september/october 2012 volume 5, number 6

EDITORIAL

Hardworking P&T CommitteesDavid B. Nash, MD, MBA

CLINICAL

“Hidden” Value: How Indirect Benefits of Health Information ExchangeFurther Promote SustainabilityAlbert 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 Levodopa-Induced Dyskinesias (ASTROID): A US Chart Review StudyBarb 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 DisorderTreated with Atypical AntipsychoticsJoette 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 ofManaging Specialty Drug Utilization in the Medical BenefitMichael T. Einodshofer, RPh, MBA; Lars N. Duren, BCNSP, PharmD

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TABLE OF CONTENTS

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EDITORIAL

330 Hardworking P&T CommitteesDavid B. Nash, MD, MBA

CLINICAL

333 “Hidden” Value: How Indirect Benefits of Health Information Exchange FurtherPromote SustainabilityAlbert 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-InducedDyskinesias (ASTROID): A US Chart Review StudyBarb 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

American Health & Drug Benefits is found-ed on the concept that health and drugbenefits have undergone a transforma-tion: the econo metric value of a drug isof equal importance to clinical outcomesas it is to serving as the basis for securingcoverage in formularies and benefitdesigns. Because benefit designs aregreatly affected by clinical, business, andpolicy conditions, this journal offers aforum for stakeholder integration andcollaboration toward the improvementof healthcare.This publication further provides benefitdesign de cision makers the integratedindustry information they require todevise formularies and benefit designsthat stand up to today’s special health-care delivery and business needs.

Mission Statement

PublisherNicholas [email protected] DirectorDalia [email protected] PublisherMaurice [email protected] EditorLara J. [email protected] AssistantJennifer [email protected] Vice PresidentEngage Managed MarketsChuck [email protected] Accounts ManagerZach [email protected] Production ManagerLynn HamiltonQuality Control DirectorBarbara MarinoBusiness ManagerBlanche Marchitto

Founding Editor-in-ChiefRobert E. Henry

Contact Information: For subscription information and edi torial queries, pleasecontact: [email protected]; tel: 732-992-1892; fax: 732-992-1881

Continued on page 327

FOR ADULT PATIENTS WITH TYPE 2 DIABETES

TRADJENTA® (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.

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.

Important Safety Information

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

WARNINGS AND PRECAUTIONSUse with Medications Known to Cause HypoglycemiaInsulin 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. Therefore, a lower dose of the insulin secretagogue may be required to reduce the risk of hypoglycemia when used in combination with TRADJENTA.

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

ADVERSE REACTIONSAdverse reactions reported in ≥5% of patients treated with TRADJENTA and more commonly than in patients treated with placebo included nasopharyngitis.

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.

P

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2

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o

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TRADJENTA monotherapy1,2*Baseline A1C 8.0%

–0.7%‡

TRADJENTA add-on to metformin2,3†

Baseline A1C 8.1%

–0.6%§

(n=513)P<0.0001

(n=333)P<0.0001

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 INTERACTIONSThe 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 POPULATIONSThere 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.

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.

TRADJENTA delivers proven glycemic control

* 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.

† 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

Find out more about TRADJENTA and the Savings Card program at www.tradjenta.com

Placebo-adjusted difference in A1C with oral mono- and dual therapy at 24 weeks (%)

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

TRADJENTA: Experience dosing simplicity

aboute mor e outFind

Savings theandA TRADJENT TA about

ogram pr od Car d Savings

.tradjenta.com wwwat aboute mor e outFind

.tradjenta.com Savings theand TRADJENT about

ogram pr od Car d Savings

Tradjenta® (linagliptin) tablets

BRIEF SUMMARY OF PRESCRIBING INFORMATION

Please see package insert for full Prescribing Information.INDICATIONS AND USAGETRADJENTA 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 treat-ment of diabetic ketoacidosis, as it would not be effective in these settings. TRADJENTA has not been studied in combination with insulin.

CONTRAINDICATIONSTRADJENTA is contraindicated in patients with a history of a hypersensitivity reac-tion to linagliptin, such as urticaria, angioedema, or bronchial hyperreactivity [see Adverse Reactions].

WARNINGS AND PRECAUTIONSUse 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 Reac-tions]. 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 con-clusive evidence of macrovascular risk reduction with TRADJENTA tablets or any other antidiabetic drug.

ADVERSE REACTIONSClinical 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 met-formin 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 nasophar-yngitis (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 sulfonyl-urea (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 clini-cal 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 addi-tional 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

was similar to placebo when linagliptin was administered as monotherapy or in combination with metformin, or with pioglitazone. When linagliptin was admin-istered 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 INTERACTIONSInducers of P-glycoprotein or CYP3A4 Enzymes: Rifampin decreased lina-gliptin 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 POPULATIONSPregnancy: 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 pre-dictive 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 devel-opmental 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. Nurs-ing 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 dif-ferences 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 sen-sitivity 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.

OVERDOSAGEIn 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 rec-ommended daily dose) there were no dose-related clinical adverse drug reactions. There is no experience with doses above 600 mg in humans.

Table 1 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 (%)

Combination with Metformin# n (%)

Combination with SU n (%)

Combination with Metformin + SU n (%)

Combination with Pioglitazone n (%)

TRADJENTA n = 907

Placebon = 530

TRADJENTA n = 876

Placebon = 539

TRADJENTAn = 161

Placebon = 84

TRADJENTAn = 791

Placebon = 263

TRADJENTAn = 259

Placebon = 130

Nasopharyngitis – – – – 7 (4.3) 1 (1.2) – – – –Hyperlipidemia – – – – – – – – 7 (2.7) 1 (0.8)Cough – – – – – – 19 (2.4) 3 (1.1) – –Hypertriglyceridemia† – – – – 4 (2.4) 0 (0.0) – – –Weight increased – – – – – – – – 6 (2.3) 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 TJ-BS (5-12) TJ291200PROF

8:32 AM



American Health & Drug Benefits, ISSN1942-2962 (print); ISSN 1942-2970(online), is published 8 times a year byEngage Healthcare Communications,LLC, 1249 South River Rd, Suite 202A,Cranbury, NJ 08512. Copyright © 2012 by Engage HealthcareCommunications, LLC. All rightsreserved. American Health & Drug Benefitsand The Peer-Reviewed Forum for Evidencein Benefit Design are trademarks of EngageHealthcare Communications, LLC. Nopart of this publication may be repro-duced or transmitted in any form or byany means now or hereafter known, elec-tronic or mechanical, including photo-copy, recording, or any informationalstorage and retrieval system, without written permission from the Publisher.Printed in the United States of America.

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BUSINESS

379 Medical Care Costs and Hospitalization in Patients with Bipolar DisorderTreated with Atypical AntipsychoticsJoette 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 TRENDS345 Payer Drug and Molecular Testing Utilization Policies

By Charles Bankhead

INDUSTRY TRENDS359 Cost Management through Care Management, Part 2: The Importance of

Managing Specialty Drug Utilization in the Medical BenefitMichael T. Einodshofer, RPh, MBA; Lars N. Duren, BCNSP, PharmD

MULTIPLE SCLEROSIS UPDATE387 Multiple Sclerosis: Patient Characteristics and Cost Concerns

By Charles Bankhead

EDITORIAL BOARD

328 l American Health & Drug Benefits l www.AHDBonline.com September/October 2012 l Vol 5, No 6

EDITOR-IN-CHIEFDavid B. Nash, MD, MBA Dean, the Dr Raymond C. and Doris N. GrandonProfessor, Jefferson School of Population HealthPhiladelphia, PA

DEPUTY EDITORSJoseph D. Jackson, PhDProgram Director, Applied Health Economics and Outcomes Research, Jefferson UniversitySchool of Population Health, Philadelphia, PALaura T. Pizzi, PharmD, MPH, RPhAssociate Professor, Dept. of Pharmacy Practice,Jefferson School of Pharmacy, Philadelphia, PA

AGING AND WELLNESSEric G. Tangalos, MD, FACP, AGSF, CMDProfessor of MedicineMayo Clinic, Rochester, MN

CANCER RESEARCHAl B. Benson, III, MD, FACPProfessor of Medicine, Associate Director for Clinical InvestigationsRobert H. Lurie Comprehensive Cancer CenterNorthwestern University, ILPast Chair, NCCN Board of Directors Samuel M. Silver, MD, PhD, FASCOProfessor of Internal MedicineHematology/OncologyAssistant Dean for ResearchAssociate Director, Faculty Group PracticeUniversity of Michigan Medical School, MI

EMPLOYERSArthur F. Shinn, PharmD, FASCPPresident, Managed Pharmacy Consultants, LLC, Lake Worth, FLF. Randy Vogenberg, RPh, PhDPrincipal, Institute for Integrated Healthcare and Bentteligence, Sharon, MA

ENDOCRINOLOGYJames V. Felicetta, MD Chairman, Dept. of Medicine Carl T. Hayden Veterans AffairsMedical Center, Phoenix, AZ Quang Nguyen, DO, FACP, FACEAdjunct Associate Professor EndocrinologyTouro University Nevada, College of Osteopathic Medicine

EPIDEMIOLOGY RESEARCHJoshua N. Liberman, PhDExecutive Director, Research, Development & DisseminationSutter Health, Concord, CA

GOVERNMENTKevin B. “Kip” Piper, MA, FACHEPresident, Health Results Group, LLCWashington, DC

HEALTH INFORMATION TECHNOLOGY Kelly Huang, PhDPresident, HealthTronics, Inc.Austin, TX J. B. Jones, PhD, MBAResearch Investigator, Geisinger Health System, Danville, PAVictor J. Strecher, PhD, MPHProfessor and Director for Innovation and Social EntrepreneurshipUniversity of Michigan, School of Public Health and Medicine, Ann Arbor, MI

HEALTH OUTCOMES RESEARCH Diana Brixner, RPh, PhDProfessor & Chair, Dept. of PharmacotherapyExecutive Director, Outcomes Research Center,Director of Outcomes Personalized Health CareProgram, University of Utah, Salt Lake City

Joseph Couto, PharmD, MBAClinical Program ManagerCigna Corporation, Bloomfield, CT Steve Miff, PhDSenior Vice PresidentVHA, Inc., Irving, TXKavita V. Nair, PhDAssociate Professor, School of PharmacyUniversity of Colorado at Denver, COGary M. Owens, MDPresident, Gary Owens AssociatesGlen Mills, PAAndrew M. Peterson, PharmD, PhDDean, Mayes School of Healthcare Business and Policy, Associate Professor, University of the Sciences, Philadelphia, PASarah A. Priddy, PhDDirector, Competitive Health AnalyticsHumana, Louisville, KY Timothy S. Regan, BPharm, RPh, CPhExecutive Director, Strategic Accounts Xcenda, Palm Harbor, FLVincent J. Willey, PharmDAssociate Professor, Philadelphia School ofPharmacy, University of the SciencesPhiladelphia, PADavid W. Wright, MPHPresident, Institute for Interactive Patient CareBethesda, MD

HEALTH & VALUE PROMOTION Craig Deligdish, MDHematologist/OncologistOncology Resource Networks, Orlando, FLThomas G. McCarter, MD, FACPChief Clinical OfficerExecutive Health Resources, PAAlbert Tzeel, MD, MHSA, FACPENational Medical DirectorHumanaOne, Waukesha, WI

MANAGED MARKETS Jeffrey A. Bourret, RPh, MS, FASHPSenior Director, Medical Lead, Payer andSpecialty Channel Strategy, Medical AffairsPfizer Specialty Care Business Unit, PARichard B. Weininger, MDChairman, CareCore National, LLCBluffton, SC

PATIENT ADVOCACY William E. Fassett, BSPharm, MBA, PhD, FAPhAProfessor of Pharmacy Law & EthicsDept. of Pharmacotherapy, College of PharmacyWashington State University, Spokane, WAMike PucciSr VP Commercial Operations and BusinessDevelopment, PhytoChem PharmaceuticalsLake Gaston, NC

PERSONALIZED MEDICINEEmma Kurnat-Thoma, PhD, MS, RNDirector, Research ServicesURAC, Washington, DC

PHARMACOECONOMICSJosh FeldsteinPresident & CEOCAVA, The Center for Applied Value Analysis, Inc., Norwalk, CTJeff Jianfei Guo, BPharm, MS, PhDProfessor of Pharmacoeconomics& Pharmacoepidemiology, College of Pharmacy, University of Cincinnati Medical Center, OH

PHARMACY BENEFIT DESIGN Joel V. Brill, MD, AGAF, CHCQMChief Medical Officer, Predictive Health, Phoenix, AZ

Teresa DeLuca, MD, MBASenior VP, PBM LeaderHumana Solutions, Louisville, KYLeslie S. Fish, PharmDVice President of Clinical ProgramsFallon Community Health Plan, MAJohn Hornberger, MD, MSCedar Associates, LLCCHP/PCOR Adjunct Associate, Menlo Park, CA Michael S. Jacobs, RPhVice President, National AccountsTruveris, Inc., New York, NYMatthew Mitchell, PharmD, MBAManager, Pharmacy ServicesSelectHealth, Salt Lake City, UTPaul Anthony Polansky, BSPharm, MBASenior Field Scientist, Health Outcomes andPharmacoEconomics (HOPE) Endo Health Solutions, Chadds Ford, PAChristina A. Stasiuk, DO, FACOISenior Medical DirectorCigna, Philadelphia, PA Scott R. Taylor, BSPharm, MBAExecutive Director, Industry RelationsGeisinger Health System, Danville, PA

POLICY & PUBLIC HEALTH Joseph R. Antos, PhDWilson H. Taylor Scholar in Health CareRetirement Policy, American Enterprise InstituteWashington, DCRobert W. Dubois, MD, PhDChief Science OfficerNational Pharmaceutical Council, Washington, DCJack E. Fincham, PhD, RPh Professor of Pharmacy, Practice and AdministrationSchool of Pharmacy, University of Missouri Kansas City, MOWalid F. Gellad, MD, MPHAssistant Professor of Medicine, University ofPittsburgh, Staff Physician, Pittsburgh VA MedicalCenter, Adjunct Scientist, RAND HealthPaul Pomerantz, MBAExecutive DirectorDrug Information Association, Horsham, PAJ. Warren Salmon, PhDProfessor of Health Policy & AdministrationSchool of Public HealthUniversity of Illinois at ChicagoRaymond L. Singer, MD, MMM, CPE, FACSChief, Division of Cardiothoracic SurgeryVice Chair, Department of Surgery for Quality &Patient Safety and OutreachLehigh Valley Health Network, PA

RESEARCH & DEVELOPMENT Frank Casty, MD, FACPChief Medical OfficerSenior VP, Clinical Development Medical ScienceEndo Pharmaceuticals, Chadds Ford, PAMichael F. Murphy, MD, PhDChief Medical Officer and Scientific Officer Worldwide Clinical TrialsKing of Prussia, PA

SPECIALTY PHARMACYAtheer A. Kaddis, PharmDSenior Vice PresidentManaged Markets/Clinical ServicesDiplomat Specialty Pharmacy Flint, MIJames T. Kenney, Jr, RPh, MBAPharmacy Operations Manager Harvard Pilgrim Health Care Wellesley, MAMichael KleinrockDirector, Research DevelopmentIMS Institute for Healthcare InformaticsCollegeville, PA

NOWAVAILABLE

©2012 Onyx Pharmaceuticals, Inc., South San Francisco, CA 1111-CARF-147a July 2012 Printed in USA KYPROLIS.com

EDITORIAL


Virtually every American hospital has a Pharmacy& Therapeutics (P&T) committee that workshard to create and maintain the hospital formu-

lary and track the quality and safety of medication ther-apy. At Thomas Jefferson University Hospital (TJUH),the P&T committee is a critically important medicalstaff committee with multiple subcommittees. As amember of the TJUH P&T committee for the past 22years, with a decade serving as Chair of the MedicationQuality subcommittee, I thought it might be of interestto our readers to provide an inside perspective of thework done in this arena.

Each year, the Medication Quality subcommitteepublishes an informal summary of its activities. I wish tohighlight some aspects of this report and draw parallelsto work going on in other sectors of our field.

The report of the Medication Quality subcommitteefor the 2011-2012 academic year is focused on 4 princi-pal areas—adverse drug event prevention and surveil-lance, medication use evaluations (MUEs), protocol andpolicy reviews, and activities to ensure compliance withregulatory compliance.

To create the annual report, we reviewed quarterlyreports about medication events and adverse drug reac-tions from our university hospital and our partner com-munity campus. These deep dives into medication safetyare among the highlights of our work together. We arefortunate to have such a dedicated staff from our phar-macy and our risk management department. Our eventrate for adverse drug reactions is stable, and we arealways striving to reduce harm and reduce errors. Wealso work regularly with the Institute for Safe Medi -cation Practices, which is located in the Philadelphiasuburbs. We view them as external, nonbiased reviewers,and often adopt their recommendations.

The committee works closely with other entitiesthroughout our institution, especially with physiciansinvolved in the constant updating of our computerizedphysician order entry system and those charged withmaintaining new technologies, such as bedside pumpsand related tools. Our subcommittee interacts with othersubcommittees and makes specific clinical recommenda-tions, for example, to the chemotherapy review commit-tee, the anesthesia care committee, and others. Constantvigilance to reduce medication-related errors is a corner-stone of our work.

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

UHC (formerly known as the University HealthSystemConsortium). We regularly compare our performance toUHC members in other areas, such as the use of protonpump inhibitors in the intensive care unit, the use of par-enteral nutrition, and, of course, the use of pain medica-tion. With the proliferation of new products rapidly dif-fusing into clinical practice, the detailed use of an MUEand a quarterly deep dive are critically important to theappropriate use of all new technologies.

As previously noted, the committee annually reviewshospital policies and protocols. This past year, wereviewed the patient’s personal medication policy, con-trolled substance policies, education for patients withpotential drug and nutrient interactions, and our ongoingwork to maintain anticoagulation safety. The goal in ourpolicy reviews is to make these reviews relevant—that is,to ensure that they don’t just stay in a loose-leaf binderon a shelf somewhere. We want to ensure that all appro-priate drug-related policies and procedures are activelyenforced, and we close the feedback loop to practitionerswhen there are changes in drug use based on newly avail-able evidence. Finally, we perform an annual review ofour performance on “look-alike, sound-alike” drugs(those medications that are often confused with othersthat are intended for a different purpose) with bench-mark hospitals within the UHC. In addition, our compli-ance with double signatures for certain high-risk medica-tions markedly improved over this past year, as did ourcompliance with medication reconciliation monitors.

It has been a true privilege to chair the MedicationQuality subcommittee of the P&T committee atTJUH. I am in a state of constant learning, especiallyfrom my colleagues in the pharmacy. We will neverhave a zero medication error rate, but I am committedto getting as close to zero as we can to make sure thatwe cause no harm to our patients. I wish that everyP&T committee in every American hospital would beas enthusiastically endorsed as our committee. The sen-ior leadership of our institution makes it very clear thatthe work of the P&T committee is essentially “unend-ing,” and of the highest priority.

What is your organization doing to ensure compli-ance with patient safety issues regarding medicationadministration? Given the epidemic of medical errors,where do you stand on these important issues? I am for-tunate to stand on firm ground with our team at TJUH.As always, I am interested in your views and your com-ments. You can reach me by e-mail at [email protected] or via the journal at [email protected]. ■

Hardworking P&T CommitteesDavid B. Nash, MD, MBA

Editor-in-Chief, American Health & Drug Benefits; Jefferson School of Population Health,Philadelphia, PA

CLINICAL


The eighteenth-century essayist and satiristJonathan Swift made the observation that “visionis the art of seeing things invisible.” So, too, is “the

art of seeing things invisible” a key for the ongoing sus-tainability of health information exchange (HIE). HIEs

have long been theorized to provide a number of tangi-ble benefits. These benefits accrue through the provi-sion of medical history at the point of care: decreases inredundant laboratory testing, improved provider effi-ciency, improved care coordination, increased quality

“Hidden” Value: How Indirect Benefits ofHealth Information Exchange FurtherPromote SustainabilityAlbert 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 admis-

sions 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 query-

ing 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 denot-

ed by bed days per 1000 members (771 fewer bed days per 1000 members) and by aver-

age 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 cal-

culated. Additional study is warranted to further the business case for HIE investment for the

various stakeholders who are interested in supporting HIE sustainability.

Am Health Drug Benefits.2012;5(6):333-341www.AHDBonline.com

Disclosures are at end of text

Stakeholder Perspective,page 340

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.

Albert Tzeel

CLINICAL


of care, and the ultimate goal of an overall decreasedcost of care.More recently, we have witnessed a seismic move-

ment from theory to practice with definitive dollar sav-ings noted for HIE use in emergency departments inIndianapolis, IN,1 and in Milwaukee, WI2 ($26 and $29savings per emergency department visit, respectively),1,2as well as in Memphis, TN (approximately net $1.1 mil-lion in savings for the community at large).3 More -over, in Memphis, the great majority of dollar savings(97.6%) resulted from the avoidance of inpatient admis-sions from the emergency department.3 Inpatient admis-sions account for the preponderance of dollars spent inhealthcare. Costs for inpatient admissions in the UnitedStates are increasing; during calendar year 2004, theaverage inpatient admission cost was $10,0304; by 2008,this increased to $15,017.5A community replicating the Memphis experience by

mitigating inpatient admissions from the emergencydepartment should experience financial savings asMemphis did. The Memphis experience showed thatHIE availability within the emergency department

decreases direct admissions from the emergency depart-ment.3 But can HIE availability in the emergency depart-ment indirectly impact admissions emanating from out-side of the emergency department? Is the risk of anyinpatient admission occurring altered by the presence ofHIE in the emergency department? If so, the communitybenefits indirectly, as well as directly, from having saidHIE occurs within the emergency department. However,achieving that benefit requires HIE sustainability, andHIE sustainability requires a stable source of funding.Enhancing the business case for HIE sustainability byuncovering such indirect or “hidden” value may helpvalidate the need for external support and funding.

BackgroundIn our previous article promoting the “business case

for payer support of a community-based HIE,” wedescribed the relationship between Humana in South -east Wisconsin and the local HIE.2 To briefly summarize,beginning in December 2008, Humana provided a finan-cial incentive to the Wisconsin Health InformationExchange (WHIE) for promoting the querying of a data-base by emergency department clinicians (as a part oftheir workflow) for fully insured members presenting tothe emergency department for care.6 WHIE links togeth-er disparate emergency departments across 5 competitivehealth systems in Milwaukee County.7Our previous evaluation showed a positive direct

financial outcome for our health plan, with an averagesavings of $29 per emergency department visit when cli-nicians queried the WHIE in the course of providingemergency department care as opposed to when theWHIE was not queried.2 We also realized a direct returnon investment (ROI) of more than 2:1.2 Further analysislooking at other potential sources of value, some ofwhich may result from indirect savings, may help furtherthe business case for external HIE support and may alsoshow that the value of HIE may even be higher thanwhat we can quantitatively measure.

MethodsStudy Design: Developing the Sample Population for EvaluationThe Humana version of an Institutional Review

Board, the clinical “Stage Gate Process,” providedapproval for this pilot assessing the impact of HIE queryin the emergency department. The planned evaluationincluded both observational and retrospective analyses.In developing the member pool from which to draw theevaluation population, Humana and the WHIE hadagreed that the plan would provide to the WHIE a finan-cial incentive to cover its costs for promoting emergencydepartment clinicians’ querying of the WHIE database.

KEY POINTS➤ Health information exchanges (HIEs) have showndirect value in controlling costs related to emergencydepartment utilization and inpatient admissions fromthe emergency department.

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

➤ Two previous studies have shown average savingsranging from $26 to $29 for HIE use in theemergency department; a third study showed adecrease in hospital admissions from the emergencydepartment as well.

➤ The current study shows that making HIE availablefor patients in the emergency department reducesthe length of hospital stays for admissions not tied toemergency department services.

➤ The noted decreased length of stay, even whencatastrophic cases are removed from the analysis,suggests that the availability of HIEs in theemergency department reduces inpatient utilizationemanating from outside of the emergencydepartment.

➤ These findings further support that incorporatingthe use of HIEs in the emergency department canreduce overall hospital admissions rates, lower thelength of hospital stay, and, therefore, decrease theassociated costs.

Although queries apply to all patients, the incentiveonly covered eligible Humana members presenting tothe emergency department for care.8Eligible members were commercial, fully insured mem -

bers only; self-funded group members, as well as memberscovered by governmental programs (eg, Medicare), werespecifically excluded. Every quarter, WHIE providedHumana specific information about each individualhealth plan member who was fully insured by Humanaand who sought emergency department care, as well aswhen the emergency department clinician accessed theWHIE database for that patient and at which facility.WHIE only provided clinical data as it would appear ona claim related to the encounter. All communicationswere HIPAA compliant and used encrypted files. Theinformation that was provided allowed Humana tomatch emergency department claims data received fromproviders with the emergency department encounter bydate of service and facility.In working with claims data, we stipulated precise

parameters for member inclusion in the evaluation sam-ple. Inclusion criteria noted in the original analysis stip-ulated that2:1. All members included in the evaluation must havehad at least 12 months of continuous coverage withour health plan

2.Members would be excluded from the evaluation ifthey had either less than 6 months of coverage beforethe start of the program or less than 3 months of cov-erage after the start of the program

3. Because admissions from the emergency departmentor prolonged emergency department holds of “24-hour observations” would have impaired our ability toperform the original analysis on emergency depart-ment costs, we excluded those members (admittedfrom or held in the emergency department) from theanalysis. These exclusions prevented potential skewing of the

data for our analyses.

Study Design: Developing the Control Group and the Test GroupIn our previous article, we discussed in great detail

how we determined who would make up the control andtest groups.2 Humana identified members seen in theemergency department when the WHIE database wasqueried in both a first emergency department visit and asubsequent emergency department visit as eligible to beincluded in the test group; members seen in the emer-gency department where the WHIE database was notqueried in neither a first emergency department visit norin a subsequent emergency department visit (becausethe facility had not yet provided WHIE access at that

time) were eligible to be included in the control group.A total of 428 plan members were deemed eligible forthe test group, whereas 1054 plan members met controlgroup eligibility.2In addition, our evaluation deliberately assumed the

need for propensity scoring, because that techniqueaffords the best way to match members, while minimizingbias. Propensity scoring provides “the conditional proba-bility of receiving the treatment given the observedcovariates.”9 In their defining article, Rosenbaum andRubin showed that “the adjustment for the scalar propen-sity score is sufficient to remove bias due to all observedcovariates.”10 Furthermore, propensity scoring has beenfound to yield estimates that are not substantially differ-ent from typical multivariable methods.11,12For the logistic regression yielding the propensity

scores, we used all of the following combinations of cost-related and demographic variables to match the 2groups: age, sex, medical net paid per participant permonth (PPPM), prescription net paid PPPM, medicalplus prescription net paid PPPM, medical inpatient netpaid PPPM, medical outpatient net paid PPPM, andmedical physician net paid PPPM. With the exceptionof age and sex, all of these variables represent dollar val-ues, because dollar values are easy to calculate fromclaims and they were unrelated to the specific exposure(ie, WHIE database querying).Propensity scores on which we matched the partici-

pants used the nearest neighbor algorithm. Matchingallows for “sampling from a large reservoir of potentialcontrols to produce a control group of modest size inwhich the distribution of covariates is similar to the dis-tribution in the treated group.”9 For member matching,MATLAB version 7.0.1.1 was used.13

Data AnalysisOnce we completed matching 325 pairs of individuals

for the test and control groups, we analyzed differencesin the metrics of interest for the 2 groups. For descriptivechi-square and other statistics, SAS Enterprise Guideversion 4.2 was used.14 We compared all claims for the 2groups for a time period beginning 1 year before an indi-vidual’s first emergency department visit date to an enddate of 1 year after that first emergency department visitdate; therefore, each individual’s length of time in thepilot was 1 full year. The pilot ran from December 2008 through March

2010. Within that 1-year time period, a group memberwould still need to have a second emergency departmentvisit before the end date. The emergency departmentvisit served to delineate a point in time where we evalu-ated member utilization; in other words, we looked atthe member’s inpatient utilization at the time of a first

Indirect Benefits of Health Information Exchange


emergency department visit and then again at the timeof 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 impactoutside of the emergency department. We used routinepayer parameters to calculate differences in admissionsper 1000 members, bed days per 1000 members, and inaverage LOS per admission at the times of a first and ofa subsequent emergency department visit for the 2 pop-ulations of interest, with adjustment for trend betweenthe 2 time periods.

ResultsDescriptive results before and after propensity score

matching for all eligible control population and testpopulation members are shown in Table 1. Table 2 out-lines inpatient admissions per 1000 members for thepropensity-matched cohort, as well as for the summedpopulation results at the time of a given emergencydepartment visit and by group designation. A chi-square test for independence of the groupings and thetime period of emergency department visit show thatthe admissions per 1000 members of each group are notindependent of the time period when a member of thegroup was seen in the emergency department. Thisfinding implies that inpatient admissions, unrelated toan emergency department visit, may be impacted bythe use of HIEs within the emergency department.Table 3 describes the conditional probabilities with-

in the 2 groups; we specifically examined the probabil-ity of an admission during a specific time frame giventhe possible use of HIEs in an emergency department.The conditional probability results show that first, theprobability for having had an admission in either groupis more likely at the time of a second emergency depart-ment visit than at the time of a first visit (eg, 67.4% ofall admissions studied occurred by the time of a secondemergency department visit).Second, the probability of having had an admission

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

CLINICAL


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

Period

Prematching Postmatching

Group participationeligibility

Members,N

Meanage,yrs

Sex, % female

Group participationdesignation

Members,N

Meanage, yrs

Sex, % female

Time of first emergency department visit

Control 1054 42.0 56.5 Control 325 42.5 55.2

Time of secondemergency department visit

Test 428 41.1 53.5 Test 326 42.7 55.8

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

Table 2 Comparison of Admissions per 1000 Members forPropensity-Matched Control and Test Groups

PeriodTest group,

NControlgroup, N

Total population, byperiod, N

Time of first emergency department visit

269 321 590

Time of secondemergency department visit

664 555 1219

Total population,by group

933 876 1809

Chi-square test for independence: χ2 = 12.34; since P�<.005, theadmissions per 1000 members for each group and the 2 timeperiods are not independent. Decrease in admissions per 1000 members for the test groupbetween emergency department visits = 269 × (555/321) – 664 = (199).

ment). Another way of viewing these results is to notethat the absolute risk of any inpatient admission by thetime 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 bythe 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 1000members, and average LOS for the propensity-matchedcohort, by time period of emergency department visitand by group designation. As seen in Tables 4 and 5,when accounting for trend, the availability of HIE inthe emergency department may be associated withshorter LOSs for admissions emanating outside theemergency department (4.27 days per admission) and adecreased number of inpatient days in total (771 beddays per 1000 members).However, the noted results, especially for the average

LOS calculations, may be skewed by an abnormally highnumber of catastrophic cases, as noted by the maximumLOSs in Table 6. Addressing such discrepancies byremoving all inpatient admissions with an LOS of at least33 days, even without further adjusting for the propensitymatches, generates the results outlined in Table 7. Theseresults show that simply having HIE available in theemergency department may yield a potential savings inLOS of nearly 1 full day (0.95 days per admission).

DiscussionApproximately 44% of all hospital admissions, or

55% of hospital admissions excluding pregnancy andchildbirth, use the emergency department as the conduitfor entry.15 Conversely, 56% of all admissions (or 45% of

all admissions, excluding pregnancy and childbirth) arenot admitted through the emergency department. Suchfindings necessitate looking at methods to alleviate hos-pital admissions that do not originate from the emer-gency department. One way of doing this is to ensureappropriate admissions.



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

Conditional probability of FormulaaResulting 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 isused in emergency department (test group)

664/933 0.711 or 71%

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

555/876 0.633 or 63%

aResults were double-checked by calculating conditional probabilities for 2 independent events: probability of any admissionby a certain emergency department visit and the probability of whether HIE was used in the emergency department. HIE indicates health information exchange.

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

Period Test group, N Control group, N

Time of first emergencydepartment visit

1381 1814

Time of second emergencydepartment visit

4077 6368

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

Table 5 Comparison of Average Length of Stay for Propensity-Matched Control and for Test Groups

PeriodTest group,average stay

Control group,average stay


5.13 days 5.65 days

Time of second emergencydepartment visit

6.14 days 11.47 days

Decrease in ALOS for the test group between emergencydepartment visits = 5.13 � (11.47/5.65) – 6.14 = 4.27 days/admission. ALOS indicates average length of stay.

Review of our results show some promising findings.In our study, an emergency department visit by a mem-ber of the test group or the control group did not resultin an admission from the emergency department.However, each group’s members had admissions fromoutside of the emergency department.When we look at the likelihood of a first admission

from outside of the emergency department by a groupmember, the results show a 28% higher probability of anadmission when HIE is not available in the emergencydepartment. Given that physician offices provide datafor HIE in the emergency department, it is more likelythat emergency departments with access to HIE havephysicians with access to HIE. We could theorize that alack of access to information at the point of care, espe-cially if that point of care is outside of the emergencydepartment, may provide the impetus for potentiallyinappropriate admissions. In his study, Campbell previously noted that 28% of

the hospital admissions deemed as “inappropriate”occurred secondary to a need for the performance oftreatment or tests that could have been performed on anoutpatient basis.16 Moreover, assumptions that appropri-ate admissions require longer LOSs do decrease what may

be considered “inappropriate,” because admissions withshorter LOSs should not have been admitted at all.17Multiple factors can play a role in potentially inap-

propriate admissions, including, but not limited to, diffi-culty in organizing continuity of care (eg, outpatientphysician follow-up)18 versus receipt of community serv-ices (eg, home healthcare)19 or even rural geography.20That members of the test group had more admissions atthe time of a second emergency department visit couldimply that the use of HIEs before then might haveplayed a role in avoiding inappropriate admissions,thereby leading to more appropriate use of inpatientresources overall.From our previous study, we were certainly aware that

the test group “required higher intensity care on a claimsdollar basis,” implying that they were “sicker” on thebasis of claims.2 Conversely, because the control grouphad more inpatient admissions by the time of a firstemergency department visit, we could surmise that alack 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 con-trol group by the second emergency department visitmakes us begin to question if there is a correlation of HIEavailability with shorter hospital stays; in fact, the notedsavings of 4.27 days per admission seemed so extreme(because of several cases of at least 33 days per admis-sion), 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 thispremise. Despite removing catastrophic cases, we stillfound a decrease of nearly 1 full day per admission for thetest group. Having HIE itself in the emergency depart-ment did not directly influence this finding, but it cer-tainly 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 ismade meaningful by, in this case, decreasing inpatientservices.22 ROI should certainly not be the only measureof the value that HIEs bring.23 HIEs can offer a clinical“value added” through providing services in a mannerthat an alternative cannot.24 In our case, the “service”provided may be the indirect promotion of more appro-priate inpatient admissions, containment of inappropri-ate admissions, and a decrease in LOS. However, toreduce costs associated with these parameters mayrequire, as Porter says, spending more on other services.25In our case, the trade-off necessitates that stakeholdersjustifiably sustain HIEs. Of all stakeholders, accountablecare organizations should be especially interested.26Aligning physicians and payers in this endeavor shouldalso optimize value.27

CLINICAL


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

PeriodTest group LOS

Control groupLOS


83 admissions;53 days


Time of second emergency departmentvisit



LOS indicates length of stay.

Table 7Unadjusted Comparison of Average Length of Stay Ratesfor Remaining Control and Test Group Participants, afterRemoval of All Outlier Admissions (LOS, ≥33 days)

Period Test group Control group


81 admissions;4.65 days


Time of second emergency departmentvisit



Decrease in ALOS for the test group between emergencydepartment visits = 4.65 � (5.73/4.75) – 4.66 = 0.95 daysper admission. ALOS indicates average length of stay; LOS, length of stay.

LimitationsWe need to account for several potential limitations to

this study. First, although the use of propensity scoringmethods to create test and control groups should mini-mize 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.28Second, the use of HIE in our study groups was limit-

ed to emergency department visits. Although we canhope for bidirectional information flow in the use ofHIEs, we cannot actually prove that. Therefore, theassociation between HIE use in the emergency depart-ment and decreased inpatient admissions from outside ofthe emergency department is just that, an association.We cannot necessarily prove a direct cause-and-effectrelationship. Nonetheless, the results remain intriguing,such that we plan further study on what we found here.Third, we cannot discount the potential impact of so-

called human factors.Although we believe that the use of HIE in emer-

gency departments influences physician behavior out-side of the emergency department, we do not actuallyknow if this is the case. As Churchman notes, “knowl-edge resides in the user and not in the collection [ofinformation]. It is how the user reacts to a collection ofinformation that matters.”29 Physicians caring forpatients have a lot of nonexchangeable information attheir disposal and that information may certainly impactpotential admissions as much as, if not more than, HIEuse in the emergency department. Last, one cannotquantify “indirect” savings. Although we can estimatepotential savings in arguing for HIE sustainability, wecannot quantify something that never happened.Nonetheless, the argument still stands through logic andthrough extension.

ConclusionsThe impact of “direct” value is easily quantified: it is

tangible, visible, and deduced from the evidence.30 Theimpact of “indirect” value is much harder to evaluate: itmust be induced from the evidence.30 By definition,then, it is much harder to “see” indirect benefits, becausethey are hidden from view. When it comes to visualizingthe impact of HIE, one can follow a similar line of rea-soning. Having clinicians access HIE in the emergencydepartment has already shown direct benefits in the formof an average savings of $26 to $29 per emergencydepartment visit,1,2 as well as avoided inpatient admis-sions directly from the emergency department.3 Our cur-rent results build on that direct confirmation by addingindirect evidence for HIE value.HIE availability in the emergency department is asso-

ciated 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 shorterLOS. An argument could be made that this is a functionof “economies of connection.”31 As Beckham notes,“technology can collapse distance by generating virtualproximities….As some networks, products, and servicesbecome more widely used, they become exponentiallymore valuable….Proximity and networks…generate realvalue by connecting intellect, facilitating collegiality,and supporting collaboration.”31 Facilitating collabora-tion through networking is especially needed, given thatthe same individual will seek care at multiple facilities.32So, coming full circle, the need for HIE becomes re -

inforced, with sustainability remaining a paramount ob -jective. For sustainability, payers, providers, and otherstakeholders need to help pave a path to that goal.Although those stakeholders need to ascertain the valuethat they receive from HIE, all must understand onething: awareness of the indirect value brought forward byHIEs is as important as the direct value received. Havingthe vision to “see” this indirect value is vital because, asit is written in Proverbs (29:18), “where there is novision, the people perish.”■

Study FundingAll funding for this project and its analysis was provided by

Humana, Inc, Louisville, KY.

Author Disclosure StatementDr Tzeel is a consultant to Amylin and is employed by and

owns stock in Humana. Dr Lawnicki is employed by andowns stock in Humana. Mr Pemble is employed by theNational Institute for Medical Informatics/WHIE.

References1.Overhage JM, Dexter PR, Perkins SM, et al. A randomized, controlled trial of clin-ical 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 com-munity-based health information exchange: a Humana pilot evaluating its effective-ness in cost control for plan members seeking emergency department care. Am HealthDrug Benefits. 2011;4:207-216.3. Frisse ME, Johnson KB, Nian H, et al. The financial impact of health informationexchange on emergency department care. J Am Med Inform Assoc. 2012;19:328-333.4. Machlin SR, Carper K. Expenses for Hospital Inpatient Stays, 2004. StatisticalBrief #164. March 2007. Agency for Healthcare Research and Quality, Rockville,MD. www.meps.ahrq.gov/mepsweb/data_files/publications/st164/stat164.pdf. AccessedSeptember 25, 2012.5. Agency for Healthcare Research and Quality. Hospital inpatient services-medianand mean expenses per person with expense and distribution of expenses by sourceof payment: United States, 2008. Medical Expenditure Panel Survey. http://meps.ahrq.gov/mepsweb/data_stats/tables_compendia_hh_interactive.jsp?_SERVICE=MEPSSocket0&_PROGRAM=MEPSPGM.TC.SAS&File=HCFY2008&Table=HCFY2008%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&VARO5=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 fortomorrow’s health system. In: Merritt D, ed. Paper Kills 2.0: How Health IT Can HelpSave Your Life and Your Money. Washington, DC: Center for Health Trans formationPress; 2010:15.



Continued

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. January29, 2009. WTN News. http://wistechnology.com/articles/5432/. Accessed September25, 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 observa-tional studies for causal effects. Biometrika. 1983;70:41-55.11. Shah BR, Laupacis A, Hux JE, Austin PC. Propensity score methods gave similarresults 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 propensityscore methods yielded increasing use, advantages in specific settings, but not substan-tially different estimates compared with conventional multivariable methods. J ClinEpidemiol. 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 theemergency 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 emergencymedical admission. Hong Kong J Emerg Med. 2003;10:30-36.18. Davido A, Nicoulet I, Levy A, Lang T. Appropriateness of admission in an emer-gency department: reliability of assessment and causes of failure. Qual Assur HealthCare. 1991;3:227-234.19.Coast J, Peters TJ, Inglis A. Factors associated with inappropriate emergency hos-pital 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 roomadmissions of IDF soldiers in northern Israeli hospitals between May 2002 and April2003. 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-invisible-roi-drivers/. Accessed December 15, 2011.22. Rauh SS, Wadsworth EB, Weeks WB, Weinstein JN. The savings illusion—whyclinical 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). InternetJ Med Inform. 2011;6(1). www.ispub.com/journal/the-internet-journal-of-medical-informatics/volume-6-number-1/clinical-value-add-for-health-information-exchange-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. AmHealth Drug Benefits. 2012;5:91-92.28. Luellen JK, Shadish WR, Clark MH. Propensity scores: an introduction andexperimental test. Eval Rev. 2005;29:530-558.29. Churchman CW. The Design of Inquiring Systems: Basic Concepts of Systems andOrganization. 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 evaluationof the distribution of emergency department care delivered in Indiana. AMIA AnnuSymp Proc. 2011;2011:409-416.

CLINICAL


Significant Potential for Health Information Exchange in EnhancingQuality 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 qualityalong with lower costs, the important variables of effi-ciency and effectiveness will become evermore impor-tant and crucial for optimum outcomes to be achieved.The potential of health information exchanges (HIEs)is significant for enhancing the quality of care, elimi-nating duplicate services, avoiding unnecessary hospi-tal admissions, and decreasing the costs of healthcare.PAYERS: This tightly controlled, well-conducted,

and properly evaluated study by Dr Tzeel and col-leagues of the indirect benefits of HIE in reducing hos-pital admissions from emergency department visits isthe type of study that is necessary to continue to eval-uate and promote HIEs as a vital segment of enhancingpositive 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 thisstudy from Humana. The question of whether HIE inthe emergency department avoids unnecessary hospitaladmissions from outside of the emergency departmentis the central tenet of this study. The authors found a28% greater probability of an admission when HIE isnot available in the emergency department setting.As has been described in the literature, the impor-

tance of enhancing and embracing health informationsystems is crucial for the overall improvement of theUS healthcare system.1 Despite its promise, muchremains to be done to fully implement HIE in theUnited States. Sharing of information in an efficientand effective manner has not been a prominent featureof the US healthcare system. Much remains to beaccomplished from an organizational framework forbenefits to accrue.2

STAKEHOLDER PERSPECTIVE

Continued



The Affordable Care Act, which was passed in 2010and was affirmed as constitutional by the US SupremeCourt in June 2012, promotes and incentivizes imple-mentation of HIEs as one cornerstone for improvinghealthcare delivery in the United States. In a studyexamining Canadian experts’ views of the progress inthe United States relative to HIEs, a recommendedstrategy is to increase the direct engagement withproviders and to develop the business case for HIEimplementation on a broad scale.3HIEs have been a prominent part of the British

National Health Service for more than 4 decades. Whatwas accomplished in the 1970s in the United Kingdomwas the establishment of a foundation of policy, infra-structure, and systems of care, and the creation andacquisition of clinical computing applications, withstrong reliance on financial and clinical incentives.4PATIENTS: A significant opportunity exists for

consumer and patient engagement in the system aswell. Recent studies have highlighted the support ofconsumers for HIE, while also pointing out the need toprovide those who have relatively less sophisticationand means of monitoring their health records electron-ically with more education, access, and informationregarding HIEs.5

Much remains to be accomplished in the UnitedStates; however, studies such as the one supported byHumana and presented here are necessary to pinpointthe exact direct benefits of HIE, as well as the indirectbenefits that must be detailed, explained, and present-ed to many stakeholders in the process of moving HIEforward with tangible benefits to various segments ofthe US healthcare system.

Jack E. Fincham, PhD, RPhProfessor of Pharmacy Practice and AdministrationDivision of Pharmacy Practice and Administration

Adjunct Professor of Health AdministrationHenry W. Bloch School of Management

University of Missouri, Kansas City

1. Adler-Milstein J, Jha AK. Sharing clinical data electronically: a critical chal-lenge for fixing the health care system. JAMA. 2012;307:1695-1696.2. Rippen HE, Pan EC, Russell C, et al. Organizational framework for health infor-mation technology. Int J Med Inform. 2012 Feb 27. [Epub ahead of print.]3. Zimlichman E, Rozenblum R, Salzberg CA, et al. Lessons from the Canadiannational health information technology plan for the United States: opinions of keyCanadian experts. J Am Med Inform Assoc. 2012;19:453-459.4. Payne TH, Detmer DE, Wyatt JC, et al. National scale clinical informationexchange in the United Kingdom: lessons for the United States. J Am Med InformAssoc. 2011;18:91-98.5. Patel VN, Dhopeshwarkar RV, Edwards A, et al. Consumer support for healthinformation exchange and personal health records: a regional health informationorganization survey. J Med Syst. 2012;36:1043-1052.

STAKEHOLDER PERSPECTIVE (Continued)

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VELCADEHCP.COM

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

If you defi ne 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 InformationINDICATIONVELCADE is indicated for the treatment of patients with multiple myeloma.

CONTRAINDICATIONSVELCADE 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 modifi cation or discontinuation. Patients with preexisting severe neuropathy should be treated with VELCADE only after careful risk-benefi t 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 infi ltrative pulmonary disease has been reported

Nausea, diarrhea, constipation, and vomiting have occurred and may require use of antiemetic and antidiarrheal medications or fl uid 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 REACTIONSMost 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 effi cacy 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-specifi ed interim analysis (median follow-up 16.3 months), VELCADE+MP resulted in signifi cantly 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.

2:18 PM

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 V-12-0095 6/12

DRUG UTILIZATION TRENDS


Payer trends in drug utilization and molecular test-ing have been the focus of several posters present-ed at the 2012 Educational Conference of the

Academy of Managed Care Pharmacy, October 3-5,Cincinnati, OH.

No Consistency in Payer Policies forTargeted Drugs, Tests

Payers have adopted a variety of policies for cover-ing expensive targeted oncologic therapies and associ-ated pharmacogenomics tests, according to a compari-son of 4 large insurers—Aetna, Cigna, Humana, andUnitedHealthcare. A search for policies related to 27drugs and 23 oncology-related pharmacogenomics testsshowed little consistency among these payers, accordingto a poster presentation by Angela Luong, PharmD, ofOptumInsight, Shakopee, MN, and colleagues. Drugsand genetic tests were covered by a mix of medical andpharmacy policies.

In only 2 cases did all 4 insurers have policies for thedrug and its related genetic test: vemurafenib and crizo-tinib. The location of the policy—under the medical orthe pharmacy benefit—differed among the companies.The analysis revealed inconsistencies across benefits andpayers. None of the payers had policies covering all ofthe drugs and related tests.

Pharmacogenomics tests offer a means to identifypatients whose tumors harbor genetic mutations thatincrease the likelihood of response to treatment with aspecific targeted therapy (so-called druggable muta-tions). Appropriate use of pharmacogenomics tests hasthe potential to minimize side effects and to increasedrug efficacy, thereby reducing costs.

The US Food and Drug Administration nowrequires drug manufacturers to include pharmacoge-nomics information in the New Drug Application forevery targeted therapy.

Using information available on each company’s web-site, Dr Luong and colleagues searched for coveragepolicies pertaining to 27 targeted oncologic therapiesand 23 related pharmacogenomics tests, all approvedsince April 2011.

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

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

Regarding the 23 tests included in the study, theresearchers found that the largest number under medicalpolicies was 18, and the highest under pharmacy benefitswas 6. The medical benefit had the largest number (ie,11) of policies requiring pharmacogenomics test resultsfor approval of the drug, whereas the requirement toppedout at 6 among pharmacy plans.

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

Policies to Manage Biologics Use HaveMinimal Impact on Costs

Implementation of a step therapy policy for the use ofbiologic agents had little if any impact on costs over a5-year period, a review of 4 large health plans showed.

Of 5 biologics included in the study, costs decreasedfor 2 and increased for 3, resulting in a net cost increaseof 10.3%. The findings suggest that policies designed tomanage utilization of biologic therapies require carefulassessment of the cost of implementing the policy versusthe potential cost-savings, reported Mike Ingham, MSc,of Janssen Scientific Affairs, Horsham, PA, and col-leagues in a poster.

Step therapy policies establish the order in whichmedications will be reimbursed, Mr Ingham and col-leagues noted. A recent survey of health plans showedthat almost 75% of the companies had policies related tostep therapy for specialty products (www.specialtydrugbenefitreport.com/executive-summary.html).

Noting that more payers are adopting policies affect-ing intravenous biologics, Mr Ingham and colleaguesassessed utilization patterns from 2006 to mid-2011 for

Payer Drug and Molecular TestingUtilization Policies By Charles Bankhead, Medical Writer

Drug Trends_Cover 10/17/12 1:53 PM Page 345

DRUG UTILIZATION TRENDS


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

Beginning with 16 health plans, investigators reducedthe number to 4 after exclusion of plans that did nothave the data required for the analysis. Eligible patientshad at least 1 pharmacy claim and at least 1 medicalclaim during the 12 months before and after implemen-tation of the step therapy policy.

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

More than 70% of the patients already had biologictherapy at the start of the observation period. Thosepatients were unlikely to be affected by a new step ther-apy policy, the investigators noted.

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

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

The investigators concluded that policies adopted tolimit the use of infused biologic therapies and to reducecosts did not achieve the goals, at least in the near-term. [Ingham MP, et al. Utilization patterns of biologicsbefore and after implementation of a managed care steptherapy policy.]

Costs of Specialty Drugs Continue to Rise at Fast Pace

The cost of using specialty drugs to treat multiplesclerosis (MS) rose substantially from 2008 to 2010,accounting for much of the overall increase in medicaland pharmacy costs associated with the condition, inves-tigators reported.

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

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

total cost increased from 61.4% to 67.4% over the 3-year period, according to a poster presented by PatrickP. Gleason, PharmD, and colleagues, of Prime Thera -peutics, Eagan, MN.

Wholesale acquisition costs (WACs) for individualMS specialty drugs increased at a compound annualgrowth rate (CAGR) of 10% to 22.6%. For some of thedrugs, the WAC increased by ≥2-fold.

Specialty drugs, many originally developed for rarediseases, have been used with increased frequency inchronic diseases, such as MS. Specialty drug costs haverisen faster than healthcare costs in general. A 2009study showed the PPPY cost of treating MS with a spe-cialty drug was $37,592, with pharmacy costs accountingfor 56.8% of the total (Schafer JA, et al. J Manag CarePharm. 2010;16:713-717). Another study showed thatthe cost of MS drugs for one large insurer increased by15.2% from 2010 to 2011 (2011 Drug Trend Insightsreport. Prime Therapeutics, LLC. www.primetherapeutics.com/PDF/2011PrimeDrugTrendInsights.pdf; 2011 PrimeTherapeutics, LLC, internal data).

To establish a complete accounting of MS cost ofcare, Dr Gleason and colleagues reviewed total medicaland pharmacy costs for patients with MS within a singlecommercial health plan covering 1.2 million patients.They searched the insurer’s integrated records forpatients aged <65 years and who had ≥2 medical claimsassociated with an MS code.

The prevalence of MS was 1742 (0.17%) in 2008,which did not change significantly through 2010. Useof specialty drugs for patients with MS increased from70.8% in 2008 to 71.8% in 2010. Glatiramer was themost 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 totalcost increased from $29,751 to $36,901 over the 3-yearperiod, resulting in a CAGR of 11.4%. Combined med-ical and pharmacy costs for MS specialty drugs increasedfrom $14,311 to $20,200, representing a CAGR of18.0%. Pharmacy costs for specialty drugs accounted for$13,745 of the PPPY for combined MS specialty drugcosts in 2008 and $19,130 (94.7%) in 2010, which alsotranslated into a CAGR of 18.0%.

An analysis limited only to the 70% of patients withMS treated with specialty drugs showed that the PPPYtotal cost increased from $32,883 in 2008 to $41,760 in2010, representing a CAGR of 12.7%. The combinedmedical and pharmacy costs for MS specialty drugsaccounted for $20,201 (61.4%) of the PPPY total costof care in 2008, increasing to $28,152 (67.4%) of$41,760 in 2010, yielding a CAGR of 18.1%. [StarnerCI, et al. Multiple sclerosis specialty drug utilizers cost ofcare trends 2008 to 2010: an integrated medical and phar-macy claims analysis.] ■

Drug Trends_Cover 10/17/12 1:53 PM Page 346

CLINICAL


Parkinson’s disease is a degenerative disorder thatis characterized by muscle rigidity, tremors, andmotor impairment that often results in progres-

sive disability and severe complications that seriouslyaffect a patient’s health-related quality of life (QOL)

and physical functioning. The worldwide prevalencerates for Parkinson’s disease range from 0.5% to 1%among individuals aged 65 to 69 years, and from 1% to3% among those aged ≥80 years.1 Parkinson’s diseaseoften develops after age 60,2 and is the second-most

Assessment of Treatment Patterns and PatientOutcomes in Levodopa-Induced Dyskinesias(ASTROID): A US Chart Review StudyBarb 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 levodopa-

induced 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 pharma-

cologic 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 dis-

ease 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 guide-

lines, and their potential impact on patient outcomes.




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 andTrends, Xcenda, LLC, Palm Harbor, FL; Ms Sacco is Director, Global Health Economics & Outcomes Research, NovartisPharmaceuticals Corporation, East Hanover, NJ; and Dr Schoor is Chief Medical Officer, Medimix International, Miami, FL.

Barb Lennert

common neurodegenerative disorder among the elderlypopulation.1

Although no curative therapy is available forParkinson’s disease, one of the main goals of treatmentis to control the motor symptoms of the disease.3,4Levodopa (also known as L-dopa), which is widely con-sidered the cornerstone of treatment for Parkinson’s dis-ease, is effective in reducing many symptoms associatedwith Parkinson’s disease during the early stages of thedisease, thereby offering patients an acceptable QOLand a reasonable functional ability with regard to theactivities of daily living (ADLs).3 However, levodopa hasbeen associated with several side effects, and prolongedlevodopa treatment in Parkinson’s disease has been asso-ciated over time with increased motor fluctuations andthe development of levodopa-induced dyskinesias(LIDs).5 The effectiveness of levodopa treatment de -creases with the progression of the disease, because of thepersistent loss of nigrostriatal neurons (ie, dopamine-containing neurons located in the substantia nigra in thebrain). Typically, the first sign of this loss is the gradualreturn of Parkinson’s disease symptoms before the nextdose of the medication is due, which is called “wearingoff.” Wearing off generally necessitates increases in le vo -dopa dosage and frequency.6

LIDs often present as chorea or choreoathetosis.“Chorea” refers to abnormal, involuntary, nonrepetitivemovements that are characterized by brief, irregular con-

tractions that appear to flow from one muscle to thenext. The severity of these movements can vary fromoccasional abnormal movements that are absent at restand provoked only during active movement (eg, walk-ing, talking) to violent, large-amplitude flinging andflailing arm movements (ie, ballismus). Often, twistingor writhing athetoid movements (ie, choreoathetosis)are added onto these movements.7 LIDs usually firstappear on the side of the patient that is most affected byParkinson’s disease, and generally present in the legsbefore the arms.7 Although dyskinesias may predomi-nantly affect the legs and arms, they may spread to otherbody parts, such as the torso, head, and neck, or to thespeech and respiratory muscles.7,8

The second-most common form of LIDs is dystonia,presenting as sustained muscle contractions. Dystoniacan occur either alone or in combination with thechorea. When combined with chorea, the dystonia canmanifest as twisting of the leg when walking or when thearm is being pulled behind the back. “On” and “off”phases are used to describe the presence of levodopa’sbenefit. Off-time dystonias, which occur when levodopaplasma levels are low, are usually quite painful andaccount for greater disability than chorea.7

Based on the relationship between LIDs and levo -dopa dosing, LIDs are classified as peak-dose, diphasic,“off-state,” “on-state,” or “yo-yo” dyskinesias (Table 1).7,9Because some dyskinesias represent a response to theconcentration of levodopa, such effects may be eliminat-ed or decreased by the reduction of the levodopa dose.However, this dose reduction can be problematic whenthe reduced dose results in the recurrence of Parkinson -ian symptoms. Because dyskinesia may recur with expo-sure to other dopamine agonists, the prevalence of LIDsmay not be correctly diagnosed and, therefore, the ratesof LIDs may be underestimated. The prevalence data forLIDs are limited.8

The incidence of LIDs appears to vary by the age atParkinson’s disease onset, the duration and progressionof the disease, the levodopa dosage, and the duration ofle vodopa treatment.10 Earlier studies have reported preva-lence rates of LIDs between 30% and 80% in patientswith Parkinson’s disease.11 Although the biologic mecha-nisms for the development of LIDs have not been estab-lished, it is clear that LIDs have a severe, negative impacton a patient’s QOL and physical functioning.11

Consensus is lacking among experts regarding theoptimal scale or instrument to be used to measure dyski-nesias accurately and reliably. Given the intermittentnature of dyskinesias, these events may not be presentduring a clinical evaluation by the physician. Somepatients may have difficulty in remembering or accurate-ly reporting dyskinesia symptoms, especially when the

CLINICAL


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 cornerstonetreatment for Parkinson’s disease, is associated withpainful and disabling dyskinesias, which limit theability to optimize treatment and reduce thepatient’s functional ability.

➤ ASTROID is the first study to quantify real-worlddata of treatment patterns and patient outcomesassociated with levodopa-induced dyskinesias (LIDs).

➤ The prevalence of LIDs is underestimated; onceestablished, LIDs are difficult to manage, and effortsshould be focused on preventive measures ratherthan on reducing their severity.

➤ Overall, 56% of dyskinesias occur when levodopalevels are highest, suggesting that dosages may oftenbe too high.

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

symptoms are mild and intermittent. The assessment ofdyskinesia, therefore, remains largely subjective andoften inaccurate. There is an underlying need for moreobjective, easy-to-use, validated scales that can beapplied by patients and physicians to accurately evalu-ate and report dyskinesias; such scales will improve clin-ical evaluation and aid physicians in prescribing theproper treatment. The Movement Disorder Society wasthe first organization to conduct a comprehensive, sys-tematic review of the psychometric properties of thescales used to measure dyskinesia in Parkinson’s disease,and this organization published its recommendations.12Scales that have been recommended for clinician use ina population of patients with Parkinson’s diseaseinclude the Abnormal Involuntary Movement Scale(AIMS)5,13 and the Unified Parkinson’s Disease RatingScale (UPDRS).5,12 Patient-rated scales include the 39-item Parkinson’s Disease Questionnaire (PDQ-39)14,15and the Parkinson Disease Dyskinesia 26-item Scale(PDYS-26)5 (Table 2).5,12-15

Once established, LIDs are difficult to manage, andtherefore efforts should be made to prevent them.Preventive and therapeutic measures for LIDs include avariety of pharmacologic strategies and/or neuro-surgery; however, current medical therapies focus onlyon reducing the severity of dyskinesia.16 Ultimately,dyskinesias limit the ability to optimize the Parkinson’sdisease treatment regimen and have a negative impacton the patient’s health-related QOL and functionalability with ADLs.16 An important unmet need forpatients with Parkinson’s disease includes the preven-tion of LIDs, as well as the early identification of LIDsand effective management that does not further com-plicate underlying Parkinson’s disease management.

The purpose of the ASTROID (Assessment ofTreat ment Patterns and Patient Outcomes inLevodopa-Induced Dyskinesia) study was to provide anoverview of current real-world treatment practices andpatient-reported outcomes (PROs) for QOL and phys-ical functioning in patients with Parkinson’s diseaseand LIDs, using 3 objectives—quantify the medicationuse and treatment patterns in LIDs management; char-acterize the current levels of health status, QOL, andphysical functioning; and identify patient characteris-tics by LIDs severity.

MethodsStudy Design

This mixed-methodology study design included across-sectional survey of neurologists practicing in theUnited States, a retrospective chart review of patientswith Parkinson’s disease and LIDs from their respectiveneurologists, and a cross-sectional survey of these same

patients’ health-related QOL and physical functioning.Survey and chart data were collected between May 2010and July 2011.

Physician and Patient SelectionThe physicians recruited for this study represent a

convenience sample based on their ability to serve asprincipal investigators and on their willingness to com-plete the necessary questionnaires, recruit patients,obtain patients’ consent, complete the InstitutionalReview Board process, and supervise the conduct of thestudy in compliance with the protocol’s requirements.

A third-party vendor sent e-mail invitations to neu-rologists with whom the vendor had established a previ-ous relationship and faxed invitations to physicians atParkinson’s Disease and Movement Disorders Centersacross the United States. The neurologists who expressed

Treatment Patterns and Patient Outcomes in LIDs


Table 1 Types of Dyskinesias

Type of dyskinesia Characteristics

Peak-dose dyskinesias

• Most common forms of LIDs; earliestappearing

• Related to peak plasma (and possibly highstriatal) levels of levodopa

• Involve the head, trunk, limbs, and some-times respiratory or speech muscles

• Dyskinesias are usually choreiform, althoughin the later stages, dystonia can superimpose

Diphasic dyskinesias

• Develop when plasma levodopa levels are ris-ing or falling, but not with the peak levels

• Also called D-I-D • Commonly dystonic in nature, althoughchorea or mixed pattern may occur

• Do not respond to levodopa dose reductionand 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 painfulspasms 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.

initial interest received a follow-up telephone call to dis-cuss the project in more detail and to verify their willing-ness and ability to fulfill all participation requirements asoutlined above.

The physician practices that were selected for thestudy provided broad US geographic coverage and variedin size, ranging from single-physician to multiple-physi-cian practices. The physicians selected patients for thestudy in accordance with the screening criteria and thepatient’s willingness to participate in the study. Allphysicians completed the Institutional Review Boardapproval process, and the patients provided writteninformed consent per the study protocol and theInstitutional Review Board requirements.

Study ProtocolThe participating physicians completed a 13-item cus-

tomized questionnaire that was developed by externalexperts and a study team with expertise in Parkinson’sdisease and LIDs. The 13-item questionnaire includedquestions that asked physicians to (1) quantify medica-tion use and treatment pathways; (2) characterize currentlevels of health status, QOL, and physical functioning,such as ADLs; (3) estimate the prevalence of LIDs amongtheir patients with Parkinson’s disease; and (4) assesstreatment timelines for patients with LIDs across variouslines of therapy (ie, first, second, and third). The overallobjective of this questionnaire was to provide a briefoverview of physician-reported treatment practices and

CLINICAL


Table 2 Outcomes and Patient-Rated Instruments

Instrument name Purpose Scale Score rangea

Clinician-rated instruments

mAIMS (modifiedAbnormal Involuntary Movement Scale)5,13

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

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

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

UPDRS (UnifiedParkinson’s Disease Rating Scale)5,12

Assess the severity ofParkinson’s diseasesymptoms using a 5-point scale with ratings from 0 (normal)to 4 (severe), with higher scores indicatinggreater disability fromParkinson’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 motorevaluation

• Part IV: Complications of therapy• Modified Hoehn and Yahr staging of severity of Parkinson’s disease

• Schwab and England ADLs scaleThese are evaluated by interview andclinical observation Some sections require multiple gradesassigned to each extremity

This study includedonly select ques-tions from Part IV(Complications oftherapy, questions 32 and 33)

Patient-rated instruments

PDYS-26 (ParkinsonDisease Dyskinesia 26-item Scale)5

Quantify the impact ofdyskinesia on ADLs during the past week

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


PDQ-39 (39-itemParkinson’s DiseaseQuestionnaire)14,15

Measure health status,covering 8 aspects ofquality of life

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


aMild, moderate, and severe ranges were determined by multiplying the number of questions by the score assigned tothat severity (eg, in the PDYS-26, a moderate severity score = 2; therefore 2 * 26 = 52) to determine the maximumscore for the moderate range. ADLs indicates activities of daily living.

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 andentered into an electronic data-collection tool. Question -naires completed by the patients were sent to a third-party vendor for entry into the study database. All patientdata were de-identified, and the patients’ responses wereverified to be within the range of possible values.

The study eligibility criteria included the followingrequirements: patients had to be aged between 50 and 90years, be treated with levodopa and have expressed LIDs,have the ability to comply with procedures for cognitiveand other testing, provide full written informed con-sent before the performance of any protocol-specifiedprocedure, and have a caregiver or family informant ifthey were unable to care for themselves. The study wasconducted after the review and approval by theGoodwyn Institutional Review Board (Cincinnati,OH) of all study documents, patient consent forms, andinvestigators’ ability.

Variables of InterestTo capture clinical outcomes of interest from the

physicians’ perspective and the PROs of interest, severalscales were used. A 33-item, multipart chart abstractionform included information on patients’ age, sex, comor-bidities, Parkinson’s disease treatment history, LID sever-ity and treatments, and drug interactions. A componentof the physician-applied questionnaire asked the physi-cians to evaluate these patients with scales that includedquestions from Part IV of the UPDRS (Complications ofTherapy, questions 32 and 33) and the modifiedAbnormal Involuntary Movement Scale (mAIMS).5,13 Inaddition, these same patients were asked to complete asurvey that included PROs of interest using the PDYS-26and the PDQ-39. Table 2 outlines the PROs and physi-cian-reported scales used in this study.

To assess treatment patterns, the key data elementscollected included medication dosage and frequency,treatment patterns (ie, first- and second-line treatmentselection), the length of time between changes in thera-py, and the time from a diagnosis of LIDs to first-linetherapy initiation. Monotherapies were categorized as adopamine agonist, a catechol-O-methyltransferase(COMT) inhibitor, a monoamine oxidase inhibitor,amantadine, or an atypical antipsychotic. Fixed combi-nations included carbidopa plus levodopa enteral infu-sion; carbidopa plus levodopa immediate-release; car-bidopa plus levodopa controlled-release; and carbidopawith levodopa and entacapone.

Analytic PlanDescriptive analyses were used to evaluate the distri-

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 characterizechanges in medications over time and correlationsbetween medication administration and disease progres-sion were recorded.

ResultsPhysician-Reported Sample Characteristics

The physician survey included 7 neurologists who pro-vided real-world information on treatment patterns andclinical outcomes of interest in patients with Parkinson’sdisease and LIDs. Each of the 7 physicians reported treat-ing between 97 and 375 patients (mean, N = 189) withParkinson’s disease, for a total of 1322 patients.

Overall, the physicians estimated that 62% of thepatients were being treated with a form of levodopa. Ofthe patients being treated with levodopa, the physiciansestimated that 27.6% demonstrated symptoms of LIDs;however, of the total of 1322 patients with Parkinson’sdisease, these 7 physicians indicated that 856 (64.8%)patients had symptoms of LIDs based on the mAIMS,indicating an underestimation of the proportion of thepopulation experiencing LIDs or the inclusion of cho -reas, but not dystonias, in these estimates. Based on themAIMS, the physicians estimated symptom severity ofLIDs as mild in 39% of patients, moderate in 38%, andsevere in 23%. LIDs can be classified based on diseasecourse and clinical phenomenology after a regular or anover-threshold dose of levodopa.11 Common categoriesare diphasic, off-state, and on-state (Table 1). The physi-cian-reported occurrences of dyskinesia among patientsincluded on-state dyskinesia in 56% of patients, diphasicdyskinesia in 26%, and off-state dyskinesia in 18%.

Physician-Reported Treatment and Prescribing Patterns

Among the 7 surveyed physicians, the preferredtherapeutic strategy in patients with Parkinson’s dis-ease and LIDs was symptomatic treatment (N = 4;57%), followed by restorative or neuroprotective treat-ment (N = 2; 29%), and other (“ideally, both”; N = 1;14%). All 7 physicians reported that they consideredincreased disability associated with functioning as themost important disease aspect in assessing the progres-sion of Parkinson’s disease.

Among this group, 6 physicians believed that theduration of treatment with levodopa was the mostimportant risk factor implicated in the onset of LIDs inpatients with Parkinson’s disease (1 physician indicatedthat “severity and duration” of Parkinson’s disease symp-toms was the most influential risk factor).



The physicians were divided on their preferred strate-gy to minimize the duration of the “off” times in patientswith motor fluctuations, as well as their preferred strategyto maximize the duration of the “on” times in thesepatients. Specifically, the most frequently selectedanswers to minimize off times and maximize on times

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

Monotherapy was favored as the first-line treatmentfor mild LIDs, and combination therapy was more fre-quently used with disease progression. Table 3 outlinesphysician-reported prescribing patterns by LID severity.

CLINICAL


Table 3 Physician-Reported Prescribing Patterns, by LID Severity

Disease severityPhysicians, N

(N = 7) Drugs, doses, and frequency

Mild LIDs, 32% (278 patients)

Monotherapy (includes fixed-dosecombination medications)

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

Combination therapy 1 Ropinirole 3 mg + carbidopa/levodopa/entacapone(Stalevo 100) 3 times daily

No medication 1 Stated did not understand the question

No answer 1 NA

Moderate LIDs, 37% (316 patients)


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

Severe LIDs, 31% (262 patients)


1 Dopamine agonists: Pramipexole (Mirapex)aevery 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 aNo dose was provided.bDoses and frequencies varied by respondent; in other instances, no dose or frequency was selected. Therefore, doseand frequency are not listed. LIDs indicates levodopa-induced dyskinesias; NA, not applicable.

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

For mild LIDs, 5 of the 7 physicians indicated theywould prescribe a medication for the management ofmild LIDs, with 4 of these 5 indicating that they wouldchoose monotherapy with a dopamine agonist, specifi-cally, pramipexole (Mirapex) or ropinirole (Requip).For moderate LIDs, 4 of the 7 physicians indicated thatthey would prescribe combination therapy from amongseveral medications, including carbidopa plus levodopaand 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

would prescribe combination therapy from among sever-al medications, including entacapone; carbidopa pluslevodopa and entacapone; pramipexole; rasagiline mesy-late; ropinirole; generic amantadine; or carbidopa pluslevodopa (Sinemet).

Medical Chart Data Sample CharacteristicsMedical chart data were collected from 172 patients

(79 male, 93 female; age range, 50-90 years, with approx-imately 80% falling into the range of 61-80 years)between May 2010 and July 2011. Table 4 presents base-line characteristics from the chart data. The mean lowestinitial total daily dose of levodopa (216 mg) was admin-istered in the population with moderate LIDs; the meantime to LID onset was 4.8 years in this subgroup. Overall,



Table 4 Patient Characteristics, by LID Severity

LID severity

CharacteristicsMild, 39%(N = 67)

Moderate, 31%(N= 53)

Severe, 30%(N = 52)

Total, 100%(N = 172)

Sex, N (%)

Male 33 (49) 23 (43) 23 (44) 79 (46)

Female 34 (51) 30 (57) 29 (56) 93 (54)

Age, N (%)

≤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 diseasediagnosisa 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, yrsb4.8 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)

aMean date range of Parkinson’s disease diagnosis: 1998-2001. bTwo patients were removed from the analysis of the mild LIDs and the overall analysis because total daily doses oflevodopa were recorded in error as 1 mg daily. cMean 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.

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

Physician- and Patient-Reported Outcomes of Interest

In comparing total scores on the PDYS-26 with themAIMS and PDQ-39, a strong alignment was seen inseverity classification among these scales (eg, a patientwho scored as “mild” on one scale was likely to score as“mild” on the other scales). The moderate and severecategories followed a similar pattern. Across all PDYS-26 severity categories, the physicians reported that dys -kinesia was present between 26% and 50% of the wakingday, according to the UPDRS. Of note, the physiciansreported that the dyskinesias were moderately disablingin the patients who scored as “mild” on the PDYS-26,but only mildly disabling in the moderate and severegroups, according to the UPDRS.

Medical Chart Timeline of LID Diagnosis to Treatment Initiation, ProgressionFigure 1 presents the timeline of progression to LIDs.

The mean time from the diagnosis of Parkinson’s diseaseto levodopa initiation was 1.4 years (standard deviation[SD], 2.2 years), and the mean time from levodopa initi-ation to the onset of LIDs was 5.4 years (SD, 4.2 years).The total mean time from the diagnosis of Parkinson’sdisease to the onset of LIDs was 6.8 years (SD, 4.5 years).The mean time from the diagnosis of LIDs to initiationof first-line treatment for LIDs was 10.7 months (SD,14.0 months).

Linear regression models were used to determinewhether there was an association between the averagelevodopa dosage and the time to the onset of LIDs. Fourregression models were used—1 overall model thatincluded all severity levels of LIDs and 3 models strati-

fied by LID severity (ie, mild, moderate, and severe).Figure 2 displays results for the overall model, indicat-ing that the relationship between the dosage and thetime to the onset of LIDs is not significant (P = .548).The results for each model that was stratified by LIDsseverity also indicate that the relationship between thedosage and the time to LID onset is not statistically sig-nificant (Figure 2).

Medical Chart Results for LID TreatmentNearly all (84.3%) patients with LIDs were treated

pharmacologically across first, second, and third lines oftreatment, and 10.5% of patients with LID were treatedwith surgical intervention only. The first-line LID treat-ment selection was most influenced by the type of con-trol and effects, particularly the ability to control wors-ening motor symptoms and ensure more stable levodopaplasma levels. Of 172 patients, 151 (approximately 88%)received pharmacologic therapy as first-line treatmentfor LIDs, with 17% receiving monotherapy; nearly 50%of the monotherapy consisted of dopamine agonists, andapproximately 33% consisted of fixed-dose combinationdrugs. (Based on the study protocol, fixed-dose combina-tions were considered “monotherapy.”) In addition, 121patients (approximately 70%) received combinationtherapy, with 49 of the 121 (approximately 40%) receiv-ing ropinirole and rasagiline mesylate and a branded, orgeneric, carbidopa plus levodopa combination (25/100-mg dose). Of the approximately 11% of patients whoreceived surgical intervention, 17 of 18 were categorizedas having severe LIDs.

For the 27 patients (16%) who required a second-linetreatment, a lack of efficacy was the most frequentlycited (74%) reason for the change in treatment. Of these27 patients, 21 (78%) received pharmacologic treat-ment, and 33% of these patients had another medicationadded. Nineteen percent received surgical intervention(4 of the 5 were classified as severe LIDs). Of the 27patients, 9 (33%) progressed from a lesser severity cate-gory 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 ofefficacy was the reason cited for the change in treatmentin all cases, 100% of whom received pharmacologic ther-apy. Figure 3 presents the timeline of disease progressionfor Parkinson’s disease diagnosis through third-line treat-ment for LIDs.

DiscussionThe purpose of the ASTROID study was to provide

an overview of current real-world treatment practicesand PROs for health-related QOL and physical func-tioning in patients with Parkinson’s disease and LIDs.

CLINICAL


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

Parkinson’s diseasediagnosis

Levodopa initiation

Onset of LIDs

1.4 years (SD, 2.2 years) 5.4 years (SD, 4.2 years)

6.8 years (SD, 4.5 years)

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

One of the main objectives was to quantify the medica-tion use and treatment patterns in the management ofLIDs. Results from the physician survey indicated thatmonotherapy was the preferred treatment for mild LIDsand that combination therapy was preferred for moder-ate and severe cases. However, there was no preferredstrategy among physicians to minimize the duration ofthe off times or to maximize the duration of the on timesin patients with motor fluctuations.

That the physicians reported the proportion of dyski-nesias in the on-state phase to be 56% suggests thatlevodopa dosages are too high and require dose reduc-tion to minimize dyskinesias. This may indicate a needfor physician education regarding appropriate levodopadosing. Alternatively, it may also indicate the need forpatient and caregiver education about not self-medicat-ing at a higher-than-prescribed dose to avoid complica-tions of therapy.

In this study, patients with Parkinson’s diseaseexpressing symptoms of LIDs were prescribed a meandaily levodopa dose of only 241 mg. This dose is consid-erably lower than the dose used in the population in theDATATOP study, in which the average daily levodopadose of 387 mg was found to produce symptoms of LIDs,17raising a question about what levodopa dose patients areactually consuming.

The physician survey reports that the duration oflevodopa treatment was selected as the most influentialrisk factor for the development of LIDs. The chartreview findings were consistent with this result, dem -onstrating the onset of LIDs at approximately 5 years,regardless of dose and across all LID severity categories.Based on these findings, the implementation of screen-ing for LIDs at regular intervals after the initiation oflevodopa treatment would seem to be a logicalapproach to proactively identify and treat patients with



700

600

500

400

300

200

100

0

1200

1000

800

600

400

200

0

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

aTwo patients were removed from the “mild” and the “overall” analyses because total daily doses of levodopa wererecorded in error as 1 mg daily.LID indicates levodopa-induced dyskinesia.

Dose, m

g

Time, years

Dose, m

g

Dose, m

g

Dose, m

g1200

1000

800

600

400

200

0

700

600

500

400

300

200

100

0

0.0 5.0 10.0 15.0 20.0

0.0 5.0 10.0 15.0 20.0

0.0 5.0 10.0 15.0 20.0

0.0 5.0 10.0 15.0 20.0

Time, years

Time, years Time, years

Overalla Milda

ModerateSevere

P = .548 P = .313

P = .130P = .650

LIDs. Of note, however, the mean time from the diag-nosis of LIDs to first-line treatment for these events was10.7 months (SD, 14.0 months), suggesting that thereis a need to raise awareness of the importance of regularand early LID screening.

Treatment guidelines from the American Academy ofNeurology recommend using entacapone and rasagilineto reduce off time (Level A evidence), and Level B evi-dence supports the use of pergolide, pramipexole, ropini-role, and tolcapone to reduce off time.18 However, noneof the medications on the Level A evidence list of rec-ommended drugs was named by the participating physi-cians as those used to treat patients with mild LIDs,although some of the medications listed by these physi-cians were supported by Level B evidence.18 This resultmay be driven by the cost of the medications, patients’insurance coverage, insurance company pharmacy man-agement strategies, or patient or prescriber preferences.Further study of the reasons for such deviations from theguidelines is warranted.

A key objective of this study was to characterize thecurrent levels of health status, QOL, and physical func-tioning, such as ADLs, in patients with Parkinson’s dis-ease and LIDs. Results from the chart review and physi-cian survey suggest that there was a strong alignment inseverity classification among the PRO scales used (ie, apatient who scored as “mild” on one scale was likely toscore as “mild” on the other scales); however, there weresome variations. For example, the physicians reportedthat the dyskinesias were moderately disabling in thepatients who scored as “mild” on the PDYS-26, but only

mildly disabling in the patients who scored as “moder-ate” or “severe” on the PDYS-26. Considering the widevariability of the disease state and the subjective natureof the assessment tools used, it is not surprising that thescales were not exactly aligned.

Another objective of the study was to identify patientcharacteristics and treatment selection by the severity ofLIDs. The surveyed physicians estimated that the preva-lence of LIDs in their practices was 28%; the true ratebased on the mAIMS was 65%, indicating either anunderestimation of the magnitude of the populationwith LIDs or estimates that did not take dystonias intoaccount but rather were based on on-state choreas only.The physicians also underestimated the severity of LIDsin their patient populations, estimating that 23% ofthem had severe LIDs versus an actual rate of 31% basedon the chart data. For first-line treatment for LIDs, 88%of patients received pharmacologic therapy, and most(70%) of them received combination therapy. Of thepatients who received surgical treatment, 94% were cat-egorized as having severe LIDs. A consideration forphysicians will be to have patients complete a validatedquestionnaire or scale that measures their QOL andfunctional ability as part of the routine visit. Assessmentat regular visits can provide the physician with a longi-tudinal record of patient response to treatment.

To our knowledge, this is the first study to analyze cur-rent real-world treatment practices and outcomes forpatients with Parkinson’s disease and LIDs. In addition,we used a mixed-methodology approach to assess howpatients’ QOL, health status, and physical functioningwere affected by the severity of LIDs. The concordantresults from the patient-reported QOL and ADL scalesand the clinician-assessed scales support the use of theseinstruments in a population of patients with Parkinson’sdisease and LIDs.

Although the sample of 7 physicians is small, thesephysicians reported practice patterns based on theirentire population of patients with Parkinson’s disease

CLINICAL


Parkinson’s disease diagnosis

First-line LIDtreatment

Levodopa initiation

Second-line LID treatment

Third-line LIDtreatment

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

• 1.4 years• SD = 2.2 years




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

➡ ➡ ➡ ➡

A key objective of this study was tocharacterize the current levels of healthstatus, QOL, and physical functioning, suchas ADLs, in patients with Parkinson’s disease and LIDs.

(N = 1322) in addition to chart review data for 172patients, making the results more robust. These 7 physi-cians use different approaches to minimize LIDs, and notall of the medications they prescribe are on the list of rec-ommended medications from the American Academy ofNeurology treatment guidelines. Perhaps these findingsrepresent a need to improve compliance with recom-mended guidelines to optimize patient outcomes.

LimitationsBecause of the retrospective, observational nature of

this study, a true causal link cannot be made between anyof the variables of interest and the outcomes, and studydesigns such as these are predisposed to selection bias.

Self-reported surveys are subject to recall bias andmay not accurately reflect characteristics of the generalpopulation. In addition, not all patients were required tohave a minimum number of years of data available intheir record for inclusion in the study. As such, theresults might have been influenced by the length of timea patient was associated with a provider.

Furthermore, not all physicians had the same numberof patients, and some of the results may possibly be over-or underrepresented by a group of patients from a partic-ular practice.

Finally, we surveyed a sample of US neurologists; there-fore, we recognize that the results may not be generaliz-able to healthcare systems outside of the United States.

ConclusionOur findings indicate that the diagnosis and the

treatment of Parkinson’s disease and LIDs are not opti-mal because of the length of time from diagnosis totreatment and the variability in treatment selection andresponse. Increased awareness and education for physi-cians to screen for LIDs and initiate treatment soonerare needed. Additional real-world studies are recom-mended to better understand the treatment patterns,patient adherence, compliance with guidelines, andimpact on patient outcomes. ■

AcknowledgmentThe 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 FundingThis study was funded by Novartis Pharmaceuticals

Corporation.

Author Disclosure StatementMs Lennert and Ms Farrelly are employees of Xcenda, a

consulting company that received funding from Novartis forthis study; Dr Bibeau was an employee of Xcenda at the timeof the study analysis and during preparation of the manu-script; Ms Sacco is a shareholder of Novartis; and Dr Schooris an employee of Medimix International, a research compa-ny that received funding from Novartis for this study.

References1.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 dis-ease: variation by age, gender, and race/ethnicity. Am J Epidemiol. 2003;157:1015-1022.3. Parkinson’s disease: hope through research. National Institute of NeurologicalDisorders 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 continuousintraduodenal 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 toassess 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 inParkinson’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: acommunity-based study. Brain. 2000;123:2297-2305.9. Fahn S. The spectrum of levodopa-induced dyskinesias. Ann Neurol. 2000;47:S2-S9, S9-S11.10. Berg D, Godau J, Trenkwalder C, et al. AFQ056 treatment of levodopa-induceddyskinesias: results of 2 randomized controlled trials. Mov Disord. 2011;26:1243-1250.11. Fabbrini G, Brotchie JM, Grandas F, et al. Levodopa-induced dyskinesias. MovDisord. 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 recommenda-tions.Mov Disord. 2003;18:738-750.13. Abnormal Involuntary Movement Scale (117-AIMS). In: Guy W, ed. ECDEUAssessment Manual for Psychopharmacology. Rockville, MD: US Department ofHealth, 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-of-life 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 inParkinson disease. Ann Neurol. 2011;69:919-927.17. Parkinson Study Group. Impact of deprenyl and tocopherol treatment on Parkinson’sdisease in DATATOP patients requiring levodopa. Ann Neurol. 1996;39:37-45.18. Pahwa R, Factor SA, Lyons KE, et al. Practice parameter: treatment of Parkinsondisease with motor fluctuations and dyskinesia (an evidence-based review). Report ofthe Quality Standards Subcommittee of the American Academy of Neurology.Neurology. 2006;66:983-995.



Stakeholder perspective on page 358

CLINICAL


Parkinson’s Disease: A Complicated but Underappreciated and Undertreated Condition

According to the Parkinson’s Disease Foundation, asmany as 1 million Americans live with Parkinson’s dis-ease, which is more than the combined number of peo-ple diagnosed with multiple sclerosis, muscular dystro-phy, and Lou Gehrig’s disease. Moreover, approximately60,000 Americans are diagnosed with Parkinson’s dis-ease annually, and this number does not reflect themany thousands of cases that go undetected.1MEDICAL/PHARMACY DIRECTORS: Yet

despite these statistics, Parkinson’s disease currentlydoes not get significant attention by health insuranceplans, largely because of the relatively lower cost of thetherapeutic interventions compared with other dis-eases, such as multiple sclerosis or rheumatoid arthritis.

One of the mainstays of therapy for Parkinson’s dis-ease is levodopa, which can control the motor symp-toms of the disease. However, treatment with levodopacan produce significant dyskinesias, which considerablyincrease the complexity of treatment.

In this issue of American Health & Drug Benefits, MsLennert and her colleagues present the findings from areal-world study designed to provide an overview ofcurrent real-world treatment practices and patient-reported outcomes for health-related quality of life andphysical functioning in patients with Parkinson’s dis-ease and levodopa-induced dyskinesias (LIDs). Notsurprisingly, the authors found that, “The diagnosis andthe treatment of Parkinson’s disease and LIDs are notoptimal, because of the length of time from diagnosis totreatment and the variability in treatment selectionand response.”

As with many other diseases, we often find that thevariability of treatment in this condition is significant,and that delays in diagnosis are common; even whenLIDs are diagnosed, treatment is often suboptimal. Asthose of us in healthcare management often have

learned, this variability is responsible for poor patientoutcomes and inefficient use of medical financialresources.

The authors appropriately call for increased aware-ness and education. Yet such steps alone will not belikely to solve the problem. In the current medicalsystem, physicians are faced with an increasingly com-plex array of diagnostic and therapeutic challenges.Evidence-based guidelines can help, but guidelines areoften out of date, lack adequate evidence for the ther-apeutic choices, and are often too complex. In a newarticle published in the British Medical Journal earlierthis month, the author notes “that unnecessary treat-ment in America accounts for 10 percent to 30 percentof healthcare spending, or up to $800 billion a year.”2Simply put, the system in the United States can nolonger afford such waste and inefficiencies.

What Ms Lennert and her colleagues have found inthis study is not isolated to a single disease state.Similar findings are common when we measure out-comes and variations in patient care. The authors ofthe present article are to be commended for their study,for it is from such data that we ultimately come to therealization that major overhauls in the system are nec-essary. The solution is certainly beyond the scope ofthis brief perspective, but such work as this article con-tinues to demand a call to action to reform the currentmedical 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 health-care to blame? BMJ. 2012 Oct 2. [Epub ahead of print.]

Gary M. Owens, MDPresident, Gary Owens Associates

Philadelphia, PA


INDUSTRY TRENDS


In our previous article, we outlined the importance ofchoosing a specialty pharmacy that is able to imple-ment clinical and utilization management programs

to maximize patient outcomes and minimize the wasteassociated with specialty pharmaceuticals.1 Those crucialcapabilities prevent unnecessary plan expenditures onspecialty medications. Each specialty medication cov-ered by a payer is a substantial investment in a patient’shealthcare, often costing $20,000 to $200,000 or moreannually. Clinical programs help to ensure that invest-ment lessens the patient’s disease burden to the fullestextent possible. Utilization management programsensure the best clinical outcome at the lowest possiblecost to treat. The best specialty pharmacies provide com-petitive unit pricing for drugs, as well as clinical and uti-lization management programs to their clients.

The primary focus of the previous article was onmedications that are typically self-administered bypatients and that usually fall under the pharmacy bene-fit.1 However, approximately 50% of the specialty drugexpense is under the medical benefit.2 These medica-tions, which are normally infused, are administered by ahealthcare provider in various sites of service, mostoften in the physician’s office, in the hospital outpatientdepartment, and in the patient’s home (Figure 1, page360). For medical claims, usually the drug and the pro-fessional fees related to the drug administration arebilled directly to the medical carrier.

The most common specialty drugs covered under themedical benefit (Figure 2, page 360) include chemo -therapeutic agents (eg, bevacizumab and rituximab) andnonchemotherapeutic agents (eg, infliximab, natal-izumab, and immunoglobulin). Chemotherapy supportagents (eg, pegfilgrastim, darbepoetin, and epoetin)also represent a significant amount of medically cov-ered specialty pharmacy utilizations. These productsare expensive, with some infusions costing more than$200,000 annually.

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

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

The result is that specialty drugs that are coveredunder the medical benefit have significant variance incost, tend to be more difficult to analyze, and do nothave the same degree of structured clinical and utiliza-tion management programs as their pharmacy-adjudicat-ed counterparts. These dynamics present challenges tothe effective management of specialty pharmaceuticalsin the medical benefit.

How can payers ensure that medically billed drugsreceive the necessary cost, clinical, and utilization man-agement safeguards for these complex long-term thera-pies? This article outlines key areas within the medicalbenefit that payers can impact, and the steps they cantake to address these opportunities.

Medical Benefit Drug ManagementPharmacy benefit managers (PBMs), such as Express

Scripts and CVS Caremark, realize that half of the spe-cialty drug utilization is reimbursed outside of their tradi-tional business models. In response, many PBMs are cre-ating medical benefit management (MBM) programs tohelp clients understand and manage these drugs. Non-PBM organizations, such as Walgreens, along with variousconsulting groups, are also developing MBM programs.The spectrum of MBM is very broad, because vendorshave developed their programs based on their own inter-pretations of the medical/specialty opportunity and on

Cost Management through CareManagement, Part 2: The Importance ofManaging Specialty Drug Utilization in theMedical BenefitMichael T. Einodshofer, RPh, MBA, and Lars N. Duren, BCNSP, PharmD

Mr Einodshofer is Director of Utilization Management, Walgreens Specialty Pharmacy, and Dr Duren is VicePresident of Infusion Solutions, Walgreens Infusion Services

INDUSTRY TRENDS


their ability to effectively build a business in this space.Some MBM programs are focusing on the manage-

ment of chemotherapy regimens and are lowering thecost of chemotherapy by requiring practicing oncologistsand hematologists to follow structured clinical prescrib-ing guidelines, which are known as “oncology path-ways.” For example, CVS Caremark has stated that a15% savings on chemotherapy costs can be achievedthrough its version of oncology pathways.3

Other programs are focusing on affecting the distribu-tion channels of specialty drugs, by requiring physician

offices to obtain specialty drugs infused in the office froma specialty pharmacy. Other MBM programs offer to man-age a health plan’s infusible fee schedule in an attempt tostandardize the cost of a drug throughout the plan’s net-work and/or recommending a medical drug formulary.

Therefore, MBM means various things to differentgroups, depending on their area of focus and expertise.This article presents a broad perspective of MBM, withsuggestions on key areas where payers should focus theirinitial efforts to manage drug-related costs within themedical benefit.

PBMs are experts on how pharmacy claims are trans-acted. Health plans are experts on how medical servicesare delivered and transacted. These transactions todayare isolated into 2 discreet worlds. Although pharmacydata enjoy National Council for Prescription DrugPrograms standards, which allows PBMs to build struc-tured claims databases on consistent standards, medicaldata standards tend to be less consistent. Standards areestablished on claim forms such as the CMS 1500(which is used for professionally billed claims, eg, forphysician offices) and the UB-04 (which is used for insti-tutionally billed claims, such as for outpatient hospitals),but each plan may require different information on theforms. In addition, the way health plans and data aggre-gators capture and store the claims information is incon-sistent throughout the industry.

To effectively discuss MBM strategies, a thoroughunderstanding of medical claims data is imperative. Inour experience, even sophisticated health plans do nothave the same level of understanding and reportingcapabilities of medically covered specialty drugs thatthey have of drugs covered through pharmacy-transacted(ie, PBM) claims. Self-insured employers tend to nothave access to accurate or thorough medical datathrough their data aggregator vendors.

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

Because medical and pharmacy claims are billedthrough 2 different systems, some argue that the bestsolution is to deny medical claims for infusions andto require that the claims be filled under the pharma-cy benefit, because it simplifies how the claims aretransacted. This solution, however, introduces signif-icant benefit design complexity and changes theunderlying pricing dynamic of the claim, both ofwhich must be fully evaluated before adopting such astrategy. Plans with a “carved-out” pharmacy benefitface additional challenges. Significant due diligenceis required before proceeding with this approach.

Outpatient hospital49%

Physician office 41%

Home infusion 10%

Figure 1 Distribution of Costs for Medically BilledDrugs, by Place of Service

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

Chemotherapy 35%

Drug administration

12%

Neupogen/ESA/5-HT3

11%

Figure 2 Medical Benefit Costs, by Service Type

ESA indicates erythropoietin-stimulating agent.Source: These data are based on client claims from 3commercial health plans representing 2,436,727 coveredlives between January 1, 2011, and December 31, 2011.

Unlisted drug 1%

Nonchemotherapy 41%

Therefore, when investigating ways to manage medical-ly covered specialty drugs, an employer or a health planoften has to engage a consultant with expertise in analyz-ing medical data. The consultant should be able to readilyproduce sample reporting, standard data layouts, and clienttestimonials that show the ability to discover and under-stand medical data. This is needed to ensure that allopportunities are uncovered, and to successfully report onthe 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 thatan effective MBM program should address all of these4 areas:• Site-of-care (SOC) optimization• Physician office specialty drug distribution• Clinical and formulary management• Fee schedule management.

INDUSTRY TRENDS


A large employer approached us to assist in manag-ing infused specialty drugs. The client was concernedabout overpaying for chronic complex therapies (eg,infliximab) that were being administered at the outpa-tient hospital setting. The first step of the analysis, ofcourse, was to review its medical claims data to deter-mine utilization patterns and the degree to which uti-lization was occurring in the outpatient hospital. Tocollect the data, the employer received a data extractdirectly from its medical carrier, according to detailedspecifications provided by Walgreens.

Initially, the health plan data appeared acceptable.The requested fields were returned, and the integrity ofthe data seemed sufficient. For example, each claim’sallowable amount was populated with the appropriatedollar values and diagnosis fields, and the provider fieldswere appropriately completed. On further inspection,however, we realized that the expected medical special-ty per-member per-year cost was materially below ourbenchmarks. It was evident that claims from the outpa-tient hospital were substantially understated.

On isolating the issue, we asked the plan to re-runthe data to include the suspected missing outpatienthospital claims. The health plan supplied a correctedfile, which contained the exact same data as the firstdata set. Further discussion helped to convince thehealth plan that yet another data extract was necessary.

After several more attempts of unsuccessfully pro-viding the outpatient hospital claims, the health planconcluded that the employer simply does not havemuch utilization occurring in the outpatient hospital.At one point, the health plan stated, “We’ve pulledevery J code claim for this client, without any filters. Iassure you that you have everything that we have.”

Armed with the knowledge that nationally approx-imately 20% to 60% of medical specialty utilizationoccurs in the hospital outpatient department, and thefact that this client’s utilization was well below our

minimum expectation, we remained skeptical that wetruly had a full data set. At that point, we recommend-ed a 3-way call with Walgreens, the employer, and thehealth plan.

The health plan began the call affirming that itincluded all of the employer’s medical claims toWalgreens. Walgreens then posed a question to theemployer, “Do you have any benefit design restrictionsthat would prevent your employees from receivinginfusions within an outpatient hospital setting?” Thehuman resources representative for the employerimmediately responded that a relative of his (who isalso an employee of the company) receives infusiontherapy at the local hospital. This patient was not rep-resented in any of the data files produced by the payer.Needless to say, this caused the health plan to recon-sider its position. A couple of weeks later, the healthplan provided yet another data extract to Walgreens,but this time with outpatient hospital claims included.

Based on these new data, Walgreens demonstratedthat 65% of the employer’s medical specialty drugswere covered in the outpatient hospital, and that theemployer could cut its infusion costs for non -chemotherapy specialty infusions by 57%; this wasalmost a missed opportunity, because of the payer’s dif-ficulty of producing an accurate utilization file.

The employer is currently implementing an SOCoptimization program to transition patients from theoutpatient setting to a more convenient and lower-cost SOC.

The significance of this story is 2-fold. First, withoutfully understanding what specific data to request, andwhat the data should look like, the opportunity for theemployer never would have materialized. Second, oncethe appropriate data were received, the SOC strategycould be put into action, thereby allowing expandedand convenient access for patients and a substantialcost-reduction for the employer.

Employer Challenges with Medical Data: An (Almost) Missed Opportunity

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

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

As ridiculous as those questions appear, a parallel existstoday in our healthcare delivery system. The cost of aninfused drug could vary by more than 100%, dependingon where patients go to receive their infusions. Consider -ing that the average specialty infusion costs between$20,000 and $200,000 annually, doubling the cost tobetween $40,000 and $400,000 has a dramatic impacton the affordability and sustainability of continuedaccess to these medications for payers and for patients.

SOC optimization programs are built around thisvariance in cost, allowing employers and health plans todirect 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, orbecause the physician is incentivized to refer the patientto the hospital through some means, often because thephysician is employed by the hospital.

Our current healthcare system is complex, and mostpatients seek infusion services wherever their physiciansrecommend, not realizing that drug costs are 110% high-er at outpatient facilities compared with alternate treat-ment sites (ATSs), such as at-home infusion, infusionsuites, and at physicians’ offices.4 The Table illustratescost variance for 2 of the common nonchemotherapeu-tic specialty infusions at a hospital outpatient depart-ment versus an ATS.Who can apply SOC strategies? The SOC strategy

can be utilized by any entity that is responsible for payinga medical claim for infusion, including commercial

health plans, government payers, self-insured employers,at-risk health systems, and at-risk independent practiceassociations. The size, location, and geographic layout ofmembership does not matter, as long as the partner orprovider who is selected has the geographic coverage ofservices to match and has access to trained infusion nurs-es with specialty drug infusion expertise. As noted below,a major factor that determines the success of such an ini-tiative is alignment of incentives through appropriatebenefit design and shared-savings programs.ASOCs and ATSs. The terms “alternate site of care”

(ASOC) and “alternate treatment site” can be usedinterchangeably. ATSs or ASOCs are infusion sites out-side of the traditional hospital (inpatient or outpatient)and skilled nursing facility settings. An ATS can be apatient’s home, a physician’s office, or an infusion suite.

The use of ATSs typically results in significant cost-savings for payers and for patients, and in an overallincreased experience for the patients. Patients canreceive acute and chronic infused medications in theATS, and infusion suites are being built throughout thecountry, in locations such as within an infusion phar-macy, within a retail pharmacy, at an employer site,within a medical clinic, or as a stand-alone dedicatedsite. In addition, to meet payer needs and the acuitylevel of patients, these sites are now being staffed byregistered nurses or by nurse practitioners. Services arefocused on providing infusion therapy, but they alsoinclude other medical procedures, such as laboratorydraws, injection training, simple wound care, andcatheter care maintenance.Keys to success. A critical component to the success

of SOC optimization is ensuring appropriate benefitdesign at the payer level. Although SOC optimizationoffers a significant savings for a payer, appropriate benefitdesign ensures that the out-of-pocket expense for thepatient is decreased (or even eliminated). If the mem-ber’s benefit design does not provide a lower patient out-of-pocket cost at an ATS versus an outpatient depart-ment, it is very unlikely that the patient will agree tochange the SOC. This dynamic can result in the payercontinuing to pay more than double the amount for theservice than is necessary.

Another component to success is alignment of incen-tives. Appropriate benefit design and/or a creativeincentive program (eg, direct financial incentives topatients to move to a lower-cost SOC) align the incen-tives of the payer and the patient. However, this align-ment must also occur between the payer and theprovider to ensure optimal success. If alignment ofincentives between the payer and the provider cannot beobtained, the probability is high that the higher-costoutpatient department will become the default location,

INDUSTRY TRENDS


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

Code DrugATS rate,

$

Outpatienthospital rate,

$

Per-unitdifference,

%

J1745 Infliximabinjection

63.4/unit

3134/claim

129.04/unit

5790/claim

103.27

J2323 Natalizumabinjection

8.35/unit

2424/claim

13.30/unit

3748/claim

59.35

Note: average claim cost is dependent on the cost per unit andthe units billed.ATS indicates alternate treatment site.Source: These data are based on Walgreens’ internal analysis of5,371,227 commercial managed care lives between January 2008and December 2010.

as was illustrated above. Emerging shared-savings pro-grams and pay-for-performance reimbursement strategiescan help to align payer and provider incentives.

It is important that the payer and the provider under-stand and agree to the measurement of success.Transparent data exchange and quarterly reporting playa critical role in making this possible. Without these ele-ments in place, it is very possible that the true savingsand value of SOC optimization may not be fully realized.

Options to Limit Physician Buy and BillMany physician specialties, such as oncology and

rheumatology, provide in-office infusion for theirpatients. Receiving infusion in the physician’s office isnormally convenient for patients, a source of revenuefor physicians, and often a cost-effective site of infusionfor payers.

However, some payers worry that paying physicianstens of thousands of dollars annually to infuse medica-tion in their offices may encourage overutilization, byinfluencing the physician to begin treating patients withtherapy earlier or by keeping patients on therapy longerthan is clinically appropriate. In addition, if a physicianis financially incentivized to provide infusion therapy,the physician may be more likely to begin infusion ther-apy instead of to prescribe a more convenient, and oftenless costly, self-injected medication. Furthermore, ratespaid to providers to infuse medications in the office,although often competitive, can vary considerably.

Therefore, some payers require that physicians’ officesobtain medications that will be infused in their officefrom a contracted specialty pharmacy. This practice isalso known as “white bagging.” The pharmacy receivesorders from physicians, fills the (patient-specific) med-ication, then mails the drug to the office before thepatient’s infusion or injection appointment. Some planshave been very successful with this strategy.5 However,each payer will have different results, because of variousunderlying physicians’ office fee schedules.6

Requiring physicians to make patients obtain infusedor injected drugs for in-office administration from a spe-cialty pharmacy is an individual decision that must beaddressed by each health plan, based on its unique net-work design and fee schedules, member benefit design,local provider political influence, and specialty phar -macy pricing.

A plan can decide if a white bagging program wouldbe an effective cost and utilization management programon completion of an analysis that accurately models howthe cost of infused therapy would change if certain drugswere limited to only specialty pharmacy distribution.The current rate-setting methodology of the healthplan’s physician fee schedule is the primary driver for

determining whether financial savings will occur if thedrugs are blocked from buy and bill and are dispensedfrom a specialty pharmacy. Once the economic impact isunderstood, other strategic factors can be taken intoconsideration to make a fully informed decision.

Why an ATS Network Is CriticalRegardless of whether a plan restricts certain in-office

drugs to a specialty pharmacy, it is critically importantthat a plan has an ATS network available to its mem-bers. Without an ATS network, infusions will, bydefault, be provided in hospital outpatient departmentsif the prescribing physician decides to no longer providein-office infusions.

With continuing price compressions and a plethora ofhigh-cost medications in the drug pipeline, this poses asignificant risk to plans: costs for the same drug will typ-ically double if infused in a hospital setting versus atother settings. In addition, because health plans areincreasingly purchasing physicians’ practices,7 we foreseeinfusion and injection at a physician’s office decreasingover time, with a corresponding increase in hospital-based infusions, unless an ATS network exists.

Clinical and Formulary ManagementHealth plans have many opportunities to introduce

clinical and utilization programs to manage appropriateutilization in the medical benefit—so many, in fact, thatit is beyond the scope of this article to detail them all.

Having a full understanding of clinical opportunitieswill lead to programs that can manage utilization trendswithin the medical benefit. For example, the effective-ness of a payer’s current prior authorization (PA) crite-ria can be evaluated, additional PA and formularyopportunities can be explored, and programs focusedon converting patients from infused drugs to self-administered drugs (injected or oral) can be evaluatedonce a payer understands the utilization patterns with-in his or her medical benefit.

Fee Schedule ManagementOne of the most straightforward ways to manage

drug-related medical costs for a payer is to maintain a

INDUSTRY TRENDS


With continuing price compressions and aplethora of high-cost medications in thedrug pipeline, this poses a significant risk toplans: costs for the same drug will typicallydouble if infused in a hospital settingversus at other settings.

competitive and continually maintained fee schedulethat determines how much a provider is paid for a drugand its administration. However, a payer must be cau-tious when adjusting fee schedules. Remember thatATSs and outpatient hospital facilities are usually con-tracted and managed separately. If fee schedules to theATS network are reduced to a point where providers feelthe level of reimbursement does not adequately compen-sate them for the drug, the ATS will likely choose to nolonger provide infusion services.

The prescribing physician will then either attemptto switch the patient to a self-administered drug, ormore likely (because there are only a few infused prod-ucts with a self-administered equivalent product), willrefer the patient to a nearby outpatient hospital to con-tinue the infusion treatment. This will result in a sig-nificant cost increase to the payer for that infusion,thereby more than eliminating the expected cost-savings the payer would otherwise have predicted fromthe lower fee schedule.

An MBM analysis should be able to provide payers aperspective on industry benchmarks and how their feeschedules are performing relative to their industrypeers. In addition to enabling payers to see if they arein line with what other payers are reimbursing for cer-tain drugs, an analysis showing that payers have anextremely deep ATS fee schedule (eg, average salesprice +6) and an unusual amount of hospital outpatientutilization may indicate that more research may help todetermine if cause and effect exists, perhaps even lead-ing payers to evaluate if increasing the ATS fee sched-ule would decrease net infusion costs resulting fromlowering hospital outpatient utilization.

The Ultimate Successful MBM StrategyPayers will be well on their way to effectively manag-

ing medical specialty drug costs if they:• Implement an ATS network (including infusion suites

and home infusion options) to mitigate hospital out-patient referrals for specialty infusion

• Maximize the use of lower-cost ATSs for infusionthrough appropriate benefit design and providerincentives

• Align financial incentives with the infusion part-ner—through a shared-savings strategy and/or a pre-ferred provider contract

• Maintain fair and competitive fee schedules across allSOCs, ensuring physicians’ offices, home infusionproviders, and infusion suites are incented to provideinfusion services

• Manage clinical appropriateness through PA pro-grams and/or clinical pathways

• Maintain fee schedules that do not encourage the useof high-cost products when lower-cost therapeuticallyequivalent options exist

• Have access to utilization reporting that tracks savingsand trends within the medical benefit.

ConclusionManaging the medical pharmacy trend is a complex

task, and many solutions are available from various ven-dors to help payers manage medical pharmacy utiliza-tion. Drug utilization within the medical benefit isincreasingly becoming better understood and managed,but not yet to the extent of pharmacy utilization.

Before committing to an MBM strategy, a plan shouldfirst feel comfortable with understanding its medicalpharmacy trend and utilization patterns within eachplace of service and type of service (eg, chemotherapy ornonchemotherapy). A payer has to understand what itstop drugs are, which physician specialties are driving theutilization, and what SOC its benefit design currentlyencourages patients to utilize.

A payer should ask any potential consulting pharma-cy partner to see examples of its MBM reporting, andthen ask what solutions that partner can provide. Doesthe vendor have a strategy and implementation plan foreach area of opportunity, or will multiple vendors berequired? If multiple vendors are needed, can the ven-dors work collaboratively to provide a uniform solutionto the payer? ■

Author Disclosure StatementMr Einodshofer and Dr Duren are employees and stock-

holders of Walgreens.

References1. Einodshofer M, Kansler S. Cost management through care management: a per-spective 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. April14, 2011. http://info.cvscaremark.com/newsroom/press-releases/cvs-caremark-offer-medical-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-orleans-health-89.pdf. Accessed September 21, 2012.5. Baldini CG, Culley EJ. Estimated cost savings associated with the transfer ofoffice-administered specialty pharmaceuticals to a specialty pharmacy provider in amedical 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. AccessedSeptember 22, 2012.7. Elliott VS. Increase in physician practice mergers and acquisitions expected tocontinue. August 14, 2012. www.ama-assn.org/amednews/2012/08/13/bisd0814.htm.Accessed September 21, 2012.

INDUSTRY TRENDS


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The risk of lactic acidosis increases with the degree of renal i

Metformin should be promptly withheld in the presence of any c

a i

In a 24-week factorial design study, adverse reactions reported i

In a 24-week factorial design study, hypoglycemia was reported i

o

Pancreatitis was reported more often in patients randomized to l

Because cationic drugs eliminated by renal tubular secretion t

The efficacy of JENTADUETO may be reduced when administered i

The concomitant use of carbonic anhydrase inhibitors (e.g., t

As there are no adequate and well-controlled studies in pregnant w

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

The safety and effectiveness of JENTADUETO in patients below the a

JENTADUETO should be used with caution as age increases, as a

t

–1.7%

–1.2%–1.3%

–0.8%

–0.6%

Linagliptin 5 mgonce daily

Baseline A1C 8.7%

Metformin 500 mgtwice daily

Baseline A1C 8.7%

JENTADUETOLinagliptin 2.5 mgMetformin 500 mg

twice daily§

Baseline A1C 8.7%

Metformin 1000 mgtwice daily

Baseline A1C 8.5%

JENTADUETOLinagliptin 2.5 mg

Metformin 1000 mgtwice daily§

Baseline A1C 8.7%

(n=135)

(n=141)

(n=137)(n=138)

(n=140)

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

INDICATION AND IMPORTANT LIMITATIONS OF USEJENTADUETO 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

CONTRAINDICATIONSJENTADUETO 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 PRECAUTIONSLactic 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.

WARNING: RISK OF LACTIC ACIDOSISLactic 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.

* 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.

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

Significant A1C reductions (placebo-adjusted) at 24 weeks1*†‡

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

P<0.0001

P<0.0001

Copyright © 2012 Boehringer Ingelheim Pharmaceuticals, Inc. All rights reserved. (08/12) JD384500PROFA

Find out more about JENTADUETO and the Savings Card program at www.jentadueto.com

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 FunctionBefore 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 FunctionImpaired 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.

HypoglycemiaInsulin 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 LevelsVitamin B12 deficiency: Metformin may lower Vitamin B12 levels. Monitor hematologic parameters annually.

Alcohol IntakeAlcohol is known to potentiate the effect of metformin on lactate metabolism. Patients should be warned against excessive alcohol intake while receiving JENTADUETO.

Hypoxic StatesCardiovascular 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 OutcomesThere 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.

Renal impairment (e.g., serum creatinine ≥1.5 mg/dL for men or ≥

Acute or chronic metabolic acidosis, including diabetic ketoacidosis.

History of hypersensitivity reaction to linagliptin (such as urticaria, a

Lactic acidosis is a serious, metabolic complication that can o

The reported incidence of lactic acidosis in patients receiving m

Patients with congestive heart failure requiring pharmacologic m

w

o 5 2

5 mg QD for the change in A1C from baseline at Week 24. L

w 2 5 mg QD (P J

1 1

Jentadueto™ (linagliptin and metformin hydrochloride) tablets

BRIEF SUMMARY OF PRESCRIBING INFORMATIONPlease see package insert for full Prescribing Information.

WARNING: RISK OF LACTIC ACIDOSISLactic 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 non-specific 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 effec-tive in these settings. JENTADUETO has not been studied in combination with insulin.

CONTRAINDICATIONS: JENTADUETO is contraindicated in patients with: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 condi-tions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia [see Warnings and Precautions]Acute or chronic metabolic acidosis, including diabetic ketoacidosis. Diabetic ketoacidosis should be treated with insulin [see Warnings and Precautions]A history of hypersensitivity reaction to linagliptin (such as urticaria, angio-edema, 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 accumula-tion 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 medica-tions. 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 demon-strates 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 lac-tate 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 Interac-tions]. 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. Gastrointesti-nal 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 prob-lems 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 symp-toms 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 impair-ment. 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 iodin-ated contrast materials (e.g., intravenous urogram, intravenous cholangiography, angiography, and computed tomography) can lead to acute alteration of renal func-tion 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 insu-lin 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 particu-larly 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 vita-min 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 inad-equate 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: Alco-hol 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 dis-continued [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.

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L

L

2

2 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

Placebon=72

Linagliptin Monotherapyn=142

Metformin Monotherapyn=291

Combination of Linagliptin with Metforminn=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 hyper-activity), 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 head-ache. 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]. Hypoglyce-mia: 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: Cat-ionic 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 interac-tions 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 rec-ommended 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, cal-cium 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, met-formin 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 tera-togenic 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 off-spring 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 malforma-tions 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). Met-formin 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. Met-formin 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 num-bers 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 perito-neal 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 tri-als 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 USAandEli 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

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American Health & Drug Benefits will be publishing a Special Issue on CardiometabolicHealth in 2013.

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

CALL FOR PAPERS

Cardiometabolic Health Special Issue

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 ofbest 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 cardiometabolichealth and prevention

• Hot topics in diabetes management

• Insulin resistance and type 2 diabetes

• Lifestyle strategies and cardiometabolichealth 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 riskreduction

• Wellness programs for patients with heartdisease, diabetes, or obesity

Articles should follow the Manuscript Instructions for Authors (www.AHDBonline.com). Submit articles to [email protected]. For more information, call 732-992-1889.

© 2012 MedImmune. All rights reserved. 11457 1-877-FLUMIST (358-6478) www.FluMistQuadrivalent.com

The fi rst and only fl u vaccine with four live attenuated viruses—two A strain subtypes and the two B lineages1

An intranasal infl uenza vaccine indicated for eligible children and adults 2 to 49 years of age1

Comparable immunogenicity and safety profi le to that of its trivalent predecessor1

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 FluMist Quadrivalent is a vaccine indicated for active immunization of persons 2-49 years of age for the

prevention of infl uenza disease caused by infl uenza A subtype viruses and type B viruses contained in the vaccine. FluMist Quadrivalent is for intranasal administration only.

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 infl uenza vaccine, and in children and adolescents receiving concomitant aspirin or aspirin-containing therapy.

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

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

NEW FLUMIST® QUADRIVALENT HELPS TO PROTECT YOUR ELIGIBLE MEMBERS AGAINST 4 DIFFERENT FLU STRAINS.1

IT’S ANYBODY’S GUESS WHICH FLU STRAIN IS AMONG US

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Brief Summary of Prescribing InformationFluMist® Quadrivalent Influenza Vaccine Live, IntranasalIntranasal Spray20XX-20XX FormulaINDICATIONS AND USAGEFluMist® Quadrivalent is a vaccine indicated for active immunization for the prevention of influenzadisease 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 ADMINISTRATIONFOR INTRANASAL ADMINISTRATION BY A HEALTHCARE PROVIDER.Dosing InformationAdminister FluMist Quadrivalent according to the following schedule:

Age Group Vaccination Status Dosage Schedule

Children age 2 years Not previously 2 doses (0.2 mL*

through 8 years vaccinated with each, at leastinfluenza vaccine 1 month apart)

Children age 2 years Previously vaccinatedthrough 8 years with influenza vaccine 1 dose (0.2 mL*)

Children, adolescents,and adults age 9 Not applicable 1 dose (0.2 mL*)through 49 years

*Administer as 0.1 mL per nostril.

CONTRAINDICATIONSSevere Allergic ReactionsDo 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, andarginine, or after a previous dose of any influenza vaccine.Concomitant Aspirin Therapy and Reye’s Syndrome in Children and AdolescentsDo not administer FluMist Quadrivalent to children and adolescents through 17 years of age whoare receiving aspirin therapy or aspirin-containing therapy because of the association of Reye’ssyndrome with aspirin and wild-type influenza infection.

WARNINGS AND PRECAUTIONSRisks of Hospitalization and Wheezing in Children Younger than 24 Months of AgeIn clinical trials, risks of hospitalization and wheezing were increased in children younger than2 years of age who received FluMist (trivalent Influenza Vaccine Live, Intranasal). This observationwith FluMist is relevant to FluMist Quadrivalent because both vaccines are manufactured using thesame process and have overlapping compositions.Asthma, Recurrent Wheezing, and Active WheezingChildren younger than 5 years of age with recurrent wheezing and persons of any age with asthmamay be at increased risk of wheezing following administration of FluMist Quadrivalent. FluMistQuadrivalent has not been studied in persons with severe asthma or active wheezing.Guillain-Barré SyndromeThe 1976 swine influenza vaccine (inactivated) was associated with an elevated risk of Guillain-Barré syndrome (GBS). Evidence for causal relation of GBS with other influenza vaccines isinconclusive; if an excess risk exists, based on data for inactivated influenza vaccines, it is proba-bly slightly more than 1 additional case per 1 million persons vaccinated. If GBS has occurredwithin 6 weeks of any prior influenza vaccination, the decision to give FluMist Quadrivalent shouldbe based on careful consideration of the potential benefits and potential risks.Altered ImmunocompetenceFluMist Quadrivalent has not been studied in immunocompromised persons. The effectiveness ofFluMist has not been studied in immunocompromised persons. Data on safety and shedding ofvaccine virus after administration of FluMist in immunocompromised persons are limited to174 persons with HIV infection and 10 mild to moderately immunocompromised children andadolescents with cancer.Medical Conditions Predisposing to Influenza ComplicationsThe safety of FluMist Quadrivalent in individuals with underlying medical conditions that maypredispose them to complications following wild-type influenza infection has not been established.Management of Acute Allergic ReactionsAppropriate medical treatment and supervision must be available to manage possible anaphylacticreactions following administration of the vaccine.Limitations of Vaccine EffectivenessFluMist Quadrivalent may not protect all individuals receiving the vaccine.

ADVERSE REACTIONSClinical Trials ExperienceBecause clinical trials are conducted under widely varying conditions, adverse reaction ratesobserved in the clinical trials of a vaccine cannot be directly compared to rates in the clinicaltrials 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 aremanufactured using the same process and have overlapping compositions. A total of 9537children and adolescents 1 through 17 years of age and 3041 adults 18 through 64 years of agereceived 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 through59 months of age received FluMist in Study MI-CP111, a randomized, active-controlled trial. Amongpediatric FluMist recipients 6 months through 17 years of age, 50% were female; in the study ofadults, 55% were female. In MI-CP111, AV006, D153-P526, AV019, and AV009, subjects wereWhite (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 through49 years of age received FluMist Quadrivalent in randomized, active-controlled StudiesMI-CP208 and MI-CP185. Among pediatric FluMist Quadrivalent recipients 2 through 17 years ofage, 51% were female; in the study of adults, 55% were female. In Studies MI-CP208 andMI-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 AdolescentsThe safety of FluMist was evaluated in an AF-SPG placebo-controlled study (AV019) conducted ina 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, wasobserved in children younger than 5 years of age who received FluMist compared to those whoreceived 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 FluMistor inactivated Influenza Virus Vaccine manufactured by Sanofi Pasteur Inc. Wheezing requiringbronchodilator therapy or accompanied by respiratory distress or hypoxia was prospectivelymonitored from randomization through 42 days post last vaccination. Hospitalization due to allcauses was prospectively monitored from randomization through 180 days post last vaccination.Increases in wheezing and hospitalization (for any cause) were observed in children 6 monthsthrough 23 months of age who received FluMist compared to those who received inactivatedInfluenza Virus Vaccine, as shown in Table 1.Table 1: Percentages of Children with Hospitalizations and Wheezing from Study MI-CP111a

Adverse Reaction Age Group FluMist Active Controlb

(n/N) (n/N)Hospitalizationsc 6-23 months 4.2 % 3.2 %

(84/1992) (63/1975)24-59 months 2.1 % 2.5 %

(46/2187) (56/2198)Wheezingd 6-23 months 5.9 % 3.8 %

(117/1992) (75/1975)24-59 months 2.1 % 2.5 %

(47/2187) (56/2198)a NCT00128167; see www.clinicaltrials.govb 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 andoccurred more than 6 weeks post vaccination. In post-hoc analysis, rates of hospitalization inchildren 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 recipientsand at a higher rate (≥ 1% rate difference after rounding) compared to placebo post Dose 1 forStudies 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 queriedafter receipt of FluMist, placebo, or control vaccine. In these studies, solicited reactions weredocumented for 10 days post vaccination. Solicited reactions following the second dose of FluMistwere 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 forFluMist and Either Placebo or Active Control Recipients in Children 2 through 6 Years of Age

Studies D153-P501a & AV006 Study MI-CP111b

FluMist Placeboc FluMist Active Controld

N=876-1759e N=424-1034e N=2170e N=2165e

Event % % % %Runny Nose/

Nasal Congestion 58 50 51 42

Decreased Appetite 21 17 13 12Irritability 21 19 12 11Decreased Activity 14 11 7 6(Lethargy)Sore Throat 11 9 5 6Headache 9 7 3 3Muscle Aches 6 3 2 2Chills 4 3 2 2Fever

> 100°F Oral 16 11 13 11> 100- ≤101°F Oral 9 6 6 4> 101- ≤102°F Oral 4 3 4 3

a NCT00192244; see www.clinicaltrials.govb NCT00128167; see www.clinicaltrials.govc 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 atleast 1% of FluMist recipients and at a higher rate (≥ 1% rate difference after rounding) comparedto 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-CP111occurring in at least 1% of FluMist recipients and at a higher rate (≥ 1% rate difference afterrounding) 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 andadolescents 9 through 17 years of age who received one dose of FluMist, the solicited adversereactions as well as unsolicited adverse reactions reported were generally consistent withobservations from the trials in Table 2. Abdominal pain was reported in 12% of FluMist recipientscompared to 4% of placebo recipients and decreased activity was reported in 6% of FluMistrecipients compared to 0% of placebo recipients.In Study AV018, in which FluMist was concomitantly administered with Measles, Mumps, andRubella Virus Vaccine Live (MMR, manufactured by Merck & Co., Inc.) and Varicella Virus VaccineLive (manufactured by Merck & Co., Inc.) to children 12 through 15 months of age, adversereactions were similar to those seen in other clinical trials of FluMist.FluMist Quadrivalent in Children and AdolescentsIn the randomized, active-controlled Study MI-CP208 that compared FluMist Quadrivalent andFluMist in children and adolescents 2 through 17 years of age, the rates of solicited adversereactions 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 occurredat a higher rate (≥ 1% rate difference after rounding) in FluMist Quadrivalent recipients compared

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

Table 3: Summary of Solicited Adverse Reactionsa Observed Within 14 Days after Dose 1for FluMist Quadrivalent and FluMist Recipients in Study MI-CP208b in Children

and Adolescents 2 through 17 Years of AgeFluMist Quadrivalent FluMistc

N = 1341-1377d N = 901-920d

Event % %Runny Nose/Nasal Congestion 32 32Headache 13 12Decreased Activity (Lethargy) 10 10Sore Throat 9 10Decreased Appetite 6 7Muscle Aches 4 5Fever

> 100°F by any route 7 5> 100 - ≤ 101°F by any route 3 2> 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 previousFluMist trials [see Table 2].

b NCT01091246; see www.clinicaltrials.govc 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) inFluMist Quadrivalent recipients compared to FluMist recipients.FluMist in AdultsIn adults 18 through 49 years of age in Study AV009, solicited adverse reactions occurring in atleast 1% of FluMist recipients and at a higher rate (≥ 1% rate difference after rounding) comparedto AF-SPG placebo include runny nose (44% FluMist vs. 27% placebo), headache (40% FluMistvs. 38% placebo), sore throat (28% FluMist vs. 17% placebo), tiredness/weakness (26% FluMistvs. 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 andat 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 AdultsIn the randomized, active-controlled Study MI-CP185 that compared FluMist Quadrivalent andFluMist in adults 18 through 49 years of age, the rates of solicited adverse reactions reported weregenerally similar between subjects who received FluMist Quadrivalent and FluMist. Table 4presents solicited adverse reactions that either occurred at a higher rate (≥ 1% rate difference afterrounding) in FluMist Quadrivalent recipients compared to FluMist recipients or were identified inStudy AV009.

Table 4: Summary of Solicited Adverse Reactionsa Observed Within 14 Days after Dose 1for FluMist Quadrivalent and FluMist Recipients in Study MI-CP185b

in Adults 18 through 49 Years of AgeFluMist Quadrivalent FluMistc

N = 1197d N = 597d

Event % %Runny Nose/Nasal Congestion 44 40Headache 28 27Sore Throat 19 20Decreased Activity (Lethargy) 18 18Cough 14 13Muscle Aches 10 10Decreased Appetite 6 5

a Solicited adverse reactions that occurred at a higher rate (≥ 1% rate difference after rounding) inFluMist Quadrivalent recipients compared to FluMist recipients or were identified in Study AV009.

b NCT00860067; see www.clinicaltrials.govc 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) inFluMist Quadrivalent recipients compared to FluMist recipients.Postmarketing ExperienceThe 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 alwayspossible to reliably estimate their frequency or establish a causal relationship to vaccine exposure.Cardiac disorders: PericarditisCongenital, familial, and genetic disorders: Exacerbation of symptoms of mitochondrialencephalomyopathy (Leigh syndrome)Gastrointestinal disorders: Nausea, vomiting, diarrheaImmune system disorders: Hypersensitivity reactions (including anaphylactic reaction, facialedema, and urticaria)Nervous system disorders: Guillain-Barré syndrome, Bell’s Palsy, meningitis, eosinophilicmeningitis, vaccine-associated encephalitisRespiratory, thoracic, and mediastinal disorders: EpistaxisSkin and subcutaneous tissue disorders: Rash

DRUG INTERACTIONSAspirin TherapyDo not administer FluMist Quadrivalent to children and adolescents through 17 years of age whoare receiving aspirin therapy or aspirin-containing therapy because of the association of Reye’ssyndrome with aspirin and wild-type influenza. Avoid aspirin-containing therapy in these age groupsduring the first 4 weeks after vaccination with FluMist Quadrivalent unless clearly needed.

Antiviral Agents Against Influenza A and/or BAntiviral drugs that are active against influenza A and/or B viruses may reduce the effectiveness ofFluMist 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 influenzaA and/or B viruses has not been evaluated. If antiviral agents and FluMist Quadrivalent areadministered concomitantly, revaccination should be considered when appropriate.Concomitant Administration with Inactivated VaccinesThe safety and immunogenicity of FluMist Quadrivalent when administered concomitantly withinactivated vaccines have not been determined. Studies of FluMist and FluMist Quadrivalentexcluded subjects who received any inactivated or subunit vaccine within two weeks of enrollment.Concomitant Administration with Other Live VaccinesConcomitant administration of FluMist Quadrivalent with Measles, Mumps, and Rubella VirusVaccine 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 FluMistwith 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 olderthan 15 months of age has not been studied.Intranasal ProductsThere are no data regarding co-administration of FluMist Quadrivalent with other intranasalpreparations.

USE IN SPECIFIC POPULATIONSPregnancyPregnancy Category BA developmental and reproductive toxicity study has been performed in female rats administeredFluMist Quadrivalent either three times (during the period of organogenesis) or six times (prior togestation and during the period of organogenesis), 200 microliter/rat/occasion (approximately150 human dose equivalents), by intranasal instillation and has revealed no evidence of impairedfertility or harm to the fetus due to FluMist Quadrivalent. There are however, no adequate and wellcontrolled studies in pregnant women. Because animal studies are not always predictive of humanresponse FluMist Quadrivalent should be administered during pregnancy only if clearly needed.Nursing MothersIt is not known whether FluMist Quadrivalent is excreted in human milk. Because some viruses areexcreted in human milk, caution should be exercised when FluMist Quadrivalent is administeredto a nursing woman.Pediatric UseSafety and effectiveness of FluMist Quadrivalent in children 24 months of age and older is basedon data from FluMist clinical studies and a comparison of post-vaccination antibody titers betweenpersons who received FluMist Quadrivalent and those who received FluMist. FluMist Quadrivalentis not approved for use in children younger than 24 months of age because use of FluMist inchildren 6 through 23 months has been associated with increased risks of hospitalization andwheezing in clinical trials.Geriatric UseFluMist Quadrivalent is not approved for use in persons 65 years of age and older because in aclinical study (AV009), effectiveness of FluMist to prevent febrile illness was not demonstrated inadults 50 through 64 years of age. In this study, solicited events among individuals 50 through64 years of age were similar in type and frequency to those reported in younger adults. In aclinical study of FluMist in persons 65 years of age and older, subjects with underlying high-riskmedical conditions (N = 200) were studied for safety. Compared to controls, FluMist recipientshad a higher rate of sore throat.

PATIENT COUNSELING INFORMATIONVaccine recipients or their parents/guardians should be informed by the healthcare provider of thepotential benefits and risks of FluMist Quadrivalent and the need for two doses at least 1 monthapart in children 2 through 8 years of age who have not previously received influenza vaccine. Thehealthcare provider should provide the Vaccine Information Statements (VIS) which are requiredby the National Childhood Vaccine Injury Act of 1986 to be given with each immunization.Asthma and Recurrent WheezingAsk the vaccinee or their parent/guardian if the vaccinee has asthma. For children youngerthan 5 years of age, also ask if the vaccinee has recurrent wheezing since this may be an asthmaequivalent in this age group. The vaccinee or their parent/guardian should be informed that theremay be an increased risk of wheezing associated with FluMist Quadrivalent in persons younger than5 years of age with recurrent wheezing and persons of any age with asthma.Vaccination with a Live Virus VaccineVaccine recipients or their parents/guardians should be informed by the healthcare provider thatFluMist Quadrivalent is an attenuated live virus vaccine and has the potential for transmission toimmunocompromised household contacts.Adverse Event ReportingThe vaccine recipient or their parent/guardian should be instructed to report adverse reactions totheir healthcare provider.FluMist® is a registered trademark of MedImmune, LLC.

Manufactured by:MedImmune, LLCGaithersburg, MD 208781-877-633-4411Issue Date: February 2012 RAL-FLUQV1U.S. Government License No. 1799 Component No.: 10951

The benefits of NovoTwist® are:

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Winner of the US Good Design™ award1

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Bipolar disorder is a chronic, recurring disorder asso-ciated with frequent episodes of mania and depres-sion. Overall costs for the treatment of bipolar dis-

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

Medical Care Costs and Hospitalizationin Patients with Bipolar Disorder Treatedwith Atypical AntipsychoticsJoette 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 disorderare attributable to patient hospitalization.

Objective: To investigate medical care costs and hospitalization rates among patients withbipolar 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 PharMetricsclaims database between January 1, 2003, and September 30, 2008. The study used a time-to-event framework. Cox proportional hazards models were used to assess the impact of eachatypical antipsychotic on time to hospitalization, including all-cause and mental health–relatedreasons. Generalized linear models were used to compare costs per treated patient per monthbetween the groups. Aripiprazole therapy was the reference group for all comparisons.

Results: Aripiprazole therapy showed a significantly lower hazard ratio (HR) for all-cause hos-pitalizations 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 olan-zapine, quetiapine, risperidone (HR, 1.3 each), and ziprasidone (HR, 1.7). Ziprasidone hadhigher unadjusted all-cause medical costs (US $1151 ± $2928) and unadjusted mentalhealth–related costs (US $711 ± $2263) than the other antipsychotics that were included inthis study, whereas aripiprazole had the lowest all-cause (US $804 ± $2523) and mentalhealth–related costs (US $475 ± $2145) compared with the other antipsychotics. Quetiapinehad the highest all-cause costs (US $1221; 95% confidence interval [CI], 1180-1263), andziprasidone had the highest mental health–related costs (US $823; 95% CI, 754-898).Adjusted inpatient and emergency department all-cause costs were significantly lower foraripiprazole compared with all other atypical antipsychotics (P <.05), except olanzapine; how-ever, the adjusted inpatient and emergency department mental health–related costs were sig-nificantly lower for aripiprazole only when compared with ziprasidone (P <.05).

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




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

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ciated with the loss of productivity.1,2 Notably, 33.5% to65.2% of the overall cost of treating patients with bi -polar disorder is attributable to patient hospitalization,3,4

with the majority of patients with bipolar disorderreporting at least 1 psychiatric hospitalization in theirlifetime.5 Indeed, patient hospitalization is thought tobe the single most costly resource in bipolar disorder,accounting for approximately 50% of the cost of medicalencounters.6

Patients with bipolar disorder have been found to uti-lize nearly 3 to 4 times more healthcare resources6 and toincur more than 4 times greater healthcare costs thanpatients without bipolar disorder.7 An analysis of claimsdata comparing approximately 28,500 patients withbipolar disorder with approximately 85,500 controlpatients over a 1-year period established that the annualcost per patient was $12,764 for a patient with bipolardisorder compared with $1340 for a control patient, asignificant difference (P <.001).7

Effective pharmacotherapy and psychosocial inter-

ventions are an essential part of the successful treatmentof bipolar disorder.8 Prescription data indicate that 63.1%to 70.8% of patients with bipolar disorder receive psy-chotropics (eg, lithium, valproate, carbamazepine),whereas 21.2% to 29.0% of patients receive antipsychot-ic augmentation therapy.9

Atypical antipsychotics, either as monotherapy or asadjunctive treatment to mood stabilizers, are an increas-ingly common treatment option for patients with bipolardisorder. There may be an association between antipsy-chotic medication half-life and hospitalization. It hasbeen shown that patients using longer-acting antipsy-chotics experienced a lower rate of hospital admissionsand emergency department visits than patients treatedwith short half-life antipsychotic agents.10 Moreover, allatypical antipsychotics have side effects; however, ari -piprazole has been shown to have a low metabolic bur-den among its class.11

Recent claims database analyses have shown thattreatment with aripiprazole was associated with a lowerrisk of and longer time to hospitalization, as well as withlower psychiatric treatment costs and lower total health-care costs compared with other adjunctive antipsychoticmedications.12-15 However, these analyses used a limitedfollow-up time period (ie, 90 days)12,13 or focused on long-term (ie, 1-year) cost outcomes using an intent-to-treat(ITT) methodology.14,15

The aim of the current analysis was to evaluate hos-pitalization and medical care costs for patients duringthe time they were receiving treatment with aripiprazolecompared with patients receiving other atypical antipsy-chotics (ie, olanzapine, quetiapine, risperidone, orziprasidone). The analysis presented here is an extensionof a previous article covering medical claims from 2003to 2006,14 with additional important changes in themethodologic approach.

MethodsStudy Design and Data Source

This retrospective cohort analysis was conductedusing the PharMetrics Patient-Centric Database, whichincludes medical and pharmacy claims from January 1,2003, through September 30, 2008. The PharMetricsdatabase encompasses a composite of 85 health plansacross the United States, and it includes information onapproximately 47 million patients. The database in -cludes inpatient and outpatient medical claims, diagno-sis and procedure codes, as well as pharmacy claims. ThePharMetrics database is geographically representative ofthe US population, and includes a variety of demograph-ic measures.

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

KEY POINTS➤ Patients with bipolar disorder use close to 3- to 4-

fold more healthcare resources and incur more than4-fold greater healthcare costs than patients withoutthe disorder.

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

➤ Atypical antipsychotics are increasingly used forpatients with bipolar disorder; this study comparedthe cost of medical care and hospitalization rates forpatients who received aripiprazole and those whoreceived olanzapine, quetiapine, risperidone, orziprasidone.

➤ The patients using longer-acting antipsychotics hada lower rate of hospital admissions and emergencydepartment visits than those using short half-lifeantipsychotic agents.

➤ Ziprasidone had higher unadjusted all-causemedical costs ($1151) and unadjusted mentalhealth–related costs ($711) than the otherantipsychotics in this study.

➤ Aripiprazole had the lowest all-cause ($804) andmental health–related costs ($475) compared withthe other antipsychotics.

➤ Furthermore, aripiprazole was associated with asignificantly lower rate of hospitalizations and alonger time to hospitalization than the othermedications in this study.

ing mental health–related services. The general ap -proach of the analysis was to use baseline measures ofhealth and disease severity, such as baseline comorbidityindices, demographics, drug utilization patterns, andhospitalization rates. Lagged costs as predictors in costmodels were not used because of issues with serial corre-lation. In particular, because healthcare data areextremely skewed, the use of a highly variable predictormay lead to an unstable model.

Selection CriteriaThe study included patients aged 18 to 64 years who

had 1 or more outpatient or inpatient claims with anInternational Classification of Diseases, Ninth Revision codefor bipolar disorder (ie, manic, mixed, or hypomanic[296.0X, 296.1, 296.4X, 6X, 7X, 8X]). A patient’s newstart index date was defined as the date of the first pre-scription claim for an atypical antipsychotic medicationin the claims database between January 1, 2003, andSeptember 30, 2008.

Patients were excluded from the study if they wereprescribed an atypical antipsychotic in the 180-daypreindex period, or if they had prescriptions for morethan 1 atypical antipsychotic agent at the index date.Eligible patients were required to have at least 180 daysof continuous enrollment before and after 90 days ofcontinuous enrollment after the index prescription date.

In addition, patients were excluded from the analysisif they resided in a nursing home, hospice facility, oranother type of long-term care facility, or if they receivedprescriptions via mail order. Patients with a diagnosis ofschizophrenia spectrum disorder (295.XX), or those whowere hospitalized at the time of the index prescription orwithin 7 days after the index prescription, were excludedfrom the study.

In the analysis evaluating the impact of atypicalantipsychotics on hospitalizations, patients were fol-lowed for up to 1 year or until the occurrence of hospi-talization, loss of continuous eligibility, or until switch-ing or discontinuation of the index medication occurred(allowing for a gap of 15 days).

In this study, the inpatient and emergency depart-ment visit costs and medical costs were also evaluated forpatients during their time receiving the index treatment.For this analysis, patients were followed from treatmentinitiation to the time of switching or discontinuation ofthe index medication (allowing for a gap of 15 days), lossof continuous eligibility, or the end of the study period(after 1 year).

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

a secondary diagnosis code ranging from 290.XX to319.XX. Costs were adjusted to 2008 US dollars using themedical care component of the Consumer Price Index.

Assessments and Statistical AnalysesThe 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, base-line hospitalization rate, and use of mood stabilizers.These control variables were computed using data fromthe 6-month period before the index date.

The models for medical costs were implemented usinga generalized linear framework with a log link andgamma distribution. For the analysis of costs of hospital-ization and emergency department visits, a 2-stage mul-tivariate modeling approach was used combining logistic

Medical Care Costs and Hospitalization in Bipolar Disorder


aQuantity and supply of atypical antipsychotic during follow-upperiod denotes patients with an atypical antipsychotic prescrip-tion that included the number of days supplied and the quantityof drug dispensed.

Patients starting atypical antipsychotic1/1/2003-9/30/2008

N = 284,485

Patients had available (1) quantity and (2) supply of atypical antipsychotic during

follow-up perioda

N = 237,560

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 dateN = 84,411

Study samplePatients with bipolar disorder and no long-term care claims

N = 19,176

➤➤

➤➤

Figure Patient Flow

regression, generalized linear models, and bootstrappingwith 200 repetitions, to account for the fact that manypatients had no hospitalizations and emergency depart-ment visits and therefore incurred no inpatient or emer-gency department costs.

All models controlled for the same set of baseline fac-tors used in the Cox proportional hazards model that wasstated above. Aripiprazole therapy was used as the refer-ence group for all of the comparisons, with an a priorilevel of significance set at 0.05 (2-sided).

ResultsPatient Disposition and Characteristics

A total of 284,485 patients were identified with a pre-scription for an atypical antipsychotic in the study data-base; 19,176 patients had been diagnosed with bipolardisorder, met the study selection criteria, and were there-fore included in this analysis. A schematic diagram ofpatient disposition is shown in the Figure (page 381).

Baseline DifferencesOf the total number of patients, 3690 were prescribed

aripiprazole; 3038 received olanzapine; 7936 quetiapine;2997 risperidone; and 1515 received ziprasidone (Table1). Baseline patient characteristics for the 5 atypicalantipsychotics are displayed in Table 1. Patients whowere treated with aripiprazole were statistically younger,more likely to be female, and had lower rates of preindexhospitalization and emergency department rates thanthe comparator atypical antipsychotics. Mean time ontreatment ranged from 67 to 74 days (aripiprazole, 71 ±76; olanzapine, 67 ± 74; quetiapine, 74 ± 84; risperidone,71 ± 78; ziprasidone, 69 ± 78).

Time to HospitalizationResults of the Cox proportional hazards model, con-

trolling for differences in baseline patient characteristics,demonstrated a significantly lower hazard ratio (HR) forall-cause and for mental health–related hospitalization

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

VariableAripiprazole(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)

Index year, N (%)

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)

Use of mood stabilizer, N (%) 1721 (46.6) 1037 (34.1)a 3342 (42.1)a 1187 (39.6)a 698 (46.1)aP <.05 versus aripiprazole. SD indicates standard deviation.

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

Medical and Inpatient Costs (on Treatment Analysis)

The unadjusted PPPM medical costs (ie, outpatientplus inpatient and emergency department) were signifi-cantly lower for aripiprazole compared with all the otheratypical antipsychotics for all-cause and for mentalhealth–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 high-er than for the other atypical antipsychotics that wereassessed, whereas the lowest all-cause (US $804 ±$2523) and mental health–related costs (US $475 ±$2145) were associated with aripiprazole treatment com-pared with the other atypical antipsychotics (Table 3).

Results of the generalized linear models regressiondemonstrated consistent findings for all-cause and formental health–related medical (ie, outpatient plus inpa-tient and emergency department) costs, with costs forpatients receiving aripiprazole being significantly lower(US $911; 95% confidence interval [CI], 866-958 andUS $576; 95% CI, 543-610, respectively) compared withother 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 men-tal health–related costs were seen with ziprasidone (US$823; 95% CI, 754-898).

The current analysis also indicates lower all-cause andmental health–related inpatient and emergency depart-ment costs for patients receiving aripiprazole comparedwith those receiving all other atypical antipsychotics(Table 5, page 385). The adjusted inpatient and emer-gency department all-cause costs were significantly lowerfor aripiprazole compared with all other atypical antipsy-chotics (P <.05), except olanzapine, whereas the adjust-ed inpatient and emergency department mental health–related costs were significantly lower for this agent onlywhen compared with ziprasidone (P <.05).

DiscussionThis analysis of commercially insured patients with

a diagnosis of bipolar disorder who were receiving atyp-ical antipsychotic treatment established that the HR ofhospitalization for patients receiving aripiprazole treat-ment was significantly lower than for patients receivingother atypical antipsychotics. This translated intolower medical costs for patients prescribed aripiprazolecompared with those receiving any of the other atypi-cal antipsychotics.



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

Medication-based hospitalizationHazard 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, baselinehospitalization rate, and use of mood stabilizers.

Table 3 Medical and Inpatient/Emergency DepartmentUnadjusted Costs: On-Treatment Analysis

Medication-specific costs

Inpatient and emergency departmentcosts, mean, $(± SD)

Medical costs (outpatient +

inpatient), mean, $ (± SD)

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.

These results are consistent with previously publishedfindings.12,14,15 For example, Kim and colleagues evaluatedcommercially insured patients with bipolar disorder whowere treated with a mood stabilizer and adjunctive atyp-ical antipsychotic therapy, and observed that after mul-tivariate adjustment for differences in baseline character-istics, aripiprazole was associated with a significantlylonger time to hospitalization compared with any of theother atypical antipsychotics.13 A companion analysis of

the study also demonstrated that treatment with adjunc-tive aripiprazole was associated with significantly lowerpsychiatric-related costs than other atypical antipsychot-ic agents (P <.001).12

In a similar study, Kim and colleagues14 compared thetime to psychiatric hospitalization and healthcare costsin commercially insured patients who had bipolar disor-der and were being treated with aripiprazole, olanzapine,quetiapine, risperidone, or ziprasidone over a 1-year peri-od after initiation of therapy. The current study is anextension of the study by Kim and colleagues.14 In thestudy by Kim and colleagues, after a multivariate adjust-ment for differences in baseline characteristics, aripipra-zole was associated with a significantly lower risk of psy-chiatric hospitalization than ziprasidone, quetiapine, andolanzapine, and significantly lower healthcare costs thanquetiapine, but not other atypical antipsychotics.14

In a real-world study of Medicaid beneficiaries withbipolar disorder who were newly initiating an atypicalantipsychotic, those prescribed aripiprazole had a signif-icantly longer time to psychiatric hospitalization thanthose who were prescribed olanzapine, quetiapine,ziprasidone, or risperidone; however, this difference didnot reach significance in the case of the latter.15 Althoughadjusted costs of psychiatric hospitalization in beneficiar-ies initiating aripiprazole were lower compared with allother beneficiaries receiving atypical antipsychotic ther-apy, this difference was only significant when comparedwith those initiating treatment with quetiapine.15

Furthermore, the current study focused solely on med-ical (ie, outpatient and inpatient) costs. Pharmacy costswere not examined, because most of the antipsychoticsexamined in the analysis (ie, olanzapine, quetiapine,risperidone, and ziprasidone) are currently available asgeneric medications. Therefore, pharmacy expendituredata based on branded antipsychotics from 2003 through2008 are not applicable for decision-making in today’smarketplace.

The present analysis focused on the relative medicalcosts of patients using each medication, which will likelyremain consistent between the study period and currentclinical practice. It is also important to note that thetime period of the analysis (2003-2008) may have led tothe inclusion of some patients in the sample with poten-tial off-label use of aripiprazole for bipolar disorder,because the US Food and Drug Admin istration approvalfor this indication was received in September 2004.

LimitationsThere are several limitations associated with this

analysis. First, the use of medical and pharmacy claimsdata did not allow for confirmation of a patient’s diagno-sis or whether the medication of interest was prescribed

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Table 4Generalized Linear Models Regression Analysis forAdjusted Mean Medical Costs: Outpatient plus Inpatient/Emergency Department

Medication-specificmedical costs

Mean adjustedmedical costs, $ (outpatient +

inpatient/emergencydepartment)

95% Confidence interval

Lower costs, $

Upper costs, $

All-cause costs

Aripiprazole 911 866 958

Olanzapine 1100a 1039 1165

Quetiapine 1221a 1180 1263

Risperidone 1040a 984 1099

Ziprasidone 1216a 1126 1312


Aripiprazole 576 543 610

Olanzapine 714a 668 762

Quetiapine 804a 773 836

Risperidone 757a 711 807

Ziprasidone 823a 754 898

aP <.05 versus aripiprazole.Costs reported as per treated patient per month in 2008 US dol-lars. Estimates are reported after controlling for age, sex, year ofindex prescription, Charlson comorbidity index, diabetes, hyper-lipidemia, glucose and lipid testing, baseline hospitalization rate,and use of mood stabilizers.

Most of the antipsychotics examined in theanalysis are currently available as genericmedications. Therefore, pharmacyexpenditure data based on brandedantipsychotics from 2003 through 2008 arenot applicable for decision-making intoday’s marketplace.

for a specific condition. However, patients included inthis study had a diagnosis of bipolar disorder during thestudy period and were treated with an atypical antipsy-chotic for that disorder.

Because this was a retrospective database study, lackof randomization may have led to selection bias.Baseline characteristics varied across the cohorts andmight have impacted the results. However, the study didadjust for preperiod psychiatric hospitalizations, moodstabilizer use, Charlson comorbidity index score, andother demographic factors to minimize confounding.

It is important to note that the current analysis hadless stringent inclusion criteria compared with previouslypublished analyses, namely, that the use of adjunctivemood stabilizers was not required, the follow-up periodwas long (ie, 365 days), and, most important, cost out-comes were calculated during the time receiving treat-ment as opposed to an ITT framework projection.

Because outcomes were assessed during a patient’stime receiving treatment with the index atypicalantipsychotic, the current data provide important infor-mation on the effect of atypical antipsychotics on hospi-talizations and related costs during the time patientswere receiving treatment as opposed to associating post-treatment events with an index medication that was dis-continued months earlier. However, it should be notedthat the average length of therapy in the current analysiswas short (ie, mean time on treatment was 67-74 days)and may not be generalizable to patients using thesedrugs for a relatively longer period of time.

ConclusionsIn this analysis, patients in a commercial plan who

were treated with aripiprazole for bipolar disorder had alonger time to hospitalization and fewer hospitalizationscompared with patients who were treated with olanza -pine, quetiapine, risperidone, or ziprasidone. In addition,patients treated with aripiprazole had the lowest all-causeand mental health–related medical costs compared withthose treated with olanzapine, quetiapine, risperidone, orziprasidone. These data are consistent with previous pub-lished findings for patients with bipolar dis order in real-world settings, and they suggest that aripiprazole mayoffer an economic advantage versus other atypicalantipsychotic medications in this patient population. ■

AcknowledgmentEditorial support for the preparation of the manuscript

was provided by Ogilvy Healthworld Medical Education.

Study FundingThis study was supported by funding from Bristol-Myers

Squibb and Otsuka Pharmaceutical Co, Ltd.

Author Disclosure StatementDr Bergeson, Dr Jing, and Dr Hebden are employed by

and own stock in Bristol-Myers Squibb, and Dr Kalsekar andMs You are employed by Bristol-Myers Squibb. Dr Forbes isa former employee of Otsuka Pharmaceutical Development& Commercialization, Inc.

References1.Wyatt RJ, Henter I, Leary MC, Taylor E. An economic evaluation of schizophre-nia—1991. Soc Psychiatry Psychiatr Epidemiol. 1995;30:196-205.2. Dean BB, Gerner D, Gerner RH. A systematic review evaluating health-relatedquality of life, work impairment, and healthcare costs and utilization in bipolar dis-order. Curr Med Res Opin. 2004;20:139-154.3. Simon GE, Unutzer J. Health care utilization and costs among patients treated forbipolar disorder in an insured population. Psychiatr Serv. 1999;50:1303-1308.4. Stender M, Bryant-Comstock L, Phillips S. Medical resource use among patientstreated for bipolar disorder: a retrospective, cross-sectional, descriptive analysis. ClinTher. 2002;24:1668-1676.5. Lish JD, Dime-Meenan S, Whybrow PC, et al. The National Depressive andManic-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 costsamong 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 meta-bolic comorbidity among individuals with bipolar disorder. J Clin Psychopharmacol.



Table 5 Two-Part Model for Adjusted Inpatient/EmergencyDepartment Costs

Medication-specific medical costs

Mean adjustedcosts, $ (inpatient/emergencydepartment)

Differencein costs, $

95% Confidence interval

Lowercosts, $

Uppercosts, $

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


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

aP <.05 versus aripiprazole. Costs are reported per treated patient per month in 2008 USdollars. Estimates are reported after controlling for age, sex,year of index prescription, Charlson comorbidity index, dia-betes, hyperlipidemia, glucose and lipid testing, baseline hospi-talization rate, and use of mood stabilizers.

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 byoutpatient psychiatrists. Am J Psychiatry. 2002;159:1005-1010.10. Broder MS, Bates JA, Jing Y, et al. Association between second-generationantipsychotic medication half-life and hospitalization in the community treatment ofadult schizophrenia. J Med Econ. 2012;15:105-111.11. Citrome L. A review of aripiprazole in the treatment of patients with schizophre-nia 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 inpatients with bipolar disorder treated with a mood stabilizer and adjunctive atypicalantipsychotics: 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 andassociated treatment costs in bipolar disorder treated with atypical antipsychotics: aretrospective claims database analysis. BMC Psychiatry. 2011;11:6.15. Jing Y, Johnston SS, Fowler R, et al. Comparison of second-generation antipsy-chotic treatment on psychiatric hospitalization in Medicaid beneficiaries with bipo-lar disorder. J Med Econ. 2011;14:777-786.

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The Potential Value of Benefit Design and Medication Selection for aTotal-Cost-of-Care Strategy in Bipolar Disease PAYERS: The influences of and direction of fund-

ing under the Affordable Care Act are shifting therisk of “episodes-of-care” management onto payersunder an accountable care organization model. Themanagement of outpatient care that is associated withMedicare and Medicaid coverage involves a risk thatis continuing to grow, whereby potentially prevent -able hospital admissions that are incurred from theinappropriate or the insufficient management ofchronic diseases will not be entitled to be reimbursedunder federal- and/or state-sponsored programs.

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

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

as generic opportunity and contracting, may not bethe final determinants in formulary placement of aspecific therapy, although these strategies are stillimportant. Mental health is an important area wherethis dynamic plays out, and as Dr Bergeson and col-leagues demonstrate in their current study in thisissue of American Health & Drug Benefits, bipolar dis-ease suggests the potential value of medication andformulary selection from an episode-of-care total-costviewpoint.PATIENTS: Although not explicitly discussed

within the current article, the obvious result from bet-ter control of a chronic disease (such as bipolar disor-der), a reduction in hospitalizations, and the mitiga-tion of exposure to nosocomial concerns lead the wayto a better patient experience, as well as to improvedquality of life and quality of care for patients.

Jeffrey Januska, PharmDDirector of Pharmacy

CenCal HealthSanta Barbara, CA


MULTIPLE SCLEROSIS UPDATE


Several new posters focusing on patients with multi-ple sclerosis (MS) were presented at the 2012Educational Conference of the Academy of

Managed Care Pharmacy (AMCP), October 3-5, 2012,Cincinnati, OH.

Relapse and Symptoms Identify Patientswith High-Risk DiseaseThe number of relapses and symptom burden predict

an increased risk of relapse in patients with MS, accord-ing to a poster presented by Karina Raimundo, BS,Economics and Health Outcomes Research Fellow atNovartis Pharmaceuticals, East Hanover, NJ, and col-leagues. More frequent relapses in the previous 12 monthsdoubled the odds for a current high-relapse status, andMS symptoms in the previous year increased the odds byalmost 90%. The number of disease-modifying therapies(DMTs) used in the past year increased the risk of high-frequency relapse by 30%.High relapse activity (HRA) in patients with MS can

lead to more rapid progression of disability and worseclinical outcomes. However, factors associated withHRA remain unclear, according to Ms Raimundo andcolleagues. In addition, the effect of reducing HRA onthe cost of care for patients with MS has not been thor-oughly evaluated.To identify predictors of HRA, Ms Raimundo and

colleagues searched records in the MarketScan Com -mercial and Medicare Database for patients who hadat least 1 International Classification of Diseases, NinthRevision (ICD-9) entry related to MS during 2009 and atleast 1 entry between 2005 and 2008. They definedHRA as ≥2 relapses during 2009.Of 13,344 patients who met study eligibility criteria,

622 had HRA. Patients with HRA were younger, had ahigher Charlson comorbidity index score (0.7 vs 0.6,respectively), and were significantly more likely to havean ICD-9 code for MS symptoms in the previous year(83.0% vs 69.4%, respectively). They also had a signifi-cantly (P <.001) higher mean number of relapses in2008 (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

1.86 for HRA versus patients who had no symptoms inthe previous year (P <.001). The relapse rates in 2007and 2008 predicted the increased likelihood of HRA in2009 (OR, 1.39 in 2007 and 2.40 in 2008; P <.001 forboth). The number of DMTs used in the previous yearsalso significantly increased the likelihood of HRA in2009 (OR, 1.29).These findings suggest that several factors may pro-

vide clues to aid early identification of patients withmore aggressive forms of MS, according to the investiga-tors. Earlier identification of patients with aggressive dis-ease would afford an opportunity for earlier initiation ofeffective MS therapies and could potentially minimizethe long-term adverse effects of the disease process.[Raimundo K, et al. Predictors of high relapse activity in a mul-tiple sclerosis population using US medical claims database.]

Adherence to MS Therapies SignificantlyImpacts Cost-EffectivenessAdherence to therapy was the deciding factor in an

analysis of the cost-effectiveness of MS therapies, MsRaimundo and colleagues reported in a second posterpresentation. They evaluated the impact of adherenceon relapse and of cost-effectiveness associated with first-line DMTs for patients with relapsing forms of MS.The lymphocyte-targeted drug fingolimod was associ-

ated with the best patient adherence, leading to a 2-yearcost of $90,566 per avoided MS relapse, more than$50,000 less than the next closest agent. This indicatesthat adherence should figure into evaluations of the valueof therapies for MS, along with efficacy and tolerability.DMTs have become the cornerstone of treatment for

MS and have demonstrated the ability to prevent ordelay progression to permanent neurologic disability.The currently available DMTs for MS vary in terms ofcost, and the contributions of patient adherence to costhave not been examined in detail.Another poster presented at the AMCP meeting

showed that adherence to first-line DMTs, defined asmedication possession ratio ≥80%, was 89.2% with fin-golimod, 72.4% for subcutaneous (SC) interferon (IFN)beta-1b, 77.8% for SC IFN beta-1a, 82.1% for glatirameracetate, and 79.2% for intramuscular (IM) IFN beta-1a(Abouzaid S, et al. Comparison of compliance with fin-

Multiple Sclerosis: Patient Characteristicsand Cost ConcernsBy Charles Bankhead, Medical Writer

MULTIPLE SCLEROSIS UPDATE


golimod and other first-line disease-modifying treat-ments among patients with multiple sclerosis). Usingthose figures, Ms Raimundo and colleagues evaluatedthe impact of adherence on the rate of relapse and cost-effectiveness for first-line DMTs in MS from the perspec-tive 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 rela-tive incidence of relapse severity was assumed to be thesame for all DMTs. Wholesale acquisition costs forDMTs were obtained from Analy$ource, a web-basedpricing tool.The impact of nonadherence was based on a pub-

lished estimate showing that adherent patients had a sta-tistically significant 29% lower risk of relapse comparedwith 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 theother DMTs, the estimated costs for each relapse episodeavoided were $142,268 (Extavia) and $153,944(Betaseron) for SC IFN beta-1b; $155,486 for SC IFNbeta-1a; $174,097 for glatiramer acetate; and $370,397for IM IFN beta-1a.The investigators concluded that adherence has a sig-

nificant effect on real-world effectiveness of DMTs inMS, which in turn influences cost-effectiveness. Higherrates of adherence with fingolimod would translate intohigher estimated real-world effectiveness in the modelused in the study. [Raimundo K, et al. Cost-effectiveness ofmultiple sclerosis treatments: effects of adherence.]

MS Relapse Exacts Heavy Toll on Direct,Indirect CostsThe relapses of MS substantially increased direct and

indirect costs, which rose even higher with the severityof relapse, according to a poster presented by HélèneParisé, MA, an economist with the Groupe d’analyseIteé, Montréal, Canada, and colleagues.Many studies have demonstrated a significant eco-

nomic burden associated with MS, which affects directand indirect costs. Nonetheless, studies assessing theeconomic 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

and Insights database for the period from January 1999through December 2011 to identify patients with ≥2 pri-mary or secondary MS-related diagnoses. Characteristicsof patients who met the diagnostic criteria were evaluat-ed beginning 180 days before the first MS diagnosis andwere extended to the first year after diagnosis.Severe relapse was defined as an MS-related episode

requiring hospitalization, and relapses of low or moder-ate severity were defined as episodes requiring an outpa-tient or emergency department visit.A total of 9421 patients with MS were identified,

including 7686 patients with no relapses, 1220 with ≥1low or moderately severe relapses, and 515 with at least 1high-severity relapse. Compared with patients who hadno relapses, those with low or moderately severe relapseswere younger and healthier (by the Quan-Charlsoncomorbidity index), and patients with high-severityrelapses had more cardiovascular disease, diabetes, and useof 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 $28,348for patients with low or moderately severe relapses and$41,969 for patients with severe relapses. MS-specificcosts averaged $8803 for patients with no relapses,$18,981 for patients with low or moderately severerelapses, 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 forpatients with low or moderately severe relapses, and$9226 for patients with severe relapses. MS-specificindirect costs averaged $1613, $3238, and $6939 forpatients with no, low or moderately severe, and severerelapses, respectively.This cost disparity for direct and indirect costs persist-

ed in an analysis to 36 months after the diagnosis of MS.Overall, the average per-patient per-year direct costsincreased by almost 60% with low-to-moderately severerelapse, and the costs more than doubled with a severerelapse. Indirect costs doubled with severe relapse andincreased by 50% with low or moderately severe relapse.Much of the difference between relapse-free patients

and those with relapses resulted from increased MS-specific costs, suggesting that interventions that reducethe frequency and severity of MS relapses can helpreduce the cost of care for patients with MS. [Parisé H,et al. Direct and indirect costs associated with relapse ofmultiple sclerosis.] ■

Karen’s doctor said taking Levemir ® (insulin detemir [rDNA origin] injection)

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Low rates of hypoglycemia

In 1 study, approximately 45% of patients in each treatmentarm achieved A1C <7% with no hypoglycemic events

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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

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

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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.

Please see brief summary of Prescribing Information on adjacent page.Needles are sold separately and may require a prescription in some states.

Indications and UsageLevemir® (insulin detemir [rDNA origin] injection) 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 orshort-acting insulin is the preferred treatment forthis condition.

Important Safety InformationLevemir® 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

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* Minor=SMPG <56 mg/dL and not requiring third-party assistance.† Intended as a guide. Lower acquisition costs alone do not necessarily refl ect a

cost advantage in the outcome of the condition treated because othervariables affect relative costs. Formulary status issubject to change.

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

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 fi le. Novo Nordisk Inc, Princeton, NJ.

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LEVEMIR® (insulin detemir [rDNA origin] injection)Rx ONLYBRIEF SUMMARY. Please consult package insert for full prescribing infor-mation.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 hypersensi-tivity 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 indi-vidual 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 intra-muscularly. 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 unconscious-ness 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: Non-diabetic 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 interac-tions: 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%)

LEVEMIR®, % (n = 767)

NPH, % (n = 388)

Upper respiratory tract infection 26.1 21.4Headache 22.6 22.7Pharyngitis 9.5 8.0Influenza-like illness 7.8 7.0Abdominal Pain 6.0 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%)

LEVEMIR®, % (n = 161)

Glargine, % (n = 159)

Upper respiratory tract infection 26.7 32.1Headache 14.3 19.5Back pain 8.1 6.3Influenza-like illness 6.2 8.2Gastroenteritis 5.6 4.4Bronchitis 5.0 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%)

LEVEMIR®, % (n = 432)

NPH, % (n = 437)

Upper respiratory tract infection 12.5 11.2Headache 6.5 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%)

LEVEMIR®, % (n = 232)

NPH, % (n = 115)

Upper respiratory tract infection 35.8 42.6Headache 31.0 32.2Pharyngitis 17.2 20.9Gastroenteritis 16.8 11.3Influenza-like illness 13.8 20.9Abdominal pain 13.4 13.0Pyrexia 10.3 6.1Cough 8.2 4.3Viral infection 7.3 7.8Nausea 6.5 7.0Rhinitis 6.5 3.5Vomiting 6.5 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 hypogly-cemia 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 admin-istration. 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).

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, gener-alized allergy, including anaphylaxis, generalized skin reactions, angioedema, bron-chospasm, 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.

For information about LEVEMIR® contact: Novo Nordisk Inc., 100 College Road West Princeton, NJ 08540 1-800-727-6500 www.novonordisk-us.comManufactured by: Novo Nordisk A/S DK-2880 Bagsvaerd, DenmarkRevised: 1/2012Novo 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

More detailed information is available upon request.

Table 5: Hypoglycemia in Patients with Type 1 DiabetesStudy A

Type 1 Diabetes Adults

16 weeks In combination with insulin aspart

Study B Type 1 Diabetes

Adults 26 weeks

In combination with insulin aspart

Study C Type 1 Diabetes

Adults 24 weeks

In combination with regular insulin

Study D Type 1 Diabetes

Pediatrics 26 weeks

In combination with insulin aspartTwice-Daily LEVEMIR® Twice-Daily NPH Twice-Daily

LEVEMIR®Once-Daily

GlargineOnce-Daily LEVEMIR® Once-Daily NPH Once- or Twice

Daily LEVEMIR®Once- or Twice

Daily NPHSevere hypo-glycemia

Percent of patients with at least 1 event (n/total N)

8.7 (24/276)

10.6 (14/132)

5.0 (8/161)

10.1 (16/159)

7.5 (37/491)

10.2 (26/256)

15.9 (37/232)

20.0 (23/115)

Event/patient/year 0.52 0.43 0.13 0.31 0.35 0.32 0.91 0.99Non-severe hypoglycemia

Percent of patients (n/total N)

88.0 (243/276)

89.4 (118/132)

82.0 (132/161)

77.4 (123/159)

88.4 (434/491)

87.9 (225/256)

93.1 (216/232)

95.7 (110/115)

Event/patient/year 26.4 37.5 20.2 21.8 31.1 33.4 31.6 37.0

Table 6: Hypoglycemia in Patients with Type 2 DiabetesStudy E

Type 2 Diabetes Adults

24 weeks In combination with oral agents

Study F Type 2 Diabetes

Adults 22 weeks

In combination with insulin aspartTwice-Daily LEVEMIR® Twice-Daily NPH Once- or Twice Daily LEVEMIR® Once- or Twice Daily NPH

Severe hypo-glycemia

Percent of patients with at least 1 event (n/total N)

0.4 (1/237)

2.5 (6/238)

1.5 (3/195)

4.0 (8/199)

Event/patient/year 0.01 0.08 0.04 0.13Non-severe hypoglycemia

Percent of patients (n/total N)

40.5 (96/237)

64.3 (153/238)

32.3 (63/195)

32.2 (64/199)

Event/patient/year 3.5 6.9 1.6 2.0


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Constipation 5.3 0.9 1.7Dyspepsia 5.2 0.9 2.6

Add-on to Metformin + GlimepirideVictoza® 1.8 + Metformin +

Glimepiride N = 230

Placebo + Metformin + Glimepiride

N = 114

Glargine + Metformin + Glimepiride

N = 232Adverse Event Term (%) (%) (%)Nausea 13.9 3.5 1.3Diarrhea 10.0 5.3 1.3Headache 9.6 7.9 5.6Dyspepsia 6.5 0.9 1.7Vomiting 6.5 3.5 0.4

Add-on to Metformin + RosiglitazoneAll Victoza® + Metformin +

Rosiglitazone N = 355Placebo + Metformin

+ Rosiglitazone N = 175Adverse Event Term (%) (%)Nausea 34.6 8.6Diarrhea 14.1 6.3Vomiting 12.4 2.9Decreased Appetite 9.3 1.1Anorexia 9.0 0.0Headache 8.2 4.6Constipation 5.1 1.1Fatigue 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)

Victoza® 1.8 mg once daily + metformin and/or

sulfonylurea N = 235

Exenatide 10 mcg twice daily + metformin and/or

sulfonylurea N = 232Preferred Term (%) (%)Diarrhea 12.3 12.1Dyspepsia 8.9 4.7Constipation 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. Gastroin-testinal adverse events occurred in 17% of comparator-treated patients. Events that occurred more commonly among Victoza®-treated patients included nausea, vomiting, diarrhea, dyspepsia and con-stipation. 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: Con-sistent 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 dilu-tion of serum) of anti-liraglutide antibodies were detected in 8.6% of these Victoza®-treated patients. Sampling was not performed uniformly across all patients in the clinical trials, and this may have resulted in an underestimate of the actual percentage of patients who developed antibodies. Cross-reacting anti-liraglutide antibodies to native glucagon-like peptide-1 (GLP-1) occurred in 6.9% of the Victoza®-treated patients in the 52-week monotherapy trial and in 4.8% of the Victoza®-treated patients in the 26-week add-on combination therapy trials. These cross-reacting antibodies were not tested for neutralizing effect against native GLP-1, and thus the potential for clinically significant neutralization of native GLP-1 was not assessed. Antibodies that had a neutralizing effect on liraglutide in an in vitro assay occurred in 2.3% of the Victoza®-treated patients in the 52-week monotherapy trial and in 1.0% of the Victoza®-treated patients in the 26-week add-on combination therapy trials. Among Victoza®-treated patients who developed anti-liraglutide antibodies, the most common category of adverse events was that of infections, which occurred among 40% of these patients compared to 36%, 34% and 35% of antibody-negative Victoza®-treated, placebo-treated and active-control-treated patients, respectively. The specific infections which occurred with greater frequency among Victoza®-treated antibody-positive patients were primarily nonserious upper respiratory tract infections, which occurred among 11% of Victoza®-treated antibody-positive patients; and among 7%, 7% and 5% of antibody-negative Victoza®-treated, placebo-treated and active-control-treated patients, respectively. Among Victoza®-treated antibody-negative patients, the most common category of adverse events was that of gastrointestinal events, which occurred in 43%, 18% and 19% of antibody-negative Victoza®-treated, placebo-treated and active-control-treated patients, respectively. Antibody formation was not associ-ated 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 compos-ite 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 immunogenic-ity 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 screen-ing 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 hypo-glycemia 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® Treatment

Active Comparator

Placebo Comparator

Monotherapy Victoza® (N = 497)

Glimepiride (N = 248)

None

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) —Add-on to Metformin

Victoza® + Metformin (N = 724)

Glimepiride + Metformin (N = 242)

Placebo + Metformin (N = 121)

Patient not able to self−treat 0.1 (0.001) 0 0Patient able to self−treat 3.6 (0.05) 22.3 (0.87) 2.5 (0.06)Add-on to Glimepiride Victoza® +

Glimepiride (N = 695)

Rosiglitazone + Glimepiride

(N = 231)

Placebo + Glimepiride

(N = 114)Patient not able to self−treat 0.1 (0.003) 0 0Patient 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) 0Add-on to Metformin + Rosiglitazone

Victoza® + Metformin +

Rosiglitazone (N = 355)

None

Placebo + Metformin +

Rosiglitazone (N = 175)

Patient not able to self−treat 0 — 0Patient able to self−treat 7.9 (0.49) — 4.6 (0.15)Not classified 0.6 (0.01) — 1.1 (0.03)Add-on to Metformin + Glimepiride

Victoza® + Metformin + Glimepiride

(N = 230)

Insulin glargine + Metformin + Glimepiride

(N = 232)

Placebo + Metformin + Glimepiride

(N = 114)Patient not able to self−treat 2.2 (0.06) 0 0Patient 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 neo-plasms (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 par-ticular 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 refer-ence 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 fol-lowing 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, 1−877-484-2869Date of Issue: May 18, 2011 Version: 3Manufactured by: Novo Nordisk A/S, DK-2880 Bagsvaerd, DenmarkVictoza® 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

© 2012 Novo Nordisk 1111-00006045-1 January 2012Victoza® is a registered trademark and VictozaCare™ is a trademark of Novo Nordisk A/S.

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%*

To see how Victoza® works for your patients, visit VictozaPro.com/GLP1.

Indications and usageVictoza® 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 fi ndings to humans, prescribe Victoza® only to patients for whom the potential benefi ts are considered to outweigh the potential risk. Victoza® is not recommended as fi rst-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 suffi ciently 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 informationLiraglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors at clinically relevant exposures in both genders of rats and mice. It is unknown whether Victoza® causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as human relevance could not be ruled out by clinical or nonclinical studies. Victoza® is contraindicated in patients with a personal or family history of MTC and in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Based on the fi ndings in rodents, monitoring with serum calcitonin or thyroid ultrasound was performed during clinical trials, but this may have increased the number of unnecessary thyroid surgeries. It is unknown whether monitoring with serum

calcitonin or thyroid ultrasound will mitigate human risk of thyroid C-cell tumors. Patients should be counseled regarding the risk and symptoms of thyroid tumors.

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

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 fi lled for existing Victoza® patients enrolled in VictozaCare™ versus a match-pair control group not enrolled in VictozaCare™ through fi rst 8 months of enrollment.

Low rate ofhypoglycemia

May reduce weight— Victoza® is not indicated

for the management of obesity, and weight change was a secondary end point in clinical trials

Flexible dosing any time of day, independent of meals

VictozaCare™ helps patients stay on track with ongoing support— Patients enrolled in

VictozaCare™ were more adherent to Victoza® than those not enrolled†

september/october 2012 volume 5, number 6

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