SEPTEMBER/OCTOBER 2012 VOLUME 5, NUMBER 6

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VOLUME 5, NUMBER 6

FOR PAYERS, PURCHASERS, POLICYMAKERS, AND OTHER HEALTHCARE STAKEHOLDERS

EDITORIAL

Hardworking P&T Committees David B. Nash, MD, MBA CLINICAL

“Hidden” Value: How Indirect Benefits of Health Information Exchange Further Promote Sustainability Albert Tzeel, MD, MHSA, FACPE; Victor Lawnicki, PhD; Kim R. Pemble, MS ™

Stakeholder Perspective by Jack E. Fincham, PhD, RPh

Assessment of Treatment Patterns and Patient Outcomes in LevodopaInduced Dyskinesias (ASTROID): A US Chart Review Study Barb Lennert, RN, BSN, MAOM; Wendy Bibeau, PhD; Eileen Farrelly, MPH; Patricia Sacco, MPH, RPh; Tessa Schoor, MD Stakeholder Perspective by Gary M. Owens, MD BUSINESS

Medical Care Costs and Hospitalization in Patients with Bipolar Disorder Treated with Atypical Antipsychotics Joette Gdovin Bergeson, PhD, MPA; Iftekhar Kalsekar, PhD; Yonghua Jing, PhD; Min You, MS; Robert A. Forbes, PhD; Tony Hebden, PhD Stakeholder Perspective by Jeffrey Januska, PharmD Drug Utilization Trends Industry Trends

Cost Management through Care Management, Part 2: The Importance of Managing Specialty Drug Utilization in the Medical Benefit Michael T. Einodshofer, RPh, MBA; Lars N. Duren, BCNSP, PharmD

©2012 Engage Healthcare Communications, LLC www.AHDBonline.com

How will you use your potential savings?

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TABLE OF CONTENTS Publisher Nicholas Englezos nick@engagehc.com 732-992-1884 Editorial Director Dalia Buffery dalia@engagehc.com 732-992-1889 Associate Publisher Maurice Nogueira maurice@engagehc.com 732-992-1895 Associate Editor Lara J. Lorton lara@engagehc.com 732-992-1892 Editorial Assistant Jennifer Brandt jbrandt@the-lynx-group.com 732-992-1536 Executive Vice President Engage Managed Markets Chuck Collins ccollins@engagehc.com 732-992-1894 National Accounts Manager Zach Ceretelle zach@engagehc.com 732-992-1898 Senior Production Manager Lynn Hamilton Quality Control Director Barbara Marino Business Manager Blanche Marchitto

EDITORIAL

330 Hardworking P&T Committees David B. Nash, MD, MBA CLINICAL

333 “Hidden” Value: How Indirect Benefits of Health Information Exchange Further Promote Sustainability Albert Tzeel, MD, MHSA, FACPE; Victor Lawnicki, PhD; Kim R. Pemble, MS 340 Stakeholder Perspective by Jack E. Fincham, PhD, RPh 347 Assessment of Treatment Patterns and Patient Outcomes in Levodopa-Induced Dyskinesias (ASTROID): A US Chart Review Study Barb Lennert, RN, BSN, MAOM; Wendy Bibeau, PhD; Eileen Farrelly, MPH; Patricia Sacco, MPH, RPh; Tessa Schoor, MD 358 Stakeholder Perspective by Gary M. Owens, MD Continued on page 327

Founding Editor-in-Chief Robert E. Henry

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

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

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.

MEMBER: Committee on Publication Ethics (COPE)

Contact Information: For subscription information and editorial queries, please contact: editorial@engagehc.com; tel: 732-992-1892; fax: 732-992-1881

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FOR ADULT PATIENTS WITH TYPE 2 DIABETES TRADJENTAÂŽ (LINAGLIPTIN) TABLETS: THE ONLY ONCE-DAILY 1-DOSE DPP-4 INHIBITOR

Focusing on what matters Improving glycemic control for adult patients with type 2 diabetes Indication and Important Limitations of Use TRADJENTA is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

in a clinical trial. Therefore, a lower dose of the insulin secretagogue may be required to reduce the risk of hypoglycemia when used in combination with TRADJENTA.

TRADJENTA should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis, and has not been studied in combination with insulin.

Macrovascular Outcomes There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with TRADJENTA or any other antidiabetic drug.

Important Safety Information

ADVERSE REACTIONS

CONTRAINDICATIONS

Adverse reactions reported in ≼5% of patients treated with TRADJENTA and more commonly than in patients treated with placebo included nasopharyngitis.

TRADJENTA is contraindicated in patients with a history of hypersensitivity reaction to linagliptin, such as urticaria, angioedema or bronchial hyperreactivity.

WARNINGS AND PRECAUTIONS Use with Medications Known to Cause Hypoglycemia Insulin secretagogues are known to cause hypoglycemia.

The use of TRADJENTA in combination with an insulin secretagogue (e.g., sulfonylurea) was associated with a higher rate of hypoglycemia compared with placebo

Hypoglycemia was more commonly reported in patients treated with the combination of TRADJENTA and sulfonylurea compared with those treated with the combination of placebo and sulfonylurea. When linagliptin was administered in combination with metformin and a sulfonylurea, 181 of 792 (22.9%) patients reported hypoglycemia compared with 39 of 263 (14.8%) patients administered placebo in combination with metformin and a sulfonylurea.

TRADJENTA delivers proven glycemic control Placebo-adjusted difference in A1C with oral monoand dual therapy at 24 weeks (%) TRADJENTA monotherapy1,2* Baseline A1C 8.0%

*A randomized, multicenter, double-blind, placebo-controlled study of adult patients with type 2 diabetes (aged 18-80) who were randomized to TRADJENTA 5 mg/day (n=336; mean baseline A1C=8.0%) or placebo (n=167; mean baseline A1C=8.0%) for 24 weeks. Primary endpoint was change from baseline in A1C at 24 weeks. 20.9% of patients in the placebo group required rescue therapy vs 10.2% of patients in the TRADJENTA group. Full analysis population using last observation on study.

TRADJENTA add-on to metformin2,3† Baseline A1C 8.1% †

A randomized, double-blind, placebo-controlled, parallel-group study of adult patients with type 2 diabetes (aged 18-80) with insufficient glycemic control despite metformin therapy who were randomized to TRADJENTA 5 mg/day (n=524; mean baseline A1C=8.1%) or placebo (n=177; mean baseline A1C=8.0%) in combination with metformin ≥1500 mg/day for 24 weeks. Primary endpoint was change from baseline in A1C at 24 weeks.

18.9% of patients in the placebo group required rescue therapy vs 7.8% of patients in the TRADJENTA group. Full analysis population using last observation on study.

‡

0.3% adjusted mean increase from baseline A1C 8.0% with placebo (n=163).2

§

0.15% adjusted mean increase from baseline A1C 8.0% with placebo plus metformin (n=175).2

–0.6%§ –0.7%‡ (n=333) P<0.0001

(n=513) P<0.0001

TRADJENTA: Experience dosing simplicity No dose adjustment required, regardless of declining renal function or hepatic impairment2 TRADJENTA is primarily nonrenally excreted: 80% eliminated via the bile and gut and 5% eliminated via the kidney within 4 days of dosing One dose, once daily for adult patients with type 2 diabetes

TRADJENTA: A safety and tolerability profile demonstrated in more than 4000 patients

In the clinical trial program, pancreatitis was reported in 8 of 5115 patients (4499 patient-years of exposure [1 per 562 patient-years]) while being treated with TRADJENTA compared with 0 of 1546 patients (589 patient-years of exposure) treated with placebo. Three additional cases of pancreatitis were reported following the last administered dose of linagliptin.

DRUG INTERACTIONS The efficacy of TRADJENTA may be reduced when administered in combination with a strong P-glycoprotein or CYP3A4 inducer (e.g., rifampin).

Therefore, use of alternative treatments to TRADJENTA is strongly recommended.

USE IN SPECIFIC POPULATIONS

The safety and effectiveness of TRADJENTA in patients below the age of 18 have not been established.

TJ PROF ISI MAY 2012

References: 1. Del Prato S, Barnett AH, Huisman H, et al. Effect of linagliptin monotherapy on glycaemic control and markers of β-cell function in patients with inadequately controlled type 2 diabetes: a randomized controlled trial. Diabetes Obes Metab. 2011;13:258-267. 2. Data on file. Boehringer Ingelheim Pharmaceuticals, Inc. 3. Taskinen M-R, Rosenstock J, Tamminen I, et al. Safety and efficacy of linagliptin as add-on therapy to metformin in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled study. Diabetes Obes Metab. 2011;13:65-74.

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

There are no adequate and well-controlled studies in pregnant women. Therefore, TRADJENTA should be used during pregnancy only if clearly needed.

It is not known whether linagliptin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when TRADJENTA is administered to a nursing woman.

Find out mor more e about TRADJENT TRADJENTA TA A and the Savings Car Card d program pro ogram at www www.tradjenta.com .tradjenta.com

Tradjenta® (linagliptin) tablets BRIEF SUMMARY OF PRESCRIBING INFORMATION Please see package insert for full Prescribing Information.

INDICATIONS AND USAGE TRADJENTA tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Important Limitations of Use: TRADJENTA should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings.

TRADJENTA has not been studied in combination with insulin.

CONTRAINDICATIONS TRADJENTA is contraindicated in patients with a history of a hypersensitivity reaction to linagliptin, such as urticaria, angioedema, or bronchial hyperreactivity [see Adverse Reactions].

WARNINGS AND PRECAUTIONS Use with Medications Known to Cause Hypoglycemia: Insulin secretagogues are known to cause hypoglycemia. The use of TRADJENTA in combination with an insulin secretagogue (e.g., sulfonylurea) was associated with a higher rate of hypoglycemia compared with placebo in a clinical trial [see Adverse Reactions]. Therefore, a lower dose of the insulin secretagogue may be required to reduce the risk of hypoglycemia when used in combination with TRADJENTA. Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with TRADJENTA tablets 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 evaluation of linagliptin 5 mg once daily in patient with type 2 diabetes is based on 13 placebo-controlled trials and 1 active-controlled study. In the 13 placebo-controlled studies, a total of 2994 patients were randomized and treated with TRADJENTA 5 mg daily and 1546 with placebo. The mean exposure across studies was 21.4 weeks. The maximum follow-up was 78 weeks. TRADJENTA 5 mg once daily was studied as monotherapy in two placebo-controlled trials of 18 and 24 weeks’ duration.

Five placebo-controlled trials investigated linagliptin in combination with other oral antihyperglycemic agents: two with metformin (12 and 24 weeks’ treatment duration); one with a sulfonylurea (18 weeks’ treatment duration); one with metformin and sulfonylurea (24 weeks’ treatment duration); and one with pioglitazone (24 weeks’ treatment duration). In placebo-controlled clinical trials, adverse reactions that occurred in *5% of patients receiving TRADJENTA (n = 2994) and more commonly than in patients given placebo (n = 1546) included nasopharyngitis (5.9% vs 4.8%). Adverse reactions reported in *2% of patients treated with TRADJENTA 5 mg daily as monotherapy or in combination with pioglitazone, sulfonylurea, or metformin and at least 2-fold more commonly than in patients treated with placebo are shown in Table 1. Following 52 weeks’ treatment in a controlled study comparing linagliptin with glimepiride in which all patients were also receiving metformin, adverse reactions reported in *5% patients treated with linagliptin (n = 776) and more frequently than in patients treated with a sulfonylurea (n = 775) were arthralgia (5.7% vs 3.5%), back pain (6.4% vs 5.2%), and headache (5.7% vs 4.2%). Other adverse reactions reported in clinical studies with treatment of TRADJENTA were hypersensitivity (e.g., urticaria, angioedema, localized skin exfoliation, or bronchial hyperreactivity), and myalgia. In the clinical trial program, pancreatitis was reported in 8 of 5115 patients (4499 patient years of exposure) while being treated with TRADJENTA compared with 0 of 1546 patients (589 patient years of exposure) treated with placebo. Three additional cases of pancreatitis were reported following the last administered dose of linagliptin.

Hypoglycemia: In the placebo-controlled studies, 199 (6.6%) of the total 2994 patients treated with TRADJENTA 5 mg reported hypoglycemia compared to 56 patients (3.6%) of 1546 placebo-treated patients. The incidence of hypoglycemia Table 1

was similar to placebo when linagliptin was administered as monotherapy or in combination with metformin, or with pioglitazone. When linagliptin was administered in combination with metformin and a sulfonylurea, 181 of 792 (22.9%) patients reported hypoglycemia compared with 39 of 263 (14.8%) patients administered placebo in combination with metformin and a sulfonylurea.

Laboratory Tests: Changes in laboratory findings were similar in patients treated with TRADJENTA 5 mg compared to patients treated with placebo. Changes in laboratory values that occurred more frequently in the TRADJENTA group and *1% more than in the placebo group were increases in uric acid (1.3% in the placebo group, 2.7% in the TRADJENTA group). No clinically meaningful changes in vital signs were observed in patients treated with TRADJENTA. DRUG INTERACTIONS Inducers of P-glycoprotein or CYP3A4 Enzymes: Rifampin decreased linagliptin exposure suggesting that the efficacy of TRADJENTA may be reduced when administered in combination with a strong P-gp or CYP3A4 inducer. Therefore, use of alternative treatments is strongly recommended when linagliptin is to be administered with a P-gp or CYP3A4 inducer.

USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category B. Reproduction studies have been performed in rats and rabbits. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Linagliptin administered during the period of organogenesis was not teratogenic at doses up to 30 mg/kg in the rat and 150 mg/kg in the rabbit, or approximately 49 and 1943 times the clinical dose based on AUC exposure. Doses of linagliptin causing maternal toxicity in the rat and the rabbit also caused developmental delays in skeletal ossification and slightly increased embryofetal loss in rat (1000 times the clinical dose) and increased fetal resorptions and visceral and skeletal variations in the rabbit (1943 times the clinical dose). Linagliptin administered to female rats from gestation day 6 to lactation day 21 resulted in decreased body weight and delays in physical and behavioral development in male and female offspring at maternally toxic doses (exposures >1000 times the clinical dose). No functional, behavioral, or reproductive toxicity was observed in offspring of rats exposed to 49 times the clinical dose. Linagliptin crossed the placenta into the fetus following oral dosing in pregnant rats and rabbits. Nursing Mothers: Available animal data have shown excretion of linagliptin in milk at a milk-to-plasma ratio of 4:1. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when TRADJENTA is administered to a nursing woman. Pediatric Use: Safety and effectiveness of TRADJENTA in pediatric patients have not been established. Geriatric Use: There were 4040 type 2 diabetes patients treated with linagliptin 5 mg from 15 clinical trials of TRADJENTA; 1085 (27%) were 65 years and over, while 131 (3%) were 75 years and over. Of these patients, 2566 were enrolled in 12 double-blind placebo-controlled studies; 591 (23%) were 65 years and over, while 82 (3%) were 75 years and over. No overall differences in safety or effectiveness were observed between patients 65 years and over and younger patients. Therefore, no dose adjustment is recommended in the elderly population. While clinical studies of linagliptin have not identified differences in response between the elderly and younger patients, greater sensitivity of some older individuals cannot be ruled out. Renal Impairment: No dose adjustment is recommended for patients with renal impairment. Hepatic Impairment: No dose adjustment is recommended for patients with hepatic impairment.

OVERDOSAGE In the event of an overdose with TRADJENTA, contact the Poison Control Center.

Employ the usual supportive measures (e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive treatment) as dictated by the patient’s clinical status. Removal of linagliptin by hemodialysis or peritoneal dialysis is unlikely. During controlled clinical trials in healthy subjects, with single doses of up to 600 mg of TRADJENTA (equivalent to 120 times the recommended daily dose) there were no dose-related clinical adverse drug reactions.

There is no experience with doses above 600 mg in humans.

Adverse Reactions Reported in *2% of Patients Treated with TRADJENTA and at Least 2-Fold Greater than with Placebo in Placebo-Controlled Clinical Studies of TRADJENTA Monotherapy or Combination Therapy Monotherapy* n (%)

Nasopharyngitis Hyperlipidemia Cough Hypertriglyceridemia† Weight increased

TRADJENTA Placebo n = 530 n = 907

Combination with Metformin# n (%) TRADJENTA Placebo n = 539 n = 876

TRADJENTA Placebo n = 161 n = 84

– – – – –

– – – – –

7 (4.3) – – 4 (2.4) –

– – – – –

– – – – –

Combination with SU n (%)

1 (1.2) – – 0 (0.0) –

Combination with Metformin + SU n (%) TRADJENTA Placebo n = 791 n = 263

Combination with Pioglitazone n (%) TRADJENTA Placebo n = 259 n = 130

– – 19 (2.4)

– 7 (2.7) – – 6 (2.3)

–

– – 3 (1.1) – –

– 1 (0.8) – – 1 (0.8)

SU = sulfonylurea *Pooled data from 8 studies #Pooled data from 3 studies †Includes reports of hypertriglyceridemia (n = 2; 1.2%) and blood triglycerides increased (n = 2; 1.2%) Copyright © 2012 Boehringer Ingelheim Pharmaceuticals, Inc. Revised: May 2012

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VOLUME 5, NUMBER 6

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TABLE OF CONTENTS

(Continued) American Health & Drug Benefits, ISSN 1942-2962 (print); ISSN 1942-2970 (online), is published 8 times a year by Engage Healthcare Communications, LLC, 1249 South River Rd, Suite 202A, Cranbury, NJ 08512.

Copyright © 2012 by Engage Healthcare Communications, LLC. All rights reserved. American Health & Drug Benefits and The Peer-Reviewed Forum for Evidence in Benefit Design are trademarks of Engage Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the Publisher.

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BUSINESS

379 Medical Care Costs and Hospitalization in Patients with Bipolar Disorder Treated with Atypical Antipsychotics Joette Gdovin Bergeson, PhD, MPA; Iftekhar Kalsekar, PhD; Yonghua Jing, PhD; Min You, MS; Robert A. Forbes, PhD; Tony Hebden, PhD 386 Stakeholder Perspective by Jeffrey Januska, PharmD DEPARTMENTS

DRUG UTILIZATION TRENDS 345 Payer Drug and Molecular Testing Utilization Policies

By Charles Bankhead

Address all editorial correspondence to: editorial@engagehc.com Telephone: 732-992-1892 Fax: 732-992-1881 American Health & Drug Benefits 1249 South River Rd, Suite 202A, Cranbury, NJ 08512

INDUSTRY TRENDS 359 Cost Management through Care Management, Part 2: The Importance of Managing Specialty Drug Utilization in the Medical Benefit Michael T. Einodshofer, RPh, MBA; Lars N. Duren, BCNSP, PharmD

The ideas and opinions expressed in American Health & Drug Benefits do not necessarily reflect those of the Editorial Board, the Editors, or the Publisher.

Publication of an advertisement or other product mentioned in American Health & Drug Benefits should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturers about any features or limitations of products mentioned. Neither the Editors nor the Publisher assume any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material mentioned in this publication.

MULTIPLE SCLEROSIS UPDATE 387 Multiple Sclerosis: Patient Characteristics and Cost Concerns

By Charles Bankhead

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EDITORIAL BOARD EDITOR-IN-CHIEF

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

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

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

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

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

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

Joseph Couto, PharmD, MBA Clinical Program Manager Cigna Corporation, Bloomfield, CT Steve Miff, PhD Senior Vice President VHA, Inc., Irving, TX Kavita V. Nair, PhD Associate Professor, School of Pharmacy University of Colorado at Denver, CO Gary M. Owens, MD President, Gary Owens Associates Glen Mills, PA Andrew M. Peterson, PharmD, PhD Dean, Mayes School of Healthcare Business and Policy, Associate Professor, University of the Sciences, Philadelphia, PA Sarah A. Priddy, PhD Director, Competitive Health Analytics Humana, Louisville, KY Timothy S. Regan, BPharm, RPh, CPh Executive Director, Strategic Accounts Xcenda, Palm Harbor, FL Vincent J. Willey, PharmD Associate Professor, Philadelphia School of Pharmacy, University of the Sciences Philadelphia, PA David W. Wright, MPH President, Institute for Interactive Patient Care Bethesda, MD HEALTH & VALUE PROMOTION

Craig Deligdish, MD Hematologist/Oncologist Oncology Resource Networks, Orlando, FL Thomas G. McCarter, MD, FACP Chief Clinical Officer Executive Health Resources, PA Albert Tzeel, MD, MHSA, FACPE National Medical Director HumanaOne, Waukesha, WI MANAGED MARKETS

Jeffrey A. Bourret, RPh, MS, FASHP Senior Director, Medical Lead, Payer and Specialty Channel Strategy, Medical Affairs Pfizer Specialty Care Business Unit, PA Richard B. Weininger, MD Chairman, CareCore National, LLC Bluffton, SC

EPIDEMIOLOGY RESEARCH

Joshua N. Liberman, PhD Executive Director, Research, Development & Dissemination Sutter Health, Concord, CA GOVERNMENT

Kevin B. “Kip” Piper, MA, FACHE President, Health Results Group, LLC Washington, DC HEALTH INFORMATION TECHNOLOGY Kelly Huang, PhD President, HealthTronics, Inc. Austin, TX J. B. Jones, PhD, MBA Research Investigator, Geisinger Health System, Danville, PA Victor J. Strecher, PhD, MPH Professor and Director for Innovation and Social Entrepreneurship University of Michigan, School of Public Health and Medicine, Ann Arbor, MI HEALTH OUTCOMES RESEARCH

Diana Brixner, RPh, PhD Professor & Chair, Dept. of Pharmacotherapy Executive Director, Outcomes Research Center, Director of Outcomes Personalized Health Care Program, University of Utah, Salt Lake City

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PATIENT ADVOCACY

William E. Fassett, BSPharm, MBA, PhD, FAPhA Professor of Pharmacy Law & Ethics Dept. of Pharmacotherapy, College of Pharmacy Washington State University, Spokane, WA Mike Pucci Sr VP Commercial Operations and Business Development, PhytoChem Pharmaceuticals Lake Gaston, NC PERSONALIZED MEDICINE

Emma Kurnat-Thoma, PhD, MS, RN Director, Research Services URAC, Washington, DC PHARMACOECONOMICS

Josh Feldstein President & CEO CAVA, The Center for Applied Value Analysis, Inc., Norwalk, CT Jeff Jianfei Guo, BPharm, MS, PhD Professor of Pharmacoeconomics & Pharmacoepidemiology, College of Pharmacy, University of Cincinnati Medical Center, OH PHARMACY BENEFIT DESIGN

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

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Teresa DeLuca, MD, MBA Senior VP, PBM Leader Humana Solutions, Louisville, KY Leslie S. Fish, PharmD Vice President of Clinical Programs Fallon Community Health Plan, MA John Hornberger, MD, MS Cedar Associates, LLC CHP/PCOR Adjunct Associate, Menlo Park, CA Michael S. Jacobs, RPh Vice President, National Accounts Truveris, Inc., New York, NY Matthew Mitchell, PharmD, MBA Manager, Pharmacy Services SelectHealth, Salt Lake City, UT Paul Anthony Polansky, BSPharm, MBA Senior Field Scientist, Health Outcomes and PharmacoEconomics (HOPE) Endo Health Solutions, Chadds Ford, PA Christina A. Stasiuk, DO, FACOI Senior Medical Director Cigna, Philadelphia, PA Scott R. Taylor, BSPharm, MBA Executive Director, Industry Relations Geisinger Health System, Danville, PA POLICY & PUBLIC HEALTH

Joseph R. Antos, PhD Wilson H. Taylor Scholar in Health Care Retirement Policy, American Enterprise Institute Washington, DC Robert W. Dubois, MD, PhD Chief Science Officer National Pharmaceutical Council, Washington, DC Jack E. Fincham, PhD, RPh Professor of Pharmacy, Practice and Administration School of Pharmacy, University of Missouri Kansas City, MO Walid F. Gellad, MD, MPH Assistant Professor of Medicine, University of Pittsburgh, Staff Physician, Pittsburgh VA Medical Center, Adjunct Scientist, RAND Health Paul Pomerantz, MBA Executive Director Drug Information Association, Horsham, PA J. Warren Salmon, PhD Professor of Health Policy & Administration School of Public Health University of Illinois at Chicago Raymond L. Singer, MD, MMM, CPE, FACS Chief, Division of Cardiothoracic Surgery Vice Chair, Department of Surgery for Quality & Patient Safety and Outreach Lehigh Valley Health Network, PA RESEARCH & DEVELOPMENT

Frank Casty, MD, FACP Chief Medical Officer Senior VP, Clinical Development Medical Science Endo Pharmaceuticals, Chadds Ford, PA Michael F. Murphy, MD, PhD Chief Medical Officer and Scientific Officer Worldwide Clinical Trials King of Prussia, PA SPECIALTY PHARMACY

Atheer A. Kaddis, PharmD Senior Vice President Managed Markets/Clinical Services Diplomat Specialty Pharmacy Flint, MI James T. Kenney, Jr, RPh, MBA Pharmacy Operations Manager Harvard Pilgrim Health Care Wellesley, MA Michael Kleinrock Director, Research Development IMS Institute for Healthcare Informatics Collegeville, PA

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EDITORIAL

Hardworking P&T Committees David B. Nash, MD, MBA Editor-in-Chief, American Health & Drug Benefits; Jefferson School of Population Health, Philadelphia, PA

V

irtually every American hospital has a Pharmacy & Therapeutics (P&T) committee that works hard to create and maintain the hospital formulary and track the quality and safety of medication therapy. At Thomas Jefferson University Hospital (TJUH), the P&T committee is a critically important medical staff committee with multiple subcommittees. As a member of the TJUH P&T committee for the past 22 years, with a decade serving as Chair of the Medication Quality subcommittee, I thought it might be of interest to our readers to provide an inside perspective of the work done in this arena.

Each year, the Medication Quality subcommittee publishes an informal summary of its activities. I wish to highlight some aspects of this report and draw parallels to work going on in other sectors of our field.

The report of the Medication Quality subcommittee for the 2011-2012 academic year is focused on 4 principal areas—adverse drug event prevention and surveillance, medication use evaluations (MUEs), protocol and policy reviews, and activities to ensure compliance with regulatory compliance.

To create the annual report, we reviewed quarterly reports about medication events and adverse drug reactions from our university hospital and our partner community campus. These deep dives into medication safety are among the highlights of our work together. We are fortunate to have such a dedicated staff from our pharmacy and our risk management department. Our event rate for adverse drug reactions is stable, and we are always striving to reduce harm and reduce errors. We also work regularly with the Institute for Safe Medication Practices, which is located in the Philadelphia suburbs. We view them as external, nonbiased reviewers, and often adopt their recommendations.

The committee works closely with other entities throughout our institution, especially with physicians involved in the constant updating of our computerized physician order entry system and those charged with maintaining new technologies, such as bedside pumps and related tools. Our subcommittee interacts with other subcommittees and makes specific clinical recommendations, for example, to the chemotherapy review committee, the anesthesia care committee, and others. Constant vigilance to reduce medication-related errors is a cornerstone of our work.

On the MUE front, we review a quarterly report of rescue drug use, and our performance remains favorable with respect to a benchmark group of hospitals within

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UHC (formerly known as the University HealthSystem Consortium). We regularly compare our performance to UHC members in other areas, such as the use of proton pump inhibitors in the intensive care unit, the use of parenteral nutrition, and, of course, the use of pain medication. With the proliferation of new products rapidly diffusing into clinical practice, the detailed use of an MUE and a quarterly deep dive are critically important to the appropriate use of all new technologies.

As previously noted, the committee annually reviews hospital policies and protocols. This past year, we reviewed the patient’s personal medication policy, controlled substance policies, education for patients with potential drug and nutrient interactions, and our ongoing work to maintain anticoagulation safety. The goal in our policy reviews is to make these reviews relevant—that is, to ensure that they don’t just stay in a loose-leaf binder on a shelf somewhere. We want to ensure that all appropriate drug-related policies and procedures are actively enforced, and we close the feedback loop to practitioners when there are changes in drug use based on newly available evidence. Finally, we perform an annual review of our performance on “look-alike, sound-alike” drugs (those medications that are often confused with others that are intended for a different purpose) with benchmark hospitals within the UHC. In addition, our compliance with double signatures for certain high-risk medications markedly improved over this past year, as did our compliance with medication reconciliation monitors.

It has been a true privilege to chair the Medication Quality subcommittee of the P&T committee at TJUH. I am in a state of constant learning, especially from my colleagues in the pharmacy. We will never have a zero medication error rate, but I am committed to getting as close to zero as we can to make sure that we cause no harm to our patients. I wish that every P&T committee in every American hospital would be as enthusiastically endorsed as our committee. The senior leadership of our institution makes it very clear that the work of the P&T committee is essentially “unending,” and of the highest priority.

What is your organization doing to ensure compliance with patient safety issues regarding medication administration? Given the epidemic of medical errors, where do you stand on these important issues? I am fortunate to stand on firm ground with our team at TJUH. As always, I am interested in your views and your comments. You can reach me by e-mail at david.nash@jefferson. edu or via the journal at editorial@engagehc.com. ■

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“Hidden” Value: How Indirect Benefits of Health Information Exchange Further Promote Sustainability Albert Tzeel, MD, MHSA, FACPE; Victor Lawnicki, PhD; Kim R. Pemble, MS Background: Health information exchanges (HIEs) have already demonstrated direct value in controlling the costs associated with utilization of emergency department services and with inpatient admissions from the emergency department. HIEs may also affect inpatient admissions originating from outside of the emergency department.

Objective: To assess if a potential association exists between a community-based HIE being used in hospital emergency departments and inpatient admissions emanating from outside of the emergency department.

Methods: The study design was observational, with an eligible population of fully insured plan members who sought emergency department care on at least 2 occasions over the study period between December 2008 and March 2010. Utilization data, obtained from medical and pharmacy claims, were matched to a list of emergency department utilizers where HIE querying could have occurred. Of the eligible members, 1482 underwent propensity score matching to create two 325-member groups—(1) a test group in which the HIE database was queried for all members in all of their emergency department visits, and (2) a control group in which the HIE database was not queried for any of the members in any emergency department visit.

Results: A post–propensity matching analysis showed that although the test group had more admissions per 1000 members overall (199 more admissions per 1000 members) than the control group, these admissions might have been more appropriate for inpatient treatment in general. The relative risk of an admission by the time of a first emergency department visit was 28% higher in the control group than the test group, although by the time of a second emergency department visit, it was only 8% lower in the control group.

Moreover, test group admissions resulted in less time spent as inpatients, which was denoted by bed days per 1000 members (771 fewer bed days per 1000 members) and by average length of stay (4.27 days per admission for all admissions and 0.95 days per admission when catastrophic cases were removed).

Conclusions: Based on these results, HIE availability in the care of patients presenting to the emergency department is associated with fewer inpatient hospital days and a shorter length of stay, even when catastrophic cases are removed from the analysis. Although many factors can play a role in this finding, it is possible that HIE promotion of more appropriate hospital admissions from outside of the emergency department is one cause. Such “indirect” value shows that the return on investment found by HIEs may even be greater than previously calculated. Additional study is warranted to further the business case for HIE investment for the various stakeholders who are interested in supporting HIE sustainability.

T

he eighteenth-century essayist and satirist Jonathan Swift made the observation that “vision is the art of seeing things invisible.” So, too, is “the art of seeing things invisible” a key for the ongoing sustainability of health information exchange (HIE). HIEs

Albert Tzeel

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have long been theorized to provide a number of tangible benefits. These benefits accrue through the provision of medical history at the point of care: decreases in redundant laboratory testing, improved provider efficiency, improved care coordination, increased quality

Dr Tzeel is National Medical Director, HumanaOne, Clinical Leadership and Policy Development, Humana, Inc, Milwaukee, WI; Dr Lawnicki is Econometrician, Business Intelligence and Informatics Competency Center, Humana, Inc, Louisville, KY; and Mr Pemble is Executive Director and Chief Executive Officer, Wisconsin Health Information Exchange, Mequon, WI.

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KEY POINTS ➤

➤

➤

➤

➤

➤

Health information exchanges (HIEs) have shown direct value in controlling costs related to emergency department utilization and inpatient admissions from the emergency department.

The costs associated with inpatient admissions, which account for the majority of healthcare dollars spent, are on the rise; 44% of all hospital admissions originate in the emergency department.

Two previous studies have shown average savings ranging from $26 to $29 for HIE use in the emergency department; a third study showed a decrease in hospital admissions from the emergency department as well.

The current study shows that making HIE available for patients in the emergency department reduces the length of hospital stays for admissions not tied to emergency department services.

The noted decreased length of stay, even when catastrophic cases are removed from the analysis, suggests that the availability of HIEs in the emergency department reduces inpatient utilization emanating from outside of the emergency department.

These findings further support that incorporating the use of HIEs in the emergency department can reduce overall hospital admissions rates, lower the length of hospital stay, and, therefore, decrease the associated costs.

of care, and the ultimate goal of an overall decreased cost of care.

More recently, we have witnessed a seismic movement from theory to practice with definitive dollar savings noted for HIE use in emergency departments in Indianapolis, IN,1 and in Milwaukee, WI2 ($26 and $29 savings per emergency department visit, respectively),1,2 as well as in Memphis, TN (approximately net $1.1 million in savings for the community at large).3 Moreover, in Memphis, the great majority of dollar savings (97.6%) resulted from the avoidance of inpatient admissions from the emergency department.3 Inpatient admissions account for the preponderance of dollars spent in healthcare. Costs for inpatient admissions in the United States are increasing; during calendar year 2004, the average inpatient admission cost was $10,0304; by 2008, this increased to $15,017.5 A community replicating the Memphis experience by mitigating inpatient admissions from the emergency department should experience financial savings as Memphis did. The Memphis experience showed that HIE availability within the emergency department

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decreases direct admissions from the emergency department.3 But can HIE availability in the emergency department indirectly impact admissions emanating from outside of the emergency department? Is the risk of any inpatient admission occurring altered by the presence of HIE in the emergency department? If so, the community benefits indirectly, as well as directly, from having said HIE occurs within the emergency department. However, achieving that benefit requires HIE sustainability, and HIE sustainability requires a stable source of funding.

Enhancing the business case for HIE sustainability by uncovering such indirect or “hidden” value may help validate the need for external support and funding.

Background In our previous article promoting the “business case for payer support of a community-based HIE,” we described the relationship between Humana in Southeast Wisconsin and the local HIE.2 To briefly summarize, beginning in December 2008, Humana provided a financial incentive to the Wisconsin Health Information Exchange (WHIE) for promoting the querying of a database by emergency department clinicians (as a part of their workflow) for fully insured members presenting to the emergency department for care.6 WHIE links together disparate emergency departments across 5 competitive health systems in Milwaukee County.7 Our previous evaluation showed a positive direct financial outcome for our health plan, with an average savings of $29 per emergency department visit when clinicians queried the WHIE in the course of providing emergency department care as opposed to when the WHIE was not queried.2 We also realized a direct return on investment (ROI) of more than 2:1.2 Further analysis looking at other potential sources of value, some of which may result from indirect savings, may help further the business case for external HIE support and may also show that the value of HIE may even be higher than what we can quantitatively measure.

Methods Study Design: Developing the Sample Population for Evaluation The Humana version of an Institutional Review Board, the clinical “Stage Gate Process,” provided approval for this pilot assessing the impact of HIE query in the emergency department. The planned evaluation included both observational and retrospective analyses.

In developing the member pool from which to draw the evaluation population, Humana and the WHIE had agreed that the plan would provide to the WHIE a financial incentive to cover its costs for promoting emergency department clinicians’ querying of the WHIE database.

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Although queries apply to all patients, the incentive only covered eligible Humana members presenting to the emergency department for care.8 Eligible members were commercial, fully insured members only; self-funded group members, as well as members covered by governmental programs (eg, Medicare), were specifically excluded. Every quarter, WHIE provided Humana specific information about each individual health plan member who was fully insured by Humana and who sought emergency department care, as well as when the emergency department clinician accessed the WHIE database for that patient and at which facility.

WHIE only provided clinical data as it would appear on a claim related to the encounter. All communications were HIPAA compliant and used encrypted files. The information that was provided allowed Humana to match emergency department claims data received from providers with the emergency department encounter by date of service and facility.

In working with claims data, we stipulated precise parameters for member inclusion in the evaluation sample. Inclusion criteria noted in the original analysis stipulated that2: 1. All members included in the evaluation must have had at least 12 months of continuous coverage with our health plan 2. Members would be excluded from the evaluation if they had either less than 6 months of coverage before the start of the program or less than 3 months of coverage after the start of the program 3. Because admissions from the emergency department or prolonged emergency department holds of “24hour observations” would have impaired our ability to perform the original analysis on emergency department costs, we excluded those members (admitted from or held in the emergency department) from the analysis.

These exclusions prevented potential skewing of the data for our analyses.

Study Design: Developing the Control Group and the Test Group In our previous article, we discussed in great detail how we determined who would make up the control and test groups.2 Humana identified members seen in the emergency department when the WHIE database was queried in both a first emergency department visit and a subsequent emergency department visit as eligible to be included in the test group; members seen in the emergency department where the WHIE database was not queried in neither a first emergency department visit nor in a subsequent emergency department visit (because the facility had not yet provided WHIE access at that

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time) were eligible to be included in the control group.

A total of 428 plan members were deemed eligible for the test group, whereas 1054 plan members met control group eligibility.2 In addition, our evaluation deliberately assumed the need for propensity scoring, because that technique affords the best way to match members, while minimizing bias. Propensity scoring provides “the conditional probability of receiving the treatment given the observed covariates.”9 In their defining article, Rosenbaum and Rubin showed that “the adjustment for the scalar propensity score is sufficient to remove bias due to all observed covariates.”10 Furthermore, propensity scoring has been found to yield estimates that are not substantially different from typical multivariable methods.11,12 For the logistic regression yielding the propensity scores, we used all of the following combinations of costrelated and demographic variables to match the 2 groups: age, sex, medical net paid per participant per month (PPPM), prescription net paid PPPM, medical plus prescription net paid PPPM, medical inpatient net paid PPPM, medical outpatient net paid PPPM, and medical physician net paid PPPM. With the exception of age and sex, all of these variables represent dollar values, because dollar values are easy to calculate from claims and they were unrelated to the specific exposure (ie, WHIE database querying).

Propensity scores on which we matched the participants used the nearest neighbor algorithm. Matching allows for “sampling from a large reservoir of potential controls to produce a control group of modest size in which the distribution of covariates is similar to the distribution in the treated group.”9 For member matching, MATLAB version 7.0.1.1 was used.13

Data Analysis Once we completed matching 325 pairs of individuals for the test and control groups, we analyzed differences in the metrics of interest for the 2 groups. For descriptive chi-square and other statistics, SAS Enterprise Guide version 4.2 was used.14 We compared all claims for the 2 groups for a time period beginning 1 year before an individual’s first emergency department visit date to an end date of 1 year after that first emergency department visit date; therefore, each individual’s length of time in the pilot was 1 full year.

The pilot ran from December 2008 through March 2010. Within that 1-year time period, a group member would still need to have a second emergency department visit before the end date. The emergency department visit served to delineate a point in time where we evaluated member utilization; in other words, we looked at the member’s inpatient utilization at the time of a first

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Table 1 Descriptive Results for All Study-Eligible Members, by Potential Group Assignment Prematching, and by Actual Group Assignment Post–Propensity Score Matching Prematching

Postmatching

Group participation eligibility

Members, N

Mean age, yrs

Sex, % female

Group participation designation

Members, N

Mean age, yrs

Sex, % female

Time of first emergency department visit

Control

1054

42.0

56.5

Control

325

42.5

55.2

Time of second emergency department visit

Test

428

41.1

53.5

Test

326

42.7

55.8

Period

Adapted from Tzeel A, et al. The business case for payer support of a community-based health information exchange: a Humana pilot evaluating its effectiveness in cost control for plan members seeking emergency department care. Am Health Drug Benefits. 2011;4:207-216.

Comparison of Admissions per 1000 Members for Table 2 Propensity-Matched Control and Test Groups Test group, N

Control group, N

Total population, by period, N

Time of first emergency department visit

269

321

590

Time of second emergency department visit

664

555

1219

Total population, by group

933

876

1809

Period

Chi-square test for independence: χ2 = 12.34; since P <.005, the admissions per 1000 members for each group and the 2 time periods are not independent.

Decrease in admissions per 1000 members for the test group between emergency department visits = 269 × (555/321) – 664 = (199).

emergency department visit and then again at the time of a second emergency department visit.

For this specific analysis, we looked at differences in inpatient admissions, inpatient days, and length of stay (LOS) to gauge a possible association for HIE impact outside of the emergency department. We used routine payer parameters to calculate differences in admissions per 1000 members, bed days per 1000 members, and in average LOS per admission at the times of a first and of a subsequent emergency department visit for the 2 populations of interest, with adjustment for trend between the 2 time periods.

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Results Descriptive results before and after propensity score matching for all eligible control population and test population members are shown in Table 1. Table 2 outlines inpatient admissions per 1000 members for the propensity-matched cohort, as well as for the summed population results at the time of a given emergency department visit and by group designation. A chisquare test for independence of the groupings and the time period of emergency department visit show that the admissions per 1000 members of each group are not independent of the time period when a member of the group was seen in the emergency department. This finding implies that inpatient admissions, unrelated to an emergency department visit, may be impacted by the use of HIEs within the emergency department.

Table 3 describes the conditional probabilities within the 2 groups; we specifically examined the probability of an admission during a specific time frame given the possible use of HIEs in an emergency department.

The conditional probability results show that first, the probability for having had an admission in either group is more likely at the time of a second emergency department visit than at the time of a first visit (eg, 67.4% of all admissions studied occurred by the time of a second emergency department visit).

Second, the probability of having had an admission at the time of a first emergency department visit is greater in the control group (37% vs 29%, in favor of admission with no HIE query in the emergency department), whereas the probability of having had an admission at the time of a second emergency department visit is greater in the test group (71% vs 63%, in favor of admission with HIE query in the emergency depart-

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Table 3 Conditional Probabilities of Any Admission, by a Specific Time Period Given Group Designation Formulaa

Resulting probability

Any admission at time of first emergency department visit, given that HIE is used in emergency department (test group)

269/933

0.288 or 29%

Any admission at time of first emergency department visit, given that HIE is used in emergency department (control group)

321/876

0.366 or 37%

Any admission at time of second emergency department visit, given that HIE is used in emergency department (test group)

664/933

0.711 or 71%

Any admission at time of second emergency department visit, given that no HIE is used in emergency department (control group)

555/876

0.633 or 63%

Conditional probability of

a

Results were double-checked by calculating conditional probabilities for 2 independent events: probability of any admission by a certain emergency department visit and the probability of whether HIE was used in the emergency department.

HIE indicates health information exchange.

ment). Another way of viewing these results is to note that the absolute risk of any inpatient admission by the time of a first emergency department visit is 8% higher (relative risk [RR], 28% higher) in the control group, whereas the absolute risk of any inpatient admission by the time of a second emergency department visit is 8% lower (RR, 11% lower) in the control group.

Table 4 and Table 5 show the results of the other standard payer metrics, inpatient bed days per 1000 members, and average LOS for the propensity-matched cohort, by time period of emergency department visit and by group designation. As seen in Tables 4 and 5, when accounting for trend, the availability of HIE in the emergency department may be associated with shorter LOSs for admissions emanating outside the emergency department (4.27 days per admission) and a decreased number of inpatient days in total (771 bed days per 1000 members).

However, the noted results, especially for the average LOS calculations, may be skewed by an abnormally high number of catastrophic cases, as noted by the maximum LOSs in Table 6. Addressing such discrepancies by removing all inpatient admissions with an LOS of at least 33 days, even without further adjusting for the propensity matches, generates the results outlined in Table 7. These results show that simply having HIE available in the emergency department may yield a potential savings in LOS of nearly 1 full day (0.95 days per admission).

Discussion Approximately 44% of all hospital admissions, or 55% of hospital admissions excluding pregnancy and childbirth, use the emergency department as the conduit for entry.15 Conversely, 56% of all admissions (or 45% of

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Comparison of Bed Days per 1000 Members for Table 4 Propensity-Matched Control and for Test Groups Period

Test group, N Control group, N

Time of first emergency department visit

1381

1814

Time of second emergency department visit

4077

6368

Decrease in bed days per 1000 members for the test group between first and second emergency department visits = 4077 ⳯ (6368/1814) – 1381 = 771.

Table 5 Comparison of Average Length of Stay for PropensityMatched Control and for Test Groups Test group, average stay

Control group, average stay

Time of first emergency department visit

5.13 days

5.65 days

Time of second emergency department visit

6.14 days

11.47 days

Period

Decrease in ALOS for the test group between emergency department visits = 5.13 ⳯ (11.47/5.65) – 6.14 = 4.27 days/ admission.

ALOS indicates average length of stay.

all admissions, excluding pregnancy and childbirth) are not admitted through the emergency department. Such findings necessitate looking at methods to alleviate hospital admissions that do not originate from the emergency department. One way of doing this is to ensure appropriate admissions.

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Table 6 Comparison of Raw Admissions and Maximum Length of Stay for Propensity-Matched Control and for Test Groups Test group LOS

Period

Control group LOS

Time of first emergency department visit

83 admissions; 109 admissions; 53 days 84 days

Time of second emergency department visit

155 admissions; 122 admissions; 120 days 78 days

LOS indicates length of stay.

Unadjusted Comparison of Average Length of Stay Rates Table 7 for Remaining Control and Test Group Participants, after Removal of All Outlier Admissions (LOS, ≥33 days) Period

Test group

Control group

Time of first emergency department visit

81 admissions; 4.65 days

107 admissions; 4.75 days

Time of second emergency department visit

152 admissions; 110 admissions; 4.66 days 5.73 days

Decrease in ALOS for the test group between emergency department visits = 4.65 ⳯ (5.73/4.75) – 4.66 = 0.95 days per admission.

ALOS indicates average length of stay; LOS, length of stay.

Review of our results show some promising findings.

In our study, an emergency department visit by a member of the test group or the control group did not result in an admission from the emergency department.

However, each group’s members had admissions from outside of the emergency department.

When we look at the likelihood of a first admission from outside of the emergency department by a group member, the results show a 28% higher probability of an admission when HIE is not available in the emergency department. Given that physician offices provide data for HIE in the emergency department, it is more likely that emergency departments with access to HIE have physicians with access to HIE. We could theorize that a lack of access to information at the point of care, especially if that point of care is outside of the emergency department, may provide the impetus for potentially inappropriate admissions.

In his study, Campbell previously noted that 28% of the hospital admissions deemed as “inappropriate” occurred secondary to a need for the performance of treatment or tests that could have been performed on an outpatient basis.16 Moreover, assumptions that appropriate admissions require longer LOSs do decrease what may

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be considered “inappropriate,” because admissions with shorter LOSs should not have been admitted at all.17 Multiple factors can play a role in potentially inappropriate admissions, including, but not limited to, difficulty in organizing continuity of care (eg, outpatient physician follow-up)18 versus receipt of community services (eg, home healthcare)19 or even rural geography.20 That members of the test group had more admissions at the time of a second emergency department visit could imply that the use of HIEs before then might have played a role in avoiding inappropriate admissions, thereby leading to more appropriate use of inpatient resources overall.

From our previous study, we were certainly aware that the test group “required higher intensity care on a claims dollar basis,” implying that they were “sicker” on the basis of claims.2 Conversely, because the control group had more inpatient admissions by the time of a first emergency department visit, we could surmise that a lack of connectivity factored in that finding as well.

Could that result prolong hospital stays?

Our finding of a significant decrease in the bed days per 1000 members for the test group relative to the control group by the second emergency department visit makes us begin to question if there is a correlation of HIE availability with shorter hospital stays; in fact, the noted savings of 4.27 days per admission seemed so extreme (because of several cases of at least 33 days per admission), that it necessitated removing 5 of 238 (2.1%) admissions from the test group and 14 of 231 (6.1%) admissions from the control group to better assess this premise. Despite removing catastrophic cases, we still found a decrease of nearly 1 full day per admission for the test group. Having HIE itself in the emergency department did not directly influence this finding, but it certainly could have acted indirectly.

Research has shown that indirect returns can account for 50% of a technology’s ROI.21 It is this ROI that is made meaningful by, in this case, decreasing inpatient services.22 ROI should certainly not be the only measure of the value that HIEs bring.23 HIEs can offer a clinical “value added” through providing services in a manner that an alternative cannot.24 In our case, the “service” provided may be the indirect promotion of more appropriate inpatient admissions, containment of inappropriate admissions, and a decrease in LOS. However, to reduce costs associated with these parameters may require, as Porter says, spending more on other services.25 In our case, the trade-off necessitates that stakeholders justifiably sustain HIEs. Of all stakeholders, accountable care organizations should be especially interested.26 Aligning physicians and payers in this endeavor should also optimize value.27

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Limitations We need to account for several potential limitations to this study. First, although the use of propensity scoring methods to create test and control groups should minimize potential bias, any time data manipulation occurs, potential new risks from bias need to be acknowledged.

Methods exist to minimize biases arising from such risks.28 Second, the use of HIE in our study groups was limited to emergency department visits. Although we can hope for bidirectional information flow in the use of HIEs, we cannot actually prove that. Therefore, the association between HIE use in the emergency department and decreased inpatient admissions from outside of the emergency department is just that, an association.

We cannot necessarily prove a direct cause-and-effect relationship. Nonetheless, the results remain intriguing, such that we plan further study on what we found here.

Third, we cannot discount the potential impact of socalled human factors.

Although we believe that the use of HIE in emergency departments influences physician behavior outside of the emergency department, we do not actually know if this is the case. As Churchman notes, “knowledge resides in the user and not in the collection [of information]. It is how the user reacts to a collection of information that matters.”29 Physicians caring for patients have a lot of nonexchangeable information at their disposal and that information may certainly impact potential admissions as much as, if not more than, HIE use in the emergency department. Last, one cannot quantify “indirect” savings. Although we can estimate potential savings in arguing for HIE sustainability, we cannot quantify something that never happened.

Nonetheless, the argument still stands through logic and through extension.

Conclusions The impact of “direct” value is easily quantified: it is tangible, visible, and deduced from the evidence.30 The impact of “indirect” value is much harder to evaluate: it must be induced from the evidence.30 By definition, then, it is much harder to “see” indirect benefits, because they are hidden from view. When it comes to visualizing the impact of HIE, one can follow a similar line of reasoning. Having clinicians access HIE in the emergency department has already shown direct benefits in the form of an average savings of $26 to $29 per emergency department visit,1,2 as well as avoided inpatient admissions directly from the emergency department.3 Our current results build on that direct confirmation by adding indirect evidence for HIE value.

HIE availability in the emergency department is associated with an effect outside of the emergency depart-

ment when it comes to hospital admissions in general.

Potentially inappropriate admissions may be avoided, whereas admissions that do occur result in a shorter LOS. An argument could be made that this is a function of “economies of connection.”31 As Beckham notes, “technology can collapse distance by generating virtual proximities….As some networks, products, and services become more widely used, they become exponentially more valuable….Proximity and networks…generate real value by connecting intellect, facilitating collegiality, and supporting collaboration.”31 Facilitating collaboration through networking is especially needed, given that the same individual will seek care at multiple facilities.32 So, coming full circle, the need for HIE becomes reinforced, with sustainability remaining a paramount objective. For sustainability, payers, providers, and other stakeholders need to help pave a path to that goal.

Although those stakeholders need to ascertain the value that they receive from HIE, all must understand one thing: awareness of the indirect value brought forward by HIEs is as important as the direct value received. Having the vision to “see” this indirect value is vital because, as it is written in Proverbs (29:18), “where there is no vision, the people perish.”■ Study Funding All funding for this project and its analysis was provided by Humana, Inc, Louisville, KY. Author Disclosure Statement Dr Tzeel is a consultant to Amylin and is employed by and owns stock in Humana. Dr Lawnicki is employed by and owns stock in Humana. Mr Pemble is employed by the National Institute for Medical Informatics/WHIE.

References 1. Overhage JM, Dexter PR, Perkins SM, et al. A randomized, controlled trial of clinical information shared from another institution. Ann Emerg Med. 2002;39:14-23.

2. Tzeel A, Lawnicki VL, Pemble KR. The business case for payer support of a community-based health information exchange: a Humana pilot evaluating its effectiveness in cost control for plan members seeking emergency department care. Am Health Drug Benefits. 2011;4:207-216.

3. Frisse ME, Johnson KB, Nian H, et al. The financial impact of health information exchange on emergency department care. J Am Med Inform Assoc. 2012;19:328-333.

4. Machlin SR, Carper K. Expenses for Hospital Inpatient Stays, 2004. Statistical Brief #164. March 2007. Agency for Healthcare Research and Quality, Rockville, MD. www.meps.ahrq.gov/mepsweb/data_files/publications/st164/stat164.pdf. Accessed September 25, 2012.

5. Agency for Healthcare Research and Quality. Hospital inpatient services-median and mean expenses per person with expense and distribution of expenses by source of payment: United States, 2008. Medical Expenditure Panel Survey. http://meps. ahrq.gov/mepsweb/data_stats/tables_compendia_hh_interactive.jsp?_SERVICE=ME PSSocket0&_PROGRAM=MEPSPGM.TC.SAS&File=HCFY2008&Table=HCFY 2008%5FPLEXP%5FD&VAR1=AGE&VAR2=SEX&VAR3=RACETH5C&VAR4 =INSURCOV&VAR5=POVCAT08&VAR6=MSA&VAR7=REGION&VAR8= HEALTH&VARO1=4+17+44+64&VARO2=1&VARO3=1&VARO4=1&VARO 5=1&VARO6=1&VARO7=1&VARO8=1&_Debug=. Accessed December 15, 2011.

6. Neupert P. Re-charting healthcare: innovations to drive a new delivery model for tomorrow’s health system. In: Merritt D, ed. Paper Kills 2.0: How Health IT Can Help Save Your Life and Your Money. Washington, DC: Center for Health Transformation Press; 2010:15.

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7. Wisconsin Health Information Exchange. Information Exchange. www.whie.org/ regional-activities/information-exchange. Accessed September 25, 2012.

8. Humana to partner with WHIE on emergency department data exchange. January 29, 2009. WTN News. http://wistechnology.com/articles/5432/. Accessed September 25, 2012.

9. Rosenbaum PR. Observational Studies. 2nd ed. New York, NY: Springer-Verlag; 2002:296.

10. Rosenbaum PR, Rubin DB. The central role of the propensity score in observational studies for causal effects. Biometrika. 1983;70:41-55.

11. Shah BR, Laupacis A, Hux JE, Austin PC. Propensity score methods gave similar results to traditional regression modeling in observational studies: a systematic review.

J Clin Epidemiol. 2005;58:550-559.

12. Stürmer T, Joshi M, Glynn RJ, et al. A review of the application of propensity score methods yielded increasing use, advantages in specific settings, but not substantially different estimates compared with conventional multivariable methods. J Clin Epidemiol. 2006;59:437-447.

13. MATLAB. The Language of Technical Computing. www.mathworks.com/ products/matlab/. Accessed June 18, 2010.

14. SAS Enterprise Guide. www.sas.com/technologies/bi/query_reporting/guide/.

Accessed June 18, 2010.

15. Elixhauser A, Owens P. Reasons for being admitted to the hospital through the emergency department, 2003. HCUP Statistical Brief #2. February 2006. Rockville, MD: Agency for Healthcare Research and Quality. www.hcup-us.ahrq.gov/reports/ statbriefs/sb2.pdf. Accessed September 25, 2012.

16. Campbell J. Inappropriate admissions: thoughts of patients and referring doctors.

J R Soc Med. 2001;94:628-631.

17. Lo CM, Leung SH, Lam CS, Yau HH. Clinical audit on short stay emergency medical admission. Hong Kong J Emerg Med. 2003;10:30-36.

18. Davido A, Nicoulet I, Levy A, Lang T. Appropriateness of admission in an emergency department: reliability of assessment and causes of failure. Qual Assur Health Care. 1991;3:227-234.

19. Coast J, Peters TJ, Inglis A. Factors associated with inappropriate emergency hospital admission in the UK. Int J Qual Health Care. 1996;8:31-39.

20. Carasso S, Shmueli T, Arnon R, Askenazi I. Characteristics of emergency room admissions of IDF soldiers in northern Israeli hospitals between May 2002 and April 2003. Harefuah. 2004;143:8-11,87,88.

21. Nucleus Research. Indirect benefits: the invisible ROI drivers. February 2007. http://nucleusresearch.com/research/notes-and-reports/indirect-benefits-the-invisibleroi-drivers/. Accessed December 15, 2011.

22. Rauh SS, Wadsworth EB, Weeks WB, Weinstein JN. The savings illusion—why clinical quality improvement fails to deliver bottom-line results. N Engl J Med. 2011;365:e48.

23. Volpp KG, Loewenstein G, Asch DA. Assessing value in health care programs.

JAMA. 2012;307:2153-2154.

24. Joshi JK. Clinical value-add for health information exchange (HIE). Internet J Med Inform. 2011;6(1). www.ispub.com/journal/the-internet-journal-of-medicalinformatics/volume-6-number-1/clinical-value-add-for-health-informationexchange-hie.html. Accessed December 7, 2011.

25. Porter ME. What is value in health care? N Engl J Med. 2010;363:2477-2481.

26. Dimick C. ACOs driving HIE development, competition. J AHIMA. May 1, 2012. http://journal.ahima.org/2012/05/01/acos-driving-hie-development-competition/.

Accessed May 17, 2012.

27. Tzeel A. Biologic therapies for rheumatoid arthritis: it’s all about value. Am Health Drug Benefits. 2012;5:91-92.

28. Luellen JK, Shadish WR, Clark MH. Propensity scores: an introduction and experimental test. Eval Rev. 2005;29:530-558.

29. Churchman CW. The Design of Inquiring Systems: Basic Concepts of Systems and Organization. New York, NY: Basic Books; 1971:10.

30. Bovee CL, Thill JV, Schatzman BE. Business Communication Today. 7th ed.

Upper Saddle River, NJ: Prentice Hall; 2002.

31. Beckham D. Economies of connection. Hosp Health Netw. August 16, 2011. www.hhnmag.com/hhnmag/HHNDaily/HHNDailyDisplay.dhtml?id=7220009058.

Accessed December 15, 2011.

32. Finnell JT, Overhage JM, Grannis S. All health care is not local: an evaluation of the distribution of emergency department care delivered in Indiana. AMIA Annu Symp Proc. 2011;2011:409-416.

STAKEHOLDER PERSPECTIVE Significant Potential for Health Information Exchange in Enhancing Quality of Care and Reducing Hospital Admissions in the United States As the US healthcare system continues a hoped-for and necessary evolution toward an increase in quality along with lower costs, the important variables of efficiency and effectiveness will become evermore important and crucial for optimum outcomes to be achieved.

The potential of health information exchanges (HIEs) is significant for enhancing the quality of care, eliminating duplicate services, avoiding unnecessary hospital admissions, and decreasing the costs of healthcare.

PAYERS: This tightly controlled, well-conducted, and properly evaluated study by Dr Tzeel and colleagues of the indirect benefits of HIE in reducing hospital admissions from emergency department visits is the type of study that is necessary to continue to evaluate and promote HIEs as a vital segment of enhancing positive patient outcomes in the US healthcare system.

The direct benefits of HIE in an emergency department

are prevalent in the literature and described well in this study from Humana. The question of whether HIE in the emergency department avoids unnecessary hospital admissions from outside of the emergency department is the central tenet of this study. The authors found a 28% greater probability of an admission when HIE is not available in the emergency department setting.

As has been described in the literature, the importance of enhancing and embracing health information systems is crucial for the overall improvement of the US healthcare system.1 Despite its promise, much remains to be done to fully implement HIE in the United States. Sharing of information in an efficient and effective manner has not been a prominent feature of the US healthcare system. Much remains to be accomplished from an organizational framework for benefits to accrue.2 Continued

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STAKEHOLDER PERSPECTIVE (Continued) The Affordable Care Act, which was passed in 2010 and was affirmed as constitutional by the US Supreme Court in June 2012, promotes and incentivizes implementation of HIEs as one cornerstone for improving healthcare delivery in the United States. In a study examining Canadian experts’ views of the progress in the United States relative to HIEs, a recommended strategy is to increase the direct engagement with providers and to develop the business case for HIE implementation on a broad scale.3 HIEs have been a prominent part of the British National Health Service for more than 4 decades. What was accomplished in the 1970s in the United Kingdom was the establishment of a foundation of policy, infrastructure, and systems of care, and the creation and acquisition of clinical computing applications, with strong reliance on financial and clinical incentives.4 PATIENTS: A significant opportunity exists for consumer and patient engagement in the system as well. Recent studies have highlighted the support of consumers for HIE, while also pointing out the need to provide those who have relatively less sophistication and means of monitoring their health records electronically with more education, access, and information regarding HIEs.5

Much remains to be accomplished in the United States; however, studies such as the one supported by Humana and presented here are necessary to pinpoint the exact direct benefits of HIE, as well as the indirect benefits that must be detailed, explained, and presented to many stakeholders in the process of moving HIE forward with tangible benefits to various segments of the US healthcare system.

Jack E. Fincham, PhD, RPh Professor of Pharmacy Practice and Administration Division of Pharmacy Practice and Administration Adjunct Professor of Health Administration Henry W. Bloch School of Management University of Missouri, Kansas City 1. Adler-Milstein J, Jha AK. Sharing clinical data electronically: a critical challenge for fixing the health care system. JAMA. 2012;307:1695-1696.

2. Rippen HE, Pan EC, Russell C, et al. Organizational framework for health information technology. Int J Med Inform. 2012 Feb 27. [Epub ahead of print.]

3. Zimlichman E, Rozenblum R, Salzberg CA, et al. Lessons from the Canadian national health information technology plan for the United States: opinions of key Canadian experts. J Am Med Inform Assoc. 2012;19:453-459.

4. Payne TH, Detmer DE, Wyatt JC, et al. National scale clinical information exchange in the United Kingdom: lessons for the United States. J Am Med Inform Assoc. 2011;18:91-98.

5. Patel VN, Dhopeshwarkar RV, Edwards A, et al. Consumer support for health information exchange and personal health records: a regional health information organization survey. J Med Syst. 2012;36:1043-1052.

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R D IV O F AN D E US ION V O EO AT R P AN STR P A UT INI BC DM U S A

VELCADEHCP.COM

If you define value as an overall survival advantage: VELCADE® (bortezomib) DELIVERED A >13-MONTH OVERALL SURVIVAL ADVANTAGE At 5-year median follow-up, VELCADE (bortezomib)+MP* provided a median overall survival of 56.4 months vs 43.1 months with MP alone (HR=0.695 [95% CI, 0.57-085]; p<0.05)† At 3-year median follow-up, VELCADE+MP provided an overall survival advantage over MP that was not regained with subsequent therapies

If you define value as defined length of therapy: Results achieved using VELCADE twice-weekly followed by weekly dosing for a median of 50 weeks (54 planned)1

If you define value as medication cost: Medication cost is an important factor when considering overall drug spend. The Wholesale Acquisition Cost for VELCADE is $1,471 per 3.5-mg vial as of January 2012 Health plans should consider medication cost, length of therapy, and dosing regimens when determining the value of a prescription drug regimen. This list of considerations is not meant to be all-inclusive; there are multiple other factors to consider when determining value for a given regimen

VELCADE Indication and Important Safety Information INDICATION VELCADE is indicated for the treatment of patients with multiple myeloma.

CONTRAINDICATIONS VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol. VELCADE is contraindicated for intrathecal administration.

WARNINGS, PRECAUTIONS AND DRUG INTERACTIONS Peripheral neuropathy, including severe cases, may occur — manage with dose modification or discontinuation. Patients with preexisting severe neuropathy should be treated with VELCADE only after careful risk-benefit assessment Hypotension can occur. Use caution when treating patients receiving antihypertensives, those with a history of syncope, and those who are dehydrated Closely monitor patients with risk factors for, or existing heart disease Acute diffuse infiltrative pulmonary disease has been reported Nausea, diarrhea, constipation, and vomiting have occurred and may require use of antiemetic and antidiarrheal medications or fluid replacement Thrombocytopenia or neutropenia can occur; complete blood counts should be regularly monitored throughout treatment Tumor Lysis Syndrome, Reversible Posterior Leukoencephalopathy Syndrome, and Acute Hepatic Failure have been reported Women should avoid becoming pregnant while being treated with VELCADE. Pregnant women should be apprised of the potential harm to the fetus Closely monitor patients receiving VELCADE in combination with strong CYP3A4 inhibitors. Concomitant use of strong CYP3A4 inducers is not recommended

ADVERSE REACTIONS Most commonly reported adverse reactions (incidence ≥30%) in clinical studies include asthenic conditions, diarrhea, nausea, constipation, peripheral neuropathy, vomiting, pyrexia, thrombocytopenia, psychiatric disorders, anorexia and decreased appetite, neutropenia, neuralgia, leukopenia, and anemia. Other adverse reactions, including serious adverse reactions, have been reported Please see Brief Summary for VELCADE on the next page of this advertisement.

To contact a reimbursement specialist: Please call 1-866-VELCADE, Option 2 (1-866-835-2233). *Melphalan+prednisone. † VISTA: a randomized, open-label, international phase 3 trial (N=682) evaluating the efficacy and safety of VELCADE administered intravenously in combination with MP vs MP in previously untreated multiple myeloma. The primary endpoint was TTP. Secondary endpoints were CR, ORR, PFS, and overall survival. At a pre-specified interim analysis (median follow-up 16.3 months), VELCADE+MP resulted in significantly superior results for TTP (median 20.7 months with VELCADE+MP vs 15.0 months with MP [p=0.000002]), PFS, overall survival, and ORR. Further enrollment was halted and patients receiving MP were offered VELCADE in addition.

Updated analyses were performed.

Reference: 1. Mateos M-V, Richardson PG, Schlag R, et al. Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: updated follow-up and impact of subsequent therapy in the phase III VISTA trial. J Clin Oncol. 2010;28(13):2259-2266.

Brief Summary INDICATIONS: VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma.

VELCADE is indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy.

CONTRAINDICATIONS: VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol.

VELCADE is contraindicated for intrathecal administration.

WARNINGS AND PRECAUTIONS: VELCADE should be administered under the supervision of a physician experienced in the use of antineoplastic therapy. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE. Peripheral Neuropathy: VELCADE treatment causes a peripheral neuropathy that is predominantly sensory. However, cases of severe sensory and motor peripheral neuropathy have been reported.

Patients with pre-existing symptoms (numbness, pain or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including ≥ Grade 3) during treatment with VELCADE. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. In the Phase 3 relapsed multiple myeloma trial comparing VELCADE subcutaneous vs. intravenous the incidence of Grade ≥ 2 peripheral neuropathy events was 24% for subcutaneous and 41% for intravenous. Grade ≥ 3 peripheral neuropathy occurred in 6% of patients in the subcutaneous treatment group, compared with 16% in the intravenous treatment group. Starting VELCADE subcutaneously may be considered for patients with pre-existing or at high risk of peripheral neuropathy.

Patients experiencing new or worsening peripheral neuropathy during VELCADE therapy may benefit from a decrease in the dose and/or a less dose-intense schedule. In the single agent phase 3 relapsed multiple myeloma study of VELCADE vs. Dexamethasone following dose adjustments, improvement in or resolution of peripheral neuropathy was reported in 51% of patients with ≥ Grade 2 peripheral neuropathy in the relapsed multiple myeloma study. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had ≥ Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma.

Hypotension: The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 13%. These events are observed throughout therapy. Caution should be used when treating patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids and/or sympathomimetics.

Cardiac Disorders: Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have been reported, including reports in patients with no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing heart disease should be closely monitored. In the relapsed multiple myeloma study of VELCADE vs. dexamethasone, the incidence of any treatment-emergent cardiac disorder was 15% and 13% in the VELCADE and dexamethasone groups, respectively. The incidence of heart failure events (acute pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock, pulmonary edema) was similar in the VELCADE and dexamethasone groups, 5% and 4%, respectively. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established.

Pulmonary Disorders: There have been reports of acute diffuse infiltrative pulmonary disease of unknown etiology such as pneumonitis, interstitial pneumonia, lung infiltration and Acute Respiratory Distress Syndrome (ARDS) in patients receiving VELCADE. Some of these events have been fatal. In a clinical trial, the first two patients given high-dose cytarabine (2 g/m2 per day) by continuous infusion with daunorubicin and VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy. There have been reports of pulmonary hypertension associated with VELCADE administration in the absence of left heart failure or significant pulmonary disease. In the event of new or worsening cardiopulmonary symptoms, a prompt comprehensive diagnostic evaluation should be conducted.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): There have been reports of RPLS in patients receiving VELCADE. RPLS is a rare, reversible, neurological disorder which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances. Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing RPLS, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previously experiencing RPLS is not known.

Gastrointestinal Adverse Events: VELCADE treatment can cause nausea, diarrhea, constipation, and vomiting sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur. Fluid and electrolyte replacement should be administered to prevent dehydration.

Thrombocytopenia/Neutropenia: VELCADE is associated with thrombocytopenia and neutropenia that follow a cyclical pattern with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and recovery remained consistent over the 8 cycles of twice weekly dosing, and there was no evidence of cumulative thrombocytopenia or neutropenia.

The mean platelet count nadir measured was approximately 40% of baseline. The severity of thrombocytopenia was related to pretreatment platelet count. In the relapsed multiple myeloma study of VELCADE vs. dexamethasone, the incidence of significant bleeding events (≥Grade 3) was similar on both the VELCADE (4%) and dexamethasone (5%) arms. Platelet counts should be monitored prior to each dose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and schedule of VELCADE. There have been reports of gastrointestinal and intracerebral hemorrhage in association with VELCADE. Transfusions may be considered. The incidence of febrile neutropenia was <1%.

Tumor Lysis Syndrome: Because VELCADE is a cytotoxic agent and can rapidly kill malignant cells, the complications of tumor lysis syndrome may occur. Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken.

Hepatic Events: Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic events include increases in liver enzymes, hyperbilirubinemia, and hepatitis. Such changes may be reversible upon discontinuation of VELCADE. There is limited re-challenge information in these patients.

Hepatic Impairment: Bortezomib is metabolized by liver enzymes. Bortezomib exposure is increased in patients with moderate or severe hepatic impairment; these patients should be treated with VELCADE at reduced starting doses and closely monitored for toxicities.

Use in Pregnancy: Pregnancy Category D. Women of childbearing potential should avoid becoming pregnant while being treated with VELCADE. Bortezomib administered to rabbits during organogenesis at a dose approximately 0.5 times the clinical dose of 1.3 mg/m2 based on body surface area caused post-implantation loss and a decreased number of live fetuses.

ADVERSE EVENT DATA: Safety data from phase 2 and 3 studies of single-agent VELCADE (bortezomib) 1.3 mg/m2/dose administered intravenously twice weekly for 2 weeks followed by a 10-day rest period in 1163 patients with previously treated multiple myeloma (N=1008, not including the phase 3, VELCADE plus DOXIL® [doxorubicin HCI liposome injection] study) and previously treated mantle cell lymphoma (N=155) were integrated and tabulated. In these studies, the safety profile of VELCADE was similar in patients with multiple myeloma and mantle cell lymphoma.

In the integrated analysis, the most commonly reported adverse events were asthenic conditions (including fatigue, malaise, and weakness); (64%), nausea (55%), diarrhea (52%), constipation (41%), peripheral neuropathy NEC (including peripheral sensory neuropathy and peripheral neuropathy aggravated); (39%), thrombocytopenia and appetite decreased (including anorexia); (each 36%), pyrexia (34%), vomiting (33%), anemia (29%), edema (23%), headache, paresthesia and dysesthesia (each 22%), dyspnea (21%), cough and insomnia (each 20%), rash (18%), arthralgia (17%), neutropenia and dizziness (excluding vertigo); (each 17%), pain in limb and abdominal pain (each 15%), bone pain (14%), back pain and hypotension (each 13%), herpes zoster, nasopharyngitis, upper respiratory tract infection, myalgia and pneumonia (each 12%), muscle cramps (11%), and dehydration and anxiety (each 10%).

Twenty percent (20%) of patients experienced at least 1 episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (5%) and neutropenia (3%). A total of 50% of patients experienced serious adverse events (SAEs) during the studies. The most commonly reported SAEs included pneumonia (7%), pyrexia (6%), diarrhea (5%), vomiting (4%), and nausea, dehydration, dyspnea and thrombocytopenia (each 3%).

In the phase 3 VELCADE + melphalan and prednisone study in previously untreated multiple myeloma, the safety profile of VELCADE administered intravenously in combination with melphalan/prednisone is consistent with the known safety profiles of both VELCADE and melphalan/prednisone. The most commonly reported adverse events in this study (VELCADE+melphalan/prednisone vs melphalan/prednisone) were thrombocytopenia (52% vs 47%), neutropenia (49% vs 46%), nausea (48% vs 28%), peripheral neuropathy (47% vs 5%), diarrhea (46% vs 17%), anemia (43% vs 55%), constipation (37% vs 16%), neuralgia (36% vs 1%), leukopenia (33% vs 30%), vomiting (33% vs 16%), pyrexia (29% vs 19%), fatigue (29% vs 26%), lymphopenia (24% vs 17%), anorexia (23% vs 10%), asthenia (21% vs 18%), cough (21% vs 13%), insomnia (20% vs 13%), edema peripheral (20% vs 10%), rash (19% vs 7%), back pain (17% vs 18%), pneumonia (16% vs 11%), dizziness (16% vs 11%), dyspnea (15% vs 13%), headache (14% vs 10%), pain in extremity (14% vs 9%), abdominal pain (14% vs 7%), paresthesia (13% vs 4%), herpes zoster (13% vs 4%), bronchitis (13% vs 8%), hypokalemia (13% vs 7%), hypertension (13% vs 7%), abdominal pain upper (12% vs 9%), hypotension (12% vs 3%), dyspepsia (11% vs 7%), nasopharyngitis (11% vs 8%), bone pain (11% vs 10%), arthralgia (11% vs 15%) and pruritus (10% vs 5%).

In the phase 3 VELCADE subcutaneous vs. intravenous study in relapsed multiple myeloma, safety data were similar between the two treatment groups. The most commonly reported adverse events in this study were peripheral neuropathy NEC (38% vs 53%), anemia (36% vs 35%), thrombocytopenia (35% vs 36%), neutropenia (29% vs 27%), diarrhea (24% vs 36%), neuralgia (24% vs 23%), leukopenia (20% vs 22%), pyrexia (19% vs 16%), nausea (18% vs 19%), asthenia (16% vs 19%), weight decreased (15% vs 3%), constipation (14% vs 15%), back pain (14% vs 11%), fatigue (12% vs 20%), vomiting (12% vs 16%), insomnia (12% vs 11%), herpes zoster (11% vs 9%), decreased appetite (10% vs 9%), hypertension (10% vs 4%), dyspnea (7% vs 12%), pain in extremities (5% vs 11%), abdominal pain and headache (each 3% vs 11%), abdominal pain upper (2% vs 11%). The incidence of serious adverse events was similar for the subcutaneous treatment group (36%) and the intravenous treatment group (35%). The most commonly reported SAEs were pneumonia (6%) and pyrexia (3%) in the subcutaneous treatment group and pneumonia (7%), diarrhea (4%), peripheral sensory neuropathy (3%) and renal failure (3%) in the intravenous treatment group.

DRUG INTERACTIONS: Bortezomib is a substrate of cytochrome P450 enzyme 3A4, 2C19 and 1A2. Co-administration of ketoconazole, a strong CYP3A4 inhibitor, increased the exposure of bortezomib by 35% in 12 patients. Therefore, patients should be closely monitored when given bortezomib in combination with strong CYP3A4 inhibitors (e.g. ketoconazole, ritonavir). Co-administration of omeprazole, a strong inhibitor of CYP2C19, had no effect on the exposure of bortezomib in 17 patients. Co-administration of rifampin, a strong CYP3A4 inducer, is expected to decrease the exposure of bortezomib by at least 45%. Because the drug interaction study (n=6) was not designed to exert the maximum effect of rifampin on bortezomib PK, decreases greater than 45% may occur. Efficacy may be reduced when VELCADE is used in combination with strong CYP3A4 inducers; therefore, concomitant use of strong CYP3A4 inducers is not recommended in patients receiving VELCADE. St. John’s Wort (Hypericum perforatum) may decrease bortezomib exposure unpredictably and should be avoided. Co-administration of dexamethasone, a weak CYP3A4 inducer, had no effect on the exposure of bortezomib in 7 patients. Co-administration of melphalan-prednisone increased the exposure of bortezomib by 17% in 21 patients.

However, this increase is unlikely to be clinically relevant.

USE IN SPECIFIC POPULATIONS: Nursing Mothers: It is not known whether bortezomib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VELCADE, 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: The safety and effectiveness of VELCADE in children has not been established.

Geriatric Use: No overall differences in safety or effectiveness were observed between patients ≥age 65 and younger patients receiving VELCADE; but greater sensitivity of some older individuals cannot be ruled out.

Patients with Renal Impairment: The pharmacokinetics of VELCADE are not influenced by the degree of renal impairment. Therefore, dosing adjustments of VELCADE are not necessary for patients with renal insufficiency. Since dialysis may reduce VELCADE concentrations, VELCADE should be administered after the dialysis procedure. For information concerning dosing of melphalan in patients with renal impairment, see manufacturer’s prescribing information.

Patients with Hepatic Impairment: The exposure of bortezomib is increased in patients with moderate and severe hepatic impairment. Starting dose should be reduced in those patients.

Patients with Diabetes: During clinical trials, hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving VELCADE treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetic medication.

Please see full Prescribing Information for VELCADE at VELCADEHCP.com.

VELCADE, MILLENNIUM and are registered trademarks of Millennium Pharmaceuticals, Inc. Other trademarks are property of their respective owners.

Millennium Pharmaceuticals, Inc., Cambridge, MA 02139 Copyright © 2012, Millennium Pharmaceuticals, Inc. All rights reserved.

Printed in USA

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DRUG UTILIZATION TRENDS

Payer Drug and Molecular Testing Utilization Policies

By Charles Bankhead, Medical Writer

P

ayer trends in drug utilization and molecular testing have been the focus of several posters presented at the 2012 Educational Conference of the Academy of Managed Care Pharmacy, October 3-5, Cincinnati, OH.

No Consistency in Payer Policies for Targeted Drugs, Tests Payers have adopted a variety of policies for covering expensive targeted oncologic therapies and associated pharmacogenomics tests, according to a comparison of 4 large insurers—Aetna, Cigna, Humana, and UnitedHealthcare. A search for policies related to 27 drugs and 23 oncology-related pharmacogenomics tests showed little consistency among these payers, according to a poster presentation by Angela Luong, PharmD, of OptumInsight, Shakopee, MN, and colleagues. Drugs and genetic tests were covered by a mix of medical and pharmacy policies.

In only 2 cases did all 4 insurers have policies for the drug and its related genetic test: vemurafenib and crizotinib. The location of the policy—under the medical or the pharmacy benefit—differed among the companies.

The analysis revealed inconsistencies across benefits and payers. None of the payers had policies covering all of the drugs and related tests.

Pharmacogenomics tests offer a means to identify patients whose tumors harbor genetic mutations that increase the likelihood of response to treatment with a specific targeted therapy (so-called druggable mutations). Appropriate use of pharmacogenomics tests has the potential to minimize side effects and to increase drug efficacy, thereby reducing costs.

The US Food and Drug Administration now requires drug manufacturers to include pharmacogenomics information in the New Drug Application for every targeted therapy.

Using information available on each company’s website, Dr Luong and colleagues searched for coverage policies pertaining to 27 targeted oncologic therapies and 23 related pharmacogenomics tests, all approved since April 2011.

Of the 27 targeted drugs included in the study, the largest number of policies included in medical benefits

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for any of the 4 companies was 17, including 13 policies that required associated tests. The largest number of drug policies included under the pharmacy benefit was 15, of which 9 required a related pharmacogenomics test.

Regarding the 23 tests included in the study, the researchers found that the largest number under medical policies was 18, and the highest under pharmacy benefits was 6. The medical benefit had the largest number (ie, 11) of policies requiring pharmacogenomics test results for approval of the drug, whereas the requirement topped out at 6 among pharmacy plans.

Aside from variations in the 4 companies’ policies, the investigators found inconsistencies in the timing of policy development and in coordination across pharmacy and medical. They recommended further evaluation of policies and policy development to achieve more effective cost management and more appropriate use of pharmacogenomics tests to optimize targeted drug therapy. [Luong A, et al. Analysis of 4 large commercial payers’ policies regarding oncology drug-related pharmacogenomic (Pgx) tests.]

Policies to Manage Biologics Use Have Minimal Impact on Costs Implementation of a step therapy policy for the use of biologic agents had little if any impact on costs over a 5-year period, a review of 4 large health plans showed.

Of 5 biologics included in the study, costs decreased for 2 and increased for 3, resulting in a net cost increase of 10.3%. The findings suggest that policies designed to manage utilization of biologic therapies require careful assessment of the cost of implementing the policy versus the potential cost-savings, reported Mike Ingham, MSc, of Janssen Scientific Affairs, Horsham, PA, and colleagues in a poster.

Step therapy policies establish the order in which medications will be reimbursed, Mr Ingham and colleagues noted. A recent survey of health plans showed that almost 75% of the companies had policies related to step therapy for specialty products (www.specialtydrug benefitreport.com/executive-summary.html).

Noting that more payers are adopting policies affecting intravenous biologics, Mr Ingham and colleagues assessed utilization patterns from 2006 to mid-2011 for

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5 drugs used extensively in rheumatology, gastroenterology, and dermatology: abatacept, adalimumab, certolizumab, etanercept, and infliximab.

Beginning with 16 health plans, investigators reduced the number to 4 after exclusion of plans that did not have the data required for the analysis. Eligible patients had at least 1 pharmacy claim and at least 1 medical claim during the 12 months before and after implementation of the step therapy policy.

Data analysis included 252 patients (mean age, 51 years) who were predominantly (68.7%) female. One plan accounted for 40.1% of the patients, and the other plans contributed 15.5% to 23.4% of the study population.

More than 70% of the patients already had biologic therapy at the start of the observation period. Those patients were unlikely to be affected by a new step therapy policy, the investigators noted.

In the 12 months before the plans implemented the stepped-therapy policies, costs averaged $277,798 for abatacept; $972,968 for adalimumab; $6164 for certolizumab; $1,365,283 for etanercept; and $604,207 for infliximab. The total cost was $3,226,419.

A year after implementation of the policies, the 12month cost for abatacept decreased by 29% to $197,238; increased by 31.7% to $1,280,952 for adalimumab; increased by 534.2% to $39,092 for certolizumab; decreased by 20.5% to $1,085,200 for etanercept; and increased by 58.3% to $956,537 for infliximab. Overall, the cost for all 5 drugs increased by 10.3% from $3,226,419 to $3,559,019.

The investigators concluded that policies adopted to limit the use of infused biologic therapies and to reduce costs did not achieve the goals, at least in the nearterm. [Ingham MP, et al. Utilization patterns of biologics before and after implementation of a managed care step therapy policy.]

Costs of Specialty Drugs Continue to Rise at Fast Pace The cost of using specialty drugs to treat multiple sclerosis (MS) rose substantially from 2008 to 2010, accounting for much of the overall increase in medical and pharmacy costs associated with the condition, investigators reported.

The total per-person per-year (PPPY) cost of care for all patients with MS increased by approximately $7000, driven primarily by a $6000 increase in the PPPY pharmacy costs for MS specialty drugs. The proportion of total PPPY costs attributable to specialty drugs increased from 48.1% to 54.7%.

For the 70% of patients with MS who were treated only with specialty drugs, the PPPY total cost of care increased by almost $9000. Specialty drugs’ share of the

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total cost increased from 61.4% to 67.4% over the 3year period, according to a poster presented by Patrick P. Gleason, PharmD, and colleagues, of Prime Therapeutics, Eagan, MN. Wholesale acquisition costs (WACs) for individual MS specialty drugs increased at a compound annual growth rate (CAGR) of 10% to 22.6%. For some of the drugs, the WAC increased by ≥2-fold.

Specialty drugs, many originally developed for rare diseases, have been used with increased frequency in chronic diseases, such as MS. Specialty drug costs have risen faster than healthcare costs in general. A 2009 study showed the PPPY cost of treating MS with a specialty drug was $37,592, with pharmacy costs accounting for 56.8% of the total (Schafer JA, et al. J Manag Care Pharm. 2010;16:713-717). Another study showed that the cost of MS drugs for one large insurer increased by 15.2% from 2010 to 2011 (2011 Drug Trend Insights report. Prime Therapeutics, LLC. www.primetherapeutics. com/PDF/2011PrimeDrugTrendInsights.pdf; 2011 Prime Therapeutics, LLC, internal data).

To establish a complete accounting of MS cost of care, Dr Gleason and colleagues reviewed total medical and pharmacy costs for patients with MS within a single commercial health plan covering 1.2 million patients.

They searched the insurer’s integrated records for patients aged <65 years and who had ≥2 medical claims associated with an MS code.

The prevalence of MS was 1742 (0.17%) in 2008, which did not change significantly through 2010. Use of specialty drugs for patients with MS increased from 70.8% in 2008 to 71.8% in 2010. Glatiramer was the most frequently used specialty drug, accounting for 28% to 30% of the health plan’s members with MS. For all members with an MS diagnosis, the PPPY total cost increased from $29,751 to $36,901 over the 3-year period, resulting in a CAGR of 11.4%. Combined medical and pharmacy costs for MS specialty drugs increased from $14,311 to $20,200, representing a CAGR of 18.0%. Pharmacy costs for specialty drugs accounted for $13,745 of the PPPY for combined MS specialty drug costs in 2008 and $19,130 (94.7%) in 2010, which also translated into a CAGR of 18.0%.

An analysis limited only to the 70% of patients with MS treated with specialty drugs showed that the PPPY total cost increased from $32,883 in 2008 to $41,760 in 2010, representing a CAGR of 12.7%. The combined medical and pharmacy costs for MS specialty drugs accounted for $20,201 (61.4%) of the PPPY total cost of care in 2008, increasing to $28,152 (67.4%) of $41,760 in 2010, yielding a CAGR of 18.1%. [Starner CI, et al. Multiple sclerosis specialty drug utilizers cost of care trends 2008 to 2010: an integrated medical and pharmacy claims analysis.] ■

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Assessment of Treatment Patterns and Patient Outcomes in Levodopa-Induced Dyskinesias (ASTROID): A US Chart Review Study Barb Lennert, RN, BSN, MAOM; Wendy Bibeau, PhD; Eileen Farrelly, MPH; Patricia Sacco, MPH, RPh; Tessa Schoor, MD Background: No curative therapy is available for Parkinson’s disease; therefore, one of the main goals of treatment is to control motor symptoms, often via the use of levodopa (also known as L-dopa). However, prolonged levodopa treatment in Parkinson’s disease has been associated with the development of motor fluctuations and the occurrence of levodopainduced dyskinesias (LIDs).

Objective: To gain a clear, empirical understanding of the current real-world approach to treatment and patient outcomes associated with Parkinson’s disease and LIDs. Methods: This study used a mixed methodology, combining a cross-sectional survey of neurologists practicing in the United States, a retrospective chart review of patients with Parkinson’s disease and LIDs, and cross-sectional surveys of health-related quality of life (QOL) and physical functioning in patients with Parkinson’s disease. The surveys included the 39-item Parkinson’s Disease Questionnaire, the Unified Parkinson’s Disease Rating Scale, the Parkinson Disease Dyskinesia 26-item Scale, and the modified Abnormal Involuntary Movement Scale (mAIMS). Survey and chart data were collected between May 2010 and July 2011. Descriptive analyses were used to evaluate the distribution of study variables, treatment patterns, patient QOL, and patient physical functioning.

Results: Data from 7 neurologists and from 172 patients with Parkinson’s disease and LIDs were collected. Results from the physician survey indicate that prescribing patterns depend largely on the severity of LIDs, assessed via mAIMS. Most patients (88%) received pharmacologic therapy as first-line treatment for LIDs, with monotherapy favored in patients with mild LIDs and combination therapy in patients with moderate-to-severe LIDs. The mean time from the diagnosis of LID to the administration of first-line treatment for the condition was 10.7 months (standard deviation, 14.0 months). The study population reflects a mean time from levodopa initiation to the onset of LIDs of slightly more than 5 years, regardless of the levodopa dosage. Results from the chart review and the physician survey suggest a strong alignment in severity classification among the assessment scales used.

Conclusion: These findings indicate that the diagnosis and the treatment of Parkinson’s disease and LIDs are not optimal, because of the length of time from diagnosis to treatment, and because of the variability in treatment selection and response. Additional real-world studies are recommended to better understand treatment patterns, compliance with guidelines, and their potential impact on patient outcomes.

P

arkinson’s disease is a degenerative disorder that is characterized by muscle rigidity, tremors, and motor impairment that often results in progressive disability and severe complications that seriously affect a patient’s health-related quality of life (QOL)

Barb Lennert

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2012;5(6):347-358 www.AHDBonline.com Disclosures are at end of text

and physical functioning. The worldwide prevalence rates for Parkinson’s disease range from 0.5% to 1% among individuals aged 65 to 69 years, and from 1% to 3% among those aged ≥80 years.1 Parkinson’s disease often develops after age 60,2 and is the second-most

Ms Lennert is Senior Director, Process Improvement, Xcenda, LLC, Palm Harbor, FL; Dr Bibeau is former Health Economics & Outcomes Research Analyst, Xcenda, LLC, Palm Harbor, FL; Ms Farrelly is Associate Director of Data Analytics and Trends, Xcenda, LLC, Palm Harbor, FL; Ms Sacco is Director, Global Health Economics & Outcomes Research, Novartis Pharmaceuticals Corporation, East Hanover, NJ; and Dr Schoor is Chief Medical Officer, Medimix International, Miami, FL.

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KEY POINTS ➤

➤

➤

➤

➤

➤

Parkinson’s disease is the second-most common neurodegenerative disorder in the elderly population, and the prevalence is greatest in those aged ≥80 years.

Prolonged use of levodopa, the cornerstone treatment for Parkinson’s disease, is associated with painful and disabling dyskinesias, which limit the ability to optimize treatment and reduce the patient’s functional ability.

ASTROID is the first study to quantify real-world data of treatment patterns and patient outcomes associated with levodopa-induced dyskinesias (LIDs).

The prevalence of LIDs is underestimated; once established, LIDs are difficult to manage, and efforts should be focused on preventive measures rather than on reducing their severity.

Overall, 56% of dyskinesias occur when levodopa levels are highest, suggesting that dosages may often be too high.

Based on this study, the mean time from a LID diagnosis to treatment initiation exceeds 10 months, indicating a less-than-optimal approach to diagnosis and treatment of this condition.

common neurodegenerative disorder among the elderly population.1 Although no curative therapy is available for Parkinson’s disease, one of the main goals of treatment is to control the motor symptoms of the disease.3,4 Levodopa (also known as L-dopa), which is widely considered the cornerstone of treatment for Parkinson’s disease, is effective in reducing many symptoms associated with Parkinson’s disease during the early stages of the disease, thereby offering patients an acceptable QOL and a reasonable functional ability with regard to the activities of daily living (ADLs).3 However, levodopa has been associated with several side effects, and prolonged levodopa treatment in Parkinson’s disease has been associated over time with increased motor fluctuations and the development of levodopa-induced dyskinesias (LIDs).5 The effectiveness of levodopa treatment decreases with the progression of the disease, because of the persistent loss of nigrostriatal neurons (ie, dopaminecontaining neurons located in the substantia nigra in the brain). Typically, the first sign of this loss is the gradual return of Parkinson’s disease symptoms before the next dose of the medication is due, which is called “wearing off.” Wearing off generally necessitates increases in levodopa dosage and frequency.6 LIDs often present as chorea or choreoathetosis.

“Chorea” refers to abnormal, involuntary, nonrepetitive movements that are characterized by brief, irregular con-

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tractions that appear to flow from one muscle to the next. The severity of these movements can vary from occasional abnormal movements that are absent at rest and provoked only during active movement (eg, walking, talking) to violent, large-amplitude flinging and flailing arm movements (ie, ballismus). Often, twisting or writhing athetoid movements (ie, choreoathetosis) are added onto these movements.7 LIDs usually first appear on the side of the patient that is most affected by Parkinson’s disease, and generally present in the legs before the arms.7 Although dyskinesias may predominantly affect the legs and arms, they may spread to other body parts, such as the torso, head, and neck, or to the speech and respiratory muscles.7,8 The second-most common form of LIDs is dystonia, presenting as sustained muscle contractions. Dystonia can occur either alone or in combination with the chorea. When combined with chorea, the dystonia can manifest as twisting of the leg when walking or when the arm is being pulled behind the back. “On” and “off” phases are used to describe the presence of levodopa’s benefit. Off-time dystonias, which occur when levodopa plasma levels are low, are usually quite painful and account for greater disability than chorea.7 Based on the relationship between LIDs and levodopa dosing, LIDs are classified as peak-dose, diphasic, “off-state,” “on-state,” or “yo-yo” dyskinesias (Table 1).7,9 Because some dyskinesias represent a response to the concentration of levodopa, such effects may be eliminated or decreased by the reduction of the levodopa dose.

However, this dose reduction can be problematic when the reduced dose results in the recurrence of Parkinsonian symptoms. Because dyskinesia may recur with exposure to other dopamine agonists, the prevalence of LIDs may not be correctly diagnosed and, therefore, the rates of LIDs may be underestimated. The prevalence data for LIDs are limited.8 The incidence of LIDs appears to vary by the age at Parkinson’s disease onset, the duration and progression of the disease, the levodopa dosage, and the duration of levodopa treatment.10 Earlier studies have reported prevalence rates of LIDs between 30% and 80% in patients with Parkinson’s disease.11 Although the biologic mechanisms for the development of LIDs have not been established, it is clear that LIDs have a severe, negative impact on a patient’s QOL and physical functioning.11 Consensus is lacking among experts regarding the optimal scale or instrument to be used to measure dyskinesias accurately and reliably. Given the intermittent nature of dyskinesias, these events may not be present during a clinical evaluation by the physician. Some patients may have difficulty in remembering or accurately reporting dyskinesia symptoms, especially when the

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symptoms are mild and intermittent. The assessment of dyskinesia, therefore, remains largely subjective and often inaccurate. There is an underlying need for more objective, easy-to-use, validated scales that can be applied by patients and physicians to accurately evaluate and report dyskinesias; such scales will improve clinical evaluation and aid physicians in prescribing the proper treatment. The Movement Disorder Society was the first organization to conduct a comprehensive, systematic review of the psychometric properties of the scales used to measure dyskinesia in Parkinson’s disease, and this organization published its recommendations.12 Scales that have been recommended for clinician use in a population of patients with Parkinson’s disease include the Abnormal Involuntary Movement Scale (AIMS)5,13 and the Unified Parkinson’s Disease Rating Scale (UPDRS).5,12 Patient-rated scales include the 39item Parkinson’s Disease Questionnaire (PDQ-39)14,15 and the Parkinson Disease Dyskinesia 26-item Scale (PDYS-26)5 (Table 2).5,12-15 Once established, LIDs are difficult to manage, and therefore efforts should be made to prevent them.

Preventive and therapeutic measures for LIDs include a variety of pharmacologic strategies and/or neurosurgery; however, current medical therapies focus only on reducing the severity of dyskinesia.16 Ultimately, dyskinesias limit the ability to optimize the Parkinson’s disease treatment regimen and have a negative impact on the patient’s health-related QOL and functional ability with ADLs.16 An important unmet need for patients with Parkinson’s disease includes the prevention of LIDs, as well as the early identification of LIDs and effective management that does not further complicate underlying Parkinson’s disease management.

The purpose of the ASTROID (Assessment of Treatment Patterns and Patient Outcomes in Levodopa-Induced Dyskinesia) study was to provide an overview of current real-world treatment practices and patient-reported outcomes (PROs) for QOL and physical functioning in patients with Parkinson’s disease and LIDs, using 3 objectives—quantify the medication use and treatment patterns in LIDs management; characterize the current levels of health status, QOL, and physical functioning; and identify patient characteristics by LIDs severity.

Methods Study Design This mixed-methodology study design included a cross-sectional survey of neurologists practicing in the United States, a retrospective chart review of patients with Parkinson’s disease and LIDs from their respective neurologists, and a cross-sectional survey of these same

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Table 1 Types of Dyskinesias Type of dyskinesia

Characteristics

Peak-dose dyskinesias

• Most common forms of LIDs; earliest appearing • Related to peak plasma (and possibly high striatal) levels of levodopa • Involve the head, trunk, limbs, and sometimes respiratory or speech muscles • Dyskinesias are usually choreiform, although in the later stages, dystonia can superimpose

Diphasic dyskinesias

• Develop when plasma levodopa levels are rising or falling, but not with the peak levels • Also called D-I-D • Commonly dystonic in nature, although chorea or mixed pattern may occur • Do not respond to levodopa dose reduction and may improve with high dose of levodopa

“Off-state” dystonias

• Occur when plasma levodopa levels are low (eg, in the morning) • Usually pure dystonia occurring as painful spasms in 1 foot • Respond to levodopa therapy

“On-state” dystonias

• Occur during higher levels of levodopa

“Yo-yo” dyskinesias

• Completely unpredictable pattern

D-I-D indicates dyskinesia-improvement-dyskinesia; LIDs, levodopa-induced dyskinesias.

Sources: References 7 and 9.

patients’ health-related QOL and physical functioning.

Survey and chart data were collected between May 2010 and July 2011.

Physician and Patient Selection The physicians recruited for this study represent a convenience sample based on their ability to serve as principal investigators and on their willingness to complete the necessary questionnaires, recruit patients, obtain patients’ consent, complete the Institutional Review Board process, and supervise the conduct of the study in compliance with the protocol’s requirements.

A third-party vendor sent e-mail invitations to neurologists with whom the vendor had established a previous relationship and faxed invitations to physicians at Parkinson’s Disease and Movement Disorders Centers across the United States. The neurologists who expressed

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Table 2 Outcomes and Patient-Rated Instruments Instrument name

Purpose

Scale

Score rangea

Clinician-rated instruments mAIMS (modified Abnormal Involuntary Movement Scale)5,13

Assess the severity of abnormal movements in 6 different areas of the body

5-point scale, with ratings from 0-4 (absent, minimal, mild, moderate, severe), with higher scores indicating more severe abnormal movements

0-24: Mild = 0-12 Moderate = 13-18 Severe = 19+

UPDRS (Unified Parkinson’s Disease Rating Scale)5,12

Assess the severity of Parkinson’s disease symptoms using a 5-point scale with ratings from 0 (normal) to 4 (severe), with higher scores indicating greater disability from Parkinson’s disease

The UPDRS is made up of the following sections5,12: • Part I: Evaluation of mentation, behavior, and mood • Part II: Self-evaluation of ADLs • Part III: Clinician-scored motor evaluation • Part IV: Complications of therapy • Modified Hoehn and Yahr staging of severity of Parkinson’s disease • Schwab and England ADLs scale These are evaluated by interview and clinical observation Some sections require multiple grades assigned to each extremity

This study included only select questions from Part IV (Complications of therapy, questions 32 and 33)

PDYS-26 (Parkinson Disease Dyskinesia 26-item Scale)5

Quantify the impact of dyskinesia on ADLs during the past week

5-point scale, where 0 = not at all and 4 = activity impossible

0-104: Mild = 0-26 Moderate = 27-52 Severe = 53+

PDQ-39 (39-item Parkinson’s Disease Questionnaire)14,15

Measure health status, covering 8 aspects of quality of life

5-point scale, where 0 = never and 4 = always

0-156: Mild = 0-39 Moderate = 40-78 Severe = 79+

Patient-rated instruments

Mild, moderate, and severe ranges were determined by multiplying the number of questions by the score assigned to that severity (eg, in the PDYS-26, a moderate severity score = 2; therefore 2 * 26 = 52) to determine the maximum score for the moderate range.

ADLs indicates activities of daily living. a

initial interest received a follow-up telephone call to discuss the project in more detail and to verify their willingness and ability to fulfill all participation requirements as outlined above.

The physician practices that were selected for the study provided broad US geographic coverage and varied in size, ranging from single-physician to multiple-physician practices. The physicians selected patients for the study in accordance with the screening criteria and the patient’s willingness to participate in the study. All physicians completed the Institutional Review Board approval process, and the patients provided written informed consent per the study protocol and the Institutional Review Board requirements.

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Study Protocol The participating physicians completed a 13-item customized questionnaire that was developed by external experts and a study team with expertise in Parkinson’s disease and LIDs. The 13-item questionnaire included questions that asked physicians to (1) quantify medication use and treatment pathways; (2) characterize current levels of health status, QOL, and physical functioning, such as ADLs; (3) estimate the prevalence of LIDs among their patients with Parkinson’s disease; and (4) assess treatment timelines for patients with LIDs across various lines of therapy (ie, first, second, and third). The overall objective of this questionnaire was to provide a brief overview of physician-reported treatment practices and

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outcomes for patients with Parkinson’s disease and LIDs. The physician or study nurse at each center extracted patient data from charts; the data were de-identified and entered into an electronic data-collection tool. Questionnaires completed by the patients were sent to a thirdparty vendor for entry into the study database. All patient data were de-identified, and the patients’ responses were verified to be within the range of possible values.

The study eligibility criteria included the following requirements: patients had to be aged between 50 and 90 years, be treated with levodopa and have expressed LIDs, have the ability to comply with procedures for cognitive and other testing, provide full written informed consent before the performance of any protocol-specified procedure, and have a caregiver or family informant if they were unable to care for themselves. The study was conducted after the review and approval by the Goodwyn Institutional Review Board (Cincinnati, OH) of all study documents, patient consent forms, and investigators’ ability.

Variables of Interest To capture clinical outcomes of interest from the physicians’ perspective and the PROs of interest, several scales were used. A 33-item, multipart chart abstraction form included information on patients’ age, sex, comorbidities, Parkinson’s disease treatment history, LID severity and treatments, and drug interactions. A component of the physician-applied questionnaire asked the physicians to evaluate these patients with scales that included questions from Part IV of the UPDRS (Complications of Therapy, questions 32 and 33) and the modified Abnormal Involuntary Movement Scale (mAIMS).5,13 In addition, these same patients were asked to complete a survey that included PROs of interest using the PDYS-26 and the PDQ-39. Table 2 outlines the PROs and physician-reported scales used in this study.

To assess treatment patterns, the key data elements collected included medication dosage and frequency, treatment patterns (ie, first- and second-line treatment selection), the length of time between changes in therapy, and the time from a diagnosis of LIDs to first-line therapy initiation. Monotherapies were categorized as a dopamine agonist, a catechol-O-methyltransferase (COMT) inhibitor, a monoamine oxidase inhibitor, amantadine, or an atypical antipsychotic. Fixed combinations included carbidopa plus levodopa enteral infusion; carbidopa plus levodopa immediate-release; carbidopa plus levodopa controlled-release; and carbidopa with levodopa and entacapone.

Analytic Plan Descriptive analyses were used to evaluate the distri-

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bution of all variables of interest. When appropriate, survey questions were stratified by the severity of LIDs (ie, mild, moderate, or severe) based on the mAIMS. The assessment of treatment patterns to characterize changes in medications over time and correlations between medication administration and disease progression were recorded.

Results Physician-Reported Sample Characteristics The physician survey included 7 neurologists who provided real-world information on treatment patterns and clinical outcomes of interest in patients with Parkinson’s disease and LIDs. Each of the 7 physicians reported treating between 97 and 375 patients (mean, N = 189) with Parkinson’s disease, for a total of 1322 patients.

Overall, the physicians estimated that 62% of the patients were being treated with a form of levodopa. Of the patients being treated with levodopa, the physicians estimated that 27.6% demonstrated symptoms of LIDs; however, of the total of 1322 patients with Parkinson’s disease, these 7 physicians indicated that 856 (64.8%) patients had symptoms of LIDs based on the mAIMS, indicating an underestimation of the proportion of the population experiencing LIDs or the inclusion of choreas, but not dystonias, in these estimates. Based on the mAIMS, the physicians estimated symptom severity of LIDs as mild in 39% of patients, moderate in 38%, and severe in 23%. LIDs can be classified based on disease course and clinical phenomenology after a regular or an over-threshold dose of levodopa.11 Common categories are diphasic, off-state, and on-state (Table 1). The physician-reported occurrences of dyskinesia among patients included on-state dyskinesia in 56% of patients, diphasic dyskinesia in 26%, and off-state dyskinesia in 18%.

Physician-Reported Treatment and Prescribing Patterns Among the 7 surveyed physicians, the preferred therapeutic strategy in patients with Parkinson’s disease and LIDs was symptomatic treatment (N = 4; 57%), followed by restorative or neuroprotective treatment (N = 2; 29%), and other (“ideally, both”; N = 1; 14%). All 7 physicians reported that they considered increased disability associated with functioning as the most important disease aspect in assessing the progression of Parkinson’s disease.

Among this group, 6 physicians believed that the duration of treatment with levodopa was the most important risk factor implicated in the onset of LIDs in patients with Parkinson’s disease (1 physician indicated that “severity and duration” of Parkinson’s disease symptoms was the most influential risk factor).

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Table 3 Physician-Reported Prescribing Patterns, by LID Severity Physicians, N (N = 7)

Disease severity

Drugs, doses, and frequency

Mild LIDs, 32% (278 patients) Monotherapy (includes fixed-dose combination medications)

4

Dopamine agonists: Pramipexole (Mirapex)a 3 times daily (n = 2) Ropinirole (Requip)a 4 times daily (n = 2)

Combination therapy

1

No medication

1

Stated did not understand the question

No answer

1

NA

Monotherapy (includes fixed-dose combination medications)

2

Dopamine agonists: Pramipexole (Mirapex)a 3 times daily (n = 2)

Combination therapy

4

Cited medicationsb: Amantadine (Symmetrel) Generic amantadine Carbidopa/levodopa/entacapone (Stalevo 100) Entacapone (Comtan) Pramipexole (Mirapex) Rasagiline mesylate (Azilect) Ropinirole (Requip)

No medication

1

Stated did not understand the question

Monotherapy (includes fixed-dose combination medications)

1

Dopamine agonists: Pramipexole (Mirapex)a every day

Combination therapy

5

Cited medicationsb: Generic amantadine Carbidopa/levodopa (Sinemet) Carbidopa/levodopa/entacapone (Stalevo 100) Entacapone (Comtan) Pramipexole (Mirapex) Rasagiline mesylate (Azilect) Ropinirole (Requip)

No medication

1

Stated did not understand the question

Ropinirole 3 mg + carbidopa/levodopa/entacapone (Stalevo 100) 3 times daily

Moderate LIDs, 37% (316 patients)

Severe LIDs, 31% (262 patients)

No dose was provided.

Doses and frequencies varied by respondent; in other instances, no dose or frequency was selected. Therefore, dose and frequency are not listed.

LIDs indicates levodopa-induced dyskinesias; NA, not applicable.

a

b

The physicians were divided on their preferred strategy to minimize the duration of the “off” times in patients with motor fluctuations, as well as their preferred strategy to maximize the duration of the “on” times in these patients. Specifically, the most frequently selected answers to minimize off times and maximize on times

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were the use of a controlled-release form (N = 2) and the addition of a COMT inhibitor (N = 2).

Monotherapy was favored as the first-line treatment for mild LIDs, and combination therapy was more frequently used with disease progression. Table 3 outlines physician-reported prescribing patterns by LID severity.

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Table 4 Patient Characteristics, by LID Severity LID severity Mild, 39% (N = 67)

Moderate, 31% (N= 53)

Severe, 30% (N = 52)

Total, 100% (N = 172)

Male

33 (49)

23 (43)

23 (44)

79 (46)

Female

34 (51)

30 (57)

29 (56)

93 (54)

≤50 yrs

2 (3)

0 (0)

0 (0)

2 (1)

51-60 yrs

8 (12)

10 (19)

5 (10)

23 (13)

61-70 yrs

43 (64)

30 (57)

24 (46)

97 (56)

71-80 yrs

14 (21)

9 (17)

19 (37)

42 (24)

81-90 yrs

0 (0)

4 (8)

4 (8)

8 (5)

Mean time from Parkinson’s disease diagnosisa to levodopa initiation, yrs

0.9

1.7

1.7

1.4

Mean total initial daily dose of levodopa, mgb

250

216

255

241

Mean time from levodopa initiationc to LID onset, yrsb

4.8

4.8

6.4

5.3

PDQ-39 sum score, mean (SD)

43 (20)

75 (14)

92 (16)

82 (20)

mAIMS, mean (SD)

10 (10)

13 (6)

15 (6)

14 (6)

Characteristics Sex, N (%)

Age, N (%)

Mean date range of Parkinson’s disease diagnosis: 1998-2001.

Two patients were removed from the analysis of the mild LIDs and the overall analysis because total daily doses of levodopa were recorded in error as 1 mg daily. c Mean date range of levodopa initiation: 1999-2002.

LID indicates levodopa-induced dyskinesia; mAIMS, modified Abnormal Involuntary Movement Scale; PDQ-39, 39-item Parkinson’s Disease Questionnaire; SD, standard deviation. a

b

Of note, not all of the physicians answered each of the survey questions completely, rendering some responses not evaluable.

For mild LIDs, 5 of the 7 physicians indicated they would prescribe a medication for the management of mild LIDs, with 4 of these 5 indicating that they would choose monotherapy with a dopamine agonist, specifically, pramipexole (Mirapex) or ropinirole (Requip).

For moderate LIDs, 4 of the 7 physicians indicated that they would prescribe combination therapy from among several medications, including carbidopa plus levodopa and entacapone (Stalevo 100); entacapone (Comtan); pramipexole; rasagiline mesylate (Azilect); ropinirole; generic amantadine; or branded amantadine (Symmetrel).

In severe LIDs, 5 of the 7 physicians indicated that they

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would prescribe combination therapy from among several medications, including entacapone; carbidopa plus levodopa and entacapone; pramipexole; rasagiline mesylate; ropinirole; generic amantadine; or carbidopa plus levodopa (Sinemet).

Medical Chart Data Sample Characteristics Medical chart data were collected from 172 patients (79 male, 93 female; age range, 50-90 years, with approximately 80% falling into the range of 61-80 years) between May 2010 and July 2011. Table 4 presents baseline characteristics from the chart data. The mean lowest initial total daily dose of levodopa (216 mg) was administered in the population with moderate LIDs; the mean time to LID onset was 4.8 years in this subgroup. Overall,

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Figure 1 Timeline to Diagnosis of LIDs in Chart Review of 172 Patients with Parkinson’s Disease

Parkinson’s disease diagnosis

1.4 years (SD, 2.2 years)

Levodopa initiation

Onset of LIDs

5.4 years (SD, 4.2 years)

6.8 years (SD, 4.5 years)

LIDs indicates levodopa-induced dyskinesias; SD, standard deviation.

the sample reflects a mean time from levodopa initiation to LID onset of slightly more than 5 years and a mean daily dose of levodopa of 241 mg.

Physician- and Patient-Reported Outcomes of Interest In comparing total scores on the PDYS-26 with the mAIMS and PDQ-39, a strong alignment was seen in severity classification among these scales (eg, a patient who scored as “mild” on one scale was likely to score as “mild” on the other scales). The moderate and severe categories followed a similar pattern. Across all PDYS26 severity categories, the physicians reported that dyskinesia was present between 26% and 50% of the waking day, according to the UPDRS. Of note, the physicians reported that the dyskinesias were moderately disabling in the patients who scored as “mild” on the PDYS-26, but only mildly disabling in the moderate and severe groups, according to the UPDRS. Medical Chart Timeline of LID Diagnosis to Treatment Initiation, Progression Figure 1 presents the timeline of progression to LIDs. The mean time from the diagnosis of Parkinson’s disease to levodopa initiation was 1.4 years (standard deviation [SD], 2.2 years), and the mean time from levodopa initiation to the onset of LIDs was 5.4 years (SD, 4.2 years).

The total mean time from the diagnosis of Parkinson’s disease to the onset of LIDs was 6.8 years (SD, 4.5 years).

The mean time from the diagnosis of LIDs to initiation of first-line treatment for LIDs was 10.7 months (SD, 14.0 months).

Linear regression models were used to determine whether there was an association between the average levodopa dosage and the time to the onset of LIDs. Four regression models were used —1 overall model that included all severity levels of LIDs and 3 models strati-

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fied by LID severity (ie, mild, moderate, and severe).

Figure 2 displays results for the overall model, indicating that the relationship between the dosage and the time to the onset of LIDs is not significant (P = .548).

The results for each model that was stratified by LIDs severity also indicate that the relationship between the dosage and the time to LID onset is not statistically significant (Figure 2).

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Medical Chart Results for LID Treatment Nearly all (84.3%) patients with LIDs were treated pharmacologically across first, second, and third lines of treatment, and 10.5% of patients with LID were treated with surgical intervention only. The first-line LID treatment selection was most influenced by the type of control and effects, particularly the ability to control worsening motor symptoms and ensure more stable levodopa plasma levels. Of 172 patients, 151 (approximately 88%) received pharmacologic therapy as first-line treatment for LIDs, with 17% receiving monotherapy; nearly 50% of the monotherapy consisted of dopamine agonists, and approximately 33% consisted of fixed-dose combination drugs. (Based on the study protocol, fixed-dose combinations were considered “monotherapy.”) In addition, 121 patients (approximately 70%) received combination therapy, with 49 of the 121 (approximately 40%) receiving ropinirole and rasagiline mesylate and a branded, or generic, carbidopa plus levodopa combination (25/100mg dose). Of the approximately 11% of patients who received surgical intervention, 17 of 18 were categorized as having severe LIDs. For the 27 patients (16%) who required a second-line treatment, a lack of efficacy was the most frequently cited (74%) reason for the change in treatment. Of these 27 patients, 21 (78%) received pharmacologic treatment, and 33% of these patients had another medication added. Nineteen percent received surgical intervention (4 of the 5 were classified as severe LIDs). Of the 27 patients, 9 (33%) progressed from a lesser severity category of LIDs by the time the second-line therapy started.

Of the patients requiring second-line treatment, 6 (22%) also required a third-line treatment. A lack of efficacy was the reason cited for the change in treatment in all cases, 100% of whom received pharmacologic therapy. Figure 3 presents the timeline of disease progression for Parkinson’s disease diagnosis through third-line treatment for LIDs. Discussion The purpose of the ASTROID study was to provide an overview of current real-world treatment practices and PROs for health-related QOL and physical functioning in patients with Parkinson’s disease and LIDs.

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Figure 2 Scatterplots of the Relationship between Levodopa Dose and LID Onset Milda

Overalla

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Two patients were removed from the “mild” and the “overall” analyses because total daily doses of levodopa were recorded in error as 1 mg daily.

LID indicates levodopa-induced dyskinesia.

One of the main objectives was to quantify the medication use and treatment patterns in the management of LIDs. Results from the physician survey indicated that monotherapy was the preferred treatment for mild LIDs and that combination therapy was preferred for moderate and severe cases. However, there was no preferred strategy among physicians to minimize the duration of the off times or to maximize the duration of the on times in patients with motor fluctuations.

That the physicians reported the proportion of dyskinesias in the on-state phase to be 56% suggests that levodopa dosages are too high and require dose reduction to minimize dyskinesias. This may indicate a need for physician education regarding appropriate levodopa dosing. Alternatively, it may also indicate the need for patient and caregiver education about not self-medicating at a higher-than-prescribed dose to avoid complications of therapy.

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In this study, patients with Parkinson’s disease expressing symptoms of LIDs were prescribed a mean daily levodopa dose of only 241 mg. This dose is considerably lower than the dose used in the population in the DATATOP study, in which the average daily levodopa dose of 387 mg was found to produce symptoms of LIDs,17 raising a question about what levodopa dose patients are actually consuming.

The physician survey reports that the duration of levodopa treatment was selected as the most influential risk factor for the development of LIDs. The chart review findings were consistent with this result, demonstrating the onset of LIDs at approximately 5 years, regardless of dose and across all LID severity categories.

Based on these findings, the implementation of screening for LIDs at regular intervals after the initiation of levodopa treatment would seem to be a logical approach to proactively identify and treat patients with

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Figure 3 Timeline of Disease Progression: Parkinson’s Disease Diagnosis Through Third-Line Treatment for LIDs

Parkinson’s disease diagnosis

➡

Levodopa initiation

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First-line LID treatment

• 6.3 years • SD = 4.5 years

• 1.4 years • SD = 2.2 years

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• 1.8 years • SD = 1.7 years

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Third-line LID treatment

• 1.2 years • SD = 1.0 years

LIDs indicates levodopa-induced dyskinesias; SD, standard deviation.

LIDs. Of note, however, the mean time from the diagnosis of LIDs to first-line treatment for these events was 10.7 months (SD, 14.0 months), suggesting that there is a need to raise awareness of the importance of regular and early LID screening.

Treatment guidelines from the American Academy of Neurology recommend using entacapone and rasagiline to reduce off time (Level A evidence), and Level B evidence supports the use of pergolide, pramipexole, ropinirole, and tolcapone to reduce off time.18 However, none of the medications on the Level A evidence list of recommended drugs was named by the participating physicians as those used to treat patients with mild LIDs, although some of the medications listed by these physicians were supported by Level B evidence.18 This result may be driven by the cost of the medications, patients’ insurance coverage, insurance company pharmacy management strategies, or patient or prescriber preferences.

Further study of the reasons for such deviations from the guidelines is warranted.

A key objective of this study was to characterize the current levels of health status, QOL, and physical functioning, such as ADLs, in patients with Parkinson’s disease and LIDs. A key objective of this study was to characterize the current levels of health status, QOL, and physical functioning, such as ADLs, in patients with Parkinson’s disease and LIDs. Results from the chart review and physician survey suggest that there was a strong alignment in severity classification among the PRO scales used (ie, a patient who scored as “mild” on one scale was likely to score as “mild” on the other scales); however, there were some variations. For example, the physicians reported that the dyskinesias were moderately disabling in the patients who scored as “mild” on the PDYS-26, but only

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mildly disabling in the patients who scored as “moderate” or “severe” on the PDYS-26. Considering the wide variability of the disease state and the subjective nature of the assessment tools used, it is not surprising that the scales were not exactly aligned.

Another objective of the study was to identify patient characteristics and treatment selection by the severity of LIDs. The surveyed physicians estimated that the prevalence of LIDs in their practices was 28%; the true rate based on the mAIMS was 65%, indicating either an underestimation of the magnitude of the population with LIDs or estimates that did not take dystonias into account but rather were based on on-state choreas only.

The physicians also underestimated the severity of LIDs in their patient populations, estimating that 23% of them had severe LIDs versus an actual rate of 31% based on the chart data. For first-line treatment for LIDs, 88% of patients received pharmacologic therapy, and most (70%) of them received combination therapy. Of the patients who received surgical treatment, 94% were categorized as having severe LIDs. A consideration for physicians will be to have patients complete a validated questionnaire or scale that measures their QOL and functional ability as part of the routine visit. Assessment at regular visits can provide the physician with a longitudinal record of patient response to treatment.

To our knowledge, this is the first study to analyze current real-world treatment practices and outcomes for patients with Parkinson’s disease and LIDs. In addition, we used a mixed-methodology approach to assess how patients’ QOL, health status, and physical functioning were affected by the severity of LIDs. The concordant results from the patient-reported QOL and ADL scales and the clinician-assessed scales support the use of these instruments in a population of patients with Parkinson’s disease and LIDs. Although the sample of 7 physicians is small, these physicians reported practice patterns based on their entire population of patients with Parkinson’s disease

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(N = 1322) in addition to chart review data for 172 patients, making the results more robust. These 7 physicians use different approaches to minimize LIDs, and not all of the medications they prescribe are on the list of recommended medications from the American Academy of Neurology treatment guidelines. Perhaps these findings represent a need to improve compliance with recommended guidelines to optimize patient outcomes.

Limitations Because of the retrospective, observational nature of this study, a true causal link cannot be made between any of the variables of interest and the outcomes, and study designs such as these are predisposed to selection bias.

Self-reported surveys are subject to recall bias and may not accurately reflect characteristics of the general population. In addition, not all patients were required to have a minimum number of years of data available in their record for inclusion in the study. As such, the results might have been influenced by the length of time a patient was associated with a provider.

Furthermore, not all physicians had the same number of patients, and some of the results may possibly be overor underrepresented by a group of patients from a particular practice.

Finally, we surveyed a sample of US neurologists; therefore, we recognize that the results may not be generalizable to healthcare systems outside of the United States.

Conclusion Our findings indicate that the diagnosis and the treatment of Parkinson’s disease and LIDs are not optimal because of the length of time from diagnosis to treatment and the variability in treatment selection and response. Increased awareness and education for physicians to screen for LIDs and initiate treatment sooner are needed. Additional real-world studies are recommended to better understand the treatment patterns, patient adherence, compliance with guidelines, and impact on patient outcomes. ■ Acknowledgment The authors would like to acknowledge Amit M. Shelat, DO, MPA, FACP, Attending Neurologist, Diplomate, American Board of Psychiatry & Neurology, for his assistance in editing this manuscript.

Study Funding This study was funded by Novartis Pharmaceuticals Corporation.

Author Disclosure Statement Ms Lennert and Ms Farrelly are employees of Xcenda, a consulting company that received funding from Novartis for this study; Dr Bibeau was an employee of Xcenda at the time of the study analysis and during preparation of the manuscript; Ms Sacco is a shareholder of Novartis; and Dr Schoor is an employee of Medimix International, a research company that received funding from Novartis for this study.

References 1. Nussbaum RL, Ellis CE. Alzheimer’s disease and Parkinson’s disease. N Engl J Med. 2003;348:1356-1364.

2. Van Den Eeden SK, Tanner CM, Bernstein AL, et al. Incidence of Parkinson’s disease: variation by age, gender, and race/ethnicity. Am J Epidemiol. 2003;157:1015-1022.

3. Parkinson’s disease: hope through research. National Institute of Neurological Disorders website. www.ninds.nih.gov/disorders/parkinsons_disease/detail_parkinsons_ disease.htm. Accessed February 7, 2012.

4. Puente V, De Fabregues O, Oliveras C, et al. Eighteen-month study of continuous intraduodenal levodopa infusion in patients with advanced Parkinson’s disease: impact on control of fluctuations and quality of life. Parkinsonism Relat Disord. 2010; 16:218-221.

5. Colosimo C, Martínez-Martín P, Fabbrini G, et al. Task force report on scales to assess dyskinesia in Parkinson’s disease: critique and recommendations. Mov Disord.

2010;25:1131-1142.

6. Aviles-Olmos I, Martinez-Fernandez R, Foltynie T. L-dopa-induced dyskinesias in Parkinson’s disease. Euro Neurolog J. 2010;2:91-100.

7. Thanvi B, Lo N, Robinson T. Levodopa induced dyskinesia in Parkinson’s disease: clinical features, pathogenesis, prevention and treatment. Postgrad Med J. 2007;83: 384-388.

8. Schrag A, Quinn N. Dyskinesias and motor fluctuations in Parkinson’s disease: a community-based study. Brain. 2000;123:2297-2305.

9. Fahn S. The spectrum of levodopa-induced dyskinesias. Ann Neurol. 2000;47:S2S9, S9-S11.

10. Berg D, Godau J, Trenkwalder C, et al. AFQ056 treatment of levodopa-induced dyskinesias: results of 2 randomized controlled trials. Mov Disord. 2011;26:1243-1250.

11. Fabbrini G, Brotchie JM, Grandas F, et al. Levodopa-induced dyskinesias. Mov Disord. 2007;22:1379-1389.

12. Movement Disorder Society Task Force on Rating Scales for Parkinson’s Disease.

The Unified Parkinson’s Disease Rating Scale (UPDRS): status and recommendations. Mov Disord. 2003;18:738-750.

13. Abnormal Involuntary Movement Scale (117-AIMS). In: Guy W, ed. ECDEU Assessment Manual for Psychopharmacology. Rockville, MD: US Department of Health, Education, and Welfare; 1976:534-537. DHEW publication (ADM) 76-338.

14. Martínez-Martín P, Jeukens-Visser M, Lyons KE, et al. Health-related quality-oflife scales in Parkinson’s disease: critique and recommendations. Mov Disord. 2011; 26:2371-2380.

15. Hagell P, Nygren C. The 39-item Parkinson’s disease questionnaire (PDQ-39) revisited: implications for evidence-based medicine. J Neurol Neurosurg Psychiatr.

2007;78:1191-1198.

16. Gottwald MD, Aminoff MJ. Therapies for dopaminergic-induced dyskinesias in Parkinson disease. Ann Neurol. 2011;69:919-927.

17. Parkinson Study Group. Impact of deprenyl and tocopherol treatment on Parkinson’s disease in DATATOP patients requiring levodopa. Ann Neurol. 1996;39:37-45.

18. Pahwa R, Factor SA, Lyons KE, et al. Practice parameter: treatment of Parkinson disease with motor fluctuations and dyskinesia (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology.

Neurology. 2006;66:983-995.

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STAKEHOLDER PERSPECTIVE Parkinson’s Disease: A Complicated but Underappreciated and Undertreated Condition According to the Parkinson’s Disease Foundation, as many as 1 million Americans live with Parkinson’s disease, which is more than the combined number of people diagnosed with multiple sclerosis, muscular dystrophy, and Lou Gehrig’s disease. Moreover, approximately 60,000 Americans are diagnosed with Parkinson’s disease annually, and this number does not reflect the many thousands of cases that go undetected.1 MEDICAL/PHARMACY DIRECTORS: Yet despite these statistics, Parkinson’s disease currently does not get significant attention by health insurance plans, largely because of the relatively lower cost of the therapeutic interventions compared with other diseases, such as multiple sclerosis or rheumatoid arthritis.

One of the mainstays of therapy for Parkinson’s disease is levodopa, which can control the motor symptoms of the disease. However, treatment with levodopa can produce significant dyskinesias, which considerably increase the complexity of treatment.

In this issue of American Health & Drug Benefits, Ms Lennert and her colleagues present the findings from a real-world study designed to provide an overview of current real-world treatment practices and patientreported outcomes for health-related quality of life and physical functioning in patients with Parkinson’s disease and levodopa-induced dyskinesias (LIDs). Not surprisingly, the authors found that, “The diagnosis and the treatment of Parkinson’s disease and LIDs are not optimal, because of the length of time from diagnosis to treatment and the variability in treatment selection and response.”

As with many other diseases, we often find that the variability of treatment in this condition is significant, and that delays in diagnosis are common; even when LIDs are diagnosed, treatment is often suboptimal. As those of us in healthcare management often have

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learned, this variability is responsible for poor patient outcomes and inefficient use of medical financial resources.

The authors appropriately call for increased awareness and education. Yet such steps alone will not be likely to solve the problem. In the current medical system, physicians are faced with an increasingly complex array of diagnostic and therapeutic challenges.

Evidence-based guidelines can help, but guidelines are often out of date, lack adequate evidence for the therapeutic choices, and are often too complex. In a new article published in the British Medical Journal earlier this month, the author notes “that unnecessary treatment in America accounts for 10 percent to 30 percent of healthcare spending, or up to $800 billion a year.”2 Simply put, the system in the United States can no longer afford such waste and inefficiencies.

What Ms Lennert and her colleagues have found in this study is not isolated to a single disease state.

Similar findings are common when we measure outcomes and variations in patient care. The authors of the present article are to be commended for their study, for it is from such data that we ultimately come to the realization that major overhauls in the system are necessary. The solution is certainly beyond the scope of this brief perspective, but such work as this article continues to demand a call to action to reform the current medical care system in the United States.

1. Parkinson’s Disease Foundation. Statistics on Parkinson’s. www.pdf.org/en/ parkinson_statistics. Accessed October 12, 2012.

2. Lenzer J. Unnecessary care: are doctors in denial and is profit driven healthcare to blame? BMJ. 2012 Oct 2. [Epub ahead of print.]

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

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Cost Management through Care Management, Part 2: The Importance of Managing Specialty Drug Utilization in the Medical Benefit Michael T. Einodshofer, RPh, MBA, and Lars N. Duren, BCNSP, PharmD Mr Einodshofer is Director of Utilization Management, Walgreens Specialty Pharmacy, and Dr Duren is Vice President of Infusion Solutions, Walgreens Infusion Services

I

n our previous article, we outlined the importance of choosing a specialty pharmacy that is able to implement clinical and utilization management programs to maximize patient outcomes and minimize the waste associated with specialty pharmaceuticals.1 Those crucial capabilities prevent unnecessary plan expenditures on specialty medications. Each specialty medication covered by a payer is a substantial investment in a patient’s healthcare, often costing $20,000 to $200,000 or more annually. Clinical programs help to ensure that investment lessens the patient’s disease burden to the fullest extent possible. Utilization management programs ensure the best clinical outcome at the lowest possible cost to treat. The best specialty pharmacies provide competitive unit pricing for drugs, as well as clinical and utilization management programs to their clients.

The primary focus of the previous article was on medications that are typically self-administered by patients and that usually fall under the pharmacy benefit.1 However, approximately 50% of the specialty drug expense is under the medical benefit.2 These medications, which are normally infused, are administered by a healthcare provider in various sites of service, most often in the physician’s office, in the hospital outpatient department, and in the patient’s home (Figure 1, page 360). For medical claims, usually the drug and the professional fees related to the drug administration are billed directly to the medical carrier.

The most common specialty drugs covered under the medical benefit (Figure 2, page 360) include chemotherapeutic agents (eg, bevacizumab and rituximab) and nonchemotherapeutic agents (eg, infliximab, natalizumab, and immunoglobulin). Chemotherapy support agents (eg, pegfilgrastim, darbepoetin, and epoetin) also represent a significant amount of medically covered specialty pharmacy utilizations. These products are expensive, with some infusions costing more than $200,000 annually.

Unlike most self-administered specialty drugs that are dispensed by specialty pharmacies, drugs covered under

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the medical benefit are billed directly to the health plan, usually via a CMS 1500 or UB-04 claim form. These claims typically do not undergo the same real-time processing as do pharmacy claims, they can be obscured by “bundle billing” (where multiple services are reimbursed under 1 code), and they are often billed to a payer after the procedure or infusion has occurred. These claims usually are not consolidated with a patient’s pharmacy claims; therefore, they often limit a payer’s visibility into cost and utilization trends. In addition, depending on the site of administration, and often on the specialty of the physician administering the drug, the cost for a drug covered by the medical benefit can vary widely.

The result is that specialty drugs that are covered under the medical benefit have significant variance in cost, tend to be more difficult to analyze, and do not have the same degree of structured clinical and utilization management programs as their pharmacy-adjudicated counterparts. These dynamics present challenges to the effective management of specialty pharmaceuticals in the medical benefit.

How can payers ensure that medically billed drugs receive the necessary cost, clinical, and utilization management safeguards for these complex long-term therapies? This article outlines key areas within the medical benefit that payers can impact, and the steps they can take to address these opportunities.

Medical Benefit Drug Management Pharmacy benefit managers (PBMs), such as Express Scripts and CVS Caremark, realize that half of the specialty drug utilization is reimbursed outside of their traditional business models. In response, many PBMs are creating medical benefit management (MBM) programs to help clients understand and manage these drugs. NonPBM organizations, such as Walgreens, along with various consulting groups, are also developing MBM programs.

The spectrum of MBM is very broad, because vendors have developed their programs based on their own interpretations of the medical/specialty opportunity and on

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Figure 1 Distribution of Costs for Medically Billed Drugs, by Place of Service Home infusion 10%

Physician office 41%

Outpatient hospital 49%

Source: These data are based on client claims from 3 commercial health plans representing 2,436,727 covered lives between January 1, 2011, and December 31, 2011.

Figure 2 Medical Benefit Costs, by Service Type Unlisted drug 1% Neupogen/ ESA/5-HT3 11% Drug administration 12% Nonchemotherapy 41% Chemotherapy 35%

offices to obtain specialty drugs infused in the office from a specialty pharmacy. Other MBM programs offer to manage a health plan’s infusible fee schedule in an attempt to standardize the cost of a drug throughout the plan’s network and/or recommending a medical drug formulary.

Therefore, MBM means various things to different groups, depending on their area of focus and expertise.

This article presents a broad perspective of MBM, with suggestions on key areas where payers should focus their initial efforts to manage drug-related costs within the medical benefit.

PBMs are experts on how pharmacy claims are transacted. Health plans are experts on how medical services are delivered and transacted. These transactions today are isolated into 2 discreet worlds. Although pharmacy data enjoy National Council for Prescription Drug Programs standards, which allows PBMs to build structured claims databases on consistent standards, medical data standards tend to be less consistent. Standards are established on claim forms such as the CMS 1500 (which is used for professionally billed claims, eg, for physician offices) and the UB-04 (which is used for institutionally billed claims, such as for outpatient hospitals), but each plan may require different information on the forms. In addition, the way health plans and data aggregators capture and store the claims information is inconsistent throughout the industry.

To effectively discuss MBM strategies, a thorough understanding of medical claims data is imperative. In our experience, even sophisticated health plans do not have the same level of understanding and reporting capabilities of medically covered specialty drugs that they have of drugs covered through pharmacy-transacted (ie, PBM) claims. Self-insured employers tend to not have access to accurate or thorough medical data through their data aggregator vendors.

ESA indicates erythropoietin-stimulating agent.

Source: These data are based on client claims from 3 commercial health plans representing 2,436,727 covered lives between January 1, 2011, and December 31, 2011. their ability to effectively build a business in this space.

Some MBM programs are focusing on the management of chemotherapy regimens and are lowering the cost of chemotherapy by requiring practicing oncologists and hematologists to follow structured clinical prescribing guidelines, which are known as “oncology pathways.” For example, CVS Caremark has stated that a 15% savings on chemotherapy costs can be achieved through its version of oncology pathways.3 Other programs are focusing on affecting the distribution channels of specialty drugs, by requiring physician

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Why Not Just Mandate Every Drug Claim Be Covered Exclusively Under the Pharmacy Benefit?

Because medical and pharmacy claims are billed through 2 different systems, some argue that the best solution is to deny medical claims for infusions and to require that the claims be filled under the pharmacy benefit, because it simplifies how the claims are transacted. This solution, however, introduces significant benefit design complexity and changes the underlying pricing dynamic of the claim, both of which must be fully evaluated before adopting such a strategy. Plans with a “carved-out” pharmacy benefit face additional challenges. Significant due diligence is required before proceeding with this approach.

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Therefore, when investigating ways to manage medically covered specialty drugs, an employer or a health plan often has to engage a consultant with expertise in analyzing medical data. The consultant should be able to readily produce sample reporting, standard data layouts, and client testimonials that show the ability to discover and understand medical data. This is needed to ensure that all opportunities are uncovered, and to successfully report on the effectiveness of any MBM program, once installed.

You’ve Collected Accurate Data—Now What?

At Walgreens, we see 4 distinct areas of opportunity to managing medical specialty trend. We believe that an effective MBM program should address all of these 4 areas: • Site-of-care (SOC) optimization • Physician office specialty drug distribution • Clinical and formulary management • Fee schedule management.

Employer Challenges with Medical Data: An (Almost) Missed Opportunity A large employer approached us to assist in managing infused specialty drugs. The client was concerned about overpaying for chronic complex therapies (eg, infliximab) that were being administered at the outpatient hospital setting. The first step of the analysis, of course, was to review its medical claims data to determine utilization patterns and the degree to which utilization was occurring in the outpatient hospital. To collect the data, the employer received a data extract directly from its medical carrier, according to detailed specifications provided by Walgreens.

Initially, the health plan data appeared acceptable.

The requested fields were returned, and the integrity of the data seemed sufficient. For example, each claim’s allowable amount was populated with the appropriate dollar values and diagnosis fields, and the provider fields were appropriately completed. On further inspection, however, we realized that the expected medical specialty per-member per-year cost was materially below our benchmarks. It was evident that claims from the outpatient hospital were substantially understated.

On isolating the issue, we asked the plan to re-run the data to include the suspected missing outpatient hospital claims. The health plan supplied a corrected file, which contained the exact same data as the first data set. Further discussion helped to convince the health plan that yet another data extract was necessary.

After several more attempts of unsuccessfully providing the outpatient hospital claims, the health plan concluded that the employer simply does not have much utilization occurring in the outpatient hospital.

At one point, the health plan stated, “We’ve pulled every J code claim for this client, without any filters. I assure you that you have everything that we have.”

Armed with the knowledge that nationally approximately 20% to 60% of medical specialty utilization occurs in the hospital outpatient department, and the fact that this client’s utilization was well below our

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minimum expectation, we remained skeptical that we truly had a full data set. At that point, we recommended a 3-way call with Walgreens, the employer, and the health plan.

The health plan began the call affirming that it included all of the employer’s medical claims to Walgreens. Walgreens then posed a question to the employer, “Do you have any benefit design restrictions that would prevent your employees from receiving infusions within an outpatient hospital setting?” The human resources representative for the employer immediately responded that a relative of his (who is also an employee of the company) receives infusion therapy at the local hospital. This patient was not represented in any of the data files produced by the payer.

Needless to say, this caused the health plan to reconsider its position. A couple of weeks later, the health plan provided yet another data extract to Walgreens, but this time with outpatient hospital claims included.

Based on these new data, Walgreens demonstrated that 65% of the employer’s medical specialty drugs were covered in the outpatient hospital, and that the employer could cut its infusion costs for nonchemotherapy specialty infusions by 57%; this was almost a missed opportunity, because of the payer’s difficulty of producing an accurate utilization file.

The employer is currently implementing an SOC optimization program to transition patients from the outpatient setting to a more convenient and lowercost SOC. The significance of this story is 2-fold. First, without fully understanding what specific data to request, and what the data should look like, the opportunity for the employer never would have materialized. Second, once the appropriate data were received, the SOC strategy could be put into action, thereby allowing expanded and convenient access for patients and a substantial cost-reduction for the employer.

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Table Cost Variance for Infusions at an ATS versus at a Hospital

Code

Drug

J1745 Infliximab injection J2323 Natalizumab injection

ATS rate, $

Outpatient Per-unit hospital rate, difference, $ %

63.4/unit

129.04/unit

3134/claim

5790/claim

8.35/unit

13.30/unit

2424/claim

3748/claim

103.27

59.35

Note: average claim cost is dependent on the cost per unit and the units billed.

ATS indicates alternate treatment site.

Source: These data are based on Walgreens’ internal analysis of 5,371,227 commercial managed care lives between January 2008 and December 2010.

Site-of-Care Optimization: Same Drug, Dose, and Prescriber, but Double the Cost?

Would you pay $50,000 for a car from one dealer that you could buy from a different dealer for $25,000? Would you pay $2000 for an economy seat on an airline when you could pay $1000 to fly first class?

As ridiculous as those questions appear, a parallel exists today in our healthcare delivery system. The cost of an infused drug could vary by more than 100%, depending on where patients go to receive their infusions. Considering that the average specialty infusion costs between $20,000 and $200,000 annually, doubling the cost to between $40,000 and $400,000 has a dramatic impact on the affordability and sustainability of continued access to these medications for payers and for patients.

SOC optimization programs are built around this variance in cost, allowing employers and health plans to direct patients to lower-cost SOCs. In most instances, patients are utilizing high-cost facilities, because they (and their physicians) are not aware of other options, or because the physician is incentivized to refer the patient to the hospital through some means, often because the physician is employed by the hospital.

Our current healthcare system is complex, and most patients seek infusion services wherever their physicians recommend, not realizing that drug costs are 110% higher at outpatient facilities compared with alternate treatment sites (ATSs), such as at-home infusion, infusion suites, and at physicians’ offices.4 The Table illustrates cost variance for 2 of the common nonchemotherapeutic specialty infusions at a hospital outpatient department versus an ATS. Who can apply SOC strategies? The SOC strategy can be utilized by any entity that is responsible for paying a medical claim for infusion, including commercial

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health plans, government payers, self-insured employers, at-risk health systems, and at-risk independent practice associations. The size, location, and geographic layout of membership does not matter, as long as the partner or provider who is selected has the geographic coverage of services to match and has access to trained infusion nurses with specialty drug infusion expertise. As noted below, a major factor that determines the success of such an initiative is alignment of incentives through appropriate benefit design and shared-savings programs.

ASOCs and ATSs. The terms “alternate site of care” (ASOC) and “alternate treatment site” can be used interchangeably. ATSs or ASOCs are infusion sites outside of the traditional hospital (inpatient or outpatient) and skilled nursing facility settings. An ATS can be a patient’s home, a physician’s office, or an infusion suite.

The use of ATSs typically results in significant costsavings for payers and for patients, and in an overall increased experience for the patients. Patients can receive acute and chronic infused medications in the ATS, and infusion suites are being built throughout the country, in locations such as within an infusion pharmacy, within a retail pharmacy, at an employer site, within a medical clinic, or as a stand-alone dedicated site. In addition, to meet payer needs and the acuity level of patients, these sites are now being staffed by registered nurses or by nurse practitioners. Services are focused on providing infusion therapy, but they also include other medical procedures, such as laboratory draws, injection training, simple wound care, and catheter care maintenance.

Keys to success. A critical component to the success of SOC optimization is ensuring appropriate benefit design at the payer level. Although SOC optimization offers a significant savings for a payer, appropriate benefit design ensures that the out-of-pocket expense for the patient is decreased (or even eliminated). If the member’s benefit design does not provide a lower patient outof-pocket cost at an ATS versus an outpatient department, it is very unlikely that the patient will agree to change the SOC. This dynamic can result in the payer continuing to pay more than double the amount for the service than is necessary.

Another component to success is alignment of incentives. Appropriate benefit design and/or a creative incentive program (eg, direct financial incentives to patients to move to a lower-cost SOC) align the incentives of the payer and the patient. However, this alignment must also occur between the payer and the provider to ensure optimal success. If alignment of incentives between the payer and the provider cannot be obtained, the probability is high that the higher-cost outpatient department will become the default location,

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as was illustrated above. Emerging shared-savings programs and pay-for-performance reimbursement strategies can help to align payer and provider incentives.

It is important that the payer and the provider understand and agree to the measurement of success.

Transparent data exchange and quarterly reporting play a critical role in making this possible. Without these elements in place, it is very possible that the true savings and value of SOC optimization may not be fully realized.

Options to Limit Physician Buy and Bill Many physician specialties, such as oncology and rheumatology, provide in-office infusion for their patients. Receiving infusion in the physician’s office is normally convenient for patients, a source of revenue for physicians, and often a cost-effective site of infusion for payers.

However, some payers worry that paying physicians tens of thousands of dollars annually to infuse medication in their offices may encourage overutilization, by influencing the physician to begin treating patients with therapy earlier or by keeping patients on therapy longer than is clinically appropriate. In addition, if a physician is financially incentivized to provide infusion therapy, the physician may be more likely to begin infusion therapy instead of to prescribe a more convenient, and often less costly, self-injected medication. Furthermore, rates paid to providers to infuse medications in the office, although often competitive, can vary considerably.

Therefore, some payers require that physicians’ offices obtain medications that will be infused in their office from a contracted specialty pharmacy. This practice is also known as “white bagging.” The pharmacy receives orders from physicians, fills the (patient-specific) medication, then mails the drug to the office before the patient’s infusion or injection appointment. Some plans have been very successful with this strategy.5 However, each payer will have different results, because of various underlying physicians’ office fee schedules.6 Requiring physicians to make patients obtain infused or injected drugs for in-office administration from a specialty pharmacy is an individual decision that must be addressed by each health plan, based on its unique network design and fee schedules, member benefit design, local provider political influence, and specialty pharmacy pricing.

A plan can decide if a white bagging program would be an effective cost and utilization management program on completion of an analysis that accurately models how the cost of infused therapy would change if certain drugs were limited to only specialty pharmacy distribution.

The current rate-setting methodology of the health plan’s physician fee schedule is the primary driver for

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determining whether financial savings will occur if the drugs are blocked from buy and bill and are dispensed from a specialty pharmacy. Once the economic impact is understood, other strategic factors can be taken into consideration to make a fully informed decision.

Why an ATS Network Is Critical Regardless of whether a plan restricts certain in-office drugs to a specialty pharmacy, it is critically important that a plan has an ATS network available to its members. Without an ATS network, infusions will, by default, be provided in hospital outpatient departments if the prescribing physician decides to no longer provide in-office infusions.

With continuing price compressions and a plethora of high-cost medications in the drug pipeline, this poses a significant risk to plans: costs for the same drug will typically double if infused in a hospital setting versus at other settings.

With continuing price compressions and a plethora of high-cost medications in the drug pipeline, this poses a significant risk to plans: costs for the same drug will typically double if infused in a hospital setting versus at other settings. In addition, because health plans are increasingly purchasing physicians’ practices,7 we foresee infusion and injection at a physician’s office decreasing over time, with a corresponding increase in hospitalbased infusions, unless an ATS network exists.

Clinical and Formulary Management Health plans have many opportunities to introduce clinical and utilization programs to manage appropriate utilization in the medical benefit—so many, in fact, that it is beyond the scope of this article to detail them all.

Having a full understanding of clinical opportunities will lead to programs that can manage utilization trends within the medical benefit. For example, the effectiveness of a payer’s current prior authorization (PA) criteria can be evaluated, additional PA and formulary opportunities can be explored, and programs focused on converting patients from infused drugs to selfadministered drugs (injected or oral) can be evaluated once a payer understands the utilization patterns within his or her medical benefit.

Fee Schedule Management One of the most straightforward ways to manage drug-related medical costs for a payer is to maintain a

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competitive and continually maintained fee schedule that determines how much a provider is paid for a drug and its administration. However, a payer must be cautious when adjusting fee schedules. Remember that ATSs and outpatient hospital facilities are usually contracted and managed separately. If fee schedules to the ATS network are reduced to a point where providers feel the level of reimbursement does not adequately compensate them for the drug, the ATS will likely choose to no longer provide infusion services.

The prescribing physician will then either attempt to switch the patient to a self-administered drug, or more likely (because there are only a few infused products with a self-administered equivalent product), will refer the patient to a nearby outpatient hospital to continue the infusion treatment. This will result in a significant cost increase to the payer for that infusion, thereby more than eliminating the expected costsavings the payer would otherwise have predicted from the lower fee schedule.

An MBM analysis should be able to provide payers a perspective on industry benchmarks and how their fee schedules are performing relative to their industry peers. In addition to enabling payers to see if they are in line with what other payers are reimbursing for certain drugs, an analysis showing that payers have an extremely deep ATS fee schedule (eg, average sales price +6) and an unusual amount of hospital outpatient utilization may indicate that more research may help to determine if cause and effect exists, perhaps even leading payers to evaluate if increasing the ATS fee schedule would decrease net infusion costs resulting from lowering hospital outpatient utilization.

The Ultimate Successful MBM Strategy Payers will be well on their way to effectively managing medical specialty drug costs if they: • Implement an ATS network (including infusion suites and home infusion options) to mitigate hospital outpatient referrals for specialty infusion • Maximize the use of lower-cost ATSs for infusion through appropriate benefit design and provider incentives • Align financial incentives with the infusion partner—through a shared-savings strategy and/or a preferred provider contract • Maintain fair and competitive fee schedules across all SOCs, ensuring physicians’ offices, home infusion providers, and infusion suites are incented to provide infusion services

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• Manage clinical appropriateness through PA programs and/or clinical pathways • Maintain fee schedules that do not encourage the use of high-cost products when lower-cost therapeutically equivalent options exist • Have access to utilization reporting that tracks savings and trends within the medical benefit.

Conclusion Managing the medical pharmacy trend is a complex task, and many solutions are available from various vendors to help payers manage medical pharmacy utilization. Drug utilization within the medical benefit is increasingly becoming better understood and managed, but not yet to the extent of pharmacy utilization.

Before committing to an MBM strategy, a plan should first feel comfortable with understanding its medical pharmacy trend and utilization patterns within each place of service and type of service (eg, chemotherapy or nonchemotherapy). A payer has to understand what its top drugs are, which physician specialties are driving the utilization, and what SOC its benefit design currently encourages patients to utilize.

A payer should ask any potential consulting pharmacy partner to see examples of its MBM reporting, and then ask what solutions that partner can provide. Does the vendor have a strategy and implementation plan for each area of opportunity, or will multiple vendors be required? If multiple vendors are needed, can the vendors work collaboratively to provide a uniform solution to the payer? ■ Author Disclosure Statement Mr Einodshofer and Dr Duren are employees and stockholders of Walgreens.

References 1. Einodshofer M, Kansler S. Cost management through care management: a perspective on choosing the right specialty pharmacy partner. Am Health Drug Benefits.

2012;5:301-304.

2. Express Scripts. 2011 Drug Trend Report. www.expressscripts.com/research/ research/dtr/archive/2012/dtrFinal.pdf. Accessed September 21, 2012.

3. CVS Caremark to offer medical benefit drug management services to clients. April 14, 2011. http://info.cvscaremark.com/newsroom/press-releases/cvs-caremark-offermedical-benefit-drug-management-services-clients. Accessed September 21, 2012.

4. Einodshofer M, Frear RS, Gomberg JB. 2012 Health Meeting Session 89 TS: Specialty Drugs. June 13-15, 2012. www.soa.org/files/pd/health/2012-new-orleanshealth-89.pdf. Accessed September 21, 2012.

5. Baldini CG, Culley EJ. Estimated cost savings associated with the transfer of office-administered specialty pharmaceuticals to a specialty pharmacy provider in a medical injectable drug program. J Manag Care Pharm. 2011;17:51-59.

6. ICORE Healthcare. Medical Injectables and Oncology Trend Report. 2010. www.magellanhealth.com/media/281539/icore_trend_report_1-20-11.pdf. Accessed September 22, 2012.

7. Elliott VS. Increase in physician practice mergers and acquisitions expected to continue. August 14, 2012. www.ama-assn.org/amednews/2012/08/13/bisd0814.htm.

Accessed September 21, 2012.

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Learn more at www.Qsymia.com Enroll now in the Qsymia™ Healthcare Provider Training Program.

Receive Important Safety Information, access patient materials and in-office tools, and more.

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

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

Areas of High Interest: • Health Information Exchange • Health Plan Initiatives • Innovations in Healthcare • Literature Reviews • Medicare/Medicaid • Patient Outcomes/Advocacy • Pharmacoeconomics • Pharmacogenomics

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

• Policy Issues • Prevention Initiatives • Reimbursement Strategies • Social Media and Health • Survey Results • Value-Based Healthcare • Wellness Programs

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

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

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

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

CANCER CARE—The growing focus on biologic agents dictates an enhanced study of these therapeutic options, including reimbursement policies and cost management.

CARDIOVASCULAR DISEASE—Original, outcomesbased research on appropriate therapies, cost comparisons, emerging prevention strategies, and best practices will enhance readers’ decision-making.

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

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

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

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

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

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

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

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Information for Authors Manuscripts submitted to American Health & Drug Benefits (AHDB) must be original and must not have been published previously, either in print or in electronic form. Manuscripts cannot be submitted elsewhere while under consideration by AHDB, and must adhere to the format described in the full Guidelines for Authors available at www.AHDBonline.com. All manuscripts undergo peer review, and acceptance is based on that review. If accepted, authors will be notified of any recommended revisions.

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LINAGLIPTIN AND METFORMIN IN A SINGLE TABLET TAKEN TWICE DAILY FOR ADULT PATIENTS WITH TYPE 2 DIABETES

Improving glycemic control for adult patients with type 2 diabetes Significant A1C reductions (placebo-adjusted) at 24 weeks1*†‡ Linagliptin 5 mg once daily Baseline A1C 8.7%

Metformin 500 mg twice daily Baseline A1C 8.7%

JENTADUETO Linagliptin 2.5 mg Metformin 500 mg twice daily§ Baseline A1C 8.7%

Metformin 1000 mg twice daily Baseline A1C 8.5%

JENTADUETO Linagliptin 2.5 mg Metformin 1000 mg twice daily§ Baseline A1C 8.7%

–0.6% (n=135)

–0.8% (n=141)

–1.3%

–1.2%

*A randomized, double-blind, placebo-controlled, parallel-group study of drug-naïve or previously treated (4 weeks washout and 2 weeks placebo run-in) adult patients with type 2 diabetes and insufficient glycemic control (aged 18-80) who were randomized to placebo (n=72), linagliptin 5 mg once daily (n=142), metformin 500 mg twice daily (n=144), linagliptin 2.5 mg twice daily + metformin 500 mg twice daily (n=143), metformin 1000 mg twice daily (n=147), or linagliptin 2.5 mg twice daily + metformin 1000 mg twice daily (n=143). Primary endpoint was change from baseline A1C at 24 weeks. Results adjusted for 0.1% mean A1C increase for placebo. 29.2% of patients in the placebo group required use of rescue therapy vs 11.1% of patients receiving linagliptin 5 mg once daily, 13.5% of patients receiving metformin 500 mg twice daily, 8.0% of patients receiving metformin 1000 mg twice daily, 7.3% of patients receiving linagliptin 2.5 mg twice daily + metformin 500 mg twice daily, and 4.3% of patients receiving linagliptin 2.5 mg twice daily + metformin 1000 mg twice daily. Full analysis population using last observation on study. †

Superiority of both free-combination therapies, consisting of the twice-daily administration of linagliptin 2.5 mg and metformin (500 mg or 1000 mg), was shown over the individual metformin components (500 mg and 1000 mg, both BID) and over linagliptin 5 mg QD for the change in A1C from baseline at Week 24.

Linagliptin 2.5 mg BID + metformin 1000 mg BID was superior to metformin 1000 mg BID (P<0.0001); linagliptin 2.5 mg BID + metformin 1000 mg BID was superior to linagliptin 5 mg QD (P<0.0001); linagliptin 2.5 mg BID + metformin 500 mg BID was superior to metformin 500 mg BID (P<0.0001); linagliptin 2.5 mg BID + metformin 500 mg BID was superior to linagliptin 5 mg QD (P<0.0001).

§

JENTADUETO studied as coadministered linagliptin and metformin tablets; total daily dose of linagliptin was equal to 5 mg.

(n=138) (n=137)

–1.7%

P<0.0001 ‡

Results are adjusted for a 0.1% mean A1C increase for placebo (n=65).

(n=140)

P<0.0001

JENTADUETO was approved based on clinical trials that evaluated linagliptin and metformin as separate tablets. Bioequivalence of JENTADUETO to linagliptin and metformin coadministered as individual tablets was demonstrated in healthy subjects

INDICATION AND IMPORTANT LIMITATIONS OF USE JENTADUETO tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both linagliptin and metformin is appropriate.

JENTADUETO should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis, and has not been studied in combination with insulin.

IMPORTANT SAFETY INFORMATION WARNING: RISK OF LACTIC ACIDOSIS Lactic acidosis is a rare, but serious, complication that can occur due to metformin accumulation. The risk increases with conditions such as renal impairment, sepsis, dehydration, excess alcohol intake, hepatic impairment, and acute congestive heart failure.

The onset is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress.

Laboratory abnormalities include low pH, increased anion gap, and elevated blood lactate.

If acidosis is suspected, JENTADUETO should be discontinued and the patient hospitalized immediately.

CONTRAINDICATIONS JENTADUETO is contraindicated in patients with: Renal impairment (e.g., serum creatinine ≥1.5 mg/dL for men or ≥1.4 mg/dL for women, or abnormal creatinine clearance).

Acute or chronic metabolic acidosis, including diabetic ketoacidosis.

History of hypersensitivity reaction to linagliptin (such as urticaria, angioedema, or bronchial hyperreactivity) or metformin.

WARNINGS AND PRECAUTIONS Lactic Acidosis Lactic acidosis is a serious, metabolic complication that can occur due to metformin accumulation during treatment with JENTADUETO and is fatal in approximately 50% of cases.

The reported incidence of lactic acidosis in patients receiving metformin is approximately 0.03 cases/1000 patient-years, with approximately 0.015 fatal cases/1000 patient-years. Reported cases have occurred primarily in diabetic patients with significant renal impairment, including both intrinsic renal disease and renal hypoperfusion, often in the setting of multiple concomitant medical/surgical problems and multiple concomitant medications.

Patients with congestive heart failure requiring pharmacologic management, particularly when accompanied by hypoperfusion and hypoxemia due to unstable or acute failure, are at increased risk of lactic acidosis.

The risk of lactic acidosis increases with the degree of renal impairment and the patient’s age. The risk of lactic acidosis may be significantly decreased by regular monitoring of renal function in patients taking metformin. Treatment of the elderly should be accompanied by careful monitoring of renal function. Metformin treatment should not be initiated in any patients unless measurement of creatinine clearance demonstrates that renal function is not reduced.

Metformin should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration, or sepsis.

Monitoring of Renal Function Before initiation of therapy with JENTADUETO and at least annually thereafter, renal function should be assessed and verified as normal.

In patients in whom development of renal impairment is anticipated (e.g., elderly), renal function should be assessed more frequently and JENTADUETO discontinued if evidence of renal impairment is present.

Radiological studies and surgical procedures: JENTADUETO should be temporarily discontinued prior to any intravascular radiocontrast study and for any surgical procedure necessitating restricted intake of food or fluids, and withheld for 48 hours subsequent to the procedure and reinstituted only after renal function has been confirmed to be normal.

Impaired Hepatic Function Impaired hepatic function has been associated with cases of lactic acidosis with metformin therapy. JENTADUETO tablets should generally be avoided in patients with clinical or laboratory evidence of hepatic impairment.

Hypoglycemia Insulin secretagogues are known to cause hypoglycemia. The use of linagliptin in combination with an insulin secretagogue (e.g., sulfonylurea) was associated with a higher rate of hypoglycemia compared with placebo in a clinical trial. A lower dose of the insulin secretagogue may be required to reduce the risk of hypoglycemia when used in combination with JENTADUETO. Vitamin B12 Levels Vitamin B12 deficiency: Metformin may lower Vitamin B12 levels.

Monitor hematologic parameters annually.

Alcohol Intake Alcohol is known to potentiate the effect of metformin on lactate metabolism. Patients should be warned against excessive alcohol intake while receiving JENTADUETO. Hypoxic States Cardiovascular collapse (shock) from whatever cause (e.g., acute congestive heart failure, acute myocardial infarction, and other conditions characterized by hypoxemia) has been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur in patients on JENTADUETO therapy, the drug should be promptly discontinued.

Macrovascular Outcomes There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with JENTADUETO or any other antidiabetic drug.

ADVERSE REACTIONS In a 24-week factorial design study, adverse reactions reported in ≥5% of patients treated with JENTADUETO and more commonly than in patients treated with placebo were nasopharyngitis and diarrhea.

In a 24-week factorial design study, hypoglycemia was reported in 4 (1.4%) of 286 subjects treated with linagliptin + metformin, 6 (2.1%) of 291 subjects treated with metformin and 1 (1.4%) of 72 subjects treated with placebo. In the placebo-controlled studies, hypoglycemia was more commonly reported in patients treated with the combination of linagliptin and metformin with SU (22.9%) compared with those treated with the combination of placebo and metformin with SU (14.8%).

Pancreatitis was reported more often in patients randomized to linagliptin (1 per 538 person-years versus 0 in 433 person-years for comparator).

DRUG INTERACTIONS Because cationic drugs eliminated by renal tubular secretion theoretically have the potential for interaction with metformin by competing for common renal tubular transport systems, careful patient monitoring and dose adjustment of JENTADUETO and/or the interfering drug is recommended in patients who are taking cationic medications that are excreted via the proximal renal tubular secretory system.

The efficacy of JENTADUETO may be reduced when administered in combination with a strong P-glycoprotein inducer and CYP3A4 inducer (e.g., rifampin). Use of alternative treatments is strongly recommended.

The concomitant use of carbonic anhydrase inhibitors (e.g., topiramate) and metformin may induce metabolic acidosis. Use these drugs with caution in patients treated with JENTADUETO, as the risk of lactic acidosis may increase.

USE IN SPECIFIC POPULATIONS As there are no adequate and well-controlled studies in pregnant women, the safety of JENTADUETO in pregnant women is not known.

JENTADUETO should be used during pregnancy only if clearly needed.

It is not known whether linagliptin is excreted in human milk.

Metformin is excreted in human milk in low concentrations.

Because the potential for hypoglycemia in nursing infants may exist, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

The safety and effectiveness of JENTADUETO in patients below the age of 18 have not been established.

JENTADUETO should be used with caution as age increases, as aging can be associated with reduced renal function.

JD PROF ISI MAR152012 Reference: 1. Data on file. Boehringer Ingelheim Pharmaceuticals, Inc.

Please see adjacent pages for brief summary of full Prescribing Information and Boxed Warning regarding the risk of lactic acidosis.

Find out more about JENTADUETO and the Savings Card program at www.jentadueto.com Copyright © 2012 Boehringer Ingelheim Pharmaceuticals, Inc. All rights reserved.

(08/12)

JD384500PROFA

Jentadueto™ (linagliptin and metformin hydrochloride) tablets BRIEF SUMMARY OF PRESCRIBING INFORMATION Please see package insert for full Prescribing Information.

WARNING: RISK OF LACTIC ACIDOSIS Lactic acidosis is a rare, but serious, complication that can occur due to metformin accumulation. The risk increases with conditions such as renal impairment, sepsis, dehydration, excess alcohol intake, hepatic impairment, and acute congestive heart failure.

The onset is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress.

Laboratory abnormalities include low pH, increased anion gap, and elevated blood lactate.

If acidosis is suspected, JENTADUETO should be discontinued and the patient hospitalized immediately.

INDICATIONS AND USAGE: Indication: JENTADUETO tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both linagliptin and metformin is appropriate.

Important Limitations of Use: JENTADUETO should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings. JENTADUETO has not been studied in combination with insulin.

CONTRAINDICATIONS: JENTADUETO is contraindicated in patients with:

s Renal impairment (e.g., serum creatinine 1.5 mg/dL for men, 1.4 mg/dL for women, or abnormal creatinine clearance) which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia [see Warnings and Precautions] s Acute or chronic metabolic acidosis, including diabetic ketoacidosis. Diabetic ketoacidosis should be treated with insulin [see Warnings and Precautions] s A history of hypersensitivity reaction to linagliptin (such as urticaria, angioedema, or bronchial hyperreactivity) or metformin [see Adverse Reactions]

WARNINGS AND PRECAUTIONS: Lactic Acidosis: Metformin: Lactic acidosis is a serious, metabolic complication that can occur due to metformin accumulation during treatment with JENTADUETO and is fatal in approximately 50% of cases.

Lactic acidosis may also occur in association with a number of pathophysiologic conditions, including diabetes mellitus, and whenever there is significant tissue hypoperfusion and hypoxemia. Lactic acidosis is characterized by elevated blood lactate levels (>5 mmol/L), decreased blood pH, electrolyte disturbances with an increased anion gap, and an increased lactate/pyruvate ratio. When metformin is implicated as the cause of lactic acidosis, metformin plasma levels of >5 µg/mL are generally found. The reported incidence of lactic acidosis in patients receiving metformin is approximately 0.03 cases/1000 patient-years, (with approximately 0.015 fatal cases/1000 patient-years). In more than 20,000 patient-years exposure to metformin in clinical trials, there were no reports of lactic acidosis. Reported cases have occurred primarily in diabetic patients with significant renal impairment, including both intrinsic renal disease and renal hypoperfusion, often in the setting of multiple concomitant medical/surgical problems and multiple concomitant medications. Patients with congestive heart failure requiring pharmacologic management, particularly when accompanied by hypoperfusion and hypoxemia due to unstable or acute failure, are at increased risk of lactic acidosis. The risk of lactic acidosis increases with the degree of renal impairment and the patient’s age. The risk of lactic acidosis may, therefore, be significantly decreased by regular monitoring of renal function in patients taking metformin. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. Metformin treatment should not be initiated in any patients unless measurement of creatinine clearance demonstrates that renal function is not reduced. In addition, metformin should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration, or sepsis. Because impaired hepatic function may significantly limit the ability to clear lactate, metformin should be avoided in patients with clinical or laboratory evidence of hepatic impairment. Patients should be cautioned against excessive alcohol intake when taking metformin, since alcohol potentiates the effects of metformin on lactate metabolism. In addition, metformin should be temporarily discontinued prior to any intravascular radiocontrast study and for any surgical procedure necessitating restricted intake of food or fluids. Use of topiramate, a carbonic anhydrase inhibitor, in epilepsy and migraine prophylaxis may cause dose-dependent metabolic acidosis and may exacerbate the risk of metformin-induced lactic acidosis [see Drug Interactions]. The onset of lactic acidosis is often subtle, and accompanied by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. More severe acidosis may be associated with signs such as hypothermia, hypotension, and resistant bradyarrhythmias. Patients should be educated to recognize and promptly report these symptoms. If present, JENTADUETO should be discontinued until lactic acidosis is ruled out. Gastrointestinal symptoms, which are commonly reported during initiation of metformin therapy are less frequently observed in subjects on a chronic, stable, dose of metformin.

Gastrointestinal symptoms in subjects on chronic, stable, dose of metformin could be caused by lactic acidosis or other serious disease. To rule out lactic acidosis, serum electrolytes, ketones, blood glucose, blood pH, lactate levels, and blood metformin levels may be useful. Levels of fasting venous plasma lactate above the upper limit of normal but less than 5 mmol/L in patients taking metformin do not necessarily indicate impending lactic acidosis and may be due to other mechanisms, such as poorly-controlled diabetes or obesity, vigorous physical activity, or technical problems in sample handling. Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis (ketonuria and ketonemia).

Lactic acidosis is a medical emergency that must be treated in a hospital setting. In a

patient with lactic acidosis who is taking metformin, the drug should be discontinued immediately and supportive measures promptly instituted. Metformin is dialyzable (clearance of up to 170 mL/min under good hemodynamic conditions) and prompt hemodialysis is recommended to remove the accumulated metformin and correct the metabolic acidosis. Such management often results in prompt reversal of symptoms and recovery [see Boxed Warning].

Monitoring of Renal Function: Although linagliptin undergoes minimal renal excretion, metformin is known to be substantially excreted by the kidney. The risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment. Therefore, JENTADUETO is contraindicated in patients with renal impairment. Before initiation of therapy with JENTADUETO and at least annually thereafter, renal function should be assessed and verified to be normal. In patients in whom development of renal impairment is anticipated (e.g., elderly), renal function should be assessed more frequently and JENTADUETO discontinued if evidence of renal impairment is present. Linagliptin may be continued as a single entity tablet at the same total daily dose of 5 mg if JENTADUETO is discontinued due to evidence of renal impairment. No dose adjustment of linagliptin is recommended in patients with renal impairment.

Use of concomitant medications that may affect renal function or metformin disposition: Concomitant medication(s) that may affect renal function or result in significant hemodynamic change or interfere with the disposition of metformin should be used with caution [see Drug Interactions]. Radiological studies and surgical procedures: Radiologic studies involving the use of intravascular iodinated contrast materials (e.g., intravenous urogram, intravenous cholangiography, angiography, and computed tomography) can lead to acute alteration of renal function and have been associated with lactic acidosis in patients receiving metformin.

Therefore, in patients in whom any such study is planned, JENTADUETO should be temporarily discontinued at the time of or prior to the procedure, and withheld for 48 hours subsequent to the procedure and reinstituted only after renal function has been confirmed to be normal. JENTADUETO should be temporarily discontinued for any surgical procedure (except minor procedures not associated with restricted intake of food and fluids) and should not be restarted until the patient’s oral intake has resumed and renal function has been evaluated as normal. Impaired Hepatic Function: Because impaired hepatic function has been associated with some cases of lactic acidosis with metformin therapy, JENTADUETO should generally be avoided in patients with clinical or laboratory evidence of hepatic disease [see Warnings and Precautions]. Hypoglycemia: Linagliptin: Insulin secretagogues are known to cause hypoglycemia. The use of linagliptin in combination with an insulin secretagogue (e.g., sulfonylurea) was associated with a higher rate of hypoglycemia compared with placebo in a clinical trial [see Adverse Reactions]. Therefore, a lower dose of the insulin secretagogue may be required to reduce the risk of hypoglycemia when used in combination with JENTADUETO. Metformin: Hypoglycemia does not occur in patients receiving metformin alone under usual circumstances of use, but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with other glucose-lowering agents (such as SUs and insulin) or ethanol. Elderly, debilitated, or malnourished patients, and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects. Hypoglycemia may be difficult to recognize in the elderly, and in people who are taking β-adrenergic blocking drugs. Vitamin B12 Levels: In controlled, 29-week clinical trials of metformin, a decrease to subnormal levels of previously normal serum vitamin B12 levels, without clinical manifestations, was observed in approximately 7% of metformin-treated patients. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, is, however, very rarely associated with anemia or neurologic manifestations due to the short duration (<1 year) of the clinical trials. This risk may be more relevant to patients receiving long-term treatment with metformin, and adverse hematologic and neurologic reactions have been reported postmarketing. The decrease in vitamin B12 levels appears to be rapidly reversible with discontinuation of metformin or vitamin B12 supplementation. Measurement of hematologic parameters on an annual basis is advised in patients on JENTADUETO and any apparent abnormalities should be appropriately investigated and managed. Certain individuals (those with inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels. In these patients, routine serum vitamin B12 measurement at 2- to 3-year intervals may be useful. Alcohol Intake: Alcohol is known to potentiate the effect of metformin on lactate metabolism. Patients, therefore, should be warned against excessive alcohol intake while receiving JENTADUETO [see Warnings and Precautions]. Hypoxic States: Cardiovascular collapse (shock) from whatever cause (e.g., acute congestive heart failure, acute myocardial infarction, and other conditions characterized by hypoxemia) have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur in patients on JENTADUETO therapy, the drug should be promptly discontinued [see Warnings and Precautions]. Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with linagliptin or metformin 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 clinical practice. Linagliptin/ Metformin: The safety of concomitantly administered linagliptin (daily dose 5 mg) and metformin (mean daily dose of approximately 1800 mg) has been evaluated in 2816 patients with type 2 diabetes mellitus treated for 12 weeks in clinical trials. Three placebo-controlled studies with linagliptin + metformin were conducted: 2 studies were 24 weeks in duration, 1 study was 12 weeks in duration. In the 3 placebo-controlled clinical studies, adverse events which occurred in 5% of patients receiving linagliptin + metformin (n=875) and were more common than in patients given placebo + metformin (n=539) included nasopharyngitis (5.7% vs 4.3%). In a 24-week factorial design study, adverse events reported in 5% of patients receiving linagliptin + metformin and were more common than in patients given placebo are shown in Table 1.

Table 1

Adverse Reactions Reported in 5% of Patients Treated with Linagliptin + Metformin and Greater than with Placebo in a 24-week Factorial-Design Study Placebo Linagliptin Metformin Combination of n=72 Monotherapy Monotherapy Linagliptin with n=142 n=291 Metformin n=286 n (%) n (%) n (%) n (%)

Nasopharyngitis

1 (1.4)

8 (5.6)

8 (2.7)

18 (6.3)

Diarrhea

2 (2.8)

5 (3.5)

11 (3.8)

18 (6.3)

Other adverse reactions reported in clinical studies with treatment of linagliptin + metformin were hypersensitivity (e.g., urticaria, angioedema, or bronchial hyperactivity), cough, decreased appetite, nausea, vomiting, pruritus, and pancreatitis.

Linagliptin Monotherapy: Nasopharyngitis was reported in 5% of patients treated with linagliptin and more commonly than in patients treated with placebo (5.8% vs 5.5%). In the clinical trial program, pancreatitis was reported in 8 of 4687 patients (4311 patient-years of exposure) while being treated with TRADJENTA compared with 0 of 1183 patients (433 patient-years of exposure) treated with placebo. Three additional cases of pancreatitis were reported following the last administered dose of linagliptin. Other adverse reactions reported in clinical studies with treatment of linagliptin monotherapy were hypersensitivity (e.g., urticaria, angioedema, localized skin exfoliation, or bronchial hyperactivity) and myalgia. Metformin Monotherapy: The most common adverse reactions due to initiation of metformin are diarrhea, nausea/vomiting, flatulence, asthenia, indigestion, abdominal discomfort, and headache. Long-term treatment with metformin has been associated with a decrease in vitamin B12 absorption which may very rarely result in clinically significant vitamin B12 deficiency (e.g., megaloblastic anemia) [see Warnings and Precautions]. Hypoglycemia: In a 24-week factorial design study, hypoglycemia was reported in 4 (1.4%) of 286 subjects treated with linagliptin + metformin, 6 (2.1%) of 291 subjects treated with metformin, and 1 (1.4%) of 72 subjects treated with placebo. When linagliptin was administered in combination with metformin and a sulfonylurea, 181 (22.9%) of 792 patients reported hypoglycemia compared with 39 (14.8%) of 263 patients administered placebo in combination with metformin and sulfonylurea. Laboratory Tests: Changes in laboratory findings were similar in patients treated with linagliptin + metformin compared to patients treated with placebo + metformin. Changes in laboratory values that occurred more frequently in the linagliptin + metformin group and 1% more than in the placebo group were not detected. No clinically meaningful changes in vital signs were observed in patients treated with linagliptin.

DRUG INTERACTIONS: Drug Interactions with Metformin: Cationic Drugs: Cationic drugs (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, or vancomycin) that are eliminated by renal tubular secretion theoretically have the potential for interaction with metformin by competing for common renal tubular transport systems. Although such interactions remain theoretical (except for cimetidine), careful patient monitoring and dose adjustment of JENTADUETO and/or the interfering drug is recommended in patients who are taking cationic medications that are excreted via the proximal renal tubular secretory system [see Warnings and Precautions]. Carbonic Anhydrase Inhibitors: Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) frequently decrease serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs may induce metabolic acidosis. Use these drugs with caution in patients treated with JENTADUETO, as the risk of lactic acidosis may increase [see Warnings and Precautions]. Drug Interactions With Linagliptin: Inducers of P-glycoprotein and CYP3A4 Enzymes: Rifampin decreased linagliptin exposure, suggesting that the efficacy of linagliptin may be reduced when administered in combination with a strong P-gp inducer or CYP 3A4 inducer. As JENTADUETO is a fixed-dose combination of linagliptin and metformin, use of alternative treatments (not containing linagliptin) is strongly recommended when concomitant treatment with a strong P-gp or CYP 3A4 inducer is necessary. Drugs Affecting Glycemic Control: Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid. When such drugs are administered to a patient receiving JENTADUETO, the patient should be closely observed to maintain adequate glycemic control. When such drugs are withdrawn from a patient receiving JENTADUETO, the patient should be observed closely for hypoglycemia.

USE IN SPECIFIC POPULATIONS: Pregnancy: Pregnancy Category B: JENTADUETO: There are no adequate and well controlled studies in pregnant women with JENTADUETO or its individual components, and some clinical data is available for metformin which indicate that the risk for major malformations was not increased when metformin is taken during the first trimester in pregnancy. In addition, metformin was not associated with increased perinatal complications. Nevertheless, because these clinical data cannot rule out the possibility of harm, JENTADUETO should be used during pregnancy only if clearly needed. JENTADUETO was not teratogenic when administered to Wistar Han rats during the period of organogenesis at doses similar to clinical exposure. At higher maternally toxic doses (9 and 23 times the clinical dose based on exposure), the metformin component of the combination was associated with an increased incidence of fetal rib and scapula malformations.

Linagliptin: Linagliptin was not teratogenic when administered to pregnant Wistar Han rats and Himalayan rabbits during the period of organogenesis at doses up to 240 mg/kg and 150 mg/kg, respectively. These doses represent approximately 943 times the clinical dose in rats and 1943 times the clinical dose in rabbits, based on exposure. No functional, behavioral, or reproductive toxicity was observed in offspring of female Wistar Han rats when administered linagliptin from gestation day 6 to lactation day 21 at a dose 49 times the maximum recommended human dose,

based on exposure. Linagliptin crosses the placenta into the fetus following oral dosing in pregnant rats and rabbits. Metformin Hydrochloride: Metformin has been studied for embryofetal effects in 2 rat strains and in rabbits. Metformin was not teratogenic in Sprague Dawley rats up to 600 mg/kg or in Wistar Han rats up to 200 mg/kg (2-3 times the clinical dose based on body surface area or exposure, respectively). At higher maternally toxic doses (9 and 23 times the clinical dose based on exposure), an increased incidence of rib and scapula skeletal malformations was observed in the Wistar Han strain. Metformin was not teratogenic in rabbits at doses up to 140 mg/kg (similar to clinical dose based on body surface area). Metformin administered to female Sprague Dawley rats from gestation day 6 to lactation day 21 up to 600 mg/kg/day (2 times the maximum clinical dose based on body surface area) had no effect on prenatal or postnatal development of offspring. Metformin crosses the placenta into the fetus in rats and humans. Nursing Mothers: No studies in lactating animals have been conducted with the combined components of JENTADUETO. In studies performed with the individual components, both linagliptin and metformin were secreted in the milk of lactating rats. It is not known whether linagliptin is excreted in human milk. Metformin is excreted in human milk in low concentrations. Because the potential for hypoglycemia in nursing infants may exist, 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 JENTADUETO in pediatric patients have not been established.

Geriatric Use: Linagliptin is minimally excreted by the kidney; however, metformin is substantially excreted by the kidney. Considering that aging can be associated with reduced renal function, JENTADUETO should be used with caution as age increases [see Warnings and Precautions]. Linagliptin: Of the total number of patients (n=4040) in clinical studies of linagliptin, 1085 patients were 65 years and over, while 131 patients were 75 years and over. No overall differences in safety or effectiveness were observed between patients 65 years and over and younger patients. Therefore, no dose adjustment is recommended in the elderly population. While clinical studies of linagliptin have not identified differences in response between the elderly and younger patients, greater sensitivity of some older individuals cannot be ruled out.

Metformin: Controlled clinical studies of metformin did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients, although other reported clinical experience has not identified differences in responses between the elderly and young patients. The initial and maintenance dosing of metformin should be conservative in patients with advanced age, due to the potential for decreased renal function in this population. Any dose adjustment should be based on a careful assessment of renal function [see Contraindications and Warnings and Precautions].

OVERDOSAGE: In the event of an overdose with JENTADUETO, employ the usual supportive measures (e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive treatment) as dictated by the patient’s clinical status. Removal of linagliptin by hemodialysis or peritoneal dialysis is unlikely. However, metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful partly for removal of accumulated metformin from patients in whom JENTADUETO overdosage is suspected. Linagliptin: During controlled clinical trials in healthy subjects, with single doses of up to 600 mg of linagliptin (equivalent to 120 times the recommended daily dose), there were no dose-related clinical adverse drug reactions. There is no experience with doses above 600 mg in humans.

Metformin: Overdose of metformin has occurred, including ingestion of amounts greater than 50 grams. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases [see Boxed Warning and Warnings and Precautions].

Distributed by: Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT 06877 USA Marketed by: Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT 06877 USA and Eli Lilly and Company Indianapolis, IN 46285 USA Licensed from: Boehringer Ingelheim International GmbH Ingelheim, Germany Copyright 2012 Boehringer Ingelheim International GmbH ALL RIGHTS RESERVED January 2012

JD/BS/01-12

JD148400PROF

CALL FOR PAPERS Cardiometabolic Health Special Issue American Health & Drug Benefits will be publishing a Special Issue on Cardiometabolic Health in 2013.

Readers are invited to submit articles for publication in this special issue on topics relevant to the clinical, business, and policy aspects of cardiometabolic health and wellness. Original research, comparative effectiveness analyses, white papers, evidence-based comprehensive reviews, and case studies are of particular interest. All articles will undergo the journal’s rigorous peer-review process and acceptance is contingent on that review.

Topics of high interest include: • Benefit designs to improve cardiometabolic patient outcomes • Best practices in insulin control, lipid management, or blood pressure control • Comparative effectiveness analyses of best therapies for cardiovascular health • Cost-effectiveness comparisons of current therapies for diabetes • Current recommendations for optimizing A1C target outcomes • Diabetes management and prevention • Employers’ strategies to enhance employees’ cardiometabolic wellness • Emerging therapies for diabetes, heart disease, and/or obesity • Health plan initiatives for cardiometabolic health and prevention

• Insulin resistance and type 2 diabetes • Lifestyle strategies and cardiometabolic health and wellness • Lipid management in patients with diabetes • Medication adherence • New biomarkers for assessing cardiometabolic risk • New therapies for diabetes, cardiovascular disease, or obesity • Optimal therapies for cardiovascular disease, diabetes, and/or obesity • Pharmacoeconomic analyses • Prevention strategies for diabetes risk reduction • Wellness programs for patients with heart disease, diabetes, or obesity

• Hot topics in diabetes management

Articles should follow the Manuscript Instructions for Authors (www.AHDBonline.com).

Submit articles to editorial@engagehc.com. For more information, call 732-992-1889.

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Vol 5, No 6

IT’S ANYBODY’S GUESS WHICH FLU STRAIN IS AMONG US NEW FLUMIST® QUADRIVALENT HELPS TO PROTECT YOUR ELIGIBLE MEMBERS AGAINST 4 DIFFERENT FLU STRAINS.1 t The first and only flu vaccine with four live attenuated viruses—two A strain subtypes and the two B lineages1 t An intranasal influenza vaccine indicated for eligible children and adults 2 to 49 years of age1 t Comparable immunogenicity and safety profile to that of its trivalent predecessor1 t The most common side effects are runny or stuffy nose; sore throat; and fever over 100°F

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch, or call 1-800-FDA-1088.

SELECT SAFETY INFORMATION t FluMist Quadrivalent is a vaccine indicated for active immunization of persons 2-49 years of age for the prevention of influenza disease caused by influenza A subtype viruses and type B viruses contained in the vaccine. FluMist Quadrivalent is for intranasal administration only. t FluMist Quadrivalent is contraindicated in persons who have had a severe allergic reaction to any vaccine component including egg protein, gentamicin, gelatin and arginine or after a previous dose of any influenza vaccine, and in children and adolescents receiving concomitant aspirin or aspirincontaining therapy.

Please see accompanying brief summary for additional safety and eligibility information.

Reference: 1. FluMist Quadrivalent [package insert]. Gaithersburg, MD: MedImmune, LLC.

© 2012 MedImmune. All rights reserved.

11457

1-877-FLUMIST (358-6478)

www.FluMistQuadrivalent.com

Brief Summary of Prescribing Information FluMist® Quadrivalent Influenza Vaccine Live, Intranasal Intranasal Spray 20XX-20XX Formula INDICATIONS AND USAGE FluMist® Quadrivalent is a vaccine indicated for active immunization for the prevention of influenza disease caused by influenza A subtype viruses and type B viruses contained in the vaccine.

FluMist Quadrivalent is approved for use in persons 2 through 49 years of age.

DOSAGE AND ADMINISTRATION FOR INTRANASAL ADMINISTRATION BY A HEALTHCARE PROVIDER. Dosing Information Administer FluMist Quadrivalent according to the following schedule: Age Group Vaccination Status Not previously Children age 2 years vaccinated with through 8 years influenza vaccine Children age 2 years Previously vaccinated with influenza vaccine through 8 years Children, adolescents, and adults age 9 Not applicable through 49 years

Dosage Schedule 2 doses (0.2 mL* each, at least 1 month apart) 1 dose (0.2 mL*) 1 dose (0.2 mL*)

*Administer as 0.1 mL per nostril.

CONTRAINDICATIONS Severe Allergic Reactions Do not administer FluMist Quadrivalent to persons who have had a severe allergic reaction (e.g., anaphylaxis) to any component of the vaccine including egg protein, gentamicin, gelatin, and arginine, or after a previous dose of any influenza vaccine.

Concomitant Aspirin Therapy and Reye’s Syndrome in Children and Adolescents Do not administer FluMist Quadrivalent to children and adolescents through 17 years of age who are receiving aspirin therapy or aspirin-containing therapy because of the association of Reye’s syndrome with aspirin and wild-type influenza infection.

WARNINGS AND PRECAUTIONS Risks of Hospitalization and Wheezing in Children Younger than 24 Months of Age In clinical trials, risks of hospitalization and wheezing were increased in children younger than 2 years of age who received FluMist (trivalent Influenza Vaccine Live, Intranasal). This observation with FluMist is relevant to FluMist Quadrivalent because both vaccines are manufactured using the same process and have overlapping compositions.

Asthma, Recurrent Wheezing, and Active Wheezing Children younger than 5 years of age with recurrent wheezing and persons of any age with asthma may be at increased risk of wheezing following administration of FluMist Quadrivalent. FluMist Quadrivalent has not been studied in persons with severe asthma or active wheezing.

Guillain-Barré Syndrome The 1976 swine influenza vaccine (inactivated) was associated with an elevated risk of GuillainBarré syndrome (GBS). Evidence for causal relation of GBS with other influenza vaccines is inconclusive; if an excess risk exists, based on data for inactivated influenza vaccines, it is probably slightly more than 1 additional case per 1 million persons vaccinated. If GBS has occurred within 6 weeks of any prior influenza vaccination, the decision to give FluMist Quadrivalent should be based on careful consideration of the potential benefits and potential risks.

Altered Immunocompetence FluMist Quadrivalent has not been studied in immunocompromised persons. The effectiveness of FluMist has not been studied in immunocompromised persons. Data on safety and shedding of vaccine virus after administration of FluMist in immunocompromised persons are limited to 174 persons with HIV infection and 10 mild to moderately immunocompromised children and adolescents with cancer.

Medical Conditions Predisposing to Influenza Complications The safety of FluMist Quadrivalent in individuals with underlying medical conditions that may predispose them to complications following wild-type influenza infection has not been established.

Management of Acute Allergic Reactions Appropriate medical treatment and supervision must be available to manage possible anaphylactic reactions following administration of the vaccine.

Limitations of Vaccine Effectiveness FluMist Quadrivalent may not protect all individuals receiving the vaccine.

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

This safety experience with FluMist is relevant to FluMist Quadrivalent because both vaccines are manufactured using the same process and have overlapping compositions. A total of 9537 children and adolescents 1 through 17 years of age and 3041 adults 18 through 64 years of age received FluMist in randomized, placebo-controlled Studies D153-P501, AV006, D153-P526, AV019, and AV009 [3 used Allantoic Fluid containing Sucrose-Phosphate-Glutamate (AF-SPG) placebo, and 2 used saline placebo] described below. In addition, 4179 children 6 through 59 months of age received FluMist in Study MI-CP111, a randomized, active-controlled trial. Among pediatric FluMist recipients 6 months through 17 years of age, 50% were female; in the study of adults, 55% were female. In MI-CP111, AV006, D153-P526, AV019, and AV009, subjects were White (71%), Hispanic (11%), Asian (7%), Black (6%), and Other (5%), while in D153-P501, 99% of subjects were Asian.

A total of 1382 children and adolescents 2 through 17 years of age and 1198 adults 18 through 49 years of age received FluMist Quadrivalent in randomized, active-controlled Studies MI-CP208 and MI-CP185. Among pediatric FluMist Quadrivalent recipients 2 through 17 years of age, 51% were female; in the study of adults, 55% were female. In Studies MI-CP208 and MI-CP185, subjects were White (73%), Asian (1%), Black or African-American (19%), and Other (7%); overall, 22% were Hispanic or Latino.

FluMist in Children and Adolescents The safety of FluMist was evaluated in an AF-SPG placebo-controlled study (AV019) conducted in a Health Maintenance Organization (HMO) in children 1 through 17 years of age (FluMist = 6473, placebo = 3216). An increase in asthma events, captured by review of diagnostic codes, was observed in children younger than 5 years of age who received FluMist compared to those who received placebo (Relative Risk 3.53, 90% CI: 1.1, 15.7).

In Study MI-CP111, children 6 through 59 months of age were randomized to receive FluMist or inactivated Influenza Virus Vaccine manufactured by Sanofi Pasteur Inc. Wheezing requiring bronchodilator therapy or accompanied by respiratory distress or hypoxia was prospectively monitored from randomization through 42 days post last vaccination. Hospitalization due to all causes was prospectively monitored from randomization through 180 days post last vaccination.

Increases in wheezing and hospitalization (for any cause) were observed in children 6 months through 23 months of age who received FluMist compared to those who received inactivated Influenza Virus Vaccine, as shown in Table 1.

Table 1: Percentages of Children with Hospitalizations and Wheezing from Study MI-CP111a Age Group FluMist Active Controlb Adverse Reaction (n/N) (n/N) 4.2 % 3.2 % 6-23 months Hospitalizationsc (84/1992) (63/1975) 2.1 % 2.5 % 24-59 months (46/2187) (56/2198) d 5.9 % 3.8 % 6-23 months Wheezing (75/1975) (117/1992) 2.1 % 2.5 % 24-59 months (47/2187) (56/2198) a

NCT00128167; see www.clinicaltrials.gov Inactivated Influenza Virus Vaccine manufactured by Sanofi Pasteur Inc., administered intramuscularly. c Hospitalization due to any cause from randomization through 180 days post last vaccination. d Wheezing requiring bronchodilator therapy or accompanied by respiratory distress or hypoxia evaluated from randomization through 42 days post last vaccination.

Most hospitalizations observed were due to gastrointestinal and respiratory tract infections and occurred more than 6 weeks post vaccination. In post-hoc analysis, rates of hospitalization in children 6 through 11 months of age were 6.1% (42/684) in FluMist recipients and 2.6% (18/683) in inactivated Influenza Virus Vaccine recipients.

Table 2 shows pooled solicited adverse reactions occurring in at least 1% of FluMist recipients and at a higher rate (≥ 1% rate difference after rounding) compared to placebo post Dose 1 for Studies D153-P501 and AV006, and solicited adverse reactions post Dose 1 for Study MI-CP111.

Solicited adverse reactions were those about which parents/guardians were specifically queried after receipt of FluMist, placebo, or control vaccine. In these studies, solicited reactions were documented for 10 days post vaccination. Solicited reactions following the second dose of FluMist were similar to those following the first dose and were generally observed at a lower frequency.

Table 2: Summary of Solicited Adverse Reactions Observed Within 10 Days after Dose 1 for FluMist and Either Placebo or Active Control Recipients in Children 2 through 6 Years of Age a b Studies D153-P501 & AV006 Study MI-CP111 c FluMist Placebo FluMist Active Controld e e e e N=876-1759 N=424-1034 N=2170 N=2165 Event % % % % Runny Nose/ 58 50 51 42 Nasal Congestion Decreased Appetite 21 17 13 12 Irritability 21 19 12 11 Decreased Activity 7 6 14 11 (Lethargy) 9 5 6 Sore Throat 11 Headache 9 7 3 3 Muscle Aches 6 3 2 2 Chills 4 3 2 2 Fever > 100°F Oral 16 11 13 11 9 6 6 4 > 100- ≤101°F Oral > 101- ≤102°F Oral 4 3 4 3 a NCT00192244; see www.clinicaltrials.gov b NCT00128167; see www.clinicaltrials.gov c Study D153-P501 used saline placebo; Study AV006 used AF-SPG placebo. d Inactivated Influenza Virus Vaccine manufactured by Sanofi Pasteur Inc., administered intramuscularly. e Number of evaluable subjects (those who returned diary cards) for each reaction. Range reflects differences in data collection between the 2 pooled studies.

In clinical studies D153-P501 and AV006, unsolicited adverse reactions in children occurring in at least 1% of FluMist recipients and at a higher rate (≥ 1% rate difference after rounding) compared to placebo were abdominal pain (2% FluMist vs. 0% placebo) and otitis media (3% FluMist vs.

1% placebo). An additional adverse reaction identified in the active-controlled trial MI-CP111 occurring in at least 1% of FluMist recipients and at a higher rate (≥ 1% rate difference after rounding) compared to active control was sneezing (2% FluMist vs. 1% active control).

In a separate saline placebo-controlled trial (D153-P526) in a subset of older children and adolescents 9 through 17 years of age who received one dose of FluMist, the solicited adverse reactions as well as unsolicited adverse reactions reported were generally consistent with observations from the trials in Table 2. Abdominal pain was reported in 12% of FluMist recipients compared to 4% of placebo recipients and decreased activity was reported in 6% of FluMist recipients compared to 0% of placebo recipients.

In Study AV018, in which FluMist was concomitantly administered with Measles, Mumps, and Rubella Virus Vaccine Live (MMR, manufactured by Merck & Co., Inc.) and Varicella Virus Vaccine Live (manufactured by Merck & Co., Inc.) to children 12 through 15 months of age, adverse reactions were similar to those seen in other clinical trials of FluMist.

FluMist Quadrivalent in Children and Adolescents In the randomized, active-controlled Study MI-CP208 that compared FluMist Quadrivalent and FluMist in children and adolescents 2 through 17 years of age, the rates of solicited adverse reactions reported were similar between subjects who received FluMist Quadrivalent and FluMist.

Table 3 includes solicited adverse reactions post Dose 1 from Study MI-CP208 that either occurred at a higher rate (≥ 1% rate difference after rounding) in FluMist Quadrivalent recipients compared b

to FluMist recipients or were identified in previous FluMist clinical studies [see Table 2]. In this study, solicited adverse reactions were documented for 14 days post vaccination. Solicited adverse reactions post Dose 2 were observed at a lower frequency compared to those post Dose 1 for FluMist Quadrivalent and were similar between subjects who received FluMist Quadrivalent and FluMist.

Table 3: Summary of Solicited Adverse Reactionsa Observed Within 14 Days after Dose 1 for FluMist Quadrivalent and FluMist Recipients in Study MI-CP208b in Children and Adolescents 2 through 17 Years of Age FluMist Quadrivalent N = 1341-1377d % 32 13 10 9 6 4

FluMistc N = 901-920d % 32 12 10 10 7 5

Event Runny Nose/Nasal Congestion Headache Decreased Activity (Lethargy) Sore Throat Decreased Appetite Muscle Aches Fever 7 5 > 100°F by any route 3 2 > 100 - ≤ 101°F by any route > 101 - ≤ 102°F by any route 2 2 a Solicited adverse reactions that occurred at a higher rate (≥ 1% rate difference after rounding) in FluMist Quadrivalent recipients compared to FluMist recipients or were identified in previous FluMist trials [see Table 2]. b NCT01091246; see www.clinicaltrials.gov c Represents pooled data from the two FluMist study arms. d Number of evaluable subjects for each event.

In Study MI-CP208, no unsolicited adverse reactions occurred at a higher rate (1% or greater) in FluMist Quadrivalent recipients compared to FluMist recipients.

FluMist in Adults In adults 18 through 49 years of age in Study AV009, solicited adverse reactions occurring in at least 1% of FluMist recipients and at a higher rate (≥ 1% rate difference after rounding) compared to AF-SPG placebo include runny nose (44% FluMist vs. 27% placebo), headache (40% FluMist vs. 38% placebo), sore throat (28% FluMist vs. 17% placebo), tiredness/weakness (26% FluMist vs. 22% placebo), muscle aches (17% FluMist vs. 15% placebo), cough (14% FluMist vs.

11% placebo), and chills (9% FluMist vs. 6% placebo).

In Study AV009, unsolicited adverse reactions occurring in at least 1% of FluMist recipients and at a higher rate (≥ 1% rate difference after rounding) compared to placebo were nasal congestion (9% FluMist vs. 2% placebo) and sinusitis (4% FluMist vs. 2% placebo).

FluMist Quadrivalent in Adults In the randomized, active-controlled Study MI-CP185 that compared FluMist Quadrivalent and FluMist in adults 18 through 49 years of age, the rates of solicited adverse reactions reported were generally similar between subjects who received FluMist Quadrivalent and FluMist. Table 4 presents solicited adverse reactions that either occurred at a higher rate (≥ 1% rate difference after rounding) in FluMist Quadrivalent recipients compared to FluMist recipients or were identified in Study AV009.

Table 4: Summary of Solicited Adverse Reactionsa Observed Within 14 Days after Dose 1 for FluMist Quadrivalent and FluMist Recipients in Study MI-CP185b in Adults 18 through 49 Years of Age FluMist Quadrivalent FluMistc N = 1197d N = 597d Event % % Runny Nose/Nasal Congestion 44 40 Headache 28 27 Sore Throat 19 20 Decreased Activity (Lethargy) 18 18 Cough 14 13 Muscle Aches 10 10 Decreased Appetite 6 5 a Solicited adverse reactions that occurred at a higher rate (≥ 1% rate difference after rounding) in FluMist Quadrivalent recipients compared to FluMist recipients or were identified in Study AV009. b NCT00860067; see www.clinicaltrials.gov c Represents pooled data from the two FluMist study arms. d Number of evaluable subjects for each event.

In Study MI-CP185, no unsolicited adverse reactions occurred at a higher rate (1% or greater) in FluMist Quadrivalent recipients compared to FluMist recipients.

Postmarketing Experience The following events have been spontaneously reported during post approval use of FluMist.

Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to vaccine exposure.

Cardiac disorders: Pericarditis Congenital, familial, and genetic disorders: Exacerbation of symptoms of mitochondrial encephalomyopathy (Leigh syndrome) Gastrointestinal disorders: Nausea, vomiting, diarrhea Immune system disorders: Hypersensitivity reactions (including anaphylactic reaction, facial edema, and urticaria) Nervous system disorders: Guillain-Barré syndrome, Bell’s Palsy, meningitis, eosinophilic meningitis, vaccine-associated encephalitis Respiratory, thoracic, and mediastinal disorders: Epistaxis Skin and subcutaneous tissue disorders: Rash DRUG INTERACTIONS Aspirin Therapy Do not administer FluMist Quadrivalent to children and adolescents through 17 years of age who are receiving aspirin therapy or aspirin-containing therapy because of the association of Reye’s syndrome with aspirin and wild-type influenza. Avoid aspirin-containing therapy in these age groups during the first 4 weeks after vaccination with FluMist Quadrivalent unless clearly needed.

Antiviral Agents Against Influenza A and/or B Antiviral drugs that are active against influenza A and/or B viruses may reduce the effectiveness of FluMist Quadrivalent if administered within 48 hours before, or within 2 weeks after vaccination.

The concurrent use of FluMist Quadrivalent with antiviral agents that are active against influenza A and/or B viruses has not been evaluated. If antiviral agents and FluMist Quadrivalent are administered concomitantly, revaccination should be considered when appropriate.

Concomitant Administration with Inactivated Vaccines The safety and immunogenicity of FluMist Quadrivalent when administered concomitantly with inactivated vaccines have not been determined. Studies of FluMist and FluMist Quadrivalent excluded subjects who received any inactivated or subunit vaccine within two weeks of enrollment.

Concomitant Administration with Other Live Vaccines Concomitant administration of FluMist Quadrivalent with Measles, Mumps, and Rubella Virus Vaccine Live (MMR, manufactured by Merck & Co., Inc.) or the Varicella Virus Vaccine Live (manufactured by Merck & Co., Inc.) has not been studied. Concomitant administration of FluMist with MMR and the varicella vaccine was studied in children 12 through 15 months of age.

Concomitant administration of FluMist with the MMR and the varicella vaccine in children older than 15 months of age has not been studied.

Intranasal Products There are no data regarding co-administration of FluMist Quadrivalent with other intranasal preparations.

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category B A developmental and reproductive toxicity study has been performed in female rats administered FluMist Quadrivalent either three times (during the period of organogenesis) or six times (prior to gestation and during the period of organogenesis), 200 microliter/rat/occasion (approximately 150 human dose equivalents), by intranasal instillation and has revealed no evidence of impaired fertility or harm to the fetus due to FluMist Quadrivalent. There are however, no adequate and well controlled studies in pregnant women. Because animal studies are not always predictive of human response FluMist Quadrivalent should be administered during pregnancy only if clearly needed.

Nursing Mothers It is not known whether FluMist Quadrivalent is excreted in human milk. Because some viruses are excreted in human milk, caution should be exercised when FluMist Quadrivalent is administered to a nursing woman.

Pediatric Use Safety and effectiveness of FluMist Quadrivalent in children 24 months of age and older is based on data from FluMist clinical studies and a comparison of post-vaccination antibody titers between persons who received FluMist Quadrivalent and those who received FluMist. FluMist Quadrivalent is not approved for use in children younger than 24 months of age because use of FluMist in children 6 through 23 months has been associated with increased risks of hospitalization and wheezing in clinical trials.

Geriatric Use FluMist Quadrivalent is not approved for use in persons 65 years of age and older because in a clinical study (AV009), effectiveness of FluMist to prevent febrile illness was not demonstrated in adults 50 through 64 years of age. In this study, solicited events among individuals 50 through 64 years of age were similar in type and frequency to those reported in younger adults. In a clinical study of FluMist in persons 65 years of age and older, subjects with underlying high-risk medical conditions (N = 200) were studied for safety. Compared to controls, FluMist recipients had a higher rate of sore throat.

PATIENT COUNSELING INFORMATION Vaccine recipients or their parents/guardians should be informed by the healthcare provider of the potential benefits and risks of FluMist Quadrivalent and the need for two doses at least 1 month apart in children 2 through 8 years of age who have not previously received influenza vaccine. The healthcare provider should provide the Vaccine Information Statements (VIS) which are required by the National Childhood Vaccine Injury Act of 1986 to be given with each immunization.

Asthma and Recurrent Wheezing Ask the vaccinee or their parent/guardian if the vaccinee has asthma. For children younger than 5 years of age, also ask if the vaccinee has recurrent wheezing since this may be an asthma equivalent in this age group. The vaccinee or their parent/guardian should be informed that there may be an increased risk of wheezing associated with FluMist Quadrivalent in persons younger than 5 years of age with recurrent wheezing and persons of any age with asthma.

Vaccination with a Live Virus Vaccine Vaccine recipients or their parents/guardians should be informed by the healthcare provider that FluMist Quadrivalent is an attenuated live virus vaccine and has the potential for transmission to immunocompromised household contacts.

Adverse Event Reporting The vaccine recipient or their parent/guardian should be instructed to report adverse reactions to their healthcare provider.

FluMist® is a registered trademark of MedImmune, LLC.

Manufactured by: MedImmune, LLC Gaithersburg, MD 20878 1-877-633-4411 Issue Date: February 2012 U.S. Government License No. 1799

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April 2011

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Medical Care Costs and Hospitalization in Patients with Bipolar Disorder Treated with Atypical Antipsychotics Joette Gdovin Bergeson, PhD, MPA; Iftekhar Kalsekar, PhD; Yonghua Jing, PhD; Min You, MS; Robert A. Forbes, PhD; Tony Hebden, PhD Background: A large proportion of costs associated with the treatment of bipolar disorder are attributable to patient hospitalization.

Objective: To investigate medical care costs and hospitalization rates among patients with bipolar disorder who were managed with aripiprazole compared with olanzapine, quetiapine, risperidone, or ziprasidone.

Methods: This retrospective cohort study assessed patients who were aged 18 to 64 years, diagnosed with bipolar disorder, and who were receiving therapy with aripiprazole, olanzapine, quetiapine, risperidone, or ziprasidone. This study was based on data from the PharMetrics claims database between January 1, 2003, and September 30, 2008. The study used a timeto-event framework. Cox proportional hazards models were used to assess the impact of each atypical antipsychotic on time to hospitalization, including all-cause and mental health–related reasons. Generalized linear models were used to compare costs per treated patient per month between the groups. Aripiprazole therapy was the reference group for all comparisons.

Results: Aripiprazole therapy showed a significantly lower hazard ratio (HR) for all-cause hospitalizations compared with olanzapine (HR, 1.4), quetiapine (HR, 1.4), risperidone (HR, 1.2), and ziprasidone (HR, 1.7); and for mental health–related hospitalizations compared with olanzapine, quetiapine, risperidone (HR, 1.3 each), and ziprasidone (HR, 1.7). Ziprasidone had higher unadjusted all-cause medical costs (US $1151 ± $2928) and unadjusted mental health–related costs (US $711 ± $2263) than the other antipsychotics that were included in this study, whereas aripiprazole had the lowest all-cause (US $804 ± $2523) and mental health–related costs (US $475 ± $2145) compared with the other antipsychotics. Quetiapine had the highest all-cause costs (US $1221; 95% confidence interval [CI], 1180-1263), and ziprasidone had the highest mental health–related costs (US $823; 95% CI, 754-898).

Adjusted inpatient and emergency department all-cause costs were significantly lower for aripiprazole compared with all other atypical antipsychotics (P <.05), except olanzapine; however, the adjusted inpatient and emergency department mental health–related costs were significantly lower for aripiprazole only when compared with ziprasidone (P <.05).

Conclusions: The costs of medical care for patients with bipolar disorder differ based on the type of medication used, which can affect the rate of hospitalization. Treatment with aripiprazole was associated with fewer hospitalizations, longer time to hospitalization, and therefore the lowest all-cause and mental health–related medical costs compared with olanzapine, quetiapine, risperidone, or ziprasidone. Therefore, aripiprazole may offer an economic advantage over other atypical antipsychotics in patients with bipolar disorder.

B

ipolar disorder is a chronic, recurring disorder associated with frequent episodes of mania and depression. Overall costs for the treatment of bipolar dis-

Stakeholder Perspective, page 386

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2012;5(6):379-386 www.AHDBonline.com Disclosures are at end of text

order are comprised of direct costs of professional services, medication, and hospitalization costs; indirect costs associated with caring for patients; as well as costs asso-

Dr Bergeson is Director of Health Services, Dr Kalsekar is Director of US Health Services (Neuroscience), Dr Jing is Associate Director of Health Economics and Outcomes Research, Ms You is a biostatistician, and Dr Hebden is Executive Director of Health Economics and Outcomes Research, all at Bristol-Myers Squibb, Plainsboro, NJ; Dr Forbes is a former Senior Director of CNS Global Medical Affairs, Neuroscience, at Otsuka Pharmaceutical Development & Commercialization, Inc, Princeton, NJ.

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KEY POINTS ➤

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Patients with bipolar disorder use close to 3- to 4fold more healthcare resources and incur more than 4-fold greater healthcare costs than patients without the disorder.

Hospitalization of patients with bipolar disorder is thought to be the single most costly resource, accounting for approximately 33% to 66% of the overall costs of treating patients with this disorder.

Atypical antipsychotics are increasingly used for patients with bipolar disorder; this study compared the cost of medical care and hospitalization rates for patients who received aripiprazole and those who received olanzapine, quetiapine, risperidone, or ziprasidone.

The patients using longer-acting antipsychotics had a lower rate of hospital admissions and emergency department visits than those using short half-life antipsychotic agents.

Ziprasidone had higher unadjusted all-cause medical costs ($1151) and unadjusted mental health–related costs ($711) than the other antipsychotics in this study.

Aripiprazole had the lowest all-cause ($804) and mental health–related costs ($475) compared with the other antipsychotics.

Furthermore, aripiprazole was associated with a significantly lower rate of hospitalizations and a longer time to hospitalization than the other medications in this study.

ciated with the loss of productivity.1,2 Notably, 33.5% to 65.2% of the overall cost of treating patients with bipolar disorder is attributable to patient hospitalization,3,4 with the majority of patients with bipolar disorder reporting at least 1 psychiatric hospitalization in their lifetime.5 Indeed, patient hospitalization is thought to be the single most costly resource in bipolar disorder, accounting for approximately 50% of the cost of medical encounters.6 Patients with bipolar disorder have been found to utilize nearly 3 to 4 times more healthcare resources6 and to incur more than 4 times greater healthcare costs than patients without bipolar disorder.7 An analysis of claims data comparing approximately 28,500 patients with bipolar disorder with approximately 85,500 control patients over a 1-year period established that the annual cost per patient was $12,764 for a patient with bipolar disorder compared with $1340 for a control patient, a significant difference (P <.001).7 Effective pharmacotherapy and psychosocial inter-

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ventions are an essential part of the successful treatment of bipolar disorder.8 Prescription data indicate that 63.1% to 70.8% of patients with bipolar disorder receive psychotropics (eg, lithium, valproate, carbamazepine), whereas 21.2% to 29.0% of patients receive antipsychotic augmentation therapy.9 Atypical antipsychotics, either as monotherapy or as adjunctive treatment to mood stabilizers, are an increasingly common treatment option for patients with bipolar disorder. There may be an association between antipsychotic medication half-life and hospitalization. It has been shown that patients using longer-acting antipsychotics experienced a lower rate of hospital admissions and emergency department visits than patients treated with short half-life antipsychotic agents.10 Moreover, all atypical antipsychotics have side effects; however, aripiprazole has been shown to have a low metabolic burden among its class.11 Recent claims database analyses have shown that treatment with aripiprazole was associated with a lower risk of and longer time to hospitalization, as well as with lower psychiatric treatment costs and lower total healthcare costs compared with other adjunctive antipsychotic medications.12-15 However, these analyses used a limited follow-up time period (ie, 90 days)12,13 or focused on longterm (ie, 1-year) cost outcomes using an intent-to-treat (ITT) methodology.14,15 The aim of the current analysis was to evaluate hospitalization and medical care costs for patients during the time they were receiving treatment with aripiprazole compared with patients receiving other atypical antipsychotics (ie, olanzapine, quetiapine, risperidone, or ziprasidone). The analysis presented here is an extension of a previous article covering medical claims from 2003 to 2006,14 with additional important changes in the methodologic approach.

Methods Study Design and Data Source This retrospective cohort analysis was conducted using the PharMetrics Patient-Centric Database, which includes medical and pharmacy claims from January 1, 2003, through September 30, 2008. The PharMetrics database encompasses a composite of 85 health plans across the United States, and it includes information on approximately 47 million patients. The database includes inpatient and outpatient medical claims, diagnosis and procedure codes, as well as pharmacy claims. The PharMetrics database is geographically representative of the US population, and includes a variety of demographic measures.

The sample for this study was restricted to health plans providing comprehensive healthcare data, includ-

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Patients (1) aged 18-64 years, (2) with 6 months preindex, and (3) 3 months postindex continuous eligibility N = 85,722

Patients not hospitalized on index date N = 84,411 ➤

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Patients had available (1) quantity and (2) supply of atypical antipsychotic during follow-up perioda N = 237,560

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Patients starting atypical antipsychotic 1/1/2003-9/30/2008 N = 284,485

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Selection Criteria The study included patients aged 18 to 64 years who had 1 or more outpatient or inpatient claims with an International Classification of Diseases, Ninth Revision code for bipolar disorder (ie, manic, mixed, or hypomanic [296.0X, 296.1, 296.4X, 6X, 7X, 8X]). A patient’s new start index date was defined as the date of the first prescription claim for an atypical antipsychotic medication in the claims database between January 1, 2003, and September 30, 2008.

Patients were excluded from the study if they were prescribed an atypical antipsychotic in the 180-day preindex period, or if they had prescriptions for more than 1 atypical antipsychotic agent at the index date.

Eligible patients were required to have at least 180 days of continuous enrollment before and after 90 days of continuous enrollment after the index prescription date.

In addition, patients were excluded from the analysis if they resided in a nursing home, hospice facility, or another type of long-term care facility, or if they received prescriptions via mail order. Patients with a diagnosis of schizophrenia spectrum disorder (295.XX), or those who were hospitalized at the time of the index prescription or within 7 days after the index prescription, were excluded from the study.

In the analysis evaluating the impact of atypical antipsychotics on hospitalizations, patients were followed for up to 1 year or until the occurrence of hospitalization, loss of continuous eligibility, or until switching or discontinuation of the index medication occurred (allowing for a gap of 15 days).

In this study, the inpatient and emergency department visit costs and medical costs were also evaluated for patients during their time receiving the index treatment.

For this analysis, patients were followed from treatment initiation to the time of switching or discontinuation of the index medication (allowing for a gap of 15 days), loss of continuous eligibility, or the end of the study period (after 1 year).

Costs were reported as costs per treated patient per month (PPPM). Both all-cause and mental health–related outcomes were evaluated. Mental health–related outcomes were identified based on claims with a primary or

Figure Patient Flow

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ing mental health–related services. The general approach of the analysis was to use baseline measures of health and disease severity, such as baseline comorbidity indices, demographics, drug utilization patterns, and hospitalization rates. Lagged costs as predictors in cost models were not used because of issues with serial correlation. In particular, because healthcare data are extremely skewed, the use of a highly variable predictor may lead to an unstable model.

Study sample Patients with bipolar disorder and no long-term care claims N = 19,176

a

Quantity and supply of atypical antipsychotic during follow-up period denotes patients with an atypical antipsychotic prescription that included the number of days supplied and the quantity of drug dispensed.

a secondary diagnosis code ranging from 290.XX to 319.XX. Costs were adjusted to 2008 US dollars using the medical care component of the Consumer Price Index.

Assessments and Statistical Analyses The primary analysis of time to hospitalization was addressed using a Cox proportional hazards model, which controlled for baseline factors, such as age, sex, year of index prescription, Charlson comorbidity index, diabetes, hyperlipidemia, glucose and lipid testing, baseline hospitalization rate, and use of mood stabilizers.

These control variables were computed using data from the 6-month period before the index date.

The models for medical costs were implemented using a generalized linear framework with a log link and gamma distribution. For the analysis of costs of hospitalization and emergency department visits, a 2-stage multivariate modeling approach was used combining logistic

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Table 1 Patient Demographics and Preindex Healthcare Treatment and Resource Use, by Drug: On-Treatment Sample Variable

Aripiprazole (N = 3690)

Olanzapine (N = 3038)

Quetiapine (N = 7936)

Risperidone (N = 2997)

Ziprasidone (N = 1515)

Mean age, yrs (SD)

38.50 (12.7)

40.16 (12.8)a

39.01 (12.2)a

39.24 (12.9)a

39.90 (12.2)a

Male, N (%)

1151 (31.2)

1423 (46.8)a

2968 (37.4)a

1241 (41.4)a

454 (30.0)

2003

130 (3.5)

523 (17.2)a

404 (5.1)a

320 (10.7)a

70 (4.6)a

2004

270 (7.3)

630 (20.7)a

860 (10.8)a

574 (19.2)a

169 (11.2)a

2005

512 (13.9)

545 (17.9)a

1306 (16.5)a

550 (18.4)a

280 (18.5)a

2006

828 (22.4)

541 (17.8)a

1777 (22.4)a

658 (22.0)a

352 (23.2)a

2007

1005 (27.2)

507 (16.7)a

2299 (29.0)a

595 (19.9)a

397 (26.2)a

2008

945 (25.6)

292 (9.6)a

1290 (16.3)a

300 (10.0)a

247 (16.3)a

Mean Charlson comorbidity index (SD)

0.32 (0.82)

0.34 (0.96)

0.34 (0.88)

0.34 (0.90)

0.38 (0.88)a

All-cause hospitalization, N (%)

831 (22.5)

922 (30.3)a

2412 (30.4)a

981 (32.7)a

489 (32.3)a

Mental health–related hospitalization, N (%)

757 (20.5)

873 (28.7)a

2246 (28.3)a

914 (30.5)a

465 (30.7)a

Diabetes, N (%)

302 (8.2)

140 (4.6)a

551 (6.9)a

214 (7.1)

148 (9.8)

Hyperlipidemia, N (%)

696 (18.9)

538 (17.7)

1413 (17.8)

559 (18.7)

311 (20.5)

Glucose testing conducted, N (%)

1360 (36.9)

1108 (36.5)

2958 (37.3)

1068 (35.6)

603 (39.8)a

Lipid testing conducted, N (%)

717 (19.4)

552 (18.2)

1508 (19.0)

535 (17.9)

329 (21.7)

Index year, N (%)

Use of mood stabilizer, N (%)

1721 (46.6)

1037 (34.1)

a

a

3342 (42.1)

1187 (39.6)

a

698 (46.1)

a

P <.05 versus aripiprazole.

SD indicates standard deviation.

regression, generalized linear models, and bootstrapping with 200 repetitions, to account for the fact that many patients had no hospitalizations and emergency department visits and therefore incurred no inpatient or emergency department costs.

All models controlled for the same set of baseline factors used in the Cox proportional hazards model that was stated above. Aripiprazole therapy was used as the reference group for all of the comparisons, with an a priori level of significance set at 0.05 (2-sided).

Results Patient Disposition and Characteristics A total of 284,485 patients were identified with a prescription for an atypical antipsychotic in the study database; 19,176 patients had been diagnosed with bipolar disorder, met the study selection criteria, and were therefore included in this analysis. A schematic diagram of patient disposition is shown in the Figure (page 381).

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Baseline Differences Of the total number of patients, 3690 were prescribed aripiprazole; 3038 received olanzapine; 7936 quetiapine; 2997 risperidone; and 1515 received ziprasidone (Table 1). Baseline patient characteristics for the 5 atypical antipsychotics are displayed in Table 1. Patients who were treated with aripiprazole were statistically younger, more likely to be female, and had lower rates of preindex hospitalization and emergency department rates than the comparator atypical antipsychotics. Mean time on treatment ranged from 67 to 74 days (aripiprazole, 71 ± 76; olanzapine, 67 ± 74; quetiapine, 74 ± 84; risperidone, 71 ± 78; ziprasidone, 69 ± 78).

Time to Hospitalization Results of the Cox proportional hazards model, controlling for differences in baseline patient characteristics, demonstrated a significantly lower hazard ratio (HR) for all-cause and for mental health–related hospitalization

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for patients who received aripiprazole compared with those receiving any of the other atypical antipsychotics (Table 2).

Results of Cox Proportional Hazards Model for Table 2 All-Cause and Mental Health–Related Hospitalization

Medical and Inpatient Costs (on Treatment Analysis) The unadjusted PPPM medical costs (ie, outpatient plus inpatient and emergency department) were significantly lower for aripiprazole compared with all the other atypical antipsychotics for all-cause and for mental health–related costs (Table 3).

The unadjusted all-cause medical costs (US $1151 ± $2928) and mental health–related costs (US $711 ± $2263) associated with ziprasidone treatment were higher than for the other atypical antipsychotics that were assessed, whereas the lowest all-cause (US $804 ± $2523) and mental health–related costs (US $475 ± $2145) were associated with aripiprazole treatment compared with the other atypical antipsychotics (Table 3).

Results of the generalized linear models regression demonstrated consistent findings for all-cause and for mental health–related medical (ie, outpatient plus inpatient and emergency department) costs, with costs for patients receiving aripiprazole being significantly lower (US $911; 95% confidence interval [CI], 866-958 and US $576; 95% CI, 543-610, respectively) compared with other atypical antipsychotics (P <.05; Table 4, page 384).

The highest all-cause costs were seen with quetiapine (US $1221; 95% CI, 1180-1263), and the highest mental health–related costs were seen with ziprasidone (US $823; 95% CI, 754-898).

The current analysis also indicates lower all-cause and mental health–related inpatient and emergency department costs for patients receiving aripiprazole compared with those receiving all other atypical antipsychotics (Table 5, page 385). The adjusted inpatient and emergency department all-cause costs were significantly lower for aripiprazole compared with all other atypical antipsychotics (P <.05), except olanzapine, whereas the adjusted inpatient and emergency department mental health– related costs were significantly lower for this agent only when compared with ziprasidone (P <.05).

Medication-based hospitalization

Discussion This analysis of commercially insured patients with a diagnosis of bipolar disorder who were receiving atypical antipsychotic treatment established that the HR of hospitalization for patients receiving aripiprazole treatment was significantly lower than for patients receiving other atypical antipsychotics. This translated into lower medical costs for patients prescribed aripiprazole compared with those receiving any of the other atypical antipsychotics.

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Hazard ratio (95% confidence interval)

All-cause hospitalization Olanzapine

1.4 (1.1-1.7)

Quetiapine

1.4 (1.2-1.6)

Risperidone

1.2 (1.0-1.5)

Ziprasidone

1.7 (1.4-2.1)

Mental health–related hospitalization Olanzapine

1.3 (1.1-1.6)

Quetiapine

1.3 (1.1-1.5)

Risperidone

1.3 (1.1-1.6)

Ziprasidone

1.7 (1.4-2.1)

Note: Aripiprazole therapy was the reference group for all comparisons. Estimates are reported after controlling for age, sex, year of index prescription, Charlson comorbidity index, diabetes, hyperlipidemia, glucose and lipid testing, baseline hospitalization rate, and use of mood stabilizers.

Medical and Inpatient/Emergency Department Table 3 Unadjusted Costs: On-Treatment Analysis Inpatient and Medical costs emergency department (outpatient + costs, mean, $ inpatient), mean, $ (± SD) (± SD)

Medicationspecific costs All-cause costs Aripiprazole

299 (± 2087)

804 (± 2523)

Olanzapine

443 (± 3106)

1038 (± 3771)

Quetiapine

468 (± 2614)

1089 (± 3450)

Risperidone

453 (± 2598)

1032 (± 3103)

Ziprasidone

588 (± 2552)

1151 (± 2928)

Mental health–related costs Aripiprazole

225 (± 1893)

475 (± 2145)

Olanzapine

301 (± 2024)

621 (± 2382)

Quetiapine

331 (± 2102)

655 (± 2479)

Risperidone

318 (± 2062)

674 (± 2453)

Ziprasidone

415 (± 2015)

711 (± 2263)

Costs reported as per treated patient per month in 2008 US dollars.

SD indicates standard deviation.

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Generalized Linear Models Regression Analysis for Table 4 Adjusted Mean Medical Costs: Outpatient plus Inpatient/Emergency Department Mean adjusted 95% Confidence medical costs, $ Medicationinterval (outpatient + specific inpatient/emergency Lower Upper medical costs department) costs, $ costs, $ All-cause costs Aripiprazole

911

866

958

Olanzapine

1100a

1039

1165

Quetiapine

1221a

1180

1263

Risperidone

1040a

984

1099

Ziprasidone

1216a

1126

1312

576

543

610

Olanzapine

714

a

668

762

Quetiapine

804a

773

836

Risperidone

757

a

711

807

Ziprasidone

823a

754

898

Mental health–related costs Aripiprazole

a

P <.05 versus aripiprazole.

Costs reported as per treated patient per month in 2008 US dollars. Estimates are reported after controlling for age, sex, year of index prescription, Charlson comorbidity index, diabetes, hyperlipidemia, glucose and lipid testing, baseline hospitalization rate, and use of mood stabilizers.

Most of the antipsychotics examined in the analysis are currently available as generic medications. Therefore, pharmacy expenditure data based on branded antipsychotics from 2003 through 2008 are not applicable for decision-making in today’s marketplace.

These results are consistent with previously published findings.12,14,15 For example, Kim and colleagues evaluated commercially insured patients with bipolar disorder who were treated with a mood stabilizer and adjunctive atypical antipsychotic therapy, and observed that after multivariate adjustment for differences in baseline characteristics, aripiprazole was associated with a significantly longer time to hospitalization compared with any of the other atypical antipsychotics.13 A companion analysis of

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the study also demonstrated that treatment with adjunctive aripiprazole was associated with significantly lower psychiatric-related costs than other atypical antipsychotic agents (P <.001).12 In a similar study, Kim and colleagues14 compared the time to psychiatric hospitalization and healthcare costs in commercially insured patients who had bipolar disorder and were being treated with aripiprazole, olanzapine, quetiapine, risperidone, or ziprasidone over a 1-year period after initiation of therapy. The current study is an extension of the study by Kim and colleagues.14 In the study by Kim and colleagues, after a multivariate adjustment for differences in baseline characteristics, aripiprazole was associated with a significantly lower risk of psychiatric hospitalization than ziprasidone, quetiapine, and olanzapine, and significantly lower healthcare costs than quetiapine, but not other atypical antipsychotics.14 In a real-world study of Medicaid beneficiaries with bipolar disorder who were newly initiating an atypical antipsychotic, those prescribed aripiprazole had a significantly longer time to psychiatric hospitalization than those who were prescribed olanzapine, quetiapine, ziprasidone, or risperidone; however, this difference did not reach significance in the case of the latter.15 Although adjusted costs of psychiatric hospitalization in beneficiaries initiating aripiprazole were lower compared with all other beneficiaries receiving atypical antipsychotic therapy, this difference was only significant when compared with those initiating treatment with quetiapine.15 Furthermore, the current study focused solely on medical (ie, outpatient and inpatient) costs. Pharmacy costs were not examined, because most of the antipsychotics examined in the analysis (ie, olanzapine, quetiapine, risperidone, and ziprasidone) are currently available as generic medications. Therefore, pharmacy expenditure data based on branded antipsychotics from 2003 through 2008 are not applicable for decision-making in today’s marketplace.

The present analysis focused on the relative medical costs of patients using each medication, which will likely remain consistent between the study period and current clinical practice. It is also important to note that the time period of the analysis (2003-2008) may have led to the inclusion of some patients in the sample with potential off-label use of aripiprazole for bipolar disorder, because the US Food and Drug Administration approval for this indication was received in September 2004.

Limitations There are several limitations associated with this analysis. First, the use of medical and pharmacy claims data did not allow for confirmation of a patient’s diagnosis or whether the medication of interest was prescribed

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Medical Care Costs and Hospitalization in Bipolar Disorder

for a specific condition. However, patients included in this study had a diagnosis of bipolar disorder during the study period and were treated with an atypical antipsychotic for that disorder.

Because this was a retrospective database study, lack of randomization may have led to selection bias.

Baseline characteristics varied across the cohorts and might have impacted the results. However, the study did adjust for preperiod psychiatric hospitalizations, mood stabilizer use, Charlson comorbidity index score, and other demographic factors to minimize confounding.

It is important to note that the current analysis had less stringent inclusion criteria compared with previously published analyses, namely, that the use of adjunctive mood stabilizers was not required, the follow-up period was long (ie, 365 days), and, most important, cost outcomes were calculated during the time receiving treatment as opposed to an ITT framework projection.

Because outcomes were assessed during a patient’s time receiving treatment with the index atypical antipsychotic, the current data provide important information on the effect of atypical antipsychotics on hospitalizations and related costs during the time patients were receiving treatment as opposed to associating posttreatment events with an index medication that was discontinued months earlier. However, it should be noted that the average length of therapy in the current analysis was short (ie, mean time on treatment was 67-74 days) and may not be generalizable to patients using these drugs for a relatively longer period of time.

Conclusions In this analysis, patients in a commercial plan who were treated with aripiprazole for bipolar disorder had a longer time to hospitalization and fewer hospitalizations compared with patients who were treated with olanzapine, quetiapine, risperidone, or ziprasidone. In addition, patients treated with aripiprazole had the lowest all-cause and mental health–related medical costs compared with those treated with olanzapine, quetiapine, risperidone, or ziprasidone. These data are consistent with previous published findings for patients with bipolar disorder in realworld settings, and they suggest that aripiprazole may offer an economic advantage versus other atypical antipsychotic medications in this patient population. ■ Acknowledgment Editorial support for the preparation of the manuscript was provided by Ogilvy Healthworld Medical Education.

Study Funding This study was supported by funding from Bristol-Myers Squibb and Otsuka Pharmaceutical Co, Ltd.

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Two-Part Model for Adjusted Inpatient/Emergency Table 5 Department Costs 95% Mean adjusted Confidence costs, $ interval (inpatient/ Medicationemergency Difference Lower Upper specific medical costs department) in costs, $ costs, $ costs, $ All-cause costs Aripiprazole

295

0

0

0

Olanzapine

377

82

–25

189

Quetiapine

421a

126

37

214

Risperidone

388a

94

1

190

Ziprasidone

538a

243

115

376

Mental health–related costs Aripiprazole

215

0

0

0

Olanzapine

247

31

–43

107

Quetiapine

283

67

–3

138

Risperidone

264

49

–26

115

Ziprasidone

368a

153

41

259

a

P <.05 versus aripiprazole.

Costs are reported per treated patient per month in 2008 US dollars. Estimates are reported after controlling for age, sex, year of index prescription, Charlson comorbidity index, diabetes, hyperlipidemia, glucose and lipid testing, baseline hospitalization rate, and use of mood stabilizers.

Author Disclosure Statement Dr Bergeson, Dr Jing, and Dr Hebden are employed by and own stock in Bristol-Myers Squibb, and Dr Kalsekar and Ms You are employed by Bristol-Myers Squibb. Dr Forbes is a former employee of Otsuka Pharmaceutical Development & Commercialization, Inc.

References 1. Wyatt RJ, Henter I, Leary MC, Taylor E. An economic evaluation of schizophrenia—1991. Soc Psychiatry Psychiatr Epidemiol. 1995;30:196-205.

2. Dean BB, Gerner D, Gerner RH. A systematic review evaluating health-related quality of life, work impairment, and healthcare costs and utilization in bipolar disorder. Curr Med Res Opin. 2004;20:139-154.

3. Simon GE, Unutzer J. Health care utilization and costs among patients treated for bipolar disorder in an insured population. Psychiatr Serv. 1999;50:1303-1308.

4. Stender M, Bryant-Comstock L, Phillips S. Medical resource use among patients treated for bipolar disorder: a retrospective, cross-sectional, descriptive analysis. Clin Ther. 2002;24:1668-1676.

5. Lish JD, Dime-Meenan S, Whybrow PC, et al. The National Depressive and Manic-depressive Association (DMDA) survey of bipolar members. J Affect Disord.

1994;31:281-294.

6. Bryant-Comstock L, Stender M, Devercelli G. Health care utilization and costs among privately insured patients with bipolar I disorder. Bipolar Disord. 2002;4:398-405.

7. Centorrino F, Mark TL, Talamo A, et al. Health and economic burden of metabolic comorbidity among individuals with bipolar disorder. J Clin Psychopharmacol.

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2009;29:595-600.

8. APA. Practice Guideline for the Treatment of Patients with Bipolar Disorder (revision). Am J Psychiatry. 2002;159(4 suppl):1-50.

9. Blanco C, Laje G, Olfson M, et al. Trends in the treatment of bipolar disorder by outpatient psychiatrists. Am J Psychiatry. 2002;159:1005-1010.

10. Broder MS, Bates JA, Jing Y, et al. Association between second-generation antipsychotic medication half-life and hospitalization in the community treatment of adult schizophrenia. J Med Econ. 2012;15:105-111.

11. Citrome L. A review of aripiprazole in the treatment of patients with schizophrenia or bipolar I disorder. Neuropsychiatr Dis Treat. 2006;2:427-443.

12. Jing Y, Kim E, You M, et al. Healthcare costs associated with treatment of bipolar

disorder using a mood stabilizer plus adjunctive aripiprazole, quetiapine, risperidone, olanzapine or ziprasidone. J Med Econ. 2009;12:104-113.

13. Kim E, Maclean R, Ammerman D, et al. Time to psychiatric hospitalization in patients with bipolar disorder treated with a mood stabilizer and adjunctive atypical antipsychotics: a retrospective claims database analysis. Clin Ther. 2009;31:836-848.

14. Kim E, You M, Pikalov A, et al. One-year risk of psychiatric hospitalization and associated treatment costs in bipolar disorder treated with atypical antipsychotics: a retrospective claims database analysis. BMC Psychiatry. 2011;11:6.

15. Jing Y, Johnston SS, Fowler R, et al. Comparison of second-generation antipsychotic treatment on psychiatric hospitalization in Medicaid beneficiaries with bipolar disorder. J Med Econ. 2011;14:777-786.

STAKEHOLDER PERSPECTIVE The Potential Value of Benefit Design and Medication Selection for a Total-Cost-of-Care Strategy in Bipolar Disease PAYERS: The influences of and direction of funding under the Affordable Care Act are shifting the risk of “episodes-of-care” management onto payers under an accountable care organization model. The management of outpatient care that is associated with Medicare and Medicaid coverage involves a risk that is continuing to grow, whereby potentially preventable hospital admissions that are incurred from the inappropriate or the insufficient management of chronic diseases will not be entitled to be reimbursed under federal- and/or state-sponsored programs.

This trend in risk exposure associated with the episode-of-care management strategy is removing the silo approach to management within health plans and is leading to greater collaboration between a plan’s various departments—including care management, pharmacy, and finance—to critically evaluate and create benefit design strategies that consider the total cost of care and not just a single benefit component, such as the pharmacy or the formulary impact alone.

With this development in pharmacy benefit design, traditional formulary-driving influences, such

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as generic opportunity and contracting, may not be the final determinants in formulary placement of a specific therapy, although these strategies are still important. Mental health is an important area where this dynamic plays out, and as Dr Bergeson and colleagues demonstrate in their current study in this issue of American Health & Drug Benefits, bipolar disease suggests the potential value of medication and formulary selection from an episode-of-care total-cost viewpoint.

PATIENTS: Although not explicitly discussed within the current article, the obvious result from better control of a chronic disease (such as bipolar disorder), a reduction in hospitalizations, and the mitigation of exposure to nosocomial concerns lead the way to a better patient experience, as well as to improved quality of life and quality of care for patients.

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Jeffrey Januska, PharmD Director of Pharmacy CenCal Health Santa Barbara, CA

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MULTIPLE SCLEROSIS UPDATE

Multiple Sclerosis: Patient Characteristics and Cost Concerns

By Charles Bankhead, Medical Writer

S

everal new posters focusing on patients with multiple sclerosis (MS) were presented at the 2012 Educational Conference of the Academy of Managed Care Pharmacy (AMCP), October 3-5, 2012, Cincinnati, OH.

Relapse and Symptoms Identify Patients with High-Risk Disease The number of relapses and symptom burden predict an increased risk of relapse in patients with MS, according to a poster presented by Karina Raimundo, BS, Economics and Health Outcomes Research Fellow at Novartis Pharmaceuticals, East Hanover, NJ, and colleagues. More frequent relapses in the previous 12 months doubled the odds for a current high-relapse status, and MS symptoms in the previous year increased the odds by almost 90%. The number of disease-modifying therapies (DMTs) used in the past year increased the risk of highfrequency relapse by 30%.

High relapse activity (HRA) in patients with MS can lead to more rapid progression of disability and worse clinical outcomes. However, factors associated with HRA remain unclear, according to Ms Raimundo and colleagues. In addition, the effect of reducing HRA on the cost of care for patients with MS has not been thoroughly evaluated.

To identify predictors of HRA, Ms Raimundo and colleagues searched records in the MarketScan Commercial and Medicare Database for patients who had at least 1 International Classification of Diseases, Ninth Revision (ICD-9) entry related to MS during 2009 and at least 1 entry between 2005 and 2008. They defined HRA as â&#x2030;Ľ2 relapses during 2009.

Of 13,344 patients who met study eligibility criteria, 622 had HRA. Patients with HRA were younger, had a higher Charlson comorbidity index score (0.7 vs 0.6, respectively), and were significantly more likely to have an ICD-9 code for MS symptoms in the previous year (83.0% vs 69.4%, respectively). They also had a significantly (P <.001) higher mean number of relapses in 2008 (1.6 vs 0.2, respectively) and in 2007 (1.3 vs 0.2, respectively).

Logistic regression analysis showed that patients with MS symptoms in 2008 had an odds ratio (OR) of

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1.86 for HRA versus patients who had no symptoms in the previous year (P <.001). The relapse rates in 2007 and 2008 predicted the increased likelihood of HRA in 2009 (OR, 1.39 in 2007 and 2.40 in 2008; P <.001 for both). The number of DMTs used in the previous years also significantly increased the likelihood of HRA in 2009 (OR, 1.29).

These findings suggest that several factors may provide clues to aid early identification of patients with more aggressive forms of MS, according to the investigators. Earlier identification of patients with aggressive disease would afford an opportunity for earlier initiation of effective MS therapies and could potentially minimize the long-term adverse effects of the disease process.

[Raimundo K, et al. Predictors of high relapse activity in a multiple sclerosis population using US medical claims database.]

Adherence to MS Therapies Significantly Impacts Cost-Effectiveness Adherence to therapy was the deciding factor in an analysis of the cost-effectiveness of MS therapies, Ms Raimundo and colleagues reported in a second poster presentation. They evaluated the impact of adherence on relapse and of cost-effectiveness associated with firstline DMTs for patients with relapsing forms of MS. The lymphocyte-targeted drug fingolimod was associated with the best patient adherence, leading to a 2-year cost of $90,566 per avoided MS relapse, more than $50,000 less than the next closest agent. This indicates that adherence should figure into evaluations of the value of therapies for MS, along with efficacy and tolerability.

DMTs have become the cornerstone of treatment for MS and have demonstrated the ability to prevent or delay progression to permanent neurologic disability.

The currently available DMTs for MS vary in terms of cost, and the contributions of patient adherence to cost have not been examined in detail.

Another poster presented at the AMCP meeting showed that adherence to first-line DMTs, defined as medication possession ratio â&#x2030;Ľ80%, was 89.2% with fingolimod, 72.4% for subcutaneous (SC) interferon (IFN) beta-1b, 77.8% for SC IFN beta-1a, 82.1% for glatiramer acetate, and 79.2% for intramuscular (IM) IFN beta-1a (Abouzaid S, et al. Comparison of compliance with fin-

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golimod and other first-line disease-modifying treatments among patients with multiple sclerosis). Using those figures, Ms Raimundo and colleagues evaluated the impact of adherence on the rate of relapse and costeffectiveness for first-line DMTs in MS from the perspective of a US commercial payer.

The cost of relapse was based on the severity of the relapse and the cost of managing the relapse. The relative incidence of relapse severity was assumed to be the same for all DMTs. Wholesale acquisition costs for DMTs were obtained from Analy$ource, a web-based pricing tool.

The impact of nonadherence was based on a published estimate showing that adherent patients had a statistically significant 29% lower risk of relapse compared with nonadherent patients (Tan H, et al. Adv Ther. 2011; 28:51-61).

The results showed that fingolimod was associated with a cost of $90,566 per avoided relapse. Among the other DMTs, the estimated costs for each relapse episode avoided were $142,268 (Extavia) and $153,944 (Betaseron) for SC IFN beta-1b; $155,486 for SC IFN beta-1a; $174,097 for glatiramer acetate; and $370,397 for IM IFN beta-1a.

The investigators concluded that adherence has a significant effect on real-world effectiveness of DMTs in MS, which in turn influences cost-effectiveness. Higher rates of adherence with fingolimod would translate into higher estimated real-world effectiveness in the model used in the study. [Raimundo K, et al. Cost-effectiveness of multiple sclerosis treatments: effects of adherence.]

MS Relapse Exacts Heavy Toll on Direct, Indirect Costs The relapses of MS substantially increased direct and indirect costs, which rose even higher with the severity of relapse, according to a poster presented by Hélène Parisé, MA, an economist with the Groupe d’analyse Iteé, Montréal, Canada, and colleagues.

Many studies have demonstrated a significant economic burden associated with MS, which affects direct and indirect costs. Nonetheless, studies assessing the economic impact of relapse severity have been lacking, Ms Parisé and colleagues noted.

To characterize the economic impact of MS relapses, the investigators searched the OptumHealth Reporting

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and Insights database for the period from January 1999 through December 2011 to identify patients with ≥2 primary or secondary MS-related diagnoses. Characteristics of patients who met the diagnostic criteria were evaluated beginning 180 days before the first MS diagnosis and were extended to the first year after diagnosis.

Severe relapse was defined as an MS-related episode requiring hospitalization, and relapses of low or moderate severity were defined as episodes requiring an outpatient or emergency department visit.

A total of 9421 patients with MS were identified, including 7686 patients with no relapses, 1220 with ≥1 low or moderately severe relapses, and 515 with at least 1 high-severity relapse. Compared with patients who had no relapses, those with low or moderately severe relapses were younger and healthier (by the Quan-Charlson comorbidity index), and patients with high-severity relapses had more cardiovascular disease, diabetes, and use of antidepressants, and were less likely to be employed.

At 12 months, patients with no relapses had mean all-cause direct costs of $17,545 compared with $28,348 for patients with low or moderately severe relapses and $41,969 for patients with severe relapses. MS-specific costs averaged $8803 for patients with no relapses, $18,981 for patients with low or moderately severe relapses, and $29,355 for patients with severe relapses.

All-cause indirect costs at 12 months of follow-up averaged $4146 for relapse-free patients, $5610 for patients with low or moderately severe relapses, and $9226 for patients with severe relapses. MS-specific indirect costs averaged $1613, $3238, and $6939 for patients with no, low or moderately severe, and severe relapses, respectively.

This cost disparity for direct and indirect costs persisted in an analysis to 36 months after the diagnosis of MS. Overall, the average per-patient per-year direct costs increased by almost 60% with low-to-moderately severe relapse, and the costs more than doubled with a severe relapse. Indirect costs doubled with severe relapse and increased by 50% with low or moderately severe relapse.

Much of the difference between relapse-free patients and those with relapses resulted from increased MSspecific costs, suggesting that interventions that reduce the frequency and severity of MS relapses can help reduce the cost of care for patients with MS. [Parisé H, et al. Direct and indirect costs associated with relapse of multiple sclerosis.] ■

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For your patients with type 2 diabetes who need more than A1C control, choose Levemir ® (insulin detemir [rDNA origin] injection)

24/7 GLUCOSE CONTROL MORE

Karen’s doctor said taking Levemir ® (insulin detemir [rDNA origin] injection) once-daily may get her the control she needs & more Low rates of hypoglycemia In 1 study, approximately 45% of patients in each treatment arm achieved A1C <7% with no hypoglycemic events within the last 4 weeks of observation.1 t A single major hypoglycemic event was reported in the 70-90 mg/dL group; no major hypoglycemic events in the 80-110 mg/dL group t Minor hypoglycemia rates were 5.09 (70-90 mg/dL) and 3.16 (80-110 mg/dL) per patient-year*

From a 20-week, randomized, controlled, multicenter, open-label, parallel-group, treat-to-target trial using a self-titration algorithm in insulin-naïve patients with type 2 diabetes, A1C ≥7% and ≤9% on OAD therapy randomized to Levemir® and OAD (1:1) to 2 different fasting plasma glucose (FPG) titration targets (70-90 mg/dL [n=121] or 80-110 mg/dL [n=122]). At study end, in the 80-110 mg/dL group, 55% of patients achieved goal (A1C <7%) with A1C decrease of 0.9%. The mean A1C was 7%.1

Covered on more than 90% of managed care plans2† hypoglycemia usually reflects the time action profile of the administered insulin formulations. Glucose monitoring is essential for all patients receiving insulin therapy. Any changes to an insulin regimen should be made cautiously and only under medical supervision.

Needles and Levemir ® FlexPen® must not be shared.

Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulin products, including Levemir ®. Adverse reactions associated with Levemir ® include hypoglycemia, allergic reactions, injection site reactions, lipodystrophy, rash and pruritus. Careful glucose monitoring and dose adjustments of insulin, including Levemir ®, may be necessary in patients with renal or hepatic impairment.

Levemir ® has not been studied in children with type 2 diabetes, and in children with type 1 diabetes under the age of six.

Indications and Usage Levemir ® (insulin detemir [rDNA origin] injection) is indicated to improve glycemic control in adults and children with diabetes mellitus.

Important Limitations of Use: Levemir ®isnotrecommendedforthetreatmentof diabetic ketoacidosis. Intravenous rapid-acting or short-acting insulin is the preferred treatment for this condition.

Important Safety Information Levemir ® is contraindicated in patients hypersensitive to insulin detemir or one of its excipients.

Do not dilute or mix Levemir® with any other insulin solution, or use in insulin infusion pumps. Do not administer Levemir® intravenously or intramuscularly because severe hypoglycemia can occur.

Hypoglycemia is the most common adverse reaction of insulin therapy, including Levemir®. The timing of

Please see brief summary of Prescribing Information on adjacent page.

Needles are sold separately and may require a prescription in some states. *Minor=SMPG <56 mg/dL and not requiring third-party assistance.

On your iPhone®

Scan the QR code to download the NovoDose™ app to know how to optimally dose Levemir®

†

Intended as a guide. Lower acquisition costs alone do not necessarily reflect a cost advantage in the outcome of the condition treated because other variables affect relative costs. Formulary status is subject to change.

References: 1. Blonde L, Merilainen M, Karwe V, Raskin P; TITRATE™ Study Group. Patient-directed titration for achieving glycaemic goals using a once-daily basal insulin analogue: an assessment of two different fasting plasma glucose targets - the TITRATE™ study. Diabetes Obes Metab. 2009;11(6):623-631. 2. Data on file. Novo Nordisk Inc, Princeton, NJ. iPhone ® is a registered trademark of Apple, Inc. FlexPen® and Levemir ® are registered trademarks and NovoDose™ is a trademark of Novo Nordisk A/S. © 2012 Novo Nordisk Printed in the U.S.A. 0911-00005042-1 April 2012

LEVEMIR® (insulin detemir [rDNA origin] injection) Rx ONLY BRIEF SUMMARY. Please consult package insert for full prescribing information.

INDICATIONS AND USAGE: LEVEMIR® is indicated to improve glycemic control in adults and children with diabetes mellitus. Important Limitations of Use: LEVEMIR® is not recommended for the treatment of diabetic ketoacidosis. Intravenous rapid-acting or short-acting insulin is the preferred treatment for this condition.

CONTRAINDICATIONS: LEVEMIR® is contraindicated in patients with hypersensitivity to LEVEMIR® or any of its excipients. Reactions have included anaphylaxis.

WARNINGS AND PRECAUTIONS: Dosage adjustment and monitoring: Glucose monitoring is essential for all patients receiving insulin therapy. Changes to an insulin regimen should be made cautiously and only under medical supervision.

Changes in insulin strength, manufacturer, type, or method of administration may result in the need for a change in the insulin dose or an adjustment of concomitant anti-diabetic treatment. As with all insulin preparations, the time course of action for LEVEMIR® may vary in different individuals or at different times in the same individual and is dependent on many conditions, including the local blood supply, local temperature, and physical activity. Administration: LEVEMIR® should only be administered subcutaneously. Do not administer LEVEMIR® intravenously or intramuscularly. The intended duration of activity of LEVEMIR® is dependent on injection into subcutaneous tissue. Intravenous or intramuscular administration of the usual subcutaneous dose could result in severe hypoglycemia. Do not use LEVEMIR® in insulin infusion pumps. Do not dilute or mix LEVEMIR® with any other insulin or solution. If LEVEMIR® is diluted or mixed, the pharmacokinetic or pharmacodynamic profile (e.g., onset of action, time to peak effect) of LEVEMIR® and the mixed insulin may be altered in an unpredictable manner. Hypoglycemia: Hypoglycemia is the most common adverse reaction of insulin therapy, including LEVEMIR®. The risk of hypoglycemia increases with intensive glycemic control. Patients must be educated to recognize and manage hypoglycemia. Severe hypoglycemia can lead to unconsciousness or convulsions and may result in temporary or permanent impairment of brain function or death. Severe hypoglycemia requiring the assistance of another person or parenteral glucose infusion, or glucagon administration has been observed in clinical trials with insulin, including trials with LEVEMIR®. The timing of hypoglycemia usually reflects the time-action profile of the administered insulin formulations. Other factors such as changes in food intake (e.g., amount of food or timing of meals), exercise, and concomitant medications may also alter the risk of hypoglycemia. The prolonged effect of subcutaneous LEVEMIR® may delay recovery from hypoglycemia. As with all insulins, use caution in patients with hypoglycemia unawareness and in patients who may be predisposed to hypoglycemia (e.g., the pediatric population and patients who fast or have erratic food intake). The patient’s ability to concentrate and react may be impaired as a result of hypoglycemia. This may present a risk in situations where these abilities are especially important, such as driving or operating other machinery. Early warning symptoms of hypoglycemia may be different or less pronounced under certain conditions, such as longstanding diabetes, diabetic neuropathy, use of medications such as beta-blockers, or intensified glycemic control. These situations may result in severe hypoglycemia (and, possibly, loss of consciousness) prior to the patient’s awareness of hypoglycemia. Hypersensitivity and allergic reactions: Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulin products, including LEVEMIR®. Renal Impairment: No difference was observed in the pharmacokinetics of insulin detemir between non-diabetic individuals with renal impairment and healthy volunteers. However, some studies with human insulin have shown increased circulating insulin concentrations in patients with renal impairment.

Careful glucose monitoring and dose adjustments of insulin, including LEVEMIR®, may be necessary in patients with renal impairment. Hepatic Impairment: Nondiabetic individuals with severe hepatic impairment had lower systemic exposures to insulin detemir compared to healthy volunteers. However, some studies with human insulin have shown increased circulating insulin concentrations in patients with liver impairment. Careful glucose monitoring and dose adjustments of insulin, including LEVEMIR®, may be necessary in patients with hepatic impairment. Drug interactions: Some medications may alter insulin requirements and subsequently increase the risk for hypoglycemia or hyperglycemia.

ADVERSE REACTIONS: The following adverse reactions are discussed elsewhere: Hypoglycemia; Hypersensitivity and allergic reactions. Clinical trial experience: Because clinical trials are conducted under widely varying designs, the adverse reaction rates reported in one clinical trial may not be easily compared to those rates reported in another clinical trial, and may not reflect the rates actually observed in clinical practice. The frequencies of adverse reactions (excluding hypoglycemia) reported during LEVEMIR® clinical trials in patients with type 1 diabetes mellitus and

type 2 diabetes mellitus are listed in Tables 1-4 below. See Tables 5 and 6 for the hypoglycemia findings.

Table 1: Adverse reactions (excluding hypoglycemia) in two pooled clinical trials of 16 weeks and 24 weeks duration in adults with type 1 diabetes (adverse reactions with incidence ≥ 5%)

Upper respiratory tract infection Headache Pharyngitis Influenza-like illness Abdominal Pain

LEVEMIR®, % (n = 767) 26.1 22.6 9.5 7.8 6.0

NPH, % (n = 388) 21.4 22.7 8.0 7.0 2.6

Table 2: Adverse reactions (excluding hypoglycemia) in a 26-week trial comparing insulin aspart + LEVEMIR® to insulin aspart + insulin glargine in adults with type 1 diabetes (adverse reactions with incidence ≥ 5%)

Upper respiratory tract infection Headache Back pain Influenza-like illness Gastroenteritis Bronchitis

LEVEMIR®, % (n = 161) 26.7 14.3 8.1 6.2 5.6 5.0

Glargine, % (n = 159) 32.1 19.5 6.3 8.2 4.4 1.9

Table 3: Adverse reactions (excluding hypoglycemia) in two pooled clinical trials of 22 weeks and 24 weeks duration in adults with type 2 diabetes (adverse reactions with incidence ≥ 5%)

Upper respiratory tract infection Headache

LEVEMIR®, % (n = 432) 12.5 6.5

NPH, % (n = 437) 11.2 5.3

Table 4: Adverse reactions (excluding hypoglycemia) in a 26-week clinical trial of children and adolescents with type 1 diabetes (adverse reactions with incidence ≥ 5%)

Upper respiratory tract infection Headache Pharyngitis Gastroenteritis Influenza-like illness Abdominal pain Pyrexia Cough Viral infection Nausea Rhinitis Vomiting

LEVEMIR®, % (n = 232) 35.8 31.0 17.2 16.8 13.8 13.4 10.3 8.2 7.3 6.5 6.5 6.5

NPH, % (n = 115) 42.6 32.2 20.9 11.3 20.9 13.0 6.1 4.3 7.8 7.0 3.5 10.4

Hypoglycemia: Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, including LEVEMIR®. Tables 5 and 6 summarize the incidence of severe and non-severe hypoglycemia in the LEVEMIR® clinical trials. Severe hypoglycemia was defined as an event with symptoms consistent with hypoglycemia requiring assistance of another person and associated with either a blood glucose below 50 mg/ dL or prompt recovery after oral carbohydrate, intravenous glucose or glucagon administration. Non-severe hypoglycemia was defined as an asymptomatic or symptomatic plasma glucose < 56 mg/dL (<50 mg/dL in Study A and C) that was self-treated by the patient. The rates of hypoglycemia in the LEVEMIR® clinical trials (see Section 14 for a description of the study designs) were comparable between LEVEMIR®-treated patients and non-LEVEMIR®-treated patients (see Tables 5 and 6).

Table 5: Hypoglycemia in Patients with Type 1 Diabetes Study A Type 1 Diabetes Adults 16 weeks In combination with insulin aspart Twice-Daily Twice-Daily NPH LEVEMIR® Severe hypo- Percent of patients 10.6 8.7 with at least 1 event glycemia (14/132) (24/276) (n/total N) Event/patient/year 0.52 0.43 Non-severe Percent of patients 88.0 89.4 hypoglycemia (n/total N) (243/276) (118/132) Event/patient/year 26.4 37.5

Study B Type 1 Diabetes Adults 26 weeks In combination with insulin aspart Twice-Daily Once-Daily LEVEMIR® Glargine

Study C Type 1 Diabetes Adults 24 weeks In combination with regular insulin Once-Daily Once-Daily NPH LEVEMIR®

Study D Type 1 Diabetes Pediatrics 26 weeks In combination with insulin aspart Once- or Twice Once- or Twice Daily LEVEMIR® Daily NPH

5.0 (8/161)

10.1 (16/159)

7.5 (37/491)

10.2 (26/256)

15.9 (37/232)

20.0 (23/115)

0.13 82.0 (132/161) 20.2

0.31 77.4 (123/159) 21.8

0.35 88.4 (434/491) 31.1

0.32 87.9 (225/256) 33.4

0.91 93.1 (216/232) 31.6

0.99 95.7 (110/115) 37.0

Table 6: Hypoglycemia in Patients with Type 2 Diabetes

Severe hypo- Percent of patients with at least 1 event glycemia (n/total N) Event/patient/year Non-severe Percent of patients hypoglycemia (n/total N) Event/patient/year

Study E Type 2 Diabetes Adults 24 weeks In combination with oral agents Twice-Daily NPH Twice-Daily LEVEMIR® 0.4 2.5 (1/237) (6/238) 0.01 0.08 40.5 64.3 (96/237) (153/238) 3.5 6.9

Insulin Initiation and Intensification of Glucose Control: Intensification or rapid improvement in glucose control has been associated with a transitory, reversible ophthalmologic refraction disorder, worsening of diabetic retinopathy, and acute painful peripheral neuropathy. However, long-term glycemic control decreases the risk of diabetic retinopathy and neuropathy. Lipodystrophy: Long-term use of insulin, including LEVEMIR®, can cause lipodystrophy at the site of repeated insulin injections.

Lipodystrophy includes lipohypertrophy (thickening of adipose tissue) and lipoatrophy (thinning of adipose tissue), and may affect insulin adsorption. Rotate insulin injection sites within the same region to reduce the risk of lipodystrophy. Weight Gain: Weight gain can occur with insulin therapy, including LEVEMIR®, and has been attributed to the anabolic effects of insulin and the decrease in glucosuria. Peripheral Edema: Insulin, including LEVEMIR®, may cause sodium retention and edema, particularly if previously poor metabolic control is improved by intensified insulin therapy. Allergic Reactions: Local Allergy: As with any insulin therapy, patients taking LEVEMIR® may experience injection site reactions, including localized erythema, pain, pruritis, urticaria, edema, and inflammation. In clinical studies in adults, three patients treated with LEVEMIR® reported injection site pain (0.25%) compared to one patient treated with NPH insulin (0.12%). The reports of pain at the injection site did not result in discontinuation of therapy. Rotation of the injection site within a given area from one injection to the next may help to reduce or prevent these reactions. In some instances, these reactions may be related to factors other than insulin, such as irritants in a skin cleansing agent or poor injection technique. Most minor reactions to insulin usually resolve in a few days to a few weeks. Systemic Allergy: Severe, life-threatening, generalized allergy, including anaphylaxis, generalized skin reactions, angioedema, bronchospasm, hypotension, and shock may occur with any insulin, including LEVEMIR®, and may be life-threatening. Antibody Production: All insulin products can elicit the formation of insulin antibodies. These insulin antibodies may increase or decrease the efficacy of insulin and may require adjustment of the insulin dose. In phase 3 clinical trials of LEVEMIR®, antibody development has been observed with no apparent impact on glycemic control. Postmarketing experience: The following adverse reactions have been identified during post approval use of LEVEMIR®. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Medication errors have been reported during post-approval use of LEVEMIR® in which other insulins, particularly rapid-acting or short-acting insulins, have been accidentally administered instead of LEVEMIR®. To avoid medication errors between LEVEMIR® and other insulins, patients should be instructed always to verify the insulin label before each injection.

Study F Type 2 Diabetes Adults 22 weeks In combination with insulin aspart Once- or Twice Daily LEVEMIR® Once- or Twice Daily NPH 1.5 4.0 (8/199) (3/195) 0.04 0.13 32.3 32.2 (63/195) (64/199) 1.6 2.0

More detailed information is available upon request.

For information about LEVEMIR® contact: Novo Nordisk Inc., 100 College Road West Princeton, NJ 08540 1-800-727-6500 www.novonordisk-us.com Manufactured by: Novo Nordisk A/S DK-2880 Bagsvaerd, Denmark Revised: 1/2012 Novo Nordisk®, Levemir®, NovoLog®, FlexPen®, and NovoFine® are registered trademarks of Novo Nordisk A/S. LEVEMIR® is covered by US Patent Nos. 5,750,497, 5,866,538, 6,011,007, 6,869,930 and other patents pending.

FlexPen® is covered by US Patent Nos. 6,582,404, 6,004,297, 6,235,400 and other patents pending. © 2005-2012 Novo Nordisk 0212-00007333-1 2/2012

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Constipation Dyspepsia

5.3 0.9 1.7 5.2 0.9 2.6 Add-on to Metformin + Glimepiride Placebo + Metformin + Glargine + Metformin Victoza® 1.8 + + Glimepiride Glimepiride Metformin + N = 232 N = 114 Glimepiride 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 All Victoza® + Metformin + Placebo + 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 Table 3: Treatment-Emergent Adverse Events in 26 Week Open-Label Trial versus Exenatide (Adverse events with frequency ≥5% and occurring more frequently with Victoza® compared to exenatide are listed) Exenatide 10 mcg twice Victoza® 1.8 mg once daily + metformin and/or daily + metformin and/or sulfonylurea N = 232 sulfonylurea N = 235 (%) (%) Preferred Term Diarrhea 12.3 12.1 Dyspepsia 8.9 4.7 Constipation 5.1 2.6 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 a 26-week study of Victoza® versus exenatide, both in combination with metformin and/ or sulfonylurea overall gastrointestinal adverse event incidence rates, including nausea, were similar in patients treated with Victoza® and exenatide. In five 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. In a 26 week study of Victoza® versus exenatide, both in combination with metformin and/ or sulfonylurea, the proportion of patients with nausea also declined over time. 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. Crossreacting 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 antibodynegative 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 two 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 4). 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 4: 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 Monotherapy Victoza® Glimepiride None (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) — Placebo + Glimepiride + Add-on to Victoza® + Metformin Metformin Metformin Metformin (N = 121) (N = 242) (N = 724) 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) Add-on to Glimepiride Victoza® + Placebo + Rosiglitazone + Glimepiride Glimepiride Glimepiride (N = 114) (N = 231) (N = 695) 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 Victoza® + Placebo + Add-on to None Metformin + Metformin + Metformin + Rosiglitazone Rosiglitazone Rosiglitazone (N = 175) (N = 355) 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) Placebo + Add-on to Victoza® + Insulin glargine Metformin + Metformin + Glimepiride + Metformin + Metformin + Glimepiride Glimepiride Glimepiride (N = 114) (N = 232) (N = 230) 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-comparator-treated patients. This finding was not accompanied by abnormalities in other liver tests. The significance of this isolated finding is unknown. Post-Marketing Experience: The following additional adverse reactions have been reported during post-approval use of Victoza®. Because these events are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Gastrointestinal: nausea, vomiting and diarrhea sometimes resulting in dehydration [see Warnings and Precautions].

Renal and Urinary Disorders: increased serum creatinine, acute renal failure or worsening of chronic renal failure, which may sometimes require hemodialysis [see Warnings and Precautions].

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 upon request.

For information about Victoza® contact: Novo Nordisk Inc., 100 College Road West, Princeton, New Jersey 08540, 1−877-484-2869 Date of Issue: May 18, 2011 Version: 3 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. © 2011 Novo Nordisk 140586-R3 6/2011

Help adult patients with type 2 diabetes gain greater access

Get to know Victoza® on a deeper level.

Powerful reductions in A1C from -0.8% to -1.5%*

Low rate of hypoglycemia

Flexible dosing any time of day, independent of meals

May reduce weight

VictozaCare™ helps patients stay on track with ongoing support

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

—Patients enrolled in VictozaCare™ were more adherent to Victoza® than those not enrolled†

To see how Victoza® works for your patients, visit VictozaPro.com/GLP1.

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 Victoza® is a registered trademark and VictozaCare™ is a trademark of Novo Nordisk A/S.

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.

Renal impairment has been reported postmarketing, usually in association with nausea, vomiting, diarrhea, or dehydration, which may sometimes require hemodialysis. Use caution when initiating or escalating doses of Victoza® in patients with renal impairment.

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 hepatic impairment.

Please see brief summary of Prescribing Information on adjacent page. *Victoza® 1.2 mg and 1.8 mg when used alone or in combination with OADs. † Crossix ScoreBoard™ Report, September 2011. Adherence measured by number of actual Victoza® prescriptions filled for existing Victoza® patients enrolled in VictozaCare™ versus a match-pair control group not enrolled in VictozaCare™ through first 8 months of enrollment.

© 2012 Novo Nordisk

1111-00006045-1

January 2012