-Meier estimate of time to first PLATO-defined ‘Total Major’ bleeding event

Annualized rates of bleeding are summarized in Table 1 below. About half of the bleeding events were in the first 30 days.

Table 1 Non-CABG related bleeds (KM%) BRILINTA Clopidogrel N=9235 N=9186 Total (Major + Minor) 8.7 7.0 Major 4.5 3.8 Fatal/Life-threatening 2.1 1.9 Fatal 0.2 0.2 Intracranial (Fatal/Life-threatening) 0.3 0.2 As shown in Table 1, BRILINTA was associated with a somewhat greater risk of non-CABG bleeding than was clopidogrel. No baseline demographic factor altered the relative risk of bleeding with BRILINTA compared to clopidogrel. In PLATO, 1584 patients underwent CABG surgery. The percentages of those patients who bled are shown in Table 2. Rates were very high but similar for BRILINTA and clopidogrel.

BRILINTA® (ticagrelor) Tablets Table 2 CABG bleeds (KM%) Patients with CABG BRILINTA Clopidogrel N=770 N=814 Total Major 85.8 86.9 Fatal/Life-threatening 48.1 47.9 Fatal 0.9 1.1 Although the platelet inhibition effect of BRILINTA has a faster offset than clopidogrel in in vitro tests and BRILINTA is a reversibly binding P2Y12 inhibitor, PLATO did not show an advantage of BRILINTA compared to clopidogrel for CABG-related bleeding. When antiplatelet therapy was stopped 5 days before CABG, major bleeding occurred in 75% of BRILINTA treated patients and 79% on clopidogrel.

No data exist with BRILINTA regarding a hemostatic benefit of platelet transfusions.

Drug Discontinuation In PLATO, the rate of study drug discontinuation attributed to adverse reactions was 7.4% for BRILINTA and 5.4% for clopidogrel. Bleeding caused permanent discontinuation of study drug in 2.3% of BRILINTA patients and 1.0% of clopidogrel patients. Dyspnea led to study drug discontinuation in 0.9% of BRILINTA and 0.1% of clopidogrel patients.

Common Adverse Events A variety of non-hemorrhagic adverse events occurred in PLATO at rates of 3% or more. These are shown in Table 3. In the absence of a placebo control, whether these are drug related cannot be determined in most cases, except where they are more common on BRILINTA or clearly related to the drug’s pharmacologic effect (dyspnea).

Table 3 Percentage of patients reporting non-hemorrhagic adverse events at least 3% or more in either group BRILINTA Clopidogrel N=9235 N=9186 Dyspnea1 13.8 7.8 Headache 6.5 5.8 Cough 4.9 4.6 Dizziness 4.5 3.9 Nausea 4.3 3.8 Atrial fibrillation 4.2 4.6 Hypertension 3.8 4.0 Non-cardiac chest pain 3.7 3.3 Diarrhea 3.7 3.3 Back pain 3.6 3.3 Hypotension 3.2 3.3 Fatigue 3.2 3.2 Chest pain 3.1 3.5 1 Includes: dyspnea, dyspnea exertional, dyspnea at rest, nocturnal dyspnea, dyspnea paroxysmal nocturnal

Bradycardia In clinical studies BRILINTA has been shown to increase the occurrence of Holterdetected bradyarrhythmias (including ventricular pauses). PLATO excluded patients at increased risk of bradycardic events (e.g., patients who have sick sinus syndrome, 2nd or 3rd degree AV block, or bradycardic-related syncope and not protected with a pacemaker). In PLATO, syncope, pre-syncope and loss of consciousness were reported by 1.7% and 1.5% of BRILINTA and clopidogrel patients, respectively. In a Holter substudy of about 3000 patients in PLATO, more patients had ventricular pauses with BRILINTA (6.0%) than with clopidogrel (3.5%) in the acute phase; rates were 2.2% and 1.6% respectively after 1 month.

Gynecomastia In PLATO, gynecomastia was reported by 0.23% of men on BRILINTA and 0.05% on clopidogrel. Other sex-hormonal adverse reactions, including sex organ malignancies, did not differ between the two treatment groups in PLATO. Lab abnormalities Serum Uric Acid: Serum uric acid levels increased approximately 0.6 mg/dL from baseline on BRILINTA and approximately 0.2 mg/dL on clopidogrel in PLATO. The difference disappeared within 30 days of discontinuing treatment. Reports of gout did not differ between treatment groups in PLATO (0.6% in each group). Serum Creatinine: In PLATO, a >50% increase in serum creatinine levels was observed in 7.4% of patients receiving BRILINTA compared to 5.9% of patients receiving clopidogrel. The increases typically did not progress with ongoing treatment and often decreased with continued therapy. Evidence of reversibility upon discontinuation was observed even in those with the greatest on treatment increases. Treatment groups in PLATO did not differ for renal-related serious adverse events such as acute renal failure, chronic renal failure, toxic nephropathy, or oliguria.

Postmarketing Experience The following adverse reactions have been identified during post-approval use of BRILINTA. Because these reactions are reported voluntarily from a population of an unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Immune system disorders – Hypersensitivity reactions including angioedema [see Contraindications (4.4) in full Prescribing Information].

DRUG INTERACTIONS Effects of other drugs Ticagrelor is predominantly metabolized by CYP3A4 and to a lesser extent by CYP3A5.

CYP3A inhibitors [see Warnings and Precautions and Clinical Pharmacology (12.3) in full Prescribing Information].

CYP3A inducers [see Warnings and Precautions and Clinical Pharmacology (12.3) in full Prescribing Information].

2

Aspirin Use of BRILINTA with aspirin maintenance doses above 100 mg reduced the effectiveness of BRILINTA [see Warnings and Precautions and Clinical Studies (14) in full Prescribing Information].

Effect of BRILINTA on other drugs Ticagrelor is an inhibitor of CYP3A4/5 and the P-glycoprotein transporter.

Simvastatin, lovastatin BRILINTA will result in higher serum concentrations of simvastatin and lovastatin because these drugs are metabolized by CYP3A4. Avoid simvastatin and lovastatin doses greater than 40 mg [see Clinical Pharmacology (12.3) in full Prescribing Information].

Digoxin Digoxin: Because of inhibition of the P-glycoprotein transporter, monitor digoxin levels with initiation of or any change in BRILINTA therapy [see Clinical Pharmacology (12.3) in full Prescribing Information].

Other Concomitant Therapy BRILINTA can be administered with unfractionated or low-molecularweight heparin, GPIIb/IIIa inhibitors, proton pump inhibitors, beta-blockers, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers.

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C: There are no adequate and well-controlled studies of BRILINTA use in pregnant women. In animal studies, ticagrelor caused structural abnormalities at maternal doses about 5 to 7 times the maximum recommended human dose (MRHD) based on body surface area. BRILINTA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In reproductive toxicology studies, pregnant rats received ticagrelor during organogenesis at doses from 20 to 300 mg/kg/day. The lowest dose was approximately the same as the MRHD of 90 mg twice daily for a 60 kg human on a mg/m2 basis. Adverse outcomes in offspring occurred at doses of 300 mg/kg/day (16.5 times the MRHD on a mg/m2 basis) and included supernumerary liver lobe and ribs, incomplete ossification of sternebrae, displaced articulation of pelvis, and misshapen/misaligned sternebrae. When pregnant rabbits received ticagrelor during organogenesis at doses from 21 to 63 mg/kg/day, fetuses exposed to the highest maternal dose of 63 mg/kg/day (6.8 times the MRHD on a mg/m2 basis) had delayed gall bladder development and incomplete ossification of the hyoid, pubis and sternebrae occurred. In a prenatal/postnatal study, pregnant rats received ticagrelor at doses of 10 to 180 mg/kg/day during late gestation and lactation. Pup death and effects on pup growth were observed at 180 mg/kg/day (approximately 10 times the MRHD on a mg/m2 basis). Relatively minor effects such as delays in pinna unfolding and eye opening occurred at doses of 10 and 60 mg/kg (approximately one-half and 3.2 times the MRHD on a mg/m2 basis).

Nursing Mothers It is not known whether ticagrelor or its active metabolites are excreted in human milk. Ticagrelor is excreted in rat milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from BRILINTA, a decision should be made whether to discontinue nursing or to discontinue drug, taking into account the importance of the drug to the mother.

Pediatric Use The safety and effectiveness of BRILINTA in pediatric patients have not been established.

Geriatric Use In PLATO, 43% of patients were ≥65 years of age and 15% were ≥75 years of age.

The relative risk of bleeding was similar in both treatment and age groups. No overall differences in safety or effectiveness were observed between these patients and younger patients. While this clinical experience has not identified differences in responses between the elderly and younger patients, greater sensitivity of some older individuals cannot be ruled out.

Hepatic Impairment BRILINTA has not been studied in the patients with moderate or severe hepatic impairment. Ticagrelor is metabolized by the liver and impaired hepatic function can increase risks for bleeding and other adverse events. Hence, BRILINTA is contraindicated for use in patients with severe hepatic impairment and its use should be considered carefully in patients with moderate hepatic impairment. No dosage adjustment is needed in patients with mild hepatic impairment [see Contraindications, Warnings and Precautions, and Clinical Pharmacology (12.3) in full Prescribing Information].

Renal Impairment No dosage adjustment is needed in patients with renal impairment. Patients receiving dialysis have not been studied [see Clinical Pharmacology (12.3) in full Prescribing Information].

OVERDOSAGE There is currently no known treatment to reverse the effects of BRILINTA, and ticagrelor is not expected to be dialyzable. Treatment of overdose should follow local standard medical practice.

Bleeding is the expected pharmacologic effect of overdosing. If bleeding occurs, appropriate supportive measures should be taken. Other effects of overdose may include gastrointestinal effects (nausea, vomiting, diarrhea) or ventricular pauses. Monitor the ECG.

NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility [see section (13.1) in full Prescribing Information] PATIENT COUNSELING INFORMATION [see section (17) in full Prescribing Information]

Issued: March 29, 2013 BRILINTA® is a trademark of the AstraZeneca group of companies.

Distributed by: AstraZeneca LP, Wilmington, DE 19850 © AstraZeneca 2011, 2013 Rev. 3/13 2574902 4/13

AMCP Highlights

Pharmacoeconomics and Health Insurance Coverage

By Charles Bankhead, Medical Writer

The following summaries of posters presented at the 2013 Annual Meeting of the Academy of Managed Care Pharmacy (AMCP), April 3-5, 2013, in San Diego, CA, represent areas of interest for payers, employers, drug manufacturers, providers, and other healthcare stakeholders.

Medication Reconciliation by Pharmacists May Cut Hospital Readmission Rates A pharmacist-driven medication reconciliation intervention led to significantly lower hospital readmission rates among older patients with chronic diseases compared with national averages, according to a pilot program presented by Adrienne Roberts, PharmD, Kelsey-Seybold Clinic, Houston, TX, and colleagues.

For the targeted conditions, readmission rates were 50% to 65% lower than national averages, and 40% to 50% lower than the readmission rates for patients in Medicare Advantage (MA) plans. Overall, 6 of the 75 patients in the medication reconciliation program were readmitted within 30 days of hospital discharge; the overall hospital readmission rate was 8%.

The rate for heart failure (HF) was approximately 8.6% less than the national MA readmission rates, and chronic obstructive pulmonary disease (COPD) was approximately 9.6% less than the national MA readmission rates.

For the targeted conditions, readmission rates were 50% to 65% lower than national averages, and 40% to 50% lower than the readmission rates for patients in Medicare Advantage plans.

“The current trend of data suggests that medication reconciliation performed by a pharmacist had a positive impact on readmission rates,” Dr Roberts and colleagues noted.

The 30-day readmission rate for Medicare beneficiaries in fee-for-service plans is approximately 19%, and the rate in MA plans is 14.5%. The Centers for Medicare & Medicaid Services (CMS) has reported national re­

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admission rates of almost 20% for myocardial infarction (MI) and pneumonia, approximately 25% for HF, and approximately 23% for COPD. Advocates of healthcare reform have identified readmission as a key area for care coordination as a means of achieving cost-savings. CMS has projected savings of $8.2 billion between 2013 and 2019 as MA plans implement quality improvement programs that will include hospital readmissions.

The program focused on members of the MA prescription drug plan. Medication reconciliation occurred within 72 hours of discharge, and was coordinated by a pharmacist in concert with a multidisciplinary team that included physicians, physician assistants, nurses, case managers, and social workers.

The program included patients diagnosed with HF (N = 24), acute MI (N = 16), pneumonia (N = 2), COPD (N = 25), and social issues (N = 8).

Using electronic medical records (EMRs), hospitalists submitted a discharge summary to a hospital readmission program pharmacist, who completed medication reconciliation, documented medication changes, and used the EMR system to perform a patient evaluation. In addition, the pharmacist documented detailed information for subsequent data analysis, including patient demographics, readmission referrals, medication-related issues, scheduled follow-up, and additional comments.

Readmission data were compared with national averages for the targeted diseases.

Medication reconciliation was associated with readmission rates of 12.5% for HF and 8% for COPD, a significant reduction from the national rates. The program also revealed potential problem areas for medication reconciliation. [Roberts A, et al. Impact of a pharmacist intervention on hospital readmission rates in a health plan.] n

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Comparative Effectiveness Research in Coverage Decision-Making Comparative effectiveness research (CER) is expected to play a key role in coverage decisions by Pharmacy & Therapeutics (P&T) committees, but useful data have been slow to materialize, according to a survey of medical and pharmacy directors.

“The coverage decision-making process is becoming increasingly complex,” Richard A. Brook, MS, MBA, Vice President of TPG National Payor Roundtable, LLC, and Vice President of Business Development at JeSTARx Group, and colleagues concluded in their poster presentation.

“The introduction of ever-greater numbers of specialty pharmaceuticals requires stakeholders to have a better understanding of the process. These cloud the question of whether they will be covered via the medical benefit or the pharmacy benefit,” Mr Brook and his colleagues noted.

The online survey was completed by 20 medical directors and 9 pharmacy directors (of 235 directors invited to participate), most of whom represented commercial health plans (Table). The objective was to outline strategies that would enhance the P&T committee process and are favored by medical and pharmacy directors.

The survey focused on the current decision-making process related to formulary coverage and the potential influence of CER on coverage decisions. The responders indicate that the managed care community regularly incorporates evidence-based medicine into coverage decisions, as reflected by an average rating of approximately 7 on a 10-point scale.

However, the medical and pharmacy directors expressed skepticism about the progress being made to obtain more usable CER information, which received a below-average (<5) rating from the respondents.

When asked about areas that CER could influence

most, guideline development was cited most often, but by only 22.6% of the respondents. Medical and pharmacy benefit management was cited second at 19.4%.

The responses to a question about how best to improve the P&T process included the greater use of CER data and emphasis on value in decisions (27.6%), concerns about insufficient physician involvement with the committees (17.2%), and more time to allow for indepth evaluations (6.6%).

“Comparative-effectiveness research will play an enhanced role in helping formulary decision makers determine the value of new therapies and how new agents will fit into clinical practice guidelines, drug formularies, and the medical benefit,” Mr Brook and colleagues concluded.

[Brook RA, et al. The 2012 US payor landscape: results from a survey of medical directors and pharmacy directors: comparative-effectiveness research in P&T decision making.] n Table Implications of Comparative Effectiveness Research Mean respondent rating Pharmacy directors (N = 9)

Medical directors (N = 20)

Managed care commonly uses evidence-based medicine today in decision-making

6.4

7.4

I expect to regularly utilize comparative effectiveness information in formulary decision-making by 2015

6.1

6.0

We are making great progress in obtaining usable information on comparative effectiveness of therapies

4.4

4.1

NOTE: Responses are based on a 1-10 scale.

Health Plans Take Minor Hit for Preventive Drug Coverage Required

by Healthcare Reform Implementation of the Affordable Care Act (ACA) so far has had only a minor effect on drug plan costs, despite large increases in the use of preventive therapies, according to a retrospective analysis of pharmacy claims data comparing pre- and postimplementation costs.

The number of patients utilizing preventive drugs more than doubled from 2010 to 2011, and utilization rate increased by 146.3%. Yet, pharmaceutical costs to health plans increased by <$1 per member per year (PMPY).

Among common preventive therapies, aspirin and folic

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acid had the most dramatic increases in utilization.

Use of tobacco-cessation products increased by 31% but accounted for almost 98% of the costs for preventive therapies.

“Pharmaceutical costs for plans increased $0.93 PMPY, with the vast majority of that increase coming from tobacco cessation products,” reported Hing Chan, MS, MBA, Analytic Consultant, CVS Caremark. Nevertheless, “even with the increase in costs, the cost of these preventive drugs constitutes less than 0.2% of the total drug plan cost.”

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The ACA requires nongrandfathered (ie, not in existence the day the legislation was enacted) health plans to provide certain preventive services without member cost-sharing when delivered within network. As of September 23, 2010, the recommendations of the US Preventive Services Task Force include the use of aspirin, fluoride, folic acid, iron, and tobacco-cessation products, which were the focus of this analysis.

As a result of the mandates, utilization of preventive services and drugs are expected to increase. Over time, healthcare costs and utilization are expected to decrease.

Comparing the preimplementation period of 2010 with the postimplementation period of 2011, 1.2% of the 1.4 million members used a preventive drug in 2011, a 90.2% increase from 2010. Preventive drug gross cost increased by 43.8% to $1.69 PMPY, and preventive drug plan cost increased by 120.6%, to $1.69 PMPY. Evidence of the effects of the ACA on pharmaceutical costs and utilization has begun to emerge, although it is too early to determine the full impact of the ACA at this point.

To examine the effect of healthcare reform on preventive care coverage and utilization from the perspective of nongrandfathered health plans, Mr Chan retrospectively evaluated an integrated database of

administrative pharmacy claims. The analysis included nongrandfathered employer plans with a total of 1.4 million members.

Comparing the preimplementation period of 2010 with the postimplementation period of 2011, 1.2% of the 1.4 million members used a preventive drug in 2011, a 90.2% increase from 2010. Preventive drug gross cost increased by 43.8% to $1.69 PMPY, and preventive drug plan cost increased by 120.6%, to $1.69 PMPY. Preventive drug days’ supply increased 143.6% to 1.06 PMPY. Tobacco-cessation products accounted for 97.9% of total preventive drug costs, followed by 1.4% of the cost for aspirin. Plan cost PMPY for tobacco-cessation products increased by $0.90, from $0.76 in 2010 to $1.66 in 2011. Days’ supply PMPY increased from 0.29 to 0.35 (a 21.2% increase).

The use of aspirin for preventive purposes increased from 75 individuals in 2010 to 7063 in 2011 (9317.3% growth). Gross cost PMPY for aspirin increased by 7992.9%, resulting in a 2011 gross cost PMPY of $0.02.

Days’ supply PMPY increased by 12,697.5% (to $0.58) for aspirin and by 353% for iron, and decreased by 13% for fluorides.

Utilizers of tobacco-cessation products increased from 6331 in 2010 to 8294 in 2011, and utilizers, as a percentage of average members, increased by 19.9% during that period.

The plan cost for fluorides increased by $0.01 PMPY but did not change for folic acid or iron. [Chan H. Impact of the Affordable Care Act (health care reform) pro­ visions for preventive care coverage on pharmaceutical costs and utilization.] n

Transitioning to a Patient-Centered Medical Home Does Not Improve Diabetes Outcomes Transitioning to a patient-centered medical home (PCMH) model of care failed to improve metabolic parameters in patients with type 2 diabetes, according to a retrospective analysis of a large claims database. Medical and pharmacy costs did not change significantly after implementation of a PCMH. The change in glycated hemoglobin A1c averaged an increase of 0.04% during the first 18 months of PCMH care compared with a decrease of 0.09% in the 18 months before implementation of the PCMH model.

The secondary goal of absolute low-density lipoprotein (LDL) cholesterol value also did not differ between the PCMH and the control groups, but the proportion of patients who achieved an LDL of <100 mg/dL did increase significantly with the PCMH.

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“The goals established by each of the medical home clinics were not standardized,” noted Anthony May, PharmD, MBA, of SelectHealth in Murray, UT, and colleagues. “Clinics were given the choice of selecting their own PCMH goals each year, and not all clinics had goals surrounding diabetes and lipid management.” This may explain some of the results.

Dr May and colleagues noted that the goal of the PCMH is not only to improve specific clinical outcomes, but rather, the model is intended to improve care coordination and patients’ navigation through the US healthcare system.

Studies of PCMH have documented reductions in hospitalization, emergency department visits, and medical costs, the authors noted in their introduction.

The impact of transition to a PCMH model of care for

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diabetes has not been studied extensively. This study included retrospective claims data from a 550,000-member integrated health system to identify patients who transitioned to a PCMH model of care, resulting in 678 diabetic patients who transitioned to the PCMH model; 385 diabetic patients who did not transition to PCMH served as a control group.

The 0.04% increase in A1c in PCMH-managed patients did not differ significantly from the control group.

The change in LDL averaged –1.64 mg/dL in the 18 months before transition, then declined by an average of 5.22 mg/dL after the transition (a nonsignificant difference). In the control group, the mean change in LDL was –9.3 mg/dL during the first 18 months and increased by 0.72 mg/dL during the second 18 months (P = .005).

The change in LDL between the study and the control group was not significant.

The proportion of patients who achieved the A1c goal

of <7% ranged between 50% and 55% in the PCMH and in the control groups, and it did not differ significantly between the 18-month intervals.

However, the proportion of patients in each group who achieved an LDL goal of <100 mg/dL differed significantly between the first and second 18-month periods in the PCMH group (P = .003). The ending value also significantly exceeded the value at the beginning of PCMH implementation (P = .01), unlike the control group.

The pharmacy and medical costs did not differ significantly between the PCMH and the control group. At the end of the follow-up, pharmacy costs averaged $3854 in the PCMH group and $3643 in the control group.

The mean medical costs at the end of the study were $2934 in the PCMH group and $3360 in the control group. [May A, et al. Comparison of treatment outcomes among commercial health plan members transitioned to a patient-centered medical home.] n

Direct Costs Soar for Patients with IBS plus Constipation The annual direct costs for the care of patients with constipation-predominant irritable bowel syndrome (IBS-C) averages >$11,000, which is >3 times the direct costs of a non-IBS control group, according to a retrospective claims review presented at the meeting.

Most of the difference came from utilization of medical services by patients with IBS-C. A similar cost disparity between patients with IBS-C and the control group existed across noncapitated HMO plans, PPO plans, and Medicare Advantage (MA) plans.

The $8000 difference far exceeded previous estimates from similar comparisons, according to Qian Cai, MS, MSPH, a health economics researcher at HealthCore, Inc, in Wilmington, DE, and colleagues.

“This study highlights the significant economic burden of IBS-C in a commercially insured population, with a consistent burden observed across different health plan benefit designs,” the researchers concluded.

“Opportunities exist to optimize the management of IBS-C to improve symptom control and minimize avoidable or unnecessary healthcare utilization, thereby reducing overall costs,” they added. IBS is a chronic functional gastrointestinal disorder characterized by abdominal pain or discomfort associated with altered bowel habits.

The cause remains undetermined.

Estimates of IBS prevalence range as high as 20% of adults in North America. The condition comprises 3 subcategories defined by symptomatology: IBS-C, IBS with predominant diarrhea, and IBS with mixed symptoms.

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Previous studies of direct healthcare costs associated with IBS-C yielded differences ranging from $1896 and $5441 versus matched control groups. However, these published studies have estimated overall healthcare costs for patients with IBS without regard to disease subtype or different types of health plans.

The researchers analyzed data from January 1, 2010, through December 31, 2010, from the HealthCore Integrated Research Database, which comprises claims from 14 health plans representing 44 million members. The analysis included adults with 12 months of continuous

The annual healthcare costs averaged $11,182 among IBS-C patients and $3116 in the control group. Medical claims accounted for 81% of healthcare costs in the IBS-C group and for 79% of the control group. medical and pharmacy benefits. Patients were identified as having IBS-C on the basis of ≥1 medical claims associated with an IBS-related diagnostic code and at least 2 medical claims for constipation or at least 1 medical claim for constipation and at least 1 pharmacy claim for an IBS-C medication. A control group consisted of patients with no claims related to IBS or constipation.

The final analysis comprised 3826 patients in each group. The health plan benefit designs included PPO in 74.9% of cases, noncapitated HMO in 14.4%, MA in

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4.3%, and a variety of other benefit designs that covered a total of 6.5% of the population.

The annual healthcare costs averaged $11,182 among IBS-C patients and $3116 in the control group. Medical claims accounted for 81% of healthcare costs in the IBS-C group and for 79% of the control group.

Analysis by plan design yielded average costs of $12,002 for IBS-C for patients in noncapitated HMO plans; $10,579 in PPOs; and $14,237 among MA plans.

The costs in the control group averaged $3345 for HMO plans, $2938 for PPOs, and $5700 for MA plans.

After adjustment for differences in demographics and

in comorbid conditions, the average annual cost for IBS-C across all health plans was $8621 compared with $4765 for the control group.

By plan design, costs averaged $8157 (PPO); $9532 (HMO); and $10,930 (MA) for IBS-C patients and $4463 (PPO); $5341 (HMO); and $8274 (MA) for the control groups. Medical service claims accounted for approximately 80% of direct costs in the IBS-C and control groups in the overall adjusted analysis and for each type of health plan. [Cai Q, et al. Economic burden of irritable bowel syndrome with constipation: a retrospective analysis of all-cause healthcare costs.] n

“Incomplete” Grade for Provider Compliance with HEDIS Recommendations for Osteoporosis Preliminary data from an ongoing quality initiative in osteoporosis suggested potential obstacles to provider compliance with the recommendation, according to a poster presented at the meeting.

The Healthcare Effectiveness Data and Information Set (HEDIS) includes the recommendation that women aged ≥67 years should have bone mineral density (BMD) testing and/or should initiate treatment to prevent osteo­ porosis within 6 months after a fracture. Ms Lauren Pusateri, a pharmacy resident at RegenceRx Pharmacy Benefit Management in Portland, OR, and colleagues reviewed pharmacy claims data to identify patients who had a fracture but who had not begun preventive treatment for osteoporosis within 6 months.

Compliance with recommendations for postfracture BMD testing and the use of bisphosphonates declined in the first 3 months of follow-up compared with the year before the quality initiative was implemented.

“By having access to claims data, managed care pharmacists are uniquely positioned to improve members’ outcomes on a large scale through the use of collaborative outreach programs and provider education,” they noted.

Phase 1 of the analysis included October, November, and December of 2012. Regence health plan members who had fractures in April 2012 would have been approaching the 6-month window of the HEDIS measure, allowing for delays in claims submissions.

The primary objective was to compare compliance with the HEDIS measure in 2012 versus 2011, before instituting the outreach program. The first phase of the study included 262 patients identified through medical records.

Early data from phase 2 (beginning in January 2013) comprised 3 patients with a recent fracture history.

Overall, 364 (19.3%) of 1890 patients were compli-

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ant with the HEDIS measure in 2011. Preliminary data for 2012 showed that 314 (18.8%) of 1673 patients were compliant.

“Because the [outreach] program was not implemented until October 2012, only a small portion of members included in the 2012 compliance rate calculation were contacted during the study,” the investigators pointed out.

Results from a provider survey showed the outreach program useful in increasing their compliance with the HEDIS measure. The providers also cited patient-specific factors that would likely preclude potential benefits of compliance with the HEDIS measure, including advanced age and physical limitations.

When managing patients at risk for osteoporosis after a fracture, most providers noted that referral to a primary care provider would be the best strategy. Use of drugs for osteoporosis prevention, BMD testing, and reliance on recommendations from a hospital were other strategies cited. When asked who should initiate follow-up treatment after a fracture, 8 respondents said the primary care provider and the rest said follow-up care should be the hospital’s responsibility.

“Varying responses from provider surveys indicate the need for continued provider contact and education,” concluded Ms Pusateri and colleagues. “Provider feedback identified limitations associated with the osteoporosis measure, including patient barriers to care and no upper age limit on the measure.” They added that “a similar [outreach] process can be used with other HEDIS measures to identify possible areas of improvement for health plans.” [Pusateri LL, et al. Impact of a col­ laborative outreach program for osteoporosis HEDIS measure compliance.] n

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For the treatment of severe hypertriglyceridemia (TG levels ≥ 500 mg/dL)

Clearly the right choice for your formulary VASCEPA® is an optimal TG-lowering agent for your formulary and your members with severe hypertriglyceridemia. VASCEPA® is the first FDA-approved, EPA-only omega-3-fatty acid that significantly lowers median placebo-adjusted TG levels by 33% without increasing LDL-C or HbA1c compared to placebo while also positively affecting a broad spectrum of lipid parameters.1 Consider VASCEPA® an affordable option for your members with severe hypertriglyceridemia (TG levels ≥ 500 mg/dL).

Indications and Usage VASCEPA® (icosapent ethyl) is indicated as an adjunct to diet to reduce triglyceride (TG) levels in adult patients with severe (≥ 500 mg/dL) hypertriglyceridemia.

• The effect of VASCEPA® on the risk for pancreatitis in patients with severe hypertriglyceridemia has not been determined • The effect of VASCEPA® on cardiovascular mortality and morbidity in patients with severe hypertriglyceridemia has not been determined Important Safety Information for VASCEPA® • VASCEPA® is contraindicated in patients with known hypersensitivity (e.g., anaphylactic reaction) to VASCEPA® or any of its components • Use with caution in patients with known hypersensitivity to fish and/or shellfish

• The most common reported adverse reaction (incidence >2% and greater than placebo) was arthralgia • Patients should be advised to swallow VASCEPA® capsules whole; not to break open, crush, dissolve, or chew VASCEPA®

Reference: 1. Bays HE, Ballantyne CM, Kastelein JJ, et al. Eicosapentaenoic acid ethyl ester (AMR101) therapy in patients with very high triglyceride levels (from the multi-center, placebo-controlled, randomized, double blind, 12-week study with an open-label extension [MARINE] trial). Am J Cardiol.

2011;108:682-690.

For more information on VASCEPA® see the brief summary or for the Full Prescribing Information please visit www.VASCEPA.com.

Amarin Pharma Inc. Bedminster, NJ 07921 www.AmarinCorp.com

© 2012 Amarin Pharmaceuticals Ireland Limited.

All rights reserved.

130033 1/2013

Reprint Code: XXXXXX

VASCEPA® (icosapent ethyl) Capsules, for oral use Brief summary of Prescribing Information Please see Full Prescribing Information for additional information about Vascepa.

1 INDICATIONS AND USAGE VASCEPA® (icosapent ethyl) is indicated as an adjunct to diet to reduce triglyceride (TG) levels in adult patients with severe (≥500 mg/dL) hypertriglyceridemia.

Usage Considerations: Patients should be placed on an appropriate lipid-lowering diet and exercise regimen before receiving VASCEPA and should continue this diet and exercise regimen with VASCEPA. Attempts should be made to control any medical problems such as diabetes mellitus, hypothyroidism, and alcohol intake that may contribute to lipid abnormalities. Medications known to exacerbate hypertriglyceridemia (such as beta blockers, thiazides, estrogens) should be discontinued or changed, if possible, prior to consideration of TG-lowering drug therapy.

Limitations of Use: The effect of VASCEPA on the risk for pancreatitis in patients with severe hypertriglyceridemia has not been determined.

The effect of VASCEPA on cardiovascular mortality and morbidity in patients with severe hypertriglyceridemia has not been determined.

2 DOSAGE AND ADMINISTRATION Assess lipid levels before initiating therapy. Identify other causes (e.g., diabetes mellitus, hypothyroidism, or medications) of high triglyceride levels and manage as appropriate. [see Indications and Usage (1)].

Patients should engage in appropriate nutritional intake and physical activity before receiving VASCEPA, which should continue during treatment with VASCEPA. The daily dose of VASCEPA is 4 grams per day taken as 2 capsules twice daily with food.

Patients should be advised to swallow VASCEPA capsules whole. Do not break open, crush, dissolve, or chew VASCEPA. 4 CONTRAINDICATIONS VASCEPA is contraindicated in patients with known hypersensitivity (e.g., anaphylactic reaction) to VASCEPA or any of its components.

5 WARNINGS AND PRECAUTIONS 5.1 Monitoring: Laboratory Tests In patients with hepatic impairment, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels should be monitored periodically during therapy with VASCEPA. 5.2 Fish Allergy VASCEPA contains ethyl esters of the omega-3 fatty acid, eicosapentaenoic acid (EPA), obtained from the oil of fish. It is not known whether patients with allergies to fish and/or shellfish are at increased risk of an allergic reaction to VASCEPA. VASCEPA should be used with caution in patients with known hypersensitivity to fish and/or shellfish.

6 ADVERSE REACTIONS 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 practice.

Adverse reactions reported in at least 2% and at a greater rate than placebo for patients treated with VASCEPA based on pooled data across two clinical studies are listed in Table 1.

Table 1. Adverse Reactions Occurring at Incidence >2% and Greater than Placebo in Double-Blind, Placebo-Controlled Trials*

Placebo (N=309) Adverse Reaction Arthralgia

n

%

VASCEPA (N=622) n %

3

1.0

14

2.3

*Studies included patients with triglycerides values of 200 to 2000 mg/dL. An additional adverse reaction from clinical studies was oropharyngeal pain.

7 DRUG INTERACTIONS 7.1 Anticoagulants Some published studies with omega-3 fatty acids have demonstrated prolongation of bleeding time. The prolongation of bleeding time reported in those studies has not exceeded normal limits and did not produce clinically significant bleeding episodes.

Patients receiving treatment with VASCEPA and other drugs affecting coagulation (e.g., anti-platelet agents) should be monitored periodically.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C: There are no adequate and well-controlled studies in pregnant women. It is unknown whether VASCEPA can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. VASCEPA should be used during pregnancy only if the potential benefit to the patient justifies the potential risk to the fetus.

In pregnant rats given oral gavage doses of 0.3, 1 and 2 g/kg/day icosapent ethyl from gestation through organogenesis all drug treated groups had visceral or skeletal abnormalities including: 13th reduced ribs, additional liver lobes, testes medially displaced and/or not descended at human systemic exposures following a maximum oral dose of 4 g/day based on body surface comparisons. Variations including incomplete or abnormal ossification of various skeletal bones were observed in the 2 g/kg/day group at 5 times

human systemic exposure following an oral dose of 4 g/day based on body surface area comparison.

In a multigenerational developmental study in pregnant rats given oral gavage doses of 0.3, 1, 3 g/kg/day ethyl-EPA from gestation day 7-17, an increased incidence of absent optic nerves and unilateral testes atrophy were observed at ≥0.3 g/kg/day at human systemic exposure following an oral dose of 4 g/day based on body surface area comparisons across species. Additional variations consisting of early incisor eruption and increased percent cervical ribs were observed at the same exposures. Pups from high dose treated dams exhibited decreased copulation rates, delayed estrus, decreased implantations and decreased surviving fetuses (F2) suggesting multigenerational effects of ethyl-EPA at 7 times human systemic exposure following 4 g/day dose based on body surface area comparisons across species.

In pregnant rabbits given oral gavage doses of 0.1, 0.3, and 1 g/kg/day from gestation through organogenesis there were increased dead fetuses at 1 g/kg/day secondary to maternal toxicity (significantly decreased food consumption and body weight loss).

In pregnant rats given ethyl-EPA from gestation day 17 through lactation day 20 at 0.3, 1, 3 g/kg/day complete litter loss was observed in 2/23 litters at the low dose and 1/23 middose dams by post-natal day 4 at human exposures based on a maximum dose of 4 g/day comparing body surface areas across species.

8.3 Nursing Mothers Studies with omega-3-acid ethyl esters have demonstrated excretion in human milk. The effect of this excretion is unknown; caution should be exercised when VASCEPA is administered to a nursing mother. In lactating rats, given oral gavage 14C-ethyl EPA, drug levels were 6 to 14 times higher in milk than in plasma.

8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use Of the total number of subjects in clinical studies of VASCEPA, 33% were 65 years of age 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.

9 DRUG ABUSE AND DEPENDENCE VASCEPA does not have any known drug abuse or withdrawal effects.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility In a 2-year rat carcinogenicity study with oral gavage doses of 0.09, 0.27, and 0.91 g/kg/day icosapent ethyl, respectively, males did not exhibit drug-related neoplasms. Hemangiomas and hemangiosarcomas of the mesenteric lymph node, the site of drug absorption, were observed in females at clinically relevant exposures based on body surface area comparisons across species relative to the maximum clinical dose of 4 g/day. Overall incidence of hemangiomas and hemangiosarcomas in all vascular tissues did not increase with treatment.

In a 6-month carcinogenicity study in Tg.rasH2 transgenic mice with oral gavage doses of 0.5, 1, 2, and 4.6 g/kg/day icosapent ethyl, drug-related incidences of benign squamous cell papilloma in the skin and subcutis of the tail was observed in high dose male mice. The papillomas were considered to develop secondary to chronic irritation of the proximal tail associated with fecal excretion of oil and therefore not clinically relevant. Drug-related neoplasms were not observed in female mice.

Icosapent ethyl was not mutagenic with or without metabolic activation in the bacterial mutagenesis (Ames) assay or in the in vivo mouse micronucleus assay. A chromosomal aberration assay in Chinese Hamster Ovary (CHO) cells was positive for clastogenicity with and without metabolic activation.

In an oral gavage rat fertility study, ethyl-EPA, administered at doses of 0.3, 1, and 3 g/kg/ day to male rats for 9 weeks before mating and to female rats for 14 days before mating through day 7 of gestation, increased anogenital distance in female pups and increased cervical ribs were observed at 3 g/kg/day (7 times human systemic exposure with 4 g/day clinical dose based on a body surface area comparison).

17 PATIENT COUNSELING INFORMATION 17.1 Information for Patients See VASCEPA Full Package Insert for Patient Counseling Information.

Distributed by: Amarin Pharma Inc. Bedminster, NJ, USA Manufactured by: Banner Pharmacaps, Tilburg, The Netherlands or Catalent Pharma Solutions, LLC, St. Petersburg, FL, USA Manufactured for: Amarin Pharmaceuticals Ireland Limited, Dublin, Ireland

Amarin Pharma Inc. Bedminster, NJ 07921 www.VASCEPA.com © 2012 Amarin Pharmaceuticals Ireland Limited.

All rights reserved.

12/2012 120707

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An Inside Look at Managed Care Executive Conversations within the Health Payer Council: What Is Evidence?

By Enid W. McDonough, JD, and Roger Green, MBA Ms McDonough is Executive Director and Mr Green is President and Chief Executive Officer, Roger Green and Associates

I

n 2010, the payer landscape was changing rapidly, with no central place for medical and pharmacy directors to exchange ideas and to expand the ways in which they viewed the ever more complex daily choices and decisions with which they were faced. In addition, there are challenges regarding speaking one’s mind publicly. Some payer organizations chastise their directors for giving their personal opinions in any setting, claiming that everything the director says reflects on the company as a whole.

From these realizations, after a year of development, the Health Payer Council (HPC) was launched by Roger Green on April 11, 2012. HPC is comprised of 105 members, including a few retired members. The working member, on average, represents a plan that covers more than 6 million lives combined (Table). The members include 48 active pharmacy directors and 54 active medical directors—14% from national plans, 32% from regional plans, 24% from state plans, and less than 1% from local plans.

Most significantly, participation in HPC is anonymous. Members do not know the identity of the colleagues with whom they engage in online conversations.

The result of this carefully guarded anonymity is a community with rich, in-depth weekly exchanges, plus a forum for biopharmaceutical companies and others to purchase open, detailed, blinded research.

What Is Evidence? The Payer’s Perspective A recent discussion focused on the thorny question, “What is evidence?” Kim D. Slocum, President of KDS Consulting, LLC, in West Chester, PA, posed the following questions: 1. What is evidence to you?

2. What is the proper balance between the definitive, but narrow information provided by randomized trials and the quicker, more real-world but less-definitive insights provided by observational studies?

3. How do you make decisions when the available information is incomplete or even contradictory?

4. Given the uncertainties that almost always accompany the launch of new medical technologies, what can developers do to help you make these difficult choices?

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The medical and pharmacy directors evaluated these questions by breaking down their observations into 4 distinct buckets: randomized clinical trials (RCTs), head-to-head trials, comparative effectiveness research (CER), and real-world data. The participants made it clear that currently there is no conversation about science that does not include money and politics, with economics trumping science almost every time when the conversation evolves from idealism to reality.

Randomized Clinical Trials Although many today have considered RCTs the “gold standard” for clarifying basic safety and efficacy issues, slightly more than 50% of the participants find the time-honored RCT model of limited value in today’s world. One national pharmacy director finds these studies to be “good for FDA [the US Food and Drug Administration] approval and nothing more.” Other participants were not so extreme, and still find value in RCTs, particularly for evaluating (1) new compounds, (2) new mechanisms of action, or (3) agents that address an unmet need or are directed toward a disease that had been undertreated or untreated.

Beyond these types of drugs, the participants perceive RCTs to be of marginal use to establish any value proposition for other agents. This is particularly so for drugs released into a mature market, in determining efficacy Table HPC Member’s Average Covered Lives, per Plana Members (N = 105) Commercial Medicare Medicaid plan plan plan

Covered lives per plan Average lives, by type of plan, Nb Average total lives, Nb

5,277,576

1,415,014

1,050,894

6,300,869

There are some overlapping numbers, because some members are in multiple buckets. b Each average calculated for members who cover >0 lives in the category.

HPC indicates Health Payer Council. a

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and/or safety for any subpopulation, or to aid in formulary placement for drugs with similar mechanisms of action and those brought to market by a pharmaceutical industry that focuses more on “follow-on patent plays” than on innovation, according to a pharmacy director at a state pharmacy benefit management (PBM).

Although the medical and pharmacy directors assess the value proposition of RCTs as strictly defined and marginal from an evidentiary standpoint, they deem RCTs necessary because of economic realities, a methodology they must accept as a result of political pressure.

Although 20 participants agree that RCTs are an effective baseline for new drugs, and that they provide basic essential information, 6 members feel that the FDA’s strict adherence to and acceptance of RCTs demonstrate acquiescence to the biopharmaceutical companies, which they believe do not want to fund more valuable studies nor want to risk undesirable outcomes.

Payers both accept and resent the role of RCTs in the approval process. Their view reflects people seeking to fix any problem from the middle rather than having the luxury of returning to the starting point. When adopting a purely scientific approach, payers discuss the needs for normative judgments, application of Bayesian logic and analysis, and a nationally standardized electronic medical records (EMRs) system.

In reality, RCTs, when well designed, provide information on a “class effect” for similar mechanisms of action, but they often leave providers with a broad range of products from which they randomly prescribe one drug to their patients, without clear evidence which drug provides the maximum benefit. One national medical director equated this approach to “throwing objects against the wall to see what sticks best.” However, as long as RCTs are all that are required, every real determination, past basic safety and efficacy, can often be left to real-world data, which often means a random trial-­ and-error approach.

Head-to-Head Trials Half of the HPC participants specifically state that they view head-to-head trials as important when other agents are available in the same drug class or agents with similar mechanisms of action. The perceived reasons for the shortage of these studies vary. Some payers flat out blame biopharmaceutical companies’ refusal to risk public failure. One national pharmacy director surmises that such studies are “vexing” for drug manufacturers because of the small difference between new and older treatments. Payers assert that incremental improvement does not merit a premium price, making head-to-head trials not only monumentally expensive, but also potentially worthless if the results do not mirror manufacturer

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claims. In the absence of head-to-head trials, payers adopt negative assumptions regarding new agents in a class that already has a current market leader.

Even in a perfect world, HPC members would most likely not view head-to-head trials as a panacea. By the time such studies are completed, if properly conducted, the “gold standard” used by the manufacturer may have become obsolete. Approximately 25% of participants specifically state that they see head-to-head trials as the best option. Yet few addressed the costs to the biopharmaceutical industry. Only 1 participant acknowledges the costs of these studies to be exorbitant; 2 others recognize them as expensive but valuable. The medical and pharmacy directors have little sympathy for any economic burdens that biopharmaceutical companies may face.

Overall, they perceive biopharmaceutical companies as adamantly avoiding head-to-head studies—not because of monetary pressures, but because they fear the results.

Payers express frustrations with the limitations of any controlled trials. For patients who do not match the study sample (eg, subpopulations, patients with comorbidities, geriatric patients, or patients on complex drug regimens), variations in study results can become apparent quickly. Some payers refer to the applications of studies as an art rather than a science, and they call for a standardized EMR system. They call for partnership between payers and manufacturers to truly obtain accurate data over time.

One medical director observed that in advisory board meetings, grading the level of evidence was a consistent theme. Advisory board members, they note, often concur that this is dependent on the maturity of the particular disease state of research. HPC’s medical and pharmacy directors agree that providing and managing care must be based on evidence, but they made clear that it is challenging at best to agree on a definition, as this discussion demonstrates.

Real-World Data Real-world data draw even more varied definitions.

Some refer to “postmarketing surveillance,” as a subjective term, or to evidence that “must be considered practically.

It cannot be black and white,” one participant noted.

Others find real-world data less valuable because of imprecision in the collection of the data and because clinicians have their own biases, of which they are unaware.

Those who seek more empirical data talk of mining medical and pharmacy claims to evaluate clinical real-­ world responses. Also, they wish for a coalition of similar plans to track off-label use of medications. To make any of these wishes a reality, a national EMR system is a necessity.

Otherwise, the available data are often incomplete, obsolete, or too slow to be applied to real-life decision-­making.

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payer’s trends

The Payer’s Challenge However payers choose to evaluate and define evidence, their view of the data source skews each payer’s reading and interpretation, depending on their trust level. One national pharmacy director admitted to automatic skepticism any time a drug manufacturer tries to “ease MCOs’ [managed care organizations] and PBMs’ concerns,” regardless of the merits of their claims or the rigor of their data. Another pharmacy director is compelled to consider the public’s perception of his decisions, even when he seeks to consider the source impartially.

As one senior medical director summed it up, no evidence can directly demonstrate to payers how to weigh benefits, harms, and costs. He noted, “These are not questions that can be answered in the absence of normative judgments. I fully agree with those who have indicated that we are in a position to provide guidance and direction to the studies that are needed for evidence-based decision-making, and that those involved with developing these studies would be well served to obtain input regarding the optimal trial designs and to be certain that the right questions are asked to enable the desired decisions to be made. As [HPC members] have indicated…, there would be great value in a consortium-type approach designed with academic, scientific principles and appropriate input, which would provide a better chance for getting us…the data we need to make informed decisions in the presence of uncertainty.”

The participants offered several examples of RCT data leading to bad decisions. Two payers discussed a “lifesaving” bone marrow transplant procedure for breast cancer. The evidence showed that over time the procedure was not only not lifesaving, but was causing more harm than good. Payers were vilified in the press for withdrawing coverage for the procedure, which was ultimately discredited by further evidence. Public pressure also plays a part in some ill-advised approvals, causing payers to give new products or procedures unwarranted benefit of the doubt.

In other cases, the RCT data were disproved by real-­ world data over time or led to conjectures that did not hold up over time. Several participants made reference to cyclooxygenase-2 drugs, especially rofecoxib (Vioxx), that illustrate the first problem, and ezetimibe (Zetia) for the second.

Ezetimibe’s approval provided challenges based on accurate RCTs reviewed with faulty assumptions. Although clinical trials accurately reported ezetimibe’s impact on high-density lipoprotein levels, the ENHANCE trial established that the drug nonetheless had no positive impact on cardiovascular morbidity or mortality.1 A head-to-head trial would not have helped here, because

Vol 6, No 4

l

May/June 2013

the outcomes would have led to the same false assumptions as the initial trials did.

The consistent themes throughout this discussion centered on timing and trust. Payers do not receive data early enough in the evaluation and approval process, and they have little faith in its source—biopharmaceutical companies. One pharmacy director discussed the case of ramipril (Altace), based on the HOPE trial,2 noting that, “Data helped in the placement of Altace on formulary in the face of multiple ACE [angiotensin-converting enzyme] inhibitors on the market. The HOPE trial demonstrated a reduction in morbidity and mortality in patients on Altace and the P & T [Pharmacy & Therapeutics] committee approved the move to preferred tier after that data was [sic] published. This was at least 5 years after the product had initially launched into the market.”

Bridging the gaps between FDA requirements, the types of evidence available, and payers’ needs and perceptions regarding the data needed to bring agents to market is critical. One national medical director noted, “Science evolves with data, and what is believed today as evidence can be disproved over time with more data.”

Conclusion According to the HPC payers, RCTs may be sufficient for products to gain market approval, but they do not provide the range and type of data on which payers rely.

Head-to-head data provide superior guidance but usually cover only a short period of time. Over a more extended period, real-world data can provide these answers. As the discipline of CER matures, CER studies may provide the most robust evidence on whether a drug has new value for patient care. Urgency and transparency are keys. If manufacturers lack the funds or the patient pools to create large head-to-head trials, collaboration with payers can support trials in offering data that payers can use to determine the value of a new medicine. A regional medical director proposed “that the game changer in most of this (drug and otherwise) will be the existence of very large EMR-based data that will (albeit postlaunch) make large population outcome research much easier.” The collection of data is a science and the application is an art. Therein lies the challenge. n Author Disclosure Statement Mr Green is a stockholder of AccuSphyg, LLC. Ms McDonough has reported no conflicts of interest.

References

1. Kastelein JJ, Akdim F, Stroes ES, et al, for the ENHANCE Investigators. Simva­ statin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med. 2008;358:1431-1443.

2. The Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-converting–enzyme inhibitor, ramipril, on cardiovascular events in highrisk patients. N Engl J Med. 2000;342:145-153.

www.AHDBonline.com

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American Health & Drug Benefits

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VISIT THE NEW ONLINE RESOURCE FOR THE ENTIRE MULTIPLE MYELOMA CARE TEAM

“Managing patients with myeloma means staying current.”

Ira Klein, MD, MBA, FACP Chief of Staff to the Chief Medical Officer Aetna Hartford, CT

Value-BasedCare IN Myeloma

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RESOURCE CENTER FOR PAYERS, PROVIDERS, AND THE ENTIRE CANCER CARE TEAM

Value-Based Care in Myeloma delivers exclusive interviews and perspectives related to cost, quality, and access issues.

Special sections for VA-based clinicians, advanced practice nurses, and pharmacists will also focus on the unique challenges in the management of multiple myeloma.

www.ValueBasedMyeloma.com Value-Based Care in Myeloma is a publication of Engage Healthcare Communications, a member of The Lynx Group. © 2012 All rights reserved.

VBCC0112_VBMAsizeEngage

AN 8-PART SERIES

Value-BasedCare IN MULTIPLE MYELOMA

â&#x201E;˘

The therapeutic paradigm for multiple myeloma continues to evolve at a rapid pace. The goal of this newsletter series, published by the Association for Value-Based Cancer CareTM, is to provide our readers with recent clinical advances in myeloma treatment, as well as stakeholder perspectives on how emerging data can be used to promote high-quality, cost-effective care. Each supplement will explore a specific topic to be considered when developing value-based strategies.

IN MULTIPLE MYELOMA

Value-BasedCare FEBRUARY 2013

Â&#x2122;

1st IN A SERIES

Treating Newly Diagnosed Multiple Myeloma: Data on Safety, EfďŹ cacy, and Dosing Regimens

Topics to include: Safety and Efficacy of Front-Line Treatment Assessing the Value of Complete Response Pharmacoeconomic Analysis of Treatment Options Therapeutic Decision Making Based on Cytogenetics Assessing the Value of Progression-Free Survival Data Safety and Efficacy of Therapies in the Relapsed Setting Using Alternate Routes of Drug Administration Cost-Effective Use of Imaging Techniques

Introduction The therapeutic paradigm for multiple myeloma (MM) continues to evolve, due to advances in our understanding of the molecular and genetic basis of the disease.1 Newly diagnosed patients typically undergo multidrug therapy that includes novel, targeted agents, often followed by consolidation with autologous stem cell transplantation (ASCT) and maintenance therapy.1,2 This therapeutic model has altered the value equation in newly diagnosed MM, because survival and life quality have increased along with cost of treatment.1 Enhanced survival, through the use of novel therapies, requires us to balance both short- and long-term outcomes. Over its clinical course, MM has one of the highest direct costs of any cancer.1 For example, in a 2007 analysis, the direct costs associated with a course of treatment with a novel agent plus a steroid (taking into account the drugs themselves, as well as prophylaxis and management of toxicities) ranged from approximately $47,000 to $72,000.1,3 Simple assessment of cost, however, is not sufďŹ cient, because value comprises not only expenses but also outcome over the increasingly prolonged survival time for MM. For example, in the VISTA trial (N=682), newly diagnosed, transplant-ineligible patients who were randomized to either triple therapy with bortezomib/melphalan/prednisone (VMP) or double therapy with melphalan/prednisone (MP) were followed for life quality over nine 6-week cycles.4 The study found that, through cycle 4, health-related quality of life (HRQoL) was lower with VMP than with MP, due to decreased treatment tolerability. However, from cycle 5 through the end of therapy, HRQoL with VMP was not compromised relative to MP, and recovered to the point where HRQoL was comparable for the 2 treatments.4 This investigation also demonstrated the link between antimyeloma efďŹ cacy and HRQoL. Among responders to therapy, HRQoL increased from the time of response to the end of treatment.4 Responders were more common in the VMP group than in the MP group in this trial, in which response rates were 71% and 35%, respectively (P<.001).5 In addition, 5-year overall survival (OS) was prolonged with VMP versus MP,6 another beneďŹ t to consider in the value equation.

Pharmacoeconomic analysis of initial treatment with melphalan/prednisone/lenalidomide (MPR) followed by lenalidomide maintenance (MPR-R) reported that this regimen, although more expensive than MPR or MP without maintenance, yielded greater cost-effectiveness.7 Although MPR-R increased progression-free survival (PFS) compared with regimens without maintenance, no This newsletter has been supported by funding from Millennium: The Takeda Oncology Company

beneďŹ t in OS has yet been reported with MPR-R, so the observation of cost-effectiveness remains provisional.7 In todayâ&#x20AC;&#x2122;s healthcare environment, when evidence changes the value equation, it changes practice. Therefore, it is critical to be aware of current and emerging data on the tolerability and efďŹ cacy of novel agents, which will inďŹ&#x201A;uence therapeutic strategies.

Tolerability: The Role of Optimized Dosing and Novel Drugs For newly diagnosed MM, current recommendations for care typically include the use of bortezomib, lenalidomide, or thalidomide in multidrug regimens, either for pre-ASCT induction or, in transplant-ineligible patients, as an initial course of therapy.2 All

OVERVIEW The therapeutic paradigm for multiple myeloma (MM) continues to evolve at a rapid pace. The goal of this newsletter series, published by the Association for Value-Based Cancer Care , is to provide our readers with recent clinical advances in myeloma treatment, as well as stakeholder perspectives on how emerging data can be used to promote high-quality, cost-ef

topic to be considered when developing value-based

newly diagnosed MM.

STAKEHOLDERSâ&#x20AC;&#x2122; PERSPECTIVES Assessing the Value of Novel Therapies for Multiple Myeloma ............................................. 5

By William J. Cardarelli, PharmD Atrius Health, Harvard Vanguard Medical Associates

Clinical and Economic Challenges in the Treatment of Multiple Myeloma........................ 6

By Kevin B. Knopf MD, MPH California PaciďŹ c Medical Center

An ofďŹ cial publication of

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PROVENGE® (sipuleucel-T) Suspension for Intravenous Infusion

Rx Only

BRIEF SUMMARY — See full Prescribing Information for complete product information

INDICATIONS AND USAGE: PROVENGE® (sipuleucel-T) is an autologous cellular immunotherapy indicated for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer.

DOSAGE AND ADMINISTRATION • For Autologous Use Only.

• The recommended course of therapy for PROVENGE is 3 complete doses, given at approximately 2-week intervals.

• Premedicate patients with oral acetaminophen and an antihistamine such as diphenhydramine.

• Before infusion, confirm that the patient’s identity matches the patient identifiers on the infusion bag.

• Do Not Initiate Infusion of Expired Product.

• Infuse PROVENGE intravenously over a period of approximately 60 minutes.

Do Not Use a Cell Filter.

• Interrupt or slow infusion as necessary for acute infusion reactions, depending on the severity of the reaction.

(See Dosage and Administration [2] of full Prescribing Information.)

CONTRAINDICATIONS: None.

WARNINGS AND PRECAUTIONS • PROVENGE is intended solely for autologous use.

• Acute infusion reactions (reported within 1 day of infusion) included, but were not limited to, fever, chills, respiratory events (dyspnea, hypoxia, and bronchospasm), nausea, vomiting, fatigue, hypertension, and tachycardia. In controlled clinical trials, 71.2% of patients in the PROVENGE group developed an acute infusion reaction.

I n controlled clinical trials, severe (Grade 3) acute infusion reactions were reported in 3.5% of patients in the PROVENGE group. Reactions included chills, fever, fatigue, asthenia, dyspnea, hypoxia, bronchospasm, dizziness, headache, hypertension, muscle ache, nausea, and vomiting. The incidence of severe events was greater following the second infusion (2.1% vs 0.8% following the first infusion), and decreased to 1.3% following the third infusion. Some (1.2%) patients in the PROVENGE group were hospitalized within 1 day of infusion for management of acute infusion reactions.

No Grade 4 or 5 acute infusion reactions were reported in patients in the PROVENGE group.

Closely monitor patients with cardiac or pulmonary conditions. In the event of an acute infusion reaction, the infusion rate may be decreased, or the infusion stopped, depending on the severity of the reaction. Appropriate medical therapy should be administered as needed.

• Handling Precautions for Control of Infectious Disease. PROVENGE is not routinely tested for transmissible infectious diseases. Therefore, patient leukapheresis material and PROVENGE may carry the risk of transmitting infectious diseases to health care professionals handling the product. Universal precautions should be followed.

• Concomitant Chemotherapy or Immunosuppressive Therapy. Use of either chemotherapy or immunosuppressive agents (such as systemic corticosteroids) given concurrently with the leukapheresis procedure or PROVENGE has not been studied. PROVENGE is designed to stimulate the immune system, and concurrent use of immunosuppressive agents may alter the efficacy and/or safety of PROVENGE. Therefore, patients should be carefully evaluated to determine whether it is medically appropriate to reduce or discontinue immunosuppressive agents prior to treatment with PROVENGE. • Product Safety Testing. PROVENGE is released for infusion based on the microbial and sterility results from several tests: microbial contamination determination by Gram stain, endotoxin content, and in-process sterility with a 2-day incubation to determine absence of microbial growth. The final (7-day incubation) sterility test results are not available at the time of infusion. If the sterility results become positive for microbial contamination after PROVENGE has been approved for infusion, Dendreon will notify the treating physician. Dendreon will attempt to identify the microorganism, perform antibiotic sensitivity testing on recovered microorganisms, and communicate the results to the treating physician. Dendreon may request additional information from the physician in order to determine the source of contamination.

(See Warnings and Precautions [5] of full Prescribing Information.)

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 to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Table 1 Incidence of Adverse Events Occurring in ≥5% of Patients The safety evaluation of PROVENGE is based on 601 prostate cancer patients in the PROVENGE group who underwent at least 1 leukapheresis procedure in four randomized, Randomized to PROVENGE controlled clinical trials. The control was non-activated autologous peripheral blood PROVENGE (N = 601) Control* (N = 303) mononuclear cells.

The most common adverse events, reported in patients in the PROVENGE group at a rate ≥15%, were chills, fatigue, fever, back pain, nausea, joint ache, and headache. Severe (Grade 3) and life-threatening (Grade 4) adverse events were reported in 23.6% and 4.0% of patients in the PROVENGE group compared with 25.1% and 3.3% of patients in the control group. Fatal (Grade 5) adverse events were reported in 3.3% of patients in the PROVENGE group compared with 3.6% of patients in the control group.

Serious adverse events were reported in 24.0% of patients in the PROVENGE group and 25.1% of patients in the control group. Serious adverse events in the PROVENGE group included acute infusion reactions (see Warnings and Precautions), cerebrovascular events, and single case reports of eosinophilia, rhabdomyolysis, myasthenia gravis, myositis, and tumor flare.

PROVENGE was discontinued in 1.5% of patients in Study 1 (PROVENGE group n=341; Control group n=171) due to adverse events. Some patients who required central venous catheters for treatment with PROVENGE developed infections, including sepsis. A small number of these patients discontinued treatment as a result. Monitoring for infectious sequelae in patients with central venous catheters is recommended.

Each dose of PROVENGE requires a standard leukapheresis procedure approximately 3 days prior to the infusion. Adverse events that were reported ≤1 day following a leukapheresis procedure in ≥5% of patients in controlled clinical trials included citrate toxicity (14.2%), oral paresthesia (12.6%), paresthesia (11.4%), and fatigue (8.3%).

Table 1 provides the frequency and severity of adverse events reported in ≥5% of patients in the PROVENGE group of randomized, controlled trials of men with prostate cancer.

The population included 485 patients with metastatic castrate resistant prostate cancer and 116 patients with non-metastatic androgen dependent prostate cancer who were scheduled to receive 3 infusions of PROVENGE at approximately 2-week intervals. The population was age 40 to 91 years (median 70 years), and 90.6% of patients were Caucasian.

Table 1 Incidence of Adverse Events Occurring in ≥5% of Patients Randomized to PROVENGE PROVENGE (N = 601)

Any Adverse Event Chills Fatigue Fever Back pain Nausea Joint ache Headache Citrate toxicity Paresthesia Vomiting Anemia Constipation Pain Paresthesia oral Pain in extremity Dizziness Muscle ache Asthenia Diarrhea Influenza-like illness Musculoskeletal pain Dyspnea Edema peripheral Hot flush Hematuria Muscle spasms

Control* (N = 303)

All Grades n (%)

Grade 3-5 n (%)

All Grades n (%)

591 (98.3) 319 (53.1) 247 (41.1) 188 (31.3) 178 (29.6) 129 (21.5) 118 (19.6) 109 (18.1) 89 (14.8) 85 (14.1) 80 (13.3) 75 (12.5) 74 (12.3) 74 (12.3) 74 (12.3) 73 (12.1) 71 (11.8) 71 (11.8) 65 (10.8) 60 (10.0) 58 (9.7) 54 (9.0) 52 (8.7) 50 (8.3) 49 (8.2) 46 (7.7) 46 (7.7)

186 (30.9) 13 (2.2) 6 (1.0) 6 (1.0) 18 (3.0) 3 (0.5) 11 (1.8) 4 (0.7) 0 (0.0) 1 (0.2) 2 (0.3) 11 (1.8) 1 (0.2) 7 (1.2) 0 (0.0) 5 (0.8) 2 (0.3) 3 (0.5) 6 (1.0) 1 (0.2) 0 (0.0) 3 (0.5) 11 (1.8) 1 (0.2) 2 (0.3) 6 (1.0) 2 (0.3)

291 (96.0) 33 (10.9) 105 (34.7) 29 (9.6) 87 (28.7) 45 (14.9) 62 (20.5) 20 (6.6) 43 (14.2) 43 (14.2) 23 (7.6) 34 (11.2) 40 (13.2) 20 (6.6) 43 (14.2) 40 (13.2) 34 (11.2) 17 (5.6) 20 (6.6) 34 (11.2) 11 (3.6) 31 (10.2) 14 (4.6) 31 (10.2) 29 (9.6) 18 (5.9) 17 (5.6)

Grade 3-5 n (%) 97 (32.0) 0 (0.0) 4 (1.3) 3 (1.0) 9 (3.0) 0 (0.0) 5 (1.7) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 7 (2.3) 3 (1.0) 3 (1.0) 0 (0.0) 1 (0.3) 0 (0.0) 0 (0.0) 2 (0.7) 3 (1.0) 0 (0.0) 3 (1.0) 3 (1.0) 1 (0.3) 1 (0.3) 3 (1.0) 0 (0.0)

Hypertension Anorexia Bone pain Upper respiratory tract infection Insomnia Musculoskeletal chest pain Cough Neck pain Weight decreased Urinary tract infection Rash Sweating Tremor

All Grades n (%)

Grade 3-5 n (%)

All Grades n (%)

Grade 3-5 n (%)

45 (7.5) 39 (6.5) 38 (6.3) 38 (6.3)

3 (0.5) 1 (0.2) 4 (0.7) 0 (0.0)

14 (4.6) 33 (10.9) 22 (7.3) 18 (5.9)

0 (0.0) 3 (1.0) 3 (1.0) 0 (0.0)

37 (6.2) 36 (6.0)

0 (0.0) 2 (0.3)

22 (7.3) 23 (7.6)

1 (0.3) 2 (0.7)

35 (5.8) 34 (5.7) 34 (5.7) 33 (5.5) 31 (5.2) 30 (5.0) 30 (5.0)

0 (0.0) 3 (0.5) 2 (0.3) 1 (0.2) 0 (0.0) 1 (0.2) 0 (0.0)

17 (5.6) 14 (4.6) 24 (7.9) 18 (5.9) 10 (3.3) 3 (1.0) 9 (3.0)

0 (0.0) 2 (0.7) 1 (0.3) 2 (0.7) 0 (0.0) 0 (0.0) 0 (0.0)

*Control was non-activated autologous peripheral blood mononuclear cells.

Cerebrovascular Events. In controlled clinical trials, cerebrovascular events, including hemorrhagic and ischemic strokes, were reported in 3.5% of patients in the PROVENGE group compared with 2.6% of patients in the control group.

(See Adverse Reactions [6] of full Prescribing Information.)

To report SUSPECTED ADVERSE REACTIONS, contact Dendreon Corporation at 1-877-336-3736 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Dendreon Corporation Seattle, Washington 98101

REFERENCES: 1. PROVENGE [package insert]. Dendreon Corporation; June 2011.

2. Kantoff PW, Higano CS, Shore ND, et al; for the IMPACT Study Investigators. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363:411-422.

©2013 Dendreon Corporation.

All rights reserved. January 2013.

Printed in the U.S.A. Dendreon, the Dendreon logo, and PROVENGE are registered trademarks of Dendreon Corporation.

P-A-01.13-002.00

In the newly metastatic CRPC patient who is asymptomatic or minimally symptomatic

STARTS THE FIGHT

AND HELPS HIS IMMUNE SYSTEM SUSTAIN* IT 1

• Targets and attacks prostate cancer cells • Statistically significant overall survival advantage1,2 • Sustained* immune response *A sustained immune response was seen out to 26 weeks in the pivotal study (the last time point measured).1 INDICATION: PROVENGE® (sipuleucel-T) is an autologous cellular immunotherapy indicated for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer.

IMPORTANT SAFETY INFORMATION: PROVENGE is intended solely for autologous use and is not routinely tested for transmissible infectious diseases.

In controlled clinical trials, serious adverse events reported in the PROVENGE group included acute infusion reactions (occurring within 1 day of infusion) and cerebrovascular events. Severe (Grade 3) acute infusion reactions were reported in 3.5% of patients in the PROVENGE group. Reactions included chills, fever, fatigue, asthenia, dyspnea, hypoxia, bronchospasm, dizziness, headache, hypertension, muscle ache, nausea, and vomiting. No Grade 4 or 5 acute infusion reactions were reported in patients in the PROVENGE group.

The most common adverse events (incidence ≥15%) reported in the PROVENGE group were chills, fatigue, fever, back pain, nausea, joint ache, and headache.

For more information on PROVENGE, please see Brief Summary of Prescribing Information on adjacent pages. www.PROVENGEHCP.com