March/April 2011, Vol 4, No 2

REGULATORY

Comparative Effectiveness Research in the United States: A Catalyst for InnovationRiaz Ali, MPP; Morgan Hanger, MPP; Tanisha Carino, PhD

BUSINESS

Comparing Treatment Persistence, Healthcare Resource Utilization, and Costs in Adult Patients with Major Depressive Disorder Treated with Escitalopram or CitalopramEric Q. Wu, PhD; Paul E. Greenberg, MA; Rym Ben-Hamadi, MSc; Andrew P. Yu, PhD; Elaine H. Yang, PhD; M. Haim Erder, PhD

Stakeholder Perspective by Matthew Mitchell, PharmD, MBA

Recent Trends in the Dispensing of 90-Day-Supply Prescriptions at RetailPharmacies: Implications for Improved Convenience and AccessJoshua N. Liberman, PhD; Charmaine Girdish, MPH

Stakeholder Perspective by Walid F. Gellad, MD, MPH

CLINICAL

Strategies to Prevent Opioid Misuse, Abuse, and Diversion That May AlsoReduce the Associated CostsKathryn L. Hahn, PharmD, DAAPM, CPE

Stakeholder Perspective by Atheer A. Kaddis, PharmD

™

©2011 Engage Healthcare Communications, LLCwww.AHDBonline.com

MARCH/APRIL 2011 VOLUME 4, NUMBER 2

THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN™

FOR PAYERS, PURCHASERS, POLICYMAKERS, AND OTHER HEALTHCARE STAKEHOLDERS

Time (h)

Mean plasma concentration (in healthy subjects; day 5; ng/mL)1

DEXILANT 60 mgDEXILANT 30 mgDEXILANT 60 mgDEXILANT 60 mgDEXILANT 30 mgDEXILANT 30 mgDEXILANT 30 mg

1200

1000

800

600

400

200

00 6 12 18 24

DEXILANT 30 mg provided full 24-hour heartburn relief in a majority of symptomatic non-erosive gastroesophageal reflux disease patients at week 41

Conclusions of comparative ef� cacy cannot be drawn from this information.

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

Important Safety Information DEXILANT is contraindicated in patients with known hypersensitivity to any component of the formulation. Hypersensitivity and anaphylaxis have been reported with DEXILANT use. Symptomatic response with DEXILANT does not preclude the presence of gastric malignancy. Long-term and multiple daily dose PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine. Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated. Most commonly reported treatment-emergent adverse reactions: diarrhea (4.8%), abdominal pain (4.0%), nausea (2.9%), upper respiratory tract infection (1.9%), vomiting (1.6%), and flatulence (1.6%). Do not co-administer atazanavir with DEXILANT because atazanavir systemic concentrations may be substantially decreased. DEXILANT may interfere with absorption of drugs for which gastric pH is important for bioavailability (e.g., ampicillin esters, digoxin, iron salts, ketoconazole). Patients taking concomitant warfarin may require monitoring for increases in international normalized ratio (INR) and prothrombin time. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Concomitant tacrolimus use may increase tacrolimus whole blood concentrations.

Please see adjacent brief summary of prescribing information for DEXILANT.

DEXILANT WORKS ASECOND SHIFT TO HELP SHUT DOWN ACID PUMPS

DEXILANT is the � rst and only PPI with a Dual Delayed Release™ (DDR) formulation, which provides a second release of drug

There are no adequate and well-controlled studies with

d

As many drugs are excreted in human milk, and because of the

p

Dexlansoprazole is not expected to be r

BRIEF SUMMARY OF FULL PRESCRIBING INFORMATIONDEXILANT (dexlansoprazole) delayed release capsulesINDICATIONS AND USAGEDEXILANT is indicated for:

CONTRAINDICATIONS

[see Adverse Reactions]WARNINGS AND PRECAUTIONSGastric Malignancy

Bone Fracture

ADVERSE REACTIONS Clinical Trials Experience

≥

Table 2: Incidence of Treatment-Emergent Adverse Reactionsin Controlled Studies

DEXILANT DEXILANT DEXILANT

Blood and Lymphatic System Disorders: Cardiac Disorders:

Ear and Labyrinth Disorders: Endocrine Disorders: Eye Disorders:

Gastrointestinal Disorders:

General Disorders and Administration Site Conditions:

Hepatobiliary Disorders:Immune System Disorders: Infections and

Infestations: Injury, Poisoning

and Procedural Complications:Laboratory Investigations:

Metabolism and Nutrition Disorders: Musculoskeletal and Connective Tissue

Disorders: Nervous System Disorders:

Psychiatric Disorders: Renal and Urinary Disorders:

Reproductive System and Breast Disorders: ; Respiratory,

Thoracic and Mediastinal Disorders:

Skin and Subcutaneous Tissue Disorders: Vascular Disorders:

Postmarketing Experience

Eye DisordersGastrointestinal DisordersGeneral Disorders and Administration Site ConditionsImmune System Disorders

Musculoskeletal System DisorderRespiratory, Thoracic and Mediastinal Disorders

Skin and Subcutaneous Tissue Disorders

DRUG INTERACTIONSDrugs with pH-Dependent Absorption Pharmacokinetics

Warfarin

Tacrolimus

a

01/11 Printed in U.S.A.

M

USE IN SPECIFIC POPULATIONSPregnancyTeratogenic EffectsPregnancy Category B. There are no adequate and well-controlled studies with dexlansoprazole in pregnant women. There were no adverse fetal effects in animal reproduction studies of dexlansoprazole in rabbits. Because animal reproduction studies are not always predictive of human response, DEXILANT should be used during pregnancy only if clearly needed.A reproduction study conducted in rabbits at oral dexlansoprazole doses up to approximately 9-times the maximum recommended human dexlansoprazole dose (60 mg per day) revealed no evidence of impaired fertility or harm to the fetus due to dexlansoprazole. In addition, reproduction studies performed in pregnant rats with oral lansoprazole at doses up to 40 times the recommended human lansoprazole dose and in pregnant rabbits at oral lansoprazole doses up to 16 times the recommended human lansoprazole dose revealed no evidence of impaired fertility or harm to the fetus due to lansoprazole.Nursing MothersIt is not known whether dexlansoprazole is excreted in human milk. However, lansoprazole and its metabolites are present in rat milk following the administration of lansoprazole. As many drugs are excreted in human milk, and because of the potential for tumorigenicity shown for lansoprazole in rat carcinogenicity studies [see Carcinogenesis, Mutagenesis, Impairment of Fertility], a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.Pediatric Use Safety and effectiveness of DEXILANT in pediatric patients (less than 18 years of age) have not been established.Geriatric UseIn clinical studies of DEXILANT, 11% of patients were aged 65 years and over. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identifi ed signifi cant differences in responses between geriatric and younger patients, but greater sensitivity of some older individuals cannot be ruled out.Renal ImpairmentNo dosage adjustment of DEXILANT is necessary in patients with renal impairment. The pharmacokinetics of dexlansoprazole in patients with renal impairment are not expected to be altered since dexlansoprazole is extensively metabolized in the liver to inactive metabolites, and no parent drug is recovered in the urine following an oral dose of dexlansoprazole.Hepatic ImpairmentNo dosage adjustment for DEXILANT is necessary for patients with mild hepatic impairment (Child-Pugh Class A). DEXILANT 30 mg should be considered for patients with moderate hepatic impairment (Child-Pugh Class B). No studies have been conducted in patients with severe hepatic impairment (Child-Pugh Class C).OVERDOSAGEThere have been no reports of signifi cant overdose of DEXILANT. Multiple doses of DEXILANT 120 mg and a single dose of DEXILANT 300 mg did not result in death or other severe adverse events. Dexlansoprazole is not expected to be removed from the circulation by hemodialysis. If an overdose occurs, treatment should be symptomatic and supportive.CLINICAL PHARMACOLOGYPharmacodynamicsAntisecretory Activity The effects of DEXILANT 60 mg (n=20) or lansoprazole 30 mg (n=23) once daily for fi ve days on 24-hour intragastric pH were assessed in healthy subjects in a multiple-dose crossover study. Serum Gastrin Effects The effect of DEXILANT on serum gastrin concentrations was evaluated in approximately 3460 patients in clinical trials up to 8 weeks and in 1023 patients for up to 6 to 12 months. The mean fasting gastrin concentrations increased from baseline during treatment with DEXILANT 30 mg and 60 mg doses. In patients treated for more than 6 months, mean serum gastrin levels increased during approximately the fi rst 3 months of treatment and were stable for the remainder of treatment. Mean serum gastrin levels returned to pre-treatment levels within one month of discontinuation of treatment.Enterochromaffi n-Like Cell (ECL) Effects There were no reports of ECL cell hyperplasia in gastric biopsy specimens obtained from 653 patients treated with DEXILANT 30 mg, 60 mg or 90 mg for up to 12 months.

During lifetime exposure of rats dosed daily with up to 150 mg per kg per day of lansoprazole, marked hypergastrinemia was observed followed by ECL cell proliferation and formation of carcinoid tumors, especially in female rats [see Nonclinical Toxicology].Effect on Cardiac Repolarization A study was conducted to assess the potential of DEXILANT to prolong the QT/QTc interval in healthy adult subjects. DEXILANT doses of 90 mg or 300 mg did not delay cardiac repolarization compared to placebo. The positive control (moxifl oxacin) produced statistically signifi cantly greater mean maximum and time-averaged QT/QTc intervals compared to placebo. NONCLINICAL TOXICOLOGYCarcinogenesis, Mutagenesis, Impairment of FertilityThe carcinogenic potential of dexlansoprazole was assessed using lansoprazole studies. In two 24-month carcinogenicity studies, Sprague-Dawley rats were treated orally with lansoprazole at doses of 5 to 150 mg per kg per day, about 1 to 40 times the exposure on a body surface (mg/m2) basis of a 50 kg person of average height [1.46 m2 body surface area (BSA)] given the recommended human dose of lansoprazole 30 mg per day.Lansoprazole produced dose-related gastric ECL cell hyperplasia and ECL cell carcinoids in both male and female rats [see Clinical Pharmacology].In rats, lansoprazole also increased the incidence of intestinal metaplasia of the gastric epithelium in both sexes. In male rats, lansoprazole produced a dose-related increase of testicular interstitial cell adenomas. The incidence of these adenomas in rats receiving doses of 15 to 150 mg per kg per day (4 to 40 times the recommended human lansoprazole dose based on BSA) exceeded the low background incidence (range = 1.4 to 10%) for this strain of rat. In a 24-month carcinogenicity study, CD-1 mice were treated orally with lansoprazole doses of 15 mg to 600 mg per kg per day, 2 to 80 times the recommended human lansoprazole dose based on BSA. Lansoprazole produced a dose-related increased incidence of gastric ECL cell hyperplasia. It also produced an increased incidence of liver tumors (hepatocellular adenoma plus carcinoma). The tumor incidences in male mice treated with 300 mg and 600 mg lansoprazole per kg per day (40 to 80 times the recommended human lansoprazole dose based on BSA) and female mice treated with 150 mg to 600 mg lansoprazole per kg per day (20 to 80 times the recommended human lansoprazole dose based on BSA) exceeded the ranges of background incidences in historical controls for this strain of mice. Lansoprazole treatment produced adenoma of rete testis in male mice receiving 75 to 600 mg per kg per day (10 to 80 times the recommended human lansoprazole dose based on BSA).The potential effects of dexlansoprazole on fertility and reproductive performance were assessed using lansoprazole studies. Lansoprazole at oral doses up to 150 mg per kg per day (40 times the recommended human lansoprazole dose based on BSA) was found to have no effect on fertility and reproductive performance of male and female rats.PATIENT COUNSELING INFORMATIONInformation for PatientsTo ensure the safe and effective use of DEXILANT, this information and instructions provided in the FDA-approved patient labeling should be discussed with the patient. Inform patients of the following:Tell your patients to watch for signs of an allergic reaction as these could be serious and may require that DEXILANT be discontinued. Advise your patients to tell you if they take atazanavir, tacrolimus, warfarin and drugs that are affected by gastric pH changes.DEXILANT is available as a delayed release capsule.DEXILANT may be taken without regard to food.DEXILANT should be swallowed whole.

as follows: – Open capsule; – Sprinkle intact granules on one tablespoon of applesauce; – Swallow immediately. Granules should not be chewed. – Do not store for later use.

Distributed byTakeda Pharmaceuticals America, Inc.Deerfi eld, IL 60015DEXILANT is a trademark of Takeda Pharmaceuticals North America, Inc. and used under license by Takeda Pharmaceuticals America, Inc.©2009, 2010 Takeda Pharmaceuticals America, Inc.For more detailed information, see the full prescribing information for DEXILANT or contact Takeda Pharmaceuticals America, Inc. at 1-877-825-3327.DEX006 R8-Brf; August 2010 L-LPD-0810-2

Reference: 1. DEXILANT (dexlansoprazole) package insert, Takeda Pharmaceuticals America, Inc.

DEXILANT and Dual Delayed Release are trademarks of Takeda Pharmaceuticals North America, Inc. and used under license by Takeda Pharmaceuticals America, Inc.

©2011Takeda Pharmaceuticals North America, Inc. LPD-01450R1 01/11 Printed in U.S.A.

EDITORIAL BOARD

61www.AHDBonline.com l American Health & Drug Benefits lVol 4, No 2 l March/April 2011

CLINICAL EDITOR Thomas G. McCarter, MD, FACPChief Clinical OfficerExecutive Health Resources, PA

GOVERNMENT EDITORKevin B. “Kip” Piper, MA, FACHEPresident, Health Results GroupSr. Counselor, Fleishman-Hillard Washington, DC

ACTUARY David WilliamsMilliman Health ConsultantWindsor, CT

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

CANCER RESEARCHAl B. Benson, III, MD, FACPProfessor of MedicineAssociate Director for ClinicalInvestigationsRobert H. Lurie Comprehensive CancerCenter, Northwestern UniversityImmediate Past President, ACCCPast Chair, NCCN Board of Directors

Samuel M. Silver, MD, PhD, FACPProfessor, Internal MedicineDirector, Cancer Center NetworkDivision of Hematology/OncologyAssistant Dean for ResearchUniversity of Michigan Health Systems

CARDIOLOGY RESEARCH Michael A. Weber, MDProfessor of MedicineDepartment of Medicine (Cardiology)State University of New York

ENDOCRINOLOGY RESEARCHJames V. Felicetta, MD Chairman, Dept. of Medicine Carl T. Hayden Veterans AffairsMedical Center, Phoenix, AZ

EMPLOYERSAlberto M. Colombi, MD, MPHCorporate Medical DirectorPPG Industries, Pittsburgh, PA

Wayne M. Lednar, MD, PhDGlobal Chief Medical OfficerDirector, Integrated Health ServicesDuPont, Wilmington, DE

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

F. Randy Vogenberg, RPh, PhDPrincipal, Institute of Integrated HealthcareSharon, MA

EPIDEMIOLOGY RESEARCHJoshua N. Liberman, PhDVice President, Research OperationsCenter for Health ResearchGeisinger Health System, Danville, PA

HEALTH INFORMATION TECHNOLOGY J. B. Jones, PhD, MBAResearch Associate, Geisinger Health System, Danville, PA

Victor J. Strecher, PhD, MPHProfessor and Director, Center for HealthCommunications ResearchUniversity of Michigan Schools of PublicHealth and Medicine, Ann ArborFounder and Chief Visionary OfficerHealthMedia, Johnson & Johnson Co.

HEALTH OUTCOMES RESEARCH Diana Brixner, RPh, PhDProfessor and ChairDepartment of PharmacotherapyExecutive Director Outcomes ResearchCenter, University of Utah College ofPharmacy, Salt Lake City

Gordon M. Cummins, MSDirector, IntegriChain

Kavita V. Nair, PhDAssociate Professor, School of PharmacyUniversity of Colorado at Denver

Gary M. Owens, MDPresident, Gary Owens AssociatesGlen Mills, PA

Timothy S. Regan, BPharm, RPhExecutive Director, XcendaPalm Harbor, FL

HEALTH & VALUE PROMOTION Albert Tzeel, MD, MHSA, FACPENational Medical DirectorHumanaOne

MANGED CARE AND MANAGEMENTSharad Mansukani, MDChief Strategic Officer, Nations HealthSenior Advisor, Texas Pacific Group, FL

MANAGED MARKETS Jeffrey A. Bourret, RPh, MS, FASHPSenior Director, Branded SpecialtyPharmacy Programs, US SpecialtyCustomers Pfizer, Specialty Care Business Unit, PA

Charles E. Collins, Jr, MS, MBAVice President, Managed Markets StrategyFusion Medical Communications

PATIENT ADVOCACY William E. Fassett, BSPharm, MBA, PhDProfessor of Pharmacy Law & EthicsVice Chair, Dept. of PharmacotherapyCollege of Pharmacy, Washington StateUniversity, Spokane, WA

PERSONALIZED MEDICINE Wayne A. Rosenkrans, Jr, PhDChairman and President, Personalized Medicine Coalition, Distinguished Fellow,MIT Center for Biomedical Innovation

PHARMACOECONOMICSJeff Jianfei Guo, BPharm, MS, PhDAssociate Professor of Pharmacoeconomics& Pharmacoepidemiology, College of Pharmacy, University of Cincinnati Medical Center, OH

PHARMACY BENEFIT DESIGN Joel V. Brill, MDChief Medical Officer, Predictive Health, Phoenix, AZ

William J. Cardarelli, PharmDDirector of Pharmacy, Atrius HealthHarvard Vanguard Medical Associates

Leslie S. Fish, PharmDSr. Director of Pharmacy ServicesFallon Community Health Plan, MA

Michael S. Jacobs, RPhNational Clinical Practice LeaderBuck Consultants, Atlanta

Matthew Mitchell, PharmD, MBAManager, Pharmacy ServicesSelectHealth, Salt Lake City, UT

Paul Anthony Polansky, BSPharm, MBASenior Field Scientist, Health Outcomesand PharmacoEconomics (HOPE) Endo Pharmaceuticals Inc., Chadds Ford, PA

Scott R. Taylor, RPh, MBAAssociate Director, Industry RelationsGeisinger Health System, Danville, PA

POLICY & PUBLIC HEALTH Joseph R. Antos, PhDWilson H. Taylor Scholar in Health CareRetirement PolicyAmerican Enterprise Institute

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

Alex Hathaway, MD, MPH, FACPMPresident & Founder, J.D. BioEdgeHealth quality and biomedical research consultancy

J. Warren Salmon, PhDProfessor of Health Policy & AdministrationSchool of Public HealthUniversity of Illinois at Chicago

REIMBURSEMENT POLICYGrant D. Lawless, BSPharm, MD, FACPExecutive Director for Payor RelationsCorporate Account, Amgen, CA

RESEARCH & DEVELOPMENT Michael F. Murphy, MD, PhDChief Medical Officer and Scientific Officer Worldwide Clinical TrialsFaculty, Center for Experimental Pharmacology and Therapeutics, Harvard-MIT Division of Health Sciences andTechnology, Cambridge, MA

SPECIALTY PHARMACYAtheer A. Kaddis, PharmDVice President, Managed MarketsDiplomat Specialty PharmacySwartz Creek, MI

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

62 l American Health & Drug Benefits l www.AHDBonline.com March/April 2011 l Vol 4, No 2

PublisherNicholas [email protected]

Associate PublisherMaurice [email protected]

Editorial DirectorDalia [email protected]

Associate EditorLara J. [email protected]

Editorial AssistantJessica A. Smith

Senior Production ManagerLynn Hamilton

Quality Control DirectorBarbara Marino

Business ManagerBlanche Marchitto

Founding Editor-in-ChiefRobert E. [email protected]

American Health & Drug Benefits is foundedon the concept that health and drug benefitshave undergone a transformation: the econo -metric value of a drug is of equal importanceto clinical outcomes as it is to serving as thebasis for securing coverage in formularies andbenefit designs. Because benefit designs aregreatly affected by clinical, business, and pol-icy conditions, this journal offers a forum forstakeholder integration and collaborationtoward the improvement of healthcare.

This publication further provides benefitdesign de cision makers the integrated industryinformation they require to devise formulariesand benefit designs that stand up to today’sspecial healthcare delivery and business needs.

Contact Information:For subscription information and edi torialqueries, please contact: editorial@AHDB online.com

T: 732-992-1892F: 732-992-1881

Mission Statement

REGULATORY

68 Comparative Effectiveness Research in the United States: A Catalyst for InnovationRiaz Ali, MPP; Morgan Hanger, MPP; Tanisha Carino, PhD

BUSINESS

78 Comparing Treatment Persistence, Healthcare Resource Utilization, and Costs in Adult Patients with Major Depressive Disorder Treated with Escitalopram or CitalopramEric Q. Wu, PhD; Paul E. Greenberg, MA; Rym Ben-Hamadi, MSc; Andrew P. Yu, PhD;Elaine H. Yang, PhD; M. Haim Erder, PhD

87 Stakeholder Perspective by Matthew Mitchell, PharmD, MBA

95 Recent Trends in the Dispensing of 90-Day-Supply Prescriptions at RetailPharmacies: Implications for Improved Convenience and AccessJoshua N. Liberman, PhD; Charmaine Girdish, MPH

99 Stakeholder Perspective by Walid F. Gellad, MD, MPH

TABLE OF CONTENTS

Continued on page 66

American Health & Drug Benefits is included in the following indexing and database services:

EMBASE/Elsevier Bibliographic DatabaseSCOPUS/Elsevier Bibliographic DatabaseCumulative Index to Nursing and Allied Health Literature (CINAHL)EBSCO research databasesStandard Periodical Directory

MEMBER: Committee on Publication Ethics (COPE)


™ ™



BPA Worldwide membership applied for August 2010.

moving millimeters

REDUCTIONS IN 24-HR MEAN AMBULATORY SBP AT WEEK 61,2

Mean ambulatory baseline: Study 1=144.9 mm Hg

EDARBI is a trademark of Takeda Pharmaceutical Company Limited registered with the U.S. Patent and Trademark Office and used under license by Takeda Pharmaceuticals America, Inc. Trademarks are the property of their respective owners. ©2011 Takeda Pharmaceuticals North America, Inc. All rights reserved. LXA-00169 03/11

EDARBI 80 mg was statistically superior to DIOVAN® 320 mg and BENICAR® 40 mg in reducing 24-hr mean ambulatory and clinic SBP1

� Similar results were observed across two other comparator studies: Study 2 vs BENICAR 40 mg and Study 3 vs DIOVAN 320 mg

� Clinic SBP differences between EDARBI and active comparators were consistent with mean ambulatory results

IMPORTANT SAFETY INFORMATION

WARNING: AVOID USE IN PREGNANCYWhen pregnancy is detected, discontinue EDARBI as soon as possible. Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.

� Avoid fetal or neonatal exposure. � Correct volume or salt depletion prior to administration of EDARBI, or start treatment at 40 mg.� Monitor for worsening renal function in patients with renal impairment.� In patients with an activated renin-angiotensin system, as by volume or salt depletion, renin-

angiotensin-aldosterone system (RAAS) blockers such as azilsartan medoxomil can cause excessive hypotension. In patients whose renal function may depend on the activity of the renin-angiotensin system, e.g., with renal artery stenosis, treatment with RAAS blockers has been associated with oliguria or progressive azotemia and rarely with acute renal failure and death.

� Monitor renal function periodically in patients receiving EDARBI and NSAIDs who are also elderly, volume-depleted, or who have compromised renal function.

� The most common adverse reaction in adults was diarrhea (2%).

For further information, please see adjacent Brief Summary of Prescribing Information.

INDICATIONEDARBI is an angiotensin II receptor blocker (ARB) indicated for the treatment of hypertension, either alone or in combination with other antihypertensive agents.

Study 1 Design: A 6-week, randomized, double-blind, placebo-controlled, forced-titration study in patients (N = 1,291) with clinic SBP ≥150 mm Hg and ≤180 mm Hg and 24-hr mean SBP ≥130 mm Hg and ≤170 mm Hg. The primary endpoint was change in 24-hr mean ambulatory SBP. Placebo lowered 24-hr mean ambulatory SBP by 0.3 mm Hg. Data shown are placebo corrected.

DRAFT

NEW EDARBI: See how many millimeters you can move with this ARB

References: 1. EDARBI Prescribing Information. 2. White WB, Weber MA, Sica D, et al. Effects of the angiotensin receptor blocker azilsartan medoxomil versus olmesartan and valsartan on ambulatory and clinic blood pressure in patients with stages 1 and 2 hypertension. Hypertension. 2011;57:413-420.

P<0.001 vs DIOVAN 320 mgP=0.009 vs BENICAR 40 mg

EDARBI 80 mg

-14.3 mm Hg

BENICAR 40 mg

-11.7 mm Hg

DIOVAN 320 mg

-10.0 mm Hg

STUDY 1

Generally, adverse reactions were mild, not dose related and similar regardless of age, gender and race.In placebo controlled monotherapy trials, diarrhea was reported up to 2% in patients treated with Edarbi 80 mg daily compared with 0.5% of patients on placebo.Other adverse reactions with a plausible relationship to treatment that have been reported with an incidence of ≥0.3% and greater than placebo in more than 3300 patients treated with Edarbi in controlled trials are listed below:Gastrointestinal Disorders: nauseaGeneral Disorders and Administration Site Conditions: asthenia, fatigueMusculoskeletal and Connective Tissue Disorders: muscle spasmNervous System Disorders: dizziness, dizziness postural Respiratory, Thoracic and Mediastinal Disorders: coughClinical Laboratory FindingsIn controlled clinical trials, clinically relevant changes in standard laboratory parameters were uncommon with administration of Edarbi.Serum creatinine: Small reversible increases in serum creatinine are seen in patients receiving 80 mg of Edarbi. The increase may be larger when coadministered with chlorthalidone or hydrochlorothiazide.In addition, patients taking Edarbi who had moderate to severe renal impairment at baseline or who were >75 years of age were more likely to report serum creatinine increases.Hemoglobin/Hematocrit: Low hemoglobin, hematocrit, and RBC counts were observed in 0.2%, 0.4%, and 0.3% of Edarbi-treated subjects, respectively. None of these abnormalities were reported in the placebo group. Low and high markedly abnormal platelet and WBC counts were observed in <0.1% of subjects.DRUG INTERACTIONSNo clinically significant drug interactions have been observed in studies of azilsartan medoxomil or azilsartan given with amlodipine, antacids, chlorthalidone, digoxin, fluconazole, glyburide, ketoconazole, metformin, pioglitazone, and warfarin. Therefore, Edarbi may be used concomitantly with these medications.Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors(COX-2 Inhibitors)In patients who are elderly, volume-depleted (including those on diuretic therapy), or who have compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with angiotensin II receptor antagonists, including azilsartan, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving azilsartan and NSAID therapy.The antihypertensive effect of angiotensin II receptor antagonists, including azilsartan, may be attenuated by NSAIDs, including selective COX-2 inhibitors.USE IN SPECIFIC POPULATIONSPregnancyPregnancy Category C (first trimester) and D (second and third trimesters). There is no clinical experience with the use of Edarbi in pregnant women.Nursing MothersIt is not known if azilsartan is excreted in human milk, but azilsartan is excreted at low concentrations in the milk of lactating rats. Because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Pediatric UseSafety and effectiveness in pediatric patients under 18 years of age have not been established.Geriatric UseNo dose adjustment with Edarbi is necessary in elderly patients. Of the total patients in clinical studies with Edarbi, 26% were elderly (65 years of age and older); 5% were75 years of age and older. Abnormally high serum creatinine values were more likely to be reported for patients age 75 or older. No other differences in safety or effectiveness were observed between elderly patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out.Renal ImpairmentDose adjustment is not required in patients with mild-to-severe renal impairment or end-stage renal disease. Patients with moderate to severe renal impairment are more likely to report abnormally high serum creatinine values.Hepatic ImpairmentNo dose adjustment is necessary for subjects with mild or moderate hepatic impairment. Edarbi has not been studied in patients with severe hepatic impairment.OVERDOSAGELimited data are available related to overdosage in humans. During controlled clinical trials in healthy subjects, once daily doses up to 320 mg of Edarbi were administered for 7 days and were well tolerated. In the event of an overdose, supportive therapy should be instituted as dictated by the patient’s clinical status. Azilsartan is not dialyzable.CLINICAL PHARMACOLOGYMechanism of ActionAngiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzymes (ACE, kinase II). Angiotensin II is the principal pressor agent of the renin-angiotensin system, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation, and renal reabsorption of sodium. Azilsartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor in many tissues, such as vascular smooth muscle and the adrenal gland. Its action is, therefore, independent of the pathway for angiotensin II synthesis.

BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION for Edarbi(azilsartan medoxomil) tablets

WARNING: AVOID USE IN PREGNANCYWhen pregnancy is detected, discontinue Edarbi as soon as possible. Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.

INDICATIONS AND USAGEEdarbi is an angiotensin II receptor blocker (ARB) indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive agents.CONTRAINDICATIONSNoneWARNINGS AND PRECAUTIONSFetal/Neonatal Morbidity and MortalityDrugs that act directly on the renin-angiotensin system can cause fetal and neonatal morbidity and death when administered to pregnant women during the second and third trimester. When pregnancy is detected, Edarbi should be discontinued as soon as possible.The use of drugs that act directly on the renin-angiotensin system during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to exposure to the drug.These adverse effects do not appear to have resulted from intrauterine drug exposure that has been limited to the first trimester. Mothers whose embryos and fetuses are exposed to an angiotensin II receptor antagonist only during the first trimester should be so informed. Nonetheless, when patients become pregnant, physicians should have the patient discontinue the use of Edarbi as soon as possible.Rarely (probably less often than once in every thousand pregnancies), no alternative to a drug acting on the renin-angiotensin system is available. In these rare cases, the mother should be apprised of the potential hazards to the fetus and serial ultrasound examinations should be performed to assess the intra-amniotic environment.If oligohydramnios is observed, Edarbi should be discontinued unless it is considered life-saving for the mother. Contraction stress testing, a nonstress test or biophysical profiling may be appropriate, depending upon the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.Infants with histories of in utero exposure to an angiotensin II receptor antagonist should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as a means of reversing hypotension and/or substituting for impaired renal function.Hypotension in Volume- or Salt-Depleted PatientsIn patients with an activated renin-angiotensin system, such as volume- and/or salt-depleted patients (eg, those being treated with high doses of diuretics), symptomatic hypotension may occur after initiation of treatment with Edarbi. Correct volume or salt depletion prior to administration of Edarbi, or start treatment at 40 mg. If hypotension does occur, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized.Impaired Renal FunctionAs a consequence of inhibiting the renin-angiotensin system, changes in renal function may be anticipated in susceptible individuals treated with Edarbi. In patients whose renal function may depend on the activity of the renin-angiotensin system (e.g., patients with severe congestive heart failure, renal artery stenosis, or volume depletion), treatment with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers has been associated with oliguria or progressive azotemia and rarely with acute renal failure and death. Similar results may be anticipated in patients treated with Edarbi.In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen have been reported. There has been no long-term use of Edarbi in patients with unilateral or bilateral renal artery stenosis, but similar results may be expected.ADVERSE REACTIONSClinical Trials ExperienceBecause 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.A total of 4814 patients were evaluated for safety when treated with Edarbi at doses of 20, 40 or 80 mg in clinical trials. This includes 1704 patients treated for at least6 months; of these, 588 were treated for at least 1 year.Treatment with Edarbi was well-tolerated with an overall incidence of adverse reactions similar to placebo. The rate of withdrawals due to adverse events in placebo-controlled monotherapy and combination therapy trials was 2.4% (19/801) for placebo, 2.2% (24/1072) for Edarbi 40 mg, and 2.7% (29/1074) for Edarbi80 mg. The most common adverse event leading to discontinuation, hypotension/orthostatic hypotension, was reported by 0.4% (8/2146) patients randomized to Edarbi 40 mg or 80 mg compared to 0% (0/801) patients randomized to placebo.

An AT2 receptor is also found in many tissues, but this receptor is not known to be associated with cardiovascular homeostasis. Azilsartan has more than a 10,000-fold greater affinity for the AT1 receptor than for the AT2 receptor.Blockade of the renin-angiotensin system with ACE inhibitors, which inhibit the biosynthesis of angiotensin II from angiotensin I, is widely used in the treatment of hypertension. ACE inhibitors also inhibit the degradation of bradykinin, a reaction catalyzed by ACE. Because azilsartan does not inhibit ACE (kinase II), it should not affect bradykinin levels. Whether this difference has clinical relevance is not yet known. Azilsartan does not bind to or block other receptors or ion channels known to be important in cardiovascular regulation.Blockade of the angiotensin II receptor inhibits the negative regulatory feedback of angiotensin II on renin secretion, but the resulting increased plasma renin activity and angiotensin II circulating levels do not overcome the effect of azilsartan on blood pressure.PharmacodynamicsAzilsartan inhibits the pressor effects of an angiotensin II infusion in a dose-related manner. An azilsartan single dose equivalent to 32 mg azilsartan medoxomil inhibited the maximal pressor effect by approximately 90% at peak, and approximately 60% at 24 hours. Plasma angiotensin I and II concentrations and plasma renin activity increased while plasma aldosterone concentrations decreased after single and repeated administration of Edarbi to healthy subjects; no clinically significant effects on serum potassium or sodium were observed.Effect on Cardiac Repolarization: A thorough QT/QTc study was conducted to assess the potential of azilsartan to prolong the QT/QTc interval in healthy subjects. There was no evidence of QT/QTc prolongation at a dose of 320 mg of Edarbi.PharmacokineticsAbsorption: Azilsartan medoxomil is hydrolyzed to azilsartan, the active metabolite, in the gastrointestinal tract during absorption. Azilsartan medoxomil is not detected in plasma after oral administration. Dose proportionality in exposure was established for azilsartan in the azilsartan medoxomil dose range of 20 mg to 320 mg after single or multiple dosing.The estimated absolute bioavailability of azilsartan following administration of azilsartan medoxomil is approximately 60%. After oral administration of azilsartan medoxomil, peak plasma concentrations (Cmax) of azilsartan are reached within1.5 to 3 hours. Food does not affect the bioavailability of azilsartan.Distribution: The volume of distribution of azilsartan is approximately 16L. Azilsartan is highly bound to human plasma proteins (>99%), mainly serum albumin. Protein binding is constant at azilsartan plasma concentrations well above the range achieved with recommended doses.In rats, minimal azilsartan-associated radioactivity crossed the blood-brain barrier. Azilsartan passed across the placental barrier in pregnant rats and was distributed to the fetus.Metabolism and Elimination: Azilsartan is metabolized to two primary metabolites. The major metabolite in plasma is formed by O-dealkylation, referred to as metabolite M-II, and the minor metabolite is formed by decarboxylation, referred to as metabolite M-I. Systemic exposures to the major and minor metabolites in humans were approximately 50% and less than 1% of azilsartan, respectively. M-I and M-II do not contribute to the pharmacologic activity of Edarbi. The major enzyme responsible for azilsartan metabolism is CYP2C9.Following an oral dose of 14C-labeled azilsartan medoxomil, approximately55% of radioactivity was recovered in feces and approximately 42% in urine, with 15% of the dose excreted in urine as azilsartan. The elimination half-life of azilsartan is approximately 11 hours and renal clearance is approximately 2.3 mL/min. Steady-state levels of azilsartan are achieved within 5 days and no accumulation in plasma occurs with repeated once-daily dosing.Special PopulationsThe effect of demographic and functional factors on the pharmacokinetics of azilsartan was studied in single and multiple dose studies. Pharmacokinetic measures indicating the magnitude of the effect on azilsartan are presented in Figure 1 as change relative to reference (test/reference). Effects are modest and do not call for dosage adjustment.Figure 1 Impact of intrinsic factors on the pharmacokinetics of azilsartan

Population Description PK Fold Change and 90% CI Recommendation

No dose adjustment

No dose adjustment

No dose adjustment

No dose adjustment

No dose adjustment

No dose adjustment

No dose adjustment

No dose adjustment

No dose adjustment

NO EXPERIENCE

NO EXPERIENCE

0.5 1.0 1.5 2.0 2.5 3.0

Change relative to reference

CmaxAUC

CmaxAUC

CmaxAUC

CmaxAUC

CmaxAUC

CmaxAUC

CmaxAUC

CmaxAUC

CmaxAUC

AGE

>65y/18-45y

GENDER

Females/Males

RACE

Whites/Blacks

RENAL IMPAIRMENT

Mild/Normal

HEPATIC IMPAIRMENT

Mild/Normal

PEDIATRIC

Moderate/Normal

Severe/Normal

Moderate/Normal

Severe/Normal

ESRD/Normal

NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis: Azilsartan medoxomil was not carcinogenic when assessed in 26-week transgenic (Tg.rasH2) mouse and 2-year rat studies. The highest doses tested (450 mg azilsartan medoxomil/kg/day in the mouse and 600 mg azilsartan medoxomil/kg/day in the rat) produced exposures to azilsartan that are 12 (mice) and 27 (rats) times the average exposure to azilsartan in humans given the maximum recommended human dose (MRHD, 80 mg azilsartan medoxomil/day). M-II was not carcinogenic when assessed in 26-week Tg.rasH2 mouse and 2-year rat studies. The highest doses tested (approximately 8000 mg M-II/kg/day (males) and 11,000 mg M-II/kg/day (females) in the mouse and 1000 mg M-II/kg/day (males) and up to 3000 mg M-II/kg/day (females) in the rat) produced exposures that are, on average, about 30 (mice) and 7 (rats) times the average exposure to M-II in humans at the MRHD.Mutagenesis: Azilsartan medoxomil, azilsartan, and M-II were positive for structural aberrations in the Chinese Hamster Lung Cytogenetic Assay. In this assay, structural chromosomal aberrations were observed with the prodrug, azilsartan medoxomil, without metabolic activation. The active moiety, azilsartan was also positive in this assay both with and without metabolic activation. The major human metabolite, M-II was also positive in this assay during a 24 hr assay without metabolic activation.Azilsartan medoxomil, azilsartan, and M-II were devoid of genotoxic potential in the Ames reverse mutation assay with Salmonella typhimurium and Escherichia coli, the in vitro Chinese Hamster Ovary Cell forward mutation assay, the in vitro mouse lymphoma (tk) gene mutation test, the ex vivo unscheduled DNA synthesis test, and the in vivo mouse and/or rat bone marrow micronucleus assay.Impairment of Fertility: There was no effect of azilsartan medoxomil on the fertility of male or female rats at oral doses of up to 1000 mg azilsartan medoxomil/kg/day [6000 mg/m2 (approximately 122 times the MRHD of 80 mg azilsartan medoxomil/60 kg on a mg/m2 basis)]. Fertility of rats also was unaffected at doses of up to 3000 mg M-II/kg/day. Animal Toxicology and/or Pharmacology Reproductive Toxicology: In peri- and postnatal rat development studies, adverse effects on pup viability, delayed incisor eruption and dilatation of the renal pelvis along with hydronephrosis were seen when azilsartan medoxomil was administered to pregnant and nursing rats at 1.2 times the MRHD on a mg/m2 basis. Reproductive toxicity studies indicated that azilsartan medoxomil was not teratogenic when administered at oral doses up to 1000 mg azilsartan medoxomil/kg/day to pregnant rats (122 times the MRHD on a mg/m2 basis) or up to 50 mg azilsartan medoxomil/kg/day to pregnant rabbits (12 times the MRHD on a mg/m2 basis). M-II also was not teratogenic in rats or rabbits at doses up to 3000 mg M-II/kg/day. Azilsartan crossed the placenta and was found in the fetuses of pregnant rats and was excreted into the milk of lactating rats.PATIENT COUNSELING INFORMATIONSee FDA-approved patient labeling (Patient Information).General InformationPregnancy: Female patients of childbearing age should be told that use of drugs like Edarbi that act on the renin-angiotensin system during pregnancy can cause serious problems in the fetus and infant including low blood pressure, poor development of skull bones, kidney failure, and death. These consequences do not appear to have resulted from intrauterine drug exposure that has been limited to the first trimester. Discuss other treatment options with female patients planning to become pregnant. Women using Edarbi who become pregnant should notify their physicians as soon as possible.Distributed byTakeda Pharmaceuticals America, Inc.Deerfield, IL 60015Edarbi is a trademark of Takeda Pharmaceutical Company Limited registered with the U.S. Patent and Trademark Office and used under license by Takeda Pharmaceuticals America, Inc.©2011 Takeda Pharmaceuticals America, Inc.For more detailed information, see the full prescribing information for Edarbi at www.edarbi.com or contact Takeda Pharmaceuticals America, Inc. at 1-877-825-3327.AZL074 R1; February 2011 L-LXA-0211-2



American Health & Drug Benefits, ISSN1942-2962 (print); ISSN 1942-2970(online), is published 6 times a year byEngage Healthcare Communications,LLC, 241 Forsgate Drive, Suite 205A,Monroe Township, NJ 08831. Copyright© 2011 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.

Address all editorial correspondence to: [email protected] Telephone: 732-992-1892 Fax: 732-992-1881 American Health & Drug Benefits241 Forsgate Drive, Suite 205A Monroe Township, NJ 08831

The ideas and opinions expressed inAmerican Health & Drug Benefits do notnecessarily reflect those of the EditorialBoard, the Editors, or the Publisher.Publication of an advertisement or otherproduct mentioned in American Health &Drug Benefits should not be construed asan endorsement of the product or themanufacturer’s claims. Readers areencouraged to contact the manufacturersabout any features or limitations of prod-ucts mentioned. Neither the Editors northe Publisher assume any responsibilityfor any injury and/or damage to personsor property arising out of or related to anyuse of the material mentioned in thispublication.

For permission to reuse material fromAmerican Health & Drug Benefits(ISSN 1942-2962), please access www.copyright.com <http://www.copyright.com/> or contact the Copyright ClearanceCenter, Inc. (CCC), 222 Rosewood Drive,Danvers, MA 01923, 978-750-8400.

™ ™

CLINICAL

107 Strategies to Prevent Opioid Misuse, Abuse, and Diversion That May Also Reduce the Associated CostsKathryn L. Hahn, PharmD, DAAPM, CPE

113 Stakeholder Perspective by Atheer A. Kaddis, PharmD

DEPARTMENTS

118 GENERIC DRUG TRENDS

New Economic Analysis Zeroes in on Low Generic Utilization and Waste in MedicaidDalia Buffery, MA, ABD

INDUSTRY TRENDS

120 CMS Invites Feedback on the Proposed Accountable Care Organizations Rules

122 The Patient-Centered Medical Home: An Essential Destination on the Road to ReformMatt Adamson

CAPTION CONTEST

TABLE OF CONTENTS (Continued)



100

POSTMASTER: CORRESPONDENCE REGARDING SUBSCRIPTIONS OR CHANGE OF ADDRESSshould be directed to CIRCULATION DIRECTOR, American Health & Drug Benefits, 241 Forsgate Drive,Suite 205A, Monroe Township, NJ 08831. Fax: 732-992-1881. YEARLY SUBSCRIPTION RATES: One year:$99.00 USD; Two years: $149.00 USD; Three years: $199.00 USD.

References: 1. Plantinga LC, Crews DC, Coresh J, et al; for the CDC CKD Surveillance Team. Prevalence of chronic kidney disease in US adults with undiagnosed diabetes or prediabetes. Clin J Am Soc Nephrol. 2010;5(4):673-682. 2. Parving H-H, Lewis JB, Ravid M, Remuzzi G, Hunsicker LG; for the DEMAND Investigators. Prevalence and risk factors for microalbuminuria in a referred cohort of type II diabetic patients: a global perspective. Kidney Int. 2006;69:2057-2063. 3. Zhang X, Saaddine JB, Chou C-F, et al. Prevalence of diabetic retinopathy in the United States, 2005-2008. JAMA. 2010;304(6):649-656. 4. Gregg EW, Gu Q, Williams D, et al. Prevalence of lower extremity diseases associated with normal glucose levels, impaired fasting glucose, and diabetes among U.S. adults aged 40 or older. Diabetes Res Clin Pract. 2007;77(3):485-488. 5. National Kidney Foundation. KDOQI clinical practice guidelines and clinical practice recommendations for diabetes and chronic kidney disease. Am J Kidney Dis. 2007;49(2 suppl 2):S1-S179. 6. American Diabetes Association. Nephropathy in diabetes. Diabetes Care. 2004;27(suppl 1):S79-S83. 7. Mogensen CE, Poulsen PL. Microalbuminuria, glycemic control, and blood pressure predicting outcome in diabetes type 1 and type 2. Kidney Int. 2004;66(suppl 92):S-40–S-41.

Renal impairment is the leading microvascular complication associated with type 2 diabetes (over 40%), followed by retinopathy (28.5%) and neuropathy (19.4%)— it is important to recognize these complications as soon as possible1-4

According to the National Kidney Foundation, diabetes and renal impairment are considerably underdiagnosed, which may lead to disease progression because of missed opportunities to provide appropriate care for patients with these conditions5

Microalbuminuria (albumin in the urine 30 mg/day or 20 µg/min) is the earliest clinical evidence of renal disease6

Patients with renal impairment may have poor glycemic control (A1C 7%), may have hypertension (BP 130/80 mm Hg), and may have dyslipidemia as well as other comorbidities 5,7

THERE COULD BE DANGER BELOW

Copyright ©2011, Boehringer Ingelheim Pharmaceuticals, Inc. All rights reserved. (1/11) DI88043PROF ExploringDiabetes.com

It’s important to recognize microvascular complications in patients with type 2 diabetes as early as possible. Microalbuminuria is the earliest sign of renal disease, the leading microvascular complication, in type 2 diabetes.

4:25:08 PM

REGULATORY


As stakeholders continue to strive for greater valuein the US healthcare system, many are calling formore research to inform treatment decisions, par-

ticularly for providers and patients choosing betweenavailable multiple interventions. This charge has helpedto ignite interest in comparative effectiveness research(CER), which aims to provide evidence on the effective-ness, benefits, and harms of competing treatment optionsfor a clinical condition. As a growing purchaser of health-care and a provider of public goods, the federal govern-ment has expanded its role in recent years, makingincreasingly significant investments in CER. With healthcare costs outpacing inflation year after

year, the policy community has been more attuned toways of controlling spending, and one popular targethas been the elimination of “wasteful” or unnecessarycare. At best, CER is seen as a potential way to identifythis excess, while simultaneously providing betterinformation for decision makers at the point of care. Atworst, CER is seen as a way for the government andpayers to rationalize cost-cutting, undermining theautonomy of providers, and limiting patient choice.

CER may even hinder innovation by increasing thecost of drug development and failing to recognize thetrue value of incremental product improvements. The research expansion will have important impli-

cations for the insurance and life sciences industries; inparticular, CER has the potential to stimulate innova-tion in healthcare. In fact, we already see 2 significantchanges in the commercial areas of the healthcare sys-tem. First, payers are using research findings on com-peting treatments to deploy innovative payment meth-ods, such as tiering and bundling, across a wider rangeof therapeutic areas. Second, drug manufacturers areanticipating payment changes, shifting their commer-cialization strategies to create novel and better-differ-entiated medications. Although the gradual marketadjustment to these new realities may bring some near-term difficulties across the healthcare system, and theirrobust application is not a foregone conclusion, anincrease in CER may help to create a more efficient,innovative system in the future.

The State of Comparative Effectiveness Research For much of the past 3 decades, US investment in

CER has been driven by myriad organizations in thepublic and private arenas, all of which pursued inde-pendently derived research agendas. These organizationsinclude the BlueCross BlueShield Technology Evalua -

Mr Ali is Director, Ms Hanger is Manager, and Dr Carino isSenior Vice President, Avalere Health, Washington, DC.Avalere Health’s core purpose is to create innovative solutionsto complex healthcare problems (www.avalerehealth.net).

PERSPECTIVE

Comparative Effectiveness Research inthe United States: A Catalyst for InnovationRiaz Ali, MPP; Morgan Hanger, MPP; Tanisha Carino, PhD

Recent calls for value in the US healthcare system have spurred an increase in com-parative effectiveness research, which generates evidence on competing treatmentoptions to inform healthcare stakeholders. As a large healthcare purchaser, the fed-eral government has made several significant investments in comparative effective-ness research. Notably, in 2009 the American Recovery and Reinvestment Act allo-cated $1.1 billion for comparative effectiveness research, and in 2010 the PatientProtection and Affordable Care Act established a federal institute to organize thefederal investment in comparative effectiveness research going forward. Over thepast several years, comparative effectiveness research from the public and privatesectors has begun to provide a foundation for innovation within the insurance andlife sciences industries. Health plans and other payers are experimenting withnuanced coverage and reimbursement policies informed by comparative effective-ness evidence. Anticipating changes in payer, patient, and provider behaviors, drugmanufacturers are refocusing their efforts on the development of novel and better-differentiated medications. As more comparative research becomes available in thefuture, continued innovation in payer and manufacturer strategies appears likely.

Am Health Drug Benefits.2011;4(2):68-72.www.AHDBonline.com

Disclosures are at end of text

Morgan Hanger Tanisha Carino

Comparative Effectiveness Research in the United States


tion Center, the Cochrane Collaboration, and the DrugEffectiveness Review Project, among others. Govern -ment organizations, such as the Agency for HealthcareResearch and Quality (AHRQ) and the NationalInstitutes of Health historically had dedicated a portionof their funding to CER, but did not influence the direc-tion of the US investment overall. As part of the effortin 2003 to expand Medicare coverage for prescriptiondrugs, the federal government made its first explicitinvestment in CER, allocating up to $50 million toAHRQ’s Effective Health Care Program for “the out-comes, comparative clinical effectiveness, and appropri-ateness of health care items and services (including pre-scription drugs); and strategies for improving theefficiency and effectiveness of such programs.”1While CER was gaining momentum, some policy-

makers and thought leaders were seeing missed opportu-nities. The fragmented CER investment was reflectingthe priorities of the entities asking the questions, andfocused on a narrow set of topics; this left importantareas of inquiry unaddressed. Existing incentives, how-ever, provided little motivation for researchers to fillthese research gaps. Furthermore, the model for deter-mining research priorities lacked the necessary partici-pant and stakeholder engagement to ensure thatresearch focused on the most clinically relevant ques-tions. Given these obstacles, many saw a role for thefederal government in providing leadership and fundingto optimize CER in the United States. Over the past 2 years, the federal government has

taken significant strides to fill this role. In 2009, theAmerican Recovery and Reinvestment Act (ARRA)allocated $1.1 billion for 2 years of research.2 In 2010,the Patient Protection and Affordable Care Act estab-lished a permanent US CER entity called the Patient-Centered Outcomes Research Institute (PCORI) toguide the federal CER enterprise. The law appropriates$1.26 billion to this public–private, stakeholder-gov-erned institute from 2010 to 2019,3 with a mandatoryfee on health plans and Medicare beneficiaries aug-menting the budget beginning in 2013. Given thatPCORI’s central function is to organize and coordinatethe federal CER investment, the model for determiningresearch priorities is at the cusp of a transformation.PCORI has already appointed a methodology commit-tee to establish research standards, and it plans torelease CER priorities later in 2011.

Federal Investment as a Marker of CER DemandTo understand the potential impact of recent federal

CER efforts, it is important to examine how the federalinvestment has been deployed. The largest part of theARRA CER awards—46%—supports projects to devel-

op more sophisticated research infrastructures andmethodologies.4 Infrastructure building includes activi-ties such as linking patient registries and adapting exist-ing data sources so that they can be used for CER.Although in the past there has been an imperative todemonstrate the immediate value of CER to policymak-ers and taxpayers, ARRA’s investment in infrastructureshows the intention to construct a more sustainedresearch program. The next largest ARRA commitment to CER—38%

of awards—supports new evidence development, primar -ily through observational trials and evidence synthesis.4Approximately 27% of these awards (or 10% of ARRAawards overall) focus on generating new evidence onpharmaceuticals. The remaining 16% of the overallARRA CER investment supports the dissemination andtranslation of evidence.4 This type of award includes thecreation of multilingual reports for subpopulations at ele-vated risk for specific diseases, among other projects. The Figure displays the 422 research grants and con-

tracts funded through ARRA, by therapeutic area. Alarge proportion of awards—41%—did not have a dis-ease focus; this includes a number of infrastructure devel-opment awards, as well as studies on healthcare deliverysystem interventions, such as accountable care organiza-tions and the medical home.4 Not surprisingly, amongawards with a therapeutic focus, many concern high-costor high-incidence diseases. Cardiovascular and oncology

KEY POINTS

� The intensifying focus on value in healthcare hashelped to fuel public and private sector interest incomparative effectiveness research (CER), whichprovides evidence on the effectiveness, benefits, andharms of competing treatment options for a clinicalcondition.

�� In 2009, the American Recovery and ReinvestmentAct allocated $1.1 billion for 2 years of CER, and in2010, the Patient Protection and Affordable CareAct established a permanent entity, the Patient-Centered Outcomes Research Institute, to organizefederally funded CER going forward.

� Concurrent with the increase in federal funding forCER, health plans and other payers are becomingmore sophisticated, data-driven organizations.

� Recognizing changes in their customer base, drugmanufacturers are beginning to reexamine theirproduct development strategies. Increasinglystringent payer standards for value are likely toencourage the development of more innovativemedications.

REGULATORY


research received the highest number of awards, whichtotaled $121 million and $124 million, respectively.4Although it is not yet clear whether the ARRA

investment will lead to the creation of meaningful toolsand resources for CER, the considerable focus on infra-structure is cause for optimism. The material questionnow is how well PCORI can build on the progress madeunder ARRA as it identifies, funds, and pursues its ownCER priorities.

Health Plans’ Business Models Build on CER Demand The federal government is one marker of the state of

CER in the United States, but it is not the only one.Health plans and other payers are important stakehold-ers and contributors in the US CER marketplace. Todaywe see 2 main manifestations of this. First, recognizingthe possible applications of CER, the commercial sectoris growing its data and analytic expertise. Second, plansare making a concerted effort to creatively leverage find-

ings (internally or externally generated) to inform theirdecisions. Taken together, these changes demonstratethe transformation of health plans and pharmacy benefitmanagers (PBMs) from risk intermediaries to moresophisticated, data-driven organizations.

Positioning Research Expertise as a Commercial AssetEarly signals of this movement date back a decade or

more, with UnitedHealth’s founding of Ingenix in 19965and WellPoint’s acquisition of HealthCore in 2003.6Both deals marked a first step toward a more research-oriented business model. More recently, in fall 2010, thePBM Medco acquired United BioSource Corporation(UBC), a global scientific and medical affairs organiza-tion, to enhance and expand its own research capabili-ties. Not surprisingly, when discussing this with theinvestor community, Medco CEO David B. Snow, Jr.,positioned CER as a healthcare reform opportunity and

Figure ARRA CER Investment by Therapeutic Area (Avalere EBM Navigator)

Neurologic disorders 2%

ARRA indicates American Recovery and Reinvestment Act; CER, comparative effectiveness research; EBM,evidence-based medicine.Courtesy of Avalere.

Other 7%

Not specified 41%

Cardiovascular andperipheral disease

13%

“Not specified”includes infrastruc-ture developmentand evidence trans-lation/disseminationawards without atherapeutic focus; italso includesawards focused onthe healthcaredelivery system

Oncology andhematology

10%

Endocrinology, metabolic disorders, and geriatrics

5%

Psychiatric disorders 5%

Alcoholism, drugdependency, and

overdose 3%

Infectious diseases and biliary tract disorders

3%

Women’s health 3%

Respiratory diseases 3%

Kidney and urinary tract disorders3%

Immune system, connective tissue, and joint disorders

2%

N = 422 research grants

Comparative Effectiveness Research in the United States


the acquisition of UBC as a component of the corporategrowth strategy.7Another marker of an evolving business model is the

increased partnership between health plans and the fed-eral government. For instance, the US Food and DrugAdministration’s (FDA’s) Sentinel Initiative, launchedafter the passage of the FDA Amendments Act in 2007,is an active drug surveillance system and includes partic-ipation from a wide range of organizations, such asAmerica’s Health Insurance Plans, Humana, HealthCore,and Kaiser Permanente Center for Effectiveness andSafety Research.8 An additional example is the contractthat the Department of Health and Human Servicesawarded to Ingenix Public Sector Solutions in 2010 tobuild a multipayer claims database for CER.9

Expanding the Use of CER in Decision-MakingThe second part of the equation is how health plans

and payers are translating the demand for CER intomeaningful healthcare purchasing decisions. A fewrecent examples illustrate potential uses:• Creation of clearer standards for evidence use. InMay 2010, WellPoint became the first health benefitscompany to release CER guidelines, making moretransparent its evaluation process for coverage andreimbursement decisions.10 This effort to explicitlystandardize the data that informs decisions signalsWellPoint’s plan to use more diverse evidence infuture decisions.

• Innovative payment methods to incentivize effic -iency. Last fall, UnitedHealth Group announced anew cancer payment model aimed at improving thequality of care for patients with breast, colon, andlung cancers.11 Under the pilot, an oncologist will bepaid a flat fee based on the wholesale price of a prede-termined drug regimen for a patient, plus a case man-agement fee. Although other services will continue tobe reimbursed on a fee-for-service basis, this paymentchange will encourage physicians to select appropri-ate products and apply them as efficiently as possible.The pilot represents a much different way to pay forcare. By considering all services, including medicaland pharmacy, as part of a single bundle, payers andclinicians are compelled to more explicitly assess thevalue of each available component of care.

• CER-infused Medicare coverage policy. In January2011, Medicare carrier Palmetto GBA announced itsintent to drop coverage of bevacizumab (Avastin) formetastatic breast cancer.12 Palmetto GBA’s statementfollowed an FDA recommendation in December2010 to remove this indication from bevacizumab’slabel. The FDA had granted accelerated approval forAvastin for metastatic breast cancer in 2008, after

promising but uncertain early results; however, in 2subsequent randomized controlled trials comparingtreatment regimens with and without bevacizumab(which the FDA required of the manufacturer), theFDA found that the drug did not perform well.13This led the agency to modify its earlier position onbevacizumab’s net benefit in patients with metastaticbreast cancer. Although Palmetto GBA has rescindedthe policy change while the FDA’s recommendationis under appeal (by the manufacturer), their initialactions, as well as the assurance that they “will con-tinue to review relevant clinical trials results and lit-erature addressing the effectiveness of Avastin in thetreatment of breast cancer,”14 illustrate payer interestin leveraging CER findings for coverage decisions.

Innovation in the Life Sciences IndustryIn response to the wider availability and broader

payer use of effectiveness data, manufacturers are alsobeginning to shift gears, modifying their approach tocommercialization. Although this is an evolving process,so far we have seen the following 3 clear ways that drugmanufacturers are adapting.

Reassessing Drug Development andCommercialization Strategy Externally generated CER may expose drugs to head-

to-head comparisons and class reviews; commercial suc-cess in a crowded or partially generic class has becomeharder to achieve than it was 10 or 20 years ago. In thisway, CER encourages 2 modifications in the traditionalprocesses for development and commercialization. The first involves the compounds and assets devel-

oped. With increasing challenges to commercial successin certain drug classes and therapeutic areas, manufac-turers are recognizing the need to invest in more targetedmedications focused on subpopulations (be they demo-graphic, genetic, or otherwise defined). The second shift, which is structural and operational,

is that drug manufacturers are seeking product differen-tiation earlier in the development pipeline. This is notsurprising, because many industry leaders have acknowl-edged for some time the need to adjust course.Comments dating as far back as 2006 reflect clearunderstanding that the pharmaceutical business modelis at a crossroad.

Reimagining Their Customer BaseAnother change we are seeing is in the way manufac-

turers are engaging their customers. As payers becomesavvier, drug manufacturers are turning more of theirenergy toward satisfying evidentiary requirements, andfocusing less on their traditional customer base—physi-

REGULATORY


cians and patients. A recent article on drug developmentsummarized this change, suggesting that “physicianshave been demoted from key decision-maker to stake-holder, while payers have gone from stakeholder to keydecision-maker.”15In line with this shift, AstraZeneca recently

announced a collaboration with WellPoint to conductreal-world CER studies using a range of electronic healthdata.16 With a focus on chronic conditions, their goal isto maximize value by identifying and encouraging themost efficient use of medications. Although it presents ameaningful risk to AstraZeneca brands (because theymay not always fare well in the research), this uniquepartnership acknowledges the need for drug manufactur-ers to work with payers to meet their increasingly strin-gent effectiveness standards.

Transform and Redeploy Clinical ResearchExpertiseFor some companies, there are more seismic changes

afoot, which may lead to a very different pharmaceuticalsector. For example, Pfizer recently announced its plansto close its research facility in Kent, England. This movewas part of an effort to refocus its research and develop-ment program, shifting away from urology and internalmedicine to maintain or expand focus in immunology,oncology, neuroscience, and inflammation.17 Pfizer CEOIan Read explained, “We continue to closely evaluateour global research and development function and willaccelerate our current strategies to improve innovationand overall productivity.”18 In other words, industry lead-ers are responding to the greater demand for differentkinds of scientific evidence with significant structuraland organizational changes.

ConclusionThe rise in CER is encouraging interesting and

important changes across the healthcare sector. The fed-eral CER investment is but one indicator of the demandfor more comparative evidence. The private sector hasalso begun to focus more on CER-generation, suggestingthat regardless of the direction of government funding,the marketplace is actively seeking inventive ways tocreate and apply this evidence. With more data avail-able, payers are experimenting with coverage and reim-bursement policies that promote the use of high-valueproducts. In turn, manufacturers have begun to rethinkways of developing products that meet payers’ high stan-dards for value.The cumulative effect of this increase in CER may

not be fully understood for some time. However, the

business environment is already changing as various par-ticipants find their role and support their value proposi-tion. For interested parties, there is a great deal of oppor-tunity to help shape the way scientific evidence is usedin healthcare decision-making in the future. �

Author Disclosure StatementMr Ali, Ms Hanger, and Dr Carino have reported no

conflicts of interest.

References1. H.R.1.ENR. Medicare Prescription Drug, Improvement, and Modernization Actof 2003. http://thomas.loc.gov/cgi-bin/query/z?c108:H.R.1.ENR:. 108th Congress(2003-2004). Accessed February 22, 2011. 2. H.R.1.ENR. American Recovery and Reinvestment Act of 2009.http://thomas.loc.gov/cgi-bin/query/D?c111:364:./temp/~c111Qob9RQ::. AccessedMarch 21, 2011. 3. H.R.3590.ENR. Patient Protection and Affordable Care Act. 2010.http://thomas.loc.gov/cgi-bin/query/D?c111:127:./temp/~c111vmT49M::. AccessedMarch 21, 2011.4. Avalere Health. EBM navigator. http://ebm.avalerehealth.net. Updated February10, 2011. Accessed February 10, 2011.5. Ingenix. The Ingenix era of collaboration. www.ingenix.com/about/history/.Accessed February 22, 2011. 6. WellPoint Health Networks. WellPoint acquires Health Core Inc. Press release.http://phx.corporate-ir.net/phoenix.zhtml?c=130104&p=irol-newsArticle_general&t=Regular&id=736587&. Accessed February 22, 2011.7. Snow DB, Jr. Medco: the next decade. Presented at the 29th Annual J.P. MorganHealthcare Conference; January 10, 2011. http://google.brand.edgar-online.com/EFX_dll/EDGARpro.dll?FetchFilingHtmlSection1?SectionID=7649149-6883-43469&SessionID=VC_WHC33MvZ9u47. Accessed February 22, 2011.8. Mini-Sentinel. Collaborators. http://mini-sentinel.org/about_us/collaborators.aspx. Accessed February 22, 2011.9. Centers for Medicare & Medicaid Services. Recovery-Multi-Payor ClaimsDatabase. 2010. www.fbo.gov/index?s=opportunity&mode=form&tab=core&id=853906cbdf5be4a8df46f7cb900a3270. Updated September 14, 2010. AccessedFebruary 22, 2011.10.WellPoint. WellPoint is first health benefits company to release CER guidelinesfor use in evaluating pharmaceuticals. WellPoint website. May 20, 2009. www.wellpoint.com/pdf/CERGuidelines.pdf. Accessed March 21, 2011.11. UnitedHealthcare. New UnitedHealthcare cancer care payment model to focuson best treatment practices and better health outcomes. News release. www.uhc.com/news_room/2010_news_release_archive/new_unitedhealthcare_cancer_care_payment_model/relatedinformation/9c7afaf31c9cb210VgnVCM1000002f10b10a____.htm. Updated October 20, 2010. Accessed February 9, 2011.12. Pollack A. Medicare contractor will pay for Avastin during appeal. New YorkTimes. January 7, 2011. http://prescriptions.blogs.nytimes.com/2011/01/07/medicare-contractor-will-pay-for-avastin-during-appeal/. Accessed March 21, 2011. 13. Pazdur R, for the FDA Center for Drug Evaluation and Research. Memorandumto the file BLA 125085 Avastin (bevacizumab). December 15, 2010. www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM237171.pdf. Accessed March 21, 2011.14. Palmetto GBA. Ohio part B carrier Avastin notice. January 7, 2011. www.palmettogba.com/palmetto/providers.nsf/docsCat/Providers~Ohio%20Part%20B%20Carrier~Browse%20by%20Specialty~Oncology%20Hematology~Avastin%20Notice?open. Accessed March 21, 2011.15. Longman R. Sex, payers & product development. The RPM Rep. 2011;4.16. Levine DS. AstraZeneca/WellPoint explore comparative effectiveness in effort tocombat generics. Seeking Alpha. February 6, 2011. http://seekingalpha.com/article/251041-astrazeneca-wellpoint-explore-comparative-effectiveness-in-effort-to-combat-generics. Accessed February 15, 2011. 17. Carroll J. Pfizer carving $1.5B from R&D budget, dropping diseases. FierceBiotech. www.fiercebiotech.com/story/pfizer-carving-15b-rd-budget-dropping-diseases/2011-02-01?utm_medium=nl&utm_source=internal. February 1, 2011. AccessedFebruary 15, 2011.18. Pfizer reports fourth-quarter and full-year 2010 results; provides 2011 financialguidance and updates 2012 financial targets. February 1, 2011. www.pfizer.com/files/investors/presentations/q4performance_020111.pdf. Accessed February 15, 2011.

70%‡

45%40%

N=1258 N=757 N=1260

75

50

25

0

0%‡

45%40%%

70

6–12 months100

ULORIC 80 mg

ULORIC 40 mg

Allopurinol300 mg†

ULORIC is a trademark of Teijin Pharma Limited registered with the U.S. Patent and Trademark Offi ce and used under license by Takeda Pharmaceuticals America, Inc. ©2010 Takeda Pharmaceuticals North America, Inc. TXF-00873 07/10

For more information, please visit www.ULORIC.com

ULORIC powerfully lowers serum uric acid levels for the long-term control of goutLong-term control of hyperuricemia to a serum uric acid level of <6 mg/dL is the key to managing gout1

SUPERIOR EFFICACY OF ULORIC 80 MG PROVEN IN HEAD-TO-HEAD STUDIES1,2

ULORIC 40 mg effectively lowered serum uric acid • similar to allopurinol1

ULORIC 80 mg was superior to allopurinol at lowering • serum uric acid1

* Based on results combined across three phase 3 studies; ULORIC 40 mg was only included in one of the studies, and ULORIC 80 mg and allopurinol were included in each of the studies.

† In APEX, allopurinol patients (n=10) with serum creatinine >1.5 mg/dL and ≤2 mg/dL were dosed at 100 mg daily. In CONFIRMS, allopurinol patients (n=145) with estimated Clcr ≥30 mL/min and Clcr ≤59 mL/min were dosed at 200 mg daily. All other patients received 300 mg daily.

‡ p<0.001 vs allopurinol.

References: 1. ULORIC® (febuxostat) full prescribing information, February 2009. 2. Data on fi le, Takeda Pharmaceuticals North America, Inc.

Proportion of p

atients with a serum

uric acid

level of <6 m

g/d

L at the fi nal visit*

IndicationULORIC is a xanthine oxidase (XO) inhibitor indicated for the chronic management of hyperuricemia in patients with gout. ULORIC is not recommended for the treatment of asymptomatic hyperuricemia.

Important Safety InformationULORIC is contraindicated in patients being treated with azathioprine, • mercaptopurine, or theophylline.

• An increase in gout fl ares is frequently observed during initiation of anti-hyperuricemic agents, including ULORIC. If a gout fl are occurs during treatment, ULORIC need not be discontinued. Prophylactic therapy (i.e. - NSAIDs or colchicine) upon initiation of treatment may be benefi cial for up to six months.Cardiovascular Events• : In randomized controlled studies, there was a higher rate of cardiovascular thromboembolic events (cardiovascular deaths, non-fatal myocardial infarctions, and non-fatal strokes) in patients treated with ULORIC [0.74 per 100 P-Y (95% CI 0.36-1.37)] than allopurinol [0.60 per 100 P-Y (95% CI 0.16-1.53)]. A causal relationship with ULORIC has not been established. Monitor for signs and symptoms of MI and stroke.

• Liver Enzyme Elevations: In randomized controlled studies, transaminase elevations greater than 3 times the upper limit of normal (ULN) were observed (AST: 2%, 2%, and ALT: 3%, 2% in ULORIC and allopurinol-treated patients, respectively). No dose-effect relationship for these transaminase elevations was noted. Laboratory assessment of liver function is recommended at, for example, 2 and 4 months following initiation of ULORIC and periodically thereafter.Adverse reactions occurring in at least 1% of ULORIC-treated patients, and, • at least 0.5% greater than placebo, are liver function abnormalities, nausea, arthralgia, and rash.

Individual results may vary based on factors such as baseline serum uric acid levels.Please see brief summary of complete Prescribing Information on adjacent pages.

BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION for ULORIC® (febuxostat) tabletsINDICATIONS AND USAGEULORIC® is a xanthine oxidase (XO) inhibitor indicated for the chronic management of hyperuricemia in patients with gout.

ULORIC is not recommended for the treatment of asymptomatic hyperuricemia.

CONTRAINDICATIONSULORIC is contraindicated in patients being treated with azathioprine, mercapto-purine, or theophylline [see Drug Interactions]. WARNINGS AND PRECAUTIONSGout FlareAfter initiation of ULORIC, an increase in gout flares is frequently observed. This increase is due to reduction in serum uric acid levels resulting in mobilization of urate from tissue deposits.

In order to prevent gout flares when ULORIC is initiated, concurrent prophylactic treatment with an NSAID or colchicine is recommended.

Cardiovascular Events In the randomized controlled studies, there was a higher rate of cardiovascular thrombo embolic events (cardiovascular deaths, non-fatal myocardial infarctions, and non-fatal strokes) in patients treated with ULORIC [0.74 per 100 P-Y (95% CI 0.36-1.37)] than allopurinol [0.60 per 100 P-Y (95% CI 0.16-1.53)] [see Adverse Reactions]. A causal relationship with ULORIC has not been established. Monitor for signs and symptoms of myocardial infarction (MI) and stroke.

Liver Enzyme Elevations During randomized controlled studies, transaminase elevations greater than 3 times the upper limit of normal (ULN) were observed (AST: 2%, 2%, and ALT: 3%, 2% in ULORIC and allopurinol-treated patients, respectively). No dose-effect relationship for these transaminase elevations was noted. Laboratory assessment of liver function is recommended at, for example, 2 and 4 months following initiation of ULORIC and periodically thereafter.

ADVERSE REACTIONSClinical Trials ExperienceBecause 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.

A total of 2757 subjects with hyperuricemia and gout were treated with ULORIC 40 mg or 80 mg daily in clinical studies. For ULORIC 40 mg, 559 patients were treated for 6 months. For ULORIC 80 mg, 1377 subjects were treated for

6 months, 674 patients were treated for 1 year and 515 patients were treated for 2 years.

Most Common Adverse ReactionsIn three randomized, controlled clinical studies (Studies 1, 2 and 3), which were 6 to 12 months in duration, the following adverse reactions were reported by the treating physician as related to study drug. Table 1 summarizes adverse reactions reported at a rate of at least 1% in ULORIC treatment groups and at least 0.5% greater than placebo.

Table 1: Adverse Reactions Occurring in 1% of ULORIC-Treated Patients and at Least 0.5% Greater than Seen in Patients

Receiving Placebo in Controlled Studies

Adverse Reactions

Placebo ULORIC allopurinol*

(N=134)

40 mg daily

(N=757)

80 mg daily

(N=1279) (N=1277)Liver Function Abnormalities 0.7% 6.6% 4.6% 4.2%

Nausea 0.7% 1.1% 1.3% 0.8%

Arthralgia 0% 1.1% 0.7% 0.7%

Rash 0.7% 0.5% 1.6% 1.6%

* Of the subjects who received allopurinol, 10 received 100 mg, 145 received 200 mg, and 1122 received 300 mg, based on level of renal impairment.

The most common adverse reaction leading to discontinuation from therapy was liver function abnormalities in 1.8% of ULORIC 40 mg, 1.2% of ULORIC 80 mg, and in 0.9% of allopurinol-treated subjects.

In addition to the adverse reactions presented in Table 1, dizziness was reported in more than 1% of ULORIC-treated subjects although not at a rate more than 0.5% greater than placebo.

Less Common Adverse ReactionsIn phase 2 and 3 clinical studies the following adverse reactions occurred in less than 1% of subjects and in more than one subject treated with doses ranging from 40 mg to 240 mg of ULORIC. This list also includes adverse reactions (less than 1% of subjects) associated with organ systems from Warnings and Precautions.

Blood and Lymphatic System Disorders: anemia, idiopathic thrombocytopenic purpura, leukocytosis/leukopenia, neutropenia, pancytopenia, splenomegaly, throm bo cytopenia; Cardiac Disorders: angina pectoris, atrial fibrillation/flutter, cardiac murmur, ECG abnormal, palpitations, sinus bradycardia, tachycardia; Ear and Labyrinth Disorders: deafness, tinnitus, vertigo; Eye Disorders: vision blurred; Gastrointestinal Disorders: abdominal distention, abdominal pain, constipation, dry mouth, dyspepsia, flatulence, frequent stools, gastritis, gastro esophageal reflux disease, gastrointestinal discomfort, gingival pain, haematemesis, hyperchlorhydria, hematochezia, mouth ulceration, pancreatitis, peptic ulcer, vomiting; General Disorders and Administration Site Conditions: asthenia, chest pain/discomfort, edema, fatigue, feeling abnormal, gait disturbance, influenza-like symptoms, mass, pain, thirst; Hepatobiliary Disorders: cholelithiasis/cholecystitis, hepatic steatosis, hepatitis, hepatomegaly; Immune System Disorder: hypersensitivity; Infections and Infestations: herpes zoster; Procedural Complications: contusion; Metabolism and Nutrition Disorders: anorexia, appetite decreased/increased, dehydration, diabetes mellitus, hyper-cholesterolemia, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypokalemia, weight decreased/increased; Musculoskeletal and Connective Tissue Disorders: arthritis, joint stiffness, joint swelling, muscle spasms/twitching/tightness/weakness, musculoskeletal pain/stiffness, myalgia; Nervous System Disorders: altered taste, balance disorder, cerebrovascular accident, Guillain-Barré syndrome, headache, hemiparesis, hypoesthesia, hyposmia, lacunar infarction, lethargy, mental impairment, migraine, paresthesia, somnolence, transient ischemic attack, tremor; Psychiatric Disorders: agitation, anxiety, depression, insomnia, irritability, libido decreased, nervousness, panic attack, personality change; Renal and Urinary Disorders: hematuria, nephrolithiasis, pollakiuria, proteinuria, renal failure, renal insufficiency, urgency, incontinence; Reproductive System and Breast Changes: breast pain, erectile dysfunction, gynecomastia; Respiratory, Thoracic and Mediastinal Disorders: bronchitis, cough, dyspnea, epistaxis, nasal dryness, paranasal sinus hypersecretion, pharyngeal edema, respiratory tract congestion, sneezing, throat irritation, upper respiratory tract infection; Skin and Subcutaneous Tissue Disorders: alopecia, angio edema, dermatitis, dermographism, ecchymosis, eczema, hair color changes, hair growth abnormal, hyperhidrosis, peeling skin, petechiae, photosensitivity, pruritus, purpura, skin discoloration/altered pigmentation, skin lesion, skin odor abnormal, urticaria; Vascular Disorders: flushing, hot flush, hypertension, hypotension; Laboratory Parameters: activated partial thromboplastin time prolonged, creatine increased, bicarbonate decreased, sodium increased, EEG abnormal, glucose increased, cholesterol increased, triglycerides increased, amylase increased, potassium increased, TSH increased, platelet count decreased, hematocrit decreased, hemoglobin decreased, MCV increased, RBC decreased, creatinine increased, blood urea increased, BUN/creatinine ratio increased, creatine phosphokinase (CPK) increased, alkaline phosphatase increased, LDH increased, PSA increased, urine output increased/decreased, lymphocyte count decreased, neutrophil count decreased, WBC increased/decreased, coagulation test abnormal, low density lipoprotein (LDL) increased, prothrombin time prolonged, urinary casts, urine positive for white blood cells and protein.

Cardiovascular SafetyCardiovascular events and deaths were adjudicated to one of the pre-defined endpoints from the Anti-Platelet Trialists’ Collaborations (APTC) (cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke) in the randomized controlled and long-term extension studies. In the Phase 3 randomized controlled studies, the incidences of adjudicated APTC events per 100 patient-years of exposure were: Placebo 0 (95% CI 0.00-6.16), ULORIC 40 mg 0 (95% CI 0.00-1.08), ULORIC 80 mg 1.09 (95% CI 0.44-2.24), and allopurinol 0.60 (95% CI 0.16-1.53).

In the long-term extension studies, the incidences of adjudicated APTC events were: ULORIC 80 mg 0.97 (95% CI 0.57-1.56), and allopurinol 0.58 (95% CI 0.02-3.24).

Overall, a higher rate of APTC events was observed in ULORIC than in allopurinol-treated patients. A causal relationship with ULORIC has not been established. Monitor for signs and symptoms of MI and stroke.

DRUG INTERACTIONSXanthine Oxidase Substrate DrugsULORIC is an XO inhibitor. Drug interaction studies of ULORIC with drugs that are metabolized by XO (e.g., theophylline, mercaptopurine, azathioprine) have not been conducted. Inhibition of XO by ULORIC may cause increased plasma concentrations of these drugs leading to toxicity [see Clinical Pharmacology]. ULORIC is contraindicated in patients being treated with azathioprine, mercaptopurine, or theophylline [see Contraindications]. Cytotoxic Chemotherapy DrugsDrug interaction studies of ULORIC with cytotoxic chemotherapy have not been conducted. No data are available regarding the safety of ULORIC during cytotoxic chemotherapy.

In Vivo Drug Interaction StudiesBased on drug interaction studies in healthy subjects, ULORIC does not have clinically significant interactions with colchicine, naproxen, indomethacin, hydrochlorothiazide, warfarin or desipramine. Therefore, ULORIC may be used concomitantly with these medications.

USE IN SPECIFIC POPULATIONS PregnancyPregnancy Category C: There are no adequate and well-controlled studies in pregnant women. ULORIC should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Febuxostat was not teratogenic in rats and rabbits at oral doses up to 48 mg per kg (40 and 51 times the human plasma exposure at 80 mg per day for equal body surface area, respectively) during organogenesis. However, increased neonatal mortality and a reduction in the neonatal body weight gain were observed when pregnant rats were treated with oral doses up to 48 mg per kg (40 times the human plasma exposure at 80 mg per day) during organogenesis and through lactation period.

Nursing MothersFebuxostat is excreted in the milk of rats. 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 ULORIC is administered to a nursing woman.

Pediatric UseSafety and effectiveness in pediatric patients under 18 years of age have not been established.

Geriatric UseNo dose adjustment is necessary in elderly patients. Of the total number of subjects in clinical studies of ULORIC, 16 percent were 65 and over, while 4 percent were 75 and over. Comparing subjects in different age groups, no clinically significant differences in safety or effectiveness were observed but greater sensitivity of some older individuals cannot be ruled out. The Cmax and AUC24 of febuxostat following multiple oral doses of ULORIC in geriatric subjects ( 65 years) were similar to those in younger subjects (18-40 years).

Renal ImpairmentNo dose adjustment is necessary in patients with mild or moderate renal impairment (Clcr 30-89 mL per min). The recommended starting dose of ULORIC is 40 mg once daily. For patients who do not achieve a sUA less than 6 mg per dL after 2 weeks with 40 mg, ULORIC 80 mg is recommended.

There are insufficient data in patients with severe renal impairment (Clcr less than 30 mL per min); therefore, caution should be exercised in these patients.

Hepatic ImpairmentNo dose adjustment is necessary in patients with mild or moderate hepatic impairment (Child-Pugh Class A or B). No studies have been conducted in patients with severe hepatic impairment (Child-Pugh Class C); therefore, caution should be exercised in these patients.

Secondary HyperuricemiaNo studies have been conducted in patients with secondary hyperuricemia (including organ transplant recipients); ULORIC is not recommended for use in patients whom the rate of urate formation is greatly increased (e.g., malignant disease and its treatment, Lesch-Nyhan syndrome). The concentration of xanthine in urine could, in rare cases, rise sufficiently to allow deposition in the urinary tract.

OVERDOSAGEULORIC was studied in healthy subjects in doses up to 300 mg daily for seven days without evidence of dose-limiting toxicities. No overdose of ULORIC was reported in clinical studies. Patients should be managed by symptomatic and supportive care should there be an overdose.

CLINICAL PHARMACOLOGY PharmacodynamicsEffect on Uric Acid and Xanthine Concentrations: In healthy subjects, ULORIC resulted in a dose dependent decrease in 24-hour mean serum uric acid concentrations, and an increase in 24-hour mean serum xanthine concentrations. In addition, there was a decrease in the total daily urinary uric acid excretion. Also, there was an increase in total daily urinary xanthine excretion. Percent reduction in 24-hour mean serum uric acid concentrations was between 40% to 55% at the exposure levels of 40 mg and 80 mg daily doses.

Effect on Cardiac Repolarization: The effect of ULORIC on cardiac repolarization as assessed by the QTc interval was evaluated in normal healthy subjects and in patients with gout. ULORIC in doses up to 300 mg daily, at steady state, did not demonstrate an effect on the QTc interval.

Special PopulationsRenal Impairment: Following multiple 80 mg doses of ULORIC in healthy subjects with mild (Clcr 50-80 mL per min), moderate (Clcr 30-49 mL per min) or severe renal impairment (Clcr 10-29 mL per min), the Cmax of febuxostat did not change relative to subjects with normal renal function (Clcr greater than 80 mL per min). AUC and half-life of febuxostat increased in subjects with renal impairment in comparison to subjects with normal renal function, but values were similar among three renal impairment groups. Mean febuxostat AUC values were up to 1.8 times higher in subjects with renal impairment compared to those with normal renal function. Mean Cmax and AUC values for 3 active metabolites increased up to 2- and 4-fold, respectively. However, the percent decrease in serum uric acid concentration for subjects with renal impairment was comparable to those with normal renal function (58% in normal renal function group and 55% in the severe renal function group).

No dose adjustment is necessary in patients with mild to moderate renal impairment [see Dosage and Administration and Use in Specific Populations]. The recommended starting dose of ULORIC is 40 mg once daily. For patients who do not achieve a sUA less than 6 mg per dL after 2 weeks with 40 mg, ULORIC 80 mg is recommended. There is insufficient data in patients with severe renal impairment; caution should be exercised in those patients [see Use in Specific Populations. ULORIC has not been studied in end stage renal impairment patients who are on dialysis. Hepatic Impairment: Following multiple 80 mg doses of ULORIC in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment, an average of 20-30% increase was observed for both Cmax and AUC24 (total and unbound) in hepatic impairment groups compared to subjects with normal hepatic function. In addition, the percent decrease in serum uric acid concentration was comparable between different hepatic groups (62% in healthy group, 49% in mild hepatic impairment group, and 48% in moderate hepatic impairment group). No dose adjustment is necessary in patients with mild or moderate hepatic impairment. No studies have been conducted in subjects with severe hepatic impairment (Child-Pugh Class C); caution should be exercised in those patients [see Use in Specific Populations. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of FertilityCarcinogenesis: Two-year carcinogenicity studies were conducted in F344 rats and B6C3F1 mice. Increased transitional cell papilloma and carcinoma of urinary bladder was observed at 24 mg per kg (25 times the human plasma exposure at maximum recommended human dose of 80 mg per day) and 18.75 mg per kg (12.5 times the human plasma exposure at 80 mg per day) in male rats and female mice, respectively. The urinary bladder neoplasms were secondary to calculus formation in the kidney and urinary bladder.Mutagenesis: Febuxostat showed a positive mutagenic response in a chromosomal aberration assay in a Chinese hamster lung fibroblast cell line with and without metabolic activation in vitro. Febuxostat was negative in the in vitro Ames assay and chromosomal aberration test in human peripheral lymphocytes, and L5178Y mouse lymphoma cell line, and in vivo tests in mouse micronucleus, rat unscheduled DNA synthesis and rat bone marrow cells.Impairment of Fertility: Febuxostat at oral doses up to 48 mg per kg per day (approximately 35 times the human plasma exposure at 80 mg per day) had no effect on fertility and reproductive performance of male and female rats. Animal ToxicologyA 12-month toxicity study in beagle dogs showed deposition of xanthine crystals and calculi in kidneys at 15 mg per kg (approximately 4 times the human plasma exposure at 80 mg per day). A similar effect of calculus formation was noted in rats in a six-month study due to deposition of xanthine crystals at 48 mg per kg (approximately 35 times the human plasma exposure at 80 mg per day).PATIENT COUNSELING INFORMATION[see FDA-Approved Patient Labeling in the full prescribing information]General InformationPatients should be advised of the potential benefits and risks of ULORIC. Patients should be informed about the potential for gout flares, elevated liver enzymes and adverse cardiovascular events after initiation of ULORIC therapy. Concomitant prophylaxis with an NSAID or colchicine for gout flares should be considered.Patients should be instructed to inform their healthcare professional if they develop a rash, chest pain, shortness of breath or neurologic symptoms suggesting a stroke. Patients should be instructed to inform their healthcare professional of any other medications they are currently taking with ULORIC, including over-the-counter medications.Distributed byTakeda Pharmaceuticals America, Inc.Deerfield, IL 60015U.S. Patent Nos. - 6,225,474; 7,361,676; 5,614,520. ULORIC® is a registered trademark of Teijin Pharma Limited and used under license by Takeda Pharmaceuticals America, Inc.All other trademark names are the property of their respective owners©2009 Takeda Pharmaceuticals America, Inc.February 2009For more detailed information, see the full prescribing information for ULORIC (febuxostat) tablets (PI1114 R1; February 2009) or contact Takeda Pharmaceuticals America, Inc. at 1.877.825.3327.PI1114 R1-Brf; February 2009L-TXF-0209-3


American Health & Drug Benefits will be publishing a Special Issue on Cardiometabolic Health & Wellnesslater this year.

The editors of AHDB invite readers to submit articles for publication in this special issue on topics relevant to theclinical, business, and policy aspects of cardiometabolic health and wellness amidst an economic downturn andinconsistent healthcare outcomes. Original research studies, white papers, evidence-based comprehensive reviews, andcase studies are of particular interest.

The editors invite all healthcare stakeholders—actuaries, employers, economists, manufacturers, patients, payers,policymakers, providers, purchasers, regulators, and researchers—to present their data, best practices, innovations, and initiatives to facilitate patient-centered management strategies and benefit design models toward the prevention ofcardiometabolic risk factors and outcomes improvement in patients with cardiovascular disease, diabetes, or obesity.

Readers are invited to submit original, outcomes-based research, white papers, evidence-based comprehensive reviews, and case studies on topics such as: • Benefit designs to improve cardiometabolic outcomes • Best practices in diabetes management and prevention• Best practices in insulin control, lipid management, or blood pressure control• Current recommendations for optimizing A1C targets• Comparative effectiveness analyses of best therapies for cardiovascular health• Cost-effectiveness comparisons of current therapies for diabetes • Employers’ strategies to enhance employees’ cardiometabolic wellness • Emerging therapies for diabetes, cardiovascular disease, obesity • Health plan initiatives for cardiometabolic health and prevention• Hot topics in diabetes management, obesity, or cardiovascular disease• Insulin resistance and type 2 diabetes• Lifestyle strategies and cardiometabolic health and wellness• Lipid management in patients with diabetes• Medication adherence and diabetes progression• New biomarkers for assessing cardiometabolic risk • New therapies for diabetes or cardiovascular disease• Optimal therapies for cardiovascular disease, diabetes, or obesity • Prevention strategies for diabetes risk reduction • Wellness programs for patients with heart disease, diabetes, or obesity

Submission deadline for this issue is June 30, 2011. Articles submitted by May 31 will be given publication priority. All articles will undergo the Journal’s standard peer-review process.

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

CALL FOR PAPERS

Cardiometabolic Health & Wellness Special Issue

Contact your GSK representative for additional information or visit www.ARZERRA.com.

©2010 The GlaxoSmithKline Group of Companies All rights reserved. Printed in USA. AZA228R0 January 2011

Announcing a NEW J-Code for ARZERRA

ARZERRA will have a permanent HCPCS code effective January 1, 2011

The new J9302 Code replaces miscellaneous HCPCS Codes J9999, J3590, J3490, and C9260 that most providers have used to bill for ARZERRA to date

HCPCS code

J9302

Effective

January 1, 2011

Description

Injection,ofatumumab, 10mg

ARZERRA® HCPCS Code J9302

BUSINESS


Major depressive disorder (MDD) often presentsas a chronic and recurrent illness. It is the mostcommon type of depression, affecting 6.6% of

adults in the United States annually, with a lifetime

prevalence of 16.2%.1 Patients with MDD are more like-ly to suffer from multiple comorbidities, including othermental illnesses or chronic conditions, compared withpatients without MDD.2 MDD is also associated with

Dr Wu is Managing Principal, Mr Greenberg is Managing Principal and Director, Health Economics, Ms Ben-Hamadi isManager, Dr Yu is Manager, and Dr Yang is Associate, Analysis Group, Boston, MA; Dr Erder was Vice President, GlobalHealth Economics and Outcomes Research, Forest Research Institute, at the time of the study. This study was presented at theAmerican Psychiatric Association’s 59th Annual Institute on Psychiatric Services, October 11-14, 2007, New Orleans, LA.

ORIGINAL RESEARCH

Comparing Treatment Persistence, HealthcareResource Utilization, and Costs in AdultPatients with Major Depressive DisorderTreated with Escitalopram or CitalopramEric Q. Wu, PhD; Paul E. Greenberg, MA; Rym Ben-Hamadi, MSc; Andrew P. Yu, PhD; Elaine H. Yang, PhD; M. Haim Erder, PhD

Background: Major depressive disorder is the most common type of depression, affecting6.6% of adults in the United States annually. Citalopram and escitalopram are commonsecond-generation antidepressants used for the treatment of patients with this disorder.Because citalopram is available in generic forms that have lower acquisition costs comparedwith the branded escitalopram, some health plans may provide incentives to encourage theuse of the generic option. Decisions based solely on drug acquisition costs may encouragethe use of a therapy that is less cost-effective when treatment persistence, healthcare utiliza-tion, and overall costs are factored in. Objective: To compare, in a real-world setting, the treatment persistence, healthcare utiliza-tion, and overall costs of managing adult patients with major depressive disorder who aretreated with escitalopram or citalopram.Methods: Administrative claims data (from January 1, 2003, to June 30, 2005) were analyzedfor patients with major depressive disorder aged ≥18 years. Patients filled ≥1 prescriptions forcitalopram or for escitalopram (first-fill time was defined as the index date) and had nosecond-generation antidepressant use during the 6-month preindex period. Treatment persis -tence, healthcare utilization, and healthcare costs were measured over the 6-month pre indexand 6-month postindex periods and compared between patients treated with citalopram orescitalopram, using unadjusted and multivariate analyses.Results: Patients receiving escitalopram (N = 10,465) were less likely to discontinue the treat-ment (hazard ratio 0.94; P = .005) and switch to another second-generation antidepressant(hazard ratio 0.83; P <.001) than patients receiving citalopram (N = 4212). Patients receivingescitalopram were also less likely to have a hospital admission (odds ratio 0.88; P = .036) oran emergency department visit and had lower total healthcare costs (–$1174) and majordepressive disorder–related costs (–$109; P <.001) during the study period.Conclusion: Although the drug acquisition costs are lower for generic citalopram than for thebrand-name escitalopram, patients treated with escitalopram had better treatment persis -tence, lower healthcare utilization, and lower overall costs compared with patients treated withcitalopram over the study period. This may suggest that other considerations, in addition toacquisition cost, may need to be factored in to assess the cost-effectiveness of drug therapy.

Eric Q. Wu

Am Health Drug Benefits.2011;4(2):78-87www.AHDBonline.com


Stakeholder Perspective,page 87

Healthcare Resource Utilization and Costs in MDD


increased risk for substance abuse, particularly alcoholabuse, leading to more severe depressive symptoms andimpairment.3 Because of its clinical features, untreated orundertreated MDD can have significant negativeimpacts on an individual’s health, quality of life, andfunctional status, as well as work productivity andemployment.2,4Consequently, patients with MDD are among the

highest users of healthcare and incur substantial indirectcosts resulting from premature deaths, reduced produc-tivity, and increased disability associated with the dis-ease.2,5 The economic burden of MDD was estimated tohave amounted to $83.1 billion in 2000 in the UnitedStates.5 Of this total cost, $26.1 billion (31%) was fordirect medical costs, $5.4 billion (7%) was for suicide-related mortality costs, and the remaining $51.5 billion(62%) was for work-related costs.5Effective treatment can substantially reduce the eco-

nomic burden assumed by the healthcare system,employers, and society. Pharmacotherapy is a major typeof treatment for MDD. Currently, the most widely pre-scribed antidepressants in the United States are selectiveserotonin reuptake inhibitors (SSRIs). These second-generation antidepressants have been shown to be effec-tive and better tolerated than older antidepressants.6Both escitalopram (Lexapro) and citalopram (Celexa)

are SSRIs, and escitalopram is the pure S-enantiomer ofthe racemic citalopram. An enantiomer is composed of2 compounds that are nonsuperimposable mirror imagesof each other. Citalopram is a racemate that comprises a1:1 mixture of S(+)-enantiomer (escitalopram) and anR(−)-enantiomer (R-citalopram). It is the S-enantiomerthat possesses the pharmacologic effect of the drug. TheR-enantiomer in citalopram counteracts the activity ofthe S-enantiomer, which may be the underlying reasonfor the differences in the pharmacologic and clinicaleffects between escitalopram and citalopram.7-9Citalopram was approved by the US Food and Drug

Administration (FDA) for acute and maintenance treat-ment of adults with MDD in July 1998, and escitalopramwas approved for acute and maintenance treatment ofMDD in adults in August 2002. Citalopram becamegeneric in October 2004.Because citalopram and escitalopram are chemically

related, payers may assume that they provide similarclinical benefits, and that the lower acquisition cost ofgeneric citalopram will lead directly to reductions inoverall treatment costs. However, citalopram and esci-talopram are different medications and may not be inter-changeable.Many clinical trials and analyses have compared

citalopram and escitalopram, and have consistentlyshown that escitalopram is more efficacious.10-14 In one

study, escitalopram 10 mg/day was found to be at least aseffective as citalopram 40 mg/day in an 8-week study of491 outpatients with MDD.10 A placebo-controlled trialof 469 patients with moderate-to-severe depressionrevealed that by the end of 8 weeks of treatment, signif-icantly more patients responded to escitalopram 10 to 20mg daily than to citalopram 20 to 40 mg daily.11Continuation of treatment with escitalopram has alsodemonstrated efficacy in preventing relapse of MDD.12,13A double-blind trial of 280 patients with MDD random-ized to escitalopram 20 mg/day or to citalopram 40mg/day over 8 weeks demonstrated significant improve-ments in depression rating scales and in treatmentresponse rates with escitalopram.14 Both groups demon-strated similar tolerability.14Furthermore, an economic evaluation that was con-

ducted parallel with a double-blind, randomized clinicaltrial in France showed that escitalopram is more cost-effective than citalopram.12 Although conducted outsidethe United States, this economic evaluation has somevalue in understanding the relative cost-effectiveness ofthese 2 treatments, especially when similar evaluation islacking in this country. Among ambulatory care patientswith MDD followed for 8 weeks, escitalopram 20 mg/day

KEY POINTS

� Major depressive disorder is the most common typeof depression, affecting 6.6% of adults in the UnitedStates annually.

� The economic burden of this disorder was estimatedto amount to $83.1 billion in 2000, of which 62%was for work-related costs, 31% for direct medicalcosts, and 7% for suicide-related costs.

� Citalopram and escitalopram are similar medicationsindicated for the treatment of major depression, butthey may not be interchangeable. Many clinical trialscomparing these agents have shown a superiorefficacy to escitalopram compared with citalopram.

� Because citalopram is now available in generic forms,with lower acquisition costs than the brandedescitalopram, health plans may offer incentives toencourage the use of a generic option.

� Decisions based solely on drug acquisition cost,however, may encourage a less cost-effective therapy;it is important to understand the cost implications ofdrugs in the real-world setting.

� This retrospective analysis shows that treatment withescitalopram was associated with greater treatmentpersistence and lower depressive disorder– relatedand overall healthcare utilization and costs than withcitalopram in this patient population.

BUSINESS


resulted in 41% lower mean per-patient costs comparedwith citalopram 40 mg/day.12 The cost differential wasmainly a result of lower hospitalization costs.12Driven by cost-containment considerations, health-

care systems have adopted a variety of policies designedto encourage physicians and patients toward lower-costdrugs, including use of generic drugs when they becomeavailable. However, without a comprehensive under-standing of the total healthcare cost implications ofthese 2 antidepressants in the real world, promoting ormandating citalopram in drug formularies to replaceescitalopram based solely on acquisition costs may notbe cost-effective. A comparison of the economic outcomes of patients

treated with escitalopram and citalopram is valuable fordecision makers to consider the total costs of MDD treat-ment. Although some published claims studies havecompared escitalopram with other SSRIs as a group,8,9 toour knowledge very few real-world studies have comparedescitalopram with citalopram—2 antidepressants that areoften assumed to be equivalent as a result of their molec-ular structure. One analysis based on claims data recentlycompared clinical and economic profiles of escitalopramand citalopram in a geriatric population with MDD.15The objective of this current study is to generalize thisreal-world comparison with adult patients with MDD.

MethodsData SourceIn this current study, we analyzed claims data from the

Ingenix Impact Database, which included completemedical and pharmacy claims for more than 25 millionnoncapitated managed care lives from more than 35health plans, covering all census regions of the UnitedStates. Data elements used in the present analysisincluded enrollment records, patient demographics,inpatient and outpatient medical services, and pharmacydispensing claims. The data collection period startedJanuary 1, 2003, because escitalopram was approved bythe FDA for MDD treatment in August 2002.

Study DesignPatients were included in the study if they had at least

1 inpatient claim or 2 medical claims of other typesincurred on different dates that were associated with anMDD diagnosis (International Classification of Diseases,Ninth Revision, Clinical Modification 296.2x, 296.3x)between January 1, 2003, and June 30, 2005, and if theyfilled at least 1 prescription either for escitalopram or forcitalopram during that same period. The first prescrip-tion filling date was defined as the index date. The anti-depressant filled on the index date (either escitalopramor citalopram) was defined as the index drug.

Patients were classified into the citalopram group orthe escitalopram group based on the index drug theyreceived. Because this study was intended to comparecitalopram and escitalopram, the brand-name and gener-ic forms of citalopram were not distinguished. Allpatients who received either brand-name or genericcitalopram and met the study criteria were included inthe same citalopram group.Because the National Committee for Quality

Assurance criteria for the appropriate treatment of MDDrequires a minimum duration of 6 months, the studyperiod was set to 6 months after therapy initiation.16 Thebaseline period was defined as the 6 months before theindex date, and the study period was defined as the 6months after the index date. Patients had to meet the following additional inclu-

sion criteria: (1) they were aged ≥18 years as of the indexdate; (2) they were continuously enrolled in the plan forat least 12 months, including a minimum of 6 monthsbefore and 6 months after the index date; (3) they didnot use any second-generation antidepressant drug (eg,SSRIs, serotonin-norepinephrine reuptake inhibitors,bupropion, nefazodone, trazodone, fluoxetine-olanza -pine, or mirtazapine) during the baseline period; and (4)they were not initiated on combination therapy (ie, didnot use any second-generation antidepressants otherthan citalopram or escitalopram within 2 weeks after theindex date).9,15

Outcome MeasuresTreatment persistence. Treatment persistence was

measured up to the time of discontinuation of therapy bythe rate of discontinuation of the index drug during thestudy period. Patients were considered to discontinuethe index drug if they did not have another refill within45 days after the last day of the latest supply of the indexdrug recorded in the claims database.17 Patients who haddiscontinued and switched to another second-genera-tion antidepressant were further identified, with switch-ing defined as filling a prescription for another second-generation antidepressant within 45 days of the last dayof the latest supply of the index drug.

Healthcare resource utilization. Healthcare re sourceutilization was observed in all-cause hospitalizations andemergency department visits during the study period. Inparticular, MDD-related hospitalizations and emergencydepartment visits were also measured. A hospitalizationor an emergency department visit was considered MDD-related if it was associated with a primary or secondarydiagnosis for MDD. The proportions of patients whoused these types of services were estimated, as well as thenumber of hospitalization days and number of emer-gency department visits for each patient.



Healthcare costs. Healthcare costs were examinedfrom the insurer’s perspective. Average costs per patientwere estimated on the basis of payment data in theclaims database for procedures, services, and prescriptiondrugs, over the 6-month study period by the type of serv-ice (ie, professional services, including physicians andother medical professionals’ care; hospitalization cost;outpatient cost; emergency department cost; and pre-scription drug cost). Total healthcare costs were calculated as the sum of

total medical services costs and total prescription drugcosts. In addition, MDD-related costs (total and by serv-ice type) were also calculated. A medical service cost wasconsidered MDD-related if it was associated with a diag-nosis of MDD. MDD-related pharmacy costs includedthe costs of antidepressants. Because MDD is often asso-ciated with multiple comorbidities,2 including othermental illnesses or chronic conditions, it is important toanalyze not only MDD-related costs but also the totalcost of disease.

Statistical AnalysisStudy outcomes were first compared between the

citalopram and escitalopram groups using unadjustedanalysis. Chi-square tests were used to compare the ratesof discontinuation and discontinuation with switchingto another second-generation antidepressant, hospital-ization, and any emergency department visit during thestudy period. Wilcoxon tests were used to compare sta-tistical differences in the number of hospitalization days,number of emergency department visits, and healthcarecosts between the 2 groups. The study outcomes were further compared using a

multivariate analysis to control for differences in base-line characteristics between the 2 treatment groups.Patient baseline characteristics were measured duringthe baseline period and included age, sex, the Deyoadaptation of the Charlson Comorbidity Index(CCI),18 individual comorbidities selected from the lit-erature, and baseline healthcare utilization and costs.(The CCI has become a common measure for comor-bidity burden in observational studies, especially thoseusing administrative claims databases. This index hasbeen used in the literature related to depression and isintended as a measure of overall health outcomes of thepatient, not as a measure of disease severity associatedwith depression.19) To compare the rates of discontinuation and discon-

tinuation with switching between the 2 groups, Cox pro-portional hazard models were used. Logistic regressionswere applied to estimate the probability of hospitaliza-tion and emergency department visits during the studyperiod. The number of hospitalization days and the num-

ber of emergency department visits were comparedbetween the 2 groups using negative binomial regres-sions. Generalized linear model (GLM) regressions withlog link and gamma distribution were used to analyzehealthcare costs. For MDD-related total medical servicescosts, a 2-part model was used, because a large portion ofpatients had no hospital and medical costs.

Sensitivity AnalysisTo assess the robustness of the study results to varia-

tions in the price of antidepressant drugs, it wasassumed that all second-generation antidepressantsused by patients in the citalopram group had zero cost,whereas the prescription drug cost in the escitalopramgroup was kept unchanged. Under this assumption, thenew total healthcare cost for the citalopram group wascalculated and compared with the total healthcare costof the escitalopram group using both Wilcoxon test andGLM regression as described above. The analysis repre-sented a conservative estimation of the cost impact ofescitalopram over citalopram by deducting all antide-pressant drug costs from the total healthcare costs forthe citalopram group.

ResultsA total of 14,677 patients met the inclusion criteria

in this study, of which 10,465 were taking escitalopram,and 4212 were taking citalopram. Patient baseline char-acteristics are presented in Table 1. Compared with patients using citalopram, patients

using escitalopram had similar age (41.7 vs 42.1; P =.0131); fewer females (67.5% vs 69.5%; P = .019); alower average CCI (0.77 vs 0.90; P = .005); a higherprevalence of generalized anxiety disorder, panic disor-der, sleep disorder, and hyperlipidemia; and a lowerprevalence of schizophrenia and cancer. In addition,patients taking escitalopram used more prescriptiondrugs at baseline (4.54 vs 4.35; P = .003) and had morephysician office visits (94.1% vs 91.0%; P <.001), buthad fewer inpatient visits (13.5% vs 15.7%; P = .001),outpatient hospital visits (54.5% vs 58.6%; P <.001),and emergency department visits (22.0% vs 23.5%; P =.040) than patients taking citalopram. In addition,patients taking escitalopram had numerically lower base-line drug, medical, and total costs compared withpatients taking citalopram, although the difference wassignificant only for the drug costs.

Treatment PersistenceDuring the 6-month study period, 57.8% of patients

taking escitalopram and 60.3% of those taking citalo-pram (P = .006) discontinued the index treatment(Table 2). The rate of discontinuation with switching

BUSINESS


Table 1 Baseline Characteristics of Adult Patients with MDD, by Index Therapy with Escitalopram or Citalopram

Baseline characteristicsaEscitalopram (N = 10,465)

Citalopram (N = 4212) Pb

Demographics

Age on index date (mean, SD) 41.7 (13.7) 42.1 (14.1) .131

Female, % 67.5 69.5 .019c

Comorbidities

Deyo Charlson Comorbidity Index (mean, SD) 0.77 (2.16) 0.90 (2.35) .005c

Mental diseases, %Dementia and Alzheimer’s disease 0.6 0.8 .299

Generalized anxiety disorder 6.2 4.2 <.001c

Obsessive-compulsive disorder 1.1 0.9 .283

Other psychotic disorders 1.0 1.4 .049c

Panic disorder 3.1 1.8 <.001c

Phobia 1.2 1.1 .709

Posttraumatic stress disorder 2.1 2.2 .796

Schizophrenia 0.5 0.8 .046c

Sleeping disorder 4.4 3.0 <.001c

Other diseases, %Cancer 3.2 4.6 <.001c

Cardiovascular disease 9.3 10.0 .243

Chronic obstructive pulmonary disease and allied conditions 8.7 9.1 .505

Diabetes 5.4 6.2 .073

Epilepsy 0.8 0.9 .733

Hyperlipidemia 14.4 13.0 .024c

Hypertension 14.3 14.1 .734

Irritable bowel syndrome 1.9 2.1 .396

Renal disease 1.3 1.5 .361

Rheumatoid arthritis and osteoarthritis 4.8 4.4 .394

Stroke 0.9 1.1 .308

Healthcare utilization

Number of prescription drugs used (mean, SD) 4.54 (4.65) 4.35 (4.58) .003c

Medical services, %Inpatient visit 13.5 15.7 .001c

Outpatient hospital visit 54.5 58.6 <.001c

Office visit 94.1 91.0 <.001c

Emergency department visit 22.0 23.5 .040c

Healthcare costs, $ (mean, SD)Prescription drug 665 (1455) 669 (1475) .005c

Medical service 4319 (11,854) 5538 (19,916) .779

Total healthcare costs 4984 (12,263) 6206 (20,216) .756aBaseline characteristics were measured during the 6-month preindex period.bWilcoxon test was used for continuous variables; chi-square test was used for categorical variables.cP <.05.MDD indicates major depressive disorder; SD, standard deviation.



to another second-generation antidepressant was alsolower in the escitalopram group (24.7% vs 29.3%; P<.001). After controlling for differences in baselinecharacteristics, results of the unadjusted analysis wereconfirmed for escitalopram by hazard ratio of 0.94 foroverall discontinuation (P = .006) and 0.83 for discon-tinuation and switching to another second-generationantidepressant (P <.001).

Healthcare Resource UtilizationAmong patients in the escitalopram group, 11.6%

experienced a hospitalization during the study periodcompared with 13.6% in the citalopram group (P =.001; Table 2). The rates of MDD-related hospitaliza-tions were not significantly different between the 2groups (4.0% vs 4.4%; P = .256). The escitalopramgroup also had shorter inpatient stays during the sameperiod (1.0 vs 1.5 hospitalization days; P = .001).Results of the multivariate analysis were consistentwith findings from the unadjusted analysis. Patients inthe escitalopram group were less likely to be hospital-ized (odds ratio [OR] 0.88; P = .036). In other words,the odds of patients in the escitalopram group being

hospitalized was 12% lower than for patients in thecitalopram group, and patients in the escitalopramgroup had 28% fewer hospitalization days than patientsin the citalopram group (P = .001). The rates of MDD-related hospitalizations were not significantly differentbetween the 2 groups.Similarly, there was a smaller proportion of patients

with emergency department visits for any reason in theescitalopram group during the study period (19.8% vs23.0%; P <.001; Table 2). Patients receiving escitalo-pram were also less likely to have an MDD-related emer-gency department visit (1.2% vs 1.9%; P = .001). Theseresults remained significant after adjustment for baselinecharacteristics, both for emergency department visits forany reason (OR 0.83; P <.001) and for MDD-relatedemergency department visits (OR 0.60; P = .001). On average, patients in the escitalopram group had

0.3 emergency department visits, whereas those in thecitalopram group had 0.4 visits during the study period(P <.001). Results from the negative binomial modelshowed that patients in the escitalopram group had19.0% fewer emergency department visits after control-ling for differences in baseline characteristics (P <.001).

Table 2 Treatment Discontinuation and Healthcare Utilization, by Index Therapy with Escitalopram or Citalopram

Unadjusted analyses Multivariate analysis

OutcomesaEscitalopram (N = 10,465)

Citalopram (N = 4212) P

Adjusted HR, OR, orIRRb and 95% CI

Discontinuation, %

All discontinuationc 57.8 60.3 .006d 0.94 (0.90, 0.98)

Discontinuation with switchingc 24.7 29.3 <.001d 0.83 (0.78, 0.88)

Healthcare utilization

Hospitalization for any reason, %e 11.6 13.6 .001d 0.88 (0.78, 0.99)

Hospitalization, MDD-related, %e 4.0 4.4 .256 0.96 (0.80, 1.16)

Number of hospitalization days (mean, SD)f 1.0 (5.1) 1.5 (7.3) .003d 0.72 (0.60, 0.85)

Emergency department visit for any reason, %e 19.8 23.0 <.001d 0.83 (0.76, 0.91)

Emergency department visit, MDD-related, %e 1.2 1.9 .003d 0.60 (0.45, 0.80)

Number of emergency department visits, anyreason (mean, SD)f

0.3 (1.1) 0.4 (1.3) <.001d 0.81 (0.74, 0.88)

aAll outcomes were observed during the 6-month study period.bAll ratios were adjusted for the baseline characteristics.cHR was used for comparison; adjustment based on Cox proportional hazard model.dP <.05 based on Wilcoxon tests for continuous variables and chi-square tests for categorical variables.eOR was used for comparison; adjustment based on logistic regression.fIRR was used for comparison; adjustment based on negative binomial model.CI indicates confidence interval; HR, hazard ratio; IRR, incidence rate ratio; MDD, major depressive disorder; OR,odds ratio; SD, standard deviation.

BUSINESS


Healthcare CostsThe average total healthcare cost per patient during

the study period was $5551 in the escitalopram group,$1459 less than that in the citalopram group (P <.001;Table 3). Patients in the escitalopram group also hadlower costs in every category. Approximately 92% of thedifference in total healthcare costs was attributable toreduction in total medical services costs in the escitalo-pram group (−$1342; P <.001), of which $558 resultedfrom lower hospitalization costs (P <.001). Significantlylower costs in the escitalopram group were also manifest-ed in outpatient visits (−$273; P <.001) and professionalservices (−$165; P = .001). Results from multivariate

analyses indicate that the total healthcare costs were anaverage of $1174 less in the escitalopram group (P <.001),and that the average total medical services costs andtotal prescription drug costs were both significantlylower in the escitalopram group (−$972 and −$170,respectively; both P <.001). MDD-related total healthcare costs during the study

period were also lower in the escitalopram group. Onaverage, patients in this group incurred $117 less perpatient during the study period than those in thecitalopram group (P <.001). The majority of the differ-ence resulted from reduction in MDD-related totalmedical services costs (−$77; P = .014), and the rest of

Table 3 Six-Month Healthcare Costs, by Index Therapy with Escitalopram or Citalopram

6-month healthcare costsa

Escitalopram (N = 10,465)

Citalopram (N = 4212) Difference Pb

[A] [B] [A] – [B] [A] vs [B]

Prescription drug (mean, SD)

Total prescription drug cost, $c 1142 (1715) 1259 (1955) –117 <.001 e

Total antidepressant cost, $ 326 (217) 366 (240) –40 <.001 e

Medical service (mean, SD)d

Professional service 1885 (2529) 2050 (2735) –165 .001 e

Professional service, MDD-related 472 (908) 509 (1041) –37 .224

Inpatient visit 1127 (7589) 1686 (10,474) –558 <.001 e

Inpatient visit, MDD-related 174 (1903) 208 (1669) –34 .023 e

Outpatient visit 786 (2910) 1059 (8751) –273 <.001 e

Outpatient visit, MDD-related 26 (290) 29 (273) –4 <.001 e

Emergency department visit 106 (495) 126 (493) –19 <.001 e

Emergency department visit, MDD-related 5 (62) 6 (58) –2 .001 e

Total medical service cost, $ 4410 (12,247) 5752 (18,704) –1342 <.001 e

Total medical service cost, MDD-related, $ 680 (2264) 758 (2282) –77 .014 e

Total healthcare cost (mean, SD)

Total healthcare cost, $ 5551 (12,772) 7010 (19,199) –1459 <.001 e

Total healthcare cost, MDD-related, $ 1006 (2297) 1124 (2326) –117 <.001 e

aCosts were measured during the 6-month study period. All numbers are the average cost per person. bAdjusted for all baseline characteristics using generalized linear models with log link and gamma distribution. For MDD-related total medicalservice costs, a 2-part model was used. cTotal prescription drug costs included total antidepressant costs and other prescription drug costs; other prescription drug costs were not presented in this table. dTotal medical services included professional services, hospitalizations, outpatient visits, emergency department visits, and other medical services;other medical services were not presented in this table. eP <.05 based on Wilcoxon tests for the unadjusted differences and generalized linear model or 2-part model for the adjusted differences.MDD indicates major depressive disorder; SD, standard deviation.



the difference was attributable to the lower antidepres-sant costs (−$40; P <.001). Among MDD-related totalmedical services costs, hospitalization, outpatient, andemergency department costs were all significantlylower in the escitalopram group. After controlling fordifferences in baseline characteristics, the adjustedMDD-related total healthcare costs were $109 lower inthe escitalopram group (P = .003). The adjusted totalantidepressant costs and MDD-related total medicalservices costs were $39 and $43 lower, respectively, inthe escitalopram group (both P ≤.001).Results from the sensitivity analysis showed that, even

assuming zero costs for all second-generation antidepres-sants used by patients in the citalopram group, the aver-age total healthcare costs were still lower in the escitalo-pram group ($5551 vs $6644; P = .010). After adjustmentfor baseline characteristics using a GLM model, patientsin the escitalopram group still showed an average savingsof $420 in total healthcare costs compared with patientsin the citalopram group (P <.001; Figure).

DiscussionIn this present retrospective study, a large adminis-

trative claims database was used to compare treatmentpersistence, healthcare utilization, and costs forpatients treated with escitalopram compared withpatients treated with citalopram in a real-world setting.Although patients taking citalopram and escitalopramhad different baseline comorbidity profiles, these differ-ences were controlled for in this study with the multi-variable regression analysis described above. Results indicate that although a majority of patients

in both treatment groups discontinued treatment with-in 6 months after the index date, patients treated withescitalopram had better treatment persistence as meas-ured by overall discontinuation rate, as well as rate ofdiscontinuation with switching to another second-gen-eration antidepressant. These results are consistentwith those in a recent clinical trial, which also showeda lower withdrawal rate in the escitalopram group com-pared with the citalopram group.14More than one third of the difference in total health-

care costs was attributable to lower hospitalization costsin the escitalopram group. The results were consistentusing both unadjusted analysis and multivariate analysisand were supported by the sensitivity analysis, in whichit was assumed that all second-generation antidepres-sants had zero costs in the citalopram group.These results are also consistent with findings from

recent claims data analyses conducted in an elderlypopulation with MDD.15 In that study of patients withMDD aged ≥65 years, those treated with escitalopramshowed significantly better treatment persistence,

fewer hospitalizations, and lower medical and totalhealthcare costs than patients treated with citalo-pram.15 Similar to findings in the current study, most ofthe cost reduction was attributable to significantlylower hospitalizations and total medical costs.15Treatment persistence not only contributes to the

therapeutic success of MDD treatment but also to thecost-effectiveness of an antidepressant.20 Previous stud-ies have provided some evidence that the lack of per-sistence is associated with higher total medical costsamong patients with depression.21,22 Lack of persistencecould prolong the disease episode and lead to a higherrate of recurrent events. Therefore, improved persis -tence will likely save the long-term cost of treatingMDD. Furthermore, better persistence in patients withMDD and better outcomes may reduce the healthcareresource utilization and costs associated with comor-bidities beyond depression itself. In this present analy-sis, a substantial portion of the difference in healthcareutilization and costs between the escitalopram andcitalopram groups was not MDD-related. The cause ofthese differences cannot be determined from claimsdata. It may be related to the potential advantage ofescitalopram in safety and effectiveness, but the extentof this factor is unknown. The economic benefits of escitalopram over citalo-

pram have been suggested by numerous cost-effective-ness analyses.23-27 Findings in this present study are con-sistent with such previous analyses. It should be noted

Figure Sensitivity Analysis: Comparing Healthcare Costs perPatient, Escitalopram versus Citalopram

7000

6000

5000

4000

3000

2000

1000

0Co

sts, $

Total drug costs during study period

Total healthcare costs during study period

Escitalopram

Citalopram

P <.001

Note: All costs were adjusted for baseline characteristics usingthe generalized linear model.

13071010

62296649

P <.001

BUSINESS


that persistence, healthcare utilization, and healthcarecosts are directly related to the clinical efficacy and thetolerability of a treatment. Thus, clinicians and third-party payers should carefully consider the relative ben-efits of different therapeutic options when makingpatient care and policy decisions rather than rely solelyon drug acquisition costs.

LimitationsThis present study has several limitations. First, it is

subject to the usual limitations associated with claimsdata as a result of the absence of detailed clinical infor-mation. Therefore, there may be selection bias ifpatients in one treatment group had more severedepression than patients in the second group. Such dif-ference may have affected treatment persistence andhealthcare utilization during the study period.However, to minimize selection bias, this study onlyincluded patients who were not treated with any othersecond-generation antidepressant during the baselineperiod, and every effort was made to control for differ-ences in observed baseline characteristics. Second, discontinuation was measured by prescription

refills in the pharmacy claims database instead of theactual use of the medications. Although not the mostaccurate measurement of treatment persistence, pharma-cy data have been extensively used in other studies oftreatment persistence.28-30 To the extent that the measure-ment error was not systematically different between the 2treatment groups, the results regarding treatment persis -tence in this study can be considered valid. Drug sampling bias could be another limitation—

because additional drug samples provided free of chargeby the physicians cannot be observed in the claims databut they may influence the persistence measure.However, the direction of the bias is unclear. In addition,the claims database used did not report any informationrelated to patient copayment for medications; such infor-mation was therefore not available for this analysis.Finally, the study focuses on relatively short-term

benefits of treatment with escitalopram versus treatmentwith citalopram, and thus does not provide empiricalevidence on long-term benefits. Future research is war-ranted to consider long-term and indirect effects of thesetherapies on work productivity and disability.

ConclusionAdding to previous literature, this study shows that

the clinical and economic benefits of escitalopram arenot only observed in clinical trials, but also manifestedin the real-world setting. In this present study, comparedwith citalopram, escitalopram was associated with highertreatment persistence and lower MDD-related and over-

all healthcare utilization and costs among adult patientswith MDD.

Funding SourceThis study was funded by Forest Laboratories, Inc.

Author Disclosure StatementMr Greenberg, Ms Ben-Hamadi, Dr Eric Wu, Dr Yang,

and Dr Andrew Yu are consultants to Forest Laboratories.Dr Erder was employed by Forest Laboratories at the time ofthe study.

References1. Kessler RC, Berglund P, Demler O, et al. The epidemiology of major depressive dis-order: results from the National Comorbidity Survey Replication (NCS-R). JAMA.2003;289:3095-3105.2. Bloom BS. Prevalence and economic effects of depression. Manag Care. 2004;13(6suppl):9-16.3. Ostacher MJ. Comorbid alcohol and substance abuse dependence in depression:impact on the outcome of antidepressant treatment. Psychiatr Clin North Am.2007;30:69-76.4. Croom KF, Plosker GL. Spotlight on the pharmacoeconomics of escitalopram indepression. CNS Drugs. 2004;18:469-473.5. Greenberg PE, Kessler RC, Birnbaum HG, et al. The economic burden of depres-sion in the United States: how did it change between 1990 and 2000? J ClinPsychiatry. 2003;64:1465-1475.6. Weilburg JB. An overview of SSRI and SNRI therapies for depression. ManagCare. 2004;13:25-33.7. Fantino B, Moore N, Verdoux H, Auray JP. Cost-effectiveness of escitalopram vs.citalopram in major depressive disorder. Int Clin Psychopharmacol. 2007;22:107-115.8. Esposito D, Wahl P, Daniel G, et al. Results of a retrospective claims databaseanalysis of differences in antidepressant treatment persistence associated with esci-talopram and other selective serotonin reuptake inhibitors in the United States. ClinTher. 2009;31:644-656.9.Wu EQ, Greenberg PE, Yang E, et al. Treatment persistence, healthcare utilisationand costs in adult patients with major depressive disorder: a comparison betweenescitalopram and other SSRI/SNRIs. J Med Econ. 2009;12:124-135.10. Burke WJ, Gergel I, Bose A. Fixed-dose trial of the single isomer SSRI escitalo-pram in depressed outpatients. J Clin Psychiatry. 2002;63:331-336.11. Lepola UM, Loft H, Reines EH. Escitalopram (10-20 mg/day) is effective andwell tolerated in a placebo-controlled study in depression in primary care. Int ClinPsychopharmacol. 2003;18:211-217.12. Rapaport MH, Bose A, Zheng H. Escitalopram continuation treatment preventsrelapse of depressive episodes. J Clin Psychiatry. 2004;65:44-49.13. Wade A, Despiegel N, Heldbo Reines E. Escitalopram in the long-term treat-ment of major depressive disorder. Ann Clin Psychiatry. 2006;18:83-89.14.Moore N, Verdoux H, Fantino B. Prospective, multicentre, randomized, double-blind study of the efficacy of escitalopram versus citalopram in outpatient treatmentof major depressive disorder. Int Clin Psychopharmacol. 2005;20:131-137.15. Wu E, Greenberg PE, Yang E, et al. Comparison of escitalopram versus citalo-pram for the treatment of major depressive disorder in a geriatric population. CurrMed Res Opin. 2008;24:2587-2595.16. Antidepressant medication management. The state of health care quality 2006.National Committee for Quality Assurance; Washington, DC; 2006. www.ncqa.org/Portals/0/Publications/Resource%20Library/SOHC/SOHC_2006.pdf. Accessed Feb -ruary 28, 2011.17. McCombs JS, Luo M, Johnstone BM, Shi L. The use of conventional antipsy-chotic medications for patients with schizophrenia in a Medicaid population: thera-peutic and cost outcomes over 2 years. Value Health. 2000;3:222-231.18. Deyo RA, Cherkin DC, Ciol MA. Adapting a clinical comorbidity index for usewith ICD-9-CM administrative databases. J Clin Epidemiol. 1992;45:613-619.19. Birnbaum HG, Ben-Hamadi R, Greenberg PE, et al. Determinant of direct costdifferences among US employees with major depressive disorders using antidepres-sants. Pharmacoeconomics. 2009;27:507-517.20. Patient compliance in depression. Based on a presentation by James Jefferson,MD. Am J Manag Care. 2000;6(2 suppl):S31-S38.21. Revicki DA, Simon GE, Chan K, et al. Depression, health-related quality of life,and medical cost outcomes of receiving recommended levels of antidepressant treat-ment. J Fam Pract. 1998;47:446-452.22. Thompson D, Buesching D, Gregor KJ, Oster G. Patterns of antidepressant useand their relation to costs of care. Am J Manag Care. 1996;2:1239-1246.23. Demyttenaere K, Hemels ME, Hudry J, Annemans L. A cost-effectiveness modelof escitalopram, citalopram,and venlafaxine as first-line treatment for major depres-



sive disorder in Belgium. Clin Ther. 2005;27:111-124.24.Hemels ME, Kasper S, Walter E, Einarson TR. Cost-effectiveness of escitalopramversus citalopram in the treatment of severe depression. Ann Pharmacother. 2004;38:954-960.25. Sullivan PW, Valuck R, Saseen J, MacFall HM. A comparison of the direct costsand cost effectiveness of serotonin reuptake inhibitors and associated adverse drugreactions. CNS Drugs. 2004;18:911-932.26. Wade AG, Toumi I, Hemels ME. A probabilistic cost-effectiveness analysis ofescitalopram, generic citalopram and venlafaxine as a first-line treatment of majordepressive disorder in the UK. Curr Med Res Opin. 2005;21:631-642.27.Wade AG, Toumi I, Hemels ME. A pharmacoeconomic evaluation of escitalo-

pram versus citalopram in the treatment of severe depression in the United Kingdom.Clin Ther. 2005;27:486-496.28. Hess LM, Raebel MA, Conner DA, Malone DC. Measurement of adherence inpharmacy administrative databases: a proposal for standard definitions and preferredmeasures. Ann Pharmacother. 2006;40:1280-1288.29. Turner BJ, Newschaffer CJ, Zhang D, et al. Antiretroviral use and pharmacy-based measurement of adherence in postpartum HIV-infected women. Med Care.2000;38:911-925.30. Wilensky J, Fiscella RG, Carlson AM, et al. Measurement of persistence andadherence to regimens of IOP-lowering glaucoma medications using pharmacyclaims data. Am J Ophthalmol. 2006;141(1 suppl):S28-S33.

Efficacy and Cost-Effectiveness: Escitalopram versus Citalopram MEDICAL/PHARMACY DIRECTORS: Despite

the availability of several generic options, antidepres-sants remain in the top 5 therapeutic drug classes interms of spending. Currently, 2 brand-name agentsmaintain substantial market share—escitalopram andduloxetine. Claims data collected from January 1, 2003, to June

30, 2005, were analyzed as part of this study. Duringthat time, few payers required step therapy with ageneric antidepressant, but many payers have sinceimplemented step therapy for antidepressants.However, few payers require the use of citalopramspecifically before escitalopram. With so many antide-pressants available, a stepwise approach using escitalo-pram after failure of citalopram may not make sense,because of their molecular similarity.The scope of the present study is a little narrow with

regard to how many plans manage the entire class ofantidepressants. Although the study results are veryinteresting, questions remain, such as what doses ofcitalopram and escitalopram were used; what was theeffect of promotion/sampling; what was the differencein patient responsibility (ie, copay/coinsurance); andwhy was the drug cost higher in the citalopram group?In a very recent study, researchers evaluated persis -

tence of brand and generic antidepressants, concludingthat the likelihood of discontinuing therapy was similarfor patients who initiated therapy with brand or withgeneric antidepressants.1 They also noted that short-term pharmacy and healthcare costs were lower inpatients starting generic therapy.1And a 2009 meta-analysis comparing the efficacy

and acceptability of 12 new-generation antidepressantsshowed that escitalopram and sertraline have the bestprofile of acceptability, leading to fewer discontinua-tions compared with other antidepressants.2 Further

analysis suggested that sertraline might be the bestchoice when starting treatment, because of the favor-able balance between benefits, acceptability, andacquisition cost.2Generic availability of escitalopram and duloxetine

are expected within the next 18 months. Therefore,the discussion of restrictions specific to escitaloprammay soon be a moot point. However, with new andfuture antidepressants becoming available, such as therecently approved vilazodone, and the expense of atyp-ical antipsychotics for the treatment of depression, uti-lization management techniques will continue to be atopic of interest. Overall healthcare costs and drugacquisition costs will continue to be evaluated to deter-mine coverage requirements.PATIENTS: As this present study shows, discon-

tinuation of antidepressant therapy within 6 months isvery high. Additional studies have demonstrated pooradherence with other antidepressants as well. Thechoice of an antidepressant should be individualized tothe patient based on past therapy, published clinicaldata, adverse event profiles, and overall cost-effective-ness of the therapy. Regardless of the therapy chosen,patient education is key. Understanding the length oftherapy required to see an effect and expected mini-mum duration of therapy, and knowing potential sideeffects, will likely increase adherence.

1. Vlahiotis A, Devine ST, Eichholz J, Kautzner A. Discontinuation rates and healthcare costs in adult patients starting generic versus brand SSRI or SNRI antidepressantsin commercial health plans. J Manag Care Pharm. 2011;17:123-132.2. Cipriani A, Furukawa TA, Salanti G, et al. Comparative efficacy and acceptabilityof 12 new-generation antidepressants: a multiple-treatments meta-analysis. Lancet.2009;373:746-758.

Matthew Mitchell, PharmD, MBAManager, Pharmacy Services

SelectHealth, Salt Lake City, UT

STAKEHOLDER PERSPECTIVE

INDICATION

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

IMPORTANT RISK INFORMATION

WARNING: POTENTIAL FOR ABUSE, IMPORTANCE OF PROPER PATIENT SELECTION AND LIMITATIONS OF USE

Potential for AbuseEXALGO contains hydromorphone, an opioid agonist and a Schedule II controlled substance with an abuse liability similar to other opioid analgesics. EXALGO can be abused in a manner similar to other opioid agonists, legal or illicit. These risks should be considered when administering, prescribing, or dispensing EXALGO in situations where the healthcare professional is concerned about increased risk of misuse, abuse, or diversion. Schedule II opioid substances which include hydromorphone, morphine, oxycodone, fentanyl, oxymorphone and methadone have the highest potential for abuse and risk of fatal overdose due to respiratory depression.

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

EXALGO is for use in opioid tolerant patients only.

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

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

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

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

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

• EXALGO is also contraindicated in patients who:

- need management of mild pain or pain not expected to persist

- have signifi cant impaired respiratory function including those with acute or severe bronchial asthma or hypercarbia.

- have or are suspected to have paralytic ileus

- have narrowed or obstructed gastrointestinal tract including those from previous surgery or “blind loops” in the GI tract

- have known hypersensitivity to any components including hydromorphone hydrochloride and sulfi tes.

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

• Not intended in patients who have received MAO inhibitors within 14 days of starting EXALGO.

• Use with caution and in reduced doses in older or debilitated patients, as well as patients with renal or hepatic insuffi ciency, Addison’s disease, delirium tremens, myxedema or hypothyroidism, prosthetic hypertrophy or urethral stricture, toxic psychosis. May aggravate convulsions in patients with convulsive disorders; may induce or aggravate seizures in some clinical settings. Consider use of an alternate

analgesic in patients with severe renal impairment.

• Respiratory depression, which occurs more frequently in elderly or debilitated patients, is the chief hazard with EXALGO.

• Most common adverse events (>10%) seen in clinical studies (N=2474) were: constipation (31%), nausea (28%), vomiting, somnolence, headache, asthenia and dizziness. Serious adverse events could also include head injury, hypotensive effects, GI effects, cardiac arrest from overdose and precipitation of withdrawal.

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

• Do not abruptly discontinue EXALGO

Please see brief summary of Full Prescribing Information, including boxed warning on following pages.

COVIDIEN, COVIDIEN with logo and Covidien logo are U.S. and internationally registered trademarks of Covidien AG.EXALGO is a registered trademark of Mallinckrodt Inc.© 2011 Mallinckrodt Inc., a Covidien company. MK20024 January 2011 Printed in USA.

4:23:19 PM

®

Up. Down. Up. Down. Up. Down. Will the lack of steady blood levels be your chronic pain patients’ downfall?

EXALGO 16 mg q24hHydromorphone IR 4 mg q6h4

3

2

1

0Plas

ma

Hyd

rom

orph

one

(ng/

mL)

Day 5 Postdose

Hour 6 Hour 12 Hour 18 Hour 24

• Comparable in bioavailability with immediate-release (IR) hydromorphone given 4 times daily

Once-daily EXALGO® reaches steady-state concentrations in 3 to 4 days, reducing peaks and troughs.1

EXALGO. The power of hydromorphone in a once-daily dose.

With 24-hour, extended-release hydromorphone, EXALGO helps minimize peaks and troughs at steady state. So, your patients don’t have to worry as much about when their medication may wear off. To fi nd out more, visit www.keeppainwaiting.com.

Reference: 1. EXALGO® Prescribing Information.

1-2 4:23:19 PM

EXALGO® (hydromorphone HCl)Extended-Release Tablets

WARNING: POTENTIAL FOR ABUSE, IMPORTANCE OF PROPER PATIENTSELECTION AND LIMITATIONS OF USE

Potential for AbuseEXALGO contains hydromorphone, an opioid agonist and a Schedule II controlled substance with an abuse liability similar to other opioid analgesics. EXALGO can be abused in a manner similar to other opioid agonists, legal or illicit. These risks should be considered when administering, prescribing, or dispensing EXALGO in situations where the healthcare professional is concerned about increased risk of misuse, abuse, or diversion. Schedule II opioid substances which include hydromorphone, morphine, oxycodone, fentanyl, oxymorphone and methadone have the highest potential for abuse and risk of fatal overdose due to respiratory depression [see Drug Abuse and Dependence (9)].

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

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

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

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

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

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

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

CONTRAINDICATIONSOpioid Non-Tolerant PatientsEXALGO is contraindicated in opioid non-tolerant patients. Fatal respiratory depression could occur in patients who are not opioid tolerant. Impaired Pulmonary FunctionEXALGO is contraindicated in patients with significant respiratory depression, especially in the absence of resuscitative equipment or in unmonitored settings and in patients with acute or severe bronchial asthma or hypercarbia.Paralytic IleusEXALGO is contraindicated in patients who have or are suspected of having a paralytic ileus. Preexisting Gastrointestinal (GI) Surgery or Narrowing of GI TractEXALGO is contraindicated in patients who have had surgical procedures and/or underlying disease that would result in narrowing of the gastrointestinal tract, or have “blind loops” of the gastrointestinal tract or gastrointestinal obstruction. Allergy or HypersensitivityEXALGO is contraindicated in patients with known hypersensitivity to any of its components including the active agent, hydromorphone hydrochloride or known allergy to sulfite-containing medications [see Warnings and Precautions (5.8)].

WARNINGS AND PRECAUTIONSInformation Essential for Safe AdministrationEXALGO tablets are to be swallowed whole, and are not to be broken, chewed, crushed, dissolved or injected. Taking broken, chewed, crushed, dissolved EXALGO or its contents leads to the rapid release and absorption of a potentially fatal dose of hydromorphone [see Boxed Warning]. EXALGO is for use only in opioid tolerant patients. Ingestion of EXALGO may cause fatal respiratory depression when administered to patients who are not opioid tolerant [see Boxed Warning].EXALGO tablets must be kept in a secure place out of the reach of children. Accidental consumption of EXALGO, especially in children, can result in a fatal overdose of hydromorphone.Misuse and AbuseEXALGO contains hydromorphone, an opioid agonist, and is a Schedule II controlled substance. Opioid agonists have the potential for being abused and are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. EXALGO can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or dispensing EXALGO in situations where the healthcare professional is concerned about an increased risk of misuse, abuse, or diversion. Breaking, crushing, chewing, or dissolving the contents of an EXALGO tablet results in the uncontrolled delivery of the opioid and poses a significant risk of overdose and death [see Drug Abuse and Dependence (9)]. If attempts are made to extract the drug from the hard outer shell for purposes of parenteral abuse, the injection of tablet excipients may be toxic and may result in lethal complications. Concerns about abuse, addiction, and diversion should not prevent the proper management of pain. However, all patients treated with opioids, including EXALGO, require careful monitoring for signs of abuse and addiction, since use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Healthcare professionals should contact their State Professional Licensing Board or State Controlled Substances Authority for information on how to prevent and detect abuse or diversion of this product.

Respiratory Depression Respiratory depression is the chief hazard of EXALGO. Respiratory depression occurs more frequently in elderly or debilitated patients as well as those suffering from conditions accompanied by hypoxia or hypercapnia when even moderate therapeutic doses may dangerously decrease pulmonary ventilation, and when opioids are given in conjunction with other agents that depress respiration.Use EXALGO with extreme caution in patients with conditions accompanied by hypoxia, hypercapnia, or decreased respiratory reserve such as asthma, chronic obstructive pulmonary disease or cor pulmonale, severe obesity, sleep apnea, myxedema, kyphoscoliosis or CNS depression. In these patients, even moderate therapeutic doses of hydromorphone may decrease respiratory drive while simultaneously increasing airway resistance to the point of apnea. In these patients, consider alternative non-opioid analgesics, and use EXALGO only under careful medical supervision at the lowest effective dose.

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

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

Hypotensive EffectEXALGO may cause severe hypotension. There is added risk to individuals whose ability to maintain blood pressure has been compromised by a depleted blood volume, or after concurrent administration with drugs such as phenothiazines, general anesthetics, or other agents that compromise vasomotor tone. Administer EXALGO with caution to patients in circulatory shock, since vasodilation produced by the drug may further reduce cardiac output and blood pressure.

Gastrointestinal EffectsBecause the EXALGO tablet is nondeformable and does not appreciably change in shape in the GI tract, do not administer EXALGO to patients with preexisting severe gastrointestinal narrowing (pathologic or iatrogenic, for example: esophageal motility disorders small bowel inflammatory disease, “short gut” syndrome due to adhesions or decreased transit time, past history of peritonitis, cystic fibrosis, chronic intestinal pseudoobstruction, or Meckel’s diverticulum). There have been reports of obstructive symptoms in patients with known strictures or risk of strictures, such as previous GI surgery, in association with the ingestion of drugs in nondeformable extended-release formulations. The administration of EXALGO may obscure the diagnosis or clinical course in patients with acute abdominal condition.It is possible that EXALGO tablets may be visible on abdominal x-rays under certain circumstances, especially when digital enhancing techniques are utilized.

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

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

Special Risk GroupsEXALGO should be administered with caution in elderly (≥ 65 years) and debilitated patients and in patients who are known to be sensitive to central nervous system depressants, such as those with cardiovascular, pulmonary, renal, or hepatic disease [see Use in Specific Populations (8)].EXALGO should also be used with caution in the following conditions: adrenocortical insufficiency (e.g., Addison’s disease); delirium tremens; myxedema or hypothyroidism; prostatic hypertrophy or urethral stricture; and, toxic psychosis. EXALGO may aggravate convulsions in patients with convulsive disorders, and all opioids may induce or aggravate seizures in some clinical settings.

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

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

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

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

Clinical Studies ExperienceBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.EXALGO was administered to a total of 2,524 patients in 15 controlled and uncontrolled clinical studies. Of these, 423 patients were exposed to EXALGO for greater than 6 months and 141 exposed for greater than one year. The overall incidence of adverse reactions in patients greater than 65 years of age was higher, with a greater than 5% difference in rates for constipation and nausea when compared with younger patients. The overall incidence of adverse reactions in female patients was higher, with a greater than 5% difference in rates for nausea, vomiting, constipation and somnolence when compared with male patients.A 12-week double-blind, placebo-controlled, randomized withdrawal study was conducted in opioid tolerant patients with moderate to severe low back pain [see Clinical Studies (14)]. A total of 447 patients were enrolled into the open-label titration phase with 268 patients randomized into the double-blind treatment phase. The adverse reactions that were reported in at least 2% of the patients are contained in Table 1.

Table 1. Number (%) of Patients with Adverse Reactions Reported in ≥2% of

Patients with Moderate to Severe Low Back Pain During the Open-Label Titration Phase or Double-Blind Treatment Phase by Preferred Term

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

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

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

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

a Fatigue was grouped and reported with asthenia b Decreased appetite was grouped and reported with anorexia c Abdominal pain upper was grouped and reported with abdominal pain d Reflux esophagitis, gastroesophageal reflux disease and Barrett’s esophagus were grouped and

reported with dyspepsia e Dyspnea exacerbated and dyspnea exertional were grouped and reported with dyspnea f Chest pain and non-cardiac chest pain were grouped and reported with chest discomfort

BRIEF SUMMARY - Consult fullprescribing information before use.

The following Adverse Reactions occurred in patients with an overall frequency of <2% and are listed in descending order within each System Organ Class:Cardiac disorders: palpitations, tachycardia, bradycardia, extrasystolesEar and labyrinth disorders: vertigo, tinnitus Endocrine disorders: hypogonadismEye disorders: vision blurred, diplopia, dry eye, miosis Gastrointestinal disorders: flatulence, dysphagia, hematochezia, abdominal distension, hemorrhoids, abnormal feces, intestinal obstruction, eructation, diverticulum, gastrointestinal motility disorder, large intestine perforation, anal fissure, bezoar, duodenitis, ileus, impaired gastric emptying, painful defecation General disorders and administration site conditions: chills, malaise, feeling abnormal, feeling hot and cold, feeling jittery, hangover, difficulty in walking, feeling drunk, hypothermiaInfections and infestations: gastroenteritis, diverticulitisInjury, poisoning and procedural complications: contusion, overdoseInvestigations: weight decreased, hepatic enzyme increased, blood potassium decreased, blood amylase increased, blood testosterone decreased, oxygen saturation decreasedMetabolism and nutrition disorders: dehydration, fluid retention, increased appetite, hyperuricemiaMusculoskeletal and connective tissue disorders: myalgia Nervous system disorders: tremor, sedation, hypoesthesia, paraesthesia, disturbance in attention, memory impairment, dysarthria, syncope, balance disorder, dysgeusia, depressed level of consciousness, coordination abnormal, hyperesthesia, myoclonus, dyskinesia, hyperreflexia, encephalopathy, cognitive disorder, convulsion, psychomotor hyperactivityPsychiatric disorders: confusional state, nervousness, restlessness, abnormal dreams, mood altered, hallucination, panic attack, euphoric mood, paranoia, dysphoria, listless, crying, suicide ideation, libido decreased, aggressionRenal and urinary disorders: dysuria, urinary retention, urinary frequency, urinary hesitation, micturition disorderReproductive system and breast disorders: erectile dysfunction, sexual dysfunction Respiratory, thoracic and mediastinal disorders: rhinorrhoea, respiratory distress, hypoxia, bronchospasm, sneezing, hyperventilation, respiratory depressionSkin and subcutaneous tissue disorders: erythema Vascular disorders: flushing, hypertension, hypotension

DRUG INTERACTIONSCNS DepressantsThe concomitant use of EXALGO with central nervous system depressants such as hypnotics, sedatives, general anesthetics, antipsychotics and alcohol may cause additive depressant effects and respiratory depression. Additionally, hypotension and profound sedation or coma could occur. When this combination is indicated, the dose of one or both agents should be reduced. The concomitant use of alcohol should be avoided [see Clinical Pharmacology (12.3)]. Monoamine Oxidase (MAO) Inhibitors MAO inhibitors may cause CNS excitation or depression, hypotension or hypertension if co-administered with opioids including EXALGO. EXALGO is not intended for patients taking MAO inhibitors or within 14 days of stopping such treatment.Mixed Agonist/Antagonist Opioid AnalgesicsThe concomitant use of EXALGO with morphine agonist/antagonists (buprenor-phone, nalbuphine, pentazocine) could lead to a reduction of the analgesic effect by competitive blocking of receptors, thus leading to risk of withdrawal symptoms. Therefore, this combination is not recommended.AnticholinergicsAnticholinergics or other medications with anticholinergic activity when used concurrently with EXALGO may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.Cytochrome P450 EnzymesIn vitro data suggest that hydromorphone in clinically relevant concentrations has minimal potential to inhibit the activity of human hepatic CYP450 enzymes including CYP1A2, 2C9, 2C19, 2D6, 3A4, and 4A11.

USE IN SPECIFIC POPULATIONSPregnancy Teratogenic Effects Pregnancy Category C: There are no adequate and well-controlled studies in pregnant women. Hydromorphone crosses the placenta. EXALGO should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus [see Use in Specific Populations (8.2)].Hydromorphone was not teratogenic in pregnant rats given oral doses up to 6.25 mg/kg/day or in pregnant rabbits administered oral doses up to 25 mg/kg/day during the period of organogenesis (~1.2 times the human exposure following 32 mg/day). Hydromorphone administration to pregnant Syrian hamsters and CF-1 mice during major organ development revealed teratogenicity likely the result of maternal toxicity associated with sedation and hypoxia. In Syrian hamsters given single subcutaneous doses from 14 to 258 mg/kg during organogenesis (gestation days 8 to 10), doses ≥ 19 mg/kg hydromorphone produced skull mal formations (exencephaly and cranioschisis). Continuous infusion of hydromorphone (5 mg/kg, s.c.) via implanted osmotic mini pumps during organogenesis (gestation days 7 to 10) produced soft tissue malformations (cryptorchidism, cleft palate, malformed ventricals and retina), and skeletal variations (supraoccipital, checkerboard and split sternebrae, delayed ossification of the paws and ectopic ossification sites). The malformations and variations observed in the hamsters and mice were at doses approximately three-fold higher and <one-fold lower, respectively, than a 32 mg human daily oral dose on a body surface area basis.Nonteratogenic EffectsIn the pre- and post-natal effects study in rats, neonatal viability was reduced at 6.25 mg/kg/day (~1.2 times the human exposure following 32 mg/day).Neonates born to mothers who have been taking opioids regularly prior to delivery will be physically dependent. The withdrawal signs include irritability and excessive crying, tremors, hyperactive reflexes, increased respiratory rate, increased stools, sneezing, yawning, vomiting, and fever. The intensity of the syndrome does not always correlate with the duration of maternal opioid use or dose. There is no consensus on the best method of managing withdrawal. Approaches to the treatment of the syndrome have included supportive care and, if indicated, drugs such as paregoric or phenobarbital.

Labor and DeliveryEXALGO is not recommended for use in women during and immediately prior to labor and delivery. Administration of EXALGO to the mother shortly before delivery may result in some degree of respiratory depression in the neonate. However, neonates whose mothers received opioid analgesics during labor should be observed closely for signs of respiratory depression. Nursing MothersLow concentrations of hydromorphone have been detected in human milk in clinical trials. Withdrawal symptoms can occur in breastfeeding infants when maternal administration of an opioid analgesic is stopped. Nursing should not be undertaken while a patient is receiving EXALGO since hydromorphone is excreted in the milk.Pediatric UseThe safety and effectiveness of EXALGO in pediatric patients 17 years of age and younger have not been established.Geriatric UseElderly patients have been shown to be more sensitive to the adverse effects of EXALGO compared to the younger population. Therefore, use extra caution when prescribing EXALGO in elderly patients and reduce the initial dose. Neonatal Withdrawal SyndromeChronic maternal use of opiates or opioids during pregnancy coexposes the fetus. The newborn may experience subsequent neonatal withdrawal syndrome (NWS). Manifestations of NWS include irritability, hyperactivity, abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea, weight loss, and failure to gain weight. The onset, duration, and severity of the disorder differ based on such factors as the addictive drug used, time and amount of mother’s last dose, and rate of elimination of the drug from the newborn. Approaches to the treatment of this syndrome have included supportive care and, when indicated, drugs such as paregoric or phenobarbital.Hepatic ImpairmentIn a study that used a single 4 mg oral dose of immediate-release hydromor-phone tablets, four-fold increases in plasma levels of hydromorphone (Cmax and AUC0- ) were observed in patients with moderate hepatic impairment (Child-Pugh Group B). Start patients with moderate hepatic impairment on a reduced dose and closely monitored during dose titration. The pharmacokinetics of hydromorphone in severe hepatic impairment patients have not been studied. Further increase in Cmax and AUC0- of hydromorphone in this group is expected, therefore, use an even more conservative starting dose [see Dosage and Administration (2.4)].Renal ImpairmentRenal impairment affected the pharmacokinetics of hydromorphone and its metabolites following administration of a single 4 mg dose of immediate-release tablets. The effects of renal impairment on hydromorphone pharmacokinetics were two-fold and four-fold increases in plasma levels of hydromorphone (Cmax and AUC0-48h) in moderate (CLcr = 40 to 60 mL/min) and severe (CLcr < 30 mL/min) impairment, respectively. In addition, in patients with severe renal impairment hydromorphone appeared to be more slowly eliminated with longer terminal elimination half-life (40 hours) compared to subjects with normal renal function (15 hours). Start patients with moderate renal impairment on a reduced dose and closely monitored during dose titration. As EXALGO is only intended for once daily administration, consider use of an alternate analgesic that may permit more flexibility with the dosing interval in patients with severe renal impairment [see Dosage and Administration (2.4)].

DRUG ABUSE AND DEPENDENCEControlled SubstanceEXALGO contains hydromorphone, a Schedule II controlled substance with a high potential for abuse similar to fentanyl, methadone, morphine, oxycodone, and oxymorphone. EXALGO can be abused and is subject to misuse, abuse, addiction, and criminal diversion [see Warnings and Precautions (5.2)]. The high drug content in the extended release formulation adds to the risk of adverse outcomes from abuse.Abuse All patients treated with opioids, including EXALGO, require careful monitoring for signs of abuse and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use.Addiction is a primary, chronic, neurobiologic disease, with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving. “Drug-seeking” behavior is very common to addicts and drug abusers. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated claims of loss of prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact information for other treating physician(s). “Doctor shopping” (visiting multiple prescribers) to obtain additional prescriptions is common among drug abusers, people suffering from untreated addiction and criminals seeking drugs to sell. Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction and is characterized by misuse for non-medical purposes, often in combination with other psychoactive substances. Since EXALGO may be diverted for non-medical use, careful record-keeping of prescribing information, including quantity, frequency, and renewal requests is strongly advised. Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. EXALGO is intended for oral use only. Misuse or abuse by breaking, crushing, chewing, or dissolving EXALGO poses a hazard of overdose and death. This risk is increased with concurrent abuse of EXALGO with alcohol and other substances. With intravenous abuse, the tablet excipients, especially polyethylene oxide, can be expected to result in necrosis and inflammation of cardiac tissues. In addition, parenteral drug abuse is commonly associated with transmission of infectious disease such as hepatitis and HIV.Healthcare professionals should contact their State Professional Licensing Board or State Controlled Substances Authority for information on how to prevent and detect abuse or diversion of this product.DependenceTolerance is a state of adaptation in which exposure to a drug induces changes that result in a diminution of one or more of the drug’s effects over time.

Tolerance could occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects.Physical dependence is a state of adaptation that is manifested by an opioid specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist. The opioid abstinence or withdrawal syndrome is characterized by some or all of the following: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, piloerection, myalgia, mydriasis, irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, increased blood pressure, respiratory rate, or heart rate.Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal symptoms [see Use in Specific Populations (8.1, 8.2)].

OVERDOSAGESymptomsAcute overdosage with opioids can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and sometimes bradycardia, hypotension and death. The extended release characteristics of EXALGO should also be taken into account when treating the overdose. Even in the face of improvement, continued medical monitoring is required because of the possibility of extended effects. Deaths due to overdose could occur with abuse and misuse of EXALGO.Due to the delayed mean apparent peak plasma level of EXALGO occurring at 16 hours following administration as well as the 11 hour mean elimination half-life of EXALGO, patients who receive an overdose will require an extended period of monitoring and treatment that may go beyond 24 to 48 hours. TreatmentGive primary attention to the re-establishment of a patent airway and institution of assisted or controlled ventilation. Employ supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema accompanying overdose as indicated. Cardiac arrest or arrhythmias will require advanced life support techniques.The pure opioid antagonists, such as naloxone and naltrexone are specific antidotes to respiratory depression from opioid overdose. Since the duration of reversal would be expected to be less than the duration of action of hydromorphone in EXALGO, the patient must be carefully monitored until spontaneous respiration is reliably re-established. EXALGO will continue to release and add to the hydromorphone load for up to 24 hours after administration and the management of an overdose should be monitored accordingly, at least 24 to 48 hours beyond the overdose.Only administer opioid antagonists in the presence of clinically significant respiratory or circulatory depression secondary to hydromorphone overdose. In patients who are physically dependent on any opioid agonist including EXALGO, an abrupt or complete reversal of opioid effects may precipitate an acute abstinence syndrome. The severity of the withdrawal syndrome produced will depend on the degree of physical dependence and the dose of the antagonist administered. Please see the prescribing information for the specific opioid antagonist for details of their proper use.

OROS is a registered trademark of ALZA Corporation.EXALGO is a registered trademark of Mallinckrodt Inc.COVIDIEN, COVIDIEN with logo and Covidien logo are U.S. and/or internationally registered trademarks of Covidien AG.

© 2010 Mallinckrodt Inc., a Covidien company

Distributed by:Mallinckrodt Brand Pharmaceuticals, Inc.Hazelwood, MO 63042 USA

Issued 11/2010

Mallinckrodt

3-4 4:23:22 PM


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

Readers are invited to submit articles that aim at improving the quality of patient care and patient well-being, the healthof communities and patient populations, as well as other topics relevant to benefit design with specific implications topolicymakers, payers, and employers.

Manuscripts should follow the Manuscript Instructions for Authors (available at www.AHDBonline.com).For more information, call 732-992-1892

CALL FOR PAPERS

Areas of High Interest Include:

• Adherence Concerns

• Benefit Design

• Case Studies

• Comparative Effectiveness Research

• Cost Analyses

• Decision-Making Tools

• Ethics in Medicine

• Health Economics Research

• Health Plan Initiatives

• Health Information Technology

• Industry Trends

• Innovations in Healthcare

• Literature Reviews

• Medicare/Medicaid

• Patient Advocacy/Patient Care

• Pharmacoeconomics

• Policy Issues

• Prevention Initiatives

• Reimbursement Strategies

• Survey Results

• Wellness Programs

AGING/DEMENTIA—With the aging of the US populationthere is a growing need for early implementation of outcome-based preventive and therapeutic strategies for older people.

ALLERGIES—Allergies, such as allergic or seasonal rhinitis,affect millions of Americans daily, resulting in a significanteconomic burden and human cost. Under treatment and lackof adherence are common obstacles to patient management.

ARTHRITIS—Musculoskeletal conditions are on theincrease, yet many patients are undiagnosed and untreated.Comparing new and available therapies is a key target forimproving patient outcomes and reducing costs.

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

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

DIABETES, OBESITY—The increasing comorbidepidemics of these twin conditions mandates a thoroughexamination of best therapies, adherence issues, access, andprevention strategies. We invite articles that will addresshow to improve patient outcomes and best patient care.

GASTROINTESTINAL CONDITIONS—RecognizingGI conditions, such as hepatitis C, Crohn’s disease, orinflammatory bowel disorder, remains a challenge.

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

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

PAIN MANAGEMENT—Chronic pain is associated witha slew of complicated medical disorders and an enormouseconomic burden, yet pain medications are still underused.

Clinical Topics of Interest Include:

NOTE TO AUTHORS: AHDB is a member of the Committee on Publication Ethics (COPE). Membership in COPEindicates that this journal upholds COPE’s Code of Conduct standards and intends to take appropriate action in cases ofpossible misconduct, such as plagiarism, attempted or actual redundant publication, any attempts to pass off fraudulentdata, unethical research, or breaches of confidentiality.

BUSINESS


Nearly 96% of all employers allow employees andcovered beneficiaries to fill medication prescrip-tions from either retail or mail-service pharma-

cy.1 In 2009, mail-service pharmacies dispensed approxi-mately 238 million prescriptions, representing 6.6% ofthe 3.6 billion prescriptions dispensed that year.2 Mail-service pharmacies have enjoyed high levels of consumersatisfaction.3 Mail-service pharmacies offer consumersthe convenience of home delivery, online ordering andrenewal processes, and prescriptions filled with a 90-daysupply of medication.Unlike mail-service pharmacies, retail pharmacies

traditionally dispensed maintenance medication pre-scriptions with a 30-day supply. However, the retail land-

scape changed in May 2008 with Walmart’s announce-ment of an extension of the $4 Prescription Program toinclude 90-day-supply prescriptions of select mainte-nance medications for $10.4 Although positioned prima-rily as a program to lower drug costs for the uninsured fora limited number of chronic medications, the programwas available to virtually all consumers. Many retailpharmacy chains followed this lead, instituting similarlow-cost, 90-day-supply drug programs. For individuals with a pharmacy insurance benefit,

access to a 90-day supply of maintenance medications,either through mail or retail pharmacy, expanded aspayers and pharmacy benefits managers (PBMs) beganenhancing their retail pharmacy networks and pharma-cy benefit designs. As a response to these initiatives,CVS Caremark, Rite Aid Health Solutions, andWalgreens Health Initiatives now offer programs thatallow consumers to receive 90-day-supply prescriptionsvia mail or retail pharmacy. Today, even stand-alone

Dr Liberman was Vice President, Strategic Research, CVSCaremark, Hunt Valley, MD, at the time of this research,and Ms Girdish is Senior Analyst, Strategic Research, CVSCaremark, Scottsdale, AZ.

ORIGINAL RESEARCH

Recent Trends in the Dispensing of 90-Day-Supply Prescriptions at RetailPharmacies: Implications for ImprovedConvenience and AccessJoshua N. Liberman, PhD; Charmaine Girdish, MPH

Background: Mail-service pharmacies offer consumers the convenience of prescriptionsfilled with a 90-day supply of medication. Unlike mail-service pharmacies, retail pharmaciestraditionally dispensed maintenance medication prescriptions with a 30-day supply. However,the retail landscape changed in May 2008 with Walmart’s announcement of an extension ofits $4 Prescription Program to include 90-day-supply prescriptions.Objective: To evaluate recent changes in access to and use of 90-day-supply maintenancemedications dispensed via retail pharmacy.Summary: As of the first quarter of 2007, the proportion of retail-dispensed maintenancemedications with a 90-day supply (compared with all maintenance prescriptions dispensed)among Medicare Part D plans, self-insured employers, and private health plans was 5.1%,5.1%, and 5.0%, respectively. As of December 2009, this ratio had risen to 8.0% for Medicareplans and 8.1% for commercial health plans; the ratio among employers had risen more mod-estly to 6.1%. Of particular interest and importance, the proportion increased similarly forbrand and for generic medications.Conclusion: There has been substantial growth in 90-day prescriptions dispensed via retailpharmacy, a trend that is likely to continue as more insurance providers adopt compatible ben-efit designs. It is important to continue monitoring these trends and to identify opportunities torigorously evaluate their impact on medication adherence and healthcare costs.




Joshua N. Liberman

BUSINESS


PBMs, such as Express Scripts and Medco HealthSolutions, have retail pharmacy networks that accom-modate 90-day prescriptions. According to the 2010-2011 Prescription Drug

Benefit Cost and Plan Design report, 96.3% of employersoffer access to mail-service pharmacy for maintenancemedications (routinely dispensed with 90-day supplies)but 58.3% also use retail pharmacies to dispense mainte-nance supplies of medications.1The availability of prescriptions with an expanded-

day supply in retail pharmacies may have importantimplications for medication adherence. Recent evalua-tions of mail-service pharmacy have documentedimproved medication adherence compared with pre-scriptions dispensed with 30-day supplies via retail phar-macy, in large part because of the availability of extend-ed-day supply dispensed with each prescription.5,6 Yetdespite the recent expansion of 90-day prescription drugaccess at retail pharmacies, little has been documentedin peer-reviewed literature about the use of these pro-

grams by consumers. Understanding this trend hasimportant implications for payers and patients.

MethodsTo document recent medication trends, we measured

changes in paid pharmacy claims purchased at retailpharmacies and adjudicated by CVS Caremark duringthe 3-year period from 2007 through 2009. To be eligi-ble, a payer had to fulfill the following criteria: • Provide covered beneficiaries with pharmacy insurancebenefits administered by CVS Caremark continuouslyfrom January 1, 2007, through December 31, 2009

• Not mandate maintenance medications to be dis-pensed by a mail-service pharmacy

• Have no more than ±15% change in average mem-bership between calendar years 2008 and 2009.During the study period (2007-2009), the use of 90-

day-supply prescriptions among Medicaid beneficiarieswas negligible and thus excluded. Eligible paid pharmacyclaims were (1) submitted by a retail pharmacy, (2) des-ignated as a maintenance medication by either Medi-Span or First DataBank, and (3) adjudicated and paidduring the 3-year study period. In January 2009, CVS Caremark launched Main -

tenance Choice—a pharmacy benefit design which, ingeneral, provides members with the choice of receivingtheir 90-day prescriptions through CVS Caremark mail-service pharmacy or at a CVS/pharmacy retail locationfor the same out-of-pocket (ie, copayment) cost as a mailprescription. Because the CVS Caremark PBM dataoverrepresents this Maintenance Choice pharmacy ben-efit, we stratified the results by retail pharmacy—CVS/pharmacy versus all other retail pharmacies. The overall trend in dispensing 90-day prescriptions

was tested for statistical significance using the Cochran-Armitage test for trend, testing the frequency of 90-day–supply prescriptions monthly over the study period.

ResultsIn total, we included 467 million claims adjudicated

for 27 million members covered by 1115 insurers.Figure 1 (page 97) displays the percent of maintenanceprescriptions dispensed with a 90-day supply (there-after, 90-day ratio) from January 2007 throughDecember 2009. As of the first quarter of 2007, the 90-day ratio was 5.1%, 5.1%, and 5.0% for Medicare PartD plans, self-insured employers, and private healthplans, respectively. As of December 2009, the 90-dayratio had risen to 8.0% for Medicare and 8.1% forhealth plans; the ratio among employers had risen moremodestly to 6.1%. Among the network of CVS/pharmacy retail stores,

the 90-day ratio increased by 13.4 percentage points

KEY POINTS

� Traditionally, retail pharmacies predominantlydispensed prescription medications for the treatmentof chronic disease with a 30-day-supply limit.

� However, in 2008 Walmart fundamentally changedaccess to retail pharmacy–dispensed 90-day-supplyprescriptions by launching a program to dispenseselect maintenance medications in 90-day suppliesfor $10 via its retail pharmacy.

� This current study measured changes in paidpharmacy claims between January 2007 andDecember 2009, using 467 million claims purchased at retail pharmacies and adjudicated byCVS Caremark.

� Results showed that in that 3-year period, the ratioof 90-day prescription dispensing increased from5.1% to 8.0% and from 5.0% to 8.1% amongbeneficiaries of select Medicare Part D andcommercial health plans, respectively.

� Recent studies have shown increased medicationadherence with expanded drug supply with mail-service pharmacies compared with retail pharmacies.It is therefore reasonable to assume that extendedaccess to medications in retail pharmacy is similarlylikely to improve adherence, which may haveimportant implications on overall healthcare costsand utilization.

� Studies are needed to investigate the impact of 90-day prescription supply at retail pharmacies onmedication adherence.

90-day-supply Prescriptions at Retail Pharmacies


among employers, with substantial increases subse-quent to the launch of Maintenance Choice. Of particular interest, the 90-day ratio increased simi-

larly for brand and generic medications, with the ratioincreasing by 3.3 percentage points for brand-name andfor generic drugs. Comparable increases were noted forgeneric drugs that were included on and omitted from the$10/90 generic drug program lists (Figure 2, page 98).The increase in dispensed 90-day prescriptions at retailpharmacies during this period was significant (P <.001).

DiscussionThe growth in the 90-day ratio reveals a preference by

consumers and further supports the growing body of evi-dence in support of offering consumers access to extend-ed-day supplies of prescriptions at mail and retail phar-macies. Consumers cite high levels of overall satisfactionwith retail and mail pharmacy services3,7,8 and valuechoice in pharmacy and prescription drug access.9According to recent market research conducted byWalgreens, nearly 4 of 5 patients stated a preference for

receiving their 90-day prescription at a retail pharmacyrather than by mail.10Furthermore, in a recent study of consumer pharmacy

preference, Liberman and colleagues showed that amongcommercially insured patients who transitioned frommandatory mail benefit to the Maintenance Choicebenefit, 66.3% of those initiating therapy without arecent mail pharmacy prescription and 23.7% of currentmail-service pharmacy users selected a retail pharmacyfor subsequent 90-day-supply prescriptions.11 This bene-fit design, however, in general charges the consumerwith the same copayment, regardless of the pharmacychannel selected. Not all pharmacy programs apply iden-tical copayments for mail or retail pharmacy dispensed as90-day prescriptions, and this will likely alter consumerpreference and program uptake. The growth in 90-day prescriptions at retail pharma-

cies has implications for medication adherence. In arecent study of 13,922 patients from the KaiserPermanente Northern California diabetes registry, Duruand colleagues reported that mail-order pharmacy users

Figure 1 Percent of Maintenance Prescriptions Filled as 90-Day Supply in Retail Pharmacies by Market Segment and Pharmacy

19.0

17.0

15.0

13.0

11.0

9.0

7.0

5.0

3.0

Walmart announces $10/90-day-supply retail drug program

CVS Caremark launchesMaintenance Choice

Pre

scriptions

, %

Period

Employer CVS/pharmacyEmployer other retailHealth plan all pharmaciesMedicare all pharmacies

Jan May Sep Jan May Sep Jan May Sep Dec 2007 2008 2009

BUSINESS


had better adherence to antiglycemic, antihypertensive,and dyslipidemic medications.6 In a study of oral anti -diabetic medication use, Devine and colleagues usedpropensity scores to match 14,600 cases to 43,800 con-trols selected from the MarketScan database.5 Afteradjustment, mail-service pharmacy users realized signifi-cantly higher adherence rates. In addition, the improvedadherence was associated with lower total and diabetes-related medical costs over time. Although we are unaware of any research that

demonstrates improved adherence with 90-day medica-tion access at retail pharmacy, it is reasonable to assumethat access to a 90-day supply of medication, regardlessof point of access (retail or mail), would be associatedwith an improvement in adherence and improved con-trol of many chronic conditions. If so, the recent studiesof mail-service pharmacy by Devine and colleagues andDuru and colleagues provide compelling, supporting evi-dence for that likely improvement in adherence.5,6

LimitationsThis analysis was limited to prescriptions managed

through insurance benefits of a major PBM. As such, itis potentially not representative of the consumer behav-ior related to prescriptions purchased without the use ofsuch insurance (ie, cash purchases) nor those related tosome government programs that provide beneficiariescopay assistance (ie, Medicaid). Furthermore, because of the increasing availability of

cash-only programs, it is possible that the actual accessto, and use of, 90-day prescription supplies are higherthan our estimates.

ConclusionOptimizing access to essential medications while

managing pharmacy expenditures is a key function ofPBMs.12 Benefit managers must weigh the potentialvalue of increased convenience against the potentialcosts of providing access through different distributionchannels. Nonetheless, the growth in 90-day prescrip-tions at retail pharmacy is likely to continue as moreinsurance providers adopt compatible benefit designs. Preliminary research indicates the potential benefits

to the consumer by providing greater convenience and

Jan May Sep Jan May Sep Jan May Sep Dec 2007 2008 2009

9.0

8.0

7.0

6.0

5.0

4.0

3.0

Pre

scriptions

, %

Figure 2 Percent of Retail Prescriptions Filled as 90-Day Supply by Brand and Generic Status

$10/90-day-supply generics

All maintenance brands

Non–$10/90-day-supply generics

Period

90-day-supply Prescriptions at Retail Pharmacies


satisfaction, and overall health benefits resulting fromimproved medication adherence. It is important to con-tinue monitoring these trends and to identify opportuni-ties to rigorously evaluate their impact on healthcarecosts and utilization. �

Author Disclosure StatementDr Liberman has reported no conflicts of interest. Ms

Girdish owns stock in CVS Caremark. CVS Caremarkprovided support for this study.

References1. Pharmacy Benefits Management Institute. Prescription Drug Benefit Cost andPlan Design Online Report, 2010-2011 Edition. www.pbmi.com/BenefitDesign.asp.Accessed December 9, 2010.2. National Association of Chain Drug Stores. Industry facts-at-a-glance. www.nacds.org/wmspage.cfm?parm1=6536#pharmpricing. Accessed September 9, 2010.3. Birtcher KK, Shepherd MD. Users’ perceptions of mail-service pharmacy. Am

Pharm. 1992;NS31:35-41.4.Walmart. Walmart launches phase three of $4 Prescription Program. May 5, 2008.http://walmartstores.com/pressroom/news/8248.aspx. Accessed September 9, 2010.5.Devine S, Vlahiotis A, Sundar H. A comparison of diabetes medication adherenceand healthcare costs in patients using mail order pharmacy and retail pharmacy. JMed Econ. 2010;13:203-211.6. Duru OK, Schmittdiel JA, Dyer WT, et al. Mail-order pharmacy use and adher-ence to diabetes-related medications. Am J Manag Care. 2010;16:33-40.7. J.D. Power and Associates. 2009 National Pharmacy Study. www.jdpower.com/healthcare/articles/2009-National-Pharmacy-Study/. Accessed February 25, 2011. 8. 90-day Rx solution. More health plans implement mandatory mail-order pharma-cy programs, yielding greater savings and adherence rates. Drug Benefit News.2010;11:1-2. www.silverlink.com/assets/pdfs/silverlinknews/dbn030510.pdf. AccessedMarch 11, 2011. 9.Desselle SP. Determinants of satisfaction with prescription drug plans. Am J HealthSyst Pharm. 2001;58:1110-1119.10. Business Wire. Walgreens to promote 90-day prescriptions at community phar-macies in Minneapolis. August 3, 2010. www.businesswire.com/news/home/20100803006228/en/Walgreens-Promote-90-Day-Prescriptions-Community-Pharmacies-Minneapolis. Accessed August 26, 2010.11. Liberman JN, Wang Y, Hutchins DS, et al. Revealed preference for retail andmail-service pharmacy. J Am Pharm Assoc. 2011;51:50-57. 12. Shrank WH, Porter ME, Jain SH, Choudhry NK. A blueprint for pharmacy ben-efit managers to increase value. Am J Manag Care. 2009;15:87-93.

When More Is Almost Always Better POLICYMAKERS/PAYERS: The current rela-

tionship between mail order versus retail dispensingand 30-day versus 90-day prescriptions seems artificial.That 90-day prescriptions come by mail and 30-dayprescriptions come from retail pharmacies is likely tobe a side effect of the marketplace and of competitionamong pharmacy benefit managers (PBMs), insurers,and pharmacies rather than a rational, patient-cen-tered approach to offering prescriptions. An alternative is seen in the Veterans Affairs (VA)

Healthcare System, where I practice. At the VA sys-tem, the 90-day prescriptions for chronic medications(ie, noncontrolled substances) is the standard, andthese typically come by mail, but some patients elect toreceive a partial fill at the window during the visit. The30-day prescriptions that are set to be dispensed at thewindow but are never picked up are subsequentlymailed directly to the patient. This synergy betweenretail and mail-order prescriptions creates rates ofabandonment of prescriptions of almost zero, unlikeoutside the VA system.1In the private sector, more options for where to fill

a prescription (and thus more competition) wouldlikely lower costs. Each of the players in the equation,however, faces financial risks if costs are lowered.

Pharmacies that fill 90-day prescriptions are likely toreceive fewer dispensing fees and lowered foot trafficthrough their pharmacies. These pharmacies couldalso, however, increase their market share if patientsbuy prescriptions at retail pharmacies instead of bymail. The mail-order operations run by PBMs facerisks of dropping market share if patients can obtain90-day prescription fills at retail pharmacies, althoughcentralized mail-order pharmacies can achieveeconomies of scale and drive generic dispensing, mak-ing it difficult for retail pharmacies to compete.Employers are likely to benefit on several levels, froma more satisfied and potentially more adherent (andthus healthier) workforce, to more choice in pharma-cy benefits.PATIENTS: From the patient’s perspective, it is

difficult to argue against the availability of 90-day sup-plies of prescriptions at retail pharmacies. The proposi-tion of offering more choices to patients for where andhow to fill their prescriptions seems, on the surface,easily justified. As the present article by Dr Libermanand Ms Girdish describes, there is some evidence ofgreater satisfaction and improved adherence with 90-day versus 30-day supplies. Although the evidence is by no means definitive,


Continued

BUSINESS


STAKEHOLDER PERSPECTIVE (Continued)

the conclusions make intuitive sense—I have yet tomeet a patient using ongoing, stable medications in myown practice who complains about having to comeback in 3 months for a prescription rather than in 1month. I do hear, however, patients who complainabout having to coordinate receiving their prescrip-tions from multiple sources, whether they get theirgenerics from low-cost retail pharmacies, their chronicdisease medications in the mail, and their acute-needmedication for their child (eg, antibiotic) from thepharmacy nearest to their workplace. The availability of 90-day supplies of medications

from retail pharmacies may offer patients the option ofreceiving their long-term medications at the same loca-tion (and from the same pharmacists) where they pickup their short-term medications or over-the-counterproducts—more choice, better adherence, lower costs.

1. Shrank WH, Choudhry NK, Fischer MA, et al. The epidemiology of prescrip-tions abandoned at the pharmacy. Ann Intern Med. 2010;153:633-640.

Walid F. Gellad, MD, MPHStaff Physician, VA Pittsburgh Healthcare System

Assistant Professor of Medicine, University of PittsburghAdjunct Scientist, RAND Health

CAPTION CONTEST

Submit your caption at

www.AHDBonline.com

Winners receive $50

Winners’ names will be posted online

Partnership. People. Programs. Passion. The Flexibility You Need. The Integrity You Deserve.

| M A N A G E D M A R K E T S Leaders in Business. Partners in Care.

Visit Takeda on the Web at www.tpna.com.

JOIN AHDB PEER REVIEWArticles fall into 3 main areas related to healthcare:Regulatory, Business, and Clinical. These main categoriesare represented from the different vantage points of allstakeholders in healthcare and are divided into manysubcategories, including (but not limited to):

® Administration/management® Benefit design® Disease management/state (eg, asthma, diabetes,

heart disease, infectious diseases, pain management, etc)® Drug therapy (including biologics, generics)® Drug utilization® Employers/health plans® Finance/health economics® Health information technology® Health policy/reform® Patient education/initiatives/quality-of-life issues ® Payer perspectives® Pharmacoeconomics analyses® Pharmacy management: pharmacology,

specialty pharmacy, pharmacy benefits® Reimbursement: Medicare/Medicaid,

health insurance, prior authorization® Research: methods, study design,

data collection/analysis

American Health & Drug Benefits(AHDB) is looking for medical

and pharmacy directors, P & T Committee members, andother healthcare experts who are

interested in joining our peerreviewers and assist in

maintaining the high quality ofarticles published in the journal.

You will be asked to review at least 1 or 2 articles per year inyour area of expertise. Reviewers’names will be published online

at the end of the year.

Please indicate at least 1 area ofexpertise in a health-related fieldfor which they feel qualified to

assess the content and quality ofmanuscripts submitted to AHDB.

To become a peer reviewer, please complete the form below and fax to: 732-992-1881or e-mail to [email protected]

Your Information

_______________________________________________________________________________________First Name Last Name Credentials

_______________________________________________________________________________________Title Company

_______________________________________________________________________________________Address

_______________________________________________________________________________________E-mail Phone

NOTE TO REVIEWERS: AHDB is a member of the Committee on Publication Ethics (COPE).Member ship in COPE indicates that this journal upholds COPE’s Code of Conduct standards and intendsto take appropriate action in cases of possible misconduct, such as plagiarism, attempted or actual redundantpublication, any attempts to pass off fraudulent data, unethical research, or breaches of confidentiality.

www.ifebp.org/pharmacy

Pharmacy Bene�ts: Plan Design and Management

New in the International Foundation Bookstore

Pharmacy Benefits: Plan Design and Management

abou

t the

auth

or

ororhhutut a aeehh t t

utut

ogenberg, R.Ph.,. Randy VFF. Randy VPh.D., pciinrs a p i

egtnr Ioe f fotuuttitsnIahe in SrachtlaaleHnts, aetsuhhuacssaMenh btlalel haniotant. Stiwen Hoh Atiader wt lehugghoht

d ole h1981, h

ogenberg, R.Ph.,ehh ttil wap

detraategn,ora

ermrod a f fontse�enceint. S

uuoobbaa

oncon ed oetluulsns coae h1981, hug bices, drvvices, drerl saictaceumrahr poffoog f foinkkinaakn msiocid deny aeggy atraatts

nmervveroh g gotin wiotcleey speraaphtts.liener cyyer clopemmp

uesssmic iote�enug b

ugr drodnt aennm

.www ifebp.org/pharmacy

/pharmacy

3 ye

ar ov

erall

survi

val a

dvan

tage

in p

revio

usly

untre

ated

Mul

tiple

Mye

loma

If You Defi ne Value as an Overall Survival Advantage:

Patients treated with VELCADE + MP as initial therapy sustained an overall survival bene� t over patients randomized to MP alone

The overall survival bene� t was sustained despite subsequent treatments

Median duration of VcMP treatment was 46 weeks/54 planned1

At the initial analysis (median 16.3-month follow-up), median TTP was 20.7 months with VELADE in combination with MP vs 15 months for MP alone (P=0.000002)

* VISTA was a randomized, open-label, international phase 3 trial (N=682) evaluating the ef� cacy and safety of VELCADE in combination with MP vs MP in previously untreated multiple myeloma. Primary endpoint was TTP and secondary endpoints were CR, ORR, PFS, and OS. At a prespeci� ed interim analysis (median follow-up 16.3 months) VcMP resulted in signi� cantly superior results for TTP, PFS, OS, and response rates. Further enrollment was halted and patients receiving MP were offered VELCADE in addition.

† VcMP=VELCADE + melphalan/prednisone (MP).

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 $1398.00 per 3.5mg vial as of January 1, 2011.

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 Warnings, Precautions, and Adverse EventsVELCADE is contraindicated where hypersensitivity to bortezomib, boron, or mannitol exists. Warnings and Precautions for VELCADE include: advising women to avoid pregnancy and breastfeeding; peripheral neuropathy, sometimes severe may occur—manage with dose modi� cations or discontinuation and carefully consider risk/bene� t in pre-existing severe neuropathy; hypotension may occur, use caution with patients on antihypertensives, history of syncope, dehydration; closely monitor patients with risk factors for or existing heart disease; acute diffuse in ltrative pulmonary disease has been reported; nausea, diarrhea, constipation, and vomiting may require symptomatic treatment; regular monitoring of blood counts throughout treatment for thrombocytopenia or neutropenia. Tumor Lysis Syndrome, Reversible Posterior Leukoencephalopathy Syndrome, and acute hepatic failure have been reported. In patients with moderate or severe hepatic impairment use a lower starting dose. In addition, patients with diabetes may require close monitoring of blood glucose and antidiabetic medication.

Most commonly reported adverse reactions (incidence ≥30%) in clinical studies include asthenic conditions, diarrhea, nausea, constipation, peripheral neuropathy, vomiting, pyrexia, thrombocytopenia, psychiatric disorders, anorexia and decreased appetite, neutropenia, neuralgia, leukopenia, and anemia. Other adverse reactions, including serious adverse reactions, have been reported.

Please see Brief Summary for VELCADE on the next page of this advertisement.To contact a reimbursement specialist: Please call 1-866-VELCADE, option 2 (1-866-835-2233).

1. San Miguel, Bortezomib plus Melphalan and Prednisone for Initial Treatment of Multiple Myeloma. New England Journal of Medicine 2008.

UPDATED VISTA* OVERALL SURVIVAL (OS) ANALYSIS: VcMP† vs MP(36.7-month median follow-up)

VELCADE+MP (n=344)MP (n=338)

% P

atie

nts

With

out E

vent

100

90

80

70

60

50

40

30

20

10

0

Months0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51

HR 0.65 (95% CI, 0.51-0.84); P=0.00084

In Previously Untreated Multiple MyelomaIMPORTANT 3-YEAR UPDATE- SUSTAINED BENEFIT

Kaplan-Meier estimate.

MEDIAN OSNOT REACHEDFOR VcMP

www.VELCADE.com

INDICATIONS:

VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma.VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with mantle cell lymphomawho have received at least 1 prior therapy.

CONTRAINDICATIONS:

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

WARNINGS AND PRECAUTIONS:

VELCADE should be administered under the supervision of a physician experienced in the use ofantineoplastic therapy. Complete blood counts (CBC) should be monitored frequently during treatment withVELCADE.

Pregnancy Category D: Women of childbearing potential should avoid becoming pregnant while beingtreated with VELCADE. Bortezomib administered to rabbits during organogenesis at a dose approximately0.5 times the clinical dose of 1.3 mg/m2 based on body surface area caused post-implantation loss and adecreased number of live fetuses.

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 withpre-existing symptoms (numbness, pain or a burning feeling in the feet or hands) and/or signs of peripheralneuropathy may experience worsening peripheral neuropathy (including ≥Grade 3) during treatment withVELCADE. Patients should be monitored for symptoms of neuropathy, such as a burning sensation,hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. Patients experiencingnew or worsening peripheral neuropathy may require change in the dose and schedule of VELCADE.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 inor resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2neuropathy or who had ≥Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies. Thelong-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%. Theseevents are observed throughout therapy. Caution should be used when treating patients with a history ofsyncope, patients receiving medications known to be associated with hypotension, and patients who aredehydrated. Management of orthostatic/postural hypotension may include adjustment of antihypertensivemedications, hydration, and administration of mineralocorticoids and/or sympathomimetics.

Cardiac Disorders: Acute development or exacerbation of congestive heart failure and new onset ofdecreased left ventricular ejection fraction have been reported, including reports in patients with no riskfactors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing heart diseaseshould be closely monitored. In the relapsed multiple myeloma study, 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% and4%, respectively. There have been isolated cases of QT-interval prolongation in clinical studies; causalityhas not been established.

Pulmonary Disorders: There have been reports of acute diffuse infiltrative pulmonary disease of unknownetiology such as pneumonitis, interstitial pneumonia, lung infiltration and Acute Respiratory DistressSyndrome (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 daunorubicinand VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy. Therehave been reports of pulmonary hypertension associated with VELCADE administration in the absence ofleft heart failure or significant pulmonary disease. In the event of new or worsening cardiopulmonarysymptoms, a prompt comprehensive diagnostic evaluation should be conducted.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): There have been reports of RPLS in patientsreceiving 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 patientsdeveloping RPLS, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previouslyexperiencing RPLS is not known.

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

Thrombocytopenia/Neutropenia: VELCADE is associated with thrombocytopenia and neutropenia thatfollow a cyclical pattern with nadirs occurring following the last dose of each cycle and typically recoveringprior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases andrecovery remained consistent over the 8 cycles of twice weekly dosing, and there was no evidence ofcumulative thrombocytopenia or neutropenia. The mean platelet count nadir measured was approximately40% of baseline. The severity of thrombocytopenia was related to pretreatment platelet count. In therelapsed multiple myeloma study, the incidence of significant bleeding events (≥Grade 3) was similar onboth the VELCADE (4%) and dexamethasone (5%) arms. Platelet counts should be monitored prior to eachdose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and scheduleof VELCADE. There have been reports of gastrointestinal and intracerebral hemorrhage in association withVELCADE. 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, thecomplications of tumor lysis syndrome may occur. Patients at risk of tumor lysis syndrome are those withhigh tumor burden prior to treatment. These patients should be monitored closely and appropriateprecautions taken.

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

Patients with Hepatic Impairment: VELCADE is metabolized by liver enzymes. VELCADE exposure isincreased in patients with moderate or severe hepatic impairment. These patients should be treated withVELCADE at reduced starting doses and closely monitored for toxicities.

ADVERSE EVENT DATA:

Safety data from phase 2 and 3 studies of single-agent VELCADE 1.3 mg/m2/dose twice weekly for 2weeks 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) andpreviously treated mantle cell lymphoma (N=155) were integrated and tabulated. In these studies, thesafety 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 (includingfatigue, malaise, and weakness); (64%), nausea (55%), diarrhea (52%), constipation (41%), peripheralneuropathy 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%), coughand 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%) ofpatients experienced at least 1 episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (5%) andneutropenia (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, the safety profile of VELCADE in combination withmelphalan/prednisone is consistentwith the known safety profiles of bothVELCADE and melphalan/prednisone.The most commonly reported adverse events in this study (VELCADE+melphalan/prednisone vsmelphalan/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%).

DRUG INTERACTIONS:

Co-administration of ketoconazole, a potent CYP3A inhibitor, increased the exposure of bortezomib.Therefore, patients should be closely monitored when given bortezomib in combination with potent CYP3A4inhibitors (e.g. ketoconazole, ritonavir). Co-administration of melphalan-prednisone increased the exposureof bortezomib. However, this increase is unlikely to be clinically relevant. Co-administration of omeprazole,a potent inhibitor of CYP2C19, had no effect on the exposure of bortezomib. Patients who are concomitantlyreceiving VELCADE and drugs that are inhibitors or inducers of cytochrome P450 3A4 should be closelymonitored for either toxicities or reduced efficacy.

USE IN SPECIFIC POPULATIONS:

Nursing Mothers: It is not known whether bortezomib is excreted in human milk. Because many drugs areexcreted in human milk and because of the potential for serious adverse reactions in nursing infants fromVELCADE, a decision should be made whether to discontinue nursing or to discontinue the drug, taking intoaccount 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 andyounger 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 renalimpairment. Therefore, dosing adjustments of VELCADE are not necessary for patients with renal insufficiency.Since dialysis may reduce VELCADE concentrations, the drug should be administered after the dialysisprocedure. For information concerning dosing of melphalan in patients with renal impairment, seemanufacturer's prescribing information.

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

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

VELCADE, MILLENNIUM and are registered trademarks of Millennium Pharmaceuticals, Inc.Other trademarks are property of their respective owners.Millennium Pharmaceuticals, Inc., The Takeda Oncology Company. Cambridge, MA 02139Copyright ©2009, Millennium Pharmaceuticals, Inc.

Brief Summary

All rights reserved. Printed in USA V1215 12/09

3:17 PM

CLINICAL


It is well known that the use of prescription opioidmedications, more than other medications, is associ-ated with risks for misuse, abuse, and diversion.1-3 The

government and pharmaceutical companies haveaddressed this issue by implementing specific strategiesto minimize the risks associated with prescription drugsin general and with opioids in particular.

In 2005, the US Food and Drug Administration(FDA) published 3 guidances for the pharmaceuticalindustry on risk management activities for drug and bio-logic products.4-6 In these publications, the FDA outlinesseveral components of risk management, including “(1)assessing a product’s benefit-risk balance, (2) developing

and implementing tools to minimize its risks while pre-serving its benefits, (3) evaluating tool effectiveness andreassessing the benefit-risk balance, and (4) makingadjustments, as appropriate, to the risk minimizationtools to further improve the benefit-risk balance.”4

In 2007, the FDA Amendments Act was passed intolaw, establishing the requirements for Risk Evaluationand Mitigation Strategies (REMS) for drugs with safetyconcerns. These REMS requirements are accompaniedby stipulations for physician and pharmacist training andcertification, and patient registries for some medications,including opioids.7

Currently, risk management strategies, includingREMS, are used by the government and by pharmaceu-tical companies to minimize the risks associated withprescription opioid use, namely, the potential for abuse,addiction, and diversion. Risk management tools can

Dr Hahn is Affiliate Faculty, Oregon State UniversityCollege of Pharmacy, and Pharmacy Manager, Bi-MartCorp, Springfield, OR.

REVIEW ARTICLE

Strategies to Prevent Opioid Misuse,Abuse, and Diversion That May AlsoReduce the Associated CostsKathryn L. Hahn, PharmD, DAAPM, CPE

Background: The use of prescription opioid drugs has the potential to lead to patient abuseof these medications, addiction, and diversion. Such an abuse is associated with increasedcosts because of excessive healthcare utilization. Finding ways to minimize the risk for abuseand addiction can enhance patient outcomes and reduce costs to patients and to payers.Objective: To review current strategies that may reduce the risk for misuse and abuse of opi-oid medications, which in turn can enhance patient outcomes and lower costs to health insur-ers and patients. Discussion: Implementing approaches that will encourage the use of safe practices (univer-sal precautions) in pain management by providers can reduce the risk for abuse and misuseassociated with chronic pain medications, especially opioids. These approaches include, butare not limited to, extensive physician and patient education regarding these medications andtheir associated risks for abuse; the development of prescription monitoring programs todetect physician or pharmacy shopping; the detection of inappropriate prescribing and med-ical errors; the use of physician–patient contracts concerning opioid treatment; the require-ment of presenting a photo identification to pick up an opioid prescription at the pharmacy;urine drug toxicology screening; provisions for safe disposal of unused opioids; referrals topain and addiction specialists; and potentially encouraging the use of opioid formulationsaimed at reducing abuse. Conclusion: Supporting such approaches by health insurers and educating providers andpatients on the risks associated with chronic pain medications can help minimize the risk ofprescription opioid abuse, addiction, and diversion; reduce health services utilization associ-ated with opioid abuse; improve patient outcomes; and reduce overall costs.




CLINICAL


also benefit health plans, by minimizing the potentialhealth and economic risks associated with prescriptionopioid use for members who are using these medications.

In this article, after reviewing the available informa-tion on the prevalence of prescription opioid abuse(the most abused of all prescription medications) andthe resulting economic costs, the author outlinesstrategies that have the potential to minimize the risksassociated with prescription opioid use and couldenhance the patient’s health and reduce costs to healthplans and patients.

The Scope of the Problem Abuse of Prescription Opioid Drugs in the United States

The increasing prevalence of prescription opioidabuse and its emergence as a major public health con-cern have been extensively documented.1-3 According to2007 data from the National Survey on Drug Use andHealth, an estimated 5.2 million persons aged ≥12 years(approximately 2.1% of the US population) abused pre-scription opioids within the past month, and 2.1 millionindividuals initiated nonmedical use of prescription opi-oids.1 A survey of 8th-, 10th-, and 12th-grade students

showed that in 2008, the annual rate of narcotic drug useother than heroin for twelfth-graders was 9%.8 Whenstudents were asked the source of the drugs, approxi-mately 56% reported obtaining them for free fromfriends or from relatives, 9% reported buying them fromfriends or relatives, and 18% reported obtaining them byprescription from a physician.1

The nonmedical use of prescription opioids is danger-ous, because the repeated recreational use of these med-ications can lead to addiction or death. Most abuseoccurs by oral administration—swallowing the tablet orcapsule whole, or chewing it and then swallowing.9-11Chewing disrupts some of the extended-release opioidformulations and releases large amounts of the drug rap-idly, increasing euphoria.12 Oral abuse, if frequent and athigh doses, can lead to medication addiction.13

However, a significant subset of abusers progress toother, more sophisticated routes of ingestion, such assnorting (62% of abusers) or intravenous injection (26%of abusers).9 Snorting and parenteral delivery increasethe rate and amount of delivery of the opioid and resultin a greater euphoria than swallowing whole or chew-ing.12 Abuse through smoking is common for some drugs(approximately 50% of fentanyl abusers smoke it), but itis relatively uncommon with prescription opioids (only2.3% of abusers smoke prescription opioids).3 Fur -thermore, although it has not been conclusively proved,it has been suggested that nonmedical prescription opi-oid use can be a gateway to abuse of other, equally dan-gerous drugs, such as heroin and crack cocaine.14

The frequency of abuse and addiction in patients withchronic pain who are treated long-term with opioids isunclear. A meta-analysis of 24 studies comprising 2507patients treated with long-term opioid therapy forchronic, nonmalignant pain showed an overallabuse/addiction rate of 3.27%.15 However, studies thatinclude routine urine toxicology screening as an objec-tive method of testing drug abuse tend to show higherrates—ranging from 16% to 47%—of abuse or misuseamong patients with chronic pain.16-19 Therefore,although many patients with chronic pain can safelybenefit from prescription opioid treatment, some ofthese patients are vulnerable to abuse and addiction.

Healthcare Utilization and Costs: PrescriptionOpioid Abuse

During the past decade, the treatment of noncancerpain with opioids has expanded.20 Between 1997 and2006, retail sales of opioids (grams per 100,000 popula-tion) have increased20: • Sales of hydrocodone increased by 244%• Oxycodone by 732%• Methadone by 1177%.

KEY POINTS

� The use of prescription drug opioids is associatedwith a risk for abuse and addiction.

� Between 1997 and 2006, retail sales of opioids haveincreased dramatically; sales of hydrocodoneincreased by 244%, oxycodone by 732%, andmethadone by 1177%.

� These trends have coincided with increased rates ofabuse and mortality associated with prescriptionopioid abuse.

� The financial cost is also substantial, resulting fromincreased healthcare utilization.

� One study reported that healthcare costs for opioidabusers were 8 times higher than for nonabusers,with an average per-person cost of $15,884 to payerfor abusers compared with $1830 for nonabusers.

� Educating providers and patients on these drugs canminimize opioid abuse; current approaches includeprescription monitoring programs, preventingprescription/medical errors, checking patientidentification at the pharmacy, referral to painspecialists, and the use of abuse-deterrent opioidformulations.

� These strategies can improve patient outcomes,prevent abuse, and reduce overall healthcareutilization and costs.

Strategies to Prevent Opioid Misuse, Abuse, and Diversion


These trends have coincided with increased rates ofabuse and mortality associated with prescription opioidabuse.1,20,21

The financial impact on payers from prescription opi-oid abuse is also substantial. White and colleaguesdemonstrated that compared with nonabusers receivingprescription opioids, prescription opioid abusers had sig-nificantly more physician visits, mental health inpatientand outpatient services, hospital admissions, emergencydepartment visits, motor vehicle accidents, cases of trau-ma, and substance abuse treatment.22 Healthcare costsfor opioid abusers were 8 times higher than fornonabusers—average per-person healthcare cost to payerwas $15,884 for abusers compared with $1830 for non-abusers (P <.01).22 Hospital inpatient visits were thelargest contributor to increased cost—$7239 for opioidabusers compared with $310 for nonabusers (P <.01).

Treatment of comorbidities—which have a higherprevalence rate in opioid abusers—is also an importantcontributor to the higher costs; comorbidities, such asnonopioid poisoning, other substance abuse, hepatitis,pancreatitis, psychiatric illnesses, and chronic cirrhosisor acute liver disease occur 78.0, 43.0, 36.0, 21.0, 8.5,and 7.6 times more often, respectively, in abusers thanin opioid users who are not abusers. Prescription costsin this study were also 5 times greater for abusers com-pared with nonabusers (mean costs, $2034 vs $386,respectively; P <.01).22

Birnbaum and colleagues reported similar findings;prescription opioid abuse resulted in approximately$9500 in annual medical costs per patient in 2001,which was 3 times more than that for matched non -abusers, amounting to a total healthcare cost of $2.6 bil-lion for prescription opioid abuse that year.23 However,prescription opioid abuse costs went beyond healthcarecosts; they also included $1.4 billion in criminal justicecosts and $4.6 billion in workplace costs—totaling $8.6billion in 2001.23

Prescription opioid abuse/misuse is also associated withincreases in:1. Visits to the emergency department22. Number of fatal opioid-related poisonings243. Admissions to addiction treatment centers.3

According to one study, the number of visits to emer-gency departments because of prescription opioid over-dose increased approximately 43% between 2004 and2006—from an estimated 172,726 to 247,669 visits.2 Inaddition, a 143% increase in mortality rates from pre-scription opioids occurred between 1999 and 2004—from 1.22 to 2.96 deaths per 100,000.24 Starting in 2004,prescription opioids have been more often shown to beinvolved in fatal overdoses than overdoses resulting fromcocaine or heroin.24 The number of admissions to sub-

stance abuse treatment programs for primary prescriptionopioid abuse increased by 342% from 1996 to 2006(from 16,605 to 73,439).3

Insurance fraud by prescription drug abusers imposesadditional costs on the healthcare system. Drug diver-sion costs to health insurers are estimated at $72.5 billionper year (including $24.9 billion for private insurers).25The costs include fraudulent claims for pre scriptions forspurious pain conditions, costs that accrue if individu-als taking the diverted drugs become addicted, andcosts as a result of additional comorbidities that occurin drug abusers.

Risk Minimization Approaches to AbuseMany approaches, which are detailed below, that can

be promoted and supported by employers and healthplans to control the abuse and diversion of prescriptionopioids are not new; they are part of a series of measuresthat have been recommended by various stakeholders toreduce the incidence of prescription opioid abuse in theUnited States. Some of these policies (detailed below)have already been put in place; others are still in theplanning stage.

Very little data exist regarding the effectiveness ofthese measures, because (1) most of them have not beensystematically implemented (they exist only in limitedgeographical areas, or are only recommended and notmandatory), which strongly limits their impact; (2) someare too recent to demonstrate a trend yet; and (3) somehave not been fully evaluated for their effectiveness inreducing abuse. Data on effectiveness, if available, areprovided for each approach in the appropriate subsec-tions below. In addition, the multifactorial aspect of pre-scription drug abuse makes it difficult to find an ade-quate measure to evaluate the impact of a particularpolicy on abuse in the real world. Nevertheless, somemeasures, such as prescription monitoring programs,have been shown to decrease abuse, as discussed below;however, the data are limited.26

Educating Physicians and PatientsA comprehensive approach to risk reduction includes

educating physicians on safe opioid prescribing. A sys-tem of universal precautions in pain medicine has beenproposed and recommended for physicians to minimizethe risk for opioid abuse by their patients, while allowingphysicians to appropriately treat patients with pain.27,28This approach is based on a comprehensive initial assess-ment of the patient and regular monitoring of patientswho are prescribed opioids. Because safe opioid prescrib-ing not only serves an important public health need butalso can have a significant impact on healthcare costs,payers could benefit from promoting universal precau-

CLINICAL


tions. Payers could help to enhance this approach byproviding physicians enrolled in their insurance planswith educational/training materials or training programs.

It has also been recommended by the SubstanceAbuse and Mental Health Services Administration thatphysicians be educated on Screening, Brief Intervention,Referral and Treatment (SBIRT) guidelines for patientswith substance abuse disorders and for those at risk forabuse.29 SBIRT measures could be promoted by providingperformance initiatives in pain management (eg, SBIRTtraining sessions) and encouraging referrals to pain andaddiction specialists when appropriate.

Establishing opioid treatment contracts has been sug-gested.30 These are written commitments between doctorsand patients stipulating the terms of treatment, in partic-ular, patient compliance with treatment and monitoring,including the potential use of urine drug testing.30

Health information on safe opioid use could also beprovided to patients. Educational and training sessionscould be offered to patients on how to use opioids safely,especially information about appropriate storage (eg,lock boxes) and disposal of pharmaceuticals that are nolonger needed.

Use of Prescription Monitoring Programs Prescription monitoring programs are data collection

systems that determine the number of physicians whoprescribe opioids for each patient and the number ofpharmacies where opioids are dispensed for that patient.26Prescription monitoring programs are administered on astate-by-state basis and are currently operational in 33states, and are at various stages of implementation in 7more states.31 Prescription monitoring programs collectinformation on the prescriber, pharmacy, product name,concentration, dose, and amount of medicine dis-pensed.26 Although the data are limited, they so far sug-gest that such programs reduce abuse practices.26

Prescription monitoring program threshold reportscan be used to limit the prescribing of opioids to “doctor-shoppers” and “pharmacy-shoppers.”32 Once a patientreaches the determined threshold, action can be taken,including notifying all the physicians who have pre-scribed an opioid to the patient, limiting the number ofpharmacies used by the patient to one, notifying thepatient of the knowledge of the suspicious activity, and ifappropriate, referring the patient to law enforcement forinvestigation.25,32

Preventing Inappropriate Prescribing andMedical Errors

An important aspect of risk minimization relevant toopioids is detecting inappropriate prescribing of opioidsand medical errors, including incorrect patient selection

(opioid-naive patients), off-label use, incorrect indica-tion (eg, “as needed” use of extended-release formula-tions), incorrect dosage, and conversion errors. Thiscould be accomplished by establishing algorithms thatidentify mismatches between diagnoses and medica-tion/dose. The purpose of such measures should not be toprosecute prescribers (unless, of course, unlawful behav-ior is clearly proved), but to educate prescribers whomade honest errors in safe opioid prescribing practicesand ultimately help them to avoid malpractice lawsuits.

Setting up systems in prescribers’ offices, such as elec-tronic prescribing, may promote safe opioid prescribingand reduce medical errors.

The US Drug Enforcement Administration issued aregulation effective June 1, 2010, approving the use ofelectronic prescribing for controlled substances in theUnited States.33 The regulation is expected to addanother barrier to the diversion of prescription drugs byreducing prescription forgery. Moreover, it is intendedto reduce the number of prescription errors caused byillegible handwriting, thereby enhancing safety. Imple -mentation of the regulation is expected to take up to 18months, because some operational issues need to beresolved and prescribing software must be updated.

Checking Patients’ Photo Identification at the Pharmacy

Pharmacists may require that photo identification bepresented by patients when they are picking up their opi-oid prescriptions at the pharmacy, because an increasingnumber of cases of abuse have involved identity theft.This could be achieved by mandating that the patient’sidentification be checked before accepting a claim forprescription opioid medication. Some states, such asVirginia, are currently considering passing a bill that willrequire individuals to present a photo identification topick up prescriptions for controlled substances.34 Toreduce insurance fraud, the Government AccountabilityOffice also recommends that insurers remove deceasedpatients and physicians from their systems to avoid pay-ing claims for fraudulent prescriptions for controlled sub-stances purportedly written by deceased physicians or todeceased patients.35

Referral to Pain SpecialistsEncouraging referrals to multidisciplinary pain man-

agement programs and referral resources for addictionspecialists is another option. In addition, although reim-bursing for services such as routine urine drug tests andreferral to specialists may be more costly in the short-term, the ability of these services to help detect and cor-rectly manage patients at risk for prescription opioidabuse may reduce costs in the long-term.



Use of Abuse-Deterrent Formulations of OpioidsOpioid manufacturers are addressing the problem of

prescription opioid abuse pharmacologically by develop-ing new opioid formulations with abuse-deterrent prop-erties. Abuse-deterrent opioid formulations (Table) use acombination of old and new strategies that fall into 3general categories: • The “fortress approach,” in which the formulation

maintains its extended-release characteristics despiteattempts to crush or dissolve it

• The “neutralizing approach,” in which the formula-tion is relatively easy to alter, but tampering with theformulation results in the release of a neutralizingantagonist

• The “aversive approach,” in which the opioid is for-mulated with an aversive agent that results in un -pleasant side effects when a large quantity of the opi-oid is ingested. Some of these formulations are alreadyon the market, including Suboxone (bupre norphine),Embeda (morphine), and the new OxyContin (oxy-codone). Others are still in development or are cur-rently under FDA review, as shown in the Table. The recently approved (April 2010) OxyContin for-

mulation exemplifies the “fortress approach.” This newtablet is coated with a plastic polymer designed to pre-vent chewing, cutting, or crushing of the tablet.36

Suboxone (approved in 2002) and Embeda (approvedin 2009) are examples of the “neutralizing approach,”characterized by extended-release opioid agonist-antago-nist combinations. Suboxone contains buprenorphineand naloxone; Embeda contains morphine and naltrex-one (which is a longer acting antagonist than naloxone).

The strategy behind these products is to blunt theeuphoric effects of the opioid if the formulation isaltered. The antagonist agent (naltrexone or naloxone)is sequestered if the medication is taken as directed, butif it is tampered with (eg, chewed, crushed, or dissolved),the antagonist is released. A recent study has shown thatSuboxone has a lower abuse liability than Subutex(buprenorphine alone).37 Similarly, crushed Embeda pro-duces less euphoria (as measured by “drug high” on avisual analog scale) in substance abusers than eitherintact Embeda or immediate-release morphine sulfate.38

An example of the “aversive approach” is the imme-diate-release formulation of oxycodone containingniacin (Acurox), which is currently under FDA review(Table).39 Niacin causes unpleasant side effects, such aswarmth or flushing, itching, sweating, and/or chills. Theformulation is designed to release no or insignificantamounts of niacin if Acurox is taken as directed, but if itis taken in higher than recommended doses, temporaryunpleasant (but not harmful) effects of niacin are expe-rienced, as demonstrated in a clinical study comparingAcurox with oxycodone.40,41 If and when approved, theaversive strategy will be the only strategy that could pre-vent abuse of a medication by swallowing excessivenumbers of tablets or capsules whole; the fortress andneutralizing approaches are likely to be inefficientagainst this form of abuse.

Practical ConsiderationsA key question for payers will be the degree to which

these new formulations deter abuse. The real question iswhether these formulations truly reduce misuse, abuse,

Table Abuse-Deterrent Opioid Formulations

Trade name Opioid Mechanism FDA status

OxyContin Oxycodone Hard plastic polymer that renders the tablet difficult to crush or dissolve

Approved in 2010

Remoxy Oxycodone Very viscous liquid intended to resist crushing, dissolution, injection, or inhalation

Under FDA review

Suboxone Buprenorphine Contains sequestered naloxone (an opioid antagonist),which is released when product is chewed/crushed andcancels the euphoric effects of buprenorphine

Approved in 2002

Embeda Morphine Contains sequestered naltrexone (an opioid antagonist),which is released when the product is chewed/crushedand cancels the euphoric effects of morphine

Approved in 2009

Acurox Oxycodone (immediate release)

Contains an aversive agent (niacin) that causesunpleasant effects when injected, inhaled, or taken orally in high doses

Under FDA review

FDA indicates US Food and Drug Administration.

addiction, and diversion on a population basis (ie, in thereal world). The payer community should have a reason-able skepticism about the real-world abuse deterrence ofthese formulations. Indeed, in the mid-1990s, claimswere made that the pharmacokinetic properties of theextended-release oxycodone were less reinforcing thanimmediate-release oxycodone, and therefore extended-release oxycodone would have a lower abuse potential.42What was not recognized, however, was the simplicity bywhich the extended-release mechanism could be sub-verted: just breaking, chewing, or crushing extended-release oxycodone tablets could lead to the rapid releaseand absorption of a high dose of oxycodone.42 The rapidincrease in OxyContin abuse after the drug waslaunched is a good lesson in how the abuse potential ofany drug is a function of the ease with which that formu-lation can be subverted.

Most abuse-deterrent formulations on the markethave been approved recently, and therefore no data areyet available to determine the impact of these formula-tions on the abuse and diversion of these opioids in thereal world. Suboxone (which was approved in 2002) hassome real-world abuse data. One study showed that of 64patients switched from Subutex to Suboxone, 5 abusedSuboxone intravenously (once each by 4 patients andtwice by 1 patient), and all reported that it provided noeuphoria or was unpleasant and that they would notrepeat the experience.43 However, real-world data showthat buprenorphine is still widely abused and diverted. Inthe United States, law enforcement and pharmacistsreport that Suboxone is being abused successfully whensnorted,44 and data from the National ForensicLaboratory Information System, which tracks drugseizures by law enforcement, suggest that diversion ofbuprenorphine has been steadily rising despite the intro-duction of Suboxone.45 Data from 2003 to 2005 from USPoison Control Centers show that Subutex andSuboxone rates of abuse are similar,46 and a study inMalaysia showed that the introduction of Suboxone didnot reduce the rate of intravenous buprenorphine abusein that country.47

ConclusionMany approaches are currently in various stages of

implementation to help decrease the incidence of pre-scription opioid misuse, abuse, and diversion. For eachmeasure, health plans, employers, and other payers mayhave to consider (1) the feasibility of implementing themeasure; (2) the cost of implementation versus the ulti-mate cost-savings; (3) the additional burden on thehealthcare system (ie, physician, pharmacist, and insur-er) that the measure creates; (4) the potential negativeconsequences on the appropriate treatment of pain

(chilling effect); and (5) the true impact of the measureon misuse, abuse, and diversion of opioid medications.Therefore, policies and recommendations should comefrom consensus decisions from various stakeholders. Theeffectiveness of these programs will have to be evaluatedand adapted for optimal reduction of prescription opioidabuse and diversion. �

Acknowledgments Writing and editorial support for the initial manuscript

was provided by Analgesic Solutions. King Pharma -ceuticals provided funding to Analgesic Solutions.

Author Disclosure StatementDr Hahn is on the Speaker’s Bureau of King Pharma -

ceuticals, Meda Pharmaceuticals, Pfizer, and PriCara. Shereceived no financial or other compensation for writingthis article.

References1. US Department of Health and Human Services, Substance Abuse and MentalHealth Services Administration. Results from the 2007 National Survey on DrugUse and Health: national findings. Rockville, MD; 2008. DHHS Publication No.(SMA) 08-4343. http://oas.samhsa.gov/nsduh/2k7nsduh/2k7Results.pdf. AccessedAugust 14, 2008.2. US Department of Health and Human Services, Substance Abuse and MentalHealth Services Administration. Drug Abuse Warning Network, 2006: national esti-mates of drug-related emergency department visits. Rockville, MD; 2008. DAWNSeries D-30; DHHS Publication No. (SMA) 08-4339. http://dawninfo.samhsa.gov/files/ED2006/DAWN2k6ED.pdf. Accessed October 15, 2009.3. US Department of Health and Human Services, Substance Abuse and MentalHealth Services Administration. Treatment episode data set (TEDS) 1996-2006.National admissions to substance abuse treatment services. Rockville, MD; 2008.DASIS Series S-43, DHHS Publication No. (SMA) 08-4347. http://wwwdasis.samhsa.gov/teds06/teds2k6aweb508.pdf. Accessed July 29, 2009.4. US Food and Drug Administration Center for Drug Evaluation and Research,Center for Biologics Evaluation and Research. Guidance for industry: developmentand use of risk minimization action plans. March 2005. www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126830.pdf. Accessed February 25, 2011.5. US Food and Drug Administration Center for Drug Evaluation and Research,Center for Biologics Evaluation and Research. Guidance for industry: premarketingrisk assessment. March 2005. www.fda.gov/downloads/RegulatoryInformation/Guidances/ucm126958.pdf. Accessed February 25, 2011.6. US Food and Drug Administration Center for Drug Evaluation and Research,Center for Biologics Evaluation and Research. Guidance for industry: good pharma-covigilance practices and pharmacoepidemiologic assessment. March 2005.www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126834.pdf.Accessed February 25, 2011.7. Food and Drug Administration Amendments Act of 2007, Public Law 110-85,Food and Drug Administration. September 27, 2007.8. Johnston LD, O’ Malley PM, Bachman JG, Schulenberg JE. Monitoring the FutureNational Results on Adolescent Drug Use: Overview of Key Findings, 2007.Bethesda, MD: National Institute on Drug Abuse; 2008. NIH Publication No. 08-6418. www.monitoringthefuture.org/pubs/monographs/overview2007.pdf. AccessedJuly 14, 2010.9. Hays LR. A profile of OxyContin addiction. J Addict Dis. 2004;23:1-9.10. Carise D, Dugosh KL, McLellan AT, et al. Prescription OxyContin abuse amongpatients entering addiction treatment. Am J Psychiatry. 2007;164:1750-1756.11. Butler SF, Budman SH, Licari A, et al. National addictions vigilance interven-tion and prevention program (NAVIPPRO): a real-time, product-specific, publichealth surveillance system for monitoring prescription drug abuse. PharmacoepidemiolDrug Saf. 2008;17:1142-1154.12. Raffa RB, Pergolizzi JV Jr. Opioid formulations designed to resist/deter abuse.Drugs. 2010;70:1657-1675.13. Compton WM, Volkow ND. Abuse of prescription drugs and the risk of addic-tion. Drug Alcohol Depend. 2006;83(suppl 1):S4-S7.14. Colliver JD, Kroutil LA, Dai L, Gfroerer JC. Misuse of prescription drugs: datafrom the 2002, 2003, and 2004 national surveys on drug use and health. Rockville,

CLINICAL


MD: US Department of Health and Human Services, Substance Abuse and MentalHealth Services Administration, Office of Applied Studies; 2006. DHHS PublicationNo. (SMA) 06-4192, Analytic Series A-28. www.oas.samhsa.gov/prescription/toc.htm.Accessed October 9, 2008.15. Fishbain DA, Cole B, Lewis J, et al. What percentage of chronic nonmalignantpain patients exposed to chronic opioid analgesic therapy develop abuse/addictionand/or aberrant drug-related behaviors? A structured evidence-based review. PainMed. 2008;9:444-459.16. Manchikanti L, Cash KA, Damron KS, et al. Controlled substance abuse andillicit drug use in chronic pain patients: an evaluation of multiple variables. PainPhysician. 2006;9:215-225.17. Ives TJ, Chelminski PR, Hammett-Stabler CA, et al. Predictors of opioid misusein patients with chronic pain: a prospective cohort study. BMC Health Serv Res.2006;6:46.18. Fishbain DA, Cutler RB, Rosomoff HL, Rosomoff RS. Validity of self-reporteddrug use in chronic pain patients. Clin J Pain. 1999;15:184-191.19. Michna E, Jamison RN, Pham LD, et al. Urine toxicology screening amongchronic pain patients on opioid therapy: frequency and predictability of abnormalfindings. Clin J Pain. 2007;23:173-179.20. Manchikanti L, Singh A. Therapeutic opioids: a ten-year perspective on thecomplexities and complications of the escalating use, abuse, and nonmedical use ofopioids. Pain Physician. 2008;11(2 suppl):S63-S88.21. Paulozzi LJ, Budnitz DS, Xi Y. Increasing deaths from opioid analgesics in theUnited States. Pharmacoepidemiol Drug Saf. 2006;15:618-627.22. White AG, Birnbaum HG, Mareva MN, et al. Direct costs of opioid abuse in aninsured population in the United States. J Manag Care Pharm. 2005;11:469-479.23. Birnbaum HG, White AG, Reynolds JL, et al. Estimated costs of prescriptionopioid analgesic abuse in the United States in 2001: a societal perspective. Clin JPain. 2006;22:667-676.24. Paulozzi LJ, Xi Y. Recent changes in drug poisoning mortality in the UnitedStates by urban-rural status and by drug type. Pharmacoepidemiol Drug Saf. 2008;17:997-1005.25. Coalition Against Insurance Fraud. Prescription for peril: how insurance fraudfinances theft and abuse of addictive prescription drugs. Washington, DC; 2007.www.insurancefraud.org/drugDiversion.htm. Accessed August 25, 2008.26. Wang J, Christo PJ. The influence of prescription monitoring programs onchronic pain management. Pain Physician. 2009;12:507-515.27. Gourlay DL, Heit HA, Almahrezi A. Universal precautions in pain medicine: arational approach to the treatment of chronic pain. Pain Med. 2005;6:107-112.28. Gourlay D, Heit H. Universal precautions: a matter of mutual trust and respon-sibility. Pain Med. 2006;7:210-211.29. Substance Abuse and Mental Health Services Administration. Screening, briefintervention, and referral to treatment: new populations, new effectiveness data.November/December 2009. www.samhsa.gov/samhsanewsletter/Volume_17_Number_6/SBIRT.aspx. Accessed March 14, 2011.30. Fishman SM, Bandman TB, Edwards A, Borsook D. The opioid contract in themanagement of chronic pain. J Pain Symptom Manage. 1999;18:27-37.31. National Alliance for Model State Drug Laws. Status of prescription drug moni-toring programs. March 7, 2011. www.namsdl.org/documents/StatusofStatesMarch72011.pdf. Accessed March 14, 2011.32. Katz N, Panas L, Kim M, et al. Usefulness of prescription monitoring programs

for surveillance—analysis of Schedule II opioid prescription data in Massachusetts,1996-2006. Pharmacoepidemiol Drug Saf. 2010;19:115-123. 33. US Drug Enforcement Administration. Electronic prescriptions for controlledsubstances. Docket No. DEA-218I; RIN 1117-AA61. Federal Register. 2010;75:16236-16319.34. Lohr M. House Bill No. 964. Commonwealth of Virginia General Assembly;February 18, 2010. http://leg1.state.va.us/cgi-bin/legp504.exe?101+ful+HB964H1.Accessed May 21, 2010. 35. United States Government Accountability Office. Medicaid fraud and abuserelated to controlled substances identified in selected states. Report to CongressionalRequestors. September 2009. GAO-09-957. www.smpresource.org/Content/NavigationMenu/HealthCareFraud/Medicaid/GAO_Medicaid_controlled_substances.pdf.Accessed May 11, 2010.36. Pharmacy Voice. FDA: Reformulated OxyContin may be less prone to abuse.April 7, 2010. http://nacds.rxpost.net/News/article.cfm?Article_ID=561428. AccessedMarch 14, 2011.37. Comer SD, Sullivan MA, Vosburg SK, et al. Abuse liability of intravenousbuprenorphine/naloxone and buprenorphine alone in buprenorphine-maintainedintravenous heroin abusers. Addiction. 2010;105:709-718.38. Stauffer J, Setnik B, Sokolowska M, et al. Subjective effects and safety of wholeand tampered morphine sulfate and naltrexone hydrochloride (ALO-01) extended-release capsules versus morphine solution and placebo in experienced non-depen-dent opioid users: a randomized, double-blind, placebo-controlled, crossover study.Clin Drug Investig. 2009;29:777-790.39. Acura Pharmaceuticals. Acurox with Niacin tablets. 2010. http://acurapharm.com/products/acurox-tablets/. Accessed May 11, 2010.40. ClinicalTrials.gov. Study of the abuse liability of oxycodone HCl/niacin in sub-jects with a history of opioid abuse. October 22, 2008. Identifier NCT00699010.www.clinicaltrials.gov/ct2/show/NCT00699010?term=acurox&rank=2. AccessedMay 11, 2010.41. Acura Pharmaceuticals. Study AP-ADF-102. 2010. http://acurapharm.com/products/acurox-tablets/study-ap-adf-102/. Accessed May 11, 2010.42. Shibuya RB. History of Oxycontin: labeling and risk management program. USFood and Drug Administration Anesthetic and Life Support Drugs and Drug Safetyand Risk Management Advisory Committees; November 13-14, 2008.43. Simojoki K, Vorma H, Alho H. A retrospective evaluation of patients switchedfrom buprenorphine (Subutex) to the buprenorphine/naloxone combination(Suboxone). Subst Abuse Treat Prev Policy. 2008;3:16.44. National Drug Intelligence Center. Intelligence bulletin: buprenorphine: poten-tial for abuse. September 2004. Document ID: 2004-L0424-013. www.justice.gov/ndic/pubs10/10123/index.htm. Accessed May 11, 2010.45. Wong LL, for the US Drug Enforcement Administration Office of DiversionControl. Buprenorphine in the treatment of opioid addiction: reassessment 2010.Presented at the SAMHSA National Advisory Council. Washington, DC; May 11-12, 2010. http://buprenorphine.samhsa.gov/bwns/2010_presentations_pdf/10a_10b_508.pdf. Accessed June 14, 2010.46. Smith MY, Bailey JE, Woody GE, Kleber HD. Abuse of buprenorphine in theUnited States: 2003-2005. J Addict Dis. 2007;26:107-111.47. Bruce RD, Govindasamy S, Sylla L, et al. Lack of reduction in buprenorphineinjection after introduction of co-formulated buprenorphine/naloxone to theMalaysian market. Am J Drug Alcohol Abuse. 2009;35:68-72.



Just Say NoPAYERS/PROVIDERS: “Just say no to drugs.”

Do you remember this phrase during the popularanti–drug abuse campaign created in the 1980s as partof the US “War on Drugs”? What you may not knowis that marijuana use by high school seniors droppedfrom 50.1% before that campaign to 12% in 1991.1 Inaddition, cocaine use by the same demographic groupdropped from 12% to 10%, and heroin use droppedfrom 1% to 0.5%, during the same time period.1

Critics, nevertheless, believed that the solutions tothe drug abuse problem were never addressed by thiscampaign, and that the problem was reduced to a verycostly catch phrase.

There are many psychological, physical, and socialfactors that lead to drug abuse problems. Psy -chological and emotional factors, such as depressionand schizophrenia, are linked to the development ofdrug abuse problems. Physical challenges, such as


Continued

CLINICAL


chronic pain or improper or undertreated pain, canlead to drug abuse. And social factors, such as stress,unemployment, poverty, and lack of education, canalso lead to drug abuse.

In her article in this issue, Dr Hahn provides anoverview of several strategies that can be employedto prevent opioid misuse, abuse, and diversion.Strategies such as education of physicians andpatients, use of prescription-monitoring programs,checking photo identification at the point of sale,referral to pain specialists, and use of abuse-deterrentopioid formulations are all legitimate strategies, andthese should be used by healthcare stakeholders, suchas payers and providers, but is it enough?

Well, the catch is, we do not know. Dr Hahn cor-rectly points out in the article that very little dataexist regarding the effectiveness of these measures formany reasons, such as a lack of systematic implemen-tation of these measures, some of the strategies are toonew, and some have not been fully evaluated regard-ing their effectiveness.

However, in addition to answering the questionsregarding effectiveness of the various strategies thatDr Hahn lists, we must also remember the other caus-es for the development of drug abuse, because theseother causes must be addressed if we want to prevent

misuse, abuse, and diversion. We can no longer onlyfocus on “policing” patients who are treated with andproviders who prescribe opioids. We must also addressthe underlying causes that lead to drug abuse.

Effectively treating depression, schizophrenia, andchronic pain is as, if not more, critical than changingthe formulation of an opioid if the goal is to preventopioid misuse and abuse. Improving the educationand financial future of our nation is as, if not more,critical than checking photo identification at thepoint of sale if we want to prevent drug diversion.

POLICYMAKERS: We have a drug abuse prob-lem in this country. If we want to prevent opioid mis-use, abuse, and diversion, we need a comprehensivestrategy that can be measured appropriately to trulyunderstand whether we are having a positive effect onthis problem. We may even want to consider a catchphrase as part of our comprehensive strategy as long aswe can measure the results.

1. Johnston LD, O’Malley PM, Bachman JG, Schulenberg JE. Monitoring theFuture National Results on Adolescent Drug Use: Overview of Key Findings,2010. Ann Arbor: Institute for Social Research, University of Michigan. 2011.www.monitoringthefuture.org/pubs/monographs/mtf-overview2010.pdf.Accessed March 30, 2011.

Atheer A. Kaddis, PharmDVice President, Managed Markets

Diplomat Specialty Pharmacy

STAKEHOLDER PERSPECTIVE (Continued)

Signature (Required) Specialty

Date (Required) Address

Name City/State/ZIP

Company E-mail

Title Phone

Request your SUBSCRIPTION to

AmeRicAn HeAltH & DRug Benefits®

Please provide all information indicated, including date and signature. INCOMPLETE CARDS WILL NOT BE PROCESSED.

� YES! I would like to receive American Health & Drug Benefits® as well as related educational supplements.� NO. Please discontinue my subscription.

Fax to: 732.992.1881

• When added to a stimulant, extended-release Kapvay™ demonstrated statistically signifi cant improvement of ADHD symptoms compared with a stimulant alone at the end of 5 weeks of treatment, as measured by the ADHD RS-IV total score

IndicationKapvay™ (clonidine hydrochloride) extended-release tablets are indicated for the treatment of attention defi cit/hyperactivity disorder (ADHD) as monotherapy or as adjunctive therapy to stimulant medications in children and adolescents ages 6-17. The effi cacy of Kapvay™ is based on the results of 2 clinical trials in children and adolescents. Kapvay™ is indicated as an integral part of a total treatment program for ADHD that may include other measures (psychological, educational, and social) for patients with this syndrome.The effectiveness of Kapvay™ for longer-term use (more than 5 weeks) has not been systematically evaluated in controlled trials; therefore, the physician electing to use Kapvay™ for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

Important Safety Information• Kapvay™ should not be used in patients with known hypersensitivity to clonidine• Kapvay™ can cause dose-related decreases in blood pressure and heart rate. Use caution in treating patients who have a history of syncope

or may have a condition that predisposes them to syncope, such as hypotension, orthostatic hypotension, bradycardia, or dehydration. Use with caution in patients treated concomitantly with antihypertensives or other drugs that can reduce blood pressure or heart rate or increase the risk of syncope

• Somnolence/Sedation were commonly reported adverse reactions in clinical studies with Kapvay™. Potential for additive sedative effects with CNS-depressant drugs. Advise patients to avoid use with alcohol. Caution patients against operating heavy equipment or driving until they know how they respond to Kapvay™

• Patients should be instructed not to discontinue Kapvay™ therapy without consulting their physician due to the potential risk of withdrawal effects. Kapvay™ should be discontinued slowly in decrements of no more than 0.1 mg every 3 to 7 days

• In patients who have developed localized contact sensitization or other allergic reaction to clonidine in a transdermal system, substitution of oral clonidine hydrochloride therapy may be associated with the development of a generalized skin rash, urticaria, or angioedema. Use cautiously in patients with vascular disease, cardiac conduction disease, or chronic renal failure: Monitor carefully and uptitrate slowly

• Clonidine may potentiate the CNS-depressive effects of alcohol, barbiturates or other sedating drugs• Use caution when Kapvay™ is administered concomitantly with antihypertensive drugs, due to the additive pharmacodynamic effects

(e.g., hypotension, syncope)• Kapvay™ should not be used during pregnancy unless clearly needed. Since clonidine hydrochloride is excreted in human milk, caution should be

exercised when Kapvay™ is administered to a nursing woman• Caution is warranted in patients receiving clonidine concomitantly with agents known to affect sinus node function or AV nodal conduction

(e.g., digitalis, calcium channel blockers and beta-blockers) due to a potential for additive effects, such as bradycardia and AV block• Clonidine, the active ingredient in Kapvay™, is also approved as an antihypertensive. Do not use

Kapvay™ in patients concomitantly taking other clonidine-containing products, (e.g., Catapres® [clonidine hydrochloride], JENLOGA)

• Common adverse reactions (incidence at least 5% and twice the rate of placebo) include: somnolence, fatigue, upper respiratory tract infection, irritability, throat pain, insomnia, nightmares, emotional disorder, constipation, nasal congestion, increased body temperature, dry mouth, and ear pain

Extended-Release Formulation

© 2011 Shionogi Pharma, Inc. Atlanta, Georgia. All rights reserved. KAP10-PAD-002-00

* Kapvay™ was FDA approved on September 28, 2010.

Kapvay™ is a trademark of Shionogi Pharma, Inc.Catapres® is a registered trademark of Boehringer Ingelheim.

Please see Brief Summary of full Prescribing Information on the adjacent page.

When you treat Attention Defi cit/Hyperactivity Disorder (ADHD) with stimulants, for some patients, a question may be...

KAPVAY (clonidine hydrochloride) extended-release tablets, oral, Rx only INDICATIONS AND USAGE

KAPVAY™ is a centrally acting alpha2-adrenergic agonist indicated for the treatment of

attention deficit hyperactivity disorder (ADHD) as monotherapy or as adjunctive therapy to stimulant medications. (1)

The efficacy of KAPVAY is based on the results of two clinical trials in children and adolescents. (14) Maintenance efficacy has not been systematically evaluated, and patients who are continued on longer-term treatment require periodic reassessment. (1)

This extended-release formulation of clonidine hydrochloride is also approved for the treatment of hypertension under the trade name JENLOGA. (1)

CONTRAINDICATIONSKAPVAY should not be used in patients with known hypersensitivity to clonidine.

WARNINGS AND PRECAUTIONS

Hypotension/BradycardiaTreatment with KAPVAY can cause dose related decreases in blood pressure and heart rate. In patients that completed 5 weeks of treatment in a controlled, fixed-dose monotherapy study in pediatric patients, during the treatment period the maximum placebo-subtracted mean change in systolic blood pressure was -4.0 mmHg on KAPVAY 0.2 mg/day and -8.8 mmHg on KAPVAY 0.4 mg/day. The maximum placebo-subtracted mean change in diastolic blood pressure was -4.0 mmHg on KAPVAY 0.2 mg/day and -7.3 mmHg on KAPVAY 0.4 mg/day. The maximum placebo-subtracted mean change in heart rate was -4.0 beats per minute on KAPVAY 0.2 mg/day and -7.7 beats per minute on KAPVAY 0.4 mg/day.During the taper period of the fixed-dose monotherapy study the maximum placebo-subtracted mean change in systolic blood pressure was +3.4 mmHg on KAPVAY 0.2 mg/day and -5.6 mmHg on KAPVAY 0.4 mg/day. The maximum placebo-subtracted mean change in diastolic blood pressure was +3.3 mmHg on KAPVAY 0.2 mg/day and -5.4 mmHg on KAPVAY 0.4 mg/day. The maximum placebo-subtracted mean change in heart rate was -0.6 beats per minute on KAPVAY 0.2 mg/day and -3.0 beats per minute on KAPVAY 0.4 mg/day.Measure heart rate and blood pressure prior to initiation of therapy, following dose increases, and periodically while on therapy. Use KAPVAY with caution in patients with a history of hypotension, heart block, bradycardia, or cardiovascular disease, because it can decrease blood pressure and heart rate. Use caution in treating patients who have a history of syncope or may have a condition that predisposes them to syncope, such as hypotension, orthostatic hypotension, bradycardia, or dehydration. Use KAPVAY with caution in patients treated concomitantly with antihypertensives or other drugs that can reduce blood pressure or heart rate or increase the risk of syncope. Advise patients to avoid becoming dehydrated or overheated.

Sedation and SomnolenceSomnolence and sedation were commonly reported adverse reactions in clinical studies. In patients that completed 5 weeks of therapy in a controlled fixed dose pediatric monotherapy study, 31% of patients treated with 0.4 mg/day and 38% treated with 0.2 mg/day vs 7% of placebo treated patients reported somnolence as an adverse event. In patients that completed 5 weeks of therapy in a controlled flexible dose pediatric adjunctive to stimulants study, 19% of patients treated with KAPVAY+stimulant vs 8% treated with placebo+stimulant reported somnolence. Before using KAPVAY with other centrally active depressants (such as phenothiazines, barbiturates, or benzodiazepines), consider the potential for additive sedative effects. Caution patients against operating heavy equipment or driving until they know how they respond to treatment with KAPVAY. Advise patients to avoid use with alcohol.

Abrupt DiscontinuationNo studies evaluating abrupt discontinuation of KAPVAY in children with ADHD have been conducted. In children and adolescents with ADHD, physicians should gradually reduce the dose of KAPVAY in decrements of no more than 0.1 mg every 3 to 7 days. Patients should be instructed not to discontinue KAPVAY therapy without consulting their physician due to the potential risk of withdrawal effects.In adults with hypertension, sudden cessation of clonidine hydrochloride extended-release formulation treatment in the 0.2 to 0.6 mg/day range resulted in reports of headache, tachycardia, nausea, flushing, warm feeling, brief lightheadedness, tightness in chest, and anxiety.In adults with hypertension, sudden cessation of treatment with immediate-release clonidine has, in some cases, resulted in symptoms such as nervousness, agitation, headache, and tremor accompanied or followed by a rapid rise in blood pressure and elevated catecholamine concentrations in the plasma.

Allergic ReactionsIn patients who have developed localized contact sensitization to clonidine transdermal system, continuation of clonidine transdermal system or substitution of oral clonidine hydrochloride therapy may be associated with the development of a generalized skin rash.In patients who develop an allergic reaction from clonidine transdermal system, substitution of oral clonidine hydrochloride may also elicit an allergic reaction (including generalized rash, urticaria, or angioedema).

Patients with Vascular Disease, Cardiac Conduction Disease, or Renal FailureClonidine hydrochloride should be used with caution in patients with severe coronary insufficiency, conduction disturbances, recent myocardial infarction, cerebrovascular disease or chronic renal failure.

Other Clonidine-Containing ProductsClonidine, the active ingredient in KAPVAY, is also approved as an antihypertensive. Do not use KAPVAY in patients concomitantly taking other clonidine-containing products, (e.g. Catapres®).

ADVERSE REACTIONS

Clinical Trial ExperienceTwo KAPVAY ADHD clinical studies evaluated 256 patients who received active therapy, in one of the two placebo-controlled studies (Studies 1 and 2) with primary efficacy end-points at 5-weeks.

Study 1: Fixed-dose KAPVAY Monotherapy Study 1 was a multi-center, randomized, double-blind, placebo-controlled study with primary efficacy endpoint at 5 weeks, of two fixed doses (0.2 mg/day or 0.4 mg/day) of KAPVAY in children and adolescents (6 to 17 years of age) who met DSM-IV criteria for ADHD hyperactive or combined inattentive/hyperactive subtypes.Commonly observed adverse reactions (incidence of ≥ 2% in either active treatment group and greater than the rate on placebo) during the treatment period are listed in Table 2.

Table 2 Common Adverse Reactions in the Fixed-Dose Monotherapy Trial- Treatment period (Study 1)

Preferred Term

Percentage of Patients Reporting Event KAPVAY

0.4 mg/day N=78

KAPVAY 0.2 mg/day

N=76

Placebo (N=76)

Somnolence1 31% 38% 5% Headache 19% 29% 18% Upper Abdominal Pain 13% 20% 17% Fatigue2 13% 16% 1% Upper Respiratory Tract Infection 6% 11% 4% Irritability 6% 9% 3% Throat Pain 6% 8% 3% Nausea 8% 5% 4% Nightmare 9% 3% 0 Dizziness 3% 7% 5% Insomnia 6% 4% 1% Emotional Disorder 5% 4% 1% Constipation 6% 1% 0 Dry Mouth 5% 0 1% Nasal Congestion 5% 3% 1% Body Temperature Increased 1% 5% 3% Gastrointestinal Viral 0% 7% 4% Diarrhea 1% 4% 3% Ear Pain 0 5% 1% Nasopharyngitis 3% 3% 1% Abnormal Sleep-Related Event 1% 3% 0 Aggression 1% 3% 1% Asthma 1% 3% 1% Bradycardia 4% 0 0 Enuresis 4% 0 0 Influenza like Illness 3% 1% 1% Tearfulness 3% 1% 0 Thirst 3% 1% 0 Tremor 3% 1% 0 Epistaxis 0 3% 0 Lower Respiratory Tract Infection

0 3% 1%

Pollakiuria 0 3% 0 Sleep Terror 0 3% 0

1. Somnolence includes the terms “somnolence” and “sedation”.2. Fatigue includes the terms “fatigue” and “lethargy”.Commonly observed adverse reactions (incidence of ≥ 2% in either active treatment group and greater than the rate on placebo) during the taper period are listed in Table 3.

Table 3 Common Adverse Reactions in the Fixed-Dose Monotherapy Trial- Taper period* (Study 1)

Preferred Term

Percentage of Patients Reporting Event KAPVAY

0.4 mg/day N=78

KAPVAY 0.2 mg/day

N=76

Placebo (N=76)

Abdominal Pain Upper 6% 0 3% Headache 2% 5% 3% Gastrointestinal Viral 5% 0 0 Somnolence 3% 2% 0 Heart Rate Increased 3% 0 0 Otitis Media Acute 0 3% 0

*Taper Period: 0.2 mg dose, week 8; 0.4 mg dose, weeks 6-8; Placebo dose, weeks 6-8

Study 2: Flexible-dose KAPVAY as Adjunctive Therapy to PsychostimulantsStudy 2 was a multi-center, randomized, double-blind, placebo-controlled study, with primary efficacy endpoint at 5 weeks, of a flexible dose of KAPVAY as adjunctive therapy to a psychostimulant in children and adolescents (6 to 17 years) who met DSM-IV criteria for ADHD hyperactive or combined inattentive/hyperactive subtypes. KAPVAY was initiated at 0.1 mg/day and titrated up to 0.4 mg/day over a 3-week period. Most KAPVAY treated patients (75.5%) were escalated to the maximum dose of 0.4 mg/day.

Commonly observed adverse reactions (incidence of ≥ 2% in the treatment group and greater than the rate on placebo) during the treatment period are listed in Table 4.

11:31 AM

USE IN SPECIFIC POPULATIONSPregnancyPregnancy Category C: Oral administration of clonidine hydrochloride to pregnant rabbits during the period of embryo/fetal organogenesis at doses of up to 80 mcg/kg/day (approximately 3 times the oral maximum recommended daily dose [MRHD] of 0.4 mg/day on a mg/m2 basis) produced no evidence of teratogenic or embryotoxic potential. In pregnant rats, however, doses as low as 15 mcg/kg/day (1/3 the MRHD on a mg/m2 basis) were associated with increased resorptions in a study in which dams were treated continuously from 2 months prior to mating and throughout gestation. Increased resorptions were not associated with treatment at the same or at higher dose levels (up to 3 times the MRHD) when treatment of the dams was restricted to gestation days 6-15. Increases in resorptions were observed in both rats and mice at 500 mcg/kg/day (10 and 5 times the MRHD in rats and mice, respectively) or higher when the animals were treated on gestation days 1-14; 500 mcg/kg/day was the lowest dose employed in this study. No adequate and well-controlled studies have been conducted in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should not be used during pregnancy unless clearly needed.

Nursing MothersSince clonidine hydrochloride is excreted in human milk, caution should be exercised when KAPVAY is administered to a nursing woman.

Pediatric UseA study was conducted in which young rats were treated orally with clonidine hydrochloride from day 21 of age to adulthood at doses of up to 300 mcg/kg/day, which is approximately 3 times the maximum recommended human dose (MRHD) of 0.4 mg/day on a mg/m2 basis. A slight delay in onset of preputial separation was seen in males treated with the highest dose (with a no-effect dose of 100 mcg/kg/day, which is approximately equal to the MRHD), but there were no drug effects on fertility or on other measures of sexual or neurobehavioral development.

KAPVAY has not been studied in children with ADHD less than 6 years old.

Patients with Renal ImpairmentThe impact of renal impairment on the pharmacokinetics of clonidine in children has not been assessed. The initial dosage of KAPVAY should be based on degree of impairment. Monitor patients carefully for hypotension and bradycardia, and titrate to higher doses cautiously. Since only a minimal amount of clonidine is removed during routine hemodialysis, there is no need to give supplemental KAPVAY following dialysis.

Adult Use in ADHDKAPVAY has not been studied in adult patients with ADHD.

DRUG ABUSE AND DEPENDENCEControlled SubstanceKAPVAY is not a controlled substance and has no known potential for abuse or dependence.

OVERDOSAGESymptomsClonidine overdose: hypertension may develop early and may be followed by hypotension, bradycardia, respiratory depression, hypothermia, drowsiness, decreased or absent reflexes, weakness, irritability and miosis. The frequency of CNS depression may be higher in children than adults. Large overdoses may result in reversible cardiac conduction defects or dysrhythmias, apnea, coma and seizures. Signs and symptoms of overdose generally occur within 30 minutes to two hours after exposure.

TreatmentConsult with a Certified Poison Control Center for up-to-date guidance and advice.

© 2010 Shionogi Pharma, Inc. Florham Park, NJ 07932 Last modified 10/2010

Table 4 Common Adverse Reactions in the Flexible-Dose Adjunctive to Stimulant Therapy Trial- Treatment Period (Study 2)

Preferred Term Percentage of Patients Reporting Event

KAPVAY+STM (N=102)

PBO+STM (N=96)

Somnolence1 19% 8% Fatigue2 16% 4%

Abdominal Pain Upper 12% 7% Nasal Congestion 6% 5% Throat Pain 6% 3% Decreased Appetite 5% 4% Body Temperature Increased 4% 2% Dizziness 4% 2% Insomnia 4% 2% Epistaxis 3% 0 Rhinorrhea 3% 0 Abdominal Pain 2% 1% Anxiety 2% 0 Pain in Extremity 2% 0

1. Somnolence includes the terms: “somnolence” and “sedation”.

2. Fatigue includes the terms “fatigue” and “lethargy”.

Commonly observed adverse reactions (incidence of ≥ 2% in the treatment group and greater than the rate on placebo) during the taper period are listed in Table 5.

Table 5 Common Adverse Reactions in the Flexible-Dose Adjunctive to Stimulant Therapy Trial- Taper Period* (Study 2)

Preferred TermPercentage of Patients Reporting EventKAPVAY+STM

(N=102)PBO+STM

(N=96)Nasal Congestion 4% 2% Headache 3% 1% Irritability 3% 2% Throat Pain 3% 1% Gastroenteritis Viral 2% 0 Rash 2% 0

*Taper Period: weeks 6-8.

Most common adverse reactions, defined as events that were reported in at least 5% of drug-treated patients and at least twice the rate as in placebo patients, during the treatment period were somnolence, fatigue, upper respiratory tract infection, irritability, throat pain, insomnia, nightmares, emotional disorder, constipation, nasal congestion, increased body temperature, dry mouth, and ear pain. The most common adverse reactions that were reported during the taper phase were upper abdominal pain and gastrointestinal virus.Adverse Reactions Leading to DiscontinuationThirteen percent (13%) of patients receiving KAPVAY discontinued from the pediatric monotherapy study due to adverse events, compared to 1% in the placebo group. The most common adverse reactions leading to discontinuation of KAPVAY monotherapy treated patients were from somnolence/sedation (5%) and fatigue (4%). Less common adverse reactions leading to discontinuation (occurring in approximately 1% of patients) included: formication, vomiting, prolonged QT, increased heart rate, and rash. In the pediatric adjunctive treatment to stimulants study, one patient discontinued from KAPVAY + stimulant group because of bradyphrenia.

Effects on Laboratory Tests, Vital Signs, and ElectrocardiogramsKAPVAY treatment was not associated with any clinically important effects on any laboratory parameters in either of the placebo-controlled studies.

Mean decreases in blood pressure and heart rate were seen [see Warnings and Precautions (5.1)].

There were no changes on ECGs to suggest a drug-related effect.

DRUG INTERACTIONSNo drug interaction studies have been conducted with KAPVAY in children. The following have been reported with other oral immediate release formulations of clonidine.

Interactions with CNS-depressant DrugsClonidine may potentiate the CNS-depressive effects of alcohol, barbiturates or other sedating drugs.

Interactions with Tricyclic AntidepressantsIf a patient is receiving clonidine hydrochloride and also taking tricyclic antidepressants the hypotensive effects of clonidine may be reduced.

Interactions with Drugs Known to Affect Sinus Node Function or AV Nodal ConductionDue to a potential for additive effects such as bradycardia and AV block, caution is warranted in patients receiving clonidine concomitantly with agents known to affect sinus node function or AV nodal conduction (e.g., digitalis, calcium channel blockers and beta-blockers).

Use with other products containing clonidineDo not use KAPVAY concomitantly with other products containing clonidine (e.g. Catapres®).

Antihypertensive DrugsUse caution when KAPVAY is administered concomitantly with antihypertensive drugs, due to the potential for additive pharmacodynamic effects (e.g., hypotension, syncope) [see Warnings and Precautions (5.2)].

11:31 AM

GENERIC DRUG TRENDS

118 American Health & Drug Benefits l www.AHDBonline.com March/April 2011 l Vol 4, No 2

Arecent report from the American EnterpriseInstitute suggests that better utilization of gener-ic drugs in the Medicaid population could save

that federal program and the states much-needed funds,by eliminating unnecessary utilization of the more expen-sive brand-name drugs for which appropriate genericsubstitutes are available.1For this report, Alex Brill, MA, former senior adviser

and chief economist to the House Ways and Means Com -mittee, examined the database of the 2009 MedicaidDrug Rebate Program, focusing on drug utilization of 20“popular prescription drugs for which both brand andgeneric versions are available.”1 The study was limited tooral medications and demonstrated that significantlymore drug sales in Medicaid involve brand-name drugsthan their generic equivalent products.1Mr Brill calculates that if the trends outlined in his

report continue, unnecessary drug spending in Medicaidcould reach up to “$430 million in 2012 as a direct resultof states not utilizing more generic drugs.”1The key findings of this analysis, based on 2009 data,

show that1: 1. For the 20 popular (oral) drugs prescribed forMedicaid patients, the program overspent $329 mil-lion by reimbursing for brand-name products whenless expensive therapeutic alternatives existed

2. Of these 20 drugs, Medicaid wasted, on average, $95per prescription

3. As much as 85% of the unrealized savings was relat-ed to only 8 compounds, totaling $279 million

4. The following states had the greatest waste in drugspending in the Medicaid program1:• California, $102 million• Texas, $32 million • Georgia, $25 million• Ohio, $21 million• New York/Pennsylvania, $19 million each• Iowa, $15 million• Illinois/Florida, $11.5 million each• North Carolina, $6.8 million

5. Projections based on the 10 brand-name drugs thatare expected to lose patent in 2011 and 2012 forwhich Medicaid reimbursement was high in 2009—assuming similar overspending patterns—wouldrange from $289 million to $433 million. In support of his findings, Mr Brill cites a 2005 study

that identified potential savings from generic substitu-

tion across all patient categories, with overspending inMedicaid and other public programs estimated at $388million in 2000.2Mr Brill suggests that an “important and relatively

simple approach to reducing wasteful spending is to max-imize the use of less costly generic drugs in the Medicaiddrug program.”1 This, however, is anything but “relative-ly simple.” In the current economic state of affairs, cut-ting costs is on the mind of all healthcare stakeholders.However, before any firm conclusions can be reachedabout waste in utilization of brand versus generic drugs, athorough investigation is needed to demonstrate the rea-sons for what appears to be overutilization of the moreexpensive options, when therapeutically equivalent andless expensive options are available.The potential for cost-savings from generic substitu-

tions is self-evident and potentially quite significant, butclinical experience and the medical literature haveshown that individual variations in patients’ responses tomedications, as well as patient variation in susceptibilityto adverse events, must be considered, both of which arealso directly related to medication adherence and patientoutcomes. These issues must be factored in when cost-effectiveness analyses are conducted. They were notincluded in this analysis.It is no longer possible to consider pure economic

analyses when discussing cost-effectiveness and utiliza-tion-based waste of medications; the issues raised by per-sonalized medicine must be considered in this area.Indeed, Mr Brill makes a small concession in that direc-tion: after saying that “to ensure the highest possiblecost‐effectiveness, it is important that Medicaid pro-grams not reimburse for a more expensive version of adrug when a less expensive, therapeutically equivalentproduct is available,” he adds in a footnote that “theremay be situations, albeit rare, in which a patient requiresa brand product.”1Whether these situations are rare needs to be further

elucidated in evidence-based studies. Perhaps someanswers would soon come from those involved in per-sonalized medicine. �

References 1. Brill A. Overspending on multi-source drugs in Medicaid. American EnterpriseInstitute. March 28, 2011. www.aei.org/docLib/Brill%20MedicaidWorkingPaper2Final.pdf. Accessed April 4, 2011.2. Haas JS, Phillips KA, Gerstenberger EP, Seger AC. Potential savings from substi-tuting generic drugs for brand-name drugs: medical expenditure panel survey, 1997-2000. Ann Intern Med. 2005;142:891-897.

New Economic Analysis Zeroes in on LowGeneric Utilization and Waste in MedicaidBy Dalia Buffery, MA, ABD

Consistency and reliability

Co

st effectiven

ess

An exte

nsiv

e se

lection of 830 products

Quality generics from the ground up.

Actavis, the leader in fi rst-class generics.Around the world, there’s a growing demand for high-quality, lower-costalternatives to brand name pharmaceuticals. At Actavis, we’re at the forefrontof meeting that need. From our rigorous research and development program,to our world-class manufacturing facilities, we’re committed to serving theglobal market – with quality generics from the ground up.

To learn more, call Actavis customer service at 888.925.2342or visit us at www.actavis.us

The release of the proposed new rules for account-able care organizations (ACOs)1 has eliciteddiverse reactions. The Centers for Medicare &

Medicaid Services (CMS) encourages healthcareproviders, suppliers, and Medicare beneficiaries to sub-mit comments on the rules, which CMS will seriouslyconsider before releasing the final rules on June 6.2 TheACO program will be launched on January 1, 2012.1On the day the rules were released, CMS Administra -

tor Donald M. Berwick, MD, wrote, “What ever formACOs eventually take, one thing is certain: the era offragmented care delivery should draw to a close. Toomany Medicare beneficiaries—like many other patients—have suffered at the hands of wasteful, ineffective, andpoorly coordinated systems of care, with consequent coststhat are proving unsustainable.”2According to CMS, these rules will enable “providers to

better coordinate care for Medicare patients through” ACOs.In addition to financial incentives for care coordination,however, “ACOs could also have to pay back Medi carefor failing to provide efficient, cost-effective care.”1The main points of the proposed ACO rules are1:

� An ACO will require teams of doctors, hospitals, andother providers to work together to coordinate care

� ACOs must meet high-quality standards to ensurepatients are happy with their care and their healthoutcomes improve

� ACOs that save money this way will share in thesesavings with Medicare

� ACOs could also have to pay back Medicare for fail-ing to provide cost-effective care

� Minimum requirements for an existing ACO to beaccepted into the program are serving ≥5000 Medicarepatients and agreeing to participate for 3 years

� Medicare providers who join an ACO that partici-pates in this program would continue to receive pay-ment under the original Medicare fee-for-service rules

� The ACO is responsible for monitoring and reportingof the care it delivers

� Each ACO will be measured against a performancebenchmark for that ACO

� An established minimum savings rate accounts forvariations in healthcare spending, representing a per-centage of the benchmark that ACO savings mustexceed to qualify for shared savings

�� ACOs that participate in the 2-sided risk model canobtain greater shared savings.

Initial responses from the medical community havebeen mixed. William F. Jessee, MD, FACMPE, Presidentand CEO of the Medical Group Management Associa -tion (MGMA) was rather encouraging, saying, “The for-mation of ACOs has the potential to greatly improve thecoordination of care received by Medicare beneficiaries,and offers the promise of safer, more efficient and effec-tive care.…MGMA and our members will develop spe-cific feedback to CMS and the other agencies to ensurethat any overly restrictive or administratively burden-some requirements are addressed so this well-intendedconcept can become a practical reality.”3Jeremy A. Lazarus, MD, speaker of the American

Medical Association House of Delegates, sounded a sim-ilar tone, “ACOs offer great promise for improving carecoordination and quality while reducing cost, but only ifall physicians who wish to are able to lead and partici-pate in them.”4By contrast, Karen Ignagni, President and CEO of

America’s Health Insurance Plans, said, “We remainconcerned that ACOs could accelerate the trend ofprovider consolidation that drives up medical prices andresult in additional cost-shifting to families and employ-ers with private coverage.”5Dr Berwick further wrote that “the Center for

Medicare and Medicaid Innovation is also now explor-ing ways to test alternative models of ACOs that differfrom the models specified in the proposed rule.”2In the spirit of collaboration that has been the impetus

for American Health & Drug Benefits, we urge all stake-holders to leave their silo’s perspective and provide com-ments to CMS, to avert potential pitfalls and encourageinnovation in healthcare, for which no one groupholds the key. It will require stakeholder integration to turn our sick

system into a wellness-promoting enterprise. �

References 1. Centers for Medicare and Medicaid Services. What providers need to know:accountable care organizations. March 31, 2011. https://aaos.aristotle.com/Shared%20Documents/ACO%20Rule/ACOs%20-%20CMS%20provider%20fact%20sheet.pdf. Accessed April 2, 2011.2. Berwick DM. Launching accountable care organizations—the proposed rule forthe Medicare shared savings program. March 31, 2011. N Engl J Med online.http://healthpolicyandreform.nejm.org/?p=14106. Accessed April 2, 2011. 3. Medical Group Management Association. MGMA comments on ACO pro-posed rule. March 31, 2011. www.mgma.com/press/default.aspx?id=1248413.Accessed April 2, 2011.4. Fiegel C. CMS releases proposed ACO rules. www.ama-assn.org/amednews/2011/03/28/gvse0331.htm. Accessed April 2, 2011.5. America’s Health Insurance Plans. AHIP statement on Medicare shared savingprogram. March 31, 2011. www.ahipcoverage.com/2011/03/31/ahip-statement-on-medicare-shared-savings-program/. Accessed April 2, 2011.

INDUSTRY TRENDS


CMS Invites Feedback on the ProposedAccountable Care Organizations Rules By Dalia Buffery, MA, ABD

There is no quick fix. The cracks in our current healthcare system did not happen overnight, and the solutions we seek will, likewise, take time to build. At AstraZeneca, we believe that a new level of connectedness and collaboration can lead to innovative breakthroughs in healthcare.

If you too want to be part of the solution for better healthcare, we welcome the opportunity to work together with you to connect new data sources, generate real-world evidence and insights, and accelerate delivery of dramatically improved patient outcomes at significantly lower costs. Are you up for the challenge?

Let’s repair healthcare one community at a time. To get connected, contact your Account Director or call us at 1-800-236-9933.

©2011 AstraZeneca LP. All rights reserved.

INDUSTRY TRENDS


In recent years, the patient-centered med-ical home (PCMH)—often referred to inits abbreviated form, the “medical home”

—care delivery model has become one of thehottest topics in healthcare. Based on a holis-tic, patient-centric approach, the PCMH rep-resents a methodology aimed at fosteringincreased collaboration among healthcarestakeholders. As such, the PCMH is widelybelieved to offer perhaps the best hope to transform andimprove the system as a whole. For example, Geisinger Health System reduced hos-

pital readmissions by 18% through its medical homeprogram and by 44% with its ProvenCare one-priceelective cardiac surgery medical home program.1 PaulGrundy, MD, MPH, Global Director of HealthcareTransforma tion for IBM and Chairman of the Patient-Centered Primary Care Collaborative, recently statedin his keynote presentation of the Medical HomeSummit in Philadelphia that his review of evidencefrom ongoing PCMH pilots has resulted in a 9.6% over-all reduction in costs.2To a certain degree, the PCMH is a reversal of the

longstanding episode-based methodology that has beenprevalent in healthcare for many years. Unlike theepisodic-based care, the PCMH encourages patients andtheir providers to work closely together to ensure thatcare is more comprehensive, coordinated, and consis-tent. In essence, the medical home necessitates an ongo-ing, full-spectrum approach to patient care that requiresthe primary healthcare provider and the patients them-selves to maintain complete awareness of the patientsand their specific healthcare needs and experiences.This approach should result in more streamlined andappropriate care, reduced waste, lower costs and, mostimportant, better outcomes.Although the PCMH model had already been building

momentum on its own, interest in this concept skyrocket-ed after it received a significant endorsement in thePatient Protection and Affordable Care Act (ACA) of2010. That legislation strongly encourages the prolifera-tion of medical homes and accountable care organizations(ACOs) as innovative means of delivering and reimburs-ing for better coordinated and cost-effective care.

The Patient-Centered Primary Care Col -laborative (PCPCC.net) is an organizationwith the goals of facilitating improvements inpatient–physician relations, and creating amore effective and efficient model of health-care delivery. They have created a stakehold-er group charged with showing that thePCMH provides the foundation for successfulimplementation of the ACO delivery model.

Moving patients through the ACO will require a strongelement of care coordination, so we look forward to see-ing the results of this group.

ACOs and the Patient-Centered Medical HomeAn ACO is a business and a medical entity that

accepts responsibility for the cost and the quality of careprovided to a given population of patients and generatesthe data on their performance. This includes physicianpractices and may include hospitals, nursing homes,home health agencies, and other provider organizations. The ACO model is called out specifically within the

ACA as a preferred solution for bending the healthcarecost curve, while improving patient outcomes. There isfunding within the bill to implement ACOs forMedicare and Medicaid,3 and the criteria have alreadybeen determined for ACOs to become involved withboth programs. Because the PCMH will provide the carecoordination that is required to make the ACO modelwork, most ACOs will likely take root in areas that havea sufficient number of medical homes.

The Benefits to Patients and Providers In addition to the system-wide improvements it is

expected to foster, the PCMH can also offer distinctsets of benefits for healthcare’s primary stakeholders—patients, providers, and health plans. In a medicalhome structure, the patient is aligned with a care coor-dinator (normally a registered nurse, physician assis-tant, or social worker) at the provider practice levelwhose primary function is to manage the patient’shealth across the care spectrum. The care coordinator interfaces on the patient’s

behalf with the health plan, specialists, pharmacists,labs, and other stakeholders to formulate a more efficient

The Patient-Centered Medical Home:An Essential Destination on the Road to ReformBy Matt AdamsonVice President, Health Solutions, MEDecision, Inc.

INDUSTRY TRENDS


and holistic approach to treatment. This generallyresults in a more informed and engaged patient—onewho, through the care coordinator, has a more simplifiedaccess to care, better understands his or her own needs,and is more likely to comply with treatment recommen-dations and suggested preventive measures.For providers, the PCMH fosters an environment of

transparent reporting on progress toward measurableoutcomes that could potentially result in certain medicalhome incentives and bonus payments. Such additionalreimbursement to the family physician also provides abenefit to society as a whole, because it addresses the pri-mary care shortage that is predicted to occur if currenttrends in healthcare continue. This is important,because primary care is the foundation of the healthcaresystem. In areas where primary care is strong, patientshave better outcomes and are more satisfied, whilehealth disparities and healthcare costs are lower.4In addition, with the ability to outsource aspects of

care coordination to the health plan or to other entities,the provider can simultaneously maximize outcomes.That is, by reducing or eliminating certain associatedadministrative functions, clinical practices can managemore patients, at a lower cost. Health plans generally maintain the most compre-

hensive clinical data available for their individual mem-bers. In the medical home, they provide this informationto provider practices electronically and establish bonusand incentive structures for relevant outcomes. Pro -viders, in turn, can plan and manage related activities tomaximize the benefits.

The Benefits to Health PlansFor health plans, the medical home model can offer

distinct competitive advantages in a number of keyareas, including:• Reduced costs and improved health outcomes. Althoughthis value proposition has yet to be fully tested, thePCMH model is the most promising way of signifi-cantly enhancing the efficiency and cost-effectivenessof care management.

• Clinical relevance.A health plan adds value to the caremanagement process with its rich patient data andexpertise. Its willingness to collaborate with cus-tomers is attractive to employers investigating thePCMH as a means of keeping their workforce produc-tive, and to providers making this paradigm shift.

• Member satisfaction and retention. Members whosehealth is managed within the medical home structuregenerally report greater overall satisfaction. Thisbecomes a significant factor under healthcare reform,wherein members will have a greater opportunity toswitch between health plans.

• Provider satisfaction. Early physician satisfaction scoresshow that primary care physicians derive greater satis-faction within the PCMH model compared with theexisting fee-for-service approach. For example, GroupHealth of Puget Sound reported after implementationof the PCMH model, “less staff burnout, with only10% of pilot clinic staff reporting high emotionalexhaustion at 12 months compared to 30% of staff atcontrol clinics, and, major improvement in recruit-ment and retention of primary care physicians.”5Therefore, the medical home creates an opportunityfor payers to strengthen relationships with providernetworks, by offering systems and reimbursementframeworks that support care coordination and ateam-based approach.

• Improved care collaboration. By fostering an environ-ment of patient-centric activity closer to the patientand leveraging the relationship patients have withtheir primary care physician, care managementadministration and oversight are shifted to the pointof care. With the right tools in place, the payerremains connected.

Technology Key to Success of the Medical HomeThe PCMH model is heavily predicated on the effec-

tive use of technology, which is clearly outlined in thehealthcare reform law. Technology is the most promisingmeans of enabling the very collaboration among health-care stakeholders that is the foundation for the medicalhome concept itself. In particular, analytics technology—especially that which is focused on optimizing care man-agement and quality reporting—will be key to the suc-cess of the medical home approach and to optimizinghealth outcomes. Technology will enable medical home participants to

receive patient data that have been analyzed and toidentify factors such as gaps in care and medicationadherence. This more inclusive, 360-degree view of thepatient’s information that spans the full continuum ofcare, regardless of where the patient is seen, will enablemore focused plans of care.An example of this involves the integration of phar-

macy services as part of the medical home, which is a

This is important, because primary care isthe foundation of the healthcare system. Inareas where primary care is strong, patientshave better outcomes and are moresatisfied, while health disparities andhealthcare costs are lower.

INDUSTRY TRENDS


critical aspect of care when managing patients withmany conditions who have received prescriptions frommultiple physicians. The American College of ClinicalPharmacy has stated in its 2009 report, Integration ofPharmacists’ Clinical Services in the Patient-CenteredPrimary Care Medical Home, that “Over the last decade,the clinical consequences and economic costs of medica-tion misuse, and medication-related problems, includingpatient non-adherence and suboptimal therapeutic out-comes, have become more fully recognized by clinicians,policymakers, and health care economists.”6 Inclusion ofthe pharmacist within the medical home workflow is anecessary first step in alleviating these issues byimproved care coordination.

The effective deployment of technical solutions canenable any physician practice, regardless of its size or itspatient population, to successfully participate in a med-ical home model by establishing what, in essence, is avirtual medical home. Within this environment, thephysician practice will be able to electronically connectwith the health plan and other outside resources todeliver the same advantages of a “true” medical home,but with significantly less financial investment andadministrative overhead. This is the result of allowingsmaller physician practices to use resources as needed

rather than being required to maintain high numbers offull-time staff to provide a full range of services.

A Rare OpportunityWith the PCMH, the healthcare reform law may

indeed be on to something—a rare instance in whicheach healthcare stakeholder stands to gain a lot, whilesacrificing or compromising little. A number of test pro-grams and pilots to date have generated favorablereturns.5 Naturally, not all have been without their shareof obstacles, and countless lessons have been learned,but evidence is mounting to indicate that the medicalhome, in practice, can deliver what many people havebelieved it can, in theory.5 If the tenets and mandates ofreform are to take hold and achieve their true potential,the PCMH will undoubtedly play a significant role inmaking it happen. ■

Author Disclosure StatementMr Adamson reported no conflicts of interest.

References1.Geisinger CEO urges Senate to change healthcare reimbursement. September 16, 2008.https://webapps.geisinger.org/ghsnews/articles/GeisingerCEOUrgesSenateto7996.html. Accessed March 28, 2011.2.Who was the shooter’s doctor? IBM. Slide 17. www.ehcca.com/presentations/medhomesummit3/grundy_1.pdf. Accessed March 28, 2011.3. Centers for Medicare & Medicaid Services. Medicare “Accountable CareOrganizations” shared savings program—new section 1899 of Title XVIII. www.cms.gov/OfficeofLegislation/Downloads/AccountableCareOrganization.pdf. AccessedMarch 22, 2011.4.Michigan Primary Care Consortium. Primary care is in crisis. www.mipcc.org/sites/mipcc.org/files/u4/crisis_part1_web.pdf. Accessed March 22, 2011.5. Patient-Centered Primary Care Collaborative. Proof in practice: a compilation ofpatient-centered medical home pilot and demonstration projects. 2009.www.pcpcc.net/files/PilotGuidePip.pdf. Accessed March 22, 2011.6. American College of Clinical Pharmacy. Integration of pharmacists’ clinical serv-ices in the patient-centered primary care medical home. March 2009. www.accp.com/docs/misc/pcmh_services.pdf. Accessed March 22, 2011.

WEB EXCLUSIVE

Accountable Care Organizations: The End ofInnovation in Medicine?By Scott Gottlieb, MD

www.AHDBonline.com

Technology will enable medical homeparticipants to receive patient data thathave been analyzed and to identify factors such as gaps in care and medication adherence.

��

PUBLISHER ASSOCIATE PUBLISHER DIRECTOR, CLIENT SERVICESNicholas Englezos Maurice Nogueira Mark [email protected] [email protected] [email protected] 732.992.1895 732.992.1897

COMING IN AUGUST

ASCO 2011:Payers’ Perspectives

Space reservations

due 7/1

Materials due 7/15

News and analysis,including coverage of plenarysessions, keynotes, abstracts,posters, and late- breaking sessions

To Subscribe:www.AHDBonline.com

ADVERTISING OPPORTUNITIES AVAILABLE

� � ��

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

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

INDICATIONS AND USAGE: Victoza® is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Important Limitations of Use: Because of the uncertain relevance of the rodent thyroid C-cell tumor findings to humans, pre-scribe Victoza® only to patients for whom the potential benefits are considered to outweigh the potential risk. Victoza® is not recommended as first-line therapy for patients who have inadequate glycemic control on diet and exercise. In clinical trials of Victoza®, there were more cases of pancreatitis with Victoza® than with comparators. Victoza® has not been studied sufficiently in patients with a history of pancreatitis to determine whether these patients are at increased risk for pancreatitis while using Victoza®. Use with caution in patients with a history of pancreatitis. Victoza® is not a substitute for insulin. Victoza® should not be used in patients with type 1 dia-betes mellitus or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings. The concurrent use of Victoza® and insulin has not been studied.CONTRAINDICATIONS: Victoza® is contraindicated in patients with a personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syn-drome type 2 (MEN 2).WARNINGS AND PRECAUTIONS: Risk of Thyroid C-cell Tumors: Liraglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors (adenomas and/or carcinomas) at clinically relevant exposures in both genders of rats and mice. Malignant thyroid C-cell carcinomas were detected in rats and mice. A statistically significant increase in cancer was observed in rats receiving liraglutide at 8-times clinical exposure compared to controls. It is unknown whether Victoza® will cause thyroid C-cell tumors, including medullary thyroid car-cinoma (MTC), in humans, as the human relevance of liraglutide-induced rodent thyroid C-cell tumors could not be determined by clinical or nonclinical studies [see Boxed Warning, Contra-indications]. In the clinical trials, there have been 4 reported cases of thyroid C-cell hyperplasia among Victoza®-treated patients and 1 case in a comparator-treated patient (1.3 vs. 0.6 cases per 1000 patient-years). One additional case of thyroid C-cell hyperplasia in a Victoza®-treated patient and 1 case of MTC in a comparator-treated patient have subsequently been reported. This comparator-treated patient with MTC had pre-treatment serum calcitonin concentrations >1000 ng/L suggesting pre-existing disease. All of these cases were diagnosed after thyroidectomy, which was prompted by abnormal results on routine, protocol-specified measurements of serum calcitonin. Four of the five liraglutide-treated patients had elevated calcitonin concentrations at baseline and throughout the trial. One liraglutide and one non-liraglutide-treated patient devel-oped elevated calcitonin concentrations while on treatment. Calcitonin, a biological marker of MTC, was measured throughout the clinical development program. The serum calcitonin assay used in the Victoza® clinical trials had a lower limit of quantification (LLOQ) of 0.7 ng/L and the upper limit of the reference range was 5.0 ng/L for women and 8.4 ng/L for men. At Weeks 26 and 52 in the clinical trials, adjusted mean serum calcitonin concentrations were higher in Victoza®-treated patients compared to placebo-treated patients but not compared to patients receiving active comparator. At these timepoints, the adjusted mean serum calcitonin values (~ 1.0 ng/L) were just above the LLOQ with between-group differences in adjusted mean serum calcitonin values of approximately 0.1 ng/L or less. Among patients with pre-treatment serum calcitonin below the upper limit of the reference range, shifts to above the upper limit of the reference range which persisted in subsequent measurements occurred most frequently among patients treated with Victoza® 1.8 mg/day. In trials with on-treatment serum calcitonin measurements out to 5-6 months, 1.9% of patients treated with Victoza® 1.8 mg/day developed new and persistent calci-tonin elevations above the upper limit of the reference range compared to 0.8-1.1% of patients treated with control medication or the 0.6 and 1.2 mg doses of Victoza®. In trials with on-treat-ment serum calcitonin measurements out to 12 months, 1.3% of patients treated with Victoza® 1.8 mg/day had new and persistent elevations of calcitonin from below or within the reference range to above the upper limit of the reference range, compared to 0.6%, 0% and 1.0% of patients treated with Victoza® 1.2 mg, placebo and active control, respectively. Otherwise, Victoza® did not produce consistent dose-dependent or time-dependent increases in serum calcitonin. Patients with MTC usually have calcitonin values >50 ng/L. In Victoza® clinical trials, among patients with pre-treatment serum calcitonin <50 ng/L, one Victoza®-treated patient and no comparator-treated patients developed serum calcitonin >50 ng/L. The Victoza®-treated patient who developed serum calcitonin >50 ng/L had an elevated pre-treatment serum calcitonin of 10.7 ng/L that increased to 30.7 ng/L at Week 12 and 53.5 ng/L at the end of the 6-month trial. Follow-up serum calci-tonin was 22.3 ng/L more than 2.5 years after the last dose of Victoza®. The largest increase in serum calcitonin in a comparator-treated patient was seen with glimepiride in a patient whose serum calcitonin increased from 19.3 ng/L at baseline to 44.8 ng/L at Week 65 and 38.1 ng/L at Week 104. Among patients who began with serum calcitonin <20 ng/L, calcitonin elevations to >20 ng/L occurred in 0.7% of Victoza®-treated patients, 0.3% of placebo-treated patients, and 0.5% of active-comparator-treated patients, with an incidence of 1.1% among patients treated with 1.8 mg/day of Victoza®. The clinical significance of these findings is unknown. Counsel patients regarding the risk for MTC and the symptoms of thyroid tumors (e.g. a mass in the neck, dysphagia, dyspnea or persistent hoarseness). It is unknown whether monitoring with serum calcitonin or thyroid ultrasound will mitigate the potential risk of MTC, and such monitoring may increase the risk of unnecessary procedures, due to low test specificity for serum calcitonin and a high background incidence of thyroid disease. Patients with thyroid nodules noted on physical examination or neck imaging obtained for other reasons should be referred to an endocrinolo-gist for further evaluation. Although routine monitoring of serum calcitonin is of uncertain value in patients treated with Victoza®, if serum calcitonin is measured and found to be elevated, the

patient should be referred to an endocrinologist for further evaluation. Pancreatitis: In clinical trials of Victoza®, there were 7 cases of pancreatitis among Victoza®-treated patients and 1 case among comparator-treated patients (2.2 vs. 0.6 cases per 1000 patient-years). Five cases with Victoza® were reported as acute pancreatitis and two cases with Victoza® were reported as chronic pancreatitis. In one case in a Victoza®-treated patient, pancreatitis, with necrosis, was observed and led to death; however clinical causality could not be established. One additional case of pan-creatitis has subsequently been reported in a Victoza®-treated patient. Some patients had other risk factors for pancreatitis, such as a history of cholelithiasis or alcohol abuse. There are no con-clusive data establishing a risk of pancreatitis with Victoza® treatment. After initiation of Victoza®, and after dose increases, observe patients carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back and which may or may not be accompanied by vomiting). If pancreatitis is suspected, Victoza® and other potentially suspect medications should be discontinued promptly, confirmatory tests should be performed and appropriate management should be initiated. If pancreatitis is confirmed, Victoza® should not be restarted. Use with caution in patients with a history of pancreatitis. Use with Medications Known to Cause Hypoglycemia: Patients receiving Victoza® in combination with an insulin secretagogue (e.g., sulfonylurea) may have an increased risk of hypoglycemia. In the clinical trials of at least 26 weeks duration, hypoglycemia requiring the assistance of another person for treat-ment occurred in 7 Victoza®-treated patients and in two comparator-treated patients. Six of these 7 patients treated with Victoza® were also taking a sulfonylurea. The risk of hypoglycemia may be lowered by a reduction in the dose of sulfonylurea or other insulin secretagogues [see Adverse Reactions]. Macrovascular Outcomes: There have been no clinical studies establishing con-clusive evidence of macrovascular risk reduction with Victoza® or any other antidiabetic drug.ADVERSE REACTIONS: Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of Victoza® was evaluated in a 52-week monotherapy trial and in five 26-week, add-on combination therapy trials. In the monotherapy trial, patients were treated with Victoza® 1.2 mg daily, Victoza® 1.8 mg daily, or glimepiride 8 mg daily. In the add-on to metformin trial, patients were treated with Victoza® 0.6 mg, Victoza® 1.2 mg, Victoza® 1.8 mg, placebo, or glimepiride 4 mg. In the add-on to glimepiride trial, patients were treated with Victoza® 0.6 mg, Victoza® 1.2 mg, Victoza® 1.8 mg, placebo, or rosiglitazone 4 mg. In the add-on to metformin + glimepiride trial, patients were treated with Victoza® 1.8 mg, placebo, or insulin glargine. In the add-on to metformin + rosiglitazone trial, patients were treated with Victoza® 1.2 mg, Victoza® 1.8 mg or placebo. Withdrawals: The incidence of withdrawal due to adverse events was 7.8% for Victoza®-treated patients and 3.4% for comparator-treated patients in the five controlled trials of 26 weeks duration or longer. This difference was driven by withdrawals due to gastrointestinal adverse reactions, which occurred in 5.0% of Victoza®-treated patients and 0.5% of comparator-treated patients. The most common adverse reactions leading to withdrawal for Victoza®-treated patients were nausea (2.8% versus 0% for comparator) and vomiting (1.5% versus 0.1% for comparator). Withdrawal due to gastrointestinal adverse events mainly occurred during the first 2-3 months of the trials. Tables 1, 2 and 3 summarize the adverse events reported in 5% of Victoza®-treated patients in the six controlled trials of 26 weeks duration or longer.Table 1: Adverse events reported in 5% of Victoza®-treated patients or 5% of glimepiride-treated patients: 52-week monotherapy trial

All Victoza® N = 497 Glimepiride N = 248Adverse Event Term (%) (%)Nausea 28.4 8.5Diarrhea 17.1 8.9Vomiting 10.9 3.6Constipation 9.9 4.8Upper Respiratory Tract Infection 9.5 5.6Headache 9.1 9.3Influenza 7.4 3.6Urinary Tract Infection 6.0 4.0Dizziness 5.8 5.2Sinusitis 5.6 6.0Nasopharyngitis 5.2 5.2Back Pain 5.0 4.4Hypertension 3.0 6.0

Table 2: Adverse events reported in 5% of Victoza®-treated patients and occur-ring more frequently with Victoza® compared to placebo: 26-week combination therapy trials

Add-on to Metformin TrialAll Victoza® +

Metformin N = 724Placebo +

Metformin N = 121Glimepiride +

Metformin N = 242Adverse Event Term (%) (%) (%)Nausea 15.2 4.1 3.3Diarrhea 10.9 4.1 3.7Headache 9.0 6.6 9.5Vomiting 6.5 0.8 0.4

Add-on to Glimepiride TrialAll Victoza® +

Glimepiride N = 695Placebo +

Glimepiride N = 114Rosiglitazone +

Glimepiride N = 231Adverse Event Term (%) (%) (%)Nausea 7.5 1.8 2.6Diarrhea 7.2 1.8 2.2Constipation 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, gastroin-testinal adverse events were reported in 41% of Victoza®-treated patients and were dose-related. Gastrointestinal adverse events occurred in 17% of comparator-treated patients. Events that occurred more commonly among Victoza®-treated patients included nausea, vomiting, diarrhea, dyspepsia and constipation. In a 26-week study of Victoza® versus exenatide, both in combination with metformin and/or sulfonylurea overall gastrointestinal adverse event incidence rates, includ-ing nausea, were similar in patients treated with Victoza® and exenatide. In five clinical trials of 26 weeks duration or longer, the percentage of patients who reported nausea declined over time. Approximately 13% of Victoza®-treated patients and 2% of comparator-treated patients reported nausea during the first 2 weeks of treatment. In a 26 week study of Victoza® versus exenatide, both in combination with metformin and/or sulfonylurea, the proportion of patients with nausea also declined over time. Immunogenicity: Consistent with the potentially immunogenic properties of protein and peptide pharmaceuticals, patients treated with Victoza® may develop anti-liraglutide antibodies. Approximately 50-70% of Victoza®-treated patients in the five clinical trials of 26 weeks duration or longer were tested for the presence of anti-liraglutide antibodies at the end of treatment. Low titers (concentrations not requiring dilution of serum) of anti-liraglutide antibodies were detected in 8.6% of these Victoza®-treated patients. Sampling was not performed uniformly across all patients in the clinical trials, and this may have resulted in an underestimate of the actual percentage of patients who developed antibodies. Cross-reacting anti-liraglutide antibod-ies 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 neutral-izing 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-con-trol-treated patients, respectively. Antibody formation was not associated with reduced efficacy of Victoza® when comparing mean HbA1c of all antibody-positive and all antibody-negative patients. However, the 3 patients with the highest titers of anti-liraglutide antibodies had no reduction in HbA1c with Victoza® treatment. In clinical trials of Victoza®, events from a composite of adverse events potentially related to immunogenicity (e.g. urticaria, angioedema) occurred among 0.8% of Victoza®-treated patients and among 0.4% of comparator-treated patients. Urticaria accounted for approximately one-half of the events in this composite for Victoza®-treated patients. Patients who developed anti-liraglutide antibodies were not more likely to develop events from the immu-nogenicity events composite than were patients who did not develop anti-liraglutide antibodies. Injection site reactions: Injection site reactions (e.g., injection site rash, erythema) were reported in approximately 2% of Victoza®-treated patients in the five clinical trials of at least 26 weeks duration. Less than 0.2% of Victoza®-treated patients discontinued due to injection site reactions.

Papillary thyroid carcinoma: In clinical trials of Victoza®, there were 6 reported cases of papillary thyroid carcinoma in patients treated with Victoza® and 1 case in a comparator-treated patient (1.9 vs. 0.6 cases per 1000 patient-years). Most of these papillary thyroid carcinomas were <1 cm in greatest diameter and were diagnosed in surgical pathology specimens after thyroidectomy prompted by findings on protocol-specified screening with serum calcitonin or thyroid ultra-sound. 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 combina-tion 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 hypoglyce-mia 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 intra-venous 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 malig-nant neoplasms (based on investigator-reported events, medical history, pathology reports, and surgical reports from both blinded and open-label study periods) was 10.9 for Victoza®, 6.3 for placebo, and 7.2 for active comparator. After excluding papillary thyroid carcinoma events [see Adverse Reactions], no particular cancer cell type predominated. Seven malignant neoplasm events were reported beyond 1 year of exposure to study medication, six events among Victoza®-treated patients (4 colon, 1 prostate and 1 nasopharyngeal), no events with placebo and one event with active comparator (colon). Causality has not been established. Laboratory Tests: In the five clinical trials of at least 26 weeks duration, mildly elevated serum bilirubin concentra-tions (elevations to no more than twice the upper limit of the reference range) occurred in 4.0% of Victoza®-treated patients, 2.1% of placebo-treated patients and 3.5% of active-comparator-treated patients. This finding was not accompanied by abnormalities in other liver tests. The significance of this isolated finding is unknown.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: December 22, 2010 Version: 2Manufactured 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-R2 2/2011

© 2011 Novo Nordisk 0311-00001944-1 April 2011

Victoza® is a registered trademark and VictozaCare™ is a trademark of Novo Nordisk A/S.

To learn how Victoza® can help your patients manage their type 2 diabetes, visit VictozaPro.com/Benefi t.

For patients who need more than metformin

Help grab type 2 diabetes by the roots.Once-daily Victoza® provides powerful and sustained* reductions in A1C and:

Impacts beta-cell function to help regulate insulin secretion

May reduce weight – Victoza® is not indicated for the management of obesity – Weight change was a secondary end point in clinical trials

* Victoza® was evaluated in a 52-week monotherapy trial and in fi ve 26-week, add-on combination trials.

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.There have been no studies establishing conclusive evidence of macrovascular risk reduction with Victoza® or any other antidiabetic drug. The most common adverse reactions, reported in ≥5% of patients treated with Victoza® and more commonly than in patients treated with placebo, are headache, nausea, diarrhea, and anti-liraglutide antibody formation. Immunogenicity-related events, including urticaria, were more common among Victoza®-treated patients (0.8%) than among comparator-treated patients (0.4%) in clinical trials. Victoza® has not been studied in type 2 diabetes patients below 18 years of age and is not recommended for use in pediatric patients. Victoza® should be used with caution in patients with renal impairment and in patients with hepatic impairment.

Please see brief summary of Prescribing Information on adjacent page.

March/April 2011, Vol 4, No 2

Documents

Transcript of March/April 2011, Vol 4, No 2