March/April 2010, Vol 3, No 2

THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN ™ MARCH/APRIL 2010

VOLUME 3, NUMBER 2

FOR PAYERS, PURCHASERS, POLICYMAKERS, AND OTHER HEALTHCARE STAKEHOLDERS

BUSINESS

Obesity: Effective Treatment Requires Change in Payers’ Perspective Rhonda Greenapple, MSPH; Jackie Ngai, MS

Stakeholder Perspective by Jeff Januska, PharmD

Health Insurance Premium Increases for the 5 Largest School Districts in the United States, 2004-2008 John R. Cantillo, MBA

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

CLINICAL

Evolving Trends in Insulin Delivery: In Pursuit of Improvements in Diabetes Management Firas Akhrass, MD; Nancy Skinner, RN, CCM; Kimberly Boswell, MD; Luther B. Travis, MD

Stakeholder Perspective by James V. Felicetta, MD

Healthcare Costs Associated with Switching from Brand to Generic Levothyroxine Michael Katz, PharmD; Joseph Scherger, MD, MPH; Scott Conard, MD; Leslie Montejano, CCRP; Stella Chang, MPH

Stakeholder Perspective by Michael S. Jacobs, RPh REGULATORY

Pay-for-Performance Initiatives: Modest Benefits for Improving Healthcare Quality Amit Sura, MD, MBA; Nirav R. Shah, MD, MPH

Stakeholder Perspective by Steven T. Kmucha, MD, JD DEPARTMENTS ◆

Industry Trends Pharmacogenomics and Drug Development Michael F. Murphy, MD, PhD

◆

Generic Drug Trends First Anti-Inflammatory Generic Drug Promising New Therapy for Diabetes

◆

Drug Pipeline

◆

NCCN Highlights

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

The name KAPIDEX™ (dexlansoprazole) will be changing to

New name. Same medication.

Why is the name changing? s After receiving reports of dispensing errors due to the similarity between the names KAPIDEX and Casodex® (bicalutamide) and KAPIDEX and Kadian® (morphine sulfate extended-release), Takeda, in coordination with the US Food and Drug Administration, determined that a name change would be the best way to minimize future medication errors s At Takeda Pharmaceuticals, we believe patient safety is of the utmost importance ONLY the name and NDC numbers are changing s The size, strength, and ingredients of the capsule will remain the same s Each capsule will still contain 30 mg or 60 mg of dexlansoprazole1 s DEXILANT is still the first and only PPI with a Dual Delayed Release™ (DDR) formulation1 – The clinical relevance of this statement is unknown Indications s Healing all grades of erosive esophagitis (EE) for up to 8 weeks s Maintaining healing of EE for up to 6 months s Treating heartburn associated with symptomatic non-erosive gastroesophageal reflux disease (GERD) for 4 weeks Important Safety Information s KAPIDEX is contraindicated in patients with known hypersensitivity to any component of the formulation.

Hypersensitivity and anaphylaxis have been reported with KAPIDEX use. s Symptomatic response with KAPIDEX does not preclude the presence of gastric malignancy. s Most commonly reported treatment-emergent adverse reactions (r2%): diarrhea (4.8%), abdominal pain (4.0%), nausea (2.9%), upper respiratory tract infection (1.9%), vomiting (1.6%), and flatulence (1.6%). s Do not co-administer atazanavir with KAPIDEX because atazanavir systemic concentrations may be substantially decreased. 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. Increases in INR and prothrombin time may lead to abnormal bleeding and even death.

Concomitant tacrolimus use may increase tacrolimus whole blood concentrations.

Please see adjacent brief summary of prescribing information for KAPIDEX.

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 GASTRO ESOPHAGEAL 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 %% MAIN TEN ANCE 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

Adverse Reaction $IARRHEA !BDOMINAL 0AIN .AUSEA 5PPER 2ESPIRATORY Tract Infection 6OMITING &LATULENCE

Placebo KAPIDEX KAPIDEX KAPIDEX 30 mg 60 mg Total (N=896) (N=455) (N=2218) (N=2621) % % % %

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 HYPER VENTILATION 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 !DDITIONAL ADVERSE REACTIONS THAT WERE REPORTED IN A LONG TERM UNCONTROLLED STUDY AND WERE CONSIDERED RELATED TO +!0)$%8 BY THE TREATING PHYSICIAN INCLUDED ANAPHYLAXIS AUDITORY HALLUCINATION " CELL LYMPHOMA BURSITIS

CENTRAL OBESITY CHOLECYSTITIS ACUTE DECREASED HEMOGLOBIN DEHYDRATION

DIABETES MELLITUS DYSPHONIA EPISTAXIS FOLLICULITIS GASTRO INTESTINAL PAIN

GOUT HERPES ZOSTER HYPERGLYCEMIA HYPERLIPIDEMIA HYPOTHYROIDISM

INCREASED NEUTROPHILS -#(# DECREASE NEUTROPENIA ORAL SOFT TISSUE DISORDER

POLYDIPSIA POLYURIA RECTAL TENESMUS RESTLESS LEGS SYNDROME SOMNOLENCE

THROMBOCYTHEMIA TONSILLITIS /THER ADVERSE REACTIONS NOT OBSERVED WITH +!0)$%8 BUT OCCURRING WITH THE RACEMATE LANSOPRAZOLE CAN BE FOUND IN THE LANSOPRAZOLE PACKAGE INSERT

!$6%23% 2%!#4)/.3 SECTION DRUG INTERACTIONS Drugs with pH-Dependent Absorption Pharmacokinetics +!0)$%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

Lansoprazole 30 mg (N=1363) %

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 Tacrolimus #ONCOMITANT ADMINISTRATION OF DEXLANSOPRAZOLE AND TACROLIMUS MAY INCREASE WHOLE BLOOD LEVELS OF TACROLIMUS ESPECIALLY IN TRANSPLANT PATIENTS WHO ARE INTERMEDIATE OR POOR METABOLIZERS OF #90 #

!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

ESOPHA GITIS GASTRIC POLYP GASTRITIS GASTROENTERITIS GASTRO INTESTINAL DISORDERS

GASTROINTESTINAL HYPERMOTILITY DISORDERS '%2$ ') ULCERS AND PERFO RATION

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: HYPER SENSITIVITY Infections and Infestations: CANDIDA INFECTIONS INmUENZA NASOPHAR YNGITIS

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

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 APPROXIMATELY FOLD THE MAXIMUM RECOMMENDED HUMAN DEXLANSOPRAZOLE DOSE MG 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 TIMES THE RECOMMENDED HUMAN DOSE AND IN PREGNANT RABBITS AT ORAL LANSOPRAZOLE DOSES UP TO TIMES THE RECOMMENDED HUMAN DOSE REVEALED NO EVIDENCE OF IMPAIRED FERTILITY OR HARM TO THE FETUS DUE TO LANSOPRAZOLE Nursing Mothers )T IS NOT KNOWN WHETHER DEXLANSOPRAZOLE IS EXCRETED IN HUMAN MILK (OWEVER

LANSOPRAZOLE AND ITS METABOLITES ARE PRESENT IN RAT MILK FOLLOWING THE ADMIN ISTRATION OF LANSOPRAZOLE !S MANY DRUGS ARE EXCRETED IN HUMAN MILK AND BECAUSE OF THE POTENTIAL FOR TUMORIGENICITY SHOWN FOR LANSOPRAZOLE IN RAT CARCINO GENICITY 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 3AFETY AND EFFECTIVENESS OF +!0)$%8 IN PEDIATRIC PATIENTS LESS THAN YEARS OF AGE HAVE NOT BEEN ESTABLISHED

Geriatric Use )N CLINICAL STUDIES OF +!0)$%8 OF PATIENTS WERE AGED YEARS AND OVER .O OVERALL DIFFERENCES IN SAFETY OR EFFECTIVENESS WERE OBSERVED BETWEEN THESE PATIENTS AND YOUNGER PATIENTS AND OTHER REPORTED CLINICAL EXPERIENCE HAS NOT IDENTIlED SIGNIlCANT DIFFERENCES IN RESPONSES BETWEEN GERIATRIC AND YOUNGER PATIENTS BUT GREATER SENSITIVITY OF SOME OLDER INDIVIDUALS CANNOT BE RULED OUT Renal Impairment .O DOSAGE ADJUSTMENT OF +!0)$%8 IS NECESSARY IN PATIENTS WITH RENAL IMPAIRMENT 4HE 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 Hepatic Impairment .O DOSAGE ADJUSTMENT FOR +!0)$%8 IS NECESSARY FOR PATIENTS WITH MILD HEPATIC IMPAIRMENT #HILD 0UGH #LASS ! +!0)$%8 MG SHOULD BE CONSIDERED FOR PATIENTS WITH MODERATE HEPATIC IMPAIRMENT #HILD 0UGH #LASS " .O STUDIES HAVE BEEN CONDUCTED IN PATIENTS WITH SEVERE HEPATIC IMPAIRMENT #HILD 0UGH #LASS # OVERDOSAGE 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 $EXLANSOPRAZOLE IS NOT EXPECTED TO BE REMOVED FROM THE CIRCULATION BY HEMODIALYSIS )F AN OVERDOSE OCCURS TREATMENT SHOULD BE SYMPTOMATIC AND SUPPORTIVE CLINICAL PHARMACOLOGY Pharmacodynamics !NTISECRETORY !CTIVITY 4HE EFFECTS OF +!0)$%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)$%8 ON SERUM GASTRIN CONCENTRATIONS WAS EVALUATED IN APPROXIMATELY PATIENTS IN CLINICAL TRIALS UP TO WEEKS AND IN PATIENTS FOR UP TO TO MONTHS 4HE MEAN FASTING GASTRIN CONCEN TRATIONS INCREASED FROM BASELINE DURING TREATMENT WITH +!0)$%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 $URING LIFETIME EXPOSURE OF RATS DOSED DAILY WITH UP TO MG PER KG PER DAY OF LANSOPRAZOLE MARKED HYPERGASTRINEMIA WAS OBSERVED FOLLOWED BY %#, CELL PROLIFERATION AND FORMATION OF CARCINOID TUMORS ESPECIALLY IN FEMALE RATS [see Nonclinical Toxicology ] %FFECT ON #ARDIAC 2EPOLARIZATION ! STUDY WAS CONDUCTED TO ASSESS THE POTENTIAL OF +!0)$%8 TO PROLONG THE 14 14c INTERVAL IN HEALTHY ADULT SUBJECTS +!0)$%8 DOSES OF MG OR MG DID NOT DELAY CARDIAC REPOLARIZATION COMPARED TO PLACEBO 4HE POSITIVE CONTROL MOXImOXACIN PRODUCED STATISTICALLY SIGNIlCANTLY GREATER MEAN MAXIMUM AND TIME AVERAGED 14 14c INTERVALS COMPARED TO PLACEBO NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility 4HE CARCINOGENIC POTENTIAL OF DEXLANSOPRAZOLE WAS ASSESSED USING LANSOPRAZOLE STUDIES )N TWO MONTH CARCINOGENICITY STUDIES 3PRAGUE $AWLEY RATS WERE TREATED ORALLY WITH LANSOPRAZOLE AT DOSES OF TO MG PER KG PER DAY ABOUT TO TIMES THE EXPOSURE ON A BODY SURFACE MG M BASIS OF A KG PERSON OF AVERAGE HEIGHT ; M BODY SURFACE AREA "3! = GIVEN THE RECOMMENDED HUMAN DOSE OF LANSOPRAZOLE MG PER DAY ,ANSOPRAZOLE PRODUCED DOSE RELATED GASTRIC %#, CELL HYPERPLASIA AND %#, CELL CARCINOIDS IN BOTH MALE AND FEMALE RATS [see Clinical Pharmacology]. )N RATS LANSOPRAZOLE ALSO INCREASED THE INCIDENCE OF INTESTINAL METAPLASIA OF THE GASTRIC EPITHELIUM IN BOTH SEXES )N MALE RATS LANSOPRAZOLE PRODUCED A DOSE RELATED INCREASE OF TESTICULAR INTERSTITIAL CELL ADENOMAS 4HE INCIDENCE OF THESE ADENOMAS IN RATS RECEIVING DOSES OF TO MG PER KG PER DAY TO TIMES THE RECOMMENDED LANSOPRAZOLE HUMAN DOSE BASED ON "3! EXCEEDED THE LOW BACKGROUND INCIDENCE RANGE TO FOR THIS STRAIN OF RAT

)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!

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 [see FDA-Approved Patient Labeling in the full prescribing information] Information for Patients 4O ENSURE THE SAFE AND EFFECTIVE USE OF +!0)$%8 THIS INFORMATION AND INSTRUCTIONS PROVIDED IN THE &$! APPROVED PATIENT LABELING SHOULD BE DISCUSSED WITH THE PATIENT )NFORM PATIENTS OF THE FOLLOWING +!0)$%8 IS AVAILABLE AS A DELAYED RELEASE CAPSULE +!0)$%8 MAY BE TAKEN WITHOUT REGARD TO FOOD +!0)$%8 SHOULD BE SWALLOWED WHOLE s !LTERNATIVELY +!0)$%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)$%8 IS A TRADEMARK OF 4AKEDA 0HARMACEUTICALS .ORTH !MERICA )NC AND USED UNDER LICENSE BY 4AKEDA 0HARMACEUTICALS !MERICA )NC !LL OTHER TRADEMARK NAMES ARE THE PROPERTY OF THEIR RESPECTIVE OWNERS Ú 4AKEDA 0HARMACEUTICALS !MERICA )NC &OR MORE DETAILED INFORMATION SEE THE FULL PRESCRIBING INFORMATION FOR +!0)$%8 OR CONTACT 4AKEDA 0HARMACEUTICALS !MERICA )NC AT +!0 2 "RF !UGUST , ,0$

Reference: 1. KAPIDEX (dexlansoprazole) package insert, Takeda Pharmaceuticals America, Inc. KAPIDEX™, DEXILANT™, and Dual Delayed Release™ are trademarks of Takeda Pharmaceuticals North America, Inc., and are used under license by Takeda Pharmaceuticals America, Inc. Casodex® (bicalutamide) is a registered trademark of AstraZeneca. Kadian® (morphine sulfate extended-release) is a registered trademark of Actavis Elizabeth LLC.

©2010 Takeda Pharmaceuticals North America, Inc. LPD-01359 03/10 Printed in U.S.A.

EDITORIAL BOARD

CLINICAL EDITOR

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

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

GOVERNMENT EDITOR

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

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

ACTUARY

HEALTH OUTCOMES RESEARCH

David Williams Milliman Health Consultant Windsor, CT CANCER RESEARCH

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

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

HEALTH INFORMATION TECHNOLOGY

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

MANAGED CARE & GOVERNMENT AFFAIRS

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

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

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

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

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

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

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

EPIDEMIOLOGY RESEARCH

PHARMACY BENEFIT DESIGN

I

NO. 2

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

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

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

PHARMACOECONOMICS

VOL. 3

POLICY & PUBLIC HEALTH

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

PATIENT ADVOCACY

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

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

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

EMPLOYERS

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

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

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

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

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

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

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

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

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

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

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

www.AHDBonline.com

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VOLUME 3, NUMBER 2

THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN ™

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

BUSINESS

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Obesity: Effective Treatment Requires Change in Payers’ Perspective Rhonda Greenapple, MSPH; Jackie Ngai, MS

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Stakeholder Perspective by Jeff Januska, PharmD

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Health Insurance Premium Increases for the 5 Largest School Districts in the United States, 2004-2008 John R. Cantillo, MBA

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

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

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

CLINICAL

Editorial Assistant Jessica A. Smith

117 Evolving Trends in Insulin Delivery: In Pursuit of Improvements in Diabetes Management Firas Akhrass, MD; Nancy Skinner, RN, CCM; Kimberly Boswell, MD; Luther B. Travis, MD

Senior Production Manager Lynn Hamilton

122 Stakeholder Perspective by James V. Felicetta, MD 127 Healthcare Costs Associated with Switching from Brand to Generic Levothyroxine Michael Katz, PharmD; Joseph Scherger, MD, MPH; Scott Conard, MD; Leslie Montejano, CCRP; Stella Chang, MPH 134 Stakeholder Perspective by Michael S. Jacobs, RPh REGULATORY

135 Pay-for-Performance Initiatives: Modest Benefits for Improving Healthcare Quality Amit Sura, MD, MBA; Nirav R. Shah, MD, MPH 141 Stakeholder Perspective by Steven T. Kmucha, MD, JD DEPARTMENTS Continued on page 76

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

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

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

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

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INDUSTRY TRENDS Pharmacogenomics and Drug Development Michael F. Murphy, MD, PhD

106 GENERIC DRUG TRENDS First Anti-Inflammatory Generic Drug Promising New Therapy for Diabetes Dalia Buffery, MA, ADB 114 DRUG PIPELINE The Cardiovascular Pipeline: ACC 2010 Features Late-Stage Drugs

By Wayne Kuznar NCCN HIGHLIGHTS 146 NCCN Panel Debates the Economics of Cancer Care 148 PET Scans Not Recommended for Most Patients with Breast Cancer: Potential New Controversy in Breast Cancer Testing

By Caroline Helwick

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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 ≼1% and greater than placebo) were headache, fatigue, dizziness, diarrhea, nausea, insomnia, chest pain, bradycardia, dyspnea, rash, and peripheral edema.

Please see brief summary of Prescribing Information on adjacent page. Š2009 Forest Laboratories, Inc

44-1014950

01/09

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

INDUSTRY TRENDS

Pharmacogenomics and Drug Development Michael F. Murphy, MD, PhD Chief Medical Officer and Scientific Officer, Worldwide Clinical Trials

W

ith the convergence of advances in multiple disciplines, including bioinformatics, the field of pharmacogenomics has emerged during the past decade as a promising platform for drug discovery and clinical development with significant therapeutic and psychosocial implications.

Pharmacogenomics refers to the study of the relationship between specific DNA-sequence variation and drug effect, for example, variation in haplotype versus variation in therapeutic outcome. Pharmacogenomics holds the promise that medications and diagnostic interventions may be tailor-made for individuals and adapted to each person’s unique genetic makeup, considering that individual’s environment, diet, age, lifestyle, and current state of health as significant modifiers. Therefore, pharmacogenomics combines traditional pharmaceutical sciences, such as biochemistry, pharmacology, or toxicology, with annotated knowledge of genes, proteins, and their variations that are capable of defining relationships across variables.

These data, as well as more traditional phenotypic information, result in an individualized profile of disease risk or a potential drug response. In few other disciplines of medicine are the clinical examples of the application of the art more striking than in oncology.

In oncology, the treatment of patients is often accomplished by using chemotherapy characterized by narrow therapeutic indexes (ie, the difference between the toxic and therapeutic dose is small).1 Proper target identification and dosage/regimen selection clearly are keys to successful therapeutic outcome.

Benefits and Challenges What are some of the anticipated benefits and challenges of discovery, development, and commercialization efforts that are built on a pharmacogenomics platform from the perspective of multiple stakeholders?

Advanced risk stratification for disease. Knowing one’s genetic code and how it affects the risk for eventual illness will allow a person to make adequate lifestyle and environmental changes at an early age to avoid or lessen the severity of a disease. Similarly,

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advanced knowledge of specific disease susceptibility will allow the creation of a personalized health plan, careful monitoring with sophisticated assessments (eg, the use of specialty biomarkers), and will facilitate the introduction of treatments at the most appropriate stage to maximize the therapeutic impact.

Improvements in the drug discovery and development process. Pharmaceutical companies will be able to identify specific molecular targets for “lead” identification and optimization, potentially identifying radically unique therapeutic strategies. Previously failed drug candidates, based on toxicity or lack of efficacy in an unselected disease population, may be resurrected when matched with a niche population prospectively defined by using clinical and genetic information.

The drug approval process will be radically transformed when the impact of genetic-based procedures for proper patient identification for treatment are appreciated. For example, the need for genetic/phenotypic risk-modeling tools, modifications in the consenting process, or restrictions in drug labeling to a genetically defined population would be part of a challenging portfolio of issues addressed during the development and commercialization process.

More accurate methods of determining appropriate drug dosage/regimen. Current methods of dosage and regimen selection that are based on empiricism or on an individual’s weight and age may be augmented by algorithms that also consider a person’s genetics and the impact of the environment and diet on genetic expression (ie, epigenetics). At minimum, this process will rationally address individual variations in drug absorption, distribution, metabolism, and elimination as has been successfully demonstrated for warfarin dose-finding.2 This will maximize a therapy’s value by decreasing the likelihood of toxicity as a result of overexposure, while enhancing the time until optimal efficacy can be achieved.

Decrease in the overall cost of healthcare. A reduction in the number of failed drug trials, the time it takes to get a drug approved, and the overall expenditures associated with clinical development may dra-

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matically alter the cost/benefit equation for investment within the pharmaceutical industry. Similarly, decreases in potential toxicity, in the length of time patients are taking medication, or in the number of medications

Decreases in potential toxicity, in the length of time patients are taking medication, or in the number of medications patients must take to find an effective therapy may, in theory, promote a net reduction in healthcare utilization. patients must take to find an effective therapy may, in theory, promote a net reduction in healthcare utilization. In contrast, an explosion in potential drug targets would accelerate the number of compounds available in any therapeutic armamentarium. Difficult decisions regarding reimbursement, prior authorizations (eg, expensive diagnostics for expensive therapeutics), and formulary design can introduce an increasingly complicated metric into the cost equation.

position and safety, pharmacogenomic-based research strategies exist. What is in ascendancy, however, is an expanded appreciation of the impact of pharmacogenomic initiatives across multiple stakeholders in an increasingly complicated healthcare environment.

Pharmaceutical research and development will be concerned with issues of development efficiencies, as well as with cost incentives (an implied market segmentation suggests a limited space for recouping research costs); regulatory policy will need to grapple with issues of evidentiary standards and appropriate labeling; healthcare providers will require actionable data, with a full appreciation of potential liabilities associated with genetically based pharmacotherapy, and patients will need assurance regarding privacy, insurability, and the overall economic value of an intervention. In essence, increasing the use of pharmacogenomic platforms for drug discovery and development will be characterized by increasing sophistication not only in medical and scientific domains but also by a commensurate mastery of implications in healthcare economics and psychosocial issues. ■

References Expanding Implications Is pharmacogenomics information in use today? To a limited degree, particularly regarding issues of drug dis-

1. Goetz MP, Ames MM, Weinshilboum RM. Primer on medical genomics. Part XII: pharmacogenomics—general principles with cancer as a model. Mayo Clin Proc. 2004;79:376-384.

2. Lesko LJ. The critical path of warfarin dosing: finding an optimal dosing strategy using pharmacogenetics. Clin Pharmacol Ther. 2008;84:301-303.

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SIMPONITM is indicated for the treatment of 1: Rheumatoid Arthritis • Moderately to severely active RA in adults, in combination with methotrexate

Psoriatic Arthritis • Active PsA in adults, alone or in combination with methotrexate

A once-monthly subcutaneous anti–TNF-α agent

Ankylosing Spondylitis • Active AS in adults

Recommended dosing1 SIMPONI™ is administered by 50 mg subcutaneous injection once a month • SIMPONI™ is intended for use under the guidance and supervision of a physician.

Patients may self-inject with SIMPONI™ after physician approval and training • There is no loading dose with SIMPONI™

Serious and sometimes fatal side effects have been reported with SIMPONI™, including infections due to tuberculosis, invasive fungal infections (eg, histoplasmosis), bacterial, viral, or other opportunistic pathogens. Prior to initiating SIMPONI™ and periodically during therapy, patients should be evaluated for active tuberculosis and tested for latent infection. Lymphoma and other malignancies, some fatal, can occur in adults and children. Other serious risks include hepatitis B reactivation, heart failure and demyelinating disorders.

Please see related and other Important Safety Information on next page.

Two delivery options1 • 50 mg/0.5 mL single dose prefilled syringe • 50 mg/0.5 mL single dose SmartJect™ autoinjector

www.simponi.com

Reference: 1. SIMPONI TM (golimumab) Prescribing Information. Centocor Ortho Biotech Inc.

IMPORTANT SAFETY INFORMATION FOR SIMPONI™ (golimumab) SERIOUS INFECTIONS Patients treated with SIMPONI™ are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. Discontinue SIMPONI™ if a patient develops a serious infection.

HEPATITIS B REACTIVATION The use of TNF-blocking agents including SIMPONI™ has been associated with reactivation of hepatitis B virus (HBV) in patients who are chronic hepatitis B carriers. In some instances, HBV reactivation occurring in conjunction with TNF-blocker therapy has been fatal. The majority of these reports have occurred in patients who received concomitant immunosuppressants.

Reported infections include:

Patients at risk for HBV infection should be evaluated for prior evidence of HBV infection before initiating SIMPONI™. Exercise caution when prescribing SIMPONI™ for patients identified as carriers of HBV and closely monitor for active HBV infection during and following termination of therapy with SIMPONI™. Discontinue SIMPONI™ in patients who develop HBV reactivation, and initiate antiviral therapy with appropriate supportive treatment. Exercise caution when considering resumption of SIMPONI™, and monitor patients closely.

• Active tuberculosis (TB), including reactivation of latent TB. Patients frequently presented with disseminated or extrapulmonary disease. Patients should be tested for latent TB before SIMPONI™ use and during therapy. Treatment for latent infection should be initiated prior to SIMPONI™ use.

• Invasive fungal infections, including histoplasmosis, coccidioidomycosis, and pneumocystosis. Patients with histoplasmosis or other invasive fungal infections may present with disseminated, rather than localized, disease. Consider empiric anti-fungal therapy in patients at risk for invasive fungal infections who develop severe systemic illness.

• Bacterial, viral, and other infections due to opportunistic pathogens.

The risks and benefits of treatment with SIMPONI™ should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection. Do not start SIMPONI™ in patients with clinically important active infections, including localized infections. Closely monitor patients for the development of signs and symptoms of infection during and after treatment with SIMPONI™, including the possible development of TB in patients who tested negative for latent TB infection prior to initiating therapy.

Other serious infections observed in patients treated with SIMPONI™ included sepsis, pneumonia, cellulitis, abscess and hepatitis B infection.

MALIGNANCIES Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers of which SIMPONI™ is a member. Approximately half the cases were lymphomas, including Hodgkin’s and non-Hodgkin’s lymphoma. The other cases represented a variety of malignancies, including rare malignancies usually associated with immunosuppression and malignancies not usually observed in children or adolescents. Malignancies occurred after a median of 30 months after the first dose of therapy. Most of the patients were receiving concomitant immunosuppressants.

In the controlled portions of clinical trials of all TNF-blocking agents including SIMPONI™, more cases of lymphoma have been observed among patients receiving TNF-blocking treatment compared with control patients.

In clinical trials, the incidence of lymphoma per 100 patient-years of follow-up was 0.21 (95% CI: 0.03, 0.77) in the combined SIMPONI™ group compared with an incidence of 0 (95% CI: 0, 0.96) in the placebo group. In clinical trials, the incidence of malignancies other than lymphoma was not increased with exposure to SIMPONI™ and was similar to what would be expected in the general population. Cases of acute and chronic leukemia have been reported with postmarketing TNF-blocker use. The risks and benefits of TNF-blocker therapy should be considered prior to initiating therapy in patients with a known malignancy or who develop a malignancy.

HEART FAILURE Cases of worsening congestive heart failure (CHF) and new-onset CHF have been reported with TNF blockers. Exercise caution and monitor patients with heart failure. Discontinue SIMPONI™ if new or worsening symptoms of heart failure appear.

DEMYELINATING DISORDERS TNF-blocking agents have been associated with cases of new-onset or exacerbation of central nervous system demyelinating disorders, including multiple sclerosis. Exercise caution in considering the use of SIMPONI™ in patients with central nervous system demyelinating disorders.

HEMATOLOGIC CYTOPENIAS There have been postmarketing reports of pancytopenia, leukopenia, neutropenia, aplastic anemia, and thrombocytopenia in patients receiving TNF blockers. Exercise caution when using SIMPONI™ in patients with significant cytopenias.

USE WITH OTHER DRUGS The concomitant use of a TNF blocker and abatacept or anakinra was associated with a higher risk of serious infections, therefore the use of SIMPONI™ in combination with these products is not recommended. A higher rate of serious infections has also been observed in RA patients treated with rituximab who received subsequent treatment with a TNF blocker. People receiving SIMPONI™ can receive vaccinations, except for live vaccines.

ADVERSE REACTIONS The most serious adverse reactions were serious infections and malignancies.

Upper respiratory tract infection and nasopharyngitis were the most common adverse reactions reported in the combined Phase 3 trials through Week 16, occurring in 7% and 6% of patients treated with SIMPONI™ as compared with 6% and 5% of patients in the control group, respectively. The rate of injection-site reactions was 6% with patients treated with SIMPONI™ compared with 2% of patients in the control group.

Cases of new-onset psoriasis, including pustular and palmoplantar, or exacerbation of pre-existing psoriasis have been reported with the use of TNF blockers, including SIMPONI™. Some of these patients required hospitalization. Most patients had improvement following discontinuation of the TNF blocker. Discontinuation of SIMPONI™ should be considered for severe cases and those that do not improve or that worsen despite topical treatments.

Please see brief summary of Full Prescribing Information on the following pages.

Representing the products of

©2010 Centocor Ortho Biotech Services, LLC

25GL10019

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SIMPONI™ (golimumab) Injection, solution for subcutaneous use See package insert for Full Prescribing Information.

WARNING SERIOUS INFECTIONS Patients treated with SIMPONI™ are at increased risk for developing serious infections that may lead to hospitalization or death (see Warnings and Precautions). Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. SIMPONI™ should be discontinued if a patient develops a serious infection.

Reported infections include: • Active tuberculosis, including reactivation of latent tuberculosis. Patients with tuberculosis have frequently presented with disseminated or extrapulmonary disease. Patients should be tested for latent tuberculosis before SIMPONI™ use and during therapy. Treatment for latent infection should be initiated prior to SIMPONI™ use.

• Invasive fungal infections, including histoplasmosis, coccidioidomycosis, and pneumocystosis. Patients with histoplasmosis or other invasive fungal infections may present with disseminated, rather than localized, disease. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. Empiric anti-fungal therapy should be considered in patients at risk for invasive fungal infections who develop severe systemic illness.

• Bacterial, viral, and other infections due to opportunistic pathogens.

The risks and benefits of treatment with SIMPONI™ should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection.

Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with SIMPONI™, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy (See Warning and Precautions).

MALIGNANCY Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers, of which SIMPONI is a member.

INDICATIONS AND USAGE: Rheumatoid Arthritis SIMPONI™, in combination with methotrexate, is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis. Psoriatic Arthritis SIMPONI™, alone or in combination with methotrexate, is indicated for the treatment of adult patients with active psoriatic arthritis.

Ankylosing Spondylitis SIMPONI™ is indicated for the treatment of adult patients with active ankylosing spondylitis. CONTRAINDICATIONS: None. WARNINGS AND PRECAUTIONS (see Boxed WARNINGS): Serious Infections Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, protozoal, or other opportunistic pathogens have been reported in patients receiving TNF-blockers including SIMPONI™. Among opportunistic infections, tuberculosis, histoplasmosis, aspergillosis, candidiasis, coccidioidomycosis, listeriosis, and pneumocystosis were the most commonly reported with TNF-blockers. Patients have frequently presented with disseminated rather than localized disease, and were often taking concomitant immunosuppressants such as methotrexate or corticosteroids. The concomitant use of a TNF-blocker and abatacept or anakinra was associated with a higher risk of serious infections; therefore, the concomitant use of SIMPONI™ and these biologic products is not recommended (see Warning and Precautions and Drug Interactions). Treatment with SIMPONI™ should not be initiated in patients with an active infection, including clinically important localized infections. The risks and benefits of treatment should be considered prior to initiating SIMPONI™ in patients: with chronic or recurrent infection; who have been exposed to tuberculosis; with a history of an opportunistic infection; who have resided or traveled in areas of endemic tuberculosis or endemic mycoses, such as histoplasmosis, coccidioidomycosis, or blastomycosis; or with underlying conditions that may predispose them to infection. Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with SIMPONI™. SIMPONI™ should be discontinued if a patient develops a serious infection, an opportunistic infection, or sepsis. A patient who develops a new infection during treatment with SIMPONI™ should undergo a prompt and complete diagnostic workup appropriate for an immunocompromised patient; appropriate antimicrobial therapy should be initiated, and the patient should be closely monitored. In controlled Phase 3 trials through Week 16 in RA, PsA, and AS, serious infections were observed in 1.4% of SIMPONI™-treated patients and 1.3% of control-treated patients. In the controlled Phase 3 trials through Week 16 in patients with RA, PsA, and AS, the incidence of serious infections per 100 patient-years of follow-up was 5.4 (95% CI: 4.0, 7.2) for the SIMPONI™ group and 5.3 (95% CI: 3.1, 8.7) for the placebo group. Serious infections observed in SIMPONI™-treated patients included sepsis, pneumonia, cellulitis, abscess, tuberculosis, invasive fungal infections, and hepatitis B infection. Tuberculosis Cases of reactivation of tuberculosis or new tuberculosis infections have been observed in patients receiving TNF-blockers, including patients who have previously received treatment for latent or active tuberculosis. Patients should be evaluated for tuberculosis risk factors and tested for latent infection prior to initiating SIMPONI™ and periodically during therapy.

Treatment of latent tuberculosis infection prior to therapy with TNF-blockers has been shown to reduce the risk of tuberculosis reactivation during therapy. Induration of 5 mm or greater with tuberculin skin testing should be considered a positive test result when assessing if treatment for latent tuberculosis is needed prior to initiating SIMPONI™, even for patients previously vaccinated with Bacille Calmette-Guerin (BCG). Anti-tuberculosis therapy should also be considered prior to initiation of SIMPONI™ in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent tuberculosis but who have risk factors for tuberculosis infection. Consultation with a physician with expertise in the treatment of tuberculosis is recommended to aid in the decision whether initiating antituberculosis therapy is appropriate for an individual patient. Patients should be closely monitored for the development of signs and symptoms of tuberculosis including patients who tested negative for latent tuberculosis infection prior to initiating therapy. Tuberculosis should be strongly considered in patients who develop a new infection during SIMPONI™ treatment, especially in patients who have previously or recently traveled to countries with

a high prevalence of tuberculosis, or who have had close contact with a person with active tuberculosis. In the controlled and uncontrolled portions of the Phase 2 RA and Phase 3 RA, PsA, and AS trials, the incidence of active TB was 0.23 and 0 per 100 patient-years in 2347 SIMPONI™-treated patients and 674 placebo-treated patients, respectively. Cases of TB included pulmonary and extra pulmonary TB. The overwhelming majority of the TB cases occured in countries with a high incidence rate of TB. Invasive Fungal Infections For SIMPONI™-treated patients who reside or travel in regions where mycoses are endemic, invasive fungal infection should be suspected if they develop a serious systemic illness.

Appropriate empiric antifungal therapy should be considered while a diagnostic workup is being performed. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. When feasible, the decision to administer empiric antifungal therapy in these patients should be made in consultation with a physician with expertise in the diagnosis and treatment of invasive fungal infections and should take into account both the risk for severe fungal infection and the risks of antifungal therapy. Hepatitis B Virus Reactivation The use of TNF-blockers including SIMPONI™ has been associated with reactivation of hepatitis B virus (HBV) in patients who are chronic hepatitis B carriers (i.e., surface antigen positive). In some instances, HBV reactivation occurring in conjunction with TNF-blocker therapy has been fatal. The majority of these reports have occurred in patients who received concomitant immunosuppressants. Patients at risk for HBV infection should be evaluated for prior evidence of HBV infection before initiating TNF-blocker therapy. The risks and benefits of treatment should be considered prior to prescribing TNF-blockers, including SIMPONI™, to patients who are carriers of HBV. Adequate data are not available on whether anti-viral therapy can reduce the risk of HBV reactivation in HBV carriers who are treated with TNF-blockers. Patients who are carriers of HBV and require treatment with TNF-blockers should be closely monitored for clinical and laboratory signs of active HBV infection throughout therapy and for several months following termination of therapy. In patients who develop HBV reactivation, TNF-blockers should be stopped and antiviral therapy with appropriate supportive treatment should be initiated. The safety of resuming TNF-blockers after HBV reactivation has been controlled is not known. Therefore, prescribers should exercise caution when considering resumption of TNF-blockers in this situation and monitor patients closely. Malignancies Malignancies, some fatal, have been reported among children, adolescents, and young adults who received treatment with TNFblocking agents (initiation of therapy ≤ 18 years of age), of which SIMPONI is a member.

Approximately half the cases were lymphomas, including Hodgkin’s and non-Hodgkin’s lymphoma. The other cases represented a variety of malignancies, including rare malignancies that are usually associated with immunosuppression, and malignancies that are not usually observed in children and adolescents. The malignancies occurred after a median of 30 months (range 1 to 84 months) after the first dose of TNF blocker therapy.

Most of the patients were receiving concomitant immunosuppressants. These cases were reported post-marketing and are derived from a variety of sources, including registries and spontaneous postmarketing reports. The risks and benefits of TNF-blocker treatment including SIMPONI™ should be considered prior to initiating therapy in patients with a known malignancy other than a successfully treated non-melanoma skin cancer (NMSC) or when considering continuing a TNF-blocker in patients who develop a malignancy. In the controlled portions of clinical trials of TNF-blockers including SIMPONI™, more cases of lymphoma have been observed among patients receiving anti-TNF treatment compared with patients in the control groups. During the controlled portions of the Phase 2 trials in RA, and the Phase 3 trials in RA, PsA and AS, the incidence of lymphoma per 100 patientyears of follow-up was 0.21 (95% CI: 0.03, 0.77) in the combined SIMPONI™ group compared with an incidence of 0 (95% CI: 0., 0.96) in the placebo group. In the controlled and uncontrolled portions of these clinical trials in 2347 SIMPONI™-treated patients with a median follow-up of 1.4 years, the incidence of lymphoma was 3.8-fold higher than expected in the general U.S. population according to the SEER database (adjusted for age, gender, and race).1 Patients with RA and other chronic inflammatory diseases, particularly patients with highly active disease and/or chronic exposure to immunosuppressant therapies, may be at higher risk (up to several fold) than the general population for the development of lymphoma, even in the absence of TNF-blocking therapy. Cases of acute and chronic leukemia have been reported with postmarketing TNF-blocker use in rheumatoid arthritis and other indications. Even in the absence of TNF blocker therapy, patients with rheumatoid arthritis may be at a higher risk (approximately 2-fold) than the general population for the development of leukemia. During the controlled portions of the Phase 2 trial in RA, and the Phase 3 trials in RA, PsA and AS, the incidence of malignancies other than lymphoma per 100 patient-years of follow-up was not elevated in the combined SIMPONI™ group compared with the placebo group. In the controlled and uncontrolled portions of these trials, the incidence of malignancies, other than lymphoma, in SIMPONI™treated patients was similar to that expected in the general U.S. population according to the SEER database (adjusted for age, gender, and race).1 In controlled trials of other TNFblockers in patients at higher risk for malignancies (e.g., patients with COPD, patients with Wegener’s granulomatosis treated with concomitant cyclophosphamide) a greater portion of malignancies occurred in the TNF-blocker group compared to the controlled group. In an exploratory 1-year clinical trial evaluating the use of 50, 100 and 200 mg of SIMPONI™ in 309 patients with severe persistent asthma, 6 patients developed malignancies other than NMSC in the SIMPONI™ groups compared to none in the control group. Three of the 6 patients were in the 200-mg SIMPONI™ group. Congestive Heart Failure Cases of worsening congestive heart failure (CHF) and new onset CHF have been reported with TNFblockers. In several exploratory trials of other TNF-blockers in the treatment of CHF, there were greater proportions of TNF-blocker treated patients who had CHF exacerbations requiring hospitalization or increased mortality. SIMPONI™ has not been studied in patients with a history of CHF and SIMPONI™ should be used with caution in patients with CHF. If a decision is made to administer SIMPONI™ to patients with CHF, these patients should be closely monitored during therapy, and SIMPONI™ should be discontinued if new or worsening symptoms of CHF appear. Demyelinating Disorders Use of TNF-blockers has been associated with cases of new onset or exacerbation of central nervous system (CNS) demyelinating disorders, including multiple sclerosis (MS). While no trials have been performed evaluating SIMPONI™ in the treatment of patients with MS, another TNF-blocker was associated with increased disease activity in patients with MS. Therefore, prescribers should exercise caution in considering the use of TNF-blockers including SIMPONI™ in patients with CNS demyelinating disorders including MS. Use with Abatacept In controlled trials, the concurrent administration of another TNF-blocker and abatacept was associated with a greater proportion of serious infections than the use of a TNF-blocker alone; and the

combination therapy, compared to the use of a TNF-blocker alone, has not demonstrated improved clinical benefit in the treatment of RA. Therefore, the combination of TNF-blockers including SIMPONI™ and abatacept is not recommended (see Drug Interactions). Use with Anakinra Concurrent administration of anakinra (an interleukin-1 antagonist) and another TNF-blocker, was associated with a greater portion of serious infections and neutropenia and no additional benefits compared with the TNF-blocker alone. Therefore, the combination of anakinra with TNF-blockers, including SIMPONI™, is not recommended (see Drug Interactions). Hematologic Cytopenias There have been post-marketing reports of pancytopenia, leukopenia, neutropenia, aplastic anemia, and thrombocytopenia in patients receiving TNF-blockers. Although, there were no cases of severe cytopenias seen in the SIMPONI™ clinical trials, caution should be exercised when using TNF-blockers, including SIMPONI™, in patients who have significant cytopenias. Vaccinations Patients treated with SIMPONI™ may receive vaccinations, except for live vaccines. No data are available on the response to live vaccination or the risk of infection, or transmission of infection after the administration of live vaccines to patients receiving SIMPONI™. In the Phase 3 PsA study, after pneumococcal vaccination, a similar proportion of SIMPONI™-treated and placebotreated patients were able to mount an adequate immune response of at least a 2-fold increase in antibody titers to pneumococcal polysaccharide vaccine. In both SIMPONI™treated and placebo-treated patients, the proportions of patients with response to pneumococcal vaccine were lower among patients receiving MTX compared with patients not receiving MTX. The data suggest that SIMPONI™ does not suppress the humoral immune response to the pneumococcal vaccine. ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Clinical Studies Experience The safety data described below are based on 5 pooled, randomized, double-blind, controlled Phase 3 trials in patients with RA, PsA, and AS (Studies RA-1, RA-2, RA-3, PsA and AS). These 5 trials included 639 control-treated patients and 1659 SIMPONI™-treated patients including 1089 with RA, 292 with PsA, and 277 with AS. The proportion of patients who discontinued treatment due to adverse reactions in the controlled Phase 3 trials through Week 16 in RA, PsA and AS was 2% for SIMPONI™-treated patients and 3% for placebo-treated patients. The most common adverse reactions leading to discontinuation of SIMPONI™ in the controlled Phase 3 trials through Week 16 were sepsis (0.2%), alanine aminotransferase increased (0.2%), and aspartate aminotransferase increased (0.2%). The most serious adverse reactions were: Serious Infections; Malignancies. Upper respiratory tract infection and nasopharyngitis, were the most common adverse reactions reported in the combined Phase 3 RA, PsA and AS trials through Week 16, occurring in 7% and 6% of SIMPONI™-treated patients as compared with 6% and 5% of control-treated patients, respectively. Infections In controlled Phase 3 trials through Week 16 in RA, PsA, and AS, infections were observed in 28% of SIMPONI™-treated patients compared to 25% of control-treated patients. Liver Enzyme Elevations There have been reports of severe hepatic reactions including acute liver failure in patients receiving TNF-blockers. In controlled Phase 3 trials of SIMPONI™ in patients with RA, PsA, and AS through Week 16, ALT elevations ≥5 x ULN occurred in 0.2% of control-treated patients and 0.7% of SIMPONI™-treated patients, and ALT elevations ≥3 x ULN occurred in 2% of control-treated patients and 2% of SIMPONI™-treated patients. Since many of the patients in the Phase 3 trials were also taking medications that cause liver enzyme elevations (e.g., NSAIDs, MTX), the relationship between golimumab and liver elevation is not clear. Autoimmune Disorders and Autoantibodies The use of TNF-blockers has been associated with the formation of autoantibodies and, rarely, with the development of a lupus-like syndrome. In the controlled Phase 3 trials in patients with RA, PsA, and AS through Week 14, there was no association of SIMPONI™ treatment and the development of newly positive anti-dsDNA antibodies.

Injection Site Reactions In controlled Phase 3 trials through Week 16 in RA, PsA and AS, 6% of SIMPONI™ treated patients had injection site reactions compared with 2% of controltreated patients. The majority of the injection site reactions were mild and the most frequent manifestation was injection site erythema. In controlled Phase 2 and 3 trials in RA, PsA, and AS, no patients treated with SIMPONI™ developed anaphylactic reactions. Psoriasis: NewOnset and Exacerbations Cases of new onset psoriasis, including pustular psoriasis and palmoplantar psoriasis, have been reported with the use of TNF-blockers, including SIMPONI. Cases of exacerbation of pre-existing psoriasis have also been reported with the use of TNF-blockers. Many of these patients were taking concomitant immunosuppressants (e.g., MTX, corticosteroids). Some of these patients required hospitalization. Most patients had improvement of their psoriasis following discontinuation of their TNF-blocker. Some patients have had recurrences of the psoriasis when they were re-challenged with a different TNF-blocker. Discontinuation of SIMPONI™ should be considered for severe cases and those that do not improve or that worsen despite topical treatments. Immunogenicity Antibodies to SIMPONI™ were detected in 57 (4%) of SIMPONI™-treated patients across the Phase 3 RA, PsA and AS trials through Week 24. Similar rates were observed in each of the 3 indications. Patients who received SIMPONI™ with concomitant MTX had a lower proportion of antibodies to SIMPONI™ than patients who received SIMPONI™ without MTX (approximately 2% versus 7%, respectively). Of the patients with a positive antibody response to SIMPONI™ in the Phase 2 and 3 trials, most were determined to have neutralizing antibodies to golimumab as measured by a cell-based functional assay. The small number of patients positive for antibodies to SIMPONI™ limits the ability to draw definitive conclusions regarding the relationship between antibodies to golimumab and clinical efficacy or safety measures. The data above reflect the percentage of patients whose test results were considered positive for antibodies to SIMPONI™ in an ELISA assay, and are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to SIMPONI™ with the incidence of antibodies to other products may be misleading. Other Adverse Reactions The adverse drug reactions that occurred at a rate of at least 1% in the combined SIMPONI™ groups during the controlled period of the 5 pooled Phase 3 trials through Week 16 in patients with RA, PsA, and AS are summarized below. Patients may have taken concomitant MTX, sulfasalazine, hydroxychloroquine, low-dose corticosteroids (≤10 mg of prednisone/day or equivalent), and/or NSAIDs during the trials. The numbers (percentages) of adverse drug reactions for Placebo ± DMARDS-treated patients (n=639) and SIMPONI™ ± DMARDS-treated patients (n=1659), respectively, were:

Upper respiratory tract infection Nasopharyngitis Alanine aminotransferase increased Injection site erythema Hypertension Aspartate aminotransferase increased Bronchitis Dizziness Sinusitis Influenza Pharyngitis Rhinitis Pyrexia Oral herpes Paraesthesia

Placebo ± DMARDS 37 (6%) 31 (5%) 18 (3%) 6 (1%) 9 (1%) 10 (2%) 9 (1%) 7 (1%) 7 (1%) 7 (1%) 8 (1%) 4 (< 1%) 4 (< 1%) 2 (< 1%) 2 (< 1%)

SIMPONI™ ± DMARDS 120 (7%) 91 (6%) 58 (4%) 56 (3%) 48 (3%) 44 (3%) 31 (2%) 32 (2%) 7 (2%) 25 (2%) 22 (1%) 20 (1%) 20 (1%) 16 (1%) 16 (1%)

DRUG INTERACTIONS: Methotrexate. For the treatment of RA, SIMPONI™ should be used with MTX. Since the presence or absence of concomitant MTX did not appear to influence the efficacy or safety of SIMPONI™ in the treatment of PsA or AS, SIMPONI™ can be used with or without MTX in the treatment of PsA and AS. Biologic Products for RA, PsA, and/or AS An increased risk of serious infections has been seen in clinical RA studies of other TNF-blockers used in combination with anakinra or abatacept, with no added benefit; therefore, use of SIMPONI™ with abatacept or anakinra is not recommended. A higher rate of serious infections has also been observed in RA patients treated with rituximab who received subsequent treatment with a TNF-blocker. There is insufficient information to provide recommendations regarding the concomitant use of SIMPONI™ and other biologic products approved to treat RA, PsA, or AS. Live Vaccines Live vaccines should not be given concurrently with SIMPONI™. Cytochrome P450 Substrates The formation of CYP450 enzymes may be suppressed by increased levels of cytokines (e.g., TNFα) during chronic inflammation. Therefore, it is expected that for a molecule that antagonizes cytokine activity, such as golimumab, the formation of CYP450 enzymes could be normalized. Upon initiation or discontinuation of SIMPONI™ in patients being treated with CYP450 substrates with a narrow therapeutic index, monitoring of the effect (e.g., warfarin) or drug concentration (e.g., cyclosporine or theophylline) is recommended and the individual dose of the drug product may be adjusted as needed. USE IN SPECIFIC POPULATIONS: Pregnancy Pregnancy Category B – There are no adequate and well-controlled studies of SIMPONI™ in pregnant women. Because animal reproduction and developmental studies are not always predictive of human response, it is not known whether SIMPONI™ can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. SIMPONI™ should be used during pregnancy only if clearly needed. An embryofetal developmental toxicology study was performed in which pregnant cynomolgus monkeys were treated subcutaneously with golimumab during the first trimester with doses up to 50 mg/kg twice weekly (360 times greater than the maximum recommended human dose-MHRD) and has revealed no evidence of harm to maternal animals or fetuses. Umbilical cord blood samples collected at the end of the second trimester showed that fetuses were exposed to golimumab during gestation. In this study, in utero exposure to golimumab produced no developmental defects to the fetus. A pre- and post-natal developmental study was performed in which pregnant cynomolgus monkeys were treated with golimumab during the second and third trimesters, and during lactation at doses up to 50 mg/kg twice weekly (860 times and 310 times greater than the maximal steady state human blood levels for maternal animals and neonates, respectively) and has revealed no evidence of harm to maternal animals or neonates.

Golimumab was present in the neonatal serum from the time of birth and for up to 6 months postpartum. Exposure to golimumab during gestation and during the postnatal period caused no developmental defects in the infants. Nursing Mothers It is not known whether SIMPONI™ is excreted in human milk or absorbed systemically after ingestion. Because many drugs and immunoglobulins are excreted in human milk, and because of the potential for adverse reactions in nursing infants from SIMPONI™, 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. In the pre- and post-natal development study in cynomolgus monkeys in which golimumab was administered subcutaneously during pregnancy and lactation, golimumab was detected in the breast milk at concentrations that were approximately 400fold lower than the maternal serum concentrations. Pediatric Use Safety and effectiveness of SIMPONI™ in patients less than 18 years of age have not been established. Geriatric Use In the Phase 3 trials in RA, PsA, and AS, there were no overall differences in SAEs, serious infections, and AEs in SIMPONI™-treated patients ages 65 or older (N=155) compared with younger SIMPONI™-treated patients. Because there is a higher incidence of infections in the geriatric population in general, caution should be used in treating geriatric patients with SIMPONI™. OVERDOSAGE In a clinical study, 5 patients received protocol-directed single infusions of 10 mg/kg of intravenous SIMPONI™ without serious adverse reactions or other significant reactions. The highest weight patient was 100 kg, and therefore received a single intravenous infusion of 1000 mg of SIMPONI™. There were no SIMPONI™ overdoses in the clinical studies. PATIENT COUNSELING INFORMATION Patient Counseling Patients should be advised of the potential benefits and risks of SIMPONI™. Physicians should instruct their patients to read the Medication Guide before starting SIMPONI™ therapy and to read it each time the prescription is renewed. Infections Inform patients that SIMPONI™ may lower the ability of their immune system to fight infections. Instruct the patient of the importance of contacting their doctor if they develop any symptoms of infection, including tuberculosis, invasive fungal infections, and hepatitis B reactivation. Malignancies Patients should be counseled about the risk of lymphoma and other malignancies while receiving SIMPONI™. Allergic Reactions Advise latex-sensitive patients that the needle cover on the prefilled syringe as well as the prefilled syringe in the prefilled SmartJect™ autoinjector contains dry natural rubber (a derivative of latex). Other Medical Conditions Advise patients to report any signs of new or worsening medical conditions such as congestive heart failure, demyelinating disorders, autoimmune diseases, liver disease, cytopenias, or psoriasis.

References: 1. SEER [database online]. U.S. Population Data—1969-2004. Bethesda, MD; National Cancer Institute. Release date: January 3, 2007. Available at: http://www.seer.cancer.gov/popdata.

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BUSINESS

Obesity: Effective Treatment Requires Change in Payers’ Perspective Rhonda Greenapple, MSPH; Jackie Ngai, MS Background: Obesity is an increasing problem in the United States, and the health problems attributed to it have a significant economic impact on the healthcare system, as well as on patients’ quality of life. In addition, childhood obesity is increasingly becoming a prominent diagnosis.

Objective: To identify physician and payer reactions to the profiles of 4 new obesity products in development and the potential that these will be prescribed by physicians and reimbursed by payers. This article examines payers’ and physicians’ perspectives in effective treatment options for this epidemic.

Method: A 2008 online survey conducted by Reimbursement Intelligence was completed by 42 physicians who are advisors to Pharmacy & Therapeutics Committees and see an average of 435 obese patients monthly, as well as 17 payers who represent more than 100 million covered lives. This research was double blinded to conceal product and client identification. Qualitative and quantitative data were collected from the survey responses.

Results: Based on the physician and payer survey responses, morbid obesity is expected to grow in the next 2 years. About 80% of morbidly obese patients have type 2 diabetes, but more than 75% of payers do not track patients who are obese, morbidly obese, or those with the metabolic syndrome. Despite its effect on business productivity and the cost of care, healthcare professionals and payers continue to have varying perspectives related to its prevention and treatment. Physicians would like to have more treatment options, but payers perceive them as ineffective and find the safety and adverse effect profiles unfavorable.

Conclusion: There is a clear need for multiple treatment alternatives to combat obesity that include plan member access to weight-loss options, such as prescription medications and bariatric surgery. There needs to be an increase in educational support from manufacturers of products for obesity, as well as increased awareness of products in the pipeline. [AHDB. 2010;3(2):88-94.]

O

besity is associated with many chronic diseases and is classified as a disease by several organizations, including the World Health Organization, the National Institutes of Health, the US Food and Drug Administration (FDA), and the Centers for Disease Control and Prevention (CDC).1-4 Observational epidemiologic studies have established a relationship between obesity and the risks for cardiovascular disease (CVD), non–insulin-dependent diabetes mellitus, certain types of cancer, gallstones, certain respiratory disorders, and an increase in overall mortality. Diabetes is on the rise in the United States, and approximately 90% of diabetes cases are attributed to excess weight.5,6 Recent studies have also stated that pediatric obesity is on the rise, particularly among

Ms Greenapple is President and Founder, and Ms Ngai is a medical writer for Reimbursement Intelligence, Madison, NJ.

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black and Latino populations, as well as those from lower socioeconomic groups.7 New research has linked endoplasmic reticulum stress to a high-fat diet; this condition is overly activated in obese people and triggers aberrant glucose production in the liver, a step in the path to insulin resistance.8 Health problems attributed to obesity have a significant impact on the US healthcare system in terms of direct and indirect medical costs. Direct medical costs include preventive, diagnostic, and treatment services, whereas indirect costs relate to morbidity and mortality. In 2000, the CDC estimated that obesity-related healthcare costs totaled $117 billion.9 In October 2008, Reimbursement Intelligence conducted an online survey titled Payer and Physician Evaluation of Obesity Treatments, with the goal of examining the perspectives of commercial and government health plans on obesity. Respondents included

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Obesity Prevalence According to the CDC, more than one third of US adults (more than 72 million persons) can currently be categorized as obese—a body mass index (BMI) ≥30 kg/m2—or morbidly obese.10 Of more concern, 30.1% of children aged 2 to 19 years are overweight or obese.7,11 Adults aged 40 to 59 years had the highest obesity prevalence compared with other age-groups, including approximately 40% of men in this age-group and 41% of women (Figure 1).12 In July 2009, a Robert Wood Johnson Foundation report indicated that obesity rates increased in 23 US states and did not decrease in a single state in the past year.13 The rate of obesity in school-aged children is rising, which will incur increased healthcare costs from use of the medical system and disease comorbidities. A recent study demonstrated that 61% of obese children aged 5 to 10 years have ≥1 risk factors for CVD, and 27% of children in that age-group have >2 CVD risk factors.14 Currently, 20 states have passed legislation requiring BMI screening for children and adolescents to facilitate early intervention and improve healthy eating habits.13 It is critical for health plans to manage obesity in younger patients, because it can save future costs that can extend for more than 60 years.

Obesity is also higher among black women and men compared with other demographics, who also have a greater incidence of diabetes and CVD.10,15 This has created a need for intervention to stop the obesity epidemic. Based on a plan’s unique patient population, the incidence and cost of obesity can be significant.

Calculation of BMI is the primary criterion for assessing obesity.7 Easily calculated in the clinical setting, BMI correlates significantly with body fat, morbidity, and mortality.

KEY POINTS u

u

u

u

u

More than one third (>72 million) of US adults can currently be categorized as obese. In 2000, the Centers for Disease Control and Prevention estimated that obesity-related healthcare costs totaled $117 billion.

This article discusses the results of a recent survey of payers representing >100 million covered lives, as well as 42 physicians who treat nearly 500 obese patients monthly to examine their perspectives on obesity management.

Only 24% of payers are tracking obese and morbidly obese patients, making it difficult to provide intervention and case management.

Weight-loss drugs are not covered by many employers, because they are seen as “lifestyle drugs” or drugs that lack efficacy.

Many physicians consider a 5% to 10% weight reduction in 6 months as needed to show efficacy of a new treatment plan. In contrast, payers require 18% weight loss to place a product on formulary.

Figure 1 Obesity Prevalence, by Age (≥20 years) and Sex, and the Healthy People 2010 Obesity Target, 2005-2006 50

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payers representing more than 100 million covered lives, as well as 42 physicians who treat nearly 500 obese and/or morbidly obese patients monthly.

30 Healthy People 2010 target

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20-39

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Obesity-Related Comorbidities A BMI of 25 kg/m2 is the generally accepted threshold for identifying a patient at increased risk for obesity-related diseases, most notably type 2 diabetes, hypertension, and CVD. For those with a BMI above 25 kg/m2, each extra 5 kg/m2 results in an increased overall mortality risk of approximately 33%.7 More than 80% of deaths estimated to result from comorbidities associated with obesity occur in patients with a BMI of at least 30 kg/m2.2 Increasing research shows that obesity-related comorbid conditions are becoming more prevalent.

Researchers at Monash University recently established

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Note: Obesity is defined as body mass index ≥30 kg/m2.

Source: Centers for Disease Control and Prevention. Revised December 4, 2007. www.cdc.gov/nchs/data/databriefs/db01.pdf.

the link between obesity and diabetes.16 Pigment epithelium-derived factor (PEDF, SerpinF1) was identified as a link between obesity and insulin resistance; increasing PEDF causes type 2 diabetes complications, while blocking the inhibitor reverses the effects.16 The link will help other researchers develop better options for the treatment of obesity and diabetes.

The incidence of diabetes is on the rise, and so are the risks of comorbidities and associated illnesses. The

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Figure 2 Is Your Plan Tracking Patients with Obesity, Morbid Obesity, or Metabolic Syndrome?

Yes No

24%

76%

metabolic syndrome is characterized by the following risk factors17: • Abdominal obesity • Atherogenic dyslipidemia: blood fat disorders—high triglycerides, low high-density lipoprotein cholesterol, and high low-density lipoprotein cholesterol levels—that foster plaque buildups in artery walls • Elevated blood pressure • Insulin resistance or glucose intolerance (ie, the body cannot properly use insulin or blood glucose) • Prothrombotic state (eg, high fibrinogen or plasminogen-activator inhibitor type 1 in the blood) • Proinflammatory state (eg, elevated C-reactive protein levels in the blood).

A predecessor to type 2 diabetes and CVD, the metabolic syndrome is a cluster of illnesses that needs to be prevented, treated, and managed.

Results of our Payer and Physician Evaluation of Obesity Treatments survey show that just 24% of payers are currently tracking obese and morbidly obese patients, making it difficult to provide intervention.

Payer and Physician Evaluation of Obesity Treatments: Survey Results Despite the importance of identifying and intervention with the population, results of our Payer and Physician Evaluation of Obesity Treatments survey show that just 24% of payers are currently tracking obese and morbidly obese patients, making it difficult to provide intervention and case management (Figure 2).

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Health plans are more likely to identify these patients through other disease management initiatives for the metabolic syndrome, coronary artery disease, diabetes, and arthritis, for which data are being collected.

Although drug treatments for obesity are currently available, and promising new drug treatments are in development, payer respondents believe that bariatric surgery is more effective than medications for obesity therapy. Eighty-eight percent of payers indicated that their plan covers bariatric surgery, whereas nearly 50% of these payers report that less than 20% of employers cover drugs under a commercial plan. Payers are therefore far more likely to cover surgery than weight-loss medications.

This disparity may stem from the safety and efficacy “baggage” of past and current pharmacologic treatments for obesity, such as sibutramine (Meridia); the combination of fenfluramine and phentermine (fen-phen); and orlistat (Xenical), now available over the counter as alli.

In July 1997, researchers at the Mayo Clinic reported 24 cases of heart valve disease in patients who were taking fenfluramine-phentermine.18 The FDA requested that fenfluramine hydrochloride (Pondimin) and dexfenfluramine hydrochloride (Redux) be withdrawn from the market in September 1997.18 Sibutramine was the first subsequent drug approved by the FDA for the treatment of obesity. According to the FDA, the long-term effects of sibutramine on morbidity and mortality associated with obesity have not been established. The drug also increases the sympathetic drive, heart rate, and blood pressure, which limit its use in hypertensive patients.19

Impact of Obesity on Employers Several studies have addressed obesity from the viewpoint of employers. Results of a study that examined whether there is a progressive correlation between BMI, healthcare costs, and absenteeism showed that employees with a high BMI were more likely to have other health risks and took twice as many sick days than those who do not have a high BMI (8.45 vs 3.73 days, respectively).20 When total mean medical costs were analyzed by BMI level, a J-shaped curve was produced. The mean healthcare costs for the BMI-related at-risk population was $6822 compared with $4496 for the not-at-risk population.20 The most important differences in healthcare costs were for employees aged ≥45 years. The excess cost associated with high BMI risk was $3514 overall.20 Obesity also has a substantial impact on healthcare costs for employers. In 2000, the estimated annual direct medical expenditures for obesity alone were $61 billion, accounting for a 12% increase in healthcare

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Evaluation of New Weight-Loss Treatments Based on survey responses, payers and physicians will be considering new drug therapies, many of which are now in late-stage development. However, their expectations regarding the level of weight loss that will be achieved with these potential new treatments vary considerably.

More than half of the physicians responding to the Reimbursement Intelligence study considered a 5% to

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Health plans reporting customer (employer) coverage, %

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40 30 20

18

18 9

10

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0 0-20

21-40

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81-100

Employers covering obesity drugs, %

Figure 4 Influences on Physician Treatment Decision-Making Efficacy Safety Reimbursement

80 68.3

65.9 61.0

60

Respondents, %

Reimbursement Issues Affect Treatment Options Currently, weight-loss drugs are not covered by many employers, because they are seen as “lifestyle drugs” or drugs that lack efficacy. For a durable outcome, an obese member must make a lifestyle change. Coverage is often linked to or associated with a concurrent lifestyle change, such as a gym membership or a formulary approval for a specific period, after which, if a weightloss goal is achieved, continued coverage is granted.

In the Reimbursement Intelligence study, payers reported that a limited number of employers cover these products under commercial plans (Figure 3). Many plans also use higher copayments and utilization restrictions to manage these products.

Reimbursement issues have had a measurable impact on physicians’ treatment plans. Respondents to the Reimbursement Intelligence study ranked reimbursement as equally important to efficacy (65.9% vs 68.3%, respectively) and safety (61.0%) in their decision to prescribe—or not prescribe—weight-loss drugs (Figure 4).

Figure 3 Percentage of Employers Who Cover Weight-Loss Medications

40

20

0

Figure 5 Minimum Weight-Loss Threshold for Demonstrating Effectiveness (Physicians) 60

Physician respondents, %

spending from 1987 through 2001.21 Additional studies showed an annual loss of 39.2 million more workdays among overweight and obese people compared with lean people (ie, BMI ≤25 kg/m2).21 Obesity also drives 85% of the total cost of treating type 2 diabetes, and 45% of the cost of treating hypertension, and points toward a $1500 increase per overweight or obese employee in annual healthcare costs.22 Based on the measurable impact of obesity on corporations’ bottom lines, many companies are willing to offer increased benefits to the most at-risk employee population to help reduce or eliminate escalating costs related to overweight and obesity. Despite the significant medical costs associated with obesity, many employers are not covering weight-loss drugs. Nearly half of health plans indicated that merely ≤20% of their customers (ie, employers) cover obesity drugs (Figure 3). However, initiatives to help employers combat obesity in the workplace are emerging. Recently, the CDC launched the LEANWorks website, which contains tools and resources to help businesses implement an effective worksite obesity prevention and weight-control program.23

56.1

Weight-loss threshold 5% 6%-10% 11%-15% 16%-20%

40 24.4 20

14.6 4.9

0

10% weight reduction as a minimum threshold to demonstrate the effectiveness of a new treatment plan after 6 months (Figure 5). In contrast, payers indicated that a minimum of 18% weight loss would influence their decision to place a product on their formulary and be reimbursed by the plan.

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Figure 6 Payers’ Comparison of Bariatric Surgery vs WeightLoss Medication Efficacy

Payer respondents, %

100

85

80 60 40 20

15 0

0

Less effective

No difference

Surgery more effective

Figure 7 Bariatric Surgery Coverage in the Past 2 Years Increased Remained the same

42% 58%

The study asked payers and physicians to evaluate 4 pharmacologic products currently in the later stages of development: • Naltrexone sustained release (SR)/bupropion SR • Zonisamide SR/bupropion SR • Lorcaserin hydrochloride • Phentermine plus topamax.

Although physicians, and their patients, desire a variety of treatment options, payers require increased efficacy to consider formulary placement and the removal of utilization restrictions. In our survey, primary and secondary end points identified by respondent payers for new treatment options that influence coverage were: • Long-term management of weight loss (1-2 years) • Efficacy better than individual genetics • Lower levels of cholesterol and blood pressure • Tolerability, adverse events, and side effects.

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Although the 4 drugs assessed in the study presented weight-loss results of 5% to 12%, nearly half of the payers surveyed indicated that they would be very unlikely to include the 4 drugs on their formulary. If covered, payers would most likely place all products on their third tier, and 50% to 90% of payers would implement prior authorization or quantity limit to control utilization. In contrast, between 23% and 35% of physicians stated that they would be very likely to prescribe some of these products (that are currently in development).

Nearly half of the payers surveyed indicated that they would be very unlikely to include the 4 drugs on their formulary.

Surgical Treatment Options Bariatric surgery is considered when the patient’s BMI is ≥40 kg/m2 and the patient cannot lose excess weight through other methods, or when BMI is ≥35 kg/m2 and is associated with comorbid conditions.

About 90% of physicians participating in the Reimbursement Intelligence study reported that they refer less than 20% of their patients for bariatric surgery. Conversely, nearly 85% of payers believe that bariatric surgery is more effective than prescription medication for obesity management (Figure 6). More than 40% of payers also indicated that bariatric surgery coverage has increased in the past 2 years (Figure 7).

New Approach to Childhood Obesity A new modality worth further investigation is a new approach to the management of childhood obesity that involves secondary care or “referral-based specialized visits” by primary care teams within community health centers.7 This new model for obesity care was developed by a team at the Healthy Weight Clinic in Massachusetts. This model promotes obesity management by combining the principles of a medical home, utilizing health information technology, and improving reimbursement to enhance the quality of care and improve outcomes.7 A Change in Perspective Needed Currently, the majority of payers and healthcare providers hold differing viewpoints with regard to what constitute the most effective treatment options for obesity. Whereas payers set the formulary bar high for new products by seeking ambitious primary and secondary end points, physicians remain in search of flexible, effective treatment options for patients at varying levels of the obesity spectrum.

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Significant steps must be taken by payers and by employers toward the availability and coverage of a variety of affordable treatment options to achieve a measurable level of obesity prevention and reduction among children and adults.

Conclusion The past 20 years have witnessed a dramatic increase in obesity in the United States. Obesity has a major impact on disability, productivity, and life expectancy. Clearly, this is a multifaceted problem that demands an equally multifaceted solution—including lifestyle changes, drug treatments, and surgical options—to address and improve the health outcomes of obese and morbidly obese persons. No one-size-fitsall option is likely to have the efficacy needed to reduce the mounting healthcare costs and comorbidities associated with obesity. ■ Disclosure Statement Ms Greenapple is a consultant to Celgene, Shire, and Takeda.

References 1. Wang Y, Beydoun MA. The obesity epidemic in the United States—gender, age, socioeconomic, racial/ethnic, and geographic characteristics: a systematic review and meta-regression analysis. Epidemiol Rev. 2007;29:6-28.

2. Drexel University College of Medicine. About morbid obesity. 2010. www.drexelmed. edu/Home/DrexelUniversityPhysicians/MedicalPractices/Surgery/ServicesCenters andPrograms/BariatricSurgery/AboutMorbidObesity.aspx. Accessed July 17, 2009.

3. US Food and Drug Administration. Questions and answers—the FDA’s Obesity Working Group report. Modified May 5, 2009. www.fda.gov/Food/Labeling Nutrition/ReportsResearch/ucm082094.htm. Accessed July 17, 2009.

4. CDC Foundation. Obesity a growing epidemic. www.cdcfoundation.org/health threats/obesity.aspx. Accessed July 17, 2009.

5. Lifescript. Diabetes rising in the U.S. November 19, 2008. www.lifescript.com/Health/ Conditions/Diabetes/Tips/Diabetes_Rising_in_the_US.aspx. Accessed July 17, 2009.

6. Hossain P, Kawar B, El Nahas M. Obesity and diabetes in the developing world— a growing challenge. N Engl J Med. 2007;356:213-215.

7. Anand SG, Adams WG, Zuckerman BS. Specialized care of overwight children in community health centers. Health Aff (Millwood). 2010 March 2 [Epub ahead of print]. http://content.healthaffairs.org/cgi/reprint/hlthaff.2009.1113v1. Accessed March 4, 2010.

8. Salk Institute. The battle for CRTC2: how obesity increases the risk for diabetes.

June 21, 2009. www.salk.edu/news/pressrelease_details.php?press_id=362. Accessed July 17, 2009.

9. Centers for Disease Control and Prevention. Obesity. Halting the epidemic by making health easier. www.cdc.gov/nccdphp/publications/AAG/pdf/obesity.pdf.

Accessed March 3, 2010.

10. Centers for Disease Control and Prevention. Obesity among adults in the United States—no statistically significant change since 2003-2004. Revised December 4, 2007. www.cdc.gov/nchs/data/databriefs/db01.pdf. Accessed June 30, 2009.

11. Ogden CL, Carroll MD, Flegal KM. High body mass index for age among US children and adolescents, 2003-2006. JAMA. 2008;299:2401-2405.

12. Centers for Disease Control and Prevention. Obesity halting the epidemic by making health easier: at a glance 2009. Last updated December 17, 2009. www.cdc. gov/chronicdisease/resources/publications/AAG/obesity.htm. Accessed June 30, 2009.

13. Trust for America’s Health, Robert Wood Johnson Foundation. F as in fat: how obesity policies are failing in America 2009. July 2009. http://healthyamericans. org/reports/obesity2009/Obesity2009Report.pdf. Accessed July 17, 2009.

14. Freedman DS, Dietz WH, Srinivasan SR, Berenson GS. The relation of overweight to cardiovascular risk factors among children and adolescents: the Bogalusa Heart Study. Pediatrics. 1999;103:1175-1182.

15. Gillum RF, Mussolino ME, Madans JH. Coronary heart disease incidence and survival in African-American women and men: the NHANES I Epidemiologic Follow-up Study. Ann Intern Med. 1997;12:111-118.

16. Crowe S, Wu LE, Economou C, et al. Pigment epithelium-derived factor contributes to insulin resistance in obesity. Cell Metab. 2009;10:40-47.

17. American Heart Association. Metabolic syndrome. 2010. www.americanheart. org/presenter.jhtml?identifier=4756. Accessed July 21, 2009.

18. Cohen K. Fen Phen Nation. PBS Frontline. November 13, 2003. www.pbs.org/ wgbh/pages/frontline/shows/prescription/hazard/fenphen.html. Accessed July 21, 2009.

19. Vettor R, Serra R, Fabris R, et al. Effect of sibutramine on weight management and metabolic control in type 2 diabetes: a meta-analysis of clinical studies. Diabetes Care. 2005;28:942-949.

20. Burton WN, Chen CY, Schultz AB, Edington DW. The economic costs associated with body mass index in a workplace. J Occup Environ Med. 1998;40:786-792.

21. Centers for Disease Control and Prevention. The power of prevention: chronic disease...the public health challenge of the 21st century. 2009. www.cdc.gov/chronicdisease/pdf/2009-Power-of-Prevention.pdf. Accessed July 21, 2009.

22. Wolf AM, Colditz GA. Current estimates of the economic cost of obesity in the United States. Obes Res. 1998;6:97-106.

23. Robert Wood Johnson Foundation. CDC launches web site to help employers implement obesity prevention programs. June 26, 2009. www.rwjf.org/public health/ digest.jsp?id=11311. Accessed July 2, 2009.

STAKEHOLDER PERSPECTIVE Payers’ Incentives Are Not Aligned to Address the Obesity Epidemic PAYERS: Payers are acutely aware of the rise in the prevalence of obesity and the economic impact associated with this phenomenon, in particular the medical costs to the healthcare system. But payers’ motivations and incentives are not aligned to address the obesity epidemic in a meaningful way.

The deleterious health consequences of obesity are manifested years after the initial diagnosis or risk identification. Because payers often have a short tenure of coverage for obese members, they are not likely to pay for long-term preventive care for a disease process that will most likely manifest years down

the road, unless they can realize a significant benefit in the shorter-term. Although a modest reduction in weight on an obese member can significantly reduce visceral fat (ie, fat surrounding the internal organs) and reduce comorbid risks, such modest improvements often fall below the threshold of outcome achievement in payers’ benefit guideline consideration and renewal criteria.

Pharmaceutical interventions that do not achieve significant and persistent weight reductions are viewed by payers as marginally effective and often are tied to sequential criteria in the consideration for surgical (ie, Continued

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STAKEHOLDER PERSPECTIVE (Continued) bariatric) interventions. Surgical interventions in obese patients have demonstrated short-term, durable benefits in terms of comorbid risk reduction, but longterm data are still relatively scarce.

Until payers align their incentives and agree to provide consistent and universal coverage for earlier, preventive interventions, even beginning with the adolescent population, the ability to address the growing epidemic of obesity in a meaningful way will not reach its full potential.

PATIENTS: Weight management, especially for those who are overweight (≥25 kg/m2) and obese (≥30 kg/m2), is difficult, because so many contributing factors influence this process. The pace of daily living, the ease and accessibility of fast foods, and the often sedentary lifestyle are just a few of these influences. Couple these with the increased financial burden associated with weight-reduction modal-

ities, gym memberships, specialty food programs, and coinsurance of medical interventions, and the durability and success of any weight-reduction program diminishes over time.

Weight management, in particular weight reduction, is a long-term lifestyle commitment. Currently, our healthcare system encourages members to have and maintain healthy lifestyles, but as of now it does not incentivize these choices in a form of taking a position, such as zero copays on weight-loss drugs, free gym memberships, or discounts on specialty foods; rather, obese members bear a greater costsharing portion of such healthy lifestyle choices.

Jeff Januska, PharmD Director of Pharmacy CenCal Health Goleta, CA

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

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

TELMISARTAN AMLODIPINE the active ingredient in MICARDIS

®

a long-acting CCB TEAM UP WITH TWYNSTA—HELP HYPERTENSIVE PATIENTS ACHIEVE SIGNIFICANT BP REDUCTIONS 1,2 All 4 dosage strengths of TWYNSTA® (telmisartan/amlodipine) tablets demonstrated significant reductions in cuff DBP and SBP compared to respective individual monotherapies.1 Study Design: A randomized, double-blind, 8-week, 4 x 4 factorial design trial of Stage-1 and Stage-2 hypertensive patients∗ (baseline BP: 153.2/ 101.7 mmHg) evaluated TWYNSTA vs telmisartan and amlodipine alone (N=1461). The primary endpoint was change in the in-clinic seated trough DBP. SBP/DBP reductions were as follows: -21.0/-16.0 mmHg, TWYNSTA 40/5 mg; -23.8/-19.6 mmHg, TWYNSTA 40/10 mg; -21.6/-17.8 mmHg, TWYNSTA 80/5 mg; -25.8/-19.6 mmHg, TWYNSTA 80/10 mg. Reduction with placebo was -1.6/-5.9 mmHg.2† ∗According to the JNC 7, Stage-1 hypertension is defined as 140-159 mmHg SBP or

90-99 mmHg DBP. Stage-2 hypertension is ≥160 mmHg SBP or ≥100 mmHg DBP.3 Standard deviation was 11.9/7.6 mmHg, TWYNSTA 40/5 mg; 13.2/7.9 mmHg, TWYNSTA 40/10 mg; 12.7/8.5 mmHg, TWYNSTA 80/5 mg; 14.2/7.9 mmHg, TWYNSTA 80/10 mg; 16.7/9.4 mmHg, placebo.2

†

ARB: Angiotensin receptor blocker. CCB: Calcium channel blocker.

DBP: Diastolic blood pressure. SBP: Systolic blood pressure.

JNC 7: The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.

Important Safety Information WARNING: AVOID USE IN PREGNANCY When used in pregnancy, drugs that act directly on the renin-angiotensin system can cause injury and even death to the developing fetus. When pregnancy is detected, TWYNSTA® (telmisartan/amlodipine) tablets and MICARDIS® (telmisartan) tablets should be discontinued as soon as possible (see Warnings and Precautions).

Indication TWYNSTA is indicated for the treatment of hypertension, alone or with other antihypertensive agents. It may also be used as initial therapy in patients who are likely to need multiple drugs to achieve their blood pressure goals. Base the choice of TWYNSTA tablets as initial therapy for hypertension on an assessment of potential benefits and risks including whether the patient is likely to tolerate the starting dose of TWYNSTA tablets. Consider the patient’s baseline blood pressure, the target goal, and the incremental likelihood of achieving goal with a combination compared with monotherapy when deciding whether to use TWYNSTA tablets as initial therapy.

Hypotension Volume depletion and/or salt depletion should be corrected in patients before initiation of therapy or start treatment under close medical supervision with a reduced dose, otherwise symptomatic hypotension may occur. Observe patients with severe aortic stenosis closely for acute hypotension when administering amlodipine.

Hepatic Impairment In patients with impaired hepatic function, initiate telmisartan at low doses and titrate slowly, or initiate amlodipine at 2.5 mg. The lowest dose of TWYNSTA is 40/5 mg; therefore, initial therapy with TWYNSTA is not recommended in hepatically impaired patients.

Renal Impairment Monitor carefully in patients with impaired renal function, especially in patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system (RAAS) (eg, patients with severe congestive heart failure or renal dysfunction); treatment of these patients with ACE inhibitors and ARBs has been associated with oliguria and/or progressive azotemia and, rarely, with acute renal failure and/or death.

In patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen may occur.

Dual RAAS Blockade When adding an ACE inhibitor to an ARB, monitor renal function closely.

Use of telmisartan with ramipril is not recommended.

Other Uncommonly, increased frequency, duration, and/or severity of angina or acute myocardial infarction have developed in patients treated with calcium channel blockers, particularly patients with severe obstructive coronary artery disease. Closely monitor patients with heart failure.

Adverse Events In clinical trials, the most commonly reported adverse events with TWYNSTA that were more frequent than with placebo were peripheral edema (4.8% vs 0%), dizziness (3.0% vs 2.2%), clinically meaningful orthostatic hypotension (6.3% vs 4.3%), and back pain (2.2% vs 0%).

Special Populations In clinical studies, the magnitude of blood pressure lowering with TWYNSTA in black patients approached that observed in non-black patients, but the number of black patients was limited. TWYNSTA is not recommended as initial therapy in patients who are 75 years or older, or who are hepatically impaired. In nursing mothers, nursing or TWYNSTA should be discontinued.

References: 1. Twynsta PI. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; 2009. 2. Data on file, Study 1235.1, Boehringer Ingelheim Pharmaceuticals, Inc. 3. Chobanian AV, Bakris GL, Black HR, et al. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA. 2003;289:2560-2572.

Please see Brief Summary of Prescribing Information on following pages.

Copyright © 2010, Boehringer Ingelheim Pharmaceuticals, Inc. All rights reserved.

Printed in U.S.A.

(02/10)

TW68600PROF

BRIEF SUMMARY OF PRESCRIBING INFORMATION INDICATIONS AND USAGE Twynsta® (telmisartan/amlodipine) tablets are indicated for the treatment of hypertension, alone or with other antihypertensive agents.

TWYNSTA tablets may also be used as initial therapy in patients who are likely to need multiple drugs to achieve their blood pressure goals.

Base the choice of TWYNSTA tablets as initial therapy for hypertension on an assessment of potential benefits and risks including whether the patient is likely to tolerate the starting dose of TWYNSTA tablets.

Consider the patient's baseline blood pressure, the target goal, and the incremental likelihood of achieving goal with a combination compared with monotherapy when deciding whether to use TWYNSTA tablets as initial therapy.

CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS Fetal/Neonatal Morbidity and Mortality Telmisartan Drugs that act directly on the renin-angiotensin system can cause fetal and neonatal morbidity and death when administered to pregnant women. Several dozen cases have been reported in the world literature in patients who were taking angiotensin converting enzyme inhibitors. When pregnancy is detected, discontinue TWYNSTA tablets as soon as possible [see Boxed Warning].

The use of drugs that act directly on the renin-angiotensin system during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to exposure to the drug.

These adverse effects do not appear to have resulted from intrauterine drug exposure that has been limited to the first trimester. Inform mothers whose embryos and fetuses are exposed to an angiotensin II receptor antagonist only during the first trimester that most reports of fetal toxicity have been associated with second or third trimester exposure. Nonetheless, when patients become pregnant or are considering pregnancy, physicians should have the patient discontinue the use of TWYNSTA tablets as soon as possible.

Rarely (probably less often than once in every thousand pregnancies), no alternative to an angiotensin II receptor antagonist will be found. In these rare cases, the mothers should be apprised of the potential hazards to their fetuses, and serial ultrasound examinations should be performed to assess the intra-amniotic environment.

If oligohydramnios is observed, TWYNSTA tablets should be discontinued unless they are considered life-saving for the mother. Contraction stress testing (CST), a non-stress test (NST), or biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.

Infants with histories of in utero exposure to an angiotensin II receptor antagonist should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function.

Hypotension Telmisartan In patients with an activated renin-angiotensin system, such as volume- and/or salt-depleted patients (e.g., those being treated with high doses of diuretics), symptomatic hypotension may occur after initiation of therapy with TWYNSTA tablets. Either correct this condition prior to administration of TWYNSTA tablets, or start treatment under close medical supervision with a reduced dose.

If hypotension does occur, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized.

Amlodipine Since the vasodilation induced by amlodipine is gradual in onset, acute hypotension has rarely been reported after oral administration. Nonetheless, observe patients with severe aortic stenosis closely when administering amlodipine, as one should with any vasodilator.

Hyperkalemia Telmisartan Hyperkalemia may occur in patients on ARBs, particularly in patients with advanced renal impairment, heart failure, on renal replacement therapy, or on potassium supplements, potassium-sparing diuretics, potassium-containing salt substitutes or other drugs that increase potassium levels. Consider periodic determinations of serum electrolytes to detect possible electrolyte imbalances, particularly in patients at risk.

Patients with Impaired Hepatic Function Telmisartan As the majority of telmisartan is eliminated by biliary excretion, patients with biliary obstructive disorders or hepatic insufficiency can be expected to have reduced clearance. Initiate telmisartan at low doses and titrate slowly in these patients.

Amlodipine Amlodipine is extensively metabolized by the liver and the plasma elimination half-life (t1/2) is 56 hours in patients with impaired hepatic function. Since patients with hepatic impairment have decreased clearance of amlodipine, start amlodipine or add amlodipine at 2.5 mg in patients with hepatic impairment. The lowest dose of TWYNSTA is 40/5 mg; therefore, initial therapy with TWYNSTA tablets is not recommended in hepatically impaired patients.

Renal Function Impairment Telmisartan As a consequence of inhibiting the renin-angiotensin-aldosterone system, anticipate changes in renal function in susceptible individuals. In patients whose renal function may depend on the activity of the renin-angiotensinaldosterone system (e.g., patients with severe congestive heart failure or renal dysfunction), treatment with angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor antagonists has been associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death. Similar results may be anticipated in patients treated with telmisartan.

In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen were observed. There has been no long term use of telmisartan in patients with unilateral or bilateral renal artery stenosis, but anticipate an effect similar to that seen with ACE inhibitors.

Dual Blockade of the Renin-Angiotensin-Aldosterone System Telmisartan As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function (including acute renal failure) have been reported. Dual blockade of the renin-angiotensin-aldosterone system (e.g., by adding an ACE-inhibitor to an angiotensin II receptor antagonist) should include close monitoring of renal function.

The ONTARGET trial enrolled 25,620 patients ≥55 years old with atherosclerotic disease or diabetes with end-organ damage, randomized them to telmisartan only, ramipril only, or the combination, and followed them for a median of 56 months. Patients receiving the combination of telmisartan and ramipril did not obtain any additional benefit compared to monotherapy, but experienced an increased incidence of renal dysfunction (e.g., acute renal failure) compared with groups receiving telmisartan alone or ramipril alone. Concomitant use of telmisartan and ramipril is not recommended.

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

TWYNSTA Tablets The concomitant use of telmisartan and amlodipine has been evaluated for safety in more than 3700 patients with hypertension; approximately 1900 of these patients were exposed for at least 6 months and over 160 of these patients were exposed for at least one year. Adverse reactions have generally been mild and transient in nature and have only infrequently required discontinuation of therapy.

In the placebo-controlled factorial design study, the population treated with a telmisartan and amlodipine combination had a mean age of 53 years and included approximately 50% males, 79% were Caucasian, 17% Blacks, and 4% Asians. Patients received doses ranging from 20/2.5 mg to 80/10 mg orally, once daily.

The frequency of adverse reactions was not related to gender, age, or race.

The adverse reactions that occurred in the placebo-controlled factorial design trial in ≥2% of patients treated with TWYNSTA and at a higher incidence in TWYNSTA-treated patients (n=789) than placebo-treated patients (n=46) were peripheral edema (4.8% vs 0%), dizziness (3.0% vs 2.2%), clinically meaningful orthostatic hypotension (defined as a decrease in DBP >10 mmHg and/or decrease in SBP >20 mmHg) (6.3% vs 4.3%), and back pain (2.2% vs 0%).

In addition, other adverse reactions that occurred in more than 1% of the patients treated with TWYNSTA tablets (n=789) were dizziness (2.0% vs 2.2% on placebo) and headache (1.4% vs 4.3% on placebo).

In the placebo-controlled factorial design trial, discontinuation due to adverse events occurred in 2.2% of all treatment cells of patients in the telmisartan/amlodipine-treated patients and in 4.3% in the placebo-treated group. The most common reasons for discontinuation of therapy with TWYNSTA tablets were peripheral edema, dizziness, and hypotension (each ≤0.5%).

Peripheral edema is a known, dose-dependent adverse reaction of amlodipine, but not of telmisartan. In the factorial design study, the incidence of peripheral edema during the 8 week, randomized, double-blind treatment period was highest with amlodipine 10 mg monotherapy. The incidence was notably lower when telmisartan was used in combination with amlodipine 10 mg.

Table 1: Incidence of Peripheral Edema during the 8 Week Treatment Period Telmisartan

Amlodipine

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

Risk of Myocardial Infarction or Increased Angina Amlodipine Uncommonly, patients, particularly those with severe obstructive coronary artery disease, have developed documented increased frequency, duration or severity of angina or acute myocardial infarction on starting calcium channel blocker therapy or at the time of dosage increase. The mechanism of this effect has not been elucidated.

Heart Failure Amlodipine Closely monitor patients with heart failure.

Amlodipine (5-10 mg per day) has been studied in a placebo-controlled trial of 1153 patients with NYHA Class III or IV heart failure on stable doses of ACE inhibitor, digoxin, and diuretics. Follow-up was at least 6 months, with a mean of about 14 months. There was no overall adverse effect on survival or cardiac morbidity (as defined by life-threatening arrhythmia, acute myocardial infarction, or hospitalization for worsened heart failure). Amlodipine has been compared to placebo in four 8-12 week studies of patients with NYHA class II/III heart failure, involving a total of 697 patients. In these studies, there was no evidence of worsening of heart failure based on measures of exercise tolerance, NYHA classification, symptoms, or LVEF. In the PRAISE-2 study, 1654 patients with NYHA class III (80%) or IV (20%) heart failure without evidence of underlying ischemic disease, on stable doses of ACE inhibitor (99%), digitalis (99%), and diuretics (99%) were randomized 1:1 to receive placebo or amlodipine and followed for a mean of 33 months. While there was no statistically significant difference between amlodipine and placebo in the primary endpoint of all cause mortality (95% confidence limits from 8% reduction to 29% increase on amlodipine), there were more reports of pulmonary edema in the patients on amlodipine.

Placebo

40 mg

80 mg

Placebo

0%

0.8%

0.7%

5 mg

0.7%

1.4%

2.1%

10 mg

17.8%

6.2%

11.3%

Telmisartan Telmisartan has been evaluated for safety in more than 3700 patients, including 1900 treated for over 6 months and more than 1300 for over one year. Adverse experiences have generally been mild and transient in nature and have only infrequently required discontinuation of therapy.

In placebo-controlled trials involving 1041 patients treated with various doses of telmisartan (20-160 mg) monotherapy for up to 12 weeks, an overall incidence of adverse events was similar to the patients treated with placebo.

Adverse events occurring at an incidence of ≥1% in patients treated with telmisartan and at a greater rate than in patients treated with placebo, irrespective of their causal association, are presented in Table 2.

Table 2: Adverse Events Occurring at an Incidence of ≥1% in Patients Treated with Telmisartan and at a Greater Rate than Patients Treated with Placebo Telmisartan (n=1455) %

Placebo (n=380) %

Upper respiratory tract infection

7

6

Back pain

3

1

Sinusitis

3

2

Diarrhea

3

2

Pharyngitis

1

0

In addition to the adverse events in the table, the following events occurred at a rate of ≥1% but were at least as frequent in the placebo group: influenza-like symptoms, dyspepsia, myalgia, urinary tract infection, abdominal pain, headache, dizziness, pain, fatigue, coughing, hypertension, chest pain, nausea, and peripheral edema. Discontinuation of therapy due to adverse events was required in 2.8% of 1455 patients treated with telmisartan tablets and 6.1% of 380 placebo patients in placebo-controlled clinical trials.

The incidence of adverse events was not dose-related and did not correlate with gender, age, or race of patients.

The incidence of cough occurring with telmisartan in 6 placebo-controlled trials was identical to that noted for placebo-treated patients (1.6%).

In addition to those listed above, adverse events that occurred in >0.3% of 3500 patients treated with telmisartan monotherapy in controlled or open trials are listed below. It cannot be determined whether these events were causally related to telmisartan tablets: Autonomic Nervous System: impotence, increased sweating, flushing; Body as a Whole: allergy, fever, leg pain, malaise; Cardiovascular: palpitation, dependent edema, angina pectoris, tachycardia, leg edema, abnormal ECG; CNS: insomnia, somnolence, migraine, vertigo, paresthesia, involuntary muscle contractions, hypoesthesia; Gastrointestinal: flatulence, constipation, gastritis, vomiting, dry mouth, hemorrhoids, gastroenteritis, enteritis, gastroesophageal reflux, toothache, non-specific gastrointestinal disorders; Metabolic: gout, hypercholesterolemia, diabetes mellitus; Musculoskeletal: arthritis, arthralgia, leg cramps; Psychiatric: anxiety, depression, nervousness; Resistance Mechanism: infection, fungal infection, abscess, otitis media; Respiratory: asthma, bronchitis, rhinitis, dyspnea, epistaxis; Skin: dermatitis, rash, eczema, pruritus; Urinary: micturition frequency, cystitis; Vascular: cerebrovascular disorder; and Special Senses: abnormal vision, conjunctivitis, tinnitus, earache.

During initial clinical studies, a single case of angioedema was reported (among a total of 3781 patients treated).

Clinical Laboratory Findings In placebo-controlled clinical trials, clinically relevant changes in standard laboratory test parameters were rarely associated with administration of telmisartan tablets.

Hemoglobin: A greater than 2 g/dL decrease in hemoglobin was observed in 0.8% telmisartan patients compared with 0.3% placebo patients. No patients discontinued therapy due to anemia.

Creatinine: A 0.5 mg/dL rise or greater in creatinine was observed in 0.4% telmisartan patients compared with 0.3% placebo patients. One telmisartan-treated patient discontinued therapy due to increases in creatinine and blood urea nitrogen.

Liver Enzymes: Occasional elevations of liver chemistries occurred in patients treated with telmisartan; all marked elevations occurred at a higher frequency with placebo. No telmisartan-treated patients discontinued therapy due to abnormal hepatic function.

Amlodipine Amlodipine has been evaluated for safety in more than 11,000 patients in U.S. and foreign clinical trials. Most adverse reactions reported during therapy with amlodipine were of mild or moderate severity. In controlled clinical trials directly comparing amlodipine (n=1730) in doses up to 10 mg to placebo (n=1250), discontinuation of amlodipine due to adverse reactions was required in only about 1.5% of amlodipine-treated patients and was not significantly different from that seen in placebo-treated patients (about 1%). The most common side effects were headache and edema. The incidence (%) of side effects which occurred in a dose-related manner are presented in Table 3.

Table 3: Incidence (%) of Dose-Related Adverse Effects with Amlodipine at Doses of 2.5 mg, 5.0 mg, and 10.0 mg or Placebo Adverse Event

Amlodipine 2.5 mg n=275 %

Amlodipine 5.0 mg n=296 %

Amlodipine 10.0 mg n=268 %

Placebo n=520 %

Edema

1.8

3.0

10.8

0.6

Dizziness

1.1

3.4

3.4

1.5

Flushing

0.7

1.4

2.6

0.0

Palpitations

0.7

1.4

4.5

0.6

Other adverse experiences which were not clearly dose related but which were reported with an incidence greater than 1% in placebo-controlled clinical trials are presented in Table 4.

Table 4: Incidence (%) of Adverse Effects Not Clearly Dose Related but Reported at an Incidence of >1% in Placebo-Controlled Clinical Trials Adverse Event

Amlodipine n=1730 %

Placebo n=1250 %

Headache

7.3

07.8

Fatigue

4.5

2.8

Nausea

2.9

1.9

Abdominal pain

1.6

0.3

Somnolence

1.4

0.6

The following events occurred in <1% but >0.1% of patients in controlled clinical trials or under conditions of open trials or marketing experience where a causal relationship is uncertain; they are listed to alert the physician to a possible relationship: Cardiovascular: arrhythmia (including ventricular tachycardia and atrial fibrillation), bradycardia, chest pain, hypotension, peripheral ischemia, syncope, tachycardia, postural dizziness, postural hypotension, vasculitis; Central and Peripheral Nervous System: hypoesthesia, neuropathy peripheral, paresthesia, tremor, vertigo; Gastrointestinal: anorexia, constipation, dyspepsia,** dysphagia, diarrhea, flatulence, pancreatitis, vomiting, gingival hyperplasia; General: allergic reaction, asthenia,** back pain, hot flushes, malaise, pain, rigors, weight gain, weight decrease; Musculoskeletal System: arthralgia, arthrosis, muscle cramps,** myalgia; Psychiatric: sexual dysfunction (male** and female), insomnia, nervousness, depression, abnormal dreams, anxiety, depersonalization; Respiratory System: dyspnea,** epistaxis; Skin and Appendages: angioedema, erythema multiforme, pruritus,** rash,** rash erythematous, rash maculopapular; Special Senses: abnormal vision, conjunctivitis, diplopia, eye pain, tinnitus; Urinary System: micturition frequency, micturition disorder, nocturia; Autonomic Nervous System: dry mouth, sweating increased; Metabolic and Nutritional: hyperglycemia, thirst; Hemopoietic: leukopenia, purpura, thrombocytopenia. **These events occurred in less than 1% in placebo-controlled trials, but the incidence of these side effects was between 1% and 2% in all multiple dose studies.

The following events occurred in <0.1% of patients: cardiac failure, pulse irregularity, extrasystoles, skin discoloration, urticaria, skin dryness, alopecia, dermatitis, muscle weakness, twitching, ataxia, hypertonia, migraine, cold and clammy skin, apathy, agitation, amnesia, gastritis, increased appetite, loose stools, coughing, rhinitis, dysuria, polyuria, parosmia, taste perversion, abnormal visual accommodation, and xerophthalmia.

Other reactions occurred sporadically and cannot be distinguished from medications or concurrent disease states such as myocardial infarction and angina.

Amlodipine has not been associated with clinically significant changes in routine laboratory tests. No clinically relevant changes were noted in serum potassium, serum glucose, total triglycerides, total cholesterol, HDL cholesterol, uric acid, blood urea nitrogen, or creatinine.

Amlodipine has been used safely in patients with chronic obstructive pulmonary disease, well-compensated congestive heart failure, coronary artery disease, peripheral vascular disease, diabetes mellitus, and abnormal lipid profiles.

Adverse reactions reported for amlodipine for indications other than hypertension may be found in the prescribing information for NorvascÂŽ.

Postmarketing Experience The following adverse reactions have been identified during post-approval use of telmisartan or amlodipine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate reliably their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causal connection to telmisartan or amlodipine.

Telmisartan The most frequently spontaneously reported events include: headache, dizziness, asthenia, coughing, nausea, fatigue, weakness, edema, face edema, lower limb edema, angioneurotic edema, urticaria, hypersensitivity, sweating increased, erythema, chest pain, atrial fibrillation, congestive heart failure, myocardial infarction, blood pressure increased, hypertension aggravated, hypotension (including postural hypotension), hyperkalemia, syncope, dyspepsia, diarrhea, pain, urinary tract infection, erectile dysfunction, back pain, abdominal pain, muscle cramps (including leg cramps), myalgia, bradycardia, eosinophilia, thrombocytopenia, uric acid increased, abnormal hepatic function/liver disorder, renal impairment including acute renal failure, anemia, and increased CPK, anaphylactic reaction, and tendon pain (including tendonitis, tenosynovitis).

Rare cases of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers, including telmisartan.

Amlodipine Gynecomastia has been reported infrequently and a causal relationship is uncertain. Jaundice and hepatic enzyme elevations (mostly consistent with cholestasis or hepatitis), in some cases severe enough to require hospitalization, have been reported in association with use of amlodipine.

DRUG INTERACTIONS Drug Interactions with TWYNSTA Tablets The pharmacokinetics of amlodipine and telmisartan are not altered when the drugs are co-administered.

No drug interaction studies have been conducted with TWYNSTA tablets and other drugs, although studies have been conducted with the individual amlodipine and telmisartan components of TWYNSTA tablets, as described below: Drug Interactions with Telmisartan Digoxin: When telmisartan was co-administered with digoxin, median increases in digoxin peak plasma concentration (49%) and in trough concentration (20%) were observed. It is, therefore, recommended that digoxin levels be monitored when initiating, adjusting, and discontinuing telmisartan to avoid possible over- or under-digitalization.

Lithium: Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with angiotensin II receptor antagonists including telmisartan. Therefore, monitor serum lithium levels during concomitant use.

Ramipril and Ramiprilat: Co-administration of telmisartan 80 mg once daily and ramipril 10 mg once daily to healthy subjects increases steady-state Cmax and AUC of ramipril 2.3- and 2.1-fold, respectively, and Cmax and AUC of ramiprilat 2.4- and 1.5-fold, respectively. In contrast, Cmax and AUC of telmisartan decrease by 31% and 16%, respectively.

When co-administering telmisartan and ramipril, the response may be greater because of the possibly additive pharmacodynamic effects of the combined drugs, and also because of the increased exposure to ramipril and ramiprilat in the presence of telmisartan. Co-administration of telmisartan and ramipril is not recommended.

Other Drugs: Co-administration of telmisartan did not result in a clinically significant interaction with acetaminophen, amlodipine, glyburide, simvastatin, hydrochlorothiazide, warfarin, or ibuprofen. Telmisartan is not metabolized

by the cytochrome P450 system and had no effects in vitro on cytochrome P450 enzymes, except for some inhibition of CYP2C19. Telmisartan is not expected to interact with drugs that inhibit cytochrome P450 enzymes; it is also not expected to interact with drugs metabolized by cytochrome P450 enzymes, except for possible inhibition of the metabolism of drugs metabolized by CYP2C19.

Drug Interactions with Amlodipine In clinical trials, amlodipine has been safely administered with thiazide diuretics, beta-blockers, angiotensinconverting enzyme inhibitors, long-acting nitrates, sublingual nitroglycerin, digoxin, warfarin, non-steroidal antiinflammatory drugs, antibiotics, and oral hypoglycemic drugs.

The following have no clinically relevant effects on the pharmacokinetics of amlodipine: cimetidine, grapefruit juice, MaaloxÂŽ, sildenafil.

Amlodipine has no clinically relevant effects on the pharmacokinetics or pharmacodynamics of the following: atorvastatin, digoxin, warfarin

USE IN SPECIFIC POPULATIONS Pregnancy Teratogenic Effects, Pregnancy Categories C (first trimester) and D (second and third trimesters). See Warnings and Precautions.

Nursing Mothers Telmisartan It is not known whether telmisartan is excreted in human milk, but telmisartan was shown to be present in the milk of lactating rats. Because of the potential for adverse effects on the nursing infant, decide whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Amlodipine It is not known whether amlodipine is excreted in human milk. In the absence of this information, it is recommended to discontinue nursing while amlodipine is administered.

Pediatric Use Safety and effectiveness of TWYNSTA in pediatric patients have not been established.

Geriatric Use TWYNSTA Tablets Of the total number of 3282 hypertensive patients receiving a telmisartan/amlodipine combination in clinical studies, 605 (18%) patients were 65 years of age or older and of these, 88 (3%) patients were 75 years and older.

No overall differences in efficacy or safety of TWYNSTA tablets were observed in this patient population.

Telmisartan Of the total number of patients receiving telmisartan in clinical studies, 551 (18.6%) were 65 to 74 years of age and 130 (4.4%) were 75 years and older. No overall differences in effectiveness and safety were observed in these patients compared to younger patients and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Amlodipine Clinical studies of amlodipine besylate tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy. Elderly patients have decreased clearance of amlodipine with a resulting increase of AUC of approximately 40-60%, and a lower initial dose may be required. Since patients age 75 and older have decreased clearance of amlodipine, start amlodipine or add amlodipine 2.5 mg to telmisartan. The lowest dose of TWYNSTA is 40/5 mg; therefore, initial therapy with TWYNSTA tablets is not recommended in patients 75 years of age and older.

Hepatic Insufficiency Monitor carefully and uptitrate slowly in patients with biliary obstructive disorders or hepatic insufficiency. Since patients with hepatic impairment have decreased clearance of amlodipine, start amlodipine or add amlodipine 2.5 mg to telmisartan. The lowest dose of TWYNSTA is 40/5 mg; therefore, initial therapy with TWYNSTA tablets is not recommended in hepatically impaired patients.

Race The magnitude of blood pressure lowering in black patients approached that observed in non-black patients but the number of black patients was limited (237 of 1461 patients).

OVERDOSAGE Telmisartan Limited data are available with regard to overdosage in humans. The most likely manifestations of overdosage with telmisartan tablets would be hypotension, dizziness, and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation. If symptomatic hypotension should occur, supportive treatment should be instituted.

Telmisartan is not removed by hemodialysis.

Amlodipine Single oral doses of amlodipine maleate equivalent to 40 mg/kg and 100 mg/kg amlodipine in mice and rats, respectively, caused deaths. Single oral doses equivalent to 4 or more mg/kg amlodipine in dogs (11 or more times the maximum recommended human dose on a mg/m2 basis) caused a marked peripheral vasodilation and hypotension.

Overdosage might be expected to cause excessive peripheral vasodilation with marked hypotension. In humans, experience with intentional overdosage of amlodipine is limited. Reports of intentional overdosage include a patient who ingested 250 mg and was asymptomatic and was not hospitalized; another (120 mg) who was hospitalized underwent gastric lavage and remained normotensive; the third (105 mg) was hospitalized and had hypotension (90/50 mmHg) which normalized following plasma expansion. A case of accidental drug overdose has been documented in a 19-month-old male who ingested 30 mg amlodipine (about 2 mg/kg). During the emergency room presentation, vital signs were stable with no evidence of hypotension, but a heart rate of 180 bpm. Ipecac was administered 3.5 hours after ingestion and on subsequent observation (overnight) no sequelae was noted.

If massive overdose should occur, active cardiac and respiratory monitoring should be instituted. Frequent blood pressure measurements are essential. Should hypotension occur, cardiovascular support including elevation of the extremities and the judicious administration of fluids should be initiated. If hypotension remains unresponsive to these conservative measures, administration of vasopressors (such as phenylephrine) should be considered with attention to circulating volume and urine output. Intravenous calcium gluconate may help to reverse the effects of calcium entry blockade. As amlodipine is highly protein bound, hemodialysis is not likely to be of benefit.

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

TW71916

BUSINESS

Health Insurance Premium Increases for the 5 Largest School Districts in the United States, 2004-2008 John R. Cantillo, MBA Background: Local school districts are often one of the largest, if not the largest, employers in their respective communities. Like many large employers, school districts offer health insurance to their employees. There is a lack of information about the rate of health insurance premiums in US school districts relative to other employers.

Objective: To assess the change in the costs of healthcare insurance in the 5 largest public school districts in the United States, between 2004 and 2008, as representative of large public employers in the country.

Methods: Data for this study were drawn exclusively from a survey sent to the 5 largest public school districts in the United States. The survey requested responses on 3 data elements for each benefit plan offered from 2004 through 2008; these included enrollment, employee costs, and employer costs.

Results: The premium growth for the 5 largest school districts has slowed down and is consistent with other purchasersâ&#x20AC;&#x201D;Kaiser/Health Research & Educational Trust and the Federal Employee Health Benefit Program. The average increase in health insurance premium for the schools was 5.9% in 2008, and the average annual growth rate over the study period was 7.5%. For family coverage, these schools provide the most generous employer contribution (80.8%) compared with the employer contribution reported by other employers (73.5%) for 2008.

Conclusions: Often the largest employers in their communities, school districts demonstrate a commitment to provide choice of benefits and affordability for employees and their families. Despite constraints typical of public employers, the 5 largest school districts in the United States have decelerated in premium growth consistent with other purchasers, albeit at a slower pace. [AHDB. 2010;3(2):98-104.]

L

ocal school districts are one of the largest employers in the United States, employing roughly 8 million employees in 2008.1 Locally, they are often one of the largest (if not the largest) employers in the communities they serve. Like many large employers, school districts offer an array of benefits to their employees, including health insurance. Employee benefits comprise 34.3% of total compensation for publicsector employees,2 with health insurance representing 10.9% of total compensation.2

Public Employer Characteristics Carolyn Watts and colleagues highlighted some of the unique constraints public employers face, including Mr Cantillo is a health insurance consultant, executive, and educator, Miami, FL.

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balancing budgets in a political climate, a unionized workforce, and the ever-present consideration of the taxpayer impact of any financial decision.3 School districts experience these same constraints. In addition, they shoulder the social responsibility that accompanies being the largest employer, and they must consider the impact their financial decisions have on wages, employment, and take-up rates.

The recent economic crisis has been particularly difficult for public employers, because tax revenues have sharply declined, and the competition for dwindling financial resources has intensified. School districts increasingly face intense pressure to balance various stakeholdersâ&#x20AC;&#x2122; needs and continue to offer affordable and competitive health benefits to their workforce.

Although surveys have reported slowing growth trends for health insurance premiums for purchasers in general,4

March/April 2010

VOL. 3

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Health Insurance Premium Increases

the specific experience related to health insurance premiums in major school districts has not been analyzed.

This article reviews the health insurance premium and employee costs for the 5 largest school districts in the United States, from 2004 through 2008. The school districts included in this survey are: • New York School District (NYSD)5 • Los Angeles Unified School District (LAUSD)6 • Chicago Public Schools (CPS)7 • Miami-Dade County Public Schools (MDCPS)8 • Clark County School District (CCSD),9 which represents the greater Las Vegas, Nevada, area.

NYSD, MDCPS, and CCSD are the largest employers in their communities. LAUSD and CPS are the second largest employers in their respective communities.6,7 The 5 school districts reflect large, diversified metropolitan communities.

The combined 2008 health insurance premium for these school districts was nearly $4.9 billion, which provided coverage for 534,237 insured enrollees. In comparison, according to James Loftin, Research Program Specialist for the California Public Employees’ Retirement System (CalPERS), CalPERS is the third largest purchaser of employee health benefits in the United States,10 providing coverage for 588,019 enrollees and $5.5 billion in premiums in 2008.11 Echoing Carolyn Watts and colleagues’ commentary,3 public employers have the ability to influence the market because of their purchasing power. Similarly, school districts have the potential to be market leaders in their communities and leverage their purchasing power to maximize coverage and affordability for their employees and dependents.

Study Data and Methods Data for this study were drawn exclusively from a survey sent to the 5 largest school districts in the United States.12 The survey requested 3 data elements for each benefit plan offered from 2004 through 2008, including enrollment, employee costs, and employer costs. All 5 school districts responded.

Enrollment Enrollment figures for each distinct benefit plan and rate tier were requested. As used in the survey, rate tier represents the distinct monthly rate charged based on the number of dependents covered by an employee.

For example, a 3-tier rate charges a different monthly premium for employee-only coverage, for employee plus 1 dependent coverage, and for employee plus ≥2 dependents coverage. Single coverage is health insurance that covers the employee only. The study defined family coverage as coverage for a family of 4. If a rate

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KEY POINTS u

u

u u

u

u

School districts are among the largest employers in the country and offer health insurance to their employees, but little information is available about the rate of their insurance premiums relative to other employers.

This study is based on a survey of 5 of the largest public school districts in the United States, aimed at assessing the change in their health insurance rates between 2004 and 2008.

Health insurance represents 10.9% of total compensation for school employees.

Results of this study show that the average annual growth rate in health insurance during the study period for the 5 schools was 7.5%.

On average, the school districts’ share of health insurance premium for family coverage is more generous than other health insurance purchasers, with the exception of 1 school.

These 5 school districts have managed to slow the rate of premium growth in health insurance, albeit at a slower pace than other employers reviewed in this analysis.

for a family of 4 is not offered, family coverage is considered coverage other than single coverage. Average single and family premiums were weighted by number of employees.

LAUSD offers a composite rate, which charges the same rate regardless of dependent coverage. Because LAUSD offers only a composite rate, it was unable to provide enrollment figures by dependent status. The enrollment distribution for LAUSD was estimated by determining the enrollment mix for single and family coverage for the remaining 4 school districts for each policy year. The resulting weighted average was used as the assumed enrollment mix for LAUSD. NYSD is part of the City of New York benefits program, which provides coverage for 3 categories of employees—civilian nonpedagogical, uniformed, and the Department of Education. Enrollment data for the Department of Education employees, however, were unavailable. The analyzed enrollment data reflect all the employees covered by the City of New York’s health insurance policy. Rates and benefits are the same for all 3 categories of employees, and therefore are included in the survey.

For CCSD, the analysis includes rates, benefits, and enrollment for the Clark County Teachers Health Trust. This is a self-funded health trust that provides benefits to all licensed employees (ie, teachers) of the

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Figure Average Premium Growth in the 5 School Districts vs Kaiser/HRET and FEHBP, 2005-2008 10 9.2

8.8

Growth in average premiums, %

9 8

Kaiser/HRET surveya FEHBPb SDI

7.9

7.9

7.7

7

7.4 6.6 6.1

6

5.9 4.7

5 4 3 2

1.8

2.0

2007

2008

1 0 2005

2006

FEHBP indicates Federal Employee Health Benefits Program; HRET, Health Research & Educational Trust; SDI, school district index. a The Henry J. Kaiser Family Foundation, Health Research & Educational Trust. http://ehbs.kff.org/pdf/7790.pdf. b US Government Accountability Office. Publication GAO-07-141. December 2006. www.gao.gov/new.items/d07141.pdf.

CCSD.13 The welfare trust is funded by the CCSD, and therefore is included in this analysis.

Premium Rates The survey captured the monthly premium rates charged by insurers for each benefit plan and rate tier.

If the benefit plan was self-funded, the survey requested the equivalent fully insured monthly rates. Rates are inclusive of medical, pharmacy, and behavioral health benefits.

The survey requested the cost of health insurance charged to employees, by benefit plan and rate tier, net of any employer subsidy. Employee costs are referred to as employee premiums. CPS employee premiums vary depending on employees’ salaries. Employee premiums are determined as a percentage of the employee’s salary.

To estimate employee cost, the analysis calculated the average salary for all district employees using financial records from CPS.14 Aggregate salary data for all school district personnel were divided by the total number of positions as reported in the financial records.

The employer’s share of premium was determined by calculating the net difference between employee premiums and insurance premiums. This calculation provides the implicit school district employer contribution toward employee health insurance, because some school districts provide additional financial contribution (ie, “flex” dollars) in excess of the premium rates charged.

The analysis utilized premium and enrollment data for policy periods from 2004 through 2008, summarized on a calendar-year basis. Not all the policy periods

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reviewed were on a calendar-year basis. In such instances, premiums for policy periods that overlap a calendar year were calculated by using the enrollment and premium rates for the corresponding months of the policy within the analyzed calendar year.

LAUSD, CCSD, and MDCPS policy years coincide with a calendar-year period. MDCPS was primarily on a calendar year policy, except for 3 months in 2006 during which there was a midyear premium change. CPS changed to a calendar-year policy beginning in 2005; only calendar year 2004 was calculated using 2 distinct policy periods. NYSD is on a July through June policyyear basis for the study period.

Data Analysis Premium growth trends are compared with other purchasers—the 2008 Kaiser/HRET (Health Research & Educational Trust) Employer Health Benefits Survey4 (all firm sizes) and the Federal Employee Health Benefits Program (FEHBP),10 the largest purchaser of employee health benefits. Premium costs, employer contribution, and employee costs, however, are compared only with the Kaiser/HRET survey.4 Data provided from the school districts were not independently verified.

This study does not analyze the value of the benefits offered by the school districts. Product types were disclosed; they included HMOs, exclusive provider organizations, point of service plans, and preferred provider organization plans.

Regarding funding mechanism, NYPS, LAUSD, and CCSD offered both fully insured and self-insured bene-

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fits. MDCPS’s benefits were exclusively offered on a fully insured basis, whereas CPS’s products were exclusively on a self-insured basis.

All data were reviewed for reasonableness and consistency, and it was determined that these data were sufficiently reliable.

Results Growth Rates, Premium The 5 public school districts’ premium data were aggregated to form the school district index (SDI). The average annual growth rate for the SDI was 7.5% for the study period. This average rate of growth is higher than the other purchasers reviewed in this analysis.

The Kaiser/HRET survey reports an average annual growth rate of 6.9%.4 The FEHBP has managed an average annual growth rate of 4.6%,10 nearly 3% less than the SDI. The SDI demonstrates a slowing in annual premium growth consistent with the Kaiser/ HRET survey and FEHBP.10 Premiums for the SDI increased by 5.9% in 2008, which is the lowest annual premium increase in the study period. However, annual premium growth has not slowed as rapidly as for other purchasers. The Kaiser/ HRET survey reflects a 4.5% reduction in the rate of annual premium growth, from a high of 9.2% in 2005 to 4.7% in 2008.4 The FEHBP rate of growth has slowed by 5.9%, from 7.9% in 2005 to 2.0% in 2008.10 The SDI showed just a 2.9% decrease in the rate of growth from a peak of 8.8% in 2005 to 5.9% in 2008 (Figure).

The SDI’s employer share of health insurance premium totaled approximately $3.96 billion (ie, $3968 million), or $7428 per employee per year (PEPY) in 2008 (Table 1), a 32.4% increase over the amount school districts spent in 2004.

Overall inflation, as measured by the Consumer Price Index, increased by 14.3% during the same time period.15 Employees paid the balance of the health insurance bill.

SDI employees paid $1646 PEPY for health insurance in 2008—39.9% more than employees spent in 2004, or 2.8 times the rate of inflation over the same time period.

The SDI’s 2008 average premium for single coverage was $5665 PEPY, or 20.4% more than the Kaiser/HRET survey average of $4704 PEPY.4 Premiums for family coverage were $12,178 PEPY, or 4.3% less than the Kaiser/HRET survey for 2008 (Table 2).

Employer Share The school districts’ share (84%) of premiums for single coverage is slightly less than the Kaiser/HRET average of 84.7% in 2008.4 The school districts’ cost for their share of a premium for single coverage increased by 27.4% since 2004. This is roughly equal to the 27%

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Table 1 SDI Aggregate Annual Premiums: Employer Contributions and PEPY SDI aggregate, $ millions

PEPY, $

SDI Employer Total Employer Employee premium contribution premium share share 2004

3505

2898

6789

5612

1176

2005

3829

3112

7389

6005

1384

2006

4158

3362

7975

6448

1528

2007

4487

3635

8565

6939

1627

2008

4848

3968

9074

7428

1646

PEPY indicates per employee per year; SDI, school district index.

Table 2 Average Annual Employer/Worker Premium Contributions for Single/Family Coverage, 2008 School district index PEPY, $ (%) Single coverage Employer contribution Employee premiums Average annual premiums Family coverage Employer contribution Employee premiums Average annual premiums

Kaiser/HRET PEPY, $ (%)a

4757 (84.0)

3983 (84.7)

908 (16.0)

721 (15.3)

5665

4704

9823 (80.9)

9325 (73.5)

2318 (19.1)

3354 (26.5)

12,141

12,680

HRET indicates Health Research & Educational Trust; PEPY, per employee per year; SDI, school district index. a The Henry J. Kaiser Family Foundation, Health Research & Educational Trust. http://ehbs.kff.org/pdf/7790.pdf.

increase in employer costs for single coverage reported by the Kaiser/HRET survey since 2004.4 For family coverage, the SDI provides the most generous employer contribution (80.9%) compared with the employer contribution reported by the Kaiser/ HRET survey (73.5%) in 2008.4 However, the school district’s cost for its share of family coverage is increasing at a faster rate than the other purchasers reviewed in this analysis. The SDI employer cost for family coverage premium has increased by 36.6% since 2004. This is substantially more than the 27.8% increase in employer costs for family coverage reported by the Kaiser/HRET survey4 (Table 3).

Employee Costs School district employees pay more for health insurance for single coverage than the national average, but pay considerably less for family coverage. In 2008, school district employees paid $908 PEPY for single coverage

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Table 3 Average Annual Employer and Worker Premium Contributions for Single and Family Coverage Employer contribution, $ Single coverage Family coverage Kaiser/ Kaiser/ SDI HRETa SDI HRETa 2004

3733

3136

7192

7298

2005

3923

3413

7810

8167

2006

4182

3615

8479

8508

2007

4484

3785

9180

8824

2008

4757

3983

9823

9325

Employee costs, $ Single coverage Family coverage Kaiser/ Kaiser/ SDI HRETa SDI HRETa 2004

602

558

1614

2661

2005

728

610

1909

2713

2006

809

627

2142

2973

2007

875

694

2302

3281

2008

908

721

2318

3354

HRET indicates Health Research & Educational Trust; SDI, school district index. a The Henry J. Kaiser Family Foundation, Health Research & Educational Trust. http://ehbs.kff.org/pdf/7790.pdf.

Table 4 Average Annual Employee Premium Contributions for Single/Family Coverage, by Region, 2008 SDI PEPY, $ (%) Single coverage Northeast-NYSD Midwest-CPS South-MDCPS West-LAUSD, CCSD All regions Family coverage Northeast-NYSD Midwest-CPS South-MDCPS West-LAUSD, CCSD All regions

Kaiser/HRET PEPY, $ (%)a

1410 (25)

899 (18)

918 (22)

755 (16)

–66 (–1)

722 (16)

53 (1)

538 (12)

908 (16)

721 (15)

2825 (21)

2949 (22)

1185 (11)

3049 (25)

4482 (30)

3760 (32)

123 (2)

3375 (28)

2318 (19)

3354 (27)

CCSD indicates Clark County School District; CPS, Chicago Public Schools; LAUSD, Los Angeles Unified School District; MDCPS, Miami-Dade County Public Schools; NYSD, New York School District; PEPY, per employee per year; SDI, school district index. a The Henry J. Kaiser Family Foundation, Health & Research Educational Trust. http://ehbs.kff.org/pdf/7790.pdf.

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and $2318 PEPY for family coverage. The Kaiser/HRET survey reflects a 2008 PEPY cost of $721 for single coverage and $3354 for family coverage (Table 2).4 Despite the comparatively lower cost for family coverage, enrollment in this coverage type has actually declined by 1%, whereas single-coverage enrollment increased by 6.6% among the school districts. The total number of covered lives in the SDI has increased 3.5% since 2004.

Although an analysis of the drivers behind this trend is outside the scope of this article, this author speculates that the relative annual cost for family coverage compared with single coverage (2.5 times) in absolute dollars is deemed unaffordable in a difficult economic climate.

Regionally, the variances are more pronounced. As shown in Table 4, NYSD and CPS employees paid more for single coverage in 2008, as a share of premium and total annual premium, than other employees in their respective regions. LAUSD, MDCPS, and CCSD employees paid substantially less for single coverage than other employees in their respective regions in terms of share of premium and total annual premium.

For family coverage, employees at LAUSD, CPS, and CCSD paid substantially less, as a share of premium and total annual premium, than other employees in their respective regions. NYSD employees paid slightly less for family coverage than their peers in the Northeast. Although MDCPS employees, as a percentage of the premium, pay slightly less for family coverage than other employees in the South, their employees pay 19.2% more for family coverage than other employees in that region and the most of all 5 school districts evaluated in this study (Table 4).

There are notable variances in employee premiums and employer contributions within the 5 school districts, as demonstrated in Table 5. LAUSD provides the most generous subsidy, paying 100% for either single or family coverage. MDCPS contributes slightly more than 100% for single coverage by providing an additional financial incentive for certain benefit plans.

MDCPS provides “flex” dollars, ranging from $10 to $50 per employee per month if employees select an HMO plan. However, MDCPS contributes the least of the school districts surveyed, in terms of employer share, toward family coverage.

Although MDCPS’s employer share as a percentage of family coverage premium was low in terms of total contribution (70%), MDCPS’s commitment was the second highest of the evaluated school districts ($10,311 PEPY), with only NYSD having a higher total employer contribution ($10,495 PEPY) toward family coverage.

The average annual employee cost in MDCPS for family coverage—$4482 PEPY—is the highest of the

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analyzed school districts, and 19.2% higher than other purchasers in the region.

Regional total premium costs for family coverage were calculated using employee premium contributions for the South region ($3760 PEPY) from the Kaiser/ HRET survey, and the corresponding employee share of total premium. The total calculated premium for family coverage in the South is $11,750 PEPY. Not surprising, family coverage enrollment for MDCPS was extremely low. The SDI reports 47.6% of employees electing family coverage in 2008.

The Kaiser/HRET survey reports that 36% of the workforce is enrolled in family coverage. Only 8.4% of MDCPS employees elected family coverage in 2008.

Compared with the other school districts surveyed, MDCPS supports the highest annual premium cost ($14,793 PEPY) for family coverage (Table 5). The drivers responsible for these high costs could not be determined from the data provided by the schools and are beyond the objectives and scope of this article.

Finally, the school districts’ health insurance benefit offerings reflect a high level of importance given to the need to provide various benefit choices to their employees. With the exception of MDCPS, all the school districts reviewed offered more than 1 insurance carrier.

MDCPS is unique in allowing employees to select 1 benefit plan, and the dependents can select a different plan.

All the 5 school districts offer their employees at least 4 benefit options, with an average of 7 options for the SDI.

Discussion The premium growth for the 5 largest school districts in the country has slowed and is consistent with other health insurance purchasers. However, the decline in premium growth in these school districts has been less than the experience of other purchasers. Although this study does not analyze the value of the benefits offered, it is the experience of this author, and is also suggested

by Carolyn Watts and colleagues,3 that school districts generally offer benefit plans that are considered richer than private companies.3 As a percentage of premiums, the school district contributions toward single health insurance coverage are on par with other purchasers.

On average, the school district’s share of health insurance premium for family coverage is more generous than other purchasers, with the notable exception of MDCPS. An opportunity exists to increase take-up rates for family coverage in this South Florida school district, which is the largest employer in a community with the highest uninsured rate (28.7%) in the state.16 Two school districts, LAUSD and CPS, reflect progressive approaches toward maximizing coverage and affordability. LAUSD’s decision to subsidize 100% of

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Table 5 Average Annual Premiums, by School District and Coverage Type, 2008

Single coverage NYSD LAUSD CPS MDCPS CCSD SDI Kaiser/HRETa Family coverage NYSD LAUSD CPS MDCPS CCSD SDI Kaiser/HRETa

SDI premium, $

Employee premium, $

Employer share, $ (%)

5696

1410

4286 (75)

6823

0

4163

918

3245 (78)

5392

–66

5457 (101)

5290

171

5120 (97)

5665

908

4757 (84)

4704

721

3983 (85)

13,320

2825

10,495 (79)

6823

0

10,741

1185

9555 (89)

14,793

4482

10,311 (70)

8593

1550

7043 (82)

12,141

2318

9842 (81)

12,680

3354

9325 (74)

6823 (100)

6823 (100)

CCSD indicates Clark County School District; CPS, Chicago Public Schools; HRET, Health Research & Educational Trust; LAUSD, Los Angeles Unified School District; MDCPS, Miami-Dade County Public Schools; NYSD, New York School District; PEPY, per employee per year; SDI, school district index. a The Henry J. Kaiser Family Foundation, Health Research & Educational Trust. http://ehbs.kff.org/pdf/7790.pdf.

the insurance premium is the most generous contribution method of any of the school districts reviewed.

CPS’s use of a variable contribution strategy minimizes the regressive impact of a defined contribution model on low-wage earners. CPS employee contributions, as a percentage of salary, range from a low of 1.3% to a maximum of 2.5%, depending on rate tier and plan selection. The Kaiser/HRET survey reports that 10% of employers vary employee contribution based on salary.4

Conclusion The 5 school districts surveyed demonstrate a commitment to provide affordable health coverage for employees and their families, by offering a choice of benefits and innovative contribution strategies. These school districts have managed to slow the rate of premium growth, albeit at a slower pace than other purchasers.

Declines in tax revenues will increase the challenge for school districts to accelerate the decline in premium growth, while maintaining coverage levels. School districts need to balance these budget constraints without undermining the various social obligations school dis-

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tricts have. Policymakers are encouraged to look at costmanagement initiatives of other purchasers, and even some of their peers, for possible solutions. ■

References 1. US Bureau of Labor Statistics. Employment, hours, and earnings from the current Employment Statistics survey (national): local government education, all employees, thousands. Series ID: CES9093161101. http://data.bls.gov/cgi-bin/dsrv. Accessed March 11, 2009.

2. US Department of Labor, Bureau of Labor Statistics. Employer costs for employee compensation-December 2008. Press release 09-0247. March 12, 2009. www.bls.gov/ news.release/archives/ecec_03122009.pdf. Accessed March 4, 2010.

3. Watts C, Christianson JB, Heineccius L, Trude S. The role of public employers in a changing health care market. Health Aff (Millwood). 2003;22:173-180.

4. The Henry J. Kaiser Family Foundation and the Health Research Education Trust.

Employer Health Benefits 2008 Annual Survey. http://ehbs.kff.org/pdf/7790.pdf.

Accessed May 20, 2009.

5. The influentials: Wall Street. New York’s largest employers. New York. May 15, 2006. http://nymag.com/news/features/influentials/16908/index2.html. Accessed May 20, 2009.

6. Los Angeles Almanac. Largest employers in Los Angeles County. www.laalmanac. com/employment/em21e.htm. Accessed May 20, 2009.

7. Chicago Fact Book. CPS is the 2nd largest employer in Cook County, Illinois. http://egov.cityofchicago.org/city/webportal/portalDeptCategoryAction.do?deptMain CategoryOID=-536886120&deptCategoryOID=-536903993&entityName =Planning+And+Development&topChannelName=Dept&contentType=COC_ EDITORIAL&Failed_Reason=Invalid+timestamp,+engine+has+been+restarted

&com.broadvision.session.new=Yes&Failed_Page=%2fwebportal%2fportalDept CategoryAction.do. Accessed May 20, 2009.

8. The Beacon Council. Major employers: top public employers. www.beaconcouncil. com/web/Content.aspx?Page=majorEmployers. Accessed May 20, 2009.

9. Nevada Department of Employment, Training, and Rehabilitation Research and Analysis Bureau. Nevada Workforce Informer. Nevada’s largest employers 3rd quarter 2009: Clark County. www.nevadaworkforce.com/?PAGEID=67&SUBID=169.

Accessed May 20, 2009.

10. US Government Accountability Office. Federal Employees Health Benefits Program: premium growth has recently slowed, and varies among participating plans.

GAO Publication No. GAO-07-141. December 2006. www.gao.gov/new.items/ d07141.pdf. Accessed July 29, 2009.

11. Personal e-mail correspondence, March 20, 2009.

12. US Department of Education. Institute of Education Sciences, National Center for Education Statistics. Table 91: Selected statistics on enrollment, teachers, dropouts, and graduates in public school districts enrolling more than 15,000 students, by state: 1990, 2000, 2004-05, and 2006. 2008 Digest of Education Statistics. http://nces.ed.gov/programs/digest/d08/tables/dt08_091.asp. Accessed June 27, 2009.

13. The Clark County Teachers Health Trust. http://teachershealthtrust.org/About Us.aspx. Accessed May 20, 2009.

14. Chicago Public Schools/CPS. FY Budget, 2006-2008. www.cps.edu/About_CPS/ Financial_information/Pages/Financialinformation.aspx. Accessed May 9, 2009.

15. Bureau of Labor Statistics. Consumer Price Index. US city average of annual inflation (April to April), 2004-2008, not seasonally adjusted data from the Current Employment Statistics Survey, 2004-2008 (April-April). http://data.bls.gov/ cgi-bin/srgate. Series ID CUUR0000SA0. Accessed May 9, 2009.

16. Duncan RP, Porter CK, Garvan CW. Miami-Dade County Health Insurance Survey. Commissioned by the Public Health Trust of Miami-Dade County. Prepared by the University of Florida Department of Health Services Administration. June 2004.

STAKEHOLDER PERSPECTIVE Health Insurance Premium Increases for Large Employers When it comes to employers, although most attention is placed on Fortune 500 companies, large local employers are key players in healthcare policy and benefits. As Mr Cantillo points out in his article, school districts are among the largest employers in the country, but little has been published about their experience with healthcare benefits and premium costs.

Results from the just-released 15th Annual National Business Group on Health/Towers Watson Survey on Purchasing Value in Health Care1 provide a comparative context for the study results reported

by Mr Cantillo. The 507 employers surveyed in the Business Group on Health/Towers Watson study reported healthcare cost increases of 7% in 2009 and an expected 6.5% in 2010. Comparing these percentages with those of the school districts, schools had slightly higher cost increases in 2009, but they share some of the same concerns with other employers regarding employees’ poor health habits, employee resistance to change, and lack of employee engagement related to health.

School districts, like most companies, continue to invest in the health of their employees and are seeking to engage them in healthier behaviors through the use of various incentives, including financial.

Schools, like municipalities and healthcare systems

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or hospitals, are encouraged today to look more closely at other purchasers of the healthcare benefits as a result of recessionary impacts on local fiscal budgets.

As many employers had shifted health benefit costsharing to employees in the past, it is becoming increasingly more important to better engage employees and their families in healthier behaviors if cost trends are to be tamed in the future.

Health plan strategies by these large self-insured employers are beginning to drive changes by traditional health insurance plans that serve the majority of insured lives in the United States. As more objective information and insight become available about health cost trends, as well as premium increases in all sectors, employers and employees will have a greater opportunity to strive toward, then achieve, their shared goal of a healthier, happier work environment.

1. National Business Group on Health/Towers Watson. Purchasing value in health care. Selected findings from the 15th Annual National Business Group on Health/ Towers Watson Survey report—2010. February 2010. www.towerswatson.com/ assets/pdf/1258/2010_15571.pdf. Accessed March 15, 2010.

March/April 2010

F. Randy Vogenberg, PhD, RPh Principal, Institute for Integrated Healthcare Strategic Pharmacy Advisor MidAtlantic Business Group on Health

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GENERIC DRUG TRENDS

First Anti-Inflammatory Generic Drug Promising New Therapy for Diabetes Dalia Buffery, MA, ABD

I

f March 2010 was any indication for the US Food and Drug Administration (FDA)’s intentions, 2010 will witness a good number of generic approvals.

Compared with the meager approval record in January (1) and February (2), by March 23 the FDA approved 15 generics in that month alone.

Nevertheless, considering that “the FDA Office of Generic Drugs is stretched too thin,”1 and that there are “nearly 2000 pending new generic drug applications” waiting to be approved,1 at this pace it would likely take quite some time for all new applications to get through the process. So even though generics currently represent 74% (10% higher than last year) of all drugs dispensed in the United States,1 this percentage should increase when all these potential generics are finally reviewed by the FDA. It is perhaps surprising that this whooping just-under three quarters of all medicines sold in the country amounts to only 22% of the dollars spent on prescription drugs,1 and yet, according to the Generic Pharmaceutical Association, FDA Commissioner Margaret Hamburg said that “the generic pharmaceutical industry saved the federal government and the entire healthcare system about $750 billion over the past decade.”2 Not bad for a mere 22% of the market share. Can you imagine the savings when generics amount to, say, 35% of the dollar share?

So it was exciting, if unexpected, to see that cost-savings was the motivation for a new clinical trial using a generic drug to cross over clinical therapeutic categories—from one type of inflammatory disease (arthritis) to another (diabetes, which has recently been linked to inflammation).3 This study may have significant implications for generics and for healthcare costsavings, especially in light of the rising epidemics of diabetes and obesity. In this 3-month, placebo-controlled, randomized trial (funded by the National Institute of Diabetes and Kidney Diseases) of 108 diabetic patients, salsalate, an anti-inflammatory generic drug normally used for arthritis, has been shown safe and effective for the treatment of type 2 diabetes (and possibly more).3

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Salsalate reduced hemoglobin A1c levels by 0.5%, significantly better than placebo. Other markers of glycemic control also improved with salsalate (as did triglyceride and adiponectin levels).

Investigator Steven Shoelson, MD, PhD, of the Joslin Diabetes Center, said that he and his colleagues approached the federal government, “which has been interested in a safe, effective, and inexpensive new drug for diabetes,” for funding, because “pharmaceutical companies were interested in the idea of an antiinflammatory drug for diabetes, but not in this compound [ie, generic], because no one can own it.”4 Lead investigator Allison Goldfine, MD, Director of Clinical Research, Joslin Diabetes Center, and Associate Professor, Harvard Medical School, commented that these results “indicate that salsalate may provide an effective, safe, and inexpensive new avenue for diabetes treatment.”4 She noted that these results are exciting, and more research is needed (a new phase 3 trial is now under way), adding that “there is reason to think that salsalate also could have beneficial effects on atherosclerosis.”4 This study is an unusual feat of innovation in the generic drug arena, motivated by cost-savings rather than cost-gaining (imagine that), with clinicians and researchers charting a new drug development model and potentially new therapeutic directions. Using inexpensive medicines to try to rein in a chronic disease epidemic that is out of control in clinical and costs terms is indeed a novelty. Whether this signals a new trend in the application of generics remains to be seen; it certainly is a welcomed first step in that direction. ■

References 1. Generic Pharmaceutical Association. White House ignores savings from increasing access to generic medicine. March 3, 2010. www.gphaonline.org/media/pressreleases. Accessed March 23, 2010.

2. Generic Pharmaceutical Association. Statement from GPhA President and CEO Kathleen Jaeger in response to remarks by FDA Commissioner Margaret Hamburg at the GPhA annual meeting. February 18, 2010. www.gphaonline.org/ media/press-releases. Accessed March 23, 2010.

3. Goldfine AB, Fonseca V, Jablonski KA, et al. The effects of salsalate on glycemic control in patients with type 2 diabetes. Ann Intern Med. 2010;152:346-357.

4. Newswise. Generic drug for type 2 diabetes passes next clinical hurdle. www. newswise.com/articles/view/562142?print-article. Accessed March 10, 2010.

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Pharmacy Essentials

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The GBR is a handbook that contains a cross-referenced listing of generic and brand pharmaceuticals as well as a color identification section that includes photographs and NDC numbers for all products in the Mylan product portfolio.

To receive your FREE 2010 GBR, go to www.mylanpharms.com and click “FREE GBR Offer.”

800.RX.MYLAN • 800.796.9526 • www.mylanpharms.com ©2010 Mylan Pharmaceuticals Inc.

MYNMKT366A

DRUG PIPELINE

The Cardiovascular Pipeline: ACC 2010 Features Late-Stage Drugs

By Wayne Kuznar

A

lthough promising late-stage drugs in the cardiovascular (CV) pipeline are few, increasing numbers of pharmaceutical manufacturers are taking a stab at oral, fixed-dose alternatives to warfarin, many of which are in phase 3 clinical trials. The following agents were featured at special sessions at the 2010 annual meeting of the American College of Cardiology (ACC).

Unique Factor X Inhibitor Betrixaban was the subject of a late-breaking session at ACC. Betrixaban is unique among the factor Xa inhibitors, because it is not cleared by the kidneys, and it is being codeveloped with an antidote to reverse its anticoagulant effect in the event that anticoagulation needs to be turned off rapidly, said Michael D. Ezekowitz, MD, PhD, Vice President, Lankenau Institute for Medical Research, Wynnewood, PA, and Professor of Medicine, Jefferson Medical College, Philadelphia.

The onset of action of betrixaban is rapid, according to Dr Ezekowitz, and therapeutic anticoagulation is achieved in 3 to 4 hours. The drug can be taken once daily and is not metabolized via the cytochrome P450 enzyme, and therefore has lower potential for drug–drug interactions.

Betrixaban was studied in 508 patients with atrial fibrillation and at least 1 other risk factor for stroke.

The patients were randomized to warfarin, with the dosage adjusted to maintain a therapeutic range (ie, international normalized ratio, 2.0-3.0), or to 40 mg, 60 mg, or 80 mg of betrixaban. The median follow-up was 4.9 months.

There was no difference in the rates of death or stroke between any betrixaban dose and warfarin. Only 1 patient had a major bleeding event with the 40-mg dose of betrixaban compared with 4 patients in the warfarin group. In addition, 5 major bleeding events occurred in patients assigned to the 60-mg and 80-mg doses of betrixaban.

Results from D-dimer testing suggest that 40 mg of betrixaban is active, said Dr Ezekowitz, adding that previous clinical experience with betrixaban demonstrated activity of 30 mg in the prophylaxis of deepvein thrombosis.

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More adverse gastrointestinal (GI) events occurred in patients randomized to betrixaban, especially at higher doses, compared with warfarin, but “only 1 patient withdrew from the study because of GI side effects,” Dr Ezekowitz said. The GI safety profile will be monitored in future trials.

Quick Onset/Offset Antiplatelet Ticagrelor, an investigational antiplatelet agent with a quick onset and offset of action, fared well against clopidogrel in patients with acute coronary syndrome (ACS) who then had coronary artery bypass graft (CABG) surgery.

The PLATO (Platelet Inhibition and Patient Outcomes) CABG trial was a subset of the much larger PLATO trial, which included 18,624 patients with ACS who were randomized to ticagrelor or to clopidogrel (Plavix). In PLATO, ticagrelor was associated with a 16% reduction in the composite end point of CV death, stroke, and heart attack.

In PLATO CABG, analysis of results in the 1261 patients who had CABG showed a similar reduction in events with randomization to ticagrelor. Mortality rate was 50% less in the patients assigned to ticagrelor (46%) versus clopidogrel (9.2%), said Claes Held, MD, PhD, Associate Professor of Cardiology, Uppsala Clinical Research Center, Uppsala University, Sweden.

The fast onset/fast offset action of ticagrelor would make it attractive for use in patients who go on to CABG, in whom bleeding is a risk.

A New Drug Application for ticagrelor was submitted to the US Food and Drug Administration in November 2009.

Novel Antihypertensive LCZ696, a first-in-class antihypertensive, lowered blood pressure more effectively than valsartan (Diovan) in a double-blind study of 1328 patients with mild-tomoderate hypertension who were treated for 8 weeks, reported Luis Miguel Ruilope, MD, Head, Hypertension Unit, Hospital 12 de Octubre, Madrid, Spain.

LCZ696 inhibits both the angiotensin II receptor and neprilysin. The latter mechanism prolongs the life of natriuretic peptides to exert antihypertensive action. ■

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1

,000 knees

1 The # bed 1 i r presc plement sup visco

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worldwide ted a a e

For osteoarthritis (OA) knee pain relief

ONE gets it done.

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The only nonsystemic therapy delivering up to 6 months of pain relief with just 1 simple injection2-4 Combining all 3 doses of SYNVISC速 in 1 injection simplifies the management of OA knee pain Statistically significant reduction from baseline in OA knee pain sustained over 26 weeks2,5 Demonstrated safety profile in both initial and repeat treatments2 Important Treatment Considerations Synvisc-One速 (hylan G-F 20) is indicated for the treatment of pain in osteoarthritis (OA) of the knee in patients who have failed to respond adequately to conservative nonpharmacologic therapy and simple analgesics, eg, acetaminophen.

Synvisc-One is contraindicated in patients with known hypersensitivity to hyaluronan products or patients with infections in or around the target knee. Use caution when injecting Synvisc-One in patients allergic to avian proteins, feathers, or egg products; who have evidence of venous or lymphatic stasis in the leg to be treated; or who have severe inflammation in the knee to be treated. The most commonly reported related local adverse events were transient, mild to moderate arthralgia, arthritis, arthropathy, injection site pain and joint effusion. No serious adverse events in knees injected with Synvisc-One were reported in clinical trials. Serious local adverse events have been reported only rarely in post-marketing use. Repeat treatment did not affect the safety profile. In the pivotal clinical trial, there was one related systemic event of syncope. The most common systemic side effects irrespective of relationship to Synvisc-One were headache, back pain, nasopharyngitis and influenza. Systemic adverse event profiles were similar between patients in the Synvisc-One and saline control groups. Other side effects, such as rash, have been reported rarely in association with SYNVISC. Patients should be advised to avoid strenuous or prolonged weight-bearing activities for approximately 48 hours after treatment. Aspiration of any effusion prior to injection is highly recommended. Strict adherence to aseptic technique must be followed to avoid joint infection. The safety and effectiveness of Synvisc-One have not been established in children or in pregnant or lactating women. It is unknown whether Synvisc-One is excreted in human milk.

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

References: 1. Data on file. Genzyme Corp. 2. Synvisc-One Prescribing Information. Cambridge, MA: Genzyme Corp; 2009. 3. Brzusek D, Petron D. Treating knee osteoarthritis with intra-articular hyaluronans.

Curr Med Res Opin. 2008;24(12):3307-3322. 4. Bellamy N, Campbell J, Robinson V, Gee T, Bourne R, Wells G. Intraarticular corticosteroid for treatment of osteoarthritis of the knee. Cochrane Database Syst Rev. 2006;(2):CD005328. doi:10.1002/14651858.CD005328.pub2. 5. Chevalier X, Jerosch J, Goupille P, et al. Single, intra-articular treatment with 6 ml of hylan G-F 20 in patients with symptomatic primary osteoarthritis of the knee: a randomised, multi-centre, double-blind, placebo controlled trial. Ann Rheum Dis. 2010;69(1):113-119.

Synvisc-One, SYNVISC, and GENZYME are registered trademarks of Genzyme Corporation.

Unique J-code J7325 simplifies reimbursement

BRIEF SUMMARY FOR THE PHYSICIAN (CONSULT PACKAGE INSERT FOR FULL PRODUCT INFORMATION) CAUTION: Federal law restricts this device to sale by or on the order of a physician (or properly licensed practitioner).

INDICATIONS FOR USE • Synvisc-One is indicated for the treatment of pain in osteoarthritis (OA) of the knee in patients who have failed to respond adequately to conservative nonpharmacologic therapy and simple analgesics, eg, acetaminophen.

CONTRAINDICATIONS • Do not administer to patients with known hypersensitivity (allergy) to hyaluronan (sodium hyaluronate) preparations. • Do not inject Synvisc-One in the knees of patients who have knee joint infections, skin diseases, or infections in the area of the injection site.

WARNINGS • Do not concomitantly use disinfectants containing quaternary ammonium salts for skin preparation, because hyaluronan can precipitate in their presence. • Do not inject Synvisc-One extra-articularly or into the synovial tissues and capsule. • Intravascular injections of Synvisc-One may cause systemic adverse events.

PRECAUTIONS General • The safety and effectiveness of Synvisc-One in locations other than the knee and for conditions other than osteoarthritis have not been established. • The safety and effectiveness of the use of Synvisc-One concomitantly with other intra-articular injectables have not been established. • Use caution when injecting Synvisc-One into patients who are allergic to avian proteins, feathers, or egg products. • The safety and effectiveness of Synvisc-One in severely inflamed knee joints have not been established. • Strict aseptic administration technique must be followed.

• STERILE CONTENTS. The syringe is intended for single use. The contents of the syringe must be used immediately after its packaging is opened. Discard any unused Synvisc-One. • Do not use Synvisc-One if the package is opened or damaged. Store in the original packaging (protected from light) at room temperature below 86°F (30°C). DO NOT FREEZE. • Remove any synovial fluid or effusion before injecting Synvisc-One. • Synvisc-One should be used with caution when there is evidence of lymphatic or venous stasis in the leg to be injected.

Information for Patients • Provide patients with a copy of the Patient Labeling prior to use.

• Mild to moderate pain, swelling, and/or effusion of the injected knee have been reported in clinical trials that were related to the intra-articular injection of Synvisc-One. These events were typically transient and usually resolved on their own or with conservative treatment. • As with any invasive joint procedure, it is recommended that the patient avoid strenuous activities (for example, high-impact sports such as soccer, tennis, or jogging) or prolonged weight-bearing activities for approximately 48 hours following the intra-articular injection. The patient should consult his or her physician regarding the appropriate time to resume such activities.

Use in Specific Populations • Pregnancy: The safety and effectiveness of Synvisc-One have not been established in pregnant women. • Nursing mothers: It is not known if Synvisc-One is excreted in human milk. The safety and effectiveness of Synvisc-One have not been established in lactating women. • Pediatrics: The safety and effectiveness of Synvisc-One have not been established in pediatric patients (i.e., ≤21 years of age).

ADVERSE EVENTS Adverse Events Involving the Injected Joint Clinical Trial: A total of 123 patients were treated with Synvisc-One in the pivotal study.

The frequency and type of adverse events (AEs) were similar between the group of patients that received Synvisc-One and the group that received saline control (n=130). In the Synvisc-One group, 5.7% of patients experienced transient, mild to moderate, device-related local adverse events, including arthralgia, arthritis, arthropathy, injection-site pain, and joint effusion. No serious AEs were reported in knees injected with Synvisc-One. The repeat treatment phase confirmed the safety profile of the initial phase. One hundred and sixty patients were treated during this phase of the study; 77 of these patients received a second injection of Synvisc-One. Of these 77 patients, 4 (5.2%) experienced five device-related AEs in the injected knee. All such events were mild to moderate and were treated symptomatically. These events were arthralgia (n=2), arthritis (n=1), injection-site hematoma (n=1), and injection-site pain (n=1). Patients who developed target knee AEs during the initial phase of the study, and who subsequently received repeat treatment, did not experience target knee AEs upon repeat exposure to Synvisc-One.

Overall Injected Knee Safety Summary: The safety profile of Synvisc-One is similar to the clinical and postmarketing experience seen with Synvisc® (3-injection regimen), where pain, swelling, and effusion were the most frequently occurring AEs in the injected knee. There have been postmarketing reports for Synvisc indicating that in some cases the joint effusion may be large and can cause pronounced pain; it is important to remove and to analyze the fluid to rule out infection or crystalline arthropathies. These types of severe AEs were not observed in either the initial or repeat treatment phase of the Synvisc-One trial; however, they have been reported rarely in post-marketing use. Joint infections did not occur in any of the clinical trials of Synvisc or Synvisc-One and have been reported only rarely during the clinical use of Synvisc.

OTHER ADVERSE EVENTS Clinical Trial: Systemic adverse event profiles were similar between patients in the Synvisc-One and saline control groups. Overall, 47 (38.2%) patients treated with Synvisc-One experienced at least one AE outside the target knee, regardless of device relatedness. The most commonly occurring (5% or greater in either group) AEs outside the target knee were headache, back pain, nasopharyngitis, and influenza. In the Synvisc-One group there was one AE of syncope considered device related.

Postmarket Experience: Postmarketing experience with Synvisc (3-injection regimen) has identified the following systemic events that occur rarely with administration: rash, hives, itching, fever, nausea, headache, dizziness, chills, muscle cramps, paresthesia, peripheral edema, malaise, respiratory difficulties, flushing, and facial swelling. There have been rare reports of thrombocytopenia coincident with Synvisc (3-injection regimen) injection. No new systemic AEs associated with Synvisc-One were identified during the pivotal study as compared to Synvisc.

DETAILED DEVICE DESCRIPTION Each syringe of Synvisc-One contains Hylan polymers (hylan A + hylan B) .............................................48 mg Sodium chloride .........................................................................51 mg Disodium hydrogen phosphate ....................................................0.96 mg Sodium dihydrogen phosphate monohydrate ...............................0.24 mg Water for injection ......................................................................q.s. to 6.0 mL HOW SUPPLIED Synvisc-One is supplied in a 10-mL glass syringe combining the three 2-mL injections of Synvisc (48 mg). The contents of the syringe are sterile and nonpyrogenic.

DIRECTIONS FOR USE Precaution: Do not use Synvisc-One if the package has been opened or damaged. Store in the original packaging (protected from light) at room temperature below 86°F (30°C). DO NOT FREEZE. Precaution: The syringe containing Synvisc-One is intended for single use. The contents of the syringe must be used immediately after the syringe has been removed from its packaging.

Precaution: Do not concomitantly use disinfectants containing quaternary ammonium salts for skin preparation, because hyaluronan can precipitate in their presence. Synvisc-One is administered as a single intra-articular injection. Strict aseptic administration technique must be followed. • Using an 18- to 20-gauge needle, remove synovial fluid or effusion before injecting Synvisc-One. • Do not use the same syringe for removing synovial fluid and for injecting Synvisc-One; however, the same 18- to 20-gauge needle should be used. • Twist the tip cap before pulling it off, as this will minimize product leakage. • To ensure a tight seal and prevent leakage during administration, secure the needle tightly while firmly holding the luer hub.

Precaution: Do not over tighten or apply excessive leverage when attaching the needle or removing the needle guard, as this may break the syringe tip. • Inject the full 6 mL in one knee only.

SONE-00042.B

A division of Genzyme Corporation 55 Cambridge Parkway Cambridge, MA 02142 1-888-3-SYNVISC www.SynviscOne.com/hcp

Synvisc-One, SYNVISC, and GENZYME are registered trademarks of Genzyme Corporation. ©2009 Genzyme Corporation. All rights reserved.

Printed in USA. SONE-00012.F(I)

12/2009

12/2009

CLINICAL

Evolving Trends in Insulin Delivery: In Pursuit of Improvements in Diabetes Management Firas Akhrass, MD; Nancy Skinner, RN, CCM; Kimberly Boswell, MD; Luther B. Travis, MD Diabetes mellitus affects 23.6 million Americans and its incidence is rapidly increasing, particularly in older, overweight patients. Large-scale studies conclusively show that elevated blood glucose levels are associated with an increased risk for microvascular complications, such as retinopathy and nephropathy. The high rates of morbidity and mortality associated with this disease, and the costs associated with it, underscore the importance of effective glycemic control. Conventional syringe/vial insulin delivery is associated with many barriers for patients with diabetes mellitus and for their healthcare providers.

Substantial developments in insulin delivery show promise in overcoming these barriers.

New technologies in insulin delivery focus on increasing patient convenience, reducing the frequency of daily injections, and improving glycemic control. This article outlines the challenges associated with conventional insulin delivery and describes recent developments that may help to overcome these barriers and, ultimately, could enhance glycemic control.

[AHDB. 2010;3(2):117-122.]

D

iabetes mellitus affects 23.6 million Americans, or about 8% of the US population.1 This includes nearly 18 million persons with diagnosed disease and about 5.7 million undiagnosed cases. The incidence of type 2 diabetes is rapidly increasing, particularly among older, overweight persons who have concomitant cardiovascular (CV) risks.2 The coexistence of diabetes mellitus and hypertension works synergistically to increase morbidity and mortality, especially renal and CV injury.3 Well-known, large-scale studies, such as the Diabetes Control and Complications Trial and the UK Prospective Diabetes Study, conclusively show that elevated levels of blood glucose are associated with an increased risk of microvascular complications, such as retinopathy and nephropathy.4-6 The high rates of morbidity and mortality associated with diabetes, coupled with the costs of treating these sequelae, underscore the importance of effective glycemic control.

Maintaining optimal glucose control—defined by the American Diabetes Association as a glycosylated hemoglobin level of <7%7—may require multiple daily

Dr Akhrass is Endocrinologist, Diabetes and Glandular Disease Clinic, San Antonio, TX. Ms Skinner is President, Riverside Healthcare Consulting, Whitwell, TN. Dr Boswell is Assistant Director, Xcenda, Palm Harbor, FL. Dr Travis is Emeritus Professor of Pediatrics, UTMB, Galveston, TX.

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insulin injections. However, conventional insulin injection techniques are a major cause of reduced patient adherence to treatment.8 Patient medication adherence and satisfaction with treatment regimens are more likely to occur with fewer medication side effects, as well as with reduced patient burden and inconvenience.9,10 Typical side effects of insulin therapy may include weight gain or hypoglycemic events.2,11 Significant advances in insulin delivery have been aimed at improving patient convenience and enhancing glycemic control.12 Alternatives to syringe/vial insulin delivery include: • Insulin pens • Injection ports • Insulin infusion pumps • Transdermal insulin patches • Inhaled insulin.

Some of these methods, however, have not met with great success. Inhalable insulin was available in the United States from September 2006 through October 2007 but was subsequently withdrawn from the market because of poor utilization rates. Other advances currently in development include oral insulin and buccal insulin spray. An international phase 3 clinical trial is ongoing for both types of insulin delivery.

This article reviews the barriers to adherence to conventional therapy and evaluates developments in

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KEY POINTS u

u

u

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Nearly 18 million Americans are diagnosed with diabetes, and about 5.7 million have the disease but have not been diagnosed.

The high rates of morbidity and mortality associated with diabetes, and the costs associated with its treatment, underscore the importance of effective glycemic control.

Conventional syringe/vial insulin delivery is associated with patient and physician barriers, such as psychological insulin resistance, patients’ fear of insulin side effects and complications, and required lifestyle changes/restrictions.

Despite evidence that many patients with type 2 diabetes do not achieve glycemic control with oral therapy alone, some physicians are still reluctant to initiate insulin therapy.

Developments in insulin delivery during the past 20 years have focused on increasing patient convenience and improved glycemic control.

The newer insulin delivery modes include insulin pens, insulin injection ports, continuous subcutaneous insulin infusion pumps, transdermal patches, and inhalable devices.

the management of insulin-requiring diabetes that may help to overcome some of these barriers, as well as improve glycemic control and quality of life for patients with diabetes.

Barriers to Conventional Insulin Injection Therapy Psychological Insulin Resistance Psychological insulin resistance, defined as reluctance to initiate insulin injection therapy, is common among healthcare professionals and patients with diabetes mellitus.8,11,13,14 Despite ample evidence that many patients with type 2 diabetes do not achieve glycemic control with oral therapy alone, some physicians are still reluctant to initiate insulin therapy.12,14 Koro and colleagues found that despite frequent failure to achieve glycemic targets, the use of insulin declined from the 24% reported in the National Health and Nutrition Examination Survey (NHANES) III (19881994) to 16% in the initial release of NHANES IV (1999-2000), whereas the use of oral glucose-lowering monotherapy increased.15 This may in part reflect the availability of more oral medications for diabetes, but it may also be the result of the perceived complexity and inconvenience of the therapeutic regimen, the belief that it is not effective in type 2 diabetes, and fears of hypoglycemic episodes and weight gain. In addition, clinicians may perceive that

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initiation of insulin therapy will require more practice resources than are readily available.14 The relationship between psychological barriers to medication adherence and glycemic control can have important therapeutic implications. In a systematic literature review covering 1985 to 2007, Brod and colleagues evaluated 116 peer-reviewed articles to assess the impact of psychological insulin resistance on diabetes management.16 The investigators concluded that this phenomenon is affected by the following components16: • Patients’ beliefs and knowledge about diabetes and insulin • Negative self-perceptions and attitudinal barriers • Fear of side effects and complications of insulin use • Lifestyle adaptations • Restrictions required by insulin use • Social stigma.

These factors may lead to delayed treatment initiation and compromised glucose control.

Reduced Medication Adherence Decreased adherence because of injection-related anxiety can influence glycemic control and quality of life in patients with insulin-treated diabetes.11,17-20 Adherence to a daily regimen of multiple injections can be difficult to maintain, interfering with lifestyle, compromising optimal glycemic control, and potentially resulting in CV complications.17,20 In one study of elderly patients (aged ≥65 years) with type 2 diabetes who were treated in a managed care setting, an inverse correlation was observed between blood glucose–lowering medication adherence and healthcare service utilization (eg, emergency department visits, outpatient visits, hospitalizations).21 In this longitudinal cohort study, an increased medication possession ratio (MPR) for diabetes medications was the strongest predictor of decreased total annual healthcare costs: between 8.6% and 28.9% decrease in annual costs for every 10% increase in the MPR (P <.001).21 Alternative Modes of Insulin Delivery Insulin may have greater patient acceptance and reduced psychological impact when administered via an alternative (ie, non-vial/syringe) delivery mode.22 Newer routes of insulin delivery have been introduced over the years that may be more convenient and less traumatic than standard multiple daily injection therapy. There is sufficient evidence supporting patient preferences for modes of insulin delivery that result in ease of use, reduced fear/anxiety about insulin injections, and reduced fear of hypoglycemia.22 The evidence suggests that novel delivery systems improve medication adherence compared with conventional injection delivery and

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Table Alternative Modes of Insulin Delivery Device Insulin pen (replaceable cartridge and prefilled)

Advantages Discreet Injection may be more comfortable and less time consuming than vial/syringe Refrigeration not required Easy to use Accurate dosing Disposable

Disadvantages Initially can be more expensive than vial/syringe Cannot mix insulin types Some insulin is wasted Possibility of air bubbles

Insulin injection port

Reduces need for multiple daily skin punctures May remain in place for 72 hrs before application of a new port Discreet

Possibility of crimping of deviceâ&#x20AC;&#x2122;s soft cannula, resulting in limited medication delivery Possible skin irritation or failure of injection port adhesive patch

Insulin infusion pump (continuous subcutaneous insulin infusion)

Uses only rapid-acting insulin (most consistent profile) Accurate dosing Allows flexible lifestyle Closest to mimicking bodyâ&#x20AC;&#x2122;s physiologic secretion of insulin

Possibility of crimping of infusion set soft cannula, resulting in limited medication delivery Possible skin irritation or failure of infusion set adhesive patch Pump and supplies expensive Undetected interruptions in insulin delivery may occur Requires high patient motivation, involvement, and commitment to use

Transdermal insulin patch

Reduces need for conventional needles

Technology is new and costly Potential damage to the skin must be more completely evaluated

Inhalable insulin

Need for fewer/no injections

Larger doses of insulin required Lack of patient/physician acceptance Pulmonary route not suitable for smokers or patients with asthma or other pulmonary problems Long-term impact on lung structure/function not clear Nasal route yields poor transport across nasal mucosa

can lead to enhanced glycemic control, patient satisfaction, and improved health-related quality of life.17,23,24 The alternative modes of insulin delivery are summarized in the Table. Various preparations of insulin and insulin analogs are available for these systems.

Administration schedules usually combine types of insulin in a regimen specific to the individual needs of each patient in an attempt to mimic physiologic secretion of insulin.

Insulin Pens The insulin pen device uses an insulin cartridge rather than a vial, as well as disposable needles. Pens are the predominant insulin delivery system in most of the world, except in the United States.25 The 2 types of insulin pens available are replaceable and prefilled cartridge. A replaceable cartridge pen

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reuses the pen portion. When the insulin is used up, the cartridge is replaced with a new cartridge. A prefilled pen is entirely disposable: when the insulin is gone, the pen is discarded.

The insulin pen was an important milestone in the delivery of insulin, because it is convenient, portable, and discreet. These characteristics are more accommodating to a patientâ&#x20AC;&#x2122;s lifestyle and may therefore improve quality of life. A randomized, open-label, crossover study was conducted at 50 physician offices in the United States.22 Patients completed several questionnaires, including the Insulin Device Preference Questionnaire. Among the entire cohort (N = 162), 72% of the patients indicated an overall preference for a disposable form of dosing (similar to an insulin pen) compared with 22% of those who preferred the vial/syringe (P <.001).22

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Other advantages for pen users include convenience, ease of use, comfort associated with use in public and social settings, as well as decreased fear of self-injection.22 When multiple daily injections are required to reach recommended glycemic targets, pens may facilitate acceptance of such regimens, even when the increased frequency of injection is perceived to be a disadvantage.

Some insulin is wasted when pens are used: 1 to 2 units of insulin are lost when the pen is primed before each injection, and usually some insulin remains in the pen or cartridge (but not enough to inject) after use.

Insulin pens do not permit mixing of insulin types; therefore, if the insulin mixture needed is not available as a premix, 2 injections must be given, 1 injection for each type of insulin.

Pens are mechanically more complex and more costly than syringes and vials, with an annual cost between $2500 and $4500.

However, these costs may be offset by decreased hospitalizations.

In addition, pens are mechanically more complex and more costly than syringes and vials,13 with an annual cost (of insulin and supplies) between $2500 and $4500. However, these costs may be offset by decreased hospitalizations. A recent study indicated that annual hypoglycemia-associated costs were reduced by $788 per patient (from $1415 to $627; P <.01), predominantly as a result of decreased hospitalization costs (from $857 to $288; P <.01). Annual diabetes-attributable costs were reduced by $600 per patient (from $8827 to $8227; P <.01).17

Insulin Injection Ports An insulin injection port is a novel, low-profile device that can reduce the impact of daily injections in adults and in children.26 This new technology offers a portal for delivering multiple doses of medication directly into the subcutaneous tissue without the need for multiple skin punctures.

The injection port is applied via a short insertion needle whereby a soft flexible cannula is guided into the subcutaneous space. Once applied, the insertion needle is removed, and only the soft, flexible cannula remains under the skin. A resealable medication port is directly atop the cannula and is kept in place on the skinâ&#x20AC;&#x2122;s surface with an adhesive pad. Through a standard insulin syringe or an insulin pen, the patient receives a dose of insulin given by injection through the port. Because the device can typically be worn for 72 hours, it can sub-

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stantially reduce the number of daily skin punctures, because insulin is injected through the port rather than the skin. Potential application sites include the abdomen and thighs. Once instructed by a healthcare provider, patients can then self-apply the injection port.

Use of the injection port can result in relief of preinjection anxiety, injection problems, and the procedural pain of repeated injections.27,28 Reported side effects include erythema and possible skin irritation.26 Measures of glycosylated albumin were within equivalence analysis limits compared with standard injections (P = .99).26 The use of injection ports is not restricted to insulin.

They can be used for other prescribed medications that require multiple daily subcutaneous injections. Indeed, the newer incretin mimetics, which mimic the effect of glucagonlike peptide-1, are injectable products that could be delivered in the same fashion.

Continuous Subcutaneous Insulin Infusion Pumps The continuous subcutaneous insulin infusion (CSII) pump, using a battery-powered pump, was introduced to treat type 1 diabetes more than 20 years ago.

Rapid-acting insulins are appropriate for use in pumps.

The CSII provides an approximation of normal plasma insulin profiles and increased flexibility regarding timing of meals and snacks compared with conventional insulin injection regimens.

Insulin pump therapy has been shown to result in improved metabolic control and reduced frequency of severe hypoglycemia.29 Pumps reduce the need for injections and are more adaptable to lifestyle modifications, such as delaying meals, variable sleep schedules, or variations in exercise patterns. Studies comparing CSII and multiple daily injections in patients with type 1 diabetes have shown outcomes (ie, improved glycemic control) that were comparable with or favored the former.29-33 However, pumps are not necessarily discreet to use, and pump infusion sets may result in site infections, abscess formation, and scarring.34 They also require a high level of patient motivation and commitment.

Furthermore, they are expensive, costing more than $5000 in initial costs (pump and supplies) and about $2500 to $4500 in subsequent annual costs. Proponents assert that insulin pump therapy produces long-term reductions in complications, which offset these costs.35 Cost-benefit may be realized primarily in patients with frequent episodes of hypoglycemia.

Transdermal Patches The insulin molecule is far too large to penetrate the skin passively. Therefore, active transdermal delivery systems have been developed that involve a chemical or mechanical disruption of the skin barrier. By using

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an applied force, such as ultrasound or an electrical current, active transdermal systems can deliver large-molecule formulations through the skin and into the bloodstream.36 However, this technology is costly and still under development; before replacing conventional needles, the safety and efficacy of these patches in delivering insulin without damage to the skin must be more completely evaluated.

Inhalable Insulin Devices The first inhaled version of insulin became available in September 2006 in the United States. However, this system failed to gain the acceptance of patients and physicians. Despite this product’s failure, one company continues the development of inhalable insulin devices, and the United States may see a return of inhalable insulin to the market in the near future.

The bioavailability of inhaled insulin is less than 20%; therefore, dosage requirements and cost per treatment are increased in comparison with insulin administered by subcutaneous injection. In addition, the long-term effects of intra-alveolar insulin deposition and immunogenic safety of inhaled insulin have not been fully elucidated.37 Delivery of inhaled insulin to the upper nasal airways suffers from poor transport across the nasal membranes. Delivery via this route requires very large doses of insulin or the use of a chemical to enhance insulin transport.38 Chemicals used to enhance insulin transport often cause nasal irritation and a runny nose.

Underlying lung disease could disrupt the absorption of the intended insulin dose.

Implications The increasing prevalence of diabetes worldwide is cause for concern, in terms of associated morbidity and increasing health costs. Insulin therapy is an integral part of the treatment of diabetes. The long-term benefits of insulin therapy to control blood glucose levels have been demonstrated in multiple clinical trials in patients with type 1 and type 2 diabetes mellitus.4-6,39,40 These studies demonstrated a correlation between tight glycemic control and a reduction in the progression of chronic complications associated with diabetes mellitus.

The insulin delivery mode is vital for its acceptance and adherence to therapy for achieving glycemic targets. Conventional multi-injection insulin delivery has been associated with perceived barriers on the part of patients and physicians. Substantial developments have occurred in insulin delivery during the past 20 years, focusing on increasing patient convenience and achieving better glycemic control to overcome barriers associated with conventional insulin injections.

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Conclusion Newer delivery devices may add a substantial upfront cost; however, the use of these devices to improve adherence could have significant implications on overall disease burden costs for patients and payers alike. These devices can also help to improve quality of life for patients with diabetes by reducing the number of daily skin punctures or providing enhanced convenience, and can help patients lead a life as normal as possible. In the long-term, cost-benefit analyses incorporating patient preferences would help gauge the cost-savings resulting from the use of these newer delivery devices. ■ Acknowledgments This manuscript was supported by a grant from Patton Medical Devices, LP. The authors would like to thank Laurie Kozbelt for her editorial assistance with this manuscript.

Disclosure Statement Dr Akhrass is a Consultant to Patton Medical Devices and is on the Speaker’s Bureau of Amylin, AstraZeneca, Daiichi Sankyo, Forest, Lilly, and Takeda. Dr Boswell is a Consultant to Patton Medical Devices. Ms Skinner is a Consultant to Patton Medical Devices and is on the Advisory Board of Boehringer Ingelheim. Dr Travis is Co-chair of the Scientific Advisory Committee of and a Consultant to Patton Medical Devices.

References 1. National Institute of Diabetes and Digestive and Kidney Diseases. National Diabetes Statistics, 2007. www.niddk.nih.gov/health/diabetes/pubs/dmstats/dmstats. htm#7. Accessed July 2, 2008.

2. Carver C. Insulin treatment and the problem of weight gain in type 2 diabetes.

Diabetes Educ. 2006;32:910-917.

3. Bakris GL, Williams M, Dworkin L, et al. Preserving renal function in adults with hypertension and diabetes: a consensus approach. National Kidney Foundation Hypertension and Diabetes Executive Committees Working Group. Am J Kidney Dis. 2000;36:646-661.

4. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N Engl J Med. 1993;329:977-986.

5. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet.

1998;352:837-853. Erratum in: Lancet. 1999;354:602.

6. Stratton IM, Adler AI, Neil HA, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ. 2000;321:405-412.

7. American Diabetes Association. Executive summary: standards of medical care in diabetes—2008. Diabetes Care. 2008;31(suppl 1):S5-S11.

8. Stotland NL. Overcoming psychological barriers in insulin therapy. Insulin.

2006;1:38-45.

9. Atkinson MJ, Sinha A, Hass SL, et al. Validation of a general measure of treatment satisfaction, the Treatment Satisfaction Questionnaire for Medication (TSQM), using a national panel study of chronic disease. Health Qual Life Outcomes.

2004;2:12-13.

10. Brod M, Skovlund SE, Wittrup-Jensen KU. Measuring the impact of diabetes through patient report of treatment satisfaction, productivity and symptom experience. Qual Life Res. 2006;15:481-491.

11. Funnell MM. Overcoming barriers to the initiation of insulin therapy. Clin Diabetes. 2007;25:36-38.

12. Siddiqui NI, Rahman S, Nessa A. Development of insulin delivery systems.

Mymensingh Med J. 2008;17:102-110.

13. Korytkowski M, Niskanen L, Asakura T. FlexPen: addressing issues of confidence and convenience in insulin delivery. Clin Ther. 2005;27(suppl B):S89-S100.

14. Davis SN, Renda SM. Psychological insulin resistance: overcoming barriers to starting insulin therapy. Diabetes Educator. 2006;32(suppl 4):146S-152S. 15. Koro CE, Bowlin SJ, Bourgeois N, Fedder DO. Glycemic control from 1988 to

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2000 among U.S. adults diagnosed with type 2 diabetes: a preliminary report. Diabetes Care. 2004;27:17-20.

16. Brod M, Kongsﾃｸ JH, Lessard S, Christensen TL. Psychological insulin resistance: patient beliefs and implications for diabetes management. Qual Life Res. 2009;18:23-32.

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

2006;28:1712-1725.

18. Donnelly LA, Morris AD, Evans JM; DARTS/MEMO Collaboration.

Adherence to insulin and its association with glycaemic control in patients with type 2 diabetes. QJM. 2007;100:345-350.

19. Hauber AB, Johnson FR, Sauriol L, Lescrauwaet B. Risking health to avoid injections: preferences of Canadians with type 2 diabetes. Diabetes Care. 2005;28:2243-2245.

20. Pladevall M, Williams LK, Potts LA, et al. Clinical outcomes and adherence to medications measured by claims data in patients with diabetes. Diabetes Care.

2004;27:2800-2805.

21. Balkrishnan R, Rajagopalan R, Camacho FT, et al. Predictors of medication adherence and associated health care costs in an older population with type 2 diabetes mellitus: a longitudinal cohort study. Clin Ther. 2003;25:2958-2971.

22. Stockl K, Ory C, Vanderplas A, et al. An evaluation of patient preference for an alternative insulin delivery system compared to standard vial and syringe. Curr Med Res Opin. 2007;23:133-146.

23. Gerber RA, Cappelleri JC, Kourides IA, Gelfand RA. Treatment satisfaction with inhaled insulin in patients with type 1 diabetes: a randomized controlled trial.

Diabetes Care. 2001;24:1556-1559.

24. Freemantle N, Blonde L, Duhot D, et al. Availability of inhaled insulin promotes greater perceived acceptance of insulin therapy in patients with type 2 diabetes.

Diabetes Care. 2005;28:427-428.

25. RNCOS. Drug delivery. Insulin delivery systems market analysis (2007-2010).

Summary. www.rncos.com/Report/IM509.htm. Accessed May 1, 2009.

26. Blevins T, Schwartz SL, Bode B, et al. A study assessing an injection port for administration of insulin. Diabetes Spectrum. 2008;21:197-202.

27. Zamudio V. Role of devices in diabetes management. US Endocrine Disease.

2007;1:32-33.

28. Rayman G, Wise PH. An indwelling subcutaneous FEP cannula for intermittent insulin injection: patient experience and effect on diabetic control. Diabet Med. 1988;5:592-595.

29. Weissberg-Benchell J, Antisdel Lomaglio J, Seshadri R. Insulin pump therapy: a meta-analysis. Diabetes Care. 2003;26:1079-1087.

30. Wood JR, Moreland EC, Volkening LK, et al. Durability of insulin pump use in pediatric patients with type 1 diabetes. Diabetes Care. 2006;29:2355-2360.

31. Doyle EA, Weinzimer SA, Steffen AT, et al. A randomized, prospective trial comparing the efficacy of continuous subcutaneous insulin infusion with multiple daily injections using insulin glargine. Diabetes Care. 2004;27:1554-1558.

32. DeVries JH, Snoek FJ, Kostense PJ, et al. A randomized trial of continuous subcutaneous insulin infusion and intensive injection therapy in type 1 diabetes for patients with long-standing poor glycemic control. Diabetes Care. 2002;25:2074-2080.

33. Tsui E, Barnie A, Ross S, et al. Intensive insulin therapy with insulin lispro: a randomized trial of continuous subcutaneous insulin infusion versus multiple daily insulin injection. Diabetes Care. 2001;24:1722-1727.

34. Richardson T, Kerr D. Skin-related complications of insulin therapy: epidemiology and emerging management strategies. Am J Clin Dermatol. 2003;4:661-667.

35. Ulahannan T, Myint NN, Lonnen KF. Making the case for insulin pump therapy. Pract Diabetes Int. 2007;24:252-256.

36. Park EJ, Dodds J, Smith NB. Dose comparison of ultrasonic transdermal insulin delivery to subcutaneous insulin injection. Int J Nanomedicine. 2008;3:335-341.

37. Mandal TK. Inhaled insulin for diabetes mellitus. Am J Health Syst Pharm.

2005;62:1359-1364.

38. Cernea S, Raz I. Noninjectable methods of insulin administration. Drugs Today (Barc). 2006;42:405-424.

39. Qaseem A, Vijan S, Snow V, et al. Clinical Efficacy Assessment Subcommittee of the American College of Physicians. Glycemic control and type 2 diabetes mellitus: the optimal hemoglobin A1c targets. A guidance statement from the American College of Physicians. Ann Intern Med. 2007;147:417-422.

40. Nathan DM, Cleary PA, Backlund JY, et al. Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med. 2005;353:2643-2653.

STAKEHOLDER PERSPECTIVE Diabetes: An Epidemic of Disastrous Proportions PAYERS/PROVIDERS: Diabetes has become an epidemic of disastrous proportions in recent years. The aging and the fattening of Western populations in recent years have been associated with a tremendous amount of insulin resistance, which has led to the development of type 2 diabetes in many of the individuals who have a genetic vulnerability to this disease as a result of limited pancreatic reserve.

The vascular sequelae of diabetes are devastating in their impact upon morbidity and mortality. The microvascular complications include retinopathy, nephropathy, and neuropathy. The macrovascular complications include coronary artery disease, cerebrovascular disease, and peripheral arterial disease.

Although patients with better control of their blood sugar levels suffer fewer vascular complications, it is extremely difficult to keep blood sugar levels in or near the normal range in a diabetic patient.

A very wide variety of factors can affect blood sugar levels, including diet, activity, and both physical and emotional stress. Even the most conscientious patients

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with diabetes experience an ongoing and very frustrating struggle to keep their blood sugar levels under control. Therefore, it is critical that there be as many options as possible available for the administration of the single most critical pharmaceutical agent in the treatment of diabetes窶馬amely, insulin.

Diabetes is a state in which inadequate insulin effect manifests itself because of a severe deficiency of insulin secretion in the patient with type 1 diabetes, and because of a combination of inadequate insulin secretory reserve and the significant insulin resistance in the patient with type 2 diabetes. Therefore, the current update, by Dr Akhrass and colleagues, of the several delivery methods for insulin is very timely indeed.

March/April 2010

James V. Felicetta, MD Chairman, Department of Medicine Chief, Medicine Service Endocrinology and Metabolism Fellowship Carl T. Hayden Veteran Affairs Medical Center, Phoenix, AZ

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Demonstrating the Value of Innovation At Genentech, we continue to research new and better ways to identify appropriate patients.

We develop innovative therapies with established product effectiveness that meet significant unmet medical needs.

And we measure our success by making a difference in patientsâ&#x20AC;&#x2122; lives.

Visit us at booth1101 during AMCP in San Diego, CA

Š2010 Genetech USA, Inc., So. San Francisco, CA 1023800 02/10

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Healthcare Costs Associated with Switching from Brand to Generic Levothyroxine Michael Katz, PharmD; Joseph Scherger, MD, MPH; Scott Conard, MD; Leslie Montejano, CCRP; Stella Chang, MPH Background: Controversy exists over the true therapeutic equivalence of branded and generic levothyroxine—the drug of choice for treating hypothyroidism—so professional societies recommend against switching between different formulations of the drug and suggest that patients who do switch be monitored. Payers typically encourage switching to generic drugs because of lower drug acquisition costs.

Objective: To evaluate the impact of switching levothyroxine formulations on actual healthcare costs.

Methods: Patients with hypothyroidism and at least 6 months of branded levothyroxine therapy were identified from a large healthcare claims database. Patients who subsequently switched to another levothyroxine formulation and could be followed for 6 months postswitch were matched to demographically similar patients who were continuous users of branded levothyroxine. Pre- and postswitch healthcare costs for each group were compared.

Results: The savings in prescription drug costs after switching from branded to generic levothyroxine are offset by increases in costs for other healthcare services, such that switching is actually associated with an increase, not a decrease, in total healthcare costs.

Conclusion: In the absence of cost-savings, there is no clear rationale for switching patients from brand to generic levothyroxine. [AHDB. 2010;3(2):127-134.]

T

he prevalence of hypothyroidism in the United States is estimated at 4% to 10%, including undiagnosed cases.1,2 Higher rates have been found in women and the elderly.1,2 The most common causes of hypothyroidism are autoimmune thyroid disease and surgical or radioiodine ablation; only a small percentage of cases result from secondary causes.3,4 Levothyroxine is the drug of choice for treating hypothyroidism.3-6 It is available in branded and in generic forms. The US Food and Drug Administration (FDA) considers generic formulations meeting bioequivalence standards to be therapeutically equivalent to the specific brand-name drug used as a reference comparator.

Such drugs, designated by the FDA as “AB-rated,” meet the FDA’s standards for bioequivalence and can

Dr Katz is Clinical Associate Professor, Department of Pharmacy Practice and Science, College of Pharmacy, Tucson, AZ. Dr Scherger is Clinical Professor of Family Medicine, Department of Family and Preventive Medicine, University of California-San Diego, CA. Dr Conard is Chief Medical Officer, MedicalEdge Healthcare Group, Dallas, TX. Ms Montejano is Researcher and Ms Chang is Director at Thomson Reuters, Washington, DC.

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be substituted for a brand-name levothyroxine with the same rating. Controversy exists, however, over the ability of the FDA’s standard bioequivalence testing methodology to identify small differences in bioequivalence that may have clinical significance. This methodology, using single-dose pharmacokinetic data in healthy volunteers, may be relatively insensitive when comparing drugs with a narrow therapeutic index, or drugs that are endogenous substances.7-10 The American Association of Clinical Endocrinologists, The Endocrine Society, and the American Thyroid Association issued a joint position statement summarizing concerns about the sensitivity of the FDA’s methodology for determining levothyroxine bioequivalence, pointing out the potential clinical importance of bioequivalence differences in levothyroxine agents, given the drug’s narrow therapeutic index.7 They recommend that for any given patient, levothyroxine formulation should not be switched, regardless of whether the change is to a branded drug or a generic. If a switch occurs, thyroid-stimulating hormone laboratory values should be monitored postswitch to ensure that levels remain consistent with appropriate treatment.3,4,7

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KEY POINTS u u u

u

u

u

The true therapeutic equivalence of branded and generic levothyroxine is still being debated.

Payers typically encourage switching to generic drugs, as a cost-saving mechanism.

Using a large healthcare claims database, this study investigated whether switching from brand to generic levothyroxine does indeed save costs to patients and payers.

Results show that the savings in drug costs from switching to generic levothyroxine are often offset by increased costs for related healthcare services.

Switching from brand to generic levothyroxine appears to be associated with an increase in total healthcare costs.

These results raise a question regarding the economic and clinical benefits of switching patients to generic levothyroxine.

In general, payers encourage switching patients from brand-name to generic drugs because of the lower drug acquisition costs of generics.11 However, the cost impact of a levothyroxine brand-to-generic switch has not been quantified. If reductions in levothyroxine drug acquisition costs are offset by increased costs for additional monitoring or by adverse clinical outcomes, the net effect may be zero cost-savings or even a cost increase.12 The present study was undertaken to evaluate the impact of levothyroxine brand-to-generic switching on healthcare costs. Although of primary importance to payers, healthcare costs are increasingly important to patients, who typically bear a portion of the costs,13 as well as to providers, who may be under pressure to minimize costs.14

Methods Sample Selection The study sample was selected from the Integrated Healthcare Information Services National Managed Care Benchmark Database (IHCIS; Waltham, MA).

This database includes the medical claims history for approximately 25 million lives covered under more than 30 different managed care health plans throughout the United States. Claims are de-identified, so the use of the database for research purposes complies with HIPAA requirements and does not require institutional review board oversight. The data extract provided by IHCIS for use in conducting this study contained the complete claims history of all patients in the database with at least 1 pharmacy claim for levothyroxine

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(brand or generic) with a date of service between January 1, 2001, and June 30, 2005.

Patients with at least 6 months of branded levothyroxine (Levoxyl, Levothroid, Synthroid, or Unithroid) therapy at a constant daily dose were considered for study inclusion. Patients were stratified into continuous users and switchers. Patients who remained using the same brand of levothyroxine during their entire claims history were termed “continuous users.” Those with claims for another brand of levothyroxine or for a generic levothyroxine preparation after at least 6 months of branded therapy were called “switchers.” Switchers were further divided into those who switched to another branded levothyroxine drug, those who switched to a generic, and those with multiple switches (brand or generic).

Study inclusion required at least 1 claim carrying a hypothyroidism diagnosis (congenital hypothyroidism, International Statistical Classification of Diseases, Ninth Revision [ICD-9] code 243.XX, or acquired hypothyroidism, ICD-9 code 244.XX) sometime during the available claims history. Diagnosis was not restricted to a particular service setting, allowing both inpatient and outpatient claims to be used to select patients.

Several exclusion criteria were applied to help ensure a homogeneous sample. Patients with claims indicative of thyroid cancer (ICD-9 code 193.XX) were excluded, as were patients with drug claims for liothyronine (LT3) or an LT3-levothyroxine combination drug, because they did not represent the typical patient with hypothyroidism. The multiple-switch group was screened to exclude patients who were quick switchers, defined as having a second switch within 14 days of the first switch. Finally, patients without mental health benefits were excluded, because their available claims may not represent their complete utilization.

Index dates were assigned to both continuous users and switchers. For switchers, the index date was the date of the first prescription claim for a levothyroxine drug other than the branded drug used during the 6 months of continuous therapy required for patient selection.

Switchers without at least 6 months of stable-dose levothyroxine therapy postindex were dropped. For continuous users, index dates were assigned during the matching process, such that the distribution of index dates by quarter and year would be similar for each matched group. Any date on which the patient had a levothyroxine drug claim was eligible for assignment as the index date, provided there were at least 6 months of stable-dose continuous use of the drug before and after the index date. The study period for all patients included a 6-month preperiod and a 6-month postperiod.

Matched groups of continuous users and switchers were created using propensity score analysis, a match-

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ing technique commonly used in retrospective claims data analyses to approximate random assignment.15 Using logistic regression, the probability (propensity score) that an individual patient would be included in the continuous-user group or a switch subgroup, given patient sex, age, census division, health plan type, levothyroxine dose, and index drug (Levoxyl, Levothroid, Synthroid, or Unithroid) was calculated.

Switchers were then matched 1 to 1 to continuous users based on their propensity score. Switchers who could not be closely matched to a continuous user were dropped from the sample.

Data Analysis A patient-level analytic file was created for the matched patients, consisting of all variables necessary to support the analyses. Variables were tabulated and compared using chi-square and t-tests to assess for differences between cohorts.

Demographic variables created as of the index date included age in years, age-group, and sex. The database also included patient geographic area at the level of census division (eg, the Northeast census region is comprised of the New England and Middle Atlantic divisions).

Insurance plan type (eg, HMO, PPO) and payer type (commercial, Medicare, or Medicaid) also were available.

The mean daily dose of levothyroxine was calculated from the tablet strength, quantity dispensed, and days supply information on drug claims. For multiple switchers, the number of switches in the postperiod was determined. The Charlson Comorbidity Index (CCI)16 was used as a global measure of comorbidity. This measure assigns a weight to each of 19 conditions identified from diagnoses on healthcare claims in the preperiod, based on their relative burden. Higher scores indicate a greater burden of comorbid illness. The presence of 8 comorbiditiesâ&#x20AC;&#x201D;depression, hyperlipidemia, atherosclerosis, angina, hypertension, myocardial infarction, stroke, and arrhythmiaâ&#x20AC;&#x201D;was also assessed, based on the relevant diagnosis codes in the pre-index claims data.

Utilization and expenditure variables were created separately for the pre- and postperiods. The percentage of continuous users and switchers with utilization of specific service types was calculated. Service types included inpatient admissions, emergency department visits, outpatient visits, outpatient laboratories, and outpatient prescriptions. Expenditures associated with each type of service were tallied from the actual amount reimbursed by the insurer after subtraction of any patient costsharing. Mean expenditures were calculated using all patients in the cohort as the denominator. All dollar figures were adjusted to 2005 dollars using the medical component of the Consumer Price Index.

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Utilization and expenditures specific to hypothyroidism also were tallied separately to determine if hypothyroidism was a driver of total costs. Inpatient and outpatient services with a primary (first) diagnosis of hypothyroidism (ICD-9 code 243.XX or 244.XX) and prescription drug claims for levothyroxine were considered hypothyroidism-specific services.

The primary outcome of interest was postswitch expenditures. Since postindex healthcare expenditures could be affected by patient-specific factors other than a levothyroxine switch, some of which were not controlled for in the matching (eg, comorbidities), the difference between pre- and postexpenditures was calculated. The significance of the difference in mean pre/post change was then assessed using t-tests. A value of P <.05 was considered evidence of a significant difference.

Results A total of 97,670 continuous users, 10,367 brand-tobrand switchers, 21,901 brand-to-generic switchers, and 6193 multiple switchers met all study inclusion and exclusion criteria. Subsequent to matching drug users, 7195 brand-to-brand switchers, 6824 brand-to-generic switchers, 5344 multiple switchers, and an equal number of corresponding continuous users for each switch subgroup remained. These matched switcher-continuous user pairs comprised the final study population included in this analysis (see the Appendix online at www.AHDBonline.com/Appendix_Katz).

The branded levothyroxine drug used in the preperiod was either Levoxyl or Synthroid for about 90% of the sample across all cohorts. The mean daily dose of levothyroxine was approximately 0.1 mg (100 Âľg), regardless of the cohort. Although levothyroxine dosing is individualized and can vary between patients, this dose is consistent with the recommended dosing range of the drug.3-6 Multiple switchers had 2.1 switches in the 6-month postperiod on average (range, 2-12).

The distribution of index dates within each matched group was similar since index dates were assigned to continuous users as part of the matching process. One half of the patients in the brand-to-brand switch group had an index date between mid-2001 and mid-2002. In the brand-to-generic switch group, however, most index dates were in 2003 and 2004. This was expected, considering that the release of the first generic drug occurred in mid-2002. In the multiple-switch group, where nearly three fourths of all first switches were to a generic drug, the index dates also fell primarily in 2003 and 2004.

Across all cohorts, the most common hypothyroidism diagnosis was ICD-9 code 244.9 or hypothyroidism not otherwise specified. Depending on the cohort, between 92% and 93% of patients in the sample had that diag-

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Table 1 Characteristics of Study Population

Mean age (SD)

Matched group Continuous Brand-brand users switchers (n = 7195) (n = 7195)

Matched group Continuous Brand-generic users switchers (n = 6824) (n = 6824)

Matched group Continuous Multiple users switchers (n = 5344) (n = 5344)

52.9 (13.3)

53.7 (13.4)

52.4 (13.3)

52.6 (13.7)

52.5 (12.8)

51.5 (13.3)

Patients in each group, % Age-group, y 0-17 18-34 35-44 45-54 55-64 â&#x2030;Ľ65 Sex Male Female Census regiona Northeast South Midwest West Other/missing Insurance plan HMO Indemnity POS PPO Other/missing Payer Commercial Medicare Medicaid Comorbiditiesb Depression Hyperlipidemia Arteriosclerosis Angina Hypertension Heart attack Stroke Arrhythmia

1.1 7.8 16.9 26.6 31.4 16.3

0.7 7.7 17.9 28.9 29.9 14.9

1.2 6.1 15.6 27.7 31.1 18.3

1.2 8.6 18.3 29.6 29.5 13.3

1.1 7.7 17.5 28.7 29.6 15.3

1.1 8.0 17.0 29.2 28.1 16.6

16.7 83.3

17.3 82.7

18.7 81.3

18.1 81.9

15.1 84.9

15.4 84.6

66.3 10.6 8.5 6.6 8.0

66.4 10.8 7.9 6.4 8.5

66.3 6.1 9.0 11.6 7.1

62.9 10.5 10.7 8.5 7.4

66.3 7.7 9.7 9.1 7.2

65.1 8.0 9.1 10.2 7.7

46.8 5.2 10.2 34.3 3.4

47.7 4.8 9.8 34.3 3.5

32.8 4.1 10.4 45.6 7.1

27.2 2.2 5.3 63.1 2.2

40.8 4.3 10.4 39.0 5.5

40.3 4.9 11.0 37.5 6.4

89.7 7.3 2.9

90.6 6.2 3.2

89.3 4.7 5.9

94.3 3.9 1.8

89.7 5.4 4.8

88.7 5.9 5.4

7.4 23.5 4.3 0.9 22.8 0.4 1.7 4.0

8.0 24.7 4.7 1.0 25.3 0.5 1.7 3.7

7.2 26.6 4.7 0.9 25.0 0.4 2.1 4.4

7.4 27.1 4.6 1.1 25.4 0.2 1.4 3.8

7.5 24.4 3.4 0.7 23.2 0.3 1.7 3.9

7.7 23.1 4.4 1.0 24.9 0.6 1.7 4.1

SD indicates standard deviation. a Each census region contains 2 to 3 census divisions, which was the unit used in matching. b Measured in the 6 months preindex.

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Table 2 Overall and Hypothyroidism-Related Healthcare Utilization Matched group Continuous Brand-brand users switchers (n = 7195) (n = 7195)

Matched group Continuous Brand-generic users switchers (n = 6824) (n = 6824)

Matched group Continuous Multiple users switchers (n = 5344) (n = 5344)

Pre

Pre

Pre

Post

Pre

Post

Post

Pre

Post

Post

Pre

Post

PROPORTION OF PATIENTS WITH ANY UTILIZATIONa

Overall Outpatient visits Prescription claims Inpatient admissions Emergency department visits Hypothyroidismb Outpatient visits Inpatient admissions Emergency department visits

93.9 100.0 4.4

93.7 100.0 5.4

95.4 100.0 5.4

93.0 100.0 5.0

95.4 100.0 4.0

94.0 100.0 4.2

93.8 100.0 4.4

93.5 100.0 4.8

94.8 100.0 3.7

94.2 100.0 4.8

93.9 100.0 5.7

95.9 100.0 5.6

10.8

10.3

10.4

10.2

11.0

10.1

9.4

9.6

10.7

10.7

11.5

11.7

55.5 —

50.2 <0.1

53.4 —

45.8 <0.1

58.1 —

51.6 <0.1

48.7 —

46.9 —

58.5 —

51.3 <0.1

49.1 —

58.9 <0.1

<0.1

—

—

—

—

<0.1

<0.1

—

—

<0.1

—

<0.1

MEAN NUMBER OF SERVICES AMONG PATIENTS WITH ANY UTILIZATION

Overall Outpatient visits Prescription claims

8.0 16.9

8.1 16.3

8.0 15.1

8.2 16.8

8.5 17.2

8.2 16.6

7.6 14.0

7.7 15.5

8.3 16.8

8.2 16.2

8.4 15.2

9.3 17.6

Hypothyroidismb Outpatient visits

1.5

1.3

1.4

1.5

1.5

1.3

1.3

1.4

1.5

1.4

1.4

1.5

a Numbers b

represent the percentage of patients in each cohort with ≥1 claim for each service listed.

Primary diagnosis on claim is hypothyroidism (International Statistical Classification of Diseases, Ninth Revision, code 243 or 244.X).

nosis. Except for less than 1% of the sample with congenital hypothyroidism (ICD-9 code 243), the rest of the sample was coded as having postsurgical, postablative, or some other form of acquired hypothyroidism (ICD-9 code 244.0-244.8).

The demographic characteristics of the study population, by matched cohort, are presented in Table 1.

Because switchers were propensity score matched to continuous users on these characteristics, few differences were seen within each matched group. Patients were predominantly female. Approximately 75% were aged ≥45 years.

These sample characteristics conform to findings from other research showing that more women than men have hypothyroidism, and that the prevalence of the condition increases with age.1,2 The majority of the sample resided in the Northeast census region and had health insurance coverage from HMO or PPO commercial payers, factors consistent with the overall distribution of patients in the IHCIS database.

A low level of comorbidity was evident in all cohorts, as measured by preindex CCI scores in the 0.5

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to 0.6 range. Although patients were not matched on preindex date comorbidities, the proportion of patients with each specific comorbidity assessed in the preperiod was similar. The most common comorbidities across all cohorts were hyperlipidemia and hypertension, each occurring in approximately 25% of the patients. Claims indicative of depression were present for 7% to 10% of patients, depending on the cohort.

Atherosclerosis, angina, myocardial infarction, stroke, and arrhythmia were seen in ≤5% of patients.

Drug Utilization All patients in the sample had prescription drug utilization as a result of the study inclusion requirement for levothyroxine therapy. The mean number of prescription drug claims (any medication) in the 6-month preperiod was between 14 and 17, depending on the cohort. The mean number of drug claims per patient increased postindex among switchers and declined slightly among continuous users (Table 2).

The majority of continuous users and switchers had claims for outpatient office visits (>90% all patients, all

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Figure Total Healthcare Expenditures, by Service Type Continuous users Pre

$1760

Post

$996

$1897

Brand-brand switchers Pre

$1807

Post

$1853

Continuous users Pre

$1880

Post

$1004 $888

$357

$1038

$1715

Total $3238

Total $3052 Total $3243

$361

$1054

$329

Total $3263 Total $3124a

$300

$953

$316

Total $2984

Post

$1778

$1034

$338

Total $3150a

Continuous users Pre

$1814

$1012

$297

Total $3123

Post

$1847

$1009

$312

Total $3168a

Multiple switchers Pre

$1854

$879

Post

$2066 $0

$1000

$363 $1017

$2000

Outpatient visits Prescription Inpatient/emergency department/laboratory

Total $3051

$337

$1029

$1786

Brand-generic switchers Pre

$295

Total $3096a $373

$3000

Total $3456 $4000

a

Pre/post increases in expenditures significantly greater for switchers compared with continuous users.

time periods). Approximately 50% of all patients had a hypothyroidism-specific outpatient visit. The proportion of patients with such a visit increased postindex for multiple switchers but decreased for other cohorts.

The mean number of outpatient visits per 6-month period was around 8, although only 1 to 2 of those visits, on average, carried a primary diagnosis of hypothyroidism. More visits were with endocrinologists or other specialists than with primary care providers.

The percentage of patients with emergency department visits (about 10%) was much smaller than the percentage of outpatient office visits and was similar across all patient groups for all time periods. This was also the case with inpatient admissions; approximately 4% to 6% of patients were hospitalized. Few patients received hypothyroidism-specific inpatient or emergency department care. Not surprising, the primary

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driver of expenditures across all cohorts was outpatient visits, followed by prescription drugs. Inpatient and emergency department services added comparatively little to total expenditures. The Figure describes overall expenditures by treatment setting.

Overall Expenditures Among the brand-brand switchers and their matched continuous users, the mean increases in total overall expenditures from the pre- to postperiods were $190 and $187, respectively. This pre/post increase in expenditures did not differ significantly by cohort (P = .969).

Comparing the pre/post difference in expenditures for the other matched groups, however, revealed that switchers had a significant increase in expenditures postindex compared with continuous users. The pre/post increase in expenditures for the brand-generic switchers

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was $165, whereas matched continuous users’ expenditures decreased $138 on average (P = .001). The increases for multiple switchers and matched continuous users were $360 and $44, respectively (P = .004).

Although hypothyroidism-specific expenditures comprised less than 5% of total expenditures, the focus of this study on patients being treated with levothyroxine for hypothyroidism warranted examination of pre/post changes in these expenditures. Each of the continuoususer groups had slightly lower hypothyroidism-specific expenditures in the postperiod compared with the preperiod, with decreases of $20, $24, and $24 for the continuous users matched to the brand-brand, brand-generic, and multiple switchers, respectively.

Expenditures increased in the postperiod for 2 of the 3 switch subgroups—$14 in the brand-brand switchers, and $42 in the multiple switchers. Hypothyroidismspecific expenditures in the brand-generic switch subgroup decreased by $5. This difference was almost entirely attributable to lower prescription expenditures. All pre-post period hypothyroidism-specific cost differences for switchers compared with the differences for their respective continuous users were significant (P <.001).

Discussion The results of this study do not demonstrate a costsavings for patients who switch among levothyroxine drugs, raising the question whether substitution of generic for branded formulations is an effective costmanagement approach for these patients. Most notably, although mean hypothyroidism-specific expenditures in the brand-generic switchers did decrease a small amount ($5) subsequent to the switch, overall total costs actually increased by $165. In contrast, matched continuous users had an overall cost decrease during their pre-post period of stable-dose branded treatment.

Of the 3 switch subgroups, multiple switchers demonstrated the greatest increase in postperiod versus preperiod hypothyroidism-specific and overall total expenditures. These switchers may be at the highest risk for adverse outcomes and increased expenditures, given the narrow therapeutic index of levothyroxine and the recommendations for monitoring after a switch.

The increase in patients with hypothyroidism-specific outpatient visits postindex among multiple switchers was notable, although it was not possible to ascertain from the claims if the increase was a result of monitoring, difficult-to-control hypothyroidism, or switch-related adverse clinical consequences.

Limitations These results should be interpreted in light of the usual caveats surrounding the use of claims data.

Although it is assumed that diagnosis codes listed on claims are correct, it is possible that some patients or services were misclassified as a result of coding errors.

In addition, hypothyroidism-specific services may have been undercounted, because classification was based on the primary diagnosis listed on each claim, and hypothyroidism diagnoses that occur on inpatient and emergency department claims may be in a secondary diagnosis field.

The results of this study are based on claims from a specific database and may not be generalizable to other populations. The study sample, however, did conform to expectations in terms of age,1,2 sex,1,2 and hypothyroidism diagnosis.3,4 Furthermore, this study did not adjust for all potential confounding variables. Although specific characteristics were used in the propensity score matching, these characteristics were not all-inclusive, and the distribution of other variables that may have had an impact on study outcomes may be dissimilar between the switch and continuous-user matched groups.

It was not possible to measure hypothyroidism severity from the claims, therefore cohorts were not matched on this characteristic. If difficult-to-manage hypothyroidism patients are more likely to switch levothyroxine preparations, this subgroup may be overrepresented in the switcher groups.

The claims of switchers were not assessed to determine if their switch was to a levothyroxine drug that has AB-rated bioequivalence to their index-branded drug. Although it is assumed that the majority of brand-generic switches involved the substitution of an AB-rated drug for a branded drug as an attempted costsaving measure, it is possible that some switches were the result of an intentional therapy change in a difficult-to-manage patient.

Finally, some levothyroxine preparations were undergoing changes in the first half of 2001. Because the study period of some patients in the brand-brand and matched continuous-user groups included data from early 2001, a small number of patients who appeared to be receiving stable therapy might have experienced a change in their levothyroxine.

Conclusion In the absence of cost-savings, and given the concerns regarding therapeutic equivalence that have been documented, there is no clear rationale for switching patients from brand to generic levothyroxine drugs. Further research is needed to better understand the factors driving increases in utilization postswitch and the clinical implications of changing levothyroxine formulations. ■ Continued

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Acknowledgments Financial support for this research was provided by Abbott Laboratories. The sponsor contributed to the study concept, but the analyses were conducted by independent researchers at Thomson Reuters. The authors acknowledge Rich Bizier, Zhun Cao, Katy Pan, and Lerissa Smith for their contributions to the data interpretation and manuscript preparation. The authors give a special thanks to Dr James Hennessey for his thorough and critical review of the manuscript.

Disclosure Statement Drs Conard, Katz, and Scherger are Consultants to Abbott Laboratories, and Dr Scherger also serves on the Speaker’s Bureau of Merck. Ms Chang and Ms Montejano have nothing to disclose.

References 1. Canaris GJ, Manowitz NR, Mayor G, Ridgway C. The Colorado thyroid disease prevalence study. Arch Intern Med. 2000;160:526-534.

2. Hallowell JG, Staehling NW, Flanders WD, et al. Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab. 2002;87:489-499.

3. Garber JR, Hennessey JV, Liebermann JA 3rd, et al. Clinical update. Managing the challenges of hypothyroidism. J Fam Pract. 2006;55:S1-S8.

4. Woeber KA. Update on the management of hyperthyroidism and hypothyroidism.

Arch Intern Med. 2000;160:1067-1071.

5. Baskin HJ, Cobin RH, Duick DS, et al. American Association of Clinical Endocrinologists Thyroid Task Force. American Association of Clinical Endocrinologists medical guidelines for the clinical practice for the evaluation and treatment of hyperthyroidism and hypothyroidism. Endocr Pract. 2002;8:457-469.

6. Singer PA, Cooper DS, Levy EG, et al. Treatment guidelines for patients with hyperthyroidism and hypothyroidism. Standards of Care Committee, American Thyroid Association. JAMA. 1995;273:808-812.

7. American Association of Clinical Endocrinologists, The Endocrine Society, American Thyroid Association. AACE, TES, and ATA Joint Position Statement on the Use and Interchangeability of Thyroxine Products. American Association of Clinical Endocrinologists website, December 8, 2004. www.aace.com/pub/pdf/ guidelines/AACE-TES-ATA-ThyroxineProducts.pdf. Accessed January 12, 2008.

8. Bolton S. Bioequivalence studies for levothyroxine. AAPS J. 2005;7:E47-E53.

9. Green WL. New questions regarding bioequivalence of levothyroxine preparations: a clinician’s response. AAPS J. 2005;7:E54-E58.

10. Hennessey JV. Levothyroxine dosage and the limitations of current bioequivalence standards. Nat Clin Pract Endocrinol Metab. 2006;2:474-475.

11. Lamb E. Payers pushing generic drugs to curb costs. Pharmacy Times. 2008;April Suppl:10-11.

12. Safer JD, Hennessey JV, Braverman LE. Substituting brand name levothyroxine preparations with generics would increase treatment costs [Letter]. Annals Online. July 21, 2005. www.annals.org/content/142/11/891.abstract/reply. Accessed March 1, 2010.

13. Gibson TB, Ozminkowski RJ, Goetzel RZ. The effects of prescription drug cost sharing: a review of the evidence. Am J Manag Care. 2005;11:730-740.

14. Bodenheimer T, Fernandez A. High and rising health care costs. Part 4: can costs be controlled while preserving quality? Ann Intern Med. 2005;143:26-31.

15. Baser O. Too much ado about propensity score models? Comparing methods of propensity score matching. Value Health. 2006;9:377-385.

16. D’Hoore W, Bouckaert A, Tilquin C. Practical considerations on the use of the Charlson comorbidity index with administrative data bases. J Clin Epidemiol.

1996;49:1429-1433.

STAKEHOLDER PERSPECTIVE Payers’ Approaches to Generic versus Brand-Name Medications PAYERS: Employers, plan sponsors, and other healthcare payers generally consider the therapeutic efficacy of brand and generic medications to be very similar. This has been demonstrated throughout the years in a variety of ways and is supported by the very fact that generic medications receive approval from the US Food and Drug Administration for marketing those products in the United States.

It is also generally accepted by payers that in some rare cases, the brand and generic versions of specific medications may not be interchangeable for some patients, for different reasons. In such cases, including the case of generic levothyroxin, as suggested in the article by Katz and colleagues, it is expected that healthcare payers will behave as they have done historically and choose one of the following common approaches: • Current utilizers can be “grandfathered” to continue to receive the current brand drug if this is medically necessary (a common benefit provision) • All new patients using this therapy could be required to begin therapy with the generic agent, and if therapy fails because of the use of the generic medication, the patient will then be allowed to use the

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brand medication (normally at a higher cost-sharing) • All patients will have to at least try to use the generic; if a treatment failure occurs, the patient can then receive the brand-name medication at the higher cost-sharing level.

PATIENTS: Plan sponsors encourage the use of generic medications for patients as a cost-savings strategy for all involved stakeholders, including patients and payers, as well as the facilitation of a consistent message to their covered populations. To alter this benefit parameter and the message of cost-savings with generics because of 1 therapeutic class would be counterproductive and potentially confusing to patients.

No healthcare payer wants patients to be denied needed medication or therapy, which is the reason why override provisions are included in a prescription drug plan benefit design. This is but one example where the system can and should work to provide the therapy that patients need at a reasonable cost.

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Michael S. Jacobs, RPh National Clinical Practice Leader Buck Consultants Atlanta, GA

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Pay-for-Performance Initiatives: Modest Benefits for Improving Healthcare Quality Amit Sura, MD, MBA; Nirav R. Shah, MD, MPH Background: Pay-for-performance initiatives have been suggested as a way to improve the quality of patient care and provide incentives to improve providers’ performance. The Centers for Medicare & Medicaid Services has endorsed such programs to improve quality of care.

Objective: To examine the state of quality initiatives endorsed by the Centers for Medicare & Medicaid Services in which institutions, provider groups, and physicians are awarded incentives based on adherence to composite metrics.

Method: A literature search was conducted using the keywords “pay-for-performance,” “quality improvement,” “medical errors,” and “physician incentive plans.”

Results: Although quality of care has improved in healthcare settings that engage in payfor-performance initiatives, what can be attributed to payer-incentive programs is uncertain.

Studies demonstrate that, of the 25 hospitals classified by the Centers for Medicare & Medicaid Services to be in the lowest decile of quality improvements, all still made significant progress in adhering to quality metrics after participation in the study. Financial rewards, however, were distributed based on a predetermined threshold established by the Centers for Medicare & Medicaid Services to be given only to participants who fell in the top 2 deciles. Penalties were incurred by the 51 hospitals that were within the bottom 2 deciles despite making substantial improvements. At such institutions, large minority communities and Medicaid populations comprise the patient populations. Other pay-for-performance schemes, such as employer-based purchasing, consumer health-spending accounts, and collaborative groups, were studied, with little data to support definite benefits.

Conclusions: Examining rates of improvement in adherence to pay-for-performance initiatives when determining how to distribute financial rewards should be studied alongside the current classification by absolute deciles. By rewarding rates of improvement, potential elimination of quality disparities for hospitals that serve large Medicaid and minority populations can be achieved, because such organizations are encouraged to invest in quality improvement as a result of substantial progress made. Although alternative strategies like employer-driven value-based purchasing and collaboratives seem promising, the long-term effects of such initiatives still need to be studied. Creating greater financial incentives for individual providers to participate in pay-for-performance programs for many years to come will remain a challenge. [AHDB. 2010;3(2):135-142.]

O

n March 1, 2001, the Institute of Medicine (IOM) released its report, “Crossing the Quality Chasm: A New Health System for the 21st Century,” in response to alarming rates of medical errors that led to thousands of unnecessary deaths. The report called for changes within information technology (IT), payment policies, and the medical workforce. By stressing a “new paradigm for healthcare delivery,” the IOM identi-

Dr Sura is a Resident in Diagnostic Radiology, St. Luke’sRoosevelt Hospital Center, New York, NY. Dr Shah is Assistant Professor of Medicine, NYU School of Medicine, and Associate Investigator, Geisinger Health System.

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fied 15 medical conditions for which improvements could be made to improve the delivery of patient care.1 By examining publicly available medical records, a seminal study found that, on average, Americans received only 50% of recommended care for acute and chronic conditions.2 Simple tasks like providing smoking-cessation counseling had only an 18.3% level of adherence. Dismal performance in diabetes management resulted in US providers achieving <25% the success of the UK’s National Health Service (NHS) in reducing microvascular complications.2 The Centers for Medicare & Medicaid Services (CMS) was called upon to quickly improve quality of care in the United States.

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KEY POINTS u

u

u

u u

u

In 2003, CMS established P4P initiatives to strengthen quality measures, improve patient outcomes, and maintain physician accountability.

Such P4P programs offer incentives to hospitals, provider groups, and physicians based on adherence to specific composite metrics.

This study raises the possibility that the quality composite scores promoted by CMS with P4P programs may also be in need of improvement.

When treating minorities, providers are less likely to use the latest evidence-based guidance.

For quality efforts to motivate doctors, it is becoming increasingly apparent that incentive programs have to represent a considerable fraction of their income.

New P4P initiatives aim at creating market competition by establishing high and low performers. Others use collaborative practice groups to influence care.

This present study was undertaken to examine the quality initiatives endorsed by CMS in response to this effort. A literature search was conducted using the keywords “pay-for-performance,” “quality improvement,” “medical errors,” and “physician incentive plans.”

CMS Establishes P4P Initiatives Responding to this call and aiming to strengthen quality measures, improve patient outcomes, and maintain physician accountability, CMS established pay-forperformance (P4P) initiatives at the end of 2003. The goals of the project were simple: if various healthcare stakeholders could not only demonstrate higher quality but also publicly report such results, financial incentives would follow. Through various initiatives and demonstrations, such as the Hospital Quality Incentive Demonstration (HQID) and Chronic Care Improvement Program, CMS developed quality metrics that targeted hospital facilities, physician groups, and individual providers to improve practice habits.

The purpose of HQID was to distribute financial rewards to hospitals that demonstrated high-quality performance on 34 quality measures established by CMS across 5 clinical conditions addressing acute care.

After 3 years of using a nationally standardized set of quality measures to evaluate individual hospital performance, composite quality scores were calculated using an aggregate of adherence to all quality measures.

A comparison was then made to a predefined threshold determined at the start of the project. For example, acute myocardial infarction (MI) was 1 of the 5 clinical conditions studied. Nine quality measures were

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intended to be met for any patient who was diagnosed with the condition. From the use of aspirin at arrival to prescribing beta-blockers at discharge, such metrics were closely followed.

Hospitals were then ranked according to their composite quality scores, with the first 10% placed in the top decile.3 Hospitals in the top decile implementing the greatest number of quality measures would receive a 2% bonus at the end of the year. In the third year of the demonstration, hospitals that fell into the last 2 deciles would incur a 1% to 2% cut from their Medicare diagnostic-related grouping payments.3 In the medical community, such metrics can seem obvious when treating each condition individually.

However, they can also quickly define and label a patient with the wrong diagnosis, leading to further tests and medications the patient does not need. For example, patients who have chest pain are often misdiagnosed with having an acute MI, when gastroesophageal reflux or musculoskeletal aches are the actual cause of their pain. Other times, the patient carries diagnoses that can confound the pathophysiology of the conditions, in which particular drugs or processes that CMS holds up to high standards are not indicated. For instance, beta-blockers, although listed as a quality metric to be given on arrival for all patients who present with acute MI, are not indicated in patients who also have a heart rate <60 beats per minute, systolic blood pressure <100 mm Hg, or moderate-to-severe stage C congestive heart failure (CHF).4 Aside from implementing quality measures, CMS established the Medicare Care Management Demonstration, which promoted the adoption of technology such as electronic medical records (EMRs). Bonus payments were awarded to practice groups whose members proceeded with IT implementation and used the EMR to collect data on meeting clinical quality measures.5 Although many practices were convinced that the use of EMRs was applicable to the needs of their practices, the transition to that technology would have to occur slowly.6 With a wide array of products, combined with a fast-paced, dynamic IT market, the uncertainty of how to integrate such software was a resonating theme.6 Indirect and direct costs of implementation, accessibility, and daily use could make it difficult to justify an EMR application when a small practice struggles to simply meet its bottom line.

CMS Hospital Quality Incentive Demonstration In November 2005, after 1 year of implementation of the HQID initiative, CMS conducted an internal review of the composite quality scores for 5 clinical conditions—acute MI, community-acquired pneumonia

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(CAP), CHF, coronary artery bypass grafts, and hip and knee replacements.3 The results demonstrated that improvement was made across all indicators by every participating hospital. From using prophylactic antibiotics before surgery to providing smoking-cessation assistance to patients with CAP, CMS participants boasted an average improvement of 6.6% in 22 of the 34 clinical indicators initially set forth. As had been promised, CMS paid more than $8.85 million in incentives to the highest 20% of performers. Hospitals in the ninth and tenth deciles faced reimbursement penalties for future care provided.3 In analyzing results through June 2007, the 255 hospitals that participated in the HQID project demonstrated a 17.3% increase over 5 years in median composite quality scores, a combination of clinical quality and outcome measures.3 Median appropriate care scores— calculated by determining whether a patient received all possible care measures within a clinical area—also improved over 5 years by an average of 52.6% across all the 5 clinical conditions. When compared with nonparticipating hospitals, hospitals participating in the HQID project achieved 6.5% higher scores for 19 publicly reported quality indicators.3

Results of Independent Studies After CMS completed its internal review, a number of studies tried to recreate these findings. At first glance, many seemed to confirm CMS’s claims. In a study examining the additive benefit of P4P over public reporting of outcomes, hospitals participating in P4P programs not only made greater progress in 7 of the 10 individual performance metrics but also made large strides on all other composite measures of quality.7 Although all baseline scores were higher after 1 year for those enrolled in P4P programs, the rate of improvement varied among those in the 5 quintiles studied.7 Hospitals in the lowest quintile at the start of the study made the largest gains in quality improvement. For instance, P4P-participating hospitals (N = 51) in the fifth and lowest quintiles had a 25.2% increase from an initial dismal 62.6% rate of adherence rate to quality metrics established in patients who presented with heart failure. For the same condition, the 51 hospitals in the first quintile actually dropped 0.1% from their previous adherence rate of 93.7%.7 This trend was true across all 10 composite measures studied. Such “high-performing” hospitals experienced a “ceiling effect” on improvement, arguing that little improvement, if any, was left to be made at the start of the study.7 Achievements made by the lowest quintile or “lowperforming” hospitals, however, were overshadowed by CMS’s method of incentive distribution. CMS rewards

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absolute performance based on what decile a hospital lies in rather than on rates of improvement, so that the 102 participants who remained in the lowest 2 deciles were anticipated to receive a 1% to 2% financial penalty placed on their Medicare payments, despite making 29.2% of the 41.2% of total improvements achieved by all participants during the course of the 2-year study period. For hospitals that were penalized at the end of the study despite achieving success in reorganizing their process flows, many may not see the value of participating in P4P programs over the long-term.7 Another study discredited not just CMS’s classification of low- and high-performing hospitals but the entire CMS initiative, citing a lack of control group for comparisons as a fatal flaw.8 According to this analysis, independent hospitals outside the CMS initiative showed the same rate of improvement for all 9 of CMS’s composite measures for patients admitted with acute MI.8 Simply by adhering to their own quality initiative programs, the American College of Cardiology standards, or the American Heart Association guidelines, independent hospitals demonstrated equivalent gains.

Clinical outcomes (which have not been a focus of the CMS initiative) were also studied in great detail in addition to process measures. Mortality scores of CMSparticipating hospitals were not incrementally greater than that of independent hospitals. P4P had little, if any, incremental impact on a patient’s care or outcome during an acute MI, as measured by 14 process measures closely looked at in the study for patients with established non–ST-segment elevations on electrocardiogram.8 Improvement in quality attributable to P4P was not as significant in the study (1.6% over 3 years8 vs 4.3% unadjusted over 2 years,7 as reported earlier by Lindenauer’s analysis of CMS7), demonstrating the lack of concrete evidence linking P4P programs to better quality of care.8 Whether improvements made at CMS-participating hospitals can be attributed to P4P is debatable, but another question arises. Are the quality composite scores that CMS hopes to improve also in need of improvement? According to some researchers, analyzing the existing process flow and level of adherence to quality indicators for a particular hospital, practice, or department is an important first step before implementing performance metrics.

For example, emergency departments and urgent care clinics nationally have implemented many of CMS’s guidelines for years. Performance metrics—such as treating an acute MI with aspirin or monitoring pulse oximetry in patients with CAP—already have high levels of adherence nationally (94.7% and 99.4%,

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respectively).9 Although the HQID-participating hospitals reported higher scores in adherence to 19 quality indicators compared with nonparticipating hospitals, nonparticipating hospitals may not see a strong need to achieve any incremental benefit if their levels of adherence are already high.

In contrast, Glickman and colleagues argue that focusing on the use of existing research networks, large quality-improvement registries, and further departmental analysis may be more beneficial.9 Understanding the dynamic structures of each department (ie, the use of IT, incentive structures, culture, treatment algorithms, patient waiting times, and treatment durations) can potentially garner greater success in developing a framework centered on composite measures that follow.9 Although some composite measures achieve high levels of compliance nationally, others lack additional detail to aid the physician in improving the patient’s clinical outcome. Merely documenting vital signs and oxygen saturation in the care of patients with CAP, as suggested by CMS, is not considered a higher standard of care if such data are not correlated with, for example, the patient’s ventilator settings or arterial blood gas. Such correlations should be included when drafting the composite metrics that CMS aims to establish.9

Potential Disparities Created by P4P Programs Disparities in medicine over the treatment of multiple conditions have been well documented.10,11 When treating minorities, providers are less likely to use the latest evidence-based trends.12-14 Black Patients Using Medicare data, researchers have examined whether hospital performance varies, after controlling for pertinent variables, as a function of the percentage of black patients the hospital serves.15 In the care of patients with acute MI and CAP, a significant inverse relationship exists between hospitals’ composite performance scores and the percentage of black persons these hospitals treat.

Such hospitals are at increased financial risk for treating blacks under the CMS P4P program.

Although explanations seem vague as to why serving minority communities results in lower performance scores, some investigators have suggested that blacks are served by physicians who have no specialty board certifications and have reduced access to state-of-the-art technology.15 Additional research must be conducted to determine why such a correlation is true. Is it a reflection of the physicians at such hospitals and their respective training, or is it the case complexity of the populations they treat?

Regardless of the reasons, with lower performance

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scores, hospitals that serve larger black populations will find it even more difficult to invest in CMS-suggested process flows that strive to improve performance if CMS classifies them in the lower deciles and penalizes them financially. With poor performance results that are publicly reported, such hospitals will likely blame the minority patients they serve, citing a strong correlation with their performance and case mix, giving rise to administrators seeking healthier, higher socioeconomic patients to serve.

Medicaid Populations Current P4P schemes are not just affecting black populations but all patients covered by Medicaid. Safety-net hospitals that serve a large percentage of Medicaid patients are finding it increasingly difficult to achieve performance metrics enforced by CMS. Of the 4464 hospitals that participated in a recent study, those that treat a higher percentage of Medicaid patients had comparatively worse performance scores and made significantly smaller improvements over time, classifying them as low performers.16 Hospitals caring for fewer Medicaid patients had an average performance gain of 39% and were subsequently classified as top performers. Top-performing hospitals serving a high percentage of Medicaid patients who presented with an acute MI had nearly a 75% decrease in performance from 2004 to 2006. At the same time, top-ranked hospitals serving a low percentage of Medicaid patients for the same composite measure, acute MI, had increased gains between 13.6% and 19.7% in performance. These patterns held true across 3 other P4P conditions for which CMS seeks to make quality improvements.16 With such results, hospitals serving primarily Medicaid patients would fall significantly below the threshold, incurring financial penalties rather than receiving the bonuses necessary to allow these facilities to make infrastructural changes.

Potential Correction It is certain that care for underserved patients concentrates at low-performing hospitals. With revenue margins for such hospitals already in the red, it becomes difficult to shift costs onto payers, while continuing to deliver healthcare. By restructuring CMS’ performance schemes to look at rates of improvement along with absolute numbers, CMS can potentially correct some of the disparities, allowing P4P financial gains to be accrued at such hospitals over time. Also, by adjusting for patient case mix and treatment opportunity mix, CMS might observe moderate changes that affect hospital performance, rankings, and eligibility for P4P financial benefits for those hospitals currently ranked lowest.17

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P4P and Its Use Outside of CMS In an effort to instill quality initiatives among healthcare providers, CMS does not remain alone. Major corporations in multiple industries have joined efforts to improve quality of care.

General Electric, Partners Healthcare, Tufts Health Plan, the Lahey Clinic, and other employers in Massachusetts have developed Bridges to Excellence, a program initiative that rewards physician offices up to $55 per patient annually for quality improvements made in IT, care-coordination systems, and decision support teams. In addition, physicians who are recognized as an American Diabetes Association provider for implementing exceptional diabetic care are paid rewards of up to $100 per patient.

Six California health plans under the collaboration called Integrated Healthcare Association seek to improve standards of care with the use of consolidated physician performance scorecards.18 The Leapfrog Group has also made significant strides in mobilizing employer purchasing power, working with corporations to encourage transparency, as well as to financially reward hospitals that have a demonstrated record of high-quality care.19 Anthem Blue Cross and Blue Shield in New Hampshire launched an incentive program to improve quality in 1999, focusing on rewarding practices for implementing preventive measures, such as cancer screening, well-child examinations, and childhood immunizations. Under this program, physicians who ranked in the top 25% of adherence to metrics relative to other providers within the network received an additional $20 per patient per year. In 2002, physician practices received up to $12,062 in bonuses for practicing higher standards of care in the previous year.18 Yet for quality efforts to motivate doctors, it is becoming increasingly apparent that incentive programs have to represent a considerable fraction of their income. Too many P4P initiatives prevent providers from engaging in such programs; the costs to enact the metrics outweigh the financial merits received from them. For example, under the current Bridges to Excellence program, incentives only cover 1% of the patient’s expenses in a general internist’s office.18 This equates to just more than $1200 of additional revenue for the entire year in a practice with 2300 patients.18 With continued Medicare cuts (5.4% in 2002), physicians may be forced to adopt other practice alternatives, such as increasing patient volume, rather than implementing payment incentives.18 New Strategies to Improve P4P Currently, P4P initiatives are aimed at creating market competition by establishing high and low perform-

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ers. The theory behind the model is to motivate groups to achieve above and beyond the threshold of their fellow competitors. Others, however, have formulated different methods to encourage quality improvement.

Coined “collaborative” practice groups, they try to influence care broadly by bringing community health centers together to learn and disseminate qualityimprovement techniques.20 The following chronology is used: • Come to learn • Implement • Intervene • Share results.

E-mail updates, monthly reports, and continuous feedback are also integral components to such a collaborative effort.

Impressive results have been reported.20 Intervention centers that participated in one such collaborative made significant gains in composite indicators. From prevention to disease management, the participating centers boasted up to a 6.2% higher rate of improvement in adherence to such indicators compared with centers that did not participate.20 One significant limitation to the study’s results, however, was that no significant improvement in outcomes was seen. Positive long-term results from the collaborative are yet to be determined.

Another innovative strategy has been to involve patients directly by allowing consumers of healthcare to examine quality data and make decisions for themselves.

Such a system has been proposed, aligning performance initiatives to that of consumer purchasing power. First, a healthcare spending account is established. The consumer has access to data that examine efficiency and quality among providers and hospitals. Assuming that consumers then make economical choices and are motivated to seek physicians who provide high-quality, lowcost, and efficient care, they are later rewarded with tax breaks for unspent funds that can be used for future unexpected healthcare expenditures.

Problems arise with fixed consumer accounts.

Consumers often like having their healthcare decisions made by others, such as their employers. For employers, wide coverage variability, with different market prices, makes assigning a fixed dollar amount to spending accounts difficult. Creating access to such quality ratings becomes problematic. How much information does one make transparent? Providers have been staunchly opposed, mainly as a result of the high direct costs they face in collecting data, as well as quality measures that are undefined and variable from practice to practice.

Yet some initial studies show that linking financial incentives to individual empowerment based on dis-

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seminated quality of care data has its benefits. In one program, patients and families who selected organ transplant centers on the basis of quality and costs, and were later rewarded financially for doing so, had a high level of measured satisfaction once their surgery was complete.21 Minnesota’s Buyers Health Care Action Group released data to consumers in the market regarding health plans that were low in cost yet high in quality ratings based on satisfaction surveys completed by enrollees. Enrollment increases ranged from 15% to 57% among the top 4 plans once the information was made public.22 In a Merck/Medco-sponsored study conducted in 2001, a more impressing approach was taken, penalizing consumers with a 10% increase in premiums if they did not select lower-cost, yet equally efficacious, medications within similar drug groups.23 Financially incentivizing the consumer worked; by 2005, the company boasted a substantial increase in the use of more costeffective drugs. Each 1% increase in the use of generics yielded an estimated $200 million in savings for the Merck/Medco plan sponsors and members.23 While incentivizing consumers may prove beneficial, pharmaceutical companies still struggle to convert efficacy in clinical trials to effectiveness in clinical practice. For example, although new medications have improved survival in patients who develop heart failure, the improvement in physician use is not as dramatic as drug companies would like to see. Despite clinical trials all concluding that angiotensin-converting enzyme inhibitors, beta-blockers, and aldosterone antagonists have some beneficial role in a patient who has suffered an acute MI, underutilization of these therapies in clinical practice reflects no significant change in epidemiologic data.24

Employers’ Use of Value-Based Purchasing Strategies In 2007, 158 million nonelderly Americans were covered under employer-based health insurance, with employers becoming the leading source of health insurance in the United States. With annual premiums averaging 5% higher than the previous year and 120% higher since 1999 after accounting for inflation, one would think firms would look to sponsor P4P initiatives and value-based plans with the goal of keeping increasing healthcare costs from translating into higher premiums.25 The Leapfrog Group and Bridges to Excellence have led many of the efforts to encourage companies to become active participants in comparing quality when selecting plans. Through the promotion of hospital safety measures profiling as well as providing tools to help employees to make healthcare decisions, such groups have assisted employers in providing greater transparency for

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their employees’ healthcare decision-making.26 Other priorities, however, are of greater concern to executives. Across 41 US markets, firms rank geographic distribution and premium rates as the most important characteristics when choosing health plans 85% of the time.26 Metrics ostensibly reflective of quality of care are given far less weight. Whereas 65% of employers are vigilant of patient satisfaction indicators for health plans, few reported making such information transparent to their employees.26 The use of report cards, bonuses in contractual plans, and premium contribution to encourage employees to choose better plans, are provided to employees making healthcare decisions by firms only 23% of the time.26 Although larger employers are engaging the concept of value-based purchasing more than their smaller counterparts, the concepts of examining IT infrastructure (shown in multiple studies to reduce errors and improve quality of care27,28) with physician and medical group quality data were studied less than 20% of the time among all employers.

Because of a lack of concrete cost-benefit analysis, 65% of employers rarely engage in value-based purchasing primarily. Many small- or medium-sized businesses incorrectly translated higher value to mean higher premiums. Others could not justify spending the additional premiums now on attractive health plans when research regarding the intangible effects on workforce productivity, benefit to cost-savings, and the ability to attract and retain employees is inconclusive.26

Conclusions In 2003, England’s NHS outlined a proposal instituting 76 quality initiatives to aid 10 clinical domains of care. The plan accompanied a substantial increase in payments to providers who adhered to such targets.29 Did CMS and private payers simply try to apply NHS’ quality initiatives to their broken system too hastily? By developing their own P4P initiatives, CMS also sought to address increasing costs and poor performance by linking reimbursement to adherence to standards purported to measure the quality of the healthcare being provided by physicians and hospitals.

Initial studies demonstrated improvement in quality for hospitals participating in the P4P initiative.

However, once comparisons were made to hospitals not participating in the CMS project, results were variable regarding differences in quality composite scores between the 2 groups. Research has shown that small financial gains are simply insufficient as currently provided and are not enough to motivate providers and hospitals to do better. Problems arose with how to distribute payments, as well as whether improvements of some of

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the metrics set forth were needed.

Hospitals categorized as low performing as a result of their current standing in a low decile made improvements but not enough to be classified as top performers, making it difficult to continue to serve their patient and payer mix, especially if the majority of their patients are covered only by Medicaid. By examining rates of improvement, along with absolute categorization in a top decile, distribution of financial incentives can motivate all participating and potentially eliminate disparities.

Other alternatives, such as collaborative, consumerdirected spending accounts, pharmaceutical initiatives, and employer-driven initiatives, have shown some success, but more data are needed. Although P4P programs in some form likely are here to stay, keeping providers invested in closing gaps in disparity, while instituting plans that work, will be challenging.

Disclosure Statement Dr Shah receives unrestricted research grants from AstraZeneca, Merck, Pfizer, and Roche.

References 1. Washburn ER. Fast forward: a blueprint for the future from the Institute of Medicine. Physician Exec. 2001;27:8-14.

2. McGlynn EA, Asch SM, Adams J, et al. The quality of health care delivered to adults in the United States. N Engl J Med. 2003;348:2635-2645.

3. Premier. Centers for Medicare & Medicaid Services (CMS)/Premier Hospital Quality Incentive Demonstration Project. April 13, 2006. http://premierinc.com/ quality-safety/tools-services/p4p/hqi/hqi-whitepaper041306.pdf. Accessed January 14, 2009.

4. Klapholz M. Beta-blocker use for the stages of heart failure. Mayo Clinic Proc. 2009; 84:718-729.

5. Centers for Medicaid & Medicare Services. Medicare “Pay for Performance (P4P)” Initiatives. Press release. January 31, 2005. www.cms.hhs.gov/apps/media/press/ release.asp?Counter=1343. Accessed January 13, 2009.

6. Hampton T. Groups push physicians and patients to embrace electronic health records. JAMA. 2008;299:507-509.

7. Lindenauer PK, Remus D, Roman S, et al. Public reporting and pay for performance in hospital quality improvement. N Engl J Med. 2007;356:486-496.

8. Glickman SW, Ou F, DeLong ER, et al. Pay for performance, quality of care, and outcomes in acute myocardial infarction. JAMA. 2007;297:2373-2380.

9. Glickman SW, Schulman KA, Peterson ED, et al. Evidence-based perspectives on

pay for performance and quality of patient care and outcomes in emergency medicine. Ann Emerg Med. 2008;51:622-631.

10. Ferguson JA, Tierney WM, Westmoreland GR, et al. Examination of racial differences in management of cardiovascular disease. J Am Coll Cardiol. 1997;30:1701-1713.

11. Mortensen EM, Cornell J, Whittle J. Racial variations in processes of care for patients with community acquired pneumonia. BMC Health Serv Res. 2004;4:20-26.

12. Sonel AF, Good CB, Mulgund J, et al. Racial variations in treatment and outcomes of black and white patients with high-risk non-ST-elevation acute coronary syndromes: insights from CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the ACC/AHA Guidelines?). Circulation. 2005;111:1225-1232.

13. Peterson ED, Wright SM, Daley J, Thibault GE. Racial variation in cardiac procedure use and survival following acute myocardial infarction in the Department of Veterans Affairs. JAMA. 1994;271:1175-1180.

14. Kaul P, Lytle BL, Spertus JA, et al. Influence of racial disparities in procedure use on functional status outcomes among patients with coronary artery disease.

Circulation. 2005;111:1284-1290.

15. Karve AM, Ou FS, Lytle BL, Peterson ED. Potential unintended financial consequences of pay-for-performance on the quality of care for minority patients. Am Heart J. 2008;155:571-576.

16. Werner RM, Goldman LE, Dudley RA. Comparison of change in quality of care between safety-net and non-safety-net hospitals. JAMA. 2008;299:2180-2187.

17. Mehta RH, Liang L, Karve AM, et al. Association of patient case-mix adjustment, hospital process performance rankings, and eligibility for financial incentives.

JAMA. 2008;300:1897-1903.

18. Epstein AM, Lee TH, Hamel MB. Paying physicians for high-quality care. N Engl J Med. 2004;350:406-410.

19. The Leapfrog Group. About us. www.leapfroggroup.org/about_us. Accessed January 26, 2009.

20. Landon BE, Hicks LS, O’Malley AJ, et al. Improving the management of chronic disease at community health centers. N Engl J Med. 2007;356:921-934.

21. Galvin R, Milstein A. Large employers’ new strategies in health care. N Engl J Med. 2002;347:939-942.

22. Christianson J, Feldman R, Weiner JP, Drury P. Early experience with a new model of employer group purchasing in Minnesota. Health Aff (Millwood). 1999;18:100-114.

23. AllBusiness. Merck-Medco Achieves 80 Percent Generic Substitution Rate for Prozac in First Week; Plan. August 21, 2001. www.allbusiness.com/health-care/ health-care-regulation-policy-health/6112721-1.html. Accessed November 1, 2009.

24. Sackner-Bernstein J. Reducing the risks of sudden death and heart failure post myocardial infarction: utility of optimized pharmacotherapy. Clin Cardiol. 2005;28 (suppl 1):19-27.

25. The Henry J. Kaiser Family Foundation. Kaiser Commission on Medicaid and the Uninsured. Health Insurance Coverage in America: 2006 Data Update. October 2007. www.kff.org/uninsured/upload/2006_DATA%20_UPDATE.pdf. Accessed March 3, 2010.

26. Rosenthal MB, Landon BE, Normand SL, et al. Employers’ use of value-based purchasing strategies. JAMA. 2007;298:2281-2288.

27. Blumenthal D, Glaser JP. Information technology comes to medicine. N Engl J Med. 2007;356:2527-2534.

28. Chaudhry B, Wang J, Wu S, et al. Systematic review: impact of health information technology on quality, efficiency, and costs of medical care. Ann Intern Med. 2006;144:742-752.

29. Shekelle P. New contract for general practitioners. BMJ. 2003;326:457-458.

STAKEHOLDER PERSPECTIVE The Many Challenges of Pay-for-Performance Programs PAYERS: Drs Sura and Shah focus their article on the benefits of pay-for-performance (P4P) programs in the hospital setting, while also noting some problems related to office-based healthcare. Although hospitalization represents a large cost for relatively brief episodes of care, the majority of patients receive their care in the physician’s office setting. Office-based P4P programs have some of the same potential benefits as in the hospital, but they have been associated with even greater concerns.

As healthcare costs have increased faster than other costs, healthcare payers and purchasers continue to search for mechanisms to ensure high-quality, costefficient care. Such value-based purchasing (VBP) has allowed these third parties to transition from passive payers to active purchasers of care. Those involved in healthcare reform have identified 4 cornerstones upon which quality improvement activities can be based.

One of these involves the adoption of incentives to promote high-quality, cost-effective care. The Deficit Continued

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STAKEHOLDER PERSPECTIVE (Continued) Reduction Act of 2005 focused on VBP and P4P efforts. Executive Order 13410, issued in August 2006

by President Bush, recommended P4P models of reimbursement. In 2007, then–Health and Human Services (HHS) Secretary Michael Leavitt encouraged major healthcare purchasers to adopt VBP. The Medicare Improvements for Patients and Providers Act of 2008 required HHS to develop a plan to transition physicians to VBP/P4P. Private payers have rapidly implemented many P4P programs.

Some initiatives, such as CMS’s Physician Quality Reporting Initiative (PQRI), reward physicians’ voluntary reporting with monetary compensation. Other initiatives levy fines for hospital nonreporting. Privatesector programs frequently reward physicians for meeting not only quality-of-care goals but also nonclinical patient satisfaction. Private payer P4P programs often purport that their goal is to improve quality, but the process can be manipulated such that the primary goal is to reduce cost. With more than 100 P4P programs in the marketplace, providers have a very difficult time meeting the reporting requirements, which vary significantly based on the clinical measures, quality metrics, and the patient population targeted.

Although it may be difficult to measure quality outcomes of care, many plans have substituted easier process measures instead of outcome measures; depending on the data, it may be very difficult to attribute care or lack thereof to a specific provider.

The goals of P4P programs are similar but their incentives vary significantly. Some P4P programs award modest bonuses to providers who meet program objectives; others offer bonuses only to providers who document improvement in meeting metrics; yet others reward only top performers. Other programs offer consumers reduced copayments, coinsurance, deductibles, or premiums for using only providers identified as “high quality.” Newer programs reward care coordination models, such as implementing a medical home or accountable-care organizations.

Among the greatest challenges facing purchasers and public/private payers in implementing P4P/VBP programs is ensuring the validity and credibility of the metrics. Many metrics are based on treatment guidelines, and many of these guidelines, as Dr Jerome Groopman has elucidated,1 are conflicting and are often produced by entities with significant potential for conflict of interest. Risk adjustment is also essential, because patients and physicians are not truly fungible entities. CMS’s PQRI and other state reporting

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experiments have experienced significant problems.

Because of flaws in these programs, most have not produced the desired results. Despite extensive and frequent physician feedback about them, many programs continue to move toward public disclosure of inherently flawed data. Simple disclosure of these flaws, however, is insufficient—correction is essential. Programs in Massachusetts, New York, Texas, and Washington have publicly released flawed data, resulting in litigation and significant monetary settlements against payers.

PROVIDERS/PATIENTS: The goal of such quality feedback programs should be to educate physicians to assist them in practice management and provision of quality care. Paramount to the success of such programs is reliable, verifiable data; however, almost every state/federal program has experienced serious data accuracy problems. Inaccurate data can increase the risk of unintended consequences, mislead patients, harm a physician’s reputation, and increase physician distrust in P4P participation. Without clinical data, claims data alone are clearly insufficient to document the full spectrum of specific patient care.

Patient adherence to recommended intervention must also be considered. Physicians must be given the opportunity to review the accuracy of the patient attribution and the clinical data. Harmonization of the metrics being studied must occur across all payers.

Physicians must also be given the right to appeal and correct inaccuracies before any data or conclusions are released to the public. Publishing poor quality measures, and making access to physicians, dependant on potentially inappropriate and/or poorly attributed metrics, make the information relatively meaningless to those aware of the lack of validity, and potentially damaging to physician practices, if patients seek care based on this poorly collected and attributed data.

Because of these many difficulties, physician participation in such flawed processes should remain voluntary until these problems are fully rectified.

1. Groopman J. How Doctors Think. New York, NY: Houghton Mifflin; 2007.

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Steven T. Kmucha, MD, JD Medical Director, Balance and Mobility Center at Seton Medical Center, CA Consultant, California Medical Association– Committee on Quality Care, and The Doctors Company Adjunct Clinical Instructor, Stanford University School of Medicine

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For your members with moderate to severe plaque psoriasis

Now Available in Prefilled Syringes

Indication STELARA™ is indicated for the treatment of adult patients (18 years or older) with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy.

Dosing STELARA™ is administered by subcutaneous injection.

• For patients weighing ≤100 kg (220 lbs), the recommended dose is 45 mg initially and 4 weeks later, followed by 45 mg every 12 weeks • For patients weighing >100 kg (220 lbs), the recommended dose is 90 mg initially and 4 weeks later, followed by 90 mg every 12 weeks In patients weighing >100 kg, 45 mg was also shown to be efficacious. However, 90 mg resulted in greater efficacy in these patients.

The safety and efficacy of STELARA™ have not been evaluated beyond two years.

Dosage forms and strengths STELARA™ contains 90 mg of ustekinumab per mL. • 45 mg/0.5 mL in a single-use, prefilled syringe, with an NDC number of 57894-060-03 • 90 mg/1 mL in a single-use, prefilled syringe, with an NDC number of 57894-061-03

Please see Important Safety Information and Brief Summary of Prescribing Information for STELARA™ on the following pages. www.STELARAinfo.com

IMPORTANT SAFETY INFORMATION Infections STELARA™ may increase the risk of infections and reactivation of latent infections. Serious bacterial, fungal, and viral infections were reported. Infections requiring hospitalization included cellulitis, diverticulitis, osteomyelitis, gastroenteritis, pneumonia, and urinary tract infections. STELARA™ should not be given to patients with a clinically important active infection and should not be administered until the infection resolves or is adequately treated.

Instruct patients to seek medical advice if signs or symptoms suggestive of an infection occur. Exercise caution when considering use of STELARA™ in patients with a chronic infection or a history of recurrent infection.

Theoretical Risk for Vulnerability to Particular Infections Individuals genetically deficient in IL-12/IL-23 are particularly vulnerable to disseminated infections from mycobacterium, Salmonella, and Bacillus Calmette-Guerin (BCG) vaccinations. Serious infections and fatal outcomes have been reported in such patients. It is not known whether patients with pharmacologic blockade of IL-12/IL-23 from treatment with STELARA™ will be susceptible to these types of infections. Consider appropriate diagnostic testing as dictated by clinical circumstances.

Pre-Treatment Evaluation of Tuberculosis (TB) Evaluate patients for TB prior to initiating treatment with STELARA™. STELARA™ should not be given to patients with active TB. Initiate treatment of latent TB before administering STELARA™. Patients should be monitored closely for signs and symptoms of active TB during and after treatment with STELARA™.

Malignancies STELARA™ is an immunosuppressant and may increase the risk of malignancy. Malignancies were reported among patients who received STELARA™ in clinical studies. The safety of STELARA™ has not been evaluated in patients who have a history of malignancy or who have a known malignancy.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS) One case of RPLS has been reported in a STELARA™-treated patient. If RPLS is suspected, discontinue STELARA™ and administer appropriate treatment.

RPLS is a neurological disorder, which is not caused by an infection or demyelination. RPLS can present with headache, seizures, confusion, and visual disturbances. RPLS has been associated with fatal outcomes.

Immunizations Prior to initiating therapy with STELARA™, patients should receive all immunizations recommended by current guidelines. Patients being treated with STELARA™ should not receive live vaccines. BCG vaccines should not be given during treatment or within one year of initiating or discontinuing STELARA™. Exercise caution when administering live vaccines to household contacts of STELARA™ patients, as shedding and subsequent transmission to STELARA™ patients may occur. Non-live vaccinations received during a course of STELARA™ may not elicit an immune response sufficient to prevent disease.

Concomitant Therapies The safety of STELARA™ in combination with other immunosuppressive agents or phototherapy has not been evaluated. Ultraviolet-induced skin cancers developed earlier and more frequently in mice genetically manipulated to be deficient in both IL-12 and IL-23 or IL-12 alone. The relevance of these findings in mouse models for malignancy risk in humans is unknown.

Please see Brief Summary of Prescribing Information for STELARA™ on the following page.

Reference: STELARA™ Prescribing Information 12/2009. Horsham, PA: Centocor Ortho Biotech Inc.

representing the products of www.STELARAinfo.com

©2010 Centocor Ortho Biotech Services, LLC

3/10

25US09294

25US10030

Most Common Adverse Reactions The most common adverse reactions (≥3% and higher than that with placebo) in clinical trials for STELARA™ 45 mg, STELARA™ 90 mg, or placebo were: nasopharyngitis (8%, 7%, 8%), upper respiratory tract infection (5%, 4%, 5%), headache (5%, 5%, 3%), and fatigue (3%, 3%, 2%), respectively.

Brief Summary of Prescribing Information for STELARA™ (ustekinumab) STELARA™ Injection, for subcutaneous use See package insert for Full Prescribing Information INDICATIONS AND USAGE: STELARA™ is indicated for the treatment of adult patients (18 years or older) with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy. CONTRAINDICATIONS: None. WARNINGS AND PRECAUTIONS: Infections STELARA™ may increase the risk of infections and reactivation of latent infections. Serious bacterial, fungal, and viral infections were observed in subjects receiving STELARA™ (see Adverse Reactions). STELARA™ should not be given to patients with any clinically important active infection. STELARA™ should not be administered until the infection resolves or is adequately treated. Instruct patients to seek medical advice if signs or symptoms suggestive of an infection occur. Exercise caution when considering the use of STELARA™ in patients with a chronic infection or a history of recurrent infection. Serious infections requiring hospitalization occurred in the psoriasis development program. These serious infections included cellulitis, diverticulitis, osteomyelitis, viral infections, gastroenteritis, pneumonia, and urinary tract infections. Theoretical Risk for Vulnerability to Particular Infections Individuals genetically deficient in IL-12/IL-23 are particularly vulnerable to disseminated infections from mycobacteria (including nontuberculous, environmental mycobacteria), salmonella (including nontyphi strains), and Bacillus Calmette-Guerin (BCG) vaccinations. Serious infections and fatal outcomes have been reported in such patients. It is not known whether patients with pharmacologic blockade of IL-12/IL-23 from treatment with STELARA™ will be susceptible to these types of infections. Appropriate diagnostic testing should be considered, e.g., tissue culture, stool culture, as dictated by clinical circumstances.

Pre-treatment Evaluation for Tuberculosis Evaluate patients for tuberculosis infection prior to initiating treatment with STELARA™. Do not administer STELARA™ to patients with active tuberculosis. Initiate treatment of latent tuberculosis prior to administering STELARA™. Consider anti-tuberculosis therapy prior to initiation of STELARA™ in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed. Patients receiving STELARA™ should be monitored closely for signs and symptoms of active tuberculosis during and after treatment. Malignancies STELARA™ is an immunosuppressant and may increase the risk of malignancy. Malignancies were reported among subjects who received STELARA™ in clinical studies (see Adverse Reactions). In rodent models, inhibition of IL-12/IL-23p40 increased the risk of malignancy (see Nonclinical Toxicology). The safety of STELARA™ has not been evaluated in patients who have a history of malignancy or who have a known malignancy. Reversible Posterior Leukoencephalopathy Syndrome One case of reversible posterior leukoencephalopathy syndrome (RPLS) was observed during the clinical development program which included 3523 STELARA™-treated subjects. The subject, who had received 12 doses of STELARA™ over approximately two years, presented with headache, seizures and confusion. No additional STELARA™ injections were administered and the subject fully recovered with appropriate treatment. RPLS is a neurological disorder, which is not caused by demyelination or a known infectious agent. RPLS can present with headache, seizures, confusion and visual disturbances. Conditions with which it has been associated include preeclampsia, eclampsia, acute hypertension, cytotoxic agents and immunosuppressive therapy.

Fatal outcomes have been reported. If RPLS is suspected, STELARA™ should be discontinued and appropriate treatment administered. Immunizations Prior to initiating therapy with STELARA™, patients should receive all immunizations appropriate for age as recommended by current immunization guidelines. Patients being treated with STELARA™ should not receive live vaccines. BCG vaccines should not be given during treatment with STELARA™ or for one year prior to initiating treatment or one year following discontinuation of treatment. Caution is advised when administering live vaccines to household contacts of patients receiving STELARA™ because of the potential risk for shedding from the household contact and transmission to patient. Non-live vaccinations received during a course of STELARA™ may not elicit an immune response sufficient to prevent disease. Concomitant Therapies The safety of STELARA™ in combination with other immunosuppressive agents or phototherapy has not been evaluated. Ultraviolet-induced skin cancers developed earlier and more frequently in mice genetically manipulated to be deficient in both IL-12 and IL-23 or IL-12 alone (see Nonclinical Toxicology). ADVERSE REACTIONS: The following serious adverse reactions are discussed elsewhere in the label: Infections (see Warnings and Precautions); Malignancies (see Warnings and Precautions); and RPLS (see Warnings and Precautions). Clinical Studies Experience The safety data reflect exposure to STELARA™ in 2266 psoriasis subjects, including 1970 exposed for at least 6 months, 1285 exposed for at least one year, and 373 exposed for at least 18 months. 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 listed below are those that occurred at a rate of at least 1% and at a higher rate in the STELARA™ groups than the placebo group during the placebo-controlled period of STUDY 1 and STUDY 2. The numbers (percentages) of adverse reactions reported for placebo-treated patients (n=665), patients treated with 45 mg STELARA™ (n=664), and patients treated with 90 mg STELARA™ (n=666), respectively, were: Nasopharyngitis: 51 (8%), 56 (8%), 49 (7%); Upper respiratory tract infection: 30 (5%), 36 (5%), 28 (4%); Headache: 23 (3%), 33 (5%), 32 (5%); Fatigue: 14 (2%), 18 (3%), 17 (3%); Diarrhea: 12 (2%), 13 (2%), 13 (2%); Back pain: 8 (1%), 9 (1%), 14 (2%); Dizziness: 8 (1%), 8 (1%), 14 (2%); Pharyngolaryngeal pain: 7 (1%), 9 (1%), 12 (2%); Pruritus: 9 (1%), 10 (2%), 9 (1%); Injection site erythema: 3 (<1%), 6 (1%), 13 (2%); Myalgia: 4 (1%), 7 (1%), 8 (1%); Depression: 3 (<1%), 8 (1%), 4 (1%). Adverse drug reactions that occurred at rates less than 1% included: cellulitis and certain injection site reactions (pain, swelling, pruritus, induration, hemorrhage, bruising, and irritation). One case of RPLS occurred during clinical trials (see Warnings and Precautions).

Infections In the placebo-controlled period of clinical studies of psoriasis subjects (average follow-up of 12.6 weeks for placebo-treated subjects and 13.4 weeks for STELARA™-treated subjects), 27% of STELARA™-treated subjects reported infections (1.39 per subject-year of follow-up) compared with 24% of placebo-treated subjects (1.21 per subject-year of follow-up).

Serious infections occurred in 0.3% of STELARA™-treated subjects (0.01 per subject-year of follow-up) and in 0.4% of placebo-treated subjects (0.02 per subject-year of follow-up) (see Warnings and Precautions). In the controlled and non-controlled portions of psoriasis clinical trials, 61% of STELARA™-treated subjects reported infections (1.24 per subject-year of follow-up).

Serious infections were reported in 0.9% of subjects (0.01 per subject-year of follow-up).

Malignancies In the controlled and non-controlled portions of psoriasis clinical trials, 0.4% of STELARA™-treated subjects reported malignancies excluding non-melanoma skin cancers (0.36 per 100 subject-years of follow-up). Non-melanoma skin cancer was reported in 0.8% of STELARA™-treated subjects (0.80 per 100 subject-years of follow-up) (see Warnings and Precautions). Serious malignancies included breast, colon, head and neck, kidney, prostate, and thyroid cancers. Immunogenicity The presence of ustekinumab in the serum can interfere with the detection of anti-ustekinumab antibodies resulting in inconclusive results due to assay interference. In STUDIES 1 and 2, antibody testing was done at time points when ustekinumab may have been present in the serum. In STUDY 1 the last ustekinumab injection was between Weeks 28 and 48 and the last test for anti-ustekinumab antibodies was at Week 52. In STUDY 2 the last ustekinumab injection was at Week 16 and the last test for anti-ustekinumab antibodies was at Week 24. In STUDY 1 (N=743), antibody results were found to be positive, negative, and inconclusive in 38 (5%), 351 (47%), and 354 (48%) patients, respectively. In STUDY 2 (N=1198), antibody results were found to be positive, negative, and inconclusive in 33 (3%), 90 (8%), and 1075 (90%) patients, respectively. The data reflect the percentage of subjects whose test results were positive for antibodies to ustekinumab in a bridging immunoassay, and are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors, including sample handling, timing of sample collection, concomitant medications and underlying disease. For these reasons, comparison of the incidence of antibodies to ustekinumab with the incidence of antibodies to other products may be misleading. DRUG INTERACTIONS: Drug interaction studies have not been conducted with STELARA™. Live Vaccines Live vaccines should not be given concurrently with STELARA™ (see Warnings and Precautions). Concomitant Therapies The safety of STELARA™ in combination with immunosuppressive agents or phototherapy has not been evaluated (see Warnings and Precautions). CYP450 Substrates The formation of CYP450 enzymes can be altered by increased levels of certain cytokines (e.g., IL-1, IL-6, IL-10, TNF , IFN) during chronic inflammation. Thus, ustekinumab could normalize the formation of CYP450 enzymes. A role for IL-12 or IL-23 in the regulation of CYP450 enzymes has not been reported.

However, upon initiation of ustekinumab in patients who are receiving concomitant CYP450 substrates, particularly those with a narrow therapeutic index, monitoring for therapeutic effect (e.g., for warfarin) or drug concentration (e.g., for cyclosporine) should be considered and the individual dose of the drug adjusted as needed (see Clinical Pharmacology). USE IN SPECIFIC POPULATIONS: Pregnancy Pregnancy Category B There are no studies of STELARA™ in pregnant women. STELARA™ should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. No teratogenic effects were observed in the developmental and reproductive toxicology studies performed in cynomolgus monkeys at doses up to 45 mg/kg ustekinumab, which is 45 times (based on mg/kg) the highest intended clinical dose in psoriasis patients (approximately 1 mg/kg based on administration of a 90 mg dose to a 90 kg psoriasis patient). Ustekinumab was tested in two embryo-fetal development toxicity studies. Pregnant cynomolgus monkeys were administered ustekinumab at doses up to 45 mg/kg during the period of organogenesis either twice weekly via subcutaneous injections or weekly by intravenous injections. No significant adverse developmental effects were noted in either study. In an embryo-fetal development and pre- and post-natal development toxicity study, three groups of 20 pregnant cynomolgus monkeys were administered subcutaneous doses of 0, 22.5, or 45 mg/kg ustekinumab twice weekly from the beginning of organogenesis in cynomolgus monkeys to Day 33 after delivery. There were no treatment-related effects on mortality, clinical signs, body weight, food consumption, hematology, or serum biochemistry in dams. Fetal losses occurred in six control monkeys, six 22.5 mg/kg-treated monkeys, and five 45 mg/kg-treated monkeys.

Neonatal deaths occurred in one 22.5 mg/kg-treated monkey and in one 45 mg/kg-treated monkey. No ustekinumab-related abnormalities were observed in the neonates from birth through six months of age in clinical signs, body weight, hematology, or serum biochemistry. There were no treatment-related effects on functional development until weaning, functional development after weaning, morphological development, immunological development, and gross and histopathological examinations of offsprings by the age of 6 months. Nursing Mothers Caution should be exercised when STELARA™ is administered to a nursing woman. The unknown risks to the infant from gastrointestinal or systemic exposure to ustekinumab should be weighed against the known benefits of breast-feeding. Ustekinumab is excreted in the milk of lactating monkeys administered ustekinumab. IgG is excreted in human milk, so it is expected that STELARA™ will be present in human milk. It is not known if ustekinumab is absorbed systemically after ingestion; however, published data suggest that antibodies in breast milk do not enter the neonatal and infant circulation in substantial amounts. Pediatric Use Safety and effectiveness of STELARA™ in pediatric patients have not been evaluated. Geriatric Use Of the 2266 psoriasis subjects exposed to STELARA™, a total of 131 were 65 years or older, and 14 subjects were 75 years or older. Although no differences in safety or efficacy were observed between older and younger subjects, the number of subjects aged 65 and over is not sufficient to determine whether they respond differently from younger subjects. OVERDOSAGE: Single doses up to 4.5 mg/kg intravenously have been administered in clinical studies without dose-limiting toxicity. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment be instituted immediately. PATIENT COUNSELING INFORMATION: Instruct patients to read the Medication Guide before starting STELARA™ therapy and to reread the Medication Guide each time the prescription is renewed.

Infections Inform patients that STELARA™ may lower the ability of their immune system to fight infections. Instruct patients of the importance of communicating any history of infections to the doctor, and contacting their doctor if they develop any symptoms of infection. Malignancies Patients should be counseled about the risk of malignancies while receiving STELARA™.

Prefilled Syringe Manufactured by: Vial Manufactured by: Centocor Ortho Biotech Inc., Centocor Ortho Biotech Inc., Horsham, PA 19044, Horsham, PA 19044, License No. 1821 at License No. 1821 at Baxter Pharmaceutical Solutions, Cilag AG, Bloomington, IN 47403 Schaffhausen, Switzerland 1-800-457-6399 25US10041 © Centocor Ortho Biotech Inc. 2009 December 2009

NCCN HIGHLIGHTS

NCCN Panel Debates the Economics of Cancer Care

By Caroline Helwick

T

he financial nonsustainability of the healthcare system and the use of evidence-based guidelines to guide clinical practice are on a collision course, according to cancer experts who participated in a roundtable discussion on the economic issues affecting cancer care. The panel was held during the 15th annual conference of the National Comprehensive Cancer Network (NCCN). The discussion focused on the challenging question of how to pay for the increasingly costly care of cancer. The panel included payers, physicians, patient advocates, and industry experts.

Guidelines Inform Coverage Representatives from Aetna and UnitedHealthcare said their companies use the NCCN guidelines to make coverage decisions. Both plans pay for any treatment that receives a category 2B or higher recommendation.

Although patients and providers argue that much of cancer treatment is not covered, these payers disagreed.

James D. Cross, MD, Head of Medical Policy and Program Administration for Aetna, said it is “extraordinarily rare that treatment is denied by Aetna in a lifethreatening illness.” He said that Aetna has found that when guidelines are followed, cost of care is 35% lower.

Controversies over reimbursement become thornier once the recommended treatments have been exhausted, the panelists agreed. Nancy Davenport-Ennis, President and CEO of the National Patient Advocate Foundation, praised “courageous” physicians who find experimental treatments that keep patients alive, but Dr Cross criticized this approach, maintaining that oncologists should not just “take things off the shelf” but should enroll patients in clinical trials.

Participants agreed that active treatments at the end of life are not only futile but are often detrimental. “Costs aside, let’s not expose patients to harm with little chance of benefit,” said Lee Newcomer, MD, Senior Vice President of Oncology Services with UnitedHealthcare. He said that the cost of end-of-life care is not necessarily much greater than other cancer care. “We busted that myth,” Dr Newcomer said, referring to a UnitedHealthcare analysis that showed most costs to be related to hospitalization for complications, except for leukemia and lymphoma. “We didn’t see a sudden surge in chemotherapy and other treatments,” he said.

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Drug Development Is Also Affected Douglas Lind, MD, of GBP Capital, a venture capital company, noted that concerns over reimbursement have also hit the research and development arena. His company no longer looks for drugs with the potential for US Food and Drug Administration approval but for drugs with the best likelihood for reimbursement. “For the first time this is the central question,” he said, adding that pharmaceutical companies “are equally asking this question.”

The oncologists on the panel, Al B. Benson, III, MD, of the Robert H. Kurie Comprehensive Cancer Center of Northwestern University, and Joseph Bailes, MD, Chair of the American Society of Clinical Oncology’s Government Relations Council, expressed dismay. “Many of the innovations in medicine are a result of thinking outside the box,” Dr Benson pointed out; Dr Bailes added that “inefficiencies often lead to innovations.”

Financial Crisis of Patients with Cancer For many patients, the talk about cost-containment comes too late, Ms Davenport-Ennis said. Her organization has witnessed an 87% increase in the number of families filing for bankruptcy because of medical debt.

Dr Newcomer acknowledged that health insurance has become unaffordable for many consumers, but Ms Davenport-Ennis said that 75% of bankrupt consumers are fully insured. “Be aware that the American consumer is bellying up to the bar to try to pay for healthcare and is slipping into bankruptcy,” she said.

Industry representatives reminded listeners that financial hardships are not the sole province of the patients. Jason Slotnik, Esq, with the Washington, DC–based legal firm Foley Hoag, said that industry needs to be able to recoup its investment, the magnitude of which is growing greater as more capital is required in drug development. Demonstrating cost-effectiveness, for example, adds about $200 million to the cost of bringing a new drug to market, Mr Slotnik said.

In closing, the participants were asked what one thing in oncology can be done to foster economic reform. “We have to eliminate care that does not add value. Otherwise, we are going to be forced to allocate funds as a result of financial collapse,” Dr Newcomer suggested. ■

March/April 2010

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NCCN HIGHLIGHTS

PET Scans Not Recommended for Most Patients with Breast Cancer: Potential New Controversy in Breast Cancer Testing

By Caroline Helwick

“There are financial issues in terms of rewards for physicians who perform them frequently. Our society assumes that any technology with a high price tag has value, but the newest technology is not necessarily the best technology.”

—Robert Carlson, MD

A

ccording to the updated 2010 practice guidelines of the National Comprehensive Cancer Network (NCCN), the work-up of patients with early breast cancer should not include imaging by positron-emission tomography (PET) or by PET/computed tomography (CT) scanning. This updated guideline has implications for healthcare stakeholders, especially providers and health plans.

In their 2010 annual review, the NCCN Breast Cancer Panel gave a thumbs down for the use of this modality in a number of settings. PET or PET/CT can be helpful in some cases of stage III disease in which standard staging studies are equivocal or suspicious, but it should not be routine in the staging of newly diagnosed stage I, II, or operable stage III breast cancer, the Breast Cancer Panel concluded.

“The implication of our recommendations is that PET/CT is overused in breast cancer,” said Robert Carlson, MD, of Stanford Cancer Center, Palo Alto, CA, who chairs the panel. “What is fueling the overuse?

I don’t really know. It is simple to order, but it is very expensive. So there are financial issues in terms of rewards for physicians who perform them frequently. Our society assumes that any technology with a high price tag has value, but the newest technology is not necessarily the best technology,” Dr Carlson said in an interview.

High Rate of False-Positives The new recommendation is based on studies showing low sensitivity and fairly low specificity in staging of the axillary lymph nodes and poor detection of metastases in patients with apparent early-stage disease. The ultimate result is a high frequency of falsepositive findings, he said.

In a retrospective analysis (presented at ASCO in 2007) from the University of Kansas, 15 of 83 (18%)

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women had suspicious PET/CT scans, but only 2 (13%) of the women were found to have confirmed metastases, and the PET and CT scanning results were often discordant.1 The NCCN Breast Cancer Panel also discourages the use of PET or PET/CT scanning in the work-up of recurrent or metastatic breast cancer. The exception is those clinical situations where other staging studies are equivocal or suspicious.

In contrast, for patients with locally advanced breast cancer, the use of PET or PET/CT scanning has been reported by several studies to detect extra-axial nodal disease in 7% to 25% of cases and distant metastases in 10% to 21% over and above routine studies.2-4 Therefore, the NCCN panel considered PET or PET/CT to be optional in locally advanced disease, but it is a category 2B recommendation based on the low level of evidence and the nonuniformity of practice among the panelists.

Under most circumstances, Dr Carlson concluded, “A positive PET scan in a woman with localized breast cancer is as likely to be a false-positive as a true-positive, and as likely to lead to an incorrect treatment decision as a correct one.” PET or PET/CT scanning for most patients, therefore, is not recommended by the NCCN. ■

References 1. Khan QJ, O’Dea AP, Dusing R, et al. Integrated FDG-PET/CT for initial staging of breast cancer. J Clin Oncol. 2007;25(18 suppl):Abstract 558.

2. Fuster D, Duch J, Paredes P, et al. Preoperative staging of large primary breast cancer with [18F]fluorodeoxyglucose positron emission tomography/computed tomography compared with conventional imaging procedures. J Clin Oncol. 2008; 10:4746-4751.

3. Bellon JR, Livingston RB, Eubank WB, et al. Evaluation of the internal mammary lymph nodes by FDG-PET in locally advanced breast cancer (LABC). Am J Clin Oncol. 2004;27:407-410.

4. Mahner S, Schirrmacher S, Brenner W, et al. Comparison between positron emission tomography using 2-[fluorine-18]fluoro-2-deoxy-D-glucose, conventional imaging and computed tomography for staging of breast cancer. Ann Oncol. 2008; 19:1249-1254.

March/April 2010

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EXECUTIVE SUMMARIES

Obesity: Effective Treatment Requires Change in Payers’ Perspective Rhonda Greenapple, MSPH; Jackie Ngai, MS

Obesity is reaching epidemic proportions in the United States. More than one third of American adults (>72 million) can currently be categorized as obese, and the rate of obesity/overweight is continuing to rise not only among adults but increasingly among teens and children. The health problems associated with obesity have a significant economic impact on the US healthcare system. In 2000, the Centers for Disease Control and Prevention estimated that obesity-related healthcare costs totaled $117 billion. Nevertheless, many health plans and employers do not cover obesity-related therapies. In 2008, Reimbursement Intelligence conducted a survey to examine payers’ perspectives on obesity management; it was completed by payers representing >100 million

covered lives and 42 physicians who treat nearly 500 obese patients monthly. According to this survey, only 24% of payers are tracking their obese/morbidly obese members, and weight-loss medications are not covered by many employers, because these are seen as “lifestyle drugs” or products with little evidence-based efficacy.

Payers require a medication to show an 18% weight loss to be placed on a formulary. The 4 pharmacologic products currently in late-stage development—naltrexone/bupropion; zonisamide/bupropion; lorcaserin hydrochloride; and phentermine plus topamax—show 5% to 12% weight-loss results, but nearly half of the payers surveyed are unlikely to include them on their formulary. In contrast, between 23% and 35% of physicians would be likely to prescribe these products.

Health Insurance Premium Increases for the 5 Largest School Districts in the United States, 2004-2008 John R. Cantillo, MBA

Local school districts are often the largest employer in their communities, yet no information is available about the rate of health insurance premiums in US school districts compared with other employers. Combining his past experience in a school system and his current experience as a healthcare consultant, Mr Cantillo undertook this study to assess the change in healthcare insurance costs in the 5 largest public school districts in the United States and compare them with other employers.

The 5 districts are New York School District, Los Angeles Unified School District, Chicago Public Schools, Miami-Dade County Public Schools, and Clark County School District (greater Las Vegas area).

The survey used as the basis for the study inquired about

enrollment, employee costs, and employer costs for each health benefits plan offered from 2004 through 2008.

All schools responded to the survey, and the results show that the premium growth for these 5 largest school districts has slowed down and is consistent with other purchasers—Kaiser/Health Research & Educational Trust and the Federal Employee Health Benefit Program. The average increase in health insurance premium for the schools was 5.9% in 2008, and the average annual growth rate over the study period was 7.5%. Mr Cantillo concludes that for family coverage, these schools provide the most generous employer contribution (80.8%) compared with the contribution reported by other employers (73.5%) for 2008.

Evolving Trends in Insulin Delivery: In Pursuit of Improvements in Diabetes Management Firas Akhrass, MD; Nancy Skinner, RN, CCM; Kimberly Boswell, MD; Luther B. Travis, MD

Diabetes continues to be one of the top 10 health problems in the United States. Nearly 18 million Americans are currently diagnosed with diabetes, and

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about 5.7 million have the disease but have not been diagnosed. The high rates of morbidity and mortality associated with diabetes, the related health problems Continued www.AHDBonline.com

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EXECUTIVE SUMMARIES

Continued

linked to this chronic disease, and the significant costs associated with its treatment and its many sequelae underscore the need to ensure proper glycemic control in patients with diabetes. Conventional syringe/vial insulin delivery is associated with patient and physician barriers, such as psychological insulin resistance, patientsâ&#x20AC;&#x2122; fear of insulin side effects and complications, and required lifestyle changes/restrictions. Despite evidence that many patients with type 2 diabetes do not achieve appropriate glycemic control with oral therapy

alone, some physicians are still reluctant to initiate insulin therapy. Developments in insulin delivery during the past 20 years have focused on increasing patient convenience and improved glycemic control. Dr Akhrass and colleagues focus on the newer insulin delivery modes, including insulin pens, insulin injection ports, continuous subcutaneous insulin infusion pumps, transdermal patches, and inhalable devices, suggesting that they may improve glycemic control and help curb the growing epidemic of diabetes.

Healthcare Costs Associated with Switching from Brand to Generic Levothyroxine Michael Katz, PharmD; Joseph Scherger, MD, MPH; Scott Conard, MD; Leslie Montejano, CCRP; Stella Chang, MPH

The therapeutic equivalence of branded and generic drugs is still often raised as an unresolved issue. In this study, Dr Katz and colleagues suggest that the true therapeutic equivalence of branded and generic levothyroxine is still being debated. Payers typically encourage switching to generic drugs as a cost-saving mechanism. Using a large healthcare claims database, the authors investigated whether switching from brand to generic levothyroxine does indeed save costs to patients and payers. Dr Katz and colleagues suggest that the savings in drug costs from switching to generic levothyroxine are often offset by increased costs for

related healthcare services; switching from brand to generic levothyroxine appears to result in an increase in total healthcare costs. These results raise a question regarding the economic and clinical benefits of switching patients to generic levothyroxine. Dr Katz and colleagues suggest that in the absence of cost-savings, and given the concerns regarding therapeutic equivalence of this medication, there is no clear rationale for switching patients from brand to generic levothyroxine. More research is needed to better understand the clinical and economic implications of switching levothyroxine formulations.

Pay-for-Performance Initiatives: Modest Benefits for Improving Healthcare Quality Amit Sura, MD, MBA; Nirav R. Shah, MD, MPH

Pay-for-performance (P4P) initiatives have been seen as a potential solution to enhance the quality of patient care and provide incentives to providers to improve their patient management. The Centers for Medicare & Medicaid Services (CMS) has endorsed these P4P efforts, establishing P4P initiatives in 2003 in the hope of strengthening quality measures, improving patient outcomes, and maintaining physician accountability.

Various P4P programs offer incentives to hospitals, provider groups, and physicians based on adherence to specific composite metrics. However, questions are being raised about the evidence for the ability of P4P programs to deliver such improvements. After reviewing the published data, Drs Sura and Shah raise the possibility that the quality composite scores promoted by CMS with P4P programs may also be in need of improvement.

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Their research further shows that when treating minorities, providers are less likely to use the latest evidencebased guidance. They suggest that research must be conducted to determine the causes of disparities in the quality of care for minority groups. Furthermore, Drs Sura and Shah say, for quality efforts to motivate doctors, it is becoming increasingly apparent that incentive programs have to represent a considerable fraction of their income; too many times, the costs to enact the P4P metrics outweigh the financial merits received from them. To address some of these issues, some new P4P initiatives are aiming at creating market competition by establishing high and low performers, and others use collaborative practice groups to influence care by bringing community health centers together to learn and disseminate quality-improvement techniques.

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Overcoming challenges to provide optimal diabetes care to underserved plan members The National Committee for Quality Assurance found a high incidence of A1C levels >9% in all insured populations • In 2006, 30% of patients on commercial plans, 27% of patients on Medicare plans, and 49% of patients on Medicaid plans had uncontrolled diabetes (A1C >9%).1 • Health plans are uniquely positioned to target members in need of type 2 diabetes treatment, but patients continue to remain noncompliant.

Early recognition and aggressive treatment of type 2 diabetes should include powerful therapeutic agents that target the two basic impairments of function: insulin resistance and beta-cell dysfunction.2

Treatment focus should remain on durable type 2 diabetes therapy to keep costs at a minimum3,4

Difference in 3-year medical costs per person ($)

Standardized cost differentials for 1% change in A1C for adults with diabetes (n=1694)4 2,900 2,400 1,900

Diabetes with heart disease and hypertension Diabetes without heart disease and hypertension

$2,675

$2,536

1,400

400

–1,100

$805

$218

6% to 7%

–100 –600

$763

$726

900

7% to 8%

8% to 9%

9% to 10%

– $301 – $1,001 Changes in A1C levels (percentage points) Adapted from Gilmer.

• Medication adherence as measured by the medication possession ratio was higher for patients who reached the target A1C goal of ≤7.0% compared with patients who did not reach the target A1C goal.5 References: 1. National Committee for Quality Assurance. Comprehensive diabetes care. In: The State of Health Care Quality 2007. Washington, DC: National Committee for Quality Assurance; 2007:35-37. 2. Rosak C. The pathophysiologic basis of efficacy and clinical experience with the new oral antidiabetic agents.

J Diabetes Complications. 2002;16:123-132. 3. Kahn SE, Haffner SM, Heise MA, et al, for the ADOPT Study Group. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med. 2006;355:2427-2443. 4. Gilmer TP, O’Connor PJ, Rush WA, et al. Predictors of health care costs in adults with diabetes.

Diabetes Care. 2005;28:59-64. 5. Lawrence DB, Ragucci KR, Long LB, Parris BS, Helfer LA. Relationship of oral antihyperglycemic (sulfonylurea or metformin) medication adherence and hemoglobin A1c goal attainment for HMO patients enrolled in a diabetes disease management program. J Manag Care Pharm.

2006;12:466-471. ©2009 Takeda Pharmaceuticals North America, Inc.

XPIO-01447

9/09

Printed in U.S.A.

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

BRIEF SUMMARY OF PRESCRIBING INFORMATION INDICATIONS AND USAGE Hypertension MICARDIS is indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive agents.

Cardiovascular Risk Reduction MICARDIS is indicated for reduction of the risk of myocardial infarction, stroke, or death from cardiovascular causes in patients 55 years of age or older at high risk of developing major cardiovascular events who are unable to take ACE inhibitors.

High risk for cardiovascular events can be evidenced by a history of coronary artery disease, peripheral arterial disease, stroke, transient ischemic attack, or high-risk diabetes (insulin-dependent or non-insulin dependent) with evidence of end-organ damage. MICARDIS can be used in addition to other needed treatment (such as antihypertensive, antiplatelet or lipid-lowering therapy).

Studies of telmisartan in this setting do not exclude that it may not preserve a meaningful fraction of the effect of the ACE inhibitor to which it was compared. Consider using the ACE inhibitor first, and, if it is stopped for cough only, consider re-trying the ACE inhibitor after the cough resolves.

Use of telmisartan with an ACE inhibitor is not recommended.

CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS Fetal/Neonatal Morbidity and Mortality Drugs that act directly on the renin-angiotensin system can cause fetal and neonatal morbidity and death when administered to pregnant women. Several dozen cases have been reported in the world literature in patients who were taking angiotensin converting enzyme inhibitors.

When pregnancy is detected, discontinue MICARDIS tablets as soon as possible [see Boxed Warning].

The use of drugs that act directly on the renin-angiotensin system during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death.

Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to exposure to the drug.

These adverse effects do not appear to have resulted from intrauterine drug exposure that has been limited to the first trimester. Inform mothers whose embryos and fetuses are exposed to an angiotensin II receptor antagonist only during the first trimester that most reports of fetal toxicity have been associated with second and third trimester exposure.

Nonetheless, when patients become pregnant or are considering pregnancy, have the patient discontinue the use of MICARDIS tablets as soon as possible.

Rarely (probably less often than once in every thousand pregnancies), no alternative to an angiotensin II receptor antagonist will be found. In these rare cases, the mothers should be apprised of the potential hazards to their fetuses, and serial ultrasound examinations should be performed to assess the intra-amniotic environment.

If oligohydramnios is observed, MICARDIS should be discontinued unless they are considered life-saving for the mother. Contraction stress testing (CST), a non-stress test (NST), or biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.

Infants with histories of in utero exposure to an angiotensin II receptor antagonist should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function.

Hypotension In patients with an activated renin-angiotensin system, such as volumeand/or salt-depleted patients (e.g., those being treated with high doses of diuretics), symptomatic hypotension may occur after initiation of ther-

apy with MICARDIS. Either correct this condition prior to administration of MICARDIS, or start treatment under close medical supervision with a reduced dose.

If hypotension does occur, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline.

A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized.

Hyperkalemia Hyperkalemia may occur in patients on ARBs, particularly in patients with advanced renal impairment, heart failure, on renal replacement therapy, or on potassium supplements, potassium-sparing diuretics, potassiumcontaining salt substitutes or other drugs that increase potassium levels.

Consider periodic determinations of serum electrolytes to detect possible electrolyte imbalances, particularly in patients at risk.

Impaired Hepatic Function As the majority of telmisartan is eliminated by biliary excretion, patients with biliary obstructive disorders or hepatic insufficiency can be expected to have reduced clearance. Initiate telmisartan at low doses and titrate slowly in these patients.

Impaired Renal Function As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system (e.g., patients with severe congestive heart failure or renal dysfunction), treatment with angiotensinconverting enzyme (ACE) inhibitors and angiotensin receptor antagonists has been associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death. Similar results have been reported with MICARDIS. In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen were observed. There has been no long term use of MICARDIS in patients with unilateral or bilateral renal artery stenosis but anticipate an effect similar to that seen with ACE inhibitors.

Dual Blockade of the Renin-Angiotensin-Aldosterone System As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function (including acute renal failure) have been reported. Dual blockade of the renin-angiotensin-aldosterone system (e.g., by adding an ACE-inhibitor to an angiotensin II receptor antagonist) should include close monitoring of renal function.

The ONTARGET trial enrolled 25,620 patients ≥55 years old with atherosclerotic disease or diabetes with end-organ damage, randomizing them to telmisartan only, ramipril only, or the combination, and followed them for a median of 56 months. Patients receiving the combination of MICARDIS and ramipril did not obtain any additional benefit compared to monotherapy, but experienced an increased incidence of renal dysfunction (e.g., acute renal failure) compared with groups receiving telmisartan alone or ramipril alone. Concomitant use of MICARDIS and ramipril is not recommended.

ADVERSE REACTIONS The following adverse reaction is described elsewhere in labeling: Renal dysfunction upon use with ramipril.

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

Hypertension MICARDIS has been evaluated for safety in more than 3700 patients, including 1900 treated for over six months and more than 1300 for over one year. Adverse experiences have generally been mild and transient in nature and have infrequently required discontinuation of therapy.

In placebo-controlled trials involving 1041 patients treated with various doses of MICARDIS (20-160 mg) monotherapy for up to 12 weeks, the overall incidence of adverse events was similar to that in patients treated with placebo.

Adverse events occurring at an incidence of ≥1% in patients treated with MICARDIS and at a greater rate than in patients treated with placebo, irrespective of their causal association, are presented in Table 1.

Table 1 Adverse Events Occurring at an Incidence of ≥ 1% in Patients Treated with MICARDIS and at a Greater Rate Than in Patients Treated with Placebo Te lmis a rt a n ( n= 1455 ) %

P l a ce bo ( n= 380 ) %

Upper respiratory tract infection

7

6

Back pain

3

1

Sinusitis

3

2

Diarrhea

3

2

Pharyngitis

1

0

In addition to the adverse events in the table, the following events occurred at a rate of ≥1% but were at least as frequent in the placebo group: influenza-like symptoms, dyspepsia, myalgia, urinary tract infection, abdominal pain, headache, dizziness, pain, fatigue, coughing, hypertension, chest pain, nausea, and peripheral edema. Discontinuation of therapy because of adverse events was required in 2.8% of 1455 patients treated with Micardis® (telmisartan) tablets and 6.1% of 380 placebo patients in placebo-controlled clinical trials.

The incidence of adverse events was not dose-related and did not correlate with gender, age, or race of patients.

The incidence of cough occurring with telmisartan in 6 placebocontrolled trials was identical to that noted for placebo-treated patients (1.6%).

In addition to those listed above, adverse events that occurred in more than 0.3% of 3500 patients treated with MICARDIS monotherapy in controlled or open trials are listed below. It cannot be determined whether these events were causally related to MICARDIS tablets: Autonomic Nervous System: impotence, increased sweating, flushing; Body as a Whole: allergy, fever, leg pain, malaise; Cardiovascular: palpitation, dependent edema, angina pectoris, tachycardia, leg edema, abnormal ECG; CNS: insomnia, somnolence, migraine, vertigo, paresthesia, involuntary muscle contractions, hypoaesthesia; Gastrointestinal: flatulence, constipation, gastritis, vomiting, dry mouth, hemorrhoids, gastroenteritis, enteritis, gastroesophageal reflux, toothache, non-specific gastrointestinal disorders; Metabolic: gout, hypercholesterolemia, diabetes mellitus; Musculoskeletal: arthritis, arthralgia, leg cramps; Psychiatric: anxiety, depression, nervousness; Resistance Mechanism: infection, fungal infection, abscess, otitis media; Respiratory: asthma, bronchitis, rhinitis, dyspnea, epistaxis; Skin: dermatitis, rash, eczema, pruritus; Urinary: micturition frequency, cystitis; Vascular: cerebrovascular disorder; and Special Senses: abnormal vision, conjunctivitis, tinnitus, earache.

During initial clinical studies, a single case of angioedema was reported (among a total of 3781 patients treated).

Clinical Laboratory Findings In placebo-controlled clinical trials, clinically relevant changes in standard laboratory test parameters were rarely associated with administration of MICARDIS tablets.

Hemoglobin: A greater than 2 g/dL decrease in hemoglobin was observed in 0.8% telmisartan patients compared with 0.3% placebo patients. No patients discontinued therapy due to anemia.

Creatinine: A 0.5 mg/dL rise or greater in creatinine was observed in 0.4% telmisartan patients compared with 0.3% placebo patients. One telmisartan-treated patient discontinued therapy due to increases in creatinine and blood urea nitrogen.

Liver Enzymes: Occasional elevations of liver chemistries occurred in patients treated with telmisartan; all marked elevations occurred at a higher frequency with placebo. No telmisartan-treated patients discontinued therapy due to abnormal hepatic function.

Cardiovascular Risk Reduction Because common adverse reactions were well characterized in studies of telmisartan in hypertension, only adverse events leading to discontinuation and serious adverse events were recorded in subsequent studies of telmisartan for cardiovascular risk reduction. In TRANSCEND (N=5926, 4 years and 8 months of follow-up), discontinuations for adverse events were 8.4% on telmisartan and 7.6% on placebo. The only serious adverse events at least 1% more common on telmisartan than placebo were intermittent claudication (7% vs 6%) and skin ulcer (3% vs 2%).

Postmarketing Experience The following adverse reactions have been identified during postapproval use of MICARDIS. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate reliably their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causal connection to MICARDIS. The most frequently spontaneously reported events include: headache, dizziness, asthenia, coughing, nausea, fatigue, weakness, edema, face edema, lower limb edema, angioneurotic edema, urticaria, hypersensitivity, sweating increased, erythema, chest pain, atrial fibrillation, congestive heart failure, myocardial infarction, blood pressure increased, hypertension aggravated, hypotension (including postural hypotension), hyperkalemia, syncope, dyspepsia, diarrhea, pain, urinary tract infection, erectile dysfunction, back pain, abdominal pain, muscle cramps (including leg cramps), myalgia, bradycardia, eosinophilia, thrombocytopenia, uric acid increased, abnormal hepatic function/liver disorder, renal impairment including acute renal failure, anemia, increased CPK, anaphylactic reaction, and tendon pain (including tendonitis, tenosynovitis).

Rare cases of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers, including MICARDIS.

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

initiating, adjusting, and discontinuing telmisartan for the purpose of keeping the digoxin level within the therapeutic range.

Lithium: Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with angiotensin II receptor antagonists including MICARDIS. Therefore, monitor serum lithium levels during concomitant use.

Ramipril and Ramiprilat: Co-administration of telmisartan 80 mg once daily and ramipril 10 mg once daily to healthy subjects increases steadystate Cmax and AUC of ramipril 2.3- and 2.1-fold, respectively, and Cmax and AUC of ramiprilat 2.4- and 1.5-fold, respectively. In contrast, Cmax and AUC of telmisartan decrease by 31% and 16%, respectively. When co-administering telmisartan and ramipril, the response may be greater because of the possibly additive pharmacodynamic effects of the combined drugs, and also because of the increased exposure to ramipril and ramiprilat in the presence of telmisartan. Concomitant use of MICARDIS and ramipril is not recommended.

Other Drugs: Co-administration of telmisartan did not result in a clinically significant interaction with acetaminophen, amlodipine, glyburide, simvastatin, hydrochlorothiazide, warfarin, or ibuprofen. Telmisartan is not metabolized by the cytochrome P450 system and had no effects in vitro on cytochrome P450 enzymes, except for some inhibition of CYP2C19. Telmisartan is not expected to interact with drugs that inhibit cytochrome P450 enzymes; it is also not expected to interact with drugs metabolized by cytochrome P450 enzymes, except for possible inhibition of the metabolism of drugs metabolized by CYP2C19.

USE IN SPECIFIC POPULATIONS Pregnancy Teratogenic Effects, Pregnancy Categories C (first trimester) and D (second and third trimesters). See Warnings and Precautions.

Nursing Mothers It is not known whether telmisartan is excreted in human milk, but telmisartan was shown to be present in the milk of lactating rats. Because of the potential for adverse effects on the nursing infant, decide whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use Safety and effectiveness in pediatric patients have not been established.

Geriatric Use Of the total number of patients receiving MICARDIS in hypertension clinical studies, 551 (19%) were 65 to 74 years of age and 130 (4%) were 75 years or older. No overall differences in effectiveness and safety were observed in these patients compared to younger patients and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Of the total number of patients receiving MICARDIS in the cardiovascular risk reduction study (ONTARGET), the percentage of patients ≥65 to <75 years of age was 42%; 15% of patients were ≥75 years old. No overall differences in effectiveness and safety were observed in these patients compared to younger patients and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Hepatic Insufficiency Monitor carefully and uptitrate slowly in patients with biliary obstructive disorders or hepatic insufficiency.

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

Rx only

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

MC-BS (11-09)

MC71754

∗

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

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

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

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

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

• MICARDIS is indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive agents.

• MICARDIS is indicated for reduction of the risk of myocardial infarction, stroke, or death from cardiovascular causes in patients 55 years of age or older at high risk of developing major cardiovascular events who are unable to take ACE inhibitors.

• High risk for cardiovascular events can be evidenced by a history of coronary artery disease, peripheral arterial disease, stroke, transient ischemic attack, or high-risk diabetes (insulin dependent or non-insulin dependent) with evidence of end-organ damage. MICARDIS can be used in addition to other needed treatment (such as antihypertensive, antiplatelet, lipid-lowering therapy, etc).

• Studies of telmisartan in this setting do not exclude that it may not preserve a meaningful fraction of the effect of the ACE inhibitor to which it was compared. Consider using the ACE inhibitor first, and, if it is stopped for cough only, consider retrying the ACE inhibitor after the cough resolves.

• Use of telmisartan with an ACE inhibitor is not recommended.

• Volume depletion and/or salt depletion should be corrected in patients before initiation of therapy or start treatment under close medical supervision with a reduced dose, otherwise symptomatic hypotension may occur.

• In patients with impaired hepatic function, initiate telmisartan at low doses and titrate slowly.

• Monitor carefully in patients with impaired renal function, especially in patients whose renal function may depend on the activity of the reninangiotensin-aldosterone system (eg, patients with severe congestive heart failure or renal dysfunction); treatment of these patients with ACE inhibitors and ARBs has been associated with oliguria and/or progressive azotemia and, rarely, with acute renal failure and/or death. In patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen may occur.

• Dual blockade of the renin-angiotensin-aldosterone system (eg, by adding an ACE-inhibitor to an ARB) should include close monitoring of renal function. Use of MICARDIS with ramipril is not recommended.

References: 1. Micardis PI. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; 2009. 2. Teo K, Yusuf S, Sleight P, et al; and the ONTARGET/TRANSCEND Investigators. Rationale, design, and baseline characteristics of 2 large, simple, randomized trials evaluating telmisartan, ramipril, and their combination in highrisk patients: the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial/Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease (ONTARGET/TRANSCEND) trials. Am Heart J. 2004;148:52-61. 3. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G; and the HOPE Study Investigators. Effects of an angiotensin-converting–enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med. 2000;342:145-153.

Please see Brief Summary of Prescribing Information on following pages.

Copyright © 2010, Boehringer Ingelheim Pharmaceuticals, Inc. All rights reserved.

Printed in U.S.A.

(02/10)

MC68700PROF