April/May 2009, Vol 2, No 3

APRIL/MAY 2009 VOLUME 2, NUMBER 3

2009 Engage Healthcare Communications, LLCwww.AHDBonline.com

THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN

The Paradox of Public Policy Reform: Change or Continuum?Robert E. Henry

Are You Kidding Me? Clinical Comparative Effectiveness or Evidence-Based Medicine Thomas Kaye RPh, MBA, FASHP

MIPPA: First Broad Changes to Medicare Part D Plan Operations Jean D. LeMasurier; Babette Edgar, PharmD, MBAStakeholder Perspective by Mark A. Newsom, MSc

ProvenCare: Geisingers Model for Care Transformation throughInnovative Clinical Initiatives and Value CreationInterview with Ronald A. Paulus, MD, MBA

Perspective

The Integrated Patient-Centered Medical Home: Tools for TransformingOur Healthcare Delivery SystemMatias A. Klein

Increased Patient Cost-Sharing, Weak US Economy, and Poor Health Habits: Implications for Employers and Insurers Melinda C. Haren, RN; Kirk McConnell; Arthur F. Shinn, PharmD, FASCPStakeholder Perspective by Paul Anthony Polansky, BSPharm, MBA

Generic Drug TrendsNew Legislations on Generics and Biosimilars Brewing in Congress

Industry Trends Paying for Cancer Care: Economic Models Start to Emerge, DovetailingHealthcare Reform

CLINICAL

BUSINESS

EDITORIAL

DEPARTMENTS

REGULATORY

This year, 1 in 5 Americans will havePHN pain after shingles1

FOR RELIEF OF PAIN ASSOCIATED WITH PHN

A Custom Fit for Their Body

Important Safety Information

LIDODERM (lidocaine patch 5%) is indicated for relief of pain associated with post-herpetic neuralgia (PHN). Apply only to intact skin.

LIDODERM is contraindicated in patients with a history of sensitivity to local anesthetics (amide type) or any product component.

Even a used LIDODERM patch contains a large amount of lidocaine (at least 665 mg). The potential exists for a small child or a pet to suffer serious adverse effectsfrom chewing or ingesting a new or used LIDODERM patch, although the risk with this formulation has not been evaluated. It is important to store and dispose ofLIDODERM out of the reach of children, pets, and others.

Excessive dosing, such as applying LIDODERM to larger areas or for longer than the recommended wearing time, could result in increased absorption of lidocaineand high blood concentrations leading to serious adverse effects.

Avoid contact of LIDODERM with the eye. If contact occurs, immediately wash the eye with water or saline and protect it until sensation returns.

Patients with severe hepatic disease are at greater risk of developing toxic blood concentrations of lidocaine, because of their inability to metabolize lidocainenormally. LIDODERM should be used with caution in patients receiving Class I antiarrhythmic drugs (such as tocainide and mexiletine) since the toxic effects are additive and potentially synergistic. LIDODERM should also be used with caution in pregnant (including labor and delivery) or nursing mothers.

Allergic reactions, although rare, can occur.

During or immediately after LIDODERM treatment, the skin at the site of application may develop blisters, bruising, burning sensation, depigmentation, dermatitis,discoloration, edema, erythema, exfoliation, irritation, papules, petechia, pruritus, vesicles, or may be the locus of abnormal sensation. These reactions are generally

A first-line therapy, alone or with oral analgesics 2,3n The first and only lidocaine-based topical medication for the treatment of PHN pain. Apply only to intact skin

More than a decade of use

n Customized application for your patients with PHN painPatches can be cut to custom fit the areas of painPatients can wear up to 3 patches simultaneously for 12 hours, followed by 12 hours off4

mild and transient, resolving spontaneously within a few minutes to hours. Other reactions may includedizziness, headache, and nausea.

When LIDODERM is used concomitantly with local anesthetic products, the amount absorbed from allformulations must be considered.

Immediately discard used patches or remaining unused portions of cut patches in household trash in amanner that prevents accidental application or ingestion by children, pets, or others.

Before prescribing LIDODERM, please refer to the accompanying brief summary

of full Prescribing Information.

References: 1. Cluff RS, Rowbotham MC. Pain caused by herpes zoster infection. Neurol Clin. 1998;16(4):813-832. 2. Dworkin RH, OConnor AB, Backonja M, et al. Pharmacologic management of neuropathic pain:evidence-based recommendations. Pain. 2007;132(3):237-251. 3. Dubinsky RM, Kabbani H, El-Chami Z,Boutwell C, Ali H. Practice parameter: treatment of postherpetic neuralgia. An evidence-based report of theQuality Standards Subcommittee of the American Academy of Neurology. Neurology. 2004;63(6):959-965. 4. Lidoderm Prescribing Information. Chadds Ford, PA: Endo Pharmaceuticals Inc; 2008.

LIDODERM(Lidocaine Patch 5%)

Rx only

Brief Summary (For full Prescribing Information refer to package insert.)

INDICATIONS AND USAGELIDODERM is indicated for relief of pain associated with post-herpeticneuralgia. It should be applied only to intact skin.

CONTRAINDICATIONSLIDODERM is contraindicated in patients with a known history of sensitivity tolocal anesthetics of the amide type, or to any other component of the product.

WARNINGSAccidental Exposure in ChildrenEven a used LIDODERM patch contains a large amount of lidocaine (at least665 mg). The potential exists for a small child or a pet to suffer seriousadverse effects from chewing or ingesting a new or used LIDODERM patch,although the risk with this formulation has not been evaluated. It is importantfor patients to store and dispose of LIDODERM out of the reach ofchildren, pets, and others. (See HANDLING AND DISPOSAL)

Excessive DosingExcessive dosing by applying LIDODERM to larger areas or for longer thanthe recommended wearing time could result in increased absorption oflidocaine and high blood concentrations, leading to serious adverse effects(see ADVERSE REACTIONS, Systemic Reactions). Lidocaine toxicity couldbe expected at lidocaine blood concentrations above 5 g/mL. The bloodconcentration of lidocaine is determined by the rate of systemic absorptionand elimination. Longer duration of application, application of more than therecommended number of patches, smaller patients, or impaired eliminationmay all contribute to increasing the blood concentration of lidocaine. Withrecommended dosing of LIDODERM, the average peak blood concentration isabout 0.13 g/mL, but concentrations higher than 0.25 g/mL have beenobserved in some individuals.

PRECAUTIONSGeneralHepatic Disease: Patients with severe hepatic disease are at greater risk ofdeveloping toxic blood concentrations of lidocaine, because of their inability tometabolize lidocaine normally.

Allergic Reactions: Patients allergic to para aminobenzoic acid derivatives(procaine, tetracaine, benzocaine, etc.) have not shown cross sensitivity tolidocaine. However, LIDODERM should be used with caution in patients witha history of drug sensitivities, especially if the etiologic agent is uncertain.

Non-intact Skin: Application to broken or inflamed skin, although not tested,may result in higher blood concentrations of lidocaine from increasedabsorption. LIDODERM is only recommended for use on intact skin.

Eye Exposure: The contact of LIDODERM with eyes, although not studied,should be avoided based on the findings of severe eye irritation with the useof similar products in animals. If eye contact occurs, immediately wash outthe eye with water or saline and protect the eye until sensation returns.

Drug InteractionsAntiarrhythmic Drugs: LIDODERM should be used with caution in patientsreceiving Class I antiarrhythmic drugs (such as tocainide and mexiletine)since the toxic effects are additive and potentially synergistic.

Local Anesthetics: When LIDODERM is used concomitantly with otherproducts containing local anesthetic agents, the amount absorbed from allformulations must be considered.

Carcinogenesis, Mutagenesis, Impairment of FertilityCarcinogenesis: A minor metabolite, 2, 6-xylidine, has been found to becarcinogenic in rats. The blood concentration of this metabolite is negligiblefollowing application of LIDODERM.

Mutagenesis: Lidocaine HCl is not mutagenic in Salmonella/mammalianmicrosome test nor clastogenic in chromosome aberration assay with humanlymphocytes and mouse micronucleus test.

Impairment of Fertility: The effect of LIDODERM on fertility has not beenstudied.

PregnancyTeratogenic Effects: Pregnancy Category B. LIDODERM (lidocaine patch5%) has not been studied in pregnancy. Reproduction studies with lidocainehave been performed in rats at doses up to 30 mg/kg subcutaneously andhave revealed no evidence of harm to the fetus due to lidocaine. There are,however, no adequate and well-controlled studies in pregnant women.Because animal reproduction studies are not always predictive of humanresponse, LIDODERM should be used during pregnancy only if clearlyneeded.

Labor and DeliveryLIDODERM has not been studied in labor and delivery. Lidocaine is notcontraindicated in labor and delivery. Should LIDODERM be usedconcomitantly with other products containing lidocaine, total doses contributedby all formulations must be considered.

Nursing MothersLIDODERM has not been studied in nursing mothers. Lidocaine is excreted inhuman milk, and the milk: plasma ratio of lidocaine is 0.4. Caution should beexercised when LIDODERM is administered to a nursing woman.

Pediatric UseSafety and effectiveness in pediatric patients have not been established.

ADVERSE REACTIONSApplication Site ReactionsDuring or immediately after treatment with LIDODERM (lidocaine patch 5%),the skin at the site of application may develop blisters, bruising, burningsensation, depigmentation, dermatitis, discoloration, edema, erythema,exfoliation, irritation, papules, petechia, pruritus, vesicles, or may be the locusof abnormal sensation. These reactions are generally mild and transient,resolving spontaneously within a few minutes to hours.

Allergic ReactionsAllergic and anaphylactoid reactions associated with lidocaine, although rare,can occur. They are characterized by angioedema, bronchospasm, dermatitis,dyspnea, hypersensitivity, laryngospasm, pruritus, shock, and urticaria. If theyoccur, they should be managed by conventional means. The detection ofsensitivity by skin testing is of doubtful value.

Other Adverse EventsDue to the nature and limitation of spontaneous reports in postmarketingsurveillance, causality has not been established for additional reportedadverse events including:

Asthenia, confusion, disorientation, dizziness, headache, hyperesthesia,hypoesthesia, lightheadedness, metallic taste, nausea, nervousness, painexacerbated, paresthesia, somnolence, taste alteration, vomiting, visualdisturbances such as blurred vision, flushing, tinnitus, and tremor.

Systemic (Dose-Related) ReactionsSystemic adverse reactions following appropriate use of LIDODERM areunlikely, due to the small dose absorbed (see CLINICAL PHARMACOLOGY,Pharmacokinetics). Systemic adverse effects of lidocaine are similar in natureto those observed with other amide local anesthetic agents, including CNSexcitation and/or depression (light-headedness, nervousness, apprehension,euphoria, confusion, dizziness, drowsiness, tinnitus, blurred or double vision,vomiting, sensations of heat, cold, or numbness, twitching, tremors,convulsions, unconsciousness, respiratory depression, and arrest). ExcitatoryCNS reactions may be brief or not occur at all, in which case the firstmanifestation may be drowsiness merging into unconsciousness.Cardiovascular manifestations may include bradycardia, hypotension, andcardiovascular collapse leading to arrest.

OVERDOSAGELidocaine overdose from cutaneous absorption is rare, but could occur. Ifthere is any suspicion of lidocaine overdose (see ADVERSE REACTIONS,Systemic Reactions), drug blood concentration should be checked. Themanagement of overdose includes close monitoring, supportive care, andsymptomatic treatment. Dialysis is of negligible value in the treatment ofacute overdose with lidocaine.

In the absence of massive topical overdose or oral ingestion, evaluation ofsymptoms of toxicity should include consideration of other etiologies for theclinical effects, or overdosage from other sources of lidocaine or other localanesthetics.

The oral LD50 of lidocaine HCl is 459 (346-773) mg/kg (as the salt) in non-fasted female rats and 214 (159-324) mg/kg (as the salt) in fasted female rats,which are equivalent to roughly 4000 mg and 2000 mg, respectively, in a 60 to70 kg man based on the equivalent surface area dosage conversion factorsbetween species.

DOSAGE AND ADMINISTRATIONApply LIDODERM to intact skin to cover the most painful area. Apply up tothree patches, only once for up to 12 hours within a 24-hour period. Patchesmay be cut into smaller sizes with scissors prior to removal of the releaseliner. (See HANDLING AND DISPOSAL) Clothing may be worn over the areaof application. Smaller areas of treatment are recommended in a debilitatedpatient, or a patient with impaired elimination.

If irritation or a burning sensation occurs during application, remove the patch (es) and do not reapply until the irritation subsides.

When LIDODERM is used concomitantly with other products containing localanesthetic agents, the amount absorbed from all formulations must beconsidered.

HANDLING AND DISPOSALHands should be washed after the handling of LIDODERM, and eye contactwith LIDODERM should be avoided. Do not store patch outside the sealedenvelope. Apply immediately after removal from the protective envelope. Foldused patches so that the adhesive side sticks to itself and safely discard usedpatches or pieces of cut patches where children and pets cannot get to them.LIDODERM should be kept out of the reach of children.

Store at 25C (77F); excursions permitted to 15-30C (59-86F). [See USPControlled Room Temperature].

Manufactured for:Endo Pharmaceuticals Inc.Chadds Ford, Pennsylvania 19317

LIDODERM is a Registered Trademark of Hind Health Care, Inc.

Copyright Endo Pharmaceuticals Inc. 2008

Rev. February, 20086524-11 E1

LD-1664 / December 2008

LIDODERM is a registered trademark of Hind Health Care, Inc.

2009 Endo Pharmaceuticals. All Rights Reserved LD-1652R/MARCH 2009 www.lidoderm.com 1-800-462-ENDOCHADDS FORD, PENNSYLVANIA 19317

99www.AHDBonline.comVOL. 2 NO. 3

EDITORIAL BOARD

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

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

ACTUARY David WilliamsHealth ConsultantMilliman, Windsor, CT

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, PhDChief Strategy OfficerEmployer-based Pharmaceutical StrategiesSenior Scholar, Department of Health Policy, Thomas Jefferson University

EPIDEMIOLOGY RESEARCHNirav R. Shah, MD, MPHAssistant Professor of MedicineNYU School of Medicine, NYCSenior Investigator, Geisinger HealthSystem, Danville, PA

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

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

HEALTH OUTCOMES RESEARCH 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

MANGED CARE & GOVERNMENT AFFAIRSSharad Mansukani, MDChief Strategic Officer, Nations HealthSenior Advisor, Texas Pacific Group, FL

MANAGED MARKETS Jeffrey A. Bourret, MS, RPh, FASHPExecutive Director, Customer-Centric Strategy and Innovation, Healthcare Systems MarketingWyeth Pharmaceuticals, Collegeville, PA

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

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

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 Jan Berger, MD, MJPresident, Health Intelligence Partners

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

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

Paul Anthony Polansky, BSPharm, MBAExecutive VP and Chief Pharmacy OfficerSanovia Corp., Philadelphia, 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 PoloicyAmerican Enterprise Institute

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

Alex Hathaway, MD, MPH, FACPMSenior Medical Policy AdvisorGovernment ProgramsGlaxoSmithKline, Philadelphia, PA

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 AccountAmgen, Thousand Oaks, CA

Michael Schaffer, PharmD, MBADirector, Pharmacy ProgramsSanovia Co., Philadelphia, PA

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

100 AMERICAN HEALTH & DRUG BENEFITS April/May 2009 VOL. 2 NO. 3


PublisherNicholas [email protected]

Associate PublisherMaurice [email protected]

Editorial DirectorDalia [email protected]

Associate EditorDawn Lagrosa732-992-1892

Senior Production ManagerLynn Hamilton

Business ManagerBlanche Marchitto

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 formulariesand benefit designs. Benefit designs aregreatly affected by clinical, business, andpolicy conditions.

This publication provides benefit design de -cision makers the integrated industry infor-mation they require to devise formularies andbenefit designs that stand up to todays spe-cial healthcare delivery and business needs.

Contact Information:For reprints, subscription information, andeditorial queries, please contact:[email protected]

T: 732-992-1880F: 732-992-1881

Mission Statement

EDITORIAL

106 The Paradox of Public Policy Reform: Change or Continuum?Robert E. Henry

108 Are You Kidding Me? Clinical Comparative Effectiveness or Evidence-Based Medicine Thomas Kaye RPh, MBA, FASHP

REGULATORY

111 MIPPA: First Broad Changes to Medicare Part D Plan Operations Jean D. LeMasurier; Babette Edgar, PharmD, MBA

117 Stakeholder Perspective by Mark A. Newsom, MSc

CLINICAL

122 ProvenCare: Geisingers Model for Care Transformation through InnovativeClinical Initiatives and Value CreationInterview with Ronald A. Paulus, MD, MBA

128 PerspectiveThe Integrated Patient-Centered Medical Home: Tools for Transforming Our Healthcare Delivery SystemMatias A. Klein

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

CINAHL: Cumulative Index to Nursing and Allied Health Literature

EBSCO: EBSCO research databases

TABLE OF CONTENTS

Continued on page 102

112

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If it matters to patients, it matters to us. Thats why Eli Lilly and Company is committed to providing the programs, services, and manpower that help you deliver positive outcomes for the patients under your care. And while health care may be a numbers game, were interested in the one number that matters most.

One focus. One promise. One patient at a time.

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American Health & Drug Benefits, ISSN 1942-2962 (print); ISSN 1942-2970 (online), ispublished 6 times a year by Engage HealthcareCommunications, LLC, 241 Forsgate Drive,Suite 205A, Monroe Township, NJ 08831.Copyright 2009 by Engage Healthcare Communications, LLC. All rights reserved.American Health & Drug Benefits and The Peer-Reviewed Forum for Evidence in BenefitDesign are trademarks of Engage HealthcareCommunications, LLC. No part of this publication may be reproduced or transmittedin any form or by any means now or hereafterknown, electronic or mechanical, includingphotocopy, recording, or any informationalstorage and retrieval system, without writtenpermission from the Publisher. Printed in theUnited States of America.

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The ideas and opinions expressed in AmericanHealth & Drug Benefits do not necessarily reflect those of the Editorial Board, the Editors,or the Publisher. Publication of an advertise-ment or other product mentioned in American Health & Drug Benefits should not beconstrued as an endorsement of the product orthe manufacturers claims. Readers are encour-aged to contact the manufacturers about anyfeatures or limitations of products mentioned.Neither the Editors nor the Publisher assumeany responsibility for any injury and/or damageto persons or property arising out of or related to any use of the material mentionedin this publication.

POSTMASTER: CORRESPONDENCE REGARDING SUBSCRIPTIONS ORCHANGE OF ADDRESS should be directedto CIRCULATION DIRECTOR, AmericanHealth & Drug Benefits, 241 Forsgate Drive,Suite 205A, Monroe Township, NJ 08831.Fax: 732-992-1881. YEARLY SUBSCRIPTIONRATES: One year: $99.00 USD; Two years:$149.00 USD; Three years: $199.00 USD.

WEB EXCLUSIVE www.AHDBonline.com

Effects of High-Deductible Plans onEmployers and Employees By Rosemary Frei, MSc

Caption Contest

BUSINESS

134 Increased Patient Cost-Sharing, Weak US Economy, and Poor Health Habits:Implications for Employers and InsurersMelinda C. Haren, RN; Kirk McConnell; Arthur F. Shinn, PharmD, FASCP

141 Stakeholder Perspective by Paul Anthony Polansky, BSPharm, MBA

DEPARTMENTS

120 GENERIC DRUG TRENDSNew Legislations on Generics and Biosimilars Brewing in Congress

Dalia Buffery, MA, ABD

131 INDUSTRY TRENDS Paying for Cancer Care: Economic Models Start to Emerge, Dovetailing

Healthcare Reform

By Caroline Helwick

142 EXECUTIVE SUMMARIES

CAPTION CONTEST UNMANAGED MOMENT

118

TABLE OF CONTENTS (Continued)

127

KAPIDEX is indicated for:

Healing all grades of erosive esophagitis (EE) for up to 8 weeks

Maintaining healing of EE for up to 6 months

Treating heartburn associated with symptomatic non-erosive gastroesophageal re ux disease (GERD) for 4 weeks

Important Safety Information

KAPIDEX is contraindicated in patients with known hypersensitivity to any component of the formulation.

Symptomatic response with KAPIDEX does not preclude the presence of gastric malignancy.

Most commonly reported treatment-emergent adverse reactions (2%): diarrhea, abdominal pain, nausea, upper respiratory tract infection, vomiting, and atulence.

KAPIDEX should not be co-administered with atazanavir. KAPIDEX may interfere with absorption of drugs for which gastric pH is important for bioavailability (e.g., ampicillin esters, digoxin, iron salts, ketoconazole). Patients taking concomitant warfarin may require monitoring for increases in international normalized ratio (INR) and prothrombin time.

Please see adjacent brief summary of prescribing information for KAPIDEX.

NOW AVAILABLE

THE PPI WITH A DUAL DELAYED RELEASE

(DDR) FORMULATION

www.KAPIDEX.com

BRIEF SUMMARY OF FULL PRESCRIBING INFORMATIONKAPIDEX (dexlansoprazole) delayed release capsules

INDICATIONS AND USAGEKAPIDEX is indicated for:

sTHEHEALINGOFALLGRADESOFEROSIVEESOPHAGITIS%%FORUPTOWEEKSsMAINTAININGHEALINGOF%%FORUPTOMONTHSAND

sTHETREATMENTOFHEARTBURNASSOCIATEDWITHNONEROSIVEGASTROESOPHAGEALREmUXDISEASE'%2$FORWEEKS

CONTRAINDICATIONS+!0)$%8 IS CONTRAINDICATED IN PATIENTS WITH KNOWN HYPERSENSITIVITY TO ANYCOMPONENT OF THE FORMULATION (YPERSENSITIVITY AND ANAPHYLAXIS HAVE BEENREPORTEDWITH+!0)$%8USE [see Adverse Reactions]

WARNINGS AND PRECAUTIONSGastric Malignancy3YMPTOMATIC RESPONSE WITH +!0)$%8 DOES NOT PRECLUDE THE PRESENCE OFGASTRICMALIGNANCY

ADVERSE REACTIONSClinical Trials Experience4HE SAFETY OF +!0)$%8 WAS EVALUATED IN PATIENTS IN CONTROLLED ANDUNCONTROLLEDCLINICALSTUDIESINCLUDINGPATIENTSTREATEDFORATLEASTMONTHSANDPATIENTSTREATEDFORONEYEAR0ATIENTSRANGEDINAGEFROMTOYEARSMEDIANAGEYEARSWITHFEMALE#AUCASIAN"LACK!SIANANDOTHERRACES3IXRANDOMIZEDCONTROLLEDCLINICALTRIALSWERECONDUCTEDFORTHETREATMENTOF%%MAINTENANCEOFHEALED%%ANDSYMPTOMATIC'%2$WHICHINCLUDEDPATIENTSONPLACEBOPATIENTSON+!0)$%8MGPATIENTSON+!0)$%8MGANDPATIENTSONLANSOPRAZOLEMGONCEDAILY

!SCLINICALTRIALSARECONDUCTEDUNDERWIDELYVARYINGCONDITIONSADVERSEREACTIONRATESOBSERVEDINTHECLINICALTRIALSOFADRUGCANNOTBEDIRECTLYCOMPAREDTORATESINTHECLINICALTRIALSOFANOTHERDRUGANDMAYNOTREmECTTHERATESOBSERVEDINPRACTICE

-OST#OMMONLY2EPORTED!DVERSE2EACTIONS4HEMOSTCOMMONADVERSEREACTIONSrTHATOCCURREDATAHIGHERINCIDENCEFOR+!0)$%8THANPLACEBOINTHECONTROLLEDSTUDIESAREPRESENTEDIN4ABLE

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

Adverse Reaction

Placebo

(N=896)%

KAPIDEX 30 mg

(N=455)%

KAPIDEX 60 mg

(N=2218)%

KAPIDEX Total

(N=2621)%

Lansoprazole30 mg

(N=1363)%

$IARRHEA

!BDOMINAL0AIN

.AUSEA

5PPER2ESPIRATORYTract Infection

6OMITING

&LATULENCE

!DVERSE2EACTIONS2ESULTINGIN$ISCONTINUATION)N CONTROLLED CLINICAL STUDIES THEMOST COMMON ADVERSE REACTION LEADING TODISCONTINUATIONFROM+!0)$%8THERAPYWASDIARRHEA

/THER!DVERSE2EACTIONS/THERADVERSEREACTIONSTHATWEREREPORTEDINCONTROLLEDSTUDIESATANINCIDENCEOFLESSTHANARELISTEDBELOWBYBODYSYSTEMBlood and Lymphatic System Disorders: ANEMIA LYMPHADENOPATHY Cardiac Disorders: ANGINA ARRHYTHMIA BRADYCARDIA CHEST PAIN EDEMA MYOCARDIALINFARCTIONPALPITATIONTACHYCARDIAEar and Labyrinth Disorders: EARPAINTINNITUSVERTIGOEndocrine Disorders: GOITEREye Disorders: EYE IRRITATION EYE SWELLINGGastrointestinal Disorders: ABDOMINAL DISCOMFORT ABDOMINAL TENDERNESSABNORMAL FECES ANAL DISCOMFORT "ARRETTS ESOPHAGUS BEZOAR BOWEL SOUNDSABNORMALBREATHODORCOLITISMICROSCOPICCOLONICPOLYPCONSTIPATIONDRYMOUTHDUODENITISDYSPEPSIADYSPHAGIAENTERITISERUCTATIONESOPHAGITISGASTRICPOLYPGASTRITISGASTROENTERITISGASTROINTESTINALDISORDERSGASTROINTESTINALHYPERMOTILITYDISORDERS '%2$ ') ULCERS AND PERFORATION HEMATEMESIS HEMATOCHEZIAHEMORRHOIDSIMPAIREDGASTRICEMPTYINGIRRITABLEBOWELSYNDROMEMUCUSSTOOLSNAUSEA AND VOMITING ORAL MUCOSAL BLISTERING PAINFUL DEFECATION PROCTITISPARESTHESIA ORAL RECTAL HEMORRHAGEGeneral Disorders and Administration Site Conditions:ADVERSEDRUGREACTIONASTHENIACHESTPAINCHILLSFEELINGABNORMALINmAMMATION MUCOSAL INmAMMATION NODULE PAIN PYREXIA Hepatobiliary Disorders:BILIARYCOLICCHOLELITHIASISHEPATOMEGALYImmune System Disorders:

HYPERSENSITIVITY Infections and Infestations: CANDIDA INFECTIONS INmUENZANASOPHARYNGITISORALHERPESPHARYNGITISSINUSITISVIRALINFECTIONVULVOVAGINALINFECTION Injury, Poisoning and Procedural Complications: FALLS FRACTURES JOINTSPRAINS OVERDOSE PROCEDURAL PAIN SUNBURN Laboratory Investigations: ALP INCREASED !,4 INCREASED !34 INCREASED BILIRUBIN DECREASEDINCREASED BLOODCREATININE INCREASED BLOOD GASTRIN INCREASED BLOOD GLUCOSE INCREASED BLOODPOTASSIUMINCREASEDLIVERFUNCTIONTESTABNORMALPLATELETCOUNTDECREASEDTOTALPROTEININCREASEDWEIGHTINCREASEMetabolism and Nutrition Disorders:APPETITECHANGES HYPERCALCEMIA HYPOKALEMIA Musculoskeletal and Connective Tissue Disorders: ARTHRALGIA ARTHRITIS MUSCLE CRAMPS MUSCULOSKELETAL PAIN MYALGIA Nervous System Disorders: ALTERED TASTE CONVULSION DIZZINESS HEADACHESMIGRAINEMEMORY IMPAIRMENT PARESTHESIA PSYCHOMOTORHYPERACTIVITY TREMORTRIGEMINALNEURALGIAPsychiatric Disorders: ABNORMALDREAMSANXIETYDEPRESSIONINSOMNIA LIBIDO CHANGES Renal and Urinary Disorders: DYSURIA MICTURITIONURGENCYReproductive System and Breast Disorders:DYSMENORRHEADYSPAREUNIAMENORRHAGIAMENSTRUALDISORDER; Respiratory, Thoracic and Mediastinal Disorders: ASPIRATIONASTHMABRONCHITISCOUGHDYSPNOEAHICCUPSHYPERVENTILATIONRESPIRATORYTRACT CONGESTION SORE THROAT Skin and Subcutaneous Tissue Disorders: ACNEDERMATITISERYTHEMAPRURITISRASHSKINLESIONURTICARIA Vascular Disorders:DEEPVEINTHROMBOSISHOTmUSHHYPERTENSION

Additional adverse reactions that were reported in a long-term uncontrolled study and were considered related to KAPIDEX by the treating physician included: anaphylaxis, auditory hallucination, B-cell lymphoma, central obesity, cholecystitis acute, decreased hemoglobin, dehydration, diabetes mellitus, dysphonia, epistaxis, folliculitis, gastrointestinal pain, gout, herpes zoster, hyperglycemia, hyperlipidemia, hypothyroidism, increased neutrophils, MCHC decrease, neutropenia, oral soft tissue disorder, rectal tenesmus, restless legs syndrome, somnolence, thrombocythemia, tonsillitis.

Other adverse reactions not observed with KAPIDEX, but occurring with the racemate lansoprazole can be found in the lansoprazole package insert, ADVERSE REACTIONS section.

DRUG INTERACTIONSDrugs with pH-Dependent Absorption Pharmacokinetics+!0)$%8CAUSESINHIBITIONOFGASTRICACIDSECRETION+!0)$%8ISLIKELYTOSUBSTANTIALLYDECREASETHESYSTEMICCONCENTRATIONSOFTHE()6PROTEASEINHIBITORATAZANAVIRWHICHISDEPENDENTUPONTHEPRESENCEOFGASTRICACIDFORABSORPTIONANDMAYRESULTINALOSS OF THERAPEUTIC EFFECT OF ATAZANAVIR AND THE DEVELOPMENT OF ()6 RESISTANCE4HEREFORE+!0)$%8SHOULDNOTBECOADMINISTEREDWITHATAZANAVIR

)T IS THEORETICALLYPOSSIBLETHAT+!0)$%8MAYINTERFEREWITHTHEABSORPTIONOFOTHERDRUGSWHEREGASTRICP(ISANIMPORTANTDETERMINANTOFORALBIOAVAILABILITYEGAMPICILLINESTERSDIGOXINIRONSALTSKETOCONAZOLE

Warfarin#OADMINISTRATIONOF+!0)$%8MGANDWARFARINMGDIDNOT AFFECT THEPHARMACOKINETICS OF WARFARIN OR ).2 (OWEVER THERE HAVE BEEN REPORTS OFINCREASED ).2ANDPROTHROMBIN TIME INPATIENTS RECEIVING00)SANDWARFARINCONCOMITANTLY)NCREASESIN).2ANDPROTHROMBINTIMEMAYLEADTOABNORMALBLEEDINGANDEVENDEATH0ATIENTSTREATEDWITH+!0)$%8ANDWARFARINCONCOMITANTLYMAYNEEDTOBEMONITOREDFORINCREASESIN).2ANDPROTHROMBINTIME

USE IN SPECIFIC POPULATIONS

PregnancyTeratogenic Effects0REGNANCY#ATEGORY"4HEREARENOADEQUATEANDWELLCONTROLLEDSTUDIESWITHDEXLANSOPRAZOLE IN PREGNANT WOMEN 4HERE WERE NO ADVERSE FETAL EFFECTS INANIMAL REPRODUCTION STUDIES OF DEXLANSOPRAZOLE IN RABBITS "ECAUSE ANIMALREPRODUCTIONSTUDIESARENOTALWAYSPREDICTIVEOFHUMANRESPONSE+!0)$%8SHOULDBEUSEDDURINGPREGNANCYONLYIFCLEARLYNEEDED

! REPRODUCTION STUDY CONDUCTED IN RABBITS AT ORAL DEXLANSOPRAZOLE DOSES UP TOMGPERKGPERDAYAPPROXIMATELYFOLDTHEMAXIMUMRECOMMENDEDHUMANDEXLANSOPRAZOLE DOSE ;MG= BASED ON BODY SURFACE AREA ;"3!= REVEALED NOEVIDENCE OF HARM TO THE FETUS DUE TO DEXLANSOPRAZOLE )N ADDITION REPRODUCTIONSTUDIESPERFORMEDINPREGNANTRATSWITHORALLANSOPRAZOLEATDOSESUPTOMGPERKGPERDAY TIMES THE RECOMMENDEDHUMANDOSEBASEDON"3!AND INPREGNANTRABBITSATORALLANSOPRAZOLEDOSESUPTOMGPERKGPERDAYTIMESTHERECOMMENDEDHUMANDOSEBASEDON"3!REVEALEDNOEVIDENCEOFIMPAIREDFERTILITYORHARMTOTHEFETUSDUETOLANSOPRAZOLE

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 KAPIDEX in pediatric patients (less than 18 years of age) have not been established.

Geriatric Use)NCLINICALSTUDIESOF+!0)$%8OFPATIENTSWEREAGEDYEARSANDOVER.OOVERALLDIFFERENCESINSAFETYOREFFECTIVENESSWEREOBSERVEDBETWEENTHESEPATIENTSANDYOUNGERPATIENTSANDOTHERREPORTEDCLINICALEXPERIENCEHASNOTIDENTIlED SIGNIlCANT DIFFERENCES IN RESPONSESBETWEENGERIATRIC AND YOUNGERPATIENTSBUTGREATERSENSITIVITYOFSOMEOLDERINDIVIDUALSCANNOTBERULEDOUT]

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

OVERDOSAGE

4HEREHAVEBEENNOREPORTSOFSIGNIlCANTOVERDOSEOF+!0)$%8-ULTIPLEDOSESOF+!0)$%8MGANDASINGLEDOSEOF+!0)$%8MGDIDNOTRESULT INDEATHOROTHERSEVEREADVERSEEVENTS$EXLANSOPRAZOLE ISNOTEXPECTED TOBEREMOVEDFROMTHECIRCULATIONBYHEMODIALYSIS)FANOVERDOSEOCCURSTREATMENTSHOULDBESYMPTOMATICANDSUPPORTIVE

CLINICAL PHARMACOLOGY

Pharmacodynamics!NTISECRETORY!CTIVITY4HEEFFECTSOF+!0)$%8MGNORLANSOPRAZOLEMGNONCEDAILYFORlVEDAYSONHOURINTRAGASTRICP(WEREASSESSEDINHEALTHYSUBJECTSINAMULTIPLEDOSECROSSOVERSTUDY

3ERUM'ASTRIN%FFECTS4HE EFFECT OF +!0)$%8 ON SERUM GASTRIN CONCENTRATIONS WAS EVALUATED INAPPROXIMATELYPATIENTSINCLINICALTRIALSUPTOWEEKSANDINPATIENTSFORUPTOTOMONTHS4HEMEANFASTINGGASTRINCONCENTRATIONSINCREASEDFROM BASELINE DURING TREATMENT WITH +!0)$%8 MG AND MG DOSES )NPATIENTSTREATEDFORMORETHANMONTHSMEANSERUMGASTRINLEVELSINCREASEDDURINGAPPROXIMATELYTHElRSTMONTHSOFTREATMENTANDWERESTABLEFORTHEREMAINDEROF TREATMENT-EANSERUMGASTRIN LEVELSRETURNEDTOPRETREATMENTLEVELSWITHINONEMONTHOFDISCONTINUATIONOFTREATMENT

%NTEROCHROMAFlN,IKE#ELL%#,%FFECTS 4HERE WERE NO REPORTS OF %#, CELL HYPERPLASIA IN GASTRIC BIOPSY SPECIMENSOBTAINEDFROMPATIENTSTREATEDWITH+!0)$%8MGMGORMGFORUPTOMONTHS

$URINGLIFETIMEEXPOSUREOFRATSDOSEDDAILYWITHUPTOMGPERKGPERDAYOFLANSOPRAZOLEMARKEDHYPERGASTRINEMIAWASOBSERVEDFOLLOWEDBY%#,CELLPROLIFERATIONANDFORMATIONOFCARCINOIDTUMORSESPECIALLYINFEMALERATS[see Nonclinical Toxicology ]

Effect on Cardiac Repolarization

A study was conducted to assess the potential of KAPIDEX to prolong the QT/QTc interval in healthy adult subjects. KAPIDEX doses of 90 mg or 300 mg did not delay cardiac repolarization compared to placebo. The positive control (moxioxacin) pro-duced statistically signicantly greater mean maximum and time-averaged QT/QTc intervals compared to placebo.

NONCLINICAL TOXICOLOGY

Carcinogenesis, 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 BSA) given the recommended human dose of lansoprazole (30 mg per day).

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

In rats, lansoprazole also increased the incidence of intestinal metaplasia of the gastric epithelium in both sexes. In male rats, lansoprazole produced a dose-related increase of testicular interstitial cell adenomas. The incidence of these adenomas in rats receiving doses of 15 to 150 mg per kg per day (4 to 40 times the recommended lansoprazole human dose based on BSA) exceeded the low background incidence (range = 1.4 to 10%) for this strain of rat. Testicular interstitial cell adenoma also occurred in 1 of 30 rats treated with 50 mg lansoprazole per kg per day (13 times the recommended lansoprazole human dose based on BSA) in a 1-year toxicity study.

)NAMONTHCARCINOGENICITYSTUDY#$MICEWERETREATEDORALLYWITHLANSOPRAZOLEDOSESOFMGTOMGPERKGPERDAYTOTIMESTHERECOMMENDEDHUMANDOSEBASEDON"3!,ANSOPRAZOLEPRODUCEDADOSERELATEDINCREASEDINCIDENCEOFGASTRIC%#,CELLHYPERPLASIA)TALSOPRODUCEDANINCREASEDINCIDENCEOFLIVERTUMORSHEPATOCELLULARADENOMAPLUSCARCINOMA4HETUMORINCIDENCESINMALEMICETREATEDWITHMGANDMGLANSOPRAZOLEPERKGPERDAYTOTIMESTHE RECOMMENDED LANSOPRAZOLE HUMANDOSE BASED ON"3! AND FEMALEMICETREATEDWITHMGTOMGLANSOPRAZOLEPERKGPERDAYTOTIMESTHERECOMMENDEDHUMANDOSEBASEDON"3!EXCEEDEDTHERANGESOFBACKGROUNDINCIDENCESINHISTORICALCONTROLSFORTHISSTRAINOFMICE,ANSOPRAZOLETREATMENTPRODUCEDADENOMAOFRETETESTISINMALEMICERECEIVINGTOMGPERKGPERDAYTOTIMESTHERECOMMENDEDLANSOPRAZOLEHUMANDOSEBASEDON"3!

4HEPOTENTIALEFFECTSOFDEXLANSOPRAZOLEONFERTILITYANDREPRODUCTIVEPERFORMANCEWEREASSESSEDUSINGLANSOPRAZOLESTUDIES,ANSOPRAZOLEATORALDOSESUPTOMGPERKGPERDAYTIMESTHERECOMMENDEDLANSOPRAZOLEHUMANDOSEBASEDON"3!WASFOUNDTOHAVENOEFFECTONFERTILITYANDREPRODUCTIVEPERFORMANCEOFMALEANDFEMALERATSPATIENT COUNSELING INFORMATION

[see FDA-Approved Patient Labeling in the full prescribing information]

Information for PatientsTo ensure the safe and effective use of KAPIDEX, this information and instructions provided in the FDA-approved patient labeling should be discussed with the patient. Inform patients of the following:

KAPIDEX is available as a delayed release capsule.

KAPIDEX may be taken without regard to food.

KAPIDEX should be swallowed whole.

s!LTERNATIVELY+!0)$%8CAPSULESCANBEOPENEDANDADMINISTEREDASFOLLOWS n/PENCAPSULE n3PRINKLEINTACTGRANULESONONETABLESPOONOFAPPLESAUCE n3WALLOWIMMEDIATELY

$ISTRIBUTEDBY Takeda Pharmaceuticals America, Inc. $EERlELD),

53 0ATENT .OS AND

+!0)$%8 ISA TRADEMARKOF4AKEDA0HARMACEUTICALS.ORTH!MERICA )NC ANDUSEDUNDERLICENSEBY4AKEDA0HARMACEUTICALS!MERICA)NC!LLOTHERTRADEMARKNAMESARETHEPROPERTYOFTHEIRRESPECTIVEOWNERS4AKEDA0HARMACEUTICALS!MERICA)NC

&ORMOREDETAILEDINFORMATIONSEETHEFULLPRESCRIBINGINFORMATIONFOR+!0)$%80)2*ANUARYORCONTACT4AKEDA0HARMACEUTICALS!MERICA)NCAT

,,0$

2009 Takeda Pharmaceuticals North America, Inc.

LPD-00021 2/09 Printed in U.S.A.

KAPIDEX and Dual Delayed Release are trademarks of Takeda Pharmaceuticals

North America, Inc., and are used under license by Takeda Pharmaceuticals America, Inc.

Reference: KAPIDEX (dexlansoprazole) package insert, Takeda Pharmaceuticals America, Inc


FROM THE EDITOR

This is shaping up to be a watershed year for publichealth reform. Pressures of cost, quality, and accessthat have been building up under the healthcareboiler are about to produce their own peculiar set of erup-tions, and the American healthcare system will look fardifferent once the ensuing systems changes have takeneffect. As they come into play, it will be instructive to keepan eye on the prize: will these changes favor cost, quality,or access, or will they produce the desired balance betweenthem? In like fashion, will there be obvious winners andlosers in the wake of these reforms, or will the needs of allstakeholders be accommodated? Above all, is public poli-cy the dominant force stimulating healthcare, or simplythe final stage in it?

Mankinds needs are infinite, and so, it would seem,are those of the healthcare system. Several front-run-ners for the foreseeable future are: biosimilars legisla-tion, com parative effectiveness research (CER), fund-ing of the National Institutes of Health (NIH), andMedicare reform.

Expect federal legislation to create a new regulatorypathway for approval of biosimilars. This must be donecarefully to prevent a disincentive for development ofnew biologics. More than 40% of Medicare Part Bspending on biologics is for oncology drugs. How willCongress use the projected $6 billion in federal savings?

CER has moved, somewhat precipitously, from agood idea to a serious proposition, displacing evidence-based medicine as the perceived best of all possibleworlds. It remains to be seen how, and how efficiently,the federal government will spend the $1.1 billion ear-marked for CER. What matters now is setting researchpriorities, and the influence that CER will have on cov-erage and reimbursement decisions in Medicare,Medicaid, and private health plans.

The economic stimulus bill injects $10 billion inadditional funding to NIH over the next 2 years, andPresident Obama has proposed to further increase NIH-funded cancer research as part of a multiyear commit-ment to double cancer research funding.

Medicare reform all by itself would have been a suffi-cient challenge; adding it to these other issues makes itall the more compelling, given the wide range of issuesfacing policymakers. Unless Congress acts to reform theMedicare physician payment formula, physicians willsuffer a 20% fee cut in January 2010. Because this is

obviously untenable, Congress knows it must act to fixpayment rates, but it also knows why the problem hasremained unresolved: it could cost more than $250 bil-lion to bring payment levels up to real-world providerneeds. Meanwhile, many on Capitol Hill are also eagerto cut payments to Medicare Advantage plans and cre-ate a government-run public plan to compete withcommercial health and drug plans in Medicare.

The American healthcare system is a force forextraordinary progress. Cancer outcomes have neverbeen better. The United States is a powerhouse for newdrug development. Quality-of-care measures are beingpursued by payers, providers, and purchasers at anunprecedented rate. Each stakeholder group is hard atwork identifying ways to bring valuethat amalgam ofcost, quality, and accessto healthcare. As Americandemographics and evidentiary standards change, it isimportant to take a step back to gain perspective onhow well we have been allocating precious healthcareresources to date. Public policy reforms are needed, butthey hardly act in a vacuum, as clinical and businesssystem changes and best practices define how publicpolicy can support them. The view should be construc-tive, optimistic, and collegial. At its core, the Amer -ican healthcare system is strong for the very reason thatit insists on improving a good thing.

As policy is proposed, it should be done in recogni-tion of the need to preserve, not shatter, a system withthe flexibility and tenacity to demand improvement andthe strength to achieve it. The public policy reform thatis about to take place has been brewing for a very longtime, proceeding along lines established over the pastdecade, often by the other 2 legs of the triangletheclinical and business sectors. If action is to take place onthe government level, it would be a mistake to concludethat we need a government-dominated healthcare sys-temthat government could solve what the clinical andbusiness sectors could not. Rather, public policy shouldconclude the issues defined for it by the clinical andbusiness sectors, thereby fulfilling its proper role in thetriad of forces that have always driven healthcare.

Robert E. HenryEditor-in-Chief

The Paradox of Public Policy Reform:Change or Continuum?

The Global Partnership for Effective Diabetes Management was established with the aim of uncovering the barriers to good glycemic control and identifying ways to help people overcome them.The Global Partnership for Effective Diabetes Management is industry supported.

References: 1. Hoerger TJ, Segel JE, Gregg EW, Saaddine JB. Is glycemic control improving in U.S. adults? Diabetes Care. 2008;31:81-86. 2. Rodgers K. Ensuring compliance in patients with diabetes. In: Diabetes: Disease Management Guide. 4th ed. Montvale, NJ: Thomson PDR; 2004:501-505. 3. Data on le, Takeda Pharmaceuticals North America, Inc. 4. AACE Diabetes Mellitus Clinical Practice Guidelines Task Force. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the management of diabetes mellitus. Endocr Pract. 2007;13(suppl 1):3-68. 5. Goldstein BJ, Gomis R, Lee H-K, Leiter LA, on behalf of the Global Partnership for Effective Diabetes Management. Type 2 diabetestreat early, treat intensively. Int J Clin Pract. 2007;61(suppl 157):16-21.

2008 Takeda Pharmaceuticals North America, Inc. XPIO-01287 11/08 Printed in U.S.A.

Are your plan members with type 2 diabetes reaching goal?The recommendation for early treatment Many patients are not reaching their ADA A1C target goal of 10%

A1C

Levels

*For patients nave to pharmacological therapy.


COMMENTARY

The panel for the new Federal Coordi -nating Council for Comparative Effec -tiveness Research has been appointedby the new administration, and the Recoveryand Reinvestment Act has allocated $1.1 bil-lion for comparative effectiveness research.

So the ministers of change agents have beenreleased, to empower and direct comparativeefficacy processes intended to fix the medical needs ofour country. But this hand-selected federal councilincludes no pharmacists or drug experts, even thoughthe major portion of the work likely will involve phar-maceuticals. Furthermore, this administration has agreat amount of explaining to do to ensure healthcarestakeholders a useful outcome could result from this.The rapid-fire implementation of rope-a-dope stimuluspackages continues to lack significant and sufficientdetails to embrace the hope for useful outcomes.

Let us not forget the noble attempts to bring usefuland fruitful clinical drug evidence to light for decision-making by the Blues, the National Institutes of Health,or by others engaged in developing clinical comparativeevidence data to seek value and improved outcomes. Allsuch previous attempts have been lacking appropriatefundingbut now there is money, yet not for programswith a solid track record for solutions, or for those whoalready have a footing and the ability to provide non -biased results. Indeed, what America needs now is com-parative effectiveness. This cannot wait; crisis loomslarge, and a rush to this cause is in full stride.

Most of the members of this enlightened council havebeen servants placed in public jobs for most of theirlives,1 sheltered from the carnage of real-life medicalpractice, life experiences, and the day-to-day drama ofactually helping our citizens plow through the never-ending bureaucratic paper maze, attempting to get asemblance of healthcare.

Why use an old term like evidence-based medicine? Itsnot snappy enough, and it is truly too descriptive. Thismay lead the public to expect to see a superior outcomeresulting from such a clear approach. The simple renam-ing of a process has worked for other projects in the eco-nomic stimulus coming from this administration. The

metamorphosis to comparative effectiveness isclever and can be effectively substituted; slightlyobscure, mysterious, with just a hint of respect -ability toward medicine. Adoption of rewordinghas been met with enthusiasm for many projectswe see coming from this administration.

Is there a difference between evidence-basedmedicine and clinical comparative effective-

ness? The creators of the latter would certainly suggestthere is. Comparative effectiveness, being voiced fromWash ington as the next solution to our healthcareproblems, is buzzing around at light speed. New pro-grams that may be adopted in these times of changemay include Medical Complementary Research Asso -ciative Program (CRAP) or Perfunctory OperationalReferendum Collaboration (PORC). Regardless of theslogans, the new and hyped term inology indicates thatthis is a charade, attempting to show advancementwhere none exists. Perhaps the new word for drug prof-its should be clinical derivatives when referencingcomparative evidence outcomes.

Dont you miss the days when we spoke in terms thathad simple and shared meaningwhen TARP(Troubled Asset Recovery Program) would have beenunderstood as stupid investing?

With the basis of solid comparative evidence for med-ications currently available from many nonbiased data-bases, it is wasteful and inefficient to reinvent this process.

Evidence-based medicine has enhanced the caredelivery and reduced mortality and morbidity, while pro-viding a logical pathway for value to follow. The Pharmalobby has exerted pressure to carefully carve out theinclination of relative clinical effectiveness associatedwith value. As with other administrative initiatives,value is not a good word any more. Pharmas strong lobbyagainst value is associated with the inability to havevalue removed from evidence-based medicine. So letsrename value, using a specifically nonspecific prestidigi-tation gyration to eulav.

Reference1. US Department of Health and Human Services. Federal CoordinatingCouncil for Comparative Effectiveness Research membership. www.hhs.gov/recovery/programs/os/cerbios.html. Accessed March 25, 2009.

Are You Kidding Me? Clinical ComparativeEffectiveness or Evidence-Based MedicineThomas Kaye, RPh, MBA, FASHP

2.5 mg, 5 mg, 10 mg and 20 mg

Brief Summary: For complete details please see full Prescribing Information for BYSTOLIC.

INDICATIONS AND USAGEBYSTOLIC is indicated for the treatment of hypertension. BYSTOLIC may be usedalone or in combination with other antihypertensive agents.

CONTRAINDICATIONSBYSTOLIC is contraindicated in patients with severe bradycardia, heart blockgreater than first degree, cardiogenic shock, decompensated cardiac failure, sick sinus syndrome (unless a permanent pacemaker is in place), or severe hepatic impairment (Child-Pugh >B), and in patients who are hypersensitive to any component of this product.

WARNINGSAbrupt Cessation of Therapy Patients with coronary artery disease treated with BYSTOLIC should be advisedagainst abrupt discontinuation of therapy. Severe exacerbation of angina and theoccurrence of myocardial infarction and ventricular arrhythmias have been reportedin patients with coronary artery disease following the abrupt discontinuation of therapy with -blockers. Myocardial infarction and ventricular arrhythmias may occurwith or without preceding exacerbation of the angina pectoris. Even patients withoutovert coronary artery disease should be cautioned against interruption or abrupt discontinuation of therapy. As with other -blockers, when discontinuation ofBYSTOLIC is planned, patients should be carefully observed and advised to minimizephysical activity. BYSTOLIC should be tapered over 1 to 2 weeks when possible. If the angina worsens or acute coronary insufficiency develops, it is recommended that BYSTOLIC be promptly reinstituted, at least temporarily.

Cardiac FailureSympathetic stimulation is a vital component supporting circulatory function in thesetting of congestive heart failure, and -blockade may result in further depressionof myocardial contractility and precipitate more severe failure. In patients who havecompensated congestive heart failure, BYSTOLIC should be administered cautiously.If heart failure worsens, discontinuation of BYSTOLIC should be considered.

Angina and Acute Myocardial InfarctionBYSTOLIC was not studied in patients with angina pectoris or who had a recent MI.

Bronchospastic DiseasesIn general, patients with bronchospastic diseases should not receive -blockers.

Anesthesia and Major SurgeryIf BYSTOLIC is to be continued perioperatively, patients should be closely monitored when anesthetic agents which depress myocardial function, such asether, cyclopropane, and trichloroethylene, are used. If -blocking therapy is withdrawn prior to major surgery, the impaired ability of the heart to respond toreflex adrenergic stimuli may augment the risks of general anesthesia and surgicalprocedures.

The -blocking effects of BYSTOLIC can be reversed by -agonists, e.g., dobuta-mine or isoproterenol. However, such patients may be subject to protracted severehypotension. Additionally, difficulty in restarting and maintaining the heartbeat hasbeen reported with -blockers.

Diabetes and Hypoglycemia

-blockers may mask some of the manifestations of hypoglycemia, particularlytachycardia. Nonselective -blockers may potentiate insulin-induced hypoglycemiaand delay recovery of serum glucose levels. It is not known whether nebivolol hasthese effects. Patients subject to spontaneous hypoglycemia, or diabetic patientsreceiving insulin or oral hypoglycemic agents, should be advised about these possibilities and nebivolol should be used with caution.

Thyrotoxicosis-blockers may mask clinical signs of hyperthyroidism, such as tachycardia.Abrupt withdrawal of -blockers may be followed by an exacerbation of the symptoms of hyperthyroidism or may precipitate a thyroid storm.

Peripheral Vascular Disease-blockers can precipitate or aggravate symptoms of arterial insufficiency in patientswith peripheral vascular disease. Caution should be exercised in these patients.

Non-dihydropyridine Calcium Channel BlockersBecause of significant negative inotropic and chronotropic effects in patients treatedwith -blockers and calcium channel blockers of the verapamil and diltiazem type,caution should be used in patients treated concomitantly with these agents and ECGand blood pressure should be monitored.

PRECAUTIONSUse with CYP2D6 InhibitorsNebivolol exposure increases with inhibition of CYP2D6 (see Drug Interactions).The dose of BYSTOLIC may need to be reduced.

Impaired Renal FunctionBYSTOLIC should be used with caution in patients with severe renal impairmentbecause of decreased renal clearance. BYSTOLIC has not been studied in patientsreceiving dialysis.

Impaired Hepatic FunctionBYSTOLIC should be used with caution in patients with moderate hepatic impairment because of decreased metabolism. Since BYSTOLIC has not been studied in patients with severe hepatic impairment, BYSTOLIC is contraindicated in this population (see CLINICAL PHARMACOLOGY, Special Populations andDOSAGE AND ADMINISTRATION).

Risk of Anaphylactic Reactions While taking -blockers, patients with a history of severe anaphylactic reactions toa variety of allergens may be more reactive to repeated challenge either accidental,diagnostic, or therapeutic. Such patients may be unresponsive to the usual dosesof epinephrine used to treat allergic reactions.

In patients with known or suspected pheochromocytoma, an -blocker should beinitiated prior to the use of any -blocker.

Information for PatientsPatients should be advised to take BYSTOLIC regularly and continuously, as directed. BYSTOLIC can be taken with or without food. If a dose is missed, thepatient should take the next scheduled dose only (without doubling it). Patientsshould not interrupt or discontinue BYSTOLIC without consulting the physician.

Patients should know how they react to this medicine before they operate auto-mobiles, use machinery, or engage in other tasks requiring alertness.

Patients should be advised to consult a physician if any difficulty in breathingoccurs, or if they develop signs or symptoms of worsening congestive heart failuresuch as weight gain or increasing shortness of breath, or excessive bradycardia.

Patients subject to spontaneous hypoglycemia, or diabetic patients receiving insulinor oral hypoglycemic agents, should be cautioned that -blockers may mask someof the manifestations of hypoglycemia, particularly tachycardia. Nebivolol should beused with caution in these patients.

Drug InteractionsBYSTOLIC should be used with care when myocardial depressants or inhibitors of AV conduction, such as certain calcium antagonists (particularly of the phenyl-alkylamine [verapamil] and benzothiazepine [diltiazem] classes), or antiarrhythmicagents, such as disopyramide, are used concurrently. Both digitalis glycosides and-blockers slow atrioventricular conduction and decrease heart rate. Concomitantuse can increase the risk of bradycardia.

BYSTOLIC should not be combined with other -blockers. Patients receiving catecholamine-depleting drugs, such as reserpine or guanethidine, should beclosely monitored, because the added -blocking action of BYSTOLIC may produceexcessive reduction of sympathetic activity. In patients who are receivingBYSTOLIC and clonidine, BYSTOLIC should be discontinued for several days beforethe gradual tapering of clonidine.

CYP2D6 Inhibitors: Use caution when BYSTOLIC is co-administered with CYP2D6inhibitors (quinidine, propafenone, fluoxetine, paroxetine, etc.) (see CLINICALPHARMACOLOGY, Drug Interactions).

Carcinogenesis, Mutagenesis, Impairment of FertilityIn a two-year study of nebivolol in mice, a statistically significant increase in the incidence of testicular Leydig cell hyperplasia and adenomas was observed at40 mg/kg/day (5 times the maximally recommended human dose of 40 mg on amg/m2 basis). Similar findings were not reported in mice administered doses equalto approximately 0.3 or 1.2 times the maximum recommended human dose. Noevidence of a tumorigenic effect was observed in a 24-month study in Wistar rats receiving doses of nebivolol 2.5, 10 and 40 mg/kg/day (equivalent to 0.6, 2.4,and 10 times the maximally recommended human dose). Co-administration ofdihydrotestosterone reduced blood LH levels and prevented the Leydig cell hyper-plasia, consistent with an indirect LH-mediated effect of nebivolol in mice and notthought to be clinically relevant in man.

A randomized, double-blind, placebo- and active-controlled, parallel-group study in healthy male volunteers was conducted to determine the effects of nebivolol on adrenal function, luteinizing hormone, and testosterone levels. This studydemonstrated that 6 weeks of daily dosing with 10 mg of nebivolol had no significant effect on ACTH-stimulated mean serum cortisol AUC0-120 min, serum LH,or serum total testosterone.

Effects on spermatogenesis were seen in male rats and mice at 40 mg/kg/day (10 and 5 times the MRHD, respectively). For rats the effects on spermatogenesiswere not reversed and may have worsened during a four-week recovery period. Theeffects of nebivolol on sperm in mice, however, were partially reversible.

Mutagenesis: Nebivolol was not genotoxic when tested in a battery of assays(Ames, in vitro mouse lymphoma TK+/-, in vitro human peripheral lymphocyte chromosome aberration, in vivo Drosophila melanogaster sex-linked recessivelethal, and in vivo mouse bone marrow micronucleus tests).

Pregnancy: Teratogenic Effects. Pregnancy Category C:Decreased pup body weights occurred at 1.25 and 2.5 mg/kg in rats, when exposedduring the perinatal period (late gestation, parturition and lactation). At 5 mg/kg andhigher doses (1.2 times the MRHD), prolonged gestation, dystocia and reducedmaternal care were produced with corresponding increases in late fetal deaths andstillbirths and decreased birth weight, live litter size and pup survival. Insufficientnumbers of pups survived at 5 mg/kg to evaluate the offspring for reproductive performance.

In studies in which pregnant rats were given nebivolol during organogenesis,reduced fetal body weights were observed at maternally toxic doses of 20 and 40 mg/kg/day (5 and 10 times the MRHD), and small reversible delays in sternaland thoracic ossification associated with the reduced fetal body weights and a smallincrease in resorption occurred at 40 mg/kg/day (10 times the MRHD). No adverseeffects on embryo-fetal viability, sex, weight or morphology were observed in studies in which nebivolol was given to pregnant rabbits at doses as high as 20 mg/kg/day (10 times the MRHD).

Labor and DeliveryNebivolol caused prolonged gestation and dystocia at doses 5 mg/kg in rats (1.2 times the MRHD). These effects were associated with increased fetal deathsand stillborn pups, and decreased birth weight, live litter size and pup survival rate, events that occurred only when nebivolol was given during the perinatal period (late gestation, parturition and lactation).

No studies of nebivolol were conducted in pregnant women. BYSTOLIC should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing MothersStudies in rats have shown that nebivolol or its metabolites cross the placental barrier and are excreted in breast milk. It is not known whether this drug is excretedin human milk.

Because of the potential for -blockers to produce serious adverse reactions innursing infants, especially bradycardia, BYSTOLIC is not recommended duringnursing.

Geriatric UseOf the 2800 patients in the U.S.-sponsored placebo-controlled clinical hypertensionstudies, 478 patients were 65 years of age or older. No overall differences in efficacyor in the incidence of adverse events were observed between older and youngerpatients.

Pediatric UseSafety and effectiveness in pediatric patients have not been established. Pediatricstudies in ages newborn to 18 years old have not been conducted because ofincomplete characterization of developmental toxicity and possible adverse effectson long-term fertility (see Carcinogenesis, Mutagenesis, and Impairment ofFertility).

ADVERSE REACTIONSThe data described below reflect worldwide clinical trial exposure to BYSTOLIC in6545 patients, including 5038 patients treated for hypertension and the remaining1507 subjects treated for other cardiovascular diseases. Doses ranged from 0.5 mgto 40 mg. Patients received BYSTOLIC for up to 24 months, with over 1900 patientstreated for at least 6 months, and approximately 1300 patients for more than one year. In placebo-controlled clinical trials comparing BYSTOLIC with placebo,discontinuation of therapy due to adverse events was reported in 2.8% of patientstreated with nebivolol and 2.2% of patients given placebo. The most commonadverse events that led to discontinuation of BYSTOLIC were headache (0.4%),nausea (0.2%) and bradycardia (0.2%).

Adverse Reactions in Controlled TrialsTable 1 lists treatment-emergent signs and symptoms that were reported in three 12-week, placebo-controlled monotherapy trials involving 1597 hypertensive patientstreated with either 5 mg, 10 mg or 20-40 mg of BYSTOLIC and 205 patients givenplacebo and for which the rate of occurrence was at least 1% of patients treated withnebivolol and greater than the rate for those treated with placebo in at least one dosegroup.

Table 1. Treatment-Emergent Adverse Events with an Incidence (over 6 weeks)1% in BYSTOLIC-Treated Patients and at a Higher Frequency than Placebo-Treated Patients

Placebo Nebivolol Nebivolol Nebivolol 5 mg 10 mg 20-40 mg

(n = 205) (n = 459) (n = 461) (n = 677)(%) (%) (%) (%)

Headache 6 9 6 7Fatigue 1 2 2 5Dizziness 2 2 3 4Diarrhea 2 2 2 3Nausea 0 1 3 2Insomnia 0 1 1 1Chest pain 0 0 1 1Bradycardia 0 0 0 1Dyspnea 0 0 1 1Rash 0 0 1 1Peripheral edema 0 1 1 1

Other Adverse Events Observed During Worldwide Clinical TrialsListed below are other reported adverse events with an incidence of at least 1% in the more than 5300 patients treated with BYSTOLIC in controlled or open-labeltrials, whether or not attributed to treatment, except for those already appearing in Table 1, terms too general to be informative, minor symptoms, or events unlikely to be attributable to drug because they are common in the population.These adverse events were in most cases observed at a similar frequency in placebo-treated patients in the controlled studies.

Body as a Whole: asthenia.

Gastrointestinal System Disorders: abdominal pain

Metabolic and Nutritional Disorders: hypercholesterolemia and hyperuricemia

Nervous System Disorders: paraesthesia

LaboratoryIn controlled monotherapy trials, BYSTOLIC was associated with an increase inBUN, uric acid, triglycerides and a decrease in HDL cholesterol and platelet count.

Events Identified from Spontaneous Reports of BYSTOLIC Received WorldwideThe following adverse events have been identified from spontaneous reports ofBYSTOLIC received worldwide and have not been listed elsewhere. These adverseevents have been chosen for inclusion due to a combination of seriousness, frequency of reporting or potential causal connection to BYSTOLIC. Events commonin the population have generally been omitted. Because these events were reportedvoluntarily from a population of uncertain size, it is not possible to estimate their frequency or establish a causal relationship to BYSTOLIC exposure: abnormal hepatic function (including increased AST, ALT and bilirubin), acute pulmonaryedema, acute renal failure, atrioventricular block (both second- and third-degree),bronchospasm, erectile dysfunction, hypersensitivity (including urticaria, allergicvasculitis and rare reports of angioedema), myocardial infarction, pruritus, psoriasis, Raynauds phenomenon, peripheral ischemia/claudication, somnolence,syncope, thrombocytopenia, various rashes and skin disorders, vertigo, and vomiting.

OVERDOSAGEIn clinical trials and worldwide postmarketing experience there were reports ofBYSTOLIC overdose. The most common signs and symptoms associated withBYSTOLIC overdosage are bradycardia and hypotension. Other important adverse events reported with BYSTOLIC overdose include cardiac failure, dizziness,hypoglycemia, fatigue and vomiting. Other adverse events associated with -blocker overdose include bronchospasm and heart block.

The largest known ingestion of BYSTOLIC worldwide involved a patient who ingested up to 500 mg of BYSTOLIC along with several 100 mg tablets of acetylsalicylic acid in a suicide attempt. The patient experienced hyperhidrosis, pallor, depressed level of consciousness, hypokinesia, hypotension, sinus bradycardia, hypoglycemia, hypokalemia, respiratory failure and vomiting. Thepatient recovered.

Due to extensive drug binding to plasma proteins, hemodialysis is not expected toenhance nebivolol clearance.

If overdose occurs, BYSTOLIC should be stopped and general supportive and specific symptomatic treatment should be provided. Based on expected pharma-cologic actions and recommendations for other -blockers, the following generalmeasures should be considered when clinically warranted:

Bradycardia: Administer IV atropine. If the response is inadequate, isoproterenol or another agent with positive chronotropic properties may be given cautiously.Under some circumstances, transthoracic or transvenous pacemaker placementmay be necessary.

Hypotension: Administer IV fluids and vasopressors. Intravenous glucagon may beuseful.

Heart Block (second or third degree): Patients should be carefully monitored and treated with isoproterenol infusion. Under some circumstances, transthoracicor transvenous pacemaker placement may be necessary.

Congestive Heart Failure: Initiate therapy with digitalis glycoside and diuretics. In certain cases, consideration should be given to the use of inotropic and vasodilating agents.

Bronchospasm: Administer bronchodilator therapy such as a short-acting inhaled2-agonist and/or aminophylline.

Hypoglycemia: Administer IV glucose. Repeated doses of IV glucose or possiblyglucagon may be required.

In the event of intoxication where there are symptoms of shock, treatment must becontinued for a sufficiently long period consistent with the 12-19 hour effectivehalf-life of BYSTOLIC. Supportive measures should continue until clinical stabilityis achieved.

Call the National Poison Control Center (800-222-1222) for the most current information on -blocker overdose treatment.

Forest Pharmaceuticals, Inc.Subsidiary of Forest Laboratories, Inc.

St. Louis, MO 63045, USALicensed from Mylan Laboratories, Inc.

Under license from JanssenPharmaceutica N.V., Beerse, Belgium

Rev. 08/08 2008 Forest Laboratories, Inc.

Rx Only

Important Safety InformationPatients being treated with BYSTOLIC should be advised against abrupt discontinuation of therapy. Severe exacerbation of angina and the occurrence of myocardial infarction and ventricular arrhythmias have been reported following the abrupt cessation of therapy with beta blockers. When discontinuation is planned, the dosage should be reduced gradually over a 1- to 2-week period and the patient carefully monitored.BYSTOLIC is contraindicated in severe bradycardia, heart block greater than first degree, cardiogenic shock, decompensated cardiac failure, sick sinus syndrome (unless a permanent pacemaker is in place), severe hepatic impairment (Child-Pugh >B), and in patients who are hypersensitive to any component of this product.BYSTOLIC should be used with caution in patients with peripheral vascular disease, thyrotoxicosis, in patients treated concomitantly with beta blockers and calcium channel blockers of the verapamil and diltiazem type (ECG and blood pressure should be monitored), severe renal impairment, and any degree of hepatic impairment or in patients undergoing major surgery. In patients who have compensated congestive heart failure, BYSTOLIC should be administered cautiously. If heart failure worsens, discontinuation of BYSTOLIC should be considered. Caution should also be used in diabetic patients as beta blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia.Use caution when BYSTOLIC is co-administered with CYP2D6 inhibitors (quinidine, propafenone, fluoxetine, paroxetine, etc). When BYSTOLIC is administered with fluoxetine, significant increases in d-nebivolol may be observed (ie, an 8-fold increase in AUC). In general, patients with bronchospastic disease should not receive beta blockers. BYSTOLIC should not be combined with other beta blockers.The most common adverse events with BYSTOLIC versus placebo (approximately 1% and greater than placebo) were headache, fatigue, dizziness, diarrhea, nausea, insomnia, chest pain, bradycardia, dyspnea, rash, and peripheral edema.

Please see brief summary of Prescribing Information on adjacent page.References: 1. BYSTOLIC [package insert]. St. Louis, Mo: Forest Pharmaceuticals, Inc.; 2008. 2. Data on file. Forest Laboratories, Inc. 3. Saunders E, Smith WB, DeSalvo KB, Sullivan WA. The efficacy and tolerability of nebivolol in hypertensive African American patients. J Clin Hypertens. 2007;9:866-875. 2009 Forest Laboratories, Inc 44-1014950 01/09

For the treatment of hypertension

BYSTOLIC.Significant blood pressure reductions with a low incidence of side effects.1-3

www.BYSTOLIC.com


REGULATORY

In July 2008, as part of broad Medicare reform, Congress passed the firstmajor legislative changes to Medicare Part D since its enactment in 2003the Medicare Improvements for Patients and Providers Act. This new leg-islation has significant implications for how Part D plans can market andenroll Medicare beneficiaries. The new legislation also strengthened ben-eficiary protections, expanded the low-income subsidy provisions original-ly included in Part D, and expanded Part D coverage. These changes havesignificant implications for the operation of Part D plans and can affectthose involved in benefit design, including specialty pharmacy coverage.This article discusses the major changes that took effect on January 1,

2009, and have immediate implications for Part D plan sponsors, including Medicare Advantage plans and stand-alone prescription drug plans. [AHDB. 2009;2(3):111-118.]

The Medicare Part D Prescription Drug Programwas enacted on December 8, 2003, as part ofthe Medicare Prescription Drug Improvementand Modernization Act of 2003 and was implementedon January 1, 2006. Because the program was thelargest major enhancement of Medicare since itsinception in 1965 and was controversial in its originaldesign, Congress chose not to amend the legislationuntil last summer.

As part of a broad Medicare reform, on July 15,2008, Congress overrode a Bush White House veto andpassed new legislationPL 110-275the MedicareImprovements for Patients and Providers Act of 2008(MIPPA).1 MIPPA includes the first broad legislativechanges to improve the Medicare Part D program,which are designed to strengthen beneficiary protec-tions, help low-income beneficiaries, address marketingabuses, and enhance Part D coverage and transparency.

The new legislation codifies the elimination of thelate-enrollment penalty for low-income subsidy (LIS)beneficiaries and the designation of protected drug cat-egories for disease states for which interruption in drugtherapy could have severe negative consequences onpatients, all changes that will affect Part D plans andtheir members. Other changes affecting those in charge

of Part D benefit design include greater compendiacoverage to be consistent with Part B drug coverage.Table 1 provides a summary of the MIPPA provisionsthat affect Part D plans.2

Most of these new Part D provisions were focused onstrengthening beneficiary protections and correctingsales and marketing abuses. These changes were drivenby Democrats who assumed the congressional majorityin the 2006 midterm elections and were responding toremaining challenges in the program. The GovernmentAccountability Office (GAO) documented some of theproblems in its reports, for example, the report on bene-ficiaries filing grievances to plan sponsors.3 In addition, aseries of GAO reports in 2007 and 2008GAO-07-555,4 GAO -08-812T,5 and GAO-08-8246documentedproblems with the low-income subsidy provisions in thePart D program and helped drive the legislative agendato expand federal subsidies to low-income Medicare ben-eficiaries and to strengthen protections for vulnerablebeneficiaries, concerns that are now reflected in MIPPA.Another goal was to improve Part D access and coverageto the extent possible under the congressional pay forrules. These rules say that when a bill expands benefitcoverage, there is a new cost, which must be funded byreduced costs elsewhere in the program. For example,MIPPA added 2 new Part D drugs, but these could notbe paid for until 2013.

The Centers for Medicare & Medicaid Services(CMS) provided the MIPPA provisions to Part D in 3

Ms LeMasurier is Director, Employer Group Practice, and Dr Edgar is Senior Vice President, Operations and QualityAssurance, Gorman Health Group, Washington, DC.

MIPPA: First Broad Changes to Medicare Part D Plan OperationsJean D. LeMasurier; Babette Edgar, PharmD, MBA

Jean D. LeMasurier Babette Edgar


REGULATORY

rules(1) a final rule (CMS-4131-F) and (2) an inter-im final rule (CMS-4138-IFC), which were publishedon September 18, 20087; and (3) an interim and finalrule with a comment period (CMS 4138-IFC4), pub-lished on January 16, 2009.8

Marketing ChangesDuring the first 2 years of the Part D program, more

than 17 million Medicare beneficiaries were enrolledin stand-alone Part D plans, and an additional 8 mil-lion beneficiaries were enrolled in Medicare Ad -vantage plans that included Part D coverage. This wasa phenomenal accomplishment in such a short amountof time and was largely made possible through plan useof contracted sales brokers and agents.

Before the introduction of the Medicare Part D pro-gram, Medicare Advantage plans primarily employedsales agents, and use of contracted sales agents was lim-ited to the Medigap supplemental insurance market.9With the establishment of the Medicare Part D pro-gram, many new plans entered the Medicare market-place for the first time, and with them many newagents who were unfamiliar with selling managed careproducts. CMSs attempts at regulating the market-place can be seen in the marketing guidelines issued in2005 and revised in 2006.10 The sales agents for the newPart D plan had the task of selling more than 5000plans nationwide, with multiple benefit designs andformulary structures that included a limited enrollmentperiod of 45 days.

Inevitably, abuses occurred in the marketplace,including large commissions that encouraged churning,misunderstanding of complicated plan designs, andoutright fraud and abuse, resulting in beneficiariesbeing enrolled in plans they did not choose, or plansthat did not meet their needs.11,12 Information on CMSscorrective action plans13 and enforcement actions14 isopen to the public and helps ensure that Medicare reg-ulations of health plans are followed properly.

MIPPA imposes major changes in the marketing ofPart D plans.1 The changes include a number of prohi-bitions and limitations on sales and marketing activi-ties by Medicare Advantage and prescription drug plan(PDP) sponsors and their agents, brokers, or other thirdparties that represent them.1

Effective January 1, 2009, Medicare Part D plansand their representatives are prohibited from the fol-lowing promotional activities: Unsolicited direct contact of prospective enrollees,

such as door-to-door sales and cold calling (tele-marketing)

Selling nonhealth-related products (cross-selling) Providing meals at promotional and sales events Selling or marketing in healthcare settings and at

educational events.Other marketing requirements in MIPPA include:

Advance agreement with a prospective enrollee on

Table 1 MIPPA: Key Provisions Affecting Medicare Part D Plans

Medicare Advantage Reduces overpayments to private Medicare Advantage plans

by phasing out an adjustment for indirect medical education Requires private fee-for-service plans to establish provider

networks and to measure and report on the quality of carethey deliver

Reduces money in the Medicare Advantage StabilizationFund

Marketing Reforms Prohibits and limits certain sales and marketing activities

under Medicare Advantage and Part D prescription drugplans

Beneficiary Improvements Provides Medicare mental health parity Offers new preventive benefits to Medicare beneficiaries Extends the exceptions process for therapy caps Provides better care for patients with kidney disease, also

known as end-stage renal disease

Low-Income Individuals Extends the qualifying individual program Raises allowed asset levels in the Medicare Savings Program Codifies suspension of the late enrollment penalty for Part

D beneficiaries who qualify for low-income subsidy Excludes the value of life insurance policies and in-kind

support from resource calculations for low-income subsidy

Part D Drug Benefit Improvements Requires Part D plans to cover benzodiazepines and

barbiturates in 2013 Codifies a requirement for Part D plans to cover most

drugs in certain important classes of drugs

Physician Services under Part B Blocks the scheduled 10.6% cut to physician fees Incentivizes adoption of electronic prescribing by physicians Increases incentives for physician quality reportingSource: National Committee to Preserve Social Security and Medicare. TheMedicare Improvements for Patients and Providers Act (MIPPA): summary ofkey provisions. July 2008.


MIPPA: First Broad Changes to Medicare Part D

the scope of products to be discussed during market-ing appointments

Limitations on the use of the name or logo of a net-work provider (co-branding)

Limitation on gifts to prospective enrollees to nomi-nal dollar value

Compensation of brokers and agents: plans mustcomply with guidelines established by the Health andHuman Services (HHS) Secretary that provideincentives to enroll individuals in plans that bestmeet their healthcare needs

Annual training and testing of agents, brokers, andother parties

Inclusion of plan type in plan name in 2010 Plans can only use state licensed agents and brokers

and must comply with state appointment laws andstate investigations of agent, broker, or third-partyconduct.CMS did its utmost to publish regulations in time for

the beneficiaries annual election period, leading up tothe January 1, 2009, enrollment. However, the develop-ment of policy on the new commission structure proveddifficult, and CMSs policy on the interim final rule withcomment (IFC) was modified twice after industry andconsumer groups responded that the initial policy wasunworkable or did not accomplish the objective toreduce churning. The final policy (in the final regula-tion) adopted a 6-year structure similar to the compen-sation structure used in the Medigap insurance industry.

It is too early to assess the impact of the new MIPPArequirements and regulations, because much activityduring the 2008 selling season was delayed as a result ofuncertainty on the commission requirements. To date,we are aware of only a few reports of potential abusesthat are currently under investigation, as noted byCMS in the draft Call Letter for 2010.15 Overall, CMSoversight has been strengthened, and congressionalscrutiny will certainly follow.

Low-Income SubsidyOne of the major changes introduced by the

Medicare Part D program was to shift dual-eligible ben-eficiaries (ie, those eligible for Medicare and Medicaid)from drug coverage under state Medicaid programs todrug coverage under the Medicare Part D program withfederal LIS.4

A number of members of Congress were concernedthat during the first 3 years of the Part D program, anestimated 3 million beneficiaries who had been expect-ed to be eligible for LIS had not signed up.5 One of theproblems that emerged was that LIS eligibility require-

ments as part of the Social Security and state MedicareSavings Program imposed eligibility processes thatproved too restrictive. As a result, MIPPA relaxed therequirements for qualifying for LIS.1

Specifically, MIPPA exempts life insurance policiesand in-kind support from family members from LIS eli-gibility determinations. In addition, MIPPA includedfunds for expanded outreach efforts. As a result of thesechanges, more beneficiaries are expected to sign up forthe Part D LIS program and enroll in Part D plans.

To further protect beneficiaries, MIPPA includes thecurrent Part D policy that eliminates the late-enroll-ment penalty for LIS beneficiaries in statute. CMS hadimplemented a demonstration project to waive thelate-enrollment penalty for LIS beneficiaries, whichhad been scheduled to expire at the end of 2008.MIPPA also codifies a beneficiarys right to federalcourt review for denial of LIS. This latter provision cor-rects an oversight in the Part D legislation and providesLIS beneficiaries the same protections that are provid-ed by Medicare and Social Security.

To ensure that low-income beneficiaries continueto be eligible for Part D, MIPPA increased the allow-able resources under the Medicare Savings Program tothe amount for full subsidy of the Part D LIS andextended the qualifying individual program throughDecember 2009.

KEY POINTS MIPPA offers the first broad legislative changes to

the Medicare Part D program that are intended toincrease beneficiary protections, provide subsidiesto low-income beneficiaries, impose major changesto the marketing of Part D plans, and enhancecoverage and transparency.

Changes directly affecting drug benefit designinclude the coverage of all drugs in 6 protectedclasses, increased compendia coverage for Part Dplans consistent with Part B, a new definition ofmedically accepted indications, and coverage ofbarbiturates and benzodiazepines.

MIPPA imposes stringent prompt paymentrequirements to pharmacies, as well as regularupdates of drug prices by Part D plans to theirnetwork pharmacies.

Despite these changes, basic structural concernswith the Part D programsuch as the coverage gapor a competing government drug program withgovernmental drug price negotiation authoritywere not addressed by MIPPA.


REGULATORY

Drug Coverage Changes Formulary Protected Classes

When Medicare Part D was enacted, CMS identifieddrug categories for disease states in which interruptionof drug therapy could have severe negative conse-quences for patients. Many of these disease states corre-late directly with conditions that are prevalent amonglow-income beneficiaries. To ensure that therapieswould not be interrupted and that vulnerable popula-tions had the widest choice of plans, CMS included pol-icy in subregulatory guidance that requires Part D plansto provide coverage substantially for all drugs within the6 drug classes of clinical concern (Table 2). BecauseCongress was concerned that a future HHS Secretarycould retrench on this coverage, it included a provisionin MIPPA to codify the current policy on protected drugclasses under the Medicare Part D program.

One of the surprising provisions in MIPPA is theestablishment of a process to potentially expand theprotected classes under Part D. MIPPA provides thatthe HHS Secretary, beginning in 2010, shall identifycategories and classes of drugs that: 1. If restricted, would have a major or life-threatening

clinical effect, and2. Are needed by individuals who use multiple drugs in

a drug category/class, because of the unique chemi-cal actions and pharmacologic effects of those class-es, such as cancer drugs. According to the statute, the HHS Secretary must use

a public rule-making process to identify protected class-es that meet these criteria. When final rules are issued,Part D plan sponsors will be required to cover all drugsin the category/class that the HHS Secretary identifiesfor that purpose, unless there are exceptions based onscientific evidence and medical standards of practice.

The January 16, 2009, regulation8 identifies theprocess that will be used to implement this new provi-sion, and indicates that there will be no changes in

2010. However, many obs

April/May 2009, Vol 2, No 3

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