January/February 2010, Vol 3, No 1

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THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN ™ JANUARY/FEBRUARY 2010

VOLUME 3, NUMBER 1

FOR PAYERS, PURCHASERS, POLICYMAKERS, AND OTHER HEALTHCARE STAKEHOLDERS

REGULATORY

Orphan Drug Pricing and Payer Management in the United States: Are We Approaching the Tipping Point? Rebecca Hyde; Diana Dobrovolny

Stakeholder Perspective by Kavita V. Nair, PhD BUSINESS

Physicians’ Perceptions of Reimbursement as a Barrier to Comprehensive Diabetes Care Alyssa Pozniak, PhD; Lois Olinger, MA; Victoria Shier, MA

Stakeholder Perspective by Gary M. Owens, MD CLINICAL

Hypertension Management: An Update Quang Nguyen, DO; Joann Dominguez, MD; Loida Nguyen, PharmD; Nageshwara Gullapalli, MD

Stakeholder Perspective by Lekshmi Dharmarajan, MD, FACP, FACC DEPARTMENTS ◆ Generic Drug Trends

Competition from Biosimilars an Incentive for Innovation ◆ Industry Trends

Emerging Trends in Breast Cancer Management ◆ Drug Pipeline

Rheumatology Pipeline Boasts Innovation, ID Line Is Drying Up: ACR/IDSA 2009 Cardiology Pipeline Is Promising: AHA 2009

©2010 Engage Healthcare Communications, LLC www.AHDBonline.com








JANUARY/FEBRUARY 2010

VOLUME 3, NUMBER 1

THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN ™

FOR PAYERS, PURCHASERS, POLICYMAKERS, AND OTHER HEALTHCARE STAKEHOLDERS

TABLE OF CONTENTS Publisher Nicholas Englezos nick@engagehc.com 732-992-1884

REGULATORY

15

22

Orphan Drug Pricing and Payer Management in the United States: Are We Approaching the Tipping Point? Rebecca Hyde; Diana Dobrovolny Stakeholder Perspective by Kavita V. Nair, PhD

Associate Publisher Maurice Nogueira maurice@engagehc.com 732-992-1895 Editorial Director Dalia Buffery dalia@AHDBonline.com 732-992-1889

BUSINESS

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Physicians’ Perceptions of Reimbursement as a Barrier to Comprehensive Diabetes Care Alyssa Pozniak, PhD; Lois Olinger, MA; Victoria Shier, MA

Associate Editor Lara J. Reiman lara@engagehc.com 732-992-1892

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Stakeholder Perspective by Gary M. Owens, MD

Senior Production Manager Lynn Hamilton Business Manager Blanche Marchitto

CLINICAL

47

Hypertension Management: An Update Quang Nguyen, DO; Joann Dominguez, MD; Loida Nguyen, PharmD; Nageshwara Gullapalli, MD

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Stakeholder Perspective by Lekshmi Dharmarajan, MD, FACP, FACC

GENERIC DRUG TRENDS Competition from Biosimilars an Incentive for Innovation Dalia Buffery, MA, ABD Continued on page 10

American Health & Drug Benefits is included in the following indexing and database services: EMBASE/Elsevier Cumulative Index to Nursing and Allied Health Literature (CINAHL) EBSCO research databases Standard Periodical Directory

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AMERICAN HEALTH & DRUG BENEFITS

Mission Statement American Health & Drug Benefits is founded on the concept that health and drug benefits have undergone a transformation: the econometric value of a drug is of equal importance to clinical outcomes as it is to serving as the basis for securing coverage in formularies and benefit designs. Benefit designs are greatly affected by clinical, business, and policy conditions.

DEPARTMENTS

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Editor-in-Chief Robert E. Henry rhenry@AHDBonline.com 732-992-1885

January/February 2010

This publication provides benefit design decision makers the integrated industry information they require to devise formularies and benefit designs that stand up to today’s special healthcare delivery and business needs.

Contact Information: For reprints, subscription information, and editorial queries, please contact: editorial@AHDBonline.com T: 732-992-1892 F: 732-992-1881

VOL. 3

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Simply illuminating.

-EETINGTHEINTENSEDEMANDFORGENERICS EETING GTHEINTENSEDEMANDFORGENERICS WITHONEOFTHEBRIGHTESTPORTFOLIOSINTHEINDUSTRY W ITHONEOFTHEBRIGHTESTPORTFOLIOSINTHEINDUSTRY Generic pharmaceuticals are playing an increasing role in healthcare worldwide. Why? Because they ’re a lower-cost alternative to name-brand drugs. At Actavis, we work around the clock and the globe to meet the need for generics—with 830 products to market and over 350 more on the way. Generics make the future of healthcare brighter for all of us. Let our extensive product portfolio help you meet the growing need for the latest generic pharmaceutical products. TTo o learn mor more, e, ccall all A Actavis ctavis customer customer ser service vice at 888.925.2342 or visit us at www w.ac .actavis.us www.actavis.us


JANUARY/FEBRUARY 2010

VOLUME 3, NUMBER 1

THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN ™

FOR PAYERS, PURCHASERS, POLICYMAKERS, AND OTHER HEALTHCARE STAKEHOLDERS

TABLE OF CONTENTS

(Continued)

DEPARTMENTS

59

INDUSTRY TRENDS Emerging Trends in Breast Cancer Management By Caroline Helwick

61

DRUG PIPELINE Rheumatology Pipeline Boasts Innovation, ID Line Is Drying Up: ACR/IDSA 2009 By Alice Goodman

63

Cardiology Pipeline Is Promising: AHA 2009 By Wayne Kuznar

American Health & Drug Benefits, ISSN 19422962 (print); ISSN 1942-2970 (online), is published 6 times a year by Engage Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205A, Monroe Township, NJ 08831. Copyright © 2010 by Engage Healthcare Communications, LLC. All rights reserved. American Health & Drug Benefits and The Peer-Reviewed Forum for Evidence in Benefit Design are trademarks of Engage Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the Publisher. Printed in the United States of America. Address all editorial correspondence to: editorial@AHDBonline. com, Telephone: 732-992-1889. Fax: 732-992-1881. American Health & Drug Benefits, 241 Forsgate Drive, Suite 205A, Monroe Township, NJ 08831.

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EDITORIAL BOARD

CLINICAL EDITOR

Thomas G. McCarter, MD, FACP Chief Clinical Officer Executive Health Resources, PA

Nirav R. Shah, MD, MPH Assistant Professor of Medicine NYU School of Medicine, NYC Senior Investigator, Geisinger Health System, Danville, PA

GOVERNMENT EDITOR

Kevin B. “Kip” Piper, MA, FACHE President, Health Results Group Sr. Counselor, Fleishman-Hillard Washington, DC

J. B. Jones, PhD, MBA Research Associate, Geisinger Health System, Danville, PA

ACTUARY

HEALTH OUTCOMES RESEARCH

David Williams Milliman Health Consultant Windsor, CT CANCER RESEARCH

Al B. Benson, III, MD, FACP Professor of Medicine Associate Director for Clinical Investigations Robert H. Lurie Comprehensive Cancer Center, Northwestern University Chair, Board of Directors, NCCN Samuel M. Silver, MD, PhD, FACP Professor, Internal Medicine Director, Cancer Center Network Division of Hematology/Oncology Assistant Dean for Research University of Michigan Health Systems CARDIOLOGY RESEARCH

Michael A. Weber, MD Professor of Medicine Department of Medicine (Cardiology) State University of New York ENDOCRINOLOGY RESEARCH

HEALTH INFORMATION TECHNOLOGY

Gordon M. Cummins, MS Director, IntegriChain Kavita V. Nair, PhD Associate Professor, School of Pharmacy University of Colorado at Denver

MANAGED CARE & GOVERNMENT AFFAIRS

Alex Hathaway, MD, MPH, FACPM Senior Medical Policy Advisor Government Programs GlaxoSmithKline, Philadelphia, PA

Sharad Mansukani, MD Chief Strategic Officer, Nations Health Senior Advisor, Texas Pacific Group, FL MANAGED MARKETS

Jeffrey A. Bourret, MS, RPh, FASHP Senior Director, Customer Marketing & Innovation, US Specialty Customers Pfizer Specialty Business Unit Collegeville, PA

William E. Fassett, BSPharm, MBA, PhD Professor of Pharmacy Law & Ethics Vice Chair, Dept. of Pharmacotherapy College of Pharmacy, Washington State University, Spokane, WA PERSONALIZED MEDICINE

Wayne A. Rosenkrans, Jr, PhD Chairman and President, Personalized Medicine Coalition, Distinguished Fellow, MIT Center for Biomedical Innovation

F. Randy Vogenberg, RPh, PhD Chief Strategy Officer Employer-based Pharmaceutical Strategies Senior Scholar, Department of Health Policy, Thomas Jefferson University

Jeff Jianfei Guo, BPharm, MS, PhD Associate Professor of Pharmacoeconomics & Pharmacoepidemiology, College of Pharmacy, University of Cincinnati Medical Center, OH

EPIDEMIOLOGY RESEARCH

PHARMACY BENEFIT DESIGN

AMERICAN HEALTH & DRUG BENEFITS

J. Warren Salmon, PhD Professor of Health Policy & Administration School of Public Health University of Illinois at Chicago REIMBURSEMENT POLICY

Grant D. Lawless, BSPharm, MD, FACP Executive Director for Payor Relations Corporate Account Amgen, Thousand Oaks, CA Michael Schaffer, PharmD, MBA Director, Pharmacy Programs Sanovia Co., Philadelphia, PA RESEARCH & DEVELOPMENT

Michael F. Murphy, MD, PhD Chief Medical Officer and Scientific Officer Worldwide Clinical Trials Faculty, Center for Experimental Pharmacology and Therapeutics, HarvardMIT Division of Health Sciences and Technology, Cambridge, MA SPECIALTY PHARMACY

PHARMACOECONOMICS

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POLICY & PUBLIC HEALTH

Jack E. Fincham, PhD, RPh Professor of Pharmacy, School of Pharmacy University of Missouri, Kansas City

PATIENT ADVOCACY

Joshua N. Liberman, PhD Vice President, Strategic Research CVS Caremark, Hunt Valley, MD

Scott R. Taylor, RPh, MBA Associate Director, Industry Relations Geisinger Health System, Danville, PA

Timothy S. Regan, BPharm, RPh Executive Director, Xcenda Palm Harbor, FL

EMPLOYERS

Arthur F. Shinn, PharmD, FASCP President, Managed Pharmacy Consultants, Lake Worth, FL

Paul Anthony Polansky, BSPharm, MBA Executive VP and Chief Pharmacy Officer Sanovia Corp., Philadelphia, PA

Joseph R. Antos, PhD Wilson H. Taylor Scholar in Health Care Retirement Policy American Enterprise Institute

Charles E. Collins, Jr, MS, MBA Associate Director, Managed Markets Marketing, Boehringer-Ingelheim Ridgefield, CT

Wayne M. Lednar, MD, PhD Global Chief Medical Officer Director, Integrated Health Services DuPont, Wilmington, DE

Leslie S. Fish, PharmD Sr. Director of Pharmacy Services Fallon Community Health Plan, MA

Gary M. Owens, MD President, Gary Owens Associates Glen Mills, PA

James V. Felicetta, MD Chairman, Dept. of Medicine Carl T. Hayden Veterans Affairs Medical Center, Phoenix, AZ Alberto M. Colombi, MD, MPH Corporate Medical Director PPG Industries, Pittsburgh, PA

William J. Cardarelli, PharmD Director of Pharmacy Atrius Health Harvard Vanguard Medical Associates

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

January/February 2010

Atheer A. Kaddis, PharmD Vice President, Managed Markets Diplomat Specialty Pharmacy Swartz Creek, MI James T. Kenney, RPh, MBA Pharmacy Operations Manager Harvard Pilgrim Health Care Wellesley, MA

VOL. 3

NO. 1


2.5 mg, 5 mg, 10 mg and 20 mg Rx Only Brief Summary: For complete details please see full Prescribing Information for BYSTOLIC. INDICATIONS AND USAGE BYSTOLIC is indicated for the treatment of hypertension. BYSTOLIC may be used alone or in combination with other antihypertensive agents. CONTRAINDICATIONS BYSTOLIC is contraindicated in patients with severe bradycardia, heart block greater than first degree, cardiogenic shock, decompensated cardiac failure, sick sinus syndrome (unless a permanent pacemaker is in place), or severe hepatic impairment (Child-Pugh >B), and in patients who are hypersensitive to any component of this product. WARNINGS Abrupt Cessation of Therapy Patients with coronary artery disease treated with BYSTOLIC should be advised against abrupt discontinuation of therapy. Severe exacerbation of angina and the occurrence of myocardial infarction and ventricular arrhythmias have been reported in patients with coronary artery disease following the abrupt discontinuation of therapy with β-blockers. Myocardial infarction and ventricular arrhythmias may occur with or without preceding exacerbation of the angina pectoris. Even patients without overt coronary artery disease should be cautioned against interruption or abrupt discontinuation of therapy. As with other β-blockers, when discontinuation of BYSTOLIC is planned, patients should be carefully observed and advised to minimize physical activity. BYSTOLIC should be tapered over 1 to 2 weeks when possible. If the angina worsens or acute coronary insufficiency develops, it is recommended that BYSTOLIC be promptly reinstituted, at least temporarily. Cardiac Failure Sympathetic stimulation is a vital component supporting circulatory function in the setting of congestive heart failure, and β-blockade may result in further depression of myocardial contractility and precipitate more severe failure. In patients who have compensated congestive heart failure, BYSTOLIC should be administered cautiously. If heart failure worsens, discontinuation of BYSTOLIC should be considered. Angina and Acute Myocardial Infarction BYSTOLIC was not studied in patients with angina pectoris or who had a recent MI. Bronchospastic Diseases In general, patients with bronchospastic diseases should not receive β-blockers. Anesthesia and Major Surgery If BYSTOLIC is to be continued perioperatively, patients should be closely monitored when anesthetic agents which depress myocardial function, such as ether, cyclopropane, and trichloroethylene, are used. If β-blocking therapy is withdrawn prior to major surgery, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures. The β-blocking effects of BYSTOLIC can be reversed by β-agonists, e.g., dobutamine or isoproterenol. However, such patients may be subject to protracted severe hypotension. Additionally, difficulty in restarting and maintaining the heartbeat has been reported with β-blockers. Diabetes and Hypoglycemia β-blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia. Nonselective β-blockers may potentiate insulin-induced hypoglycemia and delay recovery of serum glucose levels. It is not known whether nebivolol has these effects. Patients subject to spontaneous hypoglycemia, or diabetic patients receiving insulin or oral hypoglycemic agents, should be advised about these possibilities and nebivolol should be used with caution. Thyrotoxicosis β-blockers may mask clinical signs of hyperthyroidism, such as tachycardia. Abrupt withdrawal of β-blockers may be followed by an exacerbation of the symptoms of hyperthyroidism or may precipitate a thyroid storm. Peripheral Vascular Disease β-blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease. Caution should be exercised in these patients. Non-dihydropyridine Calcium Channel Blockers Because of significant negative inotropic and chronotropic effects in patients treated with β-blockers and calcium channel blockers of the verapamil and diltiazem type, caution should be used in patients treated concomitantly with these agents and ECG and blood pressure should be monitored. PRECAUTIONS Use with CYP2D6 Inhibitors Nebivolol exposure increases with inhibition of CYP2D6 (see Drug Interactions). The dose of BYSTOLIC may need to be reduced. Impaired Renal Function BYSTOLIC should be used with caution in patients with severe renal impairment because of decreased renal clearance. BYSTOLIC has not been studied in patients receiving dialysis. Impaired Hepatic Function BYSTOLIC should be used with caution in patients with moderate hepatic impairment because of decreased metabolism. Since BYSTOLIC has not been studied in patients with severe hepatic impairment, BYSTOLIC is contraindicated in this population (see CLINICAL PHARMACOLOGY, Special Populations and DOSAGE AND ADMINISTRATION). Risk of Anaphylactic Reactions While taking β-blockers, patients with a history of severe anaphylactic reactions to a variety of allergens may be more reactive to repeated challenge either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reactions. In patients with known or suspected pheochromocytoma, an α-blocker should be initiated prior to the use of any β-blocker. Information for Patients Patients should be advised to take BYSTOLIC regularly and continuously, as directed. BYSTOLIC can be taken with or without food. If a dose is missed, the patient should take the next scheduled dose only (without doubling it). Patients should not interrupt or discontinue BYSTOLIC without consulting the physician. Patients should know how they react to this medicine before they operate automobiles, use machinery, or engage in other tasks requiring alertness. Patients should be advised to consult a physician if any difficulty in breathing occurs, or if they develop signs or symptoms of worsening congestive heart failure such as weight gain or increasing shortness of breath, or excessive bradycardia.

Patients subject to spontaneous hypoglycemia, or diabetic patients receiving insulin or oral hypoglycemic agents, should be cautioned that β-blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia. Nebivolol should be used with caution in these patients. Drug Interactions BYSTOLIC should be used with care when myocardial depressants or inhibitors of AV conduction, such as certain calcium antagonists (particularly of the phenylalkylamine [verapamil] and benzothiazepine [diltiazem] classes), or antiarrhythmic agents, such as disopyramide, are used concurrently. Both digitalis glycosides and β-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia. BYSTOLIC should not be combined with other β-blockers. Patients receiving catecholamine-depleting drugs, such as reserpine or guanethidine, should be closely monitored, because the added β-blocking action of BYSTOLIC may produce excessive reduction of sympathetic activity. In patients who are receiving BYSTOLIC and clonidine, BYSTOLIC should be discontinued for several days before the gradual tapering of clonidine. CYP2D6 Inhibitors: Use caution when BYSTOLIC is co-administered with CYP2D6 inhibitors (quinidine, propafenone, fluoxetine, paroxetine, etc.) (see CLINICAL PHARMACOLOGY, Drug Interactions). Carcinogenesis, Mutagenesis, Impairment of Fertility In a two-year study of nebivolol in mice, a statistically significant increase in the incidence of testicular Leydig cell hyperplasia and adenomas was observed at 40 mg/kg/day (5 times the maximally recommended human dose of 40 mg on a mg/m2 basis). Similar findings were not reported in mice administered doses equal to approximately 0.3 or 1.2 times the maximum recommended human dose. No evidence of a tumorigenic effect was observed in a 24-month study in Wistar rats receiving doses of nebivolol 2.5, 10 and 40 mg/kg/day (equivalent to 0.6, 2.4, and 10 times the maximally recommended human dose). Co-administration of dihydrotestosterone reduced blood LH levels and prevented the Leydig cell hyperplasia, consistent with an indirect LH-mediated effect of nebivolol in mice and not thought to be clinically relevant in man. A randomized, double-blind, placebo- and active-controlled, parallel-group study in healthy male volunteers was conducted to determine the effects of nebivolol on adrenal function, luteinizing hormone, and testosterone levels. This study demonstrated that 6 weeks of daily dosing with 10 mg of nebivolol had no significant effect on ACTH-stimulated mean serum cortisol AUC0-120 min, serum LH, or serum total testosterone. Effects on spermatogenesis were seen in male rats and mice at ≥40 mg/kg/day (10 and 5 times the MRHD, respectively). For rats the effects on spermatogenesis were not reversed and may have worsened during a four-week recovery period. The effects of nebivolol on sperm in mice, however, were partially reversible. Mutagenesis: Nebivolol was not genotoxic when tested in a battery of assays (Ames, in vitro mouse lymphoma TK+/-, in vitro human peripheral lymphocyte chromosome aberration, in vivo Drosophila melanogaster sex-linked recessive lethal, and in vivo mouse bone marrow micronucleus tests). Pregnancy: Teratogenic Effects. Pregnancy Category C: Decreased pup body weights occurred at 1.25 and 2.5 mg/kg in rats, when exposed during the perinatal period (late gestation, parturition and lactation). At 5 mg/kg and higher doses (1.2 times the MRHD), prolonged gestation, dystocia and reduced maternal care were produced with corresponding increases in late fetal deaths and stillbirths and decreased birth weight, live litter size and pup survival. Insufficient numbers of pups survived at 5 mg/kg to evaluate the offspring for reproductive performance. In studies in which pregnant rats were given nebivolol during organogenesis, reduced fetal body weights were observed at maternally toxic doses of 20 and 40 mg/kg/day (5 and 10 times the MRHD), and small reversible delays in sternal and thoracic ossification associated with the reduced fetal body weights and a small increase in resorption occurred at 40 mg/kg/day (10 times the MRHD). No adverse effects on embryo-fetal viability, sex, weight or morphology were observed in studies in which nebivolol was given to pregnant rabbits at doses as high as 20 mg/kg/day (10 times the MRHD). Labor and Delivery Nebivolol caused prolonged gestation and dystocia at doses ≥5 mg/kg in rats (1.2 times the MRHD). These effects were associated with increased fetal deaths and stillborn pups, and decreased birth weight, live litter size and pup survival rate, events that occurred only when nebivolol was given during the perinatal period (late gestation, parturition and lactation). No studies of nebivolol were conducted in pregnant women. BYSTOLIC should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers Studies in rats have shown that nebivolol or its metabolites cross the placental barrier and are excreted in breast milk. It is not known whether this drug is excreted in human milk. Because of the potential for β-blockers to produce serious adverse reactions in nursing infants, especially bradycardia, BYSTOLIC is not recommended during nursing. Geriatric Use Of the 2800 patients in the U.S.-sponsored placebo-controlled clinical hypertension studies, 478 patients were 65 years of age or older. No overall differences in efficacy or in the incidence of adverse events were observed between older and younger patients. Pediatric Use Safety and effectiveness in pediatric patients have not been established. Pediatric studies in ages newborn to 18 years old have not been conducted because of incomplete characterization of developmental toxicity and possible adverse effects on long-term fertility (see Carcinogenesis, Mutagenesis, and Impairment of Fertility). ADVERSE REACTIONS The data described below reflect worldwide clinical trial exposure to BYSTOLIC in 6545 patients, including 5038 patients treated for hypertension and the remaining 1507 subjects treated for other cardiovascular diseases. Doses ranged from 0.5 mg to 40 mg. Patients received BYSTOLIC for up to 24 months, with over 1900 patients treated for at least 6 months, and approximately 1300 patients for more than one year. In placebo-controlled clinical trials comparing BYSTOLIC with placebo, discontinuation of therapy due to adverse events was reported in 2.8% of patients treated with nebivolol and 2.2% of patients given placebo. The most common adverse events that led to discontinuation of BYSTOLIC were headache (0.4%), nausea (0.2%) and bradycardia (0.2%). Adverse Reactions in Controlled Trials Table 1 lists treatment-emergent signs and symptoms that were reported in three 12week, placebo-controlled monotherapy trials involving 1597 hypertensive patients treated with either 5 mg, 10 mg or 20-40 mg of BYSTOLIC and 205 patients given placebo and for which the rate of occurrence was at least 1% of patients treated with nebivolol and greater than the rate for those treated with placebo in at least one dose group.

Table 1. Treatment-Emergent Adverse Events with an Incidence (over 6 weeks) ≥1% in BYSTOLIC-Treated Patients and at a Higher Frequency than PlaceboTreated Patients Placebo

Headache Fatigue Dizziness Diarrhea Nausea Insomnia Chest pain Bradycardia Dyspnea Rash Peripheral edema

(n = 205) (%) 6 1 2 2 0 0 0 0 0 0 0

Nebivolol 5 mg (n = 459) (%) 9 2 2 2 1 1 0 0 0 0 1

Nebivolol 10 mg (n = 461) (%) 6 2 3 2 3 1 1 0 1 1 1

Nebivolol 20-40 mg (n = 677) (%) 7 5 4 3 2 1 1 1 1 1 1

Other Adverse Events Observed During Worldwide Clinical Trials Listed below are other reported adverse events with an incidence of at least 1% in the more than 5300 patients treated with BYSTOLIC in controlled or open-label trials, whether or not attributed to treatment, except for those already appearing in Table 1, terms too general to be informative, minor symptoms, or events unlikely to be attributable to drug because they are common in the population. These adverse events were in most cases observed at a similar frequency in placebo-treated patients in the controlled studies. Body as a Whole: asthenia. Gastrointestinal System Disorders: abdominal pain Metabolic and Nutritional Disorders: hypercholesterolemia and hyperuricemia Nervous System Disorders: paraesthesia Laboratory In controlled monotherapy trials, BYSTOLIC was associated with an increase in BUN, uric acid, triglycerides and a decrease in HDL cholesterol and platelet count. Events Identified from Spontaneous Reports of BYSTOLIC Received Worldwide The following adverse events have been identified from spontaneous reports of BYSTOLIC received worldwide and have not been listed elsewhere. These adverse events have been chosen for inclusion due to a combination of seriousness, frequency of reporting or potential causal connection to BYSTOLIC. Events common in the population have generally been omitted. Because these events were reported voluntarily from a population of uncertain size, it is not possible to estimate their frequency or establish a causal relationship to BYSTOLIC exposure: abnormal hepatic function (including increased AST, ALT and bilirubin), acute pulmonary edema, acute renal failure, atrioventricular block (both second- and third-degree), bronchospasm, erectile dysfunction, hypersensitivity (including urticaria, allergic vasculitis and rare reports of angioedema), myocardial infarction, pruritus, psoriasis, Raynaud’s phenomenon, peripheral ischemia/claudication, somnolence, syncope, thrombocytopenia, various rashes and skin disorders, vertigo, and vomiting. OVERDOSAGE In clinical trials and worldwide postmarketing experience there were reports of BYSTOLIC overdose. The most common signs and symptoms associated with BYSTOLIC overdosage are bradycardia and hypotension. Other important adverse events reported with BYSTOLIC overdose include cardiac failure, dizziness, hypoglycemia, fatigue and vomiting. Other adverse events associated with β-blocker overdose include bronchospasm and heart block. The largest known ingestion of BYSTOLIC worldwide involved a patient who ingested up to 500 mg of BYSTOLIC along with several 100 mg tablets of acetylsalicylic acid in a suicide attempt. The patient experienced hyperhidrosis, pallor, depressed level of consciousness, hypokinesia, hypotension, sinus bradycardia, hypoglycemia, hypokalemia, respiratory failure and vomiting. The patient recovered. Due to extensive drug binding to plasma proteins, hemodialysis is not expected to enhance nebivolol clearance. If overdose occurs, BYSTOLIC should be stopped and general supportive and specific symptomatic treatment should be provided. Based on expected pharmacologic actions and recommendations for other β-blockers, the following general measures should be considered when clinically warranted: Bradycardia: Administer IV atropine. If the response is inadequate, isoproterenol or another agent with positive chronotropic properties may be given cautiously. Under some circumstances, transthoracic or transvenous pacemaker placement may be necessary. Hypotension: Administer IV fluids and vasopressors. Intravenous glucagon may be useful. Heart Block (second or third degree): Patients should be carefully monitored and treated with isoproterenol infusion. Under some circumstances, transthoracic or transvenous pacemaker placement may be necessary. Congestive Heart Failure: Initiate therapy with digitalis glycoside and diuretics. In certain cases, consideration should be given to the use of inotropic and vasodilating agents. Bronchospasm: Administer bronchodilator therapy such as a short-acting inhaled β2-agonist and/or aminophylline. Hypoglycemia: Administer IV glucose. Repeated doses of IV glucose or possibly glucagon may be required. In the event of intoxication where there are symptoms of shock, treatment must be continued for a sufficiently long period consistent with the 12-19 hour effective half-life of BYSTOLIC. Supportive measures should continue until clinical stability is achieved. Call the National Poison Control Center (800-222-1222) for the most current information on β-blocker overdose treatment. Forest Pharmaceuticals, Inc. Subsidiary of Forest Laboratories, Inc. St. Louis, MO 63045, USA Licensed from Mylan Laboratories, Inc. Under license from Janssen Pharmaceutica N.V., Beerse, Belgium

Rev. 08/08 © 2008 Forest Laboratories, Inc.


For the treatment of hypertension

BYSTOLIC. Significant blood pressure reductions with a low incidence of side effects.1-3 www.BYSTOLIC.com Important Safety Information Patients being treated with BYSTOLIC should be advised against abrupt discontinuation of therapy. Severe exacerbation of angina and the occurrence of myocardial infarction and ventricular arrhythmias have been reported following the abrupt cessation of therapy with beta blockers. When discontinuation is planned, the dosage should be reduced gradually over a 1- to 2-week period and the patient carefully monitored. BYSTOLIC is contraindicated in severe bradycardia, heart block greater than first degree, cardiogenic shock, decompensated cardiac failure, sick sinus syndrome (unless a permanent pacemaker is in place), severe hepatic impairment (Child-Pugh >B), and in patients who are hypersensitive to any component of this product. BYSTOLIC should be used with caution in patients with peripheral vascular disease, thyrotoxicosis, in patients treated concomitantly with beta blockers and calcium channel blockers of the verapamil and diltiazem type (ECG and blood pressure should be monitored), severe renal impairment, and any degree of hepatic impairment or in patients undergoing major surgery. In patients who have compensated congestive heart failure, BYSTOLIC should be administered cautiously. If heart failure worsens, discontinuation of BYSTOLIC should be considered. Caution should also be used in diabetic patients as beta blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia. Use caution when BYSTOLIC is co-administered with CYP2D6 inhibitors (quinidine, propafenone, fluoxetine, paroxetine, etc). When BYSTOLIC is administered with fluoxetine, significant increases in d-nebivolol may be observed (ie, an 8-fold increase in AUC). In general, patients with bronchospastic disease should not receive beta blockers. BYSTOLIC should not be combined with other beta blockers. The most common adverse events with BYSTOLIC versus placebo (approximately ≼1% and greater than placebo) were headache, fatigue, dizziness, diarrhea, nausea, insomnia, chest pain, bradycardia, dyspnea, rash, and peripheral edema. Please see brief summary of Prescribing Information on adjacent page. Š2009 Forest Laboratories, Inc

44-1014950

01/09

References: 1. BYSTOLIC [package insert]. St. Louis, Mo: Forest Pharmaceuticals, Inc.; 2008. 2. Data on file. Forest Laboratories, Inc. 3. Saunders E, Smith WB, DeSalvo KB, Sullivan WA. The efficacy and tolerability of nebivolol in hypertensive African American patients. J Clin Hypertens. 2007;9:866-875.


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Orphan Drug Pricing and Payer Management in the United States: Are We Approaching the Tipping Point? Rebecca Hyde; Diana Dobrovolny The Orphan Drug Act of 1983 paved the way for the development of drugs that treat rare diseases, defined in the United States as those affecting fewer than 200,000 patients. Orphan drugs can cost hundreds of thousands of dollars annually, but insurers have traditionally covered these therapies because the small populations involved did not typically lead to significant cost exposure. Payer sensitivity to the cost of orphan drugs is rising, however, with the accelerated rate of new launches of these agents amid intensified economic pressure. Payers are showing increasing levels of concern and scrutiny about coverage of orphan drugs. A new payer survey conducted between February 2008 and March 2009 provides insights on how payers are managing orphan drugs and the way it is likely to evolve in the future. Survey findings show that the patient share of orphan drug costs is rising and is expected to continue to rise, barring sweeping changes in public health policy. This shift in benefit design could affect patient access to orphan agents and, therefore, drug utilization. Manufacturers will have to invest in research to understand payer impact on the uptake of their orphan drugs in development. They will also benefit from being prepared to develop strategies to ensure patient access to and affordability of their orphan agents. [ AHDB. 2010;3(1):15-23.]

F

or the past 25 years, manufacturers of orphan drugs have faced few obstacles to reimbursement from private or public insurers, despite prices that can amount to hundreds of thousands of dollars annually in treatment cost. However, payer sensitivity appears to be rising, as the launch rate of orphan drugs accelerates amid increasing pressure to contain costs. Patient access to orphan drugs is rarely denied. The diseases that orphan drugs treat are rare and usually have no treatment alternatives. However, orphan drugs are not immune to management tactics and benefitdesign trends that payers apply to other expensive biologics, injectables, or specialty drugs. To varying degrees, major US payers are using the full range of existing tools to ensure appropriate use of orphan agents. Simultaneously, trends in health plan design have increased the burden on patients through costsharing. The result is that even when access to or coverage of orphan drugs is offered, providers and patients face hurdles that can affect utilization. In the absence of health policies that dictate otherwise, payers expect the management of orphan drugs to

Ms Hyde is Executive Vice President, Global Commercialization, and Ms Dobrovolny is Vice President, Integrated Client Development, InVentiv Advance Insights, Somerset, NJ.

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intensify. Manufacturers, providers, and patients can expect the following strategies from insurers that administrate commercial and Medicare health plans: • Scrutiny of orphan drug utilization up to and exceeding the $50,000 per-patient per-year threshold • Increased focus on appropriate use of orphan drugs, often restricting use to approved indications • Rising burden on patients through cost-sharing (ie, coinsurance, higher copayments), as well as existing annual or lifetime maximum payments.

Orphan Drugs: A Brief Overview The Orphan Drug Act (ODA) of 1983 paved the way for development of drugs that treat rare diseases, defined in the United States as those affecting fewer than 200,000 patients. These include “ultra-orphan” drugs that target diseases that affect fewer than 5 per 10,000 people.1 Key elements of the ODA are intended to spur research and introduce new products for patient populations who are otherwise too small for manufacturers to target profitably. When a product receives orphan drug designation, its manufacturer is provided with the following incentives to develop and submit the drug for marketing approval2: • Tax credits for the costs of clinical research • Annual grant funding to defray the costs of qualified clinical testing expenses ($14 million total for 2008)

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• Assistance in clinical research study design • Seven-year period of exclusive marketing after an orphan drug is approved • Waiver of Prescription Drug User Fee Act filing fees (about $1 million per application for fiscal year 2008) • Further incentives for development of orphan drugs were incorporated as amendments in 1984, 1985, 1988, and 2007. The ODA has achieved its goal of increasing the number of drugs available for rare diseases. Before the legislation was signed into law in 1983, 10 orphan drugs came to market, including calcitrol (Rocaltrol, Caligex), for the treatment of hypocalcemia in dialysis patients (1978); metoclopramide (Reglan), a gastric smooth-muscle relaxant for the treatment of gastroparesis (1979); and alprostadil (Prostin VR), for treating neonates with congenital heart defects before surgery (1981).3 As of May 2009, the US Food and Drug Administration (FDA) has designated 2002 drugs for orphan indications.3 Although a number of agents on the list are either in development or will be once investors can be attracted, a total of 338 agents have been granted marketing approval.3 Oncology or oncology support products, such as imatinib mesylate (Gleevec), account for 102 (30%) of the orphan products that have marketing approval. The remaining agents target a wide range of rare conditions from blood disorders (hemophilia, von Willebrand disease, paroxysmal nocturnal hemoglobinuria) and inflammatory conditions (juvenile rheumatoid arthritis, cyropyrin-assisted periodic syndrome) to metabolic disorders (Gaucher disease, Fabry disease, tyrosinemia).3 The rate of orphan product designations has accelerated. In 2008, the FDA’s Office of Orphan Drug Development achieved a record by designating 165 products for orphan diseases and conditions, up from 130 in 2007.4 Between 1983 and 2003, the greatest number of orphan drug designations for any single year was 95. In 2008, the FDA granted marketing approval for 15 orphan products for the treatment of diseases ranging from leukemia to Huntington disease.4

Large Pharmaceutical Companies Fuel Orphan Drug Arena Large pharmaceutical companies are helping to fuel the growth of orphan drugs, within the increased focus on their biologics sector, which accounts for 60% of the orphan drug market.5 Globally, it is estimated that large pharmaceutical companies account for 53% of the orphan drug market,5 and they are well represented in the list of orphan drugs with marketing approval. Each of the following companies sponsors at least 2 products on

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KEY POINTS u

u u u u

u

The Orphan Drug Act of 1983 paved the way for socalled orphan drugs that treat rare diseases, affecting <200,000 persons in the United States. As of May 2009, the US Food and Drug Administration has designated 2002 drugs for orphan indications. Cost is an issue with orphan drugs, which can amount to hundreds of thousands of dollars annually. Traditionally, insurers have covered these drugs, because of the small patient populations involved. But current cost concerns in healthcare raise new coverage issues for these expensive agents. The increase in cost-sharing is likely to affect patient access to orphan drugs. In 2003, only 4 single-indication orphan drugs were covered by Medicare; that number increased to 12 in 2005. Those with multiple indications are reimbursed by Medicare at various rates.

the list, as of May 2009—Abbott, Bayer, Bristol-Myers Squibb, GlaxoSmithKline, Johnson & Johnson, Pfizer, and Roche through its acquisitions.3 Like biologics that treat diseases such as rheumatoid arthritis, multiple sclerosis, Crohn disease, or hepatitis C, orphan agents command premium prices and offer the potential for revenue growth. The global market for orphan drugs grew an estimated 8% from 2005 to 2006 and is estimated to grow at a compounded annual rate of 7% through 2011.5 Some biologics, such as imatinib, start as orphan drugs for 1 rare disease but grow by expanding to additional orphan indications. However, other drugs expand into the nonorphan arena or benefit from off-label use. A number of today’s most successful biologics, such as epoetin alfa (Epogen/Procrit), rituximab (Rituxan), infliximab (Remicade), and 5 brandname human growth hormone products, began life as orphan drugs whose utility expanded through additional indications and/or off-label use.3

Orphan Drugs Rising on Payer Radar Primed by their experience with the burgeoning growth of biologics, injectables, and other specialty drugs, payers are showing increased concern and scrutiny when it comes to orphan drugs. In an informal member survey at the spring 2006 meeting of the Academy of Managed Care Pharmacy, members listed orphan drugs as one of their top concerns.6 Citing the rising number of orphan products in the pipeline and new approvals, most survey respondents believed that spending on orphan drugs would continue to increase as a percentage of over-

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Table Characteristics of 9 Orphan Drugs Mode of Therapeutic administration options available

Annual cost, $ thousands

Advanced renal-cell carcinoma (~90,000) Gastrointestinal stromal tumor (2040) Non–small-cell lung cancer (148,800) Pancreatic cancer (~33,000) Gaucher disease type I (~4000)

Oral

X

48,000

Oral

X

56,000-84,000

Oral

X

128,000

Growth failure (~30,000 overall, ~6000 severe form) Fabry disease (2564)

Subcutaneous injection Infusion

X

12,000-50,000

X

239,000

Hunter syndrome (~1500)

Infusion

300,000-500,000

Mucopolysaccharidosis VI (1200)

Infusion

441,000

Gaucher disease type I (~4000)

Infusion

Drug

Indication (US prevalence)

Sunitinib malate (Sutent)a Erlotinib (Tarceva)a Miglustat (Zavesca) Mecasermin (Increlex)b Agalsidase beta (Fabrazyme) Idursulfase (Elaprase) Galsulfase (Naglazyme) Imiglucerase (Cerezyme) Eculizumab (Soliris)

Paroxysmal nocturnal hemoglobinuria (~1050) Infusion

X

442,000-600,000 486,000-508,000

a

Oncology. Pediatric only. Source: InVentiv Advance Insights, Somerset, NJ. b

all drug budgets.6 Under pressure by patient advocacy groups and physicians to expand access, and plan sponsors to control healthcare spending, payers now see new challenges in the management of orphan drugs.

Orphan Drug Management by Payers To better understand payer sensitivity to orphan drug costs and how insurers manage these costs, Advance Insights, an InVentiv Health company, conducted (from February 2008 to March 2009) a web-based survey of decision makers in 26 payer organizations responsible for 106 million lives across the United States.7 Two thirds of these lives were covered in commercially sponsored medical or pharmacy plans or both, with the remainder in Medicare or Medicaid plans. Most lives enrolled in pharmacy plans were in 3-tier, open plans (90% for the commercial population and 61% for Medicare), the most common plan design nationally. Four- or 5-tier plans account for 8% of the commercial population and 54% of the Medicare population.7 The web survey focused on the current management of 9 orphan agents selected to achieve a mix of oncology and nononcology agents, orphan and ultra-orphan drugs, various modes of administration, existence of treatment alternatives, and multiple indications (Table).

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Among the most significant findings was that no new management approaches have been developed or appear to be in development specifically for managing unique orphan drugs that treat very small populations. Instead, orphan drugs are likely to be captured in the same net of tools, tactics, and benefit designs already in use or planned for controlling costs of biologics, injectables, or other expensive specialty products used for the treatment of diseases far less rare than most orphan conditions. Sensitivity to drug cost ranges considerably among surveyed plans, but for 54%, scrutiny increases when a drug is priced ≤$50,000 per patient per year. The remaining respondents cite thresholds ≥$50,001 per patient per year, with 2 plans indicating that the drug cost must exceed $250,000 per patient per year for greater scrutiny (Figure 1). Not surprisingly, clinical data associated with an orphan drug are ranked highest among the factors that drive benefit design or restrictions for orphan drugs in most plans, followed closely by overall cost exposure (Figure 2). Clinical data—FDA-approved indication, trial design and results, formulation, and requirements for administration—provide the basis for prior authorization and continued use. Overall cost exposure—a

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Figure 1 At What Price (Per Patient Per Year) Does an Orphan Drug “Hit Your Radar Screen”? Threshhold is ≤$50,000 for 54% plans

>50,000 ≤50,000

1

300,00+ 250,001-300,000

Price of drug, $

Soliris, $486K-$508K Cerezyme, $442K-$600K Naglazyme, $441K Elaprase, $300K-$500K

1

150,001-250,000

Fabrazyme, $239K

100,001-150,000

5

Zavesca, $128K

1

75,001-100,000 4

50,001-75,000

Tarceva, $56K-$84K

5

25,001-50,000

Sutent, $48K

7

10,001-25,000 ≤10,000

Increlex, $12K-$50K

2 0

5

10

15

20

25

30

Number of plans Source: InVentiv Advance Insights, Somerset, NJ.

Aggregated rank (rank ⴒ number of responses)

Figure 2 Factors Driving Benefit Design or Restrictions for Orphan Agents, in Order of Importance 150

129 111

100

97

94

92

84

Potential for off-label use

Expected no. of patients in plan

Treatment options available

Disease incidence

50 0 Clinical data of the drug

Cost exposure for plan

N = 26 health plans. Source: InVentiv Advance Insights, Somerset, NJ.

function of disease prevalence, number of indications, potential for off-label use, and the availability of less expensive treatment options—serves to further raise the visibility of an orphan drug and to guide management. Most of the plans surveyed require prior authorization to ensure that the proposed use matches the FDAapproved indication for each of the orphan drugs (Figure 3). Payers, however, are likely to vary significantly in how they use clinical information and FDA labeling to restrict access to orphan products as illustrated by 2 cases involving eculizumab (Soliris), a product for treatment of paroxysmal nocturnal hemoglobinuria. Health plan A is a regional affiliate of a national plan, with 1.9 million members. Health plan B is a 2.4million-member independent regional plan. Both required prior authorization to obtain coverage for eculizumab. For plan A, this meant confirmation of diagnosis by a specialist, which led to the approval of

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the product. In contrast, plan B had a formal medical policy in place, with criteria for use based on FDAapproved labeling and patient selection criteria and end points used in the clinical trials conducted to gain product FDA approval. Plan B’s approach resulted in denial of coverage for eculizumab for 1 patient in 2008, because clinical measure did not meet policy criteria. In this case, the plan determined that the potential risks exceeded any potential benefits, despite the prescribing specialist’s recommendation.7 The respondent for plan A indicated a price sensitivity threshold of $100,001 to $150,000 per patient per year, whereas plan B indicated increased scrutiny of orphan drugs at pricing from $25,001 to $50,000—both well below the estimated annual drug cost associated with eculizumab, but perhaps reflective of the difference in plan sensitivities and philosophies that exist among those administering health plans.

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Figure 3 Restrictions for the Commercial Population for These Drugs Small plans (n = 4): <500,000 covered lives Total: 1.3 million covered lives Orals Sutent

Number of plans

6 5 4 3 2 1 0

Tarceva

Zavesca

No PA Less restrictive PA More restrictive PA Periodic reevaluation

Subcutaneous injection Increlex

Infusibles Fabrazyme

Elaprase

Naglazyme

Cerezyme

Soliris

Increlex

Fabrazyme

Elaprase

Naglazyme

Cerezyme

Soliris

Increlex

Fabrazyme

Elaprase

Naglazyme

Cerezyme

Soliris

Number of plans

Medium plans (n = 17): 0.5 million-5 million covered lives Total: 28.8 million covered lives Sutent

25 20 15 10 5 0

Tarceva

Zavesca

Number of plans

Large plans (n = 5): >5 million covered lives Total: 75.6 million covered lives Sutent

8

Tarceva

Zavesca

6 4 2 0

Less restrictive PA includes confirmation of diagnosis, use limited to labeled indication, quantity limits, specialist only. More restrictive PA includes genetic test to confirm diagnosis, severe symptoms only, step therapy. PA indicates prior authorization. Source: InVentiv Advance Insights, Somerset, NJ.

Although most of the respondents surveyed reported using less restrictive prior authorization policies similar to that described for plan A, a significant number reported tighter policies for each of the drugs in the study (Figure 4). These more restrictive approaches may include genetic testing to confirm a diagnosis or step therapy, if appropriate. In plans with formal policies, it is common to incorporate periodic reevaluation of patient status against measures based on clinical trial results to determine if a treatment is effective.

Access Does Not Guarantee Affordability Benefit design does not distinguish between orphan and nonorphan drugs. Following patterns in the nonorphan drug arena, oral products are usually covered under the pharmacy benefit, whereas infused agents are normally covered under the medical benefit. Injectable coverage varies between the two. Where patient cost-

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sharing for drugs is used, the patterns mirror those used in the nonorphan environment. Copayments are often used in conjunction with oral agents, whereas coinsurance, defined as percent-based cost-sharing, is more common for infused drugs. As a result, coverage scenarios for orphan drugs vary widely, as illustrated by galsulfase (Naglazyme), a treatment for the enzyme-deficiency disease mucopolysaccharidosis VI, one of the drugs that was included in the current survey. A commercially insured patient receiving galsulfase under the medical benefit in 1 of the 5 plans that cover the drug under the medical benefit (Figure 4) pays only a typical office copayment, ranging from $25 to $40 each time the drug is administered in the clinic. A commercially insured patient receiving the same drug under the pharmacy benefit (20 plans in the survey) typically pays the office copay along with drug copays up to $25 per prescription or coinsurance, which ranges

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Figure 4 What Is the Average Cost-Sharing for These Drugs for the Common Commerical Plan? Copay distribution Subcutaneous injection

Number of plans

Orals 20 15

Sutent

Tarceva

Zavesca

6

6

6

9

5

10

6

3

Fabrazyme

6 9

5 0

Increlex

Infusibles

4 3

2

1 1 2 3

Elaprase

1 1 3 3

Naglazyme

Cerezyme

Soliris ≥$101 $51-$100 $26-$50 ≤$25

1 1 2 3

1 0 3 3

1 1 2 3

Soliris

Coinsurance distribution Subcutaneous injection

Number of plans

Orals 15

Sutent

Tarceva

Zavesca

Increlex

5

Fabrazyme

Elaprase

Naglazyme

Cerezyme

3

2

2

2

8

8

7

7

7

6

2

2

3

3

3

3

1

10 1

1

1

5 6

Infusibles

5 2

2

>21%-30% >11%-20% >5%-10%

0 Oncology drugs are not treated differently from nononcology drugs. Patient-assistance programs are usually available for patients who are unable to afford insurance or cost-sharing so they could gain access to treatment.

Source: InVentiv Advance Insights, Somerset, NJ.

from 11% to 20% of the cost per prescription. Under a coinsurance scenario, for a patient taking galsulfase, the annual out-of-pocket (OOP) drug costs would range between $48,500 and $88,200 per year, in the absence of a plan-imposed cap or maximum.6 Although annual OOP maximums help to mitigate these expenses, some 29% of plans surveyed by the Kaiser Family Foundation and the Health Research & Educational Trust in 2007 do not offer them and use of those that do varies widely.8 In single coverage plans, 22% of insured employees were in plans that capped annual OOP expenditures at $3000 or more and 28% were in plans with maximums of <$1500 a year. Of those enrolled in family coverage plans, 24% had annual OOP maximums of $2000 to $6000 and 10% had maximums <$2000.8 Regardless of caps on OOP maximums, copayments and coinsurance represent only 1 form of cost-sharing, with the potential to impact orphan drug use as it does for many patients with serious illnesses. Rising premiums, deductibles, variations in coverage based on plan type, and limits on benefits combine to create significant economic hardship for many with serious illnesses. For example, 22% of the employed population opts for policies that limit lifetime medical benefits to between $1

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million and $2 million.8 Patients using orphan drugs generating costs between $50,000 and $100,000 per year plus costs associated with administration and ancillary care can rapidly reach these maximums.

Medicare Reimbursement Policies Medicaid coverage and reimbursement policies for orphan drugs vary from state to state. Medicare patients seeking orphan drugs face limitations on reimbursement and potentially high OOP costs. Under provisions in the Medicare Modernization Act (MMA) of 2003, OOP costs typically reach $5700 per patient per year before catastrophic coverage kicks in for patients covered under Medicare Part D. The Centers for Medicare & Medicaid Services (CMS) has the ability to raise this maximum annually. Patients receiving care through Medicare Part B or the medical benefit may encounter reimbursement or access hurdles based on whether the drug meets Medicare’s criteria for a single-indication orphan drug. These criteria require drugs to be (1) designated as orphan drugs and approved by the FDA for the treatment of ≥1 orphan conditions, and (2) listed in the current US Pharmacopoeia Drug Quality and Information only for the orphan indication, with no

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other approved indication or off-label use.9 This policy is based on the assumption that nonorphan indications or off-label use expand income available to manufacturers, and, because they are used by a larger patient population, providers and suppliers are more motivated to supply them.

Single-Indication Orphan Drugs When this rule was passed as part of the MMA, 4 drugs were on the list of single-indication orphan drugs. The list was expanded to 12 drugs in 2005 with the input of provider groups or patient advocacy groups, such as the National Organization for Rare Diseases (NORD). The list of single-indication orphan drugs includes imiglucerase (Cerezyme) and interferon gamma 1-b (Actimmune) but not epoetin alfa, which has a number of indications that CMS considers outside the orphan arena, and botulinum toxin type A (Botox), which generates far more income from cosmetic use than it does from its orphan indications, including the treatment of dystonia.9 Single-indication orphan drugs receive special payment consideration through the Medicare’s Hospital Outpatient Prospective Payment System (OPPS). They were also excluded from the Competitive Acquisition Program (CAP) vendor program, which, until it was postponed in September 2008, supplied a list of specialty drugs and biologics to physicians as part of the MMA. This means that CAP vendors were not required to carry and provide the 12 products, forcing providers or patients to find other pathways for acquiring and obtaining reimbursement for the drug. These included arranging for administration of the drug in a hospital or hospital outpatient clinic, working with specialty pharmacy providers that are focused on orphan drug or other rare disease markets, and patching together reimbursement from Medicare and manufacturer patient-assistance programs, all of which they now do in the absence of the CAP. Orphan Drugs Not on Single-Indication List Orphan drugs that are not on the single-indication list are reimbursed by Medicare at various rates. Reimbursement under OPPS depends on whether the drugs are enfolded into a procedure or are reimbursed separately. Reimbursement rates within these groups may vary from drug to drug based on clinical and access considerations.10 For drugs administered by physicians in the office, Medicare Part B generally pays 80% of medical benefit costs, which can include the cost of infused drugs along with administration and other ancillary costs associated with the drug and patient care. For patients taking orphan drugs, the remaining 20% can amount to thousands of dollars a month, according to patient advocates.11

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Patient-Assistance Programs Are Key Patient-assistance programs are a resource for many patients and form the cornerstone of manufacturer marketing programs for orphan drugs. The amount of financial assistance varies based on individual patient income and may involve other organizations. Genzyme Corporation, for example, offers the Charitable Access Program for patients using imiglucerase, alglucerase (Ceredase), laronidase (Aldurazyme), agalsidase beta (Fabrazyme), and alglucosidase alfa (Myozyme).11 These programs offer free drugs in limited amounts to qualified patients. Other programs, such as that offered and administered by NORD, assist insured patients with insurance premiums and copayments. On its website, NORD lists 34 different patient-assistance programs that it administrates on behalf of orphan drug manufacturers.12 Future Developments Over the next 3 to 5 years, insurers who participated in the present survey expect to see increasing budget pressure from orphan products, citing new launches, price increases, and new indications for existing products. A few of them expect some of these launches to provide therapeutic alternatives or potential biosimilars that would allow contracting or the development of step edits. The majority of respondents, however, expect that commercial insurers will continue to shift more cost to patients through mechanisms such as opt-in riders for expensive drugs and increased reliance on drug health plans with fourth and fifth tiers, which are comprised of expensive injectables and/or infused drugs.13 This finding is reinforced by the recently published results of the Benefit Design Index conducted by the Zitter Group in 2008.14 Among other measures, the Benefit Design Index highlights employer and insurer satisfaction with cost-sharing. In the 12 months leading up to that study, nearly 70% of insurers increased copayments/coinsurance rates for prescription drugs. Payers in this study indicate that they can shift to patients from $354 to $377 per month in OOP costs without the member foregoing medically necessary care.14 Patient advocates view this trend with alarm, fearing that higher OOP expenses will inhibit or prevent patients from using needed medications.6 Furthermore, increased drug cost-sharing does not take into account the impact of cumulative OOP healthcare costs stemming from serious illnesses which, at the very least, can result in gaps in care. Oncology provides good examples for this. A February 2009 report by the Kaiser Family Foundation and the American Cancer Society cited cases of patients with cancer, including 1 who amassed $100,000 in med-

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ical bills, and a patient with leukemia who had nearly reached the lifetime maximum benefit of $1 million at the time of the study.15 An analysis conducted by the American Cancer Society showed that although the average OOP cost associated with breast cancer is a little more than $2600, 5% of privately insured patients accumulate ≼$31,000 in OOP expenses.15

The continued application of traditional patient cost-sharing strategies in the orphan drug arena is likely to have far-reaching effects not only for patients but also for providers and for drug manufacturers. Conclusions It is difficult to envision a scenario in which orphan drugs will be denied coverage; however, payer scrutiny is likely to increase as new products enter the market and budgets contract in a weakening economic environment. Responses will vary by payer and plan based not only on cost exposure but also on payer resources, philosophies, and available benefit design options, all of which can affect patient access. Responses are also likely to be affected by any changes that may come in public policy through healthcare reform. A clear understanding of the clinical and economic value of the drugs will play an increasingly important role in decision-making. The continued application of traditional patient cost-sharing strategies in the orphan drug arena is likely to have far-reaching effects not only for patients but also for providers and for drug manufacturers. For plans with formal medical policies, specialists must be prepared to document that patients meet specified clinical

guidelines to receive drugs. Increasingly, manufacturers will have to invest in research to understand payer impact on uptake of their orphan drugs in development. They must also be prepared to develop strategies to ensure that payers truly understand the value of their therapy and tactics to ensure that patients will be able to access and afford the orphan agents they develop. â–

References 1. US Food and Drug Administration. Developing products for rare diseases and conditions. www.fda.gov/orphan/oda.htm. Accessed August 18, 2008. 2. Borda C. The orphan drug act, 25 years, 1800 designations, 319 product approvals, and counting. PharmaVoice. April 2008. www.imshealth.com/ imshealth/Global/Content/Document/Value-based%20Medicine%20TL/ ODA_PharmaVOICE_April%202008.pdf. Accessed August 18, 2008. 3. Food and Drug Administration, Office of Orphan Products. Orphan drugs approved between 1978 and 1981 (search list). www.accessdata.fda.gov/scripts/ opdlisting/oopd/index.cfm. Accessed May 26, 2009. 4. Kurst KR. FDA orphan drug designations are on the rise. FDA Law Blog of Hyman, Phelps & McNamara, PC. www.fdalawblog.net/fda_law_blog_hyman_phelps/ 2009/02/fda-orphan-drug-designations-are-on-the-rise.html. Accessed May 6, 2009. 5. Ariyanchira S. Biomarket trends: orphan drug arena driven by biologics. Genetic Engineering Biotechnology News. 2008;28. January 1, 2008. www.genengnews.com/ articles/chitem_print.aspx?aid=2318&chid=0. Accessed May 25, 2009. 6. Hyde R, Dobrovolny D. Orphan drug pricing: have we reached the tipping point? Presented at the 20th Annual Meeting and Showcase of the Academy of Managed Care Pharmacists. San Francisco, CA; April 16-19, 2008. 7. Advance Insight. Knowledge database. Somerset, NJ. Interviews with payers conducted from February 2008 through March 2009. 8. Kaiser Family Foundation/Health Research & Educational Trust. Employer Health Benefits 2007 Annual Survey. www.kff.org/insurance/7672/upload/ 76723.pdf. Accessed May 26, 2009. 9. Centers for Medicare & Medicaid Services. Medicare program; competitive acquisition of outpatient drugs and biologicals under Part B. Interim final rule with comment period. Fed Regist. 2005;70:39021-39102. 10. Centers for Medicare & Medicaid Services, Department of Health and Human Services. OPPS payment changes for drugs, biologicals, and radiopharmaceuticals. Fed Regist. 2008;73:68502-69380. 11. Maas A. Better cost-sharing approaches can help patients on orphan drugs. AIS Health. September 19, 2008. www.aishealth.com/DrugCosts/specialty/SPN_ Orphan_Drugs.html. Accessed May 1, 2009. 12. RxAssist. Medications available by company. http://rxassist.org/Search/ Search_Results_Company_Name.cfm?Search=Genzyme&Seq=Brand&CFID=34 07005&CFTOKEN=75369314. Accessed May 26, 2009. 13. National Organization of Rare Diseases. Programs and services. www.rarediseases. org/programs/medication. Accessed May 26, 2009. 14. Haren MC, McConnell K. Patient cost-sharing on the rise: results from the benefit design index. Am Health Drug Benefits. 2009;2:70-77. 15. Kaiser Family Foundation/American Cancer Society. Spending to survive: cancer patients confront holes in the health insurance system. February 2009. www.kff.org/insurance/upload/7851.pdf. Accessed May 26, 2009.

STAKEHOLDER PERSPECTIVE Orphan Drugs: The Potential Impact of Generic Biologics PAYERS/PATIENTS/PROVIDERS: There are approximately 6000 rare diseases that affect nearly 25 million Americans, highlighting the importance of access to orphan drugs as an urgent policy issue, according to the National Organization for Rare Diseases (NORD). Among the various access-related issues to orphan drugs that Ms Hyde and Ms Dobrovolny raise in their

article, one issue they briefly describe deserves further focus, namely, the potential entry of generic biologics (also known as biosimilars) into the US marketplace. With 15 new orphan drugs launched in the past 24 months, of which at least half are priced at more than $100,000 annually, the issue of generic biologics, and their impact on access to less expensive orphan drugs, needs further discussion. Continued

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STAKEHOLDER PERSPECTIVE (Continued) Currently, Representative Henry Waxman, Chairman of the House Energy and Commerce Committee, along with the Obama administration, are proposing legislation to allow brand-name biologics used for orphan drugs to be subject to generic competition in the United States after 7 years of patent exclusivity. This proposed legislation is significant for the orphan drug market, as biotechnology drugs are key drivers of this market, which is estimated to reach $82 billion by 2011. Biologics account for approximately 60% of the global orphan drug market today. Promising categories within biologics are monoclonal antibodies, interferons/interleukins, growth hormones, and plasma products. What would the potential impact of this legislation be? First, it could increase access to affordable treatments for orphan drugs to payers, providers, and patients. Approximately 5000 of the 6000 orphan diseases involve genetic disorders, and many will need enzyme, hormone, and protein therapies, which require biologics rather than traditional small-molecule drugs. If approved, generic biologics could be sold at a 10% to 30% discount, allowing for “substantial consumer savings,� without eroding market share for brand-name pharmaceutical companies, according to a recent Federal Trade Commission report.1 Second, the physical availability of orphan drugs for patients and providers may also be influenced by the presence of generic biologics, according to NORD. Most orphan biologics are made by only 1 manufacturer, and yet providers are experiencing critical shortages of lifesaving biologic treatments (eg, recombinant factor VIII for hemophilia and Prolastin

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for alpha-1 antitrypsin deficiency). This shortage leads to rationing of orphan drugs, thereby limiting much-needed access for patients. Third, a lack of competition in biologics may also impede new treatment advances for orphan diseases. Without competition from generic manufacturers, there may be little incentive for biotechnology manufacturers to continue to innovate for orphan biologics. The Drug Price Competition Act has resulted in brand-name manufacturers innovating to make newer delivery/dosage forms of their products. But without competition for biologics there is no incentive for manufacturers to continue to innovate in developing biologics for orphan diseases. Despite the concerns about the feasibility of generic biologics (ie, can they be developed; will they be therapeutically equivalent to brand-name biologics), the future of the orphan drug industry will significantly be influenced by the entry of generic biologics. Globally, countries such as Australia, Japan, Singapore, Taiwan, and Korea have already implemented legislation for promoting research on orphan drugs. If current efforts in the United States take a similar direction, patients, providers, and payers can only stand to benefit from these advances. Reference 1. Federal Trade Commission. Follow-on biologic drug competition. June 11, 2009. www.ftc.gov/speeches/harbour/090611fobspeech.pdf. Accessed January 15, 2010.

Kavita V. Nair, PhD Associate Professor, School of Pharmacy University of Colorado at Denver Aurora, CO

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GENERIC DRUG TRENDS

Competition from Biosimilars an Incentive for Innovation Dalia Buffery, MA, ABD

T

he Generic Pharmaceutical Association (GPhA) recently praised the Obama administration’s fiscal 2011 budget proposal for the US Food and Drug Administration (FDA), which will increase the FDA’s Office of Generic Drugs to $51.5 million, a $10million increase compared with fiscal year 2010.1 In supporting the administration’s attempt to strengthen access to generics, GPhA’s President Kathleen Jaeger noted, “Generics also save our health care system money, a critical factor in these difficult economic times. GPhA’s landmark generic savings study, conducted by IMS Health, found that for every two percent increase in generic utilization, the nation’s Medicaid program could save an additional $1 billion each year. Increasing consumer access to affordable medicines reaps tremendous dividends to private and public providers as well as taxpayers.”1 Saving healthcare dollars and increasing access to medications are 2 goals shared by all healthcare stakeholders, including payers, providers, patients, drug manufacturers, and employers. These goals, however, apply not only to small-molecule generics but also to any future generic biologics, also known as biosimilars or follow-on biologics (FOBs). (That we still do not agree on the nomenclature is but one indication of the shape of things with so-called generic formulations for biologic pharmaceuticals.) Innovation is key to advances in medicine and in healthcare as much as in other areas of business and science; but innovation is used as the reason to prevent competition in biologic products that will occur with the initiation of a pathway for FDA approval of biosimilars. We know that such a pathway is inevitable, and we know it is the way of the land to provide for competition and promote innovation. The bills for that new pathway have been circulating—with twists and turns—in Congress for some time now, but the legislation has been taking longer than the “normal route of innovation” dictates. Last year we discussed the legislation for the evergrowing elephant in the room—the new pathway for biosimilars, musing that perhaps 2009 would bring in such a new track.2 It did not: will it be 2010 instead? The signs are still positive, but the wheels in

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Washington turn slow, especially now that the “big” healthcare reform has been put on hold, and the spirit of promoting competition and innovation—for the benefit of all stakeholders, including consumers and business—is all but gone from Congress for the moment. The healthcare reform bill, which was advocating for 12 years of patent exclusivity for biologics as protection from biosimilars competition, has also gone the way of the healthcare reform itself; when the discussion resumes, potentially a shorter exclusivity period will be introduced, to allow for faster access to lower-cost biologic products.

Innovation is used as the reason to prevent competition in biologic products that will occur with the initiation of a pathway for FDA approval of biosimilars. In June of last year, the Federal Trade Commission (FTC) issued a report elucidating the reasons why the introduction of biosimilars does not pose a threat to biologic drug manufacturers.3 The rationale for the report (titled “Follow-on Biologic Drug Competition”) was in line with the FTC’s role to “investigate alleged anticompetitive business practices.”4 The nature of competition that will ensue between biotechnology companies and manufacturers of biosimilars will be different from the competition between manufacturers of small-molecule pharmaceuticals and generic drugs, according to the FTC, because4: 1. The substantial costs to obtain FDA approval, and the substantial costs to develop manufacturing capacity, will limit the number of biosimilars competitors 2. The lack of automatic substitution between a biosimilar and an original biologic will slow the rate at which a biosimilar can acquire market share 3. A biosimilar may have difficulty gaining market share, because of concerns of safety and efficacy differences with the original biologic 4. Biologics are not reimbursed according to strategies that insurers often use to encourage the use of lowerpriced drugs

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5. Therefore, a biosimilar entry will be less dramatic than generic drug competition. The entry of a biosimilar is likely in biologic drug markets with annual sales >$250 million. Only 2 or 3 biosimilar manufacturers are likely to attempt entry for a given biologic. These entrants are unlikely to introduce their drugs at discounts of >10% to 30% of the original biologic’s price 6. The effect on the original biologic manufacturer will also be different; they are expected to respond to and offer competitive discounts to maintain market share and are likely to retain 70% to 90% of their market share, and continue to reap substantial profits, even after the entry of a biosimilar. Based on these findings, the FTC concludes that the introduction of biosimilars will emulate brand–brand drug competition rather than brand–generic drug competition, and that “patent protection and market-based pricing will promote competition by FOBs, as well as spur biologic innovation.”3

If the FTC is correct that competition breeds innovation even in this case, then everyone is poised to win—patients, payers, drug manufacturers, and our entire healthcare. The FTC’s prediction, rooted in the foundation of the free-market that more is better, and more competition to be introduced by generic formulations of biologic products will invite innovation rather than deter it, offers an interesting insight. The argument that biosimilars differ from small-molecule generics by necessitating similar biologic entities that will keep the price high, thereby forcing only a small price adjustment on the part of biologics, was the basis for the FTC’s position. Whether this is sufficient to convince biologic manufacturers that a new pathway for FDA approval of biosimilars is not detrimental to their market-share potential remains to be seen, but the trend is clearly leaning in that direction. If the FTC is correct that competition breeds innovation even in this case, then everyone is poised to win—patients, payers, drug manufacturers, and our entire healthcare. This point was further reiterated in a recent roundtable discussion on generics by the Directorate for Financial and Enterprise Affairs Competition Committee, saying that, “The competitive dynamic between brand-name drugs and their generic equivalents creates an incentive for brand and generic manufacturers to conspire to avoid competition and share the resulting profits.”5

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The FTC report concludes “that providing the FDA with the authority to approve such FOBs would be an efficient way to bring these lower-priced drugs to market,”4 and increasing access to all patients is an efficient way to improve health and reduce healthcare costs, as was suggested by the GPhA.1 Time, however, is of significance. Escalating costs may eventually force biologic manufacturers to bring their costs down some, with or without competition from biosimilars. The main obstacle to implementing a biosimilar pathway remains the duration and nature of patent protection. But the argument against preventing access to these life-sustaining therapies for patients is bound to win; as has been seen time and again, increasing access to good care benefits all healthcare stakeholders, not only patients. ■

References 1. Generic Pharmaceutical Association. Press release. February 1, 2010. www.gphaonline.org. Accessed February 4, 2010. 2. Buffery D. New legislations on generics and biosimilars brewing in Congress. Am Drug Health Benefits. 2009;2:120. 3. Federal Trade Commission. Emerging Health Care Issues: Follow-on Biologic Drug Competition: A Federal Trade Commission Report (June 2009). June 10, 2009. www.ftc.gov/os/2009/06/P083901biologicreport.pdf. 4. Federal Trade Commission. FTC releases report on “Follow-on Biologic Drug Competition.” June 10, 2009. www.ftc.gov/opa/2009/06/biologics.shtm. Accessed February 4, 2010. 5. Directorate for Financial and Enterprise Affairs Competition Committee. Roundtable on generic pharmaceuticals. DAF/COMP/DW(2009)116. October 14, 2009. www.konkurrensverket.se/upload/Filer/Om_Konkurrensverket/Internationell %20roll/oecd/DAF-COMP-WD(2009)113-ENG%20sweden.pdf. Accessed February 4, 2010.

Unmanaged Moment

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January/February 2010

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JOIN AHDB PEER REVIEW American Health & Drug Benefits (AHDB) is looking for medical and pharmacy directors, P & T Committee members, and other experts in benefit design who are interested in joining our peer reviewers and assist in maintaining the high quality of articles published in the journal. You will be asked to review at least 1 or 2 articles per year in your area of expertise. Reviewers’ names will be published in AHDB at the end of the year. Reviewers should have at least 1 area of expertise in a health-related field for which they feel qualified to assess the content and quality of manuscripts submitted for publication in AHDB.

Articles fall into 3 main areas related to healthcare: Regulatory, Business, and Clinical. These main categories are represented from the different vantage points of all stakeholders in healthcare and are divided into many subcategories, including (but not limited to): • Administration/Management • Benefit design • Disease management/state (eg, asthma, infectious diseases, pain management, schizophrenia) • Drug therapy (including biologics, generics) • Drug utilization • Employer benefits • Finance/economics • Health information technology • Health policy/reform • Patient education/initiatives/quality-of-life issues • Pharmacoeconomics: cost-benefit analysis, cost-effectiveness • Pharmacy management: pharmacology, specialty pharmacy, pharmacy benefits • Reimbursement: Medicare/Medicaid, health insurance, prior authorization • Research: methods, study design, data collection/analysis

To become a peer reviewer, please complete the form below and fax to: 732-992-1881 or e-mail to editorial@ahdbonline.com Reviewer Information _______________________________________________________________________________________ First Name Last Name Credentials _______________________________________________________________________________________ Title Company _______________________________________________________________________________________ Address _______________________________________________________________________________________ E-mail Phone


BUSINESS

Physicians’ Perceptions of Reimbursement as a Barrier to Comprehensive Diabetes Care Alyssa Pozniak, PhD; Lois Olinger, MA; Victoria Shier, MA Background: As the incidence of diabetes increases, there is growing concern about the adequacy of reimbursement levels for delivering comprehensive diabetes care. Objective: To investigate physicians’ perceptions of the adequacy of reimbursement, as well as resources (eg, staff, facilities, materials), for their treatment of diabetic patients. Methods: A qualitative exploration using a Web-based survey of 300 physicians (200 primary care providers and 100 endocrinologists) and an online discussion group of 12 physicians, focusing on 10 services recommended by the American Diabetes Association that may be prone to underreimbursement. The 10 services were matched with 4 general diabetes care categories to assess the adequacy of care delivery. Results: The majority of physician study participants perceived that most of the 10 identified services are inadequately reimbursed—83% to 95% of physicians said Medicaid reimbursement was inadequate, 75% to 89% for Medicare reimbursement, and 67% to 86% for private insurance reimbursement—leading them to spend less time with each patient. This reduction in time was a limiting factor to providing comprehensive diabetes care. The survey also revealed differences between endocrinologists and primary care physicians; for example, medical nutrition therapy was offered by 50% of endocrinology practices compared with only 29.5% of primary care practices. Conclusion: This study confirms previous findings that physicians perceive current reimbursement for diabetes care as too low, which limits their ability to perform all the tasks necessary to deliver comprehensive diabetes care. [AHDB. 2010;3(1):31-40. Epub 2009 Nov 19.]

A

s the number of patients with diabetes increases, there is growing concern about the adequacy of reimbursement levels for delivering comprehensive diabetes care. In 2005 diabetes was the sixth leading cause of death in the United States1; it is a major contributor to many disabilities.2 In 2007, more than 17 million Americans were diagnosed with diabetes, with associated costs of approximately $174 billion.3,4 More recent estimates of the cost of diabetes care are as high as $218 billion.5-8 These costs are likely to increase as the incidence of diabetes continues to rise. Approximately 165 recommendations are listed in the annual American Diabetes Association (ADA) clinical guidelines, “Standards of Medical Care in Diabetes.”9 The guidelines contain the ADA’s key recommendations for the standard of diabetes care. Many recommendations call for multidisciplinary teams to deliver counseling and education to patients with diabetes to establish lifestyle changes and improve outcomes. Previous research underscores the importance of patient education and its relationship to self-man-

Dr Pozniak is an Associate at Abt Associates, Cambridge, MA; Ms Olinger is Senior Study Director at Westat, Rockville, MD; and Ms Shier is a graduate student at Pardee RAND Graduate School.

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agement of diabetes and adherence.10-13 In a systematic review of the literature, Loveman and colleagues highlight 6 studies that demonstrate a significant improvement in glycated hemoglobin levels among patients who received education versus patients who did not.14 Because patients with diabetes tend to be complex and time consuming, their treatment requires significant management support and education; therefore, reimbursement can fall short of the actual costs of providing diabetes care.15,16 This may be especially true for activities where reimbursement levels do not adequately reflect the care provided (eg, care coordination and patient education) or are dependent on the setting and/or provider.17 The cost of diabetes care may be further underestimated by not accounting for other modalities of service delivery, including disease management, and nurse-managed care efforts. Misalignment between payment systems and optimal quality of care could cause some patients to go without necessary services, potentially leading to poorer outcomes and quality of life. Based on input and feedback from representatives from various medical and diabetes organizations,18 the present study focused on (1) care coordination, (2) patient education, (3) counseling, and (4) psychosocial assessments as they relate to diabetes care and reimbursement. A subset of 10 ADA-recommended activi-

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ties9 that correspond to these 4 general categories of diabetes care were selected, because these activities were identified as being prone to underreimbursement. The Figure illustrates how these 10 ADA-recommended activities map to these 4 general categories of diabetes care. Specifically, this study explored the degree to which providers offer these 10 selected ADA-recommended services in their practices, their perceptions of reimbursement for these services, and other factors affecting the care of patients with diabetes.

Methodology This qualitative exploration focused on the perceived adequacy of resources as defined by medical and administrative time, facilities, staff, and materials for the general 4 categories of diabetes care and the provision and perceived reimbursement adequacy of the 10 selected ADA-recommended activities that are suspected to be prone to underreimbursement (Figure). We collected data using (1) a Web-based survey of 200 primary care physicians (PCPs) and 100 endocrinologists, and (2) a follow-on online discussion group of 6 PCPs and 6 endocrinologists to address 3 successive waves of questions derived from the responses of the Web-based survey. A convenience sample of 300 physicians was selected from a market research panel of physicians recruited by Epocrates,19 who had agreed in advance to respond to short surveys regarding care and payment issues. The 12 physicians in the follow-up online discussion were selected from a market research panel of physicians recruited by Panel Intelligence20 who had agreed in advance to participate in online discussion groups. Participants were restricted to physicians who were treating adult patients with diabetes and were whole or part owners of their medical practice, to ensure the participants had the best understanding of billing and reimbursement for the practice. All participants were compensated for their participation.

KEY POINTS u

Diabetes care requires ongoing physician follow-up and appropriate patient education. Previous studies suggest that physicians perceive the current reimbursement for diabetes as too low. u Findings from this study suggest that providers perceive inadequate reimbursement as the culprit in decreased time spent with each patient, which limits the comprehensive care for diabetic patients and reduces patient adherence. u The majority of practices offer instructions or evaluation of self-monitoring blood glucose, but less than half offer multidisciplinary care coordination or medical nutrition therapy. u More endocrinologists than primary care providers offer multidisciplinary care coordination, but fewer primary care providers offer psychological screening or smoking-cessation counseling.

The survey asked whether the physicians offered the 10 ADA-recommended services in their practice; if so, they were asked whether they or a nonphysician staff member provided the service, and whether reimbursement was adequate. In addition, the survey asked whether the respondents felt that they had adequate resources (ie, medical and administrative time, facilities, staff, and materials) in their practice to provide the 4 more general categories of diabetes care. The online discussion was designed to gain a better understanding of the physician perceptions that were identified in the Web-based survey. Each panelist responded to 3 waves of questions: 11 initial questions, 10 follow-up questions, and 7 final follow-up questions. The survey involved an asynchronous, threaded discussion, allowing panelists to interact with each other, as well as with the moderator.

Figure Diabetes Care Areas and 10 Relevant ADA-Recommended Guidelines

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I. Physician-coordinated II. Lifestyle/behavior modification multidisciplinary team care counseling

III. Patient education on self-care/ complication prevention

1. Multidisciplinary care coordination

4. Self-monitoring blood glucose 10. Psychological/social status instruction/evaluation assessments 5. Intensive insulin therapy instruction 6. Medical nutrition therapy 7. Self-care of the feet education 8. Annual eye examination and blindness education 9. Diabetes self-management education

2. Weight-loss counseling and physical activity instruction 3. Smoking-cessation counseling

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IV. Psychological/social status assessments

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Physicians’ Perceptions of Reimbursement for Diabetes Care

To encourage candid and unbiased input, survey respondents and panelists did not know the sponsor of the study or the identities of the other participants. (The survey instrument and online panel discussion questions can be found at www.ncdp.com.)

Survey Results The majority of survey respondents were men, and their primary practice setting was a medical office (Table 1). On average, the physicians’ practices saw 239 patients each week, with PCPs’ practices seeing 30% more patients than endocrinologists’ practices (260 vs 197, respectively). Private insurance was the most common payer in endocrinology and in primary care practices, covering approximately half of all patients. PCPs had significantly more patients covered by Medicaid than endocrinologists, as well as more patients at high risk of developing diabetes (as identified by the physician respondents) than endocrinologists (P ≤.05). Conversely, PCPs had significantly fewer patients diagnosed with diabetes (types 1 or 2) than endocrinologists. The 12 panelists and the Web-based respondents had been in practice roughly the same number of years (14.6 years vs 13.9, respectively), ranging from 7 years to 19 years. On average, the panelists treated 320 patients with diabetes per month (sex and payer mix were not collected from the online discussion panelists). Services Provided by Physician Practices Among the survey respondents, the most common service provided was self-monitoring blood glucose (SMBG) instruction/evaluation: 89% of all physicians’ practices provided this service (Table 2). Conversely, less than 50% of the practices offered multidisciplinary care coordination or medical nutrition therapy (MNT) (49% and 36%, respectively). Significantly more endocrinologists than PCPs reported that their practice provided multidisciplinary care, SMBG instruction/ evaluation, intensive insulin therapy instruction, and MNT. Furthermore, significantly fewer endocrinologists than PCPs reported providing psychosocial screening and smoking-cessation counseling. These survey findings led us to explore with the online panelists the differences between PCPs and endocrinologists regarding provision of multidisciplinary care coordination and MNT, the 2 services that were offered at the lowest rates in the Web-based survey respondents’ practices. For multidisciplinary care coordination, about half of the panelists opined that endocrinologists have fewer diagnoses to address with their patients than do PCPs, and therefore have more time per patient to devote to diabetes care, and several PCPs mentioned lower reimbursement as a barrier to

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Table 1 Characteristics of Physician Survey Respondents

Average age, y Census region, % Northeast (1)a Midwest (2)

All physicians Endocrinologists PCPs (N = 300) (n = 100) (n = 200) 46 47 45 28

31

26

23

21

24

South (3)

31

30

32

West (4)

18

18

18

Sex, % Male

75

77

75

Female

20

16

21

Unknown

5

7

4

Practice setting, % Hospital/medical center outpatient clinic

12

11

13

Office setting

72

73

71

Other/unknown

16

16

16

Average experience posttraining, y

14

15

13

Average patients seen in practice/wk, N

239

197

260

Insurance coverage, % Private

50

51

49

Medicare

33

33

33

10

8

11

8

7

8

9

16

6

36

53

27

28

23

31

b

Medicaid Uninsured Patients with diabetes, % Type 1b b

Type 2 High risk for developing diabetesb,c

a Northeast states include CT, ME, MA, NH, RI, VT, NJ, NY, PA. Midwest states, IL, IN, MI, OH, WI, IA, KS, MN, MO, NE, ND, SD. South states, DE, DC, FL, GA, MD, NC, SC, VA, WV, AL, KY, MS, TN, AR, LA, OK, TX. West states, AZ, CO, ID, NM, MT, UT, NV, WY, AK, CA, HI, OR, WA. b P ≤.05 between endocrinologists and PCPs. c Physician respondents identified the percentage of their patients who were at high risk for developing diabetes. PCPs indicates primary care physicians.

providing multidisciplinary care coordination. In the absence of a multidisciplinary team, panelists offered different approaches that physicians might take, including more frequent office visits and referring patients to outside educational resources. When queried about why surveyed PCP practices were significantly less likely to provide MNT compared

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Table 2 Physician Practices Providing ADA-Recommended Services All physicians, % (N = 300)

Endocrinologists, % (n = 100)

PCPs, % (n = 200)

48.7

64.0

41.0

89.0

96.0

85.5

Intensive insulin therapy instruction Weight-loss counseling and physical activity instruction

70.7

95.0

58.5

76.0

72.0

78.0

Medical nutrition therapyb

36.3

50.0

29.5

52.0

43.0

56.5

Smoking-cessation counseling Self-care of the feet education

79.9

54.1

92.5

73.5

71.4

74.5

Annual eye examination and blindness education

74.5

80.6

71.5

Diabetes self-management education

65.4

70.4

63.0

Services/instructiona Multidisciplinary care coordinationb b

Self-monitoring blood glucose instruction and evaluation b

b

Psychosocial screening and assessment b

a

These services were not explicitly defined in the survey; the survey referenced the 2008 Standards of Medical Care in Diabetes.9 P ≤.05 between endocrinologists and PCPs. ADA indicates American Diabetes Association; PCPs, primary care physicians. b

with endocrinology practices, panelists attributed the difference to the greater volume of patients with diabetes seen by endocrinologists, making the specialist more adept at providing MNT and more likely to have a dietitian in their practice. Both PCPs and endocrinologists reported that they refer patients to other providers outside of their practice for MNT, but panelists also pointed out that providing MNT off-site is not ideal, because it makes it more difficult for the physician to ensure patient compliance. One online panelist stated that, “Providing this service at the office ensure[s] more compliance and more [interaction] with [a] nutritionist for diabetic [management]. I think onsite MNT would be ideal and would improve quality of care and patient satisfaction.”

Nonphysician Staff Providing Diabetes Services Among surveyed physicians whose practices offer each service, with the exception of SMBG instruction (49%) and MNT (29%), the services were more often provided by physicians rather than nonphysician staff within the practice (Table 3). The services most often provided by a physician (vs nonphysician staff) were smoking-cessation counseling (86%) and annual eye examinations and blindness education (91%). Significantly more PCPs than endocrinologists reported that they provided 4 of the services themselves: weightloss counseling, MNT, annual eye examination and blindness education, and diabetes self-management education. For the other 6 ADA services, there was no significant difference between provider types. The findings that only 36% of practices offer MNT

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(Table 2) and that nonphysicians provided MNT at 71% of the practices (Table 3) was consistent with comments from the online panelists, who indicated that dietitians were more likely to provide MNT than physicians, whether off-site or in the practice. Most panelists reported providing some education and counseling in their office, either personally or through a nonphysician staff member, whereas some panelists referred their patients to an outside registered dietitian. Together, the results from the Web-based survey and online focus group suggest the need for a registered dietitian or a certified diabetes educator to help patients manage their diabetes, whether co-located in the physician’s practice or off-site.

Physician Perceptions of Adequacy of Resources Less than half of the survey respondents reported that their practices had adequate resources for psychological/social status assessments, but reported adequate resources (ie, medical and administrative time, facilities, staff, and materials) for the other 3 general categories of diabetes care (Table 4). Significantly more endocrinologists than PCPs reported that they had adequate resources to provide multidisciplinary team care, whereas significantly fewer endocrinologists than PCPs reported they had adequate resources to provide psychological/social status assessments. Like the survey respondents, most online panelists did not think they had adequate resources to provide psychological/social status assessments. In particular, several mentioned time constraints and low or nonexistent reimbursement as limiting factors. However,

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Physicians’ Perceptions of Reimbursement for Diabetes Care

Table 3 Physicians Who Provide Specific Services Themselves Services/instruction

All physicians, %

Endocrinologists, %

PCPs, %

64

67

62

49

48

50

70

68

71

68

50

76

29

16

41

75

70

77

86

81

87

78

76

79

91

85

95

62

48

70

Multidisciplinary care coordination (Endocrinologists, n = 64; PCPs, n = 82) Self-monitoring blood glucose instruction and evaluation (Endocrinologists, n = 96; PCPs, n = 171) Intensive insulin therapy instruction (Endocrinologists, n = 95; PCPs, n = 117) Weight-loss counseling and physical activity instructiona (Endocrinologists, n = 72; PCPs, n = 156) Medical nutrition therapya (Endocrinologists, n = 50; PCPs, n = 59) Psychosocial screening and assessment (Endocrinologists, n = 43; PCPs, n = 113) Smoking-cessation counseling (Eendocrinologists, n = 53; PCPs, n = 185) Self-care of the feet education (Endocrinologists, n = 71; PCPs, n = 149) Annual eye examination and blindness educationa (Endocrinologists, n = 79; PCPs, n = 143) Diabetes self-management educationa (Endocrinologists, n = 69; PCPs, n = 126) a P ≤.05 between endocrinologists and PCPs. PCPs indicates primary care physicians.

Table 4 Physicians Reporting Adequate Resources for Diabetes Care All physicians, % Endocrinologists, % (N = 300) (n = 100)

Categories of care

PCPs, % (n = 200)

Physician-coordinated multidisciplinary team carea

68

79

63

Lifestyle and behavior modification counseling

72

67

74

Patient education on self-care and complication prevention

85

83

87

47

35

53

a

Psychological and social status assessments a

P ≤.05 difference between endocrinologists and PCPs. PCPs indicates primary care physicians.

unlike the survey respondents, most panelists reported that there were inadequate resources (ie, medical and administrative time, facilities, staff, and materials) for the other 3 general categories of diabetes care (ie, physician-coordinated multidisciplinary team care, lifestyle and behavior modification counseling, and patient education on self-care and complication prevention). Specifically, panelists indicated that they did not have adequate resources or that the reimbursement was insufficient.

Perceptions of Adequacy of Reimbursement Survey respondents who indicated that their prac-

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tice provided any of the 10 ADA-recommended services (Table 2) were also asked about adequacy of reimbursement by 3 payers: Medicare, Medicaid, and private insurance (Table 5). The overwhelming majority of respondents reported that all 3 of the payers have inadequate reimbursement. Two thirds of respondents who provide multidisciplinary care coordination reported reimbursement to be inadequate for all 3 payers. Psychosocial screening/assessment was perceived as being inadequately reimbursed by the largest percentage of respondents (85%). Similarly, most respondents perceived the reimbursement of specific payers to be inadequate. Medicaid reim-

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Table 5 Physicians Offering a Service Who Believe Reimbursement Is Inadequate Inadequate reimbursement All 3 payer Medicare, Medicaid, types,a % % %

Services/instruction

Private, %

Multidisciplinary care coordinationb (n = 146)

66

83

94

67

Self-monitoring blood glucose instruction and evaluationb (n = 267)

78

87

95

80

77

85

94

79

83

88

95

84

Medical nutrition therapy (n = 109) Psychosocial screening and assessment (n = 156)

72

82

94

75

85

89

93

86

Smoking-cessation counselingb (n = 238)

81

86

94

83

80

84

92

81

70

75

83

70

81

85

95

82

b

Intensive insulin therapy instruction (n = 212) b

Weight-loss counseling and physical activity instruction (n = 228) b

b

Self-care of the feet education (n = 220) b

Annual eye examination and blindness education (n = 222) b

Diabetes self-management education (n = 195) a

Percentage of respondents who report all 3 payer types’ reimbursement (ie, Medicare, Medicaid, and private health insurance) as inadequate. b P ≤.05 between payer types. Note: No significant differences were found in perceived adequacy of various payers’ reimbursement between endocrinologists and PCPs for any service. PCPs indicates primary care physicians.

bursement was most often perceived as inadequate, whereas reimbursement by private insurers was least often perceived as inadequate, with Medicare falling in between. These differences across payer types were consistent for every service. Furthermore, these differences were statistically significant for all services except psychosocial screening and assessment. Although physicians perceived reimbursement by private insurers to be the best among the 3 payer types, it was still considered inadequate by at least 67% of survey respondents for all services. More than 90% of respondents perceived Medicaid reimbursement to be inadequate for all services, except for eye examinations (83% respondents; Table 5). Similar to the survey results, a common theme among panelists was that most services were inadequately reimbursed. In addition, time for preventive care and lifestyle programs and telephonic blood glucose adjustment counseling were among the inadequately reimbursed services mentioned. Online panelists suggested that low reimbursement per visit drives physicians to see more patients and spend less time with each patient. Several panelists reported that they were not adequately reimbursed for any services, stating, “We are underreimbursed for everything we do.” Online panelists agreed with the Web-based survey respondents that reimbursement by private payers was inadequate, which concurs with the survey results in Table 5. Panelists cited prescribing restrictions and nonreimbursement for necessary ancillary services. Echoing the survey results, many online panelists cited

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low reimbursement rates from Medicaid and Medicare. Several panelists reported that they no longer saw Medicaid patients or plan to stop seeing any patient whose insurance has inadequate reimbursement, stating they “know of many physicians who have eliminated Medicaid, Medicare, and/or certain private payers because of inadequate reimbursement.”

Physician Perceptions on Barriers to Providing Comprehensive Diabetes Care The survey respondents and the online panelists reported that inadequate reimbursement and insufficient time per patient (due to underreimbursement) are major barriers in providing comprehensive diabetes care. Overall, 32% of survey respondents said they were unable to provide comprehensive diabetes care, and most cited time or reimbursement as the major barrier. Nearly all the online panelists agreed that reimbursement was a primary barrier. Online panelists advised that higher reimbursement would lead to better comprehensive diabetes care, stating, “I would have a diabetic nurse educator in my practice, and I would be able to spend more time with each of my diabetic patients.” Survey respondents and online panelists also reported other barriers to providing comprehensive diabetes care, including patient nonadherence and physician education. Several panelists mentioned patient depression, lack of patient education, and the difficulty of patients changing habits as barriers. Some indicated that they did not have the necessary training to provide

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some components (eg, behavior modification or psychological assessment) of comprehensive diabetes care.

Discussion This research yielded several important findings about physicians’ perceptions of the inadequacy of reimbursement and other barriers to providing comprehensive diabetes care. From the Web-based survey, endocrinologists’ practices appeared to offer more technical services (ie, SMBG instruction/evaluation, insulin therapy instruction, and MNT), whereas PCPs’ practices offered more primary care services (ie, psychosocial screening/assessment and smoking-cessation counseling). Some of these differences are understandable, because it was reported by participants that it might not be cost-effective for PCP practices (which see fewer patients with diabetes than endocrinology practices) to employ a registered dietitian to provide MNT. In addition, endocrinologists were more likely than PCPs to use nonphysician staff in their practice. Because of lower reimbursement levels, PCPs may be less able to afford additional staff in their practices than endocrinologists and therefore must provide the service themselves. Among practices that offered the services, there was also variation between provider types regarding which services were provided by physicians versus nonphysician staff. However, factors other than provider type may be driving the decision to engage nonphysician staff. For example, ADA guidelines promote referring patients to a registered dietitian to provide MNT,9 which is consistent with our findings of only 29% of physicians providing MNT. Practices that did not provide services may have referred patients to other sources of care, and practices that offer MNT may employ a trained nutritionist or registered dietitian (rather than the physician) to provide this service. Regardless of the underlying reason, the survey results suggest that services provided to patients with diabetes differ between endocrinology and PCP practices. Although there were differences between providers regarding which services were offered, the Web-based survey indicated that both specialties felt they had inadequate resources to provide psychological/social status assessment in their practices. The panelists agreed, and many suggested that this service was “best left to other health professionals.” Psychosocial assessments/counseling require time-intensive formal evaluation (eg, instrument administration and scoring) and interventions with follow-up and appropriate coordination/referral. Lacking adequate resources, physicians reported referring patients elsewhere for these and other services (eg, nutrition education). Virtually all the panelists indicated that having more

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time to spend with each patient would lessen the need for referrals to other providers, thereby diminishing a barrier to providing comprehensive diabetes care. Referring patients elsewhere may be necessary, but it also may contribute to the fragmentation of delivering comprehensive diabetes care. For example, patients may not receive the referred services for a variety of reasons; they may not understand the reason for the referral, the service may not be adequately covered by their insurance, or they may be unable to afford copayments for multiple visits to different clinicians. Building on the current literature that shows adherence to medications, follow-through with appointments, and participation in nutrition counseling are related to better patient outcomes,21-24 further research is needed to confirm the panelists’ view that referring patients outside of the practice impedes patient adherence. Not only were resources (ie, medical and administrative time, facilities, staff, and materials) perceived to be inadequate, but some survey respondents also cited low reimbursement as a barrier to providing comprehensive care. In addition, 10 of the 12 panelists also viewed reimbursement to be inadequate, and several thought this was true for all diabetes-related services. The widespread view of Medicaid reimbursement inadequacy has led some physicians to report that they have rejected Medicaid patients, which is likely to make it difficult for low-income patients with diabetes to find a provider. This finding echoes previous research that finds physicians less likely to accept Medicaid patients in states with lower Medicaid reimbursement levels.25 Shifting the cost of undercompensated care to other payers is unlikely, because most survey respondents and panelists indicated that all payers’ reimbursement rates were inadequate. Because physicians report they do not have adequate time with each patient, this may impair their ability to properly educate patients. Indeed, panelists reported that patients’ lack of diabetes education and poor motivation to change unhealthy habits contributed to nonadherence. In addition, participants stated that patients with complications from diabetes are more complex and require longer physician visits. Responders cited decreased time for each patient as a result of low reimbursement as a major barrier to their ability to provide comprehensive diabetes care. The information gathered from this study contributes to the national discussion on the effect inadequate reimbursement levels have on diabetes care and outcomes. These results suggest that given the complexity of diabetes, better alignment, including a higher reimbursement level, is needed between the payment systems (ie, benefit design, covered services, and

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reimbursement levels) and the ADA guidelines. At current reimbursement levels, our findings indicate that providers are unable to “do it all” in the limited amount of time they have with each patient; and, accordingly, patient care suffers. Ultimately, physicians report that they are unable to provide comprehensive diabetes care, despite the ADA’s thorough and comprehensive guidelines. As one panelist said, “guidelines without adequate reimbursements and services to patients are meaningless.” That is, physicians cannot follow guidelines without sufficient payment to support providing the services. The obvious suggestion—increase current reimbursement levels—is difficult in the current economic environment, but not impossible. In addition, insurers and policymakers can use a variety of other tools to better align reimbursement and the ADA guidelines, including: • Expanding insurance coverage (eg, covering supportive diabetes services that are not currently covered and therefore may not be provided by many physicians) • Addressing Medicare’s and other insurers’ requirements for providers to become an “approved entity” and the allowable frequency of education and training visits26,27 • Encouraging alternative approaches for physician visits, which allow for more time per patient (eg, shared or group medical appointments).28 By understanding physician perceptions of reimbursement as a barrier to providing comprehensive diabetes care, policymakers and insurers may be better able to align ADA guidelines and reimbursement and ultimately improve diabetes care.

Limitations To ensure that our sample was familiar with reimbursement issues and diabetes care, we targeted physicians who were whole or partial owners of their practices and whose practices treated a large number of diabetic patients. By using the Internet for both data sources, our convenience sample was likely to be more technologyoriented than the general population of physicians. In addition, the survey did not explicitly define each of the 10 diabetes services, hence the interpretation by the physicians of the service definitions may also vary. By focusing on activities that were suspected of being prone to underreimbursement, our results have limited generalizability to all facets of diabetes care. All survey responses were based on the physicians’ perceptions and knowledge of their practice and patients; therefore, their responses may not fully represent the patient characteristics, because the scope of this project could

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not accommodate a medical review or claims-based analysis of the physicians’ caseload. Our findings may therefore not be generalizable to the universe of physicians who treat patients with diabetes.

Conclusions There is still considerable work to be done to align the ADA guidelines with current reimbursement levels for these services. Physicians compensate for low reimbursement levels in a variety of ways, including spending less time with each patient, seeing more patients each day, prioritizing the most important aspects of diabetes care on a given visit, and scheduling more followup appointments. Regardless of the tools used, policymakers need to consider how any change would affect the entire continuum of diabetes care. For example, although increasing the time that a PCP or endocrinologist spends with the patient would increase the cost for that particular visit, the extra time may translate to lower overall costs for the payer if the view posited by the panelists—more time with patients would lessen the need for repeat visits and referrals to other providers—holds true. Alternatively, it may make more clinical and financial sense for a nonphysician to provide some of the services (eg, MNT). Further research is needed to quantify how aligning reimbursement levels and the ADA guidelines will improve diabetes care. This study provides exploratory qualitative findings supporting this endeavor. ■ Acknowledgement Funding for this study was provided by the National Changing Diabetes Program, a program of Novo Nordisk. Disclosure Statement Dr Pozniak, Ms Olinger, and Ms Shier provided consulting services to Novo Nordisk.

References 1. Kung HC, Hoyert DL, Xu JQ, Murphy SL. Deaths: final data for 2005. Natl Vital Stat Rep. 2008;56:1-120. 2. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). National Diabetes Statistics, 2007 fact sheet. Bethesda, MD: National Institutes of Health, 2008. http://diabetes.niddk.nih.gov/dm/pubs/statistics/index.htm. Accessed October 28, 2009. 3. American Diabetes Association. Economic costs of diabetes in the U.S. in 2007. Diabetes Care. 2008;31:1-20. 4. American Diabetes Association. Economic costs of diabetes in the U.S. in 2002. Diabetes Care. 2003;26:917-932. 5. Dall TM, Mann SE, Zhang Y, et al. Distinguishing the economic costs associated with type 1 and type 2 diabetes. Popul Health Manage. 2009;12:103-110. 6. Zhang Y, Dall TM, Mann SE, et al. The economic costs of undiagnosed diabetes. Popul Health Manage. 2009;12:95-101. 7. Zhang Y, Dall TM, Chen Y, et al. Medical cost associated with prediabetes. Popul Health Manage. 2009;12:157-163. 8. Chen Y, Quick WW, Yang W, et al. Cost of gestational diabetes mellitus in the United States in 2007. Popul Health Manage. 2009;12:165-174. 9. American Diabetes Association. Standards of medical care in diabetes—2008. Diabetes Care. 2008;31(suppl 1):S12-S54. 10. Funnell MM, Anderson RM. Patient empowerment: a look back, a look ahead. Diabetes Educ. 2003;29:454-458, 460, 462 passim.

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11. Peel E, Douglas M, Lawton J. Self monitoring of blood glucose in type 2 diabetes: longitudinal qualitative study of patients’ perspectives. BMJ. 2007;335:493. Epub 2007 Aug 30. 12. Lai WA, Chie WC, Lew-Ting CY. How diabetic patients’ ideas of illness course affect non-adherent behaviour: a qualitative study. Br J Gen Pract. 2007;57:296-302. 13. Heisler M, Bouknight RR, Hayward RA, et al. The relative importance of physician communication, participatory decision making, and patient understanding in diabetes self-management. J Gen Intern Med. 2002;17:243-252. 14. Loveman E, Frampton GK, Clegg AJ. The clinical effectiveness of diabetes education models for type 2 diabetes: a systematic review. Health Technol Assess. 2008;12:1-116, iii. 15. Larme AC, Pugh JA. Evidence-based guidelines meet the real world: the case of diabetes care. Diabetes Care. 2001;24:1728-1733. 16. Leichter SB. Cost and reimbursement as determinants of the quality of diabetes care: 3. Reimbursement determinants. Clin Diabetes. 2002;20:43-44. 17. Williams AR, McDougall JC, Bruggeman SK, et al. Estimation of unreimbursed patient education costs at a large group practice. J Contin Educ Health Prof. 2004; 24:12-19. 18. Novo Nordisk. NCDP Member Associates and Partners. www.ncdp.com/partners/ overview.aspx. Accessed September 4, 2008. 19. Epocrates. Market research. www.epocrates.com/services/marketresearch/. Accessed September 4, 2008.

20. Panel Intelligence. Online panel discussions. http://panelintelligence.com/ online-panel-discussions.asp. Accessed September 4, 2008. 21. Sokol MC, McGuigan KA, Verbrugge RR, Epstein RS. Impact of medication adherence on hospitalization risk and healthcare cost. Med Care. 2005;43:521-530. 22. Rhee MK, Slocum W, Ziemer DC, et al. Patient adherence improves glycemic control. Diabetes Educ. 2005;31:240-250. 23. Grey N, Maljanian R, Staff I, Cruzmarino de Aponte M. Improving care of diabetic patients through a collaborative care model. Conn Med. 2002;66:7-11. 24. 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. 25. Zuckerman S, McFeeters J, Cunningham P, Nichols L. Changes in Medicaid physician fees, 1998-2003: implications for physician participation. Health Aff (Millwood). 2004;(suppl 4):W374-W384. 26. Moore KJ. Billing Medicare for diabetes self-management training. Fam Pract Manage. 1999;6:10. 27. Moore KJ. Billing Medicare for diabetes self-management training. Fam Pract Manage. 2001;8:14-15. 28. Deitrick L, Swavely D, Merkle LN, et al. Group medical visits for patients with type 2 diabetes: patient and physician perspectives. Abstr AcademyHealth Meet. 2005;22:Abstract 4077. http://gateway.nlm.nih.gov/MeetingAbstracts/ma?f=10362 3540.html. Accessed December 1, 2008.

STAKEHOLDER PERSPECTIVE Diabetes Management Strategies: More Money Does Not Equal Better Care Diabetes clinical management strategies, the clinical outcomes associated with diabetes care, and the associated costs of that care are among the major concerns for health plans today. According to an article published in Diabetes Care in 2008, a 50-year-old person newly diagnosed with diabetes spends $4174 more on medical care annually than a person at the same age who does not have diabetes.1 In addition, the TRIAD (Translating Research Into Action for Diabetes) study acknowledges that effective diabetes management requires complex integration of primary care, specialty care, and selfcare.2 The study was necessary, because little was known about how diabetes care and outcomes are affected by health plan benefits, physician payment mechanisms, financial incentives, and referral management. The study data have shown the impact of out-of-pocket costs on utilization of selected diabetes services, the impact of sociocultural factors on diabetes outcomes, and health plan for-profit versus notfor-profit status as the differentiator of outcomes for selected diabetes measures.2 In essence, the TRIAD study shows that we have much to learn about physician, patient, economic, and cultural issues as they relate to the provision of diabetes care. In the present qualitative study by Dr Pozniak, Ms

Olinger, and Ms Shier; they explored physicians’ perceptions of the adequacy of reimbursement, as well as resource adequacy as they relate to the treatment of diabetic patients. We learn that inadequate reimbursement is perceived by primary care physicians and endocrinologists as a major contributor to inadequate performance on 10 selected diabetes services that are recommended by the American Diabetes Association guidelines. Some of the panelists surveyed in the present study were quick to conclude that higher reimbursement would lead to better comprehensive diabetes care. Even though cognitive services are undervalued and hence under-reimbursed in our current healthcare system, simply increasing reimbursement to doctors for such services would not necessarily change the outcomes of diabetes care. That would be akin to telling an underperforming employee during a performance appraisal, “I know you will perform better if I give you a substantial pay raise for next year.” In our healthcare system, we have repeatedly learned that putting more money into care does not necessarily translate to better care. Witness the country’s relatively poor performance on most public health measures compared with other industrialized nations, despite our significantly larger amount of per-capita

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STAKEHOLDER PERSPECTIVE (Continued) spending. The system is just not that simple. With regards to diabetes care, we do need to find ways to improve outcomes. Efforts such as the medical home movement or accountable health organizations may offer some solutions. Also, we need to reassess the entire payment structure for physician and other healthcare-related payments to provide more reimbursement for cognitive services, and to create meaningful financial incentives to improve outcomes through pay-for-performance programs. That will likely mean a shift of financial resources from other sectors of the system to help fund such initiatives. This is never an easy job, because those who see resources decreasing will always speak on behalf of their own interests. However, we must do this assessment and redistribute our healthcare financial resources if we are going to succeed in improving care outcomes and keep healthcare costs in check.

Increasing reimbursement in difficult economic times is indeed, difficult. We must look for creative and innovative solutions to finance the provision, not only of diabetes care, but of all care. It will not be easy—as our lawmakers in Washington have recently learned, reforming the system is not simple and cannot be done without careful planning and assessment of the consequences of change—even for the relatively small microcosm of the system that is discussed in this article. References 1. Trogdon JG, Hylands T. Nationally representative medical costs of diabetes by time since diagnosis. Diabetes Care. 2008;31:2307-2311. 2. Curb JD, Waitzfelder B, Chung R, et al, for the TRIAD Study Group. The Translating Research Into Action for Diabetes study: a multicenter study of diabetes in managed care. Diabetes Care. 2002;25:386-389.

Gary M. Owens, MD President, Gary Owens Associates Philadelphia, PA

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NEW FOR HYPERTENSION TWYNSTA is the only ARB/CCB that contains

TELMISARTAN AMLODIPINE the active ingredient in MICARDIS

®

a long-acting CCB TEAM UP WITH TWYNSTA—HELP HYPERTENSIVE PATIENTS ACHIEVE SIGNIFICANT BP REDUCTIONS 1,2 All 4 dosage strengths of TWYNSTA® (telmisartan/amlodipine) tablets demonstrated significant reductions in cuff DBP and SBP compared to respective individual monotherapies.1 Study Design: A randomized, double-blind, 8-week, 4 x 4 factorial design trial of Stage-1 and Stage-2 hypertensive patients∗ (baseline BP: 153.2/ 101.7 mmHg) evaluated TWYNSTA vs telmisartan and amlodipine alone (N=1461). The primary endpoint was change in the in-clinic seated trough DBP. SBP/DBP reductions were as follows: -21.0/-16.0 mmHg, TWYNSTA 40/5 mg; -23.8/-19.6 mmHg, TWYNSTA 40/10 mg; -21.6/-17.8 mmHg, TWYNSTA 80/5 mg; -25.8/-19.6 mmHg, TWYNSTA 80/10 mg. Reduction with placebo was -1.6/-5.9 mmHg.2† ∗

According to the JNC 7, Stage-1 hypertension is defined as 140-159 mmHg SBP or 90-99 mmHg DBP. Stage-2 hypertension is ≥160 mmHg SBP or ≥100 mmHg DBP.3 Standard deviation was 11.9/7.6 mmHg, TWYNSTA 40/5 mg; 13.2/7.9 mmHg, TWYNSTA 40/10 mg; 12.7/8.5 mmHg, TWYNSTA 80/5 mg; 14.2/7.9 mmHg, TWYNSTA 80/10 mg; 16.7/9.4 mmHg, placebo.2

ARB: Angiotensin receptor blocker. CCB: Calcium channel blocker. DBP: Diastolic blood pressure. SBP: Systolic blood pressure. JNC 7: The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.

Important Safety Information WARNING: AVOID USE IN PREGNANCY When used in pregnancy, drugs that act directly on the renin-angiotensin system can cause injury and even death to the developing fetus. When pregnancy is detected, TWYNSTA® (telmisartan/amlodipine) tablets and MICARDIS® (telmisartan) tablets should be discontinued as soon as possible (see Warnings and Precautions). Indication TWYNSTA is indicated for the treatment of hypertension, alone or with other antihypertensive agents. It may also be used as initial therapy in patients who are likely to need multiple drugs to achieve their blood pressure goals. Base the choice of TWYNSTA tablets as initial therapy for hypertension on an assessment of potential benefits and risks including whether the patient is likely to tolerate the starting dose of TWYNSTA tablets. Consider the patient’s baseline blood pressure, the target goal, and the incremental likelihood of achieving goal with a combination compared with monotherapy when deciding whether to use TWYNSTA tablets as initial therapy. Hypotension Volume depletion and/or salt depletion should be corrected in patients before initiation of therapy or start treatment under close medical supervision with a reduced dose, otherwise symptomatic hypotension may occur. Observe patients with severe aortic stenosis closely for acute hypotension when administering amlodipine. Hepatic Impairment In patients with impaired hepatic function, initiate telmisartan at low doses and titrate slowly, or initiate amlodipine at 2.5 mg. The lowest dose of TWYNSTA is 40/5 mg; therefore, initial therapy with TWYNSTA is not recommended in hepatically impaired patients.

Renal Impairment Monitor carefully in patients with impaired renal function, especially in patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system (RAAS) (eg, patients with severe congestive heart failure or renal dysfunction); treatment of these patients with ACE inhibitors and ARBs has been associated with oliguria and/or progressive azotemia and, rarely, with acute renal failure and/or death. In patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen may occur. Dual RAAS Blockade When adding an ACE inhibitor to an ARB, monitor renal function closely. Use of telmisartan with ramipril is not recommended. Other Uncommonly, increased frequency, duration, and/or severity of angina or acute myocardial infarction have developed in patients treated with calcium channel blockers, particularly patients with severe obstructive coronary artery disease. Closely monitor patients with heart failure. Adverse Events In clinical trials, the most commonly reported adverse events with TWYNSTA that were more frequent than with placebo were peripheral edema (4.8% vs 0%), dizziness (3.0% vs 2.2%), clinically meaningful orthostatic hypotension (6.3% vs 4.3%), and back pain (2.2% vs 0%). Special Populations In clinical studies, the magnitude of blood pressure lowering with TWYNSTA in black patients approached that observed in non-black patients, but the number of black patients was limited. TWYNSTA is not recommended as initial therapy in patients who are 75 years or older, or who are hepatically impaired. In nursing mothers, nursing or TWYNSTA should be discontinued. References: 1. Twynsta PI. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; 2009. 2. Data on file, Study 1235.1, Boehringer Ingelheim Pharmaceuticals, Inc. 3. Chobanian AV, Bakris GL, Black HR, et al. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA. 2003;289:2560-2572.

Please see Brief Summary of Prescribing Information on following pages. Copyright © 2010, Boehringer Ingelheim Pharmaceuticals, Inc. All rights reserved.

Printed in U.S.A.

(02/10)

TW68600PROF


BRIEF SUMMARY OF PRESCRIBING INFORMATION INDICATIONS AND USAGE Twynsta® (telmisartan/amlodipine) tablets are indicated for the treatment of hypertension, alone or with other antihypertensive agents. TWYNSTA tablets may also be used as initial therapy in patients who are likely to need multiple drugs to achieve their blood pressure goals. Base the choice of TWYNSTA tablets as initial therapy for hypertension on an assessment of potential benefits and risks including whether the patient is likely to tolerate the starting dose of TWYNSTA tablets. Consider the patient's baseline blood pressure, the target goal, and the incremental likelihood of achieving goal with a combination compared with monotherapy when deciding whether to use TWYNSTA tablets as initial therapy.

CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS Fetal/Neonatal Morbidity and Mortality Telmisartan Drugs that act directly on the renin-angiotensin system can cause fetal and neonatal morbidity and death when administered to pregnant women. Several dozen cases have been reported in the world literature in patients who were taking angiotensin converting enzyme inhibitors. When pregnancy is detected, discontinue TWYNSTA tablets as soon as possible [see Boxed Warning]. The use of drugs that act directly on the renin-angiotensin system during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to exposure to the drug. These adverse effects do not appear to have resulted from intrauterine drug exposure that has been limited to the first trimester. Inform mothers whose embryos and fetuses are exposed to an angiotensin II receptor antagonist only during the first trimester that most reports of fetal toxicity have been associated with second or third trimester exposure. Nonetheless, when patients become pregnant or are considering pregnancy, physicians should have the patient discontinue the use of TWYNSTA tablets as soon as possible. Rarely (probably less often than once in every thousand pregnancies), no alternative to an angiotensin II receptor antagonist will be found. In these rare cases, the mothers should be apprised of the potential hazards to their fetuses, and serial ultrasound examinations should be performed to assess the intra-amniotic environment. If oligohydramnios is observed, TWYNSTA tablets should be discontinued unless they are considered life-saving for the mother. Contraction stress testing (CST), a non-stress test (NST), or biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Infants with histories of in utero exposure to an angiotensin II receptor antagonist should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function. Hypotension Telmisartan In patients with an activated renin-angiotensin system, such as volume- and/or salt-depleted patients (e.g., those being treated with high doses of diuretics), symptomatic hypotension may occur after initiation of therapy with TWYNSTA tablets. Either correct this condition prior to administration of TWYNSTA tablets, or start treatment under close medical supervision with a reduced dose. If hypotension does occur, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized. Amlodipine Since the vasodilation induced by amlodipine is gradual in onset, acute hypotension has rarely been reported after oral administration. Nonetheless, observe patients with severe aortic stenosis closely when administering amlodipine, as one should with any vasodilator. Hyperkalemia Telmisartan Hyperkalemia may occur in patients on ARBs, particularly in patients with advanced renal impairment, heart failure, on renal replacement therapy, or on potassium supplements, potassium-sparing diuretics, potassium-containing salt substitutes or other drugs that increase potassium levels. Consider periodic determinations of serum electrolytes to detect possible electrolyte imbalances, particularly in patients at risk. Patients with Impaired Hepatic Function Telmisartan As the majority of telmisartan is eliminated by biliary excretion, patients with biliary obstructive disorders or hepatic insufficiency can be expected to have reduced clearance. Initiate telmisartan at low doses and titrate slowly in these patients. Amlodipine Amlodipine is extensively metabolized by the liver and the plasma elimination half-life (t1/2) is 56 hours in patients with impaired hepatic function. Since patients with hepatic impairment have decreased clearance of amlodipine, start amlodipine or add amlodipine at 2.5 mg in patients with hepatic impairment. The lowest dose of TWYNSTA is 40/5 mg; therefore, initial therapy with TWYNSTA tablets is not recommended in hepatically impaired patients. Renal Function Impairment Telmisartan As a consequence of inhibiting the renin-angiotensin-aldosterone system, anticipate changes in renal function in susceptible individuals. In patients whose renal function may depend on the activity of the renin-angiotensinaldosterone system (e.g., patients with severe congestive heart failure or renal dysfunction), treatment with angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor antagonists has been associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death. Similar results may be anticipated in patients treated with telmisartan. In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen were observed. There has been no long term use of telmisartan in patients with unilateral or bilateral renal artery stenosis, but anticipate an effect similar to that seen with ACE inhibitors. Dual Blockade of the Renin-Angiotensin-Aldosterone System Telmisartan As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function (including acute renal failure) have been reported. Dual blockade of the renin-angiotensin-aldosterone system (e.g., by adding an ACE-inhibitor to an angiotensin II receptor antagonist) should include close monitoring of renal function. The ONTARGET trial enrolled 25,620 patients ≥55 years old with atherosclerotic disease or diabetes with end-organ damage, randomized them to telmisartan only, ramipril only, or the combination, and followed them for a median of 56 months. Patients receiving the combination of telmisartan and ramipril did not obtain any additional benefit compared to monotherapy, but experienced an increased incidence of renal dysfunction (e.g., acute renal failure) compared with groups receiving telmisartan alone or ramipril alone. Concomitant use of telmisartan and ramipril is not recommended.

ADVERSE REACTIONS Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reactions rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. TWYNSTA Tablets The concomitant use of telmisartan and amlodipine has been evaluated for safety in more than 3700 patients with hypertension; approximately 1900 of these patients were exposed for at least 6 months and over 160 of these patients were exposed for at least one year. Adverse reactions have generally been mild and transient in nature and have only infrequently required discontinuation of therapy. In the placebo-controlled factorial design study, the population treated with a telmisartan and amlodipine combination had a mean age of 53 years and included approximately 50% males, 79% were Caucasian, 17% Blacks, and 4% Asians. Patients received doses ranging from 20/2.5 mg to 80/10 mg orally, once daily. The frequency of adverse reactions was not related to gender, age, or race. The adverse reactions that occurred in the placebo-controlled factorial design trial in ≥2% of patients treated with TWYNSTA and at a higher incidence in TWYNSTA-treated patients (n=789) than placebo-treated patients (n=46) were peripheral edema (4.8% vs 0%), dizziness (3.0% vs 2.2%), clinically meaningful orthostatic hypotension (defined as a decrease in DBP >10 mmHg and/or decrease in SBP >20 mmHg) (6.3% vs 4.3%), and back pain (2.2% vs 0%). In addition, other adverse reactions that occurred in more than 1% of the patients treated with TWYNSTA tablets (n=789) were dizziness (2.0% vs 2.2% on placebo) and headache (1.4% vs 4.3% on placebo). In the placebo-controlled factorial design trial, discontinuation due to adverse events occurred in 2.2% of all treatment cells of patients in the telmisartan/amlodipine-treated patients and in 4.3% in the placebo-treated group. The most common reasons for discontinuation of therapy with TWYNSTA tablets were peripheral edema, dizziness, and hypotension (each ≤0.5%). Peripheral edema is a known, dose-dependent adverse reaction of amlodipine, but not of telmisartan. In the factorial design study, the incidence of peripheral edema during the 8 week, randomized, double-blind treatment period was highest with amlodipine 10 mg monotherapy. The incidence was notably lower when telmisartan was used in combination with amlodipine 10 mg. Table 1: Incidence of Peripheral Edema during the 8 Week Treatment Period Telmisartan

Amlodipine

WARNING: AVOID USE IN PREGNANCY When used in pregnancy, drugs that act directly on the renin-angiotensin system can cause injury and even death to the developing fetus. When pregnancy is detected, TWYNSTA tablets should be discontinued as soon as possible. See Warnings and Precautions.

Risk of Myocardial Infarction or Increased Angina Amlodipine Uncommonly, patients, particularly those with severe obstructive coronary artery disease, have developed documented increased frequency, duration or severity of angina or acute myocardial infarction on starting calcium channel blocker therapy or at the time of dosage increase. The mechanism of this effect has not been elucidated. Heart Failure Amlodipine Closely monitor patients with heart failure. Amlodipine (5-10 mg per day) has been studied in a placebo-controlled trial of 1153 patients with NYHA Class III or IV heart failure on stable doses of ACE inhibitor, digoxin, and diuretics. Follow-up was at least 6 months, with a mean of about 14 months. There was no overall adverse effect on survival or cardiac morbidity (as defined by life-threatening arrhythmia, acute myocardial infarction, or hospitalization for worsened heart failure). Amlodipine has been compared to placebo in four 8-12 week studies of patients with NYHA class II/III heart failure, involving a total of 697 patients. In these studies, there was no evidence of worsening of heart failure based on measures of exercise tolerance, NYHA classification, symptoms, or LVEF. In the PRAISE-2 study, 1654 patients with NYHA class III (80%) or IV (20%) heart failure without evidence of underlying ischemic disease, on stable doses of ACE inhibitor (99%), digitalis (99%), and diuretics (99%) were randomized 1:1 to receive placebo or amlodipine and followed for a mean of 33 months. While there was no statistically significant difference between amlodipine and placebo in the primary endpoint of all cause mortality (95% confidence limits from 8% reduction to 29% increase on amlodipine), there were more reports of pulmonary edema in the patients on amlodipine.

Placebo

40 mg

80 mg

Placebo

0%

0.8%

0.7%

5 mg

0.7%

1.4%

2.1%

10 mg

17.8%

6.2%

11.3%

Telmisartan Telmisartan has been evaluated for safety in more than 3700 patients, including 1900 treated for over 6 months and more than 1300 for over one year. Adverse experiences have generally been mild and transient in nature and have only infrequently required discontinuation of therapy. In placebo-controlled trials involving 1041 patients treated with various doses of telmisartan (20-160 mg) monotherapy for up to 12 weeks, an overall incidence of adverse events was similar to the patients treated with placebo. Adverse events occurring at an incidence of ≥1% in patients treated with telmisartan and at a greater rate than in patients treated with placebo, irrespective of their causal association, are presented in Table 2. Table 2: Adverse Events Occurring at an Incidence of ≥1% in Patients Treated with Telmisartan and at a Greater Rate than Patients Treated with Placebo Telmisartan (n=1455) %

Placebo (n=380) %

Upper respiratory tract infection

7

6

Back pain

3

1

Sinusitis

3

2

Diarrhea

3

2

Pharyngitis

1

0

In addition to the adverse events in the table, the following events occurred at a rate of ≥1% but were at least as frequent in the placebo group: influenza-like symptoms, dyspepsia, myalgia, urinary tract infection, abdominal pain, headache, dizziness, pain, fatigue, coughing, hypertension, chest pain, nausea, and peripheral edema. Discontinuation of therapy due to adverse events was required in 2.8% of 1455 patients treated with telmisartan tablets and 6.1% of 380 placebo patients in placebo-controlled clinical trials. The incidence of adverse events was not dose-related and did not correlate with gender, age, or race of patients. The incidence of cough occurring with telmisartan in 6 placebo-controlled trials was identical to that noted for placebo-treated patients (1.6%). In addition to those listed above, adverse events that occurred in >0.3% of 3500 patients treated with telmisartan monotherapy in controlled or open trials are listed below. It cannot be determined whether these events were causally related to telmisartan tablets: Autonomic Nervous System: impotence, increased sweating, flushing; Body as a Whole: allergy, fever, leg pain, malaise; Cardiovascular: palpitation, dependent edema, angina pectoris, tachycardia, leg edema, abnormal ECG; CNS: insomnia, somnolence, migraine, vertigo, paresthesia, involuntary muscle contractions, hypoesthesia; Gastrointestinal: flatulence, constipation, gastritis, vomiting, dry mouth, hemorrhoids, gastroenteritis, enteritis, gastroesophageal reflux, toothache, non-specific gastrointestinal disorders; Metabolic: gout, hypercholesterolemia, diabetes mellitus; Musculoskeletal: arthritis, arthralgia, leg cramps; Psychiatric: anxiety, depression, nervousness; Resistance Mechanism: infection, fungal infection, abscess, otitis media; Respiratory: asthma, bronchitis, rhinitis, dyspnea, epistaxis; Skin: dermatitis, rash, eczema, pruritus; Urinary: micturition frequency, cystitis; Vascular: cerebrovascular disorder; and Special Senses: abnormal vision, conjunctivitis, tinnitus, earache. During initial clinical studies, a single case of angioedema was reported (among a total of 3781 patients treated). Clinical Laboratory Findings In placebo-controlled clinical trials, clinically relevant changes in standard laboratory test parameters were rarely associated with administration of telmisartan tablets. Hemoglobin: A greater than 2 g/dL decrease in hemoglobin was observed in 0.8% telmisartan patients compared with 0.3% placebo patients. No patients discontinued therapy due to anemia. Creatinine: A 0.5 mg/dL rise or greater in creatinine was observed in 0.4% telmisartan patients compared with 0.3% placebo patients. One telmisartan-treated patient discontinued therapy due to increases in creatinine and blood urea nitrogen.


Liver Enzymes: Occasional elevations of liver chemistries occurred in patients treated with telmisartan; all marked elevations occurred at a higher frequency with placebo. No telmisartan-treated patients discontinued therapy due to abnormal hepatic function. Amlodipine Amlodipine has been evaluated for safety in more than 11,000 patients in U.S. and foreign clinical trials. Most adverse reactions reported during therapy with amlodipine were of mild or moderate severity. In controlled clinical trials directly comparing amlodipine (n=1730) in doses up to 10 mg to placebo (n=1250), discontinuation of amlodipine due to adverse reactions was required in only about 1.5% of amlodipine-treated patients and was not significantly different from that seen in placebo-treated patients (about 1%). The most common side effects were headache and edema. The incidence (%) of side effects which occurred in a dose-related manner are presented in Table 3. Table 3: Incidence (%) of Dose-Related Adverse Effects with Amlodipine at Doses of 2.5 mg, 5.0 mg, and 10.0 mg or Placebo Adverse Event

Amlodipine 2.5 mg n=275 %

Amlodipine 5.0 mg n=296 %

Amlodipine 10.0 mg n=268 %

Placebo n=520 %

Edema

1.8

3.0

10.8

0.6

Dizziness

1.1

3.4

3.4

1.5

Flushing

0.7

1.4

2.6

0.0

Palpitations

0.7

1.4

4.5

0.6

Other adverse experiences which were not clearly dose related but which were reported with an incidence greater than 1% in placebo-controlled clinical trials are presented in Table 4. Table 4: Incidence (%) of Adverse Effects Not Clearly Dose Related but Reported at an Incidence of >1% in Placebo-Controlled Clinical Trials Adverse Event

Amlodipine n=1730 %

Placebo n=1250 %

Headache

7.3

07.8

Fatigue

4.5

2.8

Nausea

2.9

1.9

Abdominal pain

1.6

0.3

Somnolence

1.4

0.6

The following events occurred in <1% but >0.1% of patients in controlled clinical trials or under conditions of open trials or marketing experience where a causal relationship is uncertain; they are listed to alert the physician to a possible relationship: Cardiovascular: arrhythmia (including ventricular tachycardia and atrial fibrillation), bradycardia, chest pain, hypotension, peripheral ischemia, syncope, tachycardia, postural dizziness, postural hypotension, vasculitis; Central and Peripheral Nervous System: hypoesthesia, neuropathy peripheral, paresthesia, tremor, vertigo; Gastrointestinal: anorexia, constipation, dyspepsia,** dysphagia, diarrhea, flatulence, pancreatitis, vomiting, gingival hyperplasia; General: allergic reaction, asthenia,** back pain, hot flushes, malaise, pain, rigors, weight gain, weight decrease; Musculoskeletal System: arthralgia, arthrosis, muscle cramps,** myalgia; Psychiatric: sexual dysfunction (male** and female), insomnia, nervousness, depression, abnormal dreams, anxiety, depersonalization; Respiratory System: dyspnea,** epistaxis; Skin and Appendages: angioedema, erythema multiforme, pruritus,** rash,** rash erythematous, rash maculopapular; Special Senses: abnormal vision, conjunctivitis, diplopia, eye pain, tinnitus; Urinary System: micturition frequency, micturition disorder, nocturia; Autonomic Nervous System: dry mouth, sweating increased; Metabolic and Nutritional: hyperglycemia, thirst; Hemopoietic: leukopenia, purpura, thrombocytopenia. **These events occurred in less than 1% in placebo-controlled trials, but the incidence of these side effects was between 1% and 2% in all multiple dose studies. The following events occurred in <0.1% of patients: cardiac failure, pulse irregularity, extrasystoles, skin discoloration, urticaria, skin dryness, alopecia, dermatitis, muscle weakness, twitching, ataxia, hypertonia, migraine, cold and clammy skin, apathy, agitation, amnesia, gastritis, increased appetite, loose stools, coughing, rhinitis, dysuria, polyuria, parosmia, taste perversion, abnormal visual accommodation, and xerophthalmia. Other reactions occurred sporadically and cannot be distinguished from medications or concurrent disease states such as myocardial infarction and angina. Amlodipine has not been associated with clinically significant changes in routine laboratory tests. No clinically relevant changes were noted in serum potassium, serum glucose, total triglycerides, total cholesterol, HDL cholesterol, uric acid, blood urea nitrogen, or creatinine. Amlodipine has been used safely in patients with chronic obstructive pulmonary disease, well-compensated congestive heart failure, coronary artery disease, peripheral vascular disease, diabetes mellitus, and abnormal lipid profiles. Adverse reactions reported for amlodipine for indications other than hypertension may be found in the prescribing information for NorvascÂŽ. Postmarketing Experience The following adverse reactions have been identified during post-approval use of telmisartan or amlodipine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate reliably their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causal connection to telmisartan or amlodipine. Telmisartan The most frequently spontaneously reported events include: headache, dizziness, asthenia, coughing, nausea, fatigue, weakness, edema, face edema, lower limb edema, angioneurotic edema, urticaria, hypersensitivity, sweating increased, erythema, chest pain, atrial fibrillation, congestive heart failure, myocardial infarction, blood pressure increased, hypertension aggravated, hypotension (including postural hypotension), hyperkalemia, syncope, dyspepsia, diarrhea, pain, urinary tract infection, erectile dysfunction, back pain, abdominal pain, muscle cramps (including leg cramps), myalgia, bradycardia, eosinophilia, thrombocytopenia, uric acid increased, abnormal hepatic function/liver disorder, renal impairment including acute renal failure, anemia, and increased CPK, anaphylactic reaction, and tendon pain (including tendonitis, tenosynovitis). Rare cases of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers, including telmisartan. Amlodipine Gynecomastia has been reported infrequently and a causal relationship is uncertain. Jaundice and hepatic enzyme elevations (mostly consistent with cholestasis or hepatitis), in some cases severe enough to require hospitalization, have been reported in association with use of amlodipine.

DRUG INTERACTIONS Drug Interactions with TWYNSTA Tablets The pharmacokinetics of amlodipine and telmisartan are not altered when the drugs are co-administered. No drug interaction studies have been conducted with TWYNSTA tablets and other drugs, although studies have been conducted with the individual amlodipine and telmisartan components of TWYNSTA tablets, as described below: Drug Interactions with Telmisartan Digoxin: When telmisartan was co-administered with digoxin, median increases in digoxin peak plasma concentration (49%) and in trough concentration (20%) were observed. It is, therefore, recommended that digoxin levels be monitored when initiating, adjusting, and discontinuing telmisartan to avoid possible over- or under-digitalization. Lithium: Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with angiotensin II receptor antagonists including telmisartan. Therefore, monitor serum lithium levels during concomitant use. Ramipril and Ramiprilat: Co-administration of telmisartan 80 mg once daily and ramipril 10 mg once daily to healthy subjects increases steady-state Cmax and AUC of ramipril 2.3- and 2.1-fold, respectively, and Cmax and AUC of ramiprilat 2.4- and 1.5-fold, respectively. In contrast, Cmax and AUC of telmisartan decrease by 31% and 16%, respectively. When co-administering telmisartan and ramipril, the response may be greater because of the possibly additive pharmacodynamic effects of the combined drugs, and also because of the increased exposure to ramipril and ramiprilat in the presence of telmisartan. Co-administration of telmisartan and ramipril is not recommended. Other Drugs: Co-administration of telmisartan did not result in a clinically significant interaction with acetaminophen, amlodipine, glyburide, simvastatin, hydrochlorothiazide, warfarin, or ibuprofen. Telmisartan is not metabolized

by the cytochrome P450 system and had no effects in vitro on cytochrome P450 enzymes, except for some inhibition of CYP2C19. Telmisartan is not expected to interact with drugs that inhibit cytochrome P450 enzymes; it is also not expected to interact with drugs metabolized by cytochrome P450 enzymes, except for possible inhibition of the metabolism of drugs metabolized by CYP2C19. Drug Interactions with Amlodipine In clinical trials, amlodipine has been safely administered with thiazide diuretics, beta-blockers, angiotensinconverting enzyme inhibitors, long-acting nitrates, sublingual nitroglycerin, digoxin, warfarin, non-steroidal antiinflammatory drugs, antibiotics, and oral hypoglycemic drugs. The following have no clinically relevant effects on the pharmacokinetics of amlodipine: cimetidine, grapefruit juice, MaaloxÂŽ, sildenafil. Amlodipine has no clinically relevant effects on the pharmacokinetics or pharmacodynamics of the following: atorvastatin, digoxin, warfarin

USE IN SPECIFIC POPULATIONS Pregnancy Teratogenic Effects, Pregnancy Categories C (first trimester) and D (second and third trimesters). See Warnings and Precautions. Nursing Mothers Telmisartan It is not known whether telmisartan is excreted in human milk, but telmisartan was shown to be present in the milk of lactating rats. Because of the potential for adverse effects on the nursing infant, decide whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Amlodipine It is not known whether amlodipine is excreted in human milk. In the absence of this information, it is recommended to discontinue nursing while amlodipine is administered. Pediatric Use Safety and effectiveness of TWYNSTA in pediatric patients have not been established. Geriatric Use TWYNSTA Tablets Of the total number of 3282 hypertensive patients receiving a telmisartan/amlodipine combination in clinical studies, 605 (18%) patients were 65 years of age or older and of these, 88 (3%) patients were 75 years and older. No overall differences in efficacy or safety of TWYNSTA tablets were observed in this patient population. Telmisartan Of the total number of patients receiving telmisartan in clinical studies, 551 (18.6%) were 65 to 74 years of age and 130 (4.4%) were 75 years and older. No overall differences in effectiveness and safety were observed in these patients compared to younger patients 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. Amlodipine Clinical studies of amlodipine besylate tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy. Elderly patients have decreased clearance of amlodipine with a resulting increase of AUC of approximately 40-60%, and a lower initial dose may be required. Since patients age 75 and older have decreased clearance of amlodipine, start amlodipine or add amlodipine 2.5 mg to telmisartan. The lowest dose of TWYNSTA is 40/5 mg; therefore, initial therapy with TWYNSTA tablets is not recommended in patients 75 years of age and older. Hepatic Insufficiency Monitor carefully and uptitrate slowly in patients with biliary obstructive disorders or hepatic insufficiency. Since patients with hepatic impairment have decreased clearance of amlodipine, start amlodipine or add amlodipine 2.5 mg to telmisartan. The lowest dose of TWYNSTA is 40/5 mg; therefore, initial therapy with TWYNSTA tablets is not recommended in hepatically impaired patients. Race The magnitude of blood pressure lowering in black patients approached that observed in non-black patients but the number of black patients was limited (237 of 1461 patients).

OVERDOSAGE Telmisartan Limited data are available with regard to overdosage in humans. The most likely manifestations of overdosage with telmisartan tablets would be hypotension, dizziness, and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation. If symptomatic hypotension should occur, supportive treatment should be instituted. Telmisartan is not removed by hemodialysis. Amlodipine Single oral doses of amlodipine maleate equivalent to 40 mg/kg and 100 mg/kg amlodipine in mice and rats, respectively, caused deaths. Single oral doses equivalent to 4 or more mg/kg amlodipine in dogs (11 or more times the maximum recommended human dose on a mg/m2 basis) caused a marked peripheral vasodilation and hypotension. Overdosage might be expected to cause excessive peripheral vasodilation with marked hypotension. In humans, experience with intentional overdosage of amlodipine is limited. Reports of intentional overdosage include a patient who ingested 250 mg and was asymptomatic and was not hospitalized; another (120 mg) who was hospitalized underwent gastric lavage and remained normotensive; the third (105 mg) was hospitalized and had hypotension (90/50 mmHg) which normalized following plasma expansion. A case of accidental drug overdose has been documented in a 19-month-old male who ingested 30 mg amlodipine (about 2 mg/kg). During the emergency room presentation, vital signs were stable with no evidence of hypotension, but a heart rate of 180 bpm. Ipecac was administered 3.5 hours after ingestion and on subsequent observation (overnight) no sequelae was noted. If massive overdose should occur, active cardiac and respiratory monitoring should be instituted. Frequent blood pressure measurements are essential. Should hypotension occur, cardiovascular support including elevation of the extremities and the judicious administration of fluids should be initiated. If hypotension remains unresponsive to these conservative measures, administration of vasopressors (such as phenylephrine) should be considered with attention to circulating volume and urine output. Intravenous calcium gluconate may help to reverse the effects of calcium entry blockade. As amlodipine is highly protein bound, hemodialysis is not likely to be of benefit.

Copyright Š 2009, Boehringer Ingelheim International GmbH ALL RIGHTS RESERVED Rev: November 2009 MC-BS (11-09)

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CLINICAL

Hypertension Management: An Update Quang Nguyen, DO; Joann Dominguez, MD; Loida Nguyen, PharmD; Nageshwara Gullapalli, MD Hypertension is a significant and costly public health problem. It is a major, but modifiable contributor for the development of cardiovascular disease. Randomized controlled trials have shown that controlling hypertension reduces the risk of stroke, coronary artery disease, congestive heart failure, end-stage renal disease, peripheral vascular disease, as well as overall mortality. The risk of developing these hypertension-related complications is continuous, starting at a blood pressure level as low as 115/75 mm Hg. Despite the inherent health risks associated with uncontrolled hypertension, elevated blood presQuang Nguyen sure remains inadequately treated in the majority of patients. This article reviews guidelines for optimal evaluation of hypertension and current therapeutic options available to combat this common yet pervasive disease. [AHDB. 2010;3(1):47-56.]

H

ypertension affects approximately 1 of 3 adults in the United States, and about 2 million new cases are diagnosed each year.1,2 An additional 28% of the US population is afflicted with prehypertension, and approximately 7% of Americans are not aware that they even have hypertension.3 Globally, hypertension affects more than 1 billion people and is projected to reach 1.56 billion by 2025.4 It is the leading cause of death and the second leading cause of lost disabilityadjusted life-years worldwide.4 Randomized controlled clinical trials have shown that control of hypertension reduces the risk of stroke, coronary artery disease, congestive heart failure, end-stage renal disease, peripheral vascular disease, and mortality.1,5 The risk of developing these complications is continuous, starting at a blood pressure (BP) level as low as 115/75 mm Hg.6 The total direct and indirect cost for hypertension in the United States in 2009 is estimated at $73.4 billion.3 Approximately 10% ($15 billion) of the US total annual drug expenditure is on antihypertensive medications.7 Despite these staggering costs, only 34% of Americans with hypertension are at their BP goal (<140/90 mm Hg).1 The reason for this failure is multifactorial and only speculative, and not because of the

Dr Q. Nguyen is Assistant Professor, Department of Endocrinology, Diabetes, and Metabolism, University of Nevada School of Medicine, Reno; Dr Dominguez is an Internal Medicine Resident, California Pacific Medical Center, San Francisco; Dr L. Nguyen is a Clinical Pharmacy Specialist, VA Sierra Nevada Health Care System, Reno; Dr Gullapalli is Assistant Professor of Medicine and Associate Program Director, Internal Medicine Residency Program, University of Nevada School of Medicine, Reno.

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lack of awareness or lack of effective pharmacologic agents or lack of understanding of the role of lifestyle modification. Since hypertension will develop in most Americans in their lifetime,8 early preventive measures and prompt management, including lifestyle and pharmacologic options, are essential to minimize complications associated with this condition.

Patient Evaluation The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-7) redefined hypertension and published an updated report in 2003.1 Recognizing that the risk for cardiovascular disease (CVD) and adverse outcomes exists linearly and continuously as BP rises, the JNC-7 panel established a new hypertension category called prehypertension (120-139 mm Hg/80-89 mm Hg). Patients in this category are at risk for developing CVD and overt hypertension; therefore, intensive lifestyle modifications are strongly recommended to prevent further complications. JNC-7 also combined the previous stage 2 and 3 hypertension into just 1 stage—stage 2 hypertension. Pharmacologic intervention is strongly recommended for patients in stage 2 (Table 1). Despite the prevalence of hypertension, approximately 90% to 95% of American adults with elevated BP are found to have no identifiable cause for their condition. Of the 5% with known causes, renal parenchymal and renovascular diseases are the most common culprits.1 Other notable etiologies for hypertension include1: • Chronic kidney disease • Coarctation of the aorta • Cushing syndrome

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CLINICAL

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Obstructive sleep apnea Medications Pheochromocytoma Primary hyperaldosteronism Renovascular disease Thyroid/parathyroid disease.

KEY POINTS u

Screening and Diagnosis Hypertension screening is strongly recommended for all American adults older than age 18, according to the latest recommendations from the US Preventive Services Task Force and the American Academy of Family Physicians.9,10 Screening should be repeated every 2 years for patients with BP <120/80 mm Hg and annually for those with BP between 120 mm Hg to 39 mm Hg systolic BP and 80 mm Hg to 89 mm Hg diastolic BP.1 The key to the diagnosis of hypertension is accurate measurements of BP. Improper hand positioning, incorrect BP cuff size, and insufficient time to relax (<5 minutes) before BP measurements are common errors that can lead to falsely elevated readings. At least 2 BP readings of ≥140/90 mm Hg obtained at 3 different office visits and separated by 2 to 4 weeks are needed to make the diagnosis of hypertension.11 When classifying a patient’s BP to determine treatment, choose the highest category between the systolic and diastolic BP. Ambulatory BP monitoring or serial home BP measurements are recommended for patients suspected of having “white coat” hypertension (acute BP elevation in the clinic setting but normal BP when taken outside of the physician’s office) or for those with labile or inconsistent readings during the medical encounter. A medical history and physical examination are necessary for all patients with hypertension. The main goals are to look for reversible precipitating factors, the presence and/or extent of end-organ damage, and the presence of additional cardiovascular (CV) risk factors, such as diabetes or smoking. Laboratory testing should also be obtained in all patients with hypertension. These tests should include urinalysis, hemoglobin or hematocrit, basic metabolic panel, fasting lipids, and electrocardiogram.1 Urine microalbumin-to-creatinine ratio is an independent marker for overall CV risk and should also be obtained.12 Treatment Strategies The goal of hypertension treatment is to reduce BP to <140/90 mm Hg; however, in patients with hypertension and diabetes or renal disease, the BP goal is even lower, targeted at ≤130/80 mm Hg.1 Nonpharmacologic interventions should be instituted in all patients with hypertension. When used early, lifestyle modifications can decrease other disease risks and may

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Hypertension is a global epidemic, affecting about 1 of 3 American adults, and about 2 million new cases are diagnosed annually. u Evidence shows that controlling hypertension reduces the risk of stroke, heart disease, end-stage renal disease, peripheral vascular disease, and the associated costs. u Approximately 10% ($15 billion) of the US annual total drug expenditure is on antihypertensives. The total direct and indirect costs of hypertension in 2009 are estimated at $73.4 billion. u Despite the many therapeutic options, most patients are still not at blood pressure goals. Instituting early preventive measures is essential to minimize complications associated with this costly condition.

avoid the need for drug therapy. Maintaining a healthy lifestyle, however, is not sufficient or is difficult to comply with, and most patients will require pharmacologic interventions to control their BP.

Lifestyle Modifications JNC-7 endorses lifestyle modifications for all patients with prehypertension or hypertension. These modifications include weight loss, reduced sodium intake, physical activity, limiting alcohol consumption, and incorporating the Dietary Approaches to Stop Hypertension (DASH) eating plan.1 In the PREMIER clinical trial, researchers compared the impact of comprehensive lifestyle modifications, which incorporate the JNC-7 recommendations (“established plus DASH” group) with behavioral modification without DASH (“established” group) and with an “adviceonly” group. Results showed greater reductions in systolic BP and diastolic BP in the established group compared with the advice-only group (mean reductions were 11.1 mm Hg, 10.5 mm Hg, and 6.6 mm Hg, systolic BP, and 6.4 mm Hg, 5.5 mm Hg, and 3.8 mm Hg, diastolic BP, respectively), with the greatest reductions seen when DASH was also incorporated.13 Pharmacotherapy Drug therapy is needed if lifestyle modifications cannot adequately bring BP to goal. First-line medications used in the treatment of hypertension include diuretics, angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), beta-blockers, and calcium channel blockers (CCBs). Some patients will require 2 or more antihypertensive medications to achieve their BP target. In newly diagnosed patients

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Table 1 Classification and Management of BP for Adults BP classification

Systolic BP, Diastolic Lifestyle Follow-up mm Hga BP, mm Hga modifications recommendationb

Normal

<120

Prehypertension 120-139 Stage 1 140-159 hypertension

and <80

Encourage

Recheck in 2 y

or 80-89 or 90-99

Yes Yes

Recheck in 1 y Confirm within 2 mo

Initial drug therapy Without compelling With compelling indication indication No antihypertensive indicated

Thiazide-type diuretics Drug(s) for comfor most pelling indications May consider ACE inhibitors, ARBs, beta-blockers, CCBs, or combination

Stage 2 hypertension

≥160

or ≥100

Yes

Evaluate in 1-4 wk depending on clinical situation (evaluate and treat immediately if BP >180/110 mm Hg)

Drug(s) for compelling indications

Other antihypertensives (diuretics, ACE inhibitors, ARBs, beta-blockers, CCBs) as needed

2-drug combination for most (usually thiazide-type diuretics and ACE inhibitors, ARBs, beta-blockers, or CCBs)

a If b

there is discrepancy between systolic and diastolic BP, the higher value determines staging. Treatment is determined by highest BP category. Based on the Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. ACE indicates angiotensin-converting enzyme; ARBs, angiotensin receptor blockers; BP, blood pressure; CCBs, calcium channel blockers. Source: Chobanian AV, et al. Hypertension. 2003;42:1206-1252.

with BP >20/10 mm Hg above goal,2 antihypertensives or a combination hypertensive may be added immediately.1 To minimize side effects, a second drug with a complementary mechanism of action should be added before the initial drug is used in the maximum recommended dosing. Table 2 outlines the many antihypertensives used today. The Figure provides an algorithm for the treatment of hypertension. Table 3 lists the recommended drug classes according to compelling indications. Diuretics. Diuretics can be divided into 3 groups— thiazides, loop, and potassium-sparing diuretics. Thiazides. Thiazides act by inhibiting the absorption of sodium and chloride in the distal convoluted tubule. The benefits of thiazides for stroke, heart failure, and coronary artery disease (CAD) outcomes have been well-established in trials, such as the VA Cooperative Studies in the 1960s,14 Systolic Hypertension in the Elderly Program (SHEP) in the 1980s,15 and the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) in the 1990s.16 Based on the ALLHAT results showing thiazides’ superiority to other classes of antihypertensives in terms of secondary end points and costs, the JNC-7 issued its recommendations for thiazides as first-line therapy for hypertension.

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Recently these recommendations were challenged by the Avoiding Cardiovascular Events Through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial, which showed that the combination of benazepril and amlodipine was superior to the benazepril and hydrochlorothiazide combination in reducing CV events in high-risk patients with hypertension.17 The difference in these studies was the use of chlorthalidone in earlier trials and hydrochlorothiazide in ACCOMPLISH. In light of this evidence, it has been suggested that the benefits seen in previous trials were attributed to a class effect, when in fact hydrochlorothiazide does not provide the same benefit profile as chlorthalidone. With these data, some clinicians have now considered chlorthalidone as the preferred thiazide agent.18,19 Because of their proved efficacy and low cost, thiazides will continue to be favored as first-line drugs for hypertension. Loop diuretics. Loop diuretics act on the thick ascending loop of Henle, where they selectively inhibit the luminal Na+/K+/2Cl– symporter thereby reducing NaCl reabsorption. Loop diuretics are highly efficacious in that they target a segment of the nephron with great reabsorptive capacity.20 These agents can be used alone or in combination for the management of hypertension. Although thiazides are the preferred class of

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Table 2 Selected Oral Antihypertensive Drugs Drug

Dose range, mg/d Common side effects

Aldosterone antagonists Eplerenone (Inspra)

50-100

Spironolactone (Aldactone) 25-50

Dizziness, fatigue, GI disturbances, hyperkalemia, hypertriglyceridemia

Comments More specific in aldosterone blockade Contraindicated in patients at high risk for hyperkalemia

Cost for 30day supplya $127.88-$255.76

CNS effects (drowsiness, lethargy, headache, fatigue), GI disturbances, hyperkalemia, menstrual irregularities, gynecomastia, mastodynia

$15.99-$21.99

Dizziness, headache, lack of energy, nausea, palpitations, orthostatic hypotension

$17.99-$47.98

Alpha1-blockers Doxazosin (Cardura)

1-16

Prazosin (Minipress) Terazosin (Hytrin) Alpha2-agonists

2-20 1-20

Clonidine tablets (Catapres) Methyldopa (Aldomet)

0.1-0.8 250-1000

ACE inhibitors Benazepril (Lotensin) 10-40 Captopril (Capoten) 25-100 Enalapril (Vasotec) 2.5-40 Fosinopril (Monopril) 10-40 Lisinopril (Prinivil, Zestril) 5-40 Moexipril (Univasc) 7.5-30 Perindopril (Aceon) 4-16 Quinapril (Accupril) 10-80 Ramipril (Altace) 1.25-20 Trandolapril (Mavik) 1-4 Angiotensin II receptor antagonists Candesartan (Atacand) 8-32 Eprosartan (Teveten) 400-800 Irbesartan (Avapro) 75-300 Losartan (Cozaar) 25-100 Olmesartan (Benicar) 20-40 Telmisartan (Micardis) 20-80 Valsartan (Diovan) 80-320 Beta-blockers Atenolol (Tenormin) 25-100 Bisoprolol (Zebeta) 2.5-10 Carvedilol (Coreg) 12.5-50 Labetalol (Normodyne, 200-800 Trandate) Metoprolol tartrate (Lopressor)

$17.99-$67.98 $14.45-$27.98 Dry mouth, dizziness, drowsiness, constipation Drowsiness, decrease in mental acuity, orthostatic hypotension, nasal congestion, sexual difficulty, bradycardia

Rebound hypertension with abrupt $7-$26.65 discontinuation First-line agent when hypertension is $6.50-$25.99 first diagnosed in pregnancy Positive Coombs’ test

Hypotension, cough, hyperkalemia, dizziness, headache, diarrhea, nausea, rash (primarily captopril), alteration or loss of taste perception (primarily captopril)

Contraindicated in patients with bilateral renal artery stenosis

$23.99 $7.19-$9.40 $12.99-$23.98 $30-$30.99 $14.89-$17.99 $36.99-$69.98 $65.15-$157.91 $19.99-$43.98 $42-$123.98 $16.65-$33.60

Hypotension, hyperkalemia, dizziness, fatigue, diarrhea

Recommended after intolerance or failure with ACE inhibitors

$67.70-$88.44 $92.44 $74.85-$91.15 $58.99-$92.22 $67.06-$75.34 $75.20-$85.01 $79.31-$122.27

Bradycardia, hypotension, GI disturbances, dizziness, fatigue, insomnia, heart failure, reduced peripheral circulation, impotence, depression, nightmares, bronchospasm in patients with asthma, masks symptoms of or potentiates hypoglycemia in patients with diabetes, hypertriglyceridemia

Approved for CHF Has alpha-adrenergic–blocking activity

$5-$5.30 $16.50-$35.13 $29.98-$32

Has alpha-adrenergic–blocking activity $20.99-$57.98 Metoprolol succinate approved for CHF $12.99-$25.98

Continued

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Table 2 Selected Oral Antihypertensive Drugs (Continued) Drug

Dose range, mg/d Common side effects

Beta-blockers Metoprolol succinate (Toprol XL)

50-100

Metoprolol succinate approved for CHF $12.99-$25.98 $25.99-$33.88

40-120 40-160

$15.99-$47.97 $8.40-$10.66

Nadolol (Corgard) Propranolol (Inderal) Calcium channel blockers Dihydropyridines Amlodipine (Norvasc) Felodipine (Plendil) Nicardipine (Cardene SR) Nifedipine (Adalat CC, Procardia XL) Nondihydropyridines Diltiazem (Cardizem CD, Dilacor XR, Tiazac)

2.5-10 2.5-20 60-120 30-60

Peripheral edema, palpitations, headache, dizziness, fatigue, nausea

120-420

Dizziness, headache, bradycardia, hypotension, constipation, nausea, weakness, gingival hyperplasia, edema, AV block

Verapamil sustained-release capsule (Verelan)

Cost for 30day supplya

Comments

$5.33-$8 $37.99-$115.45 $101.19-$125.99 $54.19-$72.79

Decrease AV nodal conduction Has negative inotropic effects

$25.99-$45.66 $25.99-$75.98

120-480 Verapamil sustained-release tablet (Calan SR, Isoptin SR) Diuretics Loop Bumetanide (Bumex) Furosemide (Lasix) Torsemide (Demadex)

$21.99-$37.98

0.5-2 20-80 2.5-10

Hyperuricemia, hypokalemia, hyperglycemia, hypocalcemia, increased urination at onset of therapy, dizziness, weakness, muscle cramps, photosensitivity, hypotension

12.5-25 12.5-50

Similar electrolyte abnormalities as loop diuretics except for hypercalcemia, increased urination at onset of therapy, dizziness, weakness, muscle cramps, photosensitivity, hypotension

$5-$10 $4.80-$14.99

5-10 50-100

Hyperkalemia, GI disturbances, muscle cramps, weakness, headache, dizziness

$50.45-$100.90 $41.99-$64.04

150-300

Diarrhea, headache, dizziness, fatigue, cough

$82.38-$101.80

Vasodilators Hydralazine (Apresoline)

25-100

Tachycardia, palpitations, GI disturbances, headache

$7.80-$27.98

Minoxidil (Loniten)

2.5-80

Tachycardia, hypertrichosis, sodium and water retention

$10-$143.97

Thiazide Chlorthalidone Hydrochlorothiazide (Microzide, HydroDiuril) Indapamide (Lozol) Metolazone (Zaroxolyn) Potassium-sparing Amiloride (Midamor) Triamterene (Dyrenium) Renin inhibitor Aliskiren (Tekturna)

1.25-2.5 1.25-5

Preferred diuretics for patients with severe chronic kidney disease/failure

$5.67-$19.31 $4.20-$8.39 $9.50-$19.99

$5-$13.99 $21.50-$37.37

a Cost calculated from generic, if available, and lowest bottle size available. Cost source: www.drugstore.com. ACE indicates angiotensin-converting enzyme; AV, atrioventricular; CHF, congestive heart failure; CNS, central nervous system; GI, gastrointestinal. Sources: Lacy CF, Armstrong LL, Goldman MP, eds. Drug Information Handbook. 17th ed. Hudon, OH: Lexi-Comp; 2008; AHFS Drug Information. Bethesda, MD: American Society of Health-System Pharmacists; 2008.

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Figure Treatment Algorithm for Hypertension Average of ≥2 seated BP readings is not at goal (<140/90 mm Hg) For patients with diabetes or chronic kidney disease goal BP is <130/80 mm Hg Lifestyle modifications + drug therapy

Without compelling indications

Stage 1 hypertension Initiate thiazide-type diuretic. May consider ACE inhibitors, ARBs, beta-blockers, CCBs, or combination

Stage 2 hypertension Initiate a combination of a thiazide-type diuretic plus ACE inhibitor, or ARB, betablocker, or CCB

With compelling indications

Initiate drug(s) for the compelling indications (refer to Table 3)

If BP not at goal, optimize dosages or add drugs until BP is achieved Consider consultation with hypertension specialist ACE indicates angiotensin-converting enzyme; ARBs, angiotensin receptor blockers; CCBs, calcium channel blockers. Source: Chobanian AV, et al. Hypertension. 2003;42:1206-1252.

diuretics, loop diuretics may be preferred in patients with congestive heart failure, acute pulmonary edema, or renal disease.21 Loop diuretics are relatively inexpensive and are available in generic forms. Potassium-sparing diuretics. Potassium-sparing diuretics act on the distal and cortical collecting tubules to decrease sodium reabsorption by either blocking aldosterone receptors (spironolactone, eplerenone) or by inhibiting Na+ influx through epithelium sodium ion channels in the apical membrane of the collecting tubule (amiloride and triamterene).20 These are mild diuretics and are effective in the treatment of hypertension, but are seldom used alone.21 These agents are recommended as adjunct therapy in the treatment of hypertension, especially when their hyperkalemic effect is desired. Through their actions on aldosterone receptors, spironolactone and eplerenone have been shown to reduce morbidity and mortality in patients with heart failure.22,23 Caution must be taken when these agents are used in conjunction with an ACE

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inhibitor or ARB because clinically significant hyperkalemia can occur. ACE inhibitors. ACE inhibitors exert their BP-lowering effects by inhibiting the conversion of the inactive angiotensin I to the active angiotensin II. In addition, bradykinins and subsequently prostaglandins are increased, which contributes to ACE inhibitor BP-lowering effects.24 JNC-7 endorses the use of ACE inhibitors when any of the following compelling indications exist: heart failure, postmyocardial infarction (MI), high risk of CAD, diabetes, chronic kidney disease, and/or stroke.21 A Cochrane search revealed no difference in BP-lowering effects among the different ACE inhibitors, with BP-lowering trough levels of –8/–5 mm Hg.25 These effects were seen at half or more of the maximum manufacturer recommended doses.25 A study conducted in the Durham Veterans Affairs Medical Center (VAMC) revealed greater cost-savings when ACE inhibitors are initially used for the management of hypertension compared with ARBs.26 Because of cost-savings, an ACE inhibitor should be tried before the initiation of an ARB. Angiotensin receptor blockers. ARBs block angiotensin II from binding to its receptor, thereby preventing it from causing vasoconstriction and fluid retention. The Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) established that the ARB, telmisartan, is not inferior to the ACE inhibitor in reducing CV and renal events in high-risk patients without heart failure.27 A similar effect is seen with other ARBs and was confirmed in a recent Cochrane search, showing comparable BP-lowering effects between ARBs and ACE inhibitors.25 A recent cost-effectiveness analysis of ACE inhibitors and ARBs for hypertension conducted in the Durham VAMC revealed ARB-initiated patients incurred an expected cost of $6271 over 10 years compared with an ACE inhibitor–initiated patient cost of $2434. This study revealed a greater cost in the initiation of ARBs whether the patient continued this class of medication, switched to an ACE inhibitor, or stopped either medication.26 Because the ACE inhibitors are less costly, ARBs should be tried only as an alternative when there is intolerance (ie, cough or angioedema) or failure with ACE inhibitors. Renin inhibitors. Aliskiren is the first agent in a new class of antihypertensive drugs that inhibits the conversion of angiotensinogen to angiotensin I via renin inhibition. It is approved for monotherapy as well as in combination with other antihypertensives. One study has shown that aliskiren is not inferior to other antihypertensive agents and is significantly superior to ramipril in reducing mean systolic BP.28 Studies have

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also demonstrated greater reductions in BP in combined therapy with other antihypertensive agents compared with either agent alone.28,29 Another study even showed that aliskiren may have renoprotective effects, reducing mean urinary albumin to creatinine ratio by 20% in patients with type 2 diabetes.30 However, because of cost concerns and robust clinical outcomes of ACE inhibitors and ARBs, aliskiren is currently recommended as a second-line agent. Calcium channel blockers. CCBs lower BP by preventing the entry of calcium into vascular smooth muscles, resulting in vasodilation and reduced vascular contractility. The 2 types of CCBs are (1) dihydropyridines, which act on peripheral blood vessels, and (2) nondihydropyridines, which act on cardiac muscles and peripheral blood vessels. Randomized controlled trials have demonstrated that dihydropyridines are effective at reducing CV events, mortality, and strokes particularly in the elderly.1,31 Nondihydropyridines are useful in the treatment of cardiac arrhythmias. Both types of drugs are effective as monotherapy in reducing BP and are generally well tolerated. Recent results from the ACCOMPLISH trial have shown that CCBs are comparable first-line agents and are well tolerated when combined with another drug, especially an ACE inhibitor.17 JNC-7 recognizes CCBs as a possible firstline drug class for patients at high risk for CVD or for those with diabetes (Table 3).1 Beta-blockers. Beta-blockers lower BP primarily by blocking beta-1 adrenergic receptors resulting in slower heart rate, decreased cardiac contractility, and reduced cardiac output.24 As a result, beta-blockers are considered first-line medications in patients with acute MI. Beta-blockers also inhibit renin release and subsequently angiotensin II production and are therefore useful in the treatment of hypertensive patients with congestive heart failure and/or with asymptomatic left ventricular hypertrophy (LVH).1 Clinical differences to consider when selecting an individual beta-blocker are beta-receptor selectivity and intrinsic sympathomimetic activity (ISA). Beta-blockers (ie, atenolol, bisoprolol, and metoprolol) with a greater affinity to beta-1 receptors (heart) than beta-2 receptors (lungs, kidneys, and vasculature) are considered cardioselective. Nonselective beta-blockers have affinity to beta-1 and beta-2 receptors and may not be the preferred agents when treating a CV indication. Some beta-blockers (ie, labetalol, carvedilol) also have an alpha receptor–blocking component, thus increasing its BP-lowering capabilities. Beta-blockers with ISA (ie, pindolol) have some stimulatory effects on the receptors they block, but less than a pure agonist. These agents are preferred when bradycardia is a concern.

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Table 3 Compelling Indications Compelling indication

Recommended drugs BetaAldosterone Diuretic blocker ACEI ARB CCB antagonist

Heart failure Postmyocardial infarction

x

x x

x x

High coronary disease risk

x

x

x

Diabetes Chronic kidney disease

x

x

x x

Recurrent stroke prevention

x

x

x x x

x x

x

x

ACEI indicates angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; CCB, calcium channel blocker. Source: Chobanian AV, et al. Hypertension. 2003;42:1206-1252.

In the absence of acute MI, congestive heart failure, and asymptomatic LVH, most experts agree that betablockers should not be used as first-line treatment in patients with essential hypertension. Recent metaanalyses have shown that beta-blockers, in comparison with other antihypertensives, are less effective in lowering BP5 and may be associated with increased risk of all-cause mortality and stroke, especially in patients older than age 60.32,33 A recent Cochrane review has evaluated 13 randomized controlled trials to quantify the efficacy and safety of beta-blockers as first-line therapy for essential hypertension, concluding that beta-blockers are not effective first-line hypertensive drugs.34 More important, there was “a trend towards worst outcomes in comparison with calcium channel blockers, renin-angiotensin system inhibitors, and thiazide diuretics.�34 Alpha-blockers. Alpha-blockers lower BP by blocking vasoconstricting alpha-1 adrenoreceptors on vascular smooth muscles. They are beneficial in hypertensive men with benign prostate hypertrophy; otherwise, they are not recommended for initial monotherapy. In ALLHAT, doxazosin was associated with increased risk for CV events compared with chlorthalidone.16 Direct vasodilators. Hydralazine and minoxidil are 2 common agents in this class. Both directly relax vascular smooth muscle, primarily arterioles, through different mechanisms of action. Although both are effective antihypertensive medications, their side-effect profiles preclude their use as initial monotherapy agents or as first-line therapies and make them useful only as add-on therapy, especially in patients with

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severe hypertension or renal insufficiency. They are often prescribed in combination with a beta-blocker and a diuretic to negate side effects, such as reflex tachycardia and fluid retention. Minoxidil is given once a day, but diffuse hair/facial hair growth (hirsutism) minimizes its use in women. Hydralazine is effective in the treatment of hypertensive emergencies. A severe but less frequent adverse event that may potentially occur with chronic hydralazine use is druginduced systemic lupus erythematosus, which is reversible with discontinuation of the medication.

Combination Therapy Combination therapy is beneficial and should be initiated when BP is more than 20/10 mm Hg above goal.1 Most combination therapies utilize antihypertensive agents that act by different but complementary mechanisms to maximize BP-lowering effects. Advantages of fixed combination therapy include better compliance, fewer side effects, faster response, and possibly lower cost, depending on the choice of agents and the insurance programs. The combination of an ACE inhibitor or ARB with a diuretic is an effective and well-tolerated initial regimen. The ACCOMPLISH trial recently demonstrated that the combination of a CCB plus an ACE inhibitor is also very effective.17 Concurrent use of an ACE inhibitor and an ARB is not a preferred combination, although rarely used in heart failure or in diabetes patients with significant proteinuria; one should be cautious about increased risk of side effects, as confirmed by the ONTARGET study.27 In ONTARGET, patients receiving a combination of an ACE inhibitor and an ARB had significantly greater risk of hypotension, syncope, renal dysfunction, and hyperkalemia. Other less-effective combinations include beta-blockers/ACE inhibitors, beta-blockers/alpha-blockers or agonists, and beta-blockers/nondihydropyridines. Resistant Hypertension Resistant hypertension is the failure to achieve goal BP despite adherence to 3 antihypertensive agents, including a diuretic at maximal tolerated doses.1,21 An approach to managing resistant hypertension includes reevaluating factors that may contribute to lack of BP control and aggressive use of antihypertensive agents at maximal tolerated doses. Factors that may contribute to uncontrolled hypertension include suboptimal BP measurement technique, white-coat effect, poor adherence, and inappropriate dosing. Patients who are identified as having these factors are considered as having pseudoresistance. Factors that contribute to hypertension, as well as resistant hypertension, include medica-

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tions (inclusive of over-the-counter or nonprescribed drugs, such as decongestants, or nonsteroidals), excess alcohol consumption, excess dietary sodium intake, obesity, diabetes mellitus, and older age. Causes of secondary hypertension must also be sought. If a correctable cause is not identified, the next step is to initiate aggressive pharmacologic therapy, with a goal of blocking all possible mechanisms of BP elevation. The cornerstone of therapy is the use of diuretics, because plasma expansion is a common pathophysiologic mechanism to resistance.35,36 Consideration of kidney function is required when selecting an optimal diuretic as ineffectiveness is seen when thiazides are used in patients with an estimated glomerular filtration rate (eGFR) <30 mL/min. At lower eGFR values, loop diuretics may be used.36 Choice of other agents should be based on patient characteristics, which includes concomitant disease states (Table 3). A fourth agent may be added if goal BP is still not achieved. There is evidence that the addition of spironolactone may have significant BP reductions, as seen in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA) with a reduction of BP as much as 21.9/9.5 mm Hg that was unaffected by sex, age, smoking, or diabetes status.37 Other studies show similar reductions in persons with and without hyperaldosteronism.36 The addition of spironolactone should be considered in patients who are obese or have sleep apnea, because these conditions have been associated with aldosterone excess.38 Eplerenone is an alternative aldosterone antagonist if adverse events are experienced with spironolactone. Failure of a 4-drug regimen may require referral to a hypertension specialist. Less favorable options before referral include centrally acting alpha-agonists (clonidine and methyldopa) or vasodilators (hydralazine and minoxidil).

Conclusion Hypertension is a global epidemic, yet many guidelines and pharmacologic options are available to prevent the morbidity and mortality associated with this disease. Although lifestyle modifications are frequently neglected, they should be started early and continued indefinitely. Some patients will require more than 1 antihypertensive agent to control their BP. Combination therapies are effective and are recommended in patients with stage 2 hypertension. Regardless of which drug is used, the most important aspect of treating hypertension is reducing BP to goal. Effective communication between physicians, other healthcare professionals, and patients is paramount in the successful treatment of hypertension. â–

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References 1. Chobanian AV, Bakris GL, Black HR, et al; for the National Heart, Lung, and Blood Institute. Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension. 2003;42:1206-1252. 2. Centers for Disease Control and Prevention. High blood pressure. www.cdc. gov/bloodpressure/. Accessed March 21, 2009. 3. Lloyd-Jones D, Adams R, Carnethon M, et al; for the Writing Group Members. Heart Disease and Stroke Statistics 2009 Update: a Report from the American Heart Association Staistics Committee and Stroke Statistics Subcommittee. Circulation. 2009;119:e21-e181. 4. Alcocer L, Cueto L. Hypertension, a health economics perspective. Ther Adv Cardiovasc Dis. 2008;2:147-155. 5. Psaty BM, Lumley T, Furberg CD, et al. Health outcomes associated with various antihypertensive therapies used as first-line agents: a network meta-analysis. JAMA. 2003;289:2534-2544. 6. Lewington S, Clarke R, Qizilbash N, et al. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet. 2002;360:1903-1913. 7. Spurgeon D. NIH promotes use of lower cost drugs for hypertension. BMJ. 2004;328:539. 8. Vasan RS, Beiser A, Seshadri S, et al. Residual lifetime risk for developing hypertension in middle-aged women and men: the Framingham Heart Study. JAMA. 2002;287:1003-1010. 9. US Preventive Services Task Force. Screening for high blood pressure: US Preventive Services Task Force reaffirmation recommendation statement. Ann Intern Med. 2007;147:783-786. 10. American Academy of Family Physicians. Recommendations for clinical preventive services: high blood pressure. www.aafp.org/online/en/home/clinical/exam/ f-j.html. Accessed April 11, 2009. 11. The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med. 1997;157: 2413-2446. 12. Forman JP, Brenner BM. Hypertension and microalbuminuria: the bell tolls for thee. Kidney Int. 2006;69:22. 13. Appel LJ, Champagne CM, Harsha DW, et al. Effects of comprehensive lifestyle modification on blood pressure control: main results of the PREMIER clinical trial. JAMA. 2003;289:2083-2093. 14. Effects of treatment on morbidity in hypertension. Results in patients with diastolic blood pressures averaging 115 through 129 mm Hg. JAMA. 1967;202: 1028-1034. 15. SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP). JAMA. 1991;265:3255-3264. 16. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs. diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002;288:2981-2997. 17. Jamerson K, Weber MA, Bakris GL, et al. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med. 2008; 359:2414-2428. 18. Saklayen MG. Which diuretic should be used for the treatment of hypertension? Am Fam Physician. 2008;78:444,446.

19. Ernst ME, Carter BL, Basile JN. All thiazide-like diuretics are not chlorthalidone: putting the ACCOMPLISH study into perspective. J Clin Hypertens (Greenwich). 2009;11:5-10. 20. Jackson EK. Diuretics. In: Brunton LL, Lazo JS, Parker KL, eds. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 11th ed. Columbus, OH: McGraw-Hill Professional; 2005:737-770. 21. Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 Report. JAMA. 2003;289:2560-2572. Erratum: JAMA. 2003;290:197. 22. Pitt B, Zannad F, Remme WJ, et al; for the Randomized Aldactone Evaluation Study Investigators. The effect of spironolactone on the morbidity and mortality in patients with severe heart failure. N Engl J Med. 1999;341:709-717. 23. Pitt B, Remme W, Zannad F, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003;348:1309-1321. 24. Hoffman BB. Therapy of Hypertension. In: Brunton LL, Lazo JS, Parker KL, eds. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 11th ed. Columbus, OH: McGraw-Hill Professional; 2005:845-868. 25. Heran BS, Wong MM, Heran IK, Wright JM. Blood pressure–lowering efficacy of angiotensin receptor blockers for primary hypertension. Cochrane Database Syst Rev. 2008;(4):CD003822. 26. Powers B, Datta S, Oddone E. A cost-effectiveness analysis of ACE-inhibitors vs. angiotensin receptor blockers for the treatment of hypertension. Presented at the Health Service Research and Development Service 2009 national meeting, February 11-13, 2009; Baltimore, MD. Abstract 1049. 27. Yusuf S, Teo KK, Pogue J, et al; for the ONTARGET Investigators. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med. 2008;358:1547-1559. 28. Uresin Y, Taylor AA, Kilo C, et al. Efficacy and safety of the direct renin inhibitor aliskiren and ramipril alone or in combination in patients with diabetes and hypertension. J Renin Angiotensin Aldosterone Syst. 2007;8:190-198. 29. Villamil A, Chrysant SG, Calhoun D, et al. Renin inhibition with aliskiren provides additive antihypertensive efficacy when used in combination with hydrochlorothiazide. J Hypertens. 2007;25:217-226. 30. Parving HH, Persson F, Lewis JB, et al. Aliskiren combined with losartan in type 2 diabetes and nephropathy. N Engl J Med. 2008;358:2433-2446. 31. Neal B, MacMahon S, Chapman N; for the Blood Pressure Lowering Treatment Trialists’ Collaboration. Effects of ACE inhibitors, calcium antagonists, and other blood pressure–lowering drugs results of prospectively designed overviews of randomised trials. Lancet. 2000;355:1955-1964. 32. Carlberg B, Samuelsson O, Lindholm LH. Atenolol in hypertension: is it a wise choice? Lancet. 2004;364:1684-1689. 33. Medical Research Council trial of treatment of hypertension in older adults: principal results. MRC Working Party. BMJ. 1992;304:405-412. 34. Wiysonge CS, Bradley H, Mayosi BM, et al. Beta-blockers for hypertension. Cochrane Database Syst Rev. 2007;(1):CD002003. 35. Moser M, Setaro J. Resistant or difficult-to-control hypertension. N Engl J Med. 2006;355:385-392. 36. Sarafidis PA, Bakris GL. Resistant hypertension: an overview of evaluation and treatment. J Am Coll Cardiol. 2008;52:1749-1757. 37. Chapman N, Dobson J, Wilson S, et al. Effect of spironolactone on blood pressure in subjects with resistant hypertension. Hypertension. 2007;49:839-845. 38. Goodfriend TL, Calhoun DA. Resistant hypertension, obesity, sleep apnea, and aldosterone: theory and therapy. Hypertension. 2004;43:518-524.

STAKEHOLDER PERSPECTIVE Hypertension Management: Implications to Patients, Providers, and Payers PATIENTS: Hypertension, a common health problem, increases with age. Based on the 2005-2006 National Health and Nutrition Examination Survey data, nearly 30% of US adults have hypertension. Left untreated, the patient with hypertension is at risk for organ damage that may result in cerebrovascular disease, vascular dementia, myocardial infarc-

tion, heart failure, chronic kidney disease, and peripheral arterial disease—all preventable with blood pressure (BP) control. Normalization of BP can be achieved through lifestyle modification involving diet, exercise, and weight reduction, or with medications, and often a combination. Patients expect medications to be effective, have Continued

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STAKEHOLDER PERSPECTIVE (Continued) minimal to no adverse effects, and be affordable. Studies suggest that combination tablets are effective and that reduced dosing frequency improves patient adherence. In one study, barriers to adherence to antihypertensive medications included the following reasons, in this order1: • Failure to remember • Cost • Lack of health insurance • Side effects • Feeling that medications were unnecessary • Not having a healthcare provider. PROVIDERS: Physicians’ understanding of hypertension management is paramount to BP control. Physicians need to understand the reasons why patients do not take their medications as recommended, and why at times they do not even fill their prescriptions. Providers also need to evaluate the reasons for hypertension resistance to therapy. The most common reason for resistance is the failure of appropriate use of a diuretic, despite many trials showing that diuretics help control BP and improve outcomes in hypertension.2 Diuretics are inexpensive agents and are relatively easy to use. Although diuretics and beta-blockers have been used for decades, diuretics are likely to remain as first-line agents; in contrast, the use of beta-blockers as primary agents for hypertension may yet be reconsidered in future, except for compelling indications (eg, hypertension with coronary artery disease).3 In addition, providers may anticipate a shift within the beta-blockers class in favor of novel beta-blockers with vasodilatory properties. The Eighth Joint National Committee guidelines for hypertension are expected to come out soon and may provide new insights into the management of hypertension.

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PAYERS: Because hypertension often entails medication use, payers’ interest in hypertension is naturally directed toward medication cost-containment. Controlling hypertension can minimize both clinical complications and hospitalizations, with their attendant high costs. The choice of generics versus brand-name drugs is always an issue. In hypertension, several medications, especially the thiazides, are available in effective and inexpensive generic formulations. The increasing use of generics has helped the national health expenditures favorably.4 Finally, the majority of hypertensive patients will only require low-cost evaluation, consisting of basic laboratory tests, a chest x-ray, and an electrocardiogram. Such an evaluation is worth its cost, because it can lead to favorable clinical outcomes, thereby lowering healthcare costs. From each stakeholder’s perspective—patients, providers, and payers—it is appropriate to expect simple, effective, adverse effect–free, and affordable care for hypertension, a condition that is easily treatable and its complications preventable. References 1. Vawter L, Tong X, Gemilyan M, Yoon PW. Barriers to antihypertensive medication adherence among adults—United States, 2005. J Clin Hypertens (Greemwich). 2008;10:922-929. 2. Ernst ME, Moser M. Use of diuretics in patients with hypertension. N Engl J Med. 2009;361:2153-2164. 3. Che QI, Schreiber MJ, Rafer MA. Beta-blockers for hypertension: are they going out of style? Cleve Clin J Med. 2009;76:533-542. 4. Buffery D. Recent slowdown in national health expenditures attributed to growing use of generics. Am Health Drug Benefits. 2009;2:25-26.

Lekshmi Dharmarajan, MD, FACP, FACC Chief, Division of Cardiology, Lincoln Medical and Mental Health Center, Bronx, New York Associate Professor of Clinical Medicine Weill Medical College of Cornell University, NY

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Attend

PBMI’s 15th Anniversary Drug Benefit Conference February 17-18, 2010 • Pointe Hilton Tapatio Cliffs Resort • Phoenix, Arizona

Success stories from payers at the leading edge of pharmacy benefit management: CareFirst BlueCross BlueShield • Carpenters Health & Welfare Trust Fund of St. Louis • Caterpillar, Inc. Chatham Steel Corporation • City of Colorado Springs • Delta Air Lines • Essence Health Care ICON Health & Fitness • Manatee County Government • Molina Healthcare of Michigan Piedmont Community HealthCare Alliance • Procter & Gamble TML Intergovernmental Employee Benefits Pool/Public Employee Benefits Alliance University of Michigan

Visit www.pbmi.com/conference.asp to register today! © 2009, Pharmacy Benefit Management Institute, LP

All Rights Reserved


INDUSTRY TRENDS

Emerging Trends in Breast Cancer Management By Caroline Helwick

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he most important scientific investigations in breast cancer are presented each year at the San Antonio Breast Cancer Symposium (SABCS). In its December 2009 meeting, several trends emerged, with strong implications to patient management and direct relevance to payers, patients, and providers.

Bisphosphonates: Not Just for Bone Loss Anymore Bisphosphonates are now routinely given to postmenopausal breast cancer patients as a means of preventing bone loss associated with endocrine therapies (ie, tamoxifen and the aromatase inhibitors). As this class of agents matures, their efficacy in this setting (and their cost) is increasing. A growing body of data suggests that even the old-fashioned oral bisphosphonates may be protective not only against bone loss but also cancer. Recent evidence indicates that bisphosphonates may have direct antitumor effects outside of the bone, according to Theresa Guise, MD, the Jerry W. and Peg S. Throgmartin Professor of Oncology at Indiana University School of Medicine. Alison Stopek, MD, of the University of Arizona Cancer Center, Tucson, said that the investigational, fully humanized monoclonal antibody denosumab outperformed intravenous zoledronic acid (ZA) in preventing skeletal-related events (SREs). The study was an international phase 3 trial involving 2048 patients with metastatic breast cancer who were randomized to receive ZA or denosumab over 34 months. SREs, such as fracture, occurred in 36.5% of the patients treated with ZA compared with 30.7% in those receiving denosumab, for a 6% absolute reduction in risk and a 16% relative risk reduction. Remaining on denosumab was also beneficial. Dr Stopek predicted that the data will continue to strengthen as patients are taking this drug longer. The onset of moderate-to-severe pain was delayed with denosumab from a mean of 64 days to 88 days. Adverse event rates were similar. Bone metastases are a significant problem for patients with certain types of cancers. The economic burden of bone metastases is estimated to be nearly $13 billion per year (Mundy GR. Nat Rev Cancer. 2002;2:584-593). In October 2009, the US Food and Drug Administration rejected 2 of 6 applications for various indications for denosumab, asking for more data for its main indication—prevention of postmenopausal osteoporosis.

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Zoledronic Acid Prevents Bone Loss. ZA was also effective in preventing bone loss in the Z-FAST (Zometa-Femara Adjuvant Synergy Trial) study of 602 patients taking the aromatase inhibitor letrozole. At 5 years, the patients who started taking the drug when their breast cancer treatment was initiated had a 6.2% bone mineral density (BMD) increase in lumbar spine area compared with a 2.4% decrease in BMD in those who delayed treatment until they had evidence of bone loss or fracture—an 8.6% total difference in efficacy. “Women who are on Medicare tend to go with tamoxifen because the cost of an aromatase inhibitor puts them squarely in the doughnut hole of Medicare Part D, but once the cost barrier is removed there will likely be a mass switch to the aromatase inhibitor, which will necessitate the need for bone protection,” predicted Adam Brufsky, MD, of the University of Pittsburgh Cancer Center, PA. “There is a feeling among those of us who study these drugs that bisphosphonates of all kinds may actually prevent disease recurrence,” Dr Brufsky said. Prevention of Breast Cancer Recurrence? Bisphosphonates have also been accepted as having a protective effect on breast cancer recurrence, reducing the risk by 30% or more. This was powerfully shown in a recent study by Austrian investigators (Gnant M, et al. N Engl J Med. 2009;360:679-691) in which premenopausal patients who received intravenous ZA in addition to adjuvant endocrine therapy had a fairly unexpected, and highly significant, 36% relative reduction in risk of disease progression at 4 years. James Ingle, head of breast cancer research at the Mayo Clinic Cancer Center, Rochester, called it a landmark study and “a reason for real enthusiasm.” The study’s lead investigator, Michael Gnant, MD, of the Medical University of Vienna, suggested that bisphosphonates may squelch the population of tumor cells that migrate to the bone marrow to hide. This would affect the ability of the disease to recur, he said. Primary Breast Cancer Prevention? Women taking bisphosphonates for bone health were 32% less likely to develop breast cancer than women not taking these agents, although the incidence of ductal carcinoma in situ was increased in bisphosphonate users by 59%. This could mean that in situ lesions are being arrested, preventing them from becoming invasive tumors, said author Rowan Chlebowski, MD, PhD, of

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Harbor-UCLA Medical Center, Los Angeles, whose study was based on the Women’s Health Initiative (WHI) cohort of 154,768 postmenopausal women. This new analysis of the WHI showed that the subset of women using bisphosphonates, primarily alendronate, had a 31% lower rate of invasive breast cancer than those not taking them. In an Israeli study of 4575 postmenopausal women, those taking oral bisphosphonates for ≥5 years had a 34% reduction in breast cancer incidence by selfreporting and a 28% reduction by pharmacy records, reported Gad Rennert, MD, PhD, of Carmel Medical Center, Haifa, Israel. The cancer-reducing effect appeared after 1 year of bisphosphonate use. Cancers that developed in bisphosphonate users were more likely to have favorable characteristics, he said. However, “This is an association study, not a study of proof,” Dr Rennert pointed out. “We are raising a hypothesis.”

Other Strategies for Breast Cancer Prevention Alcohol consumption of approximately half a mixed drink per day (a few drinks per week) raised the risk of recurrence by 34% and the risk of dying from breast cancer by 51% compared with less consumption. A study involving 1897 women from Kaiser Permanente in Oakland, CA, was presented by Marilyn Kwan, PhD, Kaiser Permanente Northern California. Obesity (body mass index [BMI] ≥25 kg/m2) was associated with a 46% increased risk of distant metastases in 10 years and a 26% to 38% increased risk of dying from breast cancer. Women with a BMI ≥30 kg/m2 responded poorly to chemotherapy or endocrine treatment compared with leaner persons. A study of 18,967 patients was presented by Marianne Ewertz, MD, from the Odense University Hospital, Denmark. Treatment of Hormone-Positive Breast Cancer In the 5-year results of the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial, the long-term benefit of exemestane was the same, whether it was given initially or after 2 to 3 years of tamoxifen. Disease-free survival at 5 years was 85% with either approach, reported Daniel Rea, MD, of the University of Birmingham, England. Higher doses of fulvestrant may increase benefits without increasing toxicity, according to the international Comparison of Fulvestrant in Recurrent or Metastatic Breast Cancer (CONFIRM) trial. The approved dose is 250 mg per month, but 500 mg per month reduced progression by 20% without additional side effects, reported Angelo DiLeo, MD, of the Hospital of Prato, Italy.

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Premenopausal women who become postmenopausal during hormonal treatment benefit from extended letrozole therapy after 5 years of tamoxifen, according to a substudy presented by Paul Goss, MD, of Massachusetts General Hospital, Boston.

Novel Agents for Metastatic Breast Cancer BSI-210. For “triple-negative” breast cancer (negative for estrogen receptor, progesterone receptor, and HER2), which is hard to treat, the PARP inhibitor BSI-210 in combination with gemcitabine and carboplatin reduced breast cancer deaths by 50% in a study of 123 patients. The results, presented by Joyce O’Shaughnessy, MD, of Baylor Sammons Cancer Center, Dallas, TX, were called “spectacular” by the SABCS program committee. T-DM1, a novel form of trastuzumab with a chemotherapy-like conjugate attached, significantly improved outcomes in 110 patients who had received an average of 7 prior treatments for metastatic disease. The drug produced responses or stable disease in 44%, a result called “remarkable” by outside specialists. TKIs. For the oral multitargeted tyrosine kinase inhibitors (TKIs), findings were mixed. In the SOLTI070 trial, sorafenib in combination with capecitabine reduced the risk of disease progression by 30% to 50% in all subgroups versus capecitabine alone, reported José Baselga, MD, of Vall d’Hebron University Hospital, Barcelona, Spain. William S. Gradishar, MD, Professor of Medicine at Northwestern University School of Medicine, Chicago, reported “a signal of potential activity” with sorafenib plus paclitaxel compared with the single-agent taxane, with a delay in progression of 1.3 months. Motesanib paired with paclitaxel was comparable with bevacizumab plus paclitaxel as initial metastatic treatment, although gallbladder toxicity was of concern with this new agent, reported John Mackey, MD, of the University of Alberta Cross Cancer Institute, Edmonton, Canada. In contrast, no benefit was found for sunitinib as a single agent in a Brazilian study of 482 patients. MRI Better than Mammography in High-Risk Persons Magnetic resonance imaging (MRI) detected breast cancer at an earlier stage than mammography in women deemed at high risk due to BRCA mutations, according to Ellen Warner, MD, of Sunnybrook Health Sciences Center, Toronto. The 1275 women in her study were screened with MRI plus mammography or with conventional mammography alone. MRI was more likely to detect early-stage and smaller tumors, suggesting that MRI should be part of screening for high-risk women. ■

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ACR/IDSA PIPELINE

Rheumatology Pipeline Boasts Innovation, ID Line Is Drying Up: ACR/IDSA 2009 By Alice Goodman

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everal promising compounds for the treatment of rheumatoid diseases have been recently approved, are in phase 3 trials, or are about to undergo phase 3 evaluation. The following products are some of the main products that were featured at the 2009 annual meeting of the American College of Rheumatology (ACR).

Promising Therapies for Lupus, Gout, and More Belimumab first new lupus therapy in 50 years. The investigational agent belimumab (Benlysta) is poised to become the first new drug for systemic lupus erythematosus (SLE) in 50 years. In the 1-year, phase 3, pivotal, BLISS-52 study, belimumab significantly reduced disease activity, disease flares, and steroid use, while improving fatigue and quality of life in patients with SLE compared with placebo. A second phase 3 trial called BLISS-76 showed positive results in November 2009, and the drug is expected to be submitted to the US Food and Drug Administration (FDA) for approval in early 2010. Belimumab is a human monoclonal antibody that is a specific inhibitor of the biological activity of B-lymphocyte stimulator, a protein involved in the production of autoantibodies that destroy healthy human tissue. CP-690,550 novel oral JAK inhibitor for RA. Experts are enthusiastic about the first novel oral Janus-associated kinase (JAK) inhibitor under development as a promising treatment for rheumatoid arthritis (RA). A randomized, double-blind, 24-week phase 2B study showed that in 507 patients with active RA who are already receiving background methotrexate therapy, CP-690,550 achieved sustained responses on 5 mg, 10 mg, and 15 mg twice daily with a manageable toxicity profile. CP-690,550 also demonstrated efficacy as monotherapy in a 24-week, double-blind, placebo-controlled phase 2B study in 384 patients with active RA who had not responded to previous treatment with disease-modifying antirheumatic drugs. These patients were not taking background methotrexate. In this study, the 5-mg, 10-mg, and 15-mg twice-daily doses were the most promising. The most common treatment-emergent adverse effects, mostly mild or moder-

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ate in severity, in both studies were urinary tract infections, headache, and diarrhea. The 5-mg and 10-mg twice-daily doses are expected to be used in the phase 3 clinical trials program. Canakinumab promising for acute gout. Canakinumab (Ilaris)—an injectable drug recently approved by the FDA for 2 rare inherited inflammatory disorders— showed promising results in the treatment of 200 patients with refractory acute gouty flares or those with acute gout who are not candidates for other gout treatments. These results, presented at a late-breaking news session, were based on an 8-week, multicenter, blinded, double-dummy, active controlled trial that compared canakinumab with triamcinolone acetonide (TA) in 200 patients. The most notable finding was that 150 mg of canakinumab provided more rapid pain relief than TA for acute flares of gout and prevented recurrence of flares. The relative risk reduction was 94% at 8 weeks postdose. This well-tolerated drug selectively targets interleukin-2 beta. First plant-derived colchicine approved for gout. Colchicine (Colcrys) has been used to treat gout for many years without FDA approval. In 2009, the FDA approved Colcrys to treat acute flares of gout—the first FDA approval of a colchicine formulation. And just before the ACR meeting, the FDA approved a low dose of colchicine for gout prophylaxis. At the ACR meeting, a secondary analysis of the large, placebo-controlled, phase 3 pivotal AGREE (Acute Gout Flare Receiving Colchicine Evaluation) study showed that low-dose colchicine (1.2 mg, then 0.6 mg in 1 hour [ie, 1.8 mg total] was as effective as high doses (1.2 mg, then 0.6 mg hourly ⳯ 6 [ie, 4.8 mg total]) in reducing pain associated with gout; in addition, patients in the low-dose group had fewer adverse events. In the study, within 24 hours of initiating the active drug, 34.6% of the 52 patients who received high-dose colchicine achieved at least a 50% reduction in pain compared with 43% of the 74 patients taking low-dose colchicine; only 17.2% of the 58 patients in the placebo group met that end point. The lead investigator said that within 24 hours, “excruciating pain” became “bearable” with both doses of the drug. Tanezumab for knee pain in osteoarthritis. Tanezumab, an investigational humanized monoclonal anti-

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body specific for nerve growth factor, reduced knee pain in patients with osteoarthritis in a previously reported randomized phase 3 trial. At the ACR meeting, researchers presented results from a 1-year openlabel extension study that included 281 patients from the phase 3 trial, showing that pain relief (reduced overall knee pain intensity) was maintained during open-label treatment of up to 1 year. The drug is being studied for several types of chronic pain. Sodium oxybate for fibromyalgia. Sodium oxybate (Xyrem), a central nervous system depressant recently approved by the FDA for the treatment narcolepsy, is a controlled substance administered as an oral solution. The results of a placebo-controlled, randomized phase 3 trial were presented at ACR, showing that the drug was tolerable and efficacious as a treatment for fibromyalgia.

“Antibiotic drug development is dying. We are running out of new drugs at the same time that organisms are becoming more resistant to every drug we have.” The study included 548 subjects randomized to 2 different doses of sodium oxybate (4.5 g/night or 6 g/night) versus placebo. Clinically meaningful improvements were seen in patients who received the active drug: at least a 50% reduction in pain was reported by >40% of patients and moderate reductions in pain of at least 30% were reported by >50% of the participants. A significantly higher proportion of patients treated with either dose achieved specified reductions in the pain visual analogue scale at 14 weeks compared with placebo. Results significantly favored the active drug versus placebo on both the Fibromyalgia Impact Questionnaire and the Patient Global Impression of Change scale at week 14. Discontinuations were similar in all 3 treatment groups. Adverse events associated with sodium oxybate—most often headache, nausea, and dizziness—were generally mild or moderate in severity. Denosumab put on hold. During the ACR meeting, the FDA announced that it had delayed approval of denosumab (proposed trade name Prolia), for postmenopausal osteoporosis, asking for additional safety information. Denosumab is an anti-RANKL product that may halt progression of cancer to bone. It is given once monthly and its mechanism of action is different from that of other drugs FDA approved for osteoporosis. All clinical trials of this drug have been positive, and the FDA did not ask for more clinical trials. Earlier

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in 2009 an FDA panel voted unanimously for the approval of the drug for postmenopausal osteoporosis, with the limitation to women with a history of fractures or those at high risk for fractures.

Dearth of New Anti-Infectives, Growing Resistance Although several studies of drugs in the pipeline (see Web Exclusive, www.ahdbonline.com) were presented at the 2009 annual meeting of the Infectious Diseases Society of America (IDSA), experts were pessimistic about the lack of drug development for infectious diseases. “Antibiotic drug development is dying. We are running out of new drugs at the same time that organisms are becoming more resistant to every drug we have,” said Brad Spellberg, MD, Assistant Professor of Medicine at UCLA, Torrance. He attributed this dire situation to economic pressure and regulatory pressure. “Economic forces are dominant. A patient takes an antibiotic for 7 days and then stops. Drug companies want to develop drugs that people take over a long period of time for chronic conditions. Antibiotics are a lower return on investment.” Ever since the Vioxx debacle, the FDA’s approval process has become “a morass,” Dr Spellberg said, “with statisticians dominating the discussions. Clinicians have lost their voices.” The IDSA is trying to address this problem in several ways, including promoting appropriate use of antibiotics (antibiotic stewardship), focusing on infection control, and encouraging development of new drugs. The IDSA is currently working to develop economic incentives for drug development, and is also lobbying for passage of the Strategies to Address Antimicrobial Resistance Act in Congress. Although the rates of resistant gram-negative pathogens are rising, the drug pipeline to treat those infections is weak, said Paul G. Auwaerter, MD, Program Chair of the 2009 IDSA and Clinical Director of the Division of Infectious Diseases at Johns Hopkins School of Medicine. “We have a limited menu of drugs to treat gram-negative infections,” Dr Auwaerter said. A similar shortage exists for new antiviral drugs, stated Richard J. Whitley, MD, IDSA new President and Director of Pediatric Infectious Diseases at the University of Alabama, Birmingham. Supplies of oseltamivir (Tamiflu) for influenza A (H1N1) are running out; peramavir is now advised as an alternative for patients who cannot take oseltamivir (eg, patients with short bowel syndrome). ■

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CARDIOLOGY PIPELINE

Cardiology Pipeline Is Promising: AHA 2009 By Wayne Kuznar

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everal new drugs developed for the treatment of a variety of cardiovascular diseases are currently in the pharmaceutical pipeline. The following findings were presented at the 2009 annual meeting of the American Heart Association (AHA).

Antiplatelet Agents in Pipeline Pitted against Clopidogrel Potential competitors to clopidogrel (Plavix) are lining up in the pharmaceutical pipeline. Two investigational antiplatelet drugs—cangrelor and ticagrelor— were compared with clopidogrel in phase 3 trials of patients undergoing percutaneous coronary intervention (PCI). The results indicate that cangrelor before PCI was not superior to clopidogrel in this setting, whereas ticagrelor prevented more deaths and ischemic events than clopidogrel in patients with an ST-elevation myocardial infarction (MI) who underwent PCI. Cangrelor is a rapid and reversible blocker of the P2Y12 receptor, the same receptor that clopidogrel inhibits to exert its antiplatelet effect, but cangrelor must be given intravenously. This new agent was compared with clopidogrel in 2 studies presented at the AHA meeting. Both studies were stopped early, after interim analyses found no differences in the primary end point between the 2 treatments. In one study, CHAMPION PCI, a composite end point of death, heart attack, or the need for revascularization procedures over 48 hours, the primary end point of the study, occurred with equal frequency in the 48 hours after PCI in patients with high-risk acute coronary syndromes (ACS) who were treated with either cangrelor or clopidogrel. The 8820 patients in CHAMPION PCI were randomized to cangrelor starting 30 minutes before PCI and continued for at least 2 hours; at the end of the procedure they received 600 mg of clopidogrel. Patients randomized to clopidogrel received a 600-mg loading dose followed by a maintenance dose of 75 mg/day given with aspirin for at least 30 days thereafter. The primary end point occurred in 7.1% of the clopidogrel group and 7.5% of the cangrelor group, reported Lead Investigator Robert A. Harrington, MD, Director, Duke Clinical Research Institute, Durham, NC. Thirty-day outcomes were also not different between the 2 groups. Minor and mild bleeding were significantly more

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frequent at 48 hours in cangrelor-treated patients, and there was a trend toward more major bleeding in the cangrelor group as well. A companion trial that compared cangrelor and clopidogrel, CHAMPION PLATFORM, included 5362 patients with ACS who were randomized to intravenous cangrelor infusion started at the beginning of PCI or oral clopidogrel (600 mg) started immediately after PCI. The primary end point, which was the same as in CHAMPION PCI, was 7.0% in cangrelor recipients and 8.0% in clopidogrel recipients, which was not a significant difference, said Deepak Bhatt, MD, MPH, Chief of Cardiology, VA Boston Healthcare System. However, compared with clopidogrel, cangrelor did significantly reduce the incidence of death (0.7% vs 0.2%) and stent thrombosis (0.6% vs 0.2%) at the 48hour follow-up.

Both studies were stopped early, after interim analyses found no differences in the primary end point between the 2 treatments. David Faxon, MD, Professor of Medicine, Cardiology, Brigham and Women’s Hospital, Boston, found the reduction in death and stent thrombosis with cangrelor in CHAMPION PLATFORM to be encouraging for cangrelor. “We cannot ignore those findings,” he said. He added that the duration of the infusion—2.1 hours—may have been too short to assess benefit, and the crossover from cangrelor to clopidogrel may have left patients vulnerable to inadequate platelet inhibition for a time. Furthermore, he noted that cangrelor’s onset is rapid, and it wears off rapidly, making it a good option for very ill patients in whom rapid platelet inhibition is desired, but who may need to go to the operating room. Ticagrelor and clopidogrel went head-to-head in the PLATO trial, in which 8430 patients with ST-elevation MI who were to undergo planned PCI were randomized to ticagrelor or 300 mg of clopidogrel followed by 75 mg/day for 6 to 12 months. The primary composite end point of cardiovascular death, MI, or stroke at 1 year was experienced by 11.0%

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CARDIOLOGY PIPELINE

of patients in the clopidogrel group and only 9.3% in the ticagrelor group, said Lead Investigator Philippe Gabriel Steg, MD, of Hôpital Bichat-Claude Bernard in Paris. All-cause death and definite stent thrombosis were also significantly less frequent in the ticagrelor group. The incidence of major bleeding was equivalent between the 2 groups.

The investigational CETP inhibitor anacetrapib increased high-density lipoprotein cholesterol by up to 43.4% with the highest dose—300 mg—while decreasing low-density lipoprotein cholesterol by 15.1%. New CETP Inhibitor Raises HDL, Lowers LDL The investigational CETP (cholesteryl ester transfer protein) inhibitor anacetrapib increased high-density lipoprotein (HDL) cholesterol by up to 43.4% with the highest dose—300 mg—while decreasing low-density lipoprotein (LDL) cholesterol by 15.1% at this same dose in a placebo-controlled randomized study of 539 hypercholesterolemic patients.

In the same study, when given in addition to 20 mg of atorvastatin (Lipitor), 300 mg anacetrapib raised HDL cholesterol by 41.8% and further reduced LDL cholesterol by 11.9%. Anacetrapib is in phase 3 trials. Development of a previous CETP inhibitor—torcetrapib—was discontinued after clinical studies showed it increased the risk of major cardiovascular events despite significantly raising HDL cholesterol.

Thrombin Inhibitor Has Acceptable Rate of Bleeding The oral direct thrombin inhibitor dabigatran, a potential alternative to warfarin (Coumadin), is associated with an acceptable rate of bleeding when used in addition to clopidogrel and aspirin. In a placebo-controlled, dose-ranging study of 1861 patients who had had an acute heart attack, and for which they were being treated with aspirin and clopidogrel, major bleeding complications occurred at a rate of 0% to 2.0% in the patients who were randomized to dabigatran, 50 to 150 mg/day, for 6 months, reported researchers at Uppsala University Hospital, Sweden. Major bleeding occurred in 0.3% to 0.5% of the group randomized to placebo. Dabigatran is already approved in several countries and is awaiting US Food and Drug Administration approval. ■

CAPTION CONTEST Submit your caption at www.AHDBonline.com. Winners receive $50. Winners’ names will be posted online.

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AMERICAN HEALTH & DRUG BENEFITS

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January/February 2010

VOL. 3

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NO. 1


Copyright Š2009, Boehringer Ingelheim Pharmaceuticals, Inc. All rights reserved.

(11/09)

DI69732


WARNING: AVOID USE IN PREGNANCY When used in pregnancy, drugs that act directly on the reninangiotensin system can cause injury and even death to the developing fetus. When pregnancy is detected, MICARDIS tablets should be discontinued as soon as possible. See Warnings and Precautions.

BRIEF SUMMARY OF PRESCRIBING INFORMATION INDICATIONS AND USAGE Hypertension MICARDIS is indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive agents. Cardiovascular Risk Reduction MICARDIS is indicated for reduction of the risk of myocardial infarction, stroke, or death from cardiovascular causes in patients 55 years of age or older at high risk of developing major cardiovascular events who are unable to take ACE inhibitors. High risk for cardiovascular events can be evidenced by a history of coronary artery disease, peripheral arterial disease, stroke, transient ischemic attack, or high-risk diabetes (insulin-dependent or non-insulin dependent) with evidence of end-organ damage. MICARDIS can be used in addition to other needed treatment (such as antihypertensive, antiplatelet or lipid-lowering therapy). Studies of telmisartan in this setting do not exclude that it may not preserve a meaningful fraction of the effect of the ACE inhibitor to which it was compared. Consider using the ACE inhibitor first, and, if it is stopped for cough only, consider re-trying the ACE inhibitor after the cough resolves. Use of telmisartan with an ACE inhibitor is not recommended.

CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS Fetal/Neonatal Morbidity and Mortality Drugs that act directly on the renin-angiotensin system can cause fetal and neonatal morbidity and death when administered to pregnant women. Several dozen cases have been reported in the world literature in patients who were taking angiotensin converting enzyme inhibitors. When pregnancy is detected, discontinue MICARDIS tablets as soon as possible [see Boxed Warning]. The use of drugs that act directly on the renin-angiotensin system during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to exposure to the drug. These adverse effects do not appear to have resulted from intrauterine drug exposure that has been limited to the first trimester. Inform mothers whose embryos and fetuses are exposed to an angiotensin II receptor antagonist only during the first trimester that most reports of fetal toxicity have been associated with second and third trimester exposure. Nonetheless, when patients become pregnant or are considering pregnancy, have the patient discontinue the use of MICARDIS tablets as soon as possible. Rarely (probably less often than once in every thousand pregnancies), no alternative to an angiotensin II receptor antagonist will be found. In these rare cases, the mothers should be apprised of the potential hazards to their fetuses, and serial ultrasound examinations should be performed to assess the intra-amniotic environment. If oligohydramnios is observed, MICARDIS should be discontinued unless they are considered life-saving for the mother. Contraction stress testing (CST), a non-stress test (NST), or biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Infants with histories of in utero exposure to an angiotensin II receptor antagonist should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function. Hypotension In patients with an activated renin-angiotensin system, such as volumeand/or salt-depleted patients (e.g., those being treated with high doses of diuretics), symptomatic hypotension may occur after initiation of ther-

apy with MICARDIS. Either correct this condition prior to administration of MICARDIS, or start treatment under close medical supervision with a reduced dose. If hypotension does occur, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized. Hyperkalemia Hyperkalemia may occur in patients on ARBs, particularly in patients with advanced renal impairment, heart failure, on renal replacement therapy, or on potassium supplements, potassium-sparing diuretics, potassiumcontaining salt substitutes or other drugs that increase potassium levels. Consider periodic determinations of serum electrolytes to detect possible electrolyte imbalances, particularly in patients at risk. Impaired Hepatic Function As the majority of telmisartan is eliminated by biliary excretion, patients with biliary obstructive disorders or hepatic insufficiency can be expected to have reduced clearance. Initiate telmisartan at low doses and titrate slowly in these patients. Impaired Renal Function As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system (e.g., patients with severe congestive heart failure or renal dysfunction), treatment with angiotensinconverting enzyme (ACE) inhibitors and angiotensin receptor antagonists has been associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death. Similar results have been reported with MICARDIS. In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen were observed. There has been no long term use of MICARDIS in patients with unilateral or bilateral renal artery stenosis but anticipate an effect similar to that seen with ACE inhibitors. Dual Blockade of the Renin-Angiotensin-Aldosterone System As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function (including acute renal failure) have been reported. Dual blockade of the renin-angiotensin-aldosterone system (e.g., by adding an ACE-inhibitor to an angiotensin II receptor antagonist) should include close monitoring of renal function. The ONTARGET trial enrolled 25,620 patients ≥55 years old with atherosclerotic disease or diabetes with end-organ damage, randomizing them to telmisartan only, ramipril only, or the combination, and followed them for a median of 56 months. Patients receiving the combination of MICARDIS and ramipril did not obtain any additional benefit compared to monotherapy, but experienced an increased incidence of renal dysfunction (e.g., acute renal failure) compared with groups receiving telmisartan alone or ramipril alone. Concomitant use of MICARDIS and ramipril is not recommended.

ADVERSE REACTIONS The following adverse reaction is described elsewhere in labeling: Renal dysfunction upon use with ramipril. Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reactions rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. Hypertension MICARDIS has been evaluated for safety in more than 3700 patients, including 1900 treated for over six months and more than 1300 for over one year. Adverse experiences have generally been mild and transient in nature and have infrequently required discontinuation of therapy. In placebo-controlled trials involving 1041 patients treated with various doses of MICARDIS (20-160 mg) monotherapy for up to 12 weeks, the overall incidence of adverse events was similar to that in patients treated with placebo. Adverse events occurring at an incidence of ≥1% in patients treated with MICARDIS and at a greater rate than in patients treated with placebo, irrespective of their causal association, are presented in Table 1. Table 1 Adverse Events Occurring at an Incidence of ≥ 1% in Patients Treated with MICARDIS and at a Greater Rate Than in Patients Treated with Placebo Te lmis a rt a n ( n= 1455 ) %

P l a ce bo ( n= 380 ) %

Upper respiratory tract infection

7

6

Back pain

3

1

Sinusitis

3

2

Diarrhea

3

2

Pharyngitis

1

0


In addition to the adverse events in the table, the following events occurred at a rate of ≥1% but were at least as frequent in the placebo group: influenza-like symptoms, dyspepsia, myalgia, urinary tract infection, abdominal pain, headache, dizziness, pain, fatigue, coughing, hypertension, chest pain, nausea, and peripheral edema. Discontinuation of therapy because of adverse events was required in 2.8% of 1455 patients treated with Micardis® (telmisartan) tablets and 6.1% of 380 placebo patients in placebo-controlled clinical trials. The incidence of adverse events was not dose-related and did not correlate with gender, age, or race of patients. The incidence of cough occurring with telmisartan in 6 placebocontrolled trials was identical to that noted for placebo-treated patients (1.6%). In addition to those listed above, adverse events that occurred in more than 0.3% of 3500 patients treated with MICARDIS monotherapy in controlled or open trials are listed below. It cannot be determined whether these events were causally related to MICARDIS tablets: Autonomic Nervous System: impotence, increased sweating, flushing; Body as a Whole: allergy, fever, leg pain, malaise; Cardiovascular: palpitation, dependent edema, angina pectoris, tachycardia, leg edema, abnormal ECG; CNS: insomnia, somnolence, migraine, vertigo, paresthesia, involuntary muscle contractions, hypoaesthesia; Gastrointestinal: flatulence, constipation, gastritis, vomiting, dry mouth, hemorrhoids, gastroenteritis, enteritis, gastroesophageal reflux, toothache, non-specific gastrointestinal disorders; Metabolic: gout, hypercholesterolemia, diabetes mellitus; Musculoskeletal: arthritis, arthralgia, leg cramps; Psychiatric: anxiety, depression, nervousness; Resistance Mechanism: infection, fungal infection, abscess, otitis media; Respiratory: asthma, bronchitis, rhinitis, dyspnea, epistaxis; Skin: dermatitis, rash, eczema, pruritus; Urinary: micturition frequency, cystitis; Vascular: cerebrovascular disorder; and Special Senses: abnormal vision, conjunctivitis, tinnitus, earache. During initial clinical studies, a single case of angioedema was reported (among a total of 3781 patients treated). Clinical Laboratory Findings In placebo-controlled clinical trials, clinically relevant changes in standard laboratory test parameters were rarely associated with administration of MICARDIS tablets. Hemoglobin: A greater than 2 g/dL decrease in hemoglobin was observed in 0.8% telmisartan patients compared with 0.3% placebo patients. No patients discontinued therapy due to anemia. Creatinine: A 0.5 mg/dL rise or greater in creatinine was observed in 0.4% telmisartan patients compared with 0.3% placebo patients. One telmisartan-treated patient discontinued therapy due to increases in creatinine and blood urea nitrogen. Liver Enzymes: Occasional elevations of liver chemistries occurred in patients treated with telmisartan; all marked elevations occurred at a higher frequency with placebo. No telmisartan-treated patients discontinued therapy due to abnormal hepatic function. Cardiovascular Risk Reduction Because common adverse reactions were well characterized in studies of telmisartan in hypertension, only adverse events leading to discontinuation and serious adverse events were recorded in subsequent studies of telmisartan for cardiovascular risk reduction. In TRANSCEND (N=5926, 4 years and 8 months of follow-up), discontinuations for adverse events were 8.4% on telmisartan and 7.6% on placebo. The only serious adverse events at least 1% more common on telmisartan than placebo were intermittent claudication (7% vs 6%) and skin ulcer (3% vs 2%). Postmarketing Experience The following adverse reactions have been identified during postapproval use of MICARDIS. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate reliably their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causal connection to MICARDIS. The most frequently spontaneously reported events include: headache, dizziness, asthenia, coughing, nausea, fatigue, weakness, edema, face edema, lower limb edema, angioneurotic edema, urticaria, hypersensitivity, sweating increased, erythema, chest pain, atrial fibrillation, congestive heart failure, myocardial infarction, blood pressure increased, hypertension aggravated, hypotension (including postural hypotension), hyperkalemia, syncope, dyspepsia, diarrhea, pain, urinary tract infection, erectile dysfunction, back pain, abdominal pain, muscle cramps (including leg cramps), myalgia, bradycardia, eosinophilia, thrombocytopenia, uric acid increased, abnormal hepatic function/liver disorder, renal impairment including acute renal failure, anemia, increased CPK, anaphylactic reaction, and tendon pain (including tendonitis, tenosynovitis). Rare cases of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers, including MICARDIS.

DRUG INTERACTIONS Digoxin: When MICARDIS was co-administered with digoxin, median increases in digoxin peak plasma concentration (49%) and in trough concentration (20%) were observed. Therefore, monitor digoxin levels when

initiating, adjusting, and discontinuing telmisartan for the purpose of keeping the digoxin level within the therapeutic range. Lithium: Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with angiotensin II receptor antagonists including MICARDIS. Therefore, monitor serum lithium levels during concomitant use. Ramipril and Ramiprilat: Co-administration of telmisartan 80 mg once daily and ramipril 10 mg once daily to healthy subjects increases steadystate Cmax and AUC of ramipril 2.3- and 2.1-fold, respectively, and Cmax and AUC of ramiprilat 2.4- and 1.5-fold, respectively. In contrast, Cmax and AUC of telmisartan decrease by 31% and 16%, respectively. When co-administering telmisartan and ramipril, the response may be greater because of the possibly additive pharmacodynamic effects of the combined drugs, and also because of the increased exposure to ramipril and ramiprilat in the presence of telmisartan. Concomitant use of MICARDIS and ramipril is not recommended. Other Drugs: Co-administration of telmisartan did not result in a clinically significant interaction with acetaminophen, amlodipine, glyburide, simvastatin, hydrochlorothiazide, warfarin, or ibuprofen. Telmisartan is not metabolized by the cytochrome P450 system and had no effects in vitro on cytochrome P450 enzymes, except for some inhibition of CYP2C19. Telmisartan is not expected to interact with drugs that inhibit cytochrome P450 enzymes; it is also not expected to interact with drugs metabolized by cytochrome P450 enzymes, except for possible inhibition of the metabolism of drugs metabolized by CYP2C19.

USE IN SPECIFIC POPULATIONS Pregnancy Teratogenic Effects, Pregnancy Categories C (first trimester) and D (second and third trimesters). See Warnings and Precautions. Nursing Mothers It is not known whether telmisartan is excreted in human milk, but telmisartan was shown to be present in the milk of lactating rats. Because of the potential for adverse effects on the nursing infant, decide whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness in pediatric patients have not been established. Geriatric Use Of the total number of patients receiving MICARDIS in hypertension clinical studies, 551 (19%) were 65 to 74 years of age and 130 (4%) were 75 years or older. No overall differences in effectiveness and safety were observed in these patients compared to younger patients 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. Of the total number of patients receiving MICARDIS in the cardiovascular risk reduction study (ONTARGET), the percentage of patients ≥65 to <75 years of age was 42%; 15% of patients were ≥75 years old. No overall differences in effectiveness and safety were observed in these patients compared to younger patients 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. Hepatic Insufficiency Monitor carefully and uptitrate slowly in patients with biliary obstructive disorders or hepatic insufficiency.

OVERDOSAGE Limited data are available with regard to overdosage in humans. The most likely manifestation of overdosage with MICARDIS tablets would be hypotension, dizziness and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation. If symptomatic hypotension should occur, supportive treatment should be instituted. Telmisartan is not removed by hemodialysis.

Rx only

© Copyright 2009, Boehringer Ingelheim International GmbH ALL RIGHTS RESERVED Rev: November 2009

MC-BS (11-09)

MC71754


In high-risk patients who are unable to take an ACE-I,

REDUCE THE RISK OF MI, STROKE, OR DEATH FROM CV CAUSES ACE-I: ACE inhibitor. MI: Myocardial infarction. CV: Cardiovascular. ARB: Angiotensin receptor blocker.

MICARDIS 80 mg is now the only ARB proven to reduce CV risk in high-risk patients who are unable to take an ACE-I. Supported by ONTARGET and TRANSCEND, two studies in a large-scale clinical program with entry criteria similar to those used in the HOPE trial with ramipril— MICARDIS® (telmisartan) 80 mg tablets reduce MI, stroke, or death from CV causes in a broad range of high-risk patients with or without hypertension.1-3 ∗

High risk is evidenced by a history of coronary artery disease, peripheral arterial disease, stroke, transient ischemic attack, or high-risk diabetes (insulin dependent or non-insulin dependent) with evidence of end-organ damage.

Important Safety Information WARNING: AVOID USE IN PREGNANCY When used in pregnancy, drugs that act directly on the reninangiotensin system can cause injury and even death to the developing fetus. When pregnancy is detected, MICARDIS® (telmisartan) tablets should be discontinued as soon as possible (See Warnings and Precautions ). • MICARDIS is indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive agents. • MICARDIS is indicated for reduction of the risk of myocardial infarction, stroke, or death from cardiovascular causes in patients 55 years of age or older at high risk of developing major cardiovascular events who are unable to take ACE inhibitors. • High risk for cardiovascular events can be evidenced by a history of coronary artery disease, peripheral arterial disease, stroke, transient ischemic attack, or high-risk diabetes (insulin dependent or non-insulin dependent) with evidence of end-organ damage. MICARDIS can be used in addition to other needed treatment (such as antihypertensive, antiplatelet, lipid-lowering therapy, etc). • Studies of telmisartan in this setting do not exclude that it may not preserve a meaningful fraction of the effect of the ACE inhibitor to which it was compared. Consider using the ACE inhibitor first, and, if it is stopped for cough only, consider retrying the ACE inhibitor after the cough resolves. • Use of telmisartan with an ACE inhibitor is not recommended. • Volume depletion and/or salt depletion should be corrected in patients before initiation of therapy or start treatment under close medical supervision with a reduced dose, otherwise symptomatic hypotension may occur. • In patients with impaired hepatic function, initiate telmisartan at low doses and titrate slowly.

• Monitor carefully in patients with impaired renal function, especially in patients whose renal function may depend on the activity of the reninangiotensin-aldosterone system (eg, patients with severe congestive heart failure or renal dysfunction); treatment of these patients with ACE inhibitors and ARBs has been associated with oliguria and/or progressive azotemia and, rarely, with acute renal failure and/or death. In patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen may occur. • Dual blockade of the renin-angiotensin-aldosterone system (eg, by adding an ACE-inhibitor to an ARB) should include close monitoring of renal function. Use of MICARDIS with ramipril is not recommended. References: 1. Micardis PI. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; 2009. 2. Teo K, Yusuf S, Sleight P, et al; and the ONTARGET/TRANSCEND Investigators. Rationale, design, and baseline characteristics of 2 large, simple, randomized trials evaluating telmisartan, ramipril, and their combination in highrisk patients: the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial/Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease (ONTARGET/TRANSCEND) trials. Am Heart J. 2004;148:52-61. 3. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G; and the HOPE Study Investigators. Effects of an angiotensin-converting–enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med. 2000;342:145-153.

Please see Brief Summary of Prescribing Information on following pages. Copyright © 2010, Boehringer Ingelheim Pharmaceuticals, Inc. All rights reserved.

Printed in U.S.A.

(02/10)

MC68700PROF