AHDB September 2013, Vol 6, No 7

The Peer-Reviewed Forum for Real-World Evidence in Benefit Design ™ September 2013

Volume 6, Number 7

For Payers, Purchasers, Policymakers, and Other Healthcare Stakeholders

Cardiometabolic Health Theme Issue INTRODUCTION

Cardiometabolic Risk Factors: Novel Approaches Can Improve Patient Outcomes Dalia Buffery, MA, ABD REGULATORY ™

Assessing Medicare Beneficiary Eligibility for Medication Therapy Management Programs Using PINNACLE, a National Cardiovascular Data Registry Sarah A. Spinler, PharmD; Mark J. Cziraky, PharmD; Fengming Tang, MS; Gladys G. Dueñas, PharmD; Tyan Thomas, PharmD; Jennifer A. Reinhold, PharmD; Vincent J. Willey, PharmD Stakeholder Perspective by Albert Tzeel, MD, MHSA, FACPE BUSINESS

Impact of Glycemic Control on Healthcare Resource Utilization and Costs of Type 2 Diabetes: Current and Future Pharmacologic Approaches to Improving Outcomes Mary Ann Banerji, MD, FACP; Jeffrey D. Dunn, PharmD, MBA Stakeholder Perspective by Jeffrey A. Bourret, PharmD, MS, RPh, FASHP

Communication Strategies Must Be Tailored to a Medication’s Targeted Population: Lessons from the Case of BiDil Chamika Hawkins-Taylor, MHA, PhD; Angeline M. Carlson, PhD Stakeholder Perspective by Michael F. Murphy, MD, PhD CLINICAL

New Drug Therapies for the Treatment of Overweight and Obese Patients

ANNIVERSARY 6YEAR

Babak Mahgerefteh, DO; Michael Vigue, DO; Zachary Freestone, DO; Scott Silver, DO; Quang Nguyen, DO, FACP, FACE Stakeholder Perspective by James V. Felicetta, MD

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Table of Contents

Publishing Staff

Cardiometabolic Health Theme Issue INTRODUCTION

363 Cardiometabolic Risk Factors: Novel Approaches Can Improve Patient Outcomes

Dalia Buffery, MA, ABD REGULATORY

367 A ssessing Medicare Beneficiary Eligibility for Medication Therapy Management Programs Using PINNACLE, a National Cardiovascular Data Registry Sarah A. Spinler, PharmD; Mark J. Cziraky, PharmD; Fengming Tang, MS; Gladys G. Dueñas, PharmD; Tyan Thomas, PharmD; Jennifer A. Reinhold, PharmD; Vincent J. Willey, PharmD 373 Stakeholder Perspective: Hanging Together for Patient-Centered Medical Care

Albert Tzeel, MD, MHSA, FACPE business

382 I mpact of Glycemic Control on Healthcare Resource Utilization and Costs of Type 2 Diabetes: Current and Future Pharmacologic Approaches to Improving Outcomes

Mary Ann Banerji, MD, FACP; Jeffrey D. Dunn, PharmD, MBA 391 Stakeholder Perspective: Innovation in Patient Engagement and Management Is Critically Needed to Change Current Trends in Type 2 Diabetes

Jeffrey A. Bourret, PharmD, MS, RPh, FASHP Continued on page 360

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For Payers, Purchasers, Policymakers, and Other Healthcare Stakeholders

Table of Contents

(Continued)

business

401 C ommunication Strategies Must Be Tailored to a Medication’s Targeted Population: Lessons from the Case of BiDil

Chamika Hawkins-Taylor, MHA, PhD; Angeline M. Carlson, PhD 411 Stakeholder Perspective: Much More than Biomarkers: Sociodemographic Variables in Personalized Medicine

Michael F. Murphy, MD, PhD CLINICAL

423 New Drug Therapies for the Treatment of Overweight and Obese Patients Babak Mahgerefteh, DO; Michael Vigue, DO; Zachary Freestone, DO; Scott Silver, DO; Quang Nguyen, DO, FACP, FACE 430 Stakeholder Perspective: The Modern Epidemic of Obesity

James V. Felicetta, MD DEPARTMENT

418 Healthcare Reform

Yet Another Blow to the Medicaid Expansion

Ross Margulies, JD, MPH; Igor Gorlach, JD, MPH

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GE Healthcare Clarient Diagnostic Services

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editorial board Editor-in-Chief

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

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

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

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

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

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

Joshua N. Liberman, PhD Executive Director, Research, Development & Dissemination, Sutter Health, Concord, CA 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 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 E. Couto, PharmD, MBA Clinical Program Manager Cigna Corporation, Bloomfield, CT Steven 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, Director, Graduate Program Track in Pharmaceutical Outcomes Research Univ. of Colorado, Aurora, CO Gary M. Owens, MD President, Gary Owens Associates Ocean View, DE Andrew M. Peterson, PharmD, PhD Dean, Mayes School of Healthcare Business and Policy, Associate Professor, University of the Sciences, Philadelphia Sarah A. Priddy, PhD Director, Competitive Health Analytics Humana, Louisville, KY Timothy S. Regan, BPharm, RPh, CPh Executive Director, Strategic Accounts Xcenda, Palm Harbor, FL Vincent J. Willey, PharmD Associate Professor, School of Pharmacy, University of the Sciences, Philadelphia Paul Wilson Senior VP, Health Consumer Insights and Analytics, Blue Bell, PA David W. Wright, MPH President, Institute for Interactive Patient Care Bethesda, MD 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 Regional Medical Director Medicare Operations, North Florida Humana, Jacksonville MANAGED MARKETS

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

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 Grant D. Lawless, RPh, MD, FACP Assoc. Prof. and Director, Healthcare Decision Analysis, Dept. of Clinical Pharmacy Univ. of Southern California, Los Angeles

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PHARMACY BENEFIT DESIGN

Joel V. Brill, MD, AGAF, CHCQM Chief Medical Officer, Predictive Health, Phoenix, AZ Teresa DeLuca, MD, MBA Chief Medical Officer–Pharmacy Magellan Health Services Leslie S. Fish, PharmD Vice President of Clinical Programs Fallon Community Health Plan, MA John Hornberger, MD, MS Cedar Associates, LLC CHP/PCOR Adjunct Associate, Menlo Park, CA Michael S. Jacobs, RPh MSJ Associates, Sandy Springs, GA Matthew Mitchell, PharmD, MBA Manager, Pharmacy Services SelectHealth, Salt Lake City, UT Paul Anthony Polansky, BSPharm, MBA PAPRx, LLC Gulph Mills, PA Christina A. Stasiuk, DO, FACOI Senior Medical Director Cigna, Philadelphia, 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, School of Pharmacy University of Missouri, Kansas City, MO Walid F. Gellad, MD, MPH Assistant Professor of Medicine, University of Pittsburgh, Staff Physician, Pittsburgh VA Medical Center, Adjunct Scientist, RAND Health Paul Pomerantz, MBA CEO, American Society of Anesthesiologists Park Ridge, IL J. Warren Salmon, PhD Professor of Health Policy & Administration School of Public Health University of Illinois at Chicago Raymond L. Singer, MD, MMM, CPE, FACS Chief, Division of Cardiothoracic Surgery Vice Chair, Department of Surgery for Quality & Patient Safety and Outreach Lehigh Valley Health Network, PA 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

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introduction

Cardiometabolic Risk Factors: Novel Approaches Can Improve Patient Outcomes Dalia Buffery, MA, ABD Editorial Director, American Health & Drug Benefits

T

he outlook for cardiometabolic health remains suboptimal in 2013, despite considerable awareness of the health consequences and the associated costs of cardiometabolic risk factors, including cardiovascular disease, diabetes, dyslipidemia, hypertension, and obesity.

There is not much that has not been said about these top killers of Americans. Yet despite all the research and the published literature, new treatments, and well-documented high morbidity and mortality associated with heart disease, type 2 diabetes, and obesity, the incidence of each of these conditions continues to climb.

As an example, in 2011, 16.3 million Americans had chronic heart disease, 76.4 million had hypertension, 5.7 million had heart failure, and 7 million had a stroke—all directly increasing the mortality risk from heart disease.1 In 2007, approximately 25.8 million Americans had diabetes, and many millions more had prediabetes.2 Unless new approaches to diabetes therapy become available in the coming years, it is projected that approximately 21% of the American population will have type 2 diabetes by 2050.3 Heart disease remains the leading killer of Americans,4 and even with the many antihyperglycemic drug classes, less than 50% of patients with diabetes reach the American Diabetes Association’s glycemic goal of hemoglobin A1c <7%.5 Why has the transition from epidemiologic research and well-conducted clinical trials into standards of care apparently been so ineffective? Are the therapeutic options inadequately perceived in terms of efficacy, safety, cost or convenience, even in the presence of data that would suggest otherwise? As with so many other facets of medicine, potential contributors are diverse, and remediation requires a concerted effort on the part of many stakeholders to isolate, and then address each of the mediating variables.

For example, considering the serious health implications of obesity, it is surprising that it took until 2013 for the American Medical Association to classify it as a disease,6 possibly because obesity was mainly assumed to be the result of lifestyle or behavior. It may take yet another generation of personalized medicine research to fully identify biologically based risk factors for development of obesity and cardiometabolic complications, beyond those which already can be deduced in diabetes, and as has already begun in heart disease. As in so many other conditions, it may be the interaction of genetic, sociodemographic, and other characteristics that yield-

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ed the highest specificity and sensitivity in this regard.

A number of recent developments are noteworthy in their ability to disentangle these issues. Hulsmans and Holvoet recently noted that not all obese patients are at the same risk of developing cardiometabolic complications.7 Therefore, they say, “there is an urgent need for novel biomarkers for early identification of obese patients at high risk. Possible candidate biomarkers are microRNAs, which are highly conserved non-coding RNA molecules of approximately 22 nucleotides that exert post-transcriptional effects on gene expression.”7 This is a promising start that will enable more effective targeting of subgroups of obese patients with efficient risk-mitigation strategies.

Obviously, the costs associated with the management of illnesses linked to the presence of cardiometabolic risk factors continue to rise in tandem. In 2007, the estimated total US cost for diabetes was $174 billion.2 In 2010, the direct cost for cardiovascular disease was $272.5 billion, which is expected to reach $818.1 billion by 2030.8 Similarly, the total cost related to obesity is projected to reach $861 billion to $957 billion by 2030.9 These numbers alone are sufficient to drive home the link between clinical and economic priorities.

The articles in this theme issue of American Health & Drug Benefits provide significant contributions to the literature and highlight for all healthcare stakeholders the importance of focusing on cardiometabolic risk factors.

Spinler and colleagues have conducted the first non– claims-based analysis of data from the national cardiovascular registry PINNACLE, to identify Medicare beneficiaries with multiple chronic cardiovascular conditions who are eligible for medication therapy management (MTM), a modality that has been shown to improve outcomes and reduce costs in patients with chronic diseases.

The authors point out that many eligible patients are not participating in MTM programs, in large part because of a lack of knowledge of these programs’ benefits. These data therefore not only support tailored therapy for Medicare beneficiaries at risk, but also imply the need for an effective communication program within the subpopulation, a theme that is apparent in other articles in this issue. Spinler and colleagues charge providers to explain to patients the benefits of MTM programs and encourage their participation. They call on providers to educate patients on why enrolling in such programs can help to improve their

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introduction

health outcomes and reduce overall costs. Tzeel aptly notes in his perspective, “as the authors so eloquently state, ‘we believe that promoting the utilization of such programs to eligible patients should be the responsibility of all healthcare providers within the framework of care advocated by the ACC within the framework of the patient-centered medical home for CV care.’ ” Also in this issue, Banerji and Dunn elucidate the increasing prevalence of diabetes and the staggering economic implications, focusing their analysis of the literature on a lack of medication adherence among patients with type 2 diabetes as one of the principal culprits for the dire state of this disease. Banerji and Dunn call for innovation in drug therapies that will focus on patient convenience and ease of use to enhance adherence, suggesting that these are crucial to improving outcomes and reducing the morbidity and mortality rates far beyond the trends seen with currently available medications.

Their article serves to emphasize that issues of cost and convenience are as important as efficacy and safety in promoting adherence. They provide some hope in their review of new treatment approaches in the current pipeline that may offer new solutions to lagging adherence as well. As Bourret observes, “Banerji and Dunn aptly make the case for a call to action for aggressive change and innovation in the management of patients with type 2 diabetes and the development of new pharmaceuticals that reduce cardiovascular risk, result in less weight gain, and improve adherence and health outcomes.” The status quo, they suggest, is no longer acceptable.

And in a one-of-its-kind presentation, Hawkins-Taylor and Carlson resurrect the events surrounding the case of BiDil, noting the need to consider sociocultural parameters, including race and ethnicity, in drug development. The US Food and Drug Administration (FDA) approval of this first and only drug specifically indicated for a racial group resulted in a controversy that, the authors show, has implications for the future development of targeted therapies, especially in the age of personalized medicine. In 2005, when BiDil was approved for the treatment of heart failure in African Americans, the potential impediments associated with introducing combination therapy as a unique treatment in a self-identified patient subgroup was not fully appreciated by different stakeholders, although it was mentioned in the FDA’s approval.

As Murphy notes, “In a literature replete with references to personalized medicine tailored to variations in genetics and disease-related phenotypes, the case study presented by Hawkins-Taylor and Carlson…emphasizes the importance of incorporating sociodemographic variables into this definition.” With all the focus on race, the authors emphasize, lost was the main clinical message—

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the need to manage heart failure with a combination of vasodilator therapies in African Americans. The role of genetics and biology, extracting information from data which would resonate with a demographic minority and their providers, did not factor in within the debate about the utility of this particular therapy, but in the age of personalized medicine, resurrecting this case from its recent past has important implications for drug developers, policymakers, providers, and payers. The lesson, Murphy says, is that “failure to achieve meaningful adoption after approval, despite a methodologically rigorous pedigree, emphasizes the importance of ensuring clinical and commercial stakeholder convergence during, not after, the drug development process.”

Finally, Mahgerefteh and colleagues review the evidence for the 2 new therapies approved by the FDA in mid-2012 for the treatment of obesity, highlighting the current public crisis of obesity and the need for improved therapies. The authors focus on the potential benefits seen in clinical trials with these 2 drugs, with independent and new mechanisms of action, which, in addition to weight reduction, have also been shown to improve blood pressure, blood glucose levels, and lipid levels. As Felicetta says in his perspective, “Time, and real-world data, will tell whether these…medications are indeed able to live up to the promises they offer.”

With the aging of the US population and increasing life expectancy, the toll of heart disease, diabetes, and obesity will reach unsustainable levels that may exceed current projections. This theme issue is a call to action to patients, providers, payers, researchers, drug manufacturers, and policymakers. The challenges are many, and the needs for innovation and change are urgent. n Acknowledgment I wish to thank Michael F. Murphy, MD, PhD, for his insightful comments and assistance with this introduction.

References

1. Roger VL, Go AS, Lloyd-Jones DM, et al, for the American Heart Association. Heart disease and stroke statistics—2011 update. Circulation. 2011;123:e18-e209.

2. Centers for Disease Control and Prevention. 2011 National Diabetes Fact Sheet. www.cdc. gov/diabetes/pubs/estimates11.htm#11. Accessed September 2, 2013.

3. Boyle JP, Thompson TJ, Gregg EW, et al. Projection of the year 2050 burden of diabetes in the US adult population: dynamic modeling of incidence, mortality, and prediabetes prevalence. Popul Health Metr. 2010;8:29.

4. Kochanek K, Xu J, Murphy SL, et al. Deaths: preliminary data for 2009. Natl Vital Stat Rep. 2011;59:1-51.

5. Fitch K, Iwasaki K, Pyenson B. Improved management can help reduce the economic burden of type 2 diabetes: a 20-year actuarial projection. Milliman Client Report. April 28, 2010. http:// publications.milliman.com/publications/health-published/pdfs/improved-managementcan-help.pdf. Accessed September 2, 2013.

6. American Medical Association. AMA adopts new policies on second day of voting at annual meeting. Press release; June 18, 2013. www.ama-assn.org/ama/pub/news/news/2013/ 2013-06-18-new-ama-policies-annual-meeting.page. Accessed August 28, 2013.

7. Hulsmans M, Holvoet P. MicroRNAs as early biomarkers in obesity and related metabolic and cardiovascular diseases. Curr Pharm Des. 2013;19:5704-5717.

8. Heidenreich PA, Trogdon JG, Khavjou OA, et al; for the American Heart Association. Forecasting the future of cardiovascular disease in the United States. Circulation. 2011;123:933-944.

9. American Heart Association. Statistical Fact Sheet: Overweight and Obesity. 2013 Update. www.heart.org/idc/groups/heart-public/@wcm/@sop/@smd/documents/downloadable/ucm_ 319588.pdf. Accessed September 2, 2013.

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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.

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Original Research

Assessing Medicare Beneficiary Eligibility for Medication Therapy Management Programs Using PINNACLE, a National Cardiovascular Data Registry Sarah A. Spinler, PharmD; Mark J. Cziraky, PharmD; Fengming Tang, MS; Gladys G. Dueñas, PharmD; Tyan Thomas, PharmD; Jennifer A. Reinhold, PharmD; Vincent J. Willey, PharmD Background: Medication therapy management (MTM) is a mandated component of the 2003 Medicare Modernization Act for Part D prescription drug plans and Medicare Advantage plans, authorizing the pharmacist or other qualified provider to identify, resolve, and prevent medication-related problems for patients with chronic diseases. MTM programs have been shown to improve medication adherence and reduce medication errors while reducing overall costs in patients with cardiovascular (CV) disease; however, MTM has been greatly underutilized for patients with chronic diseases.

Objective: To identify the proportion of Medicare beneficiaries who are eligible for, and who could potentially benefit from, participating in MTM among patients enrolled in the National Cardiovascular Data Registry’s PINNACLE Registry.

Methods: Patient MTM eligibility is based on the presence of multiple chronic diseases and meeting a minimum annual insurance medication costs. We used patient data from 462 academic and private cardiology practices in the United States who participated in the PINNACLE Registry between May 1, 2008, and September 30, 2010, to determine Medicare beneficiaries’ eligibility to participate in an MTM program for patients meeting the MTM criteria of (1) a number of chronic diseases (in this case, the number of CV conditions) and (2) an estimated minimum annual medication expenses, using a weighted average cost calculated based on the average wholesale price of the most often prescribed medications, by class, as extracted from the HealthCore Integrated Research Database and weighted according to prescribing frequency within a class.

Results: Among the Medicare beneficiaries in the PINNACLE Registry, 93,089 (58%) had ≥3 chronic CV conditions, and the median annual estimated medication expenditure per patient enrolled in the PINNACLE Registry was $1329. Of the total of 93,089 Medicare beneficiaries, 21.4% were eligible for MTM, based on the 2010 minimum eligibility criterion of an annual insurer medication expenditure of $3000 or more. These costs ranged from $366 for low-cost generics to $3958 for the highest-cost drug in a class. In addition, based on the 2010 minimum eligibility rule, the proportion of patients eligible for MTM ranged from 7.9% for those eligible for MTM for low-cost generics to 64% of patients eligible for MTM for the highest-cost medication in a class.

Conclusions: These data serve to raise awareness regarding patients’ potential eligibility to receive the benefits of MTM programs. Providers caring for patients with multiple CV conditions, including specialists such as cardiologists, should explain to eligible patients about MTM programs and encourage these patients to take advantage of such programs.

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2013;6(7):367-374 www.AHDBonline.com Disclosures are at end of text

Dr Spinler is Professor of Clinical Pharmacy, Philadelphia College of Pharmacy, University of the Sciences, PA; Dr Cziraky is Vice President for Research, HealthCore, Wilmington, DE, and Adjunct Assistant Professor of Clinical Pharmacy, Philadelphia College of Pharmacy, University of the Sciences, PA; Ms Tang is Biostatistician II, Cardiovascular Outcomes Research, St Luke’s Mid America Heart Institute, Kansas City, MO; Dr Dueñas is Assistant Professor of Clinical Pharmacy, Philadelphia College of Pharmacy, University of the Sciences, PA; Dr Thomas is Associate Professor of Clinical Pharmacy, Philadelphia College of Pharmacy, University of the Sciences, PA; Dr Reinhold is Assistant Professor of Clinical Pharmacy, Philadelphia College of Pharmacy, University of the Sciences, PA; and Dr Willey is Associate Professor, Philadelphia College of Pharmacy, University of the Sciences, PA. Vol 6, No 7

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M

edication therapy management (MTM) is a mandated component of the 2003 Medicare Modernization Act for Part D prescription drug plans and Medicare Advantage plans, whereby the pharmacist or other qualified provider identifies, resolves, and prevents medication-related problems to optimize the therapeutic outcomes for individual patients.1 MTM programs typically involve a comprehensive review of all medications, both prescription and nonprescription (including natural and herbal products), that a patient is currently taking. In addition, an evaluation of the patient’s medication-taking behavior is conducted, as well as an assessment of the patient’s understanding, concerns, and expectations regarding his or her current medication regimen and health.1 MTM differs greatly from traditional counseling offered by community pharmacists that occurs as part of the drug dispensing process. As part of non-MTM medication dispensing, pharmacists review the drug and identify its indications, directions for use, storage requirements, side effects, long-term toxicity, drug interactions, food interactions, and medication adherence factors. Depending on the number of medications, and whether the patient accepts or denies counseling by a pharmacist at the point of prescription pickup, this service may take approximately 5 to 10 minutes. By contrast, MTM may take 30 to 60 minutes and is a service that is independent of, but can occur in conjunction with, the provision of a medication product.2 MTM promotes collaboration with other healthcare providers, which is especially important as patients undergo transitions in care environments.2 The pharmacist reviews the complete medication profile to explore ways to optimize the patient’s medication therapy. Strategies to optimize medication therapy may include interventions to resolve medication interactions, inappropriate dosing or formulation (eg, tablet vs patch), therapeutic duplication, and ways to improve adherence.2 These strategies are then discussed with the patient’s prescriber for his or her consideration. On prescriber approval, the pharmacist will inform the patient of any medication changes and will then educate the patient on the appropriate medication self-management.2 MTM programs and services have been shown to improve drug therapy goal attainment and medication adherence, as well as to reduce medication errors while reducing overall costs in patients with cardiovascular (CV) disease; however, MTM has been greatly underutilized for chronic diseases, including CV conditions.2-7 Beginning in 2010, Medicare Part D plans were required to implement covered MTM programs that target beneficiaries who have multiple chronic diseases, take multiple medications, and had an anticipated annual

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Key Points Medication therapy management (MTM) for chronic diseases was mandated by the 2003 Medicare Modernization Act but is greatly underutilized. ➤ To participate in an MTM, patients must have ≥3 chronic diseases and meet a set amount of drug spending. ➤ MTM has been shown to improve drug medication adherence, reduce medication errors, and lower overall costs in patients with CV disease. ➤ This is the first non–claims data study to estimate patient MTM eligibility among Medicare beneficiaries with multiple cardiovascular (CV) conditions ➤ Data used for this analysis came from the Medicare PINNACLE Registry, which collects information from outpatient cardiology practices in the United States to help improve care quality. ➤ Overall, 7.9% to 64% of patients with ≥3 chronic CV conditions are estimated to meet the $3000 minimum annual drug spending required for MTM program eligibility. ➤ Payers indicate that the most common barrier to implementing MTM programs is patient lack of willingness to participate in such programs. ➤ Providers should educate patients on the benefits of MTM programs and encourage their participation. ➤

drug spending of $4000 in 2009 and $3000 beginning in 2010.8 Health insurance plans cannot require patients to have more than 3 chronic diseases to meet MTM eligibility, and the plans must target at least 4 of 7 core chronic diseases, including hypertension, heart failure, type 2 diabetes, dyslipidemia, respiratory disease, bone disease–arthritis, or mental health.8 National surveys of payers offering MTM programs conducted by the American Pharmacists Association (APhA) indicate that payers believe that the most common challenge to implementing MTM programs is that patients are not interested in these programs or they decline to participate in them, as was indicated by 47% of respondents in a 2010 survey conducted by the APhA.9 The purpose of this present study was to identify the proportion of patients who are eligible for, and who could potentially benefit from, participating in MTM, based on Medicare beneficiaries who were enrolled in a large nationally representative outpatient cardiac registry.

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Methods The PINNACLE Registry and Study Population The PINNACLE Registry is a voluntary registry of the National Cardiovascular Data Registry (NCDR) that was initiated by the American College of Cardiology Foundation (ACCF) and that collects data from outpatient cardiology practices to enhance quality improvement. The registry has a standard data set with written definitions, uniform data entry and transmission requirements, and data quality checks. Details on the data collection process have previously been published.10,11 Within participating practices, a variety of patient data are collected at the point of care, including patients’ symptoms, vital signs, comorbidities, selected laboratory tests, medication classes, and health insurance. In addition, data for established performance measures for myocardial infarction, heart failure, dyslipidemia, and atrial fibrillation are collected.11 Data were collected through paper forms that were completed at the time of the clinic visits, or via modification of a practice’s electronic medical record data collection system to comprehensively capture the requisite PINNACLE Registry data elements. Data from practices are routinely submitted to the NCDR, and data quality checks and analyses for this study were performed at Saint Luke’s Mid America Heart Institute (Kansas City, MO), the primary analytical center for the PINNACLE program. The PINNACLE Registry has been reviewed and approved by the ACCF’s contracted Institutional Review Board.

Identification of MTM-Eligible Patients For the purpose of this study, we used patient data from 462 academic and private cardiology practices in the PINNACLE Registry between May 1, 2008, and September 30, 2010 (N = 315,973), consisting of 44 office practices representing all 5 regions of the United States. We further restricted the cohort to include only patients with Medicare insurance, which comprised 160,593 patients (Figure 1).

From the Medicare cohort of 160,593 patients, patients who were eligible for MTM were defined as (1) patients who met the criteria for the minimum number (ie, 3) of chronic diseases, and (2) patients who met the minimum drug spending requirements. Patients were included if they had ≥3 chronic diseases, including hypertension, heart failure, dyslipidemia, type 2 diabetes, or coronary artery disease. Of the total Medicare beneficiaries in the PINNACLE Registry, 93,089 (58%) had ≥3 chronic CV conditions, which constituted the final study sample.

Data extracted from the PINNACLE Registry included demographic information (ie, age, sex, race, and in-

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Figure 1 Patient Selection for the Study Patients enrolled in the NCDR’s PINNACLE Registry from May 1, 2008, to September 30, 2010 N = 315,973

Patients with Medicaid, Private Health, Indian Health Service, Military Health Care, or non-US insurance N = 155,380

Patients in the PINNACLE Registry with Medicare insurance N = 160,593

NCDR indicates National Cardiovascular Data Registry.

surance type), CV medical history, and CV-related medications. Medication information collected in the PINNACLE Registry and used in this study included the current prescribing of beta-blockers, angiotensin-­ converting enzyme (ACE) inhibitors, angiotensin receptor blockers, calcium channel blockers, diuretics, statins, nonstatin lipid-lowering medications, aspirin, aspirin plus dipyridamole, or thienopyridines.

Because the PINNACLE Registry collects data only on the medication classes that are prescribed and not at the individual medication level, and overall costs by medication class are not available, we used a weighted average cost calculation to assign costs to medication classes. The weighted average cost was calculated based on the market share data for individual medications from each medication class extracted from the HealthCore Integrated Research Database (HIRD), as well as the average wholesale price (AWP). HIRD data from 2010 were collected for 14 health plans, representing regions across the United States.

The market share for each individual medication in a class was calculated by summing all of the prescriptions for that medication and dividing by the total number of prescriptions for the medication class as a whole using the HIRD for 2010. Because the most common medications made up at least 91% of all drugs for a given medication category (range, 91%-100%), only these were used to determine the weighted average cost for each

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P atient Characteristics: Medicare Beneficiaries Table 1 in the PINNACLE Registry with ≥3 Chronic CV Conditions Eligible patients, % Patient characteristics (N = 93,089) Age, mean, yrs (± SD)

74.4 (± 9.2)

Male sex

54.4

Race White

86.5

Black

12.8

Other

0.7

Health insurance type Medicare fee for service

95.7

Medicare managed care

5.2

Chronic condition present Hypertension

95.5

Dyslipidemia

91.8

Coronary artery disease

83.1

Heart failure

49.4

Diabetes mellitus

37.1

Atrial fibrillation

23.4

Myocardial infarction

23.3

Peripheral arterial disease

16.6

Previous stroke or transient ischemic attack

9.7

Drug class used Statin

73.9

Aspirin

66.8

Beta-blocker

56.5

Diuretic

43.7

ACE inhibitor

38.6

Thienopyridine

21.2

Calcium channel blocker

17.4

Angiotensin receptor blocker

16.6

Nonstatin lipid-lowering drug

16.6

Warfarin

16.2

Aspirin plus dipyridamole

0.9

ACE indicates angiotensin-converting enzyme; CV, cardiovascular; SD, standard deviation.

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medication class. The relative market share was then calculated based on the most common medications. This relative market share of the most common medications was multiplied by the AWP for the median dose of these medications and then added together to calculate the weighted average cost for each medication class.

Sensitivity analyses for determining eligibility were performed by varying drug costs using AWP for the highest cost and a 10-person multidisciplinary clinician panel–defined most frequently prescribed drug in each class. The drugs that were identified as the most frequently prescribed within each of the drug classes noted earlier were metoprolol tartrate, lisinopril, losartan, amlodipine, hydrochlorothiazide, simvastatin, fenofibrate, aspirin, aspirin plus dipyridamole, and clopidogrel. The descriptive statistics, means, medians, and frequency counts were utilized to report the results.

Results Table 1 lists patient demographics, clinical characteristics, and medication use for the 93,089 (58%) Medicare beneficiaries enrolled in the PINNACLE Registry who had ≥3 CV conditions. The patients in the PINNACLE Registry are at high risk for CV events, as demonstrated by the high frequency of comorbid CV conditions in this patient population. More than 90% of the patients had hypertension and dyslipidemia, and more than 80% had coronary artery disease—the top 3 conditions in this population. Almost 50% of patients had heart failure, and more than 37% had type 2 diabetes.

As shown in Figure 2, the mean number of medications for CV disease prescribed per patient was 3.5 (± 1.5).

Using the weighted average cost calculation methodology, the median annual estimated medication insurer expenditure per patient was $1329 (Table 2). In the sensitivity analysis, these costs ranged from $366 (lowcost generics identified as frequently prescribed by the clinician panel) to $3958 (highest-cost medication in the class).

In addition, 21.4% of the Medicare patients enrolled in the PINNACLE Registry were eligible for MTM based on the 2010 minimum eligibility rule (ie, an annual insurer medication expenditure of ≥$3000). The percentage of Medicare beneficiaries enrolled in the PINNACLE Registry who were eligible for MTM based on the 2010 minimum eligibility rule ranged from 7.9% (low-cost generics identified as frequently prescribed by the clinician panel) to 64% (highest-cost medication in class).

Because of a lower annual expenditure requirement of $3000 for 2010 compared with $4000 for 2009, the percentage of patients eligible for MTM programs increased by more than 3-fold between 2009 and 2010 (from 6.7%

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Discussion Based on the data from the PINNACLE Registry, we conservatively estimate that 1 in 5 patients in cardiology practices who have Medicare insurance are eligible for covered MTM programs, although variability exists based on the cost method used (ie, either low-cost generics or high-cost medication in class). We regard this as a conservative estimate, because information regarding other chronic core diseases (eg, respiratory disease, bone disease–arthritis, and mental health) targeted for MTM programs by Medicare plans, as well as medications (eg, insulin for diabetes, proton pump inhibitors, and selective serotonin reuptake inhibitors) were not collected in the PINNACLE Registry and therefore are not included in our analysis. Because MTM programs have been shown to improve medication adherence and therapy goal attainment,2-7 we believe that promoting the utilization of such programs to eligible patients should be the responsibility of all healthcare providers within the framework of care advocated by the American College of Cardiology within the framework of the patient-centered medical home for CV care. To our knowledge, this is the first article that estimates MTM eligibility using non–claims-based data.

Currently, physicians cannot make determinations about insurance eligibility for reimbursement of such insurer-sponsored programs. However, patients or their designees may call their health insurance plan and request information on eligibility for such programs, and healthcare providers can directly contact plans to inquire about existing programs that their patients may be eligible for.

Examples of such programs include (1) a medication review by pharmacists, such as eliminating duplication,

such as a patient taking 2 ACE inhibitors, by communicating with prescribers; (2) monitoring by pharmacists of therapy goals, such as a pharmacist measuring a patient’s blood pressure (BP) at periodic pharmacy visits and notifying the cardiologist that his or her BP remains above goal; and (3) monitoring by pharmacists for medication adverse effects, such as a pharmacist reviewing medication adherence with a patient and notifying the prescriber that a statin secondary to myalgia has been discontinued and providing assistance with formulating a new plan for managing dyslipidemia. These programs all serve to enhance the quality of care and to assist patients with meeting their health goals.

Recently, the ACCF 2012 Health Policy Statement on Patient-Centered Care in Cardiovascular Medicine highlighted the need for a CV-focused patient-centered medical home (PCMH) that includes a recommendation Figure 2 Frequency Distribution of Number of CV Medications Taken per Medicare Beneficiary in the PINNACLE Registry 25

Patients using these drugs, %

in 2009 to 21.4% in 2010), based on the weighted average cost methodology.

20 15 10 5 0

0 1 2 3 4 5 6 7 8 9 ≥10

CV medications used per patient, N (N = 160,593)

CV indicates cardiovascular.

Table 2 Eligibility for Medication Therapy Management Cost calculation methodology Weighted average cost Frequently prescribed low-cost drugs

b

Highest-cost drugs

Median annual medication cost, $a (interquartile range)

2009 MTM eligibility, N (%)

2010 MTM eligibility, N (%)

1329 (915-2609)

6202 (6.7)

19,903 (21.4)

366 (193-1361)

1084 (1.2)

7326 (7.9)

3958 (2406-5358)

46,477 (49.9)

59,619 (64)

NOTE: MTM eligibility based on likelihood of exceeding drug cost thresholds of $4000 in 2009 and $3000 in 2010. a Costs are in US dollars. b Medications identified as most frequently prescribed by the multidisciplinary clinician panel were the low-cost generics metoprolol tartrate, lisinopril, losartan, amlodipine, hydrochlorothiazide, simvastatin, fenofibrate, aspirin, aspirin plus dipyridamole, and clopidogrel.

MTM indicates medication therapy management.

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for nonphysician healthcare team members, such as pharmacists, to be empowered to manage medication-related problems.12 Pharmacists have been involved collaboratively with physicians to provide MTM programs that improve patients’ CV health. A controlled, cluster randomized study showed that patients with hypertension achieved better BP control through physician–pharmacist collaboration than with usual care.13 Office-based, residency-trained clinical pharmacists worked alongside the patients’ primary care physicians at the intervention clinics, whereas the control clinics had no pharmacists.

All the enrolled patients had uncontrolled hypertension.

At 6 months, hypertension was controlled to goal in 29.9% of patients in the usual care control group and in 63.9% of patients in the intervention group (P <.001).13 In the randomized, controlled SCRIP-HTN trial, a pharmacist-nurse–based team significantly improved the hypertension control in patients with type 2 diabetes and uncontrolled hypertension.14 Intervention with patient lifestyle counseling, 6-week visits to the pharmacy, and faxed communication with the patient’s primary care physician were associated with a 14% absolute increase and a 46% relative increase (P <.001) in the percentage of patients meeting their goal BP of ≤130/80 mm Hg at 24 weeks compared with patients receiving a one-time– only counseling session.14

The potential for pharmacists to reduce hospital readmissions through provisions of MTM services during transitions in care has also been recently highlighted by the American College of Clinical Pharmacy and the American College of Cardiology.

Similar findings exist with respect to the management of dyslipidemia. In the SCRIP-plus study, community pharmacists in Canada assessed patient risk factors for CV disease through patient interviews, measured BP and finger-stick cholesterol levels, identified high-risk patients who were not at their goal low-density lipoprotein cholesterol (LDL-C) level, and worked with family physicians to help patients meet their goal. At 6 months, 31% of patients who were previously not at LDL-C goal achieved that goal.15 Improvement in LDL-C levels, as well as lower medication costs, were demonstrated in a study comparing pharmacist-based lipid clinic management to usual care.16 Additional benefits of pharmacist MTM have been noted by physicians. McGrath and colleagues conducted focus group sessions to explore physicians’ perceptions of

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MTM programs led by pharmacists.17 Most physicians had not experienced pharmacist-provided MTM programs, and many physicians were not aware of pharmacist training, including a 6-year professional degree and residency, and preparation, including board certification in pharmacotherapy or ambulatory care, to provide this service.17 However, physicians believed that the greatest benefit of MTM was the receipt of an up-to-date complete medication list that is generated after a pharmacist completes an MTM encounter with a patient.17 Another benefit that physicians found was that MTM programs would address common medication issues they identified in their practices, such as patient nonadherence, side effects, drug interactions, medication costs, and incomplete patient understanding of the medication regimen.17 The potential for pharmacists to reduce hospital readmissions through provisions of MTM services during transitions in care has also been recently highlighted by the American College of Clinical Pharmacy and the American College of Cardiology.18 Pharmacists are also qualified to provide many services that are central to integrated care models, such as the PCMH and accountable care organizations. Expanding services, such as MTM, in these care delivery models pre­ sents the opportunity for improved clinical, economic, and humanistic outcomes, as well as increasing the pharmacists’ value to the evolving US healthcare system.19

Limitations Although this study involved a large sample size, the patients enrolled in the PINNACLE Registry at the time of the data collection represented 46 office practices and therefore may not necessarily be representative of the entire US cardiology patient population.

Furthermore, because drug class names (eg, ACE inhibitors) and not specific drug names (eg, enalapril, lisinopril) were provided in the registry for some medications, the exact drug costs could not be calculated. Therefore, drug costs were estimated by using a 10-person multidisciplinary clinician panel to identify the most frequently prescribed agents within each class.

Finally, because the PINNACLE Registry does not collect data on non-CV conditions and non-CV medications, the number of chronic diseases per patient and the medication costs were underestimated in this study.

Conclusion This analysis serves to raise providers’ awareness of their patients’ potential eligibility to receive the benefits of MTM programs. Medicare Part D health plans often notify beneficiaries of potential eligibility for specific disease management programs, such as for hypertension, with subscriber mailings, but they do not inform cardiol-

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ogists of their individual patient’s eligibility. Payers indicate that the most common barrier to implementing MTM programs is the lack of interest and willingness of patients to participate in such programs. By taking a few minutes to ask patients with multiple CV conditions who are seeing a cardiologist whether they have been contacted by their insurer to participate in an MTM program and by encouraging patients to participate, providers are in a position to explain and to encourage patients to take advantage of such programs. n Acknowledgments PINNACLE Registry is an initiative of the American College of Cardiology Foundation, MedAxiom, and Spirit of Women. The Bristol-Myers Squibb/Sanofi Pharma­ ceuticals Partnership is a Founding Sponsor of the PINNACLE Registry.

Funding Source This research was supported by the American College of Cardiology Foundation’s National Cardiovascular Data Registry (NCDR). The views expressed in this manuscript represent those of the authors and do not necessarily represent the official views of the NCDR or its associated professional societies as identified at www.ncdr.com.

Author Disclosure Statement Dr Spinler, Dr Cziraky, Dr Dueñas, Dr Thomas, Dr Reinhold, Dr Willey, and Ms Tang have reported no conflicts of interest.

References

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2. American Pharmacists Association, National Association of Chain Drug Stores Foundation. Medication therapy management in pharmacy practice: core elements of an MTM service model. Version 2.0. March 2008. www.pharmacist.com/mtm/

coreelements2. Accessed April 19, 2013.

3. Chapman RH, Kowal SL, Cherry SB, et al. The modeled lifetime cost-effectiveness of published adherence-improving interventions for antihypertensive and lipid-lowering medications. Value Health. 2010;13:685-694.

4. Carter BL, Foppe van Mil JW. Comparative effectiveness research: evaluating pharmacist interventions and strategies to improve medication adherence. Am J Hypertens. 2010;23:949-955.

5. Nkansah N, Mostovetsky O, Yu C, et al. Effect of outpatient pharmacists’ non-dispensing roles on patient outcomes and prescribing patterns. Cochrane Database Syst Rev. 2010;(7):CD000336.

6. Machado M, Bajcar J, Guzzo GC, Einarson TR. Sensitivity of patient outcomes to pharmacist interventions: part II: systematic review and meta-analysis in hypertension management. Ann Pharmacother. 2007;41:1770-1781.

7. Gonzalez J, Noga M. Medication therapy management. J Manag Care Pharm.

2008;14(suppl S-c):S8-S11.

8. Centers for Medicare & Medicaid Services. Issuance of the 2010 Call Letter.

March 30, 2009. www.cms.gov/PrescriptionDrugCovContra/Downloads/2010Call Letter.pdf. Accessed April 19, 2013.

9. Schommer JC, Doucette WR, Johnson KA, Planas LG. Positioning and integrating medication therapy management. J Am Pharm Assoc (2003). 2012;52:12-24.

10. Chan PS, Oetgen WJ, Buchanan D, et al. Cardiac performance measure compliance in outpatients: the American College of Cardiology and National Cardiovascular Data Registry’s PINNACLE (Practice Innovation And Clinical Excellence) program. J Am Coll Cardiol. 2010;56:8-14.

11. Chan PS, Oetgen WJ, Spertus JA. The Improving Continuous Cardiac Care (IC3) program and outpatient quality improvement. Am J Med. 2010;123:217-219.

Erratum in: Am J Med. 2010;123:e13.

12. Walsh MN, Bove AA, Cross RR, et al, for the American College of Cardiology Foundation. ACCF 2012 health policy statement on patient-centered care in cardiovascular medicine: a report of the American College of Cardiology Foundation Clinical Quality Committee. J Am Coll Cardiol. 2012;59:2125-2143.

13. Carter BL, Ardery G, Dawson JD, et al. Physician and pharmacist collaboration to improve blood pressure control. Arch Intern Med. 2009;169:1996-2002.

14. McLean DL, McAlister FA, Johnson JA, et al, for the SCRIP-HTN Investigators.

A randomized trial of the effect of community pharmacist and nurse care on improving blood pressure management in patients with diabetes mellitus: study of cardiovascular risk intervention by pharmacists-hypertension (SCRIP-HTN). Arch Intern Med. 2008;168:2355-2361.

15. Tsuyuki RT, Olson KL, Dubyk AM, et al. Effect of community pharmacist intervention on cholesterol levels in patients at high risk of cardiovascular events: the Second Study of Cardiovascular Risk Intervention by Pharmacists (SCRIP-plus). Am J Med. 2004;116:130-133.

16. DiTusa L, Luzier AB, Brady PG, et al. A pharmacy-based approach to cholesterol management. Am J Manag Care. 2001;7:973-979.

17. McGrath SH, Snyder ME, Dueñas GG, et al. Physician perceptions of pharmacist-provided medication therapy management: qualitative analysis. J Am Pharm Assoc (2003). 2010;50:67-71.

18. Wiggins BS, Rodgers JE, DiDomenico RJ, et al. Discharge counseling for patients with heart failure or myocardial infarction: a best practices model developed by members of the American College of Clinical Pharmacy’s Cardiology Practice and Research Network based on the Hospital to Home (H2H) Initiative. Pharmacotherapy.

2013;33:558-580.

19. Smith M, Bates DW, Bodenheimer T, Cleary PD. Why pharmacists belong in the medical home. Health Aff (Millwood). 2010;29:906-913.

Stakeholder Perspective Hanging Together for Patient-Centered Medical Care

By Albert Tzeel, MD, MHSA, FACPE Regional Medical Director, Medicare Operations, North Florida, Humana, Jacksonville, FL

The term “patient-centered care,” first espoused by the Institute of Medicine in its Crossing the Quality Chasm report,1 serves as 1 of the 6 key tenets of high-quality medical care. Patient-centered care implies just what it states: it is up to the patient to be an engaged and fully involved participant in his or her own healthcare. Successful treatment of a given condition lies, like

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beauty, in the eye of the beholder, and if the patient does not play an active role in improving or, at least, maintaining his or her own personal health, a good outcome is less likely to be achieved.

PROVIDERS/PATIENTS: A focus on “good outcomes” also dominates the current shift in accountabilities for a given patient’s care: such outcomes have served

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REGULATORY

Stakeholder Perspective Continued as the impetus for various quality-based contracts between payers and providers. Although many of these contracts fall under the rubric of phrases such as “care coordination” or “shared risk,” others fall under the heading of “outcomes-based contracts” or “accountable care organizations” (ACOs). However, they all share the common trait that behavior change that results in aligned incentives between individual patients and their providers should promote “good outcomes.”2 To align the individual patient’s incentives for good health, a physician should, as Epstein and Street note, “invite the patient to participate” in his or her own care.3 But where should this “invitation” come from?

Most of the focus on providing patient-centered care has fallen on the primary care physician (PCP). Whether providing a patient-centered medical home for a panel of patients with chronic diseases or serving as the gatekeeper in various HMO-based products, the PCP has long been charged with the clinical and financial accountabilities for those under his or her care. Yet, in the new models of quality-based contracts noted above, such as the ACO, the PCP cannot be expected to manage the complete care of his or her patients alone. And that is where the article by Spinler and colleagues in this issue of American Health & Drug Benefits fits in.4 Spinler and colleagues’ study provides 3 key and exciting findings that enhance patient-centered care and accountability for care outcomes. First, their study shows that a non–claims-based system can be used to identify the appropriate members for outreach. It is when these members become engaged in their own healthcare that one can say that true patient-centered care is being provided and that better outcomes become possible. That a registry is being used rather than complete reliance on claims can also provide benefits in a time when the upcoming transition to the International Classification of Diseases, Tenth Revision could play havoc with multiple claims systems.

Second, their data show that we have significant room for improvement in addressing members who are eligible

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for medication therapy management (MTM); using a non–claims-based system could provide a complement to the routinely used claims-based systems and, hopefully, result in improved outreach and care.

Finally, and perhaps most important, Spinler and colleagues’ study shows that when it comes to improving the outcomes of care for members with cardiovascular (CV) disease, all providers have a responsibility to share in the accountability for improved outcomes through patient-centered care. As they so eloquently state, “we believe that promoting the utilization of such programs [ie, MTM] to eligible patients should be the responsibility of all healthcare providers within the framework of care advocated by the ACC within the framework of the patient-centered medical home for CV care.”

Although ACOs require the presence of PCPs, they can certainly include specialists, and many do. But, even if they do not, the PCPs who are accountable for the care of patients in their charge will need to make sure that the specialists they work with take an active role in making sure that their shared patients are “invited” to become engaged in their own healthcare, whether through MTM or some other entity; this is truly a shared responsibility and not one that merely falls on the PCPs. Why? Because for patient-centered care and accountable care to be successful, physicians will need to be accountable to each other, as well as to their patients: they will all need to hang together. Because, as Benjamin Franklin reminded his colleagues at the signing of the Declaration of Independence, “we must all hang together or, assuredly, we will all hang separately.”

1. Committee on Quality of Health Care in America, Institute of Medicine. Crossing the Quality Chasm: A New Health System for the 21st Century. Washington, DC: National Academies Press; 2001.

2. Center for Health Value Innovation. Outcomes-based contracting: the value-based framework for optimal accountability. 2010. www.sph.umich.edu/vbidcenter/registry/ pdfs/NayerWhitePaper2010.pdf. Accessed September 2, 2013.

3. Epstein RM, Street RL Jr. The values and value of patient-centered care. Ann Fam Med. 2011;9:100-103.

4. Spinler SA, Cziraky MJ, Tang F, et al. Assessing Medicare beneficiary eligibility for medication therapy management programs using PINNACLE, a National Cardiovascular Data Registry. Am Health Drug Benefits. 2013;6(7):367-375.

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4TH ANNUAL CONFERENCE

MAY 6-9, 2014 LOEWS HOLLYWOOD HOTEL â&#x20AC;˘ LOS ANGELES, CA Government and Employers Co-Chairs Jayson Slotnik, JD, MPH

F. Randy Vogenberg, PhD, RPh

Partner Health Policy Strategies, LLC

Principal Institute for Integrated Healthcare

Personalized Medicine and Payers Co-Chairs Michael Kolodziej, MD

National Medical Director, Oncology Solutions Aetna

Grant Lawless, RPh, MD, FACP Program Director Associate Professor University of Southern California

Oncology Practice Management, Navigation, and Advocacy Co-Chairs Linda Bosserman, MD, FACP

President Wilshire Oncology Medical Group

Vicki Kennedy, LCSW

Vice President, Program Development and Delivery Cancer Support Community

AVBCC Leadership Burt Zweigenhaft, BS President and CEO OncoMed

Gary M. Owens, MD

President Gary Owens Associates

Craig K. Deligdish, MD Hematologist/ Oncologist Oncology Resource Networks

www.AVBCConline.org AVBCC2014chairs Asize_91313

NEW FOR 2014! Principles in Value and Market Access Educational Session for Product Managers, Reimbursement Specialists, Account Managers, and Marketers focusing on access, reimbursement, proving product value, and international markets.

INDICATION: Iclusig™ (ponatinib) is a kinase inhibitor indicated for the treatment of adult patients with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia (CML) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy or Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy.

This indication is based upon response rate. There are no trials verifying an improvement in disease-related symptoms or increased survival with Iclusig.

Iclusig (ponatinib) Unlocks efficacy for your resistant or intolerant CML or Ph+ ALL plan members ™

IMPORTANT SAFETY INFORMATION WARNING: ARTERIAL THROMBOSIS and HEPATOTOXICITY See full prescribing information for complete boxed warning • Arterial Thrombosis: Cardiovascular, cerebrovascular, and peripheral vascular thrombosis, including fatal myocardial infarction and stroke have occurred in Iclusig-treated patients. In clinical trials, serious arterial thrombosis occurred in 8% of Iclusig-treated patients. Interrupt and consider discontinuation of Iclusig in patients who develop arterial thrombotic events.

• Hepatotoxicity: Hepatotoxicity, liver failure and death have occurred in Iclusigtreated patients. Monitor hepatic function prior to and during treatment. Interrupt and then reduce or discontinue Iclusig for hepatotoxicity.

Arterial Thrombosis: Cardiovascular, cerebrovascular, and peripheral vascular thrombosis, including fatal myocardial infarction and stroke, has occurred in Iclusig treated patients. Overall, 11% of patients experienced an arterial thrombosis event of any grade, and serious arterial thrombosis occurred in 8% of Iclusig-treated patients. 30 of 34 patients who experienced a serious arterial thrombosis event had one or more cardiovascular risk factors. Patients with cardiovascular risk factors are at increased risk for arterial thrombosis with Iclusig. Interrupt and consider discontinuation of Iclusig in patients who develop arterial thrombotic events.

Hepatotoxicity: Hepatotoxicity that has resulted in liver failure and death occurred in 3 Iclusig-treated patients with BP-CML or Ph+ ALL. Fulminant hepatic failure leading to death occurred in an Iclusig-treated patient within one week of starting Iclusig. Two additional fatal cases of acute liver failure also occurred. Iclusig treatment may result in elevation in ALT, AST,

or both. Monitor liver function tests at baseline, at least monthly or as clinically indicated. Interrupt, reduce or discontinue Iclusig as clinically indicated.

Congestive Heart Failure: Twenty patients treated with Iclusig (4%) experienced serious congestive heart failure (CHF) or left ventricular dysfunction (LVD), with 4 fatalities. Thirty-three patients treated with Iclusig (7%) experienced any grade of CHF or LVD. Monitor patients for signs or symptoms consistent with CHF and treat as clinically indicated, including interruption of Iclusig. Consider discontinuation of Iclusig in patients who develop serious CHF. Hypertension: Eight patients treated with Iclusig (2%) experienced treatment-emergent symptomatic hypertension as a serious adverse reaction, including one patient (<1%) with hypertensive crisis. Treatment-emergent hypertension (defined as systolic BP≥140 mm Hg or diastolic BP≥90 mm Hg on at least one occasion) occurred in 67% of patients (300/449). In 131 patients with Stage 1 hypertension at baseline, 61% (80/131) developed Stage 2 hypertension. Monitor and manage blood pressure elevations.

Pancreatitis: Clinical pancreatitis occurred in 6% (28/449) of patients (5% Grade 3) treated with Iclusig. Pancreatitis resulted in discontinuation or treatment interruption in 6% of patients (25/449).

The incidence of treatment-emergent lipase elevation was 41%. Check serum lipase every 2 weeks for the first 2 months and then monthly thereafter or as clinically indicated. Consider additional serum lipase monitoring in patients with a history of pancreatitis or alcohol abuse.

Dose interruption or reduction may be required. In cases where lipase elevations are accompanied by abdominal symptoms, interrupt treatment with Iclusig and evaluate patients for pancreatitis. Do not consider restarting Iclusig until patients have complete resolution of symptoms and lipase levels are less than 1.5 x ULN. Hemorrhage: Serious bleeding events occurred in 5% (22/449) of patients treated with Iclusig, including fatalities. Hemorrhagic events occurred in

C H R O N I C P H A S E C M L (C P - C M L ) More than half of CP-CML patients resistant or intolerant to prior tyrosine kinase inhibitor (TKI) therapy achieved major cytogenic response (MCyR).

54 % 44 %

MCyR

CCyR

Ponatinib is the only TKI recommended by the National Comprehensive Cancer Network® (NCCN®) for patients with any BCR-ABL mutation1

(144/267) 95% CI: 48-60

(118/267) 95% CI: 38-50

Most patients who achieved MCyR also achieved complete cytogenetic response (CCyR) • At baseline, 6% (16/267) of patients had received 1 prior TKI, 37% (98/267) had received 2 TKIs, and 57% (153/267) had received ≥3 TKIs2 • Median duration of follow-up was 10 months2

24% of patients. The incidence of serious bleeding events was higher in patients with AP-CML, BP-CML, and Ph+ ALL. Most hemorrhagic events occurred in patients with grade 4 thrombocytopenia. Interrupt Iclusig for serious or severe hemorrhage.

Fluid Retention: Serious fluid retention events occurred in 3% (13/449) of patients treated with Iclusig. One instance of brain edema was fatal. In total, fluid retention occurred in 23% of the patients. The most common fluid retention events were peripheral edema (16%), pleural effusion (7%), and pericardial effusion (3%). Monitor patients for fluid retention and manage patients as clinically indicated. Interrupt, reduce, or discontinue Iclusig as clinically indicated.

Cardiac Arrhythmias: Symptomatic bradyarrhythmias that led to a requirement for pacemaker implantation occurred in 3 (1%) Iclusig-treated patients. Advise patients to report signs and symptoms suggestive of slow heart rate (fainting, dizziness, or chest pain). Supraventricular tachyarrhythmias occurred in 25 (5%) Iclusig-treated patients. Atrial fibrillation was the most common supraventricular tachyarrhythmia and occurred in 20 patients. For 13 patients, the event led to hospitalization.

Advise patients to report signs and symptoms of rapid heart rate (palpitations, dizziness).

Myelosuppression: Severe (grade 3 or 4) myelosuppression occurred in 48% (215/449) of patients treated with Iclusig. The incidence of these events was greater in patients with AP-CML, BP-CML and Ph+ ALL than in patients with CP-CML. Obtain complete blood counts every 2 weeks for the first 3 months and then monthly or as clinically indicated, and adjust the dose as recommended.

Tumor Lysis Syndrome: Two patients (<1%) with advanced disease (AP-CML, BP-CML, or Ph+ ALL) treated with Iclusig developed serious tumor lysis syndrome. Hyperuricemia occurred in 7% (30/449) of patients overall; the majority had CP-CML (19 patients). Due to the potential for tumor lysis syndrome in patients with advanced disease, ensure adequate hydration and treat high uric acid levels prior to initiating therapy with Iclusig.

Mutation

ponatinib

nilotinib

dasatinib

bosutinib

imatinib

T315I

+

—

—

—

—

V299L

+

+

—

—

—

T315A

+

+

—

+

+*

F317L/V/I/C

+

+

—

+

—

Y253H

+

—

+

+

—

E255K/V

+

—

+

+

—

F359V/C/I

+

—

+

+

—

Any other mutation

+

+

+

+

+†

*If mutation is detected following dasatinib. †High-dose imatinib.

Iclusig is a once-daily oral tablet that can be taken with or without food.

Tablet is not shown at actual size.

Compromised Wound Healing and Gastrointestinal Perforation: Since Iclusig may compromise wound healing, interrupt Iclusig for at least 1 week prior to major surgery. Serious gastrointestinal perforation (fistula) occurred in one patient 38 days post-cholecystectomy.

Embryo-Fetal Toxicity: Iclusig can cause fetal harm. If Iclusig is used during pregnancy, or if the patient becomes pregnant while taking Iclusig, the patient should be apprised of the potential hazard to the fetus. Advise women to avoid pregnancy while taking Iclusig.

The most common non-hematologic adverse reactions (≥20%) were hypertension, rash, abdominal pain, fatigue, headache, dry skin, constipation, arthralgia, nausea, and pyrexia. Hematologic adverse reactions included thrombocytopenia, anemia, neutropenia, lymphopenia, and leukopenia.

Please see the full Prescribing Information for Iclusig (ponatinib), including the Boxed Warning.

References: 1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Chronic Myelogenous Leukemia V.4.2013. © National Comprehensive Cancer Network, Inc 2013. All rights reserved. Accessed June 7, 2013.

To view the most recent and complete version of the guideline, go online to www.nccn.org.

NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 2. Data on file.

Note: Unless otherwise indicated, data presented are from Iclusig [package insert].

Cambridge, MA: ARIAD Pharmaceuticals, Inc.; 2012.

For more information, please visit iclusig.com.

Iclusig is a trademark of ARIAD Pharmaceuticals, Inc. ©2013 ARIAD Pharmaceuticals, Inc. All rights reserved.

PB/0713/0065/US

BRIEF SUMMARY Iclusig (ponatinib) Rx only Please consult full Prescribing Information, including Boxed Warning, available at Iclusig.com.

WARNING: ARTERIAL THROMBOSIS and HEPATOTOXICITY Arterial Thrombosis: • Cardiovascular, cerebrovascular, and peripheral vascular thrombosis, including fatal myocardial infarction and stroke have occurred in Iclusig-treated patients. In clinical trials, serious arterial thrombosis occurred in 8% of Iclusig-treated patients. Interrupt and consider discontinuation of Iclusig in patients who develop arterial thrombotic events [see Dosage and Administration (2.3) and Warnings and Precautions (5.1)].

Hepatotoxicity: • Hepatotoxicity, liver failure and death have occurred in Iclusigtreated patients. Monitor hepatic function prior to and during treatment. Interrupt and then reduce or discontinue Iclusig for hepatotoxicity [see Dosage and Administration (2.3) and Warnings and Precautions (5.2)].

INDICATIONS AND USAGE Iclusig™ (ponatinib) is indicated for the treatment of adult patients with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia (CML) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy or Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy.

This indication is based upon response rate [see Clinical Studies (14)].

There are no trials verifying an improvement in disease-related symptoms or increased survival with Iclusig.

4 CONTRAINDICATIONS None 5 WARNINGS AND PRECAUTIONS 5.1 Thrombosis and Thromboembolism Arterial Thrombosis Cardiovascular, cerebrovascular, and peripheral vascular thrombosis, including fatal myocardial infarction and stroke have occurred in Iclusig-treated patients.

Serious arterial thrombosis occurred in 8% (34/449) of Iclusigtreated patients. Twenty-one patients required a revascularization procedure (16 patients with coronary revascularization, 4 patients with peripheral arterial revascularization, and 1 patient with cerebrovascular revascularization). Overall, fifty-one patients (11%) experienced an arterial thrombosis event of any grade.

Myocardial infarction or worsening coronary artery disease was the most common arterial thrombosis event and occurred in 21 patients (5%) of Iclusig-treated patients. Eleven of these patients developed congestive heart failure concurrent or subsequent to the myocardial ischemic event.

Serious cerebrovascular events were reported in 2% (8/449) of Iclusig-treated patients. Two patients experienced hemorrhagic conversion of the initial ischemic event. Four patients developed stenosis of large arterial vessels of the brain (e.g., carotid, vertebral, middle cerebral artery).

Serious peripheral arterial events were reported in 2% (7/449) of Iclusig-treated patients. Three patients developed digital or distal extremity necrosis; 2 of these patients had diabetes mellitus and peripheral arterial disease and required amputations.

5.2

1

5.3

5.4

5.5

Thirty of 34 Iclusig-treated patients who experienced a serious arterial thrombosis event had one or more cardiovascular risk factors (e.g., myocardial infarction, coronary artery disease, angina, stroke, transient ischemic attack, hypertension, diabetes mellitus, hyperlipidemia, and smoking). Patients with cardiovascular risk factors are at increased risk for arterial thrombosis with Iclusig. Interrupt and consider discontinuation of Iclusig in patients who develop arterial thrombotic events [see Dosage and Administration (2.3)].

Venous Thromboembolism Venous thromboembolic events occurred in 3% of Iclusig-treated patients, including deep venous thrombosis (9 patients), pulmonary embolism (4 patients), and 1 case each of portal vein thrombosis, and retinal vein thrombosis. Consider dose modification or discontinuation of Iclusig in patients who develop serious venous thromboembolism [see Dosage and Administration (2.3)].

Hepatotoxicity Hepatotoxicity that has resulted in liver failure and death occurred in Iclusig-treated patients. Fulminant hepatic failure leading to death occurred in an Iclusig-treated patient within one week of starting Iclusig. Two additional fatal cases of acute liver failure also occurred.

The fatal cases occurred in patients with BP-CML or Ph+ ALL. Severe hepatotoxicity occurred in all disease cohorts.

The incidence of aspartate aminotransferase (AST) or alanine aminotransferase (ALT) elevation was 56% (all grades) and 8% (grade 3 or 4). Iclusig treatment may result in elevation in ALT, AST, or both. ALT or AST elevation was not reversed by the date of last follow-up in 5% of patients.

Monitor liver function tests at baseline, at least monthly or as clinically indicated. Interrupt, reduce or discontinue Iclusig as clinically indicated [see Dosage and Administration (2.3)].

Congestive Heart Failure Twenty patients treated with Iclusig (4%) experienced serious congestive heart failure or left ventricular dysfunction, with 4 fatalities.

Thirty-three patients treated with Iclusig (7%) experienced any grade of congestive heart failure or left ventricular dysfunction. Monitor patients for signs or symptoms consistent with congestive heart failure and treat as clinically indicated, including interruption of Iclusig.

Consider discontinuation of Iclusig in patients who develop serious congestive heart failure [see Dosage and Administration (2.3)].

Hypertension Eight patients treated with Iclusig (2%) experienced treatmentemergent symptomatic hypertension as a serious adverse reaction, including hypertensive crisis. These patients required urgent clinical intervention for hypertension associated with confusion, headache, chest pain, or shortness of breath.

Treatment-emergent hypertension occurred in 67% of patients (300/449) [see Adverse Reactions (6)]. In patients with baseline systolic BP<140 mm Hg and baseline diastolic BP<90mm Hg, 78% (220/282) experienced treatment-emergent hypertension; 49% (139/282) developed Stage 1 hypertension (defined as systolic BP≥140 mm Hg or diastolic BP≥90 mm Hg) while 29% developed Stage 2 hypertension (defined as systolic BP≥160 mm Hg or diastolic BP≥100 mm Hg). In 131 patients with Stage 1 hypertension at baseline, 61% (80/131) developed Stage 2 hypertension. Monitor and manage blood pressure elevations.

Pancreatitis Clinical pancreatitis occurred in 6% (28/449) of patients (5% grade 3) treated with Iclusig. Pancreatitis resulted in discontinuation or treatment interruption in 6% of patients (25/449). Twenty-two of the 28 cases of pancreatitis resolved within 2 weeks with dose interruption or reduction. The incidence of treatment-emergent lipase elevation was 41%.

5.6

5.7

5.8

5.9

5.10

Check serum lipase every 2 weeks for the first 2 months and then monthly thereafter or as clinically indicated. Consider additional serum lipase monitoring in patients with a history of pancreatitis or alcohol abuse. Dose interruption or reduction may be required.

In cases where lipase elevations are accompanied by abdominal symptoms, interrupt treatment with Iclusig and evaluate patients for pancreatitis [see Dosage and Administration (2.3)]. Do not consider restarting Iclusig until patients have complete resolution of symptoms and lipase levels are less than 1.5 x ULN. Hemorrhage Serious bleeding events, occurred in 5% (22/449) of patients treated with Iclusig, including fatalities. Hemorrhagic events occurred in 24% of patients. The incidence of serious bleeding events was higher in patients with AP-CML, BP-CML, and Ph+ ALL. Cerebral hemorrhage and gastrointestinal hemorrhage were the most commonly reported serious bleeding events. Most hemorrhagic events occurred in patients with grade 4 thrombocytopenia [see Warnings and Precautions (5.9)].

Interrupt Iclusig for serious or severe hemorrhage [see Dosage and Administration (2.3)].

Fluid Retention Fluid retention events judged as serious occurred in 3% (13/449) of patients treated with Iclusig. One instance of brain edema was fatal. Serious fluid retention events in more than 1 patient included: pericardial effusion (6/449, 1%), pleural effusion (5/449, 1%), and ascites (2/449, <1%).

In total, fluid retention occurred in 23% of the patients. The most common fluid retention events were peripheral edema (16%), pleural effusion (7%), and pericardial effusion (3%).

Monitor patients for fluid retention and manage patients as clinically indicated. Interrupt, reduce, or discontinue Iclusig as clinically indicated [see Dosage and Administration (2.3)].

Cardiac Arrhythmias Symptomatic bradyarrhythmias that led to a requirement for pacemaker implantation occurred in 3 (1%) Iclusig-treated patients.

The cardiac rhythms (1 case each) identified were complete heart block, sick sinus syndrome, and atrial fibrillation with bradycardia and pauses. Advise patients to report signs and symptoms suggestive of slow heart rate (fainting, dizziness, or chest pain).

Supraventricular tachyarrhythmias occurred in 25 (5%) Iclusig-treated patients. Atrial fibrillation was the most common supraventricular tachyarrhythmia and occurred in 20 patients. The other supraventricular tachyarrhythmias were atrial flutter (4 patients), supraventricular tachycardia (4 patients), and atrial tachycardia (1 patient). For 13 patients, the event led to hospitalization. Advise patients to report signs and symptoms of rapid heart rate (palpitations, dizziness).

Myelosuppression Severe (grade 3 or 4) myelosuppression occurred in 48% (215/449) of patients treated with Iclusig. The incidence of these events was greater in patients with accelerated phase CML (AP-CML), blast phase CML (BP-CML) and Ph+ ALL than in patients with chronic phase CML (CP-CML). Obtain complete blood counts every 2 weeks for the first 3 months and then monthly or as clinically indicated, and adjust the dose as recommended [see Dosage and Administration (2.2)].

Tumor Lysis Syndrome Two patients (<1%) treated with Iclusig developed serious tumor lysis syndrome. Both cases occurred in patients with advanced CML. Hyperuricemia occurred in 7% (30/449) of patients, the majority had chronic phase CML (19 patients). Due to the potential for tumor lysis syndrome in patients with advanced disease (AP-CML, BP-CML, or Ph+ ALL), ensure adequate hydration and treat high uric acid levels prior to initiating therapy with Iclusig.

5.11 Compromised Wound Healing and Gastrointestinal Perforation No formal studies of the effect of Iclusig on wound healing have been conducted. Based on the mechanism of action [see Clinical Pharmacology (12.1)], Iclusig could compromise wound healing.

Serious gastrointestinal perforation (fistula) occurred in one patient 38 days post-cholecystectomy.

Interrupt Iclusig for at least 1 week prior to major surgery. The decision when to resume Iclusig after surgery should be based on clinical judgment of adequate wound healing.

5.12 Embryo-Fetal Toxicity Iclusig can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. Ponatinib caused embryo-fetal toxicity in rats at exposures lower than human exposures at the recommended human dose. 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 the fetus. Advise women to avoid pregnancy while taking Iclusig [see Use in Specific Populations (8.1)].

6 ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The following adverse reactions are discussed in greater detail in other sections of the prescribing information: • Thrombosis and Thromboembolism [see Warnings and Precautions (5.1)] • Hepatotoxicity [see Warnings and Precautions (5.2) and Dosage and Administration (2.3)] • Congestive Heart Failure [see Warnings and Precautions (5.3)] • Hypertension [see Warnings and Precautions (5.4)] • Pancreatitis [see Dosage and Administration (2.3) and Warnings and Precautions (5.5)] • Hemorrhage [see Warnings and Precautions (5.6)] • Fluid Retention [see Warnings and Precautions (5.7)] • Cardiac Arrhythmias [see Warnings and Precautions (5.8)] • Myelosuppression [see Dosage and Administration (2.2) and Warnings and Precautions (5.9)] The adverse reactions described in this section were identified in a single-arm, open-label, international, multicenter trial in 449 patients with CML or Ph+ ALL whose disease was considered to be resistant or intolerant to prior tyrosine kinase inhibitor (TKI) therapy including those with the BCR-ABL T315I mutation. All patients received a starting dose of 45 mg Iclusig once daily. At the time of analysis, the median duration of treatment with Iclusig was 337 days in patients with CP-CML, 362 days in patients with AP-CML, 89 days in patients with BP-CML, and 81 days in patients with Ph+ ALL. The median dose intensity was 37 mg, or 83%, of the expected 45 mg dose.

Adverse reactions reported in more than 10% of all patients treated with Iclusig in this trial are presented in Table 4. Overall, the most common non-hematologic adverse reactions (≥ 20%) were hypertension, rash, abdominal pain, fatigue, headache, dry skin, constipation, arthralgia, nausea, and pyrexia.

The rates of treatment-emergent adverse events resulting in discontinuation were 13% in CP-CML, 11% in AP-CML, 15% in BP-CML, and 9% in Ph+ ALL. The most common adverse events that led to treatment discontinuation were thrombocytopenia (4%) and infections (1%).

Dose modifications (dose delays or dose reduction) due to adverse reactions occurred in 74% of the patients. The most common adverse reactions (â&#x2030;Ľ5%) that led to dose modifications include thrombocytopenia (30%), neutropenia (13%), lipase increased (12%), rash (11%), abdominal pain (11%), pancreatitis (6%), and ALT, AST, or GGT increased (6%).

Table 4: Adverse Reactions Occurring in >10% of Patients, Any Group CP-CML AP-CML BP-CML Ph+ ALL (N=270) (N=85) (N=62) (N=32) System Organ Class Any CTCAE Any CTCAE Any CTCAE Any CTCAE Grade Grade Grade Grade Grade Grade Grade Grade (%) 3/4 (%) 3/4 (%) 3/4 (%) 3/4 (%) (%) (%) (%) Cardiac or Vascular disorders Hypertension (a) 68 39 71 36 65 26 53 31 Arterial ischemia (b) 13 7 12 6 8 5 3 0 Cardiac Failure (c) 6 4 6 2 15 11 6 6 Gastrointestinal disorders Abdominal pain (d) 49 10 40 8 34 6 44 6 Constipation 37 2 24 2 26 0 47 3 Nausea 23 1 27 0 32 2 22 0 Diarrhea 16 1 26 0 18 3 13 3 Vomiting 13 2 24 0 23 2 22 0 Oral mucositis (e) 10 1 15 1 23 0 9 3 GI hemorrhage (f) 2 <1 8 1 11 5 9 6 Blood and lymphatic system disorders Febrile neutropenia 1 <1 4 4 11 11 25 25 Infections and infestations Sepsis 1 1 5 5 8 8 22 22 Pneumonia 3 2 11 9 13 11 9 3 Urinary tract infection 7 1 12 1 0 0 9 0 Upper respiratory tract infection 11 1 8 0 11 2 0 0 Nasopharyngitis 9 0 12 0 3 0 3 0 Cellulitis 2 1 4 2 11 3 0 0 Nervous system disorders Headache 39 3 28 0 31 3 25 0 Peripheral neuropathy (g) 13 2 8 0 8 0 6 0 Dizziness 11 0 5 0 5 0 3 0 Respiratory, thoracic, and mediastinal disorders Pleural effusion 3 1 11 2 13 0 19 3 Cough 12 0 17 0 18 0 6 0 Dyspnea 11 2 15 2 21 7 6 0 Skin and subcutaneous tissue disorders Rash and related conditions 54 5 48 8 39 5 34 6 Dry skin 39 2 27 1 24 2 25 0 Musculoskeletal and connective tissue disorders Arthralgia 26 2 31 1 19 0 13 0 Myalgia 22 1 20 0 16 0 6 0 Pain in extremity 17 2 17 0 13 0 9 0 Back pain 15 1 11 2 16 2 13 0 Muscle spasms 12 0 5 0 5 0 13 0 Bone pain 12 <1 12 1 11 3 9 3 General disorders and administration site conditions Fatigue or asthenia 39 3 36 6 35 5 31 3 Pyrexia 23 1 31 5 32 3 25 0 Edema, peripheral 13 <1 19 0 13 0 22 0 Pain 8 <1 7 0 16 3 6 3 Chills 7 0 11 0 13 2 9 0 Metabolism and nutrition disorders Decreased appetite 8 <1 12 1 8 0 31 0 Investigations Weight decreased 6 <1 7 0 5 0 13 0 Psychiatric disorders 0 Insomnia 7 0 12 0 8 0 9 Adverse drug reactions, reported using MedDRA and graded using NCI-CTC-AE v 4.0 (NCI Common Terminology Criteria for Adverse Events) for assessment of toxicity.

Treatment-emergent, all causality events (a) derived from blood pressure (BP) measurement recorded monthly while on trial (b) includes cardiac, central nervous system, and peripheral arterial ischemia (c) includes cardiac failure, cardiac failure congestive, cardiogenic shock, cardiopulmonary failure, ejection fraction decreased, pulmonary edema, right ventricular failure (d) includes abdominal pain, abdominal pain upper, abdominal pain lower, abdominal discomfort (e) includes aphthous stomatitis, lip blister, mouth ulceration, oral mucosal eruption, oral pain, oropharyngeal pain, pharyngeal ulceration, stomatitis, tongue ulceration (f) includes gastric hemorrhage, gastric ulcer hemorrhage, hemorrhagic gastritis, gastrointestinal hemorrhage, hematemesis, hematochezia, hemorrhoidal hemorrhage, intra-abdominal hemorrhage, melena, rectal hemorrhage, and upper gastrointestinal hemorrhage (g) includes burning sensation, hyperesthesia, hypoesthesia, neuralgia, neuropathy peripheral, paresthesia, peripheral sensorimotor neuropathy, polyneuropathy

Table 5: Serious Adverse Reactions (SAR) N (%)

Cardiovascular disorders Arterial ischemic event Myocardial infarction or worsening coronary artery disease Stroke or TIA Peripheral arterial disease Hemorrhage CNS hemorrhage Gastrointestinal hemorrhage Cardiac failure Effusions* Atrial fibrillation Venous thromboembolism Hypertension Gastrointestinal disorders Pancreatitis Abdominal pain Blood and lymphatic system disorders Febrile neutropenia Thrombocytopenia Anemia Infections Pneumonia Sepsis General Pyrexia

34 (8%) 21 (5%) 8 (2%) 7 (2%) 22 (4%) 10 (2%) 10 (2%) 20 (4%) 13 (3%) 11 (2%) 10 (2%) 8 (2%) 23 (5%) 17 (4%) 13 (3%) 13 (3%) 12 (2%) 24 (4%) 11 (2%) 14 (3%)

*includes pericardial effusion, pleural effusion, and ascites

Laboratory Abnormalities Myelosuppression was commonly reported in all patient populations.

The frequency of grade 3 or 4 thrombocytopenia, neutropenia, and anemia was higher in patients with AP-CML, BP-CML, and Ph+ ALL than in patients with CP-CML (see Table 6).

Table 6: Incidence of Clinically Relevant Grade 3/4* Hematologic Abnormalities Laboratory Test CP-CML AP-CML BP-CML Ph+ ALL (N=270) (N=85) (N=62) (N=32) (%) (%) (%) (%) Hematology Thrombocytopenia 36 47 57 47 (platelet count decreased) Neutropenia (ANC decreased) Leukopenia (WBC decreased) Anemia (Hgb decreased) Lymphopenia

24 14 9 10

51 35 26 26

55 53 55 37

63 63 34 22

ANC=absolute neutrophil count, Hgb=hemoglobin, WBC=white blood cell count *Reported using NCI-CTC-AE v 4.0

Table 7: Incidence of Clinically Relevant Non-Hematologic Laboratory Abnormalities Laboratory Test Safety Population N=449 Any Grade* Grade 3/4 (%) (%) Liver function tests ALT increased 53 8 AST increased 41 4 Alkaline phosphatase increased 37 2 Albumin decreased 28 1 Bilirubin increased 19 1 Pancreatic enzymes Lipase increased 41 15 Amylase increased 3 <1 Chemistry Glucose increased 58 6 Phosphorus decreased 57 8 Calcium decreased 52 1 Sodium decreased 29 5 Glucose decreased 24 0 Potassium decreased 16 2 Potassium increased 15 2 Sodium increased 10 <1 Bicarbonate decreased 11 <1 Creatinine increased 7 <1 Calcium increased 5 0 Triglycerides increased 3 <1 ALT=alanine aminotransferase, AST=aspartate aminotransferase. *Graded using NCI-CTC-AE v 4.0

7

DRUG INTERACTIONS Based on in vitro studies ponatinib is a substrate of CYP3A4/5 and to a lesser extent CYP2C8 and CYP2D6. Ponatinib also inhibits the P-glycoprotein (P-gp), ATP-binding cassette G2 (ABCG2) [also known as BCRP], and bile salt export pump (BSEP) transporter systems in vitro [see Clinical Pharmacology (12.3)].

7.1 Drugs That Are Strong Inhibitors of CYP3A Enzymes

7.2

7.3

7.4

8 8.1

In a drug interaction study in healthy volunteers, co-administration of Iclusig with ketoconazole increased plasma ponatinib AUC0-inf and Cmax by 78% and 47%, respectively [see Clinical Pharmacology (12.3)]. When administering Iclusig with strong CYP3A inhibitors (e.g., boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole), the recommended starting dose should be reduced to 30 mg once daily [see Dosage and Administration (2.1)]. Patients taking concomitant strong inhibitors may be at increased risk for adverse reactions [see Clinical Pharmacology (12.3)].

Drugs That Are Strong Inducers of CYP3A Enzymes Coadministration of Iclusig with strong CYP3A inducers was not evaluated in vitro or in a clinical trial; however, a reduction in ponatinib exposure is likely [see Clinical Pharmacology (12.3)].

Coadministration of strong CYP3A inducers (e.g., carbamazepine, phenytoin, rifampin, and St. John’s Wort) with Iclusig should be avoided unless the benefit outweighs the possible risk of ponatinib underexposure. Monitor patients for signs of reduced efficacy.

Drugs That Elevate Gastric pH Coadministration of Iclusig with drugs that elevate the gastric pH was not evaluated in a clinical trial. Based on the chemical properties of ponatinib, elevated gastric pH may reduce bioavailability and exposure [see Clinical Pharmacology (12.3)]. Coadministration of Iclusig with drugs that elevate the gastric pH (e.g., proton pump inhibitors, H2 blockers, or antacids) should be avoided unless the benefit outweighs the possible risk of ponatinib underexposure.

Monitor patients for signs of reduced efficacy.

Drugs That Are Substrates of the P-gp or ABCG2 Transporter Systems In vitro studies demonstrate that Iclusig inhibits the P-gp and ABCG2 [also known as BCRP] transporter systems. The effect of coadministration of Iclusig with sensitive substrates of the P-gp (e.g., aliskiren, ambrisentan, colchicine, dabigatran etexilate, digoxin, everolimus, fexofenadine, imatinib, lapatinib, maraviroc, nilotinib, posaconazole, ranolazine, saxagliptin, sirolimus, sitagliptin, tolvaptan, topotecan) and ABCG2 [also known as BCRP] (e.g., methotrexate, mitoxantrone, imatinib, irinotecan, lapatinib, rosuvastatin, sulfasalazine, topotecan) transporter systems on exposure of these substrates has not been evaluated in clinical studies.

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category D Risk Summary Based on its mechanism of action and findings in animals, Iclusig can cause fetal harm when administered to a pregnant woman.

There are no adequate and well-controlled studies with Iclusig in pregnant women. Advise women to avoid becoming pregnant while taking Iclusig. 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.

Animal Data Ponatinib was studied for effects on embryo-fetal development in pregnant rats given oral doses of 0.3, 1, and 3 mg/kg/day during organogenesis.

At the maternally toxic dose of 3 mg/kg/day (equivalent to the AUC in patients receiving the recommended dose of 45 mg/day), ponatinib caused embryo-fetal toxicity as shown by increased resorptions, reduced body weight, external alterations, multiple soft tissue and skeletal alterations, and reduced ossification. Embryo-fetal toxicities also were observed at 1 mg/kg/day (approximately 24% the AUC in patients receiving the recommended dose) and involved multiple fetal soft tissue and skeletal alterations, including reduced ossification.

8.3 Nursing Mothers

8.4

8.5

8.6

8.7

10

It is unknown whether ponatinib 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 ponatinib, a decision should be made whether to discontinue nursing or to discontinue Iclusig, taking into account the importance of the drug to the mother.

Pediatric Use The safety and efficacy of Iclusig in patients less than 18 years of age have not been established.

Geriatric Use One hundred and fifty-five of 449 patients (35%) in the clinical trial of Iclusig were 65 years of age and over. In patients with CP-CML, patients of age ≥ 65 years had a lower major cytogenetic response rate (38%) as compared with patients < 65 years of age (64%).

In patients with AP-CML, BP-CML, and Ph+ ALL, patients of age ≥ 65 years had a higher major hematologic response rate (47%) as compared with patients < 65 years of age (40%). Patients of age ≥ 65 years may be more likely to experience adverse reactions including decreased platelet count, peripheral edema, increased lipase, dyspnea, asthenia, muscle spasms, and decreased appetite.

In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Hepatic Impairment Iclusig has not been studied in patients with hepatic impairment.

As hepatic elimination is a major route of excretion for Iclusig, hepatic impairment may result in increased ponatinib exposure. Avoid Iclusig in patients with moderate to severe (Child-Pugh B or C) hepatic impairment unless the benefit outweighs the possible risk of ponatinib overexposure [see Clinical Pharmacology (12.3)]. Patients with moderate to severe hepatic impairment may be at increased risk for adverse reactions [see Clinical Pharmacology (12.3)].

Renal Impairment Iclusig has not been studied in patients with renal impairment.

Although renal excretion is not a major route of ponatinib elimination, the potential for moderate or severe renal impairment to affect hepatic elimination has not been determined [see Clinical Pharmacology (12.3)].

OVERDOSAGE Overdoses with Iclusig were reported in clinical trials. One patient was accidentally administered the entire contents of a bottle of study medication via nasogastric tube. The investigator estimated that the patient received 540 mg of Iclusig. Two hours after the overdose, the patient had an uncorrected QT interval of 520 ms. Subsequent ECGs showed normal sinus rhythm with uncorrected QT intervals of 480 and 400 ms. The patient died 9 days after the overdose from pneumonia and sepsis. Another patient accidentally self-administered 165 mg on cycle 1 day 2. The patient experienced fatigue and noncardiac chest pain on day 3. Multiple doses of 90 mg per day for 12 days in a patient resulted in pneumonia, systemic inflammatory response, atrial fibrillation, and a moderate pericardial effusion.

In the event of an overdose of Iclusig, stop Iclusig, observe the patient and provide appropriate supportive treatment.

Manufactured for: ARIAD Pharmaceuticals, Inc. 26 Landsdowne Street Cambridge, MA 02139-4234 For information contact: 1-855-55-ARIAD (855-552-7423)

medinfo@ariad.com PB/0713/0065/US

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Review Article

Impact of Glycemic Control on Healthcare Resource Utilization and Costs of Type 2 Diabetes: Current and Future Pharmacologic Approaches to Improving Outcomes

Mary Ann Banerji, MD, FACP; Jeffrey D. Dunn, PharmD, MBA

Stakeholder Perspective, page 391

Am Health Drug Benefits.

2013;6(7):382-392 www.AHDBonline.com Disclosures are at end of text

Background: The incidence and prevalence of type 2 diabetes continue to grow in the United States and worldwide, along with the growing prevalence of obesity. Patients with type 2 diabetes are at greater risk for comorbid cardiovascular (CV) disease (CVD), which dramatically affects overall healthcare costs.

Objectives: To review the impact of glycemic control and medication adherence on morbidity, mortality, and healthcare costs of patients with type 2 diabetes, and to highlight the need for new drug therapies to improve outcomes in this patient population.

Methods: This comprehensive literature search was conducted for the period between 2000 and 2013, using MEDLINE, to identify published articles that report the associations between glycemic control, medication adherence, CV morbidity and mortality, and healthcare utilization and costs. Search terms included “type 2 diabetes,” “adherence,” “compliance,” “nonadherence,” “drug therapy,” “resource use,” “cost,” and “cost-effectiveness.”

Discussion: Despite improvements in the management of CV risk factors in patients with type 2 diabetes, outcomes remain poor. The costs associated with the management of type 2 diabetes are increasing dramatically as the prevalence of the disease increases. Medication adherence to long-term drug therapy remains poor in patients with type 2 diabetes and contributes to poor glycemic control in this patient population, increased healthcare resource utilization and increased costs, as well as increased rates of comorbid CVD and mortality.

Furthermore, poor adherence to established evidence-based guidelines for type 2 diabetes, including underdiagnosis and undertreatment, contributes to poor outcomes. New approaches to the treatment of patients with type 2 diabetes currently in development have the potential to improve medication adherence and consequently glycemic control, which in turn will help to reduce associated costs and healthcare utilization.

Conclusions: As the prevalence of type 2 diabetes and its associated comorbidities grows, healthcare costs will continue to increase, indicating a need for better approaches to achieve glycemic control and manage comorbid conditions. Drug therapies are needed that enhance patient adherence and persistence levels far above levels reported with currently available drugs. Improvements in adherence to treatment guidelines and greater rates of lifestyle modifications also are needed. A serious unmet need exists for greatly improved patient outcomes, more effective and more tolerable drugs, as well as marked improvements in adherence to treatment guidelines and drug therapy to positively impact healthcare costs and resource use.

T

he incidence and prevalence of type 2 diabetes continue to grow in the United States as the population ages and becomes more obese.1,2 The

Dr Banerji is Director, Diabetes Treatment Center, State University of New York Downstate Medical Center, Brooklyn, NY; Dr Dunn is Senior Vice President, VRx Pharmacy Services, Salt Lake City, UT.

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prevalence of type 2 diabetes is projected to increase from current estimates of 14% to at least 21% of the US population by 2050, but the prevalence rate could reach 33% of the population.3 The impact of weight on the prevalence of type 2 diabetes is dramatic. In the 1999-2002 National Health and Nutrition Examination Survey (NHANES), among patients with type 2 diabetes, the proportion of partici-

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pants who were overweight (ie, body mass index [BMI] ≥25 kg/m2) or obese (ie, BMI ≥30 kg/m2) was 85.2%, and the proportion of obese patients without diabetes was 54.8% (Figure 1).1 Obese patients with type 2 diabetes were characterized by younger age, poorer glycemic control, higher blood pressure, worse lipid profile, and use of antihypertensive and lipid-lowering drugs compared with their nondiabetic counterparts.

Patients with diabetes are at greater risk for microvascular and macrovascular disease, including coronary artery disease, stroke, peripheral vascular disease, endstage renal disease, retinopathy, and mortality, compared with persons without diabetes.4 Large-scale studies in patients with diabetes consistently report a direct association between lower hemoglobin (Hb) A1c levels and lower complication rates.5-7 The proportion of the national healthcare expenditure attributed to patients with type 2 diabetes is expected to increase from the reported 10% in 2011 to 15% by 2031.8 In addition, studies show that overall healthcare costs for type 2 diabetes are reduced with improved glycemic control in patients with diabetes.9-11 Improvements in the management of type 2 diabetes and weight control, which are linked to increased medication adherence, are a critical component of any effort to reduce the healthcare costs of type 2 diabetes.

An unmet need in the treatment of type 2 diabetes is the availability of effective, safe, and well-tolerated treatments that will achieve and maintain glycemic control, reduce body weight, and decrease cardiovascular (CV) risk, while also ensuring patient adherence and persistence with therapy.

This article provides a comprehensive review of the impact of type 2 diabetes on patient morbidity and mortality, the implications of and increased prevalence of type 2 diabetes and its associated comorbidities on the costs of healthcare, and potential new pharmacologic approaches to control the prevalence of disease and their associated costs. For the purposes of this review, comprehensive searches were conducted for the years 2000 to 2013 using MEDLINE for individual and combinations of search terms, including “type 2 diabetes,” “adherence,” “compliance,” “nonadherence,” “drug therapy,” “resource use,” “cost,” and “cost-effectiveness.” Articles in the English language and representing healthcare practices in the United States were selected for inclusion.

Impact of Type 2 Diabetes on Morbidity and Mortality Despite improvements in the management of CV risk factors in patients with type 2 diabetes in recent years, substantial proportions of patients remain with elevated HbA1c (29%-45%), blood pressure (49%), and low-­ density lipoprotein cholesterol (LDL-C; 47%) according

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Key Points Despite improvements in the management of patients with type 2 diabetes and associated cardiovascular risk factors, patient adherence and outcomes remain poor. ➤ The costs associated with this disease are increasing dramatically as its prevalence increases; estimates of the economic burden of diabetes in 2007 reached $153 billion and are estimated to increase 3-fold in the next 20 years. ➤ Improved glycemic control in patients with type 2 diabetes has been shown to improve outcomes and reduce overall costs. ➤ Important unmet needs include lack of medication adherence and suboptimal use of evidence-based guidelines and lifestyle modifications, resulting in poor outcomes. ➤ This retrospective literature review of type 2 diabetes highlights the urgent need to improve the approach to drug therapy to control glycemic levels, improve the associated cardiovascular morbidity and mortality, and reduce obesity and overall costs. ➤ A review of novel therapies currently in development suggests the potential for new approaches to drug therapies that may help to improve glycemic control, improve outcomes, and reduce costs in patients with type 2 diabetes. ➤ The authors call for therapies that will focus on patient convenience and increased safety to enhance medication adherence and reduce morbidity and mortality far beyond the levels reported with current medications. ➤

to NHANES data.12,13 As the prevalence of type 2 diabetes grows, a parallel increase in comorbidity and mortality can be expected.2,14,15 The incidence of CV disease (CVD) is markedly exacerbated by poor glycemic control in patients with type 2 diabetes.16,17 Increased rates of hypertension, dyslipidemia, heart failure, angina, and myocardial infarction are closely linked to poor glycemic control in type 2 diabetes.6 Microvascular complications also are affected by poor glycemic control.6 An analysis of the UKPDS study showed a significant association between HbA1c levels and the risk for microvascular complications.7 Each 1% reduction in mean HbA1c was associated with a 21% reduction in the risk of any adverse outcome and a 37% reduction in the risk of microvascular complications.7 An HbA1c reduction from 8% to <7%, and the associated reductions in risk, would result in savings for

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Proportion of Type 2 Diabetic Men and Women Who Figure 1 Were Overweight or Obese in the NHANES Database, 1999-2002, by Age Overweight (≥25 kg/m2) Obese (≥30 kg/m2)

100 90 80

Population, %

70 60 50 40 30 20 10 0

≤20 21-64 ≥65

Men

≤20 21-64 ≥65

Women

Age, yrs

NHANES indicates National Health and Nutrition Examination Survey.

Source: Centers for Disease Control and Prevention. MMWR Morb Mortal Wkly Rep. 2004;53:1066-1068.

hospitalization from diabetes of $486 per patient per year, with even greater cost reductions when comparing higher HbA1c levels with HbA1c levels <7%.18 Currently available hypoglycemic drugs demonstrate limited effects on CV risk factors beyond glycemic control.19 Development of CVD is a major complication of type 2 diabetes. Chronic hyperglycemia is often accompanied by dyslipidemia, hypertension, systemic inflammation, and oxidative stress, which increase the risk for microvascular and macrovascular complications of type 2 diabetes.19 Although metformin exhibits favorable effects on body weight, sulfonylureas, thiazolidinediones, and insulin have a negative impact on weight in patients with type 2 diabetes.20 Glucagon-like peptide (GLP)-1 receptor agonists enhance insulin secretion but may also exert effects beyond glycemic control. Ongoing studies are examining the effects of administering GLP-1 agonists to patients at risk for CVD, patients postangioplasty, patients post–coronary artery bypass, and patients with heart failure.21 Additional studies are evaluating the potential benefits on arrhythmias, heart failure, myocardial infarction, and death.22,23

Implications of Growing Prevalence of Type 2 Diabetes and Comorbidities on Healthcare Costs Despite current availability of a wide range of drugs for the management of patients with type 2 diabetes, a number of limitations associated with their use persist, such as

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suboptimal efficacy, poor weight control, tolerability concerns, and high rates of medication nonadherence. In addition, suboptimal control of comorbid conditions, including hypertension and dyslipidemia, are common.24 Data from NHANES were examined to assess the achievement of therapeutic targets for glycemic control, blood pressure, and LDL-C among patients with diabetes in the United States.25 The proportion of patients with diabetes achieving HbA1c levels <7%, blood pressure <130/80 mm Hg, and LDL-C <100 mg/dL had risen from 7% during 1999-2002 to 12.2% during 2003-2006, but this increased rate represents a striking indication of the need for greater efforts to manage diabetes and its comorbidities.25 The costs associated with the management of patients with type 2 diabetes are increasing dramatically as the prevalence of the disease increases.26 Estimates of the economic burden of diabetes in the United States in 2007 reached $153 billion in excess medical costs and $65 billion in lost productivity.26 Healthcare expenditures associated with type 2 diabetes are expected to increase approximately 3-fold during the next 20 years,2 and additional costs are projected to arise from poor adherence to drug therapy.27,28

Obstacles to Effective Management of Type 2 Diabetes Despite the availability of therapies to improve glycemic control and reduce the associated comorbidities, medication adherence and long-term persistence with long-term drug therapy remains inadequate. This level of poor adherence is estimated to account for 33% to 69% of hospital admissions in the United States.29 Causes of poor adherence include complex drug regimens, chronic disease, adverse effects, cost, poor communication between patients and providers, lack of symptomatology, and psychosocial issues such as lack of education and support for behavioral modification.29 From a payer perspective, this gap between investing in programs and therapies needs to be addressed to avoid consequences that may not be seen for decades for a patient who is not a member of the specific health plan.

Furthermore, the conundrum of covering weight-loss medications needs to be evaluated. Many health plans do not cover weight-loss medications, despite the association between obesity, diabetes, and CVD, because of concerns of cost, adverse plan selection, and poor sustained efficacy and tolerability of weight-loss agents.

Medication adherence to different classes of antidiabetic drugs was evaluated from pharmacy claims for 75,589 patients enrolled in 3 health plans over a 12month period in 2003, and average medication nonadherence was approximately 31% (range, 25%-55%).30 A systematic review of adherence to the prescribed dose of

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Adherence and Healthcare Resource Use Poor medication adherence in patients with diabetes is associated with poor glycemic control, which ultimately increases morbidity and mortality and further impacts healthcare costs.38-43 Extensive data exist that link poor medication adherence to increased medical resource use and higher healthcare costs in type 2 diabetes. Improved medication adherence may lead to reductions of the total healthcare costs in type 2 diabetes.

A systematic literature review investigated the economic impact of adherence and/or persistence with treatment on the overall cost of type 2 diabetes care.38 The average total annual costs per patient ranged from $4570 to $17,338. Medication adherence was inversely associated with total healthcare costs or hospitalization costs.38 In a population of patients with diabetes examined

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nnual Diabetes-Related and Total Healthcare Costs per Figure 2 A Patient with Type 2 Diabetes, by Medication Adherence Level Diabetes-related costs Total healthcare costs

18,000 16,000

Annual costs per patient, $

antidiabetic drugs showed adherence rates from 67% to 85% for oral drugs and from 62% to 64% for insulin.31 In contrast, diabetic patients using subcutaneous injection of insulin were found adherent in only 36.1% of cases before conversion to an insulin pen device (which led to 54.6% adherence).32 An analysis of therapy with GLP-1 agonists between 2005 and 2010 showed adherence rates of 31% to 34%, suggesting that the need for injection even at a weekly frequency is a barrier to adherence.33 A 2005 analysis of persistence with drug therapy for 6 chronic diseases showed 6-month persistence rates of 28% to 66%.34 For diabetes, hypertension, and dyslipidemia, the medication possession ratio (MPR) averaged 72%, but only 59% of patients were adherent to their medication for >80% of the days, annually.35 Medication adherence refers to the intensity of drug use during therapy, whereas persistence refers to the overall duration of drug therapy; therefore, a patient can have poor adherence (eg, does not take medication as prescribed) but a high persistence rate (or MPR), because the patient continues to take the medication long-term.36 Improving medication adherence offers the possibility of reducing costs and improving care for patients with a chronic illness. A 2010 analysis of nonadherence (ie, MPR <80%) to medications used to treat diabetes, dyslipidemia, or hypertension estimated that the direct cost of nonadherence was $105.8 billion in that year.27 In addition, the CVS Caremark pharmacy and administrative claims database was used to determine the effect of medication adherence from 2005 to 2008 on healthcare costs, including hospital days, emergency department visits, and outpatient visits.37 Based on this analysis, greater medication adherence was projected to reduce the average annual medical spending per patient with diabetes by $4413 for all adults and by $5170 for patients aged â&#x2030;Ľ65 years.37

14,000 12,000 10,000 8000 6000 4000 2000 0

1-19 20-39 40-59 60-79 80-100

Medication adherence, %

Source: Sokol MC, et al. Med Care. 2005;43:521-530.

from 2005 to 2008, improved adherence to diabetes medications was associated with a 13% reduction in the risk of hospitalization or emergency department visits, whereas poor adherence was associated with a 15% increase in risk.41 Based on these findings, adherence to diabetes medication was projected to save $4.7 billion annually, and eliminating poor adherence would save the US healthcare system $3.6 billion annually.41 Thus, improved medication adherence among diabetic patients has the potential for a significant impact on costs.

A retrospective analysis using an administrative claims database of 137,277 patients enrolled in a healthcare system from June 1997 to May 1999 was performed to determine the impact of adherence (percentage of days that a patient had a supply of medication) on hospitalization rates and costs related to diabetes, hypertension, congestive heart failure, and hypercholesterolemia.42 For patients with diabetes, a significant increase in adherence rates was associated with reductions in hospitalization risk from 30% to 13% (P <.05) and total costs (ie, medical and drug costs) increased from $8867 to $4570 (P <.05) over a 12-month period (Figure 2).42 A model that was created to estimate the impact of medication adherence in 56,744 patients with type 2 diabetes who were enrolled in private insurance plans from 2001 to 2002 showed that increasing medication adherence (using MPR) from 50% to 100% would reduce the hospitalization rate from 15% to 11.5% and emergency department visits from 17.3% to 9.3%.44 The cost to achieve this level of adherence was projected to be an increase of $776 annually per patient, but this added cost was projected to be offset by cost-savings from lower rates

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nadjusted Association for All-Cause Mortality, All-Cause U Figure 3 Hospitalization, and Mean HbA1c Level in Adherent/ Nonadherent Patients with Type 2 Diabetes Adherent (N = 9076) Nonadherent (N = 2456)

Proportion of the population, %

25

P <.001

20 15 10

P <.001 P <.001

5 0

All-cause mortality

All-cause hospitalization

Mean HbA1c

Source: Ho PM, et al. Arch Intern Med. 2006;166:1836-1841.

of hospitalization and emergency department visits, which were estimated at $886 per patient annually.44 A longitudinal study from 2002 to 2006 evaluated medication adherence in patients with type 2 diabetes and the cost benefits of improving adherence.39 The mean MPR over 5 years was 0.93 for the adherent group and 0.58 for the nonadherent group. The costs increased approximately 3% annually (P = .001) during the 5-year study period. Nonadherence was associated with a 37% lower pharmacy cost and a 7% lower outpatient cost, but a 41% higher inpatient cost. Improving adherence in the nonadherent group was projected to result in annual cost-savings in the range of $661 million to $1.16 billion.39 A retrospective, cross-sectional study evaluated the effect of adherence to antidiabetic medications on adherence rates, healthcare utilization, and work productivity.40 Patients with type 2 diabetes using oral antidiabetic medications with or without insulin (N = 96,734) and patients using oral medication only (N = 55,356) were evaluated. Adherence (ie, MPR >80%) was associated with fewer complications of diabetes and fewer emergency department visits and short-term disability days. Among patients taking oral antidiabetic medications only, adherence was associated with significantly lower rates of acute myocardial infarction, amputation, neuropathy, renal events, and retinopathy (P <.05).40 The impact of increased persistency with medication use on hospitalization rates and healthcare costs was evaluated in 7441 Medicare patients with type 2 diabetes between 1997 and 2004 using prescription data to estimate

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costs.43 Persistency with prescriptions for oral antidiabetic medications, antihypertensives, and statins was associated with a significantly lower risk of hospitalization, fewer hospital days, and lower healthcare costs (P <.05).

Adherence and Glycemic Control The impact of medication adherence on glycemic control in type 2 diabetes has been evaluated in a number of prospective and retrospective studies.

The effect of adherence on glycemic control was evaluated in 249 patients in a managed care plan who had recently initiated therapy with oral antidiabetic drugs between 2001 and 2004.45 Overall, mean adherence (MPR >80%) was 81%, and older age and comorbidity were associated with better adherence. Each 10% increase in adherence was associated with a 0.1% reduction in HbA1c (P = .004), and adherent patients were more likely to achieve glycemic control.

A retrospective study was conducted between 1991 and 2001 among 1560 patients with type 2 diabetes to determine the effect of medication adherence with oral drugs on glycemic control measured by HbA1c during a 1-year follow-up.46 After adjusting for age, sex, BMI, and other factors, glycemic control rates improved progressively in accordance with higher rates of medication adherence. HbA1c levels were 0.34% lower with improvements in medication adherence (P = .009).

The effect of medication adherence on glycemic control was also evaluated in a retrospective analysis of patients with type 2 diabetes enrolled in an independent practice association model HMO between 2001 and 2002.47 The HbA1c target of â&#x2030;¤7% was achieved by 42% to 46% of patients using oral antidiabetic drugs.

The mean MPR for patients who reached HbA1c goal versus patients who did not reach that goal was 0.82 and 0.72 for sulfonylureas and 0.77 and 0.62 for metformin (P <.001). An inverse relationship was observed between mean HbA1c level and MPR.47 Adherence and Mortality Poor medication adherence also is associated with an increase in mortality in type 2 diabetes. A retrospective cohort study was conducted between 2002 and 2005 to investigate the effects of poor adherence on hospitalization and mortality in 11,532 patients with type 2 diabetes in a managed care organization.36 Medication adherence was defined as the proportion of days covered for filled prescriptions of oral hypoglycemic, antihypertensive, and statin medications. Patients who were nonadherent had higher levels of HbA1c, blood pressure, and LDL-C. Medication nonadherence was significantly (P <.001) associated with an increased risk for all-cause hospitalization and for all-cause mortality (Figure 3).36

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Effect of Comorbidity on Healthcare Resource Use In addition to the effects of type 2 diabetes on costs and resource utilization, the presence of underlying CVD magnifies the costs of care. The effect of comorbid CVD on healthcare costs was evaluated in patients with type 2 diabetes enrolled in an HMO in 2003.50 Costs were compared in 9059 patients with type 2 diabetes and agematched controls. Total healthcare costs were 3-fold higher in patients with comorbid CVD versus patients without comorbidities, which was similar to the control

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8000

Costs per patient for inpatient care, $

Glycemic Control and Healthcare Resource Use A strong association has been reported between poor glycemic control in type 2 diabetes and healthcare resource use and costs. A retrospective analysis from a managed care organization evaluated the relationship between glycemic control and hospitalization rate and hospital costs among patients with type 1 or type 2 diabetes.18 The hospitalization rate was significantly higher among patients with an HbA1c ≥10% compared with patients with HbA1c <7% (P <.05). Average costs per pa­tient increased markedly from $2792 to $6759 over a 40-­month period that coincided with increasing HbA1c values (Figure 4).18 An administrative database from a healthcare plan was used to assess the effects of glycemic control on healthcare costs between 1998 and 2003 among 10,780 patients with type 2 diabetes.49 Total annual diabetes-­ related costs increased significantly (P <.05) from $1505 among patients with good glycemic control (HbA1c ≤7%) to $1871 among patients with poor control (HbA1c >9%).49 Among members of a managed care plan with type 2 diabetes who maintained HbA1c levels ≤7% during a 1-year follow-up in 2002, diabetes-related costs were significantly reduced.10 This retrospective analysis compared medical and pharmacy claims data for 3121 patients at target HbA1c levels and for 3659 patients above target. At a 1-year follow-up, average diabetes-related costs per patient were $1540 for the cohort with high HbA1c levels versus $1171 for the group at target HbA1c (P <.001). These results demonstrate that higher medical costs associated with type 2 diabetes management are linked to poor glycemic control.10

ost per Patient for Inpatient Care and Hospitalization Rate, Figure 4 C

by Mean HbA1c Level in Patients with Type 2 Diabetes

7000 6000 5000 4000 3000 2000 1000 0 HbA1c ≥10% 9%-9.9% 8%-8.9% 7%-7.9% >7%

(N = 177) (N = 312) (N = 1002) (N = 2747) (N = 5649) H ospitalization 29.7% 22.8% 21.7% 15.6% 13.2% rate

Source: Menzin J, et al. J Manag Care Pharm. 2010;16:264-275.

Figure 5 Annual Total Cost per Patient with/without Type 2 Diabetes and with/without CVD 12,000

Annual total costs per patient, $

An analysis of the association between medication adherence and mortality in patients with type 2 diabetes found that medication nonadherence and clinic non­ attendance were independent risk factors for all-cause mortality.48 Data were obtained from general practices in the United Kingdom for 15,984 patients with type 2 diabetes who were treated with an oral antidiabetic drug and insulin. Medication nonadherence was significantly more common in women, smokers, and those with a higher HbA1c.48

10,000 8000 6000 4000 2000 0

CVD (N = 2441)

No CVD (N = 6618)

Type 2 diabetes group

CVD (N = 1027)

No CVD (N = 8032)

Control group

CVD indicates cardiovascular disease.

Source: Gandra SR, et al. J Manag Care Pharm. 2006;12:546-554.

group of persons without type 2 diabetes (Figure 5).

However, the total costs were approximately 2-fold higher in patients with type 2 diabetes, regardless of the presence of comorbid CVD.50 An economic benefit from weight loss was demonstrated among patients with type 2 diabetes, especially

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among obese patients. The impact of weight change over 1 year was evaluated using a claims database among adults in an HMO between 1997 and 2005.20 Of the 458 patients included, 224 (48.9%) experienced weight gain of ≤1 lb. The average 1-year healthcare cost was $6382 per person, and the diabetes-related cost was $2002. For patients who gained weight (mean, 3.9%) during the 1-year follow-up, the average healthcare cost was $7260 per person, and the diabetes-related cost was $2141. For those with no change in weight (mean, 3.3% decrease), the average healthcare cost was $5541 per person and the average diabetes-related cost was $1869.20 Therefore, a 1% weight loss was associated with a significant 3.6% ($256) decrease in total healthcare cost and a 5.8% ($131) decrease in diabetes-related cost (P <.05).20

Unmet Needs and Future Directions in Drug Therapy for Type 2 Diabetes There remain unmet needs for better pharmacologic treatment of type 2 diabetes. The ideal therapy should halt disease progression, reduce CV complications, and have a benign safety and tolerability profile. Optimal therapy requires continuous control of glucose levels and a more intensive therapeutic effect to prevent or reduce glucose excursions.51 Progress toward developing new therapies for type 2 diabetes that satisfy the ideal profile is limited by the complex nature of diabetes and its effects on multiple organ systems, as well as the length of time required for symptoms to develop.

The goal is for effective, safe, and well-tolerated treatments that will achieve glycemic control and ensure adherence and persistence with therapy. Ideal treatments should provide additional benefits beyond glycemic control, such as significant effects on weight loss and CV risk factors (including blood pressure and lipids), with an expectation of reduced morbidity and mortality. In addition, ideal therapies will lack the inconvenience and barriers associated with frequent injections, offer patient convenience, and optimize medication adherence. An impor­ tant treatment approach to type 2 diabetes that has the potential to improve adherence and disease outcomes is the use of dual- or triple-drug combination therapy.

Treatment guidelines for type 2 diabetes include recommendations for using combination therapy, and a growing body of literature supports the early use of triple-­ drug therapy for patients who are not adequately controlled with monotherapy.52-54 A number of fixed-dose combinations of antidiabetic drugs are already marketed or are undergoing clinical evaluation. Finally, healthcare payers expect that ideal therapies will provide cost-effective solutions to the long-term management of type 2 diabetes to address the high morbidity and costs associated with CVD.

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Novel approaches for improving pharmacotherapy for type 2 diabetes include new delivery systems for existing drugs and new chemical entities, as outlined in the Table, based on ongoing clinical trials (clinicaltrials.gov; accessed July 16, 2013). Many of the new classes of drugs target comorbid CVD in patients with type 2 diabetes.

Although a once-weekly formulation of exenatide (Bydureon; Amylin) is available and other once-weekly formulations of GLP-1 receptor agonists are in development and a once-monthly formulation is undergoing evaluation, the impact of these agents on long-term adherence remains uncertain.

New formulations of older drugs are focused on improved delivery of the active ingredient to provide increased ease of use and patient convenience. ITCA 650 (Intarcia Therapeutics) is a novel drug delivery system that is designed to provide continuous subcutaneous release of exenatide for up to 1 year. Phase 3 trials are under way in patients with type 2 diabetes to demonstrate its efficacy and tolerability.

A once-monthly suspension of exenatide (BristolMyers Squibb) has completed a phase 2 trial and is poised to enter phase 3 studies. Oral formulations of GLP-1 receptor agonists are in early clinical testing.

Inhaled insulin (Afrezza; MannKind Corporation) is an ultra–rapid-acting inhaled formulation that is intended as an alternative to rapid-acting injectable insulin and offers the major advantage of avoiding frequent daily injections. Additional phase 3 studies are being conducted for submission to the US Food and Drug Administration (Exubera was withdrawn from the market by its manufacturer in 2008).

Another approach to addressing unmet needs in type 2 diabetes is drug combinations that provide 2 mechanisms of action. The dipeptidyl peptidase-4 agonist alogliptin combined with pioglitazone (Oseni; Takeda Pharmaceuticals) and alogliptin combined with metformin (Kazano; Takeda Pharmaceuticals) were both approved and launched early in 2013, and insulin degludec combined with liraglutide is in late-stage development (Novo Nordisk).

Furthermore, the cost-effectiveness of fixed-dose combinations must be demonstrated in diabetes, especially when ≥1 of the components are available as generic drugs, and when patients are likely taking multiple medications.

There is a need to establish a direct link between improved medication adherence and better outcomes.

A number of new chemical entities for type 2 diabetes are in clinical development or have recently been added to the market. The first sodium-glucose cotransporter (SGLT)2, canagliflozin (Invokana; Janssen), was approved and launched in early 2013. Other SGLT2 compounds are in late-stage development, and these agents

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Table Novel Drugs in Late-Stage Development for the Treatment of Type 2 Diabetes Drug/novel delivery system (company)

Description

Novel features

Development stage

ITCA 650 (Intarcia Therapeutics)

Novel delivery system of exenatide, GLP-1 receptor agonist

Inhaled insulin (MannKind)

Short-acting insulin (new version Inhaled to avoid need for frequent of Exubera, which was withdrawn self-injection from the market in 2008)

Phase 3

Exenatide monthly (Bristol-Myers Squibb/Amylin)

GLP-1 receptor agonist

Less frequent than currently available versions of exenatide (ie, monthly injection)

Phase 2

Long-acting insulin + GLP-1 receptor agonist

Exogenous insulin to augment insulin secretion

Phase 3

SGLT2

Increases secretion of urinary glucose; low risk of hypoglycemia, weight loss, and blood pressure reduction

Phase 3

Continuous delivery for up to 12 mo with 1 insertion

Phase 3

Combination drug Insulin degludec + liraglutide (Novo Nordisk) New chemical entities SGLT2 inhibitors (Astra Zeneca/Bristol-Myers Squibb) (Boehringer Ingelheim/Lilly) Ipragliflozin (Astellas Pharma)

Phase 3 Phase 3

Empagliflozin + simvastatin (Boehringer Ingelheim/Lilly)

SGLT2 + statin

Increases secretion of urinary glucose; low risk of hypoglycemia, weight loss, and blood pressure reduction combined with lipid-lowering properties

Phase 3

Dual SGLT1 and SGLT2 inhibitor (Lexicon)

Dual inhibition of SGLT2

Oral administration; inhibits gastrointestinal glucose absorption and renal reabsorption

Phase 3

DGAT1 inhibitor: LCQ908 (Novartis Pharmaceuticals)

Acyl-CoA:DGAT 1 inhibitor

Reduces insulin resistance and triglycerides without TZD side effects

Phase 2

NOTE: This list is not inclusive. Rather, it is focused on products that represent a novel approach to therapy, including (1) novel delivery systems, (2) novel drugs; or (3) novel combinations that are in late-stage development (ie, phase 3 or late stage 2 clinical trials).

DGAT indicates diacylglycerol acyltransferase; GLP-1, glucagon-like peptide-1; SGLT, sodium glucose cotransporter; TZD, thiazolidinedione.

Source: Clinicaltrials.gov, searched using the terms “phase 2,” “phase 3,” “industry sponsored,” and “type 2 diabetes,” focusing on novel features only (ie, delivery system, drug class, or drug combinations). Accessed July 16, 2013.

increase secretion of urinary glucose and promote weight loss, with a low risk for hypoglycemia or blood pressure reduction. A dual SGLT1 and SGLT2 agonist that inhibits glucose absorption in the stomach and renal glucose reabsorption is in phase 3 development (Lexicon Pharmaceuticals).

G protein–coupled receptor agonists act as incretin mimetics (CymaBay), and acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1) inhibitors are being developed by various manufacturers (Novartis; Pfizer) to reduce insulin resistance and lower triglycerides. These drug classes are in early-stage development.

Alternative approaches to treatment are in early clinical development and include drugs that reduce glycemia

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while providing beta-cell protection (GMC-252; Genmedica Therapeutics), selective inhibition of proinflammatory pathways, and activation of endogenous anti-­ inflammatory pathways (CAT-1004; Catabasis). More effective weight-loss agents are needed, and healthcare plans need better tools to validate the return-on-investment to employers for treating obesity.

Conclusions The information presented in this article should serve as a call to action for health insurance plans, pharmacy benefit managers, and employers to investigate the impact of medication adherence on costs and outcomes associated with type 2 diabetes. Greater effort is needed

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from these groups to assess the level of medication adherence, as well as adherence to evidence-based guidelines and connect potential improvements to quality measures in type 2 diabetes. With continuing growth in the prevalence of type 2 diabetes, its associated comorbidities, and a corresponding increase in healthcare costs, it is critical that better approaches are identified for achieving long-term glycemic control and managing comorbid conditions.

A major emphasis should be placed on achieving effective control of diabetes, but without imposing increased risks on the patient from excess weight, hypoglycemia, and other safety and tolerability concerns. Of equal importance is to find drug therapies that increase patient adherence and persistence levels beyond levels reported with currently available drugs. This combination of enhanced efficacy, better tolerability, and improved adherence has the potential to impart substantial positive benefits on healthcare costs and resource utilization and ensure a healthier population. New Centers for Medicare & Medicaid Services’ Clinical Quality Measures55 that are linking reimbursement to the attainment of quality measures may provide additional incentive to improving overall management of type 2 diabetes and its comorbidities. n Author Disclosure Statement Dr Banerji has received research/grant support from Merck, is on the Speaker’s Bureau of and has received honoraria from Merck and from Sanofi-Aventis, and is a Consultant to Novartis. Dr Dunn is a Consultant to Takeda, Sanofi-­ Aventis, and Janssen.

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MMWR Morb Mortal Wkly Rep. 2004;53:1066-1068.

2. Huang ES, Basu A, O’Grady M, Capretta JC. Projecting the future diabetes population size and related costs for the U.S. Diabetes Care. 2009;32:2225-2229.

3. Boyle JP, Thompson TJ, Gregg EW, et al. Projection of the year 2050 burden of diabetes in the US adult population: dynamic modeling of incidence, mortality, and prediabetes prevalence. Popul Health Metr. 2010;8:29.

4. Centers for Disease Control and Prevention. National diabetes fact sheet: national estimates and general information on diabetes and prediabetes in the United States, 2011. 2011. www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf. Accessed August 20, 2013.

5. Selvin E, Marinopoulos S, Berkenblit G, et al. Meta-analysis: glycosylated hemoglobin and cardiovascular disease in diabetes mellitus. Ann Intern Med. 2004;141:421-431.

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7. UK Prospective Diabetes Study Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:837-853. Erratum in: Lancet. 1999;354:602.

8. Fitch K, Iwasaki K, Pyenson B. The cost and quality gap in diabetes care: an actuarial analysis. 2012. http://publications.milliman.com/publications/health-published/ pdfs/cost-quality-gap-diabetes.pdf. Accessed August 20, 2013.

9. Gilmer TP, O’Connor PJ, Manning WG, Rush WA. The cost to health plans of poor glycemic control. Diabetes Care. 1997;20:1847-1853.

10. Shetty S, Secnik K, Oglesby AK. Relationship of glycemic control to total diabetes-related costs for managed care health plan members with type 2 diabetes. J Manag Care Pharm. 2005;11:559-564.

11. Testa MA, Simonson DC. Health economic benefits and quality of life during improved glycemic control in patients with type 2 diabetes mellitus: a randomized,

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controlled, double-blind trial. JAMA. 1998;280:1490-1496.

12. Ford ES. Trends in the control of risk factors for cardiovascular disease among adults with diagnosed diabetes: findings from the National Health and Nutrition Examination Survey 1999-2008. J Diabetes. 2011;3:337-347.

13. Ali MK, McKeever Bullard K, Imperatore G, et al; for the Centers for Disease Control and Prevention. Characteristics associated with poor glycemic control among adults with self-reported diagnosed diabetes—National Health and Nutrition Examination Survey, United States, 2007-2010. MMWR Morb Mortal Wkly Rep. 2012;61(suppl):32-37.

14. Barr EL, Zimmet PZ, Welborn TA, et al. Risk of cardiovascular and all-cause mortality in individuals with diabetes mellitus, impaired fasting glucose, and impaired glucose tolerance: the Australian Diabetes, Obesity, and Lifestyle Study (AusDiab).

Circulation. 2007;116:151-157.

15. Zhang Y, Hu G, Yuan Z, Chen L. Glycosylated hemoglobin in relationship to cardiovascular outcomes and death in patients with type 2 diabetes: a systematic review and meta-analysis. PLoS One. 2012;7:e42551.

16. Beckman JA, Creager MA, Libby P. Diabetes and atherosclerosis: epidemiology, pathophysiology, and management. JAMA. 2002;287:2570-2581.

17. Buse JB, Ginsberg HN, Bakris GL, et al; for the American Heart Association and the American Diabetes Association. Primary prevention of cardiovascular diseases in people with diabetes mellitus: a scientific statement from the American Heart Association and the American Diabetes Association. Circulation. 2007;115:114-126.

18. Menzin J, Korn JR, Cohen J, et al. Relationship between glycemic control and diabetes-related hospital costs in patients with type 1 or type 2 diabetes mellitus.

J Manag Care Pharm. 2010;16:264-275.

19. van Genugten RE, Möller-Goede DL, van Raalte DH, Diamant M. Extra-pancreatic effects of incretin-based therapies: potential benefit for cardiovascular-risk management in type 2 diabetes. Diabetes Obes Metab. 2013;15:593-606.

20. Yu AP, Wu EQ, Birnbaum HG, et al. Short-term economic impact of body weight change among patients with type 2 diabetes treated with antidiabetic agents: analysis using claims, laboratory, and medical record data. Curr Med Res Opin. 2007; 23:2157-2169.

21. Anagnostis P, Athyros VG, Adamidou F, et al. Glucagon-like peptide-1-based therapies and cardiovascular disease: looking beyond glycaemic control. Diabetes Obes Metab. 2011;13:302-312.

22. Okerson T, Chilton RJ. The cardiovascular effects of GLP-1 receptor agonists.

Cardiovasc Ther. 2012;30:e146-e155.

23. Mundil D, Cameron-Vendrig A, Husain M. GLP-1 receptor agonists: a clinical perspective on cardiovascular effects. Diab Vasc Dis Res. 2012;9:95-108.

24. Stark Casagrande S, Fradkin JE, Saydah SH, et al. The prevalence of meeting A1C, blood pressure, and LDL goals among people with diabetes, 1988-2010. Diabetes Care. 2013;36:2271-2279.

25. Cheung BM, Ong KL, Cherny SS, et al. Diabetes prevalence and therapeutic target achievement in the United States, 1999 to 2006. Am J Med. 2009;122:443-453.

26. Dall TM, Zhang Y, Chen YJ, et al. The economic burden of diabetes. Health Aff (Millwood). 2010;29:297-303.

27. Nasseh K, Frazee SG, Visaria J, et al. Cost of medication nonadherence associated with diabetes, hypertension, and dyslipidemia. Am J Pharm Benefits. 2012;4:e41-e47.

28. Wild H. The economic rationale for adherence in the treatment of type 2 diabetes mellitus. Am J Manag Care. 2012;18(3 suppl):S43-S48.

29. Osterberg L, Blaschke T. Adherence to medication. N Engl J Med. 2005;353:487-497.

30. Fischer MA, Stedman MR, Lii J, et al. Primary medication non-adherence: analysis of 195,930 electronic prescriptions. J Gen Intern Med. 2010;25:284-290.

31. Cramer JA. A systematic review of adherence with medications for diabetes.

Diabetes Care. 2004;27:1218-1224.

32. Lee WC, Balu S, Cobden D, et al. Medication adherence and the associated health-economic impact among patients with type 2 diabetes mellitus converting to insulin pen therapy: an analysis of third-party managed care claims data. Clin Ther.

2006;28:1712-1725. Erratum in: Clin Ther. 2006;28:1968-1969.

33. Chou E, Wang H, Miao W, et al. Adherence to GLP-1 agonist therapy in US managed care. Poster presented at the American Diabetes Association annual scientific sessions; June 8-12, 2012, Philadelphia, PA. 34. Yeaw J, Benner JS, Walt JG, et al. Comparing adherence and persistence across 6 chronic medication classes. J Manag Care Pharm. 2009;15:728-740.

35. Cramer JA, Benedict A, Muszbek N, et al. The significance of compliance and persistence in the treatment of diabetes, hypertension and dyslipidaemia: a review. Int J Clin Pract. 2008;62:76-87.

36. Ho PM, Rumsfeld JS, Masoudi FA, et al. Effect of medication nonadherence on hospitalization and mortality among patients with diabetes mellitus. Arch Intern Med. 2006;166:1836-1841.

37. Roebuck MC, Liberman JN, Gemmill-Toyama M, Brennan TA. Medication adherence leads to lower health care use and costs despite increased drug spending.

Health Aff (Millwood). 2011;30:91-99.

38. Breitscheidel L, Stamenitis S, Dippel FW, Schöffski O. Economic impact of compliance to treatment with antidiabetes medication in type 2 diabetes mellitus: a review paper. J Med Econ. 2010;13:8-15.

39. Egede LE, Gebregziabher M, Dismuke CE, et al. Medication nonadherence in diabetes: longitudinal effects on costs and potential cost savings from improvement.

Diabetes Care. 2012;35:2533-2539.

40. Gibson TB, Song X, Alemayehu B, et al. Cost sharing, adherence, and health

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outcomes in patients with diabetes. Am J Manag Care. 2010;16:589-600.

41. Jha AK, Aubert RE, Yao J, et al. Greater adherence to diabetes drugs is linked to less hospital use and could save nearly $5 billion annually. Health Aff (Millwood).

2012;31:1836-1846.

42. Sokol MC, McGuigan KA, Verbrugge RR, Epstein RS. Impact of medication adherence on hospitalization risk and healthcare cost. Med Care. 2005;43:521-530.

43. Stuart BC, Simoni-Wastila L, Zhao L, et al. Increased persistency in medication use by U.S. Medicare beneficiaries with diabetes is associated with lower hospitalization rates and cost savings. Diabetes Care. 2009;32:647-649.

44. Encinosa WE, Bernard D, Dor A. Does prescription drug adherence reduce hospitalizations and costs? The case of diabetes. Adv Health Econ Health Serv Res. 2010; 22:151-173.

45. Rozenfeld Y, Hunt JS, Plauschinat C, Wong KS. Oral antidiabetic medication adherence and glycemic control in managed care. Am J Manag Care. 2008;14:71-75.

46. Rhee MK, Slocum W, Ziemer DC, et al. Patient adherence improves glycemic control. Diabetes Educ. 2005;31:240-250.

47. Lawrence DB, Ragucci KR, Long LB, et al. Relationship of oral antihyperglycemic (sulfonylurea or metformin) medication adherence and hemoglobin A1c goal attainment for HMO patients enrolled in a diabetes disease management program.

J Manag Care Pharm. 2006;12:466-471.

48. Currie CJ, Peyrot M, Morgan CL, et al. The impact of treatment noncompliance

on mortality in people with type 2 diabetes. Diabetes Care. 2012;35:1279-1284.

49. Oglesby AK, Secnik K, Barron J, et al. The association between diabetes related medical costs and glycemic control: a retrospective analysis. Cost Eff Resour Alloc.

2006;4:1.

50. Gandra SR, Lawrence LW, Parasuraman BM, et al. Total and component health care costs in a non-Medicare HMO population of patients with and without type 2 diabetes and with and without macrovascular disease. J Manag Care Pharm. 2006;12: 546-554.

51. Drucker DJ, Buse JB, Taylor K, et al; for the DURATION-1 Study Group. Exenatide once weekly versus twice daily for the treatment of type 2 diabetes: a randomised, open-label, non-inferiority study. Lancet. 2008;372:1240-1250.

52. Defronzo RA, Eldor R, Abdul-Ghani M. Pathophysiologic approach to therapy in patients with newly diagnosed type 2 diabetes. Diabetes Care. 2013;36(suppl 2): S127-S138.

53. Harrison LB, Adams-Huet B, Raskin P, Lingvay I. β-cell function preservation after 3.5 years of intensive diabetes therapy. Diabetes Care. 2012;35:1406-1412.

54. Raz I. Guideline approach to therapy in patients with newly diagnosed type 2 diabetes. Diabetes Care. 2013;36(suppl 2):S139-S144.

55. Centers for Medicare & Medicaid Services. Clinical Quality Measures. www.cms. gov/Regulations-and-Guidance/Legislation/EHRIncentivePrograms/ClinicalQuality Measures.html. Accessed August 2, 2013.

Stakeholder Perspective Innovation in Patient Engagement and Management Is Critically Needed to Change Current Trends in Type 2 Diabetes

By Jeffrey A. Bourret, PharmD, MS, RPh, FASHP Senior Director, North America Medical Affairs, and Medical Lead, Specialty Payer and Channel Customer Strategy, Pfizer Inc.

PAYERS: Payers are challenged with how to use limited healthcare resources to produce quality outcomes in a healthcare system that many believe is fragmented and inefficient. One of the most challenging areas is the management of patients with type 2 diabetes mellitus. In their article in this issue of American Health & Drug Benefits, Drs Banerji and Dunn aptly make the case for a call to action for aggressive change and innovation in the management of patients with type 2 diabetes and the development of new pharmaceuticals that reduce cardiovascular risk, result in less weight gain, and improve adherence and health outcomes. This need is reflected in the heavy weighting of specific diabetes quality measures in the new Centers for Medicare & Medicaid Services Medicare Part C & D Plan Ratings Quality and Performance Measures for diabetes care.1 The aging of our population, alarming increases in obesity, poor diets, and inadequate exercise contribute to the diabetes healthcare epidemic that, if unabated, will negatively impact healthcare costs, morbidity, and mortality.

As the authors point out, the issues are complex, but there are potential short-term strategies that payers could consider to address this growing concern. Increasing member personal accountability for health and med-

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ication management through incentives and disincentives that promote behavioral change in adherence, diet, and exercise could lead to meaningful improvements in patient adherence, glycemic control, health outcomes, and cost reduction. Application of proven high-touch, high-technology models for patient care delivery that have been successful in managing patients with other complex medical conditions could help.

The specialty pharmacy model has successfully achieved medication adherence rates in excess of 90% with many complex diseases. Their care management and data capture capabilities, patient and provider interaction, and scalability warrant serious consideration of this model for improvements in adherence and outcomes. Payer collaboration with the pharmaceutical industry to develop and evaluate effective formal patient education programs is also needed. Programs that adapt existing multimedia and interactive technologies that measure learning and comprehension about the potential benefits and potential risks of their medications in the context of their medical condition could contribute to gaps in medication education. Payer incentives for members who complete formal education could ensure that all patients with diabetes are appropriately educated

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Stakeholder Perspective Continued on the pharmacologic and nonpharmacologic components of their treatment plan.

PATIENTS: The authors provide a loud wake-up call for patients with type 2 diabetes and persons with risk factors for the disease regarding the projected increases in healthcare costs, obesity, morbidity, and mortality that are related to diabetes. This information should be conveyed to patients to encourage changes in their personal lifestyles and adherence to their provider’s treatment plan, to be used as the rationale for introducing positive and negative incentives to drive individual member behavior.

PROVIDERS: Drs Banerji and Dunn document ongoing issues of poor adherence and treatment outcomes despite improvements in care delivery. This has not gone unrecognized by the federal government and quality organizations that are influencing the shift in accountability to healthcare providers for performance on quality measures that will include incentives and disincentives that are linked to reimbursement. Provider adoption of electronic medical records will also provide new opportunities for diabetes care management and for the reporting that is critical to the success of accountable care organizations in addressing diabetes quality measures.

Providers will need to play an increasing role in improving patient education and reinforcement of behaviors that are critical to treatment adherence and to

medication safe use and management, which for many practices has been a challenge because of time constraints, patient health literacy, complex medication regimens, and the lack of effective tools that they can deploy in their practices.

PHARMACEUTICAL COMPANIES: The authors appropriately introduce the need for additional drug development for therapies that effectively provide glycemic control without weight gain, that are convenient to use by patients, and that lead to high medication adherence rates in real-world clinical practices. Combination therapies that reduce “pill burden” are promising, as are new therapies with novel mechanisms of action and drug delivery systems that are designed to reduce weight gain and to improve medication adherence.

The pharmaceutical industry should consider collaborating with payers, providers, and patients to assess the impact of new therapies and collaborative care delivery models on medication adherence, outcomes, and healthcare costs and utilization. The development of comprehensive, effective patient medication education programs that address healthcare literacy and the multicultural educational needs of patients with diabetes by leveraging consumer and provider market research on gaps in education are urgently needed.

1. Centers for Medicare & Medicaid Services. 2013 Part C & D Medicare Plan Ratings Display Measures (v01.31.13). www.cms.gov/Medicare/Prescription-Drug-Coverage/ PrescriptionDrugCovGenIn/PerformanceData.html. Accessed September 3, 2013.

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Vol 6, No 7

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

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

•

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

•

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

– •

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

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

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

Indication BENLYSTA is indicated for the treatment of adult patients with active, autoantibody-positive, systemic lupus erythematosus (SLE) who are receiving standard therapy.

Limitations of Use: The efficacy of BENLYSTA has not been evaluated in patients with severe active lupus nephritis or severe active central nervous system lupus. BENLYSTA has not been studied in combination with other biologics or intravenous cyclophosphamide. Use of BENLYSTA is not recommended in these situations.

How supplied: BENLYSTA is available as 120 mg in a 5-mL single-use vial and 400 mg in a 20-mL single-use vial for injection, for intravenous use only.

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

WARNINGS AND PRECAUTIONS MORTALITY There were more deaths reported with BENLYSTA than with placebo during the controlled period of the clinical trials. Out of 2133 patients in 3 clinical trials, a total of 14 deaths occurred in the following groups: 3/675 in placebo, 5/673 in BENLYSTA 1 mg/kg, 0/111 in BENLYSTA 4 mg/kg, and 6/674 in BENLYSTA 10 mg/kg. No single cause of death predominated. Etiologies included infection, cardiovascular disease, and suicide.

SERIOUS INFECTIONS Serious and sometimes fatal infections have been reported in patients receiving immunosuppressive agents, including BENLYSTA. Caution should be exercised when considering use in patients with a history of chronic infections. Patients receiving therapy for a chronic infection should not receive BENLYSTA. Consider interrupting BENLYSTA therapy in patients who develop a new infection while receiving BENLYSTA. The most frequent serious infections included pneumonia, urinary tract infection, cellulitis, and bronchitis.

Please see additional Important Safety Information for BENLYSTA on following page.

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

www.GSKSource.com

Important Safety Information for BENLYSTA (cont’d) WARNINGS AND PRECAUTIONS (cont’d) MALIGNANCY The impact of treatment with BENLYSTA on the development of malignancies is not known. As with other immunomodulating agents, the mechanism of action of BENLYSTA could increase the risk of malignancies.

HYPERSENSITIVITY REACTIONS (INCLUDING ANAPHYLAXIS) AND INFUSION REACTIONS Hypersensitivity reactions, including anaphylaxis and death, have been reported with BENLYSTA. Delay in the onset of acute hypersensitivity reactions has been observed. Patients with a history of multiple drug allergies or significant hypersensitivity may be at increased risk. Some patients received premedication; however, there is insufficient evidence to determine whether premedication diminishes the frequency or severity of these reactions.

Healthcare providers should be aware of the risk of hypersensitivity reactions, which may present as infusion reactions, and monitor patients closely. Manifestations of hypersensitivity included hypotension, angioedema, urticaria or other rash, pruritus, and dyspnea. In the event of a serious hypersensitivity reaction, discontinue BENLYSTA immediately and administer appropriate medical therapy. Infusion-associated adverse events were also reported. Serious infusion reactions included bradycardia, myalgia, headache, rash, urticaria, and hypotension.

In the event of an infusion reaction, the infusion rate may be slowed or interrupted.

Patients should be informed of the signs and symptoms of a hypersensitivity reaction and instructed to seek immediate medical care should a reaction occur.

DEPRESSION In clinical trials, psychiatric events (primarily depression, insomnia, and anxiety) were reported more frequently with BENLYSTA than with placebo. Serious psychiatric events, serious depression, and two suicides were also reported. It is unknown if BENLYSTA treatment is associated with increased risk for these events. Instruct patients to contact their healthcare provider if they experience new or worsening depression, suicidal thoughts, or other mood changes.

IMMUNIZATION Live vaccines should not be given for 30 days before or concurrently with BENLYSTA. BENLYSTA may interfere with the response to immunizations.

USE WITH BIOLOGIC THERAPIES OR IV CYCLOPHOSPHAMIDE BENLYSTA has not been studied in combination with other biologic therapies, including B-cell targeted therapies, or IV cyclophosphamide.

Therefore, use of BENLYSTA is not recommended in combination with these therapies.

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

Other Important Information for BENLYSTA USE IN SPECIFIC POPULATIONS Pregnancy: Category C. BENLYSTA should be used during pregnancy only if the potential benefit outweighs the risk. Women of childbearing potential should use adequate contraception during BENLYSTA treatment and for at least 4 months after the last dose.

Pregnancy Registry: Healthcare professionals are encouraged to register patients and pregnant women are encouraged to enroll themselves by calling 1-877-681-6296.

Effect in black/African American patients: In exploratory analyses of 2 Phase III trials, response rates were lower for black patients (N=148) in the BENLYSTA group relative to black patients in the placebo group. In the Phase II trial, black patients (N=106) in the BENLYSTA group did not appear to have a different response than the rest of the study population. Although no definitive conclusions can be drawn from these analyses, caution should be used when considering BENLYSTA for black/African American patients.

References: 1. BENLYSTA [package insert]. Rockville, MD: Human Genome Sciences, Inc; 2012. 2. Navarra SV, Guzmán RM, Gallacher AE, et al. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial. Lancet. 2011;377(9767):721-731. 3. Furie R, Petri M, Zamani O, et al. A phase III, randomized, placebo-controlled study of belimumab, a monoclonal antibody that inhibits B lymphocyte stimulator, in patients with systemic lupus erythematosus.

Arthritis Rheum. 2011;63(12):3918-3930. 4. Wallace DJ, Stohl W, Furie RA, et al. A phase II, randomized, double-blind, placebo-controlled, dose-ranging study of belimumab in patients with active systemic lupus erythematosus. Arthritis Rheum. 2009;61(9):1168-1178. 5. Data on file, Human Genome Sciences, Inc.

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

©2013 GlaxoSmithKline group of companies.

All rights reserved. Printed in USA. BN2289R0 August 2013

BRIEF SUMMARY BENLYSTA® (belimumab) for injection, for intravenous use only.

The following is a brief summary only; see full Prescribing Information for complete product information.

INDICATIONS AND USAGE BENLYSTA® (belimumab) is indicated for the treatment of adult patients with active, autoantibody-positive, systemic lupus erythematosus (SLE) who are receiving standard therapy.

Limitations of Use The efficacy of BENLYSTA has not been evaluated in patients with severe active lupus nephritis or severe active central nervous system lupus.

BENLYSTA has not been studied in combination with other biologics or intravenous cyclophosphamide. Use of BENLYSTA is not recommended in these situations.

CONTRAINDICATIONS BENLYSTA is contraindicated in patients who have had anaphylaxis with belimumab.

WARNINGS AND PRECAUTIONS Mortality There were more deaths reported with BENLYSTA than with placebo during the controlled period of the clinical trials. Out of 2133 patients in 3 clinical trials, a total of 14 deaths occurred during the placebo-controlled, double-blind treatment periods: 3/675 (0.4%), 5/673 (0.7%), 0/111 (0%), and 6/674 (0.9%) deaths in the placebo, BENLYSTA 1 mg/kg, BENLYSTA 4 mg/kg, and BENLYSTA 10 mg/kg groups, respectively. No single cause of death predominated. Etiologies included infection, cardiovascular disease and suicide.

Serious Infections Serious and sometimes fatal infections have been reported in patients receiving immunosuppressive agents, including BENLYSTA. Physicians should exercise caution when considering the use of BENLYSTA in patients with chronic infections. Patients receiving any therapy for chronic infection should not begin therapy with BENLYSTA. Consider interrupting BENLYSTA therapy in patients who develop a new infection while undergoing treatment with BENLYSTA and monitor these patients closely.

In the controlled clinical trials, the overall incidence of infections was 71% in patients treated with BENLYSTA compared with 67% in patients who received placebo. The most frequent infections (>5% of patients receiving BENLYSTA) were upper respiratory tract infection, urinary tract infection, nasopharyngitis, sinusitis, bronchitis, and influenza. Serious infections occurred in 6.0% of patients treated with BENLYSTA and in 5.2% of patients who received placebo. The most frequent serious infections included pneumonia, urinary tract infection, cellulitis, and bronchitis.

Infections leading to discontinuation of treatment occurred in 0.7% of patients receiving BENLYSTA and 1.0% of patients receiving placebo.

Infections resulting in death occurred in 0.3% (4/1458) of patients treated with BENLYSTA and in 0.1% (1/675) of patients receiving placebo.

Malignancy The impact of treatment with BENLYSTA on the development of malignancies is not known. In the controlled clinical trials, malignancies (including non-melanoma skin cancers) were reported in 0.4% of patients receiving BENLYSTA and 0.4% of patients receiving placebo. In the controlled clinical trials, malignancies, excluding non-melanoma skin cancers, were observed in 0.2% (3/1458) and 0.3% (2/675) of patients receiving BENLYSTA and placebo, respectively. As with other immunomodulating agents, the mechanism of action of BENLYSTA could increase the risk for the development of malignancies.

Hypersensitivity Reactions, Including Anaphylaxis Hypersensitivity reactions, including anaphylaxis and death, have been reported in association with BENLYSTA. Delay in the onset of acute hypersensitivity reactions has been observed. Limited data suggest that patients with a history of multiple drug allergies or significant hypersensitivity may be at increased risk. In the controlled clinical trials, hypersensitivity reactions (occurring on the same day of infusion) were reported in 13% (191/1458) of patients receiving BENLYSTA and 11% (76/675) of patients receiving placebo. Anaphylaxis was observed in 0.6% (9/1458) of patients receiving BENLYSTA and 0.4% (3/675) of patients receiving placebo.

Manifestations included hypotension, angioedema, urticaria or other rash, pruritus, and dyspnea. Due to overlap in signs and symptoms, it was not possible to distinguish between hypersensitivity reactions and infusion reactions in all cases [see Warnings and Precautions]. Some patients (13%) received premedication, which may have mitigated or masked a hypersensitivity response; however, there is insufficient evidence to determine whether premedication diminishes the frequency or severity of hypersensitivity reactions.

BENLYSTA should be administered by healthcare providers prepared to manage anaphylaxis. In the event of a serious reaction, administration of BENLYSTA must be discontinued immediately and appropriate medical therapy administered. Patients should be monitored during and for an appropriate period of time after administration of BENLYSTA. Patients should be informed of the signs and symptoms of a hypersensitivity reaction and instructed to seek immediate medical care should a reaction occur.

Infusion Reactions In the controlled clinical trials, adverse events associated with the infusion (occurring on the same day of the infusion) were reported in 17% (251/1458) of patients receiving BENLYSTA and 15% (99/675) of patients receiving placebo. Serious infusion reactions (excluding hypersensitivity

reactions) were reported in 0.5% of patients receiving BENLYSTA and 0.4% of patients receiving placebo and included bradycardia, myalgia, headache, rash, urticaria, and hypotension. The most common infusion reactions (≥ 3% of patients receiving BENLYSTA) were headache, nausea, and skin reactions. Due to overlap in signs and symptoms, it was not possible to distinguish between hypersensitivity reactions and infusion reactions in all cases [see Warnings and Precautions]. Some patients (13%) received premedication, which may have mitigated or masked an infusion reaction; however there is insufficient evidence to determine whether premedication diminishes the frequency or severity of infusion reactions [see Adverse Reactions].

BENLYSTA should be administered by healthcare providers prepared to manage infusion reactions. The infusion rate may be slowed or interrupted if the patient develops an infusion reaction. Healthcare providers should be aware of the risk of hypersensitivity reactions, which may present as infusion reactions, and monitor patients closely.

Depression In the controlled clinical trials, psychiatric events were reported more frequently with BENLYSTA (16%) than with placebo (12%), related primarily to depression-related events (6.3% BENLYSTA and 4.7% placebo), insomnia (6.0% BENLYSTA and 5.3% placebo), and anxiety (3.9% BENLYSTA and 2.8% placebo). Serious psychiatric events were reported in 0.8% of patients receiving BENLYSTA (0.6% and 1.2% with 1 and 10 mg/kg, respectively) and 0.4% of patients receiving placebo. Serious depression was reported in 0.4% (6/1458) of patients receiving BENLYSTA and 0.1% (1/675) of patients receiving placebo. Two suicides (0.1%) were reported in patients receiving BENLYSTA. The majority of patients who reported serious depression or suicidal behavior had a history of depression or other serious psychiatric disorders and most were receiving psychoactive medications. It is unknown if BENLYSTA treatment is associated with increased risk for these events.

Patients receiving BENLYSTA should be instructed to contact their healthcare provider if they experience new or worsening depression, suicidal thoughts, or other mood changes.

Immunization Live vaccines should not be given for 30 days before or concurrently with BENLYSTA as clinical safety has not been established. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving BENLYSTA or the effect of BENLYSTA on new immunizations. Because of its mechanism of action, BENLYSTA may interfere with the response to immunizations.

Concomitant Use with Other Biologic Therapies or Intravenous Cyclophosphamide BENLYSTA has not been studied in combination with other biologic therapies, including B-cell targeted therapies, or intravenous cyclophosphamide. Therefore, use of BENLYSTA is not recommended in combination with biologic therapies or intravenous cyclophosphamide.

ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Clinical Trials Experience The data described below reflect exposure to BENLYSTA plus standard of care compared with placebo plus standard of care in 2133 patients in 3 controlled studies. Patients received BENLYSTA at doses of 1 mg/kg (N=673), 4 mg/kg (N=111; Trial 1 only), or 10 mg/kg (N=674) or placebo (N=675) intravenously over a 1-hour period on Days 0, 14, 28, and then every 28 days. In two of the studies (Trial 1 and Trial 3), treatment was given for 48 weeks, while in the other study (Trial 2) treatment was given for 72 weeks [see Clinical Studies]. Because there was no apparent dose-related increase in the majority of adverse events observed with BENLYSTA, the safety data summarized below are presented for the 3 doses pooled, unless otherwise indicated; the adverse reaction table displays the results for the recommended dose of 10 mg/kg compared with placebo.

The population had a mean age of 39 (range 18-75), 94% were female, and 52% were Caucasian. In these trials, 93% of patients treated with BENLYSTA reported an adverse reaction compared with 92% treated with placebo.

The most common serious adverse reactions were serious infections (6.0% and 5.2% in the groups receiving BENLYSTA and placebo, respectively) [see Warnings and Precautions].

The most commonly-reported adverse reactions, occurring in ≥5% of patients in clinical trials were nausea, diarrhea, pyrexia, nasopharyngitis, bronchitis, insomnia, pain in extremity, depression, migraine, and pharyngitis.

The proportion of patients who discontinued treatment due to any adverse reaction during the controlled clinical trials was 6.2% for patients receiving BENLYSTA and 7.1% for patients receiving placebo. The most common adverse reactions resulting in discontinuation of treatment (≥1% of patients receiving BENLYSTA or placebo) were infusion reactions (1.6% BENLYSTA and 0.9% placebo), lupus nephritis (0.7% BENLYSTA and 1.2% placebo), and infections (0.7% BENLYSTA and 1.0% placebo).

Brief summary of Prescribing Information continued on reverse.

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

Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women exposed to BENLYSTA, a pregnancy registry has been established.

Healthcare professionals are encouraged to register patients and pregnant women are encouraged to enroll themselves by calling 1-877-681-6296.

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

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

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

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

Placebo + Standard of Care (n = 675) %

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

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

Immunogenicity In Trials 2 and 3, anti-belimumab antibodies were detected in 4 of 563 (0.7%) patients receiving BENLYSTA 10 mg/kg and in 27 of 559 (4.8%) patients receiving BENLYSTA 1 mg/kg. The reported frequency for the group receiving 10 mg/kg may underestimate the actual frequency due to lower assay sensitivity in the presence of high drug concentrations. Neutralizing antibodies were detected in 3 patients receiving BENLYSTA 1 mg/kg. Three patients with anti-belimumab antibodies experienced mild infusion reactions of nausea, erythematous rash, pruritus, eyelid edema, headache, and dyspnea; none of the reactions was life-threatening. The clinical relevance of the presence of anti-belimumab antibodies is not known.

The data reflect the percentage of patients whose test results were positive for antibodies to belimumab in specific assays. The observed incidence of antibody positivity in an assay is highly dependent on several factors, including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to belimumab with the incidence of antibodies to other products may be misleading.

DRUG INTERACTIONS Formal drug interaction studies have not been performed with BENLYSTA. In clinical trials of patients with SLE, BENLYSTA was administered concomitantly with other drugs, including corticosteroids, antimalarials, immunomodulatory and immunosuppressive agents (including azathioprine, methotrexate, and mycophenolate), angiotensin pathway antihypertensives, HMG-CoA reductase inhibitors (statins), and NSAIDs without evidence of a clinically meaningful effect of these concomitant medications on belimumab pharmacokinetics. The effect of belimumab on the pharmacokinetics of other drugs has not been evaluated [see Pharmacokinetics].

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C. There are no adequate and well-controlled clinical studies using BENLYSTA in pregnant women. Immunoglobulin G (IgG) antibodies, including BENLYSTA, can cross the placenta. Because animal reproduction studies are not always predictive of human response, BENLYSTA should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. Women of childbearing potential should use adequate contraception during treatment with BENLYSTA and for at least 4 months after the final treatment.

Nonclinical reproductive studies have been performed in pregnant cynomolgus monkeys receiving belimumab at doses of 0, 5 and 150 mg/kg by intravenous infusion (the high dose was approximately 9 times the anticipated maximum human exposure) every 2 weeks from gestation day 20 to 150. Belimumab was shown to cross the placenta. Belimumab was not associated with direct or indirect teratogenicity under the conditions tested. Fetal deaths were observed in 14%, 24% and 15% of pregnant females in the 0, 5 and 150 mg/kg groups, respectively. Infant deaths occurred with an incidence of 0%, 8% and 5%. The cause of fetal and infant deaths is not known. The relevance of these findings to humans is not known. Other treatment-related findings were limited to the expected reversible reduction of B cells in both dams and infants and reversible reduction of IgM in infant monkeys. B-cell numbers recovered after the cessation of belimumab treatment by about 1 year post-partum in adult monkeys and by 3 months of age in infant monkeys. IgM levels in infants exposed to belimumab in utero recovered by 6 months of age.

Pediatric Use Safety and effectiveness of BENLYSTA have not been established in children.

Geriatric Use Clinical studies of BENLYSTA did not include sufficient numbers of subjects aged 65 or over to determine whether they respond differently from younger subjects. Use with caution in elderly patients.

Race In Trial 2 and Trial 3, response rates for the primary endpoint were lower for black subjects in the BENLYSTA group relative to black subjects in the placebo group [see Clinical Studies]. Use with caution in black/AfricanAmerican patients.

OVERDOSAGE There is no clinical experience with overdosage of BENLYSTA. Two doses of up to 20 mg/kg have been given by intravenous infusion to humans with no increase in incidence or severity of adverse reactions compared with doses of 1, 4, or 10 mg/kg.

PATIENT COUNSELING INFORMATION See Medication Guide.

Advice for the Patient Patients should be given the Medication Guide for BENLYSTA and provided an opportunity to read it prior to each treatment session. It is important that the patient’s overall health be assessed at each infusion visit and any questions resulting from the patient’s reading of the Medication Guide be discussed.

Mortality: Patients should be advised that more patients receiving BENLYSTA in the main clinical trials died than did patients receiving placebo treatment [see Warnings and Precautions].

Serious Infections: Patients should be advised that BENLYSTA may decrease their ability to fight infections. Patients should be asked if they have a history of chronic infections and if they are currently on any therapy for an infection [see Warnings and Precautions]. Patients should be instructed to tell their healthcare provider if they develop signs or symptoms of an infection.

Hypersensitivity/Anaphylactic and Infusion Reactions: Educate patients on the signs and symptoms of anaphylaxis, including wheezing, difficulty breathing, peri-oral or lingual edema, and rash. Patients should be instructed to immediately tell their healthcare provider if they experience symptoms of an allergic reaction during or after the administration of BENLYSTA [see Warnings and Precautions].

Depression: Patients should be instructed to contact their healthcare provider if they experience new or worsening depression, suicidal thoughts or other mood changes. [see Warnings and Precautions].

Immunizations: Patients should be informed that they should not receive live vaccines while taking BENLYSTA. Response to vaccinations could be impaired

by BENLYSTA [see Warnings and Precautions].

Pregnancy and Nursing Mothers: Patients should be informed that BENLYSTA has not been studied in pregnant women or nursing mothers so the effects of BENLYSTA on pregnant women or nursing infants are not known. Patients should be instructed to tell their healthcare provider if they are pregnant, become pregnant, or are thinking about becoming pregnant [see Use in Specific Populations]. Patients should be instructed to tell their healthcare provider if they plan to breastfeed their infant [see Use in Specific Populations].

BENLYSTA is a registered trademark of Human Genome Sciences, Inc., used under license by GlaxoSmithKline.

Manufactured by: Human Genome Sciences, Inc. Rockville, Maryland 20850 U.S. License No. 1820 Marketed by:

Human Genome Sciences, Inc. Rockville, MD 20850

GlaxoSmithKline Research Triangle Park, NC 27709

Call for Papers American Health & Drug Benefits offers an open forum for all healthcare participants to exchange ideas and present their data, innovations, and initiatives to facilitate patient-centered healthcare and benefit design models that meet the needs of all stakeholders—Distributors, Employers, Manufacturers, Patients, Payers, Providers, Purchasers, Regulators, and Researchers.

Readers are invited to submit articles that aim at improving the quality of patient care and patient well-being while reducing or controlling costs, enhancing the health of communities and patient populations, as well as other topics relevant to benefit design with specific implications to policymakers, payers, and employers.

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

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

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

Clinical Topics of High Interest: Aging—With the aging of the US population there is a growing need for early implementation of outcomes-based preventive and therapeutic strategies for older people.

Allergies—Allergies, such as allergic or seasonal rhinitis, affect millions of Americans daily, resulting in a significant economic burden and human cost. Under­treatment and lack of adherence are common obstacles to patient management.

Arthritis—Musculoskeletal conditions are on the increase, yet many patients are undiagnosed and untreated.

Comparing new and emerging therapies is a key target for improving patient outcomes and reducing costs.

Cancer care—The growing focus on high-cost biologic agents dictates an enhanced study of these therapeutic options, including reimbursement policies and cost management.

Cardiovascular disease—Outcomes-based research on appropriate therapies, cost comparisons, emerging prevention strategies, and best practices will enhance readers’ decision-making.

Diabetes, Obesity—The growing epidemics of these twin metabolic conditions mandates a thorough examination of best therapies, adherence issues, access, and prevention strategies.

Gastrointestinal conditions—Recognizing GI conditions, such as hepatitis C, Crohn’s disease, or inflammatory bowel disorder, remains a challenge.

Infectious Diseases—The spread of common and emerging pathogens within the hospital and in the community remains a major concern requiring increased vigilance.

MENTAL DISORDERS—Depression, bipolar disorder, and schizophrenia exert a huge financial and human burden on individuals, employers, and payers. Topics of interest include comparative effectiveness analyses, adherence, best practices, and reimbursement.

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

Manuscripts should follow the Manuscript Instructions for Authors available at www.AHDBonline.com.

Submit articles to editorial@engagehc.com. For more information, call 732-992-1892.

Vol 6, No 7

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AN 8-PART SERIES

Value-BasedCare IN MULTIPLE MYELOMA

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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

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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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Original Article

Communication Strategies Must Be Tailored to a Medication’s Targeted Population: Lessons from the Case of BiDil Chamika Hawkins-Taylor, MHA, PhD; Angeline M. Carlson, PhD Background: The American population’s diversity continues to grow, and its racial and ethnic mixes are changing. The US healthcare system must confront this changing reality. The introduction of isosorbide dinitrate/hydralazine hydrochloride (BiDil) to the US marketplace was a move toward recognizing these changing consumer needs. BiDil was approved specifically as a secondary treatment for heart failure in African-American patients. It remains the first and only drug approved by the US Food and Drug Administration for a race-based indication. To ensure commercial success, a drug must be made “visible” to healthcare providers and to consumers.

Objectives: To describe and analyze the case of BiDil and its potential implications for drugs developed for targeted populations to help them avoid a similar fate of market withdrawal because of commercial considerations.

Method: This analysis is based on 12 comprehensive interviews with 5 clinical investigators, 1 minority healthcare provider, and 5 pharmaceutical representatives, as well as a review of the literature. Overall, 12 one-hour semistructured interviews were conducted. Of the 11 interviewees, 10 were interviewed once and 1 was interviewed once early in the process and then had a second interview by the end of the study. When the 12 scheduled interviews were completed, the recordings were transcribed and subjected to analysis through the use of a readily available computer software package, using concepts and themes collected from the literature and the interviewees’ responses.

Results: The interviewees lacked consensus regarding the unique nature of BiDil. The clinical researchers considered it innovative in identifying that taking the 2 drugs together produced the greatest clinical effect in African-American patients with heart failure. For them, BiDil represented an innovation in the emerging field of personalized medicine. However, they were dismayed to see that these beliefs were challenged by the medical community and their physician colleagues. They reported that practicing, mainly primary care physicians considered the development of a branded medication that combined 2 older drugs to be superfluous, because the same effect could be achieved by administering each agent individually at the same time. Obtaining a patent for BiDil, therefore, was seen simply as a desire for commercial gain. During the approval hearings, representatives of the sponsored company attributed these concerns to “misinformed physicians” and “uninformed patients.”

Conclusion: The case of BiDil demonstrates that a marketing strategy for a population with unique health issues requires an understanding of underlying cultural, social, and economic underpinnings. Ignorance of these dynamics within the African-American community was blatantly reflected at the launch of the drug. Although BiDil remains a treatment option, there is no marketing effort to promote its use. The failure to capture the targeted market for the drug has important implications for the future of commercial considerations in the development of race-based medications.

Stakeholder Perspective, page 411

Am Health Drug Benefits.

2013;6(7):401-412 www.AHDBonline.com Disclosures are at end of text

Dr Hawkins-Taylor is Health Improvement Coordinator with Blue Cross Blue Shield of Minnesota, Minneapolis; Dr Carlson is Clinical Assistant Professor, Department of Pharmaceutical Care & Health Systems, University of Minnesota College of Pharmacy, Minneapolis. This article is based on Dr Hawkins-Taylor’s PhD dissertation at the University of Minnesota College of Pharmacy.

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T

he diversity of the American population is continuing to grow. Not only is the American population aging, but its racial and ethnic mixes are also changing.1 In the next 30 years, a dynamic shift will occur within the US population, in which Caucasian Americans, once the majority population, are projected to become the minority, representing less than 50% of the population.1 In response, the American marketplace has become and will continue to become more diversified; what began as ethnically focused specialty businesses (eg, Asian or African groceries and African-American beauty salons) that are located in ethnically dominant neighborhoods have expanded, and will further expand, into the commercial mainstream.

The US healthcare system must also confront this changing reality. The US pharmaceutical industry has largely been focused on product development that delivers the most rapid and largest return on the substantial investment in research and development required to bring a drug to market.2 The industry has argued that large-market drugs (ie, drugs for prevalent diseases in developed countries) offset market losses for orphan and other small-market offerings.3 Large-market drugs, however, may not have complete data sets to examine the response differences between population groups, and they are not always readily available for low-income or uninsured populations.3 As the US population continues to diversify, the pharmaceutical and the healthcare industries will face increased pressures to ensure that the healthcare needs of multiple population groups are guaranteed and that access to targeted healthcare technologies is ensured.

The Case of BiDil The move toward recognizing differences in healthcare needs for a specific population began in the early 2000s with the development, US Food and Drug Administration (FDA) approval, and introduction of isosorbide dinitrate/hydralazine hydrochloride (BiDil; Arbor Pharmaceuticals) into the US marketplace.4 BiDil was approved by the FDA on June 23, 2005, specifically as a secondary treatment for heart failure (HF) in African-American patients.5,6 It remains the first and only drug approved in the United States by the FDA for a race-based indication. The market adoption of BiDil was low, however, reaching less than 10% of its targeted population, and this once-promising drug, which was introduced to treat a very burdensome disease in the African-American community, ultimately was viewed as consumer and industry failures.7 The exploration of BiDil’s marketing efforts represents an opportunity to increase our understanding of healthcare product marketing to population subgroups.

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Key Points Isosorbide dinitrate/hydralazine hydrochloride (BiDil) was approved in 2005 as a secondary treatment for heart failure in African-American patients. ➤ It is the first and only drug approved by the US Food and Drug Administration (FDA) for a racebased indication; the FDA noted that the generic drugs were not comparable to the branded agent in efficacy. ➤ BiDil was launched into the US market with a marketing campaign focused exclusively on the African-American community. ➤ Some patients were wary of a drug targeted to African Americans only, yet many could not afford the drug. ➤ Physicians were reluctant to prescribe a drug using race-based terms with patients. ➤ Ignorance of the social and cultural underpinnings of the African-American community was reflected at the launch of BiDil, which ultimately led to its market failure. ➤ The important message regarding the need to treat heart failure in African Americans with a combination of vasodilator therapies was lost in this controversial case. ➤ The concept of personalized medicine, albeit mentioned, was never fully explored in relation to this drug. ➤ The failure to capture the market with BiDil may signal that pursuing research to understand the underlying racial and ethnic responses to medical treatment is not commercially viable. ➤

BiDil’s story begins by looking at the burden of HF in African Americans.8 Early epidemiology studies suggested that African Americans are at greater risk of developing HF because of their increased incidence of hypertension and related comorbid diseases.9 In addition, differential rates of obesity, a significant cardiovascular (CV) risk factor, were also reported based on racial and ethnic differences.9 Other studies reported the development of HF at an earlier age and with greater morbidity in the African-American population.10,11 African Americans also presented with advanced HF, which is characterized by more severe, left ventricular dysfunction that is exacerbated by decreased renal function and the presence of diabetes.10 In the 1980s and 1990s, 2 clinical trials—VasodilatorHeart Failure Trial (V-HeFT) I and V-HeFT II—were conducted to investigate protocols for the treatment of

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HF that would bring about better patient outcomes and quality of life.12 A secondary analysis of the data from these 2 trials discovered a clear survival benefit with the use of vasodilator therapy as an adjunct treatment in HF that is more pronounced in African-American patients.13 These findings brought new interest to the 2 long-established vasodilators, isosorbide dinitrate and hydralazine hydrochloride, when used in combination for the treatment of HF.13-15 The positive findings from these analyses also led to discussions among clinical investigators and representatives of NitroMed (Lexington, MA), the trial sponsor, about the commercial viability of a fixed-dose combination drug of isosorbide dinitrate and hydralazine hydrochloride. Ultimately, the decision was made to submit a New Drug Application to the FDA. The FDA requested a clinical trial that would confirm the secondary findings of the V-HeFT trials that would further establish the beneficial effects of isosorbide dinitrate and hydralazine hydrochloride when used in combination in AfricanAmerican patients; hence the African-American Heart Failure Trial (A-HeFT), sponsored by NitroMed, was subsequently undertaken.6 The A-HeFT trial compared the effect of isosorbide dinitrate/hydralazine hydrochloride combination on mortality, time to first hospitalization, and quality of life among 1050 African Americans with New York Heart Association (NYHA) stage III or IV HF.6 The combination therapy was shown to reduce all-cause mortality rates by 43% and time to first hospitalization by 39%, as well as improve quality-of-life outcomes in this patient population, as measured by the Minnesota Living With Heart Failure questionnaire, a 21-question self-administered instrument.6 Because of a significantly increased mortality rate in the cohort receiving placebo only, the study was halted early, after only 3 years.6 With this further confirmation from A-HeFT and extensive scrutiny,6 the FDA approved BiDil for the treatment of African Americans with HF.5 For the first time in the history of FDA approvals, a drug was granted an indication for use in a specific, race-based population.

The FDA specifically approved BiDil as an adjunct therapy for African Americans with severe HF (NYHA stage III or IV HF).5,16 In the US pharmaceutical industry, FDA approval of a new drug sets into motion marketing plans for a commercial launch of that medication.17 To ensure commercial success, the consumers—doctors and patients—must understand the drug’s essential benefit and must see the drug as meeting a critical need for the treatment of an illness or disease. The failure to capture the targeted market for the drug may mean market failure if the percentage of targeted users remains low. Such failure could

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Table 1 The Study Cohort Interviewees, N

Percent of total sample

Physician and/or A-HeFT researcher

5

45a

Pharmaceutical representatives

5

36

Minority healthcare provider

1

18

Interviewee category

One of these 5 interviewees was interviewed twice.

A-HeFT indicates African-American Heart Failure Trial.

a

ultimately result in the withdrawal of the drug from the marketplace. In the case of BiDil, market failure could signal to researchers, the pharmaceutical industry, and to consumers that pursuing clinical investigations to understand the underlying racial and ethnic responses to medical treatment is not a commercially viable endeavor.

Of greater importance, however, is the message that a drug combination that has been demonstrated in clinical trials to be the most effective therapy for a specific subpopulation, in this case African Americans, for the treatment of a condition that is prevalent in that population would be lost. The goals of this article are to describe how marketing missteps led to this fate for BiDil, and to explore the implications of this case for future drugs with a targeted subpopulation of patients. Interviews with key decision makers who were responsible for the commercial development and market launch of BiDil were conducted to shed light on its short-lived commercial experience to help to prevent drugs that are needed in targeted populations from experiencing a similar fate.

Methods Interview Strategy, Content, and Analytic Plan The sample cohort for this analysis included interviews with 5 clinical investigators, 1 minority healthcare provider, and 5 pharmaceutical representatives, including from upper and middle management, and a brand marketing team (Table 1).

Twelve, 1-hour semistructured interviews were conducted with adequate time for open, wide-ranging conversations. Each of the 11 interviewees was interviewed once. One interviewee, however, was interviewed early in the process and then submitted to a second interview to offer clarifications toward the end of the study. To ensure that interviewees represented a comprehensive range of job functions, each interview ended with a request for identification of any additional persons who would meet the definition of a key decision maker for the marketing of BiDil. This process of identifying qualified interviewees and eliciting input for additional interviewees is referred to as snowball sampling and is a well-­

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Figure 1 Antecedents to Brand Equity Applied to BiDil Antecedents

Consequences

Market-related • Perception of innovation • Social acceptance • Adoption

• Research community support • Physician support • Patient support • Payer coverage

Brand equity

• Guideline adherence • Prescriptions filled

• Brand awareness

Firm-related • Diffusion of innovation • Marketing strategy

• Reduced disparities

• Brand loyalty

• Patient compliance

• Brand associations

Commercial success

• National media coverage

• Perceived quality

• Firm profits • Brand extensions

Policy-related • Clinical trial success • Market exclusivity • Accessibility

NOTE: The conceptual framework for the commercial success of a drug is adapted from the Aaker model24 and considers the antecedents and consequences of drug commercialization, and how they are conceptualized around a brand equity model.

accepted process for qualitative interviews.18 The recorded and transcribed interviews began with the 5 clinical investigators who represented academic institutions and had integral roles in the design, data collection, analysis, and interpretation of the A-HeFT clinical trial outcomes. The dialogues continued with rep­ resentatives of the pharmaceutical company NitroMed, which included 5 individuals of upper- and midlevel management, and 1 minority healthcare provider representing an organization that was advocating on behalf of BiDil. The concepts and themes explored in the interviews included the need for a medication therapy specifically targeted to African Americans with HF, and the company’s ability to market to African Americans in a socially and culturally acceptable manner.

When the total 12 scheduled interviews were completed, the recordings were transcribed and subjected to classical content analysis, which was facilitated by the use of a readily available computer software package (NVivo 8, qualitative data analysis software; QSR International Pty Ltd, Melbourne, Australia). NVivo, originally named NUD*IST, was developed in 1981 to aid in the organization and management of qualitative data.19 The software is designed to manage document collections (such as the BiDil interview transcripts) and to serve as a coding system where ideas and concepts are identified and stored in a thematic, hierarchical classification that is unique to the software.19

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Results The thematic groupings identified by the software were compared with the themes that emerged during the literature review that were related to successful product marketing.20-23 The conceptual framework for the commercial success of BiDil was based on the brand equity model, using the model antecedents and the consequences of drug commercialization (Figure 1).24 The themes identified based on the brand equity model are listed in Table 2,24 along with interview findings that illustrate those ideas.

Table 3 summarizes the additional themes that emerged outside of the realm of the brand equity model and are not generally considered in the literature related to market success. These additional themes may be important considerations for establishing drugs for targeted subpopulations.

The interviewees lacked consensus about the uniqueness of BiDil or the need for it. The clinical researchers who had investigated BiDil considered it innovative and necessary, because they had identified that both agents taken together produced the greatest clinical effect in African-American patients. This group represented 45% of those who were interviewed. For them, BiDil represented an innovation in the emerging field of personalized medicine.5 This concept was acknowledged in the FDA’s announcement of the approval of the drug.5 That conviction might have begun with an underlying

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Table 2 Research Themes Organized as Antecedents to Aaker’s Brand Equity Modela Category

Theme

Marketrelated

Perception of need

• • • •

Perception of innovation

• Dissenters said BiDil was the same as the available generics (taken together) • BiDil represents personalized care approaches

Social acceptance

• Marketing failed to convince physicians and patients of BiDil’s necessity • Idea of a “blacks-only drug” made physicians and patients uncomfortable • Belief by patients that something is wrong with the drug

Diffusion of innovation

• Limited budget—more money spent on salaries than on actual marketing of the product • The company was small, with limited resources • Support from a large company partner may have helped to garner support and use

Marketing strategy

• Better marketing messages should have been used to help people understand/accept the

Accessibility, cost

• Talking to private insurers could promote use • Use of a cost-savings program might have increased use • Introduction of Medicare Part D diminished BiDil’s visibility with pharmaceutical companies

Clinical trial success

• BiDil was considered a successful clinical trial (by FDA standards) because it had: • Ensured the rigor of trial design and protocol • Had a defined lead investigator (chair) who was involved in all research activities • Sound methodology • Early signals of positive response in African Americans • Scientific rigor • Safety and efficacy • Need for research

Market exclusivity

• Early research results prompted the FDA to approve the drug for African Americans—not

Firmrelated

Policyrelated

Interview findings Different treatments work in diverse groups The disease cause may differ depending on the patient Few understand the role heredity plays in how a disease is treated High blood pressure occurs at younger ages for black patients; as a result, heart failure may be diagnosed at an early age

use of race-based marketing

consultant feedback

• The FDA said that no approved generic had the same effects as BiDil

FDA indicates US Food and Drug Administration. a Aaker DA. Managing Brand Equity: Capitalizing on the Value of a Brand Name. New York, NY: Free Press; 1991.

physiologic premise about the differences in the way that blood vessels respond to stress in African Americans and in whites,9 which led to their proposal of the hypothesis that the vasodilator actions of 2 drugs used in combination would be a better therapeutic choice for African Americans with NYHA stage IV HF.6 The A-HeFT clinical trial investigated this hypothesis using a design that the researchers who were interviewed considered to be a rigorous strategy that resulted in compelling findings.6 In contrast, the clinical investigators’ beliefs about the importance of BiDil were challenged when they presented research findings to the medical community. The interviewees described reactions of their physician colleagues with dismay. They reported that practicing, largely primary care physicians considered the establishment of a single, branded drug that combined 2 older

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drugs superfluous, because the same effect could be achieved by administering each agent separately at the same time. Therefore, they maintained that obtaining a patent for BiDil was simply a desire for commercial gain.

Discussion Factors Influencing Commercial Success An important aspect of commercial success for a drug is obtaining a patent that, by definition, ensures market exclusivity.25 The importance of a patent was reinforced by the interviewees. The issuance of a patent by the FDA indicates that the drug is safe and effective and conveys the sense that the drug is innovative, and the market exclusivity is warranted to encourage new drug development.16 In the case of BiDil, market exclusivity depended on establishing the need for a medication that combined

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Table 3 Emerging Themes beyond the Brand Equity Model Themes

Interview findings

Formulary-protected drug class

• Heart failure drug coverage should be mandated and added to the list of protected classes of

Health disparities

• Understanding race as a factor in disease etiology and therapeutic response • Real differences in how patients respond to therapies and how patients experience diseases

therapeutic categories

as a function of race Differences in the etiology of disease as a function of race Need to understand genetic differences as they relate to disease incidence and treatment response BiDil is an acknowledgment of differences in the way healthcare is accessed Race references are only appropriate in discussions of civil rights, lead to poor physician–patient communication • Lack of physician–patient rapport may result in compromised treatment • • • •

Social construct of race in America

• Historical distrust of white physicians by black patients

Physician decision-­ making

• Continuous engagement with physicians to increase chance of product buy-in • Need for more effective communication with physicians

Social capital

• • • •

Target markets

• Ensuing growth of personalized medicine and the need to define target groups by a more

Wall Street effect

• Expectation that BiDil would be widely used and therefore be a strong performer in the stock market

Potential benefits of partnership opportunities Role of opinion leaders in drug success Need to elicit government support and commitment or that of other influential source of support Media exposure substantial means than race or other surrogate characteristics

2 older, marketed drugs into a single tablet (ie, a fixeddose combination).15 Concerns about the innovativeness of and the need for a fixed-dose combination of isosorbide dinitrate and hydralazine hydrochloride were not new and were clearly noted in the FDA transcripts.26 In fact, both of these concerns were expressed during the public hearings that are a required forum in the drug approval process. The open hearings were held on June 16, 2005, to obtain public comment and opinion to inform the FDA’s final decision.26 NitroMed representatives attributed these and other concerns raised during those hearings to misinformed physicians and uninformed patients. One physician supporter from the National Minority Health Foundation who was at the hearing asked that dissenters become informed of the need for race to be considered in pharmaceutical treatment, and purported that the A-HeFT trial showed this requirement to be reasonable.26 Still, others at the hearings said that the drug did not represent an innovation, given that it had no absolute or implied correlation between social, racial, and genetic types.26 Even strong supporters of BiDil, such as the Association of Black Cardiologists and the National Association for the Advancement of Colored People (NAACP), questioned how a cost-prohibitive drug could benefit patients. Never-

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theless, 1 week after the hearings were concluded, the FDA granted market approval for BiDil.5,15

Marketing Efforts In June 2005, BiDil was launched into the US market with a nationwide campaign. Marketing representatives who participated in the interviews were part of a contracted sales force working to market BiDil to its targeted group. The representatives described a marketing strategy that at first suggested that BiDil would be a successful product; in its first 5 months, 3600 physicians wrote 14,000 BiDil prescriptions, and some Medicaid plans and a number of managed care plans began including BiDil on their formularies.27 During that same period, a partnership was formed between NitroMed and the NAACP, which would then advocate for BiDil’s health plan coverage,27 and advertisements began to appear in popular black magazines, such as Ebony and Essence.28,29 In contrast to the early favorable response, according to 1 interviewee from the pharmaceutical industry, and a report from the Wall Street Journal, sales reports for BiDil in late 2005 and throughout 2006 were “sluggish,” which was clear evidence of marginal market penetration30 (Table 4).

The concerns that were first expressed during the FDA approval hearings and later to the clinical research-

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Table 4 Targeted Drugs and Market Failure: Change in the Use of Isosorbide Dinitrate Alone, Hydralazine Hydrochloride Alone before versus after Market Introduction of BiDil Isosorbide dinitrate use only, before vs after introduction of BiDil Region Northeast, %

Patients

Midwest, %

South, %

West, %

Total use, % (N = 288,559)

Female Black

2.19 vs 0.0

0.0 vs 0.41

0.0 vs 0.0

0.0 vs 0.0

0.49 vs 0.05

Nonblack

0.13 vs 0.01

0.26 vs 4.02

3.0 vs 2.8

0.49 vs 0.0

0.31 vs 2.35

Male Black

1.7 vs 0.0

0.0 vs 0.0

0.0 vs 0.0

0.0 vs 0.0

0.47 vs 0.0

Nonblack

0.0 vs 0.63

0.02 vs 1.42

0.37 vs 0.0

0.02 vs 0.0

0.13 vs 0.38

Hydralazine hydrochloride use only, before vs after introduction of BiDil Region Northeast, %

Patients

Midwest, %

South, %

West, %

Total use, % (N = 322,130)

Female Black

0.0 vs 0.0

0.0 vs 0.39

0.0 vs 0.0

0.0 vs 0.0

0.0 vs 0.05

Nonblack

0.0 vs 1.37

0.44 vs 0.13

0.0 vs 2.28

1.19 vs 0.0

0.42 vs 1.35

0.010 vs 0.0

0.56 vs 2.30

0.0 vs 0.0

3.12 vs 2.03

2.11 vs 0.0

0.26 vs 0.21

0.0 vs 0.0

1.23 vs 0.09

Male Black

9.80 vs 14.74

Nonblack

3.95 vs 0.0

BiDil or isosorbide dinitrate/hydralazine hydrochloride use, before vs after introduction of BiDil Region

Total use, % (N = 14,247)

Northeast, %

Midwest, %

South, %

West, %

Female Black

0.0 vs 0.0

0.0 vs 7.40

0.0 vs 0.72

0.0 vs 0.0

0.0 vs 1.44

Nonblack

0.0 vs 0.0

0.0 vs 0.0

0.0 vs 0.02

0.0 vs 0.0

0.0 vs 0.01

Male Black

0.0 vs 7.23

0.0 vs 0.0

0.03 vs 0.002

0.59 vs 0.0

3.96 vs 0.27

Nonblack

0.0 vs 0.0

0.0 vs 0.0

0.0 vs 0.02

Patients

0.0 vs 0.01

0.0 vs 0.01

NOTE: Use of drugs indicated for heart failure as reported in National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey data.

ers resurfaced in an unlikely form. The BiDil controversy became a story line in the television drama House. In the pertinent episode (season 2, episode 203; 2005), Dr House’s resident, a black doctor, suggests BiDil to his patient. The therapy was only described as a drug that was proved to have positive effects in African Americans. The patient, a black man, responded in a manner that appeared to take the resident by surprise, “I don’t want any drug that’s for blacks only. Give me what the white folks are getting.”

This simple statement from a television show, which was characterized by 1 A-HeFT researcher as “shocking,” actually foreshadowed the forthcoming nonacceptance of BiDil by the African-American community and by healthcare professionals (Figure 2).

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According to the interviewees, in 2006, a second marketing strategy emerged and included targeting physicians who treated significant cohorts of black patients with HF, health fair productions with blood pressure and blood glucose assessments, presentations in black churches, and radio advertisements on predominantly urban radio stations. Print advertisements were also scheduled over a 3-month period for African-American media in the cities of Detroit, MI; Houston, TX; and Washington, DC.29 A 60-second radio advertisement introduced BiDil as an FDA-approved treatment for HF in African-American patients.29 During the interviews, the clinical researchers, NitroMed management personnel, and the marketing professionals discussed the hesitancy of patients to use and

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Figure 2 Modified Brand Equity Modela Antecedents Market-related • National media coverage • Research community support • Physician support

Consequences Commercial success • Prescriptions filled • Reduced disparities • Patient compliance • National media coverage • Firm profits • Brand extensions

Firm-related • Diffusion of innovation • Marketing strategy • Cost

Brand equity • Brand awareness • Brand loyalty • Brand associations • Perceived quality • Wall Street effect • Pharma effect

Policy-related • Payer coverage • Guideline adherence • Address disparities

Aaker DA. Managing Brand Equity: Capitalizing on the Value of a Brand Name. New York, NY: Free Press; 1991.

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physicians to prescribe a drug that was for “blacks only,” because they possessed “discomfort with using that label.”7 In the opinion of these interviewees, African Americans did not want to be singled out in physicians’ offices, and they offered the observation that “patients thought that maybe something was wrong with the drug.”7 In the end, physicians rejected the marketing messages and ultimately did not embrace the use of BiDil. NitroMed began planning advertisements that focused on quality of life rather than on black race, but such efforts never got under way.29 In 2009, BiDil’s sponsoring company, NitroMed, was acquired by Deerfield Capital Management for $36 million and was ultimately dissolved as a pharmaceutical company.31 In 2012, Deerfield Capital Management sold the rights to BiDil to Arbor Pharmaceuticals, Inc.32 Today, although BiDil remains on the market, no active marketing campaign is apparent.

Implications of the Findings BiDil’s clinical development program and subsequent marketing activity have implications for a wider audience in the US healthcare system, for the pharmaceutical industry regarding the costs of newly introduced therapies, and for the pharmaceutical industry and consumers alike regarding marketing approaches for medical conditions in African-American and other targeted populations.

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Implications for conveying scientific findings. Clinical researchers were convinced of the rigor of the trial design and the compelling nature of their findings. Effects were perceived as replicated, clinically important, and with potential applications to patients at excess risk for adverse CV outcomes. The treating physicians and the patients were not convinced. Instead of recognizing those differences in perception, and appropriately modifying the communication strategy, company representatives chose to identify the concerned stakeholders as misinformed or uninformed individuals. This stance presumed the underlying primacy of their clinical knowledge deduced from controlled studies and dismissed the experience and cultural perspectives that the perceived “nonscientists” (ie, physicians in practice and patients) possessed. Studies have shown that social factors, such as race/ethnicity, income, religiosity, social capital, and political identifications, are as important as knowledge and education in predicting trust in science.33,34 Many of the crucial scientific and technological issues that citizens need to address do not involve technical details as much as the broader issues related to environmental injustice, involuntary impositions of risk, failures of scientific research to meet genuine social needs, and manipulations of scientific information by powerful interest groups.34 The failure to present the clinical trial results in a more usable format and to address the concerns being raised in the community meant that as time

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went on, fewer prescriptions were written and therefore less patients received the medication. The presentation of science (clinical trial findings) in a socially identifiable and responsible manner is an important insight into marketing efforts for products that are introduced for population subgroups.

Implications for the US healthcare system. BiDil’s commercial demise also carries implications for the US healthcare system. The epidemiologic studies that consistently found that African Americans are at greater risk of developing HF because of their increased incidence of hypertension,35 and related comorbid diseases suggest that this may result in healthcare costs that would be avoidable with improved access to evidence-based care.

In 2010, the most recent year for which data are available, the United States spent an estimated $444 billion on CV disease treatment, medication, and lost productivity from disability related to CV disease.36 The proportion of this expenditure that can be attributed to the failure to appropriately treat the large CV burden in the African-American population has not been estimated, but it would be substantial given the unequal burden of the disease in this segment of the US population.8,35 It is known, however, that African Americans are less likely to receive drug therapy than whites who have similar diseases.37,38 The true harm done in the BiDil case is that by the inappropriate marketing of the drug, the important message—that the appropriate way to treat HF in the African-American population is with a combination of vasodilator therapies—was lost. The recommendation for this therapeutic strategy in this population exists in the American College of Cardiology (ACC) and the American Heart Association (AHA) guidelines, but the evidence for prescription utilization from a large database (ie, the Centers for Medicare & Medicaid Services Medicaid drug utilization database) indicates that the recommendation from the ACC/AHA was not followed in the years around BiDil’s active marketing period.7 If health equity between African Americans and white Americans is ever to be achieved, the burden of a disease such as HF relative to the costs to provide sufficient care and improved outcomes must be given serious consideration.

Cost implications for the pharmaceutical industry.

Health economists estimate the current cost of drug development in the United States to be between $1.3 billion and $1.7 billion.39 Because of the increasing cost of drug development, the cost of a marketed drug to the consumer may be considered exorbitant. Unless a new drug has a noticeably successful market launch based on a sophisticated communication platform, it may encounter challenges in adoption that hinder its market reach to patients who require it. The drug’s cost may be perceived as high

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and may therefore result in a lack in formulary placement and insurance payer coverage and with limited perceived value relative to other alternatives. Even if the newly marketed drug is covered by a payer, it may have an unfavorable formulary position and have high out-of-pocket costs or copayments for a patient.30 Furthermore, as it faced the typical challenges of a newly marketed drug, BiDil’s cost of therapy for chronic illness carried a harsh message. To recoup the costs of research and development and to realize a profit, NitroMed introduced BiDil at a cost of $16.20 daily. However, a 30-day supply of isosorbide dinitrate 20 mg and hydralazine hydrochloride 25 mg purchased individually was less than half of the cost of BiDil. BiDil’s higher price was not affordable for this patient population.

The true harm done in the BiDil case is that by the inappropriate marketing of the drug, the important message—that the appropriate way to treat HF in the AfricanAmerican population is with a combination of vasodilator therapies—was lost.

The target population for BiDil, while experiencing a higher burden of CV disease, also has a significant economic disadvantage, with high rates of unemployement compared with whites and therefore many patients are uninsured or underinsured.40 Whether physicians and patients accepted the arguments for the need for BiDil, its cost would still be considered prohibitive for its targeted population.40 The inability of a large portion of the African-American population to afford a $486 monthly prescription is problematic.

Implications for managing medical conditions in targeted populations, including African Americans. If marketing to a subpopulation is to be successful, BiDil’s story indicates that it requires a clear understanding of the underlying social concerns of the targeted group. For BiDil, this can be translated into an understanding of the underlying racial dynamics that exist in the United States.

At its very origins, BiDil had its commercialization strategy contaminated by a long history of perceived and genuine racial exploitation of black patients and racially biased inequities. Misinformation and failure to inform physicians and patients about the importance of clinical trial results in a fashion that was culturally appropriate, and the concordance of these findings with clinical guidelines, might have been the main culprits for unearthing old stigmas, fears, and national disgraces that

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are steeped in a not-too-distant past, which subsequently impaired adoption of the drug.

It is, however, the racial inequities to which members of NitroMed’s management team gave a perfunctory mention without much explanation. The researchers and physicians who were interviewed spoke candidly— with a tone of annoyance, concern, or sometimes exhaustion—about the persistent inequities in care, while seeming to protect nameless colleagues.

One physician who was interviewed mentioned the Tuskegee syphilis experiment and its placement within BiDil’s story. (The Tuskegee experiment was a deliberate failure to treat a group of black males with syphilis in Macon County, AL, between 1932 and 1972, even after the discovery of penicillin as a treatment in 1943.) The physician recalled the long history of distrust and discomfort of black patients concerning their physicians. These patients, even younger generations who are not fully aware, spoke of unlawful experimentation on blacks, using them as guinea pigs and not obtaining official consent to have them participate in research studies.41,42

The clinical development and commercialization failures of BiDil clearly demonstrate that to market a pharmaceutical agent to a subpopulation with unique healthcare issues, their underlying cultural, social, and economic dynamics must be understood.

The concerns about BiDil’s race-based indication began as early as the FDA’s public hearings. However, the company did not appear to give appropriate credence to what they heard in these meetings about a drug that was specifically designed for a racial subgroup. Even though NitroMed may have ignored those concerns, the physician and patient communities did not. Through editorials in professional journals,43,44 practicing physicians expressed their reluctance to prescribe BiDil, pointing largely to the idea of physicians’ discomfort using the terms “black,” “white,” or “race/ethnicity,” and inquiring about a patient’s race.

Conclusions The clinical development and commercialization failures of BiDil clearly demonstrate that to market a pharmaceutical agent to a subpopulation with unique healthcare issues, their underlying cultural, social, and economic dynamics must be understood. By their own admission, the

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group of decision makers interviewed for this study, who were in part responsible for the development, market launch, and promotion of BiDil, did not appreciate the cultural and racial perspectives that influence the interpretation of data, and the resulting patient and physician adoption of the therapy for which they ultimately sought and obtained FDA approval.

Without the acceptance of the African-American community—an acceptance that could have only been gained by overcoming long-held distrust of the medical community, presenting clinical research in a socially responsible way that recognizes the socioeconomic challenges of access to and affordability of medical care, and the presentation of clinical research in a manner that addresses the health beliefs of the community—BiDil ultimately was a market failure. Ignorance of the social and cultural underpinnings of the African-American community was reflected at the launch of BiDil, and its market failure contains important lessons for the future. The events with BiDil could signal that pursuing research to understand the underlying racial and ethnic responses to medical treatment is not a commercially viable strategy. n Author Disclosure Statement Dr Carlson is a Consultant to Medtronic Neuromodulation, BioMimetic Therapeutics, and Bayer HealthCare. Dr Hawkins-Taylor reported no conflicts of interest.

References

1. Vincent GK, Velkoff VA; US Census Bureau. The next four decades: the older population in the United States: 2010 to 2050: population estimates and projections.

May 2010. www.census.gov/prod/2010pubs/p25-1138.pdf. Accessed August 14, 2013.

2. Scherer FM. The link between gross profitability and pharmaceutical R&D spending. Health Aff (Millwood). 2001;20:216-220.

3. Simon F. Market access for biopharmaceuticals: new challenges. Health Aff (Millwood). 2006;25:1363-1370.

4. BiDil (isosorbide dinitrate and hydralazine hydrochloride) tablet [prescribing information]. Atlanta, GA: Arbor Pharmaceuticals; March 2013.

5. US Food and Drug Administration. FDA approves BiDil heart failure drug for black patients. June 23, 2005. www.fda.gov/NewsEvents/Newsroom/PressAnnounce ments/2005/ucm108445.htm. Accessed August 21, 2013.

6. Taylor AL, Ziesche S, Yancy C, et al; for the African-American Heart Failure Trial Investigators. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. N Engl J Med. 2004;351:2049-2057.

7. Hawkins C. Targeted Drugs and Market Failure: The Case of BiDil (RTM). Ann Arbor, MI: ProQuest UMI Dissertations Publishing; 2010.

8. Temple R, Stockbridge NL. BiDil for heart failure in black patients: the U.S. Food and Drug Administration perspective. Ann Intern Med. 2007;146:57-62.

9. Ishizawar D, Yancy C. Racial differences in heart failure therapeutics. Heart Fail Clin. 2010;6:65-74.

10. Kamath SA, Drazner MH, Wynne J, et al. Characteristics and outcomes in African American patients with decompensated heart failure. Arch Intern Med. 2008;168:1152-1158.

11. Schiller JS, Lucas JW, Ward BW, Peregoy JA. Summary health statistics for U.S. adults: National Health Interview Survey, 2010. Vital Health Stat 10. January 2012:1-207.

12. Cohn JN, Archibald DG, Ziesche S, et al. Effect of vasodilator therapy on mortality in chronic congestive heart failure. Results of a Veterans Administration Cooperative Study. N Engl J Med. 1986;314:1547-1552.

13. Carson P, Zeische S, Johnson G, Cohn JN. Racial differences in response to therapy for heart failure: analysis of the vasodilator-heart failure trials. Vasodilator-Heart Failure Trial Study Group. J Card Fail. 1999;5:178-187.

14. Cohn JN, inventor. Method of reducing mortality associated with congestive heart failure using hydralazine and isosorbide dinitrate. US patent 4,868,179. September 19, 1989.

15. Cheng JW. A review of isosorbide dinitrate and hydralazine in the management

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of heart failure in black patients, with a focus on a new fixed-dose combination. Clin Ther. 2006;28:666-678.

16. US Center for Drug Evaluation and Research. BiDil approval letter. June 23, 2005. www.accessdata.fda.gov/drugsatfda_docs/appletter/2005/020727ltr.pdf. Accessed April 8, 2010.

17. US Food and Drug Administration. How drugs are developed and approved.

Updated January 3, 2013. www.fda.gov/drugs/developmentapprovalprocess/howdrugs aredevelopedandapproved/. Accessed May 10, 2013.

18. Biernacki P, Waldorf D. Snowball sampling: problems and techniques of chain referral sampling. Sociol Method Res. 1981;10:141-163.

19. Bazeley P. Qualitative Data Analysis with NVivo. London: SAGE Publications; 2007.

20. Aaker DA, Biel AK, eds. Brand Equity and Advertising: Advertising’s Role in Building Strong Brands. Hillsdale, NJ: Lawrence Erlbaum Associates; 1993.

21. Aaker DA. Measuring brand equity across products and markets. Cal Manage Rev. 1996;38:102-120.

22. Farquhar PH. Managing brand equity. J Advert Res. 1990;30:RC7-RC12.

23. Balachandra R, Friar JH. Factors for success in R&D projects and new product innovation: a contextual framework. IEEE Trans Eng Manage. 1997;44:276-287.

24. Aaker DA. Managing Brand Equity: Capitalizing on the Value of a Brand Name.

New York, NY: Free Press; 1991.

25. US Food and Drug Administration. Frequently asked questions on patents and exclusivity. December 5, 2012. www.fda.gov/Drugs/DevelopmentApprovalProcess/ ucm079031.htm. Accessed May 11, 2013.

26. US Food and Drug Administration. Cardiovascular and Renal Drugs Advisory Committee: volume II. BiDil open public hearing. Transcript. June 16, 2005. www. fda.gov/ohrms/dockets/ac/05/transcripts/2005-4145T2.pdf. Accessed August 14, 2013.

27. NitroMed, Inc. Launch: NitroMed, Inc Annual Report on Form 10-K: 2005.

2006. http://library.corporate-ir.net/library/13/130/130535/items/199527/2005AR. pdf. Accessed August 14, 2013.

28. Jewell M; Associated Press State and Local Wire. Ad campaign for blacks-only heart drug touches lightly on race. Press release. September 1, 2006. www.southcoast today.com/apps/pbcs.dll/article?AID=/20060901/NEWS/309019973&cid=sitesearch.

Accessed August 14, 2013.

29. Associated Press. NitroMed plans ads for heart drug OK’d for blacks: spots aim to focus on quality of life rather than race. Press release. September 1, 2006. www.boston. com/business/globe/articles/2006/09/01/nitromed_plans_ads_for_heart_drug_okd_ for_blacks/. Accessed August 14, 2013.

30. Westphal SP. Heart medication approved for blacks faces uphill battle: as insurers debate costs and generics loom, BiDil fails to reach needy: the role of Medicare Part D. Wall Street Journal. October 1, 2006. http://online.wsj.com/article/SB1160964 45875393515.html. Accessed August 14, 2013.

31. Songini M. Deerfield buyout of NitroMed finalized. Boston Business Journal. April 27, 2009. www.bizjournals.com/boston/blog/mass-high-tech/2009/04/deerfield- buyout-of-nitromed-finalized.html. Accessed August 14, 2013.

32. Downey LJ. BiDil: alive and kicking. Lancet. 2012;379:1876.

33. Gauchat G. Politicization of science in the public sphere: a study of public trust in the United States, 1974 to 2010. Am Sociol Rev. 2012;77:167-187.

34. Weinberg J, Elliott KC. Science, expertise, and democracy. Kennedy Inst Ethics J. 2012;22:83-90.

35. Dibbins-Domingo K, Fernandez A. BiDil for heart failure in black patients: implications of the U.S. Food and Drug Administration approval. Ann Intern Med. 2007; 146:52-56.

36. National Center for Chronic Disease Prevention and Health Promotion. Heart disease and stroke prevention: addressing the nation’s leading killers. At a glance 2011. www.cdc.gov/chronicdisease/resources/publications/aag/pdf/2011/Heart-Diseaseand-Stroke-AAG-2011.pdf. Accessed August 15, 2013.

37. Kong MH, Peterson ED, Fonarow GC, et al. Addressing disparities in sudden cardiac arrest care and the underutilization of effective therapies. Am Heart J. 2010; 160:605-618.

38. Wyatt SB, Williams DR, Calvin R, et al. Racism and cardiovascular disease in African Americans. Am J Med Sci. 2003;325:315-331.

39. DiMasi JA, Grabowski HG, Vernon J. R&D costs and returns by therapeutic category. Drug Inf J. 2004;38:211-223.

40. Roberts CB, Couper DJ, Chang PP, et al. Influence of life-course socioeconomic position on incident heart failure in blacks and whites: the Atherosclerosis Risk in Communities Study. Am J Epidemiol. 2010;172:717-727.

41. Skloot R. The Immortal Life of Henrietta Lacks. New York, NY: Crown Publishers; 2010.

42. Corbie-Smith G, Thomas SB, Williams MV, Moody-Ayers S. Attitudes and beliefs of African Americans toward participation in medical research. J Gen Intern Med. 1999; 14:537-546.

43. Brody H, Hunt LM. BiDil: assessing a race-based pharmaceutical. Ann Fam Med. 2006;4:556-560.

44. Krimsky S. The short life of a race drug. Lancet. 2012;379:114-115.

Stakeholder Perspective Much More than Biomarkers: Sociodemographic Variables in Personalized Medicine

By Michael F. Murphy, MD, PhD Chief Medical Officer and Scientific Officer, Worldwide Clinical Trials, King of Prussia, PA

In a literature replete with references to personalized medicine tailored to variations in genetic- and diseaserelated phenotypes, the case study presented by Hawkins-Taylor and Carlson in this issue of the journal emphasizes the importance of incorporating sociodemographic variables into this definition. The adoption of new therapeutics results from interactions between patients and healthcare systems in a mosaic wherein scientific data must be congruent with cultural and ethnic perceptions of medication and health status. Neither a regulatory strategy facilitating approval, evidence of utility in well-controlled trials, nor the existence of unmet needs based on epidemiologic data assured acceptance of BiDil by patients and physicians in the absence of values

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that are relevant to the targeted population.

RESEARCHERS: Data leading to the approval of BiDil for the treatment of heart failure in self-identified African-American patients followed a development pathway that is recognized in other therapeutic areas. In investigations with overall favorable results, biologically plausible secondary findings within a subgroup consisting of self-identified African Americans prompted a confirmatory study yielding a statistically significant, clinically important effect in a meaningful composite end point.1,2 In addition, BiDil was approved as adjunctive therapy for a clinical condition in which neither of the constituent agents in isolation had previously demonstrated utility.3 Failure to achieve meaningful adoption after approval, Continued

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Stakeholder Perspective Continued despite a methodologically rigorous pedigree, emphasizes the importance of ensuring clinical and commercial stakeholder convergence during, not after, the drug development process.

The content and analytic plan by Hawkins-Taylor and Carlson employed “snowball sampling.”4 Used for specialized populations, this non–probability-based sampling method generated a hierarchical classification scheme contrasting variables particularly related to social acceptance and clinical trial success that offered plausible explanations for failure to achieve product adoption.

Potential qualitative and quantitative interactions by region, sex, and race suggested avenues for additional inquiry. Survey methodology, including factorial designs evaluating a respondent’s choice, would inform designs of interventional trials regarding sample composition, the use of proxies (eg, extended family), and variables to support product positioning at introduction.

PAYERS: An inability to secure adoption of a fixeddose combination drug based on 2 compounds with established efficacy and safety is counterintuitive, given the attributes of a single daily medication, and disheartening, given the implications for healthcare utilization.

Fixed-dose combination products may reduce the complexity of use, counteract therapeutic inertia, and enhance adherence in the control of hypertension, as well as adherence to therapy in patients who have risk factors for cardiovascular disease.5,6 Historically, models for drug adoption placed emphasis on the physician, the specialty, and/or the intervention. The impact of gatekeepers, such as administrators and payers, on this decision-making process was not formally considered.7 “One-to-one” communication was influential, and strategies to promote the adoption of medical evidence trended toward comparability with repetition, even if techniques were initially characterized as ineffective (dissemination of published information or didactic sessions) or influential (eg, academic detailing, audit and feedback, educational outreach).8,9 The additional dimensions of race and ethnic concerns provided by this research thus create a Gordian knot of interrelated variables impacting adoption and compliance programs that are of interest to payers. Nevertheless, structures can be created in which survey methodology is used for hypothesis generation,10 whereas quasi-experimental designs (eg, stepped-wedge, pre–post designs) can evalu-

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ate the effectiveness of communication strategies for subgroups within a membership to enhance adoption.

PATIENTS: Although insurance coverage is an important antecedent to prescription medication access, even with comparable benefits and disease status, minority patients underutilize therapy.11 Medicaid policy affecting the behavior of prescribing physicians in minority areas demonstrates spillover effects into the non-Medicaid population in that community.12 In addition, patient perceptions of disease status affect adoption and adherence, such as semistructured interviews iden­ tifying a cultural model for breast cancer within low-­ income African-American women (ie, a stigmatizing and shameful condition) expressing sentiments very different from those associated with Caucasian patients (ie, a disease to be conquered).13,14 Facilitating access to novel medication through changes in healthcare policy for targeted populations is effective only with knowledge of the underlying social concerns and provides impetus for continued research.

1. Carson P, Ziesche S, Johnson G, Cohn JN. Racial differences in response to therapy for heart failure: analysis of the vasodilator-heart failure trials. J Card Fail. 1999; 5:178-187.

2. Taylor AL, Ziesche S, Yancy C, et al; for the African-American Heart Failure Trial Investigators. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. N Engl J Med. 2004;351:2049-2057.

3. US Food and Drug Administration. FDA approves BiDil heart failure drug for black patients. Press release. June 23, 2005. Updated April 4, 2013. www.fda.gov/ NewsEvents/Newsroom/PressAnnouncements/2005/ucm108445.htm. Accessed September 9, 2013.

4. Biernacki S, Waldorf D. Snowball sampling: problems and techniques of chain referral sampling. Sociol Methods Res. 1981;10:141-163.

5. Gupta AK, Arshad S, Poulter NR. Compliance, safety, and effectiveness of fixeddose combinations of antihypertensive agents: a meta-analysis. Hypertension. 2010; 55:399-407.

6. Thom S, Poulter N, Field J, et al; for the UMPIRE Collaborative Group. Effects of a fixed-dose combination strategy on adherence and risk factors in patients with or at high risk of CVD: the UMPIRE randomized clinical trial. JAMA. 2013;310:918-929.

7. Agrawal M, Calantone RJ. New drug adoption models: a review and assessment of future needs. Health Mark Q. 1995;12:93-111.

8. McGettigan P, Golden J, Fryer J, et al. Prescribers prefer people: the sources of information used by doctors for prescribing suggest that the medium is more impor­ tant than the message. Br J Clin Pharmacol. 2001;51:184-189.

9. Borenstein J, Chiou CF, Henning JM, et al. Physician attitudes toward strategies to promote the adoption of medical evidence into clinical practice. Am J Manag Care. 2003;9:225-234.

10. Harris JR, Cheadle A, Hannon PA, et al. A framework for disseminating evidence-based health promotion practices. Prev Chronic Dis. 2012;9:E22.

11. Briesacher B, Limcangco R, Gaskin D. Racial and ethnic disparities in prescription coverage and medication use. Health Care Financ Rev. 2003;25:63-76.

12. Headen A, Masia N. Exploring the potential link between Medicaid access restrictions, physician location, and health disparities. Am J Manag Care. 2005;11(spec no): SP21-SP26.

13. Burroughs VJ. The importance of individualizing prescribing among genetically and culturally diverse groups. Group Pract J. 2003;52:1-4.

14. Barg FK, Grier SA. Enhancing breast cancer communications: a cultural models approach. Int J Res Mark. 2008;25:335-342.

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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

healthcare reform

Yet Another Blow to the Medicaid Expansion

By Ross Margulies, JD, MPH, and Igor Gorlach, JD, MPH Mr Margulies and Mr Gorlach are Associates at Foley Hoag, LLP Ross D. Margulies

Igor Gorlach

T

he Affordable Care Act extends and simplifies Medicaid eligibility beginning January 1, 2014, by replacing Medicaid’s previous multiple categorical groupings and limitations with one simplified overarching rule: all individuals aged <65 years with incomes less than 138% of the federal poverty level ($15,415 for an individual or $26,344 for a family of 3 in 2012) who meet citizenship/lawful US status and state residency requirements are entitled to Medicaid benefits. The expansion, however, has suffered several setbacks to date, including a Supreme Court ruling that states that do not wish to participate in the expansion cannot be penalized for not participating.1 The latest— and less expected—setback was a decision by the Centers for Medicare & Medicaid Services (CMS) to only provide limited drug coverage for Medicaid beneficiaries in the Medicaid expansion population.

In the final rule on essential health benefits (EHBs), published July 5, 2013, CMS noted that requiring alternative benefit plans (ie, the plans that are offered to the Medicaid expansion population) to offer the same drug coverage as what is offered under existing Medicaid would be “overinclusive,” because it would conflict with the states’ flexibility in defining the amount, duration, and scope of the benefit for covered outpatient drugs for the alternative benefit plans.2 Individuals who are enrolled in “traditional” Medicaid have access to all drugs that are manufactured by companies that participate in the Medicaid drug rebate program (meaning that Medicaid beneficiaries have access to most medications on the market).

The decision by CMS departs from the proposed rule, in which CMS proposed to require the same Medicaid coverage for alternative benefit plans as is required for the existing Medicaid program. Instead, individuals in the Medicaid expansion are entitled to a set of basic services (also known as EHBs), which include coverage of prescription drugs, along with inpatient and outpatient services, physicians’ services, laboratory services, mental health services, well-child care services, preventive services, and vision and hearing services.

The prescription drug coverage available to individ-

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uals in the expansion population will be the greater of one drug per class of drugs or the same number of drugs as contained in each class of drugs included in the state Medicaid benchmark plan that is selected by the state.

In many cases, the prescription drug benefits that are available to individuals in the expansion population will be less robust than the coverage that is available to those in traditional Medicaid.

The overall effect on specific patient populations remains to be seen. The shift of discretion from federal standards to the states could result in a patchwork of coverage models for the Medicaid expansion population among the states (because each state’s benchmark coverage will be different). The originally proposed federal standards would have constituted minimum requirements for the states as a component of EHBs. Thus, the change in policy allows alternative benefit plans to reduce the coverage of prescription drugs for the Medicaid expansion population (alternative benefit plans are always free to cover additional drugs).

For providers, CMS’s final rule means that a patient with Medicaid is no longer just a patient with Medicaid. Rather, whether an individual is enrolled in traditional Medicaid or in an alternative benefit plan (as part of the expansion population) will determine the covered drugs that are available to them, and will therefore affect the physician’s prescribing behavior.

The news is not all bad—most benchmark plans will offer robust prescription drug coverage and, in some cases, may prove less cumbersome than some of traditional Medicaid’s existing requirements, including fewer “fail-first” and “step-therapy” requirements. n

References

1. Supreme Court of the United States. National Federation of Independent Business et al v. Sebelius, Secretary of Health and Human Services, et al. Syllabus No. 11393; Decided June 28, 2012. www.supremecourt.gov/opinions/11pdf/11-393c3a2. pdf. Accessed September 6, 2013.

2. Department of Health and Human Services. Centers for Medicare & Medicaid Services. Regulations and guidance. 42 CFR Parts 431,435,436, 438, 440, 447, 457.

Medicare Program. Medicaid and Children’s Health Insurance Programs: Essential Health Benefits in Alternative Benefit Plans, Eligibility Notices, Fair Hearing and Appeal Processes, and Premiums and Cost Sharing; Exchanges: Eligibility and Enrollment; Final Rule. Fed Reg. 2013;78(135):42,160-42,322. 2006/press_release_12062006.php. Accessed December 29, 2008.

www.AHDBonline.com

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Vol 6, No 7

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

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

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Review Article

New Drug Therapies for the Treatment of Overweight and Obese Patients Babak Mahgerefteh, DO; Michael Vigue, DO; Zachary Freestone, DO; Scott Silver, DO; Quang Nguyen, DO, FACP, FACE Background: Obesity is a serious and costly disease that is growing in epidemic proportions. Obesity-related hospitalizations have nearly tripled from 1996 to 2009. If the current trend in the growth of obesity continues, the total healthcare costs attributable to obesity could reach $861 billion to $957 billion by 2030. The American Medical Association has officially recognized obesity as a disease. Obesity is a public health crisis affecting approximately more than 33% of Americans and costing the healthcare system more than $190 billion annually.

Objectives: To review the 2 new drugs that were recently approved by the US Food and Drug Administration (FDA) for the treatment of obesity, lorcaserin HCl (Belviq) and phentermine/ topiramate (Qsymia) and their potential impact on the treatment of obese patients.

Discussion: Lifestyle modification is the first and mainstay treatment for obesity. Antiobesity drugs are indicated as adjuncts to a healthy, low-fat, low-calorie diet and an exercise plan.

Currently, 4 drugs are approved by the FDA for the treatment of obesity, 2 of which were approved after June 2012. These 2 drugs, Belviq and Qsymia, have added new tools for the treatment of obesity. In addition to reducing body mass index, these drugs have been shown to reduce hemoglobin A1c levels in patients with diabetes and blood pressure levels in patients with hypertension, as well as to decrease lipid levels in patients with hyperlipidemia. This article reviews the drugs’ mechanisms of action, evaluates landmark clinical studies leading to the FDA approval of the 2 drugs, their common side effects, and the benefits these new drugs can provide toward the management of the obesity epidemic that are different from other medications currently available.

Conclusion: The weight loss seen in patients who are using the 2 new medications has been shown to further improve other cardiometabolic health parameters, including blood pressure, blood glucose levels, and serum lipid levels. Based on clinical trials evidence, it is likely that many obese patients could benefit from these therapies, if used appropriately.

O

besity is a serious and costly disease, and 154.7 million Americans aged ≥20 years are obese or overweight.1 Of these, 78.4 million US adults are categorized as having a body mass index (BMI) of ≥30 kg/m2.1 Worldwide, the rate of obesity has nearly doubled since 1980.2 According to the World Health Organization estimates, in 2008 more than 1.4 billion adults aged ≥20 years were classified as overweight (BMI,

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25-29.9 kg/m2), and more than 200 million men and nearly 300 million women were classified as obese.2

Ethnicity and Sociocultural Factors Obesity, ethnicity, and socioeconomic status are closely intertwined. Non-Hispanic blacks tend to have the highest age-adjusted rates of obesity (49.5%) compared with Mexican Americans (40.4%), all Hispanics (39.1%),

Dr Mahgerefteh is Faculty, Internal Medicine, Valley Hospital Medical Center Internal Medicine Residency Program, Las Vegas, and Adjunct Faculty, College of Osteopathic Medicine, Touro University, NV; Dr Vigue is Chief Resident, Valley Hospital Medical Center Internal Medicine Residency Program, and University of New England College of Osteopathic Medicine, Biddeford, ME; Dr Freestone is Resident, Valley Hospital Medical Center Internal Medicine Residency Program, Las Vegas, NV; Dr Silver is Resident, Valley Hospital Medical Center Internal Medicine Residency Program, Las Vegas, NV; and Dr Nguyen is Medical Director, Las Vegas Endocrinology; Clinical Associate Professor, Clinical Education, Arizona College of Osteopathic Medicine, Glendale, AZ; and Adjunct Associate Professor of Endocrinology, Touro University of Nevada College of Osteopathic Medicine.

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and non-Hispanic whites (34.3%).3 With regard to socioeconomic status, among non-Hispanic black men and Mexican-American men, those with higher incomes are more likely to be obese than those with low incomes.3 Higher-income women are less likely to be obese than women with a lower income.3 There is also a trend showing that educated women (ie, who have college degrees) are less likely to be obese than less-educated women.1 According to the recent reports from the National Health and Nutrition Examination Survey (NHANES), the prevalence of obesity has increased among adult men and women between the 1988-1994 NHANES III and the 1999-2000 NHANES.4 Although the increases have been statistically significant in all racial and sex groups, the longitudinal data related to the development of obesity indicate that the rise in obesity rates in US women has been greatest in non-Hispanic African Americans, followed by Hispanics, and finally Caucasians.5 In addition, by age 29 years, the mean BMI of African-American women was >30 kg/m2, which is the cutoff point for obesity. Similar trends were observed in men; however, for African-American men, the acceleration in weight gain did not occur until after age 30 years.5 The exception to the data related to the increase in obesity among minorities is Asian Americans.5 Although obesity is more common in African Americans than in white Americans, the effect of obesity on mortality is more lethal for the latter group.5 It has been reported that nonsmoking white men and women without a history of disease who were at the highest BMI had a significantly higher risk of mortality than their average-weight counterparts (relative risk, 2.58 and 2.00, respectively); a similar association was not seen in African Americans.6 Environmental influences, such as abundance of food, food marketing, and access to food from restaurants and large-scale supermarkets, may contribute to the promotion of overweight and obesity.7 Other cultural differences related to sedentary lifestyle and socioeconomics, including work environment and cultural expectations, may also play a role in the overall increase in obesity.7 Evidence suggests that there may also be factors associated with genetic differences to support these trends of increasing BMI. The general consensus is that overweight and obesity are truly multifactorial in nature.7

Clinical and Economic Burden As of June 2013, the American Medical Association has officially recognized obesity as a disease based on the belief that “recognizing obesity as a disease will help change the way the medical community tackles this complex issue that affects approximately 1 in 3 Americans.”8 Obesity is a public health crisis affecting more

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Key Points In 2013, the American Medical Association has officially recognized obesity as a disease. ➤ Obesity prevalence is growing in epidemic proportions and is a risk factor for a wide range of other cardiometabolic diseases. ➤ Obesity-related hospitalizations have nearly tripled from 1996 to 2009. ➤ If the current growth trend of obesity continues, total healthcare costs attributable to obesity are projected to reach up to $957 billion by 2030. ➤ By mid-2012, 2 new drugs—lorcaserin HCl (Belviq) and phentermine/topiramate (Qsymia)— were approved for the treatment of obesity. ➤ In addition to reducing body mass index, these drugs reduce hemoglobin A1c levels in patients with diabetes, blood pressure levels in patients with hypertension, and decrease lipid levels in patients with hyperlipidemia. ➤ The ability to manage obesity and other associated cardiometabolic risk factors is an important development in the treatment options for obese or overweight patients, especially those with other cardiovascular comorbidities. ➤ Based on clinical trials evidence, it is anticipated that many obese or overweight patients who have access to these therapies could benefit from them, if used appropriately. ➤

than 33% of American adults and costing the healthcare system more than $190 billion annually.9 Obesity affects many health issues and is associated with a range of cardiometabolic health issues, which exacerbate costs. Obesity-related conditions include heart disease, stroke, type 2 diabetes, and certain types of cancer (eg, endometrial, colon, and breast cancers).3 Overweight and obesity are linked to more adult deaths worldwide than underweight.2 For example, 65% of the world’s population lives in countries where overweight and obesity are more death-related than underweight (including all high-income and most middle-income countries).2 Obesity-related hospitalizations have nearly tripled from 1996 to 2009.10 In 2009, there were approximately 2.8 million hospital stays for which obesity was either the primary or secondary diagnosis.10 The overall associated cost was a staggering $33.4 billion, or roughly 10% of aggregate hospital costs in 2009.4 If the current trends in the growth of obesity continue at this pace, the total healthcare costs that are attributable to obesity could reach between $861 billion and $957 billion by 2030,

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accounting for 16% to 18% of healthcare expenditures in the United States.1 In 2006, the per-capita medical spending for patients who are obese was $1429 (42%) greater than for normal-weight patients.11

Treatment of Obesity The mainstay of treatment and prevention for overweight and obesity remains making sensible and healthier diet choices as well as regular physical activity. But these often are not enough, as can be seen by the growing rates of obese Americans. Antiobesity drugs are indicated as adjuncts to a reasonable diet and an exercise plan.

From 1996 until 2012, only 2 drugs—orlistat (Xenical) and phentermine HCl (Adipex-P)—were approved by the US Food and Drug Administration (FDA) for the treatment of overweight and obesity. However, orlistat has multiple gastrointestinal side effects, including flatulence and fecal urgency, and phentermine HCl has multiple cardiac side effects, including palpitations, hypertension, and tachycardia. This makes these 2 drugs difficult for patients to take, and they are only ideal for a select subpopulation of patients.

Recently, 2 new drugs—phentermine and topiramate extended release (PHEN/TPM ER; Qsymia; VIVUS) and lorcaserin HCl (Belviq; Arena Pharmaceuticals)— have been approved by the FDA for the treatment of obesity.12,13 This article reviews their mechanisms of action, evaluates landmark clinical studies leading to their approval by the FDA, and discusses the common side effects, and the potential benefits that these drugs can provide in the management of the obesity epidemic.

Phentermine/Topiramate (Qsymia) Qsymia was approved in July 2012 by the FDA for the treatment of obesity.12 Consisting of a combination of phentermine and topiramate, Qsymia is indicated for use in addition to a low-calorie diet and increased physical activity for adults with an elevated BMI of ≥30 kg/m2 (ie, obesity) or ≥27 kg/m2 (ie, overweight) with at least 1 obesity-related condition.14 PHEN/TPM ER acts on obesity through the 2 different mechanisms of action of each of its components.

Phentermine is a sympathomimetic amine anorectic, which works to antagonize alpha-adrenergic receptors.14 Catecholamines, such as norepinephrine, are thought to be released into the hypothalamus in response to phentermine. This results in appetite suppression from an increase in blood leptin concentration and consequently in reduced food consumption. Leptin is one of the most important adipose-derived hormones that are manufactured primarily by adipose tissue. Leptin plays a crucial role in appetite, metabolism, and behavior.

Other metabolic effects and mechanisms of action may

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CONQUER and EQUIP: Phentermine/Topiramate Extended Table 1 Release as an Adjunct to Diet and Lifestyle Modification for Weight Loss Trial

CONQUER

EQUIP

Medication Phentermine/ topiramate extended release

Phentermine/ topiramate extended release

Patients

N = 2487

N = 1267

Method

7.5/46 mg daily (N = 498) vs 15/92 mg daily (N = 995) vs placebo (N = 994)

3.75/23 mg daily (N = 241) vs 15/92 mg daily (N = 512) vs placebo (N = 514)

Primary end point

Percent weight loss, proportion of patients achieving ≥5% weight loss

Percent weight loss, proportion of patients achieving ≥5% weight loss

Secondary end point

Weight loss, proportion of patients achieving at least 10% weight loss, change in waist circumference

Systolic and diastolic blood pressure, fasting glucose, lipid measure, waist circumference

P value

<.001 for both primary and secondary outcomes

<.001 for both primary and secondary outcomes

Side effects Dry mouth, paresthesia, constipation, insomnia, dizziness, dysgeusia

Paresthesia, dry mouth, constipation, dysgeusia, irritability

Summary

17.3%, 44.9%, and 66.7% weight loss of baseline body weight with placebo, 3.75/23 mg, and 15/92 mg, respectively

21%, 62%, 70% weight loss of baseline body weight with placebo, 7.5/46 mg, and 15/92 mg, respectively

Sources: References 15, 16.

also be involved that are yet unknown.14 Topiramate is frequently used as an antiepileptic drug.14 Topiramate is believed to be beneficial for obesity management by enhancing the activity of neurotransmitter gamma-aminobutyric acid (GABA). GABA functions through its modulation of voltage-gated ion channels and by the inhibition of carbonic anhydrase or AMPA/kainite excitatory glutamate receptors. The exact mechanism of action is still not clear.14

Clinical Trials The 2 studies that have demonstrated the effectiveness of PHEN/TPM ER are the CONQUER (Effects of LowDose, Controlled-Release Phentermine plus Topiramate Combination on Weight and Associated Comorbidities in Overweight and Obese Adults) trial and EQUIP (Controlled-Release Phentermine/Topiramate in Severely Obese Adults: a Randomized Controlled Trial). Key features of these trials are listed in Table 1.15,16 CONQUER. This was a randomized, double-blind,

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placebo-controlled phase 3 trial performed in 93 US centers on 2487 patients who were aged 18 to 70 years with a BMI of 27 to 45 kg/m2.15 Primary end points included the percentage of patients who achieved ≥5% weight loss and the percentage change in body weight.

Patients were divided into 3 groups: placebo (N = 994), PHEN/TPM ER 7.5/46 mg (N = 498), and PHEN/TPM ER 15/92 mg (N = 995).

At 56 weeks, results were significantly in favor of the 2 groups of patients taking PHEN/TPM ER, with change in body weight of –8.1 kg (P <.001) and –10.2 kg (P <.001) for PHEN/TPM ER 7.5/46 mg and PHEN/TPM ER 15/92 mg, respectively, compared with –1.4 kg for patients receiving placebo. A total of 62% of the patients taking PHEN/TPM ER 7.5/46 mg and 70% of the patients taking PHEN/TPM ER 15/92 mg (P <.001 for both) achieved at least a 5% weight loss compared with 21% of patients receiving placebo. Of the patients in the 2 groups receiving PHEN/TPM ER, 37% and 48% (P <.001) had a >10% weight loss.15 EQUIP. The second trial, EQUIP, was a double-blind, parallel-group study of 91 US sites involving 1267 patients aged 18 to 70 years for a total treatment duration of 56 weeks.16 The study divided patients into 3 groups: patients receiving placebo (N = 514), PHEN/TPM ER 3.75/23 mg (N = 241), and patients receiving PHEN/TPM ER 15/92 mg (N = 512). All patients had a BMI ≥35 kg/m2; blood pressure (BP) ≤140/90 mm Hg, and were using 0 to 2 antihypertensive medications; triglycerides ≤200 mg/dL, with 0 to 1 cholesterol-lowering medication; and fasting blood glucose level ≤110 mg/dL. Similar to the CONQUER study, the primary end point was the percentage of patients who achieved at least 5% weight loss. The secondary end point included improvement in any of the complications of obesity, including fasting blood glucose, BP, cholesterol, and waist circumference. The final results were similar to those seen in the CONQUER study.16 At the end of 56 weeks, patients in the placebo, PHEN/TPM ER 3.75/23-mg, and PHEN/TPM ER 15/92mg cohorts lost 1.6%, 5.1%, and 10.9%, respectively, of their baseline body weight (P <.001), including 17.3%, 44.9%, and 66.7%, respectively, of the patients in categorical analysis (P <.001). The PHEN/TPM ER 15/92mg group also had the highest success in achieving secondary end points.16

PHEN/TPM ER are available on the market at higher starting doses.

PHEN/TPM ER was studied and compounded in its currently available forms and dosages to minimize the typical side effects that are seen with its individual components (which are available only in the higher doses).

No clinical data are available in the literature regarding PHEN/TPM ER’s impact on various BMI ranges than those approved by the FDA. In addition, unlike lorcas­ erin HCl, no published data are available regarding PHEN/TPM ER’s impact on various races.

The concurrent use of PHEN/TPM ER and other anorexiants or nonselective monoamine oxidase inhibitors have shown to increase the risk of cardiovascular effects (ie, hypertensive crisis) and central nervous system stimulatory effects. PHEN/TPM ER is contraindicated during pregnancy and is unsafe during lactation. The increased risk of oral clefts and other craniofacial defects resulting from exposure to topiramate have been identified by epidemiologic data and in animal studies.14-16 The starting dose for PHEN/TPM ER is 3.75/23 mg once daily for 14 days and is then increased to 7.5/46 mg once daily.14 Medication must be taken in the morning to prevent possible insomnia at night. The maximum recommended dose is 15/92 mg. If weight loss is <5% in 12 weeks, PHEN/TPM ER must be gradually tapered off by taking 1 capsule every other day for 1 week to prevent the incidence of a withdrawal seizure.14

Clinical Utility The most common side effects of PHEN/TPM ER identified in both studies were dry mouth, paresthesia, constipation, dysgeusia, insomnia, and dizziness.14-16 The incidence of these side effects was greater at higher doses of the medication.15,16 Of note, generic components of

Clinical Trials Lorcaserin HCl was approved by the FDA based largely on 3 major phase 3 trials—Behavioral Modification and Lorcaserin for Overweight and Obesity Management (BLOOM), Behavioral Modification and Lorcaserin Second Study for Obesity Management (BLOS-

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Lorcaserin HCl (Belviq) Lorcaserin HCl (Belviq) is a novel weight-loss medication that was approved by the FDA in June 2012 for obese patients with BMI ≥30 kg/m2 or overweight patients with BMI ≥27 kg/m2 and at least 1 of these comorbidities—hypertension, type 2 diabetes, or dyslipidemia.13 The mechanism of action is stimulation of satiety centers via selective agonistic action at the 5-HT2C serotonin receptors, which are found throughout the brain and are thought to reduce hunger by the production of opiomelanocortin neurons in the hypothalamus. Non­ selective serotonin agonists, such as fenfluramine, have previously demonstrated significant weight loss in patients, although the side-effect profile included valvulopathy by activation of 5-HT2B and were therefore withdrawn from the market.13 Lorcaserin HCl has much greater affinity for 5-HT2C over 5-HT2B.17,18

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Table 2 BLOOM, BLOSSOM, and BLOOM-DM: Evaluating Lorcaserin HCl as an Adjunct to Diet and Lifestyle Modification for Weight Loss Method

Patients, N P Value

Clinical trial

Medication

Side effects

Comments

BLOOM

Lorcaserin HCl

10 mg twice daily vs placebo (both with diet and exercise)

3182

<.001

Headache, nausea, 47.5% vs 20.3% back pain, achieving ≥5% total nasopharyngitis body weight loss

BLOSSOM

Lorcaserin HCl

10 mg twice daily vs 10 mg daily vs placebo (with diet and exercise)

4008

<.001

Headache, nausea, dizziness, fatigue, upper respiratory infection

47.2% vs 40.2% vs 25% achieving ≥5% total body weight loss

BLOOM-DM

Lorcaserin HCl

10 mg twice daily vs 10 mg daily vs placebo (all with diet and exercise) All patients with type 2 diabetes

604

<.001

Headache, nausea, back pain, nasopharyngitis, symptomatic hypoglycemia

37.5% vs 44.7% vs 16.1% achieving ≥5% total body weight loss

Sources: References 19-21.

SOM), and Behavioral Modification and Lor­caserin for Obesity and Overweight Management in Dia­ be­ tes Mellitus (BLOOM-DM). Key features of these trials are listed in Table 2.19-21 BLOOM. The BLOOM trial was double blinded and included 3182 obese or overweight adults who were assigned to either lorcaserin HCl 10 mg twice daily for 2 years, placebo for 2 years, or lorcaserin HCl for 1 year and then placebo for 1 year.19 All patients received diet and exercise counseling once at the initiation of the trial and at each subsequent follow-up visit at 2 weeks, 4 weeks, and monthly thereafter. The primary end points at the end of year 1 were loss of ≥5% body weight, change in weight between baseline and the end of year 1, or loss of ≥10% body weight.

The group receiving lorcaserin HCl lost an average of 5.8 kg compared with a 2.2-kg loss in the control arm. In the treated group, 47.5% achieved the ≥5% weight-loss goal versus 20.3% of patients in the placebo group; 22.6% in the lorcaserin HCl group achieved the ≥10% weight-loss goal versus 7.7% of patients receiving placebo. Patients who were switched to a placebo for 1 year after lorcaserin HCl regained weight and had results similar to the placebo group at the conclusion of the 2-year trial, despite monthly counseling for diet and exercise.

Side effects of patients in the treatment arm that were higher than for patients in the placebo arm included headache, nausea, back pain, and nasopharyngitis. There was no difference in valvulopathy between the groups at 2 years.19 BLOSSOM. The randomized, placebo-controlled, double-blind BLOSSOM trial included 4008 patients who were aged 18 to 65 years and were obese (BMI,

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30-45 kg/m2) or overweight (27-29.9 kg/m2) with comorbid risk factors.20 Patients were assigned to lorcaserin HCl 10 mg twice daily, lorcaserin HCl 10 mg once daily, or to placebo for 1 year; all patients received counseling on diet and exercise.20 The twice-daily treatment group lost 5.8 kg compared with 4.7 kg and 2.9 kg in the groups receiving 10 mg once daily and placebo, respectively.20 The total patients achieving ≥5% total weight loss were 47.2% in the twice-daily treated group versus 40.2% and 25%, respectively, in the groups receiving 10 mg once daily and placebo; the rates of achieving 10% total weight loss among the groups were 22.6%, 17.4%, and 9.7%, respectively. Men lost more total weight (6 kg) in the once-daily dosed cohort than in the twice-daily dosed cohort (5.6 kg), and Caucasians lost more weight than Hispanics or African Americans.20 Side effects that occurred more frequently in the active treatment groups compared with the group receiving placebo included headache, upper respiratory infection, nausea, dizziness, and fatigue. Valvulopathy was not increased in either treatment arm.20 BLOOM-DM. The BLOOM-DM trial included 604 patients aged 18 to 65 years with a BMI of 27 kg/m2 to 45 kg/m2 and with type 2 diabetes who were being treated with metformin, a sulfonylurea, or both.21 Patients were randomized to placebo or to lorcaserin HCl 10 mg once daily or to lorcaserin HCl 10 mg twice daily for 1 year.

The mean starting hemoglobin (Hb) A1c was 8.1%. Of the patients who completed the study, the weight loss was 1.9 kg in the placebo group, 5.6 kg in the once-daily lorcaserin group, and 5.9 kg in the twice-daily lorcaserin group. The patients’ mean HbA1c decreased by 0.5%, 1.0%, and 1.1%, respectively.21

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Table 3 Characteristics of Phentermine/Topiramate Extended Release and Lorcaserin HCl Drug characteristics

Qsymia (Phentermine/topiramate extended release)

Belviq (Lorcaserin HCl)

Indications

An adjunct to a low-calorie diet and increased physical activity in adults with an initial BMI of ≥30 kg/m2 or ≥27 kg/m2 in the presence of at least 1 weight-related comorbidity

An adjunct to a low-calorie diet and increased physical activity in adults with an initial BMI of ≥30 kg/m2 or ≥27 kg/m2 in the presence of at least 1 weightrelated comorbidity

Dosage forms

3.75/23 mg, 7.5/46 mg, 11.25/69 mg, 15/92 mg

10 mg

Administration

3.75/23 mg daily for 14 days then increase to 7.5/46 mg; discontinue or increase dose if 3% weight loss is not achieved after 12 weeks or discontinue if 5% weight loss is not achieved after 12 weeks on maximum daily dose of 15/92 mg

10 mg twice daily for 12 weeks, then continue in patients who lose ≥5% of body weight; otherwise discontinue

Outcome

66.7%-70% of patients achieved ≥5% weight loss on maximum daily dose of 15/92 mg

37.5%-47.5% of patients achieved at least 5% weight loss

Contraindications

Pregnancy, glaucoma, hyperthyroidism, within 14 days of taking MAOIs, hypersensitivity to sympathomimetic amines

Pregnancy; monitor for hypoglycemia in type 2 diabetes and adjust antidiabetic drug regimen if needed

Adverse reactions

Paresthesia, dizziness, dysgeusia, insomnia, constipation, dry mouth

Headache, nausea, back pain, upper respiratory infection, dizziness, fatigue

Drug interactions

Oral contraceptives, central nervous system depressants including alcohol, MAOIs, non–potassium-sparing diuretics

Sympathomimetics, selective serotonin/ norepinephrine reuptake inhibitors, MAOIs

BMI indicates body mass index; MAOI, monoamine oxidase inhibitor.

Sources: References 15, 16, 19-21.

Approximately 50% of the patients in the active treatment groups reached an HbA1c of <7% versus only approximately 25% of patients in the placebo group.21 Adverse events were similar to previous trials; however, symptomatic hypoglycemia was more common in the group receiving lorcaserin HCl (8.4%) than in the group receiving placebo (6.3%). New valvulopathy occurred in 0.5% of patients receiving placebo and in 2.5% and 2.9%, respectively, of patients in the onceand twice-daily–treated groups, respectively, which was not statistically significant. This should be followed closely, because these data indicate a possible trend toward dose-related new valvulopathy. Patients who had baseline valvulopathy had no significant increase in disease between groups.21

Clinical Utility Overall, these trials demonstrated significant weight loss compared with placebo in approximately 50% of the patients, with reduction in cardiovascular risk markers such as BP, low-density lipoprotein cholesterol (LDL-C), C-reactive protein (CRP), fasting glucose, and HbA1c.19-21 The side effects that were higher in the treatment arms compared with in the placebo arm varied, but included headache, nausea, back pain, upper respiratory infection, dizziness, and fatigue.

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Of note, echocardiography at the beginning and end of the trials did not show a statistically increased rate of valvulopathy in any of the trials. Given the slightly higher rate of symptomatic hypoglycemia, it is sensible to reassess and consider decreasing the dosages of other hypoglycemic agents for patients who are actively losing weight with lorcaserin HCl.19-21 The recommended dose of lorcaserin HCl is 10 mg twice daily for 12 weeks, at which point the medication should be continued in patients who respond favorably and lose ≥5% of body weight, or discontinued in patients who fail to meet this goal.17,18

Discussion Obesity has increased in prevalence throughout the past decade. The adverse conditions associated with obesity include type 2 diabetes, hypertension, and dys­ lipidemia. These conditions can lead to additional ailments, such as stroke, vascular disease, and neuropathy.

In addition to diet and exercise, both PHEN/TPM ER and lorcaserin HCl have shown promising results in reducing body weight compared with placebo when used for 1 year. For patients in whom traditional diet and physical activity are unable to reduce their BMI, implementation of these medications may be beneficial (Table 3). The use of these new drugs should not be a substitute for tradition-

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New Drug Therapies for Obesity

al weight-loss methods, such as appropriate diet and regular exercise, but they can be powerful tools when used simultaneously with traditional lifestyle modifications.

The use of lorcaserin HCl with diet and exercise showed a decrease in HbA1c, systolic BP, LDL-C, and CRP levels in obese patients. Reduction of these additional parameters suggests a decrease in comorbid conditions. In adult patients with a BMI ≥30 kg/m2 or a BMI ≥27 kg/m2 with comorbidities, it would be reasonable to initiate treatment with lorcaserin HCl if diet and exercise alone are ineffective. Side effects associated with lorcaserin HCl include headache, upper respiratory infection, and fatigue. Because of increased risk of upper respiratory infections, caution should be used in patients who are immunosuppressed or are prone to upper respiratory infections.

The use of PHEN/TPM ER with diet and exercise also showed significant results in decreasing BMI. Patients may see improvements in BP, waist circumference, lipid concentration, CRP, and blood glucose levels. It would be appropriate to use this medication in patients with a BMI ≥30 kg/m2 or a BMI ≥27 kg/m2 with comorbid conditions based on evidence in clinical trials. As expected, there was a greater incidence of side effects with increased doses of PHEN/TPM ER. The side effects included paresthesia, constipation, dysgeusia, and dry mouth.

There is also a concern for the development or worsening of metabolic acidosis, osteoporosis, or hypokalemia, and discretion should be used when managing patients with these conditions.

Although the addition of PHEN/TPM ER and lorcas­ erin HCl to the small list of weight-loss medications was a big step toward the management of obesity, no headto-head trials have been conducted to prove the value and superiority of one medication over the other.

In 2 major clinical trials of PHEN/TPM ER, 66.7% to 70% of patients lost ≥5% of their body weight when compared with approximately 20% of patients taking a placebo.15,16 The total number of nondiabetic patients taking PHEN/TPM ER who achieved their primary end point was 47.2% compared with approximately 20% of patients receiving placebo.

The percentage of patients who achieved a ≥10% weight loss was also significantly different between the 2 groups. Up to 48% of patients receiving lorcaserin HCl were able to achieve this secondary end point compared with 22.6% of patients taking PHEN/TPM ER. These results may appear significantly different at first glance, but they cannot be used to compare these 2 medications.

Each clinical trial was designed with different settings that focused on specific comorbidities of obesity, such as hypertension and hyperlipidemia, whereas others mainly focused on the weight loss of diabetic pa-

tients versus nondiabetic patients.

Despite the lack of direct comparison or published guideline, it is reasonable to consider changing from one of these medications to the other if a patient does not experience sufficient weight loss during a trial period.

Unfortunately, the effect of the new medications was not evaluated based on the patients’ race, ethnicity, or initial BMI.

Conclusion The weight loss in patients using these 2 new medications has been shown to improve additional health parameters, such as BP, blood glucose levels, and serum lipid levels; however, these benefits were apparent in some trials only, when the patients were using the medication. As seen in the BLOOM trial, weight was potentially regained once medication use was discontinued, and patient outcomes were no better than in patients receiving placebo. Based on the BLOSSOM trial, Caucasians appear to have greater benefit than other racial groups from this drug. The reasons for this are not entirely clear, but they may be related to genetic, environmental, cultural, or socioeconomic factors.7 Patients taking PHEN/TPM ER or lorcaserin HCl should be monitored closely, because additional medications may need to be adjusted to avoid hypotension and hypoglycemia that result from the secondary effects of these new medicines. Based on the results of the clinical trials, many patients could benefit from the use of these therapies when they are used appropriately. n Author Disclosure Statement Dr Mahgerefteh, Dr Vigue, Dr Freestone, Dr Silver, and Dr Nguyen have no conflicts of interest to report.

References

1. American Heart Association. Statistical fact sheet: overweight and obesity. 2013 Update. www.heart.org/idc/groups/heart-public/@wcm/@sop/@smd/documents/down loadable/ucm_319588.pdf. Accessed July 2, 2013.

2. World Health Organization. Obesity and overweight. Updated March 2013. www. who.int/mediacentre/factsheets/fs311/en/. Accessed July 2, 2013.

3. Centers for Disease Control and Prevention. Adult obesity facts. Updated August 16, 2013. www.cdc.gov/obesity/data/adult.html. Accessed July 2, 2013.

4. Ogden C, Carroll M. Prevalence of overweight, obesity, and extreme obesity among adults: United States, trends 1960-1962 through 2007-2008. June 2010.

Health-E Stat. www.cdc.gov/nchs/data/hestat/obesity_adult_07_08/obesity_adult_07_ 08.pdf. Accessed August 27, 2013.

5. Cossrow N, Falkner B. Race/ethnic issues in obesity and obesity-related comorbidities. J Clin Endocrinol Metab. 2004;89:2590-2594.

6. Calle EE, Thun MJ, Petrelli JM, et al. Body-mass index and mortality in a prospective cohort of U.S. adults. N Engl J Med. 1999;341:1097-1105.

7. National Heart, Lung, and Blood Institute. Treatment guidelines. In: National Heart, Lung, and Blood Institute. Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults: The Evidence Report. Bethesda, MD: National Heart, Lung, and Blood Institute; 1998:56-94. www.ncbi.nlm.nih.gov/ books/NBK2004/. Accessed July 27, 2013.

8. American Medical Association. AMA adopts new policies on second day of voting at annual meeting. Press release; June 18, 2013. www.ama-assn.org/ama/pub/news/news/ 2013/2013-06-18-new-ama-policies-annual-meeting.page. Accessed August 28, 2013.

9. Cawley J, Meyerhoefer C. The medical care costs of obesity: an instrumental variables approach. J Health Econ. 2012;31:219-230.

10. Downey M. Obesity related hospitalizations soar. Downey Obesity Report. Decem-

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ber 4, 2012. www.downeyobesityreport.com/2012/12/obesity-related-hospitalizationssoar/. Accessed July 2, 2013.

11. Finkelstein EA, Trogdon JG, Cohen JW, Dietz W. Annual medical spending attributable to obesity: payer- and service-specific estimates. Health Aff (Millwood). 2009; 28:w822-w831.

12. US Food and Drug Administration. FDA approves weight-management drug Qsymia. Press release; July 17, 2012. www.fda.gov/NewsEvents/Newsroom/Press Announcements/ucm312468.htm. Accessed August 28, 2013.

13. US Food and Drug Administration. FDA approves Belviq to treat some overweight or obese adults. Press release; July 17, 2012. www.fda.gov/NewsEvents/News room/PressAnnouncements/ucm309993.htm. Accessed July 28, 2013.

14. Qsymia (phentermine and topiramate extended-release) capsules [prescribing information]. Mountain View, CA: VIVUS; April 2013.

15. Gadde KM, Allison DB, Ryan DH, et al. Effects of low-dose, controlled-release, phentermine plus topiramate combination on weight and associated comorbidities in overweight and obese adults (CONQUER): a randomised, placebo-controlled, phase 3 trial. Lancet. 2011;377:1341-1352. Erratum in: Lancet. 2011;377:1494.

16. Allison DB, Gadde KM, Garvey WT, et al. Controlled-release phentermine/

topiramate in severely obese adults: a randomized controlled trial (EQUIP). Obesity (Silver Spring). 2012;20:330-342.

17. Belviq (lorcaserin HCl) tablets [prescribing information]. Zofingen, Switzerland: Arena Pharmaceuticals; August 2012.

18. Bray GA. Drug therapy of obesity. UpToDate. Waltham, MA: UpToDate; 2012. www.uptodate.com/contents/drug-therapy-of-obesity?detectedLanguage=en &source=search_result&search=Drug+Therapy+of+obesity&selectedTitle=1% 7E150&provider=noProvider. Accessed July 28, 2013.

19. Smith SR, Weissman NJ, Anderson CM, et al; for the Behavioral Modification and Lorcaserin for Overweight and Obesity Management (BLOOM) Study Group.

Multicenter, placebo-controlled trial of lorcaserin for weight management. N Engl J Med. 2010;363:245-256.

20. Fidler MC, Sanchez M, Raether B, et al; for the BLOSSOM Clinical Trial Group.

A one-year randomized trial of lorcaserin for weight loss in obese and overweight adults: the BLOSSOM trial. J Clin Endocrinol Metab. 2011;96:3067-3077.

21. O’Neil PM, Smith SR, Weissman NJ, et al. Randomized placebo-controlled clinical trial of lorcaserin for weight loss in type 2 diabetes mellitus: the BLOOM-DM study. Obesity (Silver Spring). 2012;20:1426-1436.

Stakeholder Perspective

The Modern Epidemic of Obesity

By James V. Felicetta, MD Chairman, Department of Medicine, Carl T. Hayden Veterans Affairs Medical Center, Phoenix, AZ

T

he modern epidemic of obesity represents a huge problem for healthcare providers and payers in the United States, let alone for obese patients.

The prevalence of obesity has truly exploded since the early 1980s, when a panoply of causative factors aligned together almost at once to turn the tide against the previously trim physique of the average American.

PATIENTS: The early 1980s saw the widespread introduction of high-fructose corn syrup—a very calorie-dense food additive that has become ubiquitous in all of our diets—into many of our daily foods and drinks.

Restaurant portions began to increase at approximately the same time, because restaurant owners sought to justify higher prices by heaping larger servings of food onto their customers’ plate.

The same period further witnessed the advent of the home computer, which made it possible for Americans to entertain themselves for endless hours, and with little physical effort. Cable television and video games, too, came along at that time, as well as the advent of the video cassette recorder, all conspiring to keep people further glued to their TV screens for longer periods of time. All of these technical achievements facilitated the ability to be entertained at home for long hours, without the need to move as much as before.

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Couple this with a growing parental paranoia about allowing children to play unattended in their neighborhoods, and we have a perfect storm of increased caloric intake and decreased physical activity.

PAYERS/PROVIDERS: Therefore, we need help.

The adverse health consequences of obesity are legion, including increased risks of diabetes, heart disease, malignancies, arthritis, depression, as well as other health conditions. Previously approved weight-loss medications have been very disappointing, to say the least, and they have often been toxic as well.

We are now, one hopes, in a new era of obesity management, with the recent approval of 2 new medications, which were approved last year by the US Food and Drug Administration as adjunct to diet and exercise. These novel agents that are described in detail in the review article by Mahgerefteh and colleagues provide new hope that pharmacologic agents may help patients and providers to effectively fight back against the obesity epidemic in the United States.

The data from clinical trials are promising for these 2 new agents. Time, and real-world data, will tell whether these can be duplicated outside of clinical trials, and if these medications are indeed able to live up to the promises they offer.

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Brief Summary of Full Prescribing Information

INJECTAFER® (ferric carboxymaltose injection)

Rx Only

INDICATIONS AND USAGE: Injectafer® (ferric carboxymaltose injection) is an iron replacement product indicated for the treatment of iron deficiency anemia in adult patients: • who have intolerance to oral iron or who have had unsatisfactory response to oral iron, • who have non-dialysis dependent chronic kidney disease.

DOSAGE AND ADMINISTRATION: For patients weighing 50 kg (110 lb) or more: Give Injectafer® in two doses separated by at least 7 days. Give each dose as 750 mg for a total cumulative dose not to exceed 1500 mg of iron per course.

For patients weighing less than 50 kg (110 lb): Give Injectafer® in two doses separated by at least 7 days. Give each dose as 15 mg/kg body weight for a total cumulative dose not to exceed 1500 mg of iron per course.

Injectafer® treatment may be repeated if iron deficiency anemia reoccurs.

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

Inspect parenteral drug products visually for the absence of particulate matter and discoloration prior to administration. The product contains no preservatives. Injectafer® is a single-use vial. Discard unused portion.

Avoid extravasation of Injectafer® since brown discoloration of the extravasation site may be long lasting. Monitor for extravasation. If extravasation occurs, discontinue the Injectafer® administration at that site.

DOSAGE FORMS AND STRENGTHS: Single-use vials containing 50 mg elemental iron per mL in the following presentation: 750 mg iron/15 mL CONTRAINDICATIONS: Hypersensitivity to Injectafer® or any of its inactive components.

WARNINGS AND PRECAUTIONS

Hypersensitivity Reactions:

Serious hypersensitivity reactions, including anaphylactic-type reactions, some of which have been life-threatening and fatal, have been reported in patients receiving Injectafer®.

Patients may present with shock, clinically significant hypotension, loss of consciousness, and/or collapse. Monitor patients for signs and symptoms of hypersensitivity during and after Injectafer® administration for at least 30 minutes and until clinically stable following completion of the infusion. Only administer Injectafer® when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. In clinical trials, serious anaphylactic/anaphylactoid reactions were reported in 0.1% (2/1775) of subjects receiving Injectafer®. Other serious or severe adverse reactions potentially associated with hypersensitivity which included, but not limited to, pruritus, rash, urticaria, wheezing, or hypotension were reported in 1.5% (26/1775) of these subjects.

Hypertension: In clinical studies, hypertension was reported in 3.8% (67/1775) of subjects in clinical trials 1 and 2. Transient elevations in systolic blood pressure, sometimes occurring with facial flushing, dizziness, or nausea were observed in 6% (106/1775) of subjects in these two clinical trials. These elevations generally occurred immediately after dosing and resolved within 30 minutes. Monitor patients for signs and symptoms of hypertension following each Injectafer® administration.

Laboratory Test Alterations: In the 24 hours following administration of Injectafer®, laboratory assays may overestimate serum iron and transferrin bound iron by also measuring the iron in Injectafer®.

ADVERSE REACTIONS Adverse Reactions in Clinical Trials: Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice.

In two randomized clinical studies, a total of 1775 patients were exposed to Injectafer® 15 mg/kg body weight up to a maximum single dose of 750 mg of iron on two occasions separated by at least 7 days up to a cumulative dose of 1500 mg of iron.

Adverse reactions reported by  1% of treated patients are shown in the following table.

Table 1. Adverse reactions reported in  1% of Study Patients in Clinical Trials 1 and 2 Injectafer® Pooled Comparatorsa Oral iron Term (N=1775) (N=1783) (N=253) % % % 1.2 1.8 7.2 Nausea 0.4 1.9 3.8 Hypertension 0.0 0.2 3.6 Flushing/Hot Flush 0.0 0.1 2.1 Blood Phosphorus Decrease 0.0 1.2 2.0 Dizziness 0.4 0.5 1.7 Vomiting 0.0 0.3 1.4 Injection Site Discoloration 0.0 0.9 1.2 Headache 0.0 0.2 1.1 Alanine Aminotransferase Increase 0.0 2.1 1.1 Dysgeusia 0.0 1.9 1.0 Hypotension 3.2 0.9 0.5 Constipation Includes oral iron and all formulations of IV iron other than Injectafer® Transient decreases in laboratory blood phosphorus levels (< 2 mg/dL) have been observed in 27% (440/1638) of patients in clinical trials.

Adverse Reactions from Post-marketing Experience: The following serious adverse reactions have been most commonly reported from the post-marketing spontaneous reports with Injectafer®: urticaria, dyspnea, pruritus, tachycardia, erythema, pyrexia, chest discomfort, chills, angioedema, back pain, arthralgia, and syncope. One case of hypophosphatemic osteomalacia was reported in a subject who received 500 mg of Injectafer® every 2 weeks for a total of 16 weeks. Partial recovery followed discontinuation of Injectafer®.

DRUG INTERACTIONS: Formal drug interaction studies have not been performed with Injectafer®.

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C: Adequate and well controlled studies in pregnant women have not been conducted. Injectafer® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers: A study to determine iron concentrations in breast milk after administration of Injectafer® (n=11) or oral ferrous sulfate (n=14) was conducted in 25 lactating women with postpartum iron deficiency anemia. Mean breast milk iron levels were higher in lactating women receiving Injectafer® than in lactating women receiving oral ferrous sulfate.

Pediatric Use: Safety and effectiveness has not been established in pediatric patients.

Geriatric Use: Of the 1775 subjects in clinical studies of Injectafer®, 50% were 65 years and over, while 25% were 75 years and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

OVERDOSAGE: Excessive dosages of Injectafer® may lead to accumulation of iron in storage sites potentially leading to hemosiderosis. A patient who received Injectafer® 18,000 mg over 6 months developed hemosiderosis with multiple joint disorder, walking disability and asthenia. Hypophosphatemic osteomalacia was reported in a patient who received Injectafer® 4000 mg over 4 months. Partial recovery followed discontinuation of Injectafer®.

DESCRIPTION: Ferric carboxymaltose, an iron replacement product, is an iron carbohydrate complex with the chemical name of polynuclear iron (III) hydroxide 4(R)-(poly-(1→4)-O-α-D-glucopyranosyl)-oxy-2(R),3(S),5(R),6-tetrahydroxy-hexanoate.

It has a relative molecular weight of approximately 150,000 Da. Injectafer® (ferric carboxymaltose injection) is a dark brown, sterile, aqueous, isotonic colloidal solution for intravenous injection. Each mL contains 50 mg iron as ferric carboxymaltose in water for injection. Sodium hydroxide and/or hydrochloric acid may have been added to adjust the pH to 5.0-7.0. The vial closure is not made with natural rubber latex.

CLINICAL PHARMACOLOGY Mechanism of Action: Ferric carboxymaltose is a colloidal iron (III) hydroxide in complex with carboxymaltose, a carbohydrate polymer that releases iron.

Pharmacodynamics: Using positron emission tomography (PET) it was demonstrated that red cell uptake of 59Fe and 52Fe from Injectafer® ranged from 61% to 99%. In patients with iron deficiency, red cell uptake of radio-labeled iron ranged from 91% to 99% after 24 days Injectafer® dose. In patients with renal anemia red cell uptake of radio-labeled iron ranged from 61% to 84% after 24 days Injectafer® dose.

Pharmacokinetics: After administration of a single dose of Injectafer® of 100 to 1000 mg of iron in iron deficient patients, maximum iron levels of 37 µg/mL to 333 µg/mL were obtained respectively after 15 minutes to 1.21 hours post dose. The volume of distribution was estimated to be 3 L. The iron injected or infused was rapidly cleared from the plasma, the terminal half life ranged from 7 to 12 hours. Renal elimination of iron was negligible.

NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, and Impairment of Fertility: Carcinogenicity studies have not been performed with ferric carboxymaltose.

Ferric carboxymaltose was not genotoxic in the following genetic toxicology studies: in vitro microbial mutagenesis (Ames) assay, in vitro chromosome aberration test in human lymphocytes, in vitro mammalian cell mutation assay in mouse lymphoma L5178Y/TK+/- cells, in vivo mouse micronucleus test at single intravenous doses up to 500 mg/kg.

In a combined male and female fertility study, ferric carboxymaltose was administered intravenously over one hour to male and female rats at iron doses of up to 30 mg/kg. Animals were dosed 3 times per week (on Days 0, 3, and 7). There was no effect on mating function, fertility or early embryonic development. The dose of 30 mg/kg in animals is approximately 40% of the human dose of 750 mg based on body surface area.

CLINICAL STUDIES: The safety and efficacy of Injectafer® for treatment of iron deficiency anemia were evaluated in two randomized, open-label, controlled clinical trials (Trial 1 and Trial 2). In these two trials, Injectafer® was administered at dose of 15 mg/kg body weight up to a maximum single dose of 750 mg of iron on two occasions separated by at least 7 days up to a cumulative dose of 1500 mg of iron.

PATIENT COUNSELING INFORMATION • Question patients regarding any prior history of reactions to parenteral iron products.

• Advise patients of the risks associated with Injectafer®.

• Advise patients to report any signs and symptoms of hypersensitivity that may develop during and following Injectafer® administration, such as rash, itching, dizziness, lightheadedness, swelling and breathing problems.

Injectafer® is manufactured under license from Vifor (International) Inc, Switzerland.

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IN0650BS Iss. 7/2013

NOW AVAILABLE

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

IMPORTANT SAFETY INFORMATION Serious hypersensitivity reactions, including anaphylactic-type reactions, some of which have been life-threatening and fatal, have been reported in patients receiving Injectafer®. Patients may present with shock, clinically significant hypotension, loss of consciousness, and/or collapse. Monitor patients for signs and symptoms of hypersensitivity during and after Injectafer® administration for at least 30 minutes and until clinically stable following completion of the infusion. Only administer Injectafer® when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. In clinical trials, serious anaphylactic/ anaphylactoid reactions were reported in 0.1% (2/1775) of subjects receiving Injectafer®. Other serious or severe adverse reactions potentially associated with hypersensitivity which included, but were not limited to, pruritus, rash, urticaria, wheezing, or hypotension were reported in 1.5% (26/1775) of these subjects.

In clinical studies, hypertension was reported in 3.8% (67/1775) of subjects. Transient elevations in systolic blood pressure, sometimes occurring with facial flushing, dizziness, or nausea were observed in 6% (106/1775) of subjects. These elevations generally occurred immediately after dosing and resolved within 30 minutes. Monitor patients for signs and symptoms of hypertension following each Injectafer® administration.

In two randomized clinical studies, a total of 1775 patients were exposed to Injectafer®, 15 mg/kg of body weight, up to a single maximum dose of 750 mg of iron on two occasions, separated by at least 7 days, up to a cumulative dose of 1500 mg of iron. Adverse reactions reported by ≥2% of Injectafer®-treated patients were nausea (7.2%); hypertension (3.8%); flushing/hot flush (3.6%); blood phosphorus decrease (2.1%); and dizziness (2.0%).

The following serious adverse reactions have been most commonly reported from the postmarketing spontaneous reports: urticaria, dyspnea, pruritus, tachycardia, erythema, pyrexia, chest discomfort, chills, angioedema, back pain, arthralgia, and syncope.

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

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

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

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

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

• Administer intravenously by

†

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

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

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

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

Injectafer® is manufactured under license from Vifor (International) Inc., Switzerland. ©2013 American Regent, Inc. Printed in USA FCM002 Iss. 08/2013