June/July 2009, Vol 2, No 4

THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN ™ JUNE/JULY 2009

VOLUME 2, NUMBER 4

EDITORIAL

Prioritizing Healthcare Resources Robert E. Henry

The View from Washington: Healthcare Reform John Gorman

REGULATORY

Applying Evidence for Medical Technologies Interview with Sean R. Tunis, MD, MSc ™

Stakeholder Perspective by F. Randy Vogenberg, RPh, PhD BUSINESS

The Working Patient with Cancer: Implications for Payers and Employers Grant D. Lawless, BSPharm, MD, FACP

Stakeholder Perspective by Gary M. Owens, MD

Predictors of First-Fill Adherence to New Asthma Prescriptions Zackary Berger, MD, PhD; William Kimbrough, MD; Colleen Gillespie, PhD; Joseph A. Boscarino, PhD, MPH; G. Craig Wood, MS; Zhengmin Qian, MD, PhD; J. B. Jones, PhD, MBA; Nirav R. Shah, MD, MPH

Stakeholder Perspective by Ronald A. Lyon, MS CLINICAL

Use Pattern and Off-Label Use of Atypical Antipsychotics in Bipolar Disorder Jeffery A. Demland, MS; Yonghua Jing, BPharm, PhD; Christina M. L. Kelton, PhD; Jeff J. Guo, BPharm, MS, PhD; Hong Li, MPH, PhD; Patricia R. Wigle, PharmD

Stakeholder Perspective by Renee Rizzo Fleming, RPh, MBA DEPARTMENTS ◆ Generic Drug Trends Biosimilars Policy Forum: Perspectives on Safety and Efficacy of Future Products ◆ Industry Trends Payer Perspectives on Healthcare Reform CONTINUING EDUCATION

Workplace Wellness and Disease Prevention: Focus on COPD David Tinkelman, MD; William B. Bunn, III, MD, JD, MPH; F. Randy Vogenberg, RPh, PhD

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EDITORIAL BOARD

CLINICAL EDITOR

EPIDEMIOLOGY RESEARCH

PHARMACY BENEFIT DESIGN

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

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

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

GOVERNMENT EDITOR

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

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

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

ACTUARY

HEALTH INFORMATION TECHNOLOGY

David Williams Health Consultant Milliman, Windsor, CT

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

CANCER RESEARCH

HEALTH OUTCOMES 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

Gordon M. Cummins, MS Director, IntegriChain Kavita V. Nair, PhD Associate Professor, School of Pharmacy University of Colorado at Denver Gary M. Owens, MD President, Gary Owens Associates Glen Mills, PA

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

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

CARDIOLOGY RESEARCH

MANAGED CARE & GOVERNMENT AFFAIRS

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

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

Alberto M. Colombi, MD, MPH Corporate Medical Director PPG Industries, Pittsburgh, PA Wayne M. Lednar, MD, PhD Global Chief Medical Officer Director, Integrated Health Services DuPont, Wilmington, DE Arthur F. Shinn, PharmD, FASCP President, Managed Pharmacy Consultants, Lake Worth, FL F. Randy Vogenberg, RPh, PhD Chief Strategy Officer Employer-based Pharmaceutical Strategies Senior Scholar, Department of Health Policy, Thomas Jefferson University

NO. 4

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

Joseph R. Antos, PhD Wilson H. Taylor Scholar in Health Care Retirement Policy American Enterprise Institute Jack E. Fincham, PhD, RPh Professor of Pharmacy, School of Pharmacy University of Missouri, Kansas City, MO 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

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

MANAGED MARKETS

REIMBURSEMENT POLICY

Jeffrey A. Bourret, MS, RPh, FASHP Executive Director, Customer-Centric Strategy and Innovation, Healthcare Systems Marketing Wyeth Pharmaceuticals, Collegeville, PA

Grant D. Lawless, BSPharm, MD, FACP Executive Director for Payor Relations Corporate Account Amgen, Thousand Oaks, CA

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

Michael Schaffer, PharmD, MBA Director, Pharmacy Programs Sanovia Co., Philadelphia, PA RESEARCH & DEVELOPMENT

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

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

PERSONALIZED MEDICINE

SPECIALTY PHARMACY

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

Atheer A. Kaddis, PharmD Vice President, Managed Markets Diplomat Specialty Pharmacy Swartz Creek, MI

PHARMACOECONOMICS

James T. Kenney, RPh, MBA Pharmacy Operations Manager Harvard Pilgrim Health Care Wellesley, MA

PATIENT ADVOCACY

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

VOL. 2

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

www.AHDBonline.com

145

JUNE/JULY 2009

VOLUME 2, NUMBER 4

™

™

TABLE OF CONTENTS EDITORIAL

152 Prioritizing Healthcare Resources to Keep the Baby Boomers Out of Nursing Homes Robert E. Henry

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

153 The View from Washington: Healthcare Reform John Gorman

Associate Publisher Maurice Nogueira maurice@engagehc.com 732-992-1895

REGULATORY

Editorial Director Dalia Buffery dalia@AHDBonline.com 732-992-1889

157 Applying Evidence for Medical Technologies: Closing the Gap between R&D and Decision Maker Needs Interview with Sean R. Tunis, MD, MSc 163 Stakeholder Perspective by F. Randy Vogenberg, RPh, PhD

Associate Editor Lara J. Reiman 732-992-1892

CLINICAL

Senior Production Manager Lynn Hamilton

184 Use Pattern and Off-Label Use of Atypical Antipsychotics in Bipolar Disorder Jeffery A. Demland, MS; Yonghua Jing, BPharm, PhD; Christina M. L. Kelton, PhD; Jeff J. Guo, BPharm, MS, PhD; Hong Li, MPH, PhD; Patricia R. Wigle, PharmD 191 Stakeholder Perspective by Renee Rizzo Fleming, RPh, MBA

Business Manager Blanche Marchitto Editor-in-Chief Robert E. Henry rhenry@AHDBonline.com 732-992-1885

BUSINESS

168 The Working Patient with Cancer: Implications for Payers and Employers Grant D. Lawless, BSPharm, MD, FACP 173 Stakeholder Perspective by Gary M. Owens, MD 174 Lower Copay and Oral Administration: Predictors of First-Fill Adherence to New Asthma Prescriptions Zackary Berger, MD, PhD; William Kimbrough, MD; Colleen Gillespie, PhD; Joseph A. Boscarino, PhD, MPH; G. Craig Wood, MS; Zhengmin Qian, MD, PhD; J. B. Jones, PhD, MBA; Nirav R. Shah, MD, MPH 179 Stakeholder Perspective by Ronald A. Lyon, MS Continued on page 148

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AMERICAN HEALTH & DRUG BENEFITS

June/July 2009

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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.

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TABLE OF CONTENTS

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DEPARTMENTS

165 GENERIC DRUG TRENDS Biosimilars Policy Forum: Perspectives on Safety and Efficacy of Future Products F. Randy Vogenberg, RPh, PhD 181 INDUSTRY TRENDS Payer Perspectives on Healthcare Reform Peyton Howell, MHA; Gene Reeder, RPh, PhD; Timothy S. Regan, BPharm, RPh, CPh 192 EXECUTIVE SUMMARIES CONTINUING EDUCATION

194 Workplace Wellness and Disease Prevention: Focus on Chronic Obstructive Pulmonary Disease 195 COPD Management in a Value-Based Healthcare System Interview with David Tinkelman, MD 198 The Economic Burden of COPD in the Workplace Interview with William B. Bunn, III, MD, JD, MPHCAPTION CONTEST

WEB EXCLUSIVE www.AHDBonline.com

ACC Highlights • Professor Reinhardt Predicts Long Struggle to Reform Healthcare • Healthcare Reform Must Include Multiple Components Caption Contest

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AMERICAN HEALTH & DRUG BENEFITS

June/July 2009

VOL. 2

NO. 4

NOW AVAILABLE

THE PPI WITH A DUAL DELAYED RELEASE (DDR) FORMULATION ™

KAPIDEX is indicated for: • Healing all grades of erosive esophagitis (EE) for up to 8 weeks • Maintaining healing of EE for up to 6 months • Treating heartburn associated with symptomatic non-erosive gastroesophageal reflux disease (GERD) for 4 weeks Important Safety Information • KAPIDEX is contraindicated in patients with known hypersensitivity to any component of the formulation.

• Symptomatic response with KAPIDEX does not preclude the presence of gastric malignancy.

• Most commonly reported treatment-emergent adverse reactions (≥2%): diarrhea, abdominal pain, nausea, upper respiratory tract infection, vomiting, and flatulence.

• KAPIDEX should not be co-administered with atazanavir. KAPIDEX may interfere with absorption of drugs for which gastric pH is important for bioavailability (e.g., ampicillin esters, digoxin, iron salts, ketoconazole). Patients taking concomitant warfarin may require monitoring for increases in international normalized ratio (INR) and prothrombin time.

Please see adjacent brief summary of prescribing information for KAPIDEX.

www.KAPIDEX.com

BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION KAPIDEXâ„¢ (dexlansoprazole) delayed release capsules INDICATIONS AND USAGE KAPIDEX is indicated for: s THE HEALING OF ALL GRADES OF EROSIVE ESOPHAGITIS %% FOR UP TO WEEKS

s MAINTAINING HEALING OF %% FOR UP TO MONTHS AND s THE TREATMENT OF HEARTBURN ASSOCIATED WITH NON EROSIVE GASTROESOPHAGEAL REmUX DISEASE '%2$ FOR WEEKS CONTRAINDICATIONS +!0)$%8 IS CONTRAINDICATED IN PATIENTS WITH KNOWN HYPERSENSITIVITY TO ANY COMPONENT OF THE FORMULATION (YPERSENSITIVITY AND ANAPHYLAXIS HAVE BEEN REPORTED WITH +!0)$%8 USE [see Adverse Reactions] WARNINGS AND PRECAUTIONS Gastric Malignancy 3YMPTOMATIC RESPONSE WITH +!0)$%8 DOES NOT PRECLUDE THE PRESENCE OF GASTRIC MALIGNANCY ADVERSE REACTIONS Clinical Trials Experience 4HE SAFETY OF +!0)$%8 WAS EVALUATED IN PATIENTS IN CONTROLLED AND UNCONTROLLED CLINICAL STUDIES INCLUDING PATIENTS TREATED FOR AT LEAST MONTHS AND PATIENTS TREATED FOR ONE YEAR 0ATIENTS RANGED IN AGE FROM TO YEARS MEDIAN AGE YEARS WITH FEMALE #AUCASIAN "LACK !SIAN

AND OTHER RACES 3IX RANDOMIZED CONTROLLED CLINICAL TRIALS WERE CONDUCTED FOR THE TREATMENT OF %% MAINTENANCE OF HEALED %% AND SYMPTOMATIC '%2$ WHICH INCLUDED PATIENTS ON PLACEBO PATIENTS ON +!0)$%8 MG PATIENTS ON +!0)$%8 MG AND PATIENTS ON LANSOPRAZOLE MG ONCE DAILY !S CLINICAL TRIALS ARE CONDUCTED UNDER WIDELY VARYING CONDITIONS ADVERSE REACTION RATES OBSERVED IN THE CLINICAL TRIALS OF A DRUG CANNOT BE DIRECTLY COMPARED TO RATES IN THE CLINICAL TRIALS OF ANOTHER DRUG AND MAY NOT REmECT THE RATES OBSERVED IN PRACTICE -OST #OMMONLY 2EPORTED !DVERSE 2EACTIONS 4HE MOST COMMON ADVERSE REACTIONS r THAT OCCURRED AT A HIGHER INCIDENCE FOR +!0)$%8 THAN PLACEBO IN THE CONTROLLED STUDIES ARE PRESENTED IN 4ABLE Table 2: Incidence of Treatment-Emergent Adverse Reactions in Controlled Studies Placebo (N=896) %

KAPIDEX 30 mg (N=455) %

KAPIDEX 60 mg (N=2218) %

$IARRHEA

!BDOMINAL 0AIN

.AUSEA

5PPER 2ESPIRATORY Tract Infection

6OMITING

&LATULENCE

Adverse Reaction

KAPIDEX Lansoprazole Total 30 mg (N=2621) (N=1363) % %

!DVERSE 2EACTIONS 2ESULTING IN $ISCONTINUATION )N CONTROLLED CLINICAL STUDIES THE MOST COMMON ADVERSE REACTION LEADING TO DISCONTINUATION FROM +!0)$%8 THERAPY WAS DIARRHEA /THER !DVERSE 2EACTIONS /THER ADVERSE REACTIONS THAT WERE REPORTED IN CONTROLLED STUDIES AT AN INCIDENCE OF LESS THAN ARE LISTED BELOW BY BODY SYSTEM Blood and Lymphatic System Disorders: ANEMIA LYMPHADENOPATHY Cardiac Disorders: ANGINA ARRHYTHMIA BRADYCARDIA CHEST PAIN EDEMA MYOCARDIAL INFARCTION PALPITATION TACHYCARDIA Ear and Labyrinth Disorders: EAR PAIN TINNITUS

VERTIGO Endocrine Disorders: GOITER Eye Disorders: EYE IRRITATION EYE SWELLING Gastrointestinal Disorders: ABDOMINAL DISCOMFORT ABDOMINAL TENDERNESS

ABNORMAL FECES ANAL DISCOMFORT "ARRETT S ESOPHAGUS BEZOAR BOWEL SOUNDS ABNORMAL BREATH ODOR COLITIS MICROSCOPIC COLONIC POLYP CONSTIPATION DRY MOUTH

DUODENITIS DYSPEPSIA DYSPHAGIA ENTERITIS ERUCTATION ESOPHAGITIS GASTRIC POLYP

GASTRITIS GASTROENTERITIS GASTROINTESTINAL DISORDERS GASTROINTESTINAL HYPERMOTILITY DISORDERS '%2$ ') ULCERS AND PERFORATION HEMATEMESIS HEMATOCHEZIA

HEMORRHOIDS IMPAIRED GASTRIC EMPTYING IRRITABLE BOWEL SYNDROME MUCUS STOOLS

NAUSEA AND VOMITING ORAL MUCOSAL BLISTERING PAINFUL DEFECATION PROCTITIS

PARESTHESIA ORAL RECTAL HEMORRHAGE General Disorders and Administration Site Conditions: ADVERSE DRUG REACTION ASTHENIA CHEST PAIN CHILLS FEELING ABNORMAL

INmAMMATION MUCOSAL INmAMMATION NODULE PAIN PYREXIA Hepatobiliary Disorders: BILIARY COLIC CHOLELITHIASIS HEPATOMEGALY Immune System Disorders:

HYPERSENSITIVITY Infections and Infestations: CANDIDA INFECTIONS INmUENZA

NASOPHARYNGITIS ORAL HERPES PHARYNGITIS SINUSITIS VIRAL INFECTION VULVO VAGINAL INFECTION Injury, Poisoning and Procedural Complications: FALLS FRACTURES JOINT SPRAINS OVERDOSE PROCEDURAL PAIN SUNBURN Laboratory Investigations: ALP INCREASED !,4 INCREASED !34 INCREASED BILIRUBIN DECREASED INCREASED BLOOD CREATININE INCREASED BLOOD GASTRIN INCREASED BLOOD GLUCOSE INCREASED BLOOD POTASSIUM INCREASED LIVER FUNCTION TEST ABNORMAL PLATELET COUNT DECREASED TOTAL PROTEIN INCREASED WEIGHT INCREASE Metabolism and Nutrition Disorders: APPETITE CHANGES HYPERCALCEMIA HYPOKALEMIA Musculoskeletal and Connective Tissue Disorders: ARTHRALGIA ARTHRITIS MUSCLE CRAMPS MUSCULOSKELETAL PAIN MYALGIA Nervous System Disorders: ALTERED TASTE CONVULSION DIZZINESS HEADACHES

MIGRAINE MEMORY IMPAIRMENT PARESTHESIA PSYCHOMOTOR HYPERACTIVITY TREMOR

TRIGEMINAL NEURALGIA Psychiatric Disorders: ABNORMAL DREAMS ANXIETY DEPRESSION

INSOMNIA LIBIDO CHANGES Renal and Urinary Disorders: DYSURIA MICTURITION URGENCY Reproductive System and Breast Disorders: DYSMENORRHEA DYSPAREUNIA

MENORRHAGIA MENSTRUAL DISORDER; Respiratory, Thoracic and Mediastinal Disorders: ASPIRATION ASTHMA BRONCHITIS COUGH DYSPNOEA HICCUPS HYPERVENTILATION RESPIRATORY TRACT CONGESTION SORE THROAT Skin and Subcutaneous Tissue Disorders: ACNE

DERMATITIS ERYTHEMA PRURITIS RASH SKIN LESION URTICARIA Vascular Disorders: DEEP VEIN THROMBOSIS HOT mUSH HYPERTENSION Additional adverse reactions that were reported in a long-term uncontrolled study and were considered related to KAPIDEX by the treating physician included: anaphylaxis, auditory hallucination, B-cell lymphoma, central obesity, cholecystitis acute, decreased hemoglobin, dehydration, diabetes mellitus, dysphonia, epistaxis, folliculitis, gastrointestinal pain, gout, herpes zoster, hyperglycemia, hyperlipidemia, hypothyroidism, increased neutrophils, MCHC decrease, neutropenia, oral soft tissue disorder, rectal tenesmus, restless legs syndrome, somnolence, thrombocythemia, tonsillitis.

Other adverse reactions not observed with KAPIDEX, but occurring with the racemate lansoprazole can be found in the lansoprazole package insert, ADVERSE REACTIONS section.

DRUG INTERACTIONS Drugs with pH-Dependent Absorption Pharmacokinetics +!0)$%8 CAUSES INHIBITION OF GASTRIC ACID SECRETION +!0)$%8 IS LIKELY TO SUBSTANTIALLY DECREASE THE SYSTEMIC CONCENTRATIONS OF THE ()6 PROTEASE INHIBITOR ATAZANAVIR WHICH IS DEPENDENT UPON THE PRESENCE OF GASTRIC ACID FOR ABSORPTION AND MAY RESULT IN A LOSS OF THERAPEUTIC EFFECT OF ATAZANAVIR AND THE DEVELOPMENT OF ()6 RESISTANCE 4HEREFORE +!0)$%8 SHOULD NOT BE CO ADMINISTERED WITH ATAZANAVIR )T IS THEORETICALLY POSSIBLE THAT +!0)$%8 MAY INTERFERE WITH THE ABSORPTION OF OTHER DRUGS WHERE GASTRIC P( IS AN IMPORTANT DETERMINANT OF ORAL BIOAVAILABILITY E G AMPICILLIN ESTERS DIGOXIN IRON SALTS KETOCONAZOLE Warfarin #O ADMINISTRATION OF +!0)$%8 MG AND WARFARIN MG DID NOT AFFECT THE PHARMACOKINETICS OF WARFARIN OR ).2 (OWEVER THERE HAVE BEEN REPORTS OF INCREASED ).2 AND PROTHROMBIN TIME IN PATIENTS RECEIVING 00)S AND WARFARIN CONCOMITANTLY )NCREASES IN ).2 AND PROTHROMBIN TIME MAY LEAD TO ABNORMAL BLEEDING AND EVEN DEATH 0ATIENTS TREATED WITH +!0)$%8 AND WARFARIN CONCOMITANTLY MAY NEED TO BE MONITORED FOR INCREASES IN ).2 AND PROTHROMBIN TIME USE IN SPECIFIC POPULATIONS Pregnancy Teratogenic Effects 0REGNANCY #ATEGORY " 4HERE ARE NO ADEQUATE AND WELL CONTROLLED STUDIES WITH DEXLANSOPRAZOLE IN PREGNANT WOMEN 4HERE WERE NO ADVERSE FETAL EFFECTS IN ANIMAL REPRODUCTION STUDIES OF DEXLANSOPRAZOLE IN RABBITS "ECAUSE ANIMAL REPRODUCTION STUDIES ARE NOT ALWAYS PREDICTIVE OF HUMAN RESPONSE +!0)$%8 SHOULD BE USED DURING PREGNANCY ONLY IF CLEARLY NEEDED ! REPRODUCTION STUDY CONDUCTED IN RABBITS AT ORAL DEXLANSOPRAZOLE DOSES UP TO MG PER KG PER DAY APPROXIMATELY FOLD THE MAXIMUM RECOMMENDED HUMAN DEXLANSOPRAZOLE DOSE ; MG= BASED ON BODY SURFACE AREA ;"3!= REVEALED NO EVIDENCE OF HARM TO THE FETUS DUE TO DEXLANSOPRAZOLE )N ADDITION REPRODUCTION STUDIES PERFORMED IN PREGNANT RATS WITH ORAL LANSOPRAZOLE AT DOSES UP TO MG PER KG PER DAY TIMES THE RECOMMENDED HUMAN DOSE BASED ON "3! AND IN PREGNANT RABBITS AT ORAL LANSOPRAZOLE DOSES UP TO MG PER KG PER DAY TIMES THE RECOMMENDED HUMAN DOSE BASED ON "3! REVEALED NO EVIDENCE OF IMPAIRED FERTILITY OR HARM TO THE FETUS DUE TO LANSOPRAZOLE

Nursing Mothers It is not known whether dexlansoprazole is excreted in human milk. However, lansoprazole and its metabolites are present in rat milk following the administration of lansoprazole. As many drugs are excreted in human milk, and because of the potential for tumorigenicity shown for lansoprazole in rat carcinogenicity studies [see Carcinogenesis, Mutagenesis, Impairment of Fertility], a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use Safety and effectiveness of KAPIDEX in pediatric patients (less than 18 years of age) have not been established.

Geriatric Use )N CLINICAL STUDIES OF +!0)$%8 OF PATIENTS WERE AGED YEARS AND OVER .O OVERALL DIFFERENCES IN SAFETY OR EFFECTIVENESS WERE OBSERVED BETWEEN THESE PATIENTS AND YOUNGER PATIENTS AND OTHER REPORTED CLINICAL EXPERIENCE HAS NOT IDENTIlED SIGNIlCANT DIFFERENCES IN RESPONSES BETWEEN GERIATRIC AND YOUNGER PATIENTS BUT GREATER SENSITIVITY OF SOME OLDER INDIVIDUALS CANNOT BE RULED OUT] Renal Impairment No dosage adjustment of KAPIDEX is necessary in patients with renal impairment.

The pharmacokinetics of dexlansoprazole in patients with renal impairment are not expected to be altered since dexlansoprazole is extensively metabolized in the liver to inactive metabolites, and no parent drug is recovered in the urine following an oral dose of dexlansoprazole.

Lansoprazole produced dose-related gastric ECL cell hyperplasia and ECL cell carcinoids in both male and female rats [see Clinical Pharmacology].

In rats, lansoprazole also increased the incidence of intestinal metaplasia of the gastric epithelium in both sexes. In male rats, lansoprazole produced a dose-related increase of testicular interstitial cell adenomas. The incidence of these adenomas in rats receiving doses of 15 to 150 mg per kg per day (4 to 40 times the recommended lansoprazole human dose based on BSA) exceeded the low background incidence (range = 1.4 to 10%) for this strain of rat. Testicular interstitial cell adenoma also occurred in 1 of 30 rats treated with 50 mg lansoprazole per kg per day (13 times the recommended lansoprazole human dose based on BSA) in a 1-year toxicity study. )N A MONTH CARCINOGENICITY STUDY #$ MICE WERE TREATED ORALLY WITH LANSOPRAZOLE DOSES OF MG TO MG PER KG PER DAY TO TIMES THE RECOMMENDED HUMAN DOSE BASED ON "3! ,ANSOPRAZOLE PRODUCED A DOSE RELATED INCREASED INCIDENCE OF GASTRIC %#, CELL HYPERPLASIA )T ALSO PRODUCED AN INCREASED INCIDENCE OF LIVER TUMORS HEPATOCELLULAR ADENOMA PLUS CARCINOMA 4HE TUMOR INCIDENCES IN MALE MICE TREATED WITH MG AND MG LANSOPRAZOLE PER KG PER DAY TO TIMES THE RECOMMENDED LANSOPRAZOLE HUMAN DOSE BASED ON "3! AND FEMALE MICE TREATED WITH MG TO MG LANSOPRAZOLE PER KG PER DAY TO TIMES THE RECOMMENDED HUMAN DOSE BASED ON "3! EXCEEDED THE RANGES OF BACKGROUND INCIDENCES IN HISTORICAL CONTROLS FOR THIS STRAIN OF MICE ,ANSOPRAZOLE TREATMENT PRODUCED ADENOMA OF RETE TESTIS IN MALE MICE RECEIVING TO MG PER KG PER DAY TO TIMES THE RECOMMENDED LANSOPRAZOLE HUMAN DOSE BASED ON "3!

Hepatic Impairment No dosage adjustment for KAPIDEX is necessary for patients with mild hepatic impairment (Child-Pugh Class A). KAPIDEX 30 mg should be considered for patients with moderate hepatic impairment (Child-Pugh Class B). No studies have been conducted in patients with severe hepatic impairment (Child-Pugh Class C).

4HE POTENTIAL EFFECTS OF DEXLANSOPRAZOLE ON FERTILITY AND REPRODUCTIVE PERFORMANCE WERE ASSESSED USING LANSOPRAZOLE STUDIES ,ANSOPRAZOLE AT ORAL DOSES UP TO MG PER KG PER DAY TIMES THE RECOMMENDED LANSOPRAZOLE HUMAN DOSE BASED ON "3! WAS FOUND TO HAVE NO EFFECT ON FERTILITY AND REPRODUCTIVE PERFORMANCE OF MALE AND FEMALE RATS PATIENT COUNSELING INFORMATION

OVERDOSAGE

[see FDA-Approved Patient Labeling in the full prescribing information]

4HERE HAVE BEEN NO REPORTS OF SIGNIlCANT OVERDOSE OF +!0)$%8 -ULTIPLE DOSES OF +!0)$%8 MG AND A SINGLE DOSE OF +!0)$%8 MG DID NOT RESULT IN DEATH OR OTHER SEVERE ADVERSE EVENTS $EXLANSOPRAZOLE IS NOT EXPECTED TO BE REMOVED FROM THE CIRCULATION BY HEMODIALYSIS )F AN OVERDOSE OCCURS TREATMENT SHOULD BE SYMPTOMATIC AND SUPPORTIVE

Information for Patients To ensure the safe and effective use of KAPIDEX, this information and instructions provided in the FDA-approved patient labeling should be discussed with the patient.

Inform patients of the following:

CLINICAL PHARMACOLOGY Pharmacodynamics !NTISECRETORY !CTIVITY 4HE EFFECTS OF +!0)$%8 MG N OR LANSOPRAZOLE MG N ONCE DAILY FOR lVE DAYS ON HOUR INTRAGASTRIC P( WERE ASSESSED IN HEALTHY SUBJECTS IN A MULTIPLE DOSE CROSSOVER STUDY 3ERUM 'ASTRIN %FFECTS 4HE EFFECT OF +!0)$%8 ON SERUM GASTRIN CONCENTRATIONS WAS EVALUATED IN APPROXIMATELY PATIENTS IN CLINICAL TRIALS UP TO WEEKS AND IN PATIENTS FOR UP TO TO MONTHS 4HE MEAN FASTING GASTRIN CONCENTRATIONS INCREASED FROM BASELINE DURING TREATMENT WITH +!0)$%8 MG AND MG DOSES )N PATIENTS TREATED FOR MORE THAN MONTHS MEAN SERUM GASTRIN LEVELS INCREASED DURING APPROXIMATELY THE lRST MONTHS OF TREATMENT AND WERE STABLE FOR THE REMAINDER OF TREATMENT -EAN SERUM GASTRIN LEVELS RETURNED TO PRE TREATMENT LEVELS WITHIN ONE MONTH OF DISCONTINUATION OF TREATMENT %NTEROCHROMAFlN ,IKE #ELL %#, %FFECTS 4HERE WERE NO REPORTS OF %#, CELL HYPERPLASIA IN GASTRIC BIOPSY SPECIMENS OBTAINED FROM PATIENTS TREATED WITH +!0)$%8 MG MG OR MG FOR UP TO MONTHS $URING LIFETIME EXPOSURE OF RATS DOSED DAILY WITH UP TO MG PER KG PER DAY OF LANSOPRAZOLE MARKED HYPERGASTRINEMIA WAS OBSERVED FOLLOWED BY %#, CELL PROLIFERATION AND FORMATION OF CARCINOID TUMORS ESPECIALLY IN FEMALE RATS [see Nonclinical Toxicology ]

KAPIDEX is available as a delayed release capsule.

KAPIDEX may be taken without regard to food.

KAPIDEX should be swallowed whole. s !LTERNATIVELY +!0)$%8 CAPSULES CAN BE OPENED AND ADMINISTERED AS FOLLOWS n /PEN CAPSULE n 3PRINKLE INTACT GRANULES ON ONE TABLESPOON OF APPLESAUCE n 3WALLOW IMMEDIATELY $ISTRIBUTED BY Takeda Pharmaceuticals America, Inc. $EERlELD ), 5 3 0ATENT .OS

AND

+!0)$%8 IS A TRADEMARK OF 4AKEDA 0HARMACEUTICALS .ORTH !MERICA )NC AND USED UNDER LICENSE BY 4AKEDA 0HARMACEUTICALS !MERICA )NC !LL OTHER TRADEMARK NAMES ARE THE PROPERTY OF THEIR RESPECTIVE OWNERS Ăš 4AKEDA 0HARMACEUTICALS !MERICA )NC &OR MORE DETAILED INFORMATION SEE THE FULL PRESCRIBING INFORMATION FOR +!0)$%8 0) 2 *ANUARY OR CONTACT 4AKEDA 0HARMACEUTICALS !MERICA )NC AT

, ,0$

Effect on Cardiac Repolarization A study was conducted to assess the potential of KAPIDEX to prolong the QT/QTc interval in healthy adult subjects. KAPIDEX doses of 90 mg or 300 mg did not delay cardiac repolarization compared to placebo. The positive control (moxifloxacin) produced statistically significantly greater mean maximum and time-averaged QT/QTc intervals compared to placebo.

NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility The carcinogenic potential of dexlansoprazole was assessed using lansoprazole studies. In two 24-month carcinogenicity studies, Sprague-Dawley rats were treated orally with lansoprazole at doses of 5 to 150 mg per kg per day, about 1 to 40 times the exposure on a body surface (mg/m2) basis of a 50 kg person of average height (1.46 m2 BSA) given the recommended human dose of lansoprazole (30 mg per day).

Reference: KAPIDEX (dexlansoprazole) package insert, Takeda Pharmaceuticals America, Inc KAPIDEX™ and Dual Delayed Release™ are trademarks of Takeda Pharmaceuticals North America, Inc., and are used under license by Takeda Pharmaceuticals America, Inc.

Š2009 Takeda Pharmaceuticals North America, Inc. LPD-00021 2/09 Printed in U.S.A.

FROM THE EDITOR

Prioritizing Healthcare Resources to Keep the Baby Boomers Out of Nursing Homes

I

n March 2009, the Institute of Medicine (IOM) undertook a study, requested by Congress in the American Recovery and Reinvestment Act of 2009, to determine national priorities for comparative effectiveness research. The Committee on Comparative Effectiveness Research Prioritization will have issued its final report by June 30, 2009.

At the recent Foundation for Managed Care Pharmacy industry symposium, Moderator Sean D. Sullivan, Director of Pharmaceutical Outcomes Research and Policy Program at the University of Washington, asked the panel what disease states they would want the IOM to prioritize. Various disease candidates were mentioned, but nothing definitive came out of it. Afterward, I suggested to Dr Sullivan a different way to approach this important matter of prioritizing research: anything that keeps patients out of nursing homes. He liked this and wished I had voiced it at the microphone; I am compensating for that deficit here.

The bald reality facing healthcare is the inexorable march of the baby boomers into old age. No matter how determined this generation is in denying the aging process, they tend to age one year at a time, and the economic implications of the epidemiologically driven healthcare needs should instill a sense of purpose and urgency into the healthcare system, by simply asking what fundamental conditions stand to tear it apart. The answers that leap to mind are pandemics, a global depression, and diseases that place large numbers of aging patients into nursing homes.

The reason this last item belongs grouped with the other two is that nothing consumes healthcare resources like hospitalized care, unless it is long-term care. The labor costs of nursing home care for the population it now serves are already straining budgets; when the baby boomers enter the retirement era, their entry into nursing homes at the current rate for the medical conditions that send today’s nursing home residents there could shock and cripple the system. Thus, the need to find significant new cures and preventive measures are vital and predicable means of preserving our healthcare system.

Alzheimer’s disease, stroke prevention, fractured hips—these are among the worthiest of targets for accelerated research and preventive management, for their containment will ensure that the basic premise of man-

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AMERICAN HEALTH & DRUG BENEFITS June/July 2009

age care is realized: the management of overall healthcare resources consistent with our ability to pay for care.

In an effort to deal with these epidemiologically predictable enemies of health, American Health & Drug Benefits hosted a summit on transient ischemic stroke and recurrent stroke this past May, which was Stroke Prevention Month. We celebrated it by observing that there is a way that healthcare stakeholders can align their energies to head off the crippling effects that stroke brings—in terms of health and of finances.

The need for payers and purchasers to aggressively pursue stroke and heed its risk factors to prevent its onset at every opportunity is just one example of how payers, providers, and other healthcare stakeholders can stumble onto formidable levels of “found money,” and with it, equally impressive levels of found lives.

The current approach to stroke is unnecessarily passive—wait until it happens, then do something about it—when the real savings in cost and life are found in aggressive preventive measures. This requires a synchronization of providers with payers, purchasers, researchers, and pharma. It means ensuring that guidelines are heeded and acted upon. Nothing is more deadly to the healthcare system than diseases/conditions that maim but do not (necessarily) kill.

The special supplement we will issue later this year on stroke prevention will show stakeholder collaborative efforts to keep patients free of the effects of just one of these priority disease states that particularly threaten the elderly. We urge payers and purchasers to keep their eyes on the prize: not just overall healthcare resource allocation in the here and now but also resource allocation as it is being redefined by demographic shifts. The effects of the baby boomer generation’s aging give a neat way of preparing for the increasing challenges coming our way very soon. Keeping patients well enough to stay at home will be the fundamental measure of a healthcare system that is fiscally sound for the best of all medical reasons: preserving the health of patients through preventive strategies. ■

Robert E. Henry Editor-in-Chief

VOL. 2

NO. 4

Now available in pharmacies

For the management of fibromyalgia

IMPORTANT SAFETY INFORMATION — Savella is a selective serotonin and norepinephrine reuptake inhibitor (SNRI), similar to some drugs used for the treatment of depression and other psychiatric disorders. Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of such drugs in a child, adolescent, or young adult must balance this risk with the clinical need.

Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on Savella should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior, especially during the initial few months of drug therapy or at times of dose changes, either increases or decreases. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Savella is not approved for use in the treatment of major depressive disorder. Savella is not approved for use in pediatric patients.

Savella is contraindicated in patients taking monoamine oxidase inhibitors (MAOIs) concomitantly or within 14 days of discontinuing treatment with an MAOI. There have been reports of serious, sometimes fatal, reactions in patients started on an MAOI who were receiving or had recently discontinued a serotonin reuptake inhibitor. At least 5 days should be allowed after stopping Savella before starting an MAOI.

Savella is contraindicated in patients with uncontrolled narrow-angle glaucoma and should be used with caution in patients with controlled narrow-angle glaucoma. In clinical trials, Savella was associated with an increased risk of mydriasis.

Prescriptions for Savella should be written for the smallest quantity of tablets, consistent with good patient management, in order to reduce the risk of overdose.

Development of a potentially life-threatening serotonin syndrome may occur with agents that inhibit serotonin reuptake, including Savella, particularly with concomitant use of serotonergic drugs (including triptans and tramadol) and with drugs that impair metabolism of serotonin (including MAOIs). The concomitant use of Savella with serotonin precursors is not recommended.

S

NRIs, including Savella, have been associated with cardiovascular effects, including cases of elevated blood pressure, requiring immediate treatment. In clinical trials, sustained increases in systolic and diastolic blood pressure occurred more frequently in Savella-treated patients compared to placebo. Among patients who were non-hypertensive at baseline, approximately twice as many patients receiving Savella, vs placebo, became hypertensive at the end of the study.

Clinically significant increases in pulse (≥20 bpm) occurred more frequently in Savella-treated than placebo-treated patients. Blood pressure and heart rate should be monitored prior to initiating treatment with Savella and periodically throughout treatment. Pre-existing hypertension, tachyarrhythmias, and other cardiac diseases should be treated before starting therapy with Savella. Savella should be used with caution in patients with significant hypertension or cardiac disease. Concomitant use of Savella with drugs that increase blood pressure and pulse has not been evaluated, and such combinations should be used with caution. For patients who experience a sustained increase in blood pressure or heart rate while receiving Savella, either dose reduction or discontinuation should be considered.

Licensed from Pierre Fabre and Cypress Bioscience, Inc.

Savella should be prescribed with caution in patients with a history of seizure disorder or mania.

Savella has been associated with mild elevations of ALT and AST (1 to 3 times the upper limit of normal). Rarely, reports of serious liver injury, including fulminant hepatitis, have been reported in patients treated with milnacipran. Savella should be discontinued in patients who develop jaundice or other evidence of liver dysfunction and should not be resumed unless another cause can be established.

Savella should ordinarily not be prescribed to patients with substantial alcohol use or evidence of chronic liver disease.

As with other SNRIs and SSRIs, withdrawal symptoms have been observed following discontinuation of milnacipran. A gradual dose reduction is recommended.

Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including Savella. Elderly patients may be at greater risk. Discontinuation should be considered for patients with symptomatic hyponatremia.

SSRIs and SNRIs, including Savella, may increase the risk of bleeding events.

Patients should be cautioned regarding the risk of bleeding associated with concomitant use of Savella and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation.

Savella can affect urethral resistance and micturition. Caution is advised in the use of Savella in patients with a history of dysuria, notably in male patients with a history of obstructive uropathies as these patients may experience higher rates of genitourinary adverse events.

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

In clinical trials, the most frequently occurring adverse reaction was nausea (37% vs 20% for placebo). The most commonly occurring adverse reactions (≥5% and greater than placebo) were headache (18% vs 14%), constipation (16% vs 4%), dizziness (10% vs 6%), insomnia (12% vs 10%), hot flush (12% vs 2%), hyperhidrosis (9% vs 2%), vomiting (7% vs 2%), palpitations (7% vs 2%), heart rate increased (6% vs 1%), dry mouth (5% vs 2%), and hypertension (5% vs 2%).

Please see brief summary of prescribing information on following pages.

For Full Prescribing Information, visit www.savella.com. © 2009 Forest Laboratories, Inc. 43-1014302 05/09

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Savella (milnacipran HCl) Tablets Rx Only Brief Summary of Full Prescribing Information Initial U.S. Approval: 2009 WARNING: SUICIDALITY AND ANTIDEPRESSANT DRUGS Savella is a selective serotonin and norepinephrine reuptake inhibitor (SNRI), similar to some drugs used for the treatment of depression and other psychiatric disorders. Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders.

Anyone considering the use of such drugs in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older.

Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on Savella should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Savella is not approved for use in the treatment of major depressive disorder. Savella is not approved for use in pediatric patients [see Warnings and Precautions, Use in Specific Populations].

INDICATIONS AND USAGE: Savella is indicated for the management of fibromyalgia. Savella is not approved for use in pediatric patients [see Use in Specific Populations].

CONTRAINDICATIONS: Monoamine Oxidase Inhibitors-Concomitant use of Savella in patients taking monoamine oxidase inhibitors (MAOIs) is contraindicated. In patients receiving a serotonin reuptake inhibitor in combination with a monoamine oxidase inhibitor (MAOI), there have been reports of serious, sometimes fatal, reactions including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma. These reactions have also been reported in patients who have recently discontinued serotonin reuptake inhibitors and have been started on an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. The effects of combined use of Savella and MAOIs have not been evaluated in humans. Therefore, it is recommended that Savella should not be used in combination with an MAOI, or within 14 days of discontinuing treatment with an MAOI. Similarly, at least 5 days should be allowed after stopping Savella before starting an MAOI [see Dosage and Administration, Warnings and Precautions]. Uncontrolled Narrow-Angle Glaucoma-In clinical trials, Savella was associated with an increased risk of mydriasis. Mydriasis has been reported with other dual reuptake inhibitors of norepinephrine and serotonin; therefore, do not use Savella in patients with uncontrolled narrow-angle glaucoma.

WARNINGS AND PRECAUTIONS: Suicide Risk-Savella is a selective serotonin and norepinephrine re-uptake inhibitor (SNRI), similar to some drugs used for the treatment of depression and other psychiatric disorders. Patients, both adult and pediatric, with depression or other psychiatric disorders may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking these medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants, including drugs that inhibit the reuptake of norepinephrine and/or serotonin, may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment.

In the placebo-controlled clinical trials of adults with fibromyalgia, among the patients who had a history of depression at treatment initiation, the incidence of suicidal ideation was 0.5% in patients treated with placebo, 0% in patients treated with Savella 100 mg/day, and 1.3% in patients treated with Savella 200 mg/day. No suicides occurred in the short-term or longer-term (up to 1 year) fibromyalgia trials. Pooled analyses of short-term placebo-controlled trials of drugs used to treat depression (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with these drugs compared to placebo in adults beyond age 24; there was a reduction in suicidality risk with antidepressants compared to placebo in adults age 65 and older. The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 drugs used to treat depression in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk of differences (drug versus placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1.

Table 1. Risk Differences (Drug–Placebo) in the number of Cases of Suicidality, per 1000 patients treated Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated < 18 14 additional cases 18-24 5 additional cases Decreases Compared to Placebo 25-64 1 fewer case ≥ 65 6 fewer cases No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide. It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression. All patients being treated with drugs inhibiting the reuptake of norepinephrine and/or serotonin for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, have been reported in adult and pediatric patients being treated with drugs inhibiting the reuptake of norepinephrine and/or serotonin for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients who may experience worsening depressive symptoms, or

287742_L01_F2.indd 2

who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe or abrupt in onset, or were not part of the patient’s presenting symptoms. If the decision has been made to discontinue treatment due to worsening depressive symptoms or emergent suicidality, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can produce withdrawal symptoms [see Dosage and Administration—Recommended Dosing, Dosage—Discontinuing Savella, and Warnings and Precautions—Discontinuation of Treatment with Savella]. Families and caregivers of patients being treated with drugs inhibiting the reuptake of norepinephrine and/or serotonin for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for Savella should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. Serotonin Syndrome-The development of a potentially life-threatening serotonin syndrome may occur with agents that inhibit serotonin reuptake, including Savella, particularly with concomitant use of serotonergic drugs (including triptans and tramadol) and with drugs which impair metabolism of serotonin (including MAOIs). Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The concomitant use of Savella with MAOIs is contraindicated [see Contraindications]. If concomitant treatment of Savella with a 5hydroxytryptamine receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases [see Drug Interactions]. The concomitant use of Savella with serotonin precursors (such as tryptophan) is not recommended [see Drug Interactions]. Effects on Blood Pressure-Inhibition of the reuptake of norepinephrine (NE) and serotonin (5-HT) can lead to cardiovascular effects. SNRIs, including Savella, have been associated with reports of increase in blood pressure. In a double-blind, placebo-controlled clinical pharmacology study in healthy subjects designed to evaluate the effects of milnacipran on various parameters, including blood pressure at supratherapeutic doses, there was evidence of mean increases in supine blood pressure at doses up to 300 mg twice daily (600 mg/day). At the highest 300 mg twice daily dose, the mean increase in systolic blood pressure was up to 8.1 mm Hg for the placebo group and up to 10.0 mm Hg for the Savella treated group over the 12 hour steady state dosing interval. The corresponding mean increase in diastolic blood pressure over this interval was up to 4.6 mm Hg for placebo and up to 11.5 mm Hg for the Savella treated group. In the 3-month placebo-controlled fibromyalgia clinical trials, Savella treatment was associated with mean increases of up to 3.1 mm Hg in systolic blood pressure (SBP) and diastolic blood pressure (DBP) [see Adverse Reactions]. In the placebo-controlled trials, among fibromyalgia patients who were non-hypertensive at baseline, approximately twice as many patients in the Savella treatment arms became hypertensive at the end of the study (SBP ≥ 140 mmHg or DBP ≥ 90 mmHg) compared with the placebo patients: 7.2% of patients in the placebo arm versus 19.5% of patients treated with Savella 100 mg/day and 16.6% of patients treated with Savella 200 mg/day. Among patients who met systolic criteria for pre-hypertension at baseline (SBP 120-139 mmHg), more patients became hypertensive at the end of the study in the Savella treatment arms than placebo: 9% of patients in the placebo arm versus 14% in both the Savella 100 mg/day and the Savella 200 mg/day treatment arms. Among fibromyalgia patients who were hypertensive at baseline, more patients in the Savella treatment arms had a >15 mmHg increase in SBP than placebo at the end of the study: 1% of patients in the placebo arm versus 7% in the Savella 100 mg/day and 2% in the Savella 200 mg/day treatment arms. Similarly, more patients who were hypertensive at baseline and were treated with Savella had DBP increases > 10 mmHg than placebo at the end of study: 3% of patients in the placebo arm versus 8% in the Savella 100 mg/day and 6% in the Savella 200 mg/day treatment arms. Sustained increases in SBP (increase of ≥ 15 mmHg on three consecutive post-baseline visits) occurred in 2% of placebo patients versus 9% of patients receiving Savella 100 mg/day and 6% of patients receiving Savella 200 mg/day. Sustained increases in DBP (increase of ≥ 10 mmHg on 3 consecutive post-baseline visits) occurred in 4% of patients receiving placebo versus 13% of patients receiving Savella 100 mg/day and 10% of patients receiving Savella 200 mg/day. Sustained increases in blood pressure could have adverse consequences. Cases of elevated blood pressure requiring immediate treatment have been reported. Concomitant use of Savella with drugs that increase blood pressure and pulse has not been evaluated and such combinations should be used with caution [see Drug Interactions]. Effects of Savella on blood pressure in patients with significant hypertension or cardiac disease have not been systematically evaluated. Savella should be used with caution in these patients. Blood pressure should be measured prior to initiating treatment and periodically measured throughout Savella treatment. Pre-existing hypertension and other cardiovascular disease should be treated before starting therapy with Savella. For patients who experience a sustained increase in blood pressure while receiving Savella, either dose reduction or discontinuation should be considered. Effects on Heart Rate-SNRIs have been associated with reports of increase in heart rate. In clinical trials, relative to placebo, Savella treatment was associated with mean increases in pulse rate of approximately 7 to 8 beats per minute [see Adverse Reactions]. Increases in pulse ≥ 20 bpm occurred more frequently in Savella-treated patients when compared to placebo: 0.3% in the placebo arm versus 8% in the Savella 100 mg/day and 8% in the 200 mg/day treatment arms.

The effect of Savella on heart rate did not appear to increase with increasing dose. Savella has not been systematically evaluated in patients with a cardiac rhythm disorder. Heart rate should be measured prior to initiating treatment and periodically measured throughout Savella treatment. Pre-existing tachyarrhythmias and other cardiac disease should be treated before starting therapy with Savella.

For patients who experience a sustained increase in heart rate while receiving Savella, either dose reduction or discontinuation should be considered. Seizures-Savella has not been systematically evaluated in patients with a seizure disorder. In clinical trials evaluating Savella in patients with fibromyalgia, seizures/convulsions have not been reported. However, seizures have been reported infrequently in patients treated with Savella for disorders other than fibromyalgia. Savella should be prescribed with care in patients with a history of a seizure disorder. Hepatotoxicity-In the placebocontrolled fibromyalgia trials, increases in the number of patients treated with Savella with mild elevations of ALT or AST (1-3 times the upper limit of normal, ULN) were observed. Increases in ALT were more frequently observed in the patients treated with Savella 100 mg/day (6%) and Savella 200 mg/day (7%), compared to the patients treated with placebo (3%). One patient receiving Savella 100 mg/day (0.2%) had an increase in ALT greater than 5 times the upper limit of normal but did not exceed 10 times the upper limit of normal. Increases in AST were more frequently observed in the patients treated with Savella 100 mg/day (3%) and Savella 200 mg/day (5%) compared to the patients treated with placebo (2%). The increases of bilirubin observed in the fibromyalgia clinical trials were not clinically significant. No case met the criteria of elevated ALT > 3x ULN and associated with an increase in bilirubin ≥ 2x ULN. There have been cases of increased liver enzymes and reports of severe liver injury, including fulminant hepatitis with milnacipran from foreign postmarketing experience. In the cases of severe liver injury there were significant underlying clinical conditions and/or the use of multiple concomitant medications. Because of underreporting, it is impossible to provide an accurate estimate of the true incidence of these reactions. Savella should be discontinued in patients who develop jaundice or other evidence of liver dysfunction. Treatment with Savella should not be resumed unless another cause can be established. Savella should ordinarily not be prescribed to patients

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with substantial alcohol use or evidence of chronic liver disease. Discontinuation of Treatment with Savella-Withdrawal symptoms have been observed in clinical trials following discontinuation of milnacipran, as with other SNRIs and SSRIs. During marketing of milnacipran, and other SNRIs and SSRIs, there have been spontaneous reports of adverse events indicative of withdrawal and physical dependence occurring upon discontinuation of these drugs, particularly when discontinuation is abrupt.

The adverse events include the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. Although these events are generally self-limiting, some have been reported to be severe. Patients should be monitored for these symptoms when discontinuing treatment with Savella. Savella should be tapered and not abruptly discontinued after extended use. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate [see Dosage and Administration]. Hyponatremia-Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including Savella. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with SNRIs, SSRIs, or Savella. Also, patients taking diuretics or who are otherwise volume-depleted may be at greater risk [see Geriatric Use]. Discontinuation of Savella should be considered in patients with symptomatic hyponatremia. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls.

Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death. Abnormal Bleeding-SSRIs and SNRIs, including Savella, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anti-coagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding.

Bleeding events related to SSRIs and SNRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages. Patients should be cautioned about the risk of bleeding associated with the concomitant use of Savella and NSAIDs, aspirin, or other drugs that affect coagulation. Activation of Mania-No activation of mania or hypomania was reported in the clinical trials evaluating effects of Savella in patients with fibromyalgia. However those clinical trials excluded patients with current major depressive episode. Activation of mania and hypomania have been reported in patients with mood disorders who were treated with other similar drugs for major depressive disorder. As with these other agents, Savella should be used cautiously in patients with a history of mania. Patients with a History of Dysuria-Because of their noradrenergic effect, SNRIs including Savella, can affect urethral resistance and micturition. In the controlled fibromyalgia trials, dysuria occurred more frequently in patients treated with Savella (1%) than in placebo-treated patients (0.5%). Caution is advised in use of Savella in patients with a history of dysuria, notably in male patients with prostatic hypertrophy, prostatitis, and other lower urinary tract obstructive disorders. Male patients are more prone to genitourinary adverse effects, such as dysuria or urinary retention, and may experience testicular pain or ejaculation disorders. Controlled Narrow-Angle Glaucoma-Mydriasis has been reported in association with SNRIs and Savella; therefore, Savella should be used cautiously in patients with controlled narrow-angle glaucoma. Do not use Savella in patients with Uncontrolled Narrow-Angle Glaucoma [see Contraindications]. Concomitant Use with Alcohol-In clinical trials, more patients treated with Savella developed elevated transaminases than did placebo treated patients [see Warnings and Precautions]. Because it is possible that milnacipran may aggravate pre-existing liver disease, Savella should not be prescribed to patients with substantial alcohol use or evidence of chronic liver disease.

ADVERSE REACTIONS: Clinical Trial Data Sources-Savella was evaluated in three double-blind placebo-controlled trials involving 2209 fibromyalgia patients (1557 patients treated with Savella and 652 patients treated with placebo) for a treatment period up to 29 weeks. The stated frequencies of adverse reactions represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse reaction of the type listed. A reaction was considered treatment emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse Reactions Leading to DiscontinuationIn placebo-controlled trials in patients with fibromyalgia, 23% of patients treated with Savella 100 mg/day, 26% of patients treated with Savella 200 mg/day discontinued prematurely due to adverse reactions, compared to 12% of patients treated with placebo. The adverse reactions that led to withdrawal in ≥ 1% of patients in the Savella treatment group and with an incidence rate greater than that in the placebo treatment group were nausea (milnacipran 6%, placebo 1%), palpitations (milnacipran 3%, placebo 1%), headache (milnacipran 2%, placebo 0%), constipation (milnacipran 1%, placebo 0%), heart rate increased (milnacipran 1%, placebo 0%), hyperhidrosis (milnacipran 1%, placebo 0%), vomiting (milnacipran 1%, placebo 0%), and dizziness (milnacipran 1% and placebo 0.5%). Discontinuation due to adverse reactions was generally more common among patients treated with Savella 200 mg/day compared to Savella 100 mg/day. Most Common Adverse Reactions-In the placebocontrolled fibromyalgia patient trials the most frequently occurring adverse reaction in clinical trials was nausea. The most common adverse reactions (incidence ≥ 5% and twice placebo) in patients treated with Savella were constipation, hot flush, hyperhidrosis, vomiting, palpitations, heart rate increased, dry mouth, and hypertension. Table 2 lists all adverse reactions that occurred in at least 2% of patients treated with Savella at either 100 or 200 mg/day and at an incidence greater than that of placebo.

Table 2. Treatment-Emergent Adverse Reaction Incidence in Placebo-Controlled Trials in Fibromyalgia Patients (Events Occurring in at Least 2% of All Savella-Treated Patients and Occurring More Frequently in Either Savella Treatment Group Than in the Placebo Treatment Group) System Organ Class– Savella Savella All Savella Placebo Preferred Term 100 mg/day 200 mg/day (n = 1557) % (n = 652) % (n = 623) % (n = 934) % Cardiac Disorders Palpitations 8 7 7 2 Tachycardia 3 2 2 1 Eye Disorders Vision blurred 1 2 2 1 Gastrointestinal Disorders Nausea 35 39 37 20 Constipation 16 15 16 4 Vomiting 6 7 7 2 Dry mouth 5 5 5 2 Abdominal pain 3 3 3 2

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Table 2. Treatment-Emergent Adverse Reaction Incidence in Placebo-Controlled Trials in Fibromyalgia Patients (Events Occurring in at Least 2% of All Savella-Treated Patients and Occurring More Frequently in Either Savella Treatment Group Than in the Placebo Treatment Group) (continued) System Organ Class– Savella Savella All Savella Placebo Preferred Term 100 mg/day 200 mg/day (n = 1557) % (n = 652) % (n = 623) % (n = 934) % General Disorders Chest pain 3 2 2 2 Chills 1 2 2 0 Chest discomfort 2 1 1 1 Infections Upper respiratory tract infection 7 6 6 6 Investigations Heart rate increased 5 6 6 1 Blood pressure increased 3 3 3 1 Metabolism and Nutrition Disorders Decreased appetite 1 2 2 0 Nervous System Disorders Headache 19 17 18 14 Dizziness 11 10 10 6 Migraine 6 4 5 3 Paresthesia 2 3 2 2 Tremor 2 2 2 1 Hypoesthesia 1 2 1 1 Tension headache 2 1 1 1 Psychiatric Disorders Insomnia 12 12 12 10 Anxiety 5 3 4 4 Respiratory Disorders Dyspnea 2 2 2 1 Skin Disorders Hyperhidrosis 8 9 9 2 Rash 3 4 3 2 Pruritus 3 2 2 2 Vascular Disorders Hot flush 11 12 12 2 Hypertension 7 4 5 2 Flushing 2 3 3 1 Weight Changes-In placebo-controlled fibromyalgia clinical trials, patients treated with Savella for up to 3 months experienced a mean weight loss of approximately 0.8 kg in both the Savella 100 mg/day and the Savella 200 mg/day treatment groups, compared with a mean weight loss of approximately 0.2 kg in placebo-treated patients. Genitourinary Adverse Reactions in Males-In the placebocontrolled fibromyalgia studies, the following treatment-emergent adverse reactions related to the genitourinary system were observed in at least 2% of male patients treated with Savella, and occurred at a rate greater than in placebo-treated male patients: dysuria, ejaculation disorder, erectile dysfunction, ejaculation failure, libido decreased, prostatitis, scrotal pain, testicular pain, testicular swelling, urinary hesitation, urinary retention, urethral pain, and urine flow decreased. Other Adverse Reactions Observed During Clinical Trials of Savella in Fibromyalgia-Following is a list of frequent (those occurring on one or more occasions in at least 1/100 patients) treatment-emergent adverse reactions reported from 1824 fibromyalgia patients treated with Savella for periods up to 68 weeks. The listing does not include those events already listed in Table 2, those events for which a drug cause was remote, those events which were so general as to be uninformative, and those events reported only once which did not have a substantial probability of being acutely life threatening. Adverse reactions are categorized by body system and listed in order of decreasing frequency. Adverse reactions of major clinical importance are described in the Warnings and Precautions section. Gastrointestinal Disorders – diarrhea, dyspepsia, gastroesophageal reflux disease, flatulence, abdominal distension; General Disorders – fatigue, peripheral edema, irritability, pyrexia; Infections – urinary tract infection, cystitis; Injury, Poisoning, and Procedural Complications – contusion, fall; Investigations – weight decreased or increased; Metabolism and Nutrition Disorders – hypercholesterolemia; Nervous System Disorders – somnolence, dysgeusia; Psychiatric Disorders – depression, stress; Skin Disorders – night sweats Postmarketing Spontaneous Reports-The following additional adverse reactions have been identified from spontaneous reports of Savella received worldwide. These adverse reactions have been chosen for inclusion because of a combination of seriousness, frequency of reporting, or potential causal connection to Savella. However, because these adverse reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events include: Blood and Lymphatic System Disorders – leukopenia, neutropenia, thrombocytopenia; Cardiac Disorders – supraventricular tachycardia; Eye Disorders – accommodation disorder; Endocrine Disorders – hyperprolactinemia; Hepatobiliary Disorders – hepatitis; Metabolism and Nutrition Disorders – anorexia, hyponatremia; Musculoskeletal and Connective Tissue Disorders – rhabdomyolysis; Nervous System Disorders – convulsions (including grand mal), loss of consciousness, neuroleptic malignant syndrome, Parkinsonism, serotonin syndrome; Psychiatric Disorders – delirium, hallucination; Renal and Urinary Disorders – acute renal failure; Reproductive System and Breast Disorders – galactorrhea; Skin Disorders – erythema multiforme, Stevens Johnson syndrome; Vascular Disorders – hypertensive crisis DRUG INTERACTIONS: Milnacipran undergoes minimal CYP450 related metabolism, with the majority of the dose excreted unchanged in urine (55%), and has a low binding to plasma proteins (13%).

In vitro and in vivo studies showed that Savella is unlikely to be involved in clinically significant pharmacokinetic drug interactions [see Pharmacokinetics in Special Populations]. Clinically Important Interactions with Other Drugs-Lithium: Serotonin syndrome may occur when lithium is co-administered with Savella and with other drugs that impair metabolism of serotonin [see Warnings and Precautions – Serotonin Syndrome]. Epinephrine and norepinephrine: Savella inhibits the reuptake of norepinephrine. Therefore concomitant use of Savella with epinephrine and norepinephrine may be associated with paroxysmal hypertension and possible arrhythmia [see Warnings and Precautions – Effects on Blood Pressure and Effects on Heart Rate] Serotonergic Drugs: Coadministration of Savella with other inhibitors of serotonin re-uptake may result in hypertension and coronary artery vasoconstriction, through additive serotonergic effects [see Warnings and Precautions]. Digoxin: Use of Savella concomitantly with digoxin may be associated with potentiation

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of adverse hemodynamic effects. Postural hypotension and tachycardia have been reported in combination therapy with intravenously administered digoxin (1 mg). Co-administration of Savella and intravenous digoxin should be avoided [see Warnings and Precautions] Clonidine: Because Savella inhibits norepinephrine reuptake, co-administration with clonidine may inhibit clonidineâ&#x20AC;&#x2122;s anti-hypertensive effect. Clomipramine: In a drug-drug interaction study, an increase in euphoria and postural hypotension was observed in patients who switched from clomipramine to Savella. CNS-active drugs: Given the primary CNS effects of Savella, caution should be used when it is taken in combination with other centrally acting drugs, including those with a similar mechanism of action. Monoamine Oxidase Inhibitors (MAOIs): [see Contraindications].

USE IN SPECIFIC POPULATIONS: Pregnancy-Pregnancy Category C. Milnacipran increased the incidence of dead fetuses in utero in rats at doses of 5 mg/kg/day (0.25 times the MRHD on a mg/m2 basis).

Administration of milnacipran to mice and rabbits during the period of organogenesis did not result in embryotoxicity or teratogenicity at doses up to 125 mg/kg/day in mice (3 times the maximum recommended human dose [MRHD] of 200 mg/day on a mg/m2 basis) and up to 60 mg/kg/day in rabbits (6 times the MRHD of 200 mg/day on a mg m2 basis). In rabbits, the incidence of the skeletal variation, extra single rib, was increased following administration of milnacipran at 15 mg/kg/day during the period of organogenesis. There are no adequate and well-controlled studies in pregnant women. Savella should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nonteratogenic Effects; Neonates exposed to dual reuptake inhibitors of serotonin and norepinephrine, or selective serotonin reuptake inhibitors late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying.

These features are consistent with either a direct toxic effect of these classes of drugs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome [see Warnings and Precautions]. In rats, a decrease in pup body weight and viability on postpartum day 4 were observed when milnacipran, at a dose of 5 mg/kg/day (approximately 0.2 times the MRHD on a mg/m2 basis), was administered orally to rats during late gestation. The no-effect dose for maternal and offspring toxicity was 2.5 mg/kg/day (approximately 0.1 times the MRHD on a mg/m2 basis). Labor and Delivery-The effect of milnacipran on labor and delivery is unknown. The use of Savella during labor and delivery is not recommended. Nursing Mothers-There are no adequate and well-controlled studies in nursing mothers. It is not known if milnacipran is excreted in human milk. Studies in animals have shown that milnacipran or its metabolites are excreted in breast milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from milnacipran, a decision should be made whether to discontinue the drug, taking into account the importance of the drug to the mother. Because the safety of Savella in infants is not known, nursing while on Savella is not recommended. Pediatric Use-Safety and effectiveness of Savella in a fibromyalgia pediatric population below the age of 17 have not been established [see Box Warning and Warnings and Precautions]. The use of Savella is not recommended in pediatric patients. Geriatric Use-In controlled clinical studies of Savella, 402 patients were 60 years or older, and no overall differences in safety and efficacy were observed between these patients and younger patients. In view of the predominant excretion of unchanged milnacipran via kidneys and the expected decrease in renal function with age renal function should be considered prior to use of Savella in the elderly [see Dosage and Administration]. SNRIs, SSRIs, and Savella, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event [see Warnings and Precautions].

DRUG ABUSE AND DEPENDENCE: Controlled Substance-Milnacipran is not a controlled substance.

Abuse-Milnacipran did not produce behavioral signs indicative of abuse potential in animal or human studies. Dependence-Milnacipran produces physical dependence, as evidenced by the emergence of withdrawal symptoms following drug discontinuation, similar to other SNRIs and SSRIs. These withdrawal symptoms can be severe. Thus, Savella should be tapered and not abruptly discontinued after extended use [see Discontinuation of Treatment with Savella].

OVERDOSAGE: There is limited clinical experience with Savella overdose in humans. In clinical trials, cases of acute ingestions up to 1000 mg, alone or in combination with other drugs, were reported with none being fatal. In postmarketing experience, fatal outcomes have been reported for acute overdoses primarily involving multiple drugs but also with Savella only. The most common signs and symptoms included increased blood pressure, cardio-respiratory arrest, changes in the level of consciousness (ranging from somnolence to coma), confusional state, dizziness, and increased hepatic enzymes.

Management of Overdose-There is no specific antidote to Savella, but if serotonin syndrome ensues, specific treatment (such as with cyproheptadine and/or temperature control) may be considered. In case of acute overdose, treatment should consist of those general measures employed in the management of overdose with any drug. An adequate airway, oxygenation, and ventilation should be assured and cardiac rhythm and vital signs should be monitored. Induction of emesis is not recommended.

Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion or in symptomatic patients. Because there is no specific antidote for Savella, symptomatic care and treatment with gastric lavage and activated charcoal should be considered as soon as possible for patients who experience a Savella overdose. Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be beneficial. In managing overdose, the possibility of multiple drug involvement should be considered. The physician should consider contacting a poison control center for additional information on the treatment of any overdose. Telephone numbers for certified poison control centers are listed in the Physiciansâ&#x20AC;&#x2122; Desk Reference (PDR).

Manufactured for: Forest Pharmaceuticals, Inc.

Manufactured by: Forest Laboratories, Inc.

Licensed from Pierre Fabre Medicament and Cypress Bioscience, Inc. Revised: April 2009

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COMMENTARY

The View from Washington: Healthcare Reform John Gorman, Chief Executive Officer, Gorman Health Group

B

y mid-June, the shapes in the fog have been emerging in the Senate Healthcare Reform proposals.

The stakeholder coalition of providers, insurers, consumers, and employers that were all on stage at the White House “photo op” is starting to fray. One after the other, the list of “must haves” is spooling out. With partisan tensions high and interest group organizing mounting, the art of compromise is going to be very difficult on this massive bill. President Obama is directly engaged in the process, saying that reform is central to the economic recovery, as it will affect one-sixth of the federal budget and 1 of 10 jobs in the US economy.

How Much Reform?

The question everyone is asking is, “Will healthcare reform be enacted?” It must, and it will. The real question is how much reform and coverage of the uninsured we will get.

By the third week of June, the Senate Committee on Health, Education, Labor, and Pensions proposal—still thin in its details—was dealt a blow in Congressional Budget Office (CBO) scoring of $1.3 trillion, to only cover 16 million to 19 million of the 46 million uninsured Americans. The US Senate Finance Committee went back to the drawing board, postponing a markup until after the July 4 holiday, and slowing the momentum of the effort.

Some form of healthcare reform legislation will pass in 2009. The new administration and the Democratic majority in Congress have placed too high a priority on getting a bill done this year to fail to act.

The president has set aside a reserve fund of more than $900 billion that involves large cuts to Medicare and Medicaid payments, which can be used to fund some form of coverage expansion. Tax reform offers another payment option. The president opposed tax changes during the campaign but has softened his opposition in view of the increasing cost estimates for comprehensive healthcare reform and the large amount of tax dollars that could be available by capping or repealing the deduction for employer-provided healthcare benefits.

And as a last resort, the budget resolution includes a fallback option that could use a budget reconciliation

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process requiring only a majority vote in Congress to reduce the ranks of the uninsured.

One issue complicating the healthcare reform effort is the proposal for a public plan option. The White House is trying to calm the fears of the insurance and the pharmaceutical industries, who are concerned that a public plan will have a competitive edge to attract large enrollments, by paying providers discounted rates (eg, Medicare fee schedules) and operating at lower administrative costs, without the need to market its products or to generate a profit. In addition, both industries fear that large enrollment in a public plan would enable the government to negotiate substantial discounts on drug prices.

A number of compromises are being discussed, such as setting a “trigger” for the public plan, not unlike the fallback plan originally contemplated for Medicare Part D. Other options include regional cooperative plans run by members rather than by the government, or plans run by states and meet the same solvency requirements and pay providers the same as private-sector plans. We do not view a public plan as an essential part of healthcare reform, and we expect that there will be a solution that few will be happy with.

Medicare Part D Issues The discussion of a public plan has temporarily taken the heat off 2 Medicare Part D issues that were discussed in the last Congress—(1) closing the Medicare Part D coverage gap, and (2) providing the government with authority to negotiate the price of Part D drugs. Closing the Part D coverage gap seems like a dream, with a price tag of $134 billion over 10 years, but the US House of Representatives has included it on their healthcare reform list.

The broader public plan issue in the overall healthcare reform debate seems to have replaced the discussion on a government-run Part D plan. Since CBO scored no savings for a Part D government negotiating authority last time, the Democrats have been discussing several other ways to reduce Part D costs, including ensuring that Medicare Part D pays no more than Medicaid for drugs for beneficiaries eligible for Medicare and

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PhRMA’s Surprise Move In a surprise move, the Pharmaceutical Research and Manufacturers of America (PhRMA) just announced that its member companies would voluntarily provide a 50% discount to most beneficiaries using brand-name drugs purchased during the Medicare Part D coverage gap. In addition, the full cost of these drugs, without discounts, would be counted toward the beneficiary’s out-of-pocket spending cap, thus further reducing beneficiary costs. Although the PhRMA proposal may not produce as many savings as CBO scored for extending the Medicaid rebate throughout the Medicare Part D benefit ($143 billion over 10 years), this may present a win-win compromise.

Means-Testing Premium Another Medicare issue that is expected to pass is means testing of the Medicare Part D premium. This proposal was included in the president’s 2010 budget and is supported by Democrats and by Republicans. Congress has already enacted a means-tested premium for Medicare Part B. Under this proposal, Congress would be expected to use the same premium formula currently used for Medicare Part B, which includes adjustments for inflation. For example, beneficiaries who have income of more than $213,000 would pay a Part D premium of 80% of Part D’s projected per-capita costs. If the formula does not adjust for inflation, more Medicare beneficiaries would be affected, and the 10-year savings will be $10 billion. The CBO estimates that approximately 6% of Medicare beneficiaries would be affected, and that about 1% of beneficiaries would decline to enroll or delay enrollment in Medicare.

Medicare Advantage One issue on which everyone seems to agree is the inevitability of Medicare Advantage (MA) plan payment cuts. There are 2 major proposals on the table—a competitive-bidding approach that was included in the president’s budget, and a modification of the current administrative pricing formula. The goal is to reduce MA payments to 100% of Medicare fee-for-service levels over several years. The cuts range from $159 billion for competitive bidding over 10 years to $79 billion for a gradual phase-down. One proposal would provide bonus payments to plans that implement care coordination programs and quality improvement mechanisms. We expect that the competitive-bidding option, which CBO estimates will cut MA enrollment by 30%, will be perceived as too draconian and too problematic to administer, so that Congress will adopt a more moderate plan, such as a phased reduction to parity, which will allow efficient MA plans to remain in markets where they can compete with fee-for-service and Medigap.

It is important to remember that the strengths of the MA program are the cornerstones of reforming the Medicare fee-for-service program, and even as the building blocks of healthcare reform; these include: • Coordinated care • Quality improvement programs • Chronic care management • Capitated payment.

All these functions will receive greater regulatory attention, regardless of the outcome on Capitol Hill, and will provide a framework for regulating a reformed commercial market in a health insurance exchange.

Physician Fee Schedule The final overarching Medicare issue on the table is to find a permanent fix for the Medicare physician payment fee schedule. Under the sustainable growth rate formula, if total Medicare payment to physicians does not meet certain targets, then fee schedules need to be reduced. Last year, Congress was able to find the funds to avert a 10% cut in physician payments, but next year the cuts are scheduled to reach 21%. The cost of this fix is very high, estimated at $318 billion over 10 years to freeze physician payment and $556 billion to provide an annual update.

These costs are substantially higher than the worst case scenario for MA payment cuts. But Congress does not want to revisit this issue every year, and it has created a backlash in the physician community, with physicians starting to turn away Medicare beneficiaries.

Fixing the Medicare fee schedule is essential for assuring provider support of healthcare reform.

The path to enactment is likely going to be decided by pay-as-go enforcers in the middle, including a handful of Republican Senate votes. This will inherently limit the size of the package. The “pack psychology” here seems to be coalescing around a bill costing $1 trillion that would be paid for with cuts to other programs or providers. Public clamor for the issue seems stale, but the president is insistent, and the majority in Congress wants to deliver—for the legacy of Senator Ted Kennedy as much as for anyone else. At his core, President Obama is a pragmatist, and he will go as far to the left as he can to still win. So again, the question is how much reform we will get. It seems certain we will know this year. ■

Medicaid, or providing Medicare Part D with the same minimum rebate—of 15%—as Medicaid for brandname drugs.

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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 â&#x2030;Ľ1% 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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Applying Evidence for Medical Technologies: Closing the Gap between R&D and Decision Maker Needs Interview with Sean R. Tunis, MD, MSc In this interview, Dr Sean Tunis, former Director of the Office of Clinical Standards and Quality and Chief Medical Officer at the Centers for Medicare & Medicaid Services, and current Director of the Center for Medical Technology Policy, discusses the need to align the demands of the industry on product development with provider and patient needs to ensure that products in the pipeline, especially those for chronic disease care, can actually provide clinical benefit. The question is how to make sure that new products and technologies are not only being approved by regulatory bodies but also serve real-world needs. This will also promote the acceptance of a product or service by all stakeholders—regulators, providers, payers, and purchasers—while meeting actual patient needs. Another question for payers and employers is how to create a benefit design that encourages the application of evidence in coverage decision-making toward value-based healthcare. [AHDB. 2009;2(4):157-163.]

Robert Henry: Our goal is to draw on your current position at the Center for Medical Technology Policy (CMTP), as well as your previous experience at the Centers for Medicare & Medicaid Services (CMS), to discuss private payer initiatives for medical technologies research and development (R&D) and the role of evidence in developing new technologies.

Sean R. Tunis, MD, MSc: Let me begin by saying that CMTP is a nonprofit organization that began in 2006 with grants from the California Healthcare Foundation and Blue Shield California Foundation, as well as some funding from the Commonwealth Fund.

The goal was to create a platform that allows different stakeholders to address the lack of good qualitative evidence for many medical technologies, including existing and emerging technologies, and its impact on policy. By medical technologies I mean drugs, medical devices, procedures, and interventions—especially interventions in a chronic care setting.

The broad question for CMTP was how to bring people together to understand why there are such systematDr Tunis is Director of the Center for Medical Technology Policy, and former Director of the Office of Clinical Standards and Quality and Chief Medical Officer, Centers for Medicare & Medicaid Services. He can be reached at sean.tunis@cmtpnet.org.

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ic gaps in the evidence for emerging medical technologies. This was based on my experience as the person in charge of clinical policy for Medicare at CMS, having spent 5 years trying to make policy decisions more explicitly evidence-based. At CMS, no matter what technology we looked at, we always concluded that the evidence was not as good as we would wish for, often leading policymakers to conclude that the evidence is inadequate and request that more trials be done. CMTP was set up to explore why policymakers never have the evidence that they want.

Henry: Do you connect this effort to benefit design?

Tunis: In terms of benefit design, my interest is in designs that encourage the development of evidence concerning the effectiveness of clinical services. The work we did at CMS, and our focus on coverage with evidence development (CED), was an effort to use benefit design as a tool for improving the quality of evidence around specific clinical services and technologies.

CED means that the drug or device will only be reimbursed under the condition that patients participate in a properly designed study. There has been a lot of effort to articulate the legal foundation for CED and to be more specific about the types of studies that would be eligible for reimbursement under CED. Medicare has done much work trying to integrate the clinical trials

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KEY POINTS

As the person in charge of clinical policy for Medicare at CMS, Dr Tunis spent 5 years trying to make policy decisions more explicitly evidencebased.

He continues this effort at the Center for Medical Technology Policy, by creating a platform that will allow different stakeholders to focus on how the lack of good evidence for many existing and emerging medical technologies affects policy decisions.

Dr Tunis stresses it is crucial to align the efforts of those involved in research and development of medical products with the needs of patients and clinicians in the real world.

CMS’s experience shows that the evidence for any new product is usually inadequate, often leading policymakers to request more trials before policy decisions can be made.

“Coverage with evidence development” programs allow for benefit design to be used as a tool for improving the quality of evidence around a specific clinical service/technology.

In the world of evidence-based decision-making, whoever controls the evidence controls the coverage decision.

chasers. The contract language would allow payers to apply it across the board of therapeutic areas, but CMTP is also developing specifications for what type of clinical services and what kind of studies would be eligible.

The point of the project is to first think about what kind of contract language would be necessary to allow health plans to do CED when they want to, but also to develop the specifications for under what conditions, in what type of studies, and for what kind of services with the user. For now, the project is not intended to be specific about which clinical services or technologies it would be applied to.

This latest initiative grew out of the regulatory framework that Medicare had developed for CED, based on their reasonable and necessary language. But it became clear that it is not sufficient to have only Medicare doing CED. Many CED questions address populations beyond the Medicare population. At CMTP, we felt it would be worthwhile to explore how to create a legal construct in the contract language that would allow private payers to do CED under the right circumstances. At the payer level, those involved in CED would include the medical directors, the pharmacy directors, and Pharmacy and Therapeutics Committee members—the people who currently do coverage policy, pharmacy, and therapeutics.

Henry: How long has this initiative been in process?

policy with CED to have a coherent, broad approach to subsidizing clinical research. CMS had meetings with the Medicare Payment Advisory Commission to discuss the research priorities that might inform when Medicare would apply CED. There have been new coverage decisions based on Medicare’s CED proposals. The most recent decision was about continuous positive airway pressure devices for treating obstructive sleep apnea, where for certain uses, it would be paid for only in the context of clinical trials, and the coverage decision articulates a fairly detailed list of criteria or what sort of studies would be eligible.

Medicare is also extending coverage under the CED paradigm for the assist device for artificial hearts. So, CMS is using CED with some degree of frequency, and there is much evidence that Medicare (and the Department of Health and Human Services more broadly) is committed to continuing the efforts to figure out how best to use CED as a tool to generate better evidence.

CMTP is aiming to replicate these efforts in the private sector; it is collaborating with several large payers and purchasers on a specific project to develop potential CED contract language for private payers and pur-

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Tunis: It started about one and a half years ago. Last year we had a meeting in Washington, DC, that included participants from Aetna, UnitedHealthcare, Blue Shield of California, National Business Group on Health, and General Electric Healthcare. We also had some patient representatives, including the Service Employees International Union. There was a lot of enthusiasm for the notion of developing a contractual framework for reimbursements for services that are limited to participation in clinical studies as a way of developing evidence for promising, but unproved, technologies and services.

Henry: What are the most promising areas that have an insufficient body of evidence?

Tunis: One area is proton beam therapy for prostate cancer. Others are new imaging technologies, such as positron-emitting tomography scanners, new applications for high-resolution computed tomography (CT) scanning, molecular diagnostic tests, gene expression tests for guided cancer therapy, minimally invasive sur-

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geries for, say, weight reduction, or any minimally invasive variation of an existing surgical procedure. Another area is the next generation of pharmaceuticals, for example, biologic versions for existing drugs for clinical categories where alternative pharmacy interventions are available (eg, osteoporosis, rheumatoid arthritis, or oncology). These next-generation technologies may have benefits over existing therapies, but there often is limited evidence on the true comparative risks and benefits involved.

Henry: Is what you are doing at CMTP going to have an impact on coverage for off-label use, say, in cancer therapy?

Tunis: There may be important clinical benefits to an off-label use of an approved product, but it is unlikely that new indications would receive US Food and Drug Administration (FDA) approval in the near-term. Some of those off-label uses could actually be paid for in the context of clinical trials under a CED initiative.

Henry: Would that generate sufficient evidence to perhaps reconcile the gap between approved indications and those listed in clinical practice guidelines?

Tunis: Yes. Our initiative at CMTP is still in the stage of developing an agenda and priorities. I would agree that this involves the questions that are important particularly to payers, patients, and clinicians—developing the information that they need to provide better care. We are trying to create a forum within which that research agenda becomes a high priority, and push a clinical and health services research agenda that is more reflective of the information needs of decision makers.

Henry: Are providers going to hear about what you are doing, or is this primarily directed at payers and purchasers?

Tunis: CMTP is equally designed to serve payers, providers, and patients—these are the subgroups of decision makers for whom we wish to generate reliable evidence. As such, we have to ascertain their most important questions, areas in which they need evidence that they don’t currently have. The point about the impact of compliance with guidelines on patient outcomes is a good example of a category of questions that are insufficiently addressed in the current research paradigm.

Henry: How did the concept for this project evolve?

Tunis: We had a small work group of about 20 people

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who were talking about creating “model benefit” parameters for CED. We were not focused on any specific question but were trying to identify what the important unanswered questions were within that particular project. I was focused on the broader notion of creating an analogy to the Medicare CED framework, and how would we set that up for private payers and purchasers.

Henry: Could you explore the issues of CED a bit more?

Tunis: A good example of a promising but unproved medical technology is coronary CT angiography, which is an initial diagnostic test for patients with chest pain.

There is a debate about whether the evidence is adequate for that to be paid for, and whether enough is known about that particular technology. Last year Medicare issued a decision saying that the evidence was not adequate, but all of its contractors had been paying for that test already. This is one example of where CMS believed the evidence was not adequate, but it could not do anything, because its contractors were already paying.

Most private health plans that have to make a decision about coronary CT angiography have got to decide whether it is a medically necessary technology or it is an investigational technology—those are their 2 choices.

We want to create a third choice, which is the category of “promising but unproved” technologies. This would allow us to determine how the test influences patient outcomes; the plans would pay for it, but only for patients who are enrolled in a large clinical study that will provide more evidence to that end.

Henry: What you are doing is helping to provide a repository for these data?

Tunis: There is no policy framework currently that allows health plans to collect evidence; benefit language says that a new service or a product is either investigational or it is medically necessary. There is no policy language in any benefit contract that says that the plan will pay for things that are promising, under the condition that data collection will be accompanying the provision of the service.

Henry: So, you are trying to construct a benefit design that allows reimbursement for promising technologies in the context of a study that will determine the degree to which they are clinically effective. How are you eliciting the input of the patients?

Tunis: For every one of our work groups and every

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project that CMTP does, we have at least 2 and sometimes 3 patient/consumer citizen representatives. They are on every work group; no matter how technical the issue is, we make sure we have them there, and as we develop the governance structure for CMTP, we are also in the process of developing our board of directors and our advisory structure to include patient and consumer representatives.

Tunis: No, we are being ad hoc about it. Obviously, there tend to be the major diseases, such as cancer or heart disease, but we probably have to be more thoughtful about making sure that we also represent less common illnesses.

Tunis: There are a number of answers. We have all the major potential users of the research involved up front in helping us to design studies, select topics, and so on. We are engaging the decision makersâ&#x20AC;&#x201D;the payers, the providers, and patientsâ&#x20AC;&#x201D;in figuring out not only which questions to ask, but also how to design the studies. And by virtue that the studies are designed from the beginning to answer the questions that are important to decision makers, there is presumably a greater chance that the results will later influence their decision-making.

Part of our work on a standard for medical technology policy is built around the assumption that there is a great need for dialogue across the different stakeholders regarding what are the evidence needs versus what type of evidence is conventionally being produced, and that better dialogue would change the nature of postmarket research.

Listening to the arguments on comparative effectiveness research, I wonder what it is that people think a National Center for Comparative Effectiveness would actually do. That is, what kind of questions would it answer, with what kind of methods? And defining those questions seems to be the hard part, yet nobody is giving much thought to that. As such, we need to be facilitating a dialogue with various stakeholders, not just payers but also product developers, clinicians, and patients.

Many of the reasons why clinical research, health services research, and other research done in healthcare does not help decision makers are because they were never involved in the beginning. Decision makers do not regularly weigh in on determining whether a study was designed to answer an important question. So a big part of making sure that there is an impact in short-term practice is to ensure that the consumers of the information are actually involved in designing the research in the first place.

Henry: Is your focus primarily on chronic diseases or is it split between chronic and acute conditions?

Henry: Are there examples that perhaps would serve as an illustration of the way this ought to be done?

Tunis: We focus on the major causes of morbidity and mortalityâ&#x20AC;&#x201D;cancer, heart disease, joint disease. As the organization matures, presumably our patient and consumer advisory committee will provide us feedback on how to most effectively focus on various disease areas, chronic disease versus acute illness, and so on.

Tunis: The prototype for CED done by Medicare was the National Emphysema Treatment Trial (January 1998 through July 2002) that investigated the efficacy of lung volume reduction surgery for patients with severe emphysema. It was a collaboration between Medicare and the National Heart, Lung, and Blood

Listening to the arguments on comparative effectiveness research, I wonder what it is that people think a National Center for Comparative Effectiveness would actually do.

That is, what kind of questions would it answer, with what kind of methods?

First, the majority of the board of directors of CMTP is going to be patients and providers. We are going to make sure that the agenda and the structure and all our activities are built around the needs of clinicians, providers, and patients, and that will be built into our governance structure. Second, we are going to have an advisory group, or a steering group, that is separate from the board of directors and is filled exclusively with patient and consumer representatives.

The job of that advisory group will be to continually monitor all our projects and activities, as well as our funding mechanisms, to make sure that ultimately our organization is serving the information needs of patients and providers.

Henry: Are these divided across specific disease states?

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Henry: And how will the research results get transmitted back to decision makers (payers and purchasers) in terms of benefit design and device/drug utilization?

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Institute. It had been determined that this surgical procedure was potentially very important for emphysema â&#x20AC;&#x201D;a common cause of morbidity and mortality. The surgical procedures were done in the context of the trial; the results showed that there was little or no benefit with this surgery for most patients, so this surgery is no longer performed today. It was a good example of a procedure that may well have been abandoned eventually, over a long period of experience, but that would probably have also been a long period during which many patients were undergoing a surgery that could have killed many of them.

Another example is the bone marrow transplant for patients with breast cancer. Again, thanks to a collaboration between the National Institutes of Health and the Blue Cross Blue Shield Association of Insurers, a large study was done for that procedure, which was becoming widely popular, because it was very profitable for cancer centers to be doing bone marrow transplants for breast cancer patients. And that too was killing patients, which was only discovered after dozens of states put in legislative mandates that it must be covered by all payers.

If we could potentially create a policy framework that allows for CED as in the case of bone marrow transplant for breast cancer patients, and it becomes a well-defined policy pathway, we could potentially get the legislators out of the business of mandating benefits that have not yet been adequately studied, because payers would have a policy tool that was appropriate for that circumstance. But nobody has tried to create a generalized policy framework for private payers to do this in an organized way.

Henry: Could you briefly discuss how this relates to evidence-based medicine, including randomized versus observational trials and meta-analyses?

Tunis: We are interested in empirical data that provide information about the risks, benefits, and costs of technologies and services. Our scope of interest is mostly in prospective studies, particularly because we are interested in new and emerging clinical services and technologies for which there would not be a lot of data in existing databases that could be analyzed retrospectively.

So our focus tends to be on prospective observational or experimental studies, generally comparing an emerging technology or service to an existing alternative.

Henry: Could this be done from administrative databases, such as insurance claims databases or Medicare data?

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Tunis: Yes, the data could be collected from electronic medical records or it could be proactively collected from clinical trials, registries, and other types of prospective study mechanisms, depending on what are the appropriate data source and methodology to answer a particular question. It is our view that we need to have the conversations about â&#x20AC;&#x153;what is the appropriate methodâ&#x20AC;? before the study is done, because once the study is done, it is too late to go back and do it differently if the decision makers decide they need different information.

We are interested in empirical data that provide information about the risks, benefits, and costs of technologies and services.

For a particular surgical procedure or a disease management program, we want to have the conversations up front about what kind of study will be sufficiently robust for us to be able to make decisions about the procedure or program. If it is a randomized controlled trial (RCT), we have to stop wasting our time collecting observational data, and do an RCT. There are some things for which an RCT is the only sufficiently robust methodology, but that is not true for all questions.

But what happens too often (and I have participated in this many times at Medicare) is that the study has been done, it has been published, and then the argument ensues between the decision makers and the providers of the service about whether that evidence is sufficient. For the most part, our view is that we need a forum within which we can move that discussion up front, before we complete the protocol design.

Henry: Are you achieving success in getting that kind of consensus?

Tunis: We are achieving success in bringing people together to have that discussion. I would not say that we have been particularly successful in reaching consensus, but it is a step forward to recognize how difficult it will be.

A great example, again, is coronary CT angiography.

Within our multistakeholder work group, we had all the vendors (GE, Philips, Siemens, Toshiba); the American College of Cardiology and the American College of Radiology; and we had multiple payers. We also had clinical researchers, patients, and a technology for which there are important unanswered questions about how this affects patient health. We asked the following

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question: What kind of a study do we need to do? And there was a huge range of opinion—some thought we needed to do a large multirandomized trial to measure the impact of this diagnostic on death and acute myocardial infarction; at the other end of the spectrum, some said we already know enough about this technology that we could say that it was the most important clinical advancement in the past decade and it should just be reimbursed. That we did not have any common ground on that question has important implications for policy and for clinical care. But it is important to have a forum within which that discussion can continue, because these are the sorts of issues that will have to be addressed for the next technology. Without this type of dialogue, how would anybody know what kind of studies they need to do?

We need to include the product developers, the clinical researchers, and the patients, so that we have a coherent guidance on what is sufficient evidence.

Henry: What’s the impact of the FDA guidance documents?

Tunis: The FDA guidance documents articulate the FDA’s perspective on what kind of scientific evidence it is going to need to approve products in particular categories—asthma drugs, cardiac defibrillators, and others—and there are hundreds of these documents.

They are useful for product developers who can look at an FDA guidance document and have a how-to manual about designing their clinical studies in ways that are most likely to obtain regulatory approval. They know what the end points should be, what the patient inclusion criteria should be, and how long to follow patients.

And those guidance documents are developed through the iterative notice-and-comment process, so they reflect not only the FDA’s perspective but also the perspectives of all the necessary experts and stakeholders. CMTP has started to develop what we are calling “effectiveness guidance documents,” but CMTP’s point is to articulate the evidential requirements from the perspective of decision makers such as payers, providers, and patients, so that product developers and technology developers will be able to know what kind of evidence is going to be required for this to be accepted in the reimbursed marketplace and by patients.

We are going to replicate the FDA notice-and-com-

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ment process, so we will develop draft guidance documents and post them on our website (www.cmtpnet.org) for anybody to comment. For example, of the first 2 we are starting with, one is on wound healing, and there are zillions of companies that are developing wound-care products, devices, drugs, and others. You cannot go anywhere to find out what is it that the payers consider to be sufficient evidence of effectiveness for a wound-care product. What is the appropriate primary outcome for a study? How long do the patients need to be followed?

What sorts of patients should be enrolled in the study?

Which patients is it okay to exclude? All these are answerable questions, but we do not want to hear solely from payers, because they do not know enough about wound care to develop a guidance document independently. So we bring them together with clinicians, research methodologists, patients, and industry representatives to design an appropriate framework for a good research study to answer these questions.

Henry: Who should be included in the creation of these documents?

Tunis: We need to include the product developers, the clinical researchers, and the patients, so that we have a coherent guidance on what is sufficient evidence, not for purposes of regulatory approval (which is a different policy decision), but for purposes of clinical use and reimbursement.

Our second example is gene-expression profiling (GEP) for breast cancer. This type of genetic testing can determine who does and does not need chemotherapy for breast cancer. That guidance document will have broad applications to many types of gene-expression tests, but we are writing it to be specific to breast cancer.

We have contracted with researchers at Johns Hopkins, who recently did an evidence report on GEP for breast cancer. They reviewed the current literature on GEP for breast cancer, so they know what has been done well or poorly in clinical studies. We have asked them to complete a draft as if we were going to be providing guidance to a product developer who wants to develop a test in this area, recommending what kind of studies it should plan on doing that would be persuasive to payers, providers, and patients.

Henry: Are there any tools that could help those making the benefit design decisions?

Tunis: Everybody wants to move toward evidencebased decision-making, but our decisions are only as

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Applying Evidence for Medical Technologies

good as our evidence. And so our mantra, if you will, is that the decision makers have to be willing to get involved in the “creation” part of the evidence, not just the “use” part. Or as I like to say, in the world of evidence-based decision-making, whoever controls the evidence controls the decisions. CMTP is trying to provide a forum for decision makers to be actively engaged in that process.

We need a more clinically and scientifically sophisticated approach to respond to the fact that technology and new clinical services are driving increased spending.

The kinds of mechanisms and approaches we are proposing are effective at both promoting the rapid adop-

tion and use of high-value technologies and services and restricting the dissemination of new technologies that do not have much value. We are trying to sort out where there is value and make sure that the payers, the providers, and the patients have the information they need to rapidly adopt the technologies that really contribute to better health outcomes.

Disclosure Statement CMTP receives funding from Aetna, Amgen, Blue Shield of California Foundation, California Healthcare Foundation, The Commonwealth Fund, Johnson & Johnson, Kaiser, National Pharmaceutical Council, Pfizer, and United Healthcare Foundation. ■

STAKEHOLDER PERSPECTIVE Policy Considerations in Evidence-Based Coverage Decisions The idea of linking benefit design and evidencebased medicine or device utilization raises timely policy considerations for private and public health insurance programs. For employers and other payers, state insurance commissions and public health agency regulatory initiatives beyond the US Food and Drug Administration (FDA) approval or the Centers for Medicare & Medicaid Services (CMS) policy can pose obstacles in plan administration. These are in addition to growing concerns about patient out-ofpocket costs and whose interest is in mind when prescribing decisions are made.

The regulatory aspects around safety concerns that have led to requirements of postmarketing surveillance and REMS (Risk Evaluation and Mitigation Strategies) studies, as well as the increasing riskaverse environment at the FDA, add significant burdens for manufacturers, beyond marketing considerations. Given the current economic downturn and the concerns that underregulation or lack of oversight had contributed to this situation, product safety will likely remain a dominant issue, along with the economics of healthcare. This can be seen in President Obama not supporting tort reform, or in the top 2 FDA appointees citing public health and safety as current priorities.

Resulting doubts and perceptions further complicate the scientific-based initiatives that strive to promote evidence-based coverage decisions for FDA-

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approved or off-label drug uses. Utilizing real-world strategies can bridge the knowledge gaps related to effectiveness and safety of new products/devices. But alignment of interests of key stakeholders remains a challenge, as Dr Tunis describes in this interview, and as illustrated by the timely and much-needed efforts

by CMS and by the Center for Medical Technology Policy (CMTP).

Turf wars for support by patients and scientific battles among interest groups are common in healthcare.

Evolving stakeholder battles have elements of the medical history of scientific inquiry versus quackery, but these are overshadowed by severe economic issues, which stipulate that healthcare expenditures can no longer continue to grow. Legislative and regulatory interventions, in the absence of market change, coupled with the government’s increasing role in determining payment for healthcare products or services, have emerged as the mechanisms to facilitate change.

CMTP providing a forum for leading stakeholders, as Dr Tunis describes, is laudable, but the sorting out of value may come too late, or provide too little hope, to avoid federal government judgments.

F. Randy Vogenberg, RPh, PhD Chief Strategic Officer Employer-Based Pharmaceutical Strategies Sharon, MA

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American Roots. Global Reach.

For 48 years, the generic products from Mylan Pharmaceuticals have met the uncompromising standards established by Co-Founder Milan (Mike) Puskar.

His philosophy—“We either do it right or we don’t do it at all”—has helped Mylan become the largest U.S.-based manufacturer of generics by total prescriptions.* As patients’ demands for a wider array of generics have increased, Mylan has responded. Under the leadership of Chairman and CEO Robert J. Coury and COO Heather Bresch, Mylan now provides products to patients in more than 140 countries and territories.

As we have expanded, one constant has remained… the philosophy upon which our company was established. That’s why all Mylan generics will continue to offer the quality and affordability that patients need and the peace of mind that pharmacists have always counted on. *IMS National Prescription Audit. Total Prescriptions: June 2007 - June 2008. ©2009 Mylan Pharmaceuticals Inc. MYNMKT335

GENERIC DRUG TRENDS

Biosimilars Policy Forum: Perspectives on Safety and Efficacy of Future Products F. Randy Vogenberg, RPh, PhD Based on the Forum on Regulation of Follow-On Biologics: Ensuring Quality and Patient Safety that was held at the National Press Club in Washington, DC, in April 2009, to review current issues related to biosimilars legislation. The forum was sponsored by the Jefferson School of Population Health, with a grant support from sanofi-aventis.

T

hings change quickly on Capitol Hill, and these changes can affect the course of new legislation. The Forum on Regulation of Follow-On Biologics was convened to discuss the implications of the current discussion on biosimilars legislation. Keynote Speaker Michael McCaughan, Editor of The Pink Sheet, FDC/Windhover Biopharma Group, reviewed the options for biosimilars regulation, noting that the new US Food and Drug Administration (FDA) biosimilars pathway being discussed in Congress remains in a long queue of major legislation pieces. McCaughan highlighted the emerging need for a new business model for drug manufacturers of biosimilars and outlined the roles of Senate Finance Committee Chairman Max Baucus (D-MT), Senate Health, Education, Labor, and Pensions Committee Chairman Edward Kennedy (D-MA), and House Energy Committee Chairman Henry Waxman (D-CA) as key figures in this legislative process.

Drug manufacturers and drug regulation have moved from a focus on large populations with low risk to smaller population cohorts with higher risks. User fees and reduced government financing have raised questions about the FDA’s credibility and its independence from drug manufacturers. Drug and agricultural safety concerns have also increased, at a time when the United States has become more risk-averse.

Brian Harvey, MD, PhD, Vice President of Regulatory Policy, sanofi-aventis, reviewed the utilization of a comparative protocol strategy for a biosimilars regulation.

Gundu H. R. Rao, PhD, University of Minnesota, discussed World Trade Organization agreements and the impact of globalization of economic and marketing practices that will necessitate a global review and approval process for biosimilars.

Unlike the small-molecule generics, biosimilars are complete biologic products, presenting new issues. The European Medicine Agency, the World Health Organization, and other organizations worldwide require or are leaning toward requiring clinical equivalence test-

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ing, because biosimilars may be similar but are not identical to the original product. Even manufacturing batch or lot variation requires definition by clinical experience; laboratory testing alone is not sufficient.

Clinician perspectives on biosimilars focus on protecting public health and patient safety, arguing that it is essential that regulatory standards not be solely based on cost-comparisons.

Key legislative aide to Rep. Waxman, Ann Witt, reported intense lobbying and pressure from all sides in the biosimilars debate in Congress, highlighting the following points.

Inconsistencies toward biologics and biosimilars: • The cost of biologics is driving concerns about open access • What will the future of the US drug supply look like?

• Products must not be priced out of reach of patients • Regulation of simple proteins (human growth hormone, insulin) as drugs and other products as biologics.

Current bills in Congress focus on the safety and efficacy of biosimilars and the need for an approval process: • Emerging science should guide legislation to allow the FDA to decide on approval and interchangeability • Bill must encourage science and allow for future knowledge to be applied; scientists, not Congress, must make scientific decisions • Safe and effective drug is still key • Biosimilars will spur innovation: monopoly on pricing is not good for competition • Comparability concerns; some manufacturers agree to forgo repeating clinical trials for the biosimilar product • While the Waxman-Hatch Act is celebrating its 25th anniversary, Rep. Waxman wants to ensure a biosimilar bill works as well as the generic bill.

Avoid unnecessary procedural delays in process for biosimilars approval: • FDA does not write guidance in this early stage, when little is known about what works or does not.

Patent resolution should be handled quickly and effi-

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GENERIC DRUG TRENDS

ciently; need proper process to avoid legal delays.

Property protection—how much more intellectual property protection is needed versus patent protection: • European Union not comparative because of price control versus unregulated US prices • Need to extend patent protection if FDA approval is delayed, but not the same as exclusivity.

Professor Larry Kotlicoff of Boston University, a Teva Pharmaceuticals consultant, argued for a business need to recoup investment to allow for adequate profits along with competition in the marketplace.

Promoting a balanced approach to marketing exclusivity, he said that continuing monopoly protection of biologics far into the future may block discoveries that would improve public health and undermine sales.

Exclusivity, innovation, and patent protection should be balanced. Prolonged monopoly protection, noted Dr Kotlicoff, distorts consumer choice by maintaining artificially high prices. Reducing the costs of biologics limits their expenditure risk, but the question is whether we can increase economic efficiency. Biologics offer great promise for improving health and well-being, but how we ensure access for all Americans to these medications at affordable prices, within a reasonable period from their discovery remains the business question for health policy legislation.

Geno Merli, MD, Thomas Jefferson University Hospital, addressed the unintended consequences of interchangeability. He listed a clinician’s concerns in determining whether a biosimilar would be appropriate for a specific patient: 1. Which disease is being treated 2. Safety considerations for the specific product 3. Use current generics that are safe and effective or expand use to include biosimilars 4. Because of the nature of biologics, there is wide variation in their components, which include proteins, polysaccharides, glycosylated proteins, polynucleotides; these may also trigger the release of antibodies 5. The 2007-2008 heparin contamination illustrates some of the risks with biologic manufacturing/ products, because of the different methods of preparation and ingredient supply chains 6. Immunogenicity of biosimilars remains difficult to detect and measure; clinicians cannot compare disparate published studies regarding this important safety concern on biologics or biosimilars.

Faculty Panel Discussion Judith K. Jones, MD, PhD, Degge Group, addressed the many challenges in assessing the safety of biologics

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and biosimilars that also relate to their approval or monitoring, such as the lack of direct relationship to pharmacokinetics; pharmacoepidemiology methods used for drugs are not always applicable; and measuring exposure, dosing.

Finally, F. Randy Vogenberg, RPh, PhD, Biologic Finance and Access Council, expanded on the theme of unintended consequences, establishing that medications are part of managing risk—the health risk continuum of people from an economic and a clinical perspective. Specifically, 2 key issues around managing risk are (1) financing and insurance underwriting; and (2) benefit design.

In less than 7 years, biologics grew from 1% in 2000 to about 4% to 10% of pharmacy benefit drug spending in 2007. Claim spending for biologics is 4 to 10 times greater than for traditional, small-molecule drug coverage or on average 22 times higher cost per daily dose.

Managed care experts expect that biosimilars will offer a smaller percent discount, because of manufacturing costs and reduced competition compared with traditional generics.

In 2008, specialty pharmacy spending was about 14% of total pharmacy cost, and this trend continues. In Medicare Part D, 90% of beneficiaries who use a specialty product hit the doughnut hole from various cost-sharing payments (copay, coinsurance, and deductible), with an average out-of-pocket expense of 12%.

Insurance modeling for financial risk management goes beyond patent and regulation discussions. In practice, drugs in the same therapeutic category with equivalent outcomes are considered therapeutically equivalent by the Centers for Medicare & Medicaid Services and by many other payers. Payers, for example, have established therapeutic equivalence for interferons, antibiotics, and growth hormones, but these are bandage approaches for an out-of-date insurance and benefit design marketplace.

Conclusion With the growth of biologics and diagnostics, we are moving into personalized medicine. Current insurance and benefit design will not accommodate branded or biosimilar biologics let alone individualized therapy.

There is a general agreement that good science must prevail in any biosimilars legislation, but the limits of science create gaps for the regulatory agencies, just as the economic recession is creating limits for business to fill needed gaps in our patient care armamentarium of biologic products. It is this uncertainty that is creating the worry of unintended consequences for Americans. ■

June/July 2009

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BUSINESS

The Working Patient with Cancer: Implications for Payers and Employers Grant D. Lawless, BSPharm, MD, FACP Cancer is seen today more often as a manageable chronic disease, resulting in changing workplace characteristics of the patient with cancer. A growing number of employees continue to work while being treated for cancer or return to work shortly after their cancer treatment is completed. To respond to these changes and the potential impact on the working patient’s attitude, employers need updated, factual information related to this patient population. This type of information will support future benefit considerations by employers on employee contributions and future employee health and productivity. In 2005, Amgen launched a 3-year initiative to better understand cancer as a chronic disease, as well as the impact on the working patient with cancer and on the employer. The data from this initiative described in this article provide insights into cancer as a chronic and manageable disease in the workforce, and the broader implications to payers and employers. [AHDB. 2009;2(4):168-173.]

A

dvances in the diagnosis and treatment of cancer in recent decades have dramatically improved the life expectancy, quality of life, and productivity of patients with cancer. Today, a growing number of employees remain in the workforce while they are being treated for cancer or return to work after their treatments are completed. Cancer is being seen as a chronic and manageable disease in the workforce, similar to diabetes or asthma. Henry and colleagues report that the most cited reasons why employees with cancer remain on the job either full-time or part-time are because they need to work, prefer to work, or feel well enough to work.1 In addition, working patients with cancer are taking on an increased burden for costs related to their cancer treatments through cost-shifting.2 In response to this costshifting environment and subsequent impact on employee cost burden and changing work patterns and productivity, it is imperative that employers and payers, like managed care organizations, work toward developing a better balance of benefit designs and employee contributions/copayments with employee health and productivity.

A 3-Year Collaborative Initiative In 2005, Amgen launched the Working Patient with Cancer (WPWC) initiative, which was a 3-year program that encompassed several studies, to gain a better understanding of the implications of cancer as a chronDr Lawless is Executive Director for Payor Relations, Corporate Accounts, Amgen Inc, Thousand Oaks, CA.

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ic and manageable disease in the active workforce, and the relevance of these implications for payers and employers. This was a collaboration among industry, employers, and payers and involved working with the RAND Corporation and Milliman, Inc; employers, including Coca-Cola and Kodak; and payers, including WellPoint and UnitedHealthcare.

The WPWC initiative was designed to create a clearer profile of the working patient with cancer, identify these patients within the workforce, better understand cancer as a chronic disease, and understand patients’ attitudes about working while receiving cancer treatment. The initiative also reviewed the healthcare spending trends of these working patients, as well as the pressures they encountered with care-related costshifting. Implementation of this initiative involved several key milestones, including: • Profiling the commercially insured working patient with cancer to better understand the impacts on productivity, relationships with coworkers, and how these resultant behaviors affected both employers and payers • Defining patients’ attitudes about working while receiving cancer treatments and understanding their motivations, behaviors, and needs • Measuring the changing workplace patterns of the working patient with cancer, including turnover, short-term and long-term disability, replacement worker costs, and the cost of goods and overhead • Demonstrating the connection between cancer treatment, cost-shifting to employees, and the changing forces driving cancer care costs.

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The Working Patient with Cancer

Employers need factual information to better balance benefit designs and employee contributions/ copayments with employee health and productivity.

If working patients with cancer are adequately supported, they can remain productive while receiving cancer treatment.

In recent years, out-of-pocket costs for health plan members increased more than 5 times faster than the cost of living.

Recent trends show changing workplace attitudes among employees with cancer. Breast cancer was the most common cancer in employees who continue to work while receiving cancer treatment: 56% of breast cancer patients remained with the same employer 5 years after their initial diagnosis; 34% remained with the same employer for 9 years.

Drug costs consistently represent 20% of the total costs across all cancer types. Costs are further increased when patients receive chemotherapy, or in the presence of 1 or more comorbidities.

Total cancer healthcare costs are greatest during the first year of cancer diagnosis and treatment.

Consequently, patient out-of-pocket costs are highest in that period.

Treating cancer patients who are working involves a continuum of interrelated direct costs—both medical and nonmedical. Included in the direct medical costs are medical testing, cancer treatment, and laboratory tests; included in the nonmedical costs are direct labor costs and replacement worker costs.

It is important to understand who high-utilizing patients are, increase awareness of their continued presence in the workforce, and create an appropriate benefit design that will have positive implications on better managing these patients. Thus, effective administrative management of the working patient with cancer, in addition to effective clinical management, should result in improved productivity and cost-savings to the payer and the employer.

Profile of the Working Patient with Cancer In the study conducted by Henry and colleagues, among employees younger than 65 years, 46% cited financial need as their primary reason for continuing to work while receiving chemotherapy or radiation therapy.1 Although financial need was the most frequently cited reason, other important reasons for continuing to work included maintaining momentum toward poten-

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A large portion of all healthcare spending is driven by identifiable subgroups

Total annualized health expenditures

Figure 1 “High-Cost Patient” Stratification: The Top 10%, by Claims Cost

Percentage of total healthcare costs

Maximum cost

Top 10% (determined by the representative plan population)

Top cluster

40%

2.5% (≥ $15,494)

of total

50% of total

Upper cluster 5% ($9713–$15,494)

60%

Lower cluster

of total

7.5% ($7312–$9713)

Bottom cluster 10% ($5876–$7312) All dollar amounts are based on paid claims Minimum cost

Source: HealthCore, 2002-2005 claims data set.

Figure 2 Annualized Health Expenditures: Impact, by Degree of Comorbidity Single-cancer type (n = 19,068) 70,000 60,000

Annual costs, $

KEY POINTS

Total cost Medical services Drug expenditures

n = 373 65,123 n = 1106 53,456

n = 3727 46,064

50,000 40,000

n = 13,862 31,559 30,000 24,444

54,421

43,669

37,243

20,000 10,000 0

77%

0

23%

81%

1

19%

10,702

9787

8821

7115

82%

18%

2

84%

16%

3+

Number of comorbiditiesa a Comorbidity combinations: All patients have only 1 cancer diagnosis. Patients with 2 or more conditions have a combination of 1 cancer condition with 1 or more of the following conditions: rheumatoid arthritis, multiple sclerosis, hepatitis C, chronic kidney disease, cerebrovascular accident, coronary artery disease, chronic obstructive pulmonary disease, diabetes, or asthma. (This excludes multicancer patients, n = 1726.)

Source: HealthCore, 2002-2005 claims data set.

tial advancement, being around coworkers and other people, and refusal to let cancer dominate their life or keep them from their routines.1 Analysis of HealthCore data showed that individuals in the top 10% of claim costs were responsible for 60% of all healthcare spending in the health plan (Figure 1).3 Furthermore, the top 2.5% of health plan members’ medical costs were responsible for 40% of the total health plan expenditures.3,4 Based upon this data set of commercially insured individuals (aged 18-65 years), 69% of patients with cancer were the primary employee, versus

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Figure 3 Medical Services and Drug-Cost Trends Complete history

Index year Total drug cost Total medical cost

40,000

30,000

30,947 ∆8.6%

50,000 43,214 ∆11.6%

48,233

33,615 ∆28.6%

20,000

10,000 8991

∆17.4%

10,557 ∆24.9%

13,188 ∆10.1% 14,518

Average cost during year (nominal), $

Average cost during year (nominal), $

50,000

Total drug cost Total medical cost

40,000

30,000

20,000

19,023 ∆1.9%

10,000 7249

∆14.2%

19,376 ∆1.9% 8276

∆1.2%

19,748

∆4.8%

20,701

8373

∆7.5%

8999

0

0 2003

2004

2005

∆x.x% indicates percent change over previous year.

2006

2003

2004

2005

2006

Source: HealthCore, 2002-2006 paid claims. Data on file.

the employee’s spouse or dependent. Breast cancer was the most common type of cancer in the study, affecting 49.7% of patients, followed by gastrointestinal (GI) cancer, affecting 20.8% of patients. The majority of patients (58%) were 51 to 64 years old; however, a relatively high percentage (39%) were in the 31 to 50 age-group.3 Drug costs for most cancer types studied, including costs for cancer treatment from inpatient and outpatient pharmacy claims, accounted for an estimated 21% of the total healthcare costs compared with 79% for other medical services. Medical service costs included non–drug-related costs, such as hospitalizations, office visits, and laboratory tests.3 In addition to the findings of higher medical service costs versus drug costs, there was a notable divergence in total expenditures for patients receiving chemotherapy versus patients not receiving chemotherapy.

Based on paid claims data from HealthCore for the period 2002-2005, the combined total annual cost for working patients undergoing chemotherapy (n = 7693) was approximately $76,000 compared with approximately $21,000 for patients not receiving chemotherapy (n = 3101).3 Secondary analysis identified that the presence of comorbid conditions also drove up costs. Based on annualized health expenditures for patients with a single cancer type (n = 19,068), both the total costs and the medical service expenditures increased with each additional comorbidity (Figure 2).3 Medical costs for patients with 3 or more comorbidities are more than twice the costs associated with patients with no comorbidities. These data demonstrated that drug costs increased slightly with each additional comorbidity, but medical services costs, and subsequently total costs,

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AMERICAN HEALTH & DRUG BENEFITS June/July 2009

increased at a far greater rate. When cancer is coupled with multiple overlapping chronic diseases, particularly complex conditions such as diabetes or chronic renal disease, the impact on cost increases considerably, especially among patients older than 50 years.4 When measuring the cost of cancer there is no representative “average cancer patient,” after considering the wide variations in spending for different types of cancer, treatment variations, and comorbid conditions. It is important to be aware of the range beyond the average, to avoid making faulty decisions based upon a misleading value. When reviewing and making decisions, subanalysis consideration must be given to the type of cancer and the presence or absence of additional chemotherapy regimens used. This more in-depth analysis should then be overlaid against secondary medical complications and comorbidities.

Workplace Impact and Productivity Patterns The study by Henry and colleagues included nearly 64,000 employees of all ages with cancer, revealing that 43% of those receiving chemotherapy or radiation therapy reported working part-time or full-time during cancer treatment.1 Side effects associated with cancer and cancer treatment cannot be overlooked as an important factor in managing working patients with cancer. Because side effects can result in lost work time, it is important to build a benefit design that provides a flexible workplace schedule for patients who choose to work while receiving chemotherapy or radiation therapy. Some of the effects of chemotherapy may require patients to limit the number of hours they

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The Working Patient with Cancer

Figure 4 Health Plan Paid versus Patient Out-of-Pocket Index Year Total paid Study year Costs, $ 2003 2004 2005 2006

39,938 44,172 56,402 62,751

Overall trend

Change from previous year, %

Plan paid Costs, $

Total, %

37,504 41,505 53,099 57,657

93.9 94.0 94.1 91.9

10.6 27.7 11.3 57

Patient paid Change from previous year, % 10.7 27.9 8.6 54

Costs, $

Total, %

2434 2666 3303 5094

6.1 6.0 5.9 8.1

Change from previous year, % 9.6 23.9 54.3 109

Complete History Total paid Study year Costs, $ 2003 2004 2005 2006

26,272 27,651 28,122 29,701

Overall trend

Change from previous year, % 5.3 1.7 5.6 13

Plan paid Costs, $

Total, %

24,335 25,554 25,949 27,044

92.6 92.4 92.3 91.1

Patient paid Change from previous year, % 5.0 1.5 4.2 11

Costs, $

Total, %

1937 2097 2172 2656

7.4 7.6 7.7 8.9

Change from previous year, % 8.2 3.6 22.3 37

Source: HealthCore, 2002-2006 paid claims. Data on file.

can work on a daily basis, particularly in cases of fatigue, nausea, and vomiting.

On average, working patients with cancer in this study missed 26 workdays because of chemotherapy or radiation therapy, and 18 days because of treatment of side effects.1 Patients with the greatest number of side effects missed significantly more workdays.1 Some employees assuming a supportive or caregiver role to a working patient with cancer may also miss time from work to accompany a spouse, a child, a friend, or a relative who is receiving active treatments. An estimated 77% of working patients with cancer indicated that they were accompanied by a caregiver on visits for active treatments.1

Oncology Healthcare Cost Drivers and Trends Two studies were conducted with HealthCore claims data to determine the year-over-year overall healthcare cost trends among oncology patients, including medical and drug costs.5,6 A secondary objective was to determine the relative contribution of cancer treatment, including biologics used in therapeutic and supportive roles, to the overall cost of healthcare. HealthCore data were used because of the comprehensive availability of relevant medical and drug cost data, in both the inpatient and ambulatory settings, and sourcing utilization claims from 12 states. The commercially insured study cohort includ-

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ed 74,630 patients with cancer.5 Because cancer has become a longitudinal multiyear condition rather than an episodic incident, costs for working patients with cancer were measured within the “index year,” defined as the year of diagnosis, and typically the year of highest utilization. In addition, the complete cost history was reviewed, including all years of continuous enrollment in the plan for the working patient with cancer, beginning with the index year and through disenrollment.

Although medical costs can increase over a patient’s history, the increase is typically much less in latter years than in the index year. The unique impact on out-ofpocket burden during the index year versus the “average” year can be seen in Figure 3.

The “complete history” graph shows that the average annual cost for a working patient with cancer in 2006 was $20,701; assuming patient coinsurance of 10%, the patient would have paid $2070 in out-ofpocket obligations.

Looking at the “index year” graph, the patient’s annual cost was $48,233. Here, with a 10% coinsurance, the patient would pay $4823 in out-of-pocket expenses, which is a substantial financial burden.5 Also, from 2003 to 2006 in the index year cases, medical costs exceeded drug cost increases in absolute dollars and in year-overyear percent increases, reflecting a changing landscape

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Annual member persistency, %

Figure 5 Annual Employee Persistency Rates for Cancer and Various Medical Conditions — Breast cancer — Lung cancer — Gastrointestinal cancer — Lymphoma cancer — Total: all claims — Total: no claims

100 90 80 70 60 50 40 30 20 10

Year 1, Year 2, Year 3, Year 4, Year 5, Year 6, Year 7, Year 8, Year 9, % % % % % % % % % — Breast cancer

100

84

71

62

56

50

43

38

34

— Lung 100 cancer — Gastrointestinal 100 cancer — Lymphoma 100 cancer

65

41

30

25

20

16

12

8

74

54

44

37

31

25

19

14

80

63

53

46

39

32

26

20

Diabetes

100

84

70

60

54

47

40

32

24

Asthma

100

84

70

61

55

49

42

35

26

— Total: all claims

100

79

65

56

51

45

39

33

25

— Total: no claims

100

64

50

43

37

32

27

23

15

Year 1 indicates base year.

Source: Milliman USA, 1996-2004 employer claims data set.

of reimbursement and utilization in both categories.

During the index year period from 2003 to 2006, total healthcare costs increased by 57%, and patients’ outof-pocket costs increased by 109% (Figure 4).5 Medical costs, including diagnostic and laboratory tests, increased at the rate of nearly 49% during the same period, whereas drug costs increased by 52%.10 Notably, this was the same period in which higher copayments and deductibles were implemented.

When out-of-pocket costs become too high for a patient, compliance has been shown to decrease, causing a ripple effect in the patient’s overall health.7 When the patient’s overall health suffers, there is potential for additional costs, including doctor visits, emergency room visits, and hospitalizations. The increasing financial burden for the working patient with cancer, particularly in the first year of diagnosis, requires payers to create flexible and affordable solutions that respond effectively to a changing healthcare environment.

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Creating a “cap,” or maximum, of out-of-pocket expenses for routine and office services may also help limit patient financial burden, particularly in the first year. Employers who create more holistic benefit designs that are responsive to the working patient with cancer may reap the rewards of a stable, loyal workforce, and a lower rate of employee turnover.

AMERICAN HEALTH & DRUG BENEFITS June/July 2009

Benefit Design for Working Patients with Cancer As the healthcare marketplace evolves, there is a growing concern over cost-shifting to the employee, because household income levels are significantly lagging increasing copayments and insurance premiums.

Between 2002 and 2004, using Milliman employer data, the domestic cost of living increased by nearly 5%, whereas health plan members’ out-of-pocket costs increased by 29%—more than 5 times faster than the cost of living.8 Since 2004, these costs have continued to rise, and some patients are headed toward a point of maximum tolerance, where out-of-pocket healthcare costs are beginning to exceed their ability to pay.9 If out-of-pocket costs become prohibitive, employees may make inappropriate choices, resulting in unintended consequences that affect total healthcare costs and quality of care.

Individuals with the highest healthcare costs bear a disproportionate share of out-of-pocket costs, as has been shown by Willey and colleagues.10 Based on a household income of $48,000, working patients with cancer who are in the top 1% of the healthcare cost range incur out-of-pocket costs equivalent to 7.5% of their total income.10 Similarly, patients in the top 5% of the healthcare cost range incur out-of-pocket costs equivalent to 6.3% of their total household income.2 It is often wrongly believed that health plan member turnover is high among patients who are severely ill.

Enrollment data for HealthCore members from 2002 to 2004 showed that 42% of severely ill health plan members remained continuously enrolled at 48 months, whereas only 4.3% of enrollments were lost due to death.3 Because patients with cancer younger than age 65 years have a higher rate of survival than the average patient with cancer older than age 65 years, many patients younger than 65 were shown to return to work after their cancer treatment was completed.3 Results from employer research conducted by Milliman on annual employee persistency rates showed that 56% of patients with breast cancer were still on the job, with the same employer, 5 years after the initial diagnosis, and 34% of patients were with the same employer after 9 years (Figure 5).11 Specifically between years 3 and 9, patients with breast cancer had the highest

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persistency rate with the same employer compared with other types of cancer, diabetes, or asthma.11 Conversely, employees who had no claims and were assumed to be healthy had a 37% persistency rate with an employer at 5 years,11 suggesting that employees with chronic illnesses may actually be more likely to continue working with the same employer than healthy employees.11 In addressing the multidimensional forces that can influence persistency with an employer, it is critical to remain clinically grounded when interpreting disparities in continuous employment rates based on factors such as aggressive cancer types, staging, and survivability. This study also showed that employees with lymphoma had a 46% persistency rate with the same employer at 5 years, and a 20% rate at 9 years.11 Those with GI cancer had a 37% persistency rate at 5 years, and 14% at 9 years; patients with lung cancer had a persistency rate of 25% at 5 years, and 8% at 9 years.11

Conclusion Although a lack of consensus exists between the approach of the payer and the employer to burgeoning healthcare challenges, both the payer and the employer face long-term issues, and both seek long-term solutions for the working patient with cancer. Bridging common goals through improved transparency of information and

data-driven benefit designs can more appropriately address the evolving role of working patients with cancer into a win-win strategy for bringing value to the employee, the employer, and the payer. â&#x2013;

References 1. Henry DH, Viswanathan HN, Elkin EP, et al. Symptoms and treatment burden associated with cancer treatment: results from a cross-sectional national survey in the U.S. Support Care Center. 2008;16:791-801.

Epub 2008 Jan 17.

2. Milliman 2004 proprietary data for commercial static population.

2006 Statistical Abstract of the United States.

3. HealthCore, 2002-2005 claims data set. (HealthCore is a wholly owned subsidiary of WellPoint.)

4. Willey VJ, Pollack MF, Lednar WM, et al. Costs of severely ill members and specialty medication use in a commercially insured population.

Health Aff (Millwood). 2008;27:824-834.

5. HealthCore/WellPoint oncology patients identified from medical claims between January 1, 2002, and December 31, 2006.

6. Data presented as a peer-reviewed podium presentation at the 2008 annual meeting of the American Society of Clinical Oncology, May 30June 3, 2008; Chicago, IL. 7. RAND Corporation. Redefining and reforming healthcare for the last years of life. 2006. www.rand.org/pubs/research_briefs/2006/RAND_ RB9178.pdf. Accessed December 19, 2008.

8. Milliman 2002-2004 proprietary data for commercial static population.

American Institute for Economic Research Cost-of-Living Calculator.

9. Goldman DP, Joyce GF, Lawless G, et al. Benefit design and specialty drug use. Health Aff (Millwood). 2006;25:1319-1331.

10. Willey VJ, Kopenski F, Lawless G. Beyond the myths: finding benefit design solutions that address the true costs of high healthcare use. Am J Manag Care. 2008;14(suppl):S252-S263.

11. Milliman USA, 1996-2004 employer claims data set.

STAKEHOLDER PERSPECTIVE Data-Driven Benefit Design for Chronic Diseases With recent advances in cancer care, many types of cancer are becoming chronic diseases. And because the incidence of cancer increases after age 55, the prevalence of cancer will be rising with the aging of the baby boomer population; therefore, more working-age patients will return to the workplace during or after their cancer treatment. In this article, Dr Lawless shows that working patients with cancer today are more likely to remain with the same employer for more than 5 years after their initial diagnosis, and that the out-of-pocket (OOP) cost for these patients is particularly high in the first year after cancer diagnosis.

Employers are struggling with how to manage the cost of medical care for their employees in these difficult economic times and escalating healthcare costs.

However, failure to manage this cost may add financial stress to an already challenged organization and may affect its ability to compete in a global economy.

Recent benefit trends have seen significant cost-shifting to employees as a way of managing medical cost

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increases. But such an approach may have unintended consequences.

The data presented in this article show that the top 10% of claimants are responsible for almost 60% of medical cost, and cancer patients often fall into this group. Increasing patient OOP cost can negatively affect treatment adherence, which in cancer patients can have serious consequences. It is therefore essential for employers and their benefit consultants to have appropriate data that can help design benefit plans that prevent overutilization yet also do not place a disproportionate financial burden on chronically ill patients. Health benefit designs must be data-driven and balance the need to manage cost effectively with the needs of patients with cancer and other chronic illnesses.

Gary M. Owens, MD P&T Committee Chairman Towers Perrin RxCollaborative

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Lower Copay and Oral Administration: Predictors of First-Fill Adherence to New Asthma Prescriptions Zackary Berger, MD, PhD; William Kimbrough, MD; Colleen Gillespie, PhD; Joseph A. Boscarino, PhD, MPH; G. Craig Wood, MS; Zhengmin Qian, MD, PhD; J. B. Jones, PhD, MBA; Nirav R. Shah, MD, MPH Background: Nonadherence to asthma medications is associated with increased emergency department visits and hospitalizations. If adherence is to be improved, first-fill adherence is the first goal to meet after the physician and patient have decided to begin treatment. Little is known about first-fill adherence with asthma medications and the factors for no-fill.

Objective: The goal of the study was to examine the proportion of patients who fill a new prescription for an asthma medication and analyze characteristics associated with this first-fill.

Methods: This retrospective cohort study linked electronic health records with pharmacy claims.

The cohort was comprised of 2023 patients aged 18 years or older who sought care from the Nirav R. Shah, MD, MPH Geisinger Clinic, had Geisinger Health Plan pharmacy benefits, and were prescribed an asthma medication for the first time between 2002 and 2006. The primary outcome of interest was first-time prescription filled by the patient within 30 days of the prescription order date. Covariates examined included factors related to the patient (ie, age, sex, and ethnicity), comorbidities and utilization (ie, Charlson comorbidity index, number of office visits, number of additional medications), asthma treatment (ie, delivery route, pharmacologic class), and pharmacy copay amount. A logistic-regression model was used to determine covariates associated with first-fill.

Results: The overall first-fill rate for new asthma medications was 78%. First-fill rate was lower for patients with a copay above the mean of $12 (odds ratio = 0.76; 95% confidence interval, 0.58-0.99) and higher for patients prescribed oral plus inhaled medications (versus inhaled only, odds ratio = 3.91; 95% confidence interval, 2.15-7.11).

Conclusions: Several factors associated with failing to fill an initial prescription for asthma can be addressed through simple interventions: screening for difficulties a patient may have in filling prescriptions, avoiding nonformulary medications, and recognizing the barrier that high copays present. In addition, for employers and policymakers, decreasing copay may improve adherence and, therefore, asthma control. [AHDB. 2009;2(4):174-180.]

Adherence to prescribed medications is necessary to improve outcomes. But “low adherence is ubiquitous and undermines treatment benefits.”1 Patients with chronic conditions in developed countries take about only half of their medications.2,3 The World Health Organization classifies adherence-related factors into 5 dimensions: healthcare-related, socioeconomic, disease-related, therapy-related, and patient-related.4 Although the adherence literature is extensive, previous studies have used disparate methods, patient popuDrs Berger, Kimbrough, Gillespie, and Shah are in the Division of General Internal Medicine, New York University School of Medicine, New York City. Mr Wood and Drs Boscarino, Qian, Jones, and Shah are Associate Researchers at the Henry Hood Center for Health Research, Geisinger Clinic, Danville, PA.

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lations, and definitions, making it difficult to determine which of these factors is most significant.5-7 Adherence in asthma is particularly important.

Medication nonadherence among patients with asthma is associated with increased emergency department visits and hospitalizations.3 In addition, adherence among the patient population is low, with adherence to inhaled corticosteroids among the lowest in all patients with chronic conditions.8 Understanding and improving patient adherence is one way to improve asthma care.

Much of the adherence literature to date has focused on whether the patient takes the medication as prescribed (assuming that the prescription has been filled) and relies on patient self-reporting, which is unreliable.9 First-fill—patient’s filling of a new prescription—is essential to adherence. An accurate estimate of adher-

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ence and treatment effects depends on prescription filling, after which other metrics of adherence (ie, medication taking) can be considered.

In addition, if prescription no-fill is not recognized as a possible cause for treatment failure, a second-line medication could be unnecessarily prescribed, exposing the patient to additional costs and potential side effects.

Although the literature on adherence is expansive, understanding first-filling of prescriptions for asthma medication is still in its preliminary stages.10-12 The present study seeks to add to that understanding.

We hypothesized that the following “dimensions of adherence”4 are associated with failure to fill a prescription, patient-related (ie, higher comorbidity index, more office visits, and greater pill burden, as well as age by means of comorbidity and loss of function); condition- and treatment-related (ie, number of asthma medications, inhaled versus oral route of delivery, and controller versus reliever medication); and healthcare system–related (ie, higher copay).

To test these hypotheses, we linked prescribing information from Geisinger Clinic electronic health records (EHRs) to pharmacy claims data of one insurer, Geisinger Health Plan (GHP). Through these linked databases we identified prescriptions that were written but ultimately not filled by patients. We used a retrospective cohort design to assess the proportion of patients who filled a first-time prescription for an asthma medication and then examined characteristics associated with first-fill.

Methods Data Source and Settings Our primary data sources were 2 large, linked data sets: Geisinger Clinic’s EHR and GHP’s claims database.

In the case of first-fill of asthma medications, reliable linking of EHR to claims data within a single healthcare system helps address recall bias (prescriptions and fills are accurately recorded), selection bias (all patients with a new asthma prescription are included), and statistical power (the data sets comprise thousands of patients).

The Geisinger Clinic is a multispecialty practice with more than 40 clinic sites and more than 600 providers.

An EHR system was installed in all Geisinger Clinic community practice sites and specialty clinics, allowing for the integration of clinical information across diverse settings of care and making all patient information available in digital form. GHP is one part of Geisinger’s diverse payer mix and accounts for 30% of the Geisinger Clinic’s patient volume. Although GHP shares its name with Geisinger Clinic, it is an independent entity and one of the nation’s largest rural health maintenance

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KEY POINTS

Little is known about first-fill adherence patterns of patients receiving first prescription for asthma medications; adherence is necessary to improve outcomes in this patient population.

This is the largest study of its kind to analyze characteristics of first-fill or no-fill for asthma medications. Of the 2023 patients with asthma in this study, 78% filled their first-time prescriptions within 30 days, and 22% did not.

Patient copay of <$12 (the mean) resulted in a higher first-fill adherence rate than a copay of >$12.

Other variables affecting first-fill medication adherence rates included therapeutic class and route of administration, as well as controller and reliever type of medications.

organizations (HMOs). Initially started as a group practice HMO, GHP has expanded into a network model and now has more than 220,000 members.

Sample Selection The Geisinger Clinic patient population includes residents from central and northeastern Pennsylvania, a predominantly white population. In this study we included patients who were 18 or older at the time of a new asthma prescription; had sought care from the Geisinger Clinic; had GHP pharmacy benefit; and were prescribed a medication to treat asthma between January 2002 and September 2006 that had not been prescribed or filled within the previous 6 months. To ensure that a new asthma prescription could be identified, the patient had to be in the Geisinger Clinic system for at least 1 year before the prescription date.

Eligible medications fell into the following subclasses: sympathomimetics, oral corticosteroids, inhaled corticosteroids, leukotriene modulators, bronchodilators, or a combination of these classes. To eliminate patients who utilized spousal pharmacy benefit, the population included only those who had used their GHP pharmacy benefit at least once prior to the date of the index medication.

Study Variables Data extracted from the EHR included variables related to the patient and the patient’s socioeconomic status (ie, age, sex, race); comorbidities, based on the Charlson index of comorbid conditions other than HIV,13 number of prescriptions for all conditions ordered

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within 10 days of the index prescription, and number of office visits 6 months before index prescription; and asthma treatment (number of asthma prescriptions and drug class). The order date was also extracted for purposes of linking to the claims database. Information on asthma severity and chronic obstructive pulmonary disease was not available.

Data from the pharmacy claims database included asthma prescription characteristics (ie, drug class, medication type [controller or reliever], route of delivery, copay amount, fill date) and the outcome (whether the prescription was filled, ie, first-fill). Identifiers from the EHR record were linked to GHP pharmacy claims data.

Statistical Analysis A patient was designated as a “first-fill” if the firsttime prescription resulted in a claim within 30 days of the EHR order date (less than 1% of prescriptions that ultimately generated claims occurred after 30 days; these data are not shown and are classified as “nonfillers”). Bivariate analysis determined characteristics related to first-fill. Categorical variables were analyzed using chi-square tests, Fisher’s exact test, and CochranArmitage trend tests. Continuous variables were assessed using t-test and Wilcoxon rank-sum test, where appropriate.

A logistic regression model was used to determine those covariates associated with first-fill. Socioeconomic variables (age, sex) and all variables related to asthma prescription characteristics were considered for inclusion in the model. Other variables were considered for inclusion, when bivariate P values were <.10, using the Bonferroni correction to safeguard against multiple tests of statistical significance on the same data.

Variables were forward-selected for inclusion in the model based on scientific plausibility. Collinear variables were not included. Separate analyses were conducted for a subset of records corresponding to controller (ie, maintenance) medications only, because adherence to these medications is of clinical interest to policymakers. Prescription fill records representing leukotriene modulators only (36/2023, or 1.7% of the total) were excluded from the logistic-regression analysis, because these medications are frequently used for conditions other than asthma. All analyses were conducted with the SPSS statistical software package (version 14.0, Chicago, IL).

Results Records for 2023 predominantly Caucasian patients met all inclusion criteria. Of these, 65% were female,

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and 96% were Caucasian. The median age was 49 years, and 3% were 65 years or older.

More than two thirds of patients (68%) were prescribed either reliever medications or both reliever plus controller medications; about one third (32%) were prescribed controller medications only. Two thirds (67%) of the current asthma prescriptions were administered via inhaler only; one third of prescriptions (33%) were either oral or oral medications plus inhalers. Most prescriptions (80%) were for 1 asthma medication; 17% were for 2 medications.

All patients in the data set had medications ordered for comorbid conditions within 10 days of the new asthma prescription. For the majority of patients (52%), the number of medications ordered for other conditions was 2 or 3; for 34%, 4 or more were ordered.

The mean copay was $12 (standard deviation 13, median 9, mode 10).

Overall, 78% (1586) of patients filled their firsttime prescriptions within a 30-day period (Table 1).

Copays less than $12 resulted in a first-fill rate of 74%; copays more than $12 resulted in a 69% first-fill rate (P = .17). In a logistic-regression model, prescriptions with copays of more than $12 were only three quarters (odds ratio = 0.76; 95% confidence interval, 0.58-0.99) as likely to be filled as prescriptions with copays less than $12 (Table 2).

First-fill rates differed by therapeutic class and route of administration (Table 1). First-fill was decreased for those prescribed inhaled steroids only (first-fill, 65%; P <.001) and leukotriene modulators only (first-fill, 56%; P <.001), whereas the subclasses (1) oral steroids, inhaled steroids, and sympathomimetics, and (2) oral steroids and sympathomimetics were positively associated with first-fill (first-fill, 92% and 95%, respectively; P <.001).

First-fill rate was associated with prescriptions for controller and for reliever medications (first-fill, 87%; P <.001), as well as prescriptions for inhaler and oral medications (first-fill, 91%; P <.001), as were the number of asthma medications (first-fill for more than 3, 88%; P <.001) and the number of total medications (first-fill for more than 1, 81%; P <.001).

Factors that had no relationship to first-fill rate include age, sex, race, Charlson comorbidity index, or total number of office visits.

Predictors of First-Fill from a Logistic-Regression Model Individual predictors were considered in a logisticregression model to determine the best predictors of firstfill (Tables 2, 3). For all asthma-specific medications,

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Table 1 Differences in First-Fill of Asthma Medications first-fill was associated with prescriptions for oral medications (as compared with the reference category of inhaled medication only) and prescriptions for both oral and inhaled medications (compared with inhaled medication only).

First-time prescriptions for asthma medications were less likely to be filled by patients whose copay was greater than the mean.

Within the subset of controller asthma medications, the effects of oral route (versus inhaled) and of higher copay were larger than for the entire set of records. In this subset, total pill burden and the number of office visits within the previous 6 months were also associated with first-fill, although the 95% confidence intervals included 1.0.

Discussion Using linked EHR and pharmacy claim data, we compiled a large sample of patients with asthma who had new prescriptions and estimated first-fill and its associations with medication type and prescription characteristics. This is the largest study of this kind to date.

First-fill in this study for all types of asthma medication was 78%. New asthma prescriptions were more likely to be filled if they were for oral medications (as compared with inhaled medications). New asthma prescriptions were less likely to be filled among patients whose copay was greater than the mean.

Lack of first-fill in this study is comparable with previous estimates in asthma of 8% to 30%,10-12,14 and studies of other conditions using similar populations.15,16 Unlike previous studies, in our study there was no significant difference in first-fill between age-groups, sex, or comorbid conditions as measured by the Charlson comorbidity index. This contradicts a previous study of first-fill of primary care medications.17 Active prescriptions for oral asthma medication, or both oral and inhaled medications, were associated with first-fill compared with inhaled medication alone. The association between inhaled controller medication and no-fill in our study is notably different from the findings of Williams and colleagues, who found a first-fill rate of 92% for inhaled corticosteroids.12 Based on our clinical experience, it appears that patients associate inhalers with short-term, symptomatic relief, making our result counterintuitive. The most likely explanation is confounding of medication route by disease severity.

Patients who feel sick and are told that steroids will make them feel better will fill their prescriptions; those with mild disease or without an active exacerbation will be less likely to fill a prescription.

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Adherent Variable patients, N (%)a 1586/2023 (78) Overall medications ordered Medications ordered, by subclass 833/1091 (76) Sympathomimetics only 324/396 (82) Oral steroids only Inhaled steroids and sympathomimetics 122/154 (79) 124/130 (95) Oral steroids and sympathomimetics 60/93 (65) Inhaled steroids only Leukotriene modulators and 36/43 (84) sympathomimetics 20/36 (56) Leukotriene modulators only Oral steroids, inhaled steroids, and 23/25 (92) sympathomimetics 8/9 (89) Bronchodilators only 36/46 (78) Other combinations Type of medication 481/646 (74) Controller only 707/1024 (78) Reliever only 308/353 (87) Controller and reliever Route of administration 1031/1353 (76) Inhaler 351/445 (79) Oral 204/225 (91) Inhaler and oral Asthma drugs ordered, N 1

1245/1625 (77)

2

298/349 (85)

3+

43/49 (88)

P <.001b

<.001b

<.001c

<.001c

<.001c

Total drugs ordered (Âą10 days), N 1

171/262 (65)

2-3

856/1062 (81)

4-7

505/632 (80)

8+

54/67 (81)

.17 b

Copay amount $0-$12.00

1197/1512 (74)

$12.01+

389/510 (69)

Office visits in previous 6 mo, N 0

.903 c 5/7 (71)

1-4

1313/1670 (79)

5-9

235/306 (77)

10+

33/40 (83)

Note: Compliance was defined as prescription fill for an asthma medication within 30 days of initial order. a b c

Because a patient can have multiple prescriptions, the totals will not add up to 100%.

Chi-square test.

Cochran-Armitage trend test.

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Table 2 Multiple-Regression Model for Predicting 30-Day First-Fill (N = 2023) Odds ratio (95% Variable confidence interval) Patient-associated Office visits

0.99 (0.94-1.04)

Table 3 Multiple-Regression Model for Predicting 30-Day First-Fill in Users of Controller Asthma Medications (N = 646) Odds ratio (95% Variable confidence interval) Patient-associated

Pill burden Route of asthma medication: treatment-associated Inhaled only

1.05 (0.98-1.12)

Office visits

1.04 (0.95-1.13) 1.08 (0.97-1.19)

Oral only

1.28 (0.96-1.71)

Pill burden Route of asthma medication: treatment-associated Inhaled only

Oral and inhaled Copay: healthcare system– associated Greater than mean

3.91 (2.15-7.11)

Oral only

1.88 (1.16-2.60)

Oral and inhaled Copay: healthcare system– associated Greater than mean

4.31 (0.90-20.6)

(reference)

0.76 (0.58-0.99)

Our most notable result is a positive relationship between copay above the $12 mean and prescription nofill. It is unlikely that this result is confounded by socioeconomic status, because this HMO-enrolled population is somewhat homogeneous; however, this remains a possibility, given our lack of income or education data. Our result agrees with previous studies, which have shown that copay increases as small as $2 can significantly reduce adherence.18 The copay effect was greater in the group that was prescribed only controller medications. Further research is needed to test the hypothesis that patients with longer-term use of asthma medications tend not to fill those requiring higher copay, explaining the stronger effect among the controller medication subgroup. This has important policy implications; public health is improved when patients are compliant with asthma controller medications. As employers turn to value-based benefit design,19 improving first-fill for these medications would be of public and economic benefit.

Successful initiatives to improve patient medication adherence in chronic medical conditions have been multifactorial.6 The present study links 2 factors to adherence—lower copay and oral medications. There are practical measures providers can take to improve first prescription fill, including screening for difficulties the patient may have in filling the prescription (eg, asking “Do you have any difficulty getting this medicine at the pharmacy?”) and optimizing regimens to avoid no-fill (eg, avoiding nonformulary medications and medications with higher copay). Reducing copay can improve compliance and thus improve asthma control,19 an important factor for employers and policymakers.

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(reference)

0.41 (0.25-0.57)

Limitations The failure of this study to find associations between lack of first-fill and age or ethnicity was most likely because of insufficient power. Only 3% of the population (n = 60) was 65 years or older, and only 4% was non-Caucasian. In contrast, if this finding is true and is not due to a type I error, it could support the conclusions of other studies on patient adherence in general, which have shown no associations with age or ethnicity in, for example, adherence with antihypertensives.20 Finally, it could be that in this population of HMO patients, ethnicity- or age-based inequities of care were not significant.

Linking EHR data with claims data allowed us to incorporate patient and prescription characteristics not available in adherence studies limited to claims data.

However, because the study was limited to electronic data, no direct contact was made with patients to determine their perception of the severity of their disease or the effectiveness of their prescribed treatment.

In addition, without patient follow-up, we might have underestimated prescription fills. A subset of patients might have been incorrectly categorized as noncompliant if they filled their prescription using a pharmacy benefit plan other than GHP, or paid out of pocket. We attempted to diminish the possibility of this error by excluding patients from analysis who did not fill at least 1 other prescription through GHP prior to the index prescription.

Conclusion Higher copays and inhaled asthma medications (as

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compared with oral medications) are associated with failure to fill first-time prescriptions for asthma medication. Our findings should be generalized with caution to other healthcare systems, minority populations, or older patients. Future research should focus on identifying the different stages of the prescription cycle, from first-fill to medication adherence to refill to requesting a new prescription from the physician, and quantifying success at each step using data from multiple linked sources. â&#x2013; Acknowledgments This work was funded by an unrestricted research grant from GlaxoSmithKline. The study sponsors played no role in the study design, execution, analysis, or the decision to publish the results.

Disclosure Statement Dr Shah receives support from the Robert Wood Johnson Foundation as a Physician Faculty Scholar. He has received unrestricted research grants from AstraZeneca, Berlex, Novartis, Roche, and Pfizer.

References 1. McDonald HP, Garg AX, Haynes RB. Interventions to enhance patient adherence to medication prescriptions: scientific review. JAMA. 2002; 288:2868-2879.

2. Haynes RB, McDonald H, Garg AX, et al. Interventions for helping patients to follow prescriptions for medications. Cochrane Database Syst Rev. 2002;(2):CD000011.

3. Thier SL, Yu-Isenberg KS, Leas BF, et al. In chronic disease, nationwide data show poor adherence by patients to medication and by physicians to guidelines. Manag Care. 2008;17:48-57.

4. World Health Organization. Adherence to Long-Term Therapies: Evidence for Action. Geneva, Switzerland: World Health Organization; 2003.

5. Gossec L, Tubach F, Dougados M, et al. Reporting of adherence to medication in recent randomized controlled trials of 6 chronic diseases: a systematic literature review. Am J Med Sci. 2007;334:248-254.

6. DiMatteo MR, Haskard KB, Williams SL. Health beliefs, disease severity, and patient adherence: a meta-analysis. Med Care. 2007;45:521-528.

7. van Dulmen S, Sluijs E, van Dijk L, et al. Patient adherence to medical treatment: a review of reviews. BMC Health Serv Res. 2007;7:55.

8. Williams LK, Pladevall M, Xi H, et al. Relationship between adherence to inhaled corticosteroids and poor outcomes among adults with asthma. J Allergy Clin Immunol. 2004;114:1288-1293.

9. Garber MC, Nau DP, Erickson SR, et al. The concordance of self-report with other measures of medication adherence: a summary of the literature.

Medical Care. 2004;42:649-652.

10. Watts RW, McLennan G, Bassham I, et al. Do patients with asthma fill their prescriptions? A primary compliance study. Aust Fam Physician.

1997;26(suppl 1):S4-S6.

11. Krigsman K, Moen JL, Nilsson JLG, et al. Refill adherence by the elderly for asthma/chronic obstructive pulmonary disease drugs dispensed over a 10-year period. J Clin Pharm Ther. 2007;32:603-611.

12. Williams LK, Joseph CL, Peterson EL, et al. Patients with asthma who do not fill their inhaled corticosteroids: a study of primary nonadherence.

J Allergy Clin Immunol. 2007;120:1153-1159.

13. Charlson ME, Pompei P, Ales KL, et al. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40:373-383.

14. Bronstein JM, Santer L, Johnson V. The use of Medicaid claims as a supplementary source of information on quality of asthma care. J Health Qual. 2000;22:13-18.

15. Shah NR, Hirsh AG, Zacker C, et al. Factors associated with first-fill adherence rates for diabetic medications: a cohort study. J Gen Intern Med. 2009;24:233-237.

16. Shah NR, Hirsh AG, Zacker C, et al. Predictors of first-fill adherence for patients with hypertension. Am J Hypertens. 2009;22:392-396. Epub 2009 Jan 29.

17. Beardon PH, McGilchrist MM, McKendrick AD, et al. Primary noncompliance with prescribed medication in primary care. BMJ. 1993; 307:846-848.

18. Johnson RE, Goodman MJ, Hornbrook MC, Eldredge MB. The effect of increased prescription drug cost-sharing on medical care utilization and expenses of elderly health maintenance organization members. Med Care.

1997;35:1119-1131.

19. Chernew ME, Shah MR, Wegh A, et al. Impact of decreasing copayments on medication adherence within a disease management environment. Health Aff (Millwood). 2008;27:103-112.

20. Kressin NR, Wang F, Long J, et al. Hypertensive patientsâ&#x20AC;&#x2122; race, health beliefs, process of care, and medication adherence. J Gen Intern Med. 2007;22:768-774.

STAKEHOLDER PERSPECTIVE Medication Adherence: Is Lower Copay the Best Strategy to Improve Care and Reduce Costs?

This study of first prescription fill rates in patients with asthma contributes unique information about the complex puzzle of medication adherence. Like many recent articles on this topic, it highlights the impact of lower patient pay on improving adherence.

But does this represent the best use of funds to improve care and lower costs?

Many studies highlight the significant impact of poor adherence on overall healthcare costs, and other studies show that adherence can be improved.

In 2001, the cost burden for the United States related to poor patient adherence was estimated at $100 billion annually.1 In 2003, the World Health Organization estimated that approximately 50% of patients with asthma did not take their medications as prescribed.2 Following diagnosis, the primary treatment issues concerning the vast majority of ambulatory patients consists of getting them on the right medication and maintaining their adherence. But we must not assume Continued

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Continued that lowering patient cost is the only strategy that can improve medication compliance. Prescribing medications with fewer side effects and less frequent dosing can also improve compliance. Should incentives include guiding patients to the highest value drugs, or apply equally to all drugs, regardless of value?

The present article highlights that only 78% of patients in this study actually filled their first prescription for asthma. This problem remains largely undetected. Future e-prescribing systems may inform physicians when their patients fail to pick up that first prescription. Other programs may include physician-dispensing or analytic systems that detect patients who have been diagnosed with a medical condition but have no follow-up therapy.

Programs to help patients maintain adherence can focus on incentives (such as lower patient pay), refill reminders, or interventions supported by analytics that detect adherence issues. Lowering copayments or coinsurance provides an easy-to-implement solution with proved short-term benefits; however, little is known about the long-term, lasting impact of this approach. Other potential incentives may tie lower patient pay, contribution to health savings accounts, or lower deductibles to completion of health risk assessments, participation in disease management programs, or maintaining adherence for defined durations (eg, every 6 months).

CAPTION CONTEST

This begs the question whether lowering patient pay offers better value than other services, such as those that detect and notify providers of poor adherence. Lowering patient pay by $5 for every chronic medication would cost upwards of 10 times more than intervention services that focus on adherence plus other medication therapy problems, missing preventive services, and gaps in evidence-based care.

How does the value of low pay compare with wellness or with care management programs? We need a lot more evidence on identifying the best services that will provide the best value to improve care and lower costs. Although improved medication adherence should be a primary area of focus, we do not yet have the evidence on what combination of approaches will deliver us the best value. Until then, I look forward to more studies that will shed light on this complex issue.

References 1. Vermeire E, Hearnshaw H, Van Royen P, et al. Patient adherence to treatment: three decades of research. A comprehensive review. J Clin Pharm Therap. 2001;26:331-342.

2. WHO. Adherence to Long-Term Therapies: Evidence for Action.

Geneva: World Health Organization; 2003.

Ronald A. Lyon, MS Vice President, Pharmacy Programs ValueOptions, Norfolk, VA

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In moderate to severe Alzheimer’s disease

Recognize the value of treatment with NAMENDA NAMENDA delivers proven efficacy and may reduce total healthcare costs1-5 Patients with Alzheimer’s disease are complex and present unique challenges to managed care organizations

The proven efficacy of NAMENDA can help you meet these challenges

Comorbid conditions, such as congestive heart failure and diabetes, are more common and more expensive to manage in patients with Alzheimer’s disease6

NAMENDA treatment benefits in cognition and function could reduce the costs of comorbid conditions1-3,6

Behavioral issues are a major contributor to increased costs in Alzheimer’s disease7

NAMENDA improves behavior and delays the onset of behavioral symptoms in combination with an acetylcholinesterase inhibitor (AChEI)1,4

Patients with Alzheimer’s disease who received NAMENDA demonstrated reduced total healthcare costs5 The value of treatment with NAMENDA n n

n n

Unique mechanism of action—in a class of its own8-13 Efficacy in cognition and function, alone or in combination with an AChEI1-3 Efficacy in behavior in combination with an AChEI1,4 Proven safety and tolerability may lead to therapy persistence5,8,14

NAMENDA® (memantine HCI) is indicated for the treatment of moderate to severe Alzheimer’s disease.

NAMENDA is contraindicated in patients with known hypersensitivity to memantine HCl or any excipients used in the formulation. The most common adverse events reported with NAMENDA vs placebo (≥5% and higher than placebo) were dizziness, confusion, headache, and constipation. In patients with severe renal impairment, the dosage should be reduced.

References: 1. Tariot PN, Farlow MR, Grossberg GT, Graham SM, McDonald S, Gergel I, for the Memantine Study Group. Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: a randomized controlled trial. JAMA. 2004;291:317-324. 2. Reisberg B, Doody R, Stöffler A, Schmitt F, Ferris S, Möbius HJ, for the Memantine Study Group. Memantine in moderate-to-severe Alzheimer's disease. N Engl J Med. 2003;348:1333-1341. 3. Reisberg B, Doody R, Stöffler A, Schmitt F, Ferris S, Möbius HJ. A 24-week open-label extension study of memantine in moderate to severe Alzheimer disease. Arch Neurol. 2006;63:49-54.

4. Cummings JL, Schneider E, Tariot PN, Graham SM, for the Memantine MEM-MD-02 Study Group. Behavioral effects of memantine in Alzheimer disease patients receiving donepezil treatment. Neurology. 2006;67:57-63. 5. Wimo A, Winblad B, Stöffler A, Wirth Y, Möbius HJ. Resource utilisation and cost analysis of memantine in patients with moderate to severe Alzheimer's disease. Pharmacoeconomics. 2003;21:327-340. 6. Hill JW, Futterman R, Duttagupta S, Mastey V, Lloyd JR, Fillit H. Alzheimer's disease and related dementias increase costs of comorbidities in managed Medicare. Neurology. 2002;58:62-70. 7. Murman DL, Chen Q, Powell MC, Kuo BS, Bradley CJ, Colenda CC. The incremental direct costs associated with behavioral symptoms in AD. Neurology. 2002;59:1721-1729. 8. NAMENDA® (memantine HCl) Prescribing Information. Forest Pharmaceuticals, Inc., St Louis, Mo. 9. Aricept® (donepezil hydrochloride tablets) Prescribing Information. Eisai Inc., Woodcliff Lake, NJ. 10. Razadyne® (galantamine HBr) Prescribing Information. Ortho-McNeil Neurologics, Inc., Titusville, NJ. 11. Exelon® (rivastigmine tartrate) Prescribing Information. Novartis Pharmaceuticals Corporation, East Hanover, NJ. 12. Cognex® (tacrine hydrochloride capsules) Prescribing Information. Sciele Pharma, Inc., Atlanta, Ga. 13. United States Pharmacopeia. Model Guidelines and Formulary Key Drug Types Version 4.0. Rockville, Md. Available at: http://www.usp.org/pdf/EN/mmg/modelGuidelinesV4.0WithFKDTs.pdf.

Accessed September 19, 2008. 14. Data on file. Forest Laboratories, Inc.

For more details, please visit www.namenda.com.

Please see brief summary of Prescribing Information on the adjacent page. © 2009 Forest Laboratories, Inc.

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Tablets/Oral Solution Rx Only

Brief Summary of Prescribing Information.

For complete details, please see full Prescribing Information for Namenda.

INDICATIONS AND USAGE Namenda (memantine hydrochloride) is indicated for the treatment of moderate to severe dementia of the Alzheimer’s type.

CONTRAINDICATIONS Namenda (memantine hydrochloride) is contraindicated in patients with known hypersensitivity to memantine hydrochloride or to any excipients used in the formulation.

PRECAUTIONS Information for Patients and Caregivers: Caregivers should be instructed in the recommended administration (twice per day for doses above 5 mg) and dose escalation (minimum interval of one week between dose increases).

Neurological Conditions Seizures: Namenda has not been systematically evaluated in patients with a seizure disorder. In clinical trials of Namenda, seizures occurred in 0.2% of patients treated with Namenda and 0.5% of patients treated with placebo.

Genitourinary Conditions Conditions that raise urine pH may decrease the urinary elimination of memantine resulting in increased plasma levels of memantine.

Special Populations Hepatic Impairment Namenda undergoes partial hepatic metabolism, with about 48% of administered dose excreted in urine as unchanged drug or as the sum of parent drug and the N-glucuronide conjugate (74%). No dosage adjustment is needed in patients with mild or moderate hepatic impairment. Namenda should be administered with caution to patients with severe hepatic impairment.

Renal Impairment No dosage adjustment is needed in patients with mild or moderate renal impairment. A dosage reduction is recommended in patients with severe renal impairment (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION in Full Prescribing Information).

Drug-Drug Interactions N-methyl-D-aspartate (NMDA) antagonists: The combined use of Namenda with other NMDA antagonists (amantadine, ketamine, and dextromethorphan) has not been systematically evaluated and such use should be approached with caution.

Effects of Namenda on substrates of microsomal enzymes: In vitro studies conducted with marker substrates of CYP450 enzymes (CYP1A2, -2A6, -2C9, -2D6, -2E1, -3A4) showed minimal inhibition of these enzymes by memantine. In addition, in vitro studies indicate that at concentrations exceeding those associated with efficacy, memantine does not induce the cytochrome P450 isoenzymes CYP1A2, CYP2C9, CYP2E1, and CYP3A4/5.

No pharmacokinetic interactions with drugs metabolized by these enzymes are expected.

Effects of inhibitors and/or substrates of microsomal enzymes on Namenda: Memantine is predominantly renally eliminated, and drugs that are substrates and/or inhibitors of the CYP450 system are not expected to alter the metabolism of memantine.

Acetylcholinesterase (AChE) inhibitors: Coadministration of Namenda with the AChE inhibitor donepezil HCl did not affect the pharmacokinetics of either compound. In a 24-week controlled clinical study in patients with moderate to severe Alzheimer’s disease, the adverse event profile observed with a combination of memantine and donepezil was similar to that of donepezil alone.

Drugs eliminated via renal mechanisms: Because memantine is eliminated in part by tubular secretion, coadministration of drugs that use the same renal cationic system, including hydrochlorothiazide (HCTZ), triamterene (TA), metformin, cimetidine, ranitidine, quinidine, and nicotine, could potentially result in altered plasma levels of both agents. However, coadministration of Namenda and HCTZ/TA did not affect the bioavailability of either memantine or TA, and the bioavailability of HCTZ decreased by 20%. In addition, coadministration of memantine with the antihyperglycemic drug Glucovance® (glyburide and metformin HCl) did not affect the pharmacokinetics of memantine, metformin and glyburide. Furthermore, memantine did not modify the serum glucose lowering effect of Glucovance®.

Drugs that make the urine alkaline: The clearance of memantine was reduced by about 80% under alkaline urine conditions at pH 8. Therefore, alterations of urine pH towards the alkaline condition may lead to an accumulation of the drug with a possible increase in adverse effects.

Urine pH is altered by diet, drugs (e.g. carbonic anhydrase inhibitors, sodium bicarbonate) and clinical state of the patient (e.g. renal tubular acidosis or severe infections of the urinary tract). Hence, memantine should be used with caution under these conditions.

Carcinogenesis, Mutagenesis and Impairment of Fertility There was no evidence of carcinogenicity in a 113-week oral study in mice at doses up to 40 mg/kg/day (10 times the maximum recommended human dose [MRHD] on a mg/m2 basis). There was also no evidence of carcinogenicity in rats orally dosed at up to 40 mg/kg/day for 71 weeks followed by 20 mg/kg/day (20 and 10 times the MRHD on a mg/m2 basis, respectively) through 128 weeks.

Memantine produced no evidence of genotoxic potential when evaluated in the in vitro S. typhimurium or E. coli reverse mutation assay, an in vitro chromosomal aberration test in human lymphocytes, an in vivo cytogenetics assay for chromosome damage in rats, and the in vivo mouse micronucleus assay. The results were equivocal in an in vitro gene mutation assay using Chinese hamster V79 cells.

No impairment of fertility or reproductive performance was seen in rats administered up to 18 mg/kg/day (9 times the MRHD on a mg/m2 basis) orally from 14 days prior to mating through gestation and lactation in females, or for 60 days prior to mating in males.

Pregnancy Pregnancy Category B: Memantine given orally to pregnant rats and pregnant rabbits during the period of organogenesis was not teratogenic up to the highest doses tested (18 mg/kg/day in rats and 30 mg/kg/day in rabbits, which are 9 and 30 times, respectively, the maximum recommended human dose [MRHD] on a mg/m2 basis).

Slight maternal toxicity, decreased pup weights and an increased incidence of non-ossified cervical vertebrae were seen at an oral dose of 18 mg/kg/day in a study in which rats were given oral memantine beginning pre-mating and continuing through the postpartum period. Slight maternal toxicity and decreased pup weights were also seen at this dose in a study in which rats were treated from day 15 of gestation through the post-partum period. The no-effect dose for these effects was 6 mg/kg, which is 3 times the MRHD on a mg/m2 basis.

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

Nursing Mothers It is not known whether memantine is excreted in human breast milk.

Because many drugs are excreted in human milk, caution should be exercised when memantine is administered to a nursing mother.

Pediatric Use There are no adequate and well-controlled trials documenting the safety and efficacy of memantine in any illness occurring in children.

ADVERSE REACTIONS The experience described in this section derives from studies in patients with Alzheimer’s disease and vascular dementia.

Adverse Events Leading to Discontinuation: In placebo-controlled trials in which dementia patients received doses of Namenda up to 20 mg/day, the likelihood of discontinuation because of an adverse event was the same in the Namenda group as in the placebo group. No individual adverse event was associated with the discontinuation of treatment in 1% or more of Namenda-treated patients and at a rate greater than placebo.

Adverse Events Reported in Controlled Trials: The reported adverse events in Namenda (memantine hydrochloride) trials reflect experience gained under closely monitored conditions in a highly selected patient population. In actual practice or in other clinical trials, these frequency estimates may not apply, as the conditions of use, reporting behavior and the types of patients treated may differ. Table 1 lists treatment-emergent signs and symptoms that were reported in at least 2% of patients in placebo-controlled dementia trials and for which the rate of occurrence was greater for patients treated with Namenda than for those treated with placebo. No adverse event occurred at a frequency of at least 5% and twice the placebo rate.

Table 1: Adverse Events Reported in Controlled Clinical Trials in at Least 2% of Patients Receiving Namenda and at a Higher Frequency than Placebotreated Patients.

Body System Adverse Event Body as a Whole Fatigue Pain Cardiovascular System Hypertension Central and Peripheral Nervous System Dizziness Headache Gastrointestinal System Constipation Vomiting Musculoskeletal System Back pain Psychiatric Disorders Confusion Somnolence Hallucination Respiratory System Coughing Dyspnea

Placebo (N = 922) %

Namenda (N = 940) %

1 1

2 3

2

4

5 3

7 6

3 2

5 3

2

3

5 2 2

6 3 3

3 1

4 2

Other adverse events occurring with an incidence of at least 2% in Namenda-treated patients but at a greater or equal rate on placebo were agitation, fall, inflicted injury, urinary incontinence, diarrhea, bronchitis, insomnia, urinary tract infection, influenza-like symptoms, abnormal gait, depression, upper respiratory tract infection, anxiety, peripheral edema, nausea, anorexia, and arthralgia.

The overall profile of adverse events and the incidence rates for individual adverse events in the subpopulation of patients with moderate to severe Alzheimer’s disease were not different from the profile and incidence rates described above for the overall dementia population.

Vital Sign Changes: Namenda and placebo groups were compared with respect to (1) mean change from baseline in vital signs (pulse, systolic blood pressure, diastolic blood pressure, and weight) and (2) the incidence of patients meeting criteria for potentially clinically significant changes from baseline in these variables. There were no clinically important changes in vital signs in patients treated with Namenda. A comparison of supine and standing vital sign measures for Namenda and placebo in elderly normal subjects indicated that Namenda treatment is not associated with orthostatic changes.

Laboratory Changes: Namenda and placebo groups were compared with respect to (1) mean change from baseline in various serum chemistry, hematology, and urinalysis variables and (2) the incidence of patients meeting criteria for potentially clinically significant changes from baseline in these variables. These analyses revealed no clinically important changes in laboratory test parameters associated with Namenda treatment.

ECG Changes: Namenda and placebo groups were compared with respect to (1) mean change from baseline in various ECG parameters and (2) the incidence of patients meeting criteria for potentially clinically significant changes from baseline in these variables. These analyses revealed no clinically important changes in ECG parameters associated with Namenda treatment.

Other Adverse Events Observed During Clinical Trials Namenda has been administered to approximately 1350 patients with dementia, of whom more than 1200 received the maximum recommended dose of 20 mg/day. Patients received Namenda treatment for periods of up to 884 days, with 862 patients receiving at least 24 weeks of treatment and 387 patients receiving 48 weeks or more of treatment.

Treatment emergent signs and symptoms that occurred during 8 controlled clinical trials and 4 open-label trials were recorded as adverse events by the clinical investigators using terminology of their own choosing. To provide an overall estimate of the proportion of individuals having similar types of events, the events were grouped into a smaller number of standardized

categories using WHO terminology, and event frequencies were calculated across all studies.

All adverse events occurring in at least two patients are included, except for those already listed in Table 1, WHO terms too general to be informative, minor symptoms or events unlikely to be drug-caused, e.g., because they are common in the study population. Events are classified by body system and listed using the following definitions: frequent adverse events - those occurring in at least 1/100 patients; infrequent adverse events- those occurring in 1/100 to 1/1000 patients. These adverse events are not necessarily related to Namenda treatment and in most cases were observed at a similar frequency in placebo-treated patients in the controlled studies.

Body as a Whole: Frequent: syncope. Infrequent: hypothermia, allergic reaction.

Cardiovascular System: Frequent: cardiac failure. Infrequent: angina pectoris, bradycardia, myocardial infarction, thrombophlebitis, atrial fibrillation, hypotension, cardiac arrest, postural hypotension, pulmonary embolism, pulmonary edema.

Central and Peripheral Nervous System: Frequent: transient ischemic attack, cerebrovascular accident, vertigo, ataxia, hypokinesia. Infrequent: paresthesia, convulsions, extrapyramidal disorder, hypertonia, tremor, aphasia, hypoesthesia, abnormal coordination, hemiplegia, hyperkinesia, involuntary muscle contractions, stupor, cerebral hemorrhage, neuralgia, ptosis, neuropathy.

Gastrointestinal System: Infrequent: gastroenteritis, diverticulitis, gastrointestinal hemorrhage, melena, esophageal ulceration.

Hemic and Lymphatic Disorders: Frequent: anemia. Infrequent: leukopenia.

Metabolic and Nutritional Disorders: Frequent: increased alkaline phosphatase, decreased weight. Infrequent: dehydration, hyponatremia, aggravated diabetes mellitus.

Psychiatric Disorders: Frequent: aggressive reaction. Infrequent: delusion, personality disorder, emotional lability, nervousness, sleep disorder, libido increased, psychosis, amnesia, apathy, paranoid reaction, thinking abnormal, crying abnormal, appetite increased, paroniria, delirium, depersonalization, neurosis, suicide attempt.

Respiratory System: Frequent: pneumonia. Infrequent: apnea, asthma, hemoptysis.

Skin and Appendages: Frequent: rash. Infrequent: skin ulceration, pruritus, cellulitis, eczema, dermatitis, erythematous rash, alopecia, urticaria.

Special Senses: Frequent: cataract, conjunctivitis. Infrequent: macula lutea degeneration, decreased visual acuity, decreased hearing, tinnitus, blepharitis, blurred vision, corneal opacity, glaucoma, conjunctival hemorrhage, eye pain, retinal hemorrhage, xerophthalmia, diplopia, abnormal lacrimation, myopia, retinal detachment.

Urinary System: Frequent: frequent micturition. Infrequent: dysuria, hematuria, urinary retention.

Events Reported Subsequent to the Marketing of Namenda, both US and Ex-US Although no causal relationship to memantine treatment has been found, the following adverse events have been reported to be temporally associated with memantine treatment and are not described elsewhere in labeling: aspiration pneumonia, asthenia, atrioventricular block, bone fracture, carpal tunnel syndrome, cerebral infarction, chest pain, cholelithiasis, claudication, colitis, deep venous thrombosis, depressed level of consciousness (including loss of consciousness and rare reports of coma), dyskinesia, dysphagia, encephalopathy, gastritis, gastroesophageal reflux, grand mal convulsions, intracranial hemorrhage, hepatitis (including increased ALT and AST and hepatic failure), hyperglycemia, hyperlipidemia, hypoglycemia, ileus, increased INR, impotence, lethargy, malaise, myoclonus, neuroleptic malignant syndrome, acute pancreatitis, Parkinsonism, acute renal failure (including increased creatinine and renal insufficiency), prolonged QT interval, restlessness, sepsis, StevensJohnson syndrome, suicidal ideation, sudden death, supraventricular tachycardia, tachycardia, tardive dyskinesia, thrombocytopenia, and hallucinations (both visual and auditory).

ANIMAL TOXICOLOGY Memantine induced neuronal lesions (vacuolation and necrosis) in the multipolar and pyramidal cells in cortical layers III and IV of the posterior cingulate and retrosplenial neocortices in rats, similar to those which are known to occur in rodents administered other NMDA receptor antagonists.

Lesions were seen after a single dose of memantine. In a study in which rats were given daily oral doses of memantine for 14 days, the no-effect dose for neuronal necrosis was 6 times the maximum recommended human dose on a mg/m2 basis. The potential for induction of central neuronal vacuolation and necrosis by NMDA receptor antagonists in humans is unknown.

DRUG ABUSE AND DEPENDENCE Controlled Substance Class: Memantine HCl is not a controlled substance.

Physical and Psychological Dependence: Memantine HCl is a low to moderate affinity uncompetitive NMDA antagonist that did not produce any evidence of drug-seeking behavior or withdrawal symptoms upon discontinuation in 2,504 patients who participated in clinical trials at therapeutic doses. Post marketing data, outside the U.S., retrospectively collected, has provided no evidence of drug abuse or dependence.

OVERDOSAGE Signs and symptoms associated with memantine overdosage in clinical trials and from worldwide marketing experience include agitation, confusion, ECG changes, loss of consciousness, psychosis, restlessness, slowed movement, somnolence, stupor, unsteady gait, visual hallucinations, vertigo, vomiting, and weakness. The largest known ingestion of memantine worldwide was 2.0 grams in a patient who took memantine in conjunction with unspecified antidiabetic medications. The patient experienced coma, diplopia, and agitation, but subsequently recovered.

Because strategies for the management of overdose are continually evolving, it is advisable to contact a poison control center to determine the latest recommendations for the management of an overdose of any drug.

As in any cases of overdose, general supportive measures should be utilized, and treatment should be symptomatic. Elimination of memantine can be enhanced by acidification of urine.

Licensed from Merz Pharmaceuticals GmbH Rev. 04/07 © 2007 Forest Laboratories, Inc.

INDUSTRY TRENDS

Payer Perspectives on Healthcare Reform Peyton Howell, MHA

Peyton Howell, MHA; Gene Reeder, RPh, PhD; Timothy S. Regan, BPharm, RPh, CPh

T

he first 100 days of the new administration have produced significant pieces of new legislation that include components of proposed healthcare reform, such as initial funding for comparative effectiveness research (CER). However, many questions remain about the potential scope of healthcare reform and how the new focus on areas such as comparative effectiveness will affect public and private health plans.

This article discusses some of the responses of 45 managed care leaders to a survey about their views and predictions on healthcare reform, and how their views have changed over the past year. These leading medical and pharmacy directors of health plans, pharmacy benefit management companies, integrated healthcare delivery systems, and other payer segments represent almost 200 million covered lives. The survey was conducted during the March 7, 2009, Managed Care Network (MCN) meeting in Dallas, Texas. The time interval is important, because this meeting occurred shortly after the new administration incorporated some components of healthcare reform in its initial legislative package. MCN meetings provide a quarterly live venue to conduct quantitative and qualitative payer market research, using anonymous audience-response on behalf of pharmaceutical, biotechnology, and medical device companies.

Despite growing economic challenges, healthcare reform remains a key component of President Obama’s goals for his administration. Several core components of his proposed health plan were included in the passage of the American Recovery and Reinvestment Act (ARRA; also known as the “stimulus package”), which was signed into law on February 17, 2009. The $787-billion stimulus plan includes key healthcare reform initiatives that support economic recovery and efficiency.

ARRA directs nearly $150 billion to healthcare initia-

Ms Howell is President, Consulting Services & Health Policy, AmerisourceBergen Specialty Group; Dr Reeder is Director, Xcenda Managed Care Network, Distinguished Professor Emeritus, University of South Carolina; Mr Regan is Executive Director, Xcenda, Customer Insights.

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tives, the highest percentage of any industry receiving stimulus funding.

Of this amount, $87 billion will be dispersed to states in the form of increased federal matching assistance funds plus extra resources for “high unemployment” states. But significant dollars are also directed at core healthcare reform components, including CER, adoption of health information technology, enhanced protection of the privacy and security of medical records, and funds for the National Institutes of Health (NIH).

Managed Care Perspectives The responses of these 45 managed care medical and pharmacy directors were consistent with surveys completed before and just after the November 2008 elections, showing that managed care leaders expect significant reform over the next few years. The majority of respondents (76%) say the progress in healthcare reform has been consistent with their expectations (Figure 1).

Overall, 69% predict that incremental reforms would be passed in 2009, including expanding coverage and implementing some cost-savings efforts; 20% think that nothing more significant would pass in 2009 beyond what has already passed (Figure 2). The uncertainty about healthcare reforms is clearly tied to the economy, with 44% of respondents predicting that further economic declines would significantly delay reforms (Figure 3).

But these managed care experts do not view the creation of a “buy-in” option to existing public programs as significant for the overall market. The buy-in option is one of the most controversial aspects being debated.

Some health policy experts are focused on creating a public payer buy-in option, but others think this would create an untenable marketplace for private payers. The latter advocate for a private payer buy-in option potentially modeled after the Federal Employee Health Benefits Programs (FEHBP), an approach discussed during the 2008 elections (Figure 4).

The majority of respondents predict that if a buy-in option is created, it will include a private model (like FEHBP) and a public payer option (Figure 5).

President Obama’s proposed budget, which was released in March 2009, includes significant cuts to

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INDUSTRY TRENDS

Figure 1 Which response best describes your view on the progress of health reform under the new administration?

(N = 45)

Figure 2 Which response best describes your prediction of the scope of healthcare reforms Congress and the new administration will pass in 2009?

Figure 3 If the economy declines further, will it affect healthcare reform for 2009?

(N = 43)

2%

(N = 45) 4%

11% 20%

20% 44%

40%

69%

76%

14%

More healthcare-related reforms have passed at this point than I had expected Consistent with expectations Slower progress than I had expected

Figure 4 Will healthcare reform in 2009 include some form of buy-in option into the Federal Employee Health Benefits Program or other public payer option?

Significant reforms will be passed, such as creating a public or private buy-in plan Incremental reforms will be passed, such as expanding coverage and some cost-savings efforts Nothing significant this year beyond what has already passed

Figure 5 Assuming that a buy-in option is created, what type of option is it likely to be?

(N = 44)

Yes, it will significantly delay reforms No, it will continue on track No, but the implementation timetables may be affected to buffer the costs Not sure

Figure 6 Will the proposed cuts in MA funds materially affect beneficiary MA options in the future?

(N = 45)

(N = 44) 7%

Not sure, 36%

Yes, 41%

18%

No, 4%

75%

Yes, 96% No, 23%

Private model similar to the FEHBP only Both a private model similar to the FEHBP and a public payer option Public payer option only FEHBP indicates Federal Employee Health Benefits Program.

Medicare Advantage (MA) plans, following the presidentâ&#x20AC;&#x2122;s campaign proposals. The stock market reacted significantly to these announcements and their potential impact for private payers with MA plans, as the

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AMERICAN HEALTH & DRUG BENEFITS June/July 2009

MA indicates Medicare Advantage.

stock prices of the major MA companies fell sharply after the news. The survey results suggest that managed care experts believe cuts to MA plans will create significant changes in the plans (Figure 6).

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Payer Perspectives on Healthcare Reform

Figure 7 Is some form of biosimilars legislation likely to pass this year as part of healthcare reform?

Figure 8 Will Congress create some form of least-costly alternative pathway this year?

(N = 42)

Figure 9 When do you think comparative effectiveness will have a trickle-down effect to private payers?

(N = 43)

(N = 44)

14% 30% No, 45%

Yes, 33%

Yes, 55%

56%

No, 67%

Significant impact in the next year or so Significant long-term impact (beyond 2 years) Limited impact as currently described

Biologics and Healthcare Reform An important area of concern for payers is the continued development of biotechnology (biologic) products and specialty pharmaceuticals. Embedded in this growing product market is the debate over biosimilars (or follow-on biologics), and how and when these alternatives may reach the market.

The survey included questions about healthcare reform issues relevant to biologics and specialty products. One of the most significant proposals being discussed today is legislation to create a regulatory pathway for biosimilars. Some 55% of respondents expect that biosimilars legislation will pass in Congress this year (Figure 7).

However, these payers are more skeptical about changes that could have a dramatic impact on biologics.

MCN members were asked about the likelihood that a pathway for a least-costly alternative would be created (Figure 8). Such a pathway would provide Medicare and other payers with a means to limit reimbursement to the lowest-priced technology across products considered to be therapeutically equivalent.

Comparative Effectiveness Research Another area of interest in healthcare reform is CER,

and how such information might be used in clinical and reimbursement decisions. The ARRA legislation allocated $1.1 billion for CER, which reflects the presidentâ&#x20AC;&#x2122;s commitment during the election to develop resources to support analysis and dissemination of health outcomes and effectiveness-related data. The ARRA funding will be used to conduct and support CER, to be overseen by the Federal Coordinating Council on Comparative Effectiveness Research. Funds will be distributed across the Agency for Healthcare Research and Quality, NIH, and the Department of Health and Human Services Secretary. The MCN respondents predict that CER will have a long-term effect (beyond the next 2 years) on private payers. No significant impact is expected until CER is first implemented for public payers (Figure 9).

Conclusion The survey results suggest that leaders across private payers and managed care organizations see a greater potential for major healthcare reform than many other industry experts, including physicians and pharmaceutical industry leaders. As the debate moves forward, it is essential for healthcare leaders to continue to monitor any reform proposals and stay engaged in the policymaking process. â&#x2013;

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183

CLINICAL

Use Pattern and Off-Label Use of Atypical Antipsychotics in Bipolar Disorder, 1998-2002 Jeffery A. Demland, MS; Yonghua Jing, BPharm, PhD; Christina M. L. Kelton, PhD; Jeff J. Guo, BPharm, MS, PhD; Hong Li, MPH, PhD; Patricia R. Wigle, PharmD Background: Postmarketing surveillance that identifies patients at high risk for receiving off-label medications will help ensure that the benefits of such treatment outweigh the risks. Because many off-label uses have little scientific support, tracking the extent to which they occur as well as the particular circumstances under which they occur is important.

Objective: To describe the drug-use pattern for patients with bipolar disorder, and to identify demographic and clinical factors associated with off-label use of atypical antipsychotics before US Jeff J. Guo Food and Drug Administration approval for this indication.

Methods: Using the PHARMetrics medical claims database, a total of 105,771 adult patients with a diagnosis of bipolar disorder were evaluated during the 5-year (1998-2002) study period. Study drugs included mood stabilizers, antipsychotics, and antidepressants. Off-label use of an atypical antipsychotic was defined as a patient taking olanzapine before March 2000 (when it received an indication for bipolar disorder) or any other atypical antipsychotic during the entire study period. Logistic regression analysis was used to determine the odds ratio of receiving a drug off-label.

Results: Utilization of and reimbursement for atypical antipsychotics increased during the 5-year period. Of the 10.5% of patients who took atypical antipsychotics, 7.1% took these drugs off-label. In addition, 11% of patients received lithium, 25% received other anticonvulsants, and 34% received antidepressants. Off-label use of atypical antipsychotics was associated with psychiatry specialist prescribers (odds ratio = 1.52; 95% CI, 1.44-1.59) and certain comorbidities, such as substance abuse (odds ratio = 1.51; 95% CI, 1.38-1.66), anxiety disorder (odds ratio = 1.20; 95% CI, 1.14-1.26), diabetes mellitus (odds ratio = 1.26; 95% CI, 1.16-1.37), cerebral vascular disease (odds ratio = 1.26; 95% CI, 1.10-1.45), and hypertension (odds ratio = 1.12; 95% CI, 1.05-1.20). Over time, there has been an increase in the number of drug therapies, including atypical antipsychotics, used to treat bipolar disorder.

Conclusion: Because of the significant association found between atypical antipsychotic use and several key comorbidities, it is important for physicians to recognize these associations and weigh the risks and benefits of atypical antipsychotics in their treatment strategies. [AHDB. 2009;2(4):184-191.]

B

ipolar disorder (BPD) is a chronic, recurrent psychiatric illness characterized by episodes of both mania and depression. It is estimated that up to 2.6% of the US adult population is affected by this disorder,1 and that the

Mr Demland is Clinical Research Associate, Medpace, Cincinnati, OH; Dr Jing is Health Outcomes Research Scientist, BristolMyers Squibb Pharmaceutical Research Institute, Hopewell, NJ; Dr Kelton is Professor of Economics, College of Business, University of Cincinnati, OH; Dr Guo is Associate Professor of Pharmacoeconomics and Pharmacoepidemiology, College of Pharmacy, University of Cincinnati Medical Center, OH; Dr Li is Director of Health Outcomes Research, Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, CT; Dr Wigle is Associate Professor of Pharmacy Practice, College of Pharmacy, University of Cincinnati Medical Center, OH.

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lifetime prevalence rate for bipolar spectrum disorders ranges from 3.0% to 6.5%.2 Direct treatment costs are sizable, at $11,600 per patient-year.3 Medication is an essential part of successful treatment for BPD. Although mood stabilizers (eg, lithium, divalproex sodium, carbamazepine, lamotrigine) have traditionally been used for primary treatment of BPD, atypical antipsychotics (ie, aripiprazole, clozapine, olanzapine, quetiapine, risperidone, and ziprasidone) have also been found helpful for stabilizing mood and have been used with increasing frequency since the mid-1990s.4,5 Atypical antipsychotics have been used for BPD even before they received a US Food and Drug Administration (FDA) indication (very recently) for this condition. Patients with BPD may need antidepres-

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sant medication during periods of depression. Because of the risk of triggering mania, physicians often prescribe antidepressants (ie, tricyclic antidepressants, monoamine oxidase inhibitors, selective serotonin reuptake inhibitors) with a mood stabilizer.

In March 2000, olanzapine was the first atypical antipsychotic to receive FDA indication for the treatment of mania. The off-label use of some atypical antipsychotics for BPD occurred before that. Subsequently, all the other atypical antipsychotics, with the exception of clozapine, received FDA approval for the treatment of BPD6: • Risperidone—in December 2003 • Quetiapine—in January 2004 • Aripiprazole—in September 2004 • Ziprasidone—in March 2006.

The use of medications for conditions other than those approved by the FDA is known as off-label use.

Although medications are often used off-label in the pediatric patient population,7-9 off-label use has also been common in adult clinical practice for diseases such as cancer, cardiovascular disorders, psychiatric disorders, and dementia.10-13 Indeed, more than 60% of patients taking antipsychotics received these medications for at least 1 off-label use.14 Off-label use of antipsychotics plays an important role in psychiatry because of the number of different indications for which there is no single, clearly preferred treatment.5,13,15 Currently, atypical antipsychotics have limited efficacy in, but are being used off-label for, dementia, non–BPD-related depression, obsessive compulsive disorder, and posttraumatic stress disorder.

Given drug safety considerations, postmarketing surveillance that can identify patients who are at high risk for receiving medications off-label will help ensure that the benefits of off-label treatment outweigh its risks. Because most off-label uses have little to no scientific support,12 it is important to keep track of the extent to which such uses occur, as well as the particular circumstances under which they occur.

We therefore proposed this study to determine the degree to which atypical antipsychotics were used offlabel in patients with BPD and to identify patient characteristics most associated with off-label use.

Although other drugs were prescribed off-label for patients with BPD, we focused specifically on atypical antipsychotics. This relatively new class of drugs has seen a tremendous rise in utilization and in spending,15 and has become a focus of attention for both private and public healthcare payers.

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KEY POINTS

Many off-label uses have little to no scientific support, so tracking the extent and circumstances under which they occur can enhance safety.

This study focused on off-label use of atypical antipsychotics for patients with bipolar disorder, because this relatively new class has seen a tremendous rise in utilization and spending, thus becoming a focus for private and public payers.

Results show a 5-year growing trend in the use of and spending on atypical antipsychotics and antidepressants for bipolar disorder. Reimbursement for atypical antipsychotics increased from $1050 per 100 patients to $4800, a more than 4-fold increase.

During the study period, psychiatrists were more likely to prescribe off-label atypical antipsychotics than general physicians, which could be the result of earlier evidence showing benefits for these agents in bipolar disorder. The majority of these medications have since received an indication for this condition.

Metabolic complications should be carefully considered when prescribing atypical antipsychotics for patients with bipolar disorder.

Methods, Materials The primary data source was the PHARMetrics managed care medical claims database, a patient-level database consisting of claims for more than 45 million patients across 70 managed care plans nationwide. This database contains information on pharmacy claims, hospital institutional claims, outpatient medical claims, patient demographics (age and geographic distributions in the database are close to those for the entire United States), provider specialty, and other patient enrollment information.16 The study period was from January 1, 1998, through December 31, 2002.

We started with 709,865 patients who had at least 1 medical claim with a diagnosis of affective disorder (ICD-9 296.xx) or cyclothymia (ICD-9 301.13). We then excluded all Medicaid recipients (n = 44,095).

Studies indicate that the Medicaid population is unique and may have different disease prevalence and drug-use patterns than the general population.17-19 Patients with schizophrenia (n = 15,199), who have been studied elsewhere in the literature, and patients (n = 633,050) with only a depression diagnosis code (ICD-9 311, 296.2x, and 296.3x) were also excluded. Because less than 0.1%

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Figure 1 Quarterly Prescriptions for Bipolar Disorder Medications per 100 Patients, 1998-2002 Antidepressants Anticonvulsants Typical antipsychotics Lithium Atypical antipsychotics

100

Prescriptions per 100 patients, N

90 80

Olanzapine BPD indication

70 60 50 40 30 20 10 0 Q1

Q2 Q3 1998

Q4

Q1

Q2 Q3 1999

Q4

Q1

Q2 Q3 2000

Q4

Q1

Q2 Q3 2001

Q4

Q1

Q2 Q3 2002

Q4

BPD indicates bipolar disorder.

of the study group had cyclothymia, patients with that disorder were not categorized separately. Although some of these individuals with depression may be expected to be diagnosed with BPD eventually, no conclusive evidence of BPD was available during this study. A total of 17,521 patients younger than age 18 were also excluded.

After these exclusions, we were left with a study cohort of 105,771 adult patients (age ≥18) who met the criterion of having a BPD diagnosis, as indicated by ICD-9 296.0, 296.1, 296.4, 296.5, 296.6, 296.7, or 296.8.

Because some patients in the PHARMetrics database have limited (or nonexistent) drug coverage, we expected them to have a lower likelihood of atypical antipsychotic use. We conducted our analyses for a subcohort of 58,918 adult patients who received at least 2 prescriptions for BPD-related medications during the study period. By excluding patients who received ≤1 prescription, we could focus on BPD-diagnosed individuals with some nonzero probability of off-label drug use.

Prescribed Drugs The study focused on 4 types of BPD medications: (1) lithium and other anticonvulsants, including divalproex sodium, carbamazepine, lamotrigine, gabapentin, topiramate, and oxcarbazepine; (2) atypical antipsychotics, including olanzapine, risperidone, ziprasidone, aripiprazole, and quetiapine; (3) typical antipsychotics, including haloperidol, chlorpromazine, and perphenazine; and

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(4) antidepressants, including nefazodone, trazodone, mirtazapine, venlafaxine, and bupropion. For each quarter during the 5-year study period, the number of prescriptions per 100 patients was calculated using the total number of prescriptions divided by the total number of patients (in 100s) in that quarter. Similarly, the quarterly reimbursement per 100 patients was calculated by dividing the total drug reimbursements by the number of patients (in 100s) in the quarter.

Off-Label Use Definition The off-label use of an atypical antipsychotic was defined as a patient’s receipt of olanzapine before March 2000 or any other atypical antipsychotic during the entire study period. Hence, the dependent variable is a dichotomous variable (off-label use = 1, non–off-label use = 0). Patients may have been taking other medications for BPD. Covariates There are 2 known major types of clinical comorbidities among patients with BPD: psychiatric disorders and general medical comorbidities.20-24 Psychiatric disorders include alcohol and substance abuse disorders, anxiety disorder, impulse-control disorder, personality disorder, and eating disorders. General medical comorbidities include diabetes mellitus, cancer, hypertension, chronic obstructive pulmonary disease, cerebrovascular disease,

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Figure 2 Quarterly Reimbursement for Bipolar Disorder Medications per 100 Patients, 1998-2002 Antidepressants Anticonvulsants Atypical antipsychotics Typical antipsychotics Lithium

8000

Reimbursement per 100 patients, $

7000

Olanzapine BPD indication

6000 5000 4000 3000 2000 1000 0 Q1

Q2 Q3 1998

Q4

Q1

Q2 Q3 1999

Q4

Q1

Q2 Q3 2000

Q4

Q1

Q2 Q3 2001

Q4

Q1

Q2 Q3 2002

Q4

BPD indicates bipolar disorder.

ischemic heart disease, arthritis, and obesity. All comorbidities were identified by their ICD-9 codes in either institutional or medical claims files after the date of first diagnosis of BPD. All comorbidities were represented by dichotomous variables in the statistical analyses.

The age of BPD onset for each patient was calculated as the year of bipolar diagnosis minus the patient’s birth year. Sex was a dichotomous variable (male = 1, female = 0). A final dichotomous variable distinguished between whether a patient visited a psychiatric specialist (yes = 1, no = 0). Because the PHARMetrics database does not provide a patient’s race or ethnicity, neither could be included in the data analysis.

Data Analysis For the patient cohort and subcohort, descriptive statistics were computed for off-label use of atypical antipsychotics, use of other BPD medications, such as mood stabilizers, as well as for the demographic and comorbidity covariates mentioned above. And a logistic regression analysis was performed to assess the association between off-label use of atypical antipsychotics and the covariates. The data were analyzed using SAS version 8.2 (SAS Institute, Cary, NC).

Results Figures 1 and 2 depict the drug-use and drug-reimbursement patterns, respectively, for patients with BPD

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in the database from 1998 to 2002. Quarterly lithium prescriptions remained steady, at approximately 10 prescriptions per 100 patients, but use of other medications—including anticonvulsants, antipsychotics, and antidepressants—increased during the study period.

Consequently, the overall drug reimbursement trend was increasing; atypical antipsychotic reimbursements alone increased from $1050 to $4800 per 100 patients, a more than 4-fold increase.

Descriptive statistics are presented in Table 1. Of the entire cohort consisting of 105,771 patients, 7499 (7.1%) received off-label prescriptions of atypical antipsychotics for the treatment of BPD. Of the subcohort of patients who received pharmaceutical prescriptions for BPD, the off-label use was 12.4%.

During the study period, 54.0% of patients in the cohort (54.4% of patients in the subcohort) visited at least 1 psychiatric specialist. Among the cohort group, 11,513 (10.9%) patients received at least 1 prescription for lithium, 26,149 (24.7%) received prescriptions for anticonvulsants, 35,472 (33.5%) received prescriptions for antidepressants, 19,138 (18.1%) received prescriptions for typical antipsychotics, and 11,065 (10.5%) received prescriptions for atypical antipsychotics.

The most common psychiatric and medical comorbidities (seen in more than 5% of the BPD-diagnosed patients) for the cohort and the subcohort included alcohol abuse and substance abuse, anxiety disorder, hyper-

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Table 1 Demographic/Clinical Features of Patients with Bipolar Disorder, 1998-2002 Patients Patients w/ ≥2 Rx Variable (n = 105,771) (n = 58,918) Mean age, yrs

40.3 (SD ± 12.8)

40.7 (SD ± 12.7)

Female, n (%)

66,783 (63.1)

38,002 (64.5)

26.6 (SD ± 14.7)

25.9 (SD ± 14.0)

18-34

35,916 (34.0)

19,086 (32.4)

35-49

45,191 (42.7)

25,796 (43.8)

50-65

21,754 (20.6)

12,228 (20.7)

2910 (2.7)

1808 (3.1)

7499 (7.1)

7317 (12.4)

57,153 (54.0)

32,027 (54.4)

Lithium

11,513 (10.9)

11,330 (19.2)

Anticonvulsants

26,419 (24.7)

25,068 (42.5)

Atypical antipsychotics

11,065 (10.5)

10,816 (18.3)

Typical antipsychotics

19,138 (18.1)

18,643 (31.6)

Antidepressants

35,472 (33.5)

34,794 (59.1)

Mean months enrolled Age-group, yrs/n (%)

65+ Prescribing features, n (%) Off-label use Psychiatric specialist Medicationsa, n (%)

Psychiatric comorbidityb, n (%) Alcohol abuse

7498 (7.1)

4155 (7.1)

Substance abuse

5759 (5.4)

3277 (5.6)

Anxiety disorder

39,210 (37.1)

23,063 (39.1)

Impulse-control disorder

1299 (1.2)

726 (1.2)

Personality disorder

4006 (3.8)

2183 (3.7)

1151 (1.1)

655 (1.1)

Diabetes mellitus

8958 (8.5)

5126 (8.7)

Cancer

1049 (1.0)

609 (1.0)

Eating disorder b

Medical comorbidity , n (%)

Hypertension Chronic obstructive pulmonary disease Cerebrovascular disease

22,211 (21.0)

12,814 (21.7)

4019 (3.8)

2258 (3.8)

3192 (3.0)

1727 (2.9)

Ischemic heart disease

4350 (4.1)

2465 (4.2)

Arthritis

2700 (2.6)

1686 (2.9)

Obesity

6983 (6.6)

3878 (6.7)

a Patients b

may receive multiple medications for bipolar disorder treatment.

Patients may have multiple comorbidities during the study period.

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tension, diabetes mellitus, and obesity. Of the cohort patients, 63% were female; mean age, 40.3 years.

Table 2 presents results from the logistic regression analysis. For the cohort and the subcohort, men were significantly less likely to receive an off-label prescription drug than women. Patients visiting a psychiatric specialist were more likely to receive off-label prescriptions for atypical antipsychotics. Patients diagnosed with substance abuse, anxiety disorder, personality disorder, or cerebrovascular disease were significantly more likely to receive off-label drugs.

Although patients diagnosed with diabetes mellitus, hypertension, or obesity were also more likely to use atypical antipsychotics off-label than those who did not have these conditions, results for these 3 comorbidities must be interpreted carefully for 2 reasons. First, these 3 comorbidities are all related to metabolic syndrome and hence may be collinear. Second, there may be some simultaneity bias, in that the use of antipsychotics may worsen these disease states. To make sure that none of the other results were affected by these 3 comorbidities, we reran the regression analyses omitting these variables.

None of the other results were affected.

Discussion These results indicate that a relatively small proportion of patients with BPD received the traditional mood stabilizer lithium for the treatment of BPD between 1998 and 2002. But there was an increasing trend in the use of other anticonvulsants, as well as the use of atypical antipsychotics and antidepressants. Overall, drug utilization among BPD patients increased during the study period, and the trend was especially pronounced for atypical antipsychotic medications.

This finding is consistent with other studies. For example, Jing and colleagues reported that the Medicaid expenditure for antipsychotics increased sharply from $166 million in 1991 to $5.5 billion in 2005 as a result of rising drug utilization and entry of new high-priced atypical antipsychotics.15 In the Medicaid program, the total number of antipsychotic prescriptions increased from 7.2 million in 1991 to 24.1 million in 2005.15 Although conventional antipsychotics were also used for the treatment of acute mania, long-term use was limited due to intolerable adverse events, including akathisia, extrapyramidal symptoms, and tardive dyskinesia. Atypical antipsychotics are generally regarded as having lower risk for causing extrapyramidal symptoms. However, with increasing evidence linking diabetes mellitus and other metabolic complications with some of the atypical antipsychotics,

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many clinicians have become cautious about prescribing specific atypical antipsychotics.23-28 Between 1998 and 2002, off-label use of atypical antipsychotics was established as a treatment for BPD. Results show that 7.1% of patients with BPD (and 12.4% of the subcohort of patients being treated with medication) received atypical antipsychotics off-label.

Moreover, atypical antipsychotics represented 10.5% of the total prescriptions (18.3% for the subcohort) used for BPD management. Because BPD is a complex disorder that can be characterized by a wide range of symptoms that vary in type and severity, treatment is likewise complicated, and it is not surprising that physicians turn to off-label therapies. According to a recommendation from the American Psychiatric Association, treatment for patients with severe BPD could involve lithium or divalproex in combination with an antipsychotic.25,29 Male patients had 22% lower odds than female patients of receiving atypical antipsychotics off-label, and patients who visited a psychiatric specialist had 52% higher odds than those seeing general physicians for receiving prescriptions for off-label atypical antipsychotics. These findings are consistent with findings from a recent study based on the Georgia Medicaid population.14 Of note, results from several clinical trials had demonstrated the efficacy of some atypical antipsychotics for BPD; the studies had been published before the FDA approved these medications for BPD.26,27 It is therefore possible that trained psychiatrists were familiar with these studies, and that could have influenced their prescribing behaviors.

Our study also shows that patients with some psychiatric comorbidities had increased odds of receiving atypical antipsychotics off-label: 51% increased risk with substance abuse, 47% with personality disorder, and 20% with anxiety disorder. These increases in risk could be related to the progression of BPD and the inability to manage symptoms effectively using conventional therapy. Moreover, these results are consistent with studies about off-label use of central nervous system pharmacotherapies.12-14 Another finding in this study is that increased odds (26.8%) of receiving atypical antipsychotic prescriptions for off-label use are associated with patients with cerebrovascular disease. Although it is not clear why this should be the case, some studies suggest that cerebrovascular events may occur in patients taking risperidone,28 olanzapine,30 or other antipsychotics.31,32 That is, there is some evidence of reverse causation. Further exploration of the link between cerebrovascular disease and atypical

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Table 2 Off-Label Use Odds Ratio for Patients with Bipolar Disorder, 1998-2002

Variables

Patients Patients w/ â&#x2030;Ľ2 Rx (n = 105,771) (n = 58,918) Odds ratio (95% Odds ratio (95% confidence interval) confidence interval)

Sex (male = 1)

0.78 (0.77-0.83)

0.82 (0.78-0.87)

Age

1.001 (0.99-1.01)

0.998 (0.99-1.00)

Psychiatric specialist

1.52 (1.44-1.59)

1.57 (1.49-1.66)

Key psychiatric comorbidities Alcohol abuse

1.01 (0.93-1.11)

1.03 (0.93-1.14)

Substance abuse

1.51 (1.37-1.66)

1.44 (1.30-1.60)

Anxiety disorder

1.20 (1.14-1.26)

1.08 (1.03-1.14)

Impulse-control disorder

1.17 (0.97-1.42)

1.14 (0.93-1.40)

Personality disorder

1.47 (1.33-1.63)

1.64 (1.47-1.83)

Eating disorder

1.18 (0.97-1.43)

1.11 (0.90-1.37)

General medical comorbidities Diabetes mellitus

1.26 (1.16-1.37)

1.24 (1.14-1.35)

Cancer

0.93 (0.73-1.18)

0.91 (0.71-1.18)

Hypertension Chronic obstructive pulmonary disease

1.12 (1.05-1.20)

1.10 (1.03-1.18)

1.07 (0.95-1.21)

1.12 (0.99-1.27)

Cerebrovascular disease

1.27 (1.12-1.44)

1.26 (1.10-1.45)

Ischemic heart disease

0.95 (0.84-1.07)

0.94 (0.83-1.07)

Arthritis

1.07 (0.93-1.23)

0.98 (0.85-1.14)

Obesity

1.19 (1.09-1.30)

1.27 (1.15-1.39)

Model goodness-of-fit Chi-square = 766.73 Chi-square = 639.76 -2 Log likelihood = 53,379, P < .001

-2 Log likelihood = 43,571, P < .001

antipsychotics is certainly warranted. Clinicians should be aware of this potential when prescribing atypical antipsychotics for patients with BPD. Similarly, the present study reveals that diabetes mellitus, obesity, and hypertension were significantly associated with the use of atypical antipsychotics. Again, why this association is more prevalent in patients with these comorbidities is unclear, but studies have linked the use of atypical antipsychotics to the development of metabolic complications.23,24,33,34 Therefore, metabolic complications should be carefully considered when prescribing atypical antipsychotics for patients with BPD. The results of this retrospective analysis can be applied to off-label drug use for other therapeutic classes.

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The use of drugs off-label is expected to continue to play an important role in clinical psychiatry and in other complicated diseases, such as cancer and cardiovascular disorders. Although off-label use is often based on scientifically sound results from clinical trials or other relevant studies, risk/benefit management should be part of any off-label drug therapy.

Limitations This study population was limited to individuals in US managed care organizations. Thus, findings should not be generalized to Medicaid or other populations.

Because we were unable to assess each patient’s drug therapy and diagnosis prior to the study period, patients who were in remission from BPD were not included in the study. Moreover, because healthcare coverage varies among health plans, the healthcare utilization and druguse patterns may reflect the characteristics of the particular managed care plans in this database.

Because of the limited information from retrospective claims, we are unable to assess treatment for patients who received a bipolar diagnosis but had no follow-up drug therapy. To minimize potential bias, we conducted analyses based on both a cohort and subcohort of patients who were treated with medication.

Conclusion BPD is a complex psychiatric condition that has proved difficult to treat. The disease severity and response to previous treatment are used to guide drug therapy. As this study has shown, off-label drug use for patients with BPD is common in clinical practice.

Because the odds of using atypical antipsychotics were greater for patients who had some key comorbidities, such as substance abuse, diabetes, or hypertension, it is important to recognize these associations and consider the risks and benefits of atypical antipsychotic use in the treatment strategies. ■ Disclosure Statement Dr Guo receives research grants from Bristol-Myers Squibb and Johnson & Johnson. Dr Kelton is a consultant to Procter & Gamble Pharmaceuticals.

Acknowledgments An earlier version of this article served as Mr Demland’s master’s capstone report, University of Cincinnati College of Pharmacy. The authors received grant support from Bristol-Myers Squibb Pharmaceutical Research Institute to access the commercially available PHARMetrics medical claims database. The conclusions reached are solely those of the authors. The authors would like to thank Paul E. Keck, Jr, MD, and Nick C. Patel, PharmD,

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PhD, for their advice on the research design; Dr Dongming Jiang for assistance with data/statistical analysis; and Raymond Jang, PhD, and Anthony Louder, PhD, for their collaboration.

Corresponding author: Dr Guo, University of Cincinnati Medical Center, 3225 Eden Ave, Cincinnati, OH 45267; jeff.guo@uc.edu

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29. American Psychiatric Association. Practice guideline for the treatment of patients with bipolar disorder (revision). Am J Psychiatry.

2002;159(4 suppl):1-50.

30. Wooltorton E. Olanzapine (Zyprexa): increased incidence of cerebrovascular events in dementia trials. CMAJ. 2004;170:1395.

31. Kortepeter C, Chen M, Knudsen JF, et al. Clozapine and venous thromboembolism. Am J Psychiatry. 2002;159:876-877.

32. Smith DA, Beier MT. Association between risperidone treatment and cerebrovascular adverse events: examining the evidence and postulating hypotheses for an underlying mechanism. J Am Med Dir Assoc.

2004;5:129-132.

33. Lund BC, Perry PJ, Brooks JM, et al. Clozapine use in patients with schizophrenia and the risk of diabetes, hyperlipidemia, and hypertension: a claims-based approach. Arch Gen Psychiatry. 2001;58:1172-1176.

34. Sumiyoshi T, Roy A, Jayathilake K, et al. The effect of hypertension and obesity on the development of diabetes mellitus in patients treated with atypical antipsychotic drugs. J Clin Psychopharmacol. 2004;24:452-454.

STAKEHOLDER PERSPECTIVE Health Plans’ Approaches to Managing Appropriate Use of Antipsychotic Drugs Outpatient prescription drug formularies were originally developed in the early 1990s, when only the first “atypical” antipsychotic—Clozaril—had entered the market. At that time, first-generation antipsychotics, such as Haldol, Mellaril, Prolixin, and Thorazine, were often prescribed. These agents, however, were associated with extrapyramidal, anticholinergic, and alpha-adrenergic side effects, leading physicians to carefully assess the risks and benefits before prescribing any of them. With limited utilization, this drug class did not hit the “radar screen” of managed care.

When the newer atypical antipsychotics—such as Risperdal, Zyprexa, and Seroquel—hit the market, they were touted as having an improved side-effect profile and reduced extrapyramidal effects. The drug companies heavily marketed these new agents as superior to their first-generation counterparts, and premium priced their products, anticipating that clinicians would quickly adopt them as their preferred drugs.

The utilization and cost of these antipsychotics quickly escalated. Pharmacy & Therapeutics Committees at health plans and pharmacy benefit management (PBM) companies across the country thoroughly reviewed the clinical attributes and limitations of the typical and atypical antipsychotic medications. Along with safety and efficacy, cost was also taken into consideration.

Some plans and PBM companies decided it was prudent to restrict the use of the newer agents to specialists and use the prior authorization mechanism to review requests from primary care physicians. Others

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decided to review all requests for the atypical antipsychotics to ensure that they were being prescribed in accordance with (1) US Food and Drug Administration–approved indications; (2) indications recognized in well-respected drug compendia; or (3) positive outcomes substantiated in well-designed and well-conducted studies published in peer-reviewed journals.

This approach to a new class of drugs was common when closed formularies—with a flat copay or a brand/generic copay structure—were prevalent. As the industry moved to a 3-tier drug benefit design, the use of prior authorization structure was reduced to an extent, although it is still practiced in some instances.

Any health plan or PBM company that has a drug or a drug class under prior authorization will periodically review the pattern associated with the requests it is receiving, and how the standard of care has changed over time. As a result, some plans and PBM companies will (1) remove the prior authorization requirement on that class entirely; (2) require reviews from nonspecialists only; or (3) use the tier structure as the only means of differentiating medications as preferred or nonpreferred.

This process occurs with many new agents and drug classes as they are used over the course of time in many different patient types. This pattern is not exclusive to atypical antipsychotics being prescribed for bipolar disorder.

Renee Rizzo Fleming, RPh, MBA PRN Managed Care Consulting Services, LLC East Amherst, NY

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Applying Evidence for Medical Technologies Interview with Sean Tunis, MD, MSc

As former Director of the Office of Clinical Standards and Quality at the Centers for Medicare & Medicaid Services (CMS), Dr Tunis spent 5 years in charge of policy for Medicare, trying to make policy decisions more explicitly based on evidence. After leaving CMS, he formed the Center for Medical Technology Policy, with the goal of creating a platform for healthcare stakeholders to explore new ideas to align the goals of those involved

in research and development of medical products with the needs of patients and clinicians in the real world. Dr Tunis stresses it is crucial to focus on coverage with evidence development as the basis for benefit design and for improving the quality of evidence around a specific clinical service/technology. Aligning stakeholder perspectives is necessary to ensure that new and emerging products and medical technologies would meet true patient needs.

The Working Patient with Cancer: Implications for Payers and Employers Grant D. Lawless, BSPharm, MD, FACP

In 2005, Amgen launched a 3-year initiative to understand the impact that cancer has on employees and their employers. The findings of this initiative provide insights into cancer as an increasingly chronic and manageable disease, allowing patients to remain in the workforce. A growing number of employees now continue to work while being treated for cancer or return to work after their treatment is complete. Among patients with breast cancer, 56% remained with the same employer 5 years after

their initial diagnosis, and 34% remained with the same employer for 9 years. These data have implications for those in charge of benefit design and can help employers to better balance employee copayments with health and productivity. Cost is a major issue for this patient population, and out-of-pocket costs can become a major obstacle. Dr Lawless shows that if working patients with cancer are adequately supported, they can remain productive while receiving cancer treatment.

Predictors of First-Fill Adherence to New Asthma Prescriptions Zackary Berger, MD, PhD; William Kimbrough, MD; Colleen Gillespie, PhD; Joseph A. Boscarino, PhD, MPH; G. Craig Wood, MS; Zhengmin Qian, MD, PhD; J. B. Jones, PhD, MBA; Nirav R. Shah, MD, MPH, FACP

Nonadherence to asthma medications is associated with increased emergency department visits and hospitalizations. This is the largest study of its kind to analyze characteristics of first-fill or no-fill of asthma prescriptions that are used to measure the level of medication adherence. Of the 2023 patients with asthma in this study, 78% filled their first-time prescriptions within 30 days, and 22% did not. Copay level had a significant role

in patients filling their asthma prescriptions. First-fill rate was lower for patients with a copay above the mean of $12 than for those with a copay of more than $12.

First-fill was higher for patients prescribed oral plus inhaled medications compared with inhaled-only agents.

Other variables affecting first-fill rates included therapeutic class, route of administration, and controller and reliever type of medications.

Use Pattern and Off-Label Use of Atypical Antipsychotics in Adults with Bipolar Disorder, 1998-2002 Jeffery A. Demland, MS; Yonghua Jing, BPharm, PhD; Christina M. L. Kelton, PhD; Jeff J. Guo, BPharm, PhD; Hong Li, MPH, PhD; Patricia R. Wigle, PharmD

Results of this study show a 5-year growing trend in the use of and spending on atypical antipsychotics and antidepressants for bipolar disorder. Reimbursement for these agents increased from $1050 per 100 patients to $4800, a more than 4-fold increase. By 2002, only 1 drug in that class received an indication for bipolar disorder, yet many of the other atypical antipsychotics were being prescribed off-label for that condition, despite potential

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risks, such as metabolic complications, associated with these agents.

Because most off-label uses have little to no scientific support, tracking the extent and circumstances under which they occur can enhance safety. The authors suggest that postmarketing surveillance to identify patients at risk for off-label drug use can ensure that the benefits of off-label treatments outweigh the risks.

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CE INFORMATION

Sponsor This activity is jointly sponsored by Medical Learning Institute, Inc., a nonprofit medical accreditation company, and Center of Excellence Media, LLC.

(ACPE) as a provider of continuing pharmacy education.

Completion of this activity provides for 1.0 contact hour (0.1 CEU) of continuing education credit. The universal program number for this activity is 468-999-09-020-H01-P.

Target Audience This activity was developed for pharmacists and other healthcare professionals practicing in a managed care environment.

Faculty Disclosures Before the activity, all faculty will disclose the existence of any financial interest and/or relationship(s) they might have with the manufacturer(s) of any commercial product(s) to be discussed during their presentation(s): honoraria, expenses, grants, consulting roles, speaker’s bureau membership, stock ownership, or other special relationships. Presenters will inform participants of any off-label discussions.

Learning Objectives At the completion of this educational activity, participants should be able to: • Increase awareness of the economic impact of COPD • Examine the impact of COPD in the workplace and on society • Encourage early recognition and treatment of COPD to reduce future economic costs • Increase investments in human capital to boost economic growth in the next generation • Heighten awareness of the overall burden of COPD on the patient, family, society, and in the workplace • Examine the comorbidities and complications associated with COPD and associated personal, social, and economic burdens Commercial Support Acknowledgment This activity is funded by an educational grant from Boehringer Ingelheim.

Instructions for Credit There is no fee for this activity. To receive credit, participants must first take the pretest for this activity. After reading this CE activity in its entirety, participants must complete the posttest and evaluation. The pretest, posttest, and evaluation can be completed online at www.mlicme.org/p09045.html.

Upon completion of the evaluation and scoring 70% or better on the posttest, you will immediately receive your certificate online. If you do not achieve a score of 70% or better on the posttest, you will be asked to take it again. Please retain a copy of the certificate for your records.

For questions regarding the accreditation of this activity, please contact Medical Learning Institute, Inc., at 609333-1693 or cgusack@mlicme.org.

Pharmacists Designation Medical Learning Institute, Inc., is accredited by the Accreditation Council for Pharmacy Education

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The associates of Medical Learning Institute, Inc., and Center of Excellence Media, LLC, have no financial relationships to disclose.

Dr William Bunn has no financial relationships with any commercial interest to disclose relevant to this supplement.

He does not intend to discuss any non–FDA-approved or investigational use of any product/device.

Dr David Tinkelman is a consultant for Amgen, Novartis, and Wyeth. He does not intend to discuss any non–FDAapproved or investigational use of any product/device.

Dr F. Randy Vogenberg is on the speaker’s bureau for Boehringer Ingelheim, Pfizer, and sanofi aventis; he is a consultant for Pfizer; and he has received research honoraria from Ethicon Endo-Surgery. He does not intend to discuss any non–FDA-approved or investigational use of any product/device.

Disclaimer The information provided in this CE activity is for continuing education purposes only and is not meant to substitute for the independent medical judgment of a healthcare provider relative to diagnostic and treatment options of a specific patient’s medical condition.

Estimated time to complete activity: 1.0 hour Initial Release Date: June 30, 2009.

Expiration Date: June 30, 2010.

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OVERVIEW

Workplace Wellness and Disease Prevention: Focus on Chronic Obstructive Pulmonary Disease

I

n the United States, chronic obstructive pulmonary disease (COPD), characterized by airflow limitation that is not fully reversible, is the fourth leading cause of death, after heart disease, cancer, and cerebrovascular disease.1,2 An estimated 12 million Americans are currently diagnosed with COPD, but at least an equal number of people are believed to have the disease and have not been diagnosed.3 More than 90% of cases of COPD are caused by smoking,2 and therefore smoking cessation is a crucial strategy in the effort to reduce the incidence of COPD. No cure has yet been found for this disease, and true breakthroughs in treatment are lacking.

The costs associated with COPD are approaching $18 billion in direct costs and $14 billion in indirect costs.2,4 Hospitalizations account for approximately 40% of the direct costs, and prescription drugs for 20%.5 In 2000, 16 million office visits were attributed to COPD-related conditions.5 Despite these disturbing figures, COPD remains largely unrecognized as a public health problem.

Comorbidities associated with COPD include pneumonia, osteoporosis, respiratory infections, myocardial infarction, and depression. Extrapulmonary features contribute to the severity of the disease.

Symptoms of an exacerbation range from increased breathlessness accompanied by cough and sputum production in mild COPD to life-threatening respiratory failure in severe disease. Infection, particularly bacterial, is frequently implicated in exacerbations. Air pollution can also trigger exacerbations, but a cause-andeffect relationship is not always discernible. COPD exacerbations can often be managed at home. Hospital admission may be required, depending on symptom intensity, lack of response to medical management, or a change in mental status.

COPD will remain a significant and growing problem for years to come. Clinicians will need to pay increasing attention to COPD and collaborate with employers, health plan administrators, and regulatory agencies to mitigate the overall burden of this disease.

Barbara Bekiesz assisted in the development of this overview.

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Pharmacotherapy Pharmacotherapy can relieve symptoms, prevent or minimize exacerbations and complications, improve exercise performance, and decrease mortality. None of the medications available today can alter the progressive deterioration in lung function typical in COPD. Bronchodilators are the mainstay of management, and glucocorticosteroids are recommended for the treatment of severe to very severe disease in patients who have repeated exacerbations.

Nonpharmacologic Interventions Rehabilitation programs generally focus on endurance exercise to increase work and exercise capacity.

Oxygen therapy is advised for patients with resting hypoxemia. Surgery to reduce lung volume is an expensive, palliative procedure that should be undertaken only in carefully selected patients.

Conclusion Businesses, providers, and health benefit managers now have much more information on COPD than in the past to help their decisions on how to reduce the workplace-related economic burden and social cost of this disease. COPD within the working population leads to direct and indirect costs to industry because of the progressive nature of this disease. Each industry sector will need to analyze the impact of COPD on its business and determine benefit solutions that will be effective in reducing lost productivity and healthcare costs, while addressing the social and cultural factors that lead to the disease. Communications about COPD must continue to address all stakeholders and emphasize smoking-cessation, accurate diagnosis, reduction of occupational exposures, and guideline-based management as key interventions for this progressive disease. â&#x2013; References 1. Murray CJ, Lopez AD. Alternative projection of mortality and disability by cause 1990-2020: Global Burden of Disease Study. Lancet. 1997;349: 1498-1504.

2. National Heart, Lung, and Blood Institute. Data Fact Sheet: Chronic Obstructive Pulmonary Disease. National Institutes of Health Publication 035229. Bethesda, MD: US Department of Health and Human Services; 2003.

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INTRODUCTION

www.nhlbi.nih.gov/health/public/lung/other/copd_fact.pdf. Accessed May 5, 2008.

3. National Heart, Lung, and Blood Institute. Morbidity and Mortality: 2007 Chart Book on Cardiovascular, Lung, and Blood Diseases. Bethesda, MD: National Institutes of Health. www.nhlbi.nih.gov/resources/docs/07 -chtbk.pdf. Accessed April 30, 2008.

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4. Skrepnek GH, Skrepnek SV. Epidemiology, clinical and economic burden, and natural history of chronic obstructive pulmonary disease and asthma. Am J Managed Care. 2004;10(5 suppl):S129-S138.

5. National Heart, Lung, and Blood Institute. Morbidity and Mortality: 2002 Chartbook on Cardiovascular, Lung, and Blood Diseases. Bethesda, MD: US Department of Health and Human Services; 2002.

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COPD Management in a Value-Based Healthcare System Interview with David Tinkelman, MD In this interview, Dr Tinkelman discusses the clinical approach to the diagnosis and treatment of chronic obstructive pulmonary disease and the effects of this airways disease on employees and employers. He stresses that smoking, much more than occupational exposure, causes this chronic and irreversible lung disease. Progressive loss of lung function reduces productivity in workers whose jobs require physical exertion. A significant number of employees with this disease become disabled. Therefore, companies would do well to support employees in their efforts to quit smoking to lower the impact of this debilitating disease in their workplace. The case study typifies the etiology and progression of this disease. [AHDB. 2009;2(4):195-197.]

F. Randy Vogenberg, RPh, PhD: Could you begin by addressing the differential diagnosis of chronic obstructive pulmonary disease (COPD) in relation to asthma?

David Tinkelman, MD: Both asthma and COPD are inflammatory airway diseases, which is an important fact because these conditions may be similar in their clinical presentation. They both involve inflammation, but the inflammation is mediated by different pathways and has entirely different triggers.1 In COPD, the inflammation leads to destruction and to irreversible airway changes.

In asthma, the inflammatory process causes the airways to become hyperresponsive, which enables them to go into spasm, and the airways become thickened due to the inflammation; but these changes are reversible. The essential difference between COPD and asthma is that asthma is a fully reversible lung disease, and COPD is an irreversible or only partially reversible lung disease.

The causes of COPD and asthma are also different.1 COPD is predominantly, although not exclusively, caused by smoking. In contrast, a large percentage of asthma cases are caused by allergy. In some people, asthma is caused by an infectious disease process. Unlike COPD, asthma is not a destructive airway disease.

Global Initiative for Obstructive Lung Disease (GOLD initiative).2 Before that, the term “COPD” was not used very much and was referred to as “emphysema” or “chronic bronchitis.” However, each of these terms describes something different: emphysema describes a pathologic change, with destruction of the terminal airways resulting in air trapping; chronic bronchitis describes a clinical presentation, with hypersecretion of mucus and months of coughing, predominantly in the morning. The original GOLD initiative guidelines adopted the term COPD, which encompasses both emphysema and chronic bronchitis, and heightened awareness to the condition.

The American Thoracic Society (ATS) also issued its own guidelines in 2004.3 Whereas the GOLD initiative criteria for COPD focused on measured lung function, by forced expiratory volume in 1 second (FEV1)and forced vital capacity, the ATS criteria incorporated clinical symptoms in addition to lung function measurements.

When the GOLD initiative guidelines were updated in 2007, clinical symptoms were added to the definition.4 Almost 60% of primary care physicians never do a lung function test on patients with respiratory symptoms.5 A COPD definition exclusive of symptoms may not lead to a correct diagnosis of this condition.

Vogenberg: What are the guidelines for COPD diagnosis?

Vogenberg: How is COPD diagnosed and confirmed?

Tinkelman: For COPD, the world truly changed in 2001, with publication of the guidelines from the Dr Tinkelman is Vice President of Health Initiatives, National Jewish Health, and Professor of Pediatrics at National Jewish Health, and the University of Colorado Health Sciences Center, Denver, CO; Dr Vogenberg is Principal, Institute for Integrated Healthcare, and Chief Strategic Officer, Employer-Based Pharmaceutical Strategies, Sharon, MA.

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Tinkelman: Patients with COPD typically present with coughing and increasing shortness of breath over time. Some features in the history are critical to the diagnosis. A critical feature is that the symptoms progressively get worse. COPD is not a condition that gets better and worse, better and worse—that is the typical history for asthma. Another key feature is a history of exposure to toxins. Predominantly, that exposure is to

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CASE STUDY cigarette smoke. Sometimes it is a work-related exposure in a specific industry. Rarely, it is a genetic cause—alpha1 antitrypsin deficiency—found in younger people.

Patients, however, generally do not tell the physician the truth about their smoking.6 They do not tell how much they smoke, and they may not admit that they are still smoking.6 To make a COPD diagnosis, the clinician has to find out whether a patient has an airway obstruction that is either partially or completely irreversible. The only way to make a definitive diagnosis is with spirometry.

Vogenberg: In the working-age population, those under 65 years, what would be a typical profile of a COPD patient?

Tinkelman: The typical patient has a loss in lung function, manifested by an increase in shortness of breath.7 The patient may say, “I used to be able to walk up the steps,” or “I used to be able to play golf.” That indicates that this patient’s lung capacity has progressively worsened. Many people deny this or attribute it to getting older. In fact, they have lost significant lung function and are unable to do things that they should be able to do at their age.

Loss of lung function—manifested as the change in their ability to function in their daily activities—is what usually brings people with COPD to the doctor. They become frightened: they can ignore the wheezing and the coughing, but when they cannot do what they used to, that is when they present at the office.

The second cardinal symptom is coughing. “I get up in the morning and I cough,” is a common complaint. Many people cough when they get up, but those with COPD regularly get up in the morning with a productive cough.

They have lung destruction, chronic bronchitis, and mucus production, and they cough to clear their lungs.

The third sign is wheezing. As soon as a patient says “wheezing” to a primary care physician, that physician often thinks that the patient may have asthma, because wheezing is a hallmark of asthma.5,8 But many patients with COPD wheeze as well.

Vogenberg: What are the comorbidities of COPD common in the working-age population?

Tinkelman: Other body systems besides the lungs are affected by cigarette smoking. Osteoporosis in postmenopausal women is a major problem, because of the risk for fractures. Smoking aggravates that risk, because tobacco changes the calcium metabolism pathway.

The incidence of depression is much higher with

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A 53-year-old woman presents to her primary care physician complaining that she has had difficulty catching her breath over the past few weeks. She admits to having more difficulty with her daily activities lately, and that has been getting worse over the past 6 months. She reports coughing regularly in the morning, but says this is “no big deal”; she coughs on and off regularly when she laughs and when she is active.

She also reports having started to smoke in her teens, about 1 pack a day, until she “quit smoking” before childbirth in her late 30s. Now she “only smokes on weekends.” She has never had spirometry testing or prescription medications for these problems.

She has been using over-the-counter drugs, including cough medications and inhalers, for years.

What is the appropriate management for this patient? This patient is exhibiting typical signs and symptoms of COPD, but a definitive diagnosis can only be made by spirometry testing. She probably should be referred to a pulmonologist, because of these ongoing problems. Given her self-reported history of ongoing smoking and the presence of classic symptoms of COPD, this diagnosis would be a logical conclusion, as opposed to asthma. However, a complete physical examination and spirometry are required to confirm this diagnosis.

This patient likely has mild-to-moderate COPD, which can be confirmed with spirometry. Consistent with the GOLD initiative guidelines, the following actions would be appropriate: 1. Strongly encourage smoking cessation 2. Prescribe a long-acting bronchodilator or anticholinergic agent, with a short-acting bronchodilator used only when needed 3. Recommend an annual flu shot 4. Encourage her to increase her level of exercise

COPD than with many other chronic diseases. This may be a direct effect of cigarette smoke on the central nervous system, but more likely, patients with COPD are depressed because they have lived a lifetime of hearing people say, “You should not smoke,” “You’re doing this to yourself,” “What are you going to do when you get older?” Now they have crossed that chasm and they are depressed. The inevitable has occurred, and they did nothing about it for the past 40 years.

The cardiovascular effects of COPD are linked to congestive heart failure rather than to the calcium buildup characteristic of atherosclerosis.

Vogenberg: Are there manifestations of COPD related to productivity that employers may be seeing and not realizing?

Tinkelman: Loss of lung function means that people lose the ability to take effective deep breaths. For working people with a sedentary job, productivity may not be affected all that much, except that, if they are still smoking, they have to go outside or move away from the building to smoke. For people in a job that requires some degree of activity, they will become short of breath earli-

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er than they would if their lungs were functioning in a normal way. With any type of exertion in which they have to take deep breaths, they will have more problems.

There are 2 types of lost productivity. Direct loss of productivity occurs when people are sick and do not show up for work. Patients with COPD are more prone to lung infections, especially in the fall and winter, and their functioning is more impaired when they have an attack. Indirect loss of productivity occurs in presenteeism, when people are at work but their productivity is reduced. Workers with COPD may have to stop more often and take more breaks. The indirect loss is hard to measure, but it is there.

In the railroad industry, for example, loss of productivity is a huge problem. Smoking is prevalent among railroad workers, as well as among truckers and blue collar workers who have jobs that require physical activity. Smoking for a long period of time is associated with a higher incidence of comorbid conditions, leading to direct and indirect effects on productivity.

Vogenberg: What is the economic impact of COPD in the workplace, as it affects the patient and the employer?

Tinkelman: Disability from COPD is not always considered a workplace issue, but it is a major problem for which billions of dollars are spent.9,10 As staggering as these figures are, the more sobering realization is that the true figures are almost double the reported numbers.

Because of misdiagnosis and underdiagnosis, the true burden of COPD is not known. For example, a 55-yearold woman who has COPD but was diagnosed with asthma for the first 5 years is counted in the economic burden associated with asthma, not with COPD. Our research showed that among patients with COPD under age 65, there is a significant amount of long-term disability.10,11 These are people who should be working.

Vogenberg: What can be done to mitigate or better manage the loss of worker productivity from COPD? Tinkelman: The first thing is to get people to stop smoking. It is important to identify whether the patient is currently smoking. The patient in the case study above exemplifies the difficulty of this task. She admits to smoking on and off, but what she admits to, and what she is truly doing, may not be the same.6 Pharmacotherapy for COPD is not the only answer; there has not been a major change in therapy for COPD in years.

Formulations of atropine, tiotropium, and beta agonists are useful, but these are not new drug classes. Inhaled

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steroids work mainly for those who have a mixed cause of COPD (up to 40% of patients).12 Many patients are diagnosed too late, and steroids do not reverse airway destruction. The number of deaths from COPD is larger than from asthma. It is the only prevalent chronic illness in which the mortality rate is increasing.

Vogenberg: What is being done to heighten awareness of COPD in the United States?

Tinkelman: Some companies have done a great job heightening awareness to this condition. They use the term COPD, and they run ads on TV. The National Institutes of Health has conducted an entire campaign to raise awareness to COPD that is directed not just to consumers but also to physicians. At many different levels, the message is getting out. The Occupational Safety and Health Administration has also been involved in raising awareness to this disease for many years.

Only about 10% to 20% of patients with COPD are nonsmokers.13 The number of people who get COPD from environmental exposure is relatively low. Different industries present different kinds of exposures to COPD risk, such as vapors, gases, toxic dusts, and certain strong odors. Smoking makes the effects of exposure to such materials much worse. Many industries recognized this several years ago and now use robotics in certain areas, such as spray painting.14 Vogenberg: When you talk with medical directors at large companies, what do you tell them they could be doing differently to prevent COPD? Tinkelman: I try to dispel their fear of making a COPD diagnosis, because they think it is going to be costly. I try to start them thinking about prevention and helping people with COPD. I suggest that they change the culture of their workplace to be nonsmoking. They also need to provide resources for their smokers, to help them get into smoking-cessation programs. Many employees do not take advantage of these programs, because they are afraid of being fired. Companies need to remove that threat. If employees are afraid to tell their employer that they want to quit smoking, they will not tell. Companies have to support them. Large companies have nurses and other medical staff who can offer smoking-cessation information and programs. Wellness programs can benefit everyone. â&#x2013;

References 1. Tinkelman DG, Price DB, Nordyke RJ, et al. Symptom-based questionnaire for differentiating COPD and asthma. Respiration. 2006;73: 296-305.

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2. Global strategy for the diagnosis, management, and prevention of chronic pulmonary disease: National Heart, Lung, and Blood Institute and World Health Organization Global Initiative for Chronic Obstructive Lung Disease (GOLD): executive summary. Respir Care. 2001; 46:798-825.

3. American Thoracic Society/European Respiratory Society Task Force.

Standards for the Diagnosis and Management of Patients with COPD. Version 1.2. September 8, 2005. www.thoracic.org/go/copd. Accessed June 11, 2009.

4. Rabe KF, Hurd S, Anzueto A, et al; for Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med. 2007;176:532-555.

5. Tinkelman DG, Price DB, Nordyke RJ, Halbert RJ. Misdiagnosis of COPD and asthma in primary care patients 40 years of age and over.

J Asthma. 2006;43:75-80.

6. Price DB, Tinkelman DG, Halbert RJ, et al. Symptom-based questionnaire for identifying COPD in smokers. Respiration. 2006;73:285-295.

7. Price DB, Tinkelman DG, Nordyke RJ, et al. Scoring system and clinical application of COPD diagnostic questionnaires. Chest. 2006;129: 1531-1539.

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8. Tinkelman DB, Price D, Nordyke RJ, Halbert RJ. COPD screening efforts in primary care: what is the yield? Prim Care Respir J. 2007;16:41-48.

9. Foster TS, Miller JD, Marton JP, et al. Assessment of the economic burden of COPD in the U.S.: a review and synthesis of the literature. COPD. 2006;3:211-218.

10. Tinkelman D, Nordyke RJ, Isonaka S, et al. The impact of chronic obstructive pulmonary disease on long-term disability costs. J Manag Care Pharm. 2005;11:25-32.

11. Tinkelman D, George D, Halbert RJ. Chronic obstructive pulmonary disease in patients under age 65: utilization and costs from a managed care sample. J Occup Environ Med. 2005;47:1125-1130.

12. Burge PS, Calverley PM, Jones PW, et al. Randomised, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial.

BMJ. 2000;320:1297-1303.

13. Global Initiative for Chronic Obstructive Lung Disease. Guidelines: global strategy for diagnosis, management, and prevention of COPD. November 2008. www.goldcopd.com/Guidelineitem.asp?l1=2&l2=1&int Id=2003. Accessed June 10, 2009.

14. Blanc PD, Iribarren C, Trupin L, et al. Occupational exposures and the risk of COPD: dusty trades revisited. Thorax. 2009;64:6-12.

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The Economic Burden of COPD in the Workplace Interview with William B. Bunn, III, MD, JD, MPH Healthcare costs, disability, and lost productivity from chronic obstructive pulmonary disease are of vital relevance to business management. In this interview conducted by Dr Vogenberg, Dr Bunn discusses the economic burden of chronic pulmonary disease on employers, and why proper management of employees with this progressive condition can save significant costs to the company, while also improving productivity. Applying his Employer Impact model, which measures the actuarial burden of illness, to chronic pulmonary disease in his company, Dr Bunn found that medical costs alone were 3 times greater for employees with this disease than for others.

Absenteeism and presenteeism are particularly prevalent to this patient population. Raising awareness to smoking cessation in the workplace and implementing successful incentives to stop smoking can greatly improve productivity and reduce costs to employers. The interaction of business and regulatory initiatives can help reduce the economic burden of this disease. [AHDB. 2009;2(4):198-200.]

F. Randy Vogenberg, RPh, PhD: How does chronic obstructive pulmonary disease (COPD) affect people in the workplace, both as patients and as family caregivers? What are the effects on productivity?

William B. Bunn, III, MD, JD, MPH: Healthcare costs, lost productivity, absenteeism, and presenteeism are the major effects of COPD in the workplace. Our research and other studies have shown that COPD translates into a high cost for the patient with this diagnosis, and a large proportion of that cost is the result of lost productivity.1,2 Vogenberg: Are there any differences in impact between a union population and a white collar or management population with COPD? Bunn: The incidence of active smoking, or of a history of smoking, is usually much greater in a union or blue collar population than in a white collar population. For us, the percentage of white collar smokers is about half that of blue collar workers, although the prevalence of smoking is decreasing in both populations. Union employees represent a higher-risk population, as well as a higher-cost population for employers.

The union population also has probably one of the Dr Bunn is Vice President, Health, Safety, Security, and Productivity, Navistar, Warrenville, IL, and Professor of Preventive Medicine, Northwestern University School of Medicine, Chicago, IL; Dr Vogenberg is Principal, Institute for Integrated Healthcare, and Chief Strategic Officer, EmployerBased Pharmaceutical Strategies, Sharon, MA.

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highest costs of care for retirees. There is a significant cost for people with COPD who have retired even if they are in Medicare, because they have wraparound coverage. Therefore, the risks of COPD and the cost per case is higher, although the prevalence of smoking and COPD is decreasing.

Vogenberg: What does the literature, as well as your research, say about the economic burden of COPD in the workplace?

Bunn: COPD has a major financial impact, particularly when we add productivity into the mix.1,3 It is an expensive disease in terms of overall cost. Our studies showed 2 aspects of the economic burden: medical costs (including disability costs and similar factors) and loss of productivity, as measured by absenteeism.1,2 However, other studies of our workforce have shown the correlate of absenteeism and presenteeism.4,5 Rates of disability and the cost of disability are substantially higher among working-age people (40-63 years old) who have COPD.6 Vogenberg: What can be done to mitigate or better manage the loss of worker productivity associated with COPD to lessen that economic burden?

Bunn: Worker education is a big piece of the puzzle.

In COPD, some education is directed toward smoking cessation, and some education relates to early and continued appropriate treatment. Smoking-cessation education should include both primary and secondary prevention, and it is essential to get workers who have been identified with COPD into smoking-cessation programs.

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The Economic Burden of COPD in the Workplace

Case management is another way of addressing health and productivity. Our company has disease management programs that cover COPD, along with other respiratory diseases. If people are out of work for a period of time because of their disease, we involve them in a specific case-management program. Education, disease management, and case management are all important approaches that can reduce the loss of productivity.

Vogenberg: Have there been measurable results from smoking-prevention efforts?

Bunn: Yes. In our company, the restrictions that we have placed on smoking in the workplace have had an effect. Workers can no longer smoke in any of our plants.

Some of these restrictions were the result of statutory changes, and some occurred through renegotiation of union contracts. These smoking restrictions make it very challenging to smoke at work, because often the workers cannot get outside the building or to the edge of the property easily.

We have also imposed financial disincentives to smoking. We charge smokers $50 more than nonsmokers in monthly healthcare premiums. Using a monetary approach in the health benefit plan appears to have a significant impact. Of course, cigarettes cost a lot more than the $50, but the additional $50 really incents people. We were one of the first companies to introduce this approach to a benefit design.

Before increasing premiums, we offered people the opportunity to join a smoking-cessation program for 6 months. Our antismoking campaigns have been very successful. We are doing a study now involving the newer, oral-based smoking-cessation drugs, and we are having success in combining drugs with psychosocial therapy.

And the corporate culture has changed. When I first came to this company 15 years ago, most of the senior management smoked; now, none does. I estimate that the number of smokers is half what it was 10 years ago.

Former Surgeon General Dr C. Everett Koop was instrumental in initiating the antismoking campaign, but now corporate leaders have gotten on the bandwagon.

Vogenberg: What are the regulatory influences on workplace smoking?

Bunn: Most states limit smoking in various places, such as restaurants, but some states prohibit smoking in all public buildings. Over the past 10 years, significant new regulations at the local, state, and federal level have all deterred people from smoking, or certainly

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deterred them from smoking as much as they used to.

Vogenberg: What about regulations in specific industries?

Bunn: Depending on the type of funding for an employer’s health plan, state or federal regulations may apply. For fully funded plans—the type of plan used by the majority of small- to medium-size companies in this country—the state’s department of insurance regulates the insurance plan offerings. Federal laws, such as the Employee Retirement Income Security Act (ERISA), apply to self-funded employer plans. All plans, of course, must be in compliance with the Americans with Disabilities Act. There are different ways to design health insurance plans and their components, such as disease prevention, but all plans must be in compliance with the applicable federal and state regulations.

Some regulations, for example, the federal Department of Transportation regulations of pilot licensing, are becoming more rigorous. With regard to COPD, however, there are no statutes, to my knowledge, that say people cannot smoke in their car or truck. The regulations that have had the biggest impact on COPD are the laws that prohibit smoking in restaurants or workplaces.

Vogenberg: Do most of those in senior management understand the true health costs of a worker with COPD? Do they understand all the different costs involved in this disease?

Bunn: Everyone knows that medical costs will be high for workers with COPD. But costs related to workers’ compensation and disability also come into the picture, along with the cost of lost productivity related to absenteeism and presenteeism. Most chief financial officers probably understand absenteeism as it relates to COPD, but we need more education on the impact of presenteeism on productivity. I am not sure that people truly appreciate that workers with COPD are less productive.

Vogenberg: When you reported the results of your research showing that the cost for an employee with COPD averaged $20,000, as opposed to $8000 for an employee without COPD, was that compelling information internally?

Bunn: Yes. Senior management is less interested in the incidence of disease or minor improvements with medication. That is not convincing in terms of making a business decision. But if they know that they are losing $12,000 per employee because of COPD, this becomes an incentive to do something. Medical costs for employees with COPD are approximately 3 times greater than

www.AHDBonline.com

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Table Cost Comparisons: Employees with and without COPD, 2005 Mean Cost per Employee With COPD, $ Without COPD, $ 12,067 3634 Medical Prescription drugs 2770 957 Short-term disability 2298 871 (absence) COPD indicates chronic obstructive pulmonary disease.

Source: Bunn W, Pikelny D, Vogenberg FR, et al. Validation of employer-focused actuarial model for measuring the economic burden of chronic obstructive pulmonary disease. J Health Productiv. 2008;3:3-8.

the costs for employees who do not have COPD (Table).1 That cost gets their attention. They realize that they cannot afford an additional $12,000 for each person with COPD, so they decide to act to reduce the incidence of that disease in their employee population.

Showing senior management clinical study results that indicate minor improvements from better therapy does not convince them to spend money on new programs.

But telling them that other companies—particularly their competitors—are intervening and saving the extra $12,000, that will make them more inclined to do the same thing, to even the playing field.

Vogenberg: What is being done, or what could be done better, by different stakeholders to increase awareness of COPD in the workplace?

Bunn: Aggressive smoking-awareness programs, such as the Great American Smokeout and similar initiatives, are important. Campaigns to get pharmaceutical companies and other stakeholders to incentivize people to use smoking-cessation drugs and measure outcomes would also be good. There is a panoply of approaches to consider. Clinical guidelines, HEDIS scores, and association recommendations for appropriate treatment are helpful.

Diseases need to be not just treated, but treated well.

Clinical guidelines provide weight to why companies and providers are recommending a certain approach.

Providing all the tools for raising awareness to COPD will be necessary. It would not hurt to have a “Thou Shalt Quit Smoking” or any workplace program supported at the congressional level, maybe tied to a corporate or individual tax break. That may come with the prevention laws that are being considered in Congress now.

Congress could apply more of the money from tobacco litigation to smoking prevention.

Vogenberg: In implementing a different premium cost structure for a smoker, what are some of the ERISA guidelines to be aware of?

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Bunn: The use of different cost structures for people with certain conditions is becoming a legal or regulatory compliance issue. Research such as ours on COPD clearly shows a quantifiable difference in the benefit cost between smokers and nonsmokers.1 The biggest difference was found between smokers and former smokers rather than between smokers and never-smokers: neversmokers accounted for one third of the difference between smokers and nonsmokers.

When we instituted our $50/month increase in premiums for smokers, we clearly worded it as a penalty, not as an incentive to quit. A couple of things permitted us to do this. As mentioned, we gave people a chance to quit during a 6-month period, and we had quantified the different cost to us for smokers and nonsmokers. We had to be able to prove that what we were charging people was equal to or less than the true cost.

Smoking was a condition for which there are data to create a cost differential, because data are available on the smoking-related increases in medical costs and productivity loss.7 Data are important. It is one thing to say that a certain behavior is a risk factor and has an adverse impact on cost, and it is another thing to know exactly how much more cost is the result of that behavior. We do not penalize people for having a disease. They can only be penalized for an activity or a behavior that can be avoided and increases cost.

Vogenberg: How can we get employers to realize the benefit of proper COPD management on productivity and cost?

Bunn: We need to increase awareness on how good medical management of COPD has an impact on cost.

We hear a lot about the merits of good diabetes management, but we do not hear much about good COPD management. We have the evidence for COPD, but no one is publicizing that if employers manage their employees with COPD effectively, they will save money.

We also do not hear much about the problem of patients with early-stage COPD who continue to smoke.

For those people, are employers doing everything possible to help them quit smoking?

Not many health plans or employers are requiring the best clinical practice management for COPD. Good medical management of COPD can improve productivity and result in cost-effective care. This is a message we need to get out to employers and to other stakeholders. ■

References 1. Bunn W, Pikelny D, Vogenberg FR, et al. Validation of employerfocused actuarial model for measuring the economic burden of chronic

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obstructive pulmonary disease. J Health Productiv. 2008;3:3-8.

2. Halbert RJ, Isonaka S, George D, Igbal A. Interpreting COPD prevalence estimates: what is the true burden of disease? Chest. 2003;123: 1684-1692.

3. Foster TS, Miller JD, Marton JP, et al. Assessment of the economic burden of COPD in the U.S.: a review and synthesis of the literature. COPD. 2006;3:211-218.

4. Bunn WB III, Pikelny DB, Paralkar S, et al. The burden of allergiesâ&#x20AC;&#x201D; and the capacity of medications to reduce this burdenâ&#x20AC;&#x201D;in a heavy man-

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ufacturing environment. J Occup Environ Med. 2003;45:941-955.

5. Allen HM Jr, Bunn WB III. Validating self-reported measures of productivity at work: a case for their credibility in a heavy manufacturing setting. J Occup Environ Med. 2003;45:926-940.

6. Darkow T, Kadlubek PJ, Shah H, et al. A retrospective analysis of disability and its related costs among employees with chronic obstructive pulmonary disease. J Occup Environ Med. 2007;49:22-30.

7. Bunn WB III, Stave GM, Downs KE, et al. Effect of smoking status on productivity loss. J Occup Environ Med. 2006;48:1099-1108.

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Are your plan members with type 2 diabetes reaching goal?

The recommendation for early treatment • Many patients are not reaching their ADA A1C target goal of <7%, and many are stopping their medications.1,2 • Recent data show a drop in the use of oral antidiabetic medications.3 • In 2008, data published showed that 44% of patients with diabetes were not at goal based on A1C values.1

Early and aggressive diabetes management has the potential to help get patients to A1C goals as quickly as possible AACE initial pharmacologic treatment recommendation*4

A1C Levels

6%–7%

Initiate monotherapy

7%–8%

Initiate combination therapy

8%–10%

Initiate/intensify combination therapy

>10%

Initiate/intensify insulin therapy

*For patients naïve to pharmacological therapy.

Early combination approach5 Diet + exercise OAD monotherapy OAD combinations

HbA1c (%)

10

OADs up-titration OAD + basal insulin p dailyy OAD + multiple insulin injections

9 8 HbA1c=7%

7

HbA1c=6.5%

6

• The Global Partnership for Effective Diabetes Management†‡ recommends a shift from the reactive “stepwise” management to a proactive approach including early introduction of combination therapy as needed, addressing underlying pathophysiology, and including treatment of insulin resistance.5

Duration of diabetes Adapted from Goldstein.

• Patients who initially started on fixed-dose combinations stayed on therapy at least 50 days longer than those who started on monotherapy.3 †The Global Partnership for Effective Diabetes Management was established with the aim of uncovering the barriers to good glycemic control and identifying ways to help people overcome them. ‡The Global Partnership for Effective Diabetes Management is industry supported.

References: 1. Hoerger TJ, Segel JE, Gregg EW, Saaddine JB. Is glycemic control improving in U.S. adults? Diabetes Care. 2008;31:81-86. 2. Rodgers K. Ensuring compliance in patients with diabetes. In: Diabetes: Disease Management Guide. 4th ed. Montvale, NJ: Thomson PDR; 2004:501-505. 3. Data on file, Takeda Pharmaceuticals North America, Inc. 4. AACE Diabetes Mellitus Clinical Practice Guidelines Task Force. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the management of diabetes mellitus. Endocr Pract. 2007;13(suppl 1):3-68. 5. Goldstein BJ, Gomis R, Lee H-K, Leiter LA, on behalf of the Global Partnership for Effective Diabetes Management. Type 2 diabetes–treat early, treat intensively. Int J Clin Pract. 2007;61(suppl 157):16-21. ©2008 Takeda Pharmaceuticals North America, Inc.

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