May/June 2010, Vol 3, No 3 Drug Update by Dalia Buffery

THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN ™ MAY/JUNE 2010

VOLUME 3, NUMBER 3, SUPPLEMENT 10

& FOR PAYERS, PURCHASERS, POLICYMAKERS, AND OTHER HEALTHCARE STAKEHOLDERS

SUPPLEMENT

Drug Update ™

A Complete Resource for New Drug Approvals and Indications in 2009

MAY/JUNE 2010

VOLUME 3, NUMBER 3, SUPPLEMENT 10 THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN ™

™

FOR PAYERS, PURCHASERS, POLICYMAKERS, AND OTHER HEALTHCARE STAKEHOLDERS

TABLE OF CONTENTS S217 INTRODUCTION: New Drug Approvals in 2009: A Transitional Year Gary M. Owens, MD S220 2009 FDA Approvals of Brand-Name Prescription Drugs S236 Embeda : Morphine and Sequestered Naltrexone Extended Release Combination Formulation for the Management of Chronic, Moderate-to-Severe Pain ®

Stakeholder Perspective by Alan G. White, PhD

Publisher Nicholas Englezos nick@engagehc.com 732-992-1884 Associate Publisher Maurice Nogueira maurice@engagehc.com 732-992-1895 Editorial Director Dalia Buffery dalia@AHDBonline.com 732-992-1889

S241 Synvisc-One (hylan G-F 20): One Gets It Done for Osteoarthritis Knee Pain Relief ®

S247 Savella (Milnacipran HCl): A New Option for the Management of Fibromyalgia Stakeholder Perspectives by Nirav R. Shah, MD, MPH; Gary M. Owens, MD; Philip Mease, MD S258 The New Drug Pipeline: What Is on the Horizon for Managed Care in 2010? Diana Papshev, PharmD; Chantell M. Reagan, PharmD S272 Dexamethasone Intravitreal Implant for Treatment of Macular Edema Following Retinal Vein Occlusion Publisher’s note: The material presented in this supplement is intended to be a thorough, objective, balanced presentation of clinical information. The opinions expressed in this professional educational supplement are those of the authors, presenters, and/or panelists and do not necessarily reflect those of the Publisher, Editors, or Editorial Board of American Health & Drug Benefits, or the sponsor. Dosages, indications, and methods of use for products referred to in this professional educational supplement may reflect the clinical experience of the authors, presenters, and/or panelists or may be derived from the professional literature or other clinical sources and are not necessarily the same as indicated in the package insert for the product. This publication may contain or discuss off-label uses of commercial products or investigational uses not cleared for marketing. Readers are advised to consult the full prescribing information before administering any product. Neither the Editors nor the Publisher assume any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material mentioned in this publication. American Health & Drug Benefits, ISSN 1942-2962 (print); ISSN 1942-2970 (online), is published 6 times a year by Engage Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205A, Monroe Twp, NJ 08831. Copyright © 2010 by Engage Healthcare Communications, LLC. All rights reserved. American Health & Drug Benefits and The Peer-Reviewed Forum for Evidence in Benefit Design are trademarks of Engage Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the Publisher. Printed in the United States of America. Address all editorial correspondence to: editorial@AHDBonline.com. Telephone: 732-992-1892. Fax: 732-992-1881. Permission requests to reprint all or part of any article published in this supplement should be addressed to REPRINT PERMISSIONS DEPARTMENT, Engage Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205A, Monroe Twp, NJ 08831. T: 732-992-1880. POSTMASTER: CORRESPONDENCE REGARDING SUBSCRIPTIONS OR CHANGE OF ADDRESS should be directed to CIRCULATION DIRECTOR, American Health & Drug Benefits, 241 Forsgate Drive, Suite 205A, Monroe Twp, NJ 08831. Fax: 732-992-1881.

The individual drug updates have been sponsored by their manufacturers. The drug manufacturers had editorial control over these articles.

Associate Editor Lara J. Reiman 732-992-1892 Editorial Assistant Jessica A. Smith Senior Production Manager Lynn Hamilton Business Manager Blanche Marchitto Editor-in-Chief Robert E. Henry rhenry@AHDBonline.com 732-992-1885

Mission Statement American Health & Drug Benefits is founded on the concept that health and drug benefits have undergone a transformation: the econometric value of a drug is of equal importance to clinical outcomes as it is to serving as the basis for securing coverage in formularies and benefit designs. Benefit designs are greatly affected by clinical, business, and policy conditions. This publication provides benefit design decision makers the integrated industry information they require to devise formularies and benefit designs that stand up to today’s special healthcare delivery and business needs.

Contact Information: For reprints, subscription information, and editorial queries, please contact: editorial@AHDBonline.com T: 732-992-1892 F: 732-992-1881 AHDB0310

S216 I AMERICAN HEALTH & DRUG BENEFITS I May/June 2010 I Supplement

INTRODUCTION

New Drug Approvals in 2009: A Transitional Year Gary M. Owens, MD President, Gary Owens Associates, Philadelphia

n 2009, in a similar fashion to 2008, a relatively small number of new drugs were approved by the US Food and Drug Administration’s (FDA) Center for Drug Evaluation and Research (CDER). In total, there were 19 new molecular entities (NMEs) and 7 biologic license applications (BLAs) approved. This represents only 2 more approved drugs than in 2008 (21 NMEs and 3 BLAs). So far, FDA approvals in the new millennium have been relatively modest, with only 2004 seeing more than 30 new drug approvals (Figure).1 Of note, however, is the approval of 7 biologic entities, representing almost 25% of the new drug approvals. The key question is whether this represents the beginning of a breakout era for biologic approvals, or if this is just a blip in the process. Only time and future approvals will tell. Last year saw big changes in the FDA, with a new presidential administration and a new commissioner. President Barack Obama tapped FDA Commissioner Margaret Hamburg and Deputy Commissioner Joshua Sharfstein last year to restore the agency’s credibility, after a string of mishandled drug safety issues. Mr Sharfstein, a former Baltimore Health Commissioner, is best known for challenging the safety of infant cough formulations, which were pulled from the market in 2007.2 Analysts who monitor the FDA say that the new leadership has put the agency on stronger footing, allowing it to act more quickly and confidently on drug approvals. “A strong FDA is good for a regulated industry,” said Ira Loss, an analyst with Washington Analysis, who has covered the agency for 3 decades. “Sharfstein and Hamburg bring confidence and certainty to an agency that was badly in need of it, and the rank-and-file staffers are now able to move with confidence that the agency has their back.”2 One of the first priorities of the agency was to increase the efficiency of the drug approval process, while maintaining a focus on public safety. In a concerted effort, the agency attempted to correct many of their staffing issues of the past, but it is still considered underfunded and overworked. Last year, the FDA failed to meet its PDUFA (Prescription Drug User Fee Act) review goals of 90% of standard and priority new drug

applications (NDAs/BLAs) in 10 months and 6 months, respectively. In fact, the FDA’s new emphasis on drug safety and postmarketing surveillance resulted in prolonged review periods. Although there is general agreement that FDA staffing has improved, there will be a lag time in which the new staff will need to be trained and gain efficiency before the current performance of 69% of priority review deadlines and 83% of standard review deadlines are improved. It is not surprising, therefore, that the number of NDAs approved was up only 2 from 2008, the last Bush administration year. Several policy changes at the FDA resulted in a heightened focus on drug safety, with 31 black box warning labels issued for existing drugs. The year 2009 also proved to be a time when the FDA and drug manufacturers gained familiarity with risk management strategies. In fact, the most common reason for delay in regulatory approvals was the requirement for risk evaluation and mitigation strategies (REMS). As a result of this focus, a number of potential drug approvals were pushed out of 2009, because of the need for further safety evaluation and the development of REMS programs.

New Drugs: The P&T Committee Perspective The Table represents a listing of NMEs and BLAs approved in 2009, and their respective manufacturers.3 Of note, only 1 manufacturer, Novartis, had more than 2 new drugs approved in 2009. Similarly, missing from the listing of manufacturers with approved products in 2009 are many of the traditionally biotechnologyfocused companies. Johnson & Johnson is the only manufacturer with 2 biologics approved in 2009. Despite the relatively small number of drugs approved, several drugs have and will continue to generate considerable discussion with P&T Committees as these new entities come up for review. For example, 2009 saw the approval of febuxostat (Uloric), the first new drug approved to treat gout in more than 40 years. This medication acts by blocking xanthine oxidase, thereby inhibiting the production of uric acid. Key issues in formulary decision-making will be balancing the safety and efficacy of this drug with the widespread use and low cost of existing agents, such as allopurinol.

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INTRODUCTION

Figure FDA Drug Approvals, 1996-2009 60 BLAs NMEs

0 1996

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1998

1999

2000

2001

2002

2003

2004

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BLAs indicates biologic license applications; FDA, US Food and Drug Administration; NMEs, new molecular entities. Reprinted with permission from Hughes B. 2009 FDA drug approvals. Nat Rev Drug Discov. 2010;9:89-92.

Another drug that will create considerable discussion with P&T Committees is milnacipran (Savella). Milnacipran is a serotonin-norepinephrine reuptake inhibitor, which has been shown in clinical trials to improve many of the symptoms associated with fibromyalgia. Most important, this drug demonstrated significant improvement in fibromyalgia composite responders (defined as those with meaningful improvements in 3 clinical domains—pain, patient global assessment, and physical function), as well as fibromyalgia pain responders (defined as the patient meeting pain and global change criteria).

P&T Committees will need to balance the safety and efficacy of this drug when comparing it with other drugs along with the costs of the existing drugs. Although milnacipran is not a cure for fibromyalgia, it does provide an additional tool for the clinician to use in the treatment of this complex syndrome. Milnacipran joins pregabalin (Lyrica) and duloxetine HCl (Cymbalta) as the only FDA-approved drugs for the management of fibromyalgia. Dronedarone (Multaq) was approved to help maintain normal heart rhythms in patients with a history of

atrial fibrillation or atrial flutter. The drug was approved to be used in patients whose hearts have returned to sinus rhythm or who will undergo drug or direct-current cardioversion to restore normal rhythm. Dronedarone may cause critical adverse reactions, including death, in patients with recent severe heart failure. The drug’s label contains a black box warning, cautioning that this medication should not be used in patients with severe heart failure. “Multaq represents a therapeutic innovation for treatment of the heart rhythm disorder of atrial fibrillation,” said Norman Stockbridge, MD, PhD, director of the Division of Cardiovascular and Renal Products at CDER.4 In a multinational clinical trial with more than 4600 patients, dronedarone reduced cardiovascular hospitalization or death from any cause by 24% when compared with placebo.5 Most of that effect represented reduced hospitalizations, especially hospitalizations related to atrial fibrillation. P&T Committees will need to balance the safety and efficacy of this drug when comparing it with other drugs (such as amiodarone) along with the costs of the existing drugs, as well as the costs of associated procedures and hospitalizations. Prasugrel (Effient) was approved in July 2009 for reducing the risk of thrombosis in patients who undergo angioplasty. Prasugrel was studied in a 13,608patient trial (TRITON-TIMI 38) comparing it to

S218 I AMERICAN HEALTH & DRUG BENEFITS I May/June 2010 I Supplement

INTRODUCTION

Table 2009 FDA NME/BLA Approvals Trade name Savella Uloric Afinitor Coartem Ulesfia Simponi Dysport Fanapt Samsca Besivance Ilaris Multaq Effient Onglyza Livalo Saphris Extavia Sabril Bepreve Vibativ Folotyn Stelara Votrient Arzerra Istodax Kalbitor

Drug manufacturer Forest Laboratories Takeda Novartis Novartis Sciele Pharmaceuticals Johnson & Johnson Ipsen, Medicis Vanda Pharmaceuticals Otsuka Pharmaceuticals Bausch & Lomb Novartis sanofi-aventis Lilly, Daiichi Sankyo AstraZeneca, BMS Kowa Research Organon USA Novartis Lundbeck Ista Pharmaceuticals Theravance, Astellas Allos Therapeutics Johnson & Johnson GlaxoSmithKline GlaxoSmithKline Gloucester Pharmaceuticals Dyax Corporation

BLA indicates biologic license application; BMS, Bristol-Myers Squibb; NME, new molecular entity.

clopidogrel (Plavix) in patients with a threatened heart attack or an actual heart attack who were about to undergo angioplasty.6 The fraction of patients who had subsequent nonfatal heart attacks was reduced from 9.7% in patients who received clopidogrel to 7.4% in patients who received prasugrel.6 Although the numbers of deaths and strokes were similar with both drugs, patients with a history of stroke were more likely to have another stroke while taking prasugrel. In addition, there was a greater risk of significant, sometimes fatal, bleeding seen in patients who took prasugrel. “Effient offers physicians an alternative treatment for preventing dangerous blood clots from forming and caus-

ing a heart attack or stroke during or after an angioplasty procedure,” said John Jenkins, MD, Director of the Office of New Drugs at CDER. “Physicians must carefully weigh the potential benefits and risks of Effient as they decide which patients should receive the drug.”7 Effient’s labeling will include a boxed warning alerting physicians that it can cause significant, sometimes fatal, bleeding. This drug should not be used in patients with active pathologic bleeding, a history of transient ischemic attacks or stroke, or urgent need for surgery, including coronary artery bypass graft surgery.

The decisions P&T Committees are faced with are becoming increasingly complex, because new drugs often come to market with advantages either in efficacy or in safety, or sometimes in both. As with other drugs in 2009, P&T Committees will need to balance the data showing improved efficacy with potential safety issues when making their formulary decisions. The drugs mentioned above represent only a few of the new drugs approved in 2009. As can be seen from these examples, the decisions P&T Committees are faced with are becoming increasingly complex, because new drugs often come to market with advantages either in efficacy or in safety, or sometimes in both. However, in many cases there is a trade-off between efficacy and safety that must be openly discussed, and the evidence must therefore be weighed carefully when formulary decisions are made to adequately balance cost, quality, and access. ■

References 1. Hughes B. 2009 FDA drug approvals. Nat Rev Drug Discov. 2010;9:89-92. 2. FDA’s drug approvals flat in 2009, safety up. January 5, 2010. www.msnbc.msn. com/id/34708085/ns/health-more_health_news/. Accessed March 2, 2010. 3. Martino M, Jones L. The FDA approvals of 2009. www.fiercebiotech.com/slide shows/fda-approvals-2009. Accessed April 7, 2010. 4. US Food and Drug Administration. FDA approves Multaq to treat heart rhythm disorder. July 2, 2009. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ ucm170276.htm. Accessed March 5, 2010. 5. Hohnloser SH, Crijns HJ, van Eickels M, et al, for the ATHENA Investigators. Effect of dronedarone on cardiovascular events in atrial fibrillation. N Engl J Med. 2009;360:668-678. 6. Wiviott SD, Braunwald E, McCabe CH, et al, for the TRITON–TIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357:2001-2015. Epub 2007 Nov 4. 7. US Food and Drug Administration. FDA approves Effient to reduce the risk of heart attack in angioplasty patients. July 10, 2009. www.fda.gov/NewsEvents/News room/PressAnnouncements/ucm171497.htm. Accessed March 5, 2010.

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2009 FDA Approvals of Brand-Name Prescription Drugs I. New Pharmaceuticals, NMEs, Biologics Afinitora (NME) (Everolimus; Novartis) Class Kinase mTOR inhibitor Indication Treatment of advanced renal-cell carcinoma after treatment failure with sunitinib or sorafenib Agriflu (BLA) (Influenza virus vaccine; Novartis) Class Inactivated virus vaccine Indication Immunization of adults aged â&#x2030;Ľ18 years against influenza caused by virus subtypes A and B in the vaccine Arzerraa,b (BLA) (Ofatumumab; GlaxoSmithKline) Class Anti-CD20 monoclonal antibody Indication Treatment of chronic lymphocytic leukemia refractory to alemtuzumab and fludarabine ATryna,b (BLA) (Antithrombin, recombinant; GTC Therapeutics) Class Therapeutic human protein produced in the milk of transgenic goats Indication Prevention of perioperative and peripartum thromboembolic events in hereditary antithrombin-deficient patients Bepreve (NME) (Bepotastine besilate; Ista) Class Histamine H1 receptor antagonist Indication Treatment of ocular itching related to allergic conjunctivitis Berinerta (BLA) (CSL Behring) Class C1 esterase inhibitor Indication

Acute abdominal or facial attacks of hereditary angioedema in adult or adolescent patients Besivance (NME) (Besifloxacin hydrochloride; Bausch & Lomb) Class Fluoroquinolone antibiotic in topical suspension Indication Treatment of bacterial conjunctivitis Cervarix (BLA) (Human papillomavirus bivalent, type 16 and 18, vaccine, recombinant; GlaxoSmithKline Biologicals) Class Vaccine Indication Prevention of cervical cancer, CIN grade 2 or worse and adenocarcinoma in situ, and CIN grade 1 caused by oncogenic HPV types 16 and 18, in females aged 10-25 years Coartema,b (NME) (Artemether/lumefantrine; Novartis) Class Fixed-dose combination of 2 blood schizontocides Indication Acute, uncomplicated malaria due to Plasmodium falciparum in patients â&#x2030;Ľ5 kg Dysport (BLA) (AbobotulinumtoxinA; Ipsen/Medicis [for aesthetic use]) Class Botulinum toxin Indication Treatment of cervical dystonia and temporary improvement in the appearance of moderate-to-severe glabellar lines associated with procerus and corrugators muscle activity in adults aged <65 years Effienta (NME) (Prasugrel; Lilly) Class Oral platelet inhibitor Indication Reduction of thrombotic CV events in patients with ACS to be managed with PCI, unstable angina, nonSTEMI, or STEMI managed with primary or delayed PCI

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2009 FDA Approvals of Brand-Name Drugs

Extavia (BLA) (Novartis) Class Interferon beta-1b Indication Treatment of relapsing MS to reduce clinical exacerbations; for patients with first clinical episode of MS Fanapt (NME) (Iloperidone; Vanda) Class Atypical antipsychotic Indication Acute treatment of schizophrenia in adults Feraheme (Ferumoxytol; AMAG Pharmaceuticals) Class Hematinic Indication Treatment of iron deficiency anemia in adult patients with chronic kidney disease Folotyna (NME) (Pralatrexate injection; Allos) Class Selective antifolate Indication Treatment of relapsed or refractory peripheral T-cell lymphoma

Istodaxb (NME) (Romidepsin; Gloucester) Class Histone deacetylase inhibitor Indication Treatment of cutaneous T-cell lymphoma in patients with ≥1 previous systemic therapy Ixiaro (BLA) (Intercell/Novartis) Class Second-generation Japanese encephalitis vaccine, inactivated, adsorbed, produced in cell culture Indication Prevention of disease caused by Japanese encephalitis virus in patients aged ≥17 years Kalbitora (BLA) (Ecallantide; Dyax) Class Plasma kallikrein inhibitor Indication Treatment of acute attacks of hereditary angioedema in patients aged ≥16 years Kapidex (now Dexilant) (Dexlansoprazole; Takeda Pharmaceuticals) Class Proton pump inhibitor Indication Treatment of heartburn associated with symptomatic nonerosive GERD, healing and maintenance of erosive esophagitis

Gammaplex (BLA) (Immune globulin intravenous [human] liquid; Bio Products Laboratory) Class Polyclonal human immunoglobulin G Indication Primary humoral immunodeficiency Hiberix (BLA) (GlaxoSmithKline) Class Haemophilus B conjugate vaccine (tetanus toxoid conjugate) Indication Prevention of invasive disease caused by Haemophilus influenzae when administered as a booster dose in children aged 15 months to 4 years (before 5th birthday) Ilarisa (BLA) (Canakinumab; Novartis) Class IL-1 beta blocker Indication

Cryopyrin-associated periodic syndromes in adults and children aged ≥4 years

Livalo (NME) (Pitavastatin; Kowa) Class HMG-CoA reductase inhibitor Indication Primary treatment of hypercholesterolemia, mixed dyslipidemia Multaqa (NME) (Dronedarone hydrochloride; sanofi-aventis) Class Antiarrhythmic drug Indication Reduce CV hospitalization risk in patients with paroxysmal/persistent atrial fibrillation or atrial flutter with a recent episode and associated CV risk factors who are in sinus rhythm or will be cardioverted

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Onglyza (NME) (Saxagliptin hydrochloride; Bristol-Myers Squibb/AstraZeneca) Class DPP-4 inhibitor Indication Treatment of type 2 diabetes in combination or monotherapy in treatment-naĂŻve patients RiaSTAPa,b (BLA) (CSL Behring) Class Human plasma-derived fibrinogen concentrate Indication Acute bleeding episodes in patients with congenital fibrinogen deficiency Sabril (NME) (Vigabatrin; Lundbeck) Class GABA-T inhibitor antiepileptic Indication Adjunctive treatment of refractory complex partial seizures in adults who responded inadequately to several alternative treatments; treatment of infantile spasmsa Samsca (NME) (Tolvaptan; Otsuka) Class Oral selective vasopressin receptor antagonist Indication Patients with clinically significant hypervolemic and euvolemic hyponatremia Saphris (NME) (Asenapine maleate; Schering-Plough) Class Atypical antipsychotic Indication Treatment of acute schizophrenia and manic/mixed episodes of bipolar I disorder in adults Savella (NME) (Milnacipran hydrochloride; Cypress Bioscience) Class Serotonin and norepinephrine reuptake inhibitor Indication Fibromyalgia Simponi (BLA) (Golimumab; Centocor Ortho Biotech) Class Tumor necrosis factor blocker

Indication Treatment of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis Stelara (BLA) (Ustekinumab; Centocor Ortho Biotech) Class Human IL-12 and IL-23 antagonist Indication Treatment of adults with moderate-to-severe plaque psoriasis who are candidates for phototherapy or systemic therapy Ulesfia (NME) (Benzyl alcohol lotion 5%; Sciele) Class Topical peliculocide Indication Treatment of head lice in patients aged â&#x2030;Ľ6 months Uloric (NME) (Febuxostat; Takeda) Class Xanthine oxidase inhibitor Indication Chronic management of hyperuricemia in patients with gout Vibativ (NME) (Telavancin hydrochloride; Theravance) Class Lipoglycopeptide antibacterial Indication Treatment of complicated skin and skin structure infections caused by susceptible gram-positive bacteria Votrient (NME) (Pazopanib; GlaxoSmithKline) Class Multitargeted angiogenesis kinase inhibitor Indication Treatment of advanced renal-cell carcinoma Wilatea (BLA) (von Willebrand factor/coagulation VIII complex; Octapharma USA) Class von Willebrand factor/coagulation VIII complex (human) Indication Spontaneous and trauma-induced bleeding episodes in patients with von Willebrand disease, as well as those with mild or moderate disease in whom use of desmopressin is known or suspected to be ineffective or contraindicated Continued on page S225

S222 I AMERICAN HEALTH & DRUG BENEFITS I May/June 2010 I Supplement

,000 knees

1 The # bed 1 i r presc plement sup visco

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worldwide ted a a e

For osteoarthritis (OA) knee pain relief

ONE gets it done.

The only nonsystemic therapy delivering up to 6 months of pain relief with just 1 simple injection2-4 Combining all 3 doses of SYNVISC速 in 1 injection simplifies the management of OA knee pain Statistically significant reduction from baseline in OA knee pain sustained over 26 weeks2,5 Demonstrated safety profile in both initial and repeat treatments2 Important Treatment Considerations Synvisc-One速 (hylan G-F 20) is indicated for the treatment of pain in osteoarthritis (OA) of the knee in patients who have failed to respond adequately to conservative nonpharmacologic therapy and simple analgesics, eg, acetaminophen. Synvisc-One is contraindicated in patients with known hypersensitivity to hyaluronan products or patients with infections in or around the target knee. Use caution when injecting Synvisc-One in patients allergic to avian proteins, feathers, or egg products; who have evidence of venous or lymphatic stasis in the leg to be treated; or who have severe inflammation in the knee to be treated. The most commonly reported related local adverse events were transient, mild to moderate arthralgia, arthritis, arthropathy, injection site pain and joint effusion. No serious adverse events in knees injected with Synvisc-One were reported in clinical trials. Serious local adverse events have been reported only rarely in post-marketing use. Repeat treatment did not affect the safety profile. In the pivotal clinical trial, there was one related systemic event of syncope. The most common systemic side effects irrespective of relationship to Synvisc-One were headache, back pain, nasopharyngitis and influenza. Systemic adverse event profiles were similar between patients in the Synvisc-One and saline control groups. Other side effects, such as rash, have been reported rarely in association with SYNVISC. Patients should be advised to avoid strenuous or prolonged weight-bearing activities for approximately 48 hours after treatment. Aspiration of any effusion prior to injection is highly recommended. Strict adherence to aseptic technique must be followed to avoid joint infection. The safety and effectiveness of Synvisc-One have not been established in children or in pregnant or lactating women. It is unknown whether Synvisc-One is excreted in human milk. Please see brief summary of full Prescribing Information on the adjacent page. References: 1. Data on file. Genzyme Corp. 2. Synvisc-One Prescribing Information. Cambridge, MA: Genzyme Corp; 2009. 3. Brzusek D, Petron D. Treating knee osteoarthritis with intra-articular hyaluronans. Curr Med Res Opin. 2008;24(12):3307-3322. 4. Bellamy N, Campbell J, Robinson V, Gee T, Bourne R, Wells G. Intraarticular corticosteroid for treatment of osteoarthritis of the knee. Cochrane Database Syst Rev. 2006;(2):CD005328. doi:10.1002/14651858.CD005328.pub2. 5. Chevalier X, Jerosch J, Goupille P, et al. Single, intra-articular treatment with 6 ml of hylan G-F 20 in patients with symptomatic primary osteoarthritis of the knee: a randomised, multi-centre, double-blind, placebo controlled trial. Ann Rheum Dis. 2010;69(1):113-119.

Synvisc-One, SYNVISC, and GENZYME are registered trademarks of Genzyme Corporation.

Unique J-code J7325 simplifies reimbursement

BRIEF SUMMARY FOR THE PHYSICIAN (CONSULT PACKAGE INSERT FOR FULL PRODUCT INFORMATION) CAUTION: Federal law restricts this device to sale by or on the order of a physician (or properly licensed practitioner). INDICATIONS FOR USE • Synvisc-One is indicated for the treatment of pain in osteoarthritis (OA) of the knee in patients who have failed to respond adequately to conservative nonpharmacologic therapy and simple analgesics, eg, acetaminophen. CONTRAINDICATIONS • Do not administer to patients with known hypersensitivity (allergy) to hyaluronan (sodium hyaluronate) preparations. • Do not inject Synvisc-One in the knees of patients who have knee joint infections, skin diseases, or infections in the area of the injection site. WARNINGS • Do not concomitantly use disinfectants containing quaternary ammonium salts for skin preparation, because hyaluronan can precipitate in their presence. • Do not inject Synvisc-One extra-articularly or into the synovial tissues and capsule. • Intravascular injections of Synvisc-One may cause systemic adverse events. PRECAUTIONS General • The safety and effectiveness of Synvisc-One in locations other than the knee and for conditions other than osteoarthritis have not been established. • The safety and effectiveness of the use of Synvisc-One concomitantly with other intra-articular injectables have not been established. • Use caution when injecting Synvisc-One into patients who are allergic to avian proteins, feathers, or egg products. • The safety and effectiveness of Synvisc-One in severely inflamed knee joints have not been established. • Strict aseptic administration technique must be followed. • STERILE CONTENTS. The syringe is intended for single use. The contents of the syringe must be used immediately after its packaging is opened. Discard any unused Synvisc-One. • Do not use Synvisc-One if the package is opened or damaged. Store in the original packaging (protected from light) at room temperature below 86°F (30°C). DO NOT FREEZE. • Remove any synovial fluid or effusion before injecting Synvisc-One. • Synvisc-One should be used with caution when there is evidence of lymphatic or venous stasis in the leg to be injected. Information for Patients • Provide patients with a copy of the Patient Labeling prior to use. • Mild to moderate pain, swelling, and/or effusion of the injected knee have been reported in clinical trials that were related to the intra-articular injection of Synvisc-One. These events were typically transient and usually resolved on their own or with conservative treatment. • As with any invasive joint procedure, it is recommended that the patient avoid strenuous activities (for example, high-impact sports such as soccer, tennis, or jogging) or prolonged weight-bearing activities for approximately 48 hours following the intra-articular injection. The patient should consult his or her physician regarding the appropriate time to resume such activities. Use in Specific Populations • Pregnancy: The safety and effectiveness of Synvisc-One have not been established in pregnant women. • Nursing mothers: It is not known if Synvisc-One is excreted in human milk. The safety and effectiveness of Synvisc-One have not been established in lactating women. • Pediatrics: The safety and effectiveness of Synvisc-One have not been established in pediatric patients (i.e., ≤21 years of age). ADVERSE EVENTS Adverse Events Involving the Injected Joint Clinical Trial: A total of 123 patients were treated with Synvisc-One in the pivotal study. The frequency and type of adverse events (AEs) were similar between the group of patients that received Synvisc-One and the group that received saline control (n=130). In the Synvisc-One group, 5.7% of patients experienced transient, mild to moderate, device-related local adverse events, including arthralgia, arthritis, arthropathy, injection-site pain, and joint effusion. No serious AEs were reported in knees injected with Synvisc-One. The repeat treatment phase confirmed the safety profile of the initial phase. One hundred and sixty patients were treated during this phase of the study; 77 of these patients received a second injection of Synvisc-One. Of these 77 patients, 4 (5.2%) experienced five device-related AEs in the injected knee. All such events were mild to moderate and were treated symptomatically. These events were arthralgia (n=2), arthritis (n=1), injection-site hematoma (n=1), and injection-site pain (n=1). Patients who developed target knee AEs during the initial phase of the study, and who subsequently received repeat treatment, did not experience target knee AEs upon repeat exposure to Synvisc-One.

Overall Injected Knee Safety Summary: The safety profile of Synvisc-One is similar to the clinical and postmarketing experience seen with Synvisc® (3-injection regimen), where pain, swelling, and effusion were the most frequently occurring AEs in the injected knee. There have been postmarketing reports for Synvisc indicating that in some cases the joint effusion may be large and can cause pronounced pain; it is important to remove and to analyze the fluid to rule out infection or crystalline arthropathies. These types of severe AEs were not observed in either the initial or repeat treatment phase of the Synvisc-One trial; however, they have been reported rarely in post-marketing use. Joint infections did not occur in any of the clinical trials of Synvisc or Synvisc-One and have been reported only rarely during the clinical use of Synvisc. OTHER ADVERSE EVENTS Clinical Trial: Systemic adverse event profiles were similar between patients in the Synvisc-One and saline control groups. Overall, 47 (38.2%) patients treated with Synvisc-One experienced at least one AE outside the target knee, regardless of device relatedness. The most commonly occurring (5% or greater in either group) AEs outside the target knee were headache, back pain, nasopharyngitis, and influenza. In the Synvisc-One group there was one AE of syncope considered device related. Postmarket Experience: Postmarketing experience with Synvisc (3-injection regimen) has identified the following systemic events that occur rarely with administration: rash, hives, itching, fever, nausea, headache, dizziness, chills, muscle cramps, paresthesia, peripheral edema, malaise, respiratory difficulties, flushing, and facial swelling. There have been rare reports of thrombocytopenia coincident with Synvisc (3-injection regimen) injection. No new systemic AEs associated with Synvisc-One were identified during the pivotal study as compared to Synvisc. DETAILED DEVICE DESCRIPTION Each syringe of Synvisc-One contains Hylan polymers (hylan A + hylan B) .............................................48 mg Sodium chloride .........................................................................51 mg Disodium hydrogen phosphate ....................................................0.96 mg Sodium dihydrogen phosphate monohydrate ...............................0.24 mg Water for injection ......................................................................q.s. to 6.0 mL HOW SUPPLIED Synvisc-One is supplied in a 10-mL glass syringe combining the three 2-mL injections of Synvisc (48 mg). The contents of the syringe are sterile and nonpyrogenic. DIRECTIONS FOR USE Precaution: Do not use Synvisc-One if the package has been opened or damaged. Store in the original packaging (protected from light) at room temperature below 86°F (30°C). DO NOT FREEZE. Precaution: The syringe containing Synvisc-One is intended for single use. The contents of the syringe must be used immediately after the syringe has been removed from its packaging. Precaution: Do not concomitantly use disinfectants containing quaternary ammonium salts for skin preparation, because hyaluronan can precipitate in their presence. Synvisc-One is administered as a single intra-articular injection. Strict aseptic administration technique must be followed. • Using an 18- to 20-gauge needle, remove synovial fluid or effusion before injecting Synvisc-One. • Do not use the same syringe for removing synovial fluid and for injecting Synvisc-One; however, the same 18- to 20-gauge needle should be used. • Twist the tip cap before pulling it off, as this will minimize product leakage. • To ensure a tight seal and prevent leakage during administration, secure the needle tightly while firmly holding the luer hub. Precaution: Do not over tighten or apply excessive leverage when attaching the needle or removing the needle guard, as this may break the syringe tip. • Inject the full 6 mL in one knee only.

SONE-00042.B

A division of Genzyme Corporation 55 Cambridge Parkway Cambridge, MA 02142 1-888-3-SYNVISC www.SynviscOne.com/hcp

12/2009

2009 FDA Approvals of Brand-Name Drugs

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II. New Combinations, Formulations, Indications Actoplus Met XR (Metformin hydrochloride/pioglitazone hydrochloride; Takeda Global) Class Antihyperglycemic combination therapy Indication Management of type 2 diabetes Adcirca (Tadalafil; Eli Lilly) Class PDE-5 inhibitor Indication Treatment of pulmonary arterial hypertension (WHO group I) to improve exercise ability Astepro (Azelastine hydrochloride; Meda Pharmaceuticals) Class H1 receptor antagonist Indication For the relief of the symptoms of seasonal and perennial allergic rhinitis in patients aged â&#x2030;Ľ12 years Avastin (Bevacizumab; Genentech) Class Recombinant humanized monoclonal IgG1 antibody Indication Treatment of metastatic colorectal cancer, nonâ&#x20AC;&#x201C;smallcell lung cancer, HER2-negative breast cancer, glioblastoma, renal-cell carcinoma Byetta (Exenatide synthetic; Amylin) Class Glucagonlike peptide-1 receptor agonist Indication Adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes Cambia (Diclofenac potassium; Kowa Pharmaceuticals) Class NSAID Indication Treatment of acute migraine with or without aura in adults Cetraxal (Ciprofloxacin hydrochloride; Wraser Pharmaceuticals) Class Quinolone antimicrobial

Indication Treatment of acute otitis externa due to susceptible isolates of Pseudomonas aeruginosa or Staphylococcus aureus Cycloset (Bromocriptine mesylate; Veroscience) Class Central-acting dopamine receptor agonist Indication Improvement of glycemic control in adults with type 2 diabetes Edluar (Zolpidem tartrate; Meda Pharmaceuticals) Class Sublingual nonbenzodiazepine hypnotic imidazopyridine Indication Short-term treatment of insomnia characterized by difficulties with sleep initiation Embedaa (Morphine sulfate/naltrexone hydrochloride; King Pharmaceuticals) Class Opioid receptor agonist/antagonist combination therapy Indication Management of moderate-to-severe pain when a continuous, around-the-clock opioid analgesic is needed for an extended period of time Exforge HCT (Amlodipine/hydrochlorothiazide/valsartan; Novartis) Class Calcium channel blocker, angiotensin receptor blocker, and diuretic combination therapy Indication Treatment of high blood pressure Gelnique (Oxybutynin chloride; Watson Laboratories) Class Urinary antispasmodic and antimuscarinic agent Indication Treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency Intuniv (Guanfacine hydrochloride; Shire) Class Selective alpha2A-adrenergic receptor agonist Indication Treatment of attention-deficit/hyperactivity disorder

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Invega Sustenna (Paliperidone palmitate; Johnson & Johnson) Class Long-acting injectable atypical antipsychotic Indication Once-monthly acute/maintenance treatment of schizophrenia; acute treatment of schizoaffective disorder Jenloga (Clonidine hydrochloride; Sciele Pharma) Class Central-acting alpha-2 adrenergic agonist Indication Treatment of hypertension Lamictal ODT (Lamotrigine; GlaxoSmithKline) Class Phenyltriazine Indication Adjunctive therapy for seizures in patients aged ≥2 years and monotherapy in patients aged ≥16 years; maintenance therapy of bipolar I disorder in adults Lamictal XR (Lamotrigine; GlaxoSmithKline) Class Phenyltriazine Indication Adjunctive therapy for primary generalized tonic-clonic seizures and partial-onset seizures with or without secondary generalization in patients aged ≥13 years Lystedaa (Tranexamic acid; Allergan, Xanodyne Pharmaceuticals) Class Coagulation modifier Indication Treatment of menorrhagia Metozolv ODT (Metoclopramide hydrochloride; Salix Pharmaceuticals) Class Dopamine receptor agonist Indication Relief of symptomatic GERD and diabetic gastroparesis in adults Micardis (Telmisartan; Boehringer Ingelheim) Class Angiotensin II receptor blocker Indication

Hypertension; cardiovascular risk reduction in patients unable to take ACE inhibitors Nexcede (Ketoprofen; Novartis) Class Analgesic Indication Temporary relief of minor aches and pains because of headache, toothache, backache, menstrual cramps, the common cold, muscular aches, arthritis; temporary relief of fever Onsolis (Fentanyl citrate; Meda Pharmaceuticals) Class Opioid analgesic Indication Management of breakthrough pain in patients aged ≥18 years with cancer who are receiving and are tolerant to opioid therapy Ozurdexa (Dexamethasone; Allergan) Class Corticosteroid Indication Treatment of macular edema after branch retinal vein occlusion or central retinal vein occlusion Pennsaid (Diclofenac sodium; Nuvo Research) Class NSAID Indication Treatment of signs and symptoms of osteoarthritis of the knee(s) Renvela (Sevelamer carbonate; Genzyme) Class Phosphate binder Indication Control of serum phosphorus in patients with chronic kidney disease on dialysis Revatio (Sildenafil citrate; Pfizer) Class PDE-5 inhibitor Indication Treatment of pulmonary arterial hypertension (WHO group I) to improve exercise ability and delay clinical worsening Continued on page S230

S226 I AMERICAN HEALTH & DRUG BENEFITS I May/June 2010 I Supplement

ULORIC powerfully lowers serum uric acid levels for long-term control of gout. In the largest phase 3 study (6 months): • 45% of patients who received ULORIC 40 mg achieved serum uric acid level <6 mg/dL (N=757) compared to 42% of patients who received allopurinol 300 mg (N=755; p=0.233)1 • 67% of patients who received ULORIC 80 mg achieved serum uric acid level <6 mg/dL (N=756) compared to 42% of patients who received allopurinol 300 mg (N=755; p<0.001)1

Indication ULORIC 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 Information • ULORIC is contraindicated in patients being treated with azathioprine, mercaptopurine, or theophylline. • An increase in gout flares is frequently observed during initiation of anti-hyperuricemic agents, including ULORIC. If a gout flare occurs during treatment, ULORIC need not be discontinued. Prophylactic therapy (i.e. - NSAIDs or colchicine) upon initiation of treatment may be beneficial 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

For more information, please visit www.ULORIC.com

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 ULORICtreated 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. Reference: 1. ULORIC® (febuxostat) full prescribing information, February 2009.

BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION for ULORIC® (febuxostat) tablets INDICATIONS AND USAGE ULORIC® 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. CONTRAINDICATIONS ULORIC is contraindicated in patients being treated with azathioprine, mercaptopurine, or theophylline [see Drug Interactions]. WARNINGS AND PRECAUTIONS Gout Flare After 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 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)] [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 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. 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 r 6 months. For ULORIC 80 mg, 1377 subjects were treated for r 6 months, 674 patients were treated for r 1 year and 515 patients were treated for r 2 years. Most Common Adverse Reactions In 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 r 1% of ULORIC-Treated Patients and at Least 0.5% Greater than Seen in Patients Receiving Placebo in Controlled Studies Placebo

Adverse Reactions Liver Function Abnormalities Nausea Arthralgia Rash

ULORIC

allopurinol*

(N=134)

40 mg daily (N=757)

80 mg daily (N=1279)

(N=1277)

0.7%

6.6%

4.6%

4.2%

0.7%

1.1%

1.3%

0.8%

1.1%

0.7%

0.5%

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 Reactions In 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, thrombocytopenia; 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, gastroesophageal 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, hypercholesterolemia, 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 Safety Cardiovascular 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 allopurinoltreated patients. A causal relationship with ULORIC has not been established. Monitor for signs and symptoms of MI and stroke. DRUG INTERACTIONS Xanthine Oxidase Substrate Drugs ULORIC 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 Drugs Drug 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 Studies Based 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 Pregnancy Pregnancy 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 Mothers Febuxostat 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 Use Safety and effectiveness in pediatric patients under 18 years of age have not been established. Geriatric Use No 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 (r 65 years) were similar to those in younger subjects (18-40 years). Renal Impairment No 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 Impairment No 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 Hyperuricemia No 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. OVERDOSAGE ULORIC 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 Pharmacodynamics Effect 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 Populations Renal 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 Fertility Carcinogenesis: 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 Toxicology A 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 Information Patients 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 by Takeda Pharmaceuticals America, Inc. Deerfield, IL 60015 U.S. Patent Nos. - 6,225,474; 7,361,676; 5,614,520. ULORICÂŽ 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 ÂŠ2009 Takeda Pharmaceuticals America, Inc. February 2009 For 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 2009 L-TXF-0209-3

Continued from page S226

Sumavel Dosepro (Sumatriptan succinate; Zogenix) Class 5-HT1B/1D receptor agonist Indication Acute treatment of migraine attacks (with or without aura) and cluster headache episodes Symbyax (Olanzapine/fluoxetine HCl; Eli Lilly) Class Selective serotonin reuptake inhibitor/atypical antipsychotic combination Indication Treatment of acute depressive episodes associated with bipolar I disorder; acute treatment of treatment-resistant depression Synvisc-One (Hylan GF-20; Genzyme Biosurgery) Class Elastoviscous high-molecular-weight fluid containing hylan polymers Indication Treatment of pain in osteoarthritis of the knee in patients who failed to respond to conservative nonpharmacologic therapy and simple analgesics Temodar (Temozolomide; Schering Plough) Class Imidazotetrazine derivative Indication Treatment of adults with newly diagnosed glioblastoma multiforme concomitant with radiotherapy, then for maintenance treatment/refractory anaplastic astrocytoma in patients experiencing disease progression on a regimen containing nitrosourea and procarbazine TobraDex ST (Dexamethasone/tobramycin; Alcon) Class Ophthalmic suspension fixed combination therapy Indication Treatment of steroid-responsive inflammatory ocular conditions for which a corticosteroid is indicated, and when significant risk exists of superficial bacterial ocular infection Twynsta (Amlodipine besylate/telmisartan; Boehringer Ingelheim) Class Angiotensin II receptor blocker and dihydropyridine calcium channel blocker combination therapy Indication

Treatment of hypertension alone or with other antihypertensive agents Tyvaso (Treprostinil; United Therapeutics) Class Prostacyclin vasodilator oral inhalation solution Indication Treatment of pulmonary arterial hypertension (WHO group I) in patients with NYHA class III symptoms, to increase walk distance; to be used only with Tyvaso Inhalation System Tyzeka (Telbivudine; Novartis) Class Hepatitis B virus nucleoside analogue reverse transcriptase inhibitor Indication Treatment of chronic hepatitis B in adults with evidence of viral replication and evidence of persistent elevations in serum aminotransferases or histologically active disease Valcytea (Valganciclovir hydrochloride; Roche Palo) Class Cytomegalovirus nucleoside analogue DNA polymerase inhibitor Indication Treatment of cytomegalovirus retinitis in patients with AIDS and to prevent cytomegalovirus disease in patients who have received a heart, kidney, or kidneypancreas transplant Valturna (Aliskiren hemifumarate/valsartan; Novartis) Class Direct renin inhibitor and angiotensin II receptor blocker combination therapy Indication Treatment of elevated blood pressure Vectical (Calcitriol; Galderma) Class Topical antipsoriatic Indication Treatment of mild-to-moderate plaque psoriasis in adults aged â&#x2030;Ľ18 years Welchol (Colesevelam hydrochloride; Daiichi Sankyo) Class Bile acid sequestrant

S230 I AMERICAN HEALTH & DRUG BENEFITS I May/June 2010 I Supplement

2009 FDA Approvals of Brand-Name Drugs

Indication Reduction of elevated LDL-C in adults with primary hyperlipidemia as monotherapy or in combination with an HMG-CoA reductase inhibitor and in boys and postmenarchal girls aged 10-17 years with heterozygous familial hypercholesterolemia; improvement of glycemic control in adults with type 2 diabetes

Zirganb (Ganciclovir; Sirion Therapeutics) Class Topical ophthalmic antiviral Indication Treatment of acute herpetic keratitis (dendritic ulcers) Zyprexa Relprevv (Olanzapine pamoate; Eli Lilly) Class Antipsychotic Indication Treatment of schizophrenia in adults

Zipsor (Diclofenac potassium; Xanodyne Pharmaceuticals) Class NSAID Indication Relief of mild-to-moderate acute pain

III. Newly Approved Old Drugs Marketed without FDA Approval (Drugs existed before the establishment of FDA) Colcrys (Colchicine; Mutual Pharmaceuticals) Class Alkaloid Indication Prophylaxis/treatment of gout flares in adults, and familial Mediterranean fever in adults and children aged â&#x2030;Ľ4 years Creon (Pancrelipase; Solvay) Class Pancreatic enzyme Indication Treatment of exocrine pancreatic insufficiency due to cystic fibrosis or other conditions a

Qutenza (Capsaicin; NeurogesX) Class Transient receptor potential vanilloid-1 channel agonist Indication Management of neuropathic pain associated with postherpetic neuralgia Zenpepa (Pancrelipase; Eurand) Class Pancreatic enzyme Indication Treatment of exocrine pancreatic insufficiency due to cystic fibrosis or other conditions

Priority review. Orphan drug. c Continues to be reviewed postmarketing. b

ACS, acute coronary syndrome; BLA, biologic license approval; CIN, cervical intraepithelial neoplasia; CV, cardiovascular; GERD, gastroesophageal reflux disease; HMG-CoA, 3-hydroxy-3-methylglutaryl coenzyme A; IL, interleukin; LDL-C, low-density lipoprotein cholesterol; MS, multiple sclerosis; NME, new molecular entity; NSAID, nonsteroidal anti-inflammatory drug; PCI, percutaneous intervention; PDE, phosphodiesterase; STEMI, STsegment elevation myocardial infarction.

Supplement

May/June 2010

www.AHDBonline.com

I S231

SIMPONITM is indicated for the treatment of 1: Rheumatoid Arthritis • Moderately to severely active RA in adults, in combination with methotrexate

Psoriatic Arthritis • Active PsA in adults, alone or in combination with methotrexate

A once-monthly subcutaneous anti–TNF-α agent

Ankylosing Spondylitis • Active AS in adults

Recommended dosing1 SIMPONI™ is administered by 50 mg subcutaneous injection once a month • SIMPONI™ is intended for use under the guidance and supervision of a physician. Patients may self-inject with SIMPONI™ after physician approval and training • There is no loading dose with SIMPONI™

Serious and sometimes fatal side effects have been reported with SIMPONI™, including infections due to tuberculosis, invasive fungal infections (eg, histoplasmosis), bacterial, viral, or other opportunistic pathogens. Prior to initiating SIMPONI™ and periodically during therapy, patients should be evaluated for active tuberculosis and tested for latent infection. Lymphoma and other malignancies, some fatal, can occur in adults and children. Other serious risks include hepatitis B reactivation, heart failure and demyelinating disorders. Please see related and other Important Safety Information on next page.

Two delivery options1 • 50 mg/0.5 mL single dose prefilled syringe • 50 mg/0.5 mL single dose SmartJect™ autoinjector

www.simponi.com

Reference: 1. SIMPONI TM (golimumab) Prescribing Information. Centocor Ortho Biotech Inc.

IMPORTANT SAFETY INFORMATION FOR SIMPONI™ (golimumab) SERIOUS INFECTIONS Patients treated with SIMPONI™ are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. Discontinue SIMPONI™ if a patient develops a serious infection.

HEPATITIS B REACTIVATION The use of TNF-blocking agents including SIMPONI™ has been associated with reactivation of hepatitis B virus (HBV) in patients who are chronic hepatitis B carriers. In some instances, HBV reactivation occurring in conjunction with TNF-blocker therapy has been fatal. The majority of these reports have occurred in patients who received concomitant immunosuppressants.

Reported infections include:

Patients at risk for HBV infection should be evaluated for prior evidence of HBV infection before initiating SIMPONI™. Exercise caution when prescribing SIMPONI™ for patients identified as carriers of HBV and closely monitor for active HBV infection during and following termination of therapy with SIMPONI™. Discontinue SIMPONI™ in patients who develop HBV reactivation, and initiate antiviral therapy with appropriate supportive treatment. Exercise caution when considering resumption of SIMPONI™, and monitor patients closely.

• Active tuberculosis (TB), including reactivation of latent TB. Patients frequently presented with disseminated or extrapulmonary disease. Patients should be tested for latent TB before SIMPONI™ use and during therapy. Treatment for latent infection should be initiated prior to SIMPONI™ use. • Invasive fungal infections, including histoplasmosis, coccidioidomycosis, and pneumocystosis. Patients with histoplasmosis or other invasive fungal infections may present with disseminated, rather than localized, disease. Consider empiric anti-fungal therapy in patients at risk for invasive fungal infections who develop severe systemic illness. • Bacterial, viral, and other infections due to opportunistic pathogens. The risks and benefits of treatment with SIMPONI™ should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection. Do not start SIMPONI™ in patients with clinically important active infections, including localized infections. Closely monitor patients for the development of signs and symptoms of infection during and after treatment with SIMPONI™, including the possible development of TB in patients who tested negative for latent TB infection prior to initiating therapy. Other serious infections observed in patients treated with SIMPONI™ included sepsis, pneumonia, cellulitis, abscess and hepatitis B infection. MALIGNANCIES Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers of which SIMPONI™ is a member. Approximately half the cases were lymphomas, including Hodgkin’s and non-Hodgkin’s lymphoma. The other cases represented a variety of malignancies, including rare malignancies usually associated with immunosuppression and malignancies not usually observed in children or adolescents. Malignancies occurred after a median of 30 months after the first dose of therapy. Most of the patients were receiving concomitant immunosuppressants. In the controlled portions of clinical trials of all TNF-blocking agents including SIMPONI™, more cases of lymphoma have been observed among patients receiving TNF-blocking treatment compared with control patients. In clinical trials, the incidence of lymphoma per 100 patient-years of follow-up was 0.21 (95% CI: 0.03, 0.77) in the combined SIMPONI™ group compared with an incidence of 0 (95% CI: 0, 0.96) in the placebo group. In clinical trials, the incidence of malignancies other than lymphoma was not increased with exposure to SIMPONI™ and was similar to what would be expected in the general population. Cases of acute and chronic leukemia have been reported with postmarketing TNF-blocker use. The risks and benefits of TNF-blocker therapy should be considered prior to initiating therapy in patients with a known malignancy or who develop a malignancy.

HEART FAILURE Cases of worsening congestive heart failure (CHF) and new-onset CHF have been reported with TNF blockers. Exercise caution and monitor patients with heart failure. Discontinue SIMPONI™ if new or worsening symptoms of heart failure appear. DEMYELINATING DISORDERS TNF-blocking agents have been associated with cases of new-onset or exacerbation of central nervous system demyelinating disorders, including multiple sclerosis. Exercise caution in considering the use of SIMPONI™ in patients with central nervous system demyelinating disorders. HEMATOLOGIC CYTOPENIAS There have been postmarketing reports of pancytopenia, leukopenia, neutropenia, aplastic anemia, and thrombocytopenia in patients receiving TNF blockers. Exercise caution when using SIMPONI™ in patients with significant cytopenias. USE WITH OTHER DRUGS The concomitant use of a TNF blocker and abatacept or anakinra was associated with a higher risk of serious infections, therefore the use of SIMPONI™ in combination with these products is not recommended. A higher rate of serious infections has also been observed in RA patients treated with rituximab who received subsequent treatment with a TNF blocker. People receiving SIMPONI™ can receive vaccinations, except for live vaccines. ADVERSE REACTIONS The most serious adverse reactions were serious infections and malignancies. Upper respiratory tract infection and nasopharyngitis were the most common adverse reactions reported in the combined Phase 3 trials through Week 16, occurring in 7% and 6% of patients treated with SIMPONI™ as compared with 6% and 5% of patients in the control group, respectively. The rate of injection-site reactions was 6% with patients treated with SIMPONI™ compared with 2% of patients in the control group. Cases of new-onset psoriasis, including pustular and palmoplantar, or exacerbation of pre-existing psoriasis have been reported with the use of TNF blockers, including SIMPONI™. Some of these patients required hospitalization. Most patients had improvement following discontinuation of the TNF blocker. Discontinuation of SIMPONI™ should be considered for severe cases and those that do not improve or that worsen despite topical treatments.

Please see brief summary of Full Prescribing Information on the following pages.

Representing the products of

25GL10019

1/10

SIMPONI™ (golimumab) Injection, solution for subcutaneous use See package insert for Full Prescribing Information. WARNING SERIOUS INFECTIONS Patients treated with SIMPONI™ are at increased risk for developing serious infections that may lead to hospitalization or death (see Warnings and Precautions). Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. SIMPONI™ should be discontinued if a patient develops a serious infection. Reported infections include: • Active tuberculosis, including reactivation of latent tuberculosis. Patients with tuberculosis have frequently presented with disseminated or extrapulmonary disease. Patients should be tested for latent tuberculosis before SIMPONI™ use and during therapy. Treatment for latent infection should be initiated prior to SIMPONI™ use. • Invasive fungal infections, including histoplasmosis, coccidioidomycosis, and pneumocystosis. Patients with histoplasmosis or other invasive fungal infections may present with disseminated, rather than localized, disease. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. Empiric anti-fungal therapy should be considered in patients at risk for invasive fungal infections who develop severe systemic illness. • Bacterial, viral, and other infections due to opportunistic pathogens. The risks and benefits of treatment with SIMPONI™ should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection. Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with SIMPONI™, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy (See Warning and Precautions). MALIGNANCY Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers, of which SIMPONI is a member. INDICATIONS AND USAGE: Rheumatoid Arthritis SIMPONI™, in combination with methotrexate, is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis. Psoriatic Arthritis SIMPONI™, alone or in combination with methotrexate, is indicated for the treatment of adult patients with active psoriatic arthritis. Ankylosing Spondylitis SIMPONI™ is indicated for the treatment of adult patients with active ankylosing spondylitis. CONTRAINDICATIONS: None. WARNINGS AND PRECAUTIONS (see Boxed WARNINGS): Serious Infections Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, protozoal, or other opportunistic pathogens have been reported in patients receiving TNF-blockers including SIMPONI™. Among opportunistic infections, tuberculosis, histoplasmosis, aspergillosis, candidiasis, coccidioidomycosis, listeriosis, and pneumocystosis were the most commonly reported with TNF-blockers. Patients have frequently presented with disseminated rather than localized disease, and were often taking concomitant immunosuppressants such as methotrexate or corticosteroids. The concomitant use of a TNF-blocker and abatacept or anakinra was associated with a higher risk of serious infections; therefore, the concomitant use of SIMPONI™ and these biologic products is not recommended (see Warning and Precautions and Drug Interactions). Treatment with SIMPONI™ should not be initiated in patients with an active infection, including clinically important localized infections. The risks and benefits of treatment should be considered prior to initiating SIMPONI™ in patients: with chronic or recurrent infection; who have been exposed to tuberculosis; with a history of an opportunistic infection; who have resided or traveled in areas of endemic tuberculosis or endemic mycoses, such as histoplasmosis, coccidioidomycosis, or blastomycosis; or with underlying conditions that may predispose them to infection. Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with SIMPONI™. SIMPONI™ should be discontinued if a patient develops a serious infection, an opportunistic infection, or sepsis. A patient who develops a new infection during treatment with SIMPONI™ should undergo a prompt and complete diagnostic workup appropriate for an immunocompromised patient; appropriate antimicrobial therapy should be initiated, and the patient should be closely monitored. In controlled Phase 3 trials through Week 16 in RA, PsA, and AS, serious infections were observed in 1.4% of SIMPONI™-treated patients and 1.3% of control-treated patients. In the controlled Phase 3 trials through Week 16 in patients with RA, PsA, and AS, the incidence of serious infections per 100 patient-years of follow-up was 5.4 (95% CI: 4.0, 7.2) for the SIMPONI™ group and 5.3 (95% CI: 3.1, 8.7) for the placebo group. Serious infections observed in SIMPONI™-treated patients included sepsis, pneumonia, cellulitis, abscess, tuberculosis, invasive fungal infections, and hepatitis B infection. Tuberculosis Cases of reactivation of tuberculosis or new tuberculosis infections have been observed in patients receiving TNF-blockers, including patients who have previously received treatment for latent or active tuberculosis. Patients should be evaluated for tuberculosis risk factors and tested for latent infection prior to initiating SIMPONI™ and periodically during therapy. Treatment of latent tuberculosis infection prior to therapy with TNF-blockers has been shown to reduce the risk of tuberculosis reactivation during therapy. Induration of 5 mm or greater with tuberculin skin testing should be considered a positive test result when assessing if treatment for latent tuberculosis is needed prior to initiating SIMPONI™, even for patients previously vaccinated with Bacille Calmette-Guerin (BCG). Anti-tuberculosis therapy should also be considered prior to initiation of SIMPONI™ in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent tuberculosis but who have risk factors for tuberculosis infection. Consultation with a physician with expertise in the treatment of tuberculosis is recommended to aid in the decision whether initiating antituberculosis therapy is appropriate for an individual patient. Patients should be closely monitored for the development of signs and symptoms of tuberculosis including patients who tested negative for latent tuberculosis infection prior to initiating therapy. Tuberculosis should be strongly considered in patients who develop a new infection during SIMPONI™ treatment, especially in patients who have previously or recently traveled to countries with

a high prevalence of tuberculosis, or who have had close contact with a person with active tuberculosis. In the controlled and uncontrolled portions of the Phase 2 RA and Phase 3 RA, PsA, and AS trials, the incidence of active TB was 0.23 and 0 per 100 patient-years in 2347 SIMPONI™-treated patients and 674 placebo-treated patients, respectively. Cases of TB included pulmonary and extra pulmonary TB. The overwhelming majority of the TB cases occured in countries with a high incidence rate of TB. Invasive Fungal Infections For SIMPONI™-treated patients who reside or travel in regions where mycoses are endemic, invasive fungal infection should be suspected if they develop a serious systemic illness. Appropriate empiric antifungal therapy should be considered while a diagnostic workup is being performed. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. When feasible, the decision to administer empiric antifungal therapy in these patients should be made in consultation with a physician with expertise in the diagnosis and treatment of invasive fungal infections and should take into account both the risk for severe fungal infection and the risks of antifungal therapy. Hepatitis B Virus Reactivation The use of TNF-blockers including SIMPONI™ has been associated with reactivation of hepatitis B virus (HBV) in patients who are chronic hepatitis B carriers (i.e., surface antigen positive). In some instances, HBV reactivation occurring in conjunction with TNF-blocker therapy has been fatal. The majority of these reports have occurred in patients who received concomitant immunosuppressants. Patients at risk for HBV infection should be evaluated for prior evidence of HBV infection before initiating TNF-blocker therapy. The risks and benefits of treatment should be considered prior to prescribing TNF-blockers, including SIMPONI™, to patients who are carriers of HBV. Adequate data are not available on whether anti-viral therapy can reduce the risk of HBV reactivation in HBV carriers who are treated with TNF-blockers. Patients who are carriers of HBV and require treatment with TNF-blockers should be closely monitored for clinical and laboratory signs of active HBV infection throughout therapy and for several months following termination of therapy. In patients who develop HBV reactivation, TNF-blockers should be stopped and antiviral therapy with appropriate supportive treatment should be initiated. The safety of resuming TNF-blockers after HBV reactivation has been controlled is not known. Therefore, prescribers should exercise caution when considering resumption of TNF-blockers in this situation and monitor patients closely. Malignancies Malignancies, some fatal, have been reported among children, adolescents, and young adults who received treatment with TNFblocking agents (initiation of therapy ≤ 18 years of age), of which SIMPONI is a member. Approximately half the cases were lymphomas, including Hodgkin’s and non-Hodgkin’s lymphoma. The other cases represented a variety of malignancies, including rare malignancies that are usually associated with immunosuppression, and malignancies that are not usually observed in children and adolescents. The malignancies occurred after a median of 30 months (range 1 to 84 months) after the first dose of TNF blocker therapy. Most of the patients were receiving concomitant immunosuppressants. These cases were reported post-marketing and are derived from a variety of sources, including registries and spontaneous postmarketing reports. The risks and benefits of TNF-blocker treatment including SIMPONI™ should be considered prior to initiating therapy in patients with a known malignancy other than a successfully treated non-melanoma skin cancer (NMSC) or when considering continuing a TNF-blocker in patients who develop a malignancy. In the controlled portions of clinical trials of TNF-blockers including SIMPONI™, more cases of lymphoma have been observed among patients receiving anti-TNF treatment compared with patients in the control groups. During the controlled portions of the Phase 2 trials in RA, and the Phase 3 trials in RA, PsA and AS, the incidence of lymphoma per 100 patientyears of follow-up was 0.21 (95% CI: 0.03, 0.77) in the combined SIMPONI™ group compared with an incidence of 0 (95% CI: 0., 0.96) in the placebo group. In the controlled and uncontrolled portions of these clinical trials in 2347 SIMPONI™-treated patients with a median follow-up of 1.4 years, the incidence of lymphoma was 3.8-fold higher than expected in the general U.S. population according to the SEER database (adjusted for age, gender, and race).1 Patients with RA and other chronic inflammatory diseases, particularly patients with highly active disease and/or chronic exposure to immunosuppressant therapies, may be at higher risk (up to several fold) than the general population for the development of lymphoma, even in the absence of TNF-blocking therapy. Cases of acute and chronic leukemia have been reported with postmarketing TNF-blocker use in rheumatoid arthritis and other indications. Even in the absence of TNF blocker therapy, patients with rheumatoid arthritis may be at a higher risk (approximately 2-fold) than the general population for the development of leukemia. During the controlled portions of the Phase 2 trial in RA, and the Phase 3 trials in RA, PsA and AS, the incidence of malignancies other than lymphoma per 100 patient-years of follow-up was not elevated in the combined SIMPONI™ group compared with the placebo group. In the controlled and uncontrolled portions of these trials, the incidence of malignancies, other than lymphoma, in SIMPONI™treated patients was similar to that expected in the general U.S. population according to the SEER database (adjusted for age, gender, and race).1 In controlled trials of other TNFblockers in patients at higher risk for malignancies (e.g., patients with COPD, patients with Wegener’s granulomatosis treated with concomitant cyclophosphamide) a greater portion of malignancies occurred in the TNF-blocker group compared to the controlled group. In an exploratory 1-year clinical trial evaluating the use of 50, 100 and 200 mg of SIMPONI™ in 309 patients with severe persistent asthma, 6 patients developed malignancies other than NMSC in the SIMPONI™ groups compared to none in the control group. Three of the 6 patients were in the 200-mg SIMPONI™ group. Congestive Heart Failure Cases of worsening congestive heart failure (CHF) and new onset CHF have been reported with TNFblockers. In several exploratory trials of other TNF-blockers in the treatment of CHF, there were greater proportions of TNF-blocker treated patients who had CHF exacerbations requiring hospitalization or increased mortality. SIMPONI™ has not been studied in patients with a history of CHF and SIMPONI™ should be used with caution in patients with CHF. If a decision is made to administer SIMPONI™ to patients with CHF, these patients should be closely monitored during therapy, and SIMPONI™ should be discontinued if new or worsening symptoms of CHF appear. Demyelinating Disorders Use of TNF-blockers has been associated with cases of new onset or exacerbation of central nervous system (CNS) demyelinating disorders, including multiple sclerosis (MS). While no trials have been performed evaluating SIMPONI™ in the treatment of patients with MS, another TNF-blocker was associated with increased disease activity in patients with MS. Therefore, prescribers should exercise caution in considering the use of TNF-blockers including SIMPONI™ in patients with CNS demyelinating disorders including MS. Use with Abatacept In controlled trials, the concurrent administration of another TNF-blocker and abatacept was associated with a greater proportion of serious infections than the use of a TNF-blocker alone; and the

combination therapy, compared to the use of a TNF-blocker alone, has not demonstrated improved clinical benefit in the treatment of RA. Therefore, the combination of TNF-blockers including SIMPONI™ and abatacept is not recommended (see Drug Interactions). Use with Anakinra Concurrent administration of anakinra (an interleukin-1 antagonist) and another TNF-blocker, was associated with a greater portion of serious infections and neutropenia and no additional benefits compared with the TNF-blocker alone. Therefore, the combination of anakinra with TNF-blockers, including SIMPONI™, is not recommended (see Drug Interactions). Hematologic Cytopenias There have been post-marketing reports of pancytopenia, leukopenia, neutropenia, aplastic anemia, and thrombocytopenia in patients receiving TNF-blockers. Although, there were no cases of severe cytopenias seen in the SIMPONI™ clinical trials, caution should be exercised when using TNF-blockers, including SIMPONI™, in patients who have significant cytopenias. Vaccinations Patients treated with SIMPONI™ may receive vaccinations, except for live vaccines. No data are available on the response to live vaccination or the risk of infection, or transmission of infection after the administration of live vaccines to patients receiving SIMPONI™. In the Phase 3 PsA study, after pneumococcal vaccination, a similar proportion of SIMPONI™-treated and placebotreated patients were able to mount an adequate immune response of at least a 2-fold increase in antibody titers to pneumococcal polysaccharide vaccine. In both SIMPONI™treated and placebo-treated patients, the proportions of patients with response to pneumococcal vaccine were lower among patients receiving MTX compared with patients not receiving MTX. The data suggest that SIMPONI™ does not suppress the humoral immune response to the pneumococcal vaccine. ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Clinical Studies Experience The safety data described below are based on 5 pooled, randomized, double-blind, controlled Phase 3 trials in patients with RA, PsA, and AS (Studies RA-1, RA-2, RA-3, PsA and AS). These 5 trials included 639 control-treated patients and 1659 SIMPONI™-treated patients including 1089 with RA, 292 with PsA, and 277 with AS. The proportion of patients who discontinued treatment due to adverse reactions in the controlled Phase 3 trials through Week 16 in RA, PsA and AS was 2% for SIMPONI™-treated patients and 3% for placebo-treated patients. The most common adverse reactions leading to discontinuation of SIMPONI™ in the controlled Phase 3 trials through Week 16 were sepsis (0.2%), alanine aminotransferase increased (0.2%), and aspartate aminotransferase increased (0.2%). The most serious adverse reactions were: Serious Infections; Malignancies. Upper respiratory tract infection and nasopharyngitis, were the most common adverse reactions reported in the combined Phase 3 RA, PsA and AS trials through Week 16, occurring in 7% and 6% of SIMPONI™-treated patients as compared with 6% and 5% of control-treated patients, respectively. Infections In controlled Phase 3 trials through Week 16 in RA, PsA, and AS, infections were observed in 28% of SIMPONI™-treated patients compared to 25% of control-treated patients. Liver Enzyme Elevations There have been reports of severe hepatic reactions including acute liver failure in patients receiving TNF-blockers. In controlled Phase 3 trials of SIMPONI™ in patients with RA, PsA, and AS through Week 16, ALT elevations ≥5 x ULN occurred in 0.2% of control-treated patients and 0.7% of SIMPONI™-treated patients, and ALT elevations ≥3 x ULN occurred in 2% of control-treated patients and 2% of SIMPONI™-treated patients. Since many of the patients in the Phase 3 trials were also taking medications that cause liver enzyme elevations (e.g., NSAIDs, MTX), the relationship between golimumab and liver elevation is not clear. Autoimmune Disorders and Autoantibodies The use of TNF-blockers has been associated with the formation of autoantibodies and, rarely, with the development of a lupus-like syndrome. In the controlled Phase 3 trials in patients with RA, PsA, and AS through Week 14, there was no association of SIMPONI™ treatment and the development of newly positive anti-dsDNA antibodies. Injection Site Reactions In controlled Phase 3 trials through Week 16 in RA, PsA and AS, 6% of SIMPONI™ treated patients had injection site reactions compared with 2% of controltreated patients. The majority of the injection site reactions were mild and the most frequent manifestation was injection site erythema. In controlled Phase 2 and 3 trials in RA, PsA, and AS, no patients treated with SIMPONI™ developed anaphylactic reactions. Psoriasis: NewOnset and Exacerbations Cases of new onset psoriasis, including pustular psoriasis and palmoplantar psoriasis, have been reported with the use of TNF-blockers, including SIMPONI. Cases of exacerbation of pre-existing psoriasis have also been reported with the use of TNF-blockers. Many of these patients were taking concomitant immunosuppressants (e.g., MTX, corticosteroids). Some of these patients required hospitalization. Most patients had improvement of their psoriasis following discontinuation of their TNF-blocker. Some patients have had recurrences of the psoriasis when they were re-challenged with a different TNF-blocker. Discontinuation of SIMPONI™ should be considered for severe cases and those that do not improve or that worsen despite topical treatments. Immunogenicity Antibodies to SIMPONI™ were detected in 57 (4%) of SIMPONI™-treated patients across the Phase 3 RA, PsA and AS trials through Week 24. Similar rates were observed in each of the 3 indications. Patients who received SIMPONI™ with concomitant MTX had a lower proportion of antibodies to SIMPONI™ than patients who received SIMPONI™ without MTX (approximately 2% versus 7%, respectively). Of the patients with a positive antibody response to SIMPONI™ in the Phase 2 and 3 trials, most were determined to have neutralizing antibodies to golimumab as measured by a cell-based functional assay. The small number of patients positive for antibodies to SIMPONI™ limits the ability to draw definitive conclusions regarding the relationship between antibodies to golimumab and clinical efficacy or safety measures. The data above reflect the percentage of patients whose test results were considered positive for antibodies to SIMPONI™ in an ELISA assay, and are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to SIMPONI™ with the incidence of antibodies to other products may be misleading. Other Adverse Reactions The adverse drug reactions that occurred at a rate of at least 1% in the combined SIMPONI™ groups during the controlled period of the 5 pooled Phase 3 trials through Week 16 in patients with RA, PsA, and AS are summarized below. Patients may have taken concomitant MTX, sulfasalazine, hydroxychloroquine, low-dose corticosteroids (≤10 mg of prednisone/day or equivalent), and/or NSAIDs during the trials. The numbers (percentages) of adverse drug reactions for Placebo ± DMARDS-treated patients (n=639) and SIMPONI™ ± DMARDS-treated patients (n=1659), respectively, were:

Upper respiratory tract infection Nasopharyngitis Alanine aminotransferase increased Injection site erythema Hypertension Aspartate aminotransferase increased Bronchitis Dizziness Sinusitis Influenza Pharyngitis Rhinitis Pyrexia Oral herpes Paraesthesia

Placebo ± DMARDS 37 (6%) 31 (5%) 18 (3%) 6 (1%) 9 (1%) 10 (2%) 9 (1%) 7 (1%) 7 (1%) 7 (1%) 8 (1%) 4 (< 1%) 4 (< 1%) 2 (< 1%) 2 (< 1%)

SIMPONI™ ± DMARDS 120 (7%) 91 (6%) 58 (4%) 56 (3%) 48 (3%) 44 (3%) 31 (2%) 32 (2%) 7 (2%) 25 (2%) 22 (1%) 20 (1%) 20 (1%) 16 (1%) 16 (1%)

DRUG INTERACTIONS: Methotrexate. For the treatment of RA, SIMPONI™ should be used with MTX. Since the presence or absence of concomitant MTX did not appear to influence the efficacy or safety of SIMPONI™ in the treatment of PsA or AS, SIMPONI™ can be used with or without MTX in the treatment of PsA and AS. Biologic Products for RA, PsA, and/or AS An increased risk of serious infections has been seen in clinical RA studies of other TNF-blockers used in combination with anakinra or abatacept, with no added benefit; therefore, use of SIMPONI™ with abatacept or anakinra is not recommended. A higher rate of serious infections has also been observed in RA patients treated with rituximab who received subsequent treatment with a TNF-blocker. There is insufficient information to provide recommendations regarding the concomitant use of SIMPONI™ and other biologic products approved to treat RA, PsA, or AS. Live Vaccines Live vaccines should not be given concurrently with SIMPONI™. Cytochrome P450 Substrates The formation of CYP450 enzymes may be suppressed by increased levels of cytokines (e.g., TNFα) during chronic inflammation. Therefore, it is expected that for a molecule that antagonizes cytokine activity, such as golimumab, the formation of CYP450 enzymes could be normalized. Upon initiation or discontinuation of SIMPONI™ in patients being treated with CYP450 substrates with a narrow therapeutic index, monitoring of the effect (e.g., warfarin) or drug concentration (e.g., cyclosporine or theophylline) is recommended and the individual dose of the drug product may be adjusted as needed. USE IN SPECIFIC POPULATIONS: Pregnancy Pregnancy Category B – There are no adequate and well-controlled studies of SIMPONI™ in pregnant women. Because animal reproduction and developmental studies are not always predictive of human response, it is not known whether SIMPONI™ can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. SIMPONI™ should be used during pregnancy only if clearly needed. An embryofetal developmental toxicology study was performed in which pregnant cynomolgus monkeys were treated subcutaneously with golimumab during the first trimester with doses up to 50 mg/kg twice weekly (360 times greater than the maximum recommended human dose-MHRD) and has revealed no evidence of harm to maternal animals or fetuses. Umbilical cord blood samples collected at the end of the second trimester showed that fetuses were exposed to golimumab during gestation. In this study, in utero exposure to golimumab produced no developmental defects to the fetus. A pre- and post-natal developmental study was performed in which pregnant cynomolgus monkeys were treated with golimumab during the second and third trimesters, and during lactation at doses up to 50 mg/kg twice weekly (860 times and 310 times greater than the maximal steady state human blood levels for maternal animals and neonates, respectively) and has revealed no evidence of harm to maternal animals or neonates. Golimumab was present in the neonatal serum from the time of birth and for up to 6 months postpartum. Exposure to golimumab during gestation and during the postnatal period caused no developmental defects in the infants. Nursing Mothers It is not known whether SIMPONI™ is excreted in human milk or absorbed systemically after ingestion. Because many drugs and immunoglobulins are excreted in human milk, and because of the potential for adverse reactions in nursing infants from SIMPONI™, 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. In the pre- and post-natal development study in cynomolgus monkeys in which golimumab was administered subcutaneously during pregnancy and lactation, golimumab was detected in the breast milk at concentrations that were approximately 400fold lower than the maternal serum concentrations. Pediatric Use Safety and effectiveness of SIMPONI™ in patients less than 18 years of age have not been established. Geriatric Use In the Phase 3 trials in RA, PsA, and AS, there were no overall differences in SAEs, serious infections, and AEs in SIMPONI™-treated patients ages 65 or older (N=155) compared with younger SIMPONI™-treated patients. Because there is a higher incidence of infections in the geriatric population in general, caution should be used in treating geriatric patients with SIMPONI™. OVERDOSAGE In a clinical study, 5 patients received protocol-directed single infusions of 10 mg/kg of intravenous SIMPONI™ without serious adverse reactions or other significant reactions. The highest weight patient was 100 kg, and therefore received a single intravenous infusion of 1000 mg of SIMPONI™. There were no SIMPONI™ overdoses in the clinical studies. PATIENT COUNSELING INFORMATION Patient Counseling Patients should be advised of the potential benefits and risks of SIMPONI™. Physicians should instruct their patients to read the Medication Guide before starting SIMPONI™ therapy and to read it each time the prescription is renewed. Infections Inform patients that SIMPONI™ may lower the ability of their immune system to fight infections. Instruct the patient of the importance of contacting their doctor if they develop any symptoms of infection, including tuberculosis, invasive fungal infections, and hepatitis B reactivation. Malignancies Patients should be counseled about the risk of lymphoma and other malignancies while receiving SIMPONI™. Allergic Reactions Advise latex-sensitive patients that the needle cover on the prefilled syringe as well as the prefilled syringe in the prefilled SmartJect™ autoinjector contains dry natural rubber (a derivative of latex). Other Medical Conditions Advise patients to report any signs of new or worsening medical conditions such as congestive heart failure, demyelinating disorders, autoimmune diseases, liver disease, cytopenias, or psoriasis. References: 1. SEER [database online]. U.S. Population Data—1969-2004. Bethesda, MD; National Cancer Institute. Release date: January 3, 2007. Available at: http://www.seer.cancer.gov/popdata.

License No. 1821 November 2009 25GL09427

EMBEDA : Morphine and Sequestered Naltrexone Extended Release Combination Formulation for the Management of Chronic, Moderate-to-Severe Pain

linical practice guidelines, including those of the American Pain Society, the American Academy of Pain Medicine, and the American Geriatrics Society, include the use of opioids as part of a multimodal strategy for the management of chronic, moderate-to-severe pain in appropriately selected and monitored patients.1,2 An increase in the use of prescription opioids, however, has been associated with an increase in the misuse, abuse, and diversion of opioids.3 In particular, oral extended-release opioid formulations, which provide the benefit of prolonged analgesia for patients who require around-the-clock pain relief, are sought by recreational drug users, who seek rapid euphoria by gaining access to the entire 8- to 24-hour dose contained within each single dosing unit.4 Therefore, the public health challenge is to balance the need to treat patients in pain with the need to reduce prescription drug abuse.5 To address the issue of unintentional deaths from drug overdose, the Centers for Disease Control and Prevention has recommended that pharmaceutical companies modify opioid formulations to make them more difficult to tamper with or to block the effect of the opioid if it is dissolved and injected.6 It is unlikely that any one formulation strategy will be able to address all the ways in which misuse and abuse might occur. The effectiveness of any formulation to reduce abuse liability, although initially assessed in clinical trials, will require evidence from postmarketing studies to assess the real-world implications.7 EMBEDA® (morphine sulfate and naltrexone hydrochloride) extended release capsules for oral use were approved by the US Food and Drug Administration in 2009 for the management of chronic, moderate-tosevere pain when a continuous around-the-clock opioid analgesic is needed for an extended period of time.8 EMBEDA capsules contain polymer-coated pellets of similar size (1.0- to 1.7-mm in diameter) of extendedrelease morphine sulfate, each with a core of sequestered naltrexone, an opioid antagonist, in a ratio of 25:1 morphine sulfate/naltrexone hydrochloride (Figure).8,9

Taken as prescribed, the morphine within EMBEDA provides effective analgesia for chronic, moderate-tosevere pain.10 If the EMBEDA capsule is tampered with by crushing, the naltrexone is released to mitigate morphine-induced subjective effects.9

Pharmacokinetics EMBEDA was designed based on the technology used in KADIAN® (morphine sulfate extended-release) capsules, which contain pellets with an inert core.11 These 2 formulations demonstrate the extended release of morphine.9,12 EMBEDA was shown to be bioequivalent to KADIAN after single-dose administration8; the formulations also had comparable bioavailability after steadystate dosing.10 When EMBEDA is taken as directed, the sequestered naltrexone is not consistently absorbed into the systemic circulation.8 After single-dose administration of EMBEDA, plasma levels of naltrexone were low or below the level of quantification (4 pg/mL) for most subjects; however, the presence of plasma 6-ß-naltrexol, a metabolite of naltrexone, in the majority of subjects indicated that most subjects were exposed to trace amounts of naltrexone.9 In a long-term safety trial during which EMBEDA was administered for up to 12 months to patients with chronic, moderate-to-severe noncancer pain, plasma concentrations of naltrexone and 6-ß-naltrexol were not clinically relevant, and there were no signs of opioid withdrawal or reduction in pain relief.13 When EMBEDA is tampered with by crushing,8,14 morphine and naltrexone are rapidly released and absorbed at a rate comparable to that of the oral solution. Clinical Trials The abuse liability of EMBEDA was evaluated in 2 trials in healthy, nondependent recreational opioid users; effectiveness in pain management was evaluated in 3 trials in patients with chronic, moderate-to-severe noncancer pain.

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Abuse-Liability Trials An oral abuse-liability trial evaluated the pharmacokinetics and pharmacodynamics after oral administration of intact and crushed pellets of EMBEDA or morphine sulfate solution to recreational, nondependent opioid users (N = 32).9 Crushing pellets of EMBEDA resulted in complete release of morphine comparable to the oral morphine solution.9 Naltrexone released from crushed EMBEDA pellets blunted morphine-induced subjective effects, including drug-liking (based on a 100-mm visual analog scale) and Cole/Addiction Research Center Inventory (ARCI) stimulationeuphoria9,15 vs morphine solution. Overall, 87.5% of subjects had some degree of reduced drug-liking, and 69% of subjects showed some degree of decrease in euphoria after receiving crushed EMBEDA compared with morphine solution.8 The subjective effects attributed to the morphine released from crushed EMBEDA pellets were not different from those after administration of the intact product, suggesting that crushing the pellets would not make the product more desirable for abuse.9 Naltrexone remained sequestered when EMBEDA was administered intact, with negligible amounts detected in only 5 of 32 subjects.9 The second abuse-liability trial was designed to clinically simulate crushing and solubilization of EMBEDA, followed by intravenous (IV) administration. IV morphine (30 mg) alone and morphine followed by naltrexone (1.2 mg) in the same ratio as found in EMBEDA capsules were administered to nondependent recreational opioid abusers (N = 28). Crushed and extracted pellets from EMBEDA capsules were not administered in this trial because of potential IV exposure to talc excipient. The intravenously administered naltrexone reduced the feeling of “high” (based on a 100-mm visual analog scale) and Cole/ARCI stimulation-euphoria versus IV morphine alone.8,16 Overall, 71% of subjects reported a reduction in euphoria when morphine plus naltrexone was administered compared with when morphine was administered alone.8 Pain Management Trials The efficacy and safety of EMBEDA were characterized in 3 clinical trials in patients with chronic, moderate-to-severe pain. In a multiple-dose, randomized, double-blind, crossover phase 2 trial, patients (N = 113) with pain caused by osteoarthritis of the hip or knee were titrated with KADIAN twice daily until pain relief (pain score ≤3; scale 0-10, where 0 = no pain, 10 = pain as bad as you can imagine).10 Patients were then randomized to 14 days of treatment with KADIAN or with EMBEDA. The 2 treatment periods were separated by 7

Figure Schematic of EMBEDA

Extended-release pH-dependent polymer-coated shell Morphine Sequestering membrane Naltrexone Reprinted with permission from Stauffer J, et al. Clin Drug Investig. 2009;29:777-790.

days of open-label treatment with KADIAN. Pain relief, assessed based on 0-to-10 numeric pain intensity scales, was maintained during treatment with EMBEDA and was equivalent to treatment with KADIAN.10 Plasma naltrexone was below the level of quantification for most patients taking EMBEDA (between 77.6% and 86.6%). Among patients with quantifiable naltrexone levels, there was no correlation with increased pain score.10 Most patients (n = 68) had at least 1 quantifiable 6-ßnaltrexol concentration (range, 0.3-21.0 pg/mL), indicating trace naltrexone exposure.10 In a pivotal 12-week, multiple-dose trial with an enriched enrollment randomized withdrawal design, patients (N = 547) with pain caused by osteoarthritis of the hip or knee8 were titrated to an effective dose of EMBEDA (Brief Pain Inventory Average 24-hour Pain Intensity ≤4 and at least a 2-point drop from screening baseline), then randomized to remain on the same dose of EMBEDA or to force-taper to placebo for the 12week treatment period using a double-dummy design. EMBEDA maintained statistically superior analgesia (mean change in weekly average pain scores from randomization baseline to week 12) over placebo.17 The safety profile was typical of that seen with opioids.8,17 In patients who took EMBEDA as directed, there was no evidence of withdrawal syndrome, as evaluated using the Clinical Opiate Withdrawal Scale (COWS) and Subjective Opiate Withdrawal Scale measures, or reported as an adverse event.17-19 In a long-term, open-label, safety trial in patients (N = 467) with chronic, moderate-to-severe pain, EMBEDA was generally safe and well tolerated. No patients who took EMBEDA as directed experienced opioid withdrawal syndrome as assessed using the COWS instrument.13 Patients also demonstrated significant improvements from baseline in pain scores, with pain relief maintained for up to the 1-year duration of the trial.13 In a pharmacokinetic analysis performed on

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a subset (n = 93) of patients from this trial, the median plasma concentrations of naltrexone and 6-ß-naltrexol over all study weeks were 10.1 pg/mL and 18.5 pg/mL, respectively, well below those considered pharmacologically active.20 There was no tendency for accumulation of naltrexone or 6-ß-naltrexol during the 12-month study period.20

Adverse Reactions Overall, the most common (≥10%) adverse events (AEs) reported in phase 2 and 3 clinical trials were constipation, nausea, and somnolence, which are typical of opioid use.8 In the comparative trials, AEs were similar to those reported with KADIAN, indicating that the presence of naltrexone did not affect safety.8,10 Dosing and Administration EMBEDA is available in dosage forms (morphine sulfate/naltrexone hydrochloride) of 20 mg/0.8 mg, 30 mg/1.2 mg, 50 mg/2 mg, 60 mg/2.4 mg, 80 mg/3.2 mg, and 100 mg/4 mg.8 EMBEDA can be taken once or twice daily, with or without food. People who have difficulty swallowing capsules can sprinkle capsule contents on apple sauce immediately prior to consumption.8 EMBEDA should not be crushed, chewed, or dissolved, and should not be consumed with alcohol or medications containing alcohol, because the resulting morphine dose may be fatal.8 As for all opioids, treatment with EMBEDA should be initiated at low doses and carefully titrated for each patient to determine the dose that provides a balance between effective analgesia and opioid side effects. Patients maintained on EMBEDA should be continuously monitored and reevaluated for the management of pain relief, incidence of side effects, and signs of aberrant drug-related behaviors.8 Use in Specific Populations EMBEDA should not be taken by persons with gastrointestinal obstruction, impaired pulmonary function, or in circulatory shock. EMBEDA should be used with caution in elderly or debilitated patients or in those with severe renal or hepatic insufficiency, Addison disease, myxedema, hypothyroidism, prostatic hypertrophy, urethral stricture, central nervous system depression, toxic psychosis, acute alcoholism, delirium tremens, or convulsive disorders. The safety of EMBEDA has not been evaluated in persons younger than age 18 years and has not been adequately studied in pregnant women or in breast-feeding mothers; EMBEDA should only be given to the mother if the potential benefit to the mother outweighs the risk to the fetus or breast-fed infant.8

Benefit Design Considerations An estimated 9% of adults in the United States suffer from chronic, moderate-to-severe noncancer pain.21 In patients with chronic, moderate-to-severe pain, EMBEDA yielded analgesic efficacy that was greater than placebo and equivalent to that of KADIAN, which has been approved in the United States since 1996.22 Results from trials in a controlled setting among nondependent recreational opioid abusers have demonstrated that EMBEDA, administered intact or tampered with by crushing, is less desirable than morphine solution. However, postmarketing epidemiologic studies will be required to assess the desirability of EMBEDA for misuse, abuse, and diversion in the real-world setting.7 A budget impact model was recently developed to assess the potential cost savings to third-party payers that would result from the introduction of a theoretical opioid formulation designed to deter or resist common methods of abuse (injecting, crushing, snorting, or chewing).23 It was estimated that cost savings (from reductions in abuse-related hospitalizations, outpatient visits, emergency department visits, injection-related diseases, and opioid abuse and substance abuse treatments) would range from $585 million to $1.6 billion, depending on market penetration and projected rates of abuse by the various routes.23 Prescribers need to assess patient risks to balance pain management and opioid misuse, abuse, and diversion. Along with office-based algorithms or thresholds, the use of medical and drug claims data may be of assistance to prescribers and payers in identifying patients at risk for prescription opioid abuse.24 Opioid formulations that offer pain control with the potential of reduced abuse liability may also contribute to that balance. Epidemiologic data, including those from prospectively designed postmarketing surveillance studies, are needed to fully assess the impact of a novel formulation such as EMBEDA. Writing and editorial services were provided by Quintiles, Parsippany, NJ, with funding from King Pharmaceuticals®, Inc., Bridgewater, NJ.

References 1. Chou R, Fanciullo GJ, Fine PG, et al. Opioid treatment guidelines. Clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain. J Pain. 2009;10:113-130. 2. American Geriatrics Society Panel on the Pharmacological Management of Persistent Pain in Older Persons. Pharmacological management of persistent pain in older persons. J Am Geriatr Soc. 2009;57:1331-1346. 3. Department of Health and Human Services, Substance Abuse and Mental Health Services Administration, Office of Applied Studies. Results from the 2008 national survey on drug use and health: national findings. September 2009. http://oas.samhsa.gov/nsduh/2k8nsduh/2k8Results.pdf. Accessed March 1, 2010. 4. Sloan P, Babul N. Extended-release opioids for the management of chronic nonmalignant pain. Expert Opin Drug Deliv. 2006;3:489-497.

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5. Kuehn BM. Opioid prescriptions soar: increase in legitimate use as well as abuse. JAMA. 2007;297:249-251. 6. Paulozzi LJ. Trends in unintentional drug overdose deaths. Testimony before Senate Judiciary Subcommittee on Crime and Drugs. US Department of Health and Human Services, March 12, 2008. www.hhs.gov/asl/testify/2008/03/t20080312b.html. Accessed March 1, 2010. 7. Katz N. Abuse-deterrent opioid formulations: are they a pipe dream? Curr Rheumatol Rep. 2008;10:11-18. 8. EMBEDA [packet insert]. Bristol, TN: King Pharmaceuticals, Inc.; June 2009. 9. Stauffer J, Setnik B, Sokolowska M, et al. Subjective effects and safety of whole and tampered morphine sulfate and naltrexone hydrochloride (ALO-01) extendedrelease capsules versus morphine solution and placebo in experienced non-dependent opioid users: a randomized, double-blind, placebo-controlled, crossover study. Clin Drug Investig. 2009;29:777-790. 10. Katz N, Sun S, Johnson F, Stauffer J. ALO-01 (morphine sulfate and naltrexone hydrochloride) extended release capsules in the treatment of chronic pain of osteoarthritis of the hip or knee: pharmacokinetics, efficacy, and safety. J Pain. 2009 Nov 26. [Epub ahead of print.] 11. KADIAN Capsules [packet insert]. Morristown, NJ: Actavis Elizabeth, LLC; February 2009. 12. Maccarrone C, West RJ, Broomhead AF, Hodsman GP. Single dose pharmacokinetics of KapanolTM, a new oral sustained-release morphine formulation. Drug Invest. 1994;7:262-274. 13. Webster L, Brewer R, Sekora D, et al. Long-term safety of ALO-01 (morphine sulfate extended-release with sequestered naltrexone hydrochloride) capsules in patients with chronic, moderate to severe, non-malignant pain [abstract]. Presented at the American Society of Regional Anesthesia & Pain Medicine Annual Fall Pain Meeting and Workshops, November 20-23, 2008; Huntington Beach, CA. Abstract 5. 14. Johnson F, Jones JB, Stauffer J. Relative bioavailability of plasma naltrexone from crushed ALO-01 (an investigational, abuse-deterrent, extended-release, morphine sulfate formulation with sequestered naltrexone) to a naltrexone oral solution [abstract]. Presented at the American Pain Society’s 27th Annual Scientific Meeting,

May 8-10, 2008; Tampa, FL. J Pain. 2008;9(4 suppl 2):35. Abstract 236. 15. Cole JO, Orzack MH, Beake B, et al. Assessment of the abuse liability of buspirone in recreational sedative users. J Clin Psychiatry. 1982;43(12 pt 2):69-75. 16. Webster L, Jones JB, Johnson F, et al. Relative drug-liking/euphoria effects of intravenous morphine alone and in combination with naltrexone in recreational opioid users [abstract]. Presented at the International Association for the Study of Pain 12th World Congress on Pain, August 17-22, 2008; Glasgow, Scotland. 17. Morris D, Stauffer J. Efficacy of morphine sulfate extended-release with sequestered naltrexone hydrochloride (ALO-01) (EMBEDA™) in patients with chronic, moderate to severe pain of osteoarthritis of the hip or knee. Presented at the American College of Rheumatology 2008 Annual Scientific Meeting, October 2429, 2008; San Francisco, CA. Abstract 865. 18. Handelsman L, Cochrane KJ, Aronson MJ, et al. Two new rating scales for opiate withdrawal. Am J Drug Alcohol Abuse. 1987;13:293-308. 19. Wesson DR, Ling W. The clinical opiate withdrawal scale (COWS). J Psychoactive Drugs. 2003;35:253-259. 20. Johnson F, Manning D, Wang C, Stauffer J. Evaluation of plasma naltrexone concentrations resulting from use of ALO-01 (morphine sulfate extended-release with sequestered naltrexone hydrochloride) capsules for chronic pain. Presented at the 71st Annual Meeting of the College on Problems of Drug Dependence, June 20-25, 2009; Reno, NV. Abstract 265. 21. American Pain Society. Chronic pain in America: roadblocks to relief. American Pain Society, 2008. www.ampainsoc.org/links/roadblocks/conclude_road.htm. Accessed March 1, 2010. 22. US Food and Drug Administration. Orange book: approved drug products with therapeutic equivalence evaluations, 2010. www.accessdata.fda.gov/scripts/cder/ob /docs/obdetail.cfm?Appl_No=020616&TABLE1=OB_Rx. Accessed March 1, 2010. 23. White AG, Birnbaum HG, Rothman DB, Katz N. Development of a budgetimpact model to quantify potential cost savings from prescription opioids designed to deter abuse or ease of extraction. Appl Health Econ Health Policy. 2009;7:61-70. 24. White AG, Birnbaum HG, Shiller M, et al. Analytic models to identify patients at risk for prescription opioid abuse. Am J Manag Care. 2009;15:897-906.

STAKEHOLDER PERSPECTIVE

Abuse-Deterrent Opioids Alan G. White, PhD Analysis Group, Inc., Boston, MA

n recent years, the abuse, dependence on, and misuse of prescription drugs has become a growing public health concern in the United States. The National Survey on Drug Use and Health reported that in 2007, an estimated 12.5 million Americans had used prescription pain relievers for nonmedical purposes, an increase from 11.0 million in 2002.1,2 In 2009, the Centers for Disease Control and Prevention (CDC) reported that the number of opioid-related poisoning deaths had more than tripled since 1999, greatly contributing to drugrelated deaths surpassing both firearm-related deaths and, in 16 states, motor vehicle-related deaths, to become the second-leading cause of injury-related deaths in the United States.3,4 Recent research shows that the economic burden and cost impact of opioid abuse, dependence, and misuse is substantial, affecting many parties, including employers, payers (public and private), and society as a whole.5-8

In an effort to curb the growth of opioid abuse, 34 states have initiated prescription drug monitoring programs, which are designed to help identify at-risk patients.9 Furthermore, the US Food and Drug Administration (FDA) has recently required manufacturers of certain opioids to develop a safety plan, or a REMS (Risk Evaluation and Mitigation Strategy), to help ensure that healthcare professionals prescribe the drug correctly and that patients use it safely.10 Reducing opioid abuse will require sustained and coordinated efforts from academic researchers, industry, healthcare providers, and government agencies to implement appropriate and effective strategies. One potentially promising initiative involves the development of opioid formulations designed to deter or resist common methods of abuse—injecting, crushing, snorting, or chewing—namely, abuse-deterrent opioids (ADOs), which is in line with the CDC’s effort to

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encourage drug manufacturers to modify opioid formulations to make them more difficult to tamper with.11 Although many opioids are approved for the management of moderate-to-severe pain, physicians are often reluctant to prescribe such opioids, because of the potential for abuse and associated medical liability that result in a “chilling effect.”12 Finding the appropriate balance between adequate access to legitimate pain relief and prevention of opioid abuse remains a delicate task. Third-party payers should give careful consideration to the potential for improved patient management, as well as to abuse deterrence that could result from the development of ADOs. The drug industry has begun to focus on ADO formulations,13 although currently there are no opioids with specific FDA indications for abuse deterrence. Research suggests that substantial cost savings might be realized by such formulations.14 ADOs that may deter or resist common methods of abuse may give rise to reduced opioid-related hospitalizations (inpatient and outpatient), emergency department visits, and stays at substance abuse treatment centers—all with cost-saving implications.14 Indeed, third-party payers should consider such costs when making formulary status decisions. Furthermore, managed care plans may be able to identify patients at risk for opioid abuse by using medical and drug claims data similar to recent research in this area.15 This strategy would be helpful in identifying patients at risk and would aid in the development of national initiatives and research studies toward the prevention of opioid abuse. Employers who pay for healthcare plans may also save, because the reduced incidence of abuse potentially attributable to ADOs may reduce work-loss absences and costly short- and long-term disability, as well as diminished on-the-job productivity. Research on the impact of drugs with formulations designed to deter or resist common methods of abuse is in its infancy. The growing and costly phenomenon of opioid abuse, dependence, and misuse, and the many

stakeholders who must absorb the cost of this public health concern, calls for additional attention to pharmaceutical companies’ important drug development initiatives and their potential economic and public health impact. Disclosure Statement Dr White has served as a paid consultant to pharmaceutical manufacturers, including King Pharmaceuticals®, Inc.

References 1. Substance Abuse and Mental Health Services Administration. Results from the 2007 national survey on drug use and health: national findings. September 2008. http://oas.samhsa.gov/nsduh/2k7nsduh/2k7Results.pdf. Accessed March 2, 2010. 2. Substance Abuse and Mental Health Services Administration. Results from the 2002 National Survey on Drug Use and Health: national findings. Rockville, MD: Office of Applied Studies; 2003. NHSDA Series H-22, DHHS Publication No. SMA 03–3836. 3. Warner M, Chen LH, Makuc DM. Increase in fatal poisonings involving opioid analgesics in the United States, 1999-2006. National Center for Health Statistics Data Brief, No. 22, September 2009: Hyattsville, MD. www.cdc.gov/nchs/data/databriefs/db22.pdf. Accessed March 2, 2010. 4. WSJ.com. Drug deaths outpace auto fatalities in more states. Wall Street J, September 30, 2009. www.online.wsj.com. 5. Birnbaum HG, White AG, Reynolds JL, et al. Estimated costs of prescription opioid analgesic abuse in the United States in 2001: a societal perspective. Clin J Pain. 2006;22:667-676. 6. White AG, Birnbaum HG, Mareva MN, et al. Direct costs of opioid abuse in an insured population in the United States. J Manag Care Pharm. 2005;11:469-479. 7. Strassels SA. Economic burden of prescription opioid misuse and abuse. J Manag Care Pharm. 2009;15:556-562. 8. Oderda G, McAdam MC, Cleveland J, Roland C. Direct costs of opioid abuse in Medicaid patients [abstract]. J Manag Care Pharm. 2009;15:189. 9. US Department of Justice, Drug Enforcement Administration, Office of Diversion Control. Questions and answers: state prescription drug monitoring programs. Updated January 2010. www.deadiversion.usdoj.gov/faq/rx_monitor.htm. Accessed March 2, 2010. 10. Food and Drug Administration. FDA identifies first steps in requirements for safety plans for certain drugs and biologics. March 27, 2008. www.fda.gov/ NewsEvents/Newsroom/PressAnnouncements/2008/ucm116872.htm. Accessed March 2, 2010. 11. Paulozzi LJ. Trends in unintentional drug overdose deaths. Testimony before Senate Judiciary Subcommittee on Crime and Drugs. US Department of Health & Human Services, March 12, 2008. www.hhs.gov/asl/testify/2008/03/t20080 312b.html. Accessed March 2, 2010. 12. Wastila LJ, Bishop C. The influence of multiple copy prescription programs on analgesic utilization. J Pharm Care Pain Symptom Control. 1996;4:3-19. 13. US Department of Health and Human Services. NDA approval. NDA 22-321. Silver Spring, MD: Food and Drug Administration; August 2009. 14. White AG, Birnbaum HG, Rothman DB, Katz N. Development of a budgetimpact model to quantify potential cost savings from prescription opioids designed to deter abuse or ease of extraction. Appl Health Econ Health Policy. 2009;7:61-70. 15. White AG, Birnbaum HG, Shiller M, et al. Analytic models to identify patients at risk for prescription opioid abuse. Am J Manag Care. 2009;15:897-906.

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Synvisc-One (hylan G-F 20): One Gets It Done for Osteoarthritis Knee Pain Relief ®

steoarthritis (OA) is the most common joint disease. It is one of the most prevalent conditions in Western populations, affecting nearly 27 million Americans.1 OA is considered to be a rising epidemic in the United States and is expected to affect approximately 67 million Americans by 2030.2 Over 61% of adults with OA (regardless of area affected) receive some form of treatment, and the economic impact is substantial.3 In the US, OA-related costs are estimated to exceed more than $60 billion per year.4 There are few studies that have focused on costs specific to OA of the knee. However, the high prevalence of knee OA and its accompanying disability suggest that it may be associated with the greatest public health burden.5 The symptoms of OA present after age 40 and progress slowly. Women are more likely to be affected by this disease than men after age 50.6 The joints that are most frequently affected by OA are the synovial joints—knees, hips, hands, low back, and neck.5 OA of the knee becomes symptomatic in approximately 13% of adults aged >55 years.7 The result of OA is often loss of joint function, which is a major cause of work disability and reduced quality of life.6 The impact of knee OA can be debilitating and is the most common cause of disability and mobility dependency.7

Osteoarthritis Management The signature features suggestive of a diagnosis of OA include pain, stiffness, reduced movement, swelling, and crepitus. The goals of management of OA are patient education, pain control, improved function and reduction of disability, and altering the disease process and outcomes. The treatment of OA should be individualized and varies with the degree of symptoms.5,6 Conservative, nonpharmacologic treatment options include patient education, weight loss, exercise, braces, orthotics, and physical therapy.5 Pharmacologic therapy includes nonsteroidal antiinflammatory drugs (NSAIDs), COX-2 inhibitors, opioids, and/or acetaminophen to reduce joint pain, stiffness, and swelling. For OA that is unresponsive to oral pharmacologic therapies, intraarticular injections of corticosteroids or viscosupplements can be admin-

istered. Injectible therapy can also complement other modalities. Surgery in the form of total knee replacement (TKR) is reserved for patients with advanced OA who have joint damage, marked by joint mobility limitations. TKR is an effective option and affords many patients pain relief and increased mobility. However, TKR is not without risk, and some patients are not candidates for TKR as a result of concomitant medical conditions, such as heart disease, diabetes, pulmonary disease, or obesity. Optimum management of OA, however, involves a combination of nonpharmacologic and pharmacologic therapies.5,6

Hylan G-F 20 for Osteoarthritis Knee Pain The purpose of intraarticular therapy with viscosupplements is to help replace diseased synovial fluid that is diluted and has lost its viscoelastic properties.8 The exact mechanism by which viscosupplements relieve OA pain of the knee is not fully known. There appear to be several potential biologic mechanisms of action in addition to the transient improvement of viscoelastic properties.8,9 Viscosupplementation is a widely accepted treatment option and is included in the treatment guidelines for pain due to OA of the knee by the Osteoarthritis Research Society International and several other professional organizations.10-15 A Cochrane review affirmed the role of viscosupplements in treatment of OA of the knee, noting superior efficacy versus placebo, comparable efficacy versus NSAIDs, and longer-term benefits versus intraarticular steroids.16 Hylan G-F 20 is an elastoviscous high molecular weight mixture containing hylan A and hylan B polymers, which are derivatives of hyaluronan.17 SynviscOne (hylan G-F 20) is indicated for the treatment of pain in OA of the knee in patients who have failed to respond adequately to conservative nonpharmacologic therapy and simple analgesics like acetaminophen. Synvisc-One® is the same formulation as SYNVISC® (hylan G-F 20); however, it is supplied in a 10-mL glass syringe containing all 3 doses (48 mg) of hylan G-F 20, administered in a single intraarticular injection.17 Synvisc-One is the only US Food and Drug Administration–approved viscosupplement in the United

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States that delivers up to 6 months of pain relief with only 1 injection.17-22

Clinical Trial Results Chevalier and colleagues evaluated the safety and efficacy of one 6-mL injection of hylan G-F 20 in a 26week, pivotal, prospective, multicenter, double-blind, randomized, placebo-controlled clinical trial.23 A total of 253 patients with primary OA of the knee were randomly assigned to receive a 6-mL injection of either hylan G-F 20 or saline. A total of 232 patients completed the trial.23 The primary end point was change in the pain subscale of the WOMAC (Western Ontario and McMaster Universities) Osteoarthritis Index over 26 weeks. Hylan G-F 20 demonstrated significant improvement in WOMAC A compared with placebo. Patients in the hylan G-F 20 treatment group reported a mean 36% change in pain from baseline over 26 weeks. A mean 29% change in pain from baseline was reported in the placebo group. The estimated treatment change from baseline to week 26 was –0.84 and –0.69 in the hylan G-F 20 and placebo groups, respectively. The difference in estimated change reported between the 2 treatment groups was significant (P = .047).23 Chevalier and colleagues reported no serious adverse events related to the study treatment or procedure.23 Treatment with hylan G-F 20 was associated with slightly more adverse events than with placebo, but the difference was not significant (P = .366). The most common adverse events reported were pain in the target knee, joint stiffness, joint effusion, and joint swelling. Similarly, in the 160 patients treated in the open, repeat-treatment phase, there were no serious adverse events in the target knee. Of the 160 patients, 77 received a second dose of hylan G-F 20 and 83 received a first injection of hylan G-F 20, having received placebo during phase 1 of the trial. Of the 77 patients who received a second injection of hylan G-F 20, only 1 had a target-knee adverse event related to the study treatment. Four of the 83 patients who received hylan G-F 20 for the first time experienced a target-knee adverse event related to the study treatment. Patients experiencing target-knee adverse events during the initial phase of the trial did not have additional adverse events with repeat treatment. All treatment- or procedure-related adverse events were mild to moderate in severity.23 Important Safety Information Synvisc-One is contraindicated in patients with known hypersensitivity to hyaluronan products or patients with infections in or around the target knee.

Do not inject Synvisc-One extra-articularly, into the synovial tissues, into the fat pad or joint capsule, or intravascularly. The safety and efficacy of Synvisc-One in locations other than the knee, or for conditions other than OA, or in combination with other intraarticular injectables have not been established. Use caution when injecting Synvisc-One in patients allergic to avian proteins, feathers, or egg products; who have evidence of lymphatic or venous stasis in the leg to be injected; or who have severe inflammation in the knee to be treated. Remove any synovial fluid or effusion before injecting Synvisc-One. Strict adherence to aseptic technique must be followed. The safety and effectiveness of Synvisc-One have not been established in children or in pregnant or lactating women. Patients should be advised to avoid strenuous or prolonged weight-bearing activities for approximately 48 hours after treatment. The most commonly reported related local adverse events (<2% each) were transient, mild-to-moderate arthralgia, arthritis, arthropathy, injection site pain and joint effusion. No serious adverse events in knees injected with Synvisc-One were reported in clinical trials. Serious local adverse events have been reported only rarely in postmarketing use. Repeat treatment did not affect the safety profile. In the pivotal trial, there was one related systemic event of syncope. The most common systemic side effects irrespective of the relationship to Synvisc-One (≥5%) were headache, back pain, nasopharyngitis, and influenza. Systemic adverse event profiles were similar between patients in the Synvisc-One and the Saline control groups. Allergic reactions, such as rash, have been reported rarely in association with SYNVISC.

Benefit Design Considerations Synvisc-One is an effective and generally well-tolerated treatment option for patients with OA of the knee who have not achieved adequate pain relief with conservative nonpharmacologic therapies or with traditional analgesic therapies.7,23,24 Synvisc-One is the only nonsystemic therapy delivering up to 6 months of pain relief with just 1 simple injection.16-22,25 Fewer injections not only reduces the risk for adverse events associated with additional intraarticular injections but may reduce the overall treatment costs associated with OA. One injection means only 1 office visit fee and 1 injection fee. Reducing the number of intraarticular injections also reduces the number of claims that an office must submit and track, or that payers need to process and pay. Eliminating the need for multiple office visits for injections also limits the patient spending on

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copayments, minimizes time off from work, and reduces travel to and from the physicianâ&#x20AC;&#x2122;s office, thereby simplifying treatment of OA knee pain.

References 1. Lawrence RC, Felson DT, Helmick CG. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Arthritis Rheum. 2008;58:26-35. 2. Hootman JM, Helmick CG. Projections of US prevalence of arthritis and associated activity limitations. Arthritis Rheum. 2006;54:226-229. 3. American Academy of Orthopedic Surgeons. Osteoarthritis of the Knee: State of the Condition; 2004. www.aaos.org/Research/documents/OAinfo_knee_state.pdf. Accessed November 6, 2006. 4. Buckwalter JA, Saltzman C, Brown T. The impact of osteoarthritis: implications for research. Clin Orthop Relat Res. 2004 Oct;(427 suppl):S6-S15. 5. Hunter DJ, Felson DT. Osteoarthritis. BMJ. 2006;332:639-642. 6. Arthritis Foundation. Osteoarthritis fact sheet. www.arthritis.org/media/ newsroom/osteoarthritis%20fact%20sheet%20from%20AF-Final%2010-10-09.pdf. Accessed March 2, 2010. 7. Hunter DJ, Lo GH. The management of osteoarthritis: an overview and call to appropriate conservative treatment. Med Clin North Am. 2009;93:127-143, xi. 8. Moreland LW. Intra-articular hyaluronan (hyaluronic acid) and hylans for the treatment of osteoarthritis: mechanisms of action. Arthritis Res Ther. 2003;5:54-67. 9. Bagga H, Burkhardt D, Sambrook P, March L. Long-term effects of intraarticular hyaluronan on synovial fluid in osteoarthritis of the knee. J Rheumatol. 2006;33:946-950. 10. Zhang W, Moskowitz RW, Nuki G, et al. OARSI recommendations for the management of hip and knee osteoarthritis, part II: OARSI evidence-based, expert consensus guidelines. Osteoarthritis Cartilage. 2008;16:137-162. 11. Institute for Clinical Systems Improvement. Health care guideline: diagnosis and treatment of adult degenerative joint disease (DJD /osteoarthritis (OA) of the knee. March 2007. www.icsi.org/degenerative_joint_disease/diagnosis_and_treatment_of_adult_ degenerative_joint_disease_of_the_knee_3.html. Accessed January 15, 2009. 12. Michigan Quality Improvement Consortium. Medical Management of Adults with Osteoarthritis. August 2007. www.mqic.org/pdf/osteoarthritis09.pdf. Accessed March 2, 2010. 13. Simon L, Lipman A, Jacox A, et al. Guideline for the Management of Pain in

Osteoarthritis, Rheumatoid Arthritis, and Juvenile Chronic Arthritis. APS Clinical Practice Guidelines Series. 2nd ed. Glenview, IL: American Pain Society; 2002. 14. American College of Rheumatology Subcommittee on Osteoarthritis Guidelines. Recommendations for the medical management of osteoarthritis of the hip and knee: 2000 update. Arthritis Rheum. 2000;43:1905-1915. 15. Jordan KM, Arden NK, Doherty M, et al. EULAR recommendations 2003: an evidence based approach to the management of knee osteoarthritis: report of a Task Force of the Standing Committee for International Clinical Studies Including Therapeutic Trials (ESCISIT). Ann Rheum Dis. 2003;62:1145-1155. 16. Bellamy N, Campbell J, Robinson V, et al. Viscosupplementation for the treatment of osteoarthritis of the knee. Cochrane Database Syst Rev. 2006;2:CD005321. 17. Synvisc-One (hylan G-F 20). Prescribing information. Ridgefield, NJ: Genzyme Biosurgery; February 2009. 18. Synvisc (hylan G-F 20). Prescribing information. Ridgefield, NJ: Genzyme Biosurgery; December 2006. 19. Hyalgan (sodium hyaluronate). Prescribing information. Bridgewater, NJ: sanofiaventis, US. January 2009. http://products.sanofi-aventis.us/hyalgan/hyalgan.html. Accessed January 2010. 20. Supartz (sodium hyaluronate). Prescribing information. Memphis, TN: Smith & Nephew. January 2007. http://global.smith-nephew.com/us/patients/images/Clinical_ Therapies/PackageInsert.pdf. Accessed January 2010. 21. Orthovisc (high molecular weight hyaluronate). Prescribing information. Woburn, MA: Anika Therapeutics. www.orthoviscline.com/sites/default/files/file/ Orthovisc_Package_Insert.pdf. Accessed January 2010. 22. Euflexxa (1% sodium hyaluronate). Prescribing information. Parsippany, NJ: Ferring Pharmaceuticals. www.euflexxa.com/files/euflexxa_physician.pdf. Accessed January 2010. 23. Chevalier X, Jerosch J, Goupille P, et al. Single, intra-articular treatment with 6 mL hylan G-F 20 in patients with symptomatic primary osteoarthritis of the knee: a randomised, multicentre, double-blind, placebo controlled trial. Ann Rheum Dis. 2010;69:113-119. 24. Conrozier T, Jerosch J, Beks P, et al. Prospective, multi-centre, randomized evaluation of the safety and efficacy of five dosing regimens of viscosupplementation with hylan G-F 20 in patients with symptomatic tibio-femoral osteoarthritis: a pilot study. Arch Orthop Trauma Surg. 2009;129:417-423. 25. Brzusek D, Petron D. Treating knee osteoarthritis with intra-articular hyaluronans. Curr Med Res Opin. 2008;24:3307-3322.

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Dex appeal

Indication: OZURDEX â&#x201E;˘ (dexamethasone intravitreal implant) 0.7 mg is indicated for the treatment of macular edema following branch retinal vein occlusion (BRVO) or central retinal vein occlusion (CRVO). Dosage and Administration: For ophthalmic intravitreal injection only. The intravitreal injection procedure should be carried out under controlled aseptic conditions. Following the intravitreal injection, patients should be monitored for elevation in intraocular pressure and for endophthalmitis. Patients should be instructed to report any symptoms suggestive of endophthalmitis without delay. Important Safety Information Contraindications: OZURDEX â&#x201E;˘ is contraindicated in patients with active or suspected ocular or periocular infections including most viral diseases of the cornea and conjunctiva, including active epithelial herpes simplex keratitis (dendritic keratitis), vaccinia, varicella, mycobacterial infections, and fungal diseases. It is also contraindicated in patients with advanced glaucoma and in patients with known hypersensitivity to any components of this product or to other corticosteroids. Warnings and Precautions: Intravitreal injections have been associated with endophthalmitis, eye inflammation, increased intraocular pressure, and retinal detachments. Patients should be monitored following the injection. Use of corticosteroids may produce posterior subcapsular cataracts, increased intraocular pressure, glaucoma, and may enhance the establishment of secondary ocular infections due to bacteria, fungi, or viruses. Corticosteroids should be used cautiously in patients with a history of ocular herpes simplex. Corticosteroids should not be used in active ocular herpes simplex.

The first and only FDA-approved treatment for macular edema following BRVO* or CRVO† employs innovative NOVADUR™ drug-delivery technology OZURDEX™ is the first injectable intravitreal implant designed to deliver dexamethasone to the vitreous—and an important therapeutic option to Retina Specialists. NOVADUR™ drug-delivery technology makes it possible.1 OZURDEX™ is injected via a specially designed applicator and may be administered as an in-office procedure. Upon injection of OZURDEX™, the NOVADUR™ solid-polymer drug-delivery system biodegrades, releasing dexamethasone.1 The OZURDEX™ implant is so small it can fit on a fingertip.Yet it is powerful enough to provide 3-line gains of vision for 20% to 30% of patients within 1 to 2 months (vs 7% to 12% with sham).1 Gains that lasted 1 to 3 months after the onset of this effect.1 Which makes OZURDEX™ a very appealing corticosteroid for the treatment of macular edema following BRVO or CRVO, and an important formulary addition.

Important Safety Information (continued) Adverse reactions: The most common ocular adverse reactions reported by greater than 2% of the patients in the first 6 months included increased intraocular pressure (25%), conjunctival hemorrhage (20%), eye pain (7%), conjunctival hyperemia (7%), ocular hypertension (4%), cataract (4%), vitreous detachment (3%), and headache (3%). Please see brief summary of prescribing information on the following page.

* Branch retinal vein occlusion † Central retinal vein occlusion 1. OZURDEX™ Prescribing Information. ©2010 Allergan, Inc., Irvine, CA 92612 ™ marks owned by Allergan, Inc. www.Ozurdex.com APC34CL10 903572

Brief Summary—Please see the OZURDEX™ package insert for full prescribing information.

INDICATIONS AND USAGE OZURDEX™ (dexamethasone intravitreal implant) is indicated for the treatment of macular edema following branch retinal vein occlusion (BRVO) or central retinal vein occlusion (CRVO). CONTRAINDICATIONS Ocular or Periocular Infections: OZURDEX™ (dexamethasone intravitreal implant) is contraindicated in patients with active or suspected ocular or periocular infections including most viral diseases of the cornea and conjunctiva, including active epithelial herpes simplex keratitis (dendritic keratitis), vaccinia, varicella, mycobacterial infections, and fungal diseases. Advanced Glaucoma: OZURDEX™ is contraindicated in patients with advanced glaucoma. Hypersensitivity: OZURDEX™ is contraindicated in patients with known hypersensitivity to any components of this product. WARNINGS AND PRECAUTIONS Intravitreal Injection-related Effects: Intravitreal injections have been associated with endophthalmitis, eye inflammation, increased intraocular pressure, and retinal detachments. Patients should be monitored following the injection. (see PATIENT COUNSELING INFORMATION) Potential Steroid-related Effects: Use of corticosteroids may produce posterior subcapsular cataracts, increased intraocular pressure, glaucoma, and may enhance the establishment of secondary ocular infections due to bacteria, fungi, or viruses. Corticosteroids should be used cautiously in patients with a history of ocular herpes simplex. Corticosteroids should not be used in active ocular herpes simplex. ADVERSE REACTIONS Clinical Studies Experience: Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. The following information is based on the combined clinical trial results from the initial 6 month masked period of two randomized, sham-controlled, parallel studies. Adverse reactions reported by greater than 2% of patients in the first six months MeDRA OZURDEX™ Sham Term N=421(%) N=423(%) 106 (25%) 5 (1%) Intraocular pressure increased 85 (20%) 63 (15%) Conjunctival hemorrhage 31 (7%) 16 (4%) Eye pain 28 (7%) 20 (5%) Conjunctival hyperemia 17 (4%) 3 (1%) Ocular hypertension 15 (4%) 6 (1%) Cataract 12 (3%) 8 (2%) Vitreous detachment 14 (3%) 7 (2%) Headache

Increased IOP with OZURDEX™ peaked at day 60 and returned to baseline levels by day 180. During the initial treatment period, 0.7% (3/421) of the patients who received OZURDEX™ required laser or surgical procedures for management of elevated IOP. Following a second injection of OZURDEX™ in cases where a second injection was indicated, the overall incidence of cataracts was higher after 1 year. USE IN SPECIFIC POPULATIONS Pregnancy: Topical dexamethasone has been shown to be teratogenic in mice, producing fetal resorptions and cleft palate. In the rabbit, dexamethasone produced fetal resorptions and multiple abnormalities involving the head, ears, limbs, palate, etc. Pregnant rhesus monkeys treated with dexamethasone sodium phosphate intramuscularly at 1 mg/kg/day every other day for 28 days or at 10 mg/kg/day once or every other day on 3 or 5 days between gestation days 23 and 49 had fetuses with minor cranial abnormalities. A 1 mg/kg/dose in pregnant rhesus monkeys would be approximately 85 times higher than an OZURDEX™ injection in humans (assuming 60 kg body weight). There are no adequate and well-controlled studies in pregnant women. OZURDEX™ (dexamethasone intravitreal implant) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers: It is not known whether ocular administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in human milk. Systemically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. Caution should be exercised when corticosteroids are administered to a nursing woman. Pediatric Use: Safety and effectiveness of OZURDEX™ in pediatric patients has not been established. Geriatric Use: No overall differences in safety or effectiveness have been observed between elderly and younger patients. PATIENT COUNSELING INFORMATION In the days following intravitreal injection of OZURDEX™, patients are at risk for potential complications including in particular, but not limited to, the development of endophthalmitis or elevated intraocular pressure. If the eye becomes red, sensitive to light, painful, or develops a change in vision, the patients should seek immediate care from an ophthalmologist. Patients may experience temporary visual blurring after receiving an intravitreal injection. They should not drive or use machines until this has resolved. ©2009 Allergan, Inc., Irvine, CA 92612, U.S.A. and ™ marks owned by Allergan, Inc. Made in Ireland 72212US10A

APC81DZ09

Savella (Milnacipran HCl): A New Option for the Management of Fibromyalgia By Loretta Fala, Medical Writer

ibromyalgia (FM) is a condition characterized by chronic, widespread soft-tissue pain with tender points along with other symptoms, often resulting in functional impairment. Affecting an estimated 2% to 4% of the US population, generally first diagnosed between the ages of 20 and 50 years, FM is about 7 times more common in women than in men.1 The incidence of FM rises with age. By age 80 years, approximately 8% of adults meet the classification of FM set forth by the American College of Rheumatology (ACR).2 Patients with lupus, rheumatoid arthritis (RA), or ankylosing spondylitis are at risk for FM.1

Burden of Illness FM is costly to the individual patient and to society. In the United States, costs attributed to FM are estimated at $12 billion to $14 billion annually and are associated with a loss of 1% to 2% of the nationâ&#x20AC;&#x2122;s overall productivity.3 According to a 2007 study, 34% of patients with FM spend between $100 to $1000 monthly above their insurance coverage to visit a clinician.3 The mean annual healthcare costs are approximately 3 times higher among patients with FM than those without FM.3 Pain-related medication costs account for about 11% of the total costs.3 In addition, twice as many patients with FM use nonpain medications, including antibiotics, cough and cold medications, and ulcer drugs.3 Employees with FM incur total annual costs nearly twice as high as other employees.4 They also incur medical and drug costs that are a staggering 86% higher than costs incurred by others.4 Moreover, based on a multicenter survey designed to assess the work and disability status of 1604 patients with FM, an estimated 26.5% of workers receive some form of disability payment.5 For employees with FM, the prevalence of disability is estimated to be twice as high as that of all employees.2 Failure to diagnose a true case of FM is costly in terms of medical resources and can result in excess visits to a general practitioner, as well as excess prescriptions, referrals, and diagnostics.2,6 Conversely, diagnosed cases of FM lead to savings and a decrease in resource utilization, particularly for tests and imaging studies.6 Fibromyalgia Diagnosis FM may be accompanied by many symptoms, including fatigue, sleep disturbances, morning stiffness,

cognitive difficulties, headaches and migraines, irritable bowel syndrome, mood disturbances, temporomandibular joint dysfunction, and environmental sensitivities.2,7,8 Often diagnosed by primary care physicians, FM accounts for an estimated 15% to 20% of visits to rheumatologists, second only to osteoarthritis as the most common presenting factor.7,9 Although FM is not life threatening,10 it can have a significant impact on a patientâ&#x20AC;&#x2122;s quality of life (QoL) and daily functioning.11 Based on a study comparing QoL of women with FM with that of women with RA, osteoarthritis, permanent ostomies, insulin-dependent diabetes, and healthy controls, women with FM consistently scored lowest in all categories.12 FM is recognized as a legitimate clinical entity by the American Medical Association, National Institutes of Health, World Health Organization, ACR, and the US Food and Drug Administration (FDA).11,13 Recent studies suggest that patients with FM have a generalized disturbance in pain processing and an amplified response to stimuli.2 Alterations occurring in the central nervous system (CNS) and at the periphery may contribute to the sensation of pain.14 The perception of pain involves a complex interaction between the ascending and descending pathways, with the ability to change the dynamic between stimulus and response.14 Moreover, the descending pathway systems may have an important role in central sensitization.14 Neurotransmitter defects in ascending and descending CNS pathways contribute to the pain associated with FM.15,16 The neurotransmitters serotonin and norepinephrine play a role in descending pain-inhibiting pathways.14,15 Another neurotransmitter, substance P, is an 11 amino acid neuropeptide being studied for its presumed role in pain transmission.14 Substance P coexists with glutamate in afferent terminals of the spinal cord.14 Abnormalities associated with norepinephrine and serotonin have been seen in patients with FM.14,15 Data suggest a potential decrease in serotonin- and norepinephrine-related activity in patients with FM.14 Conversely, increased levels of substance P and glutamate have been seen in these patients.14-16 Against this background, increasing attention is focused on the CNS and aberrant pain processing as the underlying mechanism of FM.2 Despite increasing recognition, FM continues to be overlooked and misdiagnosed, and its diagnosis is often

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delayed.7,11 Because its symptoms are similar to other disorders, FM is difficult to diagnose.7 Conditions that must be ruled out before FM diagnosis include RA, polymyalgia rheumatica, hypothyroidism, and lupus.17,18 If compelling evidence exists, other tests, such as a Lyme antibody, may be warranted.18 The diagnostic criteria for FM established by the ACR include a history of widespread pain in all 4 quadrants of the body for more than 3 months, and pain in a minimum of 11 of the 18 designated tender spots when pressure is applied.18,19 Although no cure is available, treatment can provide symptom relief and function improvement.10 The therapeutic goals of medication include the management of pain, fatigue, and reduced function, and improving other FM-associated symptoms.20 Nonpharmacologic approaches to FM include patient education, exercise, alternative therapies, and self-management.1

Drug Therapy In January 2009, milnacipran HCl (Savella), a dual serotonin-norepinephrine reuptake inhibitor (SNRI), was approved for the management of FM. It is a welcome addition to the limited arsenal of agents available for FM. The 2 other FDA-approved drugs are the anticonvulsant Lyrica (pregabalin), and the SNRI Cymbalta (duloxetine hydrochloride). Pregabalin is indicated for the management of FM, pain associated with diabetic peripheral neuropathy (DPN), postherpetic neuralgia, and partial-onset seizures.21 Duloxetine is indicated for the management of FM, depression, generalized anxiety disorder, and DPN.22 Milnacipran is currently the only agent approved solely for the management of FM.23 Milnacipran is available in 4 tablet strengths.23 Based on findings from 2 pivotal phase 3 clinical trials, treatment with milnacipran 100 mg/day (50 mg twice daily) or 200 mg/day (100 mg twice daily) showed significant and clinically meaningful concurrent improvements across 3 measures of FM—pain reduction, patient global assessment, and physical function.9,24 Milnacipran is the first and only product approved to treat the symptoms of FM using a composite responder analysis as the primary end point.21-24 Clinical Pharmacology Milnacipran is indicated for the management of FM in adults (≥18 years old). It is not approved for use in patients younger than age 18. The exact mechanism of milnacipran’s central pain inhibitory action is unknown.23 In preclinical studies, milnacipran has been shown to inhibit neuronal norepinephrine and serotonin reuptake, demonstrating a 3-fold more potent inhibition of norepinephrine uptake in vitro than sero-

tonin, without directly affecting the uptake of dopamine or other neurotransmitters.23 In in vitro studies, milnacipran was distinguished from other dual reuptake inhibitors, including duloxetine and venlafaxine, by its selectivity for norepinephrine over serotonin, whereas duloxetine and venlafaxine are more selective for serotonin reuptake inhibition over norepinephrine.24 Because milnacipran shows an affinity for the norepinephrine and serotonin receptors, without binding to dopamine, histamine, or muscarinic receptors, it is not associated with many of the side effects of tricyclic antidepressants.8,23 Milnacipran is well absorbed, with an absolute bioavailability of approximately 85% to 90%, reaching maximum concentrations within 2 to 4 hours.23 Absorption is not affected by food. Excreted primarily unchanged in urine (55%), milnacipran has a terminal elimination half-life of 6 to 8 hours. Steady-state levels are reached in 36 to 48 hours. Milnacipran has a low degree of binding to plasma proteins (13%).23

Results from Clinical Trials At the Outcomes Measures in Rheumatology 8 (OMERACT 8) meeting, 23 clinicians with expertise in FM convened to reach consensus on core symptom domains, evaluate outcome measures in clinical trials, and define research agenda. During the meeting, physicians and patients were asked to rank 40 FM-specific domains in relative importance.25 The top 4 core criteria rated as “essential,” in order of importance, were25: • Pain • Fatigue • Patient global status • Multidimensional function. OMERACT 8 participants agreed that “the ability to measure clinically meaningful change in multiple dimensions of fibromyalgia utilizing a composite responder index is desirable.”25 This formed the clinical end point framework for the milnacipran clinical studies. The FDA approval of milnacipran was based on the results of 2 randomized, multicenter, double-blind, placebo-controlled US studies that used a composite responder analysis.9,24 The 2 primary end points were rates of FM composite responders (3-measure composite) and pain responders (2-measure composite). Threemeasure composite responders were defined as patients concurrently experiencing clinically meaningful improvements in 3 domain criteria—pain (30% or more improvement in pain), patient global status (rating of very much improved, a score of 1, or much improved, a score of 2, on the patient global impression of change [PGIC] scale), and physical function, defined as a 6point or more improvement in the Short-Form 36 physical component summary score. Two-measure composite

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Table 1 Milnacipran Multimeasure Responder Analysis Demonstrating Significant Fibromyalgia Relief Threshold for response ≥30% reduction from baseline score

Area of improvement Pain relief

Measure VAS pain

Global improvement

PGIC

Score of 1 or 2: “very much improved” or “much improved”

Physical functional improvement

SF-36 PCS

≥6 point improvement

2-Measure composite respondersa √

3-Measure composite respondersb √

√

a2-measure

composite responders were required to demonstrate simultaneous pain relief and global improvement versus placebo. composite responders were required to demonstrate simultaneous pain relief, global improvement, and physical function versus placebo. PGIC indicates patient global impression of change; SF-36 PCS, Short-Form 36 physical component survey; VAS, visual analog scale. b3-measure

responders were defined as those who met the pain and the PGIC criteria.9,24 Pain data for the milnacipran trials were captured via an electronic patient diary that measured pain from a scale of 0 (no pain) to 100 (worst possible pain).9,24 Patients reported their current level of pain at specific intervals. Data collections were taken in the morning, at 3 to 5 random prompts throughout the day, and in the evening. In the morning report, patients rated their average level of pain in the previous 24 hours; and at the end of a 7-day period, patients rated their average level of pain for the previous 7 days.9,24 Milnacipran is the only agent approved for the management of FM that collected pain data with the help of an electronic patient diary, which allows for capturing real-time pain data, as well as 24-hour and 7-day pain recall. The first study included 86 centers and 1196 patients who were randomized to 15 weeks of treatment with milnacipran 100 mg/day, milnacipran 200 mg/day, or to placebo.9 The second study included 59 centers and 888 patients randomized to 15 weeks of milnacipran 100 mg/day, milnacipran 200 mg/day, or to placebo.24 Although the primary end point was 3 months, this trial also included a 27-week end point.24 Findings from both studies showed that milnacipran achieved a significant response rate compared with placebo in the 2-measure and 3-measure composite at 3 months (Table 1).9,24 In both studies, a significant decrease in pain was reported as early as week 1 of treatment with a stable dose of milnacipran in patients who reported themselves globally very much or much improved.9,23,24

Adverse Reactions Milnacipran was found to be safe and generally well tolerated in clinical trials. The most common adverse event (AE) was nausea (37% vs 20% for placebo).19,22 Other AEs more common (≥5% and greater than

placebo) with milnacipran include headache, constipation, dizziness, insomnia, hot flushes, hyperhidrosis, vomiting, palpitations, heart rate increase, dry mouth, and hypertension.23 Overall, premature treatment discontinuation in clinical trials because of AEs was 23% in patients treated with milnacipran 100 mg/day and 26% with milnacipran 200 mg/day compared with 12% of placebotreated patients.23 Milnacipran is not associated with a significant incidence of fatigue or somnolence and does not cause weight gain.23 Patients treated with milnacipran for up to 3 months in both the 100 mg/day and the 200 mg/day treatment groups experienced a weight loss of approximately 0.8 kg, compared with a mean weight loss of approximately 0.2 kg in placebotreated patients.23

Contraindications Like other dual reuptake inhibitors, milnacipran’s label includes a black box warning about the risk for increased suicidal ideation or behavior in children, adolescents, and young adults with major depressive disorder and other psychiatric disorders.1 Milnacipran is not approved for use in pediatric patients.23 The development of a potentially life-threatening serotonin syndrome or neuroleptic malignant syndrome (NMS)-like reactions have been reported with SNRIs and selective serotonin reuptake inhibitors (SSRIs) alone, including milnacipran, but particularly with concomitant use of serotonergic drugs (including triptans), with drugs that impair metabolism of serotonin, including monoamine oxidase inhibitors (MAOIs), or with antipsychotics or other dopamine antagonists. In its most severe form, serotonin syndrome can resemble NMS. Patients should be monitored for the emergence of serotonin syndrome or NMS-like signs and symptoms. Milnacipran is also contraindicated for use within

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MAOIs concomitantly, or within 14 days of discontinuing an MAOI. A minimum of 5 days should be allowed between discontinuing milnacipran and starting an MAOI.23 The SNRIs, including milnacipran, have been associated with reports of an increase in blood pressure (BP). In the 3-month placebo-controlled FM clinical trials, milnacipran treatment was associated with mean increases of up to 3.1 mm Hg in systolic BP and diastolic BP. Sustained increases in BP could have adverse consequences. BP should be measured before initiating milnacipran treatment and measured periodically throughout the treatment. Preexisting hypertension and other cardiovascular conditions should be treated before starting therapy with milnacipran. Dose reduction or discontinuation should be considered for patients with a sustained increase in BP while taking milnacipran.23 Reports of increases in heart rate have been associated with SNRIs, including milnacipran. In clinical trials, relative to placebo, milnacipran treatment was associated with mean increases in pulse rate of approximately 7 to 8 beats per minute.23 Heart rate should be measured before initiating milnacipran treatment and measured periodically throughout treatment. Preexisting tachyarrhythmias and other cardiac conditions should be treated before starting therapy with milnacipran. Dose reduction or discontinuation should be considered for patients who experience a sustained increase in heart rate while taking milnacipran.23 Withdrawal symptoms have been observed in clinical trials following discontinuation of milnacipran, as with other SNRIs and SSRIs. Patients should be monitored for these symptoms when discontinuing treatment with milnacipran. Milnacipran should be tapered and not discontinued abruptly after extended use.23 SSRIs and SNRIs, including milnacipran, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin, and other anticoagulants may contribute to this risk. Patients should be cautioned about the risk of bleeding associated with the concomitant use of milnacipran and NSAIDs or other anticoagulants.23 Milnacipran should not be used in patients with uncontrolled narrow-angle glaucoma. An increased risk of mydriasis was associated with milnacipran, as has been reported with other dual reuptake inhibitors of norepinephrine and serotonin. Milnacipran should be used cautiously in patients with controlled narrowangle glaucoma.23 Mild elevations in liver enzymes have been reported with milnacipran, and in rare instances, fulminant hepatitis.23 Increased rates of genitourinary AEs have been reported in male patients with a history of obstructive uropathies.23

Exercise caution in patients with substantial alcohol use or chronic liver disease, patients with mania or a history of seizure disorder, and in those with significant hypertension or cardiac disease. Consult the prescribing information for additional safety information.23

Drug–Drug Interactions Milnacipran is unlikely to result in clinically significant pharmacokinetic drug interactions because it undergoes minimal CYP450-related metabolism, is predominantly excreted unchanged in urine, and has a low degree of plasma protein binding.8,23 However, pharmacodynamic interactions may occur with lithium, epinephrine and norepinephrine, serotonergic drugs, digoxin, clonidine, clomipramine, CNS-active drugs, and MAOIs. As noted, concomitant use of NSAIDs and other anticoagulants with SSRIs or SNRIs, including milnacipran, may increase the risk of bleeding events.23 Dosing and Administration Milnacipran is available in 12.5-mg, 25-mg, 50-mg, and 100-mg tablet strength. Except for the first-day dose of 12.5 mg, milnacipran is administered in 2 divided doses/day, with a recommended dose of 100 mg/day (or 50 mg twice daily) after day 7. For initial dosing, milnacipran is titrated according to a specified schedule (Table 2) and is available in 2 titration pack options. The dose may be increased to 200 mg/day (or 100 mg twice/day), based on patient response. Doses above 200 mg/day have not been studied.23 Milnacipran can be taken with or without food; however, when taken with food, it may improve tolerability in patients who experience nausea. After extended use, milnacipran should be reduced gradually rather than discontinued abruptly. The maintenance dose should be reduced by 50% in patients whose creatinine clearance is <30 mL/min. No dosage adjustment is indicated for mild renal impairment or for patients with hepatic insufficiency. Milnacipran is nonnarcotic and is not categorized as a scheduled substance by the US Drug Enforcement Administration.23 Milnacipran use in specific population is as follows23: • As a pregnancy category C agent it should only be used in pregnant women if the potential benefit justifies potential risks to the fetus. Because it is not known if milnacipran is excreted in human milk and its safety in infants is not known, nursing while taking this agent is not recommended. • It is not recommended in pediatric patients; its safety and effectiveness in patients younger than age 17 years have not been established.

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Milnacipran delivers simultaneous improvements on 3 key aspects of FM, has a low potential for pharmacokinetic drug–drug interactions, and is not associated with a significant incidence of fatigue or somnolence, or weight gain. It offers economic value compared with other agents approved for the management of FM.

Table 2 Initial Dosing and Titration for Savella Timing Dose titration Day 1 12.5 mg Days 2, 3 25 mg/d or 12.5 mg bid Days 4-7 50 mg/d or 25 mg bid After day 7 100 mg/d or 50 mg bid Start-up titration pack options 2-wk titration pack Includes 1-wk titration and 1 wk of 100 mg/d dose 4-wk titration pack Includes 1-wk titration and 3 wks of 100 mg/d dose

References

Note: Although Savella is nonnarcotic, prescription should be written for the smallest quantity of tablets consistent with good patient management to reduce the risk of overdose.

• Because milnacipran is primarily excreted unchanged through the kidneys, with an expected decrease in renal function associated with age, renal function should be considered before prescribing milnacipran in elderly patients. It has been associated with hyponatremia in elderly patients, who are at increased risk for this. • This medication is not recommended in patients with end-stage renal disease, and should be used with caution in those with moderate renal impairment or severe hepatic impairment.

Cost The cost of Savella is $3.38/day. In comparison, Lyrica costs $4.28/day, and Cymbalta $4.00/day. These costs reflect wholesale acquisition cost per labeled daily dose. Net costs varies by health insurance plan. Conclusion Patients with FM have many comorbidities and high levels of healthcare utilization and costs. Increased education and awareness about FM, earlier diagnosis, and improved management approaches, including effective new treatments, may lead to improved patient outcomes and subsequent reductions in utilization and costs. Milnacipran is the most recent addition to the limited number of FDA-approved drugs for the management of FM. Milnacipran is an SNRI that blocks reuptake of norepinephrine with approximately 3 times greater potency in vitro than serotonin.

1. American College of Rheumatology. Fibromyalgia. www.rheumatology. org/public/ factsheets/diseases_and_conditions/fibromyalgia.asp?aud=pat. Accessed August 11, 2009. 2. National Fibromyalgia Association. About fibromyalgia. www.fmaware.org/site/ PageServer?pagename=fibromyalgia. Accessed April 15, 2009. 3. Berger A, Dukes, E, Edelsberg J, Oster G. Characteristics and healthcare costs of patients with fibromyalgia syndrome. Int J Clin Pract. 2007; 61:1498-1508. 4. White LA, Birnbaum HG, Kaltenboeck A, et al. Employees with fibromyalgia: medical comorbidity, healthcare costs, and work loss. J Occup Environ Med. 2008; 50:13-24. 5. Wolfe F, Anderson J, Harkness D, et al. Work and disability status of persons with fibromyalgia. J Rheumatol. 1997;24:1171-1178. 6. Annemans L, Wessely S, Spaepen E, et al. Health economic consequences related to the diagnosis of fibromyalgia syndrome. Arthritis Rheum. 2008;58:895-902. 7. Johns Hopkins Medicine. Fibromyalgia syndrome—common and difficult to diagnose. Health Alerts. www.johnshopkinshealthalerts.com/alerts/arthritis/ JohnsHopkinsHealthAlertsArthritis_427-1. Accessed August 7, 2009. 8. Cios DA, Kim JE. Milnacipran: a serotonin and norepinephrine reuptake inhibitor for the management of fibromyalgia syndrome. Formulary. 2009;44:197-202. 9. Clauw DJ, Mease P, Palmer RH, et al. Milnacipran for the treatment of fibromyalgia in adults: a 15-week, multicenter, randomized, double-blind, placebocontrolled, multiple-dose clinical trial. Clin Ther. 2008; 30:1988-2004. 10. Arthritis Foundation. Fibromyalgia. What is it? www.arthritis.org/disease-center. php?disease_id=10. Accessed August 10, 2009. 11. Navarro RP. Contemporary management strategies for fibromyalgia. Am J Manag Care. 2009;15(7 suppl):S197-S218. 12. Burckhardt CS, Clark SR, Bennett RM. Fibromyalgia and quality of life: a comparative analysis. J Rheumatol. 1993;20:475-479. 13. Gilliland RP. Fibromyalgia. Emedicine. January 5, 2009. http://emedicine.med scape.com/article/312778-print. Accessed August 9, 2008. 14. Rao SG, Gendreau JF, Kranzler JD. Understanding the fibromyalgia syndrome. Psychopharmacol Bull. 2007;40:24-67. 15. Dadabhoy D, Clauw DJ. Therapy insight: fibromyalgia—a different type of pain needing a different type of treatment. Nat Clin Pract Rheumatol. 2006;2:364-372. 16. Harris RE, Sundgren PC, Pang Y, et al. Dynamic levels of glutamate within the insula are associated with improvements in multiple pain domains in fibromyalgia. Arthritis Rheum. 2008;58:903-907. 17. Johns Hopkins Medicine. Fibromyalgia: understanding a mysterious ailment. Health Alerts. www.johnshopkinshealthalerts.com/reports/arthritis/2130-1.html. Accessed August 7, 2009. 18. Fontaine K. Fibromyalgia: diagnosis. www.hopkins-arthritis.org/ arthritisinfo/fibromyalgia/diagnosis.html. Accessed April 15, 2009. 19. Wolfe F, Smythe HA, Yunus MB, et al, for the Multicenter Criteria Committee. The American College of Rheumatology 1990 criteria for the classification of fibromyalgia. Arthritis Rheum. 1990;33:160-172. 20. Fontaine KE. Fibromyalgia: treatment. www.hopkins-arthritis.org/arthritis-info/ fibromyalgia/treatment-info.html. Accessed April 15, 2009. 21. Lyrica (pregabalin). Prescribing information. New York, NY: Pfizer; April 2009. 22. Cymbalta (duloxetine HCl). Prescribing information. Indianapolis, IN: Eli Lilly; February 16, 2009. 23. Savella (milnacipran HCl). Prescribing information. St. Louis, MO: Forest Pharmaceuticals; March 2009. 24. Mease PJ, Clauw DJ, Gendreau RM, et al. The efficacy and safety of milnacipran for treatment of fibromyalgia: a randomized, double-blind, placebo-controlled trial. J Rheumatol. 2009;36:398-409. 25. Mease P, Arnold LM, Bennett R, et al. Fibromyalgia syndrome. J Rheumatol. 2007; 34:1415-1425.

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Composite Outcomes for Fibromyalgia Nirav R. Shah, MD, MPH Assistant Professor of Medicine, NYU School of Medicine, and Senior Investigator, Geisinger Health System

RESEARCHERS: Fibromyalgia (FM) is a complicated disease. Until the American College of Rheumatology came up with standardized criteria on its classification, it has been very difficult to study. These common criteria were created from the perspective of care providers to facilitate identifying patients, not from a patient perspective. To evaluate clinical benefit, however, a patient perspective is central, and a composite outcome measure incorporating patient-centered outcomes was used in 2 milnacipran registration trials. Composite measures are appropriate when it is not clear what end point is most important or if more than 1 is thought to be important, and individual outcomes selected to be a part of the composite are related across a spectrum of benefit. For milnacipran, the composite outcome measure used met this standard and consisted of 3 measures: (1) an improvement in pain from baseline, (2) a global rating scale, and (3) an improvement in physical function. Composite measures are often used when individual ones are insufficient to determine effects of importance. For example, if events are rare, a composite of several different measures or events can be used to best capture the effects of an intervention.1 Composites are frequently used in cardiology, where composites of individual components such as cardiovascular mortality, revascularization, and myocardial infarction are lumped together into a single measure.2 Several guiding principles are paramount when using and designing good composite measures for efficacy and effectiveness. First, individual components of a composite outcome should be similar in importance when considered from a patient perspective.1 Interpreting a composite outcome is difficult enough, so that mixing “apples and oranges” in terms of clinical importance only further complicates their use. Often death is included in a composite measure. This practice is widespread, but a patient dying, by definition, disallows any subsequent events of different measures within a composite to occur. In the case of milnacipran, the 3 outcomes chosen are of similar importance, and rather

than arbitrarily selecting only 1 outcome of interest, the composite facilitates use of all 3. A second principle in using a composite measure is to increase power and ability to examine differences between the intervention and the control groups.3 If individual events are infrequent, for example, a composite measure composed of several related individual measures may increase statistical efficiency. Although not necessarily the case for FM, the measures chosen can be considered a form of “hedging bets,” so that the trial will be adequately powered. A final principle relates to the magnitude of each individual measure’s effect size. These should be similar; otherwise 1 measure may drive results in a composite.4 For example, if the pain improvement criteria were met in 80% of patients, and the functional status criteria in only 20%, the overall composite would be unbalanced and would not truly reflect functional status. For milnacipran, improvements had to occur in at least 2 measures for a given patient, further ensuring that no single component could drive the results. The composite measure for FM effectiveness represents a good application of the principles of composite design and of criteria selection. In the future, as our understanding of the disease process evolves and new types of drugs are developed, new composite measures will be required. It is hoped that they would live up to the standard set with milnacipran. Disclosure Statement: Dr Shah receives unrestricted research grants from AstraZeneca, Merck, Pfizer, and Roche, and has received honoraria from Takeda.

References 1. Ferreira-González I, Busse JW, Heels-Ansdell D, et al. Problems with use of composite end points in cardiovascular trials: systematic review of randomised controlled trials. BMJ. 2007;334:786. 2. Lim E, Brown A, Helmy A, Mussa S, Altman DG. Composite outcomes in cardiovascular research: a survey of randomized trials. Ann Intern Med. 2008;149: 612-617. 3. Freemantle N, Calvert M, Wood J, et al. Composite outcomes in randomized trials: greater precision but with greater uncertainty? JAMA. 2003;289:2554-2559. 4. Ross S. Composite outcomes in randomized clinical trials: arguments for and against. Am J Obstet Gynecol. 2007;196:119.e1-e6.

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Management of Fibromyalgia Gary M. Owens, MD President, Gary Owens Associates, Philadelphia, PA

PAYERS: Fibromyalgia is a complex syndrome that is characterized by diffuse pain associated with a host of other symptoms, including fatigue, sleep disturbances, morning stiffness, cognitive dysfunction, headaches, and feelings of anxiety and depression. This syndrome is far more prevalent in women and may affect up to 4% of the US population. Fibromyalgia often presents with vague complaints and is often incorrectly diagnosed by clinicians. This may lead patients with fibromyalgia to seek care from multiple physicians; these patients often undergo a significant number of diagnostic tests before a correct diagnosis is reached. Data have shown that patients with fibromyalgia, on average, spend more than 3 times as much money and time on healthcare as do matched populations without this condition. A significant amount of spending for these patients is for diagnostic studies and for medications, often targeted at the relief of pain. Despite this cost and the use of healthcare resources, patients with fibromyalgia often suffer a reduced quality of life, and their ability to be productive members of the workforce is affected. The present article describes a new medication, milnacipran HCl (Savella), a serotonin-norepinephrine reuptake inhibitor (SNRI), which has been shown in clinical trials to improve many of the symptoms associated with fibromyalgia. Most important, this agent demonstrated significant improvement in fibromyalgia composite responders (defined as those with meaningful improvements in 3 clinical domains—pain, patient global assessment, and physical function)—as well as fibromyalgia pain responders (defined as the patient meeting both pain and global change criteria). Although this agent is not a cure for fibromyalgia, it does add an additional tool for the clinician to use in the treatment of this complex syndrome. Milnacipran joins pregabalin (Lyrica) and duloxetine HCl (Cymbalta) as the only agents FDA-approved for the management of fibromyalgia. In addition to these 3

agents, a broad range of medication classes—anticonvulsants, antidepressants, anti-inflammatory drugs, as well as pain relievers that include opioids— are used “off-label” for the treatment of fibromyalgia. With the approval of a new SNRI for the management of fibromyalgia, P&T Committees will be asked to review the treatment options for fibromyalgia, which will include a review of the 3 FDA-approved agents and of agents frequently used “off label” for the treatment of fibromyalgia. In the absence of head-to-head data comparing the 3 FDA-approved agents, and with virtually no data to compare these agents to the many drugs that are currently used “off label” for the treatment of fibromyalgia symptoms, it will be a challenge for P&T Committees to assess this category. P&T Committees therefore must consider differences in mechanisms of action, pharmacokinetic profiles, efficacy outcomes, as well as the criteria for determining such outcomes, safety, and tolerability, when making their decisions. It is likely that we shall continue to see significant variability of formulary tier-placement decisions made by different P&T Committees. Similarly, some committees may choose to implement clinical management programs, for this agent, much as we have seen for the other agents in the class. P&T Committees will continue to be challenged in this category to provide the right balance of patient access, clinical outcomes, and cost management. Having comparative clinical trial data and outcome studies would certainly help facilitate these decisions, but this information is generally not available in the early post-approval phase. Without that information, P&T Committees will need to carefully evaluate new treatment options based on existing data to make appropriate treatment options available for this complex and costly illness. Disclosure Statement: Dr Owens is a consultant to Amgen, AstraZeneca, Genentech, Novartis, and Schering-Plough.

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Composite End Points and the Impact of Milnacipran on Patients with Fibromyalgia Philip Mease, MD Chief, Rheumatology Research, Swedish Medical Center, Clinical Professor, University of Washington School of Medicine, and is in clinical practice, Seattle Rheumatology Associates, Seattle, WA

PROVIDERS: The recent approval of milnacipran hydrochloride (Savella) for the management of fibromyalgia (FM) was based on clinical trials showing that a significantly greater proportion of patients taking milnacipran compared with those taking placebo met the prespecified criteria for being a responder based on a composite end point. Of the drugs approved for the management of FM, only clinical trials of milnacipran incorporated a composite end point to establish efficacy. Composite end points have been used to evaluate the clinical efficacy of several therapies for the treatment of asthma,1 migraine,2 organ transplantation,3 myocardial infarction,4 and diabetes,5 exemplifying a growing trend in the use of this type of end point. Moreover, several expert panels, such as the Outcome Measures in Rheumatoid Arthritis Clinical Trials (OMERACT) group, have encouraged the use of composite end points in the evaluation of new medicines. What is the relevance of composite end points when trying to understand the impact of milnacipran on patients with FM? Clinically, composite end points are considered to be more robust and meaningful than analyses of group mean changes on a single, continuous end point such as pain for several reasons. First, assessing milnacipran’s composite end points—pain,6 the patient global impression of change (PGIC),7 and physical functioning8—ensures that the therapy is producing clinically significant improvements in multiple domains simultaneously, in the same patient. In contrast, a continuous analysis of change in pain reflects only group mean differences, which may not necessarily reflect the actual change observed for any given patient. In addition, relying on multiple group-level comparisons across different end points does not ensure that reductions in pain and improvements in functioning, for example, are occurring in the same group of patients. Second, estimates of efficacy derived from composite end points reflect a conservative, worst-case profile of a drug’s efficacy. This is because patients who fail to meet the composite responder threshold may have experienced clinically meaningful changes in 1 or more domains but fail to qualify as a responder because of their response on a single domain. Third, because PGIC ratings are thought to reflect each patient’s global evaluation of the balance of the efficacy of a drug against its tolerability, incorporating PGIC ratings in the composite end point broadens the evaluation beyond efficacy to include tolerability as well.

Fourth, by incorporating a measure of function, the ability of the therapy to not only treat symptoms but also help to return the patient toward more normal functioning is assessed. Therefore, the composite end points used in milnacipran’s clinical development program speak to a more comprehensive analysis of its efficacy and tolerability from the individual patient’s perspective. Composite end points also have shortcomings. While composite end points have the potential to increase the statistical power of clinical trials by elevating the observed event rate through aggregating multiple end points, the converse can be true if the various domains are not all equally responsive to therapy.9 For example, if improvements in physical functioning are harder to achieve than reductions in pain, which is potentially the case for patients with FM, then the percentage of patients reporting improvements in physical functioning sets a ceiling for the maximum percentage of patients who can qualify as composite responders. Composite end points can only be as robust as the end point most difficult to change, and they require that the therapy produces clinically significant changes in multiple domains in the same patient. As such, they can set a high hurdle for success. The use of composite end points in drug development is likely to increase. In the case of milnacipran, the use of composite end points provides a conservative estimate of the rates of clinically meaningful, multidimensional change in patients with FM. Disclosure Statement: Dr Mease receives grant research from and is a consultant to Boehringer Ingelheim, Cypress Pharmaceuticals, Eli Lilly, Forest, Fralex Therapeutics, Pfizer, and Wyeth. He is on the Speaker’s Bureau of Cypress Pharmaceuticals, Eli Lilly, Forest, Pfizer, and Wyeth.

References 1. Bateman ED. Measuring asthma control. Curr Opin Allergy Clin Immunol. 2001;1:211-216. 2. Antonaci F, Sances G, Guaschino E, et al. Meeting patient expectations in migraine treatment: what are the key endpoints? J Headache Pain. 2008;9:207-213. 3. Washburn K. Endpoints in trials for clinical liver transplantation. Curr Opin Organ Transplant. 2008;13:252-256. 4. Cannon CP. Clinical perspectives on the use of composite endpoints. Control Clin Trials. 1997;18:517-529. 5. Betteridge DJ, DeFronzo RA, Chilton RJ. PROactive: time for a critical appraisal. Eur Heart J. 2008;29:969-983. 6. Farrar JT, Young JP Jr, LaMoreaux L, et al. Clinical importance of changes in chronic pain intensity measured on an 11-point numerical pain rating scale. Pain. 2001;94:149-158. 7. Dworkin RH, Turk DC, Wyrwich KW, et al. Interpreting the clinical importance of treatment outcomes in chronic pain clinical trials: IMMPACT recommendations. J Pain. 2008;9:105-121. 8. Glassman SD, Copay AG, Berven SH, et al. Defining substantial clinical benefit following lumbar spine arthrodesis. J Bone Joint Surg Am. 2008;90: 1839-1847. 9. Ferreira-González I, Permanyer-Miralda G, Busse JW, et al. Methodologic discussions for using and interpreting composite endpoints are limited, but still identify major concerns. J Clin Epidemiol. 2007;60:651-657.

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For your members with moderate to severe plaque psoriasis

Now Available in Prefilled Syringes

Indication STELARA™ is indicated for the treatment of adult patients (18 years or older) with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy.

Dosing STELARA™ is administered by subcutaneous injection. • For patients weighing ≤100 kg (220 lbs), the recommended dose is 45 mg initially and 4 weeks later, followed by 45 mg every 12 weeks • For patients weighing >100 kg (220 lbs), the recommended dose is 90 mg initially and 4 weeks later, followed by 90 mg every 12 weeks In patients weighing >100 kg, 45 mg was also shown to be efficacious. However, 90 mg resulted in greater efficacy in these patients. The safety and efficacy of STELARA™ have not been evaluated beyond two years.

Dosage forms and strengths STELARA™ contains 90 mg of ustekinumab per mL. • 45 mg/0.5 mL in a single-use, prefilled syringe, with an NDC number of 57894-060-03 • 90 mg/1 mL in a single-use, prefilled syringe, with an NDC number of 57894-061-03

Please see Important Safety Information and Brief Summary of Prescribing Information for STELARA™ on the following pages. www.STELARAinfo.com

IMPORTANT SAFETY INFORMATION Infections STELARA™ may increase the risk of infections and reactivation of latent infections. Serious bacterial, fungal, and viral infections were reported. Infections requiring hospitalization included cellulitis, diverticulitis, osteomyelitis, gastroenteritis, pneumonia, and urinary tract infections. STELARA™ should not be given to patients with a clinically important active infection and should not be administered until the infection resolves or is adequately treated. Instruct patients to seek medical advice if signs or symptoms suggestive of an infection occur. Exercise caution when considering use of STELARA™ in patients with a chronic infection or a history of recurrent infection. Theoretical Risk for Vulnerability to Particular Infections Individuals genetically deficient in IL-12/IL-23 are particularly vulnerable to disseminated infections from mycobacterium, Salmonella, and Bacillus Calmette-Guerin (BCG) vaccinations. Serious infections and fatal outcomes have been reported in such patients. It is not known whether patients with pharmacologic blockade of IL-12/IL-23 from treatment with STELARA™ will be susceptible to these types of infections. Consider appropriate diagnostic testing as dictated by clinical circumstances. Pre-Treatment Evaluation of Tuberculosis (TB) Evaluate patients for TB prior to initiating treatment with STELARA™. STELARA™ should not be given to patients with active TB. Initiate treatment of latent TB before administering STELARA™. Patients should be monitored closely for signs and symptoms of active TB during and after treatment with STELARA™. Malignancies STELARA™ is an immunosuppressant and may increase the risk of malignancy. Malignancies were reported among patients who received STELARA™ in clinical studies. The safety of STELARA™ has not been evaluated in patients who have a history of malignancy or who have a known malignancy. Reversible Posterior Leukoencephalopathy Syndrome (RPLS) One case of RPLS has been reported in a STELARA™-treated patient. If RPLS is suspected, discontinue STELARA™ and administer appropriate treatment. RPLS is a neurological disorder, which is not caused by an infection or demyelination. RPLS can present with headache, seizures, confusion, and visual disturbances. RPLS has been associated with fatal outcomes. Immunizations Prior to initiating therapy with STELARA™, patients should receive all immunizations recommended by current guidelines. Patients being treated with STELARA™ should not receive live vaccines. BCG vaccines should not be given during treatment or within one year of initiating or discontinuing STELARA™. Exercise caution when administering live vaccines to household contacts of STELARA™ patients, as shedding and subsequent transmission to STELARA™ patients may occur. Non-live vaccinations received during a course of STELARA™ may not elicit an immune response sufficient to prevent disease. Concomitant Therapies The safety of STELARA™ in combination with other immunosuppressive agents or phototherapy has not been evaluated. Ultraviolet-induced skin cancers developed earlier and more frequently in mice genetically manipulated to be deficient in both IL-12 and IL-23 or IL-12 alone. The relevance of these findings in mouse models for malignancy risk in humans is unknown.

Please see Brief Summary of Prescribing Information for STELARA™ on the following page. Reference: STELARA™ Prescribing Information 12/2009. Horsham, PA: Centocor Ortho Biotech Inc.

representing the products of www.STELARAinfo.com

3/10

25US09294

25US10030

Most Common Adverse Reactions The most common adverse reactions (≥3% and higher than that with placebo) in clinical trials for STELARA™ 45 mg, STELARA™ 90 mg, or placebo were: nasopharyngitis (8%, 7%, 8%), upper respiratory tract infection (5%, 4%, 5%), headache (5%, 5%, 3%), and fatigue (3%, 3%, 2%), respectively.

Brief Summary of Prescribing Information for STELARA™ (ustekinumab) STELARA™ Injection, for subcutaneous use See package insert for Full Prescribing Information INDICATIONS AND USAGE: STELARA™ is indicated for the treatment of adult patients (18 years or older) with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy. CONTRAINDICATIONS: None. WARNINGS AND PRECAUTIONS: Infections STELARA™ may increase the risk of infections and reactivation of latent infections. Serious bacterial, fungal, and viral infections were observed in subjects receiving STELARA™ (see Adverse Reactions). STELARA™ should not be given to patients with any clinically important active infection. STELARA™ should not be administered until the infection resolves or is adequately treated. Instruct patients to seek medical advice if signs or symptoms suggestive of an infection occur. Exercise caution when considering the use of STELARA™ in patients with a chronic infection or a history of recurrent infection. Serious infections requiring hospitalization occurred in the psoriasis development program. These serious infections included cellulitis, diverticulitis, osteomyelitis, viral infections, gastroenteritis, pneumonia, and urinary tract infections. Theoretical Risk for Vulnerability to Particular Infections Individuals genetically deficient in IL-12/IL-23 are particularly vulnerable to disseminated infections from mycobacteria (including nontuberculous, environmental mycobacteria), salmonella (including nontyphi strains), and Bacillus Calmette-Guerin (BCG) vaccinations. Serious infections and fatal outcomes have been reported in such patients. It is not known whether patients with pharmacologic blockade of IL-12/IL-23 from treatment with STELARA™ will be susceptible to these types of infections. Appropriate diagnostic testing should be considered, e.g., tissue culture, stool culture, as dictated by clinical circumstances. Pre-treatment Evaluation for Tuberculosis Evaluate patients for tuberculosis infection prior to initiating treatment with STELARA™. Do not administer STELARA™ to patients with active tuberculosis. Initiate treatment of latent tuberculosis prior to administering STELARA™. Consider anti-tuberculosis therapy prior to initiation of STELARA™ in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed. Patients receiving STELARA™ should be monitored closely for signs and symptoms of active tuberculosis during and after treatment. Malignancies STELARA™ is an immunosuppressant and may increase the risk of malignancy. Malignancies were reported among subjects who received STELARA™ in clinical studies (see Adverse Reactions). In rodent models, inhibition of IL-12/IL-23p40 increased the risk of malignancy (see Nonclinical Toxicology). The safety of STELARA™ has not been evaluated in patients who have a history of malignancy or who have a known malignancy. Reversible Posterior Leukoencephalopathy Syndrome One case of reversible posterior leukoencephalopathy syndrome (RPLS) was observed during the clinical development program which included 3523 STELARA™-treated subjects. The subject, who had received 12 doses of STELARA™ over approximately two years, presented with headache, seizures and confusion. No additional STELARA™ injections were administered and the subject fully recovered with appropriate treatment. RPLS is a neurological disorder, which is not caused by demyelination or a known infectious agent. RPLS can present with headache, seizures, confusion and visual disturbances. Conditions with which it has been associated include preeclampsia, eclampsia, acute hypertension, cytotoxic agents and immunosuppressive therapy. Fatal outcomes have been reported. If RPLS is suspected, STELARA™ should be discontinued and appropriate treatment administered. Immunizations Prior to initiating therapy with STELARA™, patients should receive all immunizations appropriate for age as recommended by current immunization guidelines. Patients being treated with STELARA™ should not receive live vaccines. BCG vaccines should not be given during treatment with STELARA™ or for one year prior to initiating treatment or one year following discontinuation of treatment. Caution is advised when administering live vaccines to household contacts of patients receiving STELARA™ because of the potential risk for shedding from the household contact and transmission to patient. Non-live vaccinations received during a course of STELARA™ may not elicit an immune response sufficient to prevent disease. Concomitant Therapies The safety of STELARA™ in combination with other immunosuppressive agents or phototherapy has not been evaluated. Ultraviolet-induced skin cancers developed earlier and more frequently in mice genetically manipulated to be deficient in both IL-12 and IL-23 or IL-12 alone (see Nonclinical Toxicology). ADVERSE REACTIONS: The following serious adverse reactions are discussed elsewhere in the label: Infections (see Warnings and Precautions); Malignancies (see Warnings and Precautions); and RPLS (see Warnings and Precautions). Clinical Studies Experience The safety data reflect exposure to STELARA™ in 2266 psoriasis subjects, including 1970 exposed for at least 6 months, 1285 exposed for at least one year, and 373 exposed for at least 18 months. 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. Adverse reactions listed below are those that occurred at a rate of at least 1% and at a higher rate in the STELARA™ groups than the placebo group during the placebo-controlled period of STUDY 1 and STUDY 2. The numbers (percentages) of adverse reactions reported for placebo-treated patients (n=665), patients treated with 45 mg STELARA™ (n=664), and patients treated with 90 mg STELARA™ (n=666), respectively, were: Nasopharyngitis: 51 (8%), 56 (8%), 49 (7%); Upper respiratory tract infection: 30 (5%), 36 (5%), 28 (4%); Headache: 23 (3%), 33 (5%), 32 (5%); Fatigue: 14 (2%), 18 (3%), 17 (3%); Diarrhea: 12 (2%), 13 (2%), 13 (2%); Back pain: 8 (1%), 9 (1%), 14 (2%); Dizziness: 8 (1%), 8 (1%), 14 (2%); Pharyngolaryngeal pain: 7 (1%), 9 (1%), 12 (2%); Pruritus: 9 (1%), 10 (2%), 9 (1%); Injection site erythema: 3 (<1%), 6 (1%), 13 (2%); Myalgia: 4 (1%), 7 (1%), 8 (1%); Depression: 3 (<1%), 8 (1%), 4 (1%). Adverse drug reactions that occurred at rates less than 1% included: cellulitis and certain injection site reactions (pain, swelling, pruritus, induration, hemorrhage, bruising, and irritation). One case of RPLS occurred during clinical trials (see Warnings and Precautions). Infections In the placebo-controlled period of clinical studies of psoriasis subjects (average follow-up of 12.6 weeks for placebo-treated subjects and 13.4 weeks for STELARA™-treated subjects), 27% of STELARA™-treated subjects reported infections (1.39 per subject-year of follow-up) compared with 24% of placebo-treated subjects (1.21 per subject-year of follow-up). Serious infections occurred in 0.3% of STELARA™-treated subjects (0.01 per subject-year of follow-up) and in 0.4% of placebo-treated subjects (0.02 per subject-year of follow-up) (see Warnings and Precautions). In the controlled and non-controlled portions of psoriasis clinical trials, 61% of STELARA™-treated subjects reported infections (1.24 per subject-year of follow-up).

Serious infections were reported in 0.9% of subjects (0.01 per subject-year of follow-up). Malignancies In the controlled and non-controlled portions of psoriasis clinical trials, 0.4% of STELARA™-treated subjects reported malignancies excluding non-melanoma skin cancers (0.36 per 100 subject-years of follow-up). Non-melanoma skin cancer was reported in 0.8% of STELARA™-treated subjects (0.80 per 100 subject-years of follow-up) (see Warnings and Precautions). Serious malignancies included breast, colon, head and neck, kidney, prostate, and thyroid cancers. Immunogenicity The presence of ustekinumab in the serum can interfere with the detection of anti-ustekinumab antibodies resulting in inconclusive results due to assay interference. In STUDIES 1 and 2, antibody testing was done at time points when ustekinumab may have been present in the serum. In STUDY 1 the last ustekinumab injection was between Weeks 28 and 48 and the last test for anti-ustekinumab antibodies was at Week 52. In STUDY 2 the last ustekinumab injection was at Week 16 and the last test for anti-ustekinumab antibodies was at Week 24. In STUDY 1 (N=743), antibody results were found to be positive, negative, and inconclusive in 38 (5%), 351 (47%), and 354 (48%) patients, respectively. In STUDY 2 (N=1198), antibody results were found to be positive, negative, and inconclusive in 33 (3%), 90 (8%), and 1075 (90%) patients, respectively. The data reflect the percentage of subjects whose test results were positive for antibodies to ustekinumab in a bridging immunoassay, and are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors, including sample handling, timing of sample collection, concomitant medications and underlying disease. For these reasons, comparison of the incidence of antibodies to ustekinumab with the incidence of antibodies to other products may be misleading. DRUG INTERACTIONS: Drug interaction studies have not been conducted with STELARA™. Live Vaccines Live vaccines should not be given concurrently with STELARA™ (see Warnings and Precautions). Concomitant Therapies The safety of STELARA™ in combination with immunosuppressive agents or phototherapy has not been evaluated (see Warnings and Precautions). CYP450 Substrates The formation of CYP450 enzymes can be altered by increased levels of certain cytokines (e.g., IL-1, IL-6, IL-10, TNF , IFN) during chronic inflammation. Thus, ustekinumab could normalize the formation of CYP450 enzymes. A role for IL-12 or IL-23 in the regulation of CYP450 enzymes has not been reported. However, upon initiation of ustekinumab in patients who are receiving concomitant CYP450 substrates, particularly those with a narrow therapeutic index, monitoring for therapeutic effect (e.g., for warfarin) or drug concentration (e.g., for cyclosporine) should be considered and the individual dose of the drug adjusted as needed (see Clinical Pharmacology). USE IN SPECIFIC POPULATIONS: Pregnancy Pregnancy Category B There are no studies of STELARA™ in pregnant women. STELARA™ should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. No teratogenic effects were observed in the developmental and reproductive toxicology studies performed in cynomolgus monkeys at doses up to 45 mg/kg ustekinumab, which is 45 times (based on mg/kg) the highest intended clinical dose in psoriasis patients (approximately 1 mg/kg based on administration of a 90 mg dose to a 90 kg psoriasis patient). Ustekinumab was tested in two embryo-fetal development toxicity studies. Pregnant cynomolgus monkeys were administered ustekinumab at doses up to 45 mg/kg during the period of organogenesis either twice weekly via subcutaneous injections or weekly by intravenous injections. No significant adverse developmental effects were noted in either study. In an embryo-fetal development and pre- and post-natal development toxicity study, three groups of 20 pregnant cynomolgus monkeys were administered subcutaneous doses of 0, 22.5, or 45 mg/kg ustekinumab twice weekly from the beginning of organogenesis in cynomolgus monkeys to Day 33 after delivery. There were no treatment-related effects on mortality, clinical signs, body weight, food consumption, hematology, or serum biochemistry in dams. Fetal losses occurred in six control monkeys, six 22.5 mg/kg-treated monkeys, and five 45 mg/kg-treated monkeys. Neonatal deaths occurred in one 22.5 mg/kg-treated monkey and in one 45 mg/kg-treated monkey. No ustekinumab-related abnormalities were observed in the neonates from birth through six months of age in clinical signs, body weight, hematology, or serum biochemistry. There were no treatment-related effects on functional development until weaning, functional development after weaning, morphological development, immunological development, and gross and histopathological examinations of offsprings by the age of 6 months. Nursing Mothers Caution should be exercised when STELARA™ is administered to a nursing woman. The unknown risks to the infant from gastrointestinal or systemic exposure to ustekinumab should be weighed against the known benefits of breast-feeding. Ustekinumab is excreted in the milk of lactating monkeys administered ustekinumab. IgG is excreted in human milk, so it is expected that STELARA™ will be present in human milk. It is not known if ustekinumab is absorbed systemically after ingestion; however, published data suggest that antibodies in breast milk do not enter the neonatal and infant circulation in substantial amounts. Pediatric Use Safety and effectiveness of STELARA™ in pediatric patients have not been evaluated. Geriatric Use Of the 2266 psoriasis subjects exposed to STELARA™, a total of 131 were 65 years or older, and 14 subjects were 75 years or older. Although no differences in safety or efficacy were observed between older and younger subjects, the number of subjects aged 65 and over is not sufficient to determine whether they respond differently from younger subjects. OVERDOSAGE: Single doses up to 4.5 mg/kg intravenously have been administered in clinical studies without dose-limiting toxicity. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment be instituted immediately. PATIENT COUNSELING INFORMATION: Instruct patients to read the Medication Guide before starting STELARA™ therapy and to reread the Medication Guide each time the prescription is renewed. Infections Inform patients that STELARA™ may lower the ability of their immune system to fight infections. Instruct patients of the importance of communicating any history of infections to the doctor, and contacting their doctor if they develop any symptoms of infection. Malignancies Patients should be counseled about the risk of malignancies while receiving STELARA™. Prefilled Syringe Manufactured by: Vial Manufactured by: Centocor Ortho Biotech Inc., Centocor Ortho Biotech Inc., Horsham, PA 19044, Horsham, PA 19044, License No. 1821 at License No. 1821 at Baxter Pharmaceutical Solutions, Cilag AG, Bloomington, IN 47403 Schaffhausen, Switzerland 1-800-457-6399 25US10041 © Centocor Ortho Biotech Inc. 2009 December 2009

The New Drug Pipeline: Diana Papshev

Chantell M. Reagan

What Is on the Horizon for Managed Care in 2010?

Diana Papshev, PharmD, and Chantell M. Reagan, PharmD Dr Papshev is Partner and Dr Reagan is Managing Director, InformaCeutica, Yardley, PA

epending on the source and methods for classifying drugs, there were 26 to 38 new drug approvals in 2009.1-4 The larger estimate was reported by DrugManagementForum.com (which is owned by InformaCeutica).4 In addition to reporting new molecular entity (NME) and new biologic approvals issued by the Center for Drug Evaluation and Research of the US Food and Drug Administration (FDA), this estimate also includes significant biologics approved by the Center for Biologics Evaluation and Research and a few new drugs, that could be important for managed care but were not officially categorized by the FDA as NMEs or new biologics. In 2009, the therapeutic categories with the most FDA approvals were immunology, oncology/hematology, central nervous system, and cardiovascular (CV) diseases (Figure). It appears that the scope of FDA approvals may increase in 2010. In addition to this year’s approvals so far, there are up to 100 drugs that potentially could be approved in 2010.5 Given the FDA review cycle, historic approval rates, and current focus on safety and risk management, it is safe to say that approximately 40 to 50 new drugs may get approved by the end of the year. It is quite likely that the therapeutic categories most approved in 2009 will be the same in 2010. In addition, 2 other categories will especially stand out this year—endocrinology and rare metabolic diseases—with potentially up to 10 new drugs between them.

InformaCeutica is a drug management information company focused on developing interactive tools for managed care decision makers. InformaCeutica’s offerings include DrugManagementForum.com and DrugPipelineForecast.com. DrugManagementForum.com allows managed care professionals to connect and share ideas on common issues and experiences in drug benefit management. DrugPipelineForecast.com offers a comprehensive tool for tracking late-phase drug pipeline developments from the managed care perspective.

Current 2010 Approvals There have been 10 new drug approvals as of March 18, 2010.6 Nine of these drugs may have significant implications for health plans and pharmacy benefit managers (Table 1). Furthermore, 4 of these 9 drugs have been touted by financial analysts as potential blockbusters. In the short span of 2.5 months, the FDA approved 3 drugs that became the first specific pharmacologic therapies in their respective therapeutic uses—Ampyra (dalfampridine), Carbaglu (carglumic acid), and Xiaflex (collagenase clostridium histolyticum). Until Ampyra was approved, few therapeutic options were available to complement physiotherapy for the management of ambulatory dysfunction in patients with multiple sclerosis (MS).7 Ampyra will have an incremental budgetary impact in the MS category, because it can be used in combination with disease-modifying drugs (DMDs). However, only up to 43% of patients in clinical trials responded to therapy, and there is skepticism among managed care decision makers about the cost-effectiveness of this drug, in part because of the inability to appropriately target therapy for the patients who are most likely to respond.8-10 Carbaglu was approved as a synthetic replacement of N-acetylglutamate for the treatment of patients with N-acetylglutamate synthase deficiency, a very rare, devastating disorder involving an impaired urea cycle and accumulation of ammonia. It will be used in combination with other ammonia-lowering therapies in acute management and as a primary maintenance therapy in this small patient population.11-13 Xiaflex is indicated for the treatment of adult patients with Dupuytren’s contracture, a progressively debilitating condition that affects hand ligaments in older adults (especially men) and may require surgical treatment.14,15 The remaining 6 new drugs listed in Table 1 will add to the therapeutic arsenal in a variety of established treatment categories. Many of them will also offer competitive advantages in terms of efficacy, safety profiles, and/or cost in comparison with existing drugs.

S258 I AMERICAN HEALTH & DRUG BENEFITS I May/June 2010 I Supplement

2010 Drug Pipeline

Figure Significant Brand-Name Drugs Approved by FDA in 2009 Antiinfectives

Antineoplastics

Cardiovascular

1 2

Central nervous system

Endocrine/diabetes

Enzyme replacements and modifiers

Gastrointestinal drugs 2

2 2

Renal and urologic drugs

New chemical entity New dosage/formulation OTC switch New biologics Expanded indications

2 8

Ophthalmologic drugs

Immunologic drugs and vaccines Obstetrics and gynecology

Hematologic drugs

1 4

Respiratory drugs

Topical drugs

11 0

5 7.5

22.5

FDA indicates Food and Drug Administration; OTC, over the counter. Copyright ÂŠ InformaCeutica. Used with permission.

Significant Pipeline Candidates for Approval in 2010 Within the sample of 100 drugs that may gain FDA approval in 2010, 15 products currently under review are particularly likely to capture the attention of pipeline forecasters in the managed care community. Based on their clinical profiles and projected sales estimates, these drugs/biologics have the potential to significantly impact utilization and spending trends under pharmacy and medical benefits. These 15 drugs can be divided into 2 broad categoriesâ&#x20AC;&#x201D;6 nonspecialty (Table 2) and 9 specialty drugs (Table 3). The following information is based on public information compiled by DrugPipelineForecast.com,5 using their search features to provide a high-level overview of these drugs, by therapeutic category. Cardiovascular Diseases Brilinta (ticagrelor) is a new oral antiplatelet drug that is anticipated to compete with Plavix (clopidogrel). Unlike Effient (prasugrel), Brilinta appears to be more potent than Plavix, without an incremental risk of bleeding. In a large phase 3 clinical trial of patients with acute coronary syndrome, Brilinta produced a significantly greater reduction in the composite CV event rate compared with Plavix. Moreover, Brilinta has been

shown to have adequate antiplatelet activity in patients who have not responded to previous treatment with Plavix. At this point, financial analysts predict that Brilinta can generate up to $3 billion in peak annual sales. If Brilinta is approved by the fourth quarter of 2010, it will have 1 year before a generic equivalent of Plavix will enter the market.

Central Nervous System and Pain Naproxcinod (nitronaproxen) will represent the next generation of nonopioid pain treatment; it is a naproxen derivative and a cyclooxygenase (COX)-inhibiting nitric oxide donator. Naproxcinod is being reviewed for use in patients with osteoarthritis. If approved, it is likely to compete with other nonsteroidal anti-inflammatory drugs, especially the COX-2 inhibitor, Celebrex (celecoxib). Although in clinical trials naproxcinod has not been shown to have an adverse effect on blood pressure, it remains to be seen if it may carry some of the CV risks associated with COX-2 inhibitors. Endocrinology Four of the 15 significant pipeline drug candidates are in for endocrinologic conditions: â&#x20AC;˘ Prolia (denosumab) for osteoporosis and bone metastases

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Table 1 Significant FDA Drug Approvals through March 18, 2010, Expected to Become Blockbusters Drug/Formulation

Approval date

Indication

Estimated peak annual sales, $

Implications for managed care

Actemra (tocilizumab), IV injection

1/2010

Moderate-to-severe active RA

600M-2.3B

Another biologic for RA with a novel mechanism of action and second-line indication; likely to compete with Orencia (abatacept); significant uptake potential among rheumatologists

Ampyra (dalfampridine), oral tablet

1/2010

Walking impairment in patients with MS

280M-500M

First drug approved for this indication

Cayston (aztreonam), inhaled solution

1/2010

Respiratory symptoms in patients with cystic fibrosis related to Pseudomonas aeruginosa

300M

First drug approved for cystic fibrosis in 13 years; new inhaled antimicrobial with shorter nebulization time than TOBI (tobramycin [2-3 min vs 15 min])

Carbaglu (carglumic acid), oral tablet

3/2010

Hyperammonemia caused by deficiency of the hepatic enzyme N-acetylglutamate synthase

N/A

First drug approved for hyperammonemia caused by N-acetylglutamate synthase deficiency

Menveo (meningococcal [Groups A, C, Y, and W-135] oligosaccharide diphtheria CRM197 conjugate vaccine), IM injection

2/2010

Meningococcal vaccine (ages 11-55 yrs)

>1B

Third meningococcal vaccine to enter the market; likely to compete with Menactra (another quadrivalent conjugate vaccine) based on head-to-head data; expected to receive pediatric indication in 6-12 mo

Prevnar-13 (pneumococcal 13-valent conjugate vaccine [diphtheria CRM197 Protein]), IM injection

2/2010

Pneumococcal vaccine (pediatric)

2B-3B

Expands protection provided by Prevnar-7 by covering 6 more strains; expected to get adult indication in 12-18 mo

Victoza (liraglutide), SC injection

1/2010

Type 2 diabetes

1.8B

Second glucagonlike peptide-1 analog to enter the market; likely to compete with Byetta (exenatide) based on head-tohead data/once-daily dosing

VPRIV (velaglucerase), IV injection

3/2010

Gaucher disease

300M

Second enzyme replacement for this indication to enter the market; likely to compete with Cerezyme (imiglucerase) based on lower price (~15% discount) and manufacturing issues

Xiaflex (collagenase clostridium histolyticum), IL injection

2/2010

Dupuytren’s contracture

400M

First drug approved for this indication

B indicates billion; IL, intralesional; IM, intramuscular; IV, intravenous; M, million; MS, multiple sclerosis; N/A, not available in the public domain; RA, rheumatoid arthritis; SC, subcutaneous. Sources: www.DrugManagementForum.com. Morrison T. FDA approvals could lead to launch of eight blockbuster biotech drugs. BNET. February 8, 2010. Bennett J. Drug blockbusters of the future. Barron’s. January 29, 2009. Bennett J. Five drugs that could be blockbusters. Barron’s. January 27, 2010. Evaluate Pharma. Which of 2009’s launches could be future blockbusters? February 17, 2009. Mijuk G. Novartis gets US FDA ok for Menveo, priority review for Gilenia. Wall Street Journal. February 22, 2010. Evaluate Pharma. With US backing Prevnar 13 aims for blockbuster status. February 25, 2010.

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2010 Drug Pipeline

Table 2 Significant Nonspecialty Pipeline Candidates in 2010 (Starting 3/19/10) Drug/Formulation

Estimated Therapeutic category Estimated peak a FDA approval (investigated use) annual sales, $ 1.25B

Implications for managed care

Bydureon (exenatide), long-acting subcutaneous injection

2-3Q 2010b

Endocrine (type 2 diabetes)

Long-acting formulation of Byetta (exenatide), once-weekly dosing

Daxas (roflumilast), oral tablet

2Q 2010b

Respiratory (COPD)

Naproxcinod, oral capsule

7/24/2010c

CNS/pain (osteoarthritis)

Brilinta (ticagrelor), oral

3-4Q 2010b

CV (acute coronary syndrome)

1.5B-3B

Third antiplatelet drug to compete with Plavix (clopidogrel) and Effient (prasugrel); showed superiority to clopidogrel in CV events without increased bleeding risk Unlikely to have black box warning for issues with CYP2C19 metabolism

Lorcaserin, oral

10/22/2010c

Endocrine (obesity)

850M

Novel mechanism of action; first selective serotonin 2C receptor agonist; demonstrated significant reductions in body weight (average weight loss, 10%), body composition, other CV risk factors

Qnexa (phentermine/ topiramate), oral capsule

10/28/2010c

Endocrine (obesity)

3B-5B Novel mechanism of action; (in combination first PDE-4 enzyme inhibitor; with other efficacious in combination with ingredients) a long-acting beta-agonist 1.5B

Novel mechanism of action; first COX-inhibiting nitric oxide donator; likely to compete with Celebrex (celecoxib) based on head-to-head data with rofecoxib

Combination of 2 existing agents; demonstrated significant reductions in body weight (average weight loss, 15%), A1c, and other metabolic end points

A1c indicates glycated hemoglobin; B, billion; CNS, central nervous system; COPD, chronic obstructive pulmonary disease; COX, cyclooxygenase; CV, cardiovascular; M, million; PDE, phosphodiesterase; Q, quarter. a Estimated approval as of March 2010, subject to change. b Estimated approval time is based on publicly available information. c Estimated approval time is based on announced Prescription Drug User Fee Act date. Sources: www.DrugPipelineForecast.com. www.DrugManagementForum.com.

â&#x20AC;˘ Bydureon (exenatide long-acting) for diabetes â&#x20AC;˘ Lorcaserin and Qnexa (phentermine and topiramate) for obesity. Prolia is the most prominent drug of these 4, topping blockbuster predictions with $4-billion peak sales estimates. Prolia will be the first biologic in the osteoporosis class. Prolia is a human monoclonal antibody targeting the nuclear factor-kappa B (RANK) ligand, which regu-

lates osteoclast activity. It has been shown to produce significantly greater increases in bone mineral density compared with alendronate in postmenopausal osteoporosis and greater reductions in skeletal events than Zometa (zoledronic acid) in patients with prostate or breast cancer with bone metastases. Bydureon is expected to replace Byetta (exenatide) as a longer-acting formulation with once-weekly dosing. In

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Table 3 Significant Specialty Pipeline Candidates in 2010 (Starting 3/19/10) Therapeutic category Estimated peak Implications for Estimated annual sales, $ managed care Drug/Formulation FDA approvala (investigated use) Belatacept, IV injection

5/1/2010b

Immunology (renal transplant)

500M

First transplant drug approved in 13 years; novel mechanism of action; first selective costimulation blocker for prophylaxis of acute renal graft rejection; better safety profile than cyclosporine

Provenge (sipuleucel-T), IV injection

5/1/2010b

Immunology/oncology (prostate cancer)

1.5B

First-in-class active cellular immunotherapy or â&#x20AC;&#x153;therapeutic vaccineâ&#x20AC;?; improved overall survival; likely to compete with Avastind (bevacizumab), Taxotere (docetaxel), and agents in late-stage pipeline

5/4/2010b Esbriet (pirfenidone), oral

Respiratory (IPF)

First drug approved for IPF

2Q 2010c Numax (motavizumab), IM injection (brand name to change)

Respiratory (respiratory syncytial virus)

Second-generation Synagis (palivizumab), with improved potency, possible singledose regimen per season; likely to compete with/replace Synagis based on improved regimen and fewer outpatient infections in a head-to-head study (similar rates of hospitalization)

Prolia (denosumab), SC injection

7/23/2010b

Endocrine/oncology (osteoporosis/bone metastases in breast/ prostate cancer)

Novel mechanism of action; first biologic to target nuclear factor-kappa B (RANK) ligand; likely to compete with bisphosphonates based on head-to-head data (vs Fosamax [alendronate] in osteoporosis and vs Zometa [zoledronic acid] in breast/prostate cancer with bone metastases)

Gilenia (fingolimod), oral tablet

3Q 2010c

Immunology (MS)

Novel mechanism of action; first sphingosine 1-phosphate receptor modulator; first oral disease-modifying therapy to be approved for MS; likely to compete with other DMDs based on head-tohead data (vs interferon beta-1a)

Neutroval (XM02), SC/IV injection

4Q 2010c

Hematology/oncology (neutropenia)

N/A

First biosimilar granulocyte colonystimulating factor (with full BLA submission); likely to compete with Neupogen (filgrastim) based on price and noninferiority data in head-to-head trials

Replagal (agalsidase alfa), IV injection

4Q 2010c

Rare metabolic diseases (Fabry disease)

265M

Second enzyme replacement therapy to be approved for Fabry disease; likely to compete with Fabrazyme (agalsidase beta) possibly based on lower price

Uplyso (taliglucerase), IV injection

4Q 2010c

Rare metabolic diseases (Gaucher disease)

N/A

Third enzyme replacement therapy to be approved for Gaucher disease; likely to compete with Cerezyme (imiglucerase) and VPRIV (velaglucerase)

B indicates billion; BLA, biologic license application; DMD, disease-modifying drug; IM, intramuscular; IPF, idiopathic pulmonary fibrosis; IV, intravenous; M, million; MS, multiple sclerosis; N/A, not available in the public domain; Q, quarter; SC, subcutaneous. a Estimated approval time as of March 2010, subject to change. b Expected approval time is based on the announced Prescription Drug User Fee Act date. c Expected approval time is based on publicly available information. d Avastin (bevacizumab) has not been approved for the treatment of prostate cancer (currently in phase 2). Sources: www.DrugPipelineForecast.com. www.DrugManagementForum.com.

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2010 Drug Pipeline

clinical trials, Bydureon has been shown to produce a significantly greater reduction in hemoglobin A1c levels compared with Lantus (insulin glargine), with an average reduction of 1.5% versus 1.3%, respectively, as well as a significantly greater impact on weight, with an average reduction of 5.8 pounds compared with an average gain of 3.1 pounds, respectively.5 The remaining 2 drugs are being reviewed for weight loss. Lorcaserin and Qnexa have been shown to produce an average body weight loss of at least 10%,5 along with improvement in other markers of cardiometabolic risk. It will be interesting to see how these drugs will be positioned, considering that weight-management drugs are typically excluded from commercial pharmacy benefits and are explicitly excluded from the Medicare Part D plan benefit.

reform. Neutroval is a granulocyte colony-stimulating factor, which is similar to Neupogen (filgrastim). It is expected to compete with filgrastim on the basis of price, which is the way it is positioned in Europe (under the name Tevagrastim).

Immunology This category includes 2 important pipeline prospects—belatacept and Gilenia (fingolimod). Belatacept is a new immunosuppressive drug being reviewed for the management of renal transplant patients; it has a novel mechanism of action and appears to have a better safety profile than cyclosporine. Gilenia is an oral DMD for patients with MS and will be the first sphingosine 1-phosphate receptor modulator. In a phase 3 clinical trial, compared with Avonex (interferon beta1a), patients treated with Gilenia had a significantly lower annualized relapse rate.16 However, it is too early to determine if Gilenia will be positioned as a first-line therapy, because of potential safety risks; in clinical trials, fingolimod was associated with an increased incidence of serious adverse events, including infections. Deaths in connection with herpes infection were reported in patients treated with higher doses of fingolimod.

Rare Metabolic Diseases Two more significant approvals are expected in the rare metabolic diseases category in 2010—Replagal (agalsidase alfa) for Fabry disease, and Uplyso (taliglucerase alfa) for Gaucher disease. The most significant implication of these potential drug approvals is that they will create additional therapeutic options for 2 lysosomal storage diseases, where only 1 orphan drug treatment was previously available, at an annual cost of hundreds of thousands of dollars per patient. Replagal will be the second drug to be approved for Fabry disease; Fabrazyme (agalsidase beta) has been the only enzyme replacement therapy in that market since 2003. Uplyso will be the third drug to be approved for Gaucher disease type 1, where Cerezyme (imiglucerase) has been the only enzyme replacement therapy for more than a decade until VPRIV (velaglucerase) was approved earlier this year.

Oncology and Hematology Provenge (sipuleucel-T) and Neutroval (XM02) are especially interesting, although for very different reasons. Provenge will be the first oncologic therapy to be classified as an active cellular immunotherapy, or a therapeutic vaccine that uses live human cells to elicit an immune response against cancer cells. The application for Provenge was resubmitted to the FDA in late 2009, with requested survival data in patients with advanced prostate cancer. Although the second drug in this category could be classified as a follow-on biologic, it is being reviewed through the full biologic license application submission, because there has been no established formal pathway for review of follow-on biologics in the United States until the passage of the recent healthcare

Respiratory Conditions The last therapeutic category to be highlighted in this review is respiratory diseases, with 3 potentially significant pipeline candidates, all of which may reach blockbuster sales status: • Daxas (roflumilast) for chronic obstructive respiratory disease (COPD) • Esbriet (pirfenidone) for idiopathic pulmonary fibrosis (IPF) • Motavizumab (formerly branded as Numax) for the prevention of respiratory syncytial virus (RSV) infections. Daxas is a phosphodiesterase-4 inhibitor that is being reviewed for use in patients with COPD; it is expected to be used in combination with other therapies, including long-acting bronchodilators.

Belatacept is a new immunosuppressive drug being reviewed for the management of renal transplant patients; it has a novel mechanism of action and appears to have a better safety profile than cyclosporine. Gilenia is an oral DMD for patients with MS and will be the first sphingosine 1-phosphate receptor modulator.

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Esbriet is projected to become the first specific treatment for patients with IPF. The recent controversial decision of the FDA Advisory Committee to recommend approval of Esbriet underscores the urgency in addressing this unmet medical need. Although the committee recommended approving Esbriet by a vote of 9 to 3, committee members were split on the efficacy parameter. Five of the 12 members indicated that they did not believe that Esbriet met the FDA’s standard for substantial evidence to support efficacy in IPF.

Up to 40 or 50 new drugs are expected to hit the market in 2010. At least 24 of these have the potential to significantly affect drug utilization and trend. Motavizumab is being developed by the manufacturers of Synagis (palivizumab), as the next generation of RSV therapy. It is more potent than Synagis, which could allow for a single-injection regimen in the future (this dosage regimen is in phase 2 clinical trials), but for now the biologic license application was submitted for monthly injections during the RSV season, similar to Synagis. Motavizumab has been shown to be associated with fewer outpatient infections related to RSV compared with Synagis, and it was noninferior to Synagis in terms of reduction of related hospitalizations.

Conclusion The FDA is expected to approve more new therapies in 2010 than in 2009. Up to 40 or 50 new drugs are expected to hit the market in 2010. At least 24 of these new market entrants have the potential to significantly affect drug utilization and trend; most of them can be categorized as specialty drugs. Nine of these drugs have

already been approved and are undergoing various stages of review for coverage decisions, while the managed care community is following the FDA review status for the remaining 15 drugs. ■

References 1. Goldstein J. FDA drug approvals in 2009: up (a little) from 2008. Wall Street Journal. WSJ blogs, January 5, 2010. http://blogs.wsj.com/health/ 2010/01/05/fdadrug-approvals-in-2009-up-a-little-from-2008/tab/article/. Accessed March 18, 2010. 2. US Food and Drug Administration. Drug and biologic approval reports. www.fda. gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ DrugandBiologicApprovalReports/default.htm. Accessed March 18, 2010. 3. US Food and Drug Administration. Vaccines, blood & biologics: 2009 biological approvals. www.fda.gov/BiologicsBloodVaccines/DevelopmentApprovalProcess/ BiologicalApprovalsbyYear/ucm170662.htm. Accessed March 22, 2010. 4. Drug Management Forum. Significant FDA brand approvals for 2009. www.drug managementforum.com/forum/new-brand-drug-approvals-month/16065-significantfda-brand-approvals-2009-a.html. Accessed March 22, 2010. 5. Drug Pipeline Forecast. www.drugpipelineforecast.com/pipeline/search/. Accessed March 22, 2010. 6. Drug Management Forum. New brand drug approvals by month. www.drugmanage mentforum.com/forum/new-brand-drug-approvals-month/. Accessed March 22, 2010. 7. Thompson A, Polman C. Improving function: a new treatment era for multiple sclerosis? Lancet. 2009;373:697-698. 8. Goodman AD, Brown TR, Krupp LB, et al. Sustained-release oral fampridine in multiple sclerosis: a randomised, double-blind, controlled trial. Lancet. 2009;373: 732-738. 9. National Multiple Sclerosis Society. News detail: Fampridine-SR improves walking speed in all types of MS in second phase 3 study. June 3, 2008. www.national mssociety.org/research/research-news/news-detail/index.aspx?nid=237. Accessed March 22, 2010. 10. Drug Management Forum. Ampyra. www.drugmanagementforum.com/forum/ managed-care-issues-oral-drugs/17257-ampyra.html. Accessed March 22, 2010. 11. US Food and Drug Administration. Carbaglu: highlights of prescribing information. 2010. www.accessdata.fda.gov/drugsatfda_docs/label/ 2010/022562lbl.pdf. Accessed March 22, 2010. 12. National Organization for Rare Disorders. N-acetyl glutamate synthetase deficiency. www.rarediseases.org/search/rdbdetail_abstract.html? disname=N-Acetyl% 20Glutamate%20Synthetase%20Deficiency. Accessed March 22, 2010. 13. Urea Cycle Disorders Consortium. Urea cycle disorders treatment guidelines. http://rarediseasesnetwork.epi.usf.edu/ucdc/physicians/guidelines-main.htm. Accessed March 22, 2010. 14. US Food and Drug Administration. Xiaflex: highlights of prescribing information. 2010. www.accessdata.fda.gov/drugsatfda_docs/label/2010/125338lbl.pdf. Accessed March 22, 2010. 15. Trojian TH, Chu SM. Dupuytren’s disease: diagnosis and treatment. Am Fam Physician. 2007;76:86-89. 16. Cohen JA, Barkhof F, Comi G, et al, for the TRANSFORMS Study Group. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med. 2010;362:402-415.

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

| MANAGED MARKETS

Leaders in Business. Partners in Care. Visit Takeda on the Web at www.tpna.com.

Dexamethasone Intravitreal Implant for Treatment of Macular Edema Following Retinal Vein Occlusion Retinal vein occlusion (RVO) is the second most common cause of vision loss due to retinal vascular disease.1-4 The condition occurs when a vascular obstruction prohibits normal blood flow from the eye. While the exact cause is not known, possible sources include blood clot, external vascular compression, or disease of the vein wall.5-7 There are two main subtypes of RVO, central retinal vein occlusion (CRVO) and branch retinal vein occlusion (BRVO), which are distinguished by the location of the obstruction.1,8 In CRVO, the central retinal vein is obstructed near the optic nerve, affecting most of the retina.8 In BRVO, the obstruction is located on one of the branches of the central retinal vein, affecting only a portion of the retina.2 BRVO is the more common form, occurring two to three times more frequently than CRVO.5 However, each type can lead to several vision-threatening complications, including macular edema (ME).1 ME is a common cause of vision loss in RVO.9 Retinal vein occlusions precipitate vascular leakage.2 ME occurs when sufficient fluid accumulates to cause extravascular swelling in the central retina. As a result, patients experience blurred vision and loss of portions of the field of vision. Inflammatory mediators play an important role in the disease process.10 Evidence suggests that longer duration of ME correlates with a worse visual prognosis.3,11-14 Both types of RVO often present as a sudden, painless loss of vision in the affected eye.1 BRVO is also characterized by intraretinal hemorrhages, retinal or macular edema, and cotton wool spots in the region of the affected vein. If the condition is chronic, hemorrhages may be absent, with ME as the sole symptom.6

Typical CRVO presentation includes disc edema, dilated and twisted veins, widespread deep and superficial hemorrhages, cotton wool spots, retinal edema and closure of retinal capillaries.2,15 There are two types of CRVO— ischemic (associated with significant vision loss and poor prognosis) and nonischemic (less vision-threatening).16 Management of RVO consists of observation and interventions to address modifiable risk factors and sequelae.2 Macular grid laser photocoagulation has been the standard of care for BRVO-associated ME since the publication of the Branch Vein Occlusion Study (BVOS) in 1984.3 However, the Central Vein Occlusion Study (CVOS) showed no benefit of laser treatment in CRVO-associated ME.17 OZURDEX™ (dexamethasone intravitreal implant) 0.7 mg, from Allergan, is the first and only FDA-approved pharmacotherapy indicated for ME following BRVO or CRVO. This treatment option is based on proprietary solidpolymer drug delivery technology (NOVADUR,™ Allergan), which transforms dexamethasone into a viable and effective therapeutic approach to reducing ME caused by RVO.

OZURDEX™ and NOVADUR™ Technology

OZURDEX™ is an injectable, biodegradable intravitreal implant containing 0.7 mg dexamethasone, a potent corticosteroid shown to block chemical pathways that lead to inflammation and leakage from the retinal blood vessels.18 The OZURDEX™ implant is composed of NOVADUR™ solid polymer matrix impregnated with dexamethasone.18 Upon injection into the vitreous, the implant biodegrades to lactic acid and glycolic acid,18 releasing dexamethasone to reduce ME and improve visual acuity (see Figure 1). OZURDEX™ is preloaded into a sterile, single-use, patented

Indication: OZURDEX™ is indicated for the treatment of macular edema following branch retinal vein occlusion (BRVO) or central retinal vein occlusion (CRVO). Dosage and Administration: For ophthalmic intravitreal injection only. The intravitreal injection procedure should be carried out under controlled aseptic conditions. Following the intravitreal injection, patients should be monitored for elevation in intraocular pressure and for endophthalmitis. Patients should be instructed to report any symptoms suggestive of endophthalmitis without delay. Important Safety Information Contraindications: OZURDEX™ is contraindicated in patients with active or suspected ocular or periocular infections including most viral diseases of the cornea and conjunctiva, including active epithelial herpes simplex keratitis (dendritic keratitis), vaccinia, varicella, mycobacterial infections, and fungal diseases. It is also contraindicated in patients with advanced glaucoma and in patients with known hypersensitivity to any components of this product or to other corticosteroids. Please see additional Important Safety Information on the following pages.

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BRVO.19 Patients were only included if, in the investigator’s opinion, their condition was unlikely to be adversely Actual affected if not treated for size 6 months.19 A 6-month, masked initial treatment (IT) phase was followed by a 6-month open-label (OL) phase. In the OL phase, eligible patients Before implantation 3 weeks after implantation from both the active and sham treatment groups received OZURDEX ™ Scanning Electron Microscopy (SEM) magnification of implant surface in an animal model. implant. Eligible criteria Clinical significance unknown. for OL treatment included: completing the intravitreal applicator. In an in-office procedure, the implant 6-month IT phase; BCVA < 84 letters (< 20/20 Snellen) or is injected into the vitreous via a 22-gauge needle. OCT > 250 µm in the central 1 mm macular subfield AND in the investigator’s opinion, the procedure would not put Phase 3 Clinical Trials a patient at risk.19 The efficacy of OZURDEX™ was assessed in GENEVA, Key outcome measures and follow-up were identical the Global Evaluation of ImplaNtable DExamethasone in in IT and OL phases. Patients were evaluated at baseline Retinal Vein Occlusion With Macular EdemA. GENEVA and days 1, 7, 30, 60, 90, and 180 in both phases.19 The consisted of two randomized, prospective, multicenter, primary efficacy measure was improvement in patients’ double-masked, sham-controlled, parallel-group, phase BCVA, which was measured at every study visit using 3 clinical studies involving approximately 853 patients.19 a standard Early Treatment Diabetic Retinopathy Study Eligible patients were at least 18 years of age and had (ETDRS) protocol.19 Secondary outcome measures were decreased visual acuity as a result of clinically detectable central retinal thickness (measured using OCT), fundus macular edema associated with BRVO or CRVO, photography, fluorescein angiography, contrast sensitivity, documented as best-corrected visual acuity (BCVA) of > 34 and safety parameters (including intraocular pressure [IOP] and < 68 letters (20/200 to 20/50) and retinal thickness in the assessments, biomicroscopy, ophthalmoscopy, and adverse central subfield (measured by optical coherence tomography events).19 The presence of lens opacities was measured 19 [OCT]) ≥ 300 µm in the study eye. Disease duration was during slit lamp examination.19 required to be between 6 weeks and 9 months in patients with CRVO, and between 6 weeks and 12 months in patients with Figure 1

The OZURDEX™ Intravitreal Implant in an Animal Model

Important Safety Information Contraindications: OZURDEX™ is contraindicated in patients with active or suspected ocular or periocular infections including most viral diseases of the cornea and conjunctiva, including active epithelial herpes simplex keratitis (dendritic keratitis), vaccinia, varicella, mycobacterial infections, and fungal diseases. It is also contraindicated in patients with advanced glaucoma and in patients with known hypersensitivity to any components of this product or to other corticosteroids. Warnings and Precautions: Intravitreal injections have been associated with endophthalmitis, eye inflammation, increased intraocular pressure, and retinal detachments. Patients should be monitored following the injection. Use of corticosteroids may produce posterior subcapsular cataracts, increased intraocular pressure, glaucoma, and may enhance the establishment of secondary ocular infections due to bacteria, fungi, or viruses. Corticosteroids should be used cautiously in patients with a history of ocular herpes simplex. Corticosteroids should not be used in active ocular herpes simplex. Adverse reactions: The most common ocular adverse reactions reported by greater than 2% of the patients in the first 6 months included increased intraocular pressure (25%), conjunctival hemorrhage (20%), eye pain (7%), conjunctival hyperemia (7%), ocular hypertension (4%), cataract (4%), vitreous detachment (3%), and headache (3%). Please see full OZURDEX™ prescribing information at the end of this article. Supplement

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Table 1 provides the demographic and baseline characteristics of the study population. Approximately twice as many patients had BRVO as CRVO and the overwhelming majority of patients had a disease duration of > 90 days.19 There was no statistically significant difference between the treatment groups with regard to any parameter.

Efficacy

In the masked IT phase, more patients who received OZURDEX™ (dexamethasone intravitreal implant) 0.7 mg (n = 427) gained 3 lines of vision significantly faster than did those who received sham (n = 426).18 Twenty percent to 30% of OZURDEX™ patients gained 3 lines within 1 to Table 1

Demographic and Baseline Characteristics19 Ozurdex™ (n = 427)

Sham (n = 426)

Gender (female)

49.2%

43.7%

Race (white)

75.2%

74.6%

Age (years) (range)

64.7 (33-90)

63.9 (31-91)

Diagnosis in study eye CRVO BRVO

31.9% 68.1%

34.5% 65.5%

Duration of ME (days) < 90 90-179 ≥ 180

16.4% 51.3% 32.3%

15.3% 51.6% 33.1%

Mean VA (range)

54.3 (20/80) (34-68)

54.8 (20/80) (28-80)

Mean OCT (range)

562.0 (127-1320)

538.6 (94-1218)

2 months versus 7% to 12% with sham (see Figure 2).18,19 The proportion of patients achieving at least a 15-letter improvement was significantly greater with OZURDEX™ than sham from day 30 through day 90 (P < .001).19 Importantly, OZURDEX™ proved effective in both BRVO (n = 291) and CRVO (n = 136). Regardless of RVO type, more patients who received OZURDEX™ gained 3 lines within 1 to 2 months than sham-treated patients (see Figures 3 and 4).19 Mean change in BCVA from baseline is presented in Figure 5. Overall, patients randomized to OZURDEX™ (n = 427) gained a mean of 9.8 letters at day 60, which was statistically significant (P < .001) versus the mean of 3.1 letters gained by sham-treated patients (n = 426).19 As with 3-line gains, the mean change in BCVA was similar regardless of RVO type (see Figures 6 and 7). At day 60, BRVO patients (n = 291) gained approximately 10 letters with OZURDEX™ compared with approximately 5 letters in the sham group (n = 279) (P < .001), while CRVO patients gained approximately 9 letters with OZURDEX™ (n = 136) as opposed to a decrease of 0.5 letters in the sham group (n = 147) (P < .001).19 Figure 2

crvo indicates central retinal vein occlusion; brvo, branch retinal vein occlusion; ME, macular edema; VA, visual acuity; OCT, optical coherence tomography. Source: Data on file, Allergan, Inc.

Percentage of Patients With ≥15-Letter Gains19

a NS = not significant. Source: Data on file, Allergan, Inc.

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Figure 3

Percentage of BRVO Patients With ≥ 15-Letter Gains19

Figure 4

NS = not significant. Source: Data on file, Allergan, Inc.

a NS = not significant. Source: Data on file, Allergan, Inc.

Figure 5

Percentage of CRVO Patients With ≥ 15-Letter Gains19

Mean Change in BCVA19

9.8 8.1

7.2 5.1

2.6

3.1

3.2

In addition, patients treated with OZURDEX ™ demonstrated a significantly lower incidence of 3-line vision loss from baseline BCVA compared with sham. At day 90, OZURDEX ™ implant reduced the incidence of 3-line vision loss by nearly 50% (3.5% vs 6.8% with sham; P = .030) (see Figure 8).19

2.6

Source: Data on file, Allergan, Inc.

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Mean Change in BCVA: BRVO Patients19

Figure 7

P < .001

10.3

Sham (n = 279) P = .008 7.4

6 5.1

5.0

4.9

3.8

2 0 Baseline

Day 30

Day 60

Day 90

Day 120

Day 150

OZURDEX™ (n = 136)

P < .001 8.7

8.5

Mean Change in BCVA: CRVO Patients19

OZURDEX™ (n = 291)

Mean Number of Letters Gained or Lost

Mean Number of Letters Gained

Figure 6

Day 180

Study Day

Sham (n = 147)

P < .001

7.2

8.7

P = .005

4.2

2 P = NSª 0

0.4 -0.5

-2

0.1

-0.4

-1.8

Source: Data on file, Allergan, Inc. -4 Baseline

Figure 8

Day 30

Day 60

Day 90

Day 120

Day 150

Day 180

Study Day

Percentage of Patients With ≥ 15 Letters Lost19

a NS = not significant. Source: Data on file, Allergan, Inc.

Safety

OZURDEX™ is contraindicated in patients with active or suspected ocular or periocular infections including most viral diseases of the cornea and conjunctiva, including active epithelial herpes simplex keratitis (dendritic keratitis), vaccinia, varicella, mycobacterial infections, and fungal diseases. It is also contraindicated in patients with advanced glaucoma and in patients with known hypersensitivity to any components of this product or to other corticosteroids. Intravitreal injections have been associated with endophthalmitis, eye inflammation, increased intraocular pressure, and retinal detachments. Patients should be monitored following the injection. Use of corticosteroids may produce posterior subcapsular cataracts, increased intraocular pressure, glaucoma, and may enhance the establishment of secondary ocular infections due to bacteria, fungi, or viruses. Corticosteroids should be used cautiously

Source: Data on file, Allergan, Inc.

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Table 2

Incidence of Common Adverse Events and Withdrawal18,19

Figure 9

Percentage of Patients With Increase ≥ 10 mm Hg From Baseline IOP: IT Phase19

100

(n = 421)

(n = 423) 20 15.7 15 10.2 10

7.3 4.3

1.2

0.7 0 0.0

0.2

0.7

0.8

Source: Data on file, Allergan, Inc.

Figure 10 Percentage of Patients With IOP ≥ 35 mm Hg: IT Phase19 100

in patients with a history of ocular herpes simplex. Corticosteroids should not be used in active ocular herpes simplex. Table 2 lists the incidence of common adverse events and withdrawal during the masked IT phase (OZURDEX™ n = 421; sham n = 423). There were no reports of endophthalmitis (either infectious or sterile).19 Retinal detachments occurred in 0.2% of patients in both groups.19 The incidence of cataract in patients treated with OZURDEX™ implant was also similar to those treated with sham (4% of patients with implant vs 1% of patients with sham).18 Over the course of 12 months (IT plus OL phases) a total of 4 cataract extractions were performed in the study eyes of patients who received 2 doses of OZURDEX™ (n = 341). One additional extraction was

15 10 5 0.2

0.7

0.0

1.7

3.2 0.7

0.2

0.0

0 0.0

0.0

Source: Data on file, Allergan, Inc.

performed in a nonstudy eye. 19 Other adverse events included: conjunctival hemorrhage, eye pain, conjunctival hyperemia, ocular hypertension, vitreous detachment, and retinal detachment.18,19

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Figure 11

Percentage of Patients With Increase ≥ 10 mm Hg From Baseline IOP: 12-Month Data19 Initial-treatment phase

100

Open-label phase

Percentage of Patients

OZURDEX™/OZURDEX™ (n = 341) Sham / 20

OZURDEX™ (n = 327)

17.5 13.9

13.6 15.9

8.3

7.5

5.6

3.8

0.9

0.6 0 Baseline

2.2

4.2

0.0

0.3

0.0

0.6

1.8

2.5

Day 1

Day 7

Day 30

Day 60

Day 90

Day 180

Day 1

Day 7

Study Day

10.9 8.0

2.6

Day 90

Day 180

0.9 Day 30

Day 60

Source: Data on file, Allergan, Inc.

Figure 12 Percentage of Patients With IOP ≥ 35 mm Hg: 12-Month Data19 Initial-treatment phase

100

Open-label phase

Percentage of Patients

OZURDEX™/OZURDEX™ (n = 341) Sham /

OZURDEX™ (n = 327)

0 Baseline

0.3

0.6

1.5

0.0

Day 1

Day 7

Day 30

3.0 0.6

0.0

0.3

0.0

0.3

0.0

Day 60

Day 90

Day 180

Day 1

Day 7

Study Day

2.8

2.6

1.5

2.2

2.5

1.0

0.0

Day 30

Day 60

Day 90

Day 180

0.3

Source: Data on file, Allergan, Inc.

levels by day 180 (see Figures 9 and 10).18 At day 180, 1 patient (0.2%) in the OZURDEX™ implant group had IOP ≥ 35 mm Hg and 5 patients (1.2%) had IOP ≥ 25 mm Hg.19 Most patients with increased IOP were medically managed with observation or topical medications. Approximately 30% of patients in the OZURDEX™ group were taking IOP-lowering medication on days 60 and 90 of the studies. The majority of these patients were on a single IOP medication.19 Three of 421 patients (0.7%) required surgery for increased IOP and 1 of these cases was due to neovascular glaucoma.18,19 The IOP response in the OL retreated population was similar to that seen in the IT phase (OZURDEX™ n = 341; sham n = 327) (see Figures 11 and 12). IOP increases peaked at day 60 after the second injection and returned to baseline levels by 180 days posttreatment.19 Procedures to manage elevated IOP in the retreatment phase were performed in 1.2% (n = 4) of patients who received a second OZURDEX™ implant and in 0.3% (n = 1) of patients who received an implant during the open-label phase but had received sham treatment in the initial-treatment phase.19

The most common ocular adverse reaction reported in the IT phase was increased IOP, which was reported in 25% of OZURDEX™ implant patients as compared with 1% of sham-treated patients.18 Increased IOP with OZURDEX™ peaked at day 60 and returned to baseline

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Summary

RVO is the second most common cause of vision loss due to retinal vascular disease.1 Macular edema, a sequelae of RVO, is the underlying cause of vision loss in many of these cases.9 OZURDEX™ (dexamethasone intravitreal implant) 0.7 mg is the first pharmacotherapy indicated for treatment

of macular edema following BRVO or CRVO. This important therapeutic option is the result of NOVADUR™ solid polymer drug delivery technology. Following the intravitreal injection, patients should be monitored for elevation in intraocular pressure and for endophthalmitis.

References: 1. Yau JW, Lee P, Wong TY, Best J, Jenkins A. Retinal vein occlusion: an approach to diagnosis, systemic risk factors and management. Intern Med J. 2008;38(12):904-910. 2. Royal College of Ophthalmologists. Retinal vein occlusion interim guidelines. Royal College of Ophthalmologists Web site. http://www.rcophth.ac.uk/docs/publications /published-guidelines/RVO_Guidelines_Feb_2009.pdf. Published February 2009. Accessed December 30, 2009. 3. The Branch Vein Occlusion Study Group: Argon laser photocoagulation for macular edema in branch vein occlusion. Am J Ophthalmol. 1984;98(3):271-282. 4. Orth DH, Patz A. Retinal branch vein occlusion. Surv Ophthalmol.1978;22:357-376. 5. Klein R, Klein BE, Moss SE, Meuer SM. The epidemiology of retinal vein occlusion: the Beaver Dam Eye Study. Trans Am Ophthalmol Soc. 2000;98:133-141. 6. Wu L, Evans T. Branch retinal vein occlusion. eMedicine Web site. http://emedicine. medscape.com/article/1223498-overview. Updated July 20, 2007. Accessed June 20, 2009. 7. Green WR, Chan CC, Hutchins GM, Terry JM. Central retinal vein occlusion: a prospective histopathologic study of 29 eyes in 28 cases. Retina. 1981;1(1):27-55. 8. Byrnes MJ, Sena D, Tzekov RT. Combination therapies for the treatment of retinal vein occlusion. Retina Today. March 2009:53-54.

12. Oh JY, Seo JH, Ahn JK, Heo JW, et al. Early versus late intravitreal triamcinolone acetonide for macular edema associated with branch retinal vein occlusion. Kor J Ophthalmol. 2007;21(1):18-20. 13. Shilling JS, Jones CA. Retinal branch vein occlusion: a study of argon laser photocoagulation in the treatment of macular edema. Br J Ophthalmol. 1984;68:196-198. 14. Coscas G, Gaudric A: Natural course of nonaphakic cystoid macular edema. Surv Ophthalmol. 1984;28(suppl):471-484. 15. Spalton DJ, Shilling JS. The retina: vascular diseases I. In: Spalton DJ, Hitchings RA, Hunter PA, eds. Atlas of Clinical Ophthalmology. 2nd ed. London, England: Mosby-Year Book Europe Limited;1994. 16. Hayreh SS. Central retinal vein occlusion. http://webeye.ophth.uiowa.edu/dept/CRVO/. Revised March 2003. Accessed December 28, 2009. 17. The Central Vein Occlusion Study Group. Evaluation of grid pattern photocoagulation for macular edema in central vein occlusion. Ophthalmol. 1995;102(10):1425-1433. 18. OZURDEX™ Prescribing Information. 19. Data on file, Allergan, Inc. 20. Kuppermann BD. Dexamethasone implant. Retina Today. May/June 2009:52-53.

9. Rehak J, Rehak M. Branch retinal vein occlusion: pathogenesis, visual prognosis, and treatment modalities. Curr Eye Res. 2008;33(2):111-131. 10. Noma H, Funatsu H, Yamasaki M, Tsukamoto H, et al: Aqueous humour levels of cytokines are correlated to vitreous levels and severity of macular oedema in branch retinal vein occlusion. Eye. 2008;22:42-48.

11. Stahl A, Agostini H, Hansen LL, Feltgen N. Bevacizumab in retinal vein occlusion-results of a prospective case series. Graefe’s Clin Exp Ophthalmol. 2007;245:1429-1436.

Supplement

May/June 2010

www.AHDBonline.com

S273

OZURDEX™

(dexamethasone intravitreal implant) 0.7mg HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use OZURDEX™ safely and effectively. See full prescribing information.

OZURDEX™ (dexamethasone intravitreal implant) Initial U.S. Approval: 1958

INDICATIONS AND USAGE OZURDEX™ contains a corticosteroid indicated for the treatment of macular edema following branch retinal vein occlusion (BRVO) or central retinal vein occlusion (CRVO). (1)

DOSAGE AND ADMINISTRATION • For ophthalmic intravitreal injection only. (2.1) • The intravitreal injection procedure should be carried out under controlled aseptic conditions. Following the intravitreal injection, patients should be monitored for elevation in intraocular pressure and for endophthalmitis. (2.2)

DOSAGE FORMS AND STRENGTHS • I ntravitreal implant containing dexamethasone 0.7 mg in the NOVADUR™ solid polymer drug delivery system. (3)

FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION 2.1 General Dosing Information 2.2 Administration 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 4.1 Ocular or Periocular Infections

CONTRAINDICATIONS • Ocular or periocular infections. (4.1) • Advanced glaucoma. (4.2)

WARNINGS AND PRECAUTIONS • I ntravitreal injections have been associated with endophthalmitis, eye inflammation, increased intraocular pressure, and retinal detachments. Patients should be monitored following the injection. (5.1) • Use of corticosteroids may produce posterior subcapsular cataracts, increased intraocular pressure, glaucoma, and may enhance the establishment of secondary ocular infections due to bacteria, fungi, or viruses. Corticosteroids should be used cautiously in patients with a history of ocular herpes simplex. (5.2)

ADVERSE REACTIONS The most common adverse reactions reported by ≥20% of patients included increased intraocular pressure and conjunctival hemorrhage. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Allergan at 1-800-433-8871 or www.allergan.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. See 17 for PATIENT COUNSELING INFORMATION Revised: June 2009. 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY

4.2 Advanced Glaucoma

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

4.3 Hypersensitivity

14 CLINICAL STUDIES

5 WARNINGS AND PRECAUTIONS

16 HOW SUPPLIED/STORAGE AND HANDLING

5.1 Intravitreal Injection-related Effects

17 PATIENT COUNSELING INFORMATION

5.2 Potential Steroid-related Effects 6 ADVERSE REACTIONS 6.1 Clinical Studies Experience 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy

* Sections or subsections omitted from the full prescribing information are not listed.

FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE OZURDEX™ (dexamethasone intravitreal implant) is indicated for the treatment of macular edema following branch retinal vein occlusion (BRVO) or central retinal vein occlusion (CRVO). 2 DOSAGE AND ADMINISTRATION 2.1 General Dosing Information For ophthalmic intravitreal injection only. 2.2 Administration The intravitreal injection procedure should be carried out under controlled aseptic conditions which include the use of sterile gloves, a sterile drape, and a sterile eyelid speculum (or equivalent). Adequate anesthesia and a broad-spectrum microbicide are recommended to be given prior to the injection. Remove the foil pouch from the carton and examine for damage. Then, in a sterile field, open the foil pouch and gently place the applicator on a sterile tray. Carefully remove the cap from the applicator. Hold the applicator in one hand and pull the safety tab straight off the applicator. Do not twist or flex the tab. The long axis of the applicator should be held parallel to the limbus, and the sclera should be engaged at an oblique angle with the bevel of the needle up (away from the sclera) to create a shelved scleral path. The tip of the needle is advanced within the sclera for about 1 mm (parallel to the limbus), then re-directed toward the center of the eye and advanced until penetration of the sclera is completed and the vitreous cavity is entered. The needle should not be advanced past the point where the sleeve touches the conjunctiva. Slowly depress the actuator button until an audible click is noted. Before withdrawing the applicator from the eye, make sure that the actuator button is fully depressed and has locked flush with the applicator surface. Remove the needle in the same direction as used to enter the vitreous. Following the intravitreal injection, patients should be monitored for elevation in intraocular pressure and for endophthalmitis. Monitoring may consist of a check for perfusion of the optic nerve head immediately after the injection, tonometry within 30 minutes following the injection, and biomicroscopy between two and seven days following the injection. Patients should be instructed to report any symptoms suggestive of endophthalmitis without delay. Each applicator can only be used for the treatment of a single eye. If the contralateral eye requires treatment, a new applicator must be used, and the sterile field, syringe, gloves, drapes, and eyelid speculum should be changed before OZURDEX™ is administered to the other eye.

3 DOSAGE FORMS AND STRENGTHS Intravitreal implant containing dexamethasone 0.7 mg in the NOVADUR™ solid polymer drug delivery system. 4 CONTRAINDICATIONS 4.1 Ocular or Periocular Infections OZURDEX™ (dexamethasone intravitreal implant) is contraindicated in patients with active or suspected ocular or periocular infections including most viral diseases of the cornea and conjunctiva, including active epithelial herpes simplex keratitis (dendritic keratitis), vaccinia, varicella, mycobacterial infections, and fungal diseases. 4.2 Advanced Glaucoma OZURDEX™ is contraindicated in patients with advanced glaucoma. 4.3 Hypersensitivity OZURDEX™ is contraindicated in patients with known hypersensitivity to any components of this product. 5 WARNINGS AND PRECAUTIONS 5.1 Intravitreal Injection-related Effects Intravitreal injections have been associated with endophthalmitis, eye inflammation, increased intraocular pressure, and retinal detachments. Patients should be monitored following the injection. (see PATIENT COUNSELING INFORMATION, 17) 5.2 Potential Steroid-related Effects Use of corticosteroids may produce posterior subcapsular cataracts, increased intraocular pressure, glaucoma, and may enhance the establishment of secondary ocular infections due to bacteria, fungi, or viruses. Corticosteroids should be used cautiously in patients with a history of ocular herpes simplex. Corticosteroids should not be used in active ocular herpes simplex. 6 ADVERSE REACTIONS 6.1 Clinical Studies Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. The following information is based on the combined clinical trial results from the initial 6 month masked period of two randomized, sham-controlled, parallel studies.

Adverse reactions reported by greater than 2% of patients in the first six months OZURDEX™ N=421(%)

Sham N=423(%)

Intraocular pressure increased

106 (25%)

5 (1%)

Conjunctival hemorrhage

85 (20%)

63 (15%)

Eye pain

31 (7%)

16 (4%)

Conjunctival hyperemia

28 (7%)

20 (5%)

Ocular hypertension

17 (4%)

3 (1%)

Cataract

15 (4%)

6 (1%)

Vitreous detachment

12 (3%)

8 (2%)

Headache

14 (3%)

7 (2%)

MeDRA Term

8.3 Nursing Mothers It is not known whether ocular administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in human milk. Systemically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. Caution should be exercised when corticosteroids are administered to a nursing woman. 8.4 Pediatric Use Safety and effectiveness of OZURDEX™ in pediatric patients has not been established. 8.5 Geriatric Use No overall differences in safety or effectiveness have been observed between elderly and younger patients. 11 DESCRIPTION OZURDEX™ is an intravitreal implant containing 0.7 mg (700 μg) dexamethasone in the NOVADUR™ solid polymer drug delivery system. OZURDEX™ is preloaded into a single-use, specially designed DDS® applicator to facilitate injection of the rod-shaped implant directly into the vitreous. The NOVADUR™ system contains poly (D,L-lactide-co-glycolide) PLGA intravitreal polymer matrix. OZURDEX™ is preservative-free. The chemical name for dexamethasone is pregna-1,4-diene-3,20dione, 9-fluoro-11,17,21-trihydoxy-16-methyl-,(11β,16α). Its structural formula is: MW 392.47; molecular formula: C22H29FO5. CH3

HO CH3

OH CH3

H F

Dexamethasone occurs as a white to cream-colored crystalline powder having not more than a slight odor, and is practically insoluble in water and very soluble in alcohol. The PLGA matrix slowly degrades to lactic acid and glycolic acid. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Dexamethasone, a potent corticosteroid, has been shown to suppress inflammation by inhibiting multiple inflammatory cytokines resulting in decreased edema, fibrin deposition, capillary leakage and migration of inflammatory cells.

12.3 Pharmacokinetics Plasma concentrations were obtained from 21 patients in the two, 6-month Phase 3 efficacy studies prior to dosing and on Days 7, 30, 60, and 90 following the intravitreal implant containing 0.35 mg or 0.7 mg dexamethasone. In both studies, the majority of plasma dexamethasone concentrations were below the lower limit of quantitation (LLOQ= 50 pg/mL). Plasma dexamethasone concentrations from 10 of 73 samples in the 0.7 mg dose group and from 2 of 42 samples in the 0.35 mg dose group were above the LLOQ, ranging from 52 pg/mL to 94 pg/mL. The highest plasma concentration value of 94 pg/mL was observed in one subject from the 0.7 mg group. Plasma dexamethasone concentration did not appear to be related to age, body weight, or sex of patients.

Number (Percent) of Patients with ≥15 Letters Improvement from Baseline in BCVA

In an in vitro metabolism study, following the incubation of [14C]-dexamethasone with human cornea, iris-ciliary body, choroid, retina, vitreous humor, and sclera tissues for 18 hours, no metabolites were observed.

In each individual study and in a pooled analysis, time to achieve ≥ 15 letters (3-line) improvement in BCVA cumulative response rate curves were significantly faster with OZURDEX™ compared to sham (p < 0.01), with OZURDEX™-treated patients achieving a 3-line improvement in BCVA earlier than sham-treated patients.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No adequate studies in animals have been conducted to determine whether OZURDEX™ (dexamethasone intravitreal implant) has the potential for carcinogenesis. Although no adequate studies have been conducted to determine the mutagenic potential of OZURDEX™, dexamethasone has been shown to have no mutagenic effects in bacterial and mammalian cells in vitro or in the in vivo mouse micronucleus test. 14 CLINICAL STUDIES The efficacy of OZURDEX™ was assessed in two, multicenter, double-masked, randomized, parallel studies. Following a single injection, OZURDEX™ for the treatment of macular edema following branch retinal vein occlusion (BRVO) or central retinal vein occlusion (CRVO) demonstrated the following clinical results for the percent of patients with ≥ 15 letters of improvement from baseline in best-corrected visual acuity (BCVA):

Study 1 Study Day

DEX 700 N=201

Sham N=202

Day 30

40 (20%)

Day 60

Study 2 p-value

DEX 700 N=226

Sham N=224

15 (7%)

<0.01

51 (23%)

17 (8%)

<0.01

58 (29%)

21 (10%)

<0.01

67 (30%)

27 (12%)

<0.01

Day 90

45 (22%)

25 (12%)

<0.01

48 (21%)

31 (14%)

0.039

Day 180

39 (19%)

37 (18%)

0.780

53 (24%)

38 (17%)

0.087

p-value

* P-values were based on the Pearson’s Chi-square test.

The onset of a ≥15 letter (3 line) improvement in BCVA with OZURDEX™ occurs within the first two months after implantation in approximately 20-30% of subjects. The duration of effect persists approximately one to three months after onset of this effect. 16 HOW SUPPLIED/STORAGE AND HANDLING OZURDEX™ (dexamethasone intravitreal implant) 0.7 mg is supplied in a foil pouch with 1 single-use plastic applicator, NDC 0023-3348-07. Storage: Store at 15° - 30° C (59° - 86° F). 17 PATIENT COUNSELING INFORMATION In the days following intravitreal injection of OZURDEX™, patients are at risk for potential complications including in particular, but not limited to, the development of endophthalmitis or elevated intraocular pressure. If the eye becomes red, sensitive to light, painful, or develops a change in vision, the patients should seek immediate care from an ophthalmologist. Patients may experience temporary visual blurring after receiving an intravitreal injection. They should not drive or use machines until this has resolved. © 2009 Allergan, Inc. Irvine, CA 92612, U.S.A. ® and ™ marks owned by Allergan, Inc. Made in Ireland 72212US10A Re-order: APC16MN09

BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION DEXILANT (dexlansoprazole) delayed release capsules INDICATIONS AND USAGE DEXILANT is indicated for: K D85 851<9>7 ?6 1<< 7B145C ?6 5B?C9F5 5C?@8179D9C 6?B E@ D? G55;C K =19>D19>9>7 851<9>7 ?6 6?B E@ D? =?>D8C 1>4 K D85 DB51D=5>D ?6 851BD2EB> 1CC?391D54 G9D8 >?> 5B?C9F5 71CDB?5C?@81751< B56<EH 49C51C5 ( 6?B G55;C CONTRAINDICATIONS - " $* 9C 3?>DB19>4931D54 9> @1D95>DC G9D8 ;>?G> 8I@5BC5>C9D9F9DI D? 1>I 3?=@?>5>D ?6 D85 6?B=E<1D9?> I@5BC5>C9D9F9DI 1>4 1>1@8I<1H9C 81F5 255> B5@?BD54 G9D8 - " $* EC5 [see Adverse Reactions]. WARNINGS AND PRECAUTIONS Gastric Malignancy )I=@D?=1D93 B5C@?>C5 G9D8 - " $* 4?5C >?D @B53<E45 D85 @B5C5>35 ?6 71CDB93 =1<97>1>3I ADVERSE REACTIONS Clinical Trials Experience *85 C165DI ?6 - " $* G1C 5F1<E1D54 9> @1D95>DC 9> 3?>DB?<<54 1>4 E>3?>DB?<<54 3<9>931< CDE495C 9>3<E49>7 @1D95>DC DB51D54 6?B 1D <51CD =?>D8C 1>4

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@1D95>DC ?> - " $* =7 1>4 @1D95>DC ?> <1>C?@B1J?<5 =7 ?>35 419931< DB91<C 1B5 3?>4E3D54 E>45B G9457 3?>49D9?>C 14F5BC5 B513D9?> B1D5C ?2C5BF54 9> D85 3<9>931< DB91<C ?6 1 4BE7 31>>?D 25 49B53D D85 3<9>931< DB91<C ?6 1>?D85B 4BE7 1>4 =1I >?D B56<53D D85 B1D5C ?2C5BF54 9> @B13D935 #?CD ?==?>C *85 =?CD 3?==?> 14F5BC5 B513D9?>C D81D ?33EBB54 1D 1 89785B 9>3945>35 6?B - " $* D81> @<1352? 9> D85 3?>DB?<<54 CDE495C 1B5 @B5C5>D54 9> *12<5 Table 2: Incidence of Treatment-Emergent Adverse Reactions in Controlled Studies Placebo

DEXILANT 60 mg (N=2218) %

DEXILANT Total (N=2621) %

Lansoprazole 30 mg (N=1363) %

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

(N=896) %

DEXILANT 30 mg (N=455) %

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

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A reproduction study conducted in rabbits at oral dexlansoprazole doses up to 30 mg per kg per day (approximately 9-fold the maximum recommended human dexlansoprazole dose (60 mg) revealed no evidence of harm to the fetus due to dexlansoprazole. In addition, reproduction studies performed in pregnant rats with oral lansoprazole at doses up to 40 times the recommended human dose and in pregnant rabbits at oral lansoprazole doses up to 16 times the recommended human dose revealed no evidence of impaired fertility or harm to the fetus due to lansoprazole. Nursing Mothers It is not known whether dexlansoprazole is excreted in human milk. However, lansoprazole and its metabolites are present in rat milk following the administration of lansoprazole. As many drugs are excreted in human milk, and because of the potential for tumorigenicity shown for lansoprazole in rat carcinogenicity studies [see Carcinogenesis, Mutagenesis, Impairment of Fertility], a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness of DEXILANT in pediatric patients (less than 18 years of age) have not been established. Geriatric Use In clinical studies of DEXILANT, 11% of patients were aged 65 years and over. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified significant differences in responses between geriatric and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Renal Impairment No dosage adjustment of DEXILANT is necessary in patients with renal impairment. The pharmacokinetics of dexlansoprazole in patients with renal impairment are not expected to be altered since dexlansoprazole is extensively metabolized in the liver to inactive metabolites, and no parent drug is recovered in the urine following an oral dose of dexlansoprazole. Hepatic Impairment No dosage adjustment for DEXILANT is necessary for patients with mild hepatic impairment (Child-Pugh Class A). DEXILANT 30 mg should be considered for patients with moderate hepatic impairment (Child-Pugh Class B). No studies have been conducted in patients with severe hepatic impairment (Child-Pugh Class C). OVERDOSAGE There have been no reports of significant overdose of DEXILANT. Multiple doses of DEXILANT 120 mg and a single dose of DEXILANT 300 mg did not result in death or other severe adverse events. Dexlansoprazole is not expected to be removed from the circulation by hemodialysis. If an overdose occurs, treatment should be symptomatic and supportive. CLINICAL PHARMACOLOGY Pharmacodynamics Antisecretory Activity The effects of DEXILANT 60 mg (n=20) or lansoprazole 30 mg (n=23) once daily for five days on 24-hour intragastric pH were assessed in healthy subjects in a multiple-dose crossover study. Serum Gastrin Effects The effect of DEXILANT on serum gastrin concentrations was evaluated in approximately 3460 patients in clinical trials up to 8 weeks and in 1023 patients for up to 6 to 12 months. The mean fasting gastrin concentrations increased from baseline during treatment with DEXILANT 30 mg and 60 mg doses. In patients treated for more than 6 months, mean serum gastrin levels increased during approximately the first 3 months of treatment and were stable for the remainder of treatment. Mean serum gastrin levels returned to pre-treatment levels within one month of discontinuation of treatment. Enterochromaffin-Like Cell (ECL) Effects There were no reports of ECL cell hyperplasia in gastric biopsy specimens obtained from 653 patients treated with DEXILANT 30 mg, 60 mg or 90 mg for up to 12 months. During lifetime exposure of rats dosed daily with up to 150 mg per kg per day of lansoprazole, marked hypergastrinemia was observed followed by ECL cell proliferation and formation of carcinoid tumors, especially in female rats [see Nonclinical Toxicology]. Effect on Cardiac Repolarization A study was conducted to assess the potential of DEXILANT to prolong the QT/QTc interval in healthy adult subjects. DEXILANT doses of 90 mg or 300 mg did not delay cardiac repolarization compared to placebo. The positive control (moxifloxacin) produced statistically significantly greater mean maximum and time-averaged QT/QTc intervals compared to placebo.

NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility The carcinogenic potential of dexlansoprazole was assessed using lansoprazole studies. In two 24-month carcinogenicity studies, Sprague-Dawley rats were treated orally with lansoprazole at doses of 5 to 150 mg per kg per day, about 1 to 40 times the exposure on a body surface (mg/m2) basis of a 50 kg person of average height [1.46 m2 body surface area (BSA)] given the recommended human dose of lansoprazole 30 mg per day. Lansoprazole produced dose-related gastric ECL cell hyperplasia and ECL cell carcinoids in both male and female rats [see Clinical Pharmacology]. In rats, lansoprazole also increased the incidence of intestinal metaplasia of the gastric epithelium in both sexes. In male rats, lansoprazole produced a dose-related increase of testicular interstitial cell adenomas. The incidence of these adenomas in rats receiving doses of 15 to 150 mg per kg per day (4 to 40 times the recommended lansoprazole human dose based on BSA) exceeded the low background incidence (range = 1.4 to 10%) for this strain of rat. In a 24-month carcinogenicity study, CD-1 mice were treated orally with lansoprazole doses of 15 mg to 600 mg per kg per day, 2 to 80 times the recommended human dose based on BSA. Lansoprazole produced a dose-related increased incidence of gastric ECL cell hyperplasia. It also produced an increased incidence of liver tumors (hepatocellular adenoma plus carcinoma). The tumor incidences in male mice treated with 300 mg and 600 mg lansoprazole per kg per day (40 to 80 times the recommended lansoprazole human dose based on BSA) and female mice treated with 150 mg to 600 mg lansoprazole per kg per day (20 to 80 times the recommended human dose based on BSA) exceeded the ranges of background incidences in historical controls for this strain of mice. Lansoprazole treatment produced adenoma of rete testis in male mice receiving 75 to 600 mg per kg per day (10 to 80 times the recommended lansoprazole human dose based on BSA). The potential effects of dexlansoprazole on fertility and reproductive performance were assessed using lansoprazole studies. Lansoprazole at oral doses up to 150 mg per kg per day (40 times the recommended lansoprazole human dose based on BSA) was found to have no effect on fertility and reproductive performance of male and female rats. PATIENT COUNSELING INFORMATION [see FDA-Approved Patient Labeling in the full prescribing information] Information for Patients Tell your patients to watch for signs of an allergic reaction as these could be serious and may require that DEXILANT be discontinued. To ensure the safe and effective use of DEXILANT, this information and instructions provided in the FDA-approved patient labeling should be discussed with the patient. Inform patients of the following: DEXILANT is available as a delayed release capsule. DEXILANT may be taken without regard to food. DEXILANT should be swallowed whole. K <D5B>1D9F5 25 ?@5>54 1>4 14=9>9CD5B54 1C follows: - Open capsule; - Sprinkle intact granules on one tablespoon of applesauce; - Swallow immediately. Distributed by Takeda Pharmaceuticals America, Inc. Deerfield, IL 60015 U.S. Patent Nos. - 5,045,321; 5,093,132; 5,433,959; 6,462,058; 6,664,276; 6,939,971; and 7,285,668. DEXILANT is a trademark of Takeda Pharmaceuticals North America, Inc. and used under license by Takeda Pharmaceuticals America, Inc. All other trademark names are the property of their respective owners. ÂŠ2009, 2010 Takeda Pharmaceuticals America, Inc. For more detailed information, see the full prescribing information for DEXILANT or contact Takeda Pharmaceuticals America, Inc. at 1-877-825-3327. KAP0110 R6-Brf; March 2010 L-LPD-0310-2 Reference: 1. DEXILANT (dexlansoprazole) package insert, Takeda Pharmaceuticals America, Inc. DEXILANTâ&#x201E;˘, KAPIDEXâ&#x201E;˘ (dexlansoprazole), and Dual Delayed Releaseâ&#x201E;˘ are trademarks of Takeda Pharmaceuticals North America, Inc., and are used under license by Takeda Pharmaceuticals America, Inc. KadianÂŽ (morphine sulfate extended-release) is a registered trademark of Actavis Elizabeth LLC. CasodexÂŽ (bicalutamide) is a registered trademark of AstraZeneca.

ÂŠ2010 Takeda Pharmaceuticals North America, Inc. LPD-01109 4/10 Printed in U.S.A.

DEXILANT IS NOW AVAILABLE IN PHARMACIES

The name KAPIDEX™ (dexlansoprazole) has changed to

New name. Same medication. Why has the name changed? s After receiving reports of dispensing errors due to the similarity between the names KAPIDEX and Casodex® (bicalutamide), and KAPIDEX and Kadian® (morphine sulfate extended-release), Takeda, in coordination with the US Food and Drug Administration, determined that a name change would be the best way to minimize future medication errors s At Takeda Pharmaceuticals, we believe patient safety is of the utmost importance

ONLY the name has changed s The size, strength, and ingredients of the capsule remain the same s Each capsule still contains 30 mg or 60 mg of dexlansoprazole1 s DEXILANT is still the first and only PPI with a Dual Delayed Release™ (DDR) formulation1 The clinical relevance of this statement is unknown.

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

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