November/December 2010, Vol 3, No 6

Covers_Cover 12/14/10 11:52 AM Page 357

THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN ™ NOVEMBER/DECEMBER 2010

VOLUME 3, NUMBER 6

FOR PAYERS, PURCHASERS, POLICYMAKERS, AND OTHER HEALTHCARE STAKEHOLDERS

REGULATORY

Implications of the New Political Realities on Healthcare Reform Interview with Dan Mendelson

CLINICAL

Engaging Providers in Medication Adherence: A Health Plan Case Study ™

Amy B. Scott, BSPharm, RPh; Jane E. McClure, BA, RN

Stakeholder Perspective by F. Randy Vogenberg, PhD, RPh

BUSINESS

The H-E-B Value-Based Health Management Program: Impact on Asthma Medication Adherence and Healthcare Cost Anna O. D’Souza, PhD; Roshan Rahnama, MPH; Timothy S. Regan, BPharm, RPh; Beth Common, MBA; Steven Burch, PhD

Stakeholder Perspective by Richard F. Radzin, PharmD

◆

Industry Trends

◆

Generic Drug Trends

◆

AMCP Highlights

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

Covers_Cover 12/14/10 11:52 AM Page 358

Image: Colored scanning electron micrograph (SEM) of a pancreatic cancer cell.

goal

Covers_Cover 12/14/10 11:52 AM Page 359

One goal: discovering and delivering breakthrough medicines to combat cancer.

Now the innovative science of a leading American biopharmaceutical company joins the global assets of Takeda, Japan’s largest pharmaceutical company, for a global commitment to oncology.

Millennium: The Takeda Oncology Company is developing an extensive pipeline — among the top in oncology worldwide — with more than 17 compounds in development for a broad range of solid and hematological cancers.

Our pipeline — rich in novel compounds — includes multiple candidates that target seven disease pathways: protein homeostasis, anti-angiogenesis, growth-signaling inhibition, cell-cycle inhibition, apoptosis, immunomodulators and hormone regulation.

We are dedicated to a strong partnership with the oncology community. Together we can make a dramatic impact on cancer therapeutics over the next decade.

To learn more, visit us at millennium.com. ©2010 Millennium Pharmaceuticals, Inc. All rights reserved.

TOC_EditBoard_Cover 12/14/10 11:55 AM Page 360

EDITORIAL BOARD

CLINICAL EDITOR

PHARMACY BENEFIT DESIGN

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

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

Joel V. Brill, MD Chief Medical Officer, Predictive Health, Phoenix, AZ William J. Cardarelli, PharmD Director of Pharmacy Atrius Health Harvard Vanguard Medical Associates

GOVERNMENT EDITOR

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

HEALTH INFORMATION TECHNOLOGY

J. B. Jones, PhD, MBA Research Associate, Geisinger Health System, Danville, PA Victor J. Strecher, PhD, MPH Professor and Director, Center for Health Communications Research University of Michigan Schools of Public Health and Medicine, Ann Arbor Founder and Chief Visionary Officer HealthMedia, Johnson & Johnson Co.

ACTUARY

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 President, ACCC Past Chair, Board of Directors, NCCN

HEALTH OUTCOMES RESEARCH

Gordon M. Cummins, MS Director, IntegriChain

POLICY & PUBLIC HEALTH

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

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

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

CARDIOLOGY RESEARCH MANAGED CARE & GOVERNMENT AFFAIRS

ENDOCRINOLOGY RESEARCH

MANAGED MARKETS

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

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

EMPLOYERS

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

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

Alberto M. Colombi, MD, MPH Corporate Medical Director PPG Industries, Pittsburgh, PA

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

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

EPIDEMIOLOGY RESEARCH

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

American Health & Drug Benefits

REIMBURSEMENT POLICY

PERSONALIZED MEDICINE

F. Randy Vogenberg, RPh, PhD Principal, Institute of Integrated Healthcare Sharon, MA Senior Fellow, Jefferson School of Population Health

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

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

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

360

Alex Hathaway, MD, MPH, FACPM President & Founder, J.D. BioEdge Health quality and biomedical research consultancy

PATIENT ADVOCACY

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

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Matthew Mitchell, PharmD, MBA Manager, Pharmacy Services SelectHealth, Salt Lake City, UT

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

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

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

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

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

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

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

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

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

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

November/December 2010

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NOW

AVAILABLE

www.halaven.com

HALAVEN™ is a trademark used by Eisai Inc. under license from Eisai R&D Management Co., Ltd. © 2010 Eisai Inc. All rights reserved. ERI 65A

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NOVEMBER/DECEMBER 2010

VOLUME 3, NUMBER 6

THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN ™

™

™

FOR PAYERS, PURCHASERS, POLICYMAKERS, AND OTHER HEALTHCARE STAKEHOLDERS

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

REGULATORY

368 Implications of the New Political Realities on Healthcare Reform Interview with Dan Mendelson

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

CLINICAL

372 Engaging Providers in Medication Adherence: A Health Plan Case Study Amy B. Scott, BSPharm, RPh; Jane E. McClure, BA, RN

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

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

Editorial Assistant Jessica A. Smith

BUSINESS Senior Production Manager Lynn Hamilton

394 The H-E-B Value-Based Health Management Program: Impact on Asthma Medication Adherence and Healthcare Cost Anna O. D’Souza, PhD; Roshan Rahnama, MPH; Timothy S. Regan, BPharm, RPh; Beth Common, MBA; Steven Burch, PhD

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

402 Stakeholder Perspective by Richard F. Radzin, PharmD

Mission Statement Continued on page 364

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

BPA Worldwide membership applied for August 2010.

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American Health & Drug Benefits is founded on the concept that health and drug benefits have undergone a transformation: the econometric value of a drug is of equal importance to clinical outcomes as it is to serving as the basis for securing coverage in formularies and benefit designs. Because benefit designs are greatly affected by clinical, business, and policy conditions, this journal offers a forum for stakeholder integration and collaboration toward the improvement of healthcare.

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

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

November/December 2010

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exploring

DIABETES inspired to make a

DIFFERENCE

Copyright Š2010, Boehringer Ingelheim Pharmaceuticals, Inc. All rights reserved.

(06/10)

DI77201MHC-A

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NOVEMBER/DECEMBER 2010

VOLUME 3, NUMBER 6

THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN ™

™

™

FOR PAYERS, PURCHASERS, POLICYMAKERS, AND OTHER HEALTHCARE STAKEHOLDERS

TABLE OF CONTENTS

(Continued)

DEPARTMENTS

383 INDUSTRY TRENDS Moving Beyond Good Intentions: Making Collaborative Care a Successful Reality Gordon Norman, MD, MBA 391 GENERIC DRUG TRENDS Generic Pipeline Predicts Continued Market Share Gain Through 2014 Dalia Buffery, MA, ABD AMCP HIGHLIGHTS 404 Cost May Not Drive Formulary Choice After All Method Used to Measure MPR Influences Adherence Rate Pharmacists’ Monitoring of ESAs Leads to Cost-Savings 405 Adding a Pharmacist to a Medical Home May Cut Costs Step-Therapy Program to Lower Rx Costs, Keep Members Happy 406 Disease State Impacts Medication Adherence Targeting Waste in Targeted Therapies 406 Correction 408 Manuscript Instructions for Authors 371 The Association for Value-Based Cancer Care First Annual Conference

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DEXILANT WORKS A

SECOND SHIFT TO HELP SHUT DOWN ACID PUMPS

DEXILANT is the first and only PPI with a Dual Delayed Release™ (DDR) formulation, which provides a second release of drug Mean plasma concentration (in healthy subjects; day 5; ng/mL)1 1200 1000 800 600 400

DEXILANT 60 mg 200

DEXILANT 30 mg

0 0

6

12

18

24

Time (h)

s DEXILANT 30 mg provided full 24-hour heartburn relief in a majority of symptomatic non-erosive gastroesophageal reflux disease patients at week 41 Conclusions of comparative efficacy cannot be drawn from this information.

Indications DEXILANT is indicated for healing all grades of erosive esophagitis (EE) for up to 8 weeks, maintaining healing of EE for up to 6 months, and treating heartburn associated with symptomatic non-erosive gastroesophageal reflux disease (GERD) for 4 weeks.

Important Safety Information DEXILANT is contraindicated in patients with known hypersensitivity to any component of the formulation. Hypersensitivity and anaphylaxis have been reported with DEXILANT use. Symptomatic response with DEXILANT does not preclude the presence of gastric malignancy.

Most commonly reported treatment-emergent adverse reactions: diarrhea (4.8%), abdominal pain (4.0%), nausea (2.9%), upper respiratory tract infection (1.9%), vomiting (1.6%), and flatulence (1.6%).

Do not co-administer atazanavir with DEXILANT because atazanavir systemic concentrations may be substantially decreased. DEXILANT 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 DEXILANT.

FORMERLY

KAPIDEX™ (dexlansoprazole)

11:00:12 AM

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BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION DEXILANT (dexlansoprazole) delayed release capsules INDICATIONS AND USAGE DEXILANT is indicated for: K D85 851<9>7 ?6 1<< 7B145C ?6 5B?C9F5 5C?@8179D9C 6?B E@ D? G55;C K =19>D19>9>7 851<9>7 ?6 6?B E@ D? =?>D8C 1>4 K D85 DB51D=5>D ?6 851BD2EB> 1CC?391D54 G9D8 >?> 5B?C9F5 71CDB?5C?@81751< B56<EH 49C51C5 ( 6?B G55;C CONTRAINDICATIONS - " $* 9C 3?>DB19>4931D54 9> @1D95>DC G9D8 ;>?G> 8I@5BC5>C9D9F9DI D? 1>I 3?=@?>5>D ?6 D85 6?B=E<1D9?> I@5BC5>C9D9F9DI 1>4 1>1@8I<1H9C 81F5 255> B5@?BD54 G9D8 - " $* EC5 [see Adverse Reactions].

WARNINGS AND PRECAUTIONS Gastric Malignancy )I=@D?=1D93 B5C@?>C5 G9D8 - " $* 4?5C >?D @B53<E45 D85 @B5C5>35 ?6 71CDB93 =1<97>1>3I ADVERSE REACTIONS Clinical Trials Experience *85 C165DI ?6 - " $* G1C 5F1<E1D54 9> @1D95>DC 9> 3?>DB?<<54 1>4 E>3?>DB?<<54 3<9>931< CDE495C 9>3<E49>7 @1D95>DC DB51D54 6?B 1D <51CD =?>D8C 1>4

@1D95>DC DB51D54 6?B ?>5 I51B &1D95>DC B1>754 9> 175 6B?= D? I51BC =5491> 175 I51BC G9D8 65=1<5 1E31C91> <13; C91> 1>4 ?D85B B135C )9H B1>4?=9J54 3?>DB?<<54 3<9>931< DB91<C G5B5 3?>4E3D54 6?B D85 DB51D=5>D ?6 =19>D5>1>35 ?6 851<54 1>4 CI=@D?=1D93 ( G8938 9>3<E454 @1D95>DC ?> @<1352? @1D95>DC ?> - " $* =7

@1D95>DC ?> - " $* =7 1>4 @1D95>DC ?> <1>C?@B1J?<5 =7 ?>35 419<I C 3<9>931< DB91<C 1B5 3?>4E3D54 E>45B G945<I F1BI9>7 3?>49D9?>C 14F5BC5 B513D9?> B1D5C ?2C5BF54 9> D85 3<9>931< DB91<C ?6 1 4BE7 31>>?D 25 49B53D<I 3?=@1B54 D? B1D5C 9> D85 3<9>931< DB91<C ?6 1>?D85B 4BE7 1>4 =1I >?D B56<53D D85 B1D5C ?2C5BF54 9> @B13D935 #?CD ?==?><I (5@?BD54 4F5BC5 (513D9?>C *85 =?CD 3?==?> 14F5BC5 B513D9?>C D81D ?33EBB54 1D 1 89785B 9>3945>35 6?B - " $* D81> @<1352? 9> D85 3?>DB?<<54 CDE495C 1B5 @B5C5>D54 9> *12<5

Table 2: Incidence of Treatment-Emergent Adverse Reactions in Controlled Studies Placebo

DEXILANT 60 mg (N=2218) %

DEXILANT Total (N=2621) %

Lansoprazole 30 mg (N=1363) %

Adverse Reaction 91BB851 24?=9>1< &19> $1EC51

(N=896) %

DEXILANT 30 mg (N=455) %

+@@5B (5C@9B1D?BI Tract Infection

,?=9D9>7 <1DE<5>35

4F5BC5 (513D9?>C (5CE<D9>7 9> 9C3?>D9>E1D9?> > 3?>DB?<<54 3<9>931< CDE495C D85 =?CD 3?==?> 14F5BC5 B513D9?> <5149>7 D? 49C3?>D9>E1D9?> 6B?= - " $* D85B1@I G1C 491BB851

%D85B 4F5BC5 (513D9?>C %D85B 14F5BC5 B513D9?>C D81D G5B5 B5@?BD54 9> 3?>DB?<<54 CDE495C 1D 1> 9>3945>35 ?6 <5CC D81> 1B5 <9CD54 25<?G 2I 2?4I CICD5= Blood and Lymphatic System Disorders: 1>5=91 <I=@8145>?@1D8I Cardiac Disorders: 1>79>1 1BB8ID8=91 2B14I31B491 385CD @19> 545=1 =I?31B491< 9>61B3D9?> @1<@9D1D9?> D138I31B491 Ear and Labyrinth Disorders: 51B @19> D9>>9DEC F5BD97? Endocrine Disorders: 7?9D5B Eye Disorders: 5I5 9BB9D1D9?> 5I5 CG5<<9>7 Gastrointestinal Disorders: 124?=9>1< 49C3?=6?BD 124?=9>1< D5>45B>5CC 12>?B=1< 6535C 1>1< 49C3?=6?BD 1BB5DD C 5C?@817EC 25J?1B 2?G5< C?E>4C 12>?B=1< 2B51D8 ?4?B 3?<9D9C =93B?C3?@93 3?<?>93 @?<I@ 3?>CD9@1D9?> 4BI =?ED8 4E?45>9D9C 4IC@5@C91 4IC@81791 5>D5B9D9C 5BE3D1D9?> 5C?@8179D9C 71CDB93 @?<I@ 71CDB9D9C 71CDB?5>D5B9D9C 71CDB?9>D5CD9>1< 49C?B45BC 71CDB?9>D5CD9>1< 8I@5B=?D9<9DI 49C?B45BC ( E<35BC 1>4 @5B6?B1D9?> 85=1D5=5C9C 85=1D?385J91 85=?BB8?94C 9=@19B54 71CDB93 5=@DI9>7 9BB9D12<5 2?G5< CI>4B?=5 =E3EC CD??<C >1EC51 1>4 F?=9D9>7 ?B1< =E3?C1< 2<9CD5B9>7 @19>6E< 456531D9?> @B?3D9D9C @1B5CD85C91 ?B1< B53D1< 85=?BB8175 General Disorders and Administration Site Conditions: 14F5BC5 4BE7 B513D9?> 1CD85>91 385CD @19> 389<<C 655<9>7 12>?B=1< 9>6<1==1D9?> =E3?C1< 9>6<1==1D9?> >?4E<5 @19> @IB5H91 Hepatobiliary Disorders: 29<91BI 3?<93 38?<5<9D891C9C 85@1D?=571<I Immune System Disorders: 8I@5BC5>C9D9F9DI Infections and Infestations: 31>4941 9>653D9?>C 9>6<E5>J1 >1C?@81BI>79D9C ?B1< 85B@5C @81BI>79D9C C9>EC9D9C F9B1< 9>653D9?> FE<F? F179>1< 9>653D9?> Injury, Poisoning and Procedural Complications: 61<<C 6B13DEB5C :?9>D C@B19>C ?F5B4?C5

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A reproduction study conducted in rabbits at oral dexlansoprazole doses up to 30 mg per kg per day (approximately 9-fold the maximum recommended human dexlansoprazole dose (60 mg) revealed no evidence of harm to the fetus due to dexlansoprazole. In addition, reproduction studies performed in pregnant rats with oral lansoprazole at doses up to 40 times the recommended human dose and in pregnant rabbits at oral lansoprazole doses up to 16 times the recommended human dose revealed no evidence of impaired fertility or harm to the fetus due to lansoprazole.

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

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

Geriatric Use In clinical studies of DEXILANT, 11% of patients were aged 65 years and over.

No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified significant differences in responses between geriatric and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

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

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

OVERDOSAGE There have been no reports of significant overdose of DEXILANT. Multiple doses of DEXILANT 120 mg and a single dose of DEXILANT 300 mg did not result in death or other severe adverse events. Dexlansoprazole is not expected to be removed from the circulation by hemodialysis. If an overdose occurs, treatment should be symptomatic and supportive.

CLINICAL PHARMACOLOGY Pharmacodynamics Antisecretory Activity The effects of DEXILANT 60 mg (n=20) or lansoprazole 30 mg (n=23) once daily for five days on 24-hour intragastric pH were assessed in healthy subjects in a multiple-dose crossover study.

Serum Gastrin Effects The effect of DEXILANT on serum gastrin concentrations was evaluated in approximately 3460 patients in clinical trials up to 8 weeks and in 1023 patients for up to 6 to 12 months. The mean fasting gastrin concentrations increased from baseline during treatment with DEXILANT 30 mg and 60 mg doses. In patients treated for more than 6 months, mean serum gastrin levels increased during approximately the first 3 months of treatment and were stable for the remainder of treatment. Mean serum gastrin levels returned to pre-treatment levels within one month of discontinuation of treatment.

Enterochromaffin-Like Cell (ECL) Effects There were no reports of ECL cell hyperplasia in gastric biopsy specimens obtained from 653 patients treated with DEXILANT 30 mg, 60 mg or 90 mg for up to 12 months.

During lifetime exposure of rats dosed daily with up to 150 mg per kg per day of lansoprazole, marked hypergastrinemia was observed followed by ECL cell proliferation and formation of carcinoid tumors, especially in female rats [see Nonclinical Toxicology].

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

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

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

In rats, lansoprazole also increased the incidence of intestinal metaplasia of the gastric epithelium in both sexes. In male rats, lansoprazole produced a dose-related increase of testicular interstitial cell adenomas. The incidence of these adenomas in rats receiving doses of 15 to 150 mg per kg per day (4 to 40 times the recommended lansoprazole human dose based on BSA) exceeded the low background incidence (range = 1.4 to 10%) for this strain of rat.

In a 24-month carcinogenicity study, CD-1 mice were treated orally with lansoprazole doses of 15 mg to 600 mg per kg per day, 2 to 80 times the recommended human dose based on BSA. Lansoprazole produced a dose-related increased incidence of gastric ECL cell hyperplasia. It also produced an increased incidence of liver tumors (hepatocellular adenoma plus carcinoma). The tumor incidences in male mice treated with 300 mg and 600 mg lansoprazole per kg per day (40 to 80 times the recommended lansoprazole human dose based on BSA) and female mice treated with 150 mg to 600 mg lansoprazole per kg per day (20 to 80 times the recommended human dose based on BSA) exceeded the ranges of background incidences in historical controls for this strain of mice. Lansoprazole treatment produced adenoma of rete testis in male mice receiving 75 to 600 mg per kg per day (10 to 80 times the recommended lansoprazole human dose based on BSA).

The potential effects of dexlansoprazole on fertility and reproductive performance were assessed using lansoprazole studies. Lansoprazole at oral doses up to 150 mg per kg per day (40 times the recommended lansoprazole human dose based on BSA) 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 Tell your patients to watch for signs of an allergic reaction as these could be serious and may require that DEXILANT be discontinued.

To ensure the safe and effective use of DEXILANT, this information and instructions provided in the FDA-approved patient labeling should be discussed with the patient. Inform patients of the following: DEXILANT is available as a delayed release capsule.

DEXILANT may be taken without regard to food.

DEXILANT should be swallowed whole.

K <D5B>1D9F5<I - " $* 31@CE<5C 31> 25 ?@5>54 1>4 14=9>9CD5B54 1C follows: - Open capsule; - Sprinkle intact granules on one tablespoon of applesauce; - Swallow immediately.

Distributed by Takeda Pharmaceuticals America, Inc. Deerfield, IL 60015 U.S. Patent Nos. - 5,045,321; 5,093,132; 5,433,959; 6,462,058; 6,664,276; 6,939,971; and 7,285,668.

DEXILANT is a trademark of Takeda Pharmaceuticals North America, Inc. and used under license by Takeda Pharmaceuticals America, Inc. All other trademark names are the property of their respective owners. Š2009, 2010 Takeda Pharmaceuticals America, Inc. For more detailed information, see the full prescribing information for DEXILANT or contact Takeda Pharmaceuticals America, Inc. at 1-877-825-3327.

KAP0110 R6-Brf; March 2010 L-LPD-0310-2

Reference: 1. DEXILANT (dexlansoprazole) package insert, Takeda Pharmaceuticals America, Inc. DEXILANTâ&#x201E;˘, KAPIDEXâ&#x201E;˘ (dexlansoprazole), and Dual Delayed Releaseâ&#x201E;˘ are trademarks of Takeda Pharmaceuticals North America, Inc., and are used under license by Takeda Pharmaceuticals America, Inc. Š2010 Takeda Pharmaceuticals North America, Inc. LPD-01139 6/10 Printed in U.S.A.

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COMMENTARY

Implications of the New Political Realities on Healthcare Reform Interview with Dan Mendelson

With the recent change in power in the US House of Representatives that will take effect in January, questions arise regarding potential modifications to some features in the healthcare reform bill and its implementation. With many provisions scheduled to take effect between 2011 and 2014, the political implications of the elections have an immediate practical relevance to health plans, employers, and other healthcare stakeholders.

American Health & Drug Benefits discussed some of these issues with Dan Mendelson, who served in the Clinton administration between 1997 and 2000, when there was a similar division of party power between Congress and the administration.

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Dalia Buffery: What changes can healthcare decision makers expect to see in the near future as a result of the recent national elections and their potential implications on the reform bill?

Dan Mendelson: First, it is important for everyone involved in healthcare to understand that this is a very fundamental change. The Patient Protection and Affordable Care Act (PPACA, now often referred to as the Affordable Care Act [ACA]), was passed by the Democrats without bipartisan support. Now that there will be a Republican-controlled House, we are in an environment of split government, and in such an environment, compromise and negotiation become necessary for government to run. That is the main implication of the midterm elections, and that is not going to change for at least another 2 years. In fact, we are probably going to be living with some type of power sharing for a long time. This is a fundamental change, and it is the starting point for a heated discussion of healthcare.

Some have dismissed the election, saying, “Well, it is not important, because in order to repeal reform, the Republicans would need a two-thirds majority to override a presidential veto”; in fact, there will be fundamental effects, now and in the future, by virtue of Republican oversight, appropriations, and the fact that Mr Mendelson is Chief Executive Officer and Founder of Avalere Health, LLC, Washington, DC. Ms Buffery is Editorial Director of American Health & Drug Benefits.

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many of the new Republican members effectively used the healthcare debate to get elected.

Second, it is important to think about the timing of health system change that was passed under the ACA. There are basically 3 phases of reform. The first involves payment reduction, which has resulted in reductions in profit margins that managed care organizations, hospitals, physician groups, and pharmaceutical companies will endure. That is happening now, and it will intensify through 2012. No one is talking about repealing those cuts.

The second phase of reform is an effort by the federal government to transfer risk from the government to providers. This phase of risk transfer starts in 2012 and continues to 2014. It is proceeding rapidly, and it is clearly going to happen.

The part of the reform that is at risk at this point is the third phase—the coverage expansion. The coverage expansion is not even slated to start until 2014. This is a long lead time, and there is going to be a very rancorous debate during the next couple of years as to how the coverage expansion is going to play out.

Buffery: You seem to suggest that repeal is not in the cards, even though there may be an attempt to repeal the bill?

Mendelson: Full repeal will not happen in the next 2 years. But reform is going to be modified over the coming years, and some legislation may pass that modifies the reform construct. Nobody is talking about repealing the payment reductions. More important, nobody is

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talking explicitly about repealing the expansion of health insurance coverage to low-income individuals under Medicaid. Some 16 million additional Americans earning less than 133% of the poverty line will be insured through Medicaid under the ACA, and no one is talking about repealing their coverage—a benefit that will add about $0.5 trillion to federal spending over 10 years.

The part that the new House majority will be focused on is the mandate, and all the associated changes in the commercial marketplace. The best way to think about this is that it is going to be revised serially over the next 4 years, depending on whether the 2 parties actually come together to compromise on this issue and any future changes in the balance of power going forward.

Some other changes will start now. The House majority has 2 tools that it will use to engage with the Obama administration, and having lived through split government, I am familiar with these tools. I was a political appointee in the latter period of the Clinton administration, and at the time I was there, we had split government. The Senate and House had a Republican majority, and we did not do anything of substance without consulting with the committees of jurisdiction.

House Republicans have 2 tools, or powers, in particular that they will use to engage. One is oversight; the House Republican oversight committees will increasingly be bringing the administration up to discuss the regulations, how they are evolving, and the role of different individuals in crafting the regulations. House Republicans will also exercise power through the appropriations process. To fund the government, Congress has to pass a law that says how much is going to be spent, and the House Republicans can affect every aspect of government in that appropriations process.

Buffery: What do you think will be the focus in terms of oversight in relation to the healthcare reform?

Mendelson: Congress will focus on the coverage mandate for individuals, because this mandate is unpalatable to the majority of Americans, and especially because the purchase of insurance may be burdensome for middle-income Americans. The administration is in an awkward position, because they have spent a lot of time vilifying the insurance industry, and now they are telling Americans that they must purchase that industry’s product. They will also hold oversight hearings on the effects of health reform on business, that is, the reality that for many small- and medium-sized businesses it will be more cost-effective to discontinue insurance and move their employees over to the new healthcare coverage exchanges.

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In addition, important insurance regulations are coming up within the next 6 months. The first regulation is the one that defines medical loss ratio; another will define the health insurance exchanges. These will be the focus of much debate, and depending on how aggressive Congress gets, they may try to slow down and stop these regulations through oversight hearings and through the appropriations process.

Buffery: What do you envision as the biggest changes to the mandate?

Mendelson: When thinking about “real” change in the reform construct, there are 2 possibilities. The first is compromise between the 2 sides, which would involve in-depth discussions about the bill, and possibly replacing the mandate with other policy designed to ensure that most Americans are insured. This will only happen if both sides come to the belief that they will benefit from discussions. Republicans in particular would have to believe that having responsibility for the health economy after the 2012 election is less desirable than stonewalling to try to unseat the president with this issue.

The second possibility is that the Republicans will conclude that they do not want to compromise, and they will continue to use the mandate, the expansion of government, and other issues of interest to their constituents to engage the administration in advance of the 2012 election. In that case, they would engage on the regulations, and then they would conduct hearings and talk about all the problems, and use that as a way to build momentum for the presidential candidacy of a designated person.

Frankly, based on what I have seen so far and in talking with some members of Congress, Republicans are more likely to take the second route of discussing problems, which will mean that it is likely to take an extended period of time before we get more clarity on what will be the final configuration of reform.

Buffery: Are there other implications to consider?

Mendelson: Two more clinical aspects to the ACA merit some discussion as they relate directly to health plans and those involved in clinical care. The first is the growing interest in the use of evidence-based medicine (EBM) by government and private sector payers.

Making decisions based on EBM is a growing trend, and we are going to see comparative effectiveness research and a generation of new evidence become more applicable to what health plans cover. This trend will continue, irrespective of the repeal discussion. My guess is that the Republicans will start to embrace concepts of evidence-

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generation more fully now, because it is one of the few tools that most analysts believe can be put in place to control costs in the long run. This will be a Congress that is dominated by fiscal austerity.

It is at times when there is split government that costcontrol emerges as an honest priority, as evidenced by the 1995 Budget Act and by the Balanced Budget Act of 1997. It is when the Republicans control the appropriations process and the Democrats control the administration that we can actually get some true fiscal discipline.

When we have a concept like EBMâ&#x20AC;&#x201D;which has the potential for cost-control and strong buy-in from the insurance industry and from the pharmaceutical industry at this point, within certain parametersâ&#x20AC;&#x201D;there is going to be a movement toward embracing EBM. The Republicans may take issue with some of the structures that were put in place under the ACAâ&#x20AC;&#x201D;for example, they may try to disband or modify the Independent Payment Advisory Board. But cost-reduction is going to be very popular, and that plays well in the long run for the health plans and for benefit managers, because they know how to do that.

The second clinically oriented observation is that the Center for Medicare Innovation at the Centers for Medicare & Medicaid Services (CMS) will continue to attract bipartisan support. Although CMS generally does not always have that kind of support, the Center for Medicare Innovation is responsible for cost-saving changes in the Medicare payment systems. Rick Gilfillan, who came from Geisinger Health System and is now running this center, will have solid bipartisan support.

Buffery: What about appropriations?

Mendelson: Appropriations will become a negotiation over which programs are going to flourish and which are not. And that, I think, will be shaped by their health policy priorities. Programs like the Center for Medicare Innovation and much of the EBM work should have House Republican support, but House Republicans will attempt to defund other spending, such as the consumer outreach around health insurance exchanges.

House Republicans are going to go line by line through the law and figure out what they want to appropriate and what they do not. Of course, any such bill ultimately must be signed by the president, so we can expect some compromise on both sides.

Buffery: Finally, are there any implications to drug de velopment and innovation?

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Mendelson: A couple of things relate specifically to the pharmaceutical industry and drug development.

The first is that the need to generate evidence, and in particular, evidence of the viability of the product on a postmarketing or a postapproval basis, is increasing.

That is going to be firmly cemented over the next couple of years and will have bipartisan support.

The second point is that the PDUFA (Prescription Drug User Fee Act) is up for renegotiation, and having an antiregulatory climate in the House will benefit the pharmaceutical industry significantly in that negotiation. This new climate will also give the pharmaceutical industry some leverage at the US Food and Drug Administration (FDA). It is good timing for the pharmaceutical industry.

For regulatory policy in the FDA, the presence of split government is most likely positive for the development pathways, because it creates more operating stability. It is on the commercial side that there is instability.

Buffery: As a conclusion, keeping our readers in mind, what do you expect that health insurance companies will be doing now?

Mendelson: Good question. They will do a couple of things. First, they will have a new way to engage in the regulations that are being produced by the OCIIO (Office of Consumer Information and Insurance Oversight) and by CMS. They will be able to engage in these regulations in a much fuller way. They will be testifying on them publicly; there will be much more communication about the implications of these regulations, and the insurance industry will engage fully in those discussions.

Second, the insurance industry will be able to talk more freely about the implications of some of these changes. There has been, in essence, an unwritten rule that insurance companies could not talk about premium increases that result from reform, and that now changes. At the same time, the insurance industry faces a very critical choice as to how to position itself around the mandate. The mandate is the thing that makes this entire construct work, and if they want to play with the Republicans at all, health insurance companies have to figure out whether there is a substitute that would enable them to ensure that more people are going to purchase insurance under a construct that is more palatable to the House majority, as well as to the American people.

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First Annual Stakeholder Integration Conference Integrating Payers, Providers, and the Entire Oncology Team March 29-30, 2011 Philadelphia, PA Loews Philadelphia Hotel

MEETING AGENDA*

PROGRAM OVERVIEW This is the first national stakeholder integration meeting dedicated to advancing the understanding of value in cancer care. Guided by the expertise of leaders in these fields, attendees will receive a thorough understanding of the evolution of the value equation as it relates to cancer therapies and will be able to implement, improve, and sustain their companies and institutions, while improving access for patients and ultimately patient care.

Tuesday, March 29 4:00

– 6:00 pm

Cancer Care from a Large Insurer’s Perspective The Role of Diagnostics from a PBM’s Standpoint

6:15

– 8:30 pm

Welcome/Networking Reception in the Exhibit Hall

Wednesday, March 30

WHO SHOULD ATTEND

7:30

– 8:30 am

Corporate-Sponsored Breakfast Symposium

All stakeholders in a position to impact cancer patient care are invited to join this exciting forum. Specifically this conference is intended for: • Medical Oncologists • Advanced Practitioners • Hematologists/Oncologists • Managed Care Professionals • Surgical Oncologists • Medical Directors • Nurses • Practice Managers/Administrators • Pharmacists • Pharmacy Benefit Managers (PBMs)

8:30

– 8:45 am

Intro/Opening

8:45

– 9:30 am

General Session 1 – NCCN Guidelines Acceptance and Compliance

9:30

– 10:15 am

General Session 2 – The Impact of Personalized Oncology Therapies

GOAL

11:00

10:20 – 10:50 am Morning Break in the Exhibit Hall – 12:30 pm

The Association for Value-Based Cancer Care’s First Annual Stakeholder Integration Conference will foster an open dialogue between providers, payers, and/or other members of the oncology team in order for attendees to gain a better understanding of various points of view regarding cost, quality, and access in cancer care.

Payer Track • Medicare and Reimbursement Issues • Drug Reimbursement and Administration Issues • Evolutions in Oncology Pharmacy Management

OBJECTIVES • Examine the impact of healthcare reform on all stakeholders involved in the management of patients with cancer • Identify issues and potential solutions to challenges with access and affordability of oncology therapeutics • Determine the value equation of cost, quality, and access when evaluating the diagnosis, treatment, and overall management of cancer patients • Define appropriate comparative effectiveness research and clinical pathways as tools to evaluate current recommendations for patient management • Analyze trends in the delivery of care in the management of cancer patients

Provider Track • Community Oncology: Trends • Patient Navigation: Impact • Oncology Practices: Issues with Managed Care

12:30 – 2:00 pm

CE Lunch Symposium Best Practices for Management of CINV: A Value-Based Approach

2:00

– 2:45 pm

General Session 3 – Cancer Care and the New Healthcare Legislation: What to Expect Next

2:45

– 3:30 pm

General Session 4 – Strategies for Improving Oncology Pharmacy and Care Management Models

3:35

– 4:05 pm

Afternoon Break in the Exhibit Hall

4:10

– 4:55 pm

General Session 5 – Clinical Trends: Impact of Oral, Injected, and Infused Therapies

5:00

– 6:00 pm

Cocktails/Networking in the Exhibit Hall

T H E A S S O C I AT I O N F O R

*Preliminary agenda is subject to change.

REGISTER ONLINE AT

www.ValueBasedCancer.com/association

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ORIGINAL RESEARCH

Engaging Providers in Medication Adherence: A Health Plan Case Study Amy B. Scott, BSPharm, RPh; Jane E. McClure, BA, RN

Amy B. Scott

Jane E. McClure

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Background: Nonadherence to treatment regimens is a common, costly, and complex problem that is often overlooked in a busy primary care setting.

Objective: The goals of this study were to raise providers’ awareness of nonadherence among their patients, to identify the reasons for lack of adherence, and engage physicians in addressing these barriers.

Method: Five primary care practices agreed to participate. The project began in the fall of 2008 with a therapy gap analysis, using prescription drug data from the previous 18 months to identify nonadherent patients. Initially, 237 members were identified as potential nonadherent patients. Each practice was presented with the data related to its patients; the group then narrowed its sample using a chart review and/or patient outreach. Each practice had to determine the barriers to adherence, and was then asked to create action steps to improve patient adherence based on the group’s unique results and the specific patient population.

Results: Barriers to adherence identified included prescription drug cost, multiple medications and dosing schedules, and patient as well as family level of understanding and acceptance of disease state. Each group gained an awareness of nonadherence as it related to their patients. For example, in the internal medicine practice, 33% (n = 17) of the patients reported stopping their medication because of cost. A common reason for poor adherence in the pediatric groups was that parents decided to stop their child’s medication on weekends and in the summer, without a physician’s recommendation. Using such feedback, each practice then developed its own methods to improve medication adherence within its patient population.

Conclusion: Although the final numbers in this case study were small, the providers gained valuable insights regarding nonadherence in their practice. This study shows the importance of engaging providers in medication adherence as a way to improve this common problem. Making this universal issue a personal problem for providers is key to overcoming many of the adherence barriers.

Disclosures are at end of text

“Drugs don’t work in patients who don’t take them.”1—C. Everett Koop, MD, ScD, former US Surgeon General

P

rescription drug therapy is the mainstay of treatment for many chronic conditions, such as hypertension, hyperlipidemia, diabetes, asthma, and attention-deficit/hyperactivity disorder (ADHD). It is well known that adherence to a prescribed drug regimen is crucial for positive health outcomes. Medication adherence—the extent to which patients take medica-

Ms Scott is Clinical Pharmacy Specialist, and Ms McClure is Medical Management Consultant, Highmark, Inc, Pittsburgh, PA.

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tion as prescribed by their healthcare provider—requires a shared responsibility between patient and physician.1 Nonadherence is sometimes referred to as America’s “other drug problem.”2 This widespread problem is often overlooked; nonadherence is common, costly, and complex. One of every 4 medical visits results in patients not following the advice they were given.3 Each year, nonadherence contributes between 33% and 69% of medication-related hospital admissions.1 Studies show that within 1 year of being prescribed a medication, patients stop taking 50% of their long-term

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medications, and up to 1 of 5 new prescriptions is never filled.4,5 In addition, nonadherence is estimated to contribute to 125,000 deaths annually in the United States, and nonadherence costs an estimated $100 billion annually in direct and indirect healthcare costs.4,5 Based on the available literature, adherence depends to a large extent on the patient’s perceived health benefit; however, the healthcare provider must work with the patient and/or caregiver to educate, cooperate with, and help the patient to focus on such benefits.

Barriers to Medication Adherence Many patients engage (intentionally or not) in negative medication-taking behaviors—resulting from forgetfulness, cost, inconvenience, and attitudes—that may result in negative health outcomes. These behaviors include pill splitting, drug holidays, taking medications every other day, or never filling a prescription, all of which adversely affect health outcomes.6 An important barrier to adherence is low health literacy. Health literacy can be defined as the ability to read, understand, and make appropriate health decisions.7 Poor or low literacy level results in a patient’s inability to follow treatment recommendations and a reduced ability to navigate through the prescribed treatment plan (in this case, following prescribed medication regimens).7 Contributing to nonadherence is the high cost of prescription medications and out-of-pocket (OOP) expenses. It is known that 1 of 5 patients chooses not to fill a prescription because of cost.8 Financial barriers cannot be overlooked; therefore, influencing patient behavior with monetary incentives or other rewards for appropriate adherence to medication regimens may be useful.9 However, essential to improving patient compliance and adherence—to ultimately improve health outcome—is good communication between the patient and the entire healthcare team.1 Previous studies have shown that by engaging the patient and forming collaborative relationships, healthcare professionals can significantly influence adherence.2,10,11 In their recent commentary, Cutler and Everett suggest that with an investment of time and resources, healthcare providers can optimize and reconcile patient medication regimens in an attempt to manage nonadherence directly.9 Cutler and Everett further note that using proved adherence assessment tools at the time of the visit can predict risk for nonadherence. Having this information can enable providers to encourage adherence at the point of prescribing and during any followup contact with patients.9 Participating in any negative prescription-taking be -

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KEY POINTS ➤

➤

➤

➤

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Medication nonadherence is a well-known problem that is costly and complex but is often overlooked in a busy primary care setting.

The goal of this case study was to increase physicians’ awareness of the existence of this problem among their own patients, and to engage them in this problem.

Barriers to adherence identified in the 5 practices included drug cost, multiple medications and dosing schedules, and level of understanding/acceptance of disease state.

The participating physicians were surprised to find that some of their patients were not following their recommended drug regimens.

These findings highlight the need to engage providers in the issue of medication adherence in relation to their own patients.

havior can and does affect all patient types, yet noncompliance remains largely unrecognized in clinical practice.8

Highmark’s Project Design To address this problem, in the fall of 2008, Highmark, Inc, a large regional managed care health plan located in Pittsburgh, PA, with more than 4.5 million health insurance members and approximately 2.5 million prescription drug benefit members, embarked on a project to increase the awareness of its providers to nonadherence. The authors are Highmark employees who concentrate on building relationships with network providers to improve the quality of care for the health plan members.

A total of 5 distinct network primary care practices agreed to take part in this study. The goal was to illustrate to the physicians, by the use of prescription drug claims, the extent to which many of their patients were not following their medication regimens as prescribed.

Through conversation and discussion with these network providers we found that physicians in general believe that nonadherence is a global issue but does not directly affect their own patient population. This begged the question as to who is accountable for the resolution of the problem. Is it the clinician, the health plan, or the patient? As previously suggested, nonadherence is a joint responsibility that needs to be addressed by all parties.1 This current case study was conceived as a way to engage and challenge these Highmark network primary care physicians (PCPs) and staff to develop steps to improve medication adherence rates of plan members and ultimately of all their patients. Because each group

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differed in population and targeted disease state, the project developed according to the dynamics of the individual practice. To minimize the time a practice would need to commit to this project, patient samples were kept to a minimum. However, once the prescription drug data were shared with each group, their interest peaked.

Practices Participating in Medication Table 1 Adherence Project Group/practice type

Patients identified as nonadherent, N

A: Family practice

51

B: Internal medicine

51

C: Pediatrics, rural

54

D: Pediatrics, suburban

49

E: Pediatrics, urban

32

This study was conducted from the fall of 2008 through the spring of 2009; it began with a medication gap analysis using prescription drug claims data from the previous 18 months. Once practice-specific barriers to adherence were identified, solutions were developed for the varied populations. Collaboration between the providers and the health plan consultants was key in these processes.

These claims data helped to identify potential nonadherent patients from the 5 primary care practicesâ&#x20AC;&#x201D; 1 internal medicine, 1 family practice, and 3 pediatric groups. Each group was provided with a small sample of patients (Table 1).

These groups were selected based on their positive relationship with the Highmark team and on their willingness to join in this process improvement initiative that could be submitted to QualityBLUE, the health plansâ&#x20AC;&#x2122; physician pay-for-performance (P4P) incentive program.

Once potential nonadherent patients with hypertension, hyperlipidemia, or ADHD were identified, the following questions were considered: 1. Are these patients truly nonadherent as illustrated by the claims data?

2. What are their reasons for nonadherence (barriers to adherence)?

3. What can the practice do to resolve these?

4. Is quality of care being affected by nonadherence?

The providers had to research patient charts to verify the prescription drug information and answer these questions.

To determine the specific barriers to adherence, the clinicians were asked to reach out to their patients.

Some clinicians chose to contact each patient by telephone to discuss the patientâ&#x20AC;&#x2122;s medication regimen; oth-

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ers opted to use a survey tool provided by the health plan for a more structured approach. Each practice was encouraged to create a plan of action to deal with the identified barriers.

Methodology The first step involved data collection for each of the 5 group practices; prescription drug claims were pulled for all of 2007 and for the first 6 months of 2008 (ie, 18 months). Data were extracted using membership of each practice, followed by therapeutic drug categories for hypertension, hyperlipidemia, and ADHD. This ensured that prescriptions ordered by a specialist other than the PCP would be included. Next, the project managers analyzed the information, identifying each member, and then looked for gaps or lack of claims that seemed excessive. We designated <80% adherence as the determining factor.

Sample spreadsheets were developed as a visual tool for each practice to illustrate the gaps in therapy (Figure). Each practice had to determine whether the gaps in claims corresponded to true gaps in therapy or were a result of another reason that could not be determined by claims analysis, such as physician discontinuation of medication, a patient leaving the practice, or a change in insurance coverage.

After sharing the findings with the plan consultants, a chart review was prepared for each group, and the next steps and interventions suggested. This is where each group differed.

Results Individual Practice Group Group A: Family Practice. This group was a large, urban, multiprovider practice with 3 locations and fully automated electronic medical records (EMRs). The practice administrator reviewed each of the 51 electronic charts of patients identified as nonadherent and was skeptical of these results. The administrator personally called every patient to discuss the importance of taking prescribed medications or contacted the pharmacy when the patient was unavailable. She found that 71% (n = 36) of these members were in fact getting their prescriptions filled. However, their claims were being paid for in cash and were not being submitted by the retail pharmacies, because they were part of a promotional generic drug program. This alerted the authors to a claims submission problem.

Indirectly, the lack of these claims also signified that the high cost of prescription drug therapy could be a barrier to adherence. However, these patients were satisfied with getting a generic product filled that reduced their OOP spending. In addition, of patients identified as

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Member

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5

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Time frame Drug

Lipitor

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Atenolol

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Exforge

Dynacirc

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Simvastatin

Tekturna

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Drug

Lisinopril

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Lovaza

Amlodipine

Niaspan

Benicar

Simvastatin

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Metoprolol

Practice X

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2007

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FEB

Figure Medication Compliance Sample Data Sheet

MAR

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Rx filled

APR

APR

APR

APR

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APR

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MAY

MAY

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Not filled

JUNE JULY

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AUG

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Rx filled

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Group A, Family Practice: Additional Explanations Table 2 for Nonadherence Patients, N (%) (N = 51)a

Reason for nonadherence Patient transferred to a nursing facility, medications provided in house, or no prescription claim submitted

1 (2)

Patient deceased

2 (4)

Patient moved; however, prescriptions were still filled but practice had no contact with patient

2 (4)

Patient cited high cost

2 (4)

Patient noncompliant with office appointments: did not get required written prescription

1 (2)

Patient stopped medication on his/her own for varied reasons

1 (2)

Patient taking drug twice weekly instead of daily

1 (2)

Data error: patient not part of practice

3 (6)

aOf these 51 patients, 36 were taking a generic, and 6 were taking samples of their medications.

NOTE: Patients could fall into >1 category, because many were taking multiple agents.

nonadherent, 12% (n = 6) were getting sample medication from the PCP or the specialist; samples do not generate a claim and, therefore, appear as a gap in therapy.

Patients could fall into more than 1 of these categories, because they were taking multiple medications. Other reasons for apparent gaps are listed in Table 2.

As a result, group A was confident that a high percentage of the targeted patients were adherent to their medication regimens. The authors found that flaws, errors, and discrepancies exist in the claims data, but the drug data presented a starting point for identifying nonadherence.

Group B: Internal Medicine. This rural group consisted of 4 physicians, with a cardiology subspecialty, and had a partially automated EMR. The practice manager examined each of the 51 electronic charts identified. In some cases the physician discontinued the medication in question, and in others, a lack of claim was the use of promotional generic drug programs in the marketplace (in which case claims are not submitted under a prescription benefit). Other reasons included a patient transfer to a skilled nursing facility and medication samples being provided to defray high OOP costs (which might have related to a tiered drug benefit, a nonformulary agent, or a coinsurance design).

This information again alerted the Highmark team

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that errors in drug data could be misleading. Another important finding was that 33% (n = 17) of the planidentified patients stopped the medication on their own, because of high cost. In each case, the clinician suggested an alternative therapy or recommended a patientassistance program. Without these data, this practice would not have known that those patients had stopped taking their medications.

Overall, the cliniciansâ&#x20AC;&#x2122; awareness was heightened, and they realized that chart review alone was an insufficient source of information for a subset, approximately 30% (n = 14), of the 51 patients who had been initially identified as nonadherent. A more formal approach to identifying specific barriers to adherence was needed.

The Highmark team recommended the ASK-20SM Survey as a tool to identify and address barriers to adherence. This validated survey, originally developed by GlaxoSmithKline (and used with permission for this study), examines categories related to medication-taking behaviors. The categories used in this study and the results are listed in Table 3.12-14 Again, the number of patients in this group was small, but the findings were astounding. The lead physician realized that changes were needed to reduce nonadherence among their patient population. The next step for group B was to create a gap-free system through their e-prescribing and EMR. This group is now developing an electronic alert that is built into the EMR system, which would be activated when the patient does not get a medication filled or refilled in a timely manner. This would enable the office staff to reach out to the patient and determine the reason for nonadherence.

Groups C, D, and E: Pediatrics. Three pediatric groups participated in the adherence project, using ADHD as the chronic condition studied. Pediatric group C was a large, rural, multiprovider site with multiple locations and a partially automated EMR system, which was closely aligned with a hospital system. Pediatric group D was a large, independent, suburban, multiprovider group with multiple locations yet without an EMR system. Pediatric group E was a large, independent, urban, multiprovider practice with multiple locations. In group E, a behavioral health physician specialist is employed in the practice, and it has a fully automated EMR system.

The findings for pediatric groups C and D were similar. After careful chart review identified nonadherent patients (Table 1), a few common barriers were identified (Table 4).

Some of the plan-identified gaps were determined to be appropriate, such as a change of medication by a

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physician or discontinuation of therapy. The providers rationalized that because of the high sensitivity of this diagnosis, there was no easy method of intervention to improve adherence.

Pediatric group E was the most engaged participant.

The behavioral health specialist was intrigued by the data, took ownership of the issue, and ultimately created an updated, modified management approach to ADHD for the group. Using claims data as a starting point, she reviewed each of the 32 electronic patient charts originally identified by the plan and found similar barriers to adherence compared with the other pediatric practices.

However, 11 (33%) of the 32 patients identified were found to be of college age, which encompassed a unique set of barriers to adherence (Table 5).

Discussion The main goal of this study was to increase the physicians’ awareness of medication nonadherence. Although it is well-documented in the medical and pharmacy literature that nonadherence is a significant problem, these physicians did not realize that this was a problem for some of their own patients. Overall, the physicians were surprised to learn that nonadherence existed among their patient population. Despite the small number of patients involved, the value of this study was the providers’ heightened awareness of nonadherence.

Each practice learned something about nonadherence, from simply gaining awareness of the problem to finding specific barriers to medication adherence. Some practices developed methods to improve adherence and worked toward implementing change. Practices with EMRs realized the advantage of technology in defining a problem as well as in the development of an improvement process. They learned that a gap analysis can be a valuable tool.

The providers realized that improved communication with their patients is necessary to determine adherence barriers and how to alleviate them; good communication with the patient and the entire healthcare team is essential for improving patient adherence.15 Literacy level, English-language proficiency, understanding of basic medical instruction, and socioeconomic status are factors that affect communication and adherence.7 Each factor needs to be taken into consideration when informing and educating patients on the importance of medication regimens.

Adherence issues cross over all populations of patients, regardless of age and/or condition,1,2 and interventions will vary based on that population. It is crucial that programs targeted to improve adherence are customized in a manner meaningful to the specific population being addressed.

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Table 3 Group B, Internal Medicine: ASK Survey Results Patients, N (%) (N = 14)

Survey results Lifestyle I just forget to take my medication some of the time

7 (50)

I run out of my medicine because I don’t get refills on time

7 (50)

I sometimes forget things that are important to me

1 (7)

Attitudes and beliefs I feel confident that each one of my medications help me

10 (71)

I know if I am reaching my health goals

10 (71)

Help from others I have someone I can call with questions about my medications

13 (93)

Talking with the healthcare team I understand my doctor’s/nurse’s instructions about the medicines I take

13 (93)

My doctor/nurse and I work together to make decisions

14 (100)

I am able to read and understand pill bottle labels

14 (100)

Taking medicines Taking medicines more than once daily is inconvenient

2 (14)

I have to take too many medicines daily

3 (21)

It is hard for me to swallow the pills I have to take

0 (0)

Have you…

Taken a medicine more or less often than prescribed?

7 (50)

Skipped or stopped taking a medicine because you didn’t think it was working?

5 (36)

Skipped or stopped taking a medicine because it made you feel bad?

1 (7)

Skipped, stopped, not refilled, or taken less medicine because of the cost?

7 (50)

Not had medicine with you when it was time to take it?

4 (29)

NOTE: Patients were interviewed by clinician by telephone; therefore, responses might have been inadvertently influenced by the interviewer.

The information depicted in the Figure may be useful when talking to physicians about adherence among their own patient populations. Health plans may be able to create a similar visual tool from their claims data that could be shared with providers to engage them in med-

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Table 4 Pediatric Groups C, D: Common Barriers to Adherence Parents stopped the attention-deficit/hyperactivity disorder medication on the weekend or in the summer, without a clinician’s recommendation Varying family situations (eg, children living between 2 homes where 1 parent supports medication therapy and the other does not) Insurance benefit change Appointment noncompliance Socioeconomic/health literacy/education levels of parents affected adherence Cost of medications

Table 5 Barriers to Adherence in College-Age Patients Resistance to taking medications, because it interfered with their newfound independence Difficulty remembering to take medications, because they were now expected to manage their regimen without guidance from a parent/guardian Adverse side effects interfered with their schedule and/or sleep pattern Reduced compliance with appointments and prescription renewal requests, because they were away at school

ication adherence. An unexpected value of this sample tool (Figure) was that other Highmark employees may replicate it and share it with their physician groups.

It has been shown that the quality of the doctor– patient relationship is one of the most important factors affecting adherence.16 A supportive relationship that features encouragement, reinforcement, and motivation from the provider will improve adherence; conversely, poor provider communication can contribute to medication nonadherence.16 If left unattended, nonadherent patients might have experienced negative health outcomes, and consequently medical costs for the plan could have escalated.5 In the scope of this case study, cross-referencing with medical claims was not completed. However, other health plans interested in a more quantitative approach may take the next step of cross-referencing medical and pharmacy claims to define the costs associated with nonadherence.

The clinicians did recognize the value of collaboration with the health plan consultants who could provide data as identifiers of a problem. Groups C and D were interested in reviewing similar claims data for other chronic conditions related to pediatrics, namely, asthma, but no action was taken by either group.

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Unique Features of Group E The common denominator among group E’s small subset population was that they were all college-aged students. This alerted the behavioral health specialist that college-aged patients have additional barriers to adherence that she and her colleagues were unaware of, and so this subset of patients was falling through the cracks. For each of these patients, the physician created a detailed care plan.

Just as important, the variation among the 12 pediatricians in group E—all of whom treated and managed patients with ADHD—was evident. The behavioral health physician realized yet another significant problem: ADHD was not being managed consistently among the providers in the group. Using this information, she created a quality improvement guide for ADHD management, which was to be used by all physicians in the practice, at all locations, when diagnosing patients with ADHD and interacting with their families.

This guide addressed all facets of ADHD management, including errors of monitoring and addressing compliance. The steps involved in addressing adherence in the practice include: 1. At every visit inquire about barriers to medication therapy 2. Emphasize benefits of daily medication adherence 3. At time of medication check, encourage scheduling of next appointment 4. Offer reminder options, such as an e-mail or a postcard 5. To address appointment no-show, patient or parent will be contacted by telephone to reschedule • If unable to reach after 2 attempts, a certified letter will be sent, requesting patient/parent call to schedule an appointment 6. The practice will develop a policy for college-aged patients taking ADHD medication • To monitor efficacy and side effects • To provide for timely refills to reduce nonadherence.

To improve adherence and the understanding of the value of daily medication regimens, future enhancements to the practice’s website are planned. Links to quality, reliable, evidence-based sites will be accessible; downloadable medication questionnaires will be made available for patients to fill out and bring to each appointment; and medication question-and-answer sessions, similar to a chat room, will be scheduled.

As a result of this project, group E’s physician awareness of nonadherence was increased. This pediatric practice transformed their approach to ADHD management.

They implemented new practice guidelines, disseminated the information to the clinical staff, and used their EMRs for theirs and their patients’ advantage. With these improvements, communication between patient

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and provider is expected to be enhanced, reduce nonadherence, and improve patient outcomes.

Participating in this case study also enabled group E to document improvements regarding medication adherence to the health plan, which fulfilled a P4P requirement.

Collaboration and Care Coordination We realized the value of physician buy-in and collaboration as critical elements to the success of this project.

It became evident that the practice with a physician champion—one who was very engaged and passionate— made the greatest effort to develop process improvements. In addition, we learned that it is crucial to identify the responsible parties, develop a work plan with targeted dates, and use telephone and e-mail reminders as a way to guide and direct the participants, while being careful to appreciate time constraints common to busy primary care practices.

With current shifts in healthcare and payment methodology, adherence is being affected by a lack of coordination of care. This includes provider and patient communication, increased use of technology (including data-sharing among providers), and expanded P4P programs, which promote patient-centered medical homes and care transitions. Collectively, advancements in these areas will improve coordination of care and healthcare delivery, particularly in primary care, where the crisis of nonadherence is most evident.9

Limitations Various limitations to this case study exist. We recognize that the limitations of prescription drug claim data (eg, nonsubmission of claims, errors of membership or eligibility, and lack of integration of medical and pharmacy claims) may have affected the results. However, the claims data were useful as a starting point.

The small sample size was another limitation of the project, but this was necessary to keep the workload manageable for the staff.

In addition, medical claims and pharmacy claims were both available but were not cross-referenced because of the limited scope of this study. This proved to be a limitation in that escalation of care costs was not truly determined in this case study; the care costs were simply assumed. Also, it was not validated that quality of care was being affected by the nonadherence.

Finally, a major limitation of this case study was the realization that this problem is widespread and there is no simple solution. Recognizing this, some physician groups chose to avoid the challenge; they were not pressured to assume the responsibility of improving nonadherence. This reinforces the question of who is account-

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able for the resolution of the problem—is it the clinician, the health plan, or the patient?

Conclusions Ultimately, all involved parties learned that nonadherence is a reality and affects the patients they treat.

The authors learned that using prescription drug data can provide valuable information, including the need to tailor any intervention to the individual patient’s characteristics (ie, age, disease state, socioeconomic status).

Three key potential benefits of improved adherence are a decrease in total healthcare costs, a decline in hospitalizations, and improved health outcomes.

However, for these benefits to be realized, providers must become a part of the solution. By identifying barriers to adherence, steps to improve adherence rates can be put into place. These include collaboration, open communication between healthcare professionals and patients regarding medication regimens, as well as education provided to patients about the benefits of medication adherence.12-14 Changing patient behavior is difficult. It involves more than simply telling patients what to do or prescribing a medication. Healthcare professionals need to identify barriers to adherence and then help motivate patients to take control of their disease. Much of this revolves around medication-taking behavior and education on the disease state. Increasing primary care physicians’ and staff awareness of medication nonadherence and working toward improving medication adherence rates may lead to a decrease in total healthcare costs, a decline in hospitalizations, and improved patients’ health outcomes. ■ Disclosure Statement Ms Scott and Ms McClure have nothing to disclose.

References 1. Osterberg L, Blaschke T. Adherence to medication. N Engl J Med. 2005;353:487-497.

2. National Council on Patient Information and Education. Enhancing Prescription Medicine Adherence: a National Action Plan. August 2007. www.talkaboutrx.org/ documents/enhancing_prescription_medicine_adherence.pdf. Accessed July 14, 2009.

3. DiMatteo MR. Variations in patients’ adherence to medical recommendations: a quantitative review of 50 years of research. Med Care. 2004;42:200-209.

4. Peterson AM, Takiya L, Finley R. Meta-analysis of trials of interventions to improve medication adherence. Am J Health Syst Pharm. 2003;60:657-665.

5. The Task Force for Compliance. Noncompliance with medications: an economic tragedy with important implications for health care reform. Baltimore, MD; 1993.

6. Zwillich T. Patients, Doctors Don’t Discuss Rx Prices. WebMD Health News.

March 17, 2009. www.webmd.com/news/20090317/patients-doctors-dont-discuss-rxprices. Accessed July 14, 2009.

7. American Society on Aging and American Society of Consultant Pharmacists Foundation. Adult Meducation. Overview of medication adherence. www.adult meducation.com/OverviewofMedicationAdherence.html. Accessed July 14, 2009.

8. Taylor H, Leitman R, eds. Out-of-pocket costs are a substantial barrier to prescription drug compliance. Health Care News. 2001;1:1-2.

9. Cutler DM, Everett W. Thinking outside the pillbox—medication adherence as a priority for health care reform. N Engl J Med. 2010;362:1553-1555. Epub 2010 Apr 7.

10. Lowes R. Patient-centered care for better patient adherence. Fam Pract Manag.

1998;5:46-47,51-54,57. www.aafp.org/fpm/980300fm/patient.html. Accessed November 10, 2010.

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11. Haynes RB, Yao X, Degani A, et al. Interventions to enhance medication adherence. Cochrane Database Syst Rev. 2005;(4):CD000011.

12. Hahn SR, Park J, Skinner EP, et al. Development of the ASK-20 adherence barrier survey. Curr Med Res Opin. 2008;24:2127-2138. Epub 2008 Jun 12.

13. GlaxoSmithKline. ASK-20 Taking Medicine: What Gets in the Way [Survey].

August 2008. www.takingmeds.com/pdf/hcp/HMI719R0_ASK20SurveyEngl.pdf.

Accessed August 25, 2010.

14. Matza LS, Yu-Isenberg KS, Coyne KS, et al. Further testing of the reliability and validity of the ASK-20 adherence barrier questionnaire in a medical center outpa-

tient population. Curr Med Res Opin. 2008;24:3197-3206.

15. Burnier M. Long-term compliance with antihypertensive therapy: another facet of chronotherapeutics in hypertension. Blood Press Monit. 2000;5(suppl 1):S31-S34.

16. Krueger KP, Berger BA, Felkey B. Appendix D. Medication adherence and persistence. In: Wu HW, Nishimi RY, Kizer KW, eds. Improving use of prescription medications: a national action plan. Washington, DC: National Quality Forum; 2005. www.qualityforum.org/Publications/2005/10/Improving_Use_of_ Prescription_Medications__A_National_Action_Plan.aspx. Accessed November 16, 2010.

STAKEHOLDER PERSPECTIVE Stakeholder Integration Crucial to Improved Patient Outcomes: Lessons from a Health Planâ&#x20AC;&#x2122;s Experience PAYERS: The issue of medication adherence has implications for many healthcare stakeholders, as this study from a large health plan indicates. For Highmark in Pennsylvania and for many other health insurance plans, this study may also have value in preparing for the various pay-for-performance programs that are being encouraged by employers and other payers, as well as by the 2010 Patient Protection and Affordable Care Act. In the course of their research, the authors identified different reasons for medication nonadherence that were both expected and unexpected. Many of the reasons have been known for many years in the medical and pharmacy provider community, as well as by pharmacy benefit managers, but there had been little incentive to aggressively act on that knowledge. With the recessionary impact on discretionary income, along with loss of jobs and insurance coverage, cost issues for patients have become even more of a major concern.

This concern influences other cost issues for employers who pay premiums and shared costs of prescribed drugs, providers who are at risk for total dollars spent by patients, and health insurance plans that are unable to offer cost-effective products that could result in positive patient outcomes.

PROVIDERS: Studies have shown that improved medication adherence will increase pharmacy costs while lowering medical costs, as was seen in the wellknown cases of the City of Asheville Project in North Carolina and Pitney Bowes in Connecticut. This finding is further reinforced by the present study by Scott and McClure, which also sheds an unexpected light on primary care providersâ&#x20AC;&#x2122; lack of awareness of nonadherence among their own patients. Having a health plan

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focus on this subject adds weight to the need for expanded multistakeholder collaborations to address the issue of medication adherence.

MANUFACTURERS: Value-based quality improvements to reach better patient outcomes with appropriate medication use should involve not only patients themselves but also manufacturers of drugs, medical devices, and diagnostic products. Because care for patients with chronic diseases consumes a lot of time for primary care providers and a good portion of health plan coverage resources, all healthcare stakeholders can play a role toward improving outcomes as opposed to the continuing divisiveness and distrust we have observed in the marketplace. Such multistakeholder collaborations will increase in importance as we move toward personalized medicine in the coming decade.

In the end, all stakeholders have a role to play in, and can benefit from, improved medication adherence by patients. Engaging patients is consistently emerging as one of the key drivers toward achieving improved outcomes. In addition, this study by Scott and McClure shows that engaging providers in medication adherence is an important piece to the patient engagement puzzle. It is time that all healthcare system participants work together with employees, members, or patients to reach the common goal of increased efficiencies, better cost management, and improved patient outcomes.

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F. Randy Vogenberg, PhD, RPh Principal, Institute for Integrated Healthcare and Strategic Pharmacy Advisor, Business Group Pharmacy Collaborative Sharon, MA

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PERSPECTIVE

Moving Beyond Good Intentions: Making Collaborative Care a Successful Reality Gordon Norman, MD, MBA Chief Innovation Officer, Alere Health, Atlanta, GA

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inding ways to care for chronically ill Americans is quickly becoming one of the singular most critical healthcare challenges of our nation. Nearly 1 of 2 Americans has diabetes, heart disease, or another chronic disease.1 Millions more are at risk, and this generation of youngsters may be the first in history to have poorer health at an earlier age and lower levels of longevity than their parents.2 Government initiatives, as well as programs from private payers, are championing more collaborative approaches to care. Although they show promise, such programs will require more than legislation, increased payment to providers, and good intentions to be successful; they will demand a concerted effort from all participants along the healthcare continuum to work together toward a common goal to control costs and improve the health of all Americans.3-8

The Promise of Collaborative Care The new emphasis on collaborative approaches to care holds the promise to: • Enable care providers to function as an effective, coordinated team to access and manage patient information across dispersed organizations and settings, ensuring that patients receive recommended, evidence-based care • Improve health outcomes through aligned efforts that harness the physician–patient relationship and achieve shared clinical goals • Support physicians who seek to practice efficient, team-based clinical care and the realization of patient-centered medical homes.

To reach their potential, collaborative care programs must ensure connectivity between all parties, the use of decision support, the alignment of goals and financial incentives, and a focus on finding innovative ways to better engage and involve patients in their own care.

The Obstacles to Coordinated Care In the past several years, private and public health plans, large employers, and coalitions have created small yet promising programs designed to achieve bet-

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ter care. These programs, however, are currently the exception, not the rule. Overall, the nation’s chronic care system is fragmented, poorly coordinated, and often of inferior quality and value.6,9 Most troubling is that even patients with access to healthcare often receive poor care.10 For example, patients with chronic diseases frequently receive treatments from multiple primary and specialty care physicians across various sites of care, and rarely are all treating providers able to readily access relevant patient information. Even providers utilizing electronic medical records (EMRs) often struggle with electronic forms in structured and unstructured formats, making accessing and sharing information difficult.11 Such an environment leads to substandard care and makes it difficult to ascertain the scope of impact for chronic diseases and to aggregate critical health information on a patient- or population-specific basis. In addition, this lack of coordination makes it challenging to provide more proactive care, as well as meaningful analysis and healthcare decision support based on evidence-based care guidelines.

Need for New Payment Structures Although multiple factors contribute to poor adoption of the technology and processes necessary to create a more united care environment, it is clear that the current fee-for-service payment structure does not encourage cooperation or collaboration among payers and providers.12 But change is coming. The Patient Protection and Affordable Care Act (PPACA) and the American Recovery and Reinvestment Act, along with the Health Information Technology for Economic and Clinical Health Act that came with it, together are helping to establish a basis for greater collaborative care.

Demonstration pilots for accountable care organizations (ACOs) made possible under the PPACA are gathering considerable attention. ACOs are defined as provider groups that accept responsibility for the cost and quality of care delivered to a specific population of patients cared for by the groups’ clinicians. The US Department of Health and Human Services’ efforts to

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relax antitrust provisions (eg, the Stark law) are expected to help foster greater physician and hospital collaboration. Another key feature of ACOs—bundled payments for episodes of care, including acute and 30-day postdischarge—could also encourage hospitals and community physicians to work more closely together.

Healthcare advocates and executives also believe that the government’s push for adoption of technology, particularly through electronic health records, will create more opportunities for collaborative care.13 Strong incentives—up to $44,000 per physician with a large Medicare patient population and $64,000 for physicians serving predominantly Medicaid patients—as well as hefty fines for nonadoption beginning in 2015, may be an important impetus required to finally move physicians toward greater use of technology.

Collaborative care initiatives strive to establish more personalized and proactive care at convenient sites of care, while providing more efficient care and optimized healthcare resource use.

Roots of Collaborative Care If the tenets of collaborative care sound familiar, it is for a good reason. Historically, what is now referred to as collaborative care was once considered more of a healthcare philosophy or movement. Over time, the concept had many names, including integrated care, primary care behavioral health, and shared care.

Today’s approach to collaborative care is much broader than its predecessors, because there is collaboration across and among: • Sites of care, including ambulatory care clinics, urgent care, retail clinics, worksite clinics, hospitals, surgery centers, pharmacies, home, online and other virtual care (disease management vendors), alternative care, and fitness centers • Care providers, specifically primary care, specialists, pharmacists, nutritionists, health coaches, case managers, caregivers, social workers, and therapists • Data repositories at clinics (eg, paper, EMRs), hospitals (eg, laboratory information systems, hospital information systems), pharmacies and pharmacy benefit managers, reference laboratories (eg, LabCorp), imaging centers, personal health records, health plans, and associated care management vendors.

Collaborative care initiatives also strive to establish more personalized and proactive care at convenient sites of care (eg, home, work, retail), while providing more

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efficient care and optimized healthcare resource use.

Some of the most promising care initiatives involve corporate and community partnerships, in which employers focus on what happens with employees at home as well as on the job. Additional characteristics of collaborative care programs include: • Avoidance of duplicative care • Emphasis on error reduction • Promotion of more comprehensive services, including mental health • Establishing a clearly defined team with roles and responsibilities for each person • Focus on improved quality and reduced costs.

Example of Collaborative Care: Optimal Prescription Therapy, Medication Adherence Although considerable emphasis is placed on technology within collaborative care programs, technology alone is not the solution. To more readily see how collaborative care works in the real world of healthcare today, consider what happens during the seemingly simple process of prescribing a new medication, beginning with the simple question—Is there strong evidence for prescribing a specific medication for a patient? Under collaborative care, answering this question begins with evidence-based guidelines— specifically class A evidence—and continues with issues such as the impact of direct-to-consumer and physician marketing.

Once a medication is prescribed, providers must consider a range of additional issues, including polypharmacy, potential drug–drug interactions, contraindications, and the patient-specific formulary and benefit design, because affordability is a leading cause of low medication adherence.

Next, consider what happens once the patient begins taking the medication. Is it taken as prescribed? How can we confirm persistency and adherence? Options for answering these questions include patient-reported data, pill counts, devices, caregiver statements, and refill analysis. If the medication is not taken as reported, providers must then determine the reason, which can range from affordability and side effects to the patient’s own perception of medication effectiveness.

Medication use must also be monitored over time for efficacy, and titrated as necessary to meet patients’ needs (eg, age, weight). All this information must be recorded in a practice management and/or e-prescribing system for optimal provider communication and overall coordination of care. Without every element involved, providers and payers have insufficient knowledge and data, and ultimately, costs and outcomes could be negatively impacted.

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Key Attributes Needed for Optimal Outcomes in Collaborative Care Collaborative care initiatives cannot exist in a vacuum.

All healthcare stakeholders must take responsibility for decisions as well as health outcomes. There must also be clear insight and transparency across the care continuum, as well as role definition and clarity among care sites and providers. As Sevin and colleagues suggest, the following attributes are necessary for the success of collaborative care14: Empowered primary care physicians. The primary care physician must have the tools and authority to act as the care team leader, coordinating and working with practice staff, specialists, and other care providers.

Providers must always recognize that patient needs, values, and the context of their lives must dictate all healthcare decisions.

Appropriate structure. Operational issues must also be addressed. For example, it is important to address organizing principles, including business models and payment reforms, to ensure coordination and cooperation. Such models are exemplified by emerging ACOs and patient-centered medical homes, which encompass tactics such as bundled payments, quality-based payments, and care coordination fees. Care collaboration is also enhanced by gainsharing agreements and riskadjusted capitation.

Effective technology. Data exchange, interoperability, and aggregation are ultimately controlled by connected patient EMRs/health information technology.

EMRs often represent data silos; current EMRs are good at storage, not communication and connectivity (think “meaningful use”). Robust data integration aggregated across silos and transformed into computable data for more automated analysis and timely decision support at the point of care are important considerations.

Connection between providers, payers, and patients.

Although steps are being made to better connect providers, effective collaborative models must extend that connectivity to payers, and most important, to patients. Engaging patient portals that provide relevant and tailored information, personalized health support available via cell phones and the internet, and expansion of communication to smartphones are all necessary to a successful care model.

Care architecture. Connectivity and technology are important, but the next step in the process must be the necessary architecture to take patient data and conduct analysis and research. Such findings can then be used to help in care management, evidence-based decision support, and population management. Of equal importance, the data and insights contained would be of significant interest and value to payers and providers through

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reports and analyses that confirm guideline compliance, highlight quality achievements, and provide other valuable insights for measuring and improving care.

A Model for Our Future Although factors ranging from new models of care to technology will help collaborative care programs become a reality, ultimately such programs will not work unless steps are taken to educate, engage, and fully involve patients in their own health. The onus is on providers, as well as plan sponsors, to develop the education, technology, and outreach to help foster more engaged patients who take an active role in the collaborative care process.15 The coming years will remain challenging for the healthcare industry—providers and payers alike. Without a commitment to change, the best intentions of current healthcare reform efforts will fail. Collaborative care programs represent an innovative approach that can address these challenges with pragmatic solutions.

When we, as an industry, embrace such approaches, we can begin to lead our nation toward necessary, meaningful, and lasting changes in our healthcare system. ■ Disclosure Statement Dr Gordon has nothing to disclose.

References 1. Partnership for Solutions. Chronic conditions: making the case for ongoing care.

September 2004 update. www.partnershipforsolutions.org/DMS/files/chronicbook 2004.pdf. Accessed October 18, 2010.

2. Olshansky SJ, Passaro DJ, Hershow RC, et al. A potential decline in life expectancy in the United States in the 21st century. N Engl J Med. 2005;352:1138-1145.

3. Rosenthal TC. The medical home: growing evidence to support a new approach to primary care. J Am Board Fam Med. 2008;21:427-440.

4. Rittenhouse DR, Casolino LP, Gillies RR, et al. Measuring the medical home infrastructure in large medical groups. Health Aff (Millwood). 2008;5:1246-1258.

5. DMAA: The Care Continuum Alliance. The medical home and population health improvement: common ground. October 2008: 1-13. http://carecontinuum. org/pdf/DMAA_PHI-PCMH_102108.pdf. Accessed October 18, 2010.

6. Ginsburg PB, Maxfield M, O’Malley AS, et al; for the Center for Studying Health System Change. Making medical homes work: moving from concept to practice.

2008;1:1-20. www.rwjf.org/files/research/1208.policyperspective1.pdf. Accessed October 18, 2010.

7. Nutting PA, Miller WL, Crabtree BF, et al. Initial lessons from the first national demonstration project on practice transformation to a patient-centered medical home. Ann Fam Med. 2009;7:254-260.

8. Reid RJ, Fishman PA, Yu O, et al. Patient-centered medical home demonstration: a prospective, quasi-experimental, before and after evaluation. Am J Manag Care.

2009;15:e71-e87.

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

10. Kohn KT, Corrigan JM, Donaldson MS, eds. To Err Is Human: Building a Safer Health System. Washington, DC: National Academy Press; 1999.

11. Chen TL, Chung YF, Lin FY. A study on agent-based secure scheme for electronic medical record system. J Med Syst. 2010 Sep 21. Epub ahead of print.

12. Tynan A, Draper D; for the Center for Studying Health System Change. Getting what we pay for: innovations lacking in provider payment reform for chronic disease care. Research Brief No 6. June 2008. www.hschange.com/CONTENT/995/.

Accessed October 18, 2010.

13. Dorr DA, Jones SS, Wilcox A. A framework for information system usage in collaborative care. J Biomed Inform. 2007;40:282-287.

14. Sevin C, Moore G, Shepherd J, et al. Transforming care teams to provide the best possible patient-centered, collaborative care. J Ambul Care Manage. 2009;32:24-31.

15. Epstein RM, Fiscella K, Lesser CS, Stange KR. Why the nation needs a policy push on patient-centered health care. Health Aff (Millwood). 2010;29:1489-1495.

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INDICATION EXALGO® tablets are an extended release oral formulation of the opioid agonist hydromorphone hydrochloride that is indicated for once daily administration for the management of moderate to severe pain in opioid tolerant patients requiring continuous, around-the-clock opioid analgesia for an extended period of time.

IMPORTANT RISK INFORMATION WARNING: POTENTIAL FOR ABUSE, IMPORTANCE OF PROPER PATIENT SELECTION AND LIMITATIONS OF USE Potential for Abuse EXALGO contains hydromorphone, an opioid agonist and a Schedule II controlled substance with an abuse liability similar to other opioid analgesics. EXALGO can be abused in a manner similar to other opioid agonists, legal or illicit. These risks should be considered when administering, prescribing, or dispensing EXALGO in situations where the healthcare professional is concerned about increased risk of misuse, abuse, or diversion. Schedule II opioid substances which include hydromorphone, morphine, oxycodone, fentanyl, oxymorphone and methadone have the highest potential for abuse and risk of fatal overdose due to respiratory depression.

Proper Patient Selection EXALGO is an extended-release formulation of hydromorphone hydrochloride indicated for the management of moderate to severe pain in opioid tolerant patients when a continuous around-the-clock opioid analgesic is needed for an extended period of time. Patients considered opioid tolerant are those who are taking at least 60 mg oral morphine per day, 25 mcg transdermal fentanyl/hour, 30 mg oral oxycodone/day, 8 mg oral hydromorphone/day, 25 mg oral oxymorphone/day or an equianalgesic dose of another opioid, for a week or longer.

EXALGO is for use in opioid tolerant patients only.

Fatal respiratory depression could occur in patients who are not opioid tolerant.

Accidental consumption of EXALGO, especially in children, can result in a fatal overdose of hydromorphone.

Limitations of Use EXALGO is not indicated for the management of acute or postoperative pain.

EXALGO is not intended for use as an as-needed analgesic.

EXALGO tablets are to be swallowed whole and are not to be broken, chewed, dissolved, crushed or injected. Taking broken, chewed, dissolved or crushed EXALGO or its contents leads to rapid release and absorption of a potentially fatal dose of hydromorphone.

• EXALGO is also contraindicated in patients who: - need management of mild pain or pain not expected to persist - have significant impaired respiratory function including those with acute or severe bronchial asthma or hypercarbia.

- have or are suspected to have paralytic ileus - have narrowed or obstructed gastrointestinal tract including those from previous surgery or “blind loops” in the GI tract - have known hypersensitivity to any components including hydromorphone hydrochloride and sulfites.

• Avoid concurrent use of alcohol and EXALGO. Concurrent use of EXALGO with CNS depressants, including alcohol, increases risk of respiratory depression, hypotension, and profound sedation, potentially resulting in coma or death. EXALGO may impair the ability to drive a car or operate machinery.

• Not intended in patients who have received MAO inhibitors within 14 days of starting EXALGO. • Use with caution and in reduced doses in older or debilitated patients, as well as patients with renal or hepatic insufficiency, Addison’s disease, delirium tremens, myxedema or hypothyroidism, prosthetic hypertrophy or urethral stricture, toxic psychosis. May aggravate convulsions in patients with convulsive disorders; may induce or aggravate seizures in some clinical settings. Consider use of an alternate analgesic in patients with severe renal impairment.

• Respiratory depression, which occurs more frequently in elderly or debilitated patients, is the chief hazard with EXALGO. • Most common adverse events (>10%) seen in clinical studies (N=2474) were: constipation (31%), nausea (28%), vomiting, somnolence, headache, asthenia and dizziness. Serious adverse events could also include head injury, hypotensive effects, GI effects, cardiac arrest from overdose and precipitation of withdrawal.

• Use EXALGO with extreme caution in patients susceptible to intracranial effects of CO2 retention.

• Do not abruptly discontinue EXALGO Please see brief summary of Full Prescribing Information, including boxed warning on following pages.

COVIDIEN, COVIDIEN with logo and Covidien logo are U.S. and internationally registered trademarks of Covidien AG. EXALGO is a registered trademark of Mallinckrodt Inc. © 2010 Mallinckrodt Inc., a Covidien company. MK20010 September 2010 Printed in USA.

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Keep pain waiting.

With once-daily EXALGO速, he might as well get used to it.

With 24-hour extended-release hydromorphone, EXALGO helps you keep pain at bay. You can minimize peaks and troughs at steady state for your opioid tolerant patients with moderate to severe chronic pain, and they can reduce their pill burden. To find out more, visit www.keeppainwaiting.com.

速

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BRIEF SUMMARY - Consult full prescribing information before use.

EXALGO™ (hydromorphone HCl) Extended-Release Tablets WARNING: POTENTIAL FOR ABUSE, IMPORTANCE OF PROPER PATIENT SELECTION AND LIMITATIONS OF USE Potential for Abuse EXALGO contains hydromorphone, an opioid agonist and a Schedule II controlled substance with an abuse liability similar to other opioid analgesics. EXALGO can be abused in a manner similar to other opioid agonists, legal or illicit. These risks should be considered when administering, prescribing, or dispensing EXALGO in situations where the healthcare professional is concerned about increased risk of misuse, abuse, or diversion. Schedule II opioid substances which include hydromorphone, morphine, oxycodone, fentanyl, oxymorphone and methadone have the highest potential for abuse and risk of fatal overdose due to respiratory depression [see Drug Abuse and Dependence (9)].

Proper Patient Selection EXALGO is an extended-release formulation of hydromorphone hydrochloride indicated for the management of moderate to severe pain in opioid tolerant patients when a continuous around-the-clock opioid analgesic is needed for an extended period of time. Patients considered opioid tolerant are those who are taking at least 60 mg oral morphine per day, 25 mcg transdermal fentanyl/hour, 30 mg of oral oxycodone/ day, 8 mg oral hydromorphone/day, 25 mg of oral oxymorphone/day or an equianalgesic dose of another opioid, for a week or longer [see Indications and Usage (1) and Dosage and Administration (2)].

EXALGO is for use in opioid tolerant patients only [see Indications and Usage (1) and Dosage and Administration (2)].

Fatal respiratory depression could occur in patients who are not opioid tolerant.

Accidental consumption of EXALGO, especially in children, can result in a fatal overdose of hydromorphone [see Warnings and Precautions (5.1)].

Limitations of Use EXALGO is not indicated for the management of acute or postoperative pain [see Indications and Usage (1)].

EXALGO is not intended for use as an as-needed analgesic [see Indications and Usage (1)].

EXALGO tablets are to be swallowed whole and are not to be broken, chewed, dissolved, crushed or injected. Taking broken, chewed, dissolved or crushed EXALGO or its contents leads to rapid release and absorption of a potentially fatal dose of hydromorphone [see Warnings and Precautions (5)].

CONTRAINDICATIONS Opioid Non-Tolerant Patients EXALGO is contraindicated in opioid non-tolerant patients. Fatal respiratory depression could occur in patients who are not opioid tolerant.

Impaired Pulmonary Function EXALGO is contraindicated in patients with significant respiratory depression, especially in the absence of resuscitative equipment or in unmonitored settings and in patients with acute or severe bronchial asthma or hypercarbia.

Paralytic Ileus EXALGO is contraindicated in patients who have or are suspected of having a paralytic ileus.

Preexisting Gastrointestinal (GI) Surgery or Narrowing of GI Tract EXALGO is contraindicated in patients who have had surgical procedures and/or underlying disease that would result in narrowing of the gastrointestinal tract, or have “blind loops” of the gastrointestinal tract or gastrointestinal obstruction.

Allergy or Hypersensitivity EXALGO is contraindicated in patients with known hypersensitivity to any of its components including the active agent, hydromorphone hydrochloride or known allergy to sulfite-containing medications [see Warnings and Precautions (5.8)].

WARNINGS AND PRECAUTIONS Information Essential for Safe Administration EXALGO tablets are to be swallowed whole, and are not to be broken, chewed, crushed, dissolved or injected. Taking broken, chewed, crushed, dissolved EXALGO or its contents leads to the rapid release and absorption of a potentially fatal dose of hydromorphone [see Boxed Warning].

EXALGO is for use only in opioid tolerant patients. Ingestion of EXALGO may cause fatal respiratory depression when administered to patients who are not opioid tolerant [see Boxed Warning].

EXALGO tablets must be kept in a secure place out of the reach of children. Accidental consumption of EXALGO, especially in children, can result in a fatal overdose of hydromorphone.

Misuse and Abuse EXALGO contains hydromorphone, an opioid agonist, and is a Schedule II controlled substance. Opioid agonists have the potential for being abused and are sought by drug abusers and people with addiction disorders and are subject to criminal diversion.

EXALGO can be abused in a manner similar to other opioid agonists, legal or illicit.

This should be considered when prescribing or dispensing EXALGO in situations where the healthcare professional is concerned about an increased risk of misuse, abuse, or diversion.

Breaking, crushing, chewing, or dissolving the contents of an EXALGO tablet results in the uncontrolled delivery of the opioid and poses a significant risk of overdose and death [see Drug Abuse and Dependence (9)].

If attempts are made to extract the drug from the hard outer shell for purposes of parenteral abuse, the injection of tablet excipients may be toxic and may result in lethal complications.

Concerns about abuse, addiction, and diversion should not prevent the proper management of pain. However, all patients treated with opioids, including EXALGO, require careful monitoring for signs of abuse and addiction, since use of opioid analgesic products carries the risk of addiction even under appropriate medical use.

Healthcare professionals should contact their State Professional Licensing Board or State Controlled Substances Authority for information on how to prevent and detect abuse or diversion of this product.

Respiratory Depression Respiratory depression is the chief hazard of EXALGO. Respiratory depression occurs more frequently in elderly or debilitated patients as well as those suffering from conditions accompanied by hypoxia or hypercapnia when even moderate therapeutic doses may dangerously decrease pulmonary ventilation, and when opioids are given in conjunction with other agents that depress respiration.

Use EXALGO with extreme caution in patients with conditions accompanied by hypoxia, hypercapnia, or decreased respiratory reserve such as asthma, chronic obstructive pulmonary disease or cor pulmonale, severe obesity, sleep apnea, myxedema, kyphoscoliosis or CNS depression. In these patients, even moderate therapeutic doses of hydromorphone may decrease respiratory drive while simultaneously increasing airway resistance to the point of apnea. In these patients, consider alternative non-opioid analgesics, and use EXALGO only under careful medical supervision at the lowest effective dose.

Interactions with Alcohol and Other CNS Depressants The concurrent use of EXALGO with other central nervous system (CNS) depressants, including but not limited to other opioids, illicit drugs, sedatives, hypnotics, general anesthetics, phenothiazines, muscle relaxants, other tranquilizers, and alcohol, increases the risk of respiratory depression, hypotension, and profound sedation, potentially resulting in coma or death. Use with caution and in reduced dosages in patients taking CNS depressants. Avoid concurrent use of alcohol and EXALGO [see Clinical Pharmacology (12.3)].

Head Injury and Increased Intracranial Pressure In the presence of head injury, intracranial lesions or a preexisting increase in intracranial pressure, the respiratory depressant effects of EXALGO and its potential to elevate cerebrospinal fluid pressure (resulting from vasodilation following CO2 retention) may be markedly exaggerated. Furthermore, EXALGO can produce effects on pupillary response and consciousness, which may obscure neurologic signs of further increases in intracranial pressure in patients with head injuries.

Hypotensive Effect EXALGO may cause severe hypotension. There is added risk to individuals whose ability to maintain blood pressure has been compromised by a depleted blood volume, or after concurrent administration with drugs such as phenothiazines, general anesthetics, or other agents that compromise vasomotor tone.

Administer EXALGO with caution to patients in circulatory shock, since vasodilation produced by the drug may further reduce cardiac output and blood pressure.

Gastrointestinal Effects Because the EXALGO tablet is nondeformable and does not appreciably change in shape in the GI tract, do not administer EXALGO to patients with preexisting severe gastrointestinal narrowing (pathologic or iatrogenic, for example: esophageal motility disorders small bowel inflammatory disease, “short gut” syndrome due to adhesions or decreased transit time, past history of peritonitis, cystic fibrosis, chronic intestinal pseudoobstruction, or Meckel’s diverticulum). There have been reports of obstructive symptoms in patients with known strictures or risk of strictures, such as previous GI surgery, in association with the ingestion of drugs in nondeformable extended-release formulations.

The administration of EXALGO may obscure the diagnosis or clinical course in patients with acute abdominal condition.

It is possible that EXALGO tablets may be visible on abdominal x-rays under certain circumstances, especially when digital enhancing techniques are utilized.

Sulfites EXALGO contains sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people.

MAO Inhibitors EXALGO is not recommended for use in patients who have received MAO inhibitors within 14 days, because severe and unpredictable potentiation by MAO inhibitors has been reported with opioid analgesics.

Special Risk Groups EXALGO should be administered with caution in elderly (≥ 65 years) and debilitated patients and in patients who are known to be sensitive to central nervous system depressants, such as those with cardiovascular, pulmonary, renal, or hepatic disease [see Use in Specific Populations (8)].

EXALGO should also be used with caution in the following conditions: adrenocortical insufficiency (e.g., Addison’s disease); delirium tremens; myxedema or hypothyroidism; prostatic hypertrophy or urethral stricture; and, toxic psychosis.

EXALGO may aggravate convulsions in patients with convulsive disorders, and all opioids may induce or aggravate seizures in some clinical settings.

Use in Pancreatic/Biliary Tract Disease EXALGO can cause an increase in biliary tract pressure as a result of spasm in the sphincter of Oddi. Caution should be exercised in the administration of EXALGO to patients with inflammatory or obstructive bowel disorders, acute pancreatitis secondary to biliary tract disease and in patients about to undergo biliary surgery.

Driving and Operating Machinery EXALGO may impair the mental and/or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Caution patients accordingly. Also warn patients about the potential combined effects of EXALGO with other CNS depressants, including other opioids, phenothiazines, sedative/hypnotics, and alcohol [see Drug Interactions (7)].

Precipitation of Withdrawal Mixed agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, and butorphanol) should not be administered to patients who have received or are receiving a course of therapy with a pure opioid agonist analgesic, including EXALGO. In these patients, mixed agonists/antagonists analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms. Do not abruptly discontinue EXALGO. Clinical conditions or medicinal products that cause a sudden and significant shortening of gastrointestinal transit time may result in decreased hydromorphone absorption with EXALGO and may potentially lead to withdrawal symptoms in patients with a physical dependence on opioids.

ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: • Respiratory Depression [see Warnings and Precautions (5.3)] • Head Injury and Increased Intracranial Pressure [see Warnings and Precautions (5.5)] • Hypotensive Effect [see Warnings and Precautions (5.6)] • Gastrointestinal Effects [see Warnings and Precautions (5.7)] • Cardiac Arrest [see Overdosage (10)] • Precipitation of Withdrawal [see Warnings and Precautions (5.13)]

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

EXALGO was administered to a total of 2,524 patients in 15 controlled and uncontrolled clinical studies. Of these, 423 patients were exposed to EXALGO for greater than 6 months and 141 exposed for greater than one year.

The overall incidence of adverse reactions in patients greater than 65 years of age was higher, with a greater than 5% difference in rates for constipation and nausea when compared with younger patients. The overall incidence of adverse reactions in female patients was higher, with a greater than 5% difference in rates for nausea, vomiting, constipation and somnolence when compared with male patients.

A 12-week double-blind, placebo-controlled, randomized withdrawal study was conducted in opioid tolerant patients with moderate to severe low back pain [see Clinical Studies (14)]. A total of 447 patients were enrolled into the open-label titration phase with 268 patients randomized into the double-blind treatment phase. The adverse reactions that were reported in at least 2% of the patients are contained in Table 1.

Table 1.

Number (%) of Patients with Adverse Reactions Reported in ≥2% of Patients with Moderate to Severe Low Back Pain During the Open-Label Titration Phase or Double-Blind Treatment Phase by Preferred Term Preferred Term Open-Label Double-Blind Treatment Phase Titration Phase EXALGO (N=447) EXALGO (N=134) Placebo (N=134) Constipation 69 (15) 10 (7) 5 (4) Nausea 53 (12) 12 (9) 10 (7) Somnolence 39 (9) 1 (1) 0 (0) Headache 35 (8) 7 (5) 10 (7) Vomiting 29 (6) 8 (6) 6 (4) Drug Withdrawal Syndrome 22 (5) 13 (10) 16 (12) Pruritus 21 (5) 1 (1) 0 (0) Dizziness 17 (4) 3 (2) 2 (1) 16 (4) 2 (1) 6 (4) Asthenia a Insomnia 13 (3) 7 (5) 5 (4) Diarrhea 13 (3) 5 (4) 9 (7) Back Pain 13 (3) 6 (4) 8 (6) Dry Mouth 13 (3) 2 (1) 0 (0) Edema Peripheral 13 (3) 3 (2) 1 (1) Hyperhidrosis 13 (3) 2 (1) 2 (1) b 10 (2) 2 (1) 0 (0) Anorexia Arthralgia 9 (2) 8 (6) 3 (2) Anxiety 9 (2) 0 (0) 4 (3) 9 (2) 4 (3) 3 (2) Abdominal Pain c Muscle Spasms 5 (1) 3 (2) 1 (1) Weight Decreased 3 (1) 4 (3) 3 (2) a b c

Fatigue was grouped and reported with asthenia Decreased appetite was grouped and reported with anorexia Abdominal pain upper was grouped and reported with abdominal pain

The adverse reactions that were reported in at least 2% of the total treated patients (N=2,474) in the 14 chronic clinical trials are contained in Table 2.

Table 2.

Number (%) of Patients with Adverse Reactions Reported in ≥2% of Patients with Chronic Pain Receiving EXALGO in 14 Clinical Studies by Preferred Term Preferred Term All Patients (N=2,474) Constipation 765 (31) Nausea 684 (28) Vomiting 337 (14) Somnolence 367 (15) Headache 308 (12) Asthenia a 272 (11) Dizziness 262 (11) Diarrhea 201 (8) Pruritus 193 (8) Insomnia 161 (7) Hyperhidrosis 143 (6) Edema Peripheral 135 (5) Anorexia b 139 (6) Dry Mouth 121 (5) Abdominal Pain c 115 (5) Anxiety 95 (4) Back Pain 95 (4) Dyspepsia d 88 (4) Depression 81 (3) Dyspnea e 76 (3) Muscle Spasms 74 (3) Arthralgia 72 (3) Rash 64 (3) Pain in Extremity 63 (3) Pain 58 (2) Drug Withdrawal Syndrome 55 (2) Pyrexia 52 (2) Fall 51 (2) Chest Discomfort f 51 (2) a b c d e f

Fatigue was grouped and reported with asthenia Decreased appetite was grouped and reported with anorexia Abdominal pain upper was grouped and reported with abdominal pain Reflux esophagitis, gastroesophageal reflux disease and Barrett’s esophagus were grouped and reported with dyspepsia Dyspnea exacerbated and dyspnea exertional were grouped and reported with dyspnea Chest pain and non-cardiac chest pain were grouped and reported with chest discomfort

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The following Adverse Reactions occurred in patients with an overall frequency of <2% and are listed in descending order within each System Organ Class: Cardiac disorders: palpitations, tachycardia, bradycardia, extrasystoles Ear and labyrinth disorders: vertigo, tinnitus Endocrine disorders: hypogonadism Eye disorders: vision blurred, diplopia, dry eye, miosis Gastrointestinal disorders: flatulence, dysphagia, hematochezia, abdominal distension, hemorrhoids, abnormal feces, intestinal obstruction, eructation, diverticulum, gastrointestinal motility disorder, large intestine perforation, anal fissure, bezoar, duodenitis, ileus, impaired gastric emptying, painful defecation General disorders and administration site conditions: chills, malaise, feeling abnormal, feeling hot and cold, feeling jittery, hangover, difficulty in walking, feeling drunk, hypothermia Infections and infestations: gastroenteritis, diverticulitis Injury, poisoning and procedural complications: contusion, overdose Investigations: weight decreased, hepatic enzyme increased, blood potassium decreased, blood amylase increased, blood testosterone decreased, oxygen saturation decreased Metabolism and nutrition disorders: dehydration, fluid retention, increased appetite, hyperuricemia Musculoskeletal and connective tissue disorders: myalgia Nervous system disorders: tremor, sedation, hypoesthesia, paraesthesia, disturbance in attention, memory impairment, dysarthria, syncope, balance disorder, dysgeusia, depressed level of consciousness, coordination abnormal, hyperesthesia, myoclonus, dyskinesia, hyperreflexia, encephalopathy, cognitive disorder, convulsion, psychomotor hyperactivity Psychiatric disorders: confusional state, nervousness, restlessness, abnormal dreams, mood altered, hallucination, panic attack, euphoric mood, paranoia, dysphoria, listless, crying, suicide ideation, libido decreased, aggression Renal and urinary disorders: dysuria, urinary retention, urinary frequency, urinary hesitation, micturition disorder Reproductive system and breast disorders: erectile dysfunction, sexual dysfunction Respiratory, thoracic and mediastinal disorders: rhinorrhoea, respiratory distress, hypoxia, bronchospasm, sneezing, hyperventilation, respiratory depression Skin and subcutaneous tissue disorders: erythema Vascular disorders: flushing, hypertension, hypotension DRUG INTERACTIONS CNS Depressants The concomitant use of EXALGO with central nervous system depressants such as hypnotics, sedatives, general anesthetics, antipsychotics and alcohol may cause additive depressant effects and respiratory depression. Additionally, hypotension and profound sedation or coma could occur. When this combination is indicated, the dose of one or both agents should be reduced. The concomitant use of alcohol should be avoided [see Clinical Pharmacology (12.3)].

Monoamine Oxidase (MAO) Inhibitors MAO inhibitors may cause CNS excitation or depression, hypotension or hypertension if co-administered with opioids including EXALGO. EXALGO is not intended for patients taking MAO inhibitors or within 14 days of stopping such treatment.

Mixed Agonist/Antagonist Opioid Analgesics The concomitant use of EXALGO with morphine agonist/antagonists (buprenorphone, nalbuphine, pentazocine) could lead to a reduction of the analgesic effect by competitive blocking of receptors, thus leading to risk of withdrawal symptoms. Therefore, this combination is not recommended.

Anticholinergics Anticholinergics or other medications with anticholinergic activity when used concurrently with EXALGO may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.

Cytochrome P450 Enzymes In vitro data suggest that hydromorphone in clinically relevant concentrations has minimal potential to inhibit the activity of human hepatic CYP450 enzymes including CYP1A2, 2C9, 2C19, 2D6, 3A4, and 4A11.

USE IN SPECIFIC POPULATIONS Pregnancy Teratogenic Effects Pregnancy Category C: There are no adequate and well-controlled studies in pregnant women. Hydromorphone crosses the placenta. EXALGO should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus [see Use in Specific Populations (8.2)].

Hydromorphone was not teratogenic in pregnant rats given oral doses up to 6.25 mg/kg/day or in pregnant rabbits administered oral doses up to 25 mg/kg/day during the period of organogenesis (~1.2 times the human exposure following 32 mg/day).

Hydromorphone administration to pregnant Syrian hamsters and CF-1 mice during major organ development revealed teratogenicity likely the result of maternal toxicity associated with sedation and hypoxia. In Syrian hamsters given single subcutaneous doses from 14 to 258 mg/kg during organogenesis (gestation days 8 to 10), doses ≥ 19 mg/kg hydromorphone produced skull malformations (exencephaly and cranioschisis). Continuous infusion of hydromorphone (5 mg/kg, s.c.) via implanted osmotic mini pumps during organogenesis (gestation days 7 to 10) produced soft tissue malformations (cryptorchidism, cleft palate, malformed ventricals and retina), and skeletal variations (supraoccipital, checkerboard and split sternebrae, delayed ossification of the paws and ectopic ossification sites). The malformations and variations observed in the hamsters and mice were at doses approximately three-fold higher and <one-fold lower, respectively, than a 32 mg human daily oral dose on a body surface area basis.

Nonteratogenic Effects In the pre- and post-natal effects study in rats, neonatal viability was reduced at 6.25 mg/kg/day (~1.2 times the human exposure following 32 mg/day).

Neonates born to mothers who have been taking opioids regularly prior to delivery will be physically dependent. The withdrawal signs include irritability and excessive crying, tremors, hyperactive reflexes, increased respiratory rate, increased stools, sneezing, yawning, vomiting, and fever. The intensity of the syndrome does not always correlate with the duration of maternal opioid use or dose. There is no consensus on the best method of managing withdrawal.

Approaches to the treatment of the syndrome have included supportive care and, if indicated, drugs such as paregoric or phenobarbital.

Labor and Delivery EXALGO is not recommended for use in women during and immediately prior to labor and delivery. Administration of EXALGO to the mother shortly before delivery may result in some degree of respiratory depression in the neonate.

However, neonates whose mothers received opioid analgesics during labor should be observed closely for signs of respiratory depression.

Nursing Mothers Low concentrations of hydromorphone have been detected in human milk in clinical trials. Withdrawal symptoms can occur in breastfeeding infants when maternal administration of an opioid analgesic is stopped. Nursing should not be undertaken while a patient is receiving EXALGO since hydromorphone is excreted in the milk.

Pediatric Use The safety and effectiveness of EXALGO in pediatric patients 17 years of age and younger have not been established.

Geriatric Use Elderly patients have been shown to be more sensitive to the adverse effects of EXALGO compared to the younger population. Therefore, use extra caution when prescribing EXALGO in elderly patients and reduce the initial dose.

Neonatal Withdrawal Syndrome Chronic maternal use of opiates or opioids during pregnancy coexposes the fetus. The newborn may experience subsequent neonatal withdrawal syndrome (NWS). Manifestations of NWS include irritability, hyperactivity, abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea, weight loss, and failure to gain weight. The onset, duration, and severity of the disorder differ based on such factors as the addictive drug used, time and amount of mother’s last dose, and rate of elimination of the drug from the newborn. Approaches to the treatment of this syndrome have included supportive care and, when indicated, drugs such as paregoric or phenobarbital.

Hepatic Impairment In a study that used a single 4 mg oral dose of immediate-release hydromorphone tablets, four-fold increases in plasma levels of hydromorphone (Cmax and AUC0- ) were observed in patients with moderate hepatic impairment (Child-Pugh Group B). Start patients with moderate hepatic impairment on a reduced dose and closely monitored during dose titration.

The pharmacokinetics of hydromorphone in severe hepatic impairment patients have not been studied. Further increase in Cmax and AUC0- of hydromorphone in this group is expected, therefore, use an even more conservative starting dose [see Dosage and Administration (2.4)].

Renal Impairment Renal impairment affected the pharmacokinetics of hydromorphone and its metabolites following administration of a single 4 mg dose of immediate-release tablets. The effects of renal impairment on hydromorphone pharmacokinetics were two-fold and four-fold increases in plasma levels of hydromorphone (Cmax and AUC0-48h) in moderate (CLcr = 40 to 60 mL/min) and severe (CLcr < 30 mL/min) impairment, respectively. In addition, in patients with severe renal impairment hydromorphone appeared to be more slowly eliminated with longer terminal elimination half-life (40 hours) compared to subjects with normal renal function (15 hours). Start patients with moderate renal impairment on a reduced dose and closely monitored during dose titration. As EXALGO is only intended for once daily administration, consider use of an alternate analgesic that may permit more flexibility with the dosing interval in patients with severe renal impairment [see Dosage and Administration (2.4)].

DRUG ABUSE AND DEPENDENCE Controlled Substance EXALGO contains hydromorphone, a Schedule II controlled substance with a high potential for abuse similar to fentanyl, methadone, morphine, oxycodone, and oxymorphone. EXALGO can be abused and is subject to misuse, abuse, addiction, and criminal diversion [see Warnings and Precautions (5.2)]. The high drug content in the extended release formulation adds to the risk of adverse outcomes from abuse.

Abuse All patients treated with opioids, including EXALGO, require careful monitoring for signs of abuse and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use.

Addiction is a primary, chronic, neurobiologic disease, with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving.

“Drug-seeking” behavior is very common to addicts and drug abusers. Drugseeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated claims of loss of prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact information for other treating physician(s). “Doctor shopping” (visiting multiple prescribers) to obtain additional prescriptions is common among drug abusers, people suffering from untreated addiction and criminals seeking drugs to sell.

Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts.

In addition, abuse of opioids can occur in the absence of true addiction and is characterized by misuse for non-medical purposes, often in combination with other psychoactive substances. Since EXALGO may be diverted for non-medical use, careful record-keeping of prescribing information, including quantity, frequency, and renewal requests is strongly advised.

Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.

EXALGO is intended for oral use only. Misuse or abuse by breaking, crushing, chewing, or dissolving EXALGO poses a hazard of overdose and death. This risk is increased with concurrent abuse of EXALGO with alcohol and other substances.

With intravenous abuse, the tablet excipients, especially polyethylene oxide, can be expected to result in necrosis and inflammation of cardiac tissues. In addition, parenteral drug abuse is commonly associated with transmission of infectious disease such as hepatitis and HIV. Healthcare professionals should contact their State Professional Licensing Board or State Controlled Substances Authority for information on how to prevent and detect abuse or diversion of this product.

Dependence Tolerance is a state of adaptation in which exposure to a drug induces changes that result in a diminution of one or more of the drug’s effects over time.

Tolerance could occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects.

Physical dependence is a state of adaptation that is manifested by an opioid specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist. The opioid abstinence or withdrawal syndrome is characterized by some or all of the following: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, piloerection, myalgia, mydriasis, irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, increased blood pressure, respiratory rate, or heart rate.

Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal symptoms [see Use in Specific Populations (8.1, 8.2)].

OVERDOSAGE Symptoms Acute overdosage with opioids can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and sometimes bradycardia, hypotension and death. The extended release characteristics of EXALGO should also be taken into account when treating the overdose. Even in the face of improvement, continued medical monitoring is required because of the possibility of extended effects.

Deaths due to overdose could occur with abuse and misuse of EXALGO. Due to the delayed mean apparent peak plasma level of EXALGO occurring at 16 hours following administration as well as the 11 hour mean elimination half-life of EXALGO, patients who receive an overdose will require an extended period of monitoring and treatment that may go beyond 24 to 48 hours.

Treatment Give primary attention to the re-establishment of a patent airway and institution of assisted or controlled ventilation. Employ supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema accompanying overdose as indicated. Cardiac arrest or arrhythmias will require advanced life support techniques.

The pure opioid antagonists, such as naloxone and naltrexone are specific antidotes to respiratory depression from opioid overdose. Since the duration of reversal would be expected to be less than the duration of action of hydromorphone in EXALGO, the patient must be carefully monitored until spontaneous respiration is reliably re-established. EXALGO will continue to release and add to the hydromorphone load for up to 24 hours after administration and the management of an overdose should be monitored accordingly, at least 24 to 48 hours beyond the overdose.

Only administer opioid antagonists in the presence of clinically significant respiratory or circulatory depression secondary to hydromorphone overdose. In patients who are physically dependent on any opioid agonist including EXALGO, an abrupt or complete reversal of opioid effects may precipitate an acute abstinence syndrome. The severity of the withdrawal syndrome produced will depend on the degree of physical dependence and the dose of the antagonist administered. Please see the prescribing information for the specific opioid antagonist for details of their proper use.

OROS is a registered trademark of ALZA Corporation.

EXALGO is a trademark of Mallinckrodt Inc. COVIDIEN, COVIDIEN with logo and Covidien logo are U.S. and/or internationally registered trademarks of Covidien AG. © 2010 Mallinckrodt Inc., a Covidien company Distributed by: Mallinckrodt Brand Pharmaceuticals, Inc. Hazelwood, MO 63042 USA Issued 03/2010-B

Mallinckrodt

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Generic Drug Trends_Cover 12/14/10 11:44 AM Page 391

GENERIC DRUG TRENDS

Generics “Pipeline” Predicts Continued Market Share Gains Through 2014

By Dalia Buffery, MA, ABD

T

he outlook for generics for the next 4 or 5 years continues to shine, judging from patent expiration dates for many of the top-selling drugs. The generics “pipeline,” therefore, practically ensures that the past several years’ trend of increasing market share for generics will continue with a vengeance. This does not bode well for brand-name manufacturers, which will each be losing billions in annual sales (Table), but it does foretell greater access to top-rated yet lessexpensive medications—a positive step overall in the current state of economic morass.

But while the success of nonbiologic generics continues, the future for biogenerics or biosimilars remains in limbo, despite the passing of the Biologic Price Competition and Innovation Act earlier this year. This first legislation toward the creation of a path for biosimilars still requires much work, as Rasmus Rojkajaer, MD, PhD, Head of Global Biologics Research & Development at Mylan, suggested on behalf of the Generic Pharmaceutical Association to industry attendees at the November 3 public hearing convened by the US Food and Drug Administration.

Dr Rojkajaer stressed the need to ensure “that patients gain access to more affordable biogeneric and biosimilar products, while at the same time maintaining incentives to innovate new medicines.”1 As a result, the predictable increased growth in generics market share will continue to consist for the most part of nonspecialty drugs, even while the pharmaceutical research and development efforts are leaning heavily on specialty rather than nonspecialty products.

Of the current 50 top-selling nonspecialty drugs, 25 should become available in a generic formulation within the next 5 years, according to Brian W. Kolling, PharmD, Director, Pipeline and Trend Forecasting, Part D, at Prescription Solutions.2 Specifically, significant generic activity will occur in 5 key clinical areas— cardiovascular (CV) disease, central nervous system (CNS), diabetes, gastrointestinal (GI), and respiratory conditions. This includes the patent expiration for 2 of

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the top-selling statins—Lipitor in 2011 and Crestor in 2016, which garnered >$5 billion and >$2 billion, respectively, in 2009 sales, and the top GI drug (Nexium), with >$5 billion (Table).3 As shown in the Table, of the 29 major nonspecialty drugs to lose patent in the next 5 years, almost half (N = 14) had billions of dollars in sales in 2009, amounting to just under $43 billion ($42.8 billion)3 combined.

Of the 10 top-selling agents worldwide, 3 top CV agents in 3 different classes—a statin (Lipitor), an angiotensin receptor blocker (Diovan), and an antiplatelet (Plavix)—will lose patent by 2012, to the tune of $10.94 billion (in 2009) combined3 in lost revenue to their manufacturers.

In addition, the patent expiration of 8 key CNS drugs—with billions of dollars in 2009 sales, each, for 5 of them (Abilify, Cymbalta, Lexapro, Seroquel, and Zyprexa)3—further reinforces the potential impact of this trend toward greater access to generic medications on patient management, as well as on overall drug cost reductions for patients and health plans.

Therefore, despite the lack of significant progress on the biosimilars front by the end of 2010, the outlook for nonspecialty generic drug activity remains bright and will continue to lead the rapidly approaching 80% in generic market share as a percentage of total prescriptions written in the United States, and with it the increased access to popular drugs, albeit wrapped in new clothes, as well as considerable cost reductions for patients, health plans, and employers.

References 1. Rojkajaer R. GPhA tells FDA that science-based biogeneric approval process is needed to assure lower costs for patients. Generic Pharmaceutical Association press release. November 3, 2010. http://www.gphaonline.org/media/press-releases/2010/ gpha-tells-fda-science-based-biogeneric-approval-process-needed-assure-low.

Accessed November 29, 2010.

2. Kolling BW. Scanning the pharmaceutical pipeline: what’s on the horizon? 2010 Educational Conference, Academy of Managed Care Pharmacy, St. Louis, MO, October 14, 2010.

3. Pharmaceutical sales 2009-top US drugs by sales. www.drugs.com/top200.html.

Accessed December 7, 2010.

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GENERIC DRUG TRENDS

Continued from page 391

Table Generics Pipeline: Major Nonspecialty Drugs to Lose Patent in the Next 5 Years Manufacturer

Expected generic launcha

TriCor (fenofibrate)

Abbott

March 2011-July 2012

1,224,894

Lipitor (atorvastatin calcium)

Pfizer

November 2011

5,363,193

Avapro (irbesartan)

Bristol-Myers Squibb

March 2012

Plavix (clopidogrel bisulfate)

Bristol-Myers Squibb

May 2012

Atacand (candesartan cilexetil)

AstraZeneca

December 2012

152,603

Diovan (valsartan and hydrochlorothiazide, USP)

Novartis

September 2012

1,328,515

Niaspan (niacin)

Abbott

September 2013

716,589

Crestor (rosuvastatin calcium)

AstraZeneca

July 2016

2,308,138

Zyprexa (olanzapine)

Eli Lilly

October 2011

1,855,436

Lexapro (escitalopram oxalate)

Forest

March 2012

2,334,422

Seroquel (quetiapine fumarate)

AstraZeneca

March 2012

3,117,591

Geodon (ziprasidone hydrochloride)

Pfizer

September 2012

873,952

Provigil (modafinil)

Cephalon

April 2012

883,339

Abilify (aripiprazole)

Bristol-Myers Squibb

April 2015

3,083,351

Lunesta (eszopiclone)

Sepracor

May 2014

813,087

Cymbalta (duloxetine hydrochloride)

Eli Lilly

July 2014

2,404,353

Avandia (rosiglitazone maleate)

GlaxoSmithKline

March 2012

407,906

Actos (pioglitazone hydrochloride)

Takeda

August 2012

2,531,621

Aciphex (rabeprazole sodium)

Eisai

May 2013

996,052

Nexium (esomeprazole sodium)

AstraZeneca

April 2014

5,014,827

Clarinex (desloratadine)

Schering/Merck

January 2012

181,215

Xopenex nebulizer (levalbuterol)

Sepracor

August 2012

356,898

Singulair (montelukast sodium)

Merck

August 2012

3,027,378

Advair (fluticasone propionate, salmeterol xinafoate)

GlaxoSmithKline

TBD

3,653,410

Xalatan (latanoprost)

Pfizer

March 2011

Levaquin (levofloxacin)

Ortho-McNeil-Janssen

June 2011

1,373,131

Uroxatral (alfuzosin hydrochloride)

sanofi-aventis

July 2011

174,034

Boniva (ibandronate sodium)

Genentech

March 2012

511,277

Actonel (risedronate sodium, calcium carbonate)

Warner Chilcott

June 2014

435,977

Drug brand name (generic) CARDIOVASCULAR

CENTRAL

2009 Annual sales ($ thousands)b

DISEASES

398,768 4,223,124

NERVOUS SYSTEM CONDITIONS

DIABETES

GASTROINTESTINAL

RESPIRATORY

OTHER

CONDITIONS

CONDITIONS

CATEGORIES

457,121

a

Source: Brian W. Kolling, PharmD. 2010 Educational Conference, Academy of Managed Care Pharmacy, October 13-15, 2010; St. Louis, MO.

bSource: Pharmaceutical sales 2009-top US drugs by sales. www.drugs.com/top200.html. Accessed December 7, 2010. Used with permission.

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Page 1

One And The Same

For nearly 50 years, Mylan Pharmaceuticals has helped set the standards for quality in generic medicines. Today, the same standards that guide our manufacturing facilities in the U.S. also guide our facilities around the globe.

By meticulously adhering to time-tested procedures and following rigorous quality assurance steps, we are confident that every batch of every product manufactured by Mylan is the same as the one before. It’s a consistency that comes from the commitment made by more than 7,400 employees in our manufacturing facilities … and it’s why pharmacists continue to rank our products highest in quality.*

800.RX.MYLAN • www.mylanpharms.com *U.S. Pharmacist Generic Company Surveys. 2006-2009 ©2010 Mylan Pharmaceuticals Inc.

MYNMKT394A

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ORIGINAL RESEARCH

The H-E-B Value-Based Health Management Program: Impact on Asthma Medication Adherence and Healthcare Cost Anna O. D’Souza, PhD; Roshan Rahnama, MPH; Timothy S. Regan, BPharm, RPh; Beth Common, MBA; Steven Burch, PhD

Timothy S. Regan

Stakeholder Perspective, page 402

Am Health Drug Benefits.

2010;3(6):394-402. www.AHDBonline.com Disclosures are at end of text

Background: Recent publications have shown that copayment reductions increase medication adherence above the effects of existing disease management programs, demonstrating an additive effect of combining a value-based insurance design with a disease management program. This effect, however, has yet to be demonstrated for medications used for the treatment of asthma.

Objective: To evaluate the impact of a value-based health management asthma program— which included providing patient education and lowering copayments for select asthma controller medications—on medication adherence and healthcare utilization and costs.

Study Design: The study involved a quasi-experimental intervention versus control group design of insured patients diagnosed with asthma.

Method: After applying the inclusion/exclusion criteria for study participation, we obtained informed consent from the intervention group; those eligible to participate who did not return the forms served as the control group. The final sample size included 764 patients with asthma—298 in the intervention group and 466 in the control group. The intervention consisted of a reduction in copayment for select asthma controller medications from an average of $20 to $30 down to $5, as well as 3 mailings of educational materials for asthma management. Medical and pharmacy claims data for the study population were used to evaluate all study parameters and outcomes. Medication possession ratio was used to measure adherence to asthma controller medications. Statistical models were used to study differences in the 2 study groups during the 12-month follow-up period for adherence and cost outcomes.

Results: Participation in the value-based health management asthma program increased patients’ 12-month medication adherence by 10 absolute percentage points in the intervention group (53.9% for intervention vs 43.9% for control group, P <.001) and significantly decreased average monthly medical costs ($170 intervention vs $229 control, P = .004). This increase in adherence resulted in greater monthly pharmacy costs ($181 intervention vs $124 control, P <.001). However, the increase in pharmacy costs was offset by lower medical costs, leading to a nonsignificant increase in average monthly total healthcare costs ($362 intervention vs $337 control, P = .276).

Conclusion: Adoption of a value-based health management program that combines patient education with lowered copayments has a positive impact on medication adherence, resulting in a reduction in associated medical costs and no significant increase in total costs.

A

sthma is one of the nation’s most common, costly, and increasingly prevalent diseases. In 2008, approximately 23.3 million people had asthma

Dr D’Souza is a Manager, Ms Rahnama is a Healthcare Strategy Consultant, and Mr Regan is an Executive Director, Xcenda, Palm Harbor, FL; Ms Common is Corporate Benefits Manager, H-E-B, San Antonio, TX; and Dr Burch is a Director, GlaxoSmithKline, Durham, NC.

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in the United States, of whom 12.7 million had experienced asthma attacks.1 The economic cost of asthma for 2010 is projected at $20.7 billion, of which $15.6 billion is expected to reflect direct costs of healthcare-related expenditures (ie, hospital care, physician services, and prescription drugs).1,2 Asthma medications, combined with patient education, are the cornerstones of asthma management.2 In

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addition, the clinical effectiveness of asthma treatment depends on patient adherence to prescribed medications.3 However, only 37% of patients adhere to prescribed inhaled corticosteroids4,5 and adequately control their asthma.6 The consequences of nonadherence may include poor symptom control, excessive use of betaagonist agents, increased emergency department use, hospitalization, and death.4,7 Recent drug benefit design trends, including increasing patient copayments, may also contribute to medication nonadherence.8-11 In the case of patients with asthma, high copayments have been associated with significant reductions in the use of necessary asthma medications,12,13 as well as increases in emergency department visits and hospitalization days.8 The adoption of a value-based health management (VBHM) approach that recognizes the role of preventive public health and patient education may help to reduce advanced health complications and control rising healthcare costs. VBHM includes disease state management (DM) and value-based insurance design (VBID).

DM involves a system of coordinated interventions and communications, usually for patients with chronic conditions, with the ultimate goal of reducing avoidable complications, such as hospitalizations and emergency department visits.14 The focus of VBID programs is to decrease patient cost-sharing for high-value services and increase costsharing for low-value services, thereby avoiding the demand-dampening advantages and lessening the adverse health consequences of increased cost-sharing.15 With 83% of health plans utilizing asthma DM programs,16 VBID programs are becoming a common means of augmenting provider-oriented strategies, aligning patient and provider incentives.

H-E-B—a large retail/grocery store chain in Texas and Mexico, with approximately 300 stores and 65,000 employees—has implemented aspects of a VBHM program, specifically the DM components, for their employees and employees’ dependents diagnosed with asthma.

H-E-B subsequently partnered with GlaxoSmithKline to implement a VBID program, with the goal of improving medication adherence and healthcare utilization and reducing costs (asthma-related and overall). This present study assesses the impact of VBHM interventions within the H-E-B population, offering a real-world case study evaluation of a comprehensive VBHM program.

Study objectives were to compare the participants in the intervention group and the control group in terms of their adherence to select asthma controller medications, asthma-related healthcare costs and resource utilization, and overall (ie, any medical or pharmacy) healthcare costs.

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KEY POINTS ➤

➤

➤

➤

➤

➤

Adherence to asthma medication is key to patient outcomes but is often subpar.

This study evaluated the effect of a value-based health management program on medication adherence and overall costs in patients with asthma who were employed at H-E-B. The program consisted of 2 main components— disease management and value-based insurance design. The latter reduced the cost of copayment for select asthma medications from an average of $20 to $30 down to $5 for patients in the intervention group but not in the control group.

During the 12-month follow-up period, medication adherence increased by 10 absolute percentage points in the intervention group (53.9% for intervention vs 43.9% for control group, P <.001).

In addition, a significant reduction was found in overall medical cost, which offset the increase in pharmacy costs.

This analysis contributes to the growing body of evidence demonstrating that decreases in copayment amounts may increase asthma medication adherence and reduce associated medical costs.

Methodology Study Design We used a quasi-experimental, intervention group versus control group design. The study period was 24 months, with the start of the intervention being the index date (June 1, 2006), the 12-month period before the index date being the preindex period (June 1, 2005-May 31, 2006), and the 12-month period after the index date (June 1, 2006-May 31, 2007) used as the follow-up period. Patients’ baseline characteristics were measured during the preindex period. Medication adherence and asthma-related resource utilization, costs, and overall healthcare costs were measured during the preindex and follow-up periods.

Data Source Medical and pharmacy claims data of H-E-B employees and their dependents were used for this analysis. All patients were enrolled in a preferred provider organization plan. Claims data included inpatient and outpatient diagnoses, as well as prescription records classified by the National Drug Code. Paid and charged amounts, as well as dates of service, were available for all claims.

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Study Inclusion and Exclusion Criteria Insured H-E-B employees with asthma and their dependents with asthma who provided informed consent were eligible for inclusion in the intervention group; those who met the inclusion criteria but did not provide informed consent comprised the control group.

Additional inclusion and exclusion criteria were applied to enhance the study’s validity. To be included, employees had to (1) have at least 1 pharmacy claim for the selected asthma controller medications in the preindex period, (2) have a diagnosis of asthma at baseline, (3) be between age 4 and 64 years at baseline, and (4) be continuously eligible during the preindex and follow-up periods.

Asthma diagnosis was defined as (1) a hospital or emergency department visit with a primary diagnosis of asthma (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] code 493.xx), (2) at least 2 physician visits with asthma listed in any diagnostic field, or (3) at least 2 pharmacy claims for asthma-related medications, except oral corticosteroids and decongestants.

Exclusion criteria included (1) diagnosis of cystic fibrosis (ICD-9-CM code 277.0x) in the preindex period, (2) diagnosis of chronic obstructive pulmonary disease (ICD-9-CM codes 491.xx, 492.xx, 493.2x, 496) in the preindex period, or (3) age ≥45 years at baseline and having ≥2 pharmacy claims for ipratropium bromide or combination albuterol plus ipratropium in the preindex period.

Table 1 Selected Asthma Controller Medications Advair Diskus (fluticasone propionate and salmeterol) Flovent (fluticasone) Flovent HFA (fluticasone) Flovent Rotadisk (fluticasone) Foradil (formoterol fumarate) Gastrocrom (cromolyn) Intal (cromolyn sodium) Pulmicort (budesonide) Qvar (beclomethasone dipropionate) Serevent (salmeterol xinafoate) Serevent Diskus (salmeterol xinafoate) Singulair (montelukast sodium) Slo-Bid 50 (theophylline) Slo-Bid 75 (theophylline) Theochron (theophylline) Tilade (nedocromil sodium) Uniphyl (theophylline)

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Study Intervention H-E-B employees and dependents with at least 1 medical claim for asthma during the preindex period were the target population. Participation was voluntary and was requested by an invitation letter that described the intervention and included consent and enrollment forms. The intervention consisted of 2 components: (1) An average reduction in the copayment from between $20 and $30 to $5 for selected (Table 1) asthma controller medications (2) Three mailings of educational materials for asthma management.

All asthma controller medications in the preferred formulary list were eligible for copayment reduction (Table 1). Educational topics included medication guides, asthma myths, patient–doctor action plan, asthma triggers, acute asthma management strategies, and the Asthma Control Test.17 Sources referenced in developing the patient communication materials included the Staywell Company, Asthma Action America, the Respiratory Institute, and QualityMetric Incorporated.

English was the primary language, at an eighth-grade reading level, for all the educational materials.

Before the start of the study intervention in 2006, study participants were already enrolled in the Blue Care Connection (BCC) program, which provides patientfocused services to help H-E-B employees improve their health outcomes and manage their healthcare costs. The BCC program began in 2004 and was in effect until the end of the current study. Participation in the BCC program was voluntary. Among the final patient sample included in the current study, 99% of patients in the intervention group and 25% of those in the control group were enrolled in the BCC program.

The BCC program services included 24/7 access to health information for patients provided by licensed nurses for managing their disease, periodic calls from licensed nurses to monitor patients’ health, access to an online resource and information tool to manage their health, and discounts on health-related products and services that help to support healthy lifestyles (eg, gym membership).

Outcome Definitions Adherence Medication possession ratio (MPR) was used to measure adherence to asthma controller medications. MPR represents the proportion of time that an asthma controller medication was available to a patient during the duration of therapy, and was calculated as the sum of the total days’ supply of medication for all prescriptions, except the last prescription, divided by the duration of therapy (ie, total number of days from the first fill date to

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Table 2 Baseline Characteristics, by Study Intervention Group Status Baseline characteristics

Intervention (N = 298)

Control (N = 466)

P

Age in years, mean (SD)

29.1 (19.4)

25.7 (18.6)

.016a

Male, N (%)

139 (46.6)

229 (49.1)

.500

Blue Care Connection program, N (%)

297 (99.7)

118 (25.3)

<.001a

Charlson Comorbidity Index, mean (SD)

0.93 (0.98)

0.81 (0.84)

.081

2.4 (3.9)

2.0 (3.3)

.294

0.64 (1.15)

0.61 (1.07)

.651

Inhaled corticosteroids

219 (73.5)

299 (64.2)

.007a

Leukotriene antagonists

195 (65.4)

314 (67.4)

.578

Total copayment for asthma medications in preindex period, mean (SD)

191.5 (124.2)

158.1 (106.8)

<.001a

Total copayment for nonasthma medications in preindex period, mean (SD)

313.1 (361.7)

261.8 (342.8)

.003a

Pulmonologist/allergist care, N (%)

69 (23.2)

107 (23.0)

.951

Asthma-related hospitalization/ED visit in preindex period, N (%)

19 (6.4)

26 (5.6)

.648

1.68 (2.9)

1.25 (2.1)

.031a

Prescription utilization metrics to assess asthma severity Number of SABA canisters in preindex period, mean (SD) Number of oral corticosteroid Rxs in preindex period, mean (SD) Presence of anti-inflammatory controller asthma medications in preindex period, N (%)

Medical utilization metrics to assess asthma severity

Number of asthma-related outpatient visits in preindex period, mean (SD) a

P <.05.

ED indicates emergency department; SABA, short-acting beta-agonist; SD, standard deviation.

the last fill date). MPR usually ranges from 0%, indicating no adherence, to 100%, indicating perfect adherence. Therefore, a patient with a 50% MPR during a 90-day therapy duration had 45 days of treatment (90 days ⳯ 50% = 45 days).

All prescriptions had a start date (ie, fill date) and an end date (ie, fill date plus days’ supply). When prescriptions overlapped (ie, a patient refilled an additional prescription before the end date of the preceding prescription), residual days were added to the end date of the next prescription. Therefore, patients were assumed to have consumed all medications acquired during the study period. With the addition of overlapped prescription claims, it was possible for adherence to be >100%, particularly for patients who consistently received early refills; in these instances, adherence was truncated to 100%. For patients having only 1 prescription claim, MPR was assumed to be 0%. For patients who used >1 of the selected asthma controller drugs (Table 1) concomitantly, MPR was computed as the sum of total days’ sup-

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ply of each of the medications, divided by the sum of the total duration of therapy for each medication.

Some researchers have questioned the use of MPR as a measure of adherence for inhaled medications, particularly short-acting medications,18 because these are often used on an as-needed basis, which renders the days’ supply variable inaccurate for MPR calculations.

However, we do not believe this applies to the asthma controller medications, because they are not indicated to be used on an as-needed basis and have specific dosage instructions.

Healthcare Resource Utilization and Costs Resource utilization in this study refers to the number of different types of healthcare visits and/or prescription units. These include the number of physician visits, hospitalizations, emergency department visits, short-acting beta-agonist (SABA) canisters, and oral corticosteroid prescriptions. An asthma controller ratio was calculated as the ratio of the number of controller medications (ie,

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Figure 1 Study Sample Selection Algorithm Target population N = 3885 H-E-B employees and/or dependents who were enrolled in the H-E-B health insurance plan and had ≥1 asthma-related claim were mailed invitation letters to participate in the study ➤

Initial sample size N = 3496 (100%) H-E-B employees and/or dependents whose complete eligibility and claims information were obtained Patients excluded, N (%)

Exclusion criteria a No diagnosis of asthma in preindex period, based on study definition

1670 (47.8)

Not continuously eligible during preindex and postindex periods

626 (17.9)

Age at baseline not between 4 and 64 years

89 (2.6)

Diagnosis of cystic fibrosis in preindex period

25 (0.7)

Diagnosis of COPD in preindex period

205 (5.9)

Age ≥45 years at baseline and having ≥2 pharmacy claims for ipratropium or combination ipratropium + albuterol during preindex period

60 (1.7)

1814 (51.9)

No claim for any of the select asthma controller medications in preindex period Final sample size N = 764 ➤

➤

Intervention group 298 (39%)

Control group 466 (61%)

Patient education materials and copayment reduction provided concurrently

No patient education materials or copayment reduction provided

a

Exclusion criteria are not mutually exclusive.

COPD indicates chronic obstructive pulmonary disease.

inhaled corticosteroid, cromolyn, nedocromil canisters, and oral leukotriene) dispensed, divided by the sum of the number of controller medications and canisters of inhaled SABAs dispensed during the study period.6 Costs were defined as the total amount paid for physician visits, hospitalizations, emergency department visits, and prescription drugs. Asthma-specific and overall healthcare costs were obtained for each patient during the 12-month follow-up period.

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Asthma-specific medical resource utilization and costs were identified by the presence of a primary diagnosis code for asthma (ICD-9-CM 493.xx) on a claim.

Asthma-related prescription drugs included reliever and controller medications (SABAs, oral corticosteroids, xanthines, long-acting beta-agonists, leukotriene antagonists, cromolyn/nedocromil, and inhaled corticosteroids). Monthly cost, rather than total costs incurred during the study period, was used as the target outcome to permit comparison of baseline and follow-up periods.

Covariate and Statistical Analyses Covariates included in multivariate analyses were age, sex, comorbidity, preindex healthcare costs, and asthma severity. For overall comorbidity, a DartmouthManitoba model adaptation of the Charlson Comorbidity Index score was calculated for each patient, based on the presence of ICD-9-CM codes during the 12-month preindex period,19 with greater scores representing a greater burden of comorbidity. The Dartmouth-Manitoba adaptation of the Charlson Comorbidity Index uses ICD-9-CM codes to represent etiologies and manifestations or sequelae of the 19 comorbidities specified in the original Charlson index.

Overall healthcare costs for the preindex period were computed and categorized as medical or pharmacy costs and were included in the model as separate variables. For determining asthma severity, prescription and medical utilization metrics were used (Table 2).

Demographic and other baseline characteristics were summarized by group using measures such as means and percentages. Inferential statistics were used to assess intergroup differences in these parameters. Differences between groups in adherence, resource utilization, and costs were tested for statistical significance. Parametric or nonparametric tests were used, depending on distributional characteristics of these outcomes. Parametric tests for continuous variables included t-tests, and nonparametric tests included Mann-Whitney tests. Chisquare tests were used for categorical variables.

Differences between baseline and follow-up measures were assessed by paired t-tests or Wilcoxon signed-rank tests, as appropriate. Ordinary least square (OLS) regression models, semi-log OLS models, or generalized linear models with a gamma distribution and log-link were used for assessing differences in groups during follow-up for adherence and cost outcomes, after controlling for baseline covariates.

Results Figure 1 illustrates the sample selection procedure, which yielded a final sample size of 764 patients with asthma, 298 in the intervention group and 466 in the

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Figure 2 Adjusted Adherence Rate Estimates During Follow-Up Period Intervention Control

Medication possession ratio, %

control group. Table 2 describes the study sample at baseline. Intervention group participants were significantly older than those in the control group, by an average of 3.4 years (P = .016), but gender proportions were similar (P = .500). A significantly greater proportion of the intervention group than the control group filled an inhaled corticosteroid prescription (73.5% vs 64.2%, respectively; P = .007) and had a greater mean number of asthma-related outpatient visits in the preindex period (1.68 vs 1.25, respectively; P = .031). Compared with the control group, the intervention group had significantly greater mean total copayments for asthmarelated medications ($192 vs $158, respectively; P <.001) and nonâ&#x20AC;&#x201C;asthma-related medications ($313 vs $262, respectively; P = .003) during the preindex period. In general, asthma severity for the intervention group was greater than for the control group, which might have led to greater patient activation during the study intervention; adjustments for differences in asthma severity were made in the analysis.

Adherence. During the 12-month preindex period, the control group had an average MPR of 45.7% compared with 52.4% in the intervention group (P = .002).

During the 1-year follow-up period, adherence rates in the intervention group increased by 4.5 absolute percentage points compared with a decrease of 3.7 absolute percentage points for the control group, which resulted in the intervention group having a significantly higher MPR during the 12-month postindex than the control group (56.9% vs 42.0%, respectively; P <.001). After controlling for other covariates, the intervention group had a statistically higher adjusted MPR of 53.9% at the end of 1 year, compared with 43.9% for the control group (Figure 2).

Asthma-related costs, utilization. Monthly asthmarelated costs were compared between the intervention and the control groups. The intervention group had significantly greater asthma-related monthly medical costs at baseline ($43 vs $23, respectively; P = .030); however, by study end, the average monthly cost reduction was greater in the intervention group compared with the control group (â&#x20AC;&#x201C;$15 vs â&#x20AC;&#x201C;$6, respectively). After controlling for covariates and baseline differences in costs, the intervention group had a lower (but not significant) adjusted monthly cost at 12 months of follow-up compared with the control group ($18 vs $23, respectively; P = .067).

Asthma-related hospitalization and emergency department visit costs were incurred by a very small number of patients (1 patient in the intervention and 1 in the control group had 1 hospitalization each, and 6 patients in the control cohort and 2 in the intervention cohort had 1 emergency department visit each), precluding stable mean estimates of number of visits, cost, and

60

50

P <.001 53.9%

P = .007 47.3%

43.9% 40.5%

40

30

6 months

12 months Follow-up period

multivariate analyses. At baseline, the intervention cohort had a nonsignificant greater mean number of physician visits than the control group (1.38 vs 1.08, respectively; P = .123). At follow-up, no differences were seen between the 2 groups in the mean number of physician visits (1.20 vs 0.96, respectively; P = .108).

In contrast to asthma-related medical costs, asthmarelated monthly pharmacy costs were significantly greater in the intervention group compared with the control group during follow-up ($89 vs $53, respectively; P <.001); this, however, was expected with the reduced copayment for the intervention group. The reduced copayment essentially increased the cost per prescription for the health plan for the intervention group compared with the control cohort after the intervention (data not shown).

The number of SABA canisters was greater in the intervention group compared with the control cohort, but this difference was not significant at baseline (1.72 vs 1.57, respectively; P = .324) or after 12 months of follow-up (1.76 vs 1.49, respectively; P = .114). However, both cohorts had asthma controller ratios close to 1, indicating a good ratio of controller to SABA use. The asthma controller ratio was significantly greater in the intervention cohort compared with the control cohort at 6 months of follow-up (0.80 vs 0.74, respectively; P = .014), but not at 12 months (0.79 vs 0.76, respectively; P = .051). The number of oral corticosteroid prescriptions was similar between cohorts at baseline (0.64 vs 0.61, respectively; P = .756) and at 12 months of followup (0.68 vs 0.60, respectively; P = .314).

Overall healthcare costs. At baseline, the intervention cohort had significantly greater overall medical ($224 vs $155, respectively; P = .002) and pharmacy ($145 vs $113, respectively; P <.001) costs compared with the control cohort. At follow-up, differences in

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Figure 3 Adjusted Overall Monthly Medical, Pharmacy, and Total Costs Intervention Control

Mean adjusted monthly cost, $

400

P = .276

P = .281

$362

$348

350

$337

$323 300

P = .004

P = .037

250

$229

$216 200

$173

P <.001

P <.001

$181

$170

$160

150

$124

$119 100

Medical

Pharmacy

6 months

Total

Medical

Pharmacy

Total

12 months

Costs

overall medical costs between the intervention and control groups were similar to the asthma-related medical costs. After controlling for covariates, the intervention group had significantly smaller overall monthly medical costs compared with the control group during 12 months of follow-up ($170 vs $229, respectively; P = .004) (Figure 3). Although overall pharmacy costs were higher ($181 vs $124, respectively; P <.001), total overall costs were not statistically different between the intervention group and the control group ($362 vs $337, respectively; P = .276).

Discussion This study demonstrates that the VBHM asthma program significantly improved adherence, as measured

by MPR, and reduced overall medical costs for the sample of H-E-B employees and their dependents with asthma. During the 12-month follow-up study period, asthma medication adherence rates for patients in the intervention group were substantially greater than those in the control group. In addition, asthma-related medical costs decreased for the intervention group after adjusting for covariates, whereas asthma-related pharmacy costs increased.

When the impact on overall healthcare costs was calculated, a significant reduction in overall medical costs was successful in offsetting the higher overall pharmacy costs, resulting in no significant differences for the intervention group compared with the control group in total overall healthcare costs.

Increased asthma-related pharmacy expenditure is particularly significant, because it implies that patients

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were refilling their asthma medications, adhering to therapy, and improving asthma management. The higher pharmacy costs found in this study reflect the effects of the DM and VBID components of the VBHM program found in other studies.8,12,13,20,21 DM programs in asthma have been reported to increase awareness of the effectiveness of controller medications, as well as increase use and costs.20,21 Similarly, changes in copayment policies have been shown to influence medication adherence.8,12,13 A recent study evaluated the effect of a VBID program by reducing the cost of inhaled corticosteroids, resulting in a small positive (although not significant) increase in medication adherence.22 The authors attributed the insignificant result to the difficulty of measuring adherence to inhaled medications that involve multiple doses in a single inhaler compared with other medications with individual doses, such as oral tablets.22 In the present study, copayment was reduced for inhaled and for oral asthma medications.

In effect, a lower copayment for patients with certain chronic conditions requiring ongoing medication use may be a preventive public health measure. Despite the initial higher short-term drug costs for insurers, a reduced copayment may increase patient adherence and improve health status and, in turn, decrease long-term healthcare costs for insurers. This study shows that a VBHM intervention can improve patient medication adherence and decrease medical costs. Even with an increase in pharmacy costs as a result of improved adherence, the overall healthcare costs in this study were similar between the intervention and the control groups of insured H-E-B employees and their dependents.

Practice/Policy Implications Reduced medication adherence because of high copayments is a complex issue that requires a multifaceted strategy and collaborative approach.10 Research suggests that adherence to inhaled corticosteroids diminishes over time,23 but patient education on the regular use of asthma medications can be critical to increasing adherence. Developing mechanisms to report adherence status on a regular basis to providers and patients may also improve medication adherence and asthma control.4 Furthermore, providers and payers may help to reduce costs by taking a more proactive role in assessing patient medication need against any financial constraints and communicating potential approaches to confront these issues.24 Limitations Interpretation of the study results must consider several potential limitations. First, adherence to asthma medications was determined based on pharmacy

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claims; as such, actual consumption of a medication was not available.

In addition, it was not determined in this study if patients read and understood the educational materials.

Because the study’s sample population was only selected from insured employees and their dependents from the H-E-B grocery store chain in Texas, the geographical concentration and health insurance status may pose a problem for the ability to generalize this study’s results to other populations. Further research is necessary to understand if and how barriers to adherence may vary for other populations.

Finally, the voluntary participation in the VBHM program could possibly have influenced the findings in the intervention cohort, because these patients were perhaps more motivated to manage their disease. However, despite an almost 100% participation rate in the intervention cohort in the BCC program—demonstrating significant motivation—the intervention cohort still had more severe disease than the control group before the study intervention. However, selection of a control group from another source to avoid self-selection bias could have resulted in comparing patients in a different geographic, economic, and social environment, all of which are minimized in this study.

Conclusions This study indicates that the H-E-B asthma program improved patient adherence to controller medications, reduced medical costs, and increased prescription costs.

Specifically, the program increased adherence by 10 absolute percentage points without a significant increase in asthma-related resource utilization and total overall healthcare costs.

The H-E-B VBHM asthma program analysis contributes to the growing body of research evidence demonstrating that decreases in copayment amounts may yield increased asthma medication adherence and reduce associated medical costs. Rapidly increasing copayment costs can create a financial barrier and differential access to necessary medications, affect patient adherence ability, and contribute to widening the economically driven disparities of health outcomes that currently exist. Adopting a VBHM approach can minimize advanced medical complications and rising healthcare costs associated with asthma management. ■ Acknowledgments We sincerely appreciate the original vision for this study provided by Sandy Debussey and contributions from other GlaxoSmithKline, H-E-B, and Xcenda team members.

Source of Funding This research was funded in part by GlaxoSmithKline.

H-E-B was responsible for all healthcare services reimbursement, including copayments.

Disclosure Statement Dr D’Souza, Ms Rahnama, and Mr Regan are consultants to GlaxoSmithKline; Dr Burch is an employee of GlaxoSmithKline. Ms Common has nothing to disclose.

References 1. American Lung Association. Asthma in adults fact sheet. February 2010. www.lung usa.org/lung-disease/asthma/resources/facts-and-figures/asthma-in-adults.html#1.

Accessed June 29, 2010.

2. National Heart, Lung, and Blood Institute, National Institutes of Health. www.nhlbi. nih.gov/health/prof/lung/asthma/naci/asthma-info/. Accessed November 15, 2010.

3. Rand C, Bilderback A, Schiller K, et al. Adherence with montelukast or fluticasone in a long-term clinical trial: results from the mild asthma montelukast versus inhaled corticosteroid trial. J Allergy Clin Immunol. 2007;119:916-923. Epub 2007 Mar 8.

4. Williams LK, Pladevall M, Xi H, et al. Relationship between adherence to inhaled corticosteroids and poor outcomes among adults with asthma. J Allergy Clin Immunol.

2004;114:1288-1293.

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

6. Schatz M, Zeiger RS, Vollmer WM, et al. The controller-to-total asthma medication ratio is associated with patient-centered as well as utilization outcomes. Chest.

2006;130:43-50.

7. Bauman LJ, Wright E, Leickly FE, et al. Relationship of adherence to pediatric asthma morbidity among inner-city children. Pediatrics. 2002;110:e6.

8. Goldman DP, Joyce GF, Escarce JJ, et al. Pharmacy benefits and the use of drugs by the chronically ill. JAMA. 2004;291:2344-2350.

9. 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.

10. Thiebaud P, Patel BV, Nichol MB. The demand for statin: the effect of copay on utilization and compliance. Health Econ. 2007;17:83-97.

11. Anis AH, Guh DP, Lacaille D, et al. When patients have to pay a share of drug costs: effects of frequency of physician visits, hospital admissions and filling of prescriptions. CMAJ. 2005;173:1335-1340.

12. Dormuth CR, Glynn RJ, Neumann P, et al. Impact of two sequential drug costsharing policies on the use of inhaled medications in older patients with chronic obstructive pulmonary disease or asthma. Clin Ther. 2006;28:964-978.

13. Bender BG, Pedan A, Varasteh LT. Adherence and persistence with fluticasone propionate/salmeterol combination therapy. J Allergy Clin Immunol. 2006;118:899-904.

Epub 2006 Sep 8.

14. Bodenheimer T. Disease management—promises and pitfalls. N Engl J Med. 1999; 340:1202-1205.

15. Fendrick AM, Chernew ME. Value based insurance design: maintaining a focus on health in an era of cost containment. Am J Manag Care. 2009;15:338-343.

16. America’s Health Insurance Plans. 2002 AHIP Survey of Health Insurance Plans: Chart Book of Findings. April 2004. www.ahip.org/content/default.aspx?bc=38| 82|2244. Accessed July 3, 2010.

17. GlaxoSmithKline. Asthma control test. www.asthmacontrol.com/. Accessed July 20, 2008.

18. Fairman K, Motheral B. Evaluating medication adherence: which measure is right for your program? J Manag Care Pharm. 2000;696:499-504. www.amcp.org/data/ jmcp/ce_v6_499-506.pdf. Accessed July 20, 2010.

19. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chron Dis. 1987;40:373-383.

20. Lukacs SL, France EK, Barón AE, Crane LA. Effectiveness of an asthma management program for pediatric members of a large health maintenance organization.

Arch Pediatr Adolesc Med. 2002;156:872-876.

21. NGA Center for Best Practices. Disease management: the new tool for cost containment and quality care. Issue Brief. 2003. www.nga.org/Files/pdf/031403DISEASE MGMT.pdf. Accessed October 12, 2010.

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

23. Suissa S, Ernst P, Kezouh A. Regular use of inhaled corticosteroids and the long term prevention of hospitalisation for asthma. Thorax. 2002;57:880-884.

24. Heisler M, Langa KM, Eby EL, et al. The health effects of restricting prescription medication use because of cost. Med Care. 2004;42:626-634.

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STAKEHOLDER PERSPECTIVE Value-Based Insurance Design: Evolving Strategies to Improve Medication Adherence, Control Healthcare Utilization PAYERS: Value-based health management strives to optimize the medical benefit received for the healthcare resource purchased. It is frequently introduced to individuals by what is now referred to as value-based insurance design (VBID), through a member’s employer or health plan. This benefit design rewards the use of evidence-based practices through incentives such as waived or reduced copayment/coinsurance to individuals for services purchased or supplemental payment to providers for services rendered. VBID typically focuses on benefits by a specific service (eg, cost waiver/reduction for specific drugs or services for all patients); condition (eg, cost waiver/reduction for drug or service related to a specific medical condition); condition severity (eg, cost waiver/reduction for drugs or services for an individual classified as high risk); or as mentioned in the present article by D’Souza and colleagues, by involving “health management participation” (eg, cost waiver/reduction for drugs or services with participation in a particular program).1 Such strategies are thought to overcome the issues demonstrated by the increase in individuals’ cost-sharing of prescription drugs through the rise in drug copayments/coinsurance by means of improving drug adherence and reducing potentially preventable healthcare resource utilization (eg, emergency department visits).

Increased access to medications is an important tool in improving care. Rates of nonadherence to asthma medication have been reported to be as high as 70%.2 Reduced inpatient and emergency department visits have been associated with adherence to asthma controller medication.3 Additional access to medication must also be tempered with the opportunity for increased fraud or abuse of the new benefits. Providers or individuals may be

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encouraged to misrepresent information to benefit from reduced copayment/coinsurance or supplemental reimbursement for services. Expansion in fraud detection services may be necessary. Organizations will also need to be vigilant in monitoring shifts in healthcare resource utilization, in particular the purchase of lowvalue or less clinically supported medical services, because individuals may then have increased capacity to purchase such services.

PATIENTS: Patients will need to understand that value-based benefit offerings, such as the H-E-B program, are meant to optimize the quality of care they receive. Members/patients should be encouraged to engage in the process and take full advantage of the opportunity presented to help improve their health.

Patients should also be on alert for potential abuse of the process and advise their organization if they suspect that abuse of services may have occurred. Value-based benefit strategies that provide a “carrot” to the individual through reduced out-of-pocket expenses have not been embraced by all organizations, but they continue to grow in acceptance. Abuse of the system could slow the use of such benefits and shift incentives away from the carrot and more toward the use of the “stick” (eg, excluded coverage, higher out-of-pocket expenses).

1. Frederick AM. Value-Based Insurance Design Landscape Digest. National Pharmaceutical Council. July 2009. www.sph.umich.edu/vbidcenter/publications/ pdfs/NPC_VBIDreport_7-22-09.pdf. Accessed November 29, 2010.

2. Rand CS, Wise RA. Measuring adherence to asthma medication regimens. Am J Respir Crit Care Med. 1994;149:S69-S76;discussion S77-S78.

3. Tan H, Sarawate C, Singer J, et al. Impact of asthma controller medications on clinical, economic, and patient-reported outcomes. Mayo Clin Proc. 2009;84:675-684.

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Richard F. Radzin, PharmD Executive Consultant CGI Federal Cleveland, OH

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Now Available

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The 2010 Eisai Oncology and Senior Health Digest provides consumer data that may help optimize your organization’s strategies in developing impactful oncology and senior initiatives. Additionally, the data is segmented by 3 age cohorts spanning from 21 to 84 years old to help you benchmark and compare different member populations.

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A broad range of research, including poster sessions with direct relevance to pharmacy and medical directors and other healthcare stakeholders, was presented at the Academy of Managed Care Pharmacy’s 2010 Educational Conference, which was held October 13-15 in St Louis, MO. The following summaries reflect some of the major research trends presented at the meeting.

Cost May Not Drive Formulary Choice After All There may be discordance between what pharmacists say influences their formulary decision choices, and what actually influences those choices, according to an exploratory study examining the importance of product and manufacturer attributes.

Researchers from Mercer University College of Pharmacy and Health Sciences in Atlanta, GA, were interested in understanding how pharmacists’ perceptions of various product and manufacturer attributes impacted formulary decision-making. To do so, they conducted an online survey in January 2010 using a convenience sample of 176 managed care pharmacists. Participants were asked to rate the importance of and performance of 14 product and manufacturer attributes, and were asked to make 2 hypothetical product choices in lipid-lowering agents and proton pump inhibitors (PPIs).

A total of 30 (17%) surveys were completed. Factors rated as high performance/high importance in formula-

ry decision-making were related to product (ie, safety, efficacy, net ingredient cost, product superiority, and available outcomes data).

Factors given low performance/low importance were related to manufacturers (ie, size, customer programs, current market share, and ability to drive market share). If safety and efficacy were the same among products, 87% of respondents indicated that cost would be the final basis for their decision.

Costs were also professed as the decision-making basis for the hypothetical scenarios; however, an examination of published formularies reveals that only 27% had the lowest cost PPI on formulary and only 7% had the lowest cost fibrate.

Despite rating net ingredient cost as important, “most plans do not have branded products with the lowest ingredient cost in preferred positions on the formulary,” the authors concluded.

Method Used to Measure MPR Influences Adherence Rate The method used to measure medication adherence impacts the results of that measurement, and therefore researchers should use various methods depending on the overall goals of the study, according to researchers from the Accredo Health Group and Medco Health Solutions.

They compared 4 different ways of measuring medication possession ratio (MPR) in 8 specialty pharmacy therapeutic categories using 18 months of claims data. A patient’s first use of a drug was recorded (index date), and then all subsequent claims for 360 days were recorded. The 8 drug categories were multiple sclerosis, rheumatoid arthritis, hepatitis C, pulmonary hypertension, growth hormone, osteoporosis, oral oncology, and finally, the drug omalizumab (Xolair).

The 4 methods included (1) continuously eligible

patients are followed for 360 days from the indexed prescription; (2) all patients with 2 or more prescriptions are included, but the last prescription is not included; (3) the third approach is the same as the second one, but the last prescription is included; and (4) all patients with 1 prescription filled are included, which includes the last prescription.

In every case, the first method provides the lowest estimate of adherence rate, and each of the following methods provides lower estimates than the next one above it.

The difference in adherence rate between method 1 and method 4 for each of the drug categories was: 13% (multiple sclerosis); 16.6% (rheumatoid arthritis); 44.4% (hepatitis C); 17.7% (pulmonary hypertension); 21.6% (growth hormone); 26.9% (osteoporosis); 16.4% (oral oncology); and finally, 21.6% (omalizumab).

Pharmacists’ Monitoring of ESAs Leads to Cost-Savings A pilot program in which specialty pharmacists monitored hemoglobin levels in patients whose physicians had requested refills of erythropoiesis-stimulating agents (ESAs) resulted in some dosing changes and significant drug cost-savings for payers.

The program was run by the Accredo Health Group

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in Memphis, TN, and took place for 4.5 months between June 2009 and October 2009. When an ESA refill was requested, specialty pharmacists requested hemoglobin levels from prescribers. If data were more than 8 weeks old, or if the hemoglobin level was ≥12 g/dL, the pharmacists called prescribers to discuss US Food and Drug

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Administration warnings, recommend therapy changes, and document prescribing decisions.

Requests for hemoglobin measures were made for 6572 ESA refills, and 713 hemoglobin levels were not obtained. Of the total 6572 refills, 1447 (22%) required specialty pharmacist intervention (746 for elevated laboratories, 421 for outdated laboratories, and 280 others). Of the 1447 refills, 610 (42.2%) were not dispensed because of therapy holds (416), dose changes (107), cancellations (85), or other (2) reasons. Therapy was continued in 337 patients, despite

elevated/outdated hemoglobin levels. The authors estimate that $3761 was saved per therapy hold, and $2498 per dose change; $555 was saved per member per month for therapy dose changes.

For each program month, the total drug cost-savings was estimated at $398,796; total savings during the course of the program was estimated at $1,794,529.

Although the pilot program has officially ended, ESA monitoring continues, and the authors report continued favorable acceptance by providers to supplying laboratory values and to the entire intervention.

Adding a Pharmacist to a Medical Home May Cut Costs Preliminary research on incorporating a clinical pharmacist specialist into a team managing a patientcentered medical home (PCMH) shows an emerging body of evidence to support the integration of these specialists, and the potential for cost-savings once these caregivers are added to the team.

The researchers note that there is currently no standard guideline for determining clinical pharmacist specialist staffing needs or responsibilities in the PCMH model, and so they reviewed the published literature on PCMH pilot programs with available outcomes. The ultimate goal was to analyze the impact of clinical pharmacy services and potential cost-savings associated with implementing a PCMH model at the Kansas City VA Medical Center (KCVA).

The literature review revealed positive contributions of a clinical pharmacist specialist in prescreenings, fol-

low-up care, and disease management. Outcome measures included reductions in emergency department visits and hospitalizations, and total per-patient cost-savings.

The pharmacy leadership at KCVA determined necessary staffing levels and clinical pharmacist specialist procedures and responsibilities. Clinical pharmacist specialist responsibilities focused on identifying patients at high risk for poor medication-related outcomes and working with patients in need of improved continuity of care.

Potential cost-savings for KCVA extrapolated from the literature/data review were: â&#x20AC;˘ $6 million-$12 million in hospitalizations â&#x20AC;˘ $1 million-$8 million in emergency department visits â&#x20AC;˘ $630,000-$24 million in total patient costs.

A 1-year evaluation of the PCMH program at this institution will commence in the coming year.

Step-Therapy Program to Lower Rx Costs, Keep Members Happy A year-long step-therapy program focusing on 10 therapeutic drug classes that also attempted to minimize member dissatisfaction with any changes among these drugs lowered the average gross cost per claim by nearly 13% while denying only 10.2% of prior authorization (PA) requests.

The program was initiated by CVS/Caremark; the drugs it focused on included proton pump inhibitors (PPIs), nonsedating antihistamines (NSAs), selective serotonin reuptake inhibitors, 3-hydroxy-3-methyl glutaryl-coenzyme A reductase inhibitors, angiotensinconverting enzyme inhibitors/angiotensin receptor blockers, nasal steroids, hypnotics, bisphosphonates, urinary incontinence drugs, and cyclooxygenase-2 (COX-2) inhibitors.

As with other step-therapy programs, members are required to fill a prescription for a generic before selecting single-source brands, but the program also allows a choice of 1 select preferred brand in most classes.

Members and physicians were notified about the pro-

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gram 60 days and 30 days before implementation, and a dedicated call center was set up to handle PAs and other questions. The program effectiveness was measured through average gross cost per claim and average generic-dispensing rate.

Following program implementation, gross cost per claim fell from $72.75 to $64.50 per average claim, and generic-dispensing rate rose from 57.5% in August 2009 to 72.8% by July 2010. Generic-dispensing rate improved significantly in all classes except for COX-2 inhibitors; the program had the greatest impact among the PPI and NSA classes, which saw average gross cost per claim drop by $41.14 and $15.25, respectively. The call center handled 7600 calls between August 2009 and March 2010; 16.7% of callers began the PA process but were converted to a preferred brand or generic; and 54.1% of PA requests were approved.

The analysis did not adjust savings for increases in wholesale price inflation or for the effects of new brand medications.

Continued

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Disease State Impacts Medication Adherence Medication adherence varies widely depending on the condition for which a patient is taking that medication, according to a retrospective study of more than 15,000 patients in an integrated health system.

Researchers investigated medication adherence among patients with multiple sclerosis, cancer, hyper cholesterolemia, hypertension, osteoporosis, depression, diabetes, and asthma/chronic obstructive pulmonary disease (COPD). Patients were required to have only 1 disease for which they were taking a single medication.

By examining pharmacy claims records, the researchers identified patients with a minimum of 2 prescription

fills for â&#x2030;Ľ28 days of medication supply within 1 year.

Adherence was calculated using the medication possession ratio, which had to be â&#x2030;Ľ80% for the patient to be determined adherent.

There was wide variation in adherence by condition, ranging from 85% for multiple sclerosis to 32% for asthma/COPD. Efforts to improve adherence in conditions with the lowest compliance levels are needed, and, as such, the authors are now conducting follow-up research among patients with diabetes and asthma/ COPD to better understand facilitators and barriers to optimal medication use.

Targeting Waste in Targeted Therapies Employing mandatory 90-day supply requirements for oral chemotherapy agents leads to drug waste and increased costs, and a shorter-term (30-day) supply should be considered for these agents, according to a pharmacy claims database analysis.

Researchers from Prime Therapeutics examined a database of 5.7 million members from 3 Blue Cross Blue Shield plans from the Midwest and South, and extracted claims for erlotinib and imatinib between 2006 and 2010. Members were tracked by the amount of time they spent under the insurance plan; the amount of erlotinib or imatinib supplied to members during their time in the plan was also tracked. Waste was calculated as the difference between the memberâ&#x20AC;&#x2122;s total days of supply of the drugs and the number of days in the plan. Projected waste was then calculated if members had been given 30-day supplies instead.

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During the study period, the wholesale acquisition costs for erlotinib and imatinib increased anywhere from 26.7% (for imatinib 100-mg tablets) to 57.8% (for imatinib 400-mg tablets). Seventy of 418 members had at least 1 fill with a 90-day supply; 19 of the 418 members had actual waste (estimated to cost $23,952). Calculating projected waste, the authors determined that more than 11,700 days of waste would have occurred if 90-day supplies were used instead of 30-day supplies. This excess waste totaled $1,433,723.

The range of average excess supply per member was 34 days to 56 days (for 90-day supplies) and 13 days to 16 days (for 30-day supplies).

The authors caution that actual waste cannot be definitively known because of dosing changes and the estimation of time that members were in the plans. A further limitation is the small sample size (418 members of the total 5.7 million) in the plan.

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American Health & Drug Benefits (AHDB) is an independent, peer-reviewed journal founded in 2008 on the concept that health and drug benefits have undergone a transformation: the econometric value of a therapy is currently of equal importance to clinical outcomes as it is to serving as the basis for coverage decisions and benefit designs. Because benefit designs are greatly affected by clinical, business, and

policy conditions, the journal offers a forum for stakeholder integration and collaboration toward the promotion of value-based healthcare. AHDB further provides benefit design makers the integrated information they need to devise benefit designs and make coverage decisions that stand up to today’s demand for value-based healthcare that is founded on quality, cost, and access considerations.

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2. McGrath JJ, Murray RM. Risk factors for schizophrenia: from conception to birth. In: Hirsch SR, Weinberger DR, eds.

Schizophrenia. Oxford, England: Blackwell Press; 2003.

3. Waters R, Pettypiece S. Drug sales in the US grow at slower pace as generic use surges. Bloomberg news, March 12, 2008. www.bloomberg.com/apps/news?pid=newsarchive&sid=aLfUw 7_sYMRY. Accessed March 13, 2008.

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1. AMA Manual of Style, 10th ed. New York, NY: Oxford University Press; 2007.

2. International Committee of Medical Journal Editors. Uniform Requirements for Manuscripts Submitted to Biomedical Journals. Updated April 2010. www.icmje.org/urm_full.pdf.

Accessed June 1, 2010.

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Victoza® (liraglutide [rDNA origin] injection) Rx only BRIEF SUMMARY. Please consult package insert for full prescribing information.

WARNING: RISK OF THYROID C-CELL TUMORS: Liraglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors at clinically relevant exposures in both genders of rats and mice. It is unknown whether Victoza® causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as human relevance could not be ruled out by clinical or nonclinical studies. Victoza® is contraindicated in patients with a personal or family history of MTC and in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Based on the findings in rodents, monitoring with serum calcitonin or thyroid ultrasound was performed during clinical trials, but this may have increased the number of unnecessary thyroid surgeries. It is unknown whether monitoring with serum calcitonin or thyroid ultrasound will mitigate human risk of thyroid C-cell tumors. Patients should be counseled regarding the risk and symptoms of thyroid tumors [see Contraindications and Warnings and Precautions].

INDICATIONS AND USAGE: Victoza® is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Important Limitations of Use: Because of the uncertain relevance of the rodent thyroid C-cell tumor findings to humans, prescribe Victoza® only to patients for whom the potential benefits are considered to outweigh the potential risk. Victoza® is not recommended as first-line therapy for patients who have inadequate glycemic control on diet and exercise. In clinical trials of Victoza®, there were more cases of pancreatitis with Victoza® than with comparators. Victoza® has not been studied sufficiently in patients with a history of pancreatitis to determine whether these patients are at increased risk for pancreatitis while using Victoza®. Use with caution in patients with a history of pancreatitis.

Victoza® is not a substitute for insulin. Victoza® should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings. The concurrent use of Victoza® and insulin has not been studied.

CONTRAINDICATIONS: Victoza® is contraindicated in patients with a personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2).

WARNINGS AND PRECAUTIONS: Risk of Thyroid C-cell Tumors: Liraglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors (adenomas and/or carcinomas) at clinically relevant exposures in both genders of rats and mice. Malignant thyroid C-cell carcinomas were detected in rats and mice. A statistically significant increase in cancer was observed in rats receiving liraglutide at 8-times clinical exposure compared to controls. It is unknown whether Victoza® will cause thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as the human relevance of liraglutide-induced rodent thyroid C-cell tumors could not be determined by clinical or nonclinical studies [see Boxed Warning, Contraindications]. In the clinical trials, there have been 4 reported cases of thyroid C-cell hyperplasia among Victoza®-treated patients and 1 case in a comparator-treated patient (1.3 vs. 0.6 cases per 1000 patient-years). One additional case of thyroid C-cell hyperplasia in a Victoza®-treated patient and 1 case of MTC in a comparator-treated patient have subsequently been reported. This comparator-treated patient with MTC had pre-treatment serum calcitonin concentrations >1000 ng/L suggesting pre-existing disease. All of these cases were diagnosed after thyroidectomy, which was prompted by abnormal results on routine, protocol-specified measurements of serum calcitonin. Four of the five liraglutide-treated patients had elevated calcitonin concentrations at baseline and throughout the trial. One liraglutide and one non-liraglutide-treated patient developed elevated calcitonin concentrations while on treatment. Calcitonin, a biological marker of MTC, was measured throughout the clinical development program. The serum calcitonin assay used in the Victoza® clinical trials had a lower limit of quantification (LLOQ) of 0.7 ng/L and the upper limit of the reference range was 5.0 ng/L for women and 8.4 ng/L for men. At Weeks 26 and 52 in the clinical trials, adjusted mean serum calcitonin concentrations were higher in Victoza®treated patients compared to placebo-treated patients but not compared to patients receiving active comparator. At these timepoints, the adjusted mean serum calcitonin values (~ 1.0 ng/L) were just above the LLOQ with between-group differences in adjusted mean serum calcitonin values of approximately 0.1 ng/L or less. Among patients with pre-treatment serum calcitonin below the upper limit of the reference range, shifts to above the upper limit of the reference range which persisted in subsequent measurements occurred most frequently among patients treated with Victoza® 1.8 mg/day. In trials with on-treatment serum calcitonin measurements out to 5-6 months, 1.9% of patients treated with Victoza® 1.8 mg/day developed new and persistent calcitonin elevations above the upper limit of the reference range compared to 0.8-1.1% of patients treated with control medication or the 0.6 and 1.2 mg doses of Victoza®. In trials with on-treatment serum calcitonin measurements out to 12 months, 1.3% of patients treated with Victoza® 1.8 mg/day had new and persistent elevations of calcitonin from below or within the reference range to above the upper limit of the reference range, compared to 0.6%, 0% and 1.0% of patients treated with Victoza® 1.2 mg, placebo and active control, respectively. Otherwise, Victoza® did not produce consistent dose-dependent or time-dependent increases in serum calcitonin. Patients with MTC usually have calcitonin values >50 ng/L. In Victoza® clinical trials, among patients with pre-treatment serum calcitonin <50 ng/L, one Victoza®-treated patient and no comparator-treated patients developed serum calcitonin >50 ng/L. The Victoza®-treated patient who developed serum calcitonin >50 ng/L had an elevated pre-treatment serum calcitonin of 10.7 ng/L that increased to 30.7 ng/L at Week 12 and 53.5 ng/L at the end of the 6-month trial. Follow-up serum calcitonin was 22.3 ng/L more than 2.5 years after the last dose of Victoza®. The largest increase in serum calcitonin in a comparator-treated patient was seen with glimepiride in a patient whose serum calcitonin increased from 19.3 ng/L at baseline to 44.8 ng/L at Week 65 and 38.1 ng/L at Week 104. Among patients who began with serum calcitonin <20 ng/L, calcitonin elevations to >20 ng/L occurred in 0.7% of Victoza®-treated patients, 0.3% of placebo-treated patients, and 0.5% of active-comparator-treated patients, with an incidence of 1.1% among patients treated with 1.8 mg/day of Victoza®. The clinical significance of these findings is unknown. Counsel patients regarding the risk for MTC and the symptoms of thyroid tumors (e.g. a mass in the neck, dysphagia, dyspnea or persistent hoarseness). It is unknown whether monitoring with serum calcitonin or thyroid ultrasound will mitigate the potential risk of MTC, and such monitoring may increase the risk of unnecessary procedures, due to low test specificity for serum calcitonin and a high background incidence of thyroid disease. Patients with thyroid nodules noted on physical examination or neck imaging obtained for other reasons should be referred to an endocrinologist for further evaluation. Although routine monitoring of serum calcitonin is of uncertain value in patients treated with Victoza®, if serum calcitonin is measured and found to be elevated, the patient should be referred to an endocrinologist for further evaluation. Pancreatitis: In clinical

trials of Victoza®, there were 7 cases of pancreatitis among Victoza®-treated patients and 1 case among comparator-treated patients (2.2 vs. 0.6 cases per 1000 patient-years). Five cases with Victoza® were reported as acute pancreatitis and two cases with Victoza® were reported as chronic pancreatitis. In one case in a Victoza®-treated patient, pancreatitis, with necrosis, was observed and led to death; however clinical causality could not be established. One additional case of pancreatitis has subsequently been reported in a Victoza®-treated patient. Some patients had other risk factors for pancreatitis, such as a history of cholelithiasis or alcohol abuse. There are no conclusive data establishing a risk of pancreatitis with Victoza® treatment. After initiation of Victoza®, and after dose increases, observe patients carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back and which may or may not be accompanied by vomiting). If pancreatitis is suspected, Victoza® and other potentially suspect medications should be discontinued promptly, confirmatory tests should be performed and appropriate management should be initiated. If pancreatitis is confirmed, Victoza® should not be restarted. Use with caution in patients with a history of pancreatitis. Use with Medications Known to Cause Hypoglycemia: Patients receiving Victoza® in combination with an insulin secretagogue (e.g., sulfonylurea) may have an increased risk of hypoglycemia. In the clinical trials of at least 26 weeks duration, hypoglycemia requiring the assistance of another person for treatment occurred in 7 Victoza®-treated patients and in no comparator-treated patients. Six of these 7 patients treated with Victoza® were also taking a sulfonylurea. The risk of hypoglycemia may be lowered by a reduction in the dose of sulfonylurea or other insulin secretagogues [see Adverse Reactions]. Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Victoza® or any other antidiabetic drug.

ADVERSE REACTIONS: Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of Victoza® was evaluated in a 52-week monotherapy trial and in four 26-week, add-on combination therapy trials. In the monotherapy trial, patients were treated with Victoza® 1.2 mg daily, Victoza® 1.8 mg daily, or glimepiride 8 mg daily. In the add-on to metformin trial, patients were treated with Victoza® 0.6 mg, Victoza® 1.2 mg, Victoza® 1.8 mg, placebo, or glimepiride 4 mg. In the add-on to glimepiride trial, patients were treated with Victoza® 0.6 mg, Victoza® 1.2 mg, Victoza® 1.8 mg, placebo, or rosiglitazone 4 mg. In the add-on to metformin + glimepiride trial, patients were treated with Victoza® 1.8 mg, placebo, or insulin glargine. In the add-on to metformin + rosiglitazone trial, patients were treated with Victoza® 1.2 mg, Victoza® 1.8 mg or placebo. Withdrawals: The incidence of withdrawal due to adverse events was 7.8% for Victoza®-treated patients and 3.4% for comparator-treated patients in the five controlled trials of 26 weeks duration or longer. This difference was driven by withdrawals due to gastrointestinal adverse reactions, which occurred in 5.0% of Victoza®-treated patients and 0.5% of comparator-treated patients. The most common adverse reactions leading to withdrawal for Victoza®-treated patients were nausea (2.8% versus 0% for comparator) and vomiting (1.5% versus 0.1% for comparator). Withdrawal due to gastrointestinal adverse events mainly occurred during the first 2-3 months of the trials. Tables 1 and 2 summarize the adverse events reported in ≥5% of Victoza®-treated patients in the five controlled trials of 26 weeks duration or longer.

Table 1: Adverse events reported in ≥ 5% of Victoza®-treated patients or ≥5% of glimepiride-treated patients: 52-week monotherapy trial All Victoza® N = 497 Glimepiride N = 248 (%) (%) Adverse Event Term Nausea 28.4 8.5 Diarrhea 17.1 8.9 Vomiting 10.9 3.6 Constipation 9.9 4.8 Upper Respiratory Tract Infection 9.5 5.6 Headache 9.1 9.3 Influenza 7.4 3.6 Urinary Tract Infection 6.0 4.0 Dizziness 5.8 5.2 Sinusitis 5.6 6.0 Nasopharyngitis 5.2 5.2 Back Pain 5.0 4.4 Hypertension 3.0 6.0 Table 2: Adverse events reported in ≥ 5% of Victoza®-treated patients and occurring more frequently with Victoza® compared to placebo: 26-week combination therapy trials

Adverse Event Term Nausea Diarrhea Headache Vomiting

Adverse Event Term Nausea Diarrhea Constipation Dyspepsia

Add-on to Metformin Trial Glimepiride + Placebo + All Victoza® + Metformin Metformin Metformin N = 242 N = 121 N = 724 (%) (%) (%) 15.2 4.1 3.3 10.9 4.1 3.7 9.0 6.6 9.5 6.5 0.8 0.4 Add-on to Glimepiride Trial All Victoza® + Placebo + Glimepiride Rosiglitazone + Glimepiride N = 695 N = 114 Glimepiride N = 231 (%) (%) (%) 7.5 1.8 2.6 7.2 1.8 2.2 5.3 0.9 1.7 5.2 0.9 2.6

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Add-on to Metformin + Glimepiride Placebo + Metformin Glargine + Metformin Victoza® 1.8 + Metformin + + Glimepiride + Glimepiride Glimepiride N =114 N =232 N =230 (%) (%) (%) Adverse Event Term Nausea 13.9 3.5 1.3 Diarrhea 10.0 5.3 1.3 Headache 9.6 7.9 5.6 Dyspepsia 6.5 0.9 1.7 Vomiting 6.5 3.5 0.4 Add-on to Metformin + Rosiglitazone Placebo + Metformin All Victoza® + Metformin + Rosiglitazone N = 355 + Rosiglitazone N = 175 (%) (%) Adverse Event Term Nausea 34.6 8.6 Diarrhea 14.1 6.3 Vomiting 12.4 2.9 Decreased Appetite 9.3 1.1 Anorexia 9.0 0.0 Headache 8.2 4.6 Constipation 5.1 1.1 Fatigue 5.1 1.7 Gastrointestinal adverse events: In the five clinical trials of 26 weeks duration or longer, gastrointestinal adverse events were reported in 41% of Victoza®-treated patients and were dose-related.

Gastrointestinal adverse events occurred in 17% of comparator-treated patients. Events that occurred more commonly among Victoza®-treated patients included nausea, vomiting, diarrhea, dyspepsia and constipation. In clinical trials of 26 weeks duration or longer, the percentage of patients who reported nausea declined over time. Approximately 13% of Victoza®-treated patients and 2% of comparator-treated patients reported nausea during the first 2 weeks of treatment. Immunogenicity: Consistent with the potentially immunogenic properties of protein and peptide pharmaceuticals, patients treated with Victoza® may develop anti-liraglutide antibodies.

Approximately 50-70% of Victoza®-treated patients in the five clinical trials of 26 weeks duration or longer were tested for the presence of anti-liraglutide antibodies at the end of treatment.

Low titers (concentrations not requiring dilution of serum) of anti-liraglutide antibodies were detected in 8.6% of these Victoza®-treated patients. Sampling was not performed uniformly across all patients in the clinical trials, and this may have resulted in an underestimate of the actual percentage of patients who developed antibodies. Cross-reacting anti-liraglutide antibodies to native glucagon-like peptide-1 (GLP-1) occurred in 6.9% of the Victoza®-treated patients in the 52-week monotherapy trial and in 4.8% of the Victoza®-treated patients in the 26-week add-on combination therapy trials. These cross-reacting antibodies were not tested for neutralizing effect against native GLP-1, and thus the potential for clinically significant neutralization of native GLP-1 was not assessed. Antibodies that had a neutralizing effect on liraglutide in an in vitro assay occurred in 2.3% of the Victoza®-treated patients in the 52-week monotherapy trial and in 1.0% of the Victoza®-treated patients in the 26-week add-on combination therapy trials.

Among Victoza®-treated patients who developed anti-liraglutide antibodies, the most common category of adverse events was that of infections, which occurred among 40% of these patients compared to 36%, 34% and 35% of antibody-negative Victoza®-treated, placebo-treated and active-control-treated patients, respectively. The specific infections which occurred with greater frequency among Victoza®-treated antibody-positive patients were primarily nonserious upper respiratory tract infections, which occurred among 11% of Victoza®-treated antibody-positive patients; and among 7%, 7% and 5% of antibody-negative Victoza®-treated, placebo-treated and active-control-treated patients, respectively. Among Victoza®-treated antibody-negative patients, the most common category of adverse events was that of gastrointestinal events, which occurred in 43%, 18% and 19% of antibody-negative Victoza®-treated, placebo-treated and active-control-treated patients, respectively. Antibody formation was not associated with reduced efficacy of Victoza® when comparing mean HbA1c of all antibody-positive and all antibody-negative patients.

However, the 3 patients with the highest titers of anti-liraglutide antibodies had no reduction in HbA1c with Victoza® treatment. In clinical trials of Victoza®, events from a composite of adverse events potentially related to immunogenicity (e.g. urticaria, angioedema) occurred among 0.8% of Victoza®-treated patients and among 0.4% of comparator-treated patients. Urticaria accounted for approximately one-half of the events in this composite for Victoza®-treated patients. Patients who developed anti-liraglutide antibodies were not more likely to develop events from the immunogenicity events composite than were patients who did not develop anti-liraglutide antibodies.

Injection site reactions: Injection site reactions (e.g., injection site rash, erythema) were reported in approximately 2% of Victoza®-treated patients in the five clinical trials of at least 26 weeks duration. Less than 0.2% of Victoza®-treated patients discontinued due to injection site reactions.

Papillary thyroid carcinoma: In clinical trials of Victoza®, there were 6 reported cases of papillary thyroid carcinoma in patients treated with Victoza® and 1 case in a comparator-treated patient (1.9 vs. 0.6 cases per 1000 patient-years). Most of these papillary thyroid carcinomas were <1 cm in greatest diameter and were diagnosed in surgical pathology specimens after thyroidectomy prompted by findings on protocol-specified screening with serum calcitonin or thyroid ultrasound. Hypoglycemia: In the clinical trials of at least 26 weeks duration, hypoglycemia requiring the assistance of another person for treatment occurred in 7 Victoza®-treated patients (2.6 cases per 1000 patient-years) and in no comparator-treated patients. Six of these 7 patients treated

with Victoza® were also taking a sulfonylurea. One other patient was taking Victoza® in combination with metformin but had another likely explanation for the hypoglycemia (this event occurred during hospitalization and after insulin infusion) (Table 3). Two additional cases of hypoglycemia requiring the assistance of another person for treatment have subsequently been reported in patients who were not taking a concomitant sulfonylurea. Both patients were receiving Victoza®, one as monotherapy and the other in combination with metformin. Both patients had another likely explanation for the hypoglycemia (one received insulin during a frequently-sampled intravenous glucose tolerance test, and the other had intracranial hemorrhage and uncertain food intake).

Table 3: Incidence (%) and Rate (episodes/patient year) of Hypoglycemia in the 52-Week Monotherapy Trial and in the 26-Week Combination Therapy Trials Victoza® Active Placebo Treatment Comparator Comparator Glimepiride None Monotherapy Victoza® (N = 497) (N = 248) Patient not able to self−treat 0 0 — Patient able to self−treat 9.7 (0.24) 25.0 (1.66) — Not classified 1.2 (0.03) 2.4 (0.04) — Glimepiride + Placebo + Add-on to Victoza® + Metformin Metformin Metformin Metformin (N = 724) (N = 242) (N = 121) Patient not able to self−treat 0.1 (0.001) 0 0 Patient able to self−treat 3.6 (0.05) 22.3 (0.87) 2.5 (0.06) Rosiglitazone + Placebo + Add-on to Glimepiride Victoza® + Glimepiride Glimepiride Glimepiride (N = 695) (N = 231) (N = 114) Patient not able to self−treat 0.1 (0.003) 0 0 Patient able to self−treat 7.5 (0.38) 4.3 (0.12) 2.6 (0.17) Not classified 0.9 (0.05) 0.9 (0.02) 0 Placebo + Add-on to Victoza® + Metformin + None Metformin + Metformin + Rosiglitazone Rosiglitazone Rosiglitazone (N = 355) (N = 175) Patient not able to self−treat 0 — 0 Patient able to self−treat 7.9 (0.49) — 4.6 (0.15) Not classified 0.6 (0.01) — 1.1 (0.03) Insulin glargine Placebo + Add-on to Victoza® + Metformin + + Metformin + Metformin + Metformin + Glimepiride Glimepiride Glimepiride Glimepiride (N = 230) (N = 232) (N = 114) Patient not able to self−treat 2.2 (0.06) 0 0 Patient able to self−treat 27.4 (1.16) 28.9 (1.29) 16.7 (0.95) Not classified 0 1.7 (0.04) 0 In a pooled analysis of clinical trials, the incidence rate (per 1,000 patient-years) for malignant neoplasms (based on investigator-reported events, medical history, pathology reports, and surgical reports from both blinded and open-label study periods) was 10.9 for Victoza®, 6.3 for placebo, and 7.2 for active comparator. After excluding papillary thyroid carcinoma events [see Adverse Reactions], no particular cancer cell type predominated. Seven malignant neoplasm events were reported beyond 1 year of exposure to study medication, six events among Victoza®treated patients (4 colon, 1 prostate and 1 nasopharyngeal), no events with placebo and one event with active comparator (colon). Causality has not been established. Laboratory Tests: In the five clinical trials of at least 26 weeks duration, mildly elevated serum bilirubin concentrations (elevations to no more than twice the upper limit of the reference range) occurred in 4.0% of Victoza®-treated patients, 2.1% of placebo-treated patients and 3.5% of active-comparatortreated patients. This finding was not accompanied by abnormalities in other liver tests. The significance of this isolated finding is unknown.

OVERDOSAGE: In a clinical trial, one patient with type 2 diabetes experienced a single overdose of Victoza® 17.4 mg subcutaneous (10 times the maximum recommended dose). Effects of the overdose included severe nausea and vomiting requiring hospitalization. No hypoglycemia was reported. The patient recovered without complications. In the event of overdosage, appropriate supportive treatment should be initiated according to the patient’s clinical signs and symptoms.

More detailed information is available on request.

For information about Victoza® contact: Novo Nordisk Inc., 100 College Road West, Princeton, New Jersey 08540, 1−877-484-2869 Date of Issue: January 2010 Version: 1 Manufactured by: Novo Nordisk A/S, DK-2880 Bagsvaerd, Denmark Victoza® is a registered trademark of Novo Nordisk A/S. Victoza® is covered by US Patent Nos. 6,268,343; 6,458,924; and 7,235,627 and other patents pending. Victoza® Pen is covered by US Patent Nos. 6,004,297; 6,235,004; 6,582,404 and other patents pending. © 2010 Novo Nordisk A/S 140586-R1 4/2010

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Once-daily Victoza® : Can provide the additional benefit of weight loss Safety and tolerability were studied in clinical trials that included nearly 4000 patients

Targets beta cells Provides powerful and sustained reductions in A1C*

Victoza® is not indicated for the management of obesity, and weight change was a secondary end point in clinical trials.

Visit VictozaPro.com to learn more.

Indications and usage Victoza® is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Because of the uncertain relevance of the rodent thyroid C-cell tumor findings to humans, prescribe Victoza® only to patients for whom the potential benefits are considered to outweigh the potential risk.

Victoza® is not recommended as first-line therapy for patients who have inadequate glycemic control on diet and exercise.

In clinical trials of Victoza®, there were more cases of pancreatitis with Victoza® than with comparators. Victoza® has not been studied sufficiently in patients with a history of pancreatitis to determine whether these patients are at increased risk for pancreatitis while using Victoza®. Use with caution in patients with a history of pancreatitis.

Victoza® is not a substitute for insulin. Victoza® should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings.

The concurrent use of Victoza® and insulin has not been studied.

Important safety information Liraglutide causes dose-dependent and treatment-durationdependent thyroid C-cell tumors at clinically relevant exposures in both genders of rats and mice. It is unknown whether Victoza® causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as human relevance could not be ruled out by clinical or nonclinical studies. Victoza® is contraindicated in patients with a personal or family history of MTC and in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Based on the findings in rodents, monitoring with serum calcitonin or thyroid ultrasound was performed during clinical trials, but this may have increased the number of unnecessary thyroid surgeries. It is unknown whether monitoring with serum calcitonin or thyroid ultrasound will mitigate human risk of thyroid C-cell tumors. Patients should be counseled regarding the risk and symptoms of thyroid tumors.

If pancreatitis is suspected, Victoza® should be discontinued. Victoza® should not be re-initiated if pancreatitis is confirmed.

When Victoza® is used with an insulin secretagogue (e.g. a sulfonylurea) serious hypoglycemia can occur. Consider lowering the dose of the insulin secretagogue to reduce the risk of hypoglycemia.

There have been no studies establishing conclusive evidence of macrovascular risk reduction with Victoza ® or any other antidiabetic drug.

The most common adverse reactions, reported in ≥5% of patients treated with Victoza® and more commonly than in patients treated with placebo, are headache, nausea, diarrhea, and anti-liraglutide antibody formation. Immunogenicity-related events, including urticaria, were more common among Victoza®-treated patients (0.8%) than among comparator-treated patients (0.4%) in clinical trials.

Victoza® has not been studied in type 2 diabetes patients below 18 years of age and is not recommended for use in pediatric patients.

Victoza® should be used with caution in patients with renal impairment and in patients with hepatic impairment.

Please see brief summary of Prescribing Information on adjacent page. *Victoza® was evaluated in a 52-week monotherapy trial and in four 26-week, add-on combination trials.

Victoza® is a registered trademark of Novo Nordisk A/S. © 2010 Novo Nordisk A/S

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May 2010