American Health & Drug Benefits: Payers’ Guide to New FDA Approvals

April 2013

Volume 6 I Number 3 I Special Feature

THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN™

For Payers, Purchasers, Policymakers, and Other Healthcare Stakeholders

Payers’ Guide to New FDA Approvals ™

Foreword The Fourth Annual Payers’ Guide to FDA Approvals Introduction New FDA Drug Approvals in 2012: A 15-Year High FDA Approvals of Brand-Name Prescription Drugs in 2012 Trends in the 2013 Pharmaceutical Pipeline Product Profiles of Select Drugs Approved in 2012

Special Feature

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EST. 2008

YEAR ANNIVERSARY

©2013 Engage Healthcare Communications, LLC www.AHDBonline.com

The median age of patients in the VISTA† trial was 71 years (range: 48-91).

Indication and Important safety Information for VELCADE® (bortezomib) InDICAtIon VELCADE (bortezomib) is indicated for the treatment of patients with multiple myeloma.

ContrAInDICAtIons VELCADE is contraindicated in patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol, including anaphylactic reactions. VELCADE is contraindicated for intrathecal administration.

WArnIngs, prECAutIons, AnD Drug IntErACtIons ▼ Peripheral neuropathy: Manage with dose modification or discontinuation. Patients with preexisting severe neuropathy should be treated with VELCADE only after careful risk-benefit assessment. ▼ Hypotension: Use caution when treating patients taking antihypertensives, with a history of syncope, or with dehydration.

▼ Cardiac toxicity: Worsening of and development of cardiac failure have occurred. Closely monitor patients with existing heart disease or risk factors for heart disease. ▼ Pulmonary toxicity: Acute respiratory syndromes have occurred. Monitor closely for new or worsening symptoms. ▼ Posterior reversible encephalopathy syndrome: Consider MRI imaging for onset of visual or neurological symptoms; discontinue VELCADE if suspected. ▼ Gastrointestinal toxicity: Nausea, diarrhea, constipation, and vomiting may require use of antiemetic and antidiarrheal medications or fluid replacement. ▼ Thrombocytopenia or Neutropenia: Monitor complete blood counts regularly throughout treatment. ▼ Tumor lysis syndrome: Closely monitor patients with high tumor burden. ▼ Hepatic toxicity: Monitor hepatic enzymes during treatment.

In treating multiple myeloma

What is the value of ® VELCADE (bortezomib)? ▼ Overall survival advantage ▼ Defined length of therapy ▼ Medication cost If you DEfInE VALuE As An oVErALL surVIVAL ADVAntAgE: VELCADE (bortezomib) combination delivered a >13-month overall survival advantage At 5-year median follow-up, VELCADE+MP* provided a median overall survival of 56.4 months vs 43.1 months with MP alone (HR=0.695 [95% CI, 0.57-0.85]; p<0.05)† At 3-year median follow-up, VELCADE+MP provided an overall survival advantage over MP that was not regained with subsequent therapies

If you DEfInE VALuE As DEfInED LEngth of thErApy: Results achieved using VELCADE twice-weekly followed by weekly dosing for a median of 50 weeks (54 planned)1

If you DEfInE VALuE As MEDICAtIon Cost: Medication cost is an important factor when considering overall drug spend. The Wholesale Acquisition Cost for VELCADE is $1,540 per 3.5-mg vial as of January 2013 When determining the value of a prescription drug regimen, it may be worth considering medication cost, length of therapy, and dosing regimens. This list is not all-inclusive; there are additional factors to consider when determining value for a given regimen

▼ Embryo-fetal risk: Women should avoid becoming pregnant while being treated with VELCADE. Advise pregnant women of potential embryo-fetal harm. ▼ Closely monitor patients receiving VELCADE in combination with strong CYP3A4 inhibitors. Avoid concomitant use of strong CYP3A4 inducers.

ADVErsE rEACtIons Most commonly reported adverse reactions (incidence ≥20%) in clinical studies include nausea, diarrhea, thrombocytopenia, neutropenia, peripheral neuropathy, fatigue, neuralgia, anemia, leukopenia, constipation, vomiting, lymphopenia, rash, pyrexia, and anorexia.

Please see Brief Summary for VELCADE on the next page of this advertisement.

For Reimbursement Assistance, call 1-866-VELCADE (835-2233), Option 2, or visit VELCADEHCP.com.

Reference: 1. Mateos M-V, Richardson PG, Schlag R, et al. Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: updated follow-up and impact of subsequent therapy in the phase III VISTA trial.

J Clin Oncol. 2010;28(13):2259-2266. *Melphalan+prednisone. † VISTA TRIAL: a randomized, open-label, international phase 3 trial (N=682) evaluating the efficacy and safety of VELCADE administered intravenously in combination with MP vs MP in previously untreated multiple myeloma. The primary endpoint was TTP. Secondary endpoints were CR, ORR, PFS, and overall survival. At a prespecified interim analysis (median follow-up 16.3 months), VELCADE+MP resulted in significantly superior results for TTP (median 20.7 months with VELCADE+MP vs 15.0 months with MP [p=0.000002]), PFS, overall survival, and ORR. Further enrollment was halted and patients receiving MP were offered VELCADE in addition. Updated analysis was performed.

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

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

CONTRAINDICATIONS: VELCADE is contraindicated in patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol, including anaphylactic reactions. VELCADE is contraindicated for intrathecal administration.

WARNINGS AND PRECAUTIONS: Peripheral Neuropathy: VELCADE treatment causes a peripheral neuropathy that is predominantly sensory; however, cases of severe sensory and motor peripheral neuropathy have been reported.

Patients with pre-existing symptoms (numbness, pain, or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including ≥Grade 3) during treatment with VELCADE. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. In the Phase 3 relapsed multiple myeloma trial comparing VELCADE subcutaneous vs intravenous, the incidence of Grade ≥2 peripheral neuropathy events was 24% for subcutaneous and 39% for intravenous. Grade ≥3 peripheral neuropathy occurred in 6% of patients in the subcutaneous treatment group, compared with 15% in the intravenous treatment group. Starting VELCADE subcutaneously may be considered for patients with pre-existing or at high risk of peripheral neuropathy.

Patients experiencing new or worsening peripheral neuropathy during VELCADE therapy may require a decrease in the dose and/or a less dose-intense schedule. In the VELCADE vs dexamethasone phase 3 relapsed multiple myeloma study, improvement in or resolution of peripheral neuropathy was reported in 48% of patients with ≥Grade 2 peripheral neuropathy following dose adjustment or interruption. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had ≥Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma.

Hypotension: The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 8%.

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

Cardiac Toxicity: Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have occurred during VELCADE therapy, including reports in patients with no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing, heart disease should be closely monitored. In the relapsed multiple myeloma study of VELCADE vs dexamethasone, the incidence of any treatment-related cardiac disorder was 8% and 5% in the VELCADE and dexamethasone groups, respectively. The incidence of adverse reactions suggestive of heart failure (acute pulmonary edema, pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock) was ≤1% for each individual reaction in the VELCADE group. In the dexamethasone group, the incidence was ≤1% for cardiac failure and congestive cardiac failure; there were no reported reactions of acute pulmonary edema, pulmonary edema, or cardiogenic shock. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established.

Pulmonary Toxicity: Acute Respiratory Distress Syndrome (ARDS) and acute diffuse infiltrative pulmonary disease of unknown etiology, such as pneumonitis, interstitial pneumonia, and lung infiltration have occurred in patients receiving VELCADE. Some of these events have been fatal.

In a clinical trial, the first two patients given high-dose cytarabine (2 g/m2 per day) by continuous infusion with daunorubicin and VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy. There have been reports of pulmonary hypertension associated with VELCADE administration in the absence of left heart failure or significant pulmonary disease. In the event of new or worsening cardiopulmonary symptoms, consider interrupting VELCADE until a prompt, comprehensive, diagnostic evaluation is conducted.

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

Gastrointestinal Toxicity: VELCADE treatment can cause nausea, diarrhea, constipation, and vomiting, sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur.

Fluid and electrolyte replacement should be administered to prevent dehydration. Interrupt VELCADE for severe symptoms.

Thrombocytopenia/Neutropenia: VELCADE is associated with thrombocytopenia and neutropenia that follow a cyclical pattern, with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and recovery remained consistent over the 8 cycles of twice-weekly dosing, and there was no evidence of cumulative thrombocytopenia or neutropenia. The mean platelet count nadir measured was approximately 40% of baseline.

The severity of thrombocytopenia was related to pretreatment platelet count. In the relapsed multiple myeloma study of VELCADE vs dexamethasone, the incidence of bleeding (≥Grade 3) was 2% on the VELCADE arm and <1% on the dexamethasone arm. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE. Platelet counts should be monitored prior to each dose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and schedule of VELCADE. Gastrointestinal and intracerebral hemorrhage has been reported in association with VELCADE. Transfusions may be considered.

Tumor Lysis Syndrome: Tumor lysis syndrome has been reported with VELCADE therapy.

Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment.

Monitor patients closely and take appropriate precautions.

Hepatic Toxicity: Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic reactions include hepatitis, increases in liver enzymes, and hyperbilirubinemia. Interrupt VELCADE therapy to assess reversibility. There is limited re-challenge information in these patients.

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

ADVERSE EVENT DATA: Safety data from phase 2 and 3 studies of single-agent VELCADE 1.3 mg/m2/dose administered intravenously twice weekly for 2 weeks followed by a 10-day rest period in 1163 patients with previously-treated multiple myeloma (N=1008) and previously-treated mantle cell lymphoma (N=155) were integrated and tabulated. In these studies, the safety profile of VELCADE was similar in patients with multiple myeloma and mantle cell lymphoma.

In the integrated analysis, the most commonly reported (≥10%) adverse reactions were nausea (49%), diarrhea NOS (46%), fatigue (41%), peripheral neuropathies NEC (38%), thrombocytopenia (32%), vomiting NOS (28%), constipation (25%), pyrexia (21%), anorexia (20%), anemia NOS (18%), headache NOS (15%), neutropenia (15%), rash NOS (13%), paresthesia (13%), dizziness (excl vertigo 11%), and weakness (11%). Eleven percent (11%) of patients experienced at least 1 episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (4%) and neutropenia (2%).

A total of 26% of patients experienced a serious adverse reaction during the studies. The most commonly reported serious adverse reactions included diarrhea, vomiting, and pyrexia (3% each), nausea, dehydration, and thrombocytopenia (2% each), and pneumonia, dyspnea, peripheral neuropathies NEC, and herpes zoster (1% each).

In the phase 3 VELCADE+melphalan and prednisone study in previously untreated multiple myeloma, the safety profile of VELCADE administered intravenously in combination with melphalan/prednisone is consistent with the known safety profiles of both VELCADE and melphalan/prednisone. The most commonly reported adverse reactions in this study (VELCADE+melphalan/prednisone vs melphalan/prednisone) were thrombocytopenia (48% vs 42%), neutropenia (47% vs 42%), peripheral neuropathy (46% vs 1%), nausea (39% vs 21%), diarrhea (35% vs 6%), neuralgia (34% vs <1%), anemia (32% vs 46%), leukopenia (32% vs 28%), vomiting (26% vs 12%), fatigue (25% vs 14%), lymphopenia (23% vs 15%), constipation (23% vs 4%), anorexia (19% vs 6%), asthenia (16% vs 7%), pyrexia (16% vs 6%), paresthesia (12% vs 1%), herpes zoster (11% vs 3%), rash (11% vs 2%), abdominal pain upper (10% vs 6%), and insomnia (10% vs 6%).

In the phase 3 VELCADE subcutaneous vs intravenous study in relapsed multiple myeloma, safety data were similar between the two treatment groups. The most commonly reported adverse reactions in this study were peripheral neuropathy NEC (37% vs 50%), thrombocytopenia (30% vs 34%), neutropenia (23% vs 27%), neuralgia (23% vs 23%), anemia (19% vs 23%), diarrhea (19% vs 28%), leukopenia (18% vs 20%), nausea (16% vs 14%), pyrexia (12% vs 8%), vomiting (9% vs 11%), asthenia (7% vs 16%), and fatigue (7% vs 15%). The incidence of serious adverse reactions was similar for the subcutaneous treatment group (20%) and the intravenous treatment group (19%). The most commonly reported SARs were pneumonia and pyrexia (2% each) in the subcutaneous treatment group and pneumonia, diarrhea, and peripheral sensory neuropathy (3% each) in the intravenous treatment group.

DRUG INTERACTIONS: Bortezomib is a substrate of cytochrome P450 enzyme 3A4, 2C19 and 1A2. Co-administration of ketoconazole, a strong CYP3A4 inhibitor, increased the exposure of bortezomib by 35% in 12 patients. Monitor patients for signs of bortezomib toxicity and consider a bortezomib dose reduction if bortezomib must be given in combination with strong CYP3A4 inhibitors (eg, ketoconazole, ritonavir). Co-administration of omeprazole, a strong inhibitor of CYP2C19, had no effect on the exposure of bortezomib in 17 patients. Co-administration of rifampin, a strong CYP3A4 inducer, is expected to decrease the exposure of bortezomib by at least 45%.

Because the drug interaction study (n=6) was not designed to exert the maximum effect of rifampin on bortezomib PK, decreases greater than 45% may occur. Efficacy may be reduced when VELCADE is used in combination with strong CYP3A4 inducers; therefore, concomitant use of strong CYP3A4 inducers is not recommended in patients receiving VELCADE. St. John’s wort (Hypericum perforatum) may decrease bortezomib exposure unpredictably and should be avoided. Co-administration of dexamethasone, a weak CYP3A4 inducer, had no effect on the exposure of bortezomib in 7 patients. Co-administration of melphalan-prednisone increased the exposure of bortezomib by 17% in 21 patients. However, this increase is unlikely to be clinically relevant.

USE IN SPECIFIC POPULATIONS: Nursing Mothers: It is not known whether bortezomib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VELCADE, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use: The safety and effectiveness of VELCADE in children has not been established.

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

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

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

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

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

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

Millennium Pharmaceuticals, Inc., Cambridge, MA 02139 Copyright © 2013, Millennium Pharmaceuticals, Inc. All rights reserved.

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editorial board Editor-in-Chief

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

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

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

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

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

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

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

Kevin B. “Kip” Piper, MA, FACHE President, Health Results Group, LLC Washington, DC HEALTH INFORMATION TECHNOLOGY

Kelly Huang, PhD President, HealthTronics, Inc. Austin, TX J. B. Jones, PhD, MBA Research Investigator, Geisinger Health System, Danville, PA Victor J. Strecher, PhD, MPH Professor and Director for Innovation and Social Entrepreneurship, University of Michigan School of Public Health and Medicine HEALTH OUTCOMES RESEARCH

Diana Brixner, RPh, PhD Professor & Chair, Dept. of Pharmacotherapy Executive Director, Outcomes Research Center, Director of Outcomes Personalized Health Care Program, University of Utah, Salt Lake City Joseph Couto, PharmD, MBA Clinical Program Manager Cigna Corporation, Bloomfield, CT Steve Miff, PhD Senior Vice President VHA, Inc., Irving, TX

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Terri S. Moore, PhD, RPh, MBA Senior Manager, Product Development URAC, Washington, DC Kavita V. Nair, PhD Associate Professor, School of Pharmacy University of Colorado at Denver, CO Gary M. Owens, MD President, Gary Owens Associates Glen Mills, PA Andrew M. Peterson, PharmD, PhD Dean, Mayes School of Healthcare Business and Policy, Associate Professor, University of the Sciences, Philadelphia, PA Sarah A. Priddy, PhD Director, Competitive Health Analytics Humana, Louisville, KY Timothy S. Regan, BPharm, RPh, CPh Executive Director, Strategic Accounts Xcenda, Palm Harbor, FL Vincent J. Willey, PharmD Associate Professor, Philadelphia School of Pharmacy, University of the Sciences Philadelphia, PA Paul Wilson Senior VP, Health Consumer Insights and Analytics, Blue Bell, PA David W. Wright, MPH President, Institute for Interactive Patient Care Bethesda, MD health & value promotion

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

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

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

Amalia M. Issa, PhD, MPH Director, Program in Personalized Medicine & Targeted Therapeutics University of the Sciences, Philadelphia PHARMACOECONOMICs

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

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

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

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

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

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

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Vol 6, No 3

April 2013

Volume 6, Number 3, Special Feature The Peer-Reviewed Forum for Evidence in Benefit Design ™

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Table of Contents

Publishing Staff

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Foreword The Fourth Annual Payers’ Guide to New FDA Approvals

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Introduction New FDA Drug Approvals in 2012: A 15-Year High Gary M. Owens, MD

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FDA Approvals of Brand-Name Prescription Drugs in 2012

19 Abraxane Receives New Indication for Locally Advanced or Metastatic Non–Small-Cell Lung Cancer When Curative Surgery or Radiation Therapy Is Not an Option 28

Belviq: A New Prescription Weight-Loss Treatment for Overweight or Obese Patients

33

The Health Burden of Multiple Myeloma: Subcutaneous Velcade a New, Convenient Route of Administration Option

43

Kyprolis: A New Treatment Option for Patients with Relapsed/Refractory Multiple Myeloma Previously Treated with Bortezomib and an Immunomodulatory Agent

47

Eliquis Approved by the FDA to Reduce the Risks of Stroke and Systemic Embolism in Patients with Atrial Fibrillation

52

Jentadueto: A New Oral Antihyperglycemic Combination Therapy for Patients with Type 2 Diabetes

57 Linzess: A Novel Treatment Option for Constipation Associated with Irritable Bowel Syndrome 61

Trends in the 2013 Pharmaceutical Pipeline

Mission Statement American Health & Drug Benefits is founded on the concept that health and drug benefits have undergone a transformation: the econo­metric value of a drug is of equal importance to clinical outcomes as it is to serving as the basis for securing coverage in formularies and benefit designs. Because benefit designs are greatly affected by clinical, business, and policy conditions, this journal offers a forum for stakeholder integration and collaboration toward the im­provement of healthcare.

This publication further provides benefit design de­cision makers the integrated industry information they require to devise formularies and benefit designs that stand up to today’s special healthcare delivery and business needs.

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

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Senior Vice President/Group Publisher Nicholas Englezos nick@engagehc.com Editorial Director Dalia Buffery dalia@engagehc.com Associate Editor Lara J. Lorton Editorial Assistants Jennifer Brandt Cara Guglielmon Projects Manager John Welz Senior Production Manager Lynn Hamilton The Lynx Group

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Volume 6, Number 3, Special Feature The Peer-Reviewed Forum for Evidence in Benefit Design ™

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Table of Contents

(Continued)

72

Perjeta: A New Option for Patients with HER2-Positive Metastatic Breast Cancer

77

Iclusig: A New Treatment Option for Adults with CML or Ph+ ALL that Is Resistant/ Intolerant to Previous Therapy with TKIs

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81 Qsymia: Combination Oral Therapy a New Weight-Loss Option for Obese or Overweight Patients 94 Rayos: A Novel Oral Delayed-Release Prednisone for the Treatment of Rheumatoid Arthritis and Other Inflammatory Diseases 99

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For Payers, Purchasers, Policymakers, and Other Healthcare Stakeholders

Xeljanz: A New Treatment Option for Patients with Rheumatoid Arthritis

103 Tudorza Pressair: A Novel Oral Inhalation Therapy for the Maintenance Treatment

of Chronic Obstructive Pulmonary Disease­–Associated Bronchospasm

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107 Vascepa: First EPA-Only Omega-3 Therapy Approved by the FDA for Severe Hypertriglyceridemia 111 Zioptan Receives FDA Approval for Patients with Open-Angle Glaucoma and/or Ocular Hypertension 115 Zaltrap: A New Option for the Treatment of Patients with Metastatic Colorectal Cancer

Resistant to or Progressing After an Oxaliplatin-Containing Regimen 120 Zytiga Receives an Expanded Indication for Treatment of Metastatic Castration-Resistant

Prostate Cancer Before Chemotherapy

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Foreword

The Fourth Annual Payers’ Guide to New FDA Approvals

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Payers’ Guide to New FDA Approvals is published annually by American Health & Drug Benefits to offer payers and other healthcare stakeholders a detailed analysis of new drugs approved by the US Food and Drug Administration (FDA) in the previous year, as well as an overview of the key drugs in the pipeline.

This Guide includes in-depth updates on some of the new drugs that have either recently been launched or are soon to be launched, providing an important resource for medical and pharmacy directors for their benefit design decision-making. This edition represents the fourth year of publication of this Guide by American Health & Drug Benefits; it was first published in 2010. Each edition has expanded the scope of drug profiles coverage and the discussion of FDA approvals.

The 2013 edition includes in-depth updates on 17 of the drugs that had been approved by the FDA in 2012. This edition also includes a

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detailed introduction, “New FDA Drug Approvals in 2012: A 15-Year High” (page 9), focusing on some of the key trends that became apparent in the FDA approval process in 2012.

In addition, the “Trends in the 2013 Pharmaceutical Pipeline” (page 61) features key players in the current pharmaceutical pipeline, highlighting the major clinical categories in drug development in the 2013 pipeline, as well as some of the main trends in pharmaceutical research and development.

American Health & Drug Benefits will continue to expand the scope of this Guide in the coming years to offer healthcare stakeholders a tool for applying up-to-date information on new pharmaceuticals to their benefit design.

We hope you find this Guide useful, and we welcome your feedback. Send any comments to editorial@engagehc.com. This Guide is also available online at www.AHDBonline.com.

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introduction

New FDA Drug Approvals in 2012: A 15-Year High Gary M. Owens, MD President, Gary Owens Associates

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he year 2012 was marked by the largest number of new drug approvals in the past 15 years. The US Food and Drug Administration (FDA) issued 39 new drug approvals, of which 33 were new molecular entities and 6 were biologics (depending on how you count these).1 This number is approximately 33% higher than the average over the past 2 decades. This group of approvals included1: • 16 emerging sponsors (companies receiving their first FDA drug approval) • Nearly an 80% first-cycle approval rate (a new high) • 20 drugs that were first-in-class compounds • 13 new oncology medications • 8 new respiratory agents • The first disease-modifying therapy for cystic fibrosis • The first oral nontraditional disease-modifying antirheu­ matic drug (DMARD) for rheumatoid arthritis (RA) • 13 orphan drugs.

Specialty Drugs Remained the Growth Area in 2012 The 2012 approvals continue to cast the spotlight on the growth of specialty pharmaceuticals. Among the newly approved drugs last year, 25 can be classified as specialty agents. Of those 25 specialty drugs, more than 50% (13 agents) were for cancer (Table).1 Furthermore, many of these new specialty drugs were approved as orphan drugs, including several of the cancer drugs (Table). The emphasis on specialty drug development is here to stay, and it will likely remain the major focus of pharmacy innovation in the future.

In its 2012 Drug Trend Report, Express Scripts reported an 18.4% increased spending in 2012 for biotechnology and specialty drugs, which was led by medications for cancer and for inflammatory diseases such as RA, HIV/AIDS, and multiple sclerosis (MS).2 The report further notes that specialty drug growth shows no signs of slowing in the near future, because of the combination of price inflation and new drug approvals.2 In fact, some industry experts have predicted that specialty drugs will represent 45% of pharmaceutical manufacturer sales by 2017.3 This trend is further accentuated by the Pharmaceutical Research and Manufacturers of America (PhRMA) report, which indicates that 907 new biologics are in development, including 338

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treatments for cancer, 134 vaccines for infectious diseases, 71 medicines for autoimmune disorders, and 58 treatments for cardiovascular disease.4,5

Cancer Drugs Dominate 2012 FDA Approvals For the second year in a row, cancer drugs dominated the new drug approvals. The FDA approved 13 new agents for cancer (Table), which is a significant increase from the 8 cancer drugs that were approved in 2011.

Hematologic Malignancies Hematologic malignancies were a major area of new drug approvals in 2012. There were 3 new drugs entering the market for the treatment of chronic myelogenous leukemia (CML): ponatinib (Iclusig), a multikinase inhibitor; bosutinib (Bosulif), a BCR-ABL tyrosine kinase inhibitor/SRC family kinase inhibitor; and omacetaxine mepesuccinate (Synribo). More important, in the patients with CML who are receiving these drugs, we are seeing greater percentages of benefits from the new treatments. For example, ponatinib induces a major cytogenic response in 54% of patients overall, as well as in an astonishing 70% of patients with the T315I mutation.

Furthermore, on the leukemia front, vincristine sulfate liposome (Marqibo) was approved for patients with acute lymphoblastic leukemia (ALL) that has relapsed 2 times or more and for patients with ALL that has progressed after 2 regimens or more of antileukemia therapy. Marqibo contains vincristine, a frequently used anticancer drug, which is encased within a liposome, a drug delivery vehicle composed of material similar to that of cell membranes.

Carfilzomib (Kyprolis), a second-generation proteasome inhibitor, was approved for the treatment of patients with multiple myeloma who have received at least 2 previous therapies, including bortezomib and an immunomodulatory drug, and have demonstrated disease progression. Carfilzomib is the second proteasome inhibitor to be approved, joining bortezomib (Velcade) intravenous (IV), which was approved in 2008. In January 2012, the FDA approved the subcutaneous version of bortezomib, based on study results that showed subcutaneous bortezomib is as effective as the IV form, but subcutaneous administration reduces the frequency and

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Table Specialty Drugs: Cancer and Orphan Drugs Approved in 2012 Trade (generic) name

Indication

Cancer drugs Bosulif (bosutinib monohydrate)

Chronic-, accelerated-, or blast-phase Ph+ CML

Choline C 11

PET imaging of suspected prostate cancer recurrence and noninformative bone scintigraphy

Cometriq (cabozantinib)

Progressive, metastatic medullary thyroid cancer

Erivedge (vismodegib)

Metastatic or locally advanced basal-cell carcinoma recurring after surgery, or when surgery/radiation is not an option

Iclusig (ponatinib hydrochloride)

Chronic-, accelerated-, or blast-phase CML or Ph+ ALL resistant/ intolerant to previous TKI therapy

Inlyta (axitinib)

Advanced renal-cell carcinoma after failure of 1 prior systemic therapy

Kyprolis (carfilzomib)

Multiple myeloma that has relapsed/progressed after ≥2 prior therapies, including bortezomib and an immunomodulatory drug

Marqibo (vincristine sulfate liposome)

Ph-negative ALL that has relapsed/progressed ≥2 times or after ≥2 leukemia therapies

Perjeta (pertuzumab)

HER2-postive metastatic breast cancer, in combination with trastuzumab and docetaxel

Stivarga (regorafenib)

Metastatic colorectal cancer

Synribo (omacetaxine mepesuccinate)

Chronic- or accelerated-phase CML resistant/intolerant to ≥2 TKIs

Xtandi (enzalutamide)

Metastatic castration-resistant prostate cancer, after docetaxel therapy

Zaltrap (ziv-aflibercept)

Metastatic colorectal cancer resistant to/progressed after oxaliplatincontaining regimen; used in combination with 5-fluorouracil, leucovorin, and irinotecan

Orphan drugs Bosulif (bosutinib monohydrate)

Chronic-, accelerated-, or blast-phase Ph+ CML

Cometriq (cabozantinib)

Progressive, metastatic medullary thyroid cancer

Elelyso (taliglucerase alfa)

Type 1 Gaucher disease

Gattex (teduglutide recombinant)

Short bowel syndrome

Iclusig (ponatinib hydrochloride)

Chronic-, accelerated-, or blast-phase CML or Ph+ ALL resistant/ intolerant to TKI

Juxtapid (lomitapide mesylate)

Homozygous familial hypercholesterolemia

Kalydeco (ivacaftor)

Cystic fibrosis; for patients aged ≥6 years with G551D mutation

Kyprolis (carfilzomib)

Multiple myeloma after ≥2 prior therapies, including bortezomib and an immunomodulatory drug

Marqibo (vincristine sulfate liposome)

Ph-negative ALL that has relapsed ≥2 times or progressed after ≥2 leukemia therapies

Signifor (pasireotide diaspartate)

Cushing’s disease

Sirturo (bedaquiline fumarate)

For adults (≥18 years) with multidrug-resistant tuberculosis, part of a combination therapy

Synribo (omacetaxine mepesuccinate)

Chronic- or accelerated-phase CML resistant/intolerant to ≥2 TKIs

ALL indicates acute lymphoblastic leukemia; CML, chronic myelogenous leukemia; PET, positron emission tomography; Ph, Philadelphia-chromosome; TKI, tyrosine kinase inhibitor.

Source: US Food and Drug Administration. Drugs. www.fda.gov/Drugs/default.htm.

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seriousness of side effects, especially peripheral neuropathy, which is a common side effect of this agent.

Solid Organ Tumors There were also significant approvals for the solid organ tumors. Several agents were approved for the treatment of metastatic colorectal cancer, including ziv-aflib­ ercept (Zaltrap) and regorafenib (Stivarga)—a monoclonal antibody that binds vascular endothelial growth factor (VEGF), and a multikinase inhibitor that targets VEGF, respectively. Enzalutamide (Xtandi), an androgen receptor inhibitor, was also approved for the treatment of metastatic prostate cancer. In addition, at the end of 2012, abiraterone (Zytiga) was approved by the FDA for an expanded indication, for the treatment of patients with metastatic prostate cancer before chemotherapy. With this approval, abiraterone, in combination with prednisone, may now be used earlier in the treatment continuum for metastatic castration-resistant disease before the use of chemotherapy.

The hedgehog pathway inhibitor vismodegib (Erivedge) was approved as a first-in-class agent for the treatment of metastatic or locally advanced basal-cell carcinoma, a rare and difficult-to-treat advanced-stage skin cancer. Axitinib (Inlyta), an oral VEGF inhibitor, was approved for the treatment of advanced renal-cell carcinoma.

Another common solid organ tumor, breast cancer, strikes more than 250,000 women annually in the United States. Approximately 20% of these patients have tumors that overexpress the HER2 protein, which is a significant contributor to cancer-cell growth. Pertuzu­ mab (Perjeta) was approved in June 2012 and is intended for patients who have not received previous treatment for metastatic breast cancer with an anti-HER2 therapy or chemotherapy. Pertuzumab is used in combination with trastuzumab, another anti-HER2 therapy, and docetaxel, a type of chemotherapy.

Overall, 2012 was a very active year for cancer drug launches, and this trend shows no signs of change. According to the PhRMA report from March 2013, 337 of the drugs currently in development are targeted for cancer.4 Based on these numbers, we can anticipate significant numbers of cancer drugs to be approved well into the foreseeable future.

New Oral Therapies for RA and MS Two new agents were approved in 2012 for disease categories that traditionally have been dominated by injectable medications—RA and MS. Tofacitinib (Xeljanz) is the first oral, nontraditional DMARD to be approved by the FDA; its approval has been highly anticipated by patients and physicians. This

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new RA agent belongs to a class of drugs known as Janus kinase inhibitors. Tofacitinib blocks a signaling molecule that is released when a cytokine binds to the surface of a cell, thereby inhibiting the activity of the cytokine.

Based on its mechanism of action, the clinical features of this medication are very similar to those of the interleukin-6 receptor antagonists. Because the FDA approved tofacitinib as a second-line agent for RA, treatment with a biologic agent is not required before a physician can prescribe this agent. Tofacitinib is indicated for the treatment of adults with moderately to severely active RA who have had an inadequate response to or intolerance to methotrexate.

From a therapeutic and scientific standpoint, one of the most interesting new products of 2012 is ivacaftor, which is the first disease-modifying agent to be approved for a select group of patients with cystic fibrosis.

The second oral agent approved in 2012 for the treatment of MS is teriflunomide (Aubagio). Teriflunomide is a once-daily oral agent for the treatment of relapsing forms of MS. Teriflunomide, a pyrimidine synthesis inhibitor that inhibits the function of T- and B-cells, is related to leflunomide, a drug used for the treatment of RA.

Significant Advances in Other Therapeutic Categories Many other important approvals or expanded indications for existing drugs occurred in 2012. For example, adalimumab (Humira), which has been approved for the treatment of RA since 2002, saw its multiple indications expanded to include the treatment of moderate-to-­ severe ulcerative colitis in adults. Adalimumab was approved to control ulcerative colitis when immunosuppressant medicines, such as corticosteroids, azathioprine, and 6-mercaptopurine, have not worked.

From a therapeutic and scientific standpoint, one of the most interesting new products of 2012 is ivacaftor (Kaly­ deco), which is the first disease-modifying agent to be approved for a select group of patients with cystic fibrosis.

Ivacaftor is a transmembrane conductance regulator stabilizer, and it was designated as an orphan drug and a “breakthrough drug” that could ultimately lead to the development of additional treatments for cystic fibrosis.

Antiobesity drugs were also prominent in 2012, with the approval of 2 new therapies. Qsymia, a new combination of phentermine and topiramate, which are 2 existing drugs, was approved in July 2012, to be used in combination with diet and exercise by adults with body

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mass index (BMI) >30 kg/m2, or BMI >27 kg/m2 along with a weight-related condition, such as type 2 diabetes, high blood pressure, or high cholesterol levels. The second antiobesity agent approved in 2012, lorcaserin (Belviq), is a serotonin 2C receptor agonist that is indicated for chronic weight management in adults when used in conjunction with a caloric restriction diet and increased physical activity.

To date, the uptake of the phentermine plus topiramate combination has been gradual, and lorcaserin has not yet launched. Other 2012 approvals of note include mirabegron (Myrbetriq) for overactive bladder, linaclotide (Linzess) for irritable bowel syndrome, and apixaban (Eliquis), the second factor Xa inhibitor.

Looking Forward For the drug industry and for all healthcare stakeholders, 2012 certainly was an exciting year. The approvals of new drugs reached a 15-year high, with many of these approvals being for novel agents that offer first-in-class treatments for patients with chronic or life-threatening diseases. For the second year in a row, a significant increase was seen in the number of FDA approvals.

This trend of novel drug approvals and industry growth, which became evident in 2011, is expected to continue. As we enter 2013 with a robust pipeline, we can anticipate another year of significant growth for the drug industry and for patients. n Author Disclosure Statement Dr Owens is consultant to Allergan, Biogen Idec, Boston Scientific, CardioDx, Crescendo Biosciences, Genzyme, Iroko, Johnson & Johnson, Lilly, and Novocure.

References

1. Mullard A. 2012 FDA drug approvals. Nat Rev Drug Discov. 2012;12:87-90.

2. Express Scripts. 2012 Drug Trend Report. March 2013. www.drugtrendreport.com/ docs/ExpressScripts_DTR_0320.pdf. Accessed March 7, 2012.

3. Artemetrx. Specialty drug trend across the pharmacy and medical benefit. 2013. www.artemetrx.com/docs/ARTEMETRX_Specialty_Trend_Rpt.pdf. Accessed March 12, 2013.

4. Dearment A. PhRMA: 907 biotech drugs, vaccines under development. March 11, 2013. Drug Store News. http://drugstorenews.com/article/phrma-907-biotech-drugsvaccines-under-development. Accessed March 14, 2013.

5. Pharmaceutical Research and Manufacturers of America. Biologics research promises to bolster future of medicine: more than 900 biologic medicines and vaccines in development. March 11, 2013. www.phrma.org/media/releases/biologics-researchpromises-bolster-future-medicine. Accessed March 17, 2013.

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

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

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

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

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

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

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

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FDA Approvals of Brand-Name Prescription Drugs in 2012 I. New Pharmaceuticals, NMEs, Biologics Amyvid (NME) (Florbetapir F18; Avid Radiopharmaceuticals) Class/route: Diagnostic radiopharmaceutical; intravenous solution Indication: To estimate beta-amyloid neuritic plaque density in adult patients with cognitive impairment who are being evaluated for positron emission tomography imaging of the brain for Alzheimer’s disease and other causes of cognitive decline Approval consideration: Priority review Aubagio (NME) (Teriflunomide; Genzyme) Class/route: Pyrimidine synthesis inhibitor; oral Indication: Treatment of patients with relapsing forms of multiple sclerosis Belviq (NME) (Lorcaserin hydrochloride; Eisai) Class/route: Serotonin 2C receptor agonist; oral Indication: For chronic weight management in adults with an initial body mass index of ≥30 kg/m2 (obese) or ≥27 kg/m2 (overweight) in the presence of at least 1 weight-related comorbid condition, an adjunct to a reduced-calorie diet and increased physical activity Bosulif (NME) (Bosutinib monohydrate; Pfizer) Class/route: Kinase inhibitor; oral Indication: Treatment of adult patients with chronic-, accelerated-, or blast-phase Ph-chromosome–positive chronic myelogenous leukemia with resistance to or intolerance of previous therapy Approval consideration: Orphan drug Choline C 11 (NME) (Mayo Clinic PET Radiochemistry Facility) Class/route: Radiopharmaceutical; intravenous Indication: For use in positron emission tomography imaging of patients with suspected prostate cancer recurrence and noninformative bone scintigraphy, computerized tomography, or magnetic resonance imaging Approval consideration: Priority review Cometriq (NME) (Cabozantinib; Exelixis)

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Class/route: Kinase inhibitor; oral Indication: Treatment of patients with progressive, metastatic medullary thyroid cancer Approval considerations: Priority review, orphan drug Elelyso (NME) (Taliglucerase alfa; Pfizer) Class/route: Hydrolytic lysosomal glucocerebroside– specific enzyme; intravenous solution Indication: For long-term enzyme replacement therapy for adults with a confirmed diagnosis of type 1 Gaucher disease Approval consideration: Orphan drug Eliquis (NME) (Apixaban; Bristol-Myers Squibb) Class/route: Factor Xa inhibitor anticoagulant; oral Indication: To reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation Approval considerations: Priority review, REMS Erivedge (NME) (Vismodegib; Genentech) Class/route: Hedgehog pathway inhibitor; oral Indication: Treatment of adults with metastatic basalcell carcinoma, or with locally advanced basal-cell carcinoma that has recurred after surgery, or who are not candidates for surgery and are not candidates for radiation Approval consideration: Priority review Fulyzaq (NME) (Crofelemer; Salix Pharmaceuticals) Class/route: Antidiarrheal; oral Indication: For the symptomatic relief of noninfectious diarrhea in adult patients with HIV/AIDS who are receiving antiretroviral therapy Approval consideration: Priority review Fycompa (NME) (Perampanel; Eisai) Class/route: Noncompetitive AMPA glutamate receptor antagonist; oral Indication: Adjunctive therapy for the treatment of partial-onset seizures with or without secondarily generalized seizures in patients with epilepsy aged ≥12 years

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2012 FDA Drug Approvals

Gattex (NME) (Teduglutide recombinant; NPS Pharmaceuticals) Class/route: Glucagon-like peptide-2 analog; subcutaneous injection Indication: Treatment of adult patients with short bowel syndrome who are dependent on parenteral support Approval considerations: Orphan drug, REMS Gintuit (BLA) (Allogeneic cultured keratinocytes and fibroblasts in bovine collagen; Organogenesis) Class/route: Allogeneic cellularized scaffold product; topical Indication: For application to vascular wound beds in the treatment of mucogingival conditions in adults HPC, Cord Blood (BLA) (ClinImmune Labs) Class/route: Allogeneic cord blood hematopoietic progenitor cell therapy; intravenous Indication: Use in unrelated donor hematopoietic progenitor cell transplantation in patients with certain blood disorders Iclusig (NME) (Ponatinib hydrochloride; Ariad Pharmaceuticals) Class/route: Kinase inhibitor; oral Indication: Treatment of adult patients with chronic-, accelerated-, or blast-phase chronic myelogenous leukemia that is resistant or intolerant to previous TKI therapy or Ph-positive acute lymphoblastic leukemia that is resistant or intolerant to previous TKI therapy Approval considerations: Priority review, orphan drug Inlyta (NME) (Axitinib; Pfizer) Class/route: Kinase inhibitor; oral Indication: Treatment of advanced renal-cell carcinoma after failure of 1 prior systemic therapy Jetrea (BLA) (Ocriplasmin; ThromboGenics) Class/route: Proteolytic enzyme; intravitreal injection Indication: Treatment of symptomatic vitreomacular adhesion Approval consideration: Priority review Juxtapid (NME) (Lomitapide mesylate; Aegerion Pharmaceuticals) Class/route: Microsomal triglyceride transfer protein inhibitor; oral Indication: An adjunct to a low-fat diet and other lipid-­ lowering treatments, including low-density lipoprotein apheresis where available, to reduce low-density lipoprotein cholesterol, total cholesterol, apolipoprotein B,

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and non–high-density lipoprotein cholesterol in patients with homozygous familial hypercholesterolemia Approval considerations: Orphan drug, REMS Kalydeco (NME) (Ivacaftor; Vertex Pharmaceuticals) Class/route: Cystic fibrosis transmembrane conductive regulator potentiator; oral Indication: Treatment of a rare form of cystic fibrosis in patients aged ≥6 years who have a G551D mutation in the CFTR gene Approval considerations: Priority review, orphan drug Korlym (NME) (Mifepristone; Corcept Therapeutics) Class/route: Cortisol receptor blocker; oral Indication: To control hyperglycemia secondary to hypercortisolism in adults with endogenous Cushing’s syndrome who have type 2 diabetes mellitus or glucose intolerance and have failed or are not candidates for surgery Kyprolis (NME) (Carfilzomib; Onyx Pharmaceuticals) Class/route: Proteasome inhibitor; intravenous Indication: Treatment of patients with multiple myeloma who have received at least 2 previous therapies, including bortezomib and an immunomodulatory agent, and have demonstrated disease progression on or within 60 days of completion of the last therapy Approval consideration: Orphan drug Linzess (NME) (Linclotide; Forest Laboratories) Class/route: Guanylate cyclase-C agonist; oral Indication: Treatment of adult patients with irritable bowel syndrome with constipation and chronic idiopathic constipation Marqibo (NME) (Vincristine sulfate liposome; Talon Therapeutics) Class/route: Vinca alkaloid; intravenous Indication: Treatment of adult patients with Ph-negative acute lymphoblastic leukemia that has relapsed ≥2 times or whose disease has progressed after ≥2 antileukemia therapies Approval consideration: Orphan drug MenHibrix (BLA) (GlaxoSmithKline Biologicals) Class/route: Haemophilus B and meningococcal conjugate vaccine; intramuscular Indication: Prevent meningococcal disease and Haemophilus influenzae type B in children

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2012 FDA Drug Approvals

Myrbetriq (NME) (Mirabegron; Astellas Pharma US) Class/route: Beta-3 adrenergic agonist; oral Indication: Treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency Neutroval (BLA) (tbo-filgrastim; Sicor Biotech UAB) Class/route: Human granulocyte colony-stimulating factor; subcutaneous Indication: To reduce the duration of severe neutropenia in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia Omontys (NME) (Peginesatide acetate; Affymax/Takeda) Class/routes: Erythropoiesis-stimulating agent; subcutaneous, intravenous Indication: Treatment of anemia associated with chronic kidney disease in adult patients on dialysis Approval consideration: REMS Update: This drug was removed from the market by the manufacturer on February 23, 2013 Perjeta (BLA) (Pertuzumab; Genentech) Class/route: HER2/neu receptor antagonist; intravenous infusion Indication: Treatment of patients with HER2-positive metastatic breast cancer who have not received previous anti-HER2 therapy or chemotherapy for metastatic disease, to be used in combination with trastuzumab and docetaxel Approval consideration: Priority review Picato (NME) (Ingenol mebutate; Leo Pharma) Class/route: Antineoplastic; topical gel Indication: Treatment of actinic keratosis Prepopik (NME) (Sodium picosulfate, magnesium oxide, anhydrous citric acid; Ferring Pharmaceuticals) Class/route: Osmotic laxative; oral Indication: For cleansing of the colon as a preparation for colonoscopy in adults Signifor (NME) (Pasireotide diaspartate; Novartis) Class/route: Somatostatin analog; subcutaneous Indication: Treatment of adult patients with Cushing’s disease for whom pituitary surgery is not an option or has not been curative Approval consideration: Orphan drug

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Sirturo (NME) (Bedaquiline fumarate; Janssen Therapeutics) Class/route: Diarylquinoline antimycobacterial; oral Indication: For adults (≥18 years) with pulmonary multidrug-resistant tuberculosis, as part of a combination therapy, when an effective treatment regimen cannot otherwise be provided Approval considerations: Priority review, orphan drug Stendra (NME) (Avanafil; Vivus) Class/route: Phosphodiesterase type 5 inhibitor; oral Indication: Treatment of erectile dysfunction Stivarga (NME) (Regorafenib; Bayer Healthcare Pharmaceuticals/Onyx Pharmaceuticals) Class/route: Kinase inhibitor; oral Indication: Treatment of patients with metastatic colorectal cancer who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecanbased chemotherapy, and anti–vascular endothelial growth factor therapy, and, if KRAS wild type, an anti–endothelial growth factor receptor therapy Approval consideration: Priority review Stribild (NME) (Elvitegravir, cobicistat, emtricitabine, tenofovir disoproxil fumarate; Gilead) Class/route: Integrase inhibitor antiretroviral; oral Indication: A complete regimen for treatment of HIV-1 infection in adults who are antiretroviral treatment naïve Surfaxin (NME) (Lucinactant; Discovery Laboratories) Class/route: Lung surfactant; intratracheal Indication: Prevention of respiratory distress syndrome in premature infants at high risk for respiratory distress syndrome Synribo (NME) (Omacetaxine mepesuccinate; Teva) Class/route: Protein synthesis inhibitor; subcutaneous Indication: Treatment of adult patients with chronicor accelerated-phase chronic myelogenous leukemia with resistance and/or intolerance to ≥2 TKIs Approval consideration: Orphan drug Tudorza Pressair (NME) (Aclidinium bromide; Forest Laboratories) Class/route: Anticholinergic; oral inhalation Indication: Long-term maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease, including bronchitis and emphysema

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2012 FDA Drug Approvals

Vascepa (NME) (Icosapent ethyl; Amarin Pharmaceuticals) Class/route: Antihypertriglyceredemia; oral Indication: Adjunct to diet to reduce triglyceride levels in adult patients with severe (≥500 mg/dL) hypertriglyceridemia Voraxaze (BLA) (Glucarpidase; BTG International) Class/route: Carboxypeptidase enzyme; intravenous Indication: Treatment of toxic plasma methotrexate concentrations (>1 µmol/L) in patients with delayed methotrexate clearance due to impaired renal function Approval considerations: Priority review, orphan drug Xeljanz (NME) (Tofacitinib citrate; Pfizer) Class/route: JAK inhibitor; oral Indication: Treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to or intolerance of methotrexate Approval consideration: REMS

Xtandi (NME) (Enzalutamide; Astellas Pharma/Medivation) Class/route: Androgen receptor inhibitor; oral Indication: Treatment of patients with metastatic castration-resistant prostate cancer who have previously received docetaxel Approval consideration: Priority review Zaltrap (BLA) (Ziv-aflibercept; sanofi-aventis US) Class/route: Angiogenesis inhibitor; intravenous infusion Indication: In combination with 5-fluorouracil, leuco­ vorin, and irinotecan for the treatment of patients with metastatic colorectal cancer that is resistant to or has progressed after an oxaliplatin-containing regimen Approval consideration: Priority review Zioptan (NME) (Tafluprost; Merck Sharp & Dohme Corp) Class/route: Prostaglandin analog; ophthalmic solution Indication: To reduce elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension

II. New Combinations, Formulations, Indications Abraxane (new indication) (Paclitaxel; Abraxis BioScience) Class/route: Microtubule inhibitor; intravenous New indication: First-line treatment of locally advanced or metastatic non–small-cell lung cancer, in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy; already indicated for the treatment of metastatic breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy Afinitor (new indications) (Everolimus; Novartis) Class/route: mTOR kinase inhibitor; oral New indications: Treatment of postmenopausal women with advanced hormone receptor–positive, HER2negative breast cancer in combination with exemestane after failure of treatment with letrozole or anastrozole, and adults with renal angiomyolipoma and tuberous sclerosis complex, not requiring immediate surgery; already indicated for the treatment of progressive neuroendocrine tumors of pancreatic origin that are unresectable, locally advanced or metastatic; adults

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with advanced renal-cell carcinoma after failure with sunitinib or sorafenib; and pediatric and adult patients with tuberous sclerosis complex who have subependymal giant-cell astrocytoma Approval consideration: Priority review Afinitor Disperz (new formulation) (Everolimus; Novartis) Class/route: mTOR kinase inhibitor; oral New formulation: Pediatric form, tablets for oral suspension Indication: Treatment of pediatric patients aged ≥1 years with tuberous sclerosis complex who have subependymal giant-cell astrocytoma that requires therapeutic intervention but cannot be curatively resected Approval considerations: Priority review, orphan drug Eylea (new indication) (Aflibercept; Regeneron Pharmaceuticals) Class/route: Recombinant fusion protein; ophthalmic intravitreal injection New indication: Treatment of patients with neovascular (wet) age-related macular degeneration; already indicated for the treatment of macular edema after central retinal vein occlusion

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2012 FDA Drug Approvals

Gleevec (new indication) (Imatinib mesylate; Novartis) Class/route: Kinase inhibitor; oral New indication: Adjuvant treatment of adult patients after resection of Kit (CD117)-positive gastrointestinal stromal tumors (GISTs); already indicated for the treatment of CD117-positive unresectable and/or metastatic malignant GISTs; newly diagnosed adult and pediatric patients with chronic-, blast crisis–, accelerated-, or chronic-phase Ph-positive chronic myelogenous leukemia; relapsed or refractory Ph-positive acute lymphoblastic leukemia; myelodysplastic/myeloproliferative diseases; aggressive systemic mastocytosis without the D816V c-Kit mutation or with unknown c-Kit mutational status; hypereosinophilic syndrome and/or chronic eosinophilic leukemia who have the FIP1L1–plateletderived growth factor receptor alpha fusion kinase; patients with hypereosinophilic syndrome and/or chronic eosinophilic leukemia who are FIP1L1– platelet-derived growth factor receptor alpha fusion kinase negative or unknown; unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans Humira (new indication) (Adalimumab; Abbott Laboratories) Class/route: Tumor necrosis factor blocker; subcutaneous New indication: For inducing and sustaining clinical remission in adult patients with moderately to severely active ulcerative colitis; already indicated to reduce the signs and symptoms of moderate-to-severe rheumatoid arthritis, moderate-to-severe active polyarticular juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, and moderateto-severe chronic plaque psoriasis Approval consideration: Orphan drug Jentadueto (new combination) (Linagliptin and metformin hydrochloride; Boehringer Ingelheim/Lilly) Class/route: Dipeptidyl peptidase-4 inhibitor and biguanide combination; oral tablets Indication: To improve glycemic control in adult patients with type 2 diabetes, as an adjunct to diet and exercise, when treatment with both linagliptin and meformin is appropriate Levaquin (new indication) (Levofloxacin; Janssen Pharmaceuticals) Class/routes: Fluoroquinolone antibacterial; oral, intravenous New indication: Treatment and prophylaxis of plague resulting from Yersinia pestis in adults and pediatric

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patients aged ≥6 months; already indicated for the treatment of pneumonia (nosocomial and community acquired), acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis, skin and skin structure infections (complicated and uncomplicated), chronic bacterial prostatitis, urinary tract infections (complicated and uncomplicated), acute pyelonephritis, inhalational anthrax (postexposure) Lucentis (new indication) (Ranibizumab; Genentech) Class/route: Vascular endothelial growth factor inhibitor; ophthalmic intravitreal injection New indication: Treatment of diabetic macular edema; already indicated for the neovascular (wet) age-related macular degeneration and macular edema after retinal-vein occlusion Qsymia (new combination) (Phentermine hydrochloride and topiramate extendedrelease; Vivus) Class/route: Combination sympathomimetic amine anorectic and antiepileptic; oral Indication: For chronic weight management in adults with an initial body mass index of ≥30 kg/m2 (obese) or ≥27 kg/m2 (overweight) in the presence of ≥1 weight-related comorbidity, such as hypertension, type 2 diabetes mellitus, or dyslipidemia, as an adjunct to a reduced-calorie diet and increased physical activity Approval consideration: REMS Truvada (new indication) (Emtricitabine, tenofovir disoproxil fumarate; Gilead) Class/route: Nucleoside analog HIV-1 reverse transcriptase inhibitor; oral New indication: In combination with safer sex practices for pre-exposure prophylaxis to reduce the risk of sexually acquired HIV-1 in adults at high risk; already indicated for the treatment of HIV-1 infection in adults and pediatric patients aged ≥12 years Approval considerations: Priority review, REMS Velcade Subcutaneous (new formulation) (Bortezomib subcutaneous; Millennium) Class/route: Proteasome inhibitor; subcutaneous New formulation: Subcutaneous administration; already available as intravenous Indication: Treatment of multiple myeloma or mantlecell lymphoma in patients who have received at least 1 prior therapy; intravenous or subcutaneous administration Approval considerations: Priority review, orphan drug

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2012 FDA Drug Approvals

Zetonna (new formulation) (Ciclesonide; Sunovion) Class/route: Corticosteroid; nasal aerosol New formulation: Formulated with a hydrofluoroalkane propellant in a delivery system designed to dispense ciclesonide as a fine, dry mist in a small volume; already approved as Omnaris Indication: Treatment of symptoms associated with seasonal and perennial allergic rhinitis in adults and adolescents aged ≥12 years

Votrient (new indication) (Pazopanib hydrochloride; GlaxoSmithKline) Class/route: Kinase inhibitor; oral New indication: Treatment of patients with advanced soft-tissue sarcoma who have received prior chemotherapy; already indicated for the treatment of advanced renal-cell carcinoma Xarelto (new indication) (Rivaroxaban; Janssen Pharmaceuticals) Class/route: Factor Xa inhibitor; oral New indication: Treatment of deep-vein thrombosis, pulmonary embolism, and for the reduction in the risk of recurrence of deep-vein thrombosis and of pulmonary embolism; already indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation, and for the prophylaxis of deep-vein thrombosis, which may lead to pulmonary embolism in patients undergoing knee or hip replacement surgery Approval consideration: REMS

Zytiga (new indication) (Abiraterone acetate; Janssen Biotech) Class/route: Cytochrome P17 inhibitor; oral New indication: Treatment of men with late-stage metastatic castration-resistant prostate cancer before chemotherapy, in combination with prednisone; already indicated for the treatment for patients whose prostate cancer progressed after chemotherapy containing docetaxel Approval consideration: Priority review

BLA indicates biologic license application; FDA, US Food and Drug Administration; NME, new molecular entity; Ph, Philadelphia chromosome; REMS, Risk Evaluation and Mitigation Strategy; TKI, tyrosine kinase inhibitor.

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Vol 6, No 3

Abraxane Receives New Indication for Locally Advanced or Metastatic Non–Small-Cell Lung Cancer When Curative Surgery or Radiation Therapy Is Not an Option

By Lynne Lederman, PhD, Medical Writer

F

or the purposes of treatment, lung cancer is classified as non–small cell, which accounts for approximately 85% of cases, or as small cell, representing 14% of cases.1 Non–small-cell lung cancer (NSCLC) is the leading cause of cancer death worldwide.2 The greatest risk factor for lung cancer is cigarette smoking. Other risk factors include smoking pipes or cigars and exposure to agents such as radon gas, secondhand smoke, asbes­tos, chromium, cadmium, arsenic, some organic chemicals, radiation, and air pollution. The rate of lung cancer may be increased in individuals with a history of tuberculosis or a genetic susceptibility to the disease.1,3

sure. The risks of screening include cumulative radiation exposure and unnecessary biopsies and surgery.1 The 1-year relative survival for patients with lung cancer—which has been increasing over the past several decades as a result of better surgical techniques and combination therapies—was 43% in the period between 2003 and 2006.1 The 5-year survival rate for all stages of lung cancer combined is only 16%. Early detection at the localized stage results in a 5-year survival rate of 52%, but localized lung cancer represents only 15% of all cases.

The overall 5-year survival for NSCLC is 17%,1 but the 5-year survival rate for stage IV NSCLC is only 1%.6

The Burden and Impact of Lung Cancer In 2012, the American Cancer Society estimated there would be 226,160 individuals with new cases of lung cancer, representing approximately 14% of all cancer diagnoses, and 160,340 deaths from lung cancer in the United States, which is approximately 28% of all cancer deaths.1 Lung cancer is the second leading cause of new cases of cancer (other than nonmelanoma skin cancer or noninvasive cancers other than bladder cancer) in both men and women in the United States, and the leading cause of death for both sexes.1 The likelihood of developing lung cancer increases with age.1 Although the rate of lung cancer has been decreasing in men over the past 20 years, it has only recently started decreasing in women. Sex differences in the incidence of lung cancer and in death rates are a result of historic rates of smoking and smoking cessation in men and women over the past 50 years.4 Lung cancer is usually diagnosed at later stages and is rarely cured.4 Symptoms can include persistent cough, blood-tinged sputum, chest pain, change in the voice, and recurrent pneumonia or bronchitis.1 Median age at diagnosis is age 70 years for men and age 71 years for women.5 Annual chest x-rays do not decrease mortality from lung cancer. Although a screening trial using low-dose spiral computed tomography reduced the death rate by 20% for high-risk individuals (ie, current and former heavy smokers), it is not known if this technology is applicable for screening of those with less cigarette expo-

Current Treatments for Lung Cancer The current treatments for lung cancer are based on the type and stage of the tumor, and include surgery, radiation therapy, chemotherapy, and targeted therapies, such as bevacizumab, erlotinib, or crizotinib.1,3 Surgery is the most common treatment choice for localized NSCLC (stage I or stage II).3 Chemotherapy after surgery usually improves survival.

However, NSCLC is usually diagnosed at a more ad­ vanced stage, and treatment often in­ cludes radiation therapy and chemo­therapy, which can be combined with sur­gery. Patients with advanced NSCLC usually receive chemotherapy, targeted therapy, or both.1 Platinum-based regimens are recommended for patients with stage IV NSCLC.3 Al­though many combinations of new agents have been tested in patients with advanced, inoperable NSCLC, their prognosis is still poor, suggesting a need for new therapeutic options.3

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Abraxane Receives a New Indication for NSCLC On October 11, 2012, paclitaxel protein-bound particles for injectable suspension (Abraxane for Injectable Suspension), an albumin-bound form of paclitaxel, was approved for the first-line treatment of locally advanced or metastatic NSCLC in combination with carboplatin in patients who are not candidates for curative surgery or radiation therapy.7 Abraxane is a nanoparticle protein-bound paclitaxel, which may therefore also be referred to as nab-paclitaxel.6

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aseline Demographics and Disease Characteristics in Table 1 B the Phase 3 NSCLC Trial, ITT Population Abraxane Paclitaxel All patients Characteristic (N = 521) (N = 531) (N = 1052) 60 60 60 Median age, yrs 75 75 75 Male, % 25 25 25 Female, % Asian/black/white/ 15/2/80/2/<1 15/2/82/<1/<1 15/2/81/2/<1 Hispanic/other, % 21 21 21 Stage IIIB at random assignment, % 79 79 79 Stage IV at random assignment, % 7/3 9/2 8/3 Prior radiation/prior chemotherapy, % 26 27 27 Never smoked, % 32 29 30 Smoked and quit, % 41 44 43 Still smokes, % ITT indicates intention-to-treat; NSCLC, non–small-cell lung cancer.

Source: Socinski MA, et al. Weekly nab-paclitaxel in combination with carboplatin versus solvent-based paclitaxel plus carboplatin as first-line therapy in patients with advanced non–smallcell lung cancer: final results of a phase III trial. J Clin Oncol.

2012;30:2055-2062.

Abraxane is already indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or for relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated.8 The new indication for NSCLC was based on a clinical trial comparing weekly infusions of Abraxane at a dose of 100 mg/m2 (ITT [intention to treat], n = 521) to infusions of paclitaxel every 3 weeks at a dose of 200 mg/m2 (ITT, n = 531). All patients also received carboplatin (AUC [area under the curve], 6 mg•min/mL) every 3 weeks.6,7 The study design and results are described in detail below.

Clinical Pharmacology: Development and Mechanism of Action Abraxane is an albumin-bound form of paclitaxel, the active component. Abraxane has a mean particle size of approximately 130 nm.8,10 Abraxane does not contain any solvents or ethanol. The 130-nm particle size will not obstruct capillaries when the agent is delivered by intravenous (IV) infusion.10 Abraxane was developed to avoid toxicities associated with the vehicle polyoxyethylated castor oil (Cremophor EL), which is used to deliver paclitaxel because of its poor solubility.10,11 Paclitaxel is contraindicated in pa­tients with a his-

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tory of hypersensitivity reactions to the drug itself or to other drugs formulated in polyoxy­ethylated castor oil.

Patients receiving paclitaxel require pretreatment with cor­ticosteroids, diphenhydramine, and H2 antagonists to avoid hypersensitivity reactions.12 Severe hypersensitivity reactions that re­quired treatment occurred in 2% to 4% of patients receiving paclitaxel in clinical trials, and some of these reactions were fatal, despite premedication.12 Unlike paclitaxel, Abraxane does not require premedication and can be infused over a shorter period of time.8,12 Abraxane was also designed to increase intratumor concentrations of the active drug using endogenous albumin pathways.11 The mechanism of action of Abrax­ane is microtubule inhibition, the same as that of paclitaxel. Abraxane promotes the assembly of microtubules from tubulin dimers and stabilizes these microtubules, by preventing de­ polymerization. This stabilization prevents microtubules from reorganizing properly and from maintaining their normal structure during mitosis, thereby inhibiting cancer-cell division, motility, and intracellular transport.8,10

Phase 3 Clinical Trial in Locally Advanced or Metastatic NSCLC The new indication for Abraxane as first-line treatment of locally advanced or metastatic NSCLC, in combination with carboplatin in patients who are not candidates for curative surgery or for radiation therapy, was approved on the basis of one phase 3 clinical trial, showing significantly improved overall response rates (ORRs) in all patients receiving Abraxane, regardless of histology results.6,7,9 Trial Design This randomized, multicenter, open-label phase 3 trial compared the efficacy and safety of Abraxane plus carboplatin with that of solvent-based paclitaxel (paclitaxel injection) plus carboplatin as first-line systemic treatment in patients with locally advanced (stage IIIB) or metastatic (stage IV) NSCLC. A total of 1052 patients were randomly assigned in a 1:1 ratio to receive weekly 30-minute infusions of Abraxane 100 mg/m2 or 3-hour infusions of paclitaxel 200 mg/m2 after premedication every 3 weeks.

All patients also received IV carboplatin (AUC, 6 mg•min/mL) every 3 weeks after infusion with Abraxane or paclitaxel. The primary objective was ORR.6,8 Patient Population Key baseline demographic and disease characteristics of the enrolled patients are listed in Table 1. The 2 treatment groups were well-balanced.6

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Safety Profile Adverse reactions (ie, safety) were assessed in the 514 patients who received Abraxane plus carboplatin, and in the 524 patients who received paclitaxel injection plus carboplatin.6,8 The median number of treatment cycles was 6 for each treatment group. The doses and schedules for the 2 treatment groups were different; therefore, direct dose-dependent and schedule-dependent comparisons concerning safety cannot be made.8 The ad­verse reactions seen most frequently (≥10% incidence) for the patients re­ceiving Abraxane plus carboplatin are listed in Table 2.8 These common adverse reactions occurred at a similar incidence in the paclitaxel injection plus carboplatin–treated patients.

The frequency and severity of hematologic abnormalities occurring with a difference of ≥5% for all grades (grades 1-4) or ≥2% for grade 3 and 4 toxicities for the 2 treatment groups are listed in Table 3.8 Only 1% of patients in each arm developed febrile neutropenia, and 1 treatment-related death was reported in each arm.6 Thrombo­cytopenia and anemia associated with Abraxane plus carboplatin were readily manageable.6 The frequency and severity of nonhematologic adverse reactions occurring with a difference of ≥5% for all grades (grades 1-4) or ≥2% for grade 3 and 4 toxicities between the 2 treatment groups are listed in Table 4.8 The incidences of severe neuropathy, myalgia, and arthralgia were lower in the Abraxane plus carboplatin group.6 In the Abraxane plus carboplatin–treated group, 17 of 514 (3%) patients developed grade 3 peripheral neuropathy (PN), and none developed grade 4 PN. In 10 (59%) of these patients, the grade 3 neuropathy resolved or improved to grade 1 after interruption or discontinuation of Abraxane.8 Median time to improvement of grades 3 or 4 sensory neuropathy was shorter (38 days) for patients in the Abraxane plus carboplatin group than the median time (104 days) for those in the paclitaxel injection plus carboplatin group.6

ommon (≥10% Incidence) Adverse Reactions Table 2 C in Patients Receiving Abraxane plus Carboplatin Incidence Adverse reaction (N = 514), % 56 Alopecia 27 Nausea 25 Fatigue 17 Decreased appetite 16 Asthenia 16 Constipation 15 Diarrhea 12 Vomiting 12 Dyspnea 10 Rash Source: Abraxane for Injectable Suspension [package insert]. Summit, NJ: Celgene Corporation; October 2012.

Response The trial met its primary end point.7 The ORR was significantly higher in the Abraxane plus carboplatin group than in the paclitaxel injection plus carboplatin group (33% vs 25%, re­spectively; P = .005). No significant difference was found in overall survival between the 2 treatment groups.8 The efficacy results are summarized in Table 5.

Dosing and Administration Unlike paclitaxel, Abraxane does not require premedication.8 The recommended dose of Abraxane for patients with NSCLC is 100 mg/m2, which is administered as an IV infusion over 30 minutes on days 1, 8, and 15 of each 21-day cycle. The recommended dose of carboplatin is AUC 6 mg•min/mL on day 1 only of each 21-day cycle, beginning immediately after administration of Abraxane is completed.8

Table 3 Selected Hematologic Toxicities between Treatment Groups Abraxane (100 mg/m2 weekly) plus carboplatin Grades 1-4, % Grades 3-4, %

Paclitaxel injection (200 mg/m2 every 3 weeks) plus carboplatin Grades 1-4, % Grades 3-4, %

98 28 91 7 Anemiaa,b 85 47 83 58 Neutropeniaa,c a,c 68 18 55 9 Thrombocytopenia a 508 patients assessed in the Abraxane plus carboplatin–treated group. b 514 patients assessed in the paclitaxel injection plus carboplatin–treated group. c 513 patients assessed in the paclitaxel injection plus carboplatin–treated group.

Adapted from Abraxane for Injectable Suspension [package insert]. Summit, NJ: Celgene Corporation; October 2012.

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Table 4 Selected Nonhematologic Toxicities between Treatment Groups

System organ class Nervous system disorders General disorders, administration-site conditions Respiratory thoracic and mediastinal disorders Musculoskeletal, connective-­tissue disorders

Paclitaxel injection (200 mg/m2 Abraxane (100 mg/m2 weekly) plus carboplatin every 3 weeks) plus (N = 514) carboplatin (N = 524) MedDRA v 12.1 preferred term Grades 1-4, % Grades 3-4, % Grades 1-4, % Grades 3-4, % 48 3 64 12 Peripheral neuropathya Edema, 10 0 4 <1 peripheral Epistaxis

7

0

2

0

Arthralgia 13 <1 25 2 Myalgia 10 <1 19 2 a Peripheral neuropathy is defined by the MedDRA Version 14.0 SMQ neuropathy (broad scope).

Adapted from Abraxane for Injectable Suspension [package insert]. Summit, NJ: Celgene Corporation; October 2012.

Table 5 Efficacy Results from the Phase 3 NSCLC Trial, ITT Population Abraxane (100 mg/m2 weekly) Paclitaxel injection (200 mg/m2 every plus carboplatin (N = 521) 3 weeks) plus carboplatin (N = 531) Overall response rate 170 (33) 132 (25) Confirmed complete or partial overall response, N (%) 28.6-36.7 21.2-28.5 95% CI .005 P value (chi-square test) 6.9 (5.6-8.0) 6.0 (5.6-7.1) Median DoR in months (95% CI) Overall response rate, by histology 66/254 (26%) 71/264 (27%) Carcinoma/adenocarcinoma 94/229 (41%) 54/221 (24%) Squamous-cell carcinoma 3/9 (33%) 2/13 (15%) Large-cell carcinoma 7/29 (24%) 5/33 (15%) Other CI indicates confidence interval; DoR, duration of response; ITT, intention-to-treat; NSCLC, non–small-cell lung cancer.

Adapted from Abraxane for Injectable Suspension [package insert]. Summit, NJ: Celgene Corporation; October 2012.

Dose Modifications Dose modifications are not required for patients with mild hepatic impairment (AST [aspartate aminotransferase] <10 times the upper limit of normal [ULN], or bilirubin up to 1.25 times ULN). Abraxane should not be administered to patients with AST >10 times ULN or bilirubin >5 times ULN. The starting doses for patients with NSCLC who have moderate hepatic impairment (AST <10 times ULN and bilirubin 1.26-2 times ULN) or severe hepatic impairment (AST <10 times ULN and bilirubin 2.01-5 times ULN) should be reduced to 75 mg/ m2 or to 50 mg/m2, respectively. Subsequent dose increases or adjustments should be based on individual tolerance.8

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Patients with NSCLC should not receive Abraxane on day 1 of a cycle if they do not have an absolute neutro­phil count (ANC) of ≥1500 cells/mm3 and platelet counts of ≥100,000 cells/ mm3. Treatment should be withheld until counts reach these levels on day 1 or until ANC is ≥500 cells/mm3 and platelet counts are ≥50,000 cells/mm3 on days 8 and 15 of a cycle. Abraxane should be withheld for grades 3 or 4 PN. Permanent modifications to Abrax­ane and to carboplatin doses are required when treatment is resumed after neutropenia, neutropenic fever, thrombocytopenia, or PN.8 These dose reductions are summarized in Table 6.

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Table 6 Permanent Dose Reductions for Hematologic and Neurologic Adverse Drug Reactions in NSCLC Adverse drug reaction Neutropenic fever (ANC <500 cells/mm3 with fever >38°C) or delay of next cycle by >7 days for ANC <1500 cells/mm3 or ANC <500 cells/mm3 for >7 days Platelet count <50,000/mm3 Severe sensory neuropathy, grade 3 or 4

Occurrence First Second Third First Second First Second

Weekly Abraxane dose, mg/m2

Every 3-week carboplatin dose, AUC mg•min/mL

75

4.5

50

3.0

Discontinue treatment 75

4.5

Discontinue treatment 75

4.5

50

3.0

Third

Discontinue treatment

ANC indicates absolute neutrophil count; AUC, area under the curve; NSCLC, non–small-cell lung cancer.

Adapted from Abraxane for Injectable Suspension [package insert]. Summit, NJ: Celgene Corporation; October 2012.

Warnings and Precautions The prescribing information for Abraxane contains a Boxed Warning concerning neutropenia. The Boxed Warning states the following8: • Do not administer Abraxane therapy to patients with baseline neutrophil counts of <1500 cells/mm3; to monitor bone marrow suppression, primarily neutropenia, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving Abraxane • An albumin form of paclitaxel may substantially affect a drug’s functional properties relative to those of drug in solution. Do not substitute pac­litaxel formulations.

Other warnings, precautions, and contraindications for Abraxane in­clude8: • Abraxane is contraindicated in patients with neutrophil counts of <1500 cells/mm3 • Patients who experience a severe reaction to Abrax­ ane should not be rechallenged with the drug • Abraxane causes myelosuppression; complete blood counts should be mon­itored and doses reduced as needed • Sensory neuropathy is a frequent adverse event and may require dose reduction or treatment interruption • Severe, fatal hypersensitivity reactions have been reported; do not rechallenge patients with Abraxane • Hepatic impairment can increase exposure and toxicity of paclitaxel; Abraxane should be administered with caution in patients with hepatic impairment • Abraxane contains albumin derived from human blood, which has a theoretical risk of viral transmission • Abraxane may cause fetal harm when administered to pregnant women; women of childbearing age should avoid becoming pregnant while receiving Abraxane • Men should be advised not to father a child while receiving Abraxane.

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Conclusion NSCLC is the most common type of lung cancer, which is the leading cause of cancer-related mortality in the United States. There have not been many new treatment options ap­proved for NSCLC. The approval of Abraxane for the treatment of NSCLC offers a new treatment option for all patients with this type of malignancy whose treatment options are limited, especially those who are not candidates for curative surgery or for radiation therapy. n References

1. American Cancer Society. Cancer Facts & Figures 2012. Atlanta, GA: American Cancer Society; 2012. www.cancer.org/acs/groups/content/@epidemiologysurveilance/ documents/document/acspc-031941.pdf. Accessed October 29, 2012.

2. Chien C-R, Shih Y-C T. Economic evaluation of beva­cizumab in the treatment of non-small cell lung cancer (NSCLC). Clinicoecon Outcomes Res. 2012;24:201-208.

3. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Non–small-cell lung cancer. Version 2.2012. www.nccn.org. Accessed October 29, 2012.

4. Vera-Llonch M, Weycker D, Glass A, et al. Health care costs in patients with metastatic lung cancer re­ceiving chemotherapy. BMC Health Serv Res. 2011;11:305-312.

5. American Cancer Society. Cancer Treatment and Sur­vivorship Facts & Figures 2012-2013. Atlanta, GA: American Cancer Society; 2012.

6. Socinski MA, Bonderenko I, Karaseva NA, et al. Week­ly nab-paclitaxel in combination with carboplatin versus solvent-based paclitaxel plus carboplatin as first-line therapy in patients with advanced non-small-cell lung cancer: final results of a phase III trial. J Clin Oncol. 2012;30:2055-2062.

7. US Food and Drug Administration. Drugs. Pac­litaxel (Abraxane). October 11, 2012. www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm323668.htm. Accessed October 29, 2012.

8. Abraxane for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) [package insert]. Summit, NJ: Celgene Corporation; October 2012.

9. Celgene Corporation. FDA approves ABRAXANE for the first-line treatment of advanced non-small cell lung cancer. October 12, 2012. http://ir.celgene.com/phoenix. zhtml?c=111960&p=irol-newsArticle&ID=1744792&highlight=. Accessed October 29, 2012.

10. Desai N, Trieu V, Yao Z, et al. Increased antitumor activity, intratumor paclitaxel concentrations, and endothelial cell transport of cremophor-free, albumin-bound pac­ litaxel, ABI-007, compared with cremophor-based paclitaxel. Clin Cancer Res. 2006;12: 1317-1324.

11. Green MR, Manikhas GM, Orlov S, et al. Abraxane, a novel Cremophor-free, albumin-bound particle form of paclitaxel for the treatment of advanced non-smallcell lung cancer. Ann Oncol. 2006;17:1263-1268.

12. Taxol (paclitaxel) injection [package insert]. Prince­ ton, NJ: Bristol-Myers Squibb Corporation; April 2011.

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Indication Qsymiaâ&#x201E;˘ (phentermine and topiramate extended-release) capsules CIV is a combination of phentermine, a sympathomimetic amine anorectic, and topiramate extended-release, an antiepileptic drug, indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m2 or greater (obese) or 27 kg/m2 or greater (overweight) in the presence of at least one weight-related comorbidity such as hypertension, type 2 diabetes mellitus, or dyslipidemia Limitations of Use: The effect of Qsymia on cardiovascular morbidity and mortality has not been established The safety and effectiveness of Qsymia in combination with other products intended for weight loss, including prescription and over-the-counter drugs, and herbal preparations, have not been established

Important Safety Information Qsymia (phentermine and topiramate extended-release) capsules CIV is contraindicated in pregnancy; in patients with glaucoma; in hyperthyroidism; in patients receiving treatment or within 14 days following treatment with monoamine oxidase inhibitors (MAOIs); or in patients with hypersensitivity to sympathomimetic amines, topiramate, or any of the inactive ingredients in Qsymia.

Qsymia can cause fetal harm. A fetus exposed to topiramate, a component of Qsymia, in the first trimester of pregnancy has an increased risk of oral clefts (cleft lip with or without cleft palate).

Females of reproductive potential should have a negative pregnancy test before treatment and monthly thereafter and use effective contraception consistently during Qsymia therapy.

If a patient becomes pregnant while taking Qsymia, treatment should be discontinued immediately, and the patient should be informed of the potential hazard to the fetus.

Achieve and maintain weight loss that is clinically meaningful for 1 year1 In Study 2, the CONQUER Trial, 2,487 overweight or obese patients (BMI* 27 or greater and less than or equal to 45) with 2 or more weight-related comorbidities were evaluated for 1 year 1 5% weight loss or greater† was achieved by 70% of patients who took the Qsymia™ 15 mg/92 mg dose and 62% who took the 7.5 mg/46 mg dose, compared with 21% in the placebo group (P<0.0001)1 • In CONQUER, patients randomized to Qsymia 7.5 mg/46 mg or 15 mg/92 mg achieved, on average, at least 5% weight loss within 8 weeks1,2 In CONQUER, 84% of patients randomized to Qsymia 7.5 mg/46 mg responded to treatment. Responders were defined as patients who achieved at least 3% weight loss at 12 weeks1,2 In CONQUER, Qsymia provided clinically meaningful weight loss, even in obese patients taking SSRIs, SNRIs, or bupropion1,2

QSYMIA (phentermine and topiramate extended-release) capsules CIV VS PLACEBO FOR 1 YEAR OF TREATMENT (P<0.0001) 1,2‡ COMPLETERS

Percent Weight Loss (LS mean)

0

1.6%

ITT-LOCF†

1.2%

Placebo (n=564) Qsymia 7.5 mg/ 46 mg (n=344)

4

7.8%

8

9.6% 9.8%

Qsymia 15 mg/ 92 mg (n=634)

12.4%

12

16 8

12

24

36

48

56

56

Time (Weeks) At the beginning of the study, the average weight and BMI of patients were 227 pounds and 36.6, respectively.1 Eligible comorbidities included hypertension with an elevated blood pressure (greater than or equal to 140/90 mmHg, or greater than or equal to 130/85 mmHg for diabetics) or requirement for greater than or equal to 2 antihypertensive medications; high cholesterol with triglycerides greater than 200-400 mg/dL or were receiving treatment with 2 or more lipid-lowering agents; diabetes with an elevated fasting blood glucose (greater than 100 mg/dL) or diabetes; waist circumference of 102 cm or greater in men, 88 cm or greater in women.1 For all patients, a well-balanced, reduced-calorie diet (decrease of 500 kcal/day) was recommended, and nutritional and lifestyle modification counseling was also offered.1 66% of patients in the Qsymia groups completed 1 year of treatment vs 57% in the placebo group.2

Qsymia is not indicated for the treatment of hypertension, type 2 diabetes mellitus, or dyslipidemia1

Safety profile evaluated for 1 year1 Most common adverse reactions (incidence 5% or greater and at least 1.5 times placebo) are: paraesthesia,§ dizziness, dysgeusia, insomnia, constipation, and dry mouth1 *BMI is measured in kg/m2. †Primary endpoint. Intent-to-treat, last observation carried forward.1 ‡Completers data (from subjects who had a 1-year evaluation within 7 days of their last dose). 2 § Reports of paraesthesia were typically characterized as tingling in the hands, feet, or face.1

Please see brief summary of Qsymia Prescribing Information on the following pages and Qsymia Full Prescribing Information available at www.Qsymia.com.

© 2012-2013 VIVUS, Inc. All rights reserved. 100009.01-USP

LEARN MORE AT WWW.QSYMIA.COM

QSYMIA™ (phentermine and topiramate extended-release) capsules CIV BRIEF SUMMARY: Consult package insert or www.Qsymia.com for Full Prescribing Information. For more information about Qsymia, please call VIVUS Medical Information at 1-888-998-4887 or visit our Web site at www.Qsymia.com.

INDICATIONS AND USAGE: Qsymia is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adult patients with an initial body mass index (BMI) of 30 kg/m2 or greater (obese), or 27 kg/m2 or greater (overweight) in the presence of at least one weight related comorbidity such as hypertension, type 2 diabetes mellitus, or dyslipidemia. The indication includes the following limitations of use: The effect of Qsymia on cardiovascular morbidity and mortality has not been established, and the safety and effectiveness of Qsymia in combination with other products intended for weight loss, including prescription and over-the-counter drugs and herbal preparations have not been established.

CONTRAINDICATIONS: Qsymia is contraindicated in the following conditions: Pregnancy, glaucoma, hyperthyroidism, during or within 14 days following the administration of monoamine oxidase inhibitors, and known hypersensitivity or idiosyncrasy to the sympathomimetic amines.

DOSAGE AND ADMINISTRATION: In adults with an initial BMI of 30 kg/m2 or greater or 27 kg/m2 or greater when accompanied by weight-related co-morbidities such as hypertension, type 2 diabetes mellitus, or dyslipidemia prescribe Qsymia as follows: 1) Take Qsymia once daily in the morning with or without food. Avoid dosing with Qsymia in the evening due to the possibility of insomnia. 2) Start treatment with Qsymia 3.75 mg/23 mg (phentermine 3.75 mg/topiramate 23 mg extended-release) daily for 14 days; after 14 days increase to the recommended dose of Qsymia 7.5 mg/46 mg (phentermine 7.5 mg/topiramate 46 mg extended-release) once daily. 3) Evaluate weight loss after 12 weeks of treatment with Qsymia 7.5 mg/46 mg. If a patient has not lost at least 3% of baseline body weight on Qsymia 7.5 mg/46 mg, discontinue Qsymia or escalate the dose, as it is unlikely that the patient will achieve and sustain clinically meaningful weight loss at the Qsymia 7.5 mg/ 46 mg dose. To escalate the dose: Increase to Qsymia 11.25 mg/69 mg (phentermine 11.25 mg/ topiramate 69 mg extended-release) daily for 14 days; followed by dosing Qsymia 15 mg/ 92 mg (phentermine 15 mg/topiramate 92 mg extended-release) daily. 4) Evaluate weight loss following dose escalation to Qsymia 15 mg/92 mg after an additional 12 weeks of treatment. If a patient has not lost at least 5% of baseline body weight on Qsymia 15 mg/ 92 mg, discontinue Qsymia as directed, as it is unlikely that the patient will achieve and sustain clinically meaningful weight loss with continued treatment. 5) Qsymia 3.75 mg/23 mg and Qsymia 11.25 mg/69 mg are for titration purposes only. 6) Discontinuing Qsymia: Discontinue Qsymia 15 mg/92 mg gradually by taking a dose every other day for at least 1 week prior to stopping treatment altogether, due to the possibility of precipitating a seizure (see WARNINGS AND PRECAUTIONS). Dosing in Patients with Renal Impairment: In patients with moderate (creatinine clearance [CrCl] greater than or equal to 30 and less than 50 mL/min) or severe (CrCl less than 30 mL/min) renal impairment dosing should not exceed Qsymia 7.5 mg/46 mg once daily. Renal impairment is determined by calculating CrCl using the Cockcroft-Gault equation with actual body weight (see WARNINGS AND PRECAUTIONS).

Dosing in Patients with Hepatic Impairment: In patients with moderate hepatic impairment (Child-Pugh score 7-9), dosing should not exceed Qsymia 7.5 mg/46 mg once daily (see WARNINGS AND PRECAUTIONS).

DOSAGE FORMS AND STRENGTHS: Qsymia capsules are formulated in the following four strength combinations (phentermine mg/topiramate mg extended-release): • 3.75 mg/23 mg [Purple cap imprinted with VIVUS, Purple body imprinted with 3.75/23] • 7.5 mg/46 mg [Purple cap imprinted with VIVUS, Yellow body imprinted with 7.5/46] • 11.25 mg/69 mg [Yellow cap imprinted with VIVUS, Yellow body imprinted with 11.25/69] • 15 mg/92 mg [Yellow cap imprinted with VIVUS, White body imprinted with 15/92] QSYMIA RISK EVALUATION AND MITIGATION STRATEGY (REMS): Because of the teratogenic risk associated with Qsymia therapy, Qsymia is available through a limited program under the REMS. Under the Qsymia REMS, only certified pharmacies may distribute Qsymia. Further information is available at www.QsymiaREMS.com or by telephone at 1-888-998-4887.

WARNINGS AND PRECAUTIONS: Fetal Toxicity: Qsymia can cause fetal harm. Data from pregnancy registries and epidemiology studies indicate that a fetus exposed to topiramate, a component of Qsymia, in the first trimester of pregnancy has an increased risk of oral clefts (cleft lip with or without cleft palate). If Qsymia is used during pregnancy or if a patient becomes pregnant while taking Qsymia, treatment should be discontinued immediately, and the patient should be apprised of the potential hazard to a fetus. Females of reproductive potential should have a negative pregnancy test before starting Qsymia and monthly thereafter during Qsymia therapy. Females of reproductive potential should use effective contraception during Qsymia therapy. Increase in Heart Rate: Qsymia can cause an increase in resting heart rate. A higher percentage of Qsymia-treated overweight and obese adults experienced heart rate increases from baseline of more than 5, 10, 15, and 20 beats per minute (bpm) compared to placebo-treated overweight and obese adults. The clinical significance of a heart rate elevation with Qsymia treatment is unclear, especially for patients with cardiac and cerebrovascular disease (such as patients with a history of myocardial infarction or stroke in the previous 6 months, life-threatening arrhythmias, or congestive heart failure). Regular measurement of resting heart rate is recommended for all patients taking Qsymia, especially patients with cardiac or cerebrovascular disease or when initiating or increasing the dose of Qsymia.

Qsymia has not been studied in patients with recent or unstable cardiac or cerebrovascular disease and therefore use is not recommended. Patients should inform healthcare providers of palpitations

or feelings of a racing heartbeat while at rest during Qsymia™ (phentermine and topiramate extended-release) capsules CIV treatment. For patients who experience a sustained increase in resting heart rate while taking Qsymia, the dose should be reduced or Qsymia discontinued. Suicidal Behavior and Ideation: Antiepileptic drugs (AEDs), including topiramate, a component of Qsymia, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication.

Patients treated with Qsymia should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Discontinue Qsymia in patients who experience suicidal thoughts or behaviors. Avoid Qsymia in patients with a history of suicidal attempts or active suicidal ideation. Acute Myopia and Secondary Angle Closure Glaucoma: A syndrome consisting of acute myopia associated with secondary angle closure glaucoma has been reported in patients treated with topiramate, a component of Qsymia.

Symptoms include acute onset of decreased visual acuity and/or ocular pain. Ophthalmologic findings can include myopia, anterior chamber shallowing, ocular hyperemia (redness), and increased intraocular pressure. Mydriasis may or may not be present. This syndrome may be associated with supraciliary effusion resulting in anterior displacement of the lens and iris, with secondary angle closure glaucoma. Symptoms typically occur within 1 month of initiating treatment with topiramate but may occur at any time during therapy. The primary treatment to reverse symptoms is immediate discontinuation of Qsymia. Elevated intraocular pressure of any etiology, if left untreated, can lead to serious adverse events including permanent loss of vision. Mood and Sleep Disorders: Qsymia can cause mood disorders, including depression, and anxiety, as well as insomnia. Patients with a history of depression may be at increased risk of recurrent depression or other mood disorders while taking Qsymia. The majority of these mood and sleep disorders resolved spontaneously, or resolved upon discontinuation of dosing (see ADVERSE REACTIONS). For clinically significant or persistent symptoms consider dose reduction or withdrawal of Qsymia. If patients have symptoms of suicidal ideation or behavior, discontinue Qsymia. Cognitive Impairment: Qsymia can cause cognitive dysfunction (e.g., impairment of concentration/attention, difficulty with memory, and speech or language problems, particularly word-finding difficulties). Rapid titration or high initial doses of Qsymia may be associated with higher rates of cognitive events such as attention, memory, and language/word-finding difficulties (see ADVERSE REACTIONS). Since Qsymia has the potential to impair cognitive function, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain Qsymia therapy does not affect them adversely. If cognitive dysfunction persists consider dose reduction or withdrawal of Qsymia for symptoms that are moderate to severe, bothersome, or those which fail to resolve with dose reduction. Metabolic Acidosis: Hyperchloremic, non-anion gap, metabolic acidosis (decreased serum bicarbonate below the normal reference range in the absence of chronic respiratory alkalosis) has been reported in patients treated with Qsymia (see ADVERSE REACTIONS). Conditions or therapies that predispose to acidosis (i.e., renal disease, severe respiratory disorders, status epilepticus, diarrhea, surgery or ketogenic diet) may be additive to the bicarbonate lowering effects of topiramate. Concomitant use of Qsymia and a carbonic anhydrase inhibitor (e.g., zonisamide, acetazolamide, or dichlorphenamide) may increase the severity of metabolic acidosis and may also increase the risk of kidney stone formation. Therefore, if Qsymia is given concomitantly with another carbonic anhydrase inhibitor to a patient with a predisposing condition for metabolic acidosis the patient should be monitored for the appearance or worsening of metabolic acidosis. Some manifestations of acute or chronic metabolic acidosis may include hyperventilation, nonspecific symptoms such as fatigue and anorexia, or more severe sequelae including cardiac arrhythmias or stupor. Chronic, untreated metabolic acidosis may increase the risk for nephrolithiasis or nephrocalcinosis, and may also result in osteomalacia (referred to as rickets in pediatric patients) and/or osteoporosis with an increased risk for fractures. The effect of Qsymia on growth and bonerelated sequelae has not been systematically investigated in long-term, placebo-controlled trials.

Measurement of electrolytes including serum bicarbonate prior to starting Qsymia and during Qsymia treatment is recommended. In Qsymia clinical trials, the peak reduction in serum bicarbonate occurred by week 4, and in most subjects there was a correction of bicarbonate by week 56, without any change to study drug. However, if persistent metabolic acidosis develops while taking Qsymia, reduce the dose or discontinue Qsymia. Elevation in Creatinine: Qsymia can cause an increase in serum creatinine. Peak increases in serum creatinine were observed after 4 to 8 weeks of treatment.

On average, serum creatinine gradually declined but remained elevated over baseline creatinine values. Elevations in serum creatinine often signify a decrease in renal function, but the cause for Qsymia-associated changes in serum creatinine has not been definitively established. Therefore, measurement of serum creatinine prior to starting Qsymia and during Qsymia treatment is recommended. If persistent elevations in creatinine occur while taking Qsymia, reduce the dose or discontinue Qsymia (see ADVERSE REACTIONS). Potential Risk of Hypoglycemia in Patients with Type 2 Diabetes Mellitus on Anti-Diabetic Therapy: Weight loss may increase the risk of hypoglycemia in patients with type 2 diabetes mellitus treated with insulin and/or insulin secretagogues (e.g., sulfonylureas). Qsymia has not been studied in combination with insulin.

Measurement of blood glucose levels prior to starting Qsymia and during Qsymia treatment is recommended in patients with type 2 diabetes. Decreases in medication doses for antidiabetic medications which are non-glucose-dependent should be considered to mitigate the risk of hypoglycemia. If a patient develops hypoglycemia after starting Qsymia, appropriate changes should be made to the antidiabetic drug regimen. Potential Risk of Hypotension in Patients Treated with Antihypertensive Medications: In hypertensive patients being treated with antihypertensive medications, weight loss may increase the risk of hypotension, and associated symptoms including dizziness, lightheadedness, and syncope. Measurement of blood pressure prior to starting Qsymia and during Qsymia treatment is recommended in patients being treated for hypertension. If a patient develops symptoms associated with low blood pressure after starting Qsymia, appropriate changes should be made to the antihypertensive drug regimen. CNS Depression with Concomitant CNS Depressants Including Alcohol: The concomitant use of alcohol or central nervous system (CNS) depressant drugs (e.g., barbiturates, benzodiazepines, and sleep medications) with phentermine or topiramate may potentiate CNS depression or other centrally mediated effects of these agents, such

as dizziness, cognitive adverse reactions, drowsiness, light-headedness, impaired coordination and somnolence. Therefore, avoid concomitant use of alcohol with Qsymia™ (phentermine and topiramate extended-release) capsules CIV. Potential Seizures with Abrupt Withdrawal of Qsymia: Abrupt withdrawal of topiramate, a component of Qsymia, has been associated with seizures in individuals without a history of seizures or epilepsy. In situations where immediate termination of Qsymia is medically required, appropriate monitoring is recommended. Patients discontinuing Qsymia 15 mg/92 mg should be gradually tapered as recommended to reduce the possibility of precipitating a seizure (see DOSAGE AND ADMINISTRATION). Patients with Renal Impairment: Phentermine and topiramate, the components of Qsymia, are cleared by renal excretion. Therefore, exposure to phentermine and topiramate is higher in patients with moderate (creatinine clearance [CrCl] greater than or equal to 30 and less than 50 mL/min) or severe (CrCl less than 30 mL/min) renal impairment. Adjust dose of Qsymia for both patient populations. Qsymia has not been studied in patients with end-stage renal disease on dialysis. Avoid use of Qsymia in this patient population (see DOSAGE AND ADMINISTRATION). Patients with Hepatic Impairment: In patients with mild (Child-Pugh score 5-6) or moderate (Child-Pugh score 7-9) hepatic impairment, exposure to phentermine was higher compared to healthy volunteers. Adjust dose of Qsymia for patients with moderate hepatic impairment. Qsymia has not been studied in patients with severe hepatic impairment (Child-Pugh score 10-15). Avoid use of Qsymia in this patient population (see DOSAGE AND ADMINISTRATION). Kidney Stones: Use of Qsymia has been associated with kidney stone formation. Topiramate, a component of Qsymia, inhibits carbonic anhydrase activity and promotes kidney stone formation by reducing urinary citrate excretion and increasing urine pH. Avoid the use of Qsymia with other drugs that inhibit carbonic anhydrase (e.g., zonisamide, acetazolamide or methazolamide). Use of topiramate by patients on a ketogenic diet may also result in a physiological environment that increases the likelihood of kidney stone formation. Increase fluid intake to increase urinary output which can decrease the concentration of substances involved in kidney stone formation (see ADVERSE REACTIONS). Oligohidrosis and Hyperthermia: Oligohidrosis (decreased sweating), infrequently resulting in hospitalization, has been reported in association with the use of topiramate, a component of Qsymia. Decreased sweating and an elevation in body temperature above normal characterized these cases. Some of the cases have been reported with topiramate after exposure to elevated environmental temperatures. Patients treated with Qsymia should be advised to monitor for decreased sweating and increased body temperature during physical activity, especially in hot weather. Caution should be used when Qsymia is prescribed with other drugs that predispose patients to heat-related disorders; these drugs include, but are not limited to, other carbonic anhydrase inhibitors and drugs with anticholinergic activity. Hypokalemia: Qsymia can increase the risk of hypokalemia through its inhibition of carbonic anhydrase activity. In addition, when Qsymia is used in conjunction with non-potassium sparing diuretics such as furosemide (loop diuretic) or hydrochlorothiazide (thiazide-like diuretic) this may further potentiate potassiumwasting. When prescribing Qsymia, patients should be monitored for hypokalemia (see ADVERSE REACTIONS). Monitoring: Laboratory Tests: Qsymia was associated with changes in several clinical laboratory analytes in randomized, double-blind, placebo-controlled studies. Obtain a blood chemistry profile that includes bicarbonate, creatinine, potassium, and glucose at baseline and periodically during treatment (see WARNINGS AND PRECAUTIONS).

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 studies of another drug and may not reflect the rates observed in practice. Common Adverse Reactions: Adverse reactions occurring at a rate of greater than or equal to 5% and at a rate at least 1.5 times placebo include paraesthesia, dizziness, dysgeusia, insomnia, constipation, and dry mouth.

Incidence in Controlled Trials: Adverse reactions reported in greater than or equal to 2% of Qsymiatreated patients and more frequently than in the placebo group are listed below. Consult Full Prescribing Information on adverse reactions. Nervous System Disorders: Paraesthesia, headache, dizziness, dysgeusia, hypoesthesia, disturbance in attention. Psychiatric Disorders: Insomnia, depression, anxiety. Gastrointestinal Disorders: Constipation, dry mouth, nausea, diarrhea, dyspepsia, gastroesophageal reflux disease, paraesthesia oral. General Disorders and Administration Site Conditions: Fatigue, irritability, thirst, chest discomfort. Eye Disorders: Vision blurred, eye pain, dry eye. Cardiac Disorders: Palpitations. Skin and Subcutaneous Tissue Disorders: Rash, alopecia. Metabolism and Nutrition Disorders: Hypokalemia, decreased appetite. Reproductive System and Breast Disorders: Dysmenorrhea. Infections and Infestations: Upper respiratory tract infection, nasopharyngitis, sinusitis, bronchitis, influenza, urinary tract infection, gastroenteritis. Musculoskeletal and Connective Tissue Disorders: Back pain, pain in extremity, muscle spasms, musculoskeletal pain, neck pain. Respiratory, Thoracic, and Mediastinal Disorders: Cough, sinus congestion, pharyngolaryngeal pain, nasal congestion. Injury, Poisoning, and Procedural Complications: Procedural pain. Paraesthesias/ Dysgeusia: Reports of Paraesthesia, characterized as tingling in hands, feet, or face, occurred in 4.2%, 13.7%, and 19.9% of patients treated with Qsymia 3.75 mg/23 mg, 7.5 mg/46 mg, and 15 mg/ 92 mg, respectively, compared to 1.9% of patients treated with placebo. Dysgeusia was characterized as a metallic taste, and occurred in 1.3%, 7.4%, and 9.4% of patients treated with Qsymia 3.75 mg/23 mg, 7.5 mg/46 mg, and 15 mg/92 mg, respectively, compared to 1.1% of patients treated with placebo. Mood and Sleep Disorders: The proportion of patients in 1-year controlled trials of Qsymia reporting one or more adverse reactions related to mood and sleep disorders was 15.8%, 14.5%, and 20.6% with Qsymia 3.75 mg/23 mg, 7.5 mg/46 mg, and 15 mg/92 mg, respectively, compared to 10.3% with placebo. These events were further categorized into sleep disorders, anxiety, and depression. Reports of sleep disorders were typically characterized as insomnia, and occurred in 6.7%, 8.1%, and 11.1% of patients treated with Qsymia 3.75 mg/23 mg, 7.5 mg/46 mg, and 15 mg/92 mg, respectively, compared to 5.8% of patients treated with placebo. Reports of anxiety occurred in 4.6%, 4.8%, and 7.9% of patients treated with Qsymia 3.75 mg/23 mg, 7.5 mg/46 mg, and 15 mg/92 mg, respectively, compared to 2.6% of patients treated with placebo.

Reports of depression/mood problems occurred in 5.0%, 3.8%, and 7.6% of patients treated with

Qsymia™ (phentermine and topiramate extended-release) capsules CIV 3.75 mg/23 mg, 7.5 mg/46 mg, and 15 mg/92 mg, respectively, compared to 3.4% of patients treated with placebo. The majority of these events first occurred within the initial 12 weeks of drug therapy; however, in some patients, events were reported later in the course of treatments. Cognitive Disorders: In the 1-year controlled trials of Qsymia, the proportion of patients who experienced one or more cognitive-related adverse reactions was 2.1% for Qsymia 3.75 mg/ 23 mg, 5.0% for Qsymia 7.5 mg/46 mg, and 7.6% for Qsymia 15 mg/92 mg, compared to 1.5% for placebo. These adverse reactions were comprised primarily of reports of problems with attention/ concentration, memory, and language (word finding). These events typically began within the first 4 weeks of treatment, had a median duration of approximately 28 days or less, and were reversible upon discontinuation of treatment; however, individual patients did experience events later in treatment, and events of longer duration. Drug Discontinuation Due to Adverse Reactions: In the 1-year placebo-controlled clinical studies, 11.6% of Qsymia 3.75 mg/23 mg, 11.6% of Qsymia 7.5 mg/46 mg, 17.4% of Qsymia 15 mg/92 mg, and 8.4% of placebo-treated patients discontinued treatment due to reported adverse reactions. The most common adverse reactions (greater than or equal to 1% in any treatment group) that led to discontinuation of treatment are: Vision blurred, headache, irritability, dizziness, paraesthesia, insomnia, depression, anxiety.

DRUG ABUSE AND DEPENDENCE: Controlled Substance: Qsymia is controlled in Schedule IV of the Controlled Substances Act because it contains phentermine, a Schedule IV drug. Any material, compound, mixture, or preparation that contains any quantity of phentermine is controlled as a Schedule IV drug. Topiramate is not controlled in the Controlled Substances Act. Abuse: Phentermine, a component of Qsymia, has a known potential for abuse.

Phentermine, a component of Qsymia, is related chemically and pharmacologically to the amphetamines. Amphetamines and other stimulant drugs have been extensively abused and the possibility of abuse of phentermine should be kept in mind when evaluating the desirability of including Qsymia as part of a weight reduction program. Abuse of amphetamines and related drugs (e.g., phentermine) may be associated with impaired control over drug use and severe social dysfunction. There are reports of patients who have increased the dosage of these drugs to many times that recommended. Dependence: Qsymia has not been systematically studied for its potential to produce physical dependence. Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use. Physical dependence manifests by drug-class-specific withdrawal symptoms after abrupt discontinuation or a significant dose reduction of a drug.

OVERDOSAGE: In the event of a significant overdose with Qsymia, if the ingestion is recent, the stomach should be emptied immediately by gastric lavage or by induction of emesis.

Appropriate supportive treatment should be provided according to the patient’s clinical signs and symptoms. Management of acute phentermine intoxication is largely symptomatic and includes lavage and sedation with a barbiturate. Acidification of the urine increases phentermine excretion. Intravenous phentolamine has been suggested for possible acute, severe hypertension, if this complicates phentermine overdosage. Activated charcoal has been shown to adsorb topiramate in vitro. Hemodialysis is an effective means of removing topiramate from the body.

Brief summary of Qsymia Full Prescribing Information, revised July 2012.

Manufactured for: VIVUS, Inc. For more information about Qsymia, please call VIVUS Medical Information at 1-888-998-4887 or visit our Web site at www.Qsymia.com.

References: 1. Qsymia [package insert]. Mountain View, CA: VIVUS, Inc; 2012. 2. Data on file. VIVUS, Inc.

© 2012-2013 VIVUS, Inc. All rights reserved. 100162.01-USP

Belviq: A New Prescription Weight-Loss

Treatment for Overweight or Obese Patients

By Loretta Fala, Medical Writer

O

verweight and obesity are major health concerns in the United States and worldwide, and they are associated with increased health risks.

The Impact and Burden of Obesity and Overweight Being overweight or obese is associated with specific health risks. Obesity increases the risk for type 2 diabetes, hypertension, adverse lipid concentrations, heart disease, stroke, and certain types of cancer—some of the leading causes of preventable deaths.1,2 Obesity is defined as a body mass index (BMI) of ≥30 kg/m2, and overweight is defined as a BMI of ≥25 kg/m2.3 Based on data from the 2009-2010 National Health and Nutrition Examination Survey, approximately 78.1 million (35%) men and women and 12.5 million (16.9%) children (aged ≤19 years) in the United States are obese; overall, older adults (aged ≥60 years) have a greater likelihood of being obese than younger adults (aged <60 years).2 Furthermore, more than 34% of American adults aged ≥20 years are overweight.4 A number of serious comorbidities are associated with obesity, including cardiovascular (CV) disease, type 2 diabetes, hypertension, sleep apnea, and some types of cancer. Obesity and overweight can also lead to cardiac complications, such as congestive heart disease, heart failure, and even sudden death.5 Even a weight loss of 5% to <10% of initial body weight is associated with significant reductions in CV risk factors, including improvements in glycemic control, blood pressure, high-density lipoprotein cholesterol, and triglycerides at 1 year in overweight and obese patients with type 2 diabetes.6 Moreover, a weight loss of 10% to 15% of initial body weight is associated with a greater improvement in these risk factors.6 Traditionally, achieving meaningful weight loss has been more challenging for patients with diabetes—particularly those taking insulin and other oral medications that treat type 2 diabetes—than for nondiabetic populations.7,8 In addition, according to the Centers for Disease Control and Prevention, obesity and overweight impose a substantial economic burden on the US healthcare system.1 The total annual medical costs associated with obesity are estimated at $147 billion.1 The per-person medical costs are $1429 higher for obese people than for normal-weight individuals.1 Given the impact of obesity on overall health and

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outcomes—and its as­sociation with increased morbidity and mortality and a reduced life expectancy—approaches to meaningful weight loss may help improve outcomes in appropriate patients.

First Weight-Loss Prescription Therapy Approved in 13 Years In June 2012, the US Food and Drug Administration (FDA) approved lorcaserin hydrochloride (Belviq; Arena Pharmaceuticals) as an addition to a reduced-­ calorie diet and exercise for the treatment of chronic-weight management. This was the first FDA approval of a prescription weight-loss treatment in the past 13 years.9 Lorcaserin hydrochloride, a novel oral serotonin 2C receptor antagonist, is indicated as an adjunct to a reduced-calorie diet and to increased physical activity in adults with an initial BMI of ≥30 kg/m2 (ie, obese) or a BMI of ≥27 kg/m2 (ie, overweight) in the presence of at least 1 weight-related comorbid condition, including hypertension, dyslipidemia, or type 2­ diabetes.10 A Risk Evaluation and Mitigation Strategy program for lorcaserin was not required by the FDA; however, postmarketing studies are being conducted to evaluate the safety and efficacy of this medication for weight management in obese pediatric patients and for the longterm treatment effect of lorcaserin on the incidence of major CV adverse events (AEs) in overweight and obese persons with CV risk factors.9 Mechanism of Action Lorcaserin is believed to decrease food consumption and promote satiety by selective activation of 5-HT2C receptors on anorexigenic pro-opiomelanocortin neurons that are located in the hypothalamus. At therapeutic concentrations, lorcaserin is selective for 5-HT2C receptors compared with 5-HT2B receptors. The exact mechanism of action is not known.10 Pharmacodynamics (cardiac electrophysiology) The effect of oral lorcaserin 15 mg and 40 mg once daily with corrected QT (QTc) interval was evaluated in a randomized, placebo- and active (moxifloxacin 400 mg)-controlled 4-treatment arm parallel in 244 healthy subjects. In a study designed to detect small effects, the upper bound of the one-sided 95% confidence interval for the largest placebo-adjusted, baseline-corrected QTc

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interval based on individual correction method was below 10 ms (the regulatory threshold).10

Pharmacokinetics Peak plasma concentration occurs 1.5 to 2 hours after oral dosing of lorcaserin. The absolute bioavailability of lorcaserin has not been determined. Lorcaserin has a plasma half-life of approximately 11 hours; steady state is reached within 3 days after twice-daily dosing, and accumulation is estimated to be approximately 70%.

Lorcaserin can be administered with or without food.

Lorcaserin is extremely metabolized by the liver.10 Dosing Lorcaserin is available as a 10-mg, film-coated tablet; its recommended dose is 10 mg, administered orally twice daily.10 If a 5% weight loss is not achieved with this treatment by week 12, lorcaserin should be discontinued.10 Clinical Studies Data The FDA approval of lorcaserin was based on safety and efficacy data from 3 randomized, placebo-controlled trials, which included more than 7700 overweight and obese participants.7,11,12 These studies are described in the product prescribing information10 and in relevant published articles; the key data are highlighted below.

The BLOOM-DM Trial The safety and efficacy of lorcaserin for weight loss in patients with type 2 diabetes were evaluated in the Behavioral Modification and Lorcaserin for Overweight and Obesity Management in Diabetes Mellitus (BLOOMDM) study, a 1-year, placebo-controlled trial that followed 604 adult overweight patients (BMI ≥27 kg/m2) with inadequately controlled type 2 diabetes (hemoglobin [Hb] A1c range, 7%-10%).7 Patients were randomized in a 1:1:1 ratio to receive placebo, lorcaserin 10 mg once daily, or lorcaserin 10 mg twice daily. The majority of patients (91.7%) received metformin, and 50.2% received a sulfonylurea. All the patients received diet and exercise counseling.7 Lorcaserin was associated with significant weight loss compared with placebo (Table 1).7,10 The least squares mean weight change was –4.5% (± 0.35%) with lorcaserin twice daily compared with −1.5% (± 0.36%) with placebo (P <.001). Lorcaserin was also associated with significant improvements in cardiometabolic parameters with lorcaserin twice daily versus placebo, including reductions in HbA1c and fasting glucose levels, improved lipid profile, and lower dia­stolic blood pressure (Table 2).7,10 The most common AEs included headache, back pain, nasopharyngitis, and nausea. Symptomatic hypogly­ cemia occurred in 7.4% of patients of the lorcaserin

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LOOM-DM: Weight-Loss Changes from Baseline Table 1 B to 1 Year Study populationa Lorcaserin 10 mg twice daily Placebo P value vs (N = 251) (N = 248) placebo

End point Patients with ≥5% weight loss, %

37.5

16.1

<.001

Patients with ≥10% weight loss, %

16.3

4.4

<.001

All patients who received the study medication and had a postbaseline measurement. Of the total patients, 34% of those receiving lorcaserin and 38% of those receiving placebo dropped out before the 52-week end point.

Sources: References 7, 10.

a

twice-daily group, 10.5% of the lorcaserin once-daily group, and in 6.3% of the placebo group.7

The BLOOM Trial The Behavioral Modification and Lorcaserin for Overweight and Obesity Management (BLOOM) trial evaluated weight loss at 1 year and the maintenance of weight loss at 2 years.11 In this double-blind study, 3182 obese or overweight adults (mean BMI, 36.2 kg/m2) were randomly assigned to receive lorcaserin 10 mg, or placebo, twice daily for 52 weeks. All patients received diet and exercise counseling. At week 52, the placebo group continued to receive a placebo, but patients who were receiving lorcaserin were randomly reassigned to receive a placebo or lorcaserin.

At 1 year, 55.4% (883:1595) of patients in the lorcaserin group and 45.1% (716:1587) of patients in the placebo group remained in the study; of these, 1553 patients continued into year 2.11 Lorcaserin, in combination with behavioral modification, was associated with significant weight loss and improved maintenance of weight loss compared with placebo (Table 3).11 In the group of patients who received lorcaserin in year 1 and lost ≥5% of their baseline weight at 1 year, weight loss was maintained in 67.9% of patients who continued to receive lorcaserin in year 2 compared with 50.3% of patients who received placebo during year 2 (P <.001).11 During year 1, significant decreases in waist circumference and in BMI were seen in those receiving lorcaserin compared with patients receiving placebo.11 There was no increase in the rate of cardiac valvulopathy with lorcaserin in the 2472 patients evaluated at 1 year and in the 1127 patients evaluated at 2 years.11 The most common AEs were upper respiratory infections, headache, dizziness, nasopharyngitis, and nausea. The rates of serious AEs were similar in the lorcaserin and the placebo groups.11

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LOOM-DM: Mean Changes in Cardiometabolic Parameters and Waist Circumference in Patients Table 2 B with Type 2 Diabetes Placebo (N = 252)a Lorcaserin (N = 256)a Change from baseline, Change from baseline Baseline (LS meanb) Baseline (LS meanb) 8.1 –0.9 8.0 –0.4 HbA1c, % Fasting glucose, mg/dL Systolic BP, mm Hg Diastolic BP, mm Hg Heart rate, bpm

163.3

–27.4

160.0

–11.9

126.6

–0.8

126.5

–0.9

77.9

–1.1

78.7

–0.7

72.3

–2.0

72.7

–0.4

Baseline

Change from baseline (LS meanb)

Baseline

Change from baseline (LS meanb)

173.5 –0.7 172.0 –0.1 Total cholesterol, mg/dL 95.0 4.2 94.6 5.0 LDL cholesterol, mg/dL 45.3 5.2 45.7 1.6 HDL cholesterol, mg/dL 172.1 –10.7 163.50 –4.8 Triglycerides, mg/dL 115.8 –5.5 113.50 –3.3 Waist circumference, cm a Including intent-to-treat population using last-observation-carried-forward method and all patients who received the study medication and had a postbaseline body weight measurement. b Least squares means adjusted for baseline value, baseline HbA1c stratum, and prior antihyperglycemic medication stratum.

BP indicates blood pressure; bpm, beats per minute; Hb, hemoglobin; HDL, high-density lipoprotein; LDL, low-density lipoprotein; LS, least squares.

Sources: References 7, 10.

Table 3 BLOOM: Weight-Loss Changes from Baseline to 1 Year Intention-to-treat analysis of LOCF imputation Coprimary end points

Lorcaserin 10 mg twice daily Placebo P value (N = 1538) (N = 1499) vs placebo

Loss of ≥5% body weight Patients, %

47.5

20.3

Weight change, kg (SE) −5.8 (± 0.2) −2.2 (± 0.1)

<.001 <.001

Loss of ≥10% body weight Patients, %

22.6

7.7

<.001

LOCF indicates last-observation-carried-forward; SE, standard error.

Source: Reference 11.

The BLOSSOM Trial The Behavioral Modification and Lorcaserin Second Study for Obesity Management (BLOSSOM) trial, a double-blind, randomized, placebo-controlled study conducted at 97 US research centers, evaluated the effects of lorcaserin on body weight, CV risk factors, and safety in 4008 obese and overweight patients.12 Patients were ran-

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domized in a 2:1:2 ratio to receive lorcaserin 10 mg twice daily, lorcaserin 10 mg once daily, or placebo. All patients received diet and exercise counseling.12 Lorcaserin, in conjunction with lifestyle modification, was associated with a significantly greater dose-dependent weight loss compared with placebo (Table 4).

The most frequent AEs were headache, nausea, and dizziness. At 1 year, lorcaserin did not increase the rate of echocardiographic valvulopathy (as defined by the FDA), which occurred in 2% of patients receiving placebo and in 2% of patients in the 10-mg twice-daily lorcaserin group.12 Table 5 compares the cardiometabolic changes seen with lorcaserin and placebo in the BLOOM and BLOSSOM trials.

Safety Profile and Metabolic Properties The most common AEs associated with lorcaserin (>5%) in nondiabetic patients are headache, dizziness, fatigue, nausea, dry mouth, and constipation; in diabetic patients, the most common AEs are hypoglycemia, headache, back pain, cough, and fatigue.10 Response to lorcaserin should be evaluated at 12 weeks of treatment to determine if therapy should be discontinued. (There are no black box warnings associated with the use of lorcaserin.)

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The safety and efficacy of lorcaserin coadministration with other products for weight loss, including prescription drugs (eg, phentermine), over-the-counter drugs, and herbal preparations, have not been established. The effects of lorcaserin on CV morbidity and mortality have not been established.

Contraindications Lorcaserin is contraindicated during pregnancy, because weight loss offers no potential benefit to pregnant women and may result in fetal harm. It should not be taken during pregnancy or by women who are planning to become pregnant.10 Drug Interactions Serotonin syndrome or neuroleptic malignant syndrome–like reactions. Based on the mechanism of action of lorcaserin and the theoretical potential for serotonin syndrome, lorcaserin should be used with extreme caution in combination with other drugs that may affect the serotonergic neurotransmitter systems, including, but not limited to, triptans, monoamine oxidase inhibitors (MAOIs; including linezolid, an antibiotic which is a reversible nonselective MAOI), selective serotonin reuptake inhibitors, selective serotonin norepinephrine reuptake inhibitors, dextro­ methorphan, tricyclic anti­ depressants, bupropion, lithium, tramadol, tryptophan, and St John’s wort.10 CYP450 (2D6) substrates. Caution should be used when administering lorcaserin together with drugs that are cytochrome (CY)P450 2D6 substrates, because lorcaserin can increase exposure of these drugs.

Important Safety Information Valvular heart disease. Lorcaserin should not be taken in combination with drugs that have been associated with valvular heart disease (eg, cabergoline).

Patients who develop valvular heart disease while taking lorcaserin should be evaluated.10 Changes in attention or memory. Problems with somnolence, confusion, and fatigue have been reported in patients taking lorcaserin. Patients should be cautioned not to drive a car or operate heavy machinery until they know how lorcaserin affects them.10 Psychiatric disorders. Higher-than-recommended doses of lorcaserin may cause hallucinations, feelings of euphoria, and dissociation; the recommended dose of 10 mg twice daily should not be exceeded.10 Hypoglycemia. Weight loss may cause low blood glucose in people with type 2 diabetes who are receiving medications to treat it, such as metformin, insulin, or sulfonylureas. Lorcaserin has not been studied in combination with insulin. Blood glucose levels should be mon-

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LOSSOM: Weight-Loss Changes from Baseline B to 1 Year Lorcaserin 10 mg Placebo twice daily P value End point (N = 1541) (N = 1561) vs placeboa Table 4

Patients with ≥5% weight loss, %

25.0

47.2

<.001

Patients with ≥10% weight loss, %

9.7

22.6

<.001

Least squares mean weight loss (change from baseline), kg

−2.8

−5.8

<.001

Analysis of difference in proportions or least squares means.

Source: Reference 12.

a

itored for patients who take lorcaserin.10 Priapism. Patients with an erection lasting more than 4 hours should stop using lorcaserin and should call their doctor or go to the nearest emergency department immediately. Lorcaserin should be taken with caution by men who have conditions that may predispose them to priapism (eg, sickle-cell anemia, multiple myeloma, or leukemia) or in men with a deformed penis.10 Heart rate decrease. Lorcaserin may cause a slow heartbeat. It should be used with caution in patients with bradycardia or with a history of heart block greater than first degree.10 Hematologic changes. Lorcaserin may cause decreases in red or white blood–cell count. The period monitoring of complete blood count during treatment with lorcas­ erin should be considered.10 Prolactin elevation. Lorcaserin moderately elevates prolactin levels. Prolactin should be measured when symptoms and signs of prolactin excess are suspected.

Pulmonary hypertension. Certain weight-loss drugs have been associated with the rare but life-threatening side effect of increased pressure in the arteries of the lung. It is unknown if lorcaserin increases the risk for this condition.

Specific Populations It is not known whether lorcaserin is excreted in human milk. Lorcaserin should not be taken while breastfeeding. The safety and effectiveness of lorcas­erin in pediatric patients aged <18 years have not been established, and the use of lorcaserin is not recommended in pediatric patients. Clinical studies of lorcaserin did not include sufficient numbers of patients aged ≥65 years to determine whether they respond differently from younger subjects, but greater sensitivity of some older individuals cannot be ruled out. No dose adjustment of lorcaserin is required in patients with mild renal impairment.

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ean Changes in Cardiometabolic Parameters and Waist Circumference in the BLOOM and BLOSSOM Table 5 M Studies, Year 1 Lorcaserin (N = 3096) Placebo (N = 3039) Baseline, Change from baseline Baseline, Change from baseline mg/dL (LS meana), % Parameter mg/dL (LS meana), % 194.4 –0.9 194.8 0.4 Total cholesterol 114.3 1.6 114.1 2.9 LDL cholesterol 53.2 1.8 1.8 0.6 HDL cholesterol 135.4 –5.3 137.0 –0.5 Triglycerides Change from baseline Change from baseline Baseline (LS meana) Baseline (LS meana) Systolic BP 121.4 mm Hg –1.8 mm Hg 121.5 mm Hg –0.1 mm Hg Diastolic BP 77.4 mm Hg –1.6 mm Hg 77.7 mm Hg –0.1 mm Hg Heart rate 69.5 bpm –1.2 bpm 69.5 bpm –0.4 bpm Fasting glucose 92.1 mg/dL –0.2 mg/dL 92.4 mg/dL 0.6 mg/dL b Fasting insulin 15.9 μIU/mL –3.3 μIU/mL 15.8 μIU/mL –1.3 μIU/mL Waist circumference 109.3 cm –6.6 cm 109.6 cm –4.0 cm a Least squares means adjusted for baseline value, treatment, study and treatment by study interaction. b Measured in the BLOOM study only (N = 1538).

BP indicates blood pressure; bpm, beats per minute; HDL, high-density lipoprotein; LDL, low-density lipoprotein; LS, least squares.

Adapted from Reference 10.

Lorcaserin should be used with caution in patients with moderate renal impairment. Dose adjustment is not required for patients with mild-to-moderate hepatic impairment (Child-Pugh score of 5-9).

and efficacy studies are being conducted. Lorcaserin is a new treatment option that may help to address some of the unmet medical needs of the growing population of overweight and obese persons in the United States. n

Potential for Abuse and Dependence In short-term studies with healthy individuals, euphoria after oral administration of lorcaserin was seen in 16% of patients after receiving 40 mg and in 19% of patients after receiving 60 mg. However, in clinical studies with obese patients with durations of 4 weeks to 2 years, the incidence of euphoria and hallucinations after oral doses of lorcaserin up to 40 mg was low (<1.0%).10 The ability of lorcaserin to produce hallucinations, euphoria, and positive subjective responses at supra­therapeutic doses suggests that lorcaserin may produce psychic dependence. There are no data on overdosing with lorcaserin.

References

Conclusion Evidence from randomized, placebo-controlled clinical trials indicate that lorcaserin, in combination with diet and exercise, is more effective than diet and exercise alone at helping patients lose ≥5% of body weight after taking this medication for 1 year. In addition, the use of lorcaserin helps to maintain the weight loss for up to 2 years, based on current evidence. As part of the FDA approval of lorcaserin, additional postmarketing safety

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1. Centers for Disease Control and Prevention. Adult obesity facts. www.cdc.gov/ obesity/data/adult.html. Accessed August 25, 2012.

2. Ogden CL, Carroll MD, Kit BK, Flegal KM. Prevalence of obesity in the United States, 2009-2010. NCHS Data Brief. 2012;82:1-8.

3. Centers for Disease Control and Prevention. Causes and consequences. www.cdc. gov/obesity/adult/causes/index.html. Accessed August 25, 2012.

4. Centers for Disease Control and Prevention. Obesity and overweight. www.cdc. gov/nchs/fastats/overwt.htm. Accessed August 25, 2012.

5. Poirier P, Giles TD, Bray GA, et al. Obesity and cardiovascular disease: pathophysiology, evaluation, and effect of weight loss: an update of the 1997 American Heart Association Scientific Statement on Obesity and Heart Disease from the Obesity Committee of the Council on Nutrition, Physician Activity, and Metabolism.

Circulation. 2006;113:898-918.

6. Wing RR, Lang W, Wadden TA, et al. Benefits of modest weight loss in improving cardiovascular risk factors in overweight and obese individuals with type 2 diabetes.

Diabetes Care. 2011;34:1481-1486.

7. O’Neil PM, Smith SR, Weissman NJ, et al. Randomized placebo-controlled clinical trial of lorcaserin for weight loss in type 2 diabetes mellitus: the BLOOM-DM study. Obesity (Silver Spring). 2012;20:1426-1436.

8. Mavian AA, Miller S, Henry RR. Managing type 2 diabetes: balancing HbA1c and body weight. Postgrad Med. 2010;122:106-117.

9. US FDA approves antiobesity agent BELVIQ (lorcaserin HCl) for adults [press release]. Woodcliff Lake, NJ: Eisai; June 28, 2012. www.eisai.com/news/news201238. html. Accessed December 10, 2012.

10. Belviq (lorcaserin hydrochloride) tablets [prescribing information]. Woodcliff Lake, NJ: Eisai; 2012.

11. Smith SR, Weissman NJ, Anderson CM, et al. Multicenter, placebo-controlled trial of lorcaserin for weight management. N Engl J Med. 2010;363:245-256.

12. Fidler MC, Sanchez M, Raether B, et al. A one-year randomized trial of lorcas­erin for weight loss in obese and overweight adults: the BLOSSOM trial. J Clin Endocrinol Metab. 2011;96:3067-3077.

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Vol 6, No 3

The Health Burden of Multiple Myeloma: Subcutaneous Velcade a New, Convenient Route of Administration Option

By Rhonda Williams, Medical Writer

I

n 2011, the American Cancer Society projected there would be 20,520 cases of newly diagnosed multiple myeloma (MM) and 10,610 deaths from the disease that year.1 MM is an incurable hematologic cancer marked by great heterogeneity, in terms of its biology and clinical course. Morbidity and survival rates vary widely, even in the age of novel, molecularly based targeted therapies. Many factors account for differences in prognoses among patients with MM, including genomic aberrations in the plasma cells of the myeloma neoplasm. Survival outcomes range from <1 year in patients with aggressive disease to >10 years in those with indolent disease.2 A variety of patient-, disease-, and therapy-related characteristics have been identified to predict the disease course and outcomes among patients with MM. Evaluation of prognostic factors and risk stratification is impor­ tant in defining appropriate treatment strategies and comparing therapeutic outcomes, to predict survival.2

The Approach to Therapy in MM Use of the proteasome inhibitor bortezomib (Velcade), the immuno­ modulatory agents lenalidomide (Rev­li­mid) and thalidomide (Thalomid), and bisphosphonates such as zoledronic acid (Zometa) and pami­ dronate (Aredia) has revolutionized the management of patients with MM. These therapies, however, are all associated with potentially serious side effects, which can negatively affect a patient’s quality of life.

The majority of preferred regimens for initial therapy are 3-drug combinations, although some 2-drug combinations are also recommended in the current guidelines from the National Com­ prehensive Cancer Network, be­cause these multidrug regimens are associated with the best response rates.3 New Route of Administration Option The proteasome is an enzyme complex that exists in all cells and plays an important role in degrading proteins that control the cell cycle and cellular processes. By blocking the proteasome, bortezomib disrupts biologic pathways related to the growth and survival of cancer cells.4 Bortezomib was initially approved by the US Food and Drug Administration (FDA) in 2003 for intravenous

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(IV) injection for the treatment of patients with MM who had received at least 2 previous therapies and had demonstrated disease progression on their last therapy.4 In 2008, the FDA approved an expanded indication for bortezomib for the first-line treatment of patients with previously untreated MM. The approval was based on data from the VISTA trial, which compared the addition of bortezomib to melphalan plus prednisone (MP) versus MP without bortezomib (ie, control group) in 682 patients with newly diagnosed MM. At a median follow-up of 16.3 months, the addition of bortezomib to the MP regimen resulted in significantly improved outcomes, including improved re­ sponse rates, increased time to disease progression, overall survival (OS), and progression-free survival.5 The trial was stopped early and patients in the control group were permitted to cross over to the bortezomib regimen.

In December 2011, results of 5-year median follow-up of the VISTA trial con­firmed a >13-month OS advantage of the bortezomib plus MP regimen for patients with previously untreated MM. In January 2012, the FDA approved a new, subcutaneous (SC) route of administration for bor­tezomib; the new SC form of bortezomib for injection offers patients an easier mode of administration, with a safety profile comparable to the IV form but with significantly reduced peripheral neuropathy (6% vs 15%, respectively),5 providing patients with MM a new option in the choice of the route of administration.

Bortezomib is also indicated for the treatment of patients with mantle-cell lymphoma who have received at least 1 previous therapy.5

Clinical Pharmacology of Bortezomib Mechanism of action. Bortezomib is a reversible inhibitor of the chymo­trypsin-like activity of the 26S pro­ tea­some in mammalian cells; the 26S proteasome degrades ubiquitinated proteins. The ubiquitin-proteasome pathway plays an essential role in regulating the intracellular concen­tration of specific proteins, thereby maintaining homeo­ stasis within cells. Inhibition of this pathway can therefore affect multiple signaling cascades within the cell and can lead to cell death.5

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ummary of Efficacy Analyses in the Relapsed MM Table 1 S Study of Bortezomib SC versus IV Bortezomib SC Bortezomib IV Intent-to-treat population (N = 148) (N = 74) Primary end point Response rate at 4 cycles ORR (CR+PR), N (%)

63 (43)

Ratio of response rates (95% CI)

1.01 (0.73-1.40)

31 (42)

CR, N (%)

11 (7)

6 (8)

PR, N (%)

52 (35)

25 (34)

9 (6)

4 (5)

ORR (CR+PR), N (%)

78 (53)

38 (51)

CR, N (%)

17 (11)

9 (12)

PR, N (%)

61 (41)

29 (39)

nCR, N (%)

14 (9)

7 (9)

nCR, N (%) Secondary end points Response rate at 8 cycles

Median time to progression, months

10.4

9.4

Median progression-free survival, months

10.2

8.0

1-year overall survival, %a 72.6

76.7

Median duration of follow up is 11.8 months.

CI indicates confidence interval; CR, complete response; IV, intravenous; MM, multiple myeloma; nCR, near-complete response; ORR, overall response rate; PR, partial response; SC, subcutaneous.

Source: VELCADE prescribing information. Cambridge, MA: Millennium Pharmaceuticals, Inc; 2012.

a

Pharmacodynamics. After twice-weekly administration of bortezomib 1 mg/m2 and bortezomib 1.3 mg/m2, the maximum inhibition of 20S proteasome activity, relative to baseline, occurred 5 minutes after drug administration.5 Pharmacokinetics. After IV admin­istration of bor­ tezomib 1 mg/m2 and bortezomib 1.3 mg/m2 in 24 patients with MM, the mean maximum plasma concentrations (Cmax) of bortezomib were 57 ng/mL and 112 ng/ mL, respectively. The mean elimination half-life of bortezomib with multiple dosing ranged from 40 to 193 hours after administration of the 1-mg/m2 dose and 76 to 108 hours after ad­ministration of the 1.3-mg/m2 dose.

After an IV or a SC bolus injection of a 1.3-mg/m2 dose in patients with MM, the total systemic exposure with a repeat-dose administration was equivalent for the

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SC and the IV routes of administration. The Cmax after SC administration (20.4 ng/mL) was lower than that after IV administration (223 ng/mL).5 In vitro studies suggest that bortez­omib is primarily oxidatively metabolized via the cytochrome P450 enzymes 3A4, 2C19, and 1A2.5

Dosing Bortezomib is for IV or SC administration only and should not be administered by any other route. The recommended starting dose of bortezomib is 1.3 mg/m2 for both SC and IV forms of administration. Because each route of administration has a different reconstituted concentration, caution should be used when calculating the volume of drug to be administered. With IV administration, the recommended con­centration of bortezomib is 1 mg/mL; with SC administration, the recommended concentration of bortezomib is 2.5 mg/mL.5 Patients with pre­viously un­treated MM. In patients with pre­viously untreated MM, bortezomib is admin­ istered in combi­nation with oral melphalan and oral prednisone for a total of nine 6-week treatment cycles.

In cycles 1 through 4, bortezomib is administered twice weekly (on days 1, 4, 8, 11, 22, 25, 29, and 32). In cycles 5 through 9, bortezomib is administered once weekly (on days 1, 8, 22, and 29). At least 72 hours should elapse between consecutive doses of bortezomib.5 Patients with relapsed MM or mantle-cell lymphoma. In patients with relapsed MM or mantle-cell lymphoma, bortezomib 1.3 mg/m2 per dose is administered twice weekly for 2 weeks (on days 1, 4, 8, and 11), followed by a 10-day rest period (days 12-21). For extended therapy of more than 8 cycles, bortezomib may be admin­ istered according to the standard schedule or on a maintenance, once-weekly schedule for 4 weeks (days 1, 8, 15, and 22), followed by a 13-day rest period.5 Dose modifications. A patient’s platelet count should be ≥70 × 109/L and his or her absolute neutrophil count should be ≥1.0 × 109/L before receiving any cycle of therapy with bortezomib in combination with MP. All nonhematologic toxicities should have resolved to grade 1 or to baseline level.5 Dose modification guidelines for patients with relapsed MM or mantle-cell lymphoma state that bortezomib therapy should be withheld at the onset of any grade 3 nonhematologic or grade 4 hema­ tologic toxicities excluding neuropathy, which is discussed separately. Once the symptoms of the toxicity have resolved, bortez­omib therapy may be reinitiated at a 25% reduced dose.5 Phase 3 Clinical Trials: Bortezomib SC versus IV The FDA approval of SC bortezomib was based on a randomized, open-label, phase 3, noninferiority trial that

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compared the efficacy and safety of SC versus IV administration of bortezomib in patients with relapsed MM. A total of 222 bortezomib-naïve patients were randomly assigned, in a 2:1 ratio, to receive bortezomib 1.3 mg/m2 by either SC injection (N = 148) or IV infusion (N = 74) for 8 cycles. Patients were stratified according to the number of lines of previous therapy they had received (1 previous line vs >1 previous line of therapy) and stage of disease, using International Staging System (ISS) stage I, II, or III.5 The primary study end point was to demonstrate noninferiority of single-agent SC bortezomib with respect to overall response rate (ORR)—complete response (CR) plus partial response. In this study, noninferiority was defined as retaining at least 60% of the ORR relative to single-agent IV bor­tezomib after 4 cycles of therapy.5 Patients who did not obtain an optimal response (less than CR) to treatment with bortezomib alone after 4 cycles were allowed to receive oral dexamethasone 20 mg daily on the day of and after bortezomib administration (N = 82 in the SC treatment group; N = 39 in the IV treatment group). Patients with baseline grade ≥2 peripheral neuropathy or neuropathic pain, or platelet counts <50,000/L, were excluded from trial participation. A total of 218 patients were evaluable for response.5 The baseline demographic and other characteristics of the 2 treatment groups were similar. The median patient age was approximately 64 years (range, 38-88 years), and the majority of patients were male (SC, 50%; IV, 64%). The primary type of myeloma was immunoglobulin G. ISS stage I/II/III was 27%, 41%, and 32%, respectively, with both SC and IV routes of administration.

The Karnofsky performance status score was ≤70% in 22% of SC-treated patients and 16% of IV-treated pa­ tients. Creatinine clearance was 67.5 mL/min in the SC group and 73 mL/min in the IV group. The median years from diagnosis were 2.68 years and 2.93 years in the SC and IV groups, respectively. The proportion of patients with >1 prior line of therapy was 38% with SC treatment versus 35% with IV treatment.5 This study met its primary (nonin­feriority) objective that treatment with single-agent SC bortezomib retains at least 60% of the ORR after 4 cycles relative to IV bortezomib (Table 1).5

Safety Profile: Reduced Peripheral Neuropathy with SC Bortezomib A randomized, open-label study compared the SC administration of bortezomib with IV administration of bortezomib at the recommended dose of 1.3 mg/m2 in 221 patients with relapsed MM.

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Most Common (≥10%) Adverse Reactions Grades 3 and Table 2 ≥4 in the Relapsed Multiple Myeloma Study of

Bortezomib SC versus IV Subcutaneous (n = 147), N (%) System Organ Class Preferred Term

Grade 3

Grade ≥4

Intravenous (n = 74), N (%) Grade 3

Grade ≥4

Blood and lymphatic system disorders Anemia

8 (5)

0

3 (4)

0

Leukopenia

8 (5)

0

4 (5)

1 (1)

Neutropenia

15 (10)

4 (3)

10 (14)

3 (4)

7 (5)

5 (3)

7 (9)

5 (7)

1 (1)

0

3 (4)

0

0

0

0

0

3 (2)

0

0

0

Thrombocytopenia

Gastrointestinal disorders Diarrhea Nausea Vomiting

General disorders and administration site conditions Asthenia

1 (1)

0

4 (5)

0

Fatigue

3 (2)

0

3 (4)

0

Pyrexia

0

0

0

0

Neuralgia

5 (3)

0

7 (9)

0

Peripheral neuropathies not specified elsewherea

8 (5)

1 (1)

10 (14)

1 (1)

Nervous system disorders

NOTE: Safety population: 147 patients in the SC treatment group and 74 patients in the IV treatment group who received at least 1 dose of study medication. a Represents MedDRA High Level Term.

IV indicates intravenous; SC, subcutaneous.

Source: VELCADE prescribing information. Cambridge, MA: Millennium Pharmaceuticals, Inc; 2012.

Overall, the safety data were similar between the SC and IV treatment groups, but with significant differences in some adverse events (AEs) favoring the SC form of bortez­omib (Table 2). Differences of ≥5% between the 2 groups favoring the SC administration were reported for neuralgia (3% SC vs 9% IV), peripheral neuropathy grade ≥3 (6% SC vs 15% IV) and all grades (38% vs 53%), and thrombocytopenia (13% SC vs 19% IV).5 In the SC treatment group, local reactions, primarily redness, were reported in 6% of patients; 2 patients (1%) experienced local reactions that were considered severe (1 case of pruritus and 1 case of redness). These reactions resolved in a median of 6 days. Local reaction led to

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ecommended Dose Modification for Bortezomib-Related Neuropathic Pain and/or Peripheral Sensory Table 3 R or Motor Neuropathy Modification of dose and regimen Severity of peripheral neuropathy signs and symptomsa Grade 1 (asymptomatic; loss of deep tendon reflexes or paresthesia), without pain or loss of function

No action

Grade 1 with pain or grade 2 (moderate symptoms; limiting instrumental ADL)b

Reduce bortezomib to 1 mg/m2

Grade 2 with pain or grade 3 (severe symptoms; limiting self-care ADL)c

Withhold bortezomib therapy until toxicity resolves; when toxicity resolves, reinitiate with a reduced dose of bortezomib at 0.7 mg/m2 once weekly

Grade 4 (life-threatening consequences; urgent intervention indicated)

Discontinue bortezomib

Grading is based on NCI Common Terminology Criteria for Adverse Events (CTCAE) v4.0.

Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using telephone, managing money. c Self-care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden.

ADL indicates activities of daily living; NCI, National Cancer Institute.

Source: VELCADE prescribing information. Cambridge, MA: Millennium Pharmaceuticals, Inc; 2012. a

b

study discontinuation in 1 patient and reduction in dose concentration in 1 patient.5 Dose reductions associated with drug-related AEs were reported in 31% of patients in the SC group compared with 43% of patients in the IV group. The most common AEs leading to dose reduction included sensory peripheral neuropathy (17% SC vs 31% IV) and neuralgia (11% SC vs 19% IV).5

Warnings and Precautions Peripheral neuropathy. Peripheral neuropathy has long been recognized as a problem, because it is frequently associated with both MM and its treatment. The peripheral neuropathy associated with bortezomib use is primarily sensory; however, cases of severe sensory and motor peripheral neuropathy have been reported with use of the agent. Patients with such pre­existing symptoms as numbness, pain, or a burning sensation in the feet or hands, and/or signs of peripheral neu­r­op­athy, may experience worsening of peripheral neuropathy, including grade ≥3, during treatment with bortezomib.5 A paradigm shift regarding bortez­omib use currently exists, with recent data suggesting that changing the mode of administration or dosing schedule can substantially impact the incidence of neuropathy. The results of a phase 3 study by Moreau and colleagues, which included patients with relapsed MM who had received 1 to 3 previous lines of therapy, concluded that SC administration of bortezomib 1.3 mg/m2 twice weekly significantly reduced the incidence of peripheral neuropathy compared with IV administration at the same dose and schedule, with no deleterious effect on efficacy.6

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The protocol of this study provided for a robust comparison of the 2 routes of administration, since it specified 4 cycles of single-agent bortezomib with the addition of oral dexamethasone 20 mg to enhance response at the end of cycle 4 in patients who achieved a suboptimum response.6 In this trial, the incidence of grade ≥2 peripheral neuropathy was 24% in patients who received SC bortezomib and 41% in those who received IV bortezomib (a significant difference).5,6 Also in this trial, grade ≥3 peripheral neuropathy occurred in 6% of patients in the SC treatment group and 16% of those in the IV treatment group.5,6 When initiating bortezomib therapy, SC administration may be considered for patients with preexisting peripheral neuropathy or those who are at high risk for developing peripheral neuropathy. In patients with preexisting, severe peripheral neuropathy, the risk-benefit should be carefully assessed prior to beginning bortezomib therapy.5 Prevention is the best approach to use when addressing bortezomib-related neuropathy. One advantage of bortezomib is that most episodes of grade 3/4 neuropathy can be prevented by closely adhering to the algorithm for dose modification and interruption provided in the prescribing information (Table 3). By following these recommendations, the severity of peripheral neuropathy can usually be decreased to grade 1 or 2, and in many cases, patients may resume bortezomib therapy.5 Hypotension. The incidence of hy­po­tension, which included postural hypo­­tension, orthostatic hypotension, and hypotension not otherwise specified, reported with the use of bortezomib was 8%. These events occurred throughout treatment. Caution should be used when administering bortezomib to patients with a history of

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syncope, those receiving medications known to be associated with hypo­tension (eg, antihypertensive agents), and persons who are dehy­drated.5 Cardiac disorders. Exacerbation or acute development of congestive heart failure and new onset of decreased left ventricular ejection fraction (LVEF) have been reported in patients receiving treatment with bortezomib, including those with no known risk factors for decreased LVEF. Thus, patients at risk for the development of heart disease or those with a history of existing heart disease should be monitored closely.5 Pulmonary disorders. Reports of acute diffuse infiltrative pulmonary disease of unknown etiology, such as pneumonitis, interstitial pneumonia, acute respiratory distress syndrome, and lung infiltration, have been noted among patients receiving treatment with bortezomib.5 Reversible posterior leukoen­cepha­lopathy syndrome.

Reversible pos­terior leukoencepha­lopathy syn­drome (RPLS), a rare, reversible neu­rologic disorder that can present with seizure, hypertension, lethargy, head­ache, blindness, confusion, and other visual and neurologic dis­ turbances, has been reported in pa­tients receiving bortezomib therapy. Bortezomib should be discontinued in patients who develop RPLS that has been confirmed by brain imaging, pre­ferably magnetic resonance imaging.5 Gastrointestinal events. Nausea, diarrhea, constipation, and vomiting, at times requiring the use of antiemetic therapy and antidiarrheal agents, have been reported in patients receiving bortezomib. In order to prevent de­hy­dration, fluid and electrolyte replace­ment should be administered to these patients.5 Thrombocytopenia and neutro­penia. Bortezomib is associated with the development of thrombocytopenia and neutropenia that follows a cyclical pattern, with nadirs that generally occur following the last dose of each cycle and typically recover prior to initiation of the next cycle of therapy. This cyclical pattern remained con­ sistent over 8 cycles of twice-weekly therapy, with no evidence of cumu­ lative thrombocytopenia or neu­ tropenia observed. In patients exper­ iencing throm­­ ­b­ocytopenia, platelet counts should be monitored prior to the administration of each dose; an adjustment in dose and/or schedule may be required. There have been reports of gastro­intestinal and intra­cerebral hemorrhage associated with the use of bortezomib.5 Tumor lysis syndrome. Tumor lysis syndrome may occur with the use of bortezomib because the agent is cytotoxic and can rapidly kill ma­lignant cells. Patients with a high tumor burden prior to therapy may be at a higher risk for the development of tumor lysis syndrome.5 Hepatic events. Acute liver failure has occurred in bortezomib-treated pa­tients receiving multiple conco­m­ itant medications and in those with serious underlying

Vol 6, No 3

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April 2013

medical con­ditions. Other hepatic events reported with the use of bor­tezomib include elevations in liver en­zymes, hyper­bilirubinemia, and hepatitis.5

Hepatic Impairment Because bortezomib is metabolized by the liver, exposure is increased in patients with moderate or severe hepatic impairment. Therefore, such patients should be started on reduced doses of bortezomib and closely monitored for the development of toxicities.5 Use in Pregnancy Women of childbearing potential should avoid becoming pregnant while being treated with bortezomib.5 Administration Precautions When the SC route of administration is used, the site for each injection (thigh or abdomen) should be rotated.

New injections should be given at least 1 inch from an old site and never into areas where the site is tender, bruised, erythematous, or indurated.5 If local injection-site reactions occur after SC bortezomib administration, a less concentrated bortezomib solution (1 mg/mL instead of 2.5 mg/mL) may be used for SC administration. Alternatively, the IV route of administration may be considered.5 Conclusion The FDA approval of a SC formulation of bortezomib offers patients with myeloma a new and more convenient route of administration, with a side effects profile that is similar to the IV formulation but with a significant reduction of peripheral neuropathy, a common AE associated with medications used for the treatment of this patient population. Patients who experience new or worsening peripheral neuropathy may benefit from a lower dose of bortezomib. Initiating therapy with SC bortezomib rather than the IV route of administration may be a good option for patients with preexisting peripheral neuropathy or for those at high risk for this serious complication. n References

1. American Cancer Society. Cancer Facts & Figures 2011. Atlanta, GA: American Cancer Society; 2011.

2. Munshi NC, Anderson AC, Bergsagel PL, et al; for the International Myeloma Workshop Consensus Panel 2. Consensus recommendations for risk stratification in multiple myeloma: report of the Inter­national Myeloma Workshop Consensus Panel 2. Blood. 2011;117:4696-4700.

3. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines™). Multiple Myeloma, Version 1. 2012. www.nccn.org. February 5, 2012.

4. CenterWatch. Drug information. Velcade (bortezo­mib). www.centerwatch.com/druginformation/fda-approvals/ drug-details.aspx?DrugID=830. Accessed February 5, 2012.

5. VELCADE prescribing information. Cambridge, MA: Millennium Pharmaceuticals, Inc; 2012.

6. Moreau P, Pylypenko H, Grosicki S, et al. Subcuta­neous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol. 2011;12:431-440.

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NEW INDICATION: ZYTIGA® (abiraterone acetate) is indicated in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC).

ADRENALS

NOW APPROVED FOR PATIENTS WITH mCRPC WHO HAVE PROGRESSED ON ADT

PROSTATE TUMOR TISSUE

TESTES

ADT = androgen-deprivation therapy.

IMPORTANT SAFETY INFORMATION Contraindications—ZYTIGA® is not indicated for use in women.

ZYTIGA® can cause fetal harm (Pregnancy Category X) when administered to a pregnant woman and is contraindicated in women who are or may become pregnant.

Hypertension, Hypokalemia, and Fluid Retention Due to Mineralocorticoid Excess—Use with caution in patients with a history of cardiovascular disease or with medical conditions that might be compromised by increases in blood pressure, hypokalemia, or fluid retention. ZYTIGA® may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition. Safety has not been established in patients with LVEF < 50% or New York Heart Association (NYHA) Class III or IV heart failure (in study 1) or NYHA Class II to IV heart failure (in study 2) because these patients were excluded from these randomized clinical trials. Control hypertension and correct hypokalemia before and during treatment. Monitor blood pressure, serum potassium, and symptoms of fluid retention at least monthly.

Adrenocortical Insufficiency (AI)—AI was reported in patients receiving ZYTIGA® in combination with prednisone, after an interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of AI if prednisone is stopped or withdrawn, if prednisone dose is reduced, or if the patient experiences unusual stress. Symptoms and signs of AI may be masked by adverse reactions associated

with mineralocorticoid excess seen in patients treated with ZYTIGA®. Perform appropriate tests, if indicated, to confirm AI. Increased dosages of corticosteroids may be used before, during, and after stressful situations.

Hepatotoxicity—Monitor liver function and modify, withhold, or discontinue ZYTIGA® dosing as recommended (see Prescribing Information for more information). Measure serum transaminases [alanine aminotransferase (ALT) and aspartate aminotransferase (AST)] and bilirubin levels prior to starting treatment with ZYTIGA®, every two weeks for the first three months of treatment, and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the upper limit of normal (ULN) or the bilirubin rises above three times the ULN, interrupt ZYTIGA® treatment and closely monitor liver function.

Increased ZYTIGA® Exposures With Food—ZYTIGA® must be taken on an empty stomach. No food should be eaten for at least two hours before the dose of ZYTIGA® is taken and for at least one hour after the dose of ZYTIGA® is taken. Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state.

I N T R O D U C I N G

AN EXPANDED BODY OF

EVIDENCE

More than 20,000 patients with mCRPC have received ZYTIGA® (post-chemotherapy with docetaxel) to date.†1

MECHANISM OF ACTION ZYTIGA® is a CYP17 (17 -hydroxylase/C17, 20-lyase) inhibitor that inhibits androgen production at 3 sources: the testes, adrenal glands, and the prostate tumor tissue itself.

NEW EFFICACY DATA —In a recent Phase 3 clinical trial in patients with mCRPC who had progressed on ADT and had not received chemotherapy.* Efficacy was also demonstrated in a Phase 3 trial of patients who had received prior chemotherapy containing docetaxel.*

ZytigaOne™ is your single source for personalized access services for you and your patients: Visit www.zytigahcp.com or call 1-855-998-4421. *Study Designs: ZYTIGA®, in combination with prednisone, was evaluated in 2 Phase 3, randomized, double-blind, placebo-controlled, multicenter trials in patients with mCRPC. Study 1 enrolled patients who received prior chemotherapy containing docetaxel (N = 1,195), whereas Study 2 enrolled patients who had not received prior chemotherapy (N = 1,088). In both studies, patients were using a luteinizing hormone-releasing hormone agonist or were previously treated with orchiectomy. In the active treatment arms, patients received ZYTIGA® 1,000 mg orally once daily + prednisone 5 mg orally twice daily. In the control arms, patients received placebo orally once daily + prednisone 5 mg orally twice daily. In Study 1, the primary efficacy endpoint was overall survival. In Study 2, the coprimary efficacy endpoints were overall survival and radiographic progression-free survival. † Estimate based on sales and use data from May 2011 to November 2012.

Reference: 1. Data on file. Janssen Biotech, Inc.

www.zytigahcp.com Please see adjacent pages for brief summary of full Prescribing Information.

K08Z121176

Adverse Reactions—The most common adverse reactions (≥ 10%) are fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection, and contusion.

The most common laboratory abnormalities (> 20%) are anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT, and hypokalemia.

Drug Interactions—ZYTIGA® is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. Avoid co-administration with CYP2D6 substrates that have a narrow therapeutic index.

If an alternative cannot be used, exercise caution and consider a dose reduction of the CYP2D6 substrate. In vitro, ZYTIGA® inhibits CYP2C8. There are no clinical data on its use with drugs that are substrates of CYP2C8. Patients should be monitored closely for signs of toxicity related to the CYP2C8 substrate if used concomitantly with abiraterone acetate.

Based on in vitro data, ZYTIGA® is a substrate of CYP3A4. The effects of strong CYP3A4 inhibitors or inducers on the pharmacokinetics of abiraterone have not been evaluated, in vivo. Strong inhibitors and inducers of CYP3A4 should be avoided or used with caution during treatment with ZYTIGA®.

Use in Specific Populations—Do not use ZYTIGA® in patients with baseline severe hepatic impairment (Child-Pugh Class C).

Janssen Biotech, Inc. © Janssen Biotech, Inc. 2013 2/13 K08Z12264A

ZYTIGA® (abiraterone acetate) Tablets Brief Summary of Prescribing Information.

INDICATIONS AND USAGE ZYTIGA is a CYP17 inhibitor indicated in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer.

CONTRAINDICATIONS Pregnancy: ZYTIGA can cause fetal harm when administered to a pregnant woman. ZYTIGA is not indicated for use in women. ZYTIGA is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss [see Use in Specific Populations].

WARNINGS AND PRECAUTIONS Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess: ZYTIGA may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition [see Clinical Pharmacology (12.1) in full Prescribing Information]. In the two randomized clinical trials, grade 3 to 4 hypertension occurred in 2% of patients, grade 3 to 4 hypokalemia in 4% of patients, and grade 3 to 4 edema in 1% of patients treated with ZYTIGA [see Adverse Reactions].

Co-administration of a corticosteroid suppresses adrenocorticotropic hormone (ACTH) drive, resulting in a reduction in the incidence and severity of these adverse reactions. Use caution when treating patients whose underlying medical conditions might be compromised by increases in blood pressure, hypokalemia or fluid retention, e.g., those with heart failure, recent myocardial infarction or ventricular arrhythmia. Use ZYTIGA with caution in patients with a history of cardiovascular disease. The safety of ZYTIGA in patients with left ventricular ejection fraction < 50% or New York Heart Association (NYHA) Class III or IV heart failure (in Study 1) or NYHA Class II to IV heart failure (in Study 2) was not established because these patients were excluded from these randomized clinical trials [see Clinical Studies (14) in full Prescribing Information]. Monitor patients for hypertension, hypokalemia, and fluid retention at least once a month. Control hypertension and correct hypokalemia before and during treatment with ZYTIGA. Adrenocortical Insufficiency: Adrenal insufficiency occurred in the two randomized clinical studies in 0.5% of patients taking ZYTIGA and in 0.2% of patients taking placebo. Adrenocortical insufficiency was reported in patients receiving ZYTIGA in combination with prednisone, following interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of adrenocortical insufficiency, particularly if patients are withdrawn from prednisone, have prednisone dose reductions, or experience unusual stress. Symptoms and signs of adrenocortical insufficiency may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA. If clinically indicated, perform appropriate tests to confirm the diagnosis of adrenocortical insufficiency. Increased dosage of corticosteroids may be indicated before, during and after stressful situations [see Warnings and Precautions].

Hepatotoxicity: In the two randomized clinical trials, grade 3 or 4 ALT or AST increases (at least 5X ULN) were reported in 4% of patients who received ZYTIGA, typically during the first 3 months after starting treatment. Patients whose baseline ALT or AST were elevated were more likely to experience liver test elevation than those beginning with normal values. Treatment discontinuation due to liver enzyme increases occurred in 1% of patients taking ZYTIGA. No deaths clearly related to ZYTIGA were reported due to hepatotoxicity events.

Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with ZYTIGA, every two weeks for the first three months of treatment and monthly thereafter. In patients with baseline moderate hepatic impairment receiving a reduced ZYTIGA dose of 250 mg, measure ALT, AST, and bilirubin prior to the start of treatment, every week for the first month, every two weeks for the following two months of treatment and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the ULN, or the bilirubin rises above three times the ULN, interrupt ZYTIGA treatment and closely monitor liver function.

Re-treatment with ZYTIGA at a reduced dose level may take place only after return of liver function tests to the patient’s baseline or to AST and ALT less than or equal to 2.5X ULN and total bilirubin less than or equal to 1.5X ULN [see Dosage and Administration (2.2) in full Prescribing Information].

The safety of ZYTIGA re-treatment of patients who develop AST or ALT greater than or equal to 20X ULN and/or bilirubin greater than or equal to 10X ULN is unknown.

Increased ZYTIGA Exposures with Food: ZYTIGA must be taken on an empty stomach. No food should be consumed for at least two hours before the dose of ZYTIGA is taken and for at least one hour after the dose of ZYTIGA is taken. Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state. The safety of these increased exposures when multiple doses of abiraterone acetate are taken with food has not been assessed [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information].

ZYTIGA® (abiraterone acetate) Tablets ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: • Hypertension, Hypokalemia, and Fluid Retention due to Mineralocorticoid Excess [see Warnings and Precautions].

• Adrenocortical Insufficiency [see Warnings and Precautions].

• Hepatotoxicity [see Warnings and Precautions].

• Increased ZYTIGA Exposures with Food [see Warnings and Precautions].

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

Two randomized placebo-controlled, multicenter clinical trials enrolled patients who had metastatic castration-resistant prostate cancer who were using a gonadotropin-releasing hormone (GnRH) agonist or were previously treated with orchiectomy. In both Study 1 and Study 2 ZYTIGA was administered at a dose of 1,000 mg daily in combination with prednisone 5 mg twice daily in the active treatment arms. Placebo plus prednisone 5 mg twice daily was given to control patients.

The most common adverse drug reactions (≥10%) reported in the two randomized clinical trials that occurred more commonly (>2%) in the abiraterone acetate arm were fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection and contusion.

The most common laboratory abnormalities (>20%) reported in the two randomized clinical trials that occurred more commonly (≥2%) in the abiraterone acetate arm were anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT and hypokalemia.

Study 1: Metastatic CRPC Following Chemotherapy: Study 1 enrolled 1195 patients with metastatic CRPC who had received prior docetaxel chemotherapy. Patients were not eligible if AST and/or ALT ≥ 2.5X ULN in the absence of liver metastases. Patients with liver metastases were excluded if AST and/or ALT > 5X ULN. Table 1 shows adverse reactions on the ZYTIGA arm in Study 1 that occurred with a ≥2% absolute increase in frequency compared to placebo or were events of special interest. The median duration of treatment with ZYTIGA was 8 months.

Table 1: Adverse Reactions due to ZYTIGA in Study 1 ZYTIGA with Placebo with Prednisone (N=791) Prednisone (N=394) System/Organ Class All Grades1 Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % Musculoskeletal and connective tissue disorders Joint swelling/discomfort2 29.5 4.2 23.4 4.1 Muscle discomfort3 26.2 3.0 23.1 2.3 General disorders Edema4 26.7 1.9 18.3 0.8 Vascular disorders Hot flush 19.0 0.3 16.8 0.3 Hypertension 8.5 1.3 6.9 0.3 Gastrointestinal disorders Diarrhea 17.6 0.6 13.5 1.3 Dyspepsia 6.1 0 3.3 0 Infections and infestations Urinary tract infection 11.5 2.1 7.1 0.5 Upper respiratory tract infection 5.4 0 2.5 0 Respiratory, thoracic and mediastinal disorders Cough 10.6 0 7.6 0 Renal and urinary disorders Urinary frequency 7.2 0.3 5.1 0.3 Nocturia 6.2 0 4.1 0 Injury, poisoning and procedural complications Fractures5 5.9 1.4 2.3 0 Cardiac disorders Arrhythmia6 7.2 1.1 4.6 1.0 Chest pain or chest discomfort7 3.8 0.5 2.8 0 Cardiac failure8 2.3 1.9 1.0 0.3 1 Adverse

events graded according to CTCAE version 3.0 terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness terms Muscle spasms, Musculoskeletal pain, Myalgia, Musculoskeletal discomfort, and Musculoskeletal stiffness

2 Includes 3 Includes

ZYTIGA® (abiraterone acetate) Tablets

ZYTIGA® (abiraterone acetate) Tablets

4 Includes

1 Adverse

terms Edema, Edema peripheral, Pitting edema, and Generalized edema 5 Includes all fractures with the exception of pathological fracture 6 Includes terms Arrhythmia, Tachycardia, Atrial fibrillation, Supraventricular tachycardia, Atrial tachycardia, Ventricular tachycardia, Atrial flutter, Bradycardia, Atrioventricular block complete, Conduction disorder, and Bradyarrhythmia 7 Includes terms Angina pectoris, Chest pain, and Angina unstable.

Myocardial infarction or ischemia occurred more commonly in the placebo arm than in the ZYTIGA arm (1.3% vs. 1.1% respectively).

8 Includes terms Cardiac failure, Cardiac failure congestive, Left ventricular dysfunction, Cardiogenic shock, Cardiomegaly, Cardiomyopathy, and Ejection fraction decreased Table 2 shows laboratory abnormalities of interest from Study 1. Grade 3-4 low serum phosphorus (7%) and low potassium (5%) occurred at a greater than or equal to 5% rate in the ZYTIGA arm.

Table 2: Laboratory Abnormalities of Interest in Study 1 Abiraterone (N=791) Placebo (N=394) Laboratory All Grades Grade 3-4 All Grades Grade 3-4 Abnormality (%) (%) (%) (%) Hypertriglyceridemia 62.5 0.4 53.0 0 High AST 30.6 2.1 36.3 1.5 Hypokalemia 28.3 5.3 19.8 1.0 Hypophosphatemia 23.8 7.2 15.7 5.8 High ALT 11.1 1.4 10.4 0.8 High Total Bilirubin 6.6 0.1 4.6 0 Study 2: Metastatic CRPC Prior to Chemotherapy Study 2 enrolled 1088 patients with metastatic CRPC who had not received prior cytotoxic chemotherapy. Patients were ineligible if AST and/or ALT ≥ 2.5X ULN and patients were excluded if they had liver metastases.

Table 3 shows adverse reactions on the ZYTIGA arm in Study 2 that occurred with a ≥ 2% absolute increase in frequency compared to placebo.

The median duration of treatment with ZYTIGA was 13.8 months.

Table 3: Adverse Reactions in ≥5% of Patients on the ZYTIGA Arm in Study 2 ZYTIGA with Placebo with Prednisone (N=542) Prednisone (N=540) System/Organ Class All Grades1 Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % General disorders Fatigue 39.1 2.2 34.3 1.7 Edema2 25.1 0.4 20.7 1.1 Pyrexia 8.7 0.6 5.9 0.2 Musculoskeletal and connective tissue disorders Joint swelling/ discomfort3 30.3 2.0 25.2 2.0 Groin pain 6.6 0.4 4.1 0.7 Gastrointestinal disorders Constipation 23.1 0.4 19.1 0.6 Diarrhea 21.6 0.9 17.8 0.9 Dyspepsia 11.1 0.0 5.0 0.2 Vascular disorders Hot flush 22.3 0.2 18.1 0.0 Hypertension 21.6 3.9 13.1 3.0 Respiratory, thoracic and mediastinal disorders Cough 17.3 0.0 13.5 0.2 Dyspnea 11.8 2.4 9.6 0.9 Psychiatric disorders Insomnia 13.5 0.2 11.3 0.0 Injury, poisoning and procedural complications Contusion 13.3 0.0 9.1 0.0 Falls 5.9 0.0 3.3 0.0 Infections and infestations Upper respiratory tract infection 12.7 0.0 8.0 0.0 Nasopharyngitis 10.7 0.0 8.1 0.0 Renal and urinary disorders Hematuria 10.3 1.3 5.6 0.6 Skin and subcutaneous tissue disorders Rash 8.1 0.0 3.7 0.0

events graded according to CTCAE version 3.0 terms Edema peripheral, Pitting edema, and Generalized edema 3 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness 2 Includes

Table 4 shows laboratory abnormalities that occurred in greater than 15% of patients, and more frequently (>5%) in the ZYTIGA arm compared to placebo in Study 2. Grade 3-4 lymphopenia (9%), hyperglycemia (7%) and high alanine aminotransferase (6%) occurred at a greater than 5% rate in the ZYTIGA arm.

Table 4: Laboratory Abnormalities in > 15% of Patients in the ZYTIGA Arm of Study 2 Abiraterone (N = 542) Placebo (N = 540) 1-4 Grade 3-4 Grade 1-4 Grade 3-4 Laboratory Abnormality Grade % % % % Hematology Lymphopenia 38.2 8.7 31.7 7.4 Chemistry Hyperglycemia1 56.6 6.5 50.9 5.2 High ALT 41.9 6.1 29.1 0.7 High AST 37.3 3.1 28.7 1.1 Hypernatremia 32.8 0.4 25.0 0.2 Hypokalemia 17.2 2.8 10.2 1.7 1Based on non-fasting blood draws Cardiovascular Adverse Reactions: In the combined data for studies 1 and 2, cardiac failure occurred more commonly in patients treated with ZYTIGA compared to patients on the placebo arm (2.1% versus 0.7%). Grade 3-4 cardiac failure occurred in 1.6% of patients taking ZYTIGA and led to 5 treatment discontinuations and 2 deaths. Grade 3-4 cardiac failure occurred in 0.2% of patients taking placebo. There were no treatment discontinuations and one death due to cardiac failure in the placebo group.

In Study 1 and 2, the majority of arrhythmias were grade 1 or 2. There was one death associated with arrhythmia and one patient with sudden death in the ZYTIGA arms and no deaths in the placebo arms. There were 7 (0.5%) deaths due to cardiorespiratory arrest in the ZYTIGA arms and 3 (0.3%) deaths in the placebo arms. Myocardial ischemia or myocardial infarction led to death in 3 patients in the placebo arms and 2 deaths in the ZYTIGA arms.

DRUG INTERACTIONS Effects of Abiraterone on Drug Metabolizing Enzymes: ZYTIGA is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. In a CYP2D6 drug-drug interaction trial, the Cmax and AUC of dextromethorphan (CYP2D6 substrate) were increased 2.8- and 2.9-fold, respectively, when dextromethorphan was given with abiraterone acetate 1,000 mg daily and prednisone 5 mg twice daily. Avoid co-administration of abiraterone acetate with substrates of CYP2D6 with a narrow therapeutic index (e.g., thioridazine). If alternative treatments cannot be used, exercise caution and consider a dose reduction of the concomitant CYP2D6 substrate drug [see Clinical Pharmacology (12.3) in full Prescribing Information].

In vitro, ZYTIGA inhibits CYP2C8. There are no clinical data on the use of ZYTIGA with drugs that are substrates of CYP2C8. However, patients should be monitored closely for signs of toxicity related to the CYP2C8 substrate if used concomitantly with abiraterone acetate.

Drugs that Inhibit or Induce CYP3A4 Enzymes: Based on in vitro data, ZYTIGA is a substrate of CYP3A4. The effects of strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) or inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) on the pharmacokinetics of abiraterone have not been evaluated, in vivo. Avoid or use with caution, strong inhibitors and inducers of CYP3A4 during ZYTIGA treatment [see Clinical Pharmacology (12.3) in full Prescribing Information].

USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category X [see Contraindications].: ZYTIGA can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. While there are no adequate and well-controlled studies with ZYTIGA in pregnant women and ZYTIGA is not indicated for use in women, it is important to know that maternal use of a CYP17 inhibitor could affect development of the fetus. Abiraterone acetate caused developmental toxicity in pregnant rats at exposures that were lower than in patients receiving the recommended dose. ZYTIGA is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during treatment with ZYTIGA.

ZYTIGA® (abiraterone acetate) Tablets

ZYTIGA® (abiraterone acetate) Tablets

In an embryo-fetal developmental toxicity study in rats, abiraterone acetate caused developmental toxicity when administered at oral doses of 10, 30 or 100 mg/kg/day throughout the period of organogenesis (gestational days 6-17). Findings included embryo-fetal lethality (increased post implantation loss and resorptions and decreased number of live fetuses), fetal developmental delay (skeletal effects) and urogenital effects (bilateral ureter dilation) at doses ≥10 mg/kg/day, decreased fetal ano-genital distance at ≥30 mg/kg/day, and decreased fetal body weight at 100 mg/kg/ day. Doses ≥10 mg/kg/day caused maternal toxicity. The doses tested in rats resulted in systemic exposures (AUC) approximately 0.03, 0.1 and 0.3 times, respectively, the AUC in patients.

Nursing Mothers: ZYTIGA is not indicated for use in women. It is not known if abiraterone acetate is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from ZYTIGA, a decision should be made to either discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother.

Pediatric Use: Safety and effectiveness of ZYTIGA in pediatric patients have not been established.

Geriatric Use: Of the total number of patients receiving ZYTIGA in phase 3 trials, 73% of patients were 65 years and over and 30% were 75 years and over. No overall differences in safety or effectiveness were observed between these elderly patients and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Patients with Hepatic Impairment: The pharmacokinetics of abiraterone were examined in subjects with baseline mild (n = 8) or moderate (n = 8) hepatic impairment (Child-Pugh Class A and B, respectively) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone after a single oral 1,000 mg dose of ZYTIGA increased by approximately 1.1-fold and 3.6-fold in subjects with mild and moderate baseline hepatic impairment, respectively compared to subjects with normal hepatic function.

No dosage adjustment is necessary for patients with baseline mild hepatic impairment. In patients with baseline moderate hepatic impairment (ChildPugh Class B), reduce the recommended dose of ZYTIGA to 250 mg once daily. If elevations in ALT or AST >5X ULN or total bilirubin >3X ULN occur in patients with baseline moderate hepatic impairment, discontinue ZYTIGA treatment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information].

The safety of ZYTIGA in patients with baseline severe hepatic impairment has not been studied. These patients should not receive ZYTIGA. For patients who develop hepatotoxicity during treatment, interruption of treatment and dosage adjustment may be required [see Dosage and Administration (2.2) in full Prescribing Information, Warnings and Precautions, and Clinical Pharmacology (12.3) in full Prescribing Information].

Patients with Renal Impairment: In a dedicated renal impairment trial, the mean PK parameters were comparable between healthy subjects with normal renal function (N=8) and those with end stage renal disease (ESRD) on hemodialysis (N=8) after a single oral 1,000 mg dose of ZYTIGA. No dosage adjustment is necessary for patients with renal impairment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information].

OVERDOSAGE There have been no reports of overdose of ZYTIGA during clinical studies.

There is no specific antidote. In the event of an overdose, stop ZYTIGA, undertake general supportive measures, including monitoring for arrhythmias and cardiac failure and assess liver function.

Storage and Handling: Store at 20oC to 25oC (68oF to 77oF); excursions permitted in the range from 15oC to 30oC (59oF to 86°F) [see USP controlled room temperature].

Based on its mechanism of action, ZYTIGA may harm a developing fetus.

Therefore, women who are pregnant or women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves [see Use in Specific Populations].

• Patients receiving GnRH agonists should be informed that they need to maintain this treatment during the course of treatment with ZYTIGA and prednisone.

• Patients should be informed that ZYTIGA must not be taken with food and that no food should be consumed for at least two hours before the dose of ZYTIGA is taken and for at least one hour after the dose of ZYTIGA is taken. They should be informed that the tablets should be swallowed whole with water without crushing or chewing. Patients should be informed that taking ZYTIGA with food causes increased exposure and this may result in adverse reactions.

• Patients should be informed that ZYTIGA is taken once daily and prednisone is taken twice daily according to their physician’s instructions.

• Patients should be informed that in the event of a missed daily dose of ZYTIGA or prednisone, they should take their normal dose the following day. If more than one daily dose is skipped, patients should be told to inform their physician.

• Patients should be apprised of the common side effects associated with ZYTIGA, including peripheral edema, hypokalemia, hypertension, elevated liver function tests, and urinary tract infection. Direct the patient to a complete list of adverse drug reactions in PATIENT INFORMATION. • Patients should be advised that their liver function will be monitored using blood tests.

• Patients should be informed that ZYTIGA may harm a developing fetus; thus, women who are pregnant or women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves. Patients should also be informed that it is not known whether abiraterone or its metabolites are present in semen and they should use a condom if having sex with a pregnant woman. The patient should use a condom and another effective method of birth control if he is having sex with a woman of child-bearing potential. These measures are required during and for one week after treatment with ZYTIGA.

PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information) • Patients should be informed that ZYTIGA and prednisone are used together and that they should not interrupt or stop either of these medications without consulting their physician.

Manufactured by: Patheon Inc. Mississauga, Canada Manufactured for: Janssen Biotech, Inc. Horsham, PA 19044 © Janssen Biotech, Inc. 2012 Revised: December 2012 2000005445 K08Z121174A

Kyprolis: A New Treatment Option for

Patients with Relapsed/Refractory Multiple Myeloma Previously Treated with Bortezomib and an Immunomodulatory Agent

By Lynne Lederman, PhD, Medical Writer

M

ultiple myeloma (MM), a clonal malignancy of plasma cells, is responsible for 10% to 15% of all hematologic malignancies and for 20% of deaths resulting from hematologic cancers.1,2 In most patients, MM evolves from monoclonal gammopathy of undetermined significance (MGUS), an asymptomatic plasma-cell disorder. In some patients, MGUS progresses through an intermediate, asymptom­atic, premalignant stage, smoldering MM, before the disease is diagnosed.1,2 Although the cause of MM is not known, it is more common in older individuals aged >65 years than in younger persons, is more common in blacks than in whites, and is slightly more common in men than in women. Other factors associated with MM include exposure to certain chemicals, being overweight or obese, having been exposed to radiation, or having another plasma-cell disorder.3

The Burden and Impact of Multiple Myeloma In 2012, the American Cancer Society estimated that there would be 21,700 patients diagnosed with MM and 10,710 deaths would occur from MM.4 Patients with MM frequently experience fatigue, bone pain, osteo­lytic bone lesions, and/or compression fractures.5 End-organ damage, including hypercalcemia, anemia, renal dysfunction, or bone lesions caused by proliferation of myeloma cells, is considered diagnostic of symptomatic MM.6 Patients with MM experience leukopenia and thrombocytopenia in addition to anemia, and they are at risk for recurrent infections. Also, peripheral neuropathy (PN) can be present at diagnosis. This is important, because cytopenias and PN are significant toxicities associated with some anti­myeloma therapies.2 The median survival for patients with MM was less than 1 year before the introduction of alkylating agents in the 1960s. Median survival increased with the introduction of high-dose chemotherapy and autologous stem-cell transplant (ASCT) in the 1980s.7 Supportive therapies, such as growth factors, bisphosphonates, and im­proved modalities to treat fractures, have also played a role in increasing survival.2,7

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Much of the increased survival for patients with MM since approximately 2000 can be attributed to the development of novel, targeted therapies, including the immunomodulatory agents thalidomide and lenalidomide, and the proteasome inhibitor bortezomib.7 Current treatment approaches for newly diagnosed or relapsed MM are based on patient-specific factors, such as eligibility for ASCT and the presence of comorbidities, and disease-related factors, such as high-risk characteristics.2 Almost all patients with MM will eventually experience a relapse. The duration of remission in patients with relapsed MM is shorter with each successive treatment regimen.8 Once MM relapses, it tends to become more resistant to chemotherapy over time, and patients are likely to require continuous treatment with one regimen after another as their disease progresses.2 Therefore, despite the pro­gress in developing novel, tar­ geted therapies, MM remains incurable.7

FDA Approves Carfilzomib for Myeloma On July 20, 2012, the US Food and Drug Administration (FDA) granted accelerated approval for carfilzomib for injection (Kyprolis; Onyx Pharma­ ceuticals), which is indicated for the treatment of patients with MM who have received at least 2 prior therapies, including bortezomib and an im­munomodulatory agent (thalidomide or lenalidomide), and have demonstrated disease progression on or within 60 days of the completion of the last therapy.9 The approval of carfilzomib was based on the response rate determined in a single-arm clinical trial and is not based on survival. Furthermore, a clinical benefit (eg, increased survival or improved symptoms) has not been confirmed.

Carfilzomib Fills an Unmet Need Currently, the median survival for patients with MM that is refractory to bortez­omib is 9 months; for those with MM refractory to lenalidomide, the median survival is only 5 months.8 As the second-in-class–approved proteasome inhibitor, carfilzomib should provide a new option

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Table 1 Carfilzomib Dosing Regimen Dosing for cycle 1 Week 1 Carfilzomib 2 20 mg/m Day 1 Day 2 Days 3-7 20

20

No dosing

Week 2

Week 3

Week 4

Day 8 Day 9 Days 10-14 Day 15 Day 16 Days 17-21 Days 22-28 20

20

No dosing

20

20

No dosing No dosing

Dosing for cycles 2 and beyond

a

Week 1 Carfilzomib 27 mg/m2 Day 1 Day 2 Days 3-7 27

27

No dosing

Week 2 Day 8 Day 9 27

27

Week 3

Week 4

Days 10-14

Day 15

Day 16

Days 17-21

Days 22-28

No dosing

27

27

No dosing

No dosing

If previous cycle dosing is tolerated.

Source: Kyprolis (carfilzomib) for Injection [prescribing information]. South San Francisco, CA: Onyx Pharmaceuticals, Inc; July 2012.

a

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for patients whose MM has become resistant to bortezomib, the first approved proteasome in­hibitor for MM.10 As a condition of the accelerated approval, Onyx Pharmaceuticals will submit the results of an ongoing phase 3 randomized trial comparing lenalidomide plus low-dose dexa­methasone with lenalidomide plus lowdose dexamethasone plus carfilzomib in patients with MM that has relapsed or is refractory after 1 to 3 prior therapies. The primary end point of this phase 3 trial is progression-free survival.9 Carfilzomib is not currently indicated for the treatment of newly diagnosed MM. According to Jamie Shapiro, PharmD, BCOP, Clinical Coordinator at H. Lee Moffitt Cancer Center, Tampa, FL, “Carfilzomib is an exciting new option for our patients with progressive disease after receiving treatment with bortezomib and lenalidomide. Carfilzomib is an important addition to our antimyeloma therapies and meets an unmet need in our patients with progressive multiple myeloma.”

Page Bertolotti, RN, BSN, OCN, of Cedars-Sinai Outpatient Cancer Cen­ter at the Samuel Oschin Comprehensive Cancer Institute, Los Angeles, CA, commented that, “Carfilzomib is an important treatment option for our patients with refractory multiple myeloma. We had several patients who missed the clinical trial enrollment and waited anxiously for the approval.”

Dosing and Administration Carfilzomib is administered intravenously over 2 to 10 minutes on 2 consecutive days each week for 3 weeks on days 1, 2, 8, 9, 15, and 16, followed by a 12-day rest period from days 17 to 28. These 28 days constitute 1 treatment cycle.11 This dosing regimen is shown in Table 1.

The dose for cycle 1 is 20 mg/m2 using the baseline patient’s body surface area. If this dose is tolerated, the dose is increased to 27 mg/m2 beginning at cycle 2, and the dose is maintained at this level for subsequent cycles.11

Clinical Pharmacology Mechanism of Action Carfilzomib is in the epoxyketone class of proteasome inhibitors and irreversibly binds to the proteolytic core particle within the 26S proteasome. Carfilzomib has selectivity for the chymotrypsin-like activity of proteasome, and in preclinical studies it has induced cell-cycle arrest and programmed cell death and activated stress response pathways.10,11

Dose Modifications Based on Toxicity The dose of carfilzomib may be modified if hematologic or nonhematologic toxicities occur, in­cluding grade 3 or grade 4 cytopenias; cardiac, hepatic, or renal toxicities; pulmonary complications; PN; or other toxicities.

In general, carfilzomib is withheld until resolution, followed by restarting therapy at the same or at a reduced dose, depending on the type of toxicity and whether it was attributable to carfilzomib.11

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Hydration and Premedication Patients should be hydrated with intravenous (IV) normal saline or with another appropriate IV fluid before each dose of carfilzomib in cycle 1 and after administration, as needed, to reduce the risk of renal toxicity and tumor lysis syndrome. Maintaining adequate hydration and monitoring blood chemistries is recommended. Hydration can be continued for subsequent cycles if needed.11 To reduce the incidence and severity of infusion reactions, patients should receive premedication with 4-mg oral or IV dexamethasone before all doses in cycle 1 and the first cycle of escalation to the higher dose. Pre­ medication with this dose of dexamethasone may be administered if infusion reactions occur or recur during treatment.11

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Pivotal Phase 2 Clinical Trial Carfilzomib was approved by the FDA based on the results of a single-arm, multicenter phase 2 clinical trial enrolling 266 patients with relapsed MM who had received at least 2 pre­vious therapies that included bor­ tezomib and either thalidomide or lenalidomide.9 The results of this trial have recently been published.12 Trial Design The trial included patients with MM who had a response rate of ≤25% to the most recent therapy or had disease progression during or within 60 days of the most recent therapy they received before enrolling in the trial.

Patients received carfilzomib by IV infusion over 2 to 10 minutes on 2 consecutive days weekly for 3 weeks followed by a 12-day rest period (one 28-day cycle) until disease progression, unacceptable toxicity, or for a maximum of 12 cycles. The carfilzomib dose was 20 mg/m2 for the first cycle and was escalated to 27 mg/m2 for subsequent cycles.

Premedication with 4 mg of dexamethasone was administered before each dose during cycle 1 and during the first dose escalation cycle and subsequently, when needed, to reduce the incidence and severity of infusion reactions.11 Patient Population Key baseline patient demographic and disease characteristics are listed in Table 2.

Safety Profile The most common adverse reactions experienced by ≥30% of patients in clinical trials included fatigue, anemia, nausea, thrombocytopenia, dyspnea, diarrhea, and pyrexia.

The safety of carfilzomib as monotherapy or with premedication with dexamethasone has been assessed in 526 patients with relapsed and/or refractory myeloma.

This patient population includes the 266 patients treated in the phase 2 approval trial. Patients received a median of 4 treatment cycles of carfilzomib.

Of the total population, there were 37 deaths (7%) within 30 days of the last carfilzomib dose, including 21 from disease progression; 5 from cardiac issues (eg, acute coronary syndrome, cardiac arrest, and cardiac disorder); 4 from end-organ failure (ie, multiorgan, hepatic, and renal); 4 from infection; and 1 each from dyspnea, intracranial hemorrhage, and un­known causes.11 Serious adverse reactions were reported in 45% of patients receiving carfilzomib—the most common being pneumonia (10%), acute renal failure (4%), pyrexia (3%), and congestive heart failure (3%). In addition, 15% of the patients had serious adverse reactions that led to the discontinuation of carfilzomib monotherapy.11 Peripheral neuropathy. PN is often associated with

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isease Characteristics and Patient Baseline Table 2 D Demographics Patient characteristic Total patients, N

266

Median age, yr (range)

63 (37-87)

Sex, N (%) Male Female

155 (58.3) 111 (41.7)

Race, N (%) White Black Asian Other

190 (71.4) 53 (19.9) 6 (2.3) 17 (6.4)

Years since diagnosis, median, N (range) Prior regimens, median, N (range) Prior transplants, N (%)

5.3 (0.5-22.3) 5 (1-2) 198 (74.4)

Source: Kyprolis (carfilzomib) for Injection [prescribing information]. South San Francisco, CA: Onyx Pharmaceuticals, Inc; July 2012.

MM therapies. Any-grade PN occurred in 14% of patients enrolled in carfilzomib clinical trials, but only 1% of patients experienced grade 3 PN. Serious PN events resulting in dose reductions or treatment discontinuations occurred in <1% of patients.11 The incidence of PN associated with carfilzomib is lower than that associated with thalidomide or with bortezomib, and the low rate of new-onset or worsening PN suggests that patients with PN associated with other therapies may be able to tolerate treatment with carfilzomib.12 Commenting on carfilzomib, Dr Shapiro noted that, “One of the most beneficial aspects with carfilzomib is the low incidence of peripheral neuropathy.”

Renal events. The most common renal adverse reactions of any grade were increased blood creatinine (24%) and renal failure (9%). Grade 3 renal events occurred in 6% of patients and grade 4 in 1%. Discontinuations resulting from increased blood creatinine and acute renal failure, each, occurred in 1% of patients.

Furthermore, 1 patient died from concurrent sepsis and worsening renal function.11

Response Response rates for the phase 2 ap­proval trial population were determined by an independent review committee.11 The overall response rate was 22.9% (n = 61); of these, 17.6% of pa­tients (n = 47) achieved a partial re­sponse (PR); 4.9% (n = 13) achieved a very good PR; and 0.4% (n = 1) achieved a complete response. The median duration of response was 7.8 months.11

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Table 3 Carfilzomib Warnings and Precautions Potential adverse reactions

Description

Cardiac events

• Cardiac failure in 7% of patients • Death resulting from cardiac arrest within 1 day of administration reported • Patients with heart failure, myocardial infarction within preceding 6 months, and uncontrolled conduction abnormalities may be at increased risk

Pulmonary arterial hypertension

• Reported in 2% of patients • ≥Grade 3 in <1%

Pulmonary complications

• Dyspnea in 35% of patients in clinical trials • Grade 3 in 5% • 1 death reported

Infusion reactions

• Characterized by fever, chills, arthralgia, myalgia, facial flushing, facial edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina • Can occur immediately or up to 24 hours after administration • Premedication with dexamethasone reduces incidence and severity

Tumor lysis syndrome

• Occurred in <1% of patients • High tumor burden may increase risk • Ensure patients are well hydrated before administration

Thrombocytopenia

• Occurred in 36% of patients • Grade 4 in 10% • Platelet nadirs around day 8 of each cycle, recover to baseline by start of next cycle • Monitor platelet counts frequently

Hepatic toxicity and hepatic failure

• Hepatic failure including deaths in <1% of patients • Carfilzomib can cause elevated serum transaminases and bilirubin • Monitor liver enzymes frequently

Source: Kyprolis (carfilzomib) for Injection [prescribing information]. South San Francisco, CA: Onyx Pharmaceuticals, Inc; July 2012.

Overall survival (OS) was 15.6 months in this group of patients with heavily pretreated MM refractory to or intolerant of bortezomib and lenalidomide, and compares favorably to an OS of 9 months in similar settings.

Response and survival may have been affected by treatment discontinuation resulting from progressive disease in almost 23% of patients in the first 2 treatment cycles.12

Warnings and Precautions A number of adverse reactions associated with carfilz­omib are discussed in the “Warnings and Precautions” section of the prescribing information (Table 3).11 These reactions, which may require dose modification, include cardiac arrest, congestive heart failure, myocardial ischemia, pulmonary hypertension and other complications, infusion reactions, tumor lysis syndrome, thrombocytopenia, and hepatic toxicity and failure.11 Women of child-bearing potential are advised to avoid becoming pregnant during treatment with carfilz­

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omib, because it has been shown to cause fetal harm in animal studies.11 n

References

1. Kyle RA, Rajkumar SV. Multiple myeloma. Blood. 2008;111:2962-2972.

2. Laubach J, Richardson P, Anderson K. Multiple my­el­oma. Ann Rev Med. 2011;62: 249-264.

3. American Cancer Society. Multiple myeloma over­view. 2011. www.cancer.org/ acs/groups/cid/documents/webcontent/003065-pdf.pdf. Accessed August 28, 2012.

4. American Cancer Society. Cancer Facts & Figures 2012. Atlanta, GA: American Cancer Society; 2012. www.cancer.org/acs/groups/content/@epidemiologsurveilance/ documents/document/acspc-031941.pdf. Accessed August 28, 2012.

5. Rajkumar SV. Multiple myeloma. Curr Probl Cancer. 2009;33:7-64.

6. International Myeloma Working Group. Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group. Br J Haematol. 2003;121:749-757.

7. Kumar SK, Rakjumar SV, Dispenzieri A, et al. Im­proved survival in multiple myeloma and the impact of novel therapies. Blood. 2008;111:2516-2520.

8. Rajkumar SV. Multiple myeloma: 2011 update on diagnosis, risk-stratification, and management. Am J Hematol. 2010;86:57-65.

9. US FDA Drug Approvals and Databases. Carfilzomib. www.fda.gov/Drugs/Infor mationOnDrugs/ApprovedDrugs/ucm312945.htm. Accessed July 21, 2012.

10. Moreau P, Richardson PG, Cavo M, et al. Protea­some inhibitors in multiple myeloma: 10 years later. Blood. 2012;120:947-959.

11. Kyprolis (carfilzomib) for Injection [prescribing information]. South San Francisco, CA: Onyx Phar­maceuticals, Inc; July 2012.

12. Siegel DS, Martin T, Wang M, et al. A phase 2 study of single-agent carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma. Blood.

2012 Jul 25. [Epub ahead of print].

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Eliquis Approved by the FDA to Reduce the Risks of Stroke and Systemic Embolism in Patients with Atrial Fibrillation

By Loretta Fala, Medical Writer

A

trial fibrillation (AF), the most common cardiac arrhythmia, is a compelling, independent risk factor for stroke. In fact, AF is associated with a 5-fold increased risk for stroke.1,2 An estimated 15% to 20% of ischemic strokes are caused by AF.2 Aside from its link to stroke, AF is associated with an increased risk of mortality as well as increased risks of morbidity, heart failure, and cognitive impairment. Given that AF is often asymptomatic and may go undetected clinically, its impact may be underestimated.1 AF affects an estimated 2.6 million people in the United States.2 The prevalence of AF increases with age.

Similarly, the percentage of strokes attributed to AF increases with age, jumping from a 1.5% risk in patients aged 50 to 55 years to 23.5% in patients aged 80 to 89 years.1 A retrospective study of Medicare patients aged ≥65 years who were diagnosed with AF between 1993 and 2007 showed that although the incidence of AF remained relatively stable for more than a decade, the prevalence of AF increased across the study period (mean, 5% annually). Moreover, the age- and sex-adjusted mortality rate was 11% at 30 days and a staggering 25% at 1 year (in 2007).3 By 2030, the number of people living with stroke is predicted to increase by 4 million.4 Stroke is one of the leading causes of mortality in the United States, accounting for 1 of 19 deaths annually.5 Of the 795,000 people who have a stroke annually, an estimated 610,000 of these occurrences are first strokes and 185,000 are recurrent strokes.5 Furthermore, the number of deaths attributed to ischemic stroke are projected to nearly double between 2002 and 2032.6 Stroke is also a leading cause of disability and accounts for reduced mobility in >50% of stroke survivors aged ≥65 years.5 In addition, stroke is associated with substantial healthcare costs, accounting for $38.6 billion annually in the United States, including medications, healthcare services, and lost productivity.5 The impact and burden of AF and other risk factors underscore a need for the aggressive prevention of stroke and thromboembolic events, including anticoagulation therapy in appropriate patients. The American Heart

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Association generated a new set of impact goals, with the following commitment: “By 2020, to improve the cardiovascular health of all Americans by 20%, while reducing deaths from [cardiovascular diseases] and stroke by 20%.”1 However, many patients with AF are not receiving adequate levels of anticoagulation, and therefore, they may not be receiving optimal prevention from stroke.7 Vitamin K antagonists have been used as oral anticoagulant therapy for more than 5 decades.8 In patients with AF, treatment with warfarin, a vitamin K antagonist, has been shown to reduce the risk of stroke by approximately 60%, and antiplatelet agents have shown to provide an approximate 20% reduction in stroke risk.9 A study showed that in patients with AF aged ≥65 years, only 51% were receiving warfarin at the time of hospital discharge.10 The reasons cited for not treating the patients with warfarin included past intolerance to warfarin, hemorrhage, falls, and patient refusal or nonadherence.10 The vitamin K antagonists have a number of challenges and limitations: a narrow therapeutic window and dose response, drug and food interactions, the need for monitoring and difficulty standardizing laboratory control, and bleeding risk.8,11 More recently, the emergence and US Food and Drug Administration (FDA) approval of novel anticoagulant agents, including the direct thrombin (factor IIa) inhibitors and direct factor Xa inhibitors, may provide clinicians with additional options for managing patients with nonvalvular AF who are at risk for stroke and systemic embolism.

Eliquis a New Therapeutic Option to Reduce the Risk of Stroke in Patients with AF In December 2012, apixaban (Eliquis; Bristol-Myers Squibb) was approved by the FDA to reduce the risk of stroke and systemic embolism in patients with nonvalvular AF.12 Apixaban is an oral, selective active-site inhibitor of factor Xa that does not require antithrombin III for antithrombotic activity.13 According to Renato Lopes, MD, a cardiologist and the lead investigator of a follow-up analysis of the ARISTOTLE study, “With new oral anticoagulants, such as apixaban, we might not need risk scores to guide treat-

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Table 1 Characteristics of Patients in the ARISTOTLE Trial Category

Characteristics

Mean age, yrs

69

Mean CHADS2 score

2.1

Patients who were vitamin K antagonist naïve,b %

43

a

Population breakdown, %

65 male, 83 white, 14 Asian, 1 black

Patients with a history of stroke, TIA, or non-CNS systemic embolism, %

19

Patients with specific concomitant diseases, % Hypertension Diabetes Congestive heart failure or left ventricular ejection fraction ≤40 Previous myocardial infarction

88 25 35 14

62 Patients treated with warfarin who had a mean percentage of time in therapeutic range (ie, an INR of 2.0-3.0), % a A scale from 0-6 was used to estimate the risk of stroke, with higher scores predicting greater risk. b Received ≤30 consecutive days of treatment with warfarin or another vitamin K antagonist before study entry.

CNS indicates central nervous system; INR, international normalized ratio (standardized results of prothrombin time tests); TIA, transient ischemic attack.

Source: Eliquis (apixaban) tablets. Prescribing information.

Princeton, NJ: Bristol-Myers Squibb; December 2012.

ment decisions for stroke prevention in patients with atrial fibrillation. This may simplify how physicians make decisions and also improve patient care.”14,15 The FDA has required a Risk Evaluation and Mitigation Strategy for apixaban to communicate the following information to healthcare providers: there is an increased risk of thrombotic events, including stroke, in patients with nonvalvular AF when apixaban is discontinued without introducing an adequate alternative anticoagulant; and it is important to follow apixaban’s prescribing information recommendations when patients with nonvalvular AF are converted from apixaban to warfarin or to other anticoagulant agents.16

Dosing Apixaban is available in a 2.5-mg tablet and a 5-mg tablet. The recommended dose of apixaban is 5 mg orally twice daily. For patients with at least 2 of the following factors—age ≥80 years, body weight ≤60 kg, or serum creatinine ≥1.5 mg/dL—the recommended dose is 2.5 mg orally twice daily.

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When apixaban is coadministered with dual inhibitors of cytochrome (CY)P450 3A4 (CYP3A4) and P-glycoprotein (P-gp; eg, ketoconazole, itraconazole, ritonavir, clarithromycin), the recommended dose is 2.5 mg twice daily. In patients already taking 2.5 mg of apixaban twice daily, the coadministration of apixaban with strong dual inhibitors of CYP3A4 and P-gp should be avoided.

The concomitant use of apixaban with strong dual inducers of CYP3A4 and P-gp (eg, rifampin, carbamazepine, phenytoin, St John’s wort) should be avoided, because these agents will decrease exposure to apixaban.13

Mechanism of Action Apixaban inhibits free and clot-bound factor Xa and prothrombinase activity. Apixaban has no direct effect on platelet aggregation, but it indirectly inhibits platelet aggregation that is induced by thrombin. By inhibiting factor Xa, apixaban decreases thrombin generation and thrombus development.

In pharmacodynamic drug interaction studies, no pharmacodynamic interactions were observed with aspirin or with clopidogrel; however, a 50% to 60% increase in anti–factor Xa activity was observed when apixaban was coadministered with enoxaparin or naproxen.

Apixaban displays prolonged absorption. Despite a short clearance half-life of approximately 6 hours, the apparent half-life during repeat dosing is approximately 12 hours, which allows twice-daily dosing to provide effective anticoagulation; however, when the drug is stopped for surgery, anticoagulation persists for at least a day.

The absolute bioavailability of apixaban is approximately 50% for doses up to 10 mg. Food does not affect the bioavailability of apixaban. Maximum concentrations of apixaban appear 3 to 4 hours after oral administration.13 Clinical Trials The FDA approval of apixaban was based on 2 clinical trials, ARISTOTLE and AVERROES. ARISTOTLE Trial The ARISTOTLE trial, a multinational, double-blind study, compared the effects of apixaban and warfarin on the risks of stroke (ischemic or hemorrhagic), non–central nervous system systemic embolism, major bleeding, and death from any cause in patients with nonvalvular AF and at least 1 additional risk factor for stroke.11,13 In this study, a total of 18,201 patients were randomized and followed on study treatment for a median of 89 weeks. The patients were randomized to apixaban 5 mg orally twice daily (or 2.5 mg twice daily in patients with least 2 of the following factors: age ≥80 years, body weight ≤60 kg, or serum creatinine ≥1.5 mg/dL) or to warfarin (targeted to an international normalized ratio

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RISTOTLE Trial: Key Efficacy Outcomes in Patients with Nonvalvular Atrial Fibrillation (Intent-to-Treat Table 2 A Analysis) Apixaban Aspirin Hazard ratio (N = 9120) (N = 9081) (95% confidence Efficacy end point N (% annually) N (% annually) interval) P value Stroke or systemic embolism

212 (1.27)

265 (1.60)

0.79 (0.66-0.95)

Stroke

199 (1.19)

250 (1.51)

0.79 (0.65-0.95)

Ischemic without hemorrhage

140 (0.83)

136 (0.82)

1.02 (0.81-1.29)

Ischemic with hemorrhagic conversion

12 (0.07)

20 (0.12)

0.60 (0.29-1.23)

Hemorrhagic

40 (0.24)

78 (0.47)

0.51 (0.35-0.75)

Unknown

14 (0.08)

21 (0.13)

0.65 (0.33-1.29)

15 (0.09)

17 (0.10)

0.87 (0.44-1.75)

Systemic embolism

.01

Source: Eliquis (apixaban) tablets. Prescribing information. Princeton, NJ: Bristol-Myers Squibb; December 2012.

range of 2.0-3.0). The baseline characteristics of the patients in this study appear in Table 1.13 Apixaban was shown to be superior to warfarin for the primary end point of reducing the risks of stroke and systemic embolism. The efficacy outcomes from the intent-to-treat analysis of this trial are shown in Table 2.13 The superiority of apixaban to warfarin was primarily attributable to reductions in hemorrhagic stroke and ischemic strokes with hemorrhagic conversion compared with warfarin. Purely ischemic strokes occurred with similar rates in patients in both treatment groups. Reductions in the primary efficacy outcomes with apixaban were consistent across all major subgroups.11,13 Apixaban was associated with significantly fewer major bleeds than warfarin.13 Moreover, treatment with apixaban resulted in a significantly lower rate of allcause death (P = .046) than treatment with warfarin, primarily because of a reduction in cardiovascular death, particularly stroke deaths. Nonvascular death rates were similar in both treatment arms. The apixaban group had a lower rate of discontinuation from the study than the warfarin group.11,13

AVERROES Trial The primary objective of the AVERROES trial was to evaluate whether apixaban was superior to aspirin in preventing the composite outcomes of stroke or systemic embolism. This study included 5598 patients with nonvalvular AF who were not considered to be candidates for warfarin therapy and who were randomized to receive treatment with apixaban 5 mg orally twice daily (or 2.5 mg twice daily in selected patients) or to aspirin 81 to 324 mg once daily.13,17 The AVERROES study was stopped early, based on a

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prespecified interim analysis demonstrating significant reductions in stroke and systemic embolism with apixaban compared with aspirin that was associated with a modest increase in major bleeding. The key efficacy findings from this study are shown in Table 3.13

Adverse Events The most common adverse reactions (>1%) reported with apixaban were related to bleeding. Apixaban increases the risk of bleeding and can cause serious, potentially fatal bleeding (Table 4).13 The concomitant use of drugs affecting hemostasis increases the risk of bleeding, including aspirin and other antiplatelet agents, other anticoagulants, heparin, thrombolytic agents, selective serotonin reuptake inhibitors, serotoninâ&#x20AC;&#x201C;norepinephrine reuptake inhibitors, and nonsteroidal anti-inflammatory drugs. Patients should be made aware of the signs or symptoms of blood loss, and they should be instructed to immediately report to an emergency department if they experience any of these signs or symptoms.13 Warning and Precautions The prescribing information for apixaban includes a Boxed Warning stating that discontinuation of apixaban places patients at an increased risk of thrombotic events.

An increased rate of stroke was observed after discontinuation of apixaban in clinical trials that included patients with nonvalvular AF. The warning also states that if anticoagulation with apixaban must be discontinued for a reason other than pathologic bleeding, coverage with another anticoagulant should be strongly considered.

The safety and efficacy of apixaban have not been studied in patients with prosthetic heart valves and is not recommended in these patients.

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Table 3 AVERROES Trial: Key Efficacy Findings in Patients with Nonvalvular Atrial Fibrillation Apixaban (N = 2807) N (% annual)

Efficacy end point Stroke or systemic embolism

Aspirin (N = 2791) N (% annual)

Hazard ratio (95% confidence interval)

51 (1.62)

113 (3.63)

0.45 (0.32-0.62)

Ischemic or undetermined

43 (1.37)

97 (3.11)

0.44 (0.31-0.63)

Hemorrhagic

6 (0.19)

9 (0.28)

0.67 (0.24-1.88)

Systemic embolism

2 (0.06)

13 (0.41)

0.15 (0.03-0.68)

Myocardial infarction

24 (0.76)

28 (0.89)

0.86 (0.50-1.48)

All-cause death

111 (3.51)

140 (4.42)

0.79 (0.62-1.02)

Vascular death

84 (2.65)

96 (3.03)

0.87 (0.65-1.17)

P value <.001

Stroke

.068

Source: Eliquis (apixaban) tablets. Prescribing information. Princeton, NJ: Bristol-Myers Squibb; December 2012.

Table 4 Bleeding Events in Patients with Nonvalvular Atrial Fibrillation ARISTOTLE

AVERROES

Bleeding event

Apixaban Warfarin Apixaban Aspirin (N = 9088) (N = 9052) Hazard ratio (N = 2798) (N = 2780) Hazard ratio N (% annual) N (% annual) (95% CI) P value N (% annual) N (% annual) (95% CI) P value

Major

327 (2.13)

462 (3.09)

0.69 (0.60-0.80) <.001

45 (1.41)

29 (0.92)

1.54 (0.96-2.45)

Intracranial 52 (0.33)

125 (0.82)

0.41 (0.30-0.57)

11 (0.34)

11 (0.35)

0.99 (0.39-2.51)

Fatal

0.27 (0.13-0.53)

5 (0.16)

11 (0.35)

0.99 (0.23-4.29)

10 (0.06)

a

37 (0.24)

.07

NOTE: Events associated with each end point were counted once per subject, but subjects may have contributed events to multiple end points. a Fatal bleeding is an adjudicated death because of bleeding during the treatment period and includes both fatal extracranial bleeds and fatal hemorrhagic stroke.

CI indicates confidence interval.

Source: Eliquis (apixaban) tablets. Prescribing information. Princeton, NJ: Bristol-Myers Squibb; December 2012.

Apixaban is contraindicated in patients with active pathologic bleeding or severe hypersensitivity reaction to apixaban. Apixaban is not recommended for pregnant or nursing women or for patients with severe hepatic impairment.13 There is no way to reverse the anticoagulant effect of apixaban, which can persist for approximately 24 hours after the last administered dose (ie, approximately 2 halflives), and there is no specific antidote for apixaban.13 As a result of high plasma protein binding, apixaban is not considered to be dialyzable. The anticoagulant effects of apixaban are not affected by protamine sulfate or by vitamin K. There are no available data on the effects of antifibrinolytic agents (eg, tranexamic acid, aminocaproic acid) on patients receiving apixaban, and there is no scientific rationale for reversal or for experience with systemic hemostatics (ie, desmopressin and aprotinin).

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The use of procoagulant reversal agents (eg, prothrombin complex concentrate, activated prothrombin complex concentrate, or recombinant factor VIIa) may be considered, but there are no clinical studies to evaluate their use. The plasma concentrations of apixaban can be lowered with the use of activated charcoal, which reduces the absorption of apixaban.13

Conclusion The FDA approval of apixaban marks the availability of a new therapeutic option to reduce the risk of stroke and systemic embolism in patients with nonvalvular AF. Apixaban inhibits free and clot-bound factor Xa and prothrombinase activity without requiring antithrombin III for antithrombotic activity.

In patients with AF and at least 1 additional risk factor for stroke, apixaban was shown to be superior to

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warfarin in preventing stroke or systemic embolism and was associated with less bleeding and a lower mortality rate. Compared with warfarin, treatment with apixaban significantly reduced the risk of stroke or systemic embolism by 21%, major bleeding by 31%, and death by 11%.

The most common adverse events (>1%) were related to bleeding.11,13 n

References

1. Go AS, Mozaffarian D, Roger VL, et al; for the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics—2013 update: a report from the American Heart Association. Circulation.

2013;127:e6-e245.

2. Centers for Disease Control and Prevention. Atrial fibrillation fact sheet. Updated December 20, 2010. www.cdc.gov/dhdsp/data_statistics/fact_sheets/docs/fs_atrial_ fibrillation.pdf. Accessed March 27, 2013.

3. Piccini JP, Hammill BG, Sinner MF, et al. Incidence and prevalence of atrial fibrillation and associated mortality among Medicare beneficiaries: 1993-2007. Circ Cardiovasc Qual Outcomes. 2012;5:85-93.

4. Heidenreich PA, Trogdon JG, Khavjou OA, et al. Forecasting the future of cardiovascular disease in the United States: a policy statement from the American Heart Association. Circulation. 2011;123:933-944.

5. Centers for Disease Control and Prevention. Stroke fact sheet. Updated March 19, 2013. www.cdc.gov/dhdsp/data_statistics/fact_sheets/docs/fs_stroke.pdf. Accessed March 27, 2013.

6. Elkins JS, Johnston SC. Thirty-year projections for deaths from ischemic stroke in the United States. Stroke. 2003;34:2109-2112.

7. Furie KL, Kasner SE, Adams RJ, et al; for the American Heart Association Stroke Council, Council on Cardiovascular Nursing, Council on Clinical Cardiology, and Interdisciplinary Council on Quality of Care and Outcomes Research. Guidelines for the prevention of stroke in patients with stroke or transient ischemic attack: a guide-

line for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2011;42:227-276.

8. Ansell J, Hirsh J, Hylek E, et al. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians evidence-based clinical practice guidelines (8th edition). Chest. 2008;133:160S-198S. 9. Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med. 2007;146:857-867.

10. Hylek EM, D’Antonio J, Evans-Molina C, et al. Translating the results of randomized trials into clinical practice: the challenge of warfarin candidacy among hospitalized elderly patients with atrial fibrillation. Stroke. 2006;37:1075-1080.

11. Granger CB, Alexander JH, McMurray JJ, et al; for the ARISTOTLE committees and investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365:981-992.

12. US Food and Drug Administration. FDA approves Eliquis to reduce the risk of stroke, blood clots in patients with non-valvular atrial fibrillation. News release; December 28, 2012. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ ucm333634.htm. Accessed April 2, 2013.

13. Eliquis (apixaban) [package insert]. Princeton, NJ: Bristol-Myers Squibb; December 2012.

14. Duke Medicine News and Communications. Apixaban superior to warfarin across wide range of patient risk scores. Press release; October 1, 2012. www.duke health.org/health_library/news/apixaban-superior-to-warfarin-across-wide-range-ofpatient-risk-scores. Accessed March 28, 2012.

15. Lopes, RD, Al-Khatib SM, Wallentin L, et al. Efficacy and safety of apixaban compared with warfarin according to patient risk of stroke and of bleeding in atrial fibrillation: a secondary analysis of a randomised controlled trial. Lancet. 2012;380: 1749-1758.

16. US Food and Drug Administration. Eliquis (apixaban) tablets: Risk Evaluation and Mitigation Strategy (REMS). December 2012. www.fda.gov/downloads/Drugs/ DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM 333723.pdf. Accessed March 25, 2013.

17. Flaker GC, Eikelboom JW, Shestakovska O, et al. Bleeding during treatment with aspirin versus apixaban in patients with atrial fibrillation unsuitable for warfarin: the Apixaban versus Acetylsalicylic Acid to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment (AVERROES) trial. Stroke. 2012;43:3291-3297.

AVBCC_2014 Conference_40513_layout 4/16/13 12:30 PM Page 1

4TH ANNUAL CONFERENCE

May 7-9, 2014 Loews Hollywood Hotel • Los Angeles, CA

www.AVBCConline.org AVBCC2014_40913

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Jentadueto: A New Oral Antihyperglycemic

Combination Therapy for Patients with Type 2 Diabetes

By Wayne Kuznar, Medical Writer

E

arly type 2 diabetes is characterized by impaired insulin action known as insulin resistance, which is manifested by overproduction of glucose as the ability of insulin to suppress hepatic glucose production is reduced. As the need for insulin increases, insulin production by the pancreas is impaired, and pancreatic beta-cell mass and function decline and worsen progressively. When combined with an excessive rate of hepatic glucose production and a decrease in glucose uptake in the muscle, the progressive decline in insulin secretion leads to hyperglycemia.

The gastrointestinal tract has recently been implicated in the pathogenesis of type 2 diabetes, with the recognition that the insulin secretory response is greater to oral glucose than it is to intravenously administered glucose (called the “incretin effect”). Incretins are gut hormones that promote glucose homeostasis through the glucose-dependent regulation of insulin and glucagon. The gut hormone glucagon-like peptide-1 (GLP-1) is released in response to an ingested meal and glucose load, which stimulates insulin secretion. The release of GLP-1 is deficient in type 2 diabetes, which contributes to the development of impaired insulin secretion. The incretin effect is therefore reduced in patients with type 2 diabetes.

The Burden of Type 2 Diabetes The prevalence of type 2 diabetes continues to increase. Approximately 26 million Americans have type 1 and type 2 diabetes, with type 2 diabetes accounting for 90% to 95% of the cases.1 In the pooled 2003-2006 National Health and Nutrition Examination Surveys, the national prevalence of diabetes among US adults aged ≥30 years was 13.7% for men and 11.7% for women.2 The incidence of type 2 diabetes in children and adolescents is increasing among American youth. The SEARCH for Diabetes in Youth study documented that the prevalence of type 2 diabetes in the American population under age 20 years increased from 2.9 per 10,000 persons to 3.6 per 10,000 persons, a 21% increase between 2001 and 2009.3,4 Premature mortality, which is frequently caused by cardiovascular disease (CVD), is a consequence of type 2 diabetes, especially when the disease is poorly con-

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trolled. Cardiovascular (CV) mortality increases as levels of hemoglobin (Hb)A1c rise.5 In addition to increasing the risk for macrovascular complications, poor glucose control is also a major risk factor for microvascular disease.6 Microvascular complications of type 2 diabetes and of hyperglycemia include retinal, renal, and neuropathic diseases.

HbA1c Target Levels A 2012 position statement issued jointly by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) recommends an HbA1c target of <7% when instituting antihyperglycemic therapy, but individualization of treatment targets is deemed important.7 The HbA1c target levels are lower for younger, healthier patients (target, 6.0%6.5%) than they are for older patients, who have comorbidities and may be prone to hypoglycemia (target, 7.5%-≥8.0%).7 Therapy should be selected and titrated to avoid hypoglycemia.

Pharmacologic Treatment Options for Type 2 Diabetes Metformin Metformin (Glucophage) is the first-line oral antihyperglycemic agent for most patients with type 2 diabetes who cannot achieve glycemic control through diet and lifestyle interventions. Metformin is a biguanide that reduces hepatic glucose production; its predominant mechanism of action is to achieve glycemic control. The drug is weight-neutral and does not increase the risk of hypoglycemia.

The 2012 ADA/EASD position statement supports the recommendation of metformin as the preferred initial antihyperglycemic therapy.7 Type 2 diabetes is a progressive disease; therefore, metformin alone often eventually fails to provide adequate glycemic control.

However, there are few data to guide therapy after treatment with metformin. Advancing to combination therapy with 1 or 2 additional oral or injectable agents is reasonable if a 3-month trial of monotherapy does not maintain an HbA1c target level. Initial dual-combination therapy can be considered when HbA1c levels are ≥9%.7

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Oral therapies other than metformin include sulfonyl­ ureas, thiazolidinediones, alpha-glucosidase inhibitors, meglitinides, bromocriptine, GLP-1 receptor agonists, and dipeptidyl peptidase (DPP)-4 inhibitors.

DPP-4 Inhibitors DPP-4 inhibitors increase the levels of endogenous GLP-1 by 3- to 4-fold within 5 minutes of oral administration, improve glucose tolerance, and enhance pancreatic insulin secretion. These agents are weight-neutral and have a low propensity for severe hypoglycemia, which makes them an attractive add-on therapy to metformin for patients with type 2 diabetes.

Because patients with type 2 diabetes are at a high risk for CVD, the therapeutic choice should take CV risk potential into consideration. Preliminary reports show an improvement in CV risk with DPP-4 inhibitors, although clinical outcomes data are few. The results of a recent meta-analysis showed a relative risk of 0.48 for any adverse CV event and a relative risk of 0.40 for nonfatal myocardial infarction or acute coronary syndrome when managing type 2 diabetes with a DPP-4 inhibitor compared with other oral antidiabetes drugs.8 The analysis included 18 trials with 4998 patients who received DPP-4 inhibitors and 3546 patients who received comparative oral antidiabetes drugs. The risk for adverse CV events was not significantly different with DPP-4 inhibitors compared with placebo; however, when compared with metformin and other oral agents (ie, sulfonylureas and thiazolidinediones), the risk was lower by a significant 58% with DPP-4 inhibitor therapy.8 FDA Approves Jentadueto Combination Tablets In January 2012, the US Food and Drug Administration (FDA) approved the new oral tablet Jentadueto (linagliptin and metformin hydrochloride; Boehringer Ingelheim/Lilly), which is a combination of linagliptin (Tradjenta) and metformin hydrochloride, for use with diet and exercise to improve glycemic control in adult patients with type 2 diabetes when treatment with both linagliptin and metformin is appropriate.9 Dosing and Schedule Linagliptin plus metformin hydrochloride combination is available in the following strengths: • 2.5-mg linagliptin plus 500-mg metformin hydrochloride • 2.5-mg linagliptin plus 850-mg metformin hydrochloride • 2.50-mg linagliptin plus 1000-mg metformin hydrochloride.9 The dosage of linagliptin plus metformin hydrochloride should be individualized based on effectiveness and

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tolerability, and should not exceed the maximum recommended dosage of 2.5-mg linagliptin plus 1000-mg metformin hydrochloride twice daily.

The recommended starting dose is 2.5-mg linagliptin plus 500-mg metformin hydrochloride twice daily for patients who are currently not receiving metformin, and 2.5-mg linagliptin and the current dose of metformin taken at each of 2 daily meals for patients who are already receiving metformin. Patients who are already receiving linagliptin and metformin as individual tablets may be switched to the combination tablet that contains the same doses of each component.9

Clinical Pharmacology of Linagliptin plus Metformin Mechanism of Action Linagliptin inhibits the enzyme DPP-4 to prevent the inactivation of the incretin hormones GLP-1 and glucose-dependent insulinotropic peptide (GIP). By doing so, linagliptin increases the concentrations of GLP-1 and GIP, which are involved in the physiologic regulation of glucose homeostasis. Preventing the inactivation of GLP-1 through selective inhibition of DPP-4 increases plasma insulin in response to meals.9 Pharmacodynamics and Pharmacokinetics Linagliptin binds selectively to DPP-4 in a reversible manner, thereby increasing the concentrations of incretin hormones. Linagliptin increases insulin secretion and lowers glucagon secretion in a glucose-dependent manner, resulting in better regulation of glucose homeostasis.9 In healthy individuals, peak plasma concentrations occurred at approximately 1.5 hours after the administration of a 5-mg dose of linagliptin; the mean plasma area under the curve (AUC) was 139 nmol*h/L, and the maximum concentration (Cmax) was 8.9 nmol/L. The effective half-life for the accumulation of oral linagliptin, as determined from the administration of multiple 5-mg doses, is approximately 12 hours. After once-daily dosing, steady-state plasma concentrations of linagliptin were reached by the third dose, and the Cmax and the plasma AUC increased by a factor of 1.3 at steady state compared with the first dose. Plasma AUC of linagliptin increased in a less-than-dose-proportional manner in the dose range of 1 to 10 mg. The pharmacokinetics of linagliptin is similar in patients with type 2 diabetes.9 The results of a bioequivalence study in healthy individuals demonstrated that the combination tablets of linagliptin plus metformin hydrochloride at doses of 2.5 mg plus 500 mg, 2.5 mg plus 850 mg, and 2.5 mg plus 1000 mg, respectively, are bioequivalent to coadministration of corresponding doses of linagliptin and metformin as individual tablets.9

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lycemic Parameters with Linagliptin and Metformin, Alone and in Combination, in Patients with Table 1 G Type 2 Diabetes: 24-Week Study Linagliptin Linagliptin 2.5 mga + 2.5 mga + metformin metformin Metformin Linagliptin Metformin 500 mg, 1000 mg, 500 mg, 1000 mg, 5 mg, once twice daily twice daily twice daily twice daily Placebo dailya A1c Patients, N

65

135

141

137

138

140

Baseline, mean, %

8.7

8.7

8.7

8.7

8.5

8.7

Change from baseline, adjusted mean, %

0.1

–0.5

–0.6

–1.2

–1.1

–1.6

Difference from placebo, adjusted mean, %

—

–0.6

–0.8

–1.3

–1.2

–1.7

7 (10.8)

14 (10.4)

27 (19.1)

42 (30.7)

43 (31.2)

76 (54.3)

Patients, N

61

134

136

135

132

136

Baseline, mean, mg/dL

203

195

191

199

191

196

Change from baseline, adjusted mean, mg/dL

10

–9

–16

–33

–32

–49

Difference from placebo, adjusted mean, mg/dL

—

–19

–26

–43

–42

–60

Patients achieving A1c <7%, N (%) FPG

Total daily dose of linagliptin is 5 mg.

FPG indicates fasting plasma glucose.

Source: Jentadueto (linagliptin/metformin HCl) tablets. Prescribing information. Ridgefield, CT: Boehringer Ingelheim; January 2012.

a

Phase 3 Clinical Trials The safety and efficacy of concomitantly administered linagliptin, 5 mg daily, and metformin, mean daily dose of approximately 1800 mg, has been evaluated in patients with type 2 diabetes that is inadequately controlled with diet and exercise. Four placebo-controlled studies of linagliptin in combination with metformin were conducted, including (1) as initial combination therapy, (2) as linagliptin added on to metformin, (3) an active-controlled study versus glimepiride in combination with metformin, and (4) add-on combination therapy with metformin and a sulfonylurea.9 Initial Combination Therapy Trial In a 24-week, placebo-controlled factorial study, 791 patients with type 2 diabetes (who had not been treated previously or who had received antihyperglycemic therapy) and had inadequate glycemic control with diet and exercise were randomized in a double-blind fashion to 1 of 6 arms as initial therapy: placebo, linagliptin 5

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mg once daily as monotherapy, metformin 500 mg twice daily as monotherapy, linagliptin 2.5 mg twice daily plus metformin 500 mg twice daily, metformin 1000 mg twice daily as monotherapy, or linagliptin 2.5 mg twice daily plus metformin 1000 mg twice daily (Table 1).10

Linagliptin as Add-On to Metformin Study In a 24-week, double-blind, placebo-controlled study, 701 patients who were receiving metformin ≥1500 mg daily were randomized to the addition of linagliptin 5 mg once daily or to placebo after completing a 2-week, open-label, placebo run-in period.11 Patients who received metformin and another antihyperglycemic agent were randomized to the addition of linagliptin 5 mg once daily or to placebo after a run-in period of approximately 6 weeks of metformin ≥1500 mg daily monotherapy. Patients who failed to meet specific glycemic goals during the studies received glimepiride rescue.11

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Active Controlled Study versus Glimepiride in Combination with Metformin Study Linagliptin plus metformin was compared with glimep­ iride plus metformin in a 104-week, double-blind noninferiority study in 1552 patients with type 2 diabetes who had inadequate glycemic control despite metformin therapy.12 Patients who received metformin monotherapy entered a 2-week run-in period; those who had previously received metformin and 1 additional antihyperglycemic agent entered a 6-week run-in treatment period with metformin monotherapy 1500 mg daily and washout of the other agent. After an additional 2-week placebo run-in period, patients with inadequate glycemic control were randomized in a 1:1 ratio to the addition of linagliptin 5 mg once daily or to glimepiride 1 mg daily titrated to a maximum of 4 mg daily to optimize glycemic control.12 Add-On Combination Therapy with Metformin and a Sulfonylurea Study In a randomized, double-blind, placebo-controlled study, 1058 patients with type 2 diabetes who received a sulfonylurea and metformin were randomized to receive linagliptin 5 mg once daily or placebo for 24 weeks (Table 2).13 The most common sulfonylureas used in the study were glimepiride, glibenclamide, and gliclazide (not available in the United States). Patients who failed to meet specific glycemic goals during the study received pioglitazone rescue. The primary glycemic end points were levels of HbA1c and fasting plasma glucose (FPG) levels.

Efficacy Initial Combination Therapy Initial therapy with linagliptin and metformin hydrochloride combination provided significant improvements in HbA1c and FPG levels compared with placebo, metformin alone, and linagliptin alone (Table 1).10 Linagliptin as Add-On to Metformin At the end of this placebo-controlled study of linagliptin as add-on therapy to metformin, the reduction in HbA1c was –0.49% with linagliptin versus an increase of 0.15% with placebo, for a treatment difference of –0.64% (P <.001).11 A significantly higher percentage of patients in the linagliptin group achieved HbA1c <7% compared with the placebo group (26% vs 9%, respectively; P = .001). Rescue glycemic therapy was used in 7.8% of the patients who received linagliptin versus 18.9% of the placebo recipients.11 Active Controlled Study versus Glimepiride in Combination with Metformin In this study, reductions in adjusted mean HbA1c levels were similar in the linagliptin (–0.16%) and glimepiride

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lycemic Parameters with Linagliptin in Combination Table 2 G with Metformin and a Sulfonylurea: 24-Week Study Linagliptin 5 mg + Placebo + metformin + metformin + sulfonylurea sulfonylurea A1c Patients, N

778

262

Baseline, mean, %

8.2

8.1

Change from baseline, adjusted mean, %

–0.7

–0.1

–0.6 (95% CI, –0.7, –0.5)

—

243 (31.2)

24 (9.2)

Patients, N

739

248

Baseline, mean, mg/dL

159

163

Change from baseline, adjusted mean, mg/dL

–5

8

Difference from placebo, adjusted mean, % Patients achieving A1c <7%, N (%) FPG

Difference from placebo, –13 (95% CI, –18, –7) adjusted mean, mg/dL

—

CI indicates confidence interval; FPG, fasting plasma glucose.

Source: Jentadueto (linagliptin/metformin HCl) tablets.

Prescribing information. Ridgefield, CT: Boehringer Ingelheim; January 2012.

(–0.36%) groups, with a difference of 0.20%, which met the predefined noninferiority criterion of 0.35%.12 Fewer patients had hypoglycemia (7% vs 36%, respectively; P <.001) or severe hypoglycemia (<1% vs 2%, respectively) with linagliptin compared with glimepiride.12

Add-On Combination Therapy with Metformin and a Sulfonylurea In combination with a sulfonylurea and metformin, linagliptin was associated with significant improvements in HbA1c and FPG levels compared with placebo (Table 2).13 In this study comprised of patients receiving linagliptin in combination with a sulfonylurea and metformin, the mean reductions from baseline were HbA1c –0.6% and FPG –12.7 mg/dL relative to placebo. Rescue therapy was used in 5.4% of the patients receiving linagliptin versus 13% of those receiving placebo.12 Safety Profile, Warnings, and Precautions The safety of linagliptin at a 5-mg daily dose and metformin hydrochloride at a mean daily dose of approximately 1800 mg administered concomitantly has been evaluated in 2816 patients with type 2 diabetes for at

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dverse Reactions in ≥5% of Patients Receiving Linagliptin plus Metformin and More than with Placebo: Table 3 A 24-Week Factorial-Design Study Linagliptin Metformin Linagliptin + Placebo monotherapy monotherapy metformin (N = 72) N (%) (N = 142) N (%) (N = 291) N (%) (N = 286) N (%) Nasopharyngitis

1 (1.4)

8 (5.6)

8 (2.7)

18 (6.3)

Diarrhea

2 (2.8)

5 (3.5)

11 (3.8)

18 (6.3)

Source: Jentadueto (linagliptin/metformin HCl) tablets. Prescribing information. Ridgefield, CT: Boehringer Ingelheim; January 2012.

least 12 weeks. In the 3 placebo-controlled clinical studies, nasopharyngitis and nausea occurred in ≥5% of the patients receiving linagliptin and metformin together, and were more common in the linagliptin plus metformin hydrochloride cohort than in those randomized to placebo plus metformin hydrochloride (Table 3).9 Hypoglycemia was more common in patients treated with the combination of linagliptin plus metformin and sulfonylurea compared with those treated with the combination of placebo, sulfonylurea, and metformin. Pancreatitis was reported more often in patients randomized to linagliptin than in those receiving comparator agents (1 per 538 person-years vs 0 per 433 person-years, respectively).9 The FDA approval of Jentadueto includes a Boxed Warning regarding the risk for lactic acidosis. Lactic acidosis is a rare risk of metformin accumulation. In more than 20,000 patient-years of exposure to metformin in clinical trials, there were no reports of lactic acidosis.

The risk of lactic acidosis with metformin increases with renal impairment, sepsis, dehydration, excess alcohol intake, hepatic impairment, and acute congestive heart failure. The risk can be minimized by regularly monitoring renal function. If lactic acidosis is suspected, linagliptin plus metformin hydrochloride should be discontinued and the patient should be hospitalized immediately.

Drug Interactions Linagliptin is a weak-to-moderate inhibitor of the cytochrome (CY)P isozyme CYP3A4, but it does not inhibit other CYP enzymes. It is a P-glycoprotein (P-gp) substrate, and it inhibits P-gp–mediated transport of digoxin at high concentrations. Linagliptin is considered unlikely to cause interactions with other P-gp substrates at therapeutic concentrations.14 Inducers of CYP3A4 or P-gp (eg, rifampin) decrease exposure to linagliptin to subtherapeutic, and likely ineffective, concentrations. For patients requiring the use of such drugs, an alternative to linagliptin is strongly recommended. No dose adjustment of linagliptin is recommended based on the results of the described pharmacokinetic studies.14

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Conclusion The combination of linagliptin plus metformin hydrochloride in a single tablet provides another therapeutic option to achieve glycemic control in patients with type 2 diabetes whose disease is inadequately controlled by lifestyle measures alone or by lifestyle measures combined with metformin monotherapy. According to recent guidelines, initiating therapy with dual antihyperglycemic agents may be appropriate in certain populations of patients with HbA1c levels >9%. Preliminary evidence suggests that there is a reduction in CV risk when patients are treated with DPP-4 inhibitors relative to other oral antidiabetic agents. n References

1. Centers for Disease Control and Prevention. National diabetes fact sheet, 2011. www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf. Accessed October 25, 2012.

2. Danaei G, Friedman AB, Oza S, et al. Diabetes prevalence and diagnosis in US states: analysis of health surveys. Popul Health Metr. 2009;7:16-28.

3. Liese AD, D’Agostino RB Jr, Hamman RF, et al, for the SEARCH for Diabetes in Youth Study Group. The burden of diabetes mellitus among US youth: prevalence estimates from the SEARCH for Diabetes in Youth study. Pediatrics. 2006;118:1510-1518.

4. Hamman RF, Pettitt DJ, Dabelea D, et al. Estimates of the burden of diabetes in United States youth 2009. Presented at 72nd Scientific Sessions of the American Diabetes Association; June 8-12, 2012; Philadelphia, PA: Poster 1369-P. 5. Khaw KT, Wareham N, Luben R, et al. Glycated haemoglobin, diabetes, and mortality in men in Norfolk cohort of european prospective investigation of cancer and nutrition (EPIC-Norfolk). BMJ. 2001;322:15-18.

6. Stratton IM, Adler AI, Weil AW, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ. 2000;321:405-412.

7. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2012;35:1364-1379.

8. Patil HR, Al Badarin FJ, Al Shami HA, et al. Meta-analysis of effect of dipeptidyl peptidase-4 inhibitors on cardiovascular risk in type 2 diabetes mellitus. Am J Cardiol.

2012;110:826-833.

9. Jentadueto (linagliptin/metformin HCl) tablets. Prescribing information. Ridgefield, CT: Boehringer Ingelheim; January 2012.

10. Haak T, Meinicke T, Jones R, et al. Initial combination of linagliptin and metformin improves glycaemic control in type 2 diabetes: a randomised, double-blind, placebo-controlled study. Diabetes Obes Metab. 2012;14:565-574.

11. Taskinen MR, Rosenstock J, Tamminen I, et al. Safety and efficacy of linagliptin as add-on therapy to metformin in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled study. Diabetes Obes Metab. 2011;13:65-74.

12. Gallwitz B, Rosenstock J, Rauch T, et al. 2-year efficacy and safety of linagliptin compared with glimepiride in patients with type 2 diabetes inadequately controlled on metformin: a randomised, double-blind, non-inferiority trial. Lancet. 2012;380:475-483.

13. Owens DR, Swallow R, Dugi KA, Woerle HJ. Efficacy and safety of linagliptin in persons with type 2 diabetes inadequately controlled by a combination of metformin and sulphonylurea: a 24-week randomized study. Diabet Med. 2011;28:1352-1361.

14. Baetta R, Corsini A. Pharmacology of dipeptidyl peptidase-4 inhibitors: similarities and differences. Drugs. 2011;71:1441-1467.

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Vol 6, No 3

Linzess: A Novel Treatment Option for

Constipation Associated with Irritable Bowel Syndrome

By Alice Goodman, Medical Writer

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onstipation is the most common gastrointestinal (GI) complaint in the United States, affecting between 2% and 28% of the population.1 Although it is usually relatively benign, the condition can be serious and can negatively affect a patient’s quality of life, as well as the ability to perform daily activities and overall work productivity.2 Constipation represents a substantial economic burden on the US healthcare system.3,4 Constipation can have various etiologies, and diseases and conditions associated with constipation can be difficult to diagnose and to treat.3 Laxatives are the mainstay of treatment for patients who self-diagnose constipation. More recently, newer drugs have been approved for the treatment of constipation in association with irritable bowel syndrome (IBS) and chronic idiopathic constipation.3

Irritable Bowel Syndrome IBS affects between 25 million and 55 million people in the United States, the majority of them female. IBS is often described as constipation predominant, diarrhea predominant, or an alternating pattern of constipation and diarrhea. Each of these types accounts for approximately 33% of all people with IBS.5 An estimated 13 million Americans have IBS with constipation, which is considered a chronic GI disorder with symptoms that can be severe enough to compromise one’s ability to carry out daily activities.

IBS with constipation is associated with a substantial economic burden related to the direct costs of care and the indirect costs, including reduced employment and work productivity.6 The symptoms associated with IBS include recurrent abdominal pain associated with defecation or a change in bowel habits with features of abnormal defecation that can include diarrhea, excess bloating, and either harder or looser stools than normal (hard stools in >25% of bowel movements and soft/watery stools in <25%).5 According to the Rome III criteria for IBS, the symptoms of IBS involve recurrent abdominal pain or discomfort and a marked change in bowel habits for at least 6 months, with symptoms experienced on at least 3 days

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within at least 3 months.7 Two or more of the following symptoms must apply for the diagnosis of IBS: • Pain is relieved by a bowel movement7 • Onset of pain is related to a change in frequency of stool7 • Onset of pain is related to a change in the appearance of stool.3 The causes of IBS are not completely understood. The proposed causes of IBS include bowel motility problems, hypersensitivity of the colon, dysregulation of neuro­ transmitters, and hormonal factors. None of these presumptive causes has been established with certainty. The triggers of IBS include specific foods, medications, the presence of gas or stool, and emotional stress.

Chronic Idiopathic Constipation Chronic idiopathic constipation is a functional disorder with no identified anatomic or physiologic causes.

Chronic idiopathic constipation is not relieved by standard therapy. Chronic idiopathic constipation can also be accompanied by a sensation of incomplete bowel movements and hard stools. Unlike IBS with constipation, patients with chronic idiopathic constipation do not have pain as a primary symptom.

The Rome III diagnostic criteria for chronic idiopathic constipation include the onset of ≥2 of the following symptoms for at least 6 months7: • Straining for at least 25% of bowel movements • Lumpy or hard stools in at least 25% of bowel move­ ments • Sensation of incomplete evacuation at least 25% of the time • Sensation of anorectal blockage/obstruction at least 25% of the time • Manual maneuvers to facilitate at least 25% of bowel movements • Fewer than 3 bowel movements weekly.

Medications Used to Treat Constipation Laxatives are frequently used to treat chronic idiopathic constipation, with between 16% and 40% of patients with chronic idiopathic constipation using laxatives; no less than 66% of patients used them at least monthly.8

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Table 1 Efficacy Rates in Trials 1 and 2 in Patients with IBS Associated with Constipation for at Least 9

of 12 Weeks Trial 1

Efficacy

Trial 2

Linaclotide 290 mcg Placebo Treatment Linaclotide Placebo Treatment (N = 405), (N = 395), difference, 290 mcg (N = 403), difference, % % % (N = 401), % % %

Combined respondera (abdominal pain and CSBM responder)

12.1

5.1

7.0 (95% CI, 3.2-10.9)

12.7

3.0

9.7 (95% CI, 6.1-13.4)

Abdominal pain respondera (≥30% abdominal pain reduction)

34.3

27.1

7.2 (95% CI, 0.9-13.6)

38.9

19.6

19.3 (95% CI, 13.2-25.4)

CSBM respondera (≥3 CSBMs and increase ≥1 CSBM from baseline)

19.5

6.3

13.2 (95% CI, 8.6-17.7)

18.0

5.0

13.0 (95% CI, 8.7-17.3)

a Primary end points.

Analyses based on first 12 weeks of treatment for both trials 1 and 2.

CI indicates confidence interval; CSBM, complete spontaneous bowel movement; IBS, irritable bowel syndrome.

Source: Linzess [package insert]. St Louis, MO: Forest Laboratories, Inc; August 2012.

However, many patients are dissatisfied with laxatives as a treatment, and these agents do not target the pathophysio­ logic abnormalities associated with constipation.8 Newer drugs developed for the treatment of chronic idiopathic constipation over the past decade include prucalopride (Resolor) and lubiprostone (Amitiza). A meta-­ analysis of randomized controlled trials of laxatives and some of these newer agents conducted in 2010 showed that laxatives (with the exception of lactulose) and the newer agents were more effective than placebo in the treatment of chronic idiopathic constipation.9 The most recent agent was approved at the end of 2012.10

Linzess Receives FDA Approval Linaclotide (Linzess; Ironwood Pharmaceuticals/Forest Laboratories) was approved in December 2012 by the US Food and Drug Administration (FDA) for the treatment of constipation in adults in association with IBS or chronic idiopathic constipation. Linaclotide’s approval is limited to treatment of adults; the drug should not be used in pediatric patients or in patients younger than age 17.10 Linaclotide is the only FDA-approved guanylate cyclase-C (GC-C) agonist that acts locally in the intestinal tract. Furthermore, linaclotide is the first new FDA-­ approved treatment option for adults with constipation in 6 years.

Mechanism of Action Linaclotide is believed to exert its effects via 2 mechanisms. The drug binds to the GC-C receptor within the

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intestinal epithelium. Activation of GC-C leads to increased secretion of intestinal fluid and then transit through the intestinal tract, as well as reduced visceral pain, which is mediated by reduced activity of sensory nerves that are involved in the perception of pain.5

Dosing The oral capsule linaclotide that is taken once daily has been shown to alleviate the pain and constipation associated with IBS associated with constipation and the hard stools observed in patients with chronic idiopathic constipation. The recommended doses are 290 mcg for IBS with constipation and 145 mcg for patients with chronic idiopathic constipation.11 Linaclotide should be swallowed whole once daily on an empty stomach as prescribed.11 Clinical Trials Data with Linaclotide Randomized, placebo-controlled clinical trials with a total of more than 2800 adults demonstrated that linaclotide alleviated abdominal pain in patients with constipation-predominant IBS and improved the frequency of bowel movements in these patients, as well as in patients with chronic idiopathic constipation.11 Trials 1 and 2: IBS with Constipation Two double-blind, placebo-controlled, randomized, multicenter trials established the efficacy of linaclotide for the management of symptoms of IBS with constipation. Trial 1 and Trial 2 enrolled 800 and 804 patients, respectively, who met the Rome II criteria for IBS, and

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Table 2 Efficacy Rates in Trials 3 and 4 in Patients with Chronic Idiopathic Constipation for at Least 9 of 12 Weeks Trial 3 Efficacy Complete spontaneous bowel movement overall responder

Trial 4

Linaclotide, %

Placebo, %

Linaclotide, %

Placebo, %

20.3

3.3

15.5

5.6

Source: Linzess [package insert]. St Louis, MO: Forest Laboratories, Inc; August 2012. randomized them to treatment with linaclotide 290 mcg or placebo once daily.11 Both trials had identical designs for the first 12 weeks; after that, Trial 1 included a 4-week randomized withdrawal period and Trial 2 continued double-blind treatment for 14 additional weeks, for a total of 26 weeks.

Efficacy was based on responder analyses and change from baseline based on individual patient diaries. Efficacy end points included analysis of response for at least 9 of the first 12 weeks of treatment or at least 6 of the first 12 weeks of treatment (Table 1). Both end points, which were complex, required at least a 30% reduction from baseline in mean abdominal pain and an increase in complete spontaneous bowel movements. For all efficacy end points, the percentage of patients who responded to linaclotide 290 mcg was statistically superior to placebo.

In Trial 1, 12.1% of the linaclotide group and 5.1% of the placebo-receiving patients met the primary end point of combined responseâ&#x20AC;&#x201D;abdominal pain and complete spontaneous bowel movement response for at least 9 of 12 weeks. In Trial 2, the percentages were 12.7% and 3.0%, respectively, for response for at least 9 of 12 weeks. For efficacy response rates in at least 6 of 12 weeks, in Trial 1 the combined responder rates were 33.6% in the linaclotide group and 21.0% for placebo. In Trial 2, 33.7% and 13.9%, respectively, responded in at least 6 of 12 weeks.11 In each trial, abdominal pain and complete spontaneous bowel movement frequency improved over the first 12 weeks of treatment. The use of linaclotide began to show distinct improvement in abdominal pain compared with placebo during the first week of treatment.

The maximum effects of linaclotide were observed in weeks 6 through 9 and maintained until the studies were ended. At 12 weeks, according to an 11-point pain scale, the mean difference between linaclotide and placebo was 1 point in both trials. A beneficial effect on complete spontaneous bowel movement was seen during the first week of treatment, and the change from baseline in frequency of complete spontaneous bowel movement at week 12 was a difference between linaclotide and placebo of approximately 1.5 complete spontaneous bowel movements weekly in both trials.

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In Trial 1, during the 4-week built-in randomized withdrawal period, linaclotide-treated patients who were then rerandomized to placebo experienced a return of abdominal pain severity and complete spontaneous bowel movement to baseline levels. By contrast, patients in the placebo arm who were rerandomized to linaclotide experienced an increase in complete spontaneous bowel movement frequency and a similar abdominal pain level as that observed in patients who were randomized to linaclotide during the treatment period.

Trials 3 and 4: Chronic Idiopathic Constipation Two double-blind, placebo-controlled, randomized, multicenter clinical trials established the efficacy of linaclotide in adults with chronic idiopathic constipation. Trials 3 and 4 enrolled 642 and 630 patients, respectively, and randomized them to treatment with linaclotide 145 mcg, linaclotide 290 mcg, or to placebo, all once daily.10 All patients met the modified Rome II criteria for functional constipation. Patients with IBS with constipation and those with fecal impaction requiring emergency treatment were excluded from Trials 3 and 4.11 Trials 3 and 4 had identical designs. Trial 3 also included an additional 4-week withdrawal period. As in Trials 1 and 2, efficacy was based on overall responder analyses and change from baseline end points according to patientsâ&#x20AC;&#x2122; daily diaries. The higher dose (ie, 290 mcg) of linaclotide did not offer any benefit over the 145-mcg daily dose in these trials, so the 145-mcg daily dose has been deemed the appropriate and recommended dose.

In both trials, the proportion of patients who responded to linaclotide with a complete spontaneous bowel movement was significantly greater with the recommended dose of linaclotide than with placebo. Criteria for overall response were at least 3 complete spontaneous bowel movements and an increase of at least 1 complete spontaneous bowel movement from baseline for 9 of 12 weeks (Table 2).

In Trial 3, the absolute treatment difference favoring linaclotide was 16.9% (95% confidence interval [CI], 11.0%-22.8%). In Trial 4, the absolute difference favoring linaclotide was 9.9% (95% CI, 4.2%-15.7%).11

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Adverse Reactions in ≥2% of Patients Receiving Table 3 Linaclotide in Trials 1 and 2 of Patients with IBS

with Constipation Linaclotide 290 mcg (N = 807), %

Placebo (N = 798), %

Gastrointestinal Diarrhea Abdominal paina Flatulence Abdominal distension

20 7 4 2

3 5 2 1

Infections and infestations Viral gastroenteritis

3

1

Nervous system disorders Headache

4

3

Adverse reactions

The term “abdominal pain” includes abdominal pain, upper abdominal pain, and lower abdominal pain.

IBS indicates irritable bowel syndrome.

Source: Linzess [package insert]. St Louis, MO: Forest Laboratories, Inc; August 2012.

a

Adverse Events and Precautions Linaclotide should not be used for children under age 17 years or for patients with known or suspected obstruction of the GI tract.11 Pooled data from Trials 1, 2, 3, and 4 show that diarrhea was the most common adverse event related to linaclotide. Severe diarrhea occurred in 2% of the linaclotide-treated patients in these clinical trials, with a similar incidence in patients with IBS with constipation and those with chronic idiopathic constipation (Table 3).11 In the pooled IBS-with-constipation pivotal trials, diarrhea was reported in 20% of the linaclotide-receiving patients and in 3% of the placebo-receiving patients.

Severe diarrhea was reported in 2% and 1%, respectively, of the patients. Diarrhea-related treatment discontinuations occurred in 5% of those randomized to lina-

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clotide versus <1% of the placebo group.

In the pooled chronic idiopathic constipation trials, diarrhea was the most frequently reported adverse event in the linaclotide-treated patients (16% vs 5% of placebo patients). Severe diarrhea was reported in 2% and less than 1%, respectively. Diarrhea-related treatment discontinuations were reported in 5% and less than 1%, respectively.11

Conclusion Constipation in association with IBS or chronic idiopathic constipation affects millions of people and can be difficult to treat. Linaclotide is the first oral medication to be approved by the FDA in the past 6 years for the treatment of patients with IBS associated with constipation or for those with chronic idiopathic constipation.

This approval adds a new treatment option for these 2 patient populations, by reducing abdominal pain that is associated with chronic idiopathic constipation and improving complete spontaneous bowel movements in both groups of patients. n References

1. Drossman DA, Li Z, Toner BB, et al Functional bowel disorders. A multicenter comparison of health status and development of illness severity index. Dig Dis Sci. 1995;40:986-995.

2. Sweeney M. Constipation diagnosis and treatment. Home Care Provid. 1997;2:250-255.

3. Johanson JF. Review of the treatment options for chronic constipation. MedGenMed. 2007;9:25.

4. Harris LA. Prevalence and ramifications of chronic constipation. Manag Care Interface.

2005;18:23-30.

5. Quigley EMM, Tack J, Chey WD, et al. Randomised clinical trials: linaclotide phase 3 studies in IBS-C—a prespecified analysis based on European Medicines Agency-specified endpoints. Aliment Pharmacol Ther. 2013;37:49-61.

6. Longstreth GF, Wilson A, Knight K, et al. Irritable bowel syndrome, health care use, and costs: a US managed care perspective. Am J Gastroenterol. 2003;98:600-607.

7. Longstreth GF, Thomson WG, Chey WD, et al. Functional bowel disorders.

Gastroenterology. 2006;130:1480-1491. [Erratum Gastroenterology. 2006;131:688].

8. Wald A, Scarpignato C, Mueller-Lissner S, et al. A multinational survey of prevalence and patterns of laxative use among adults with self-defined constipation. Aliment Pharmacol Ther. 2008;28:917-930.

9. Ford AC, Suares NC. Effect of laxatives and pharmacologic therapies in chronic idiopathic constipation: systematic review and meta-analysis. Gut. 2011;60:209-218.

10. US Food and Drug Administration. FDA approves Linzess. www.fda.gov/news events/newsroom/pressannouncements/ucm317505.htm. Accessed December 12, 2012.

11. Linzess [package insert]. St Louis, MO: Forest Laboratories, Inc; August 2012.

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Vol 6, No 3

Trends in the 2013 Pharmaceutical Pipeline Dalia Buffery, MA, ABD, and Atheer A. Kaddis, PharmD Ms Buffery is Editorial Director of American Health & Drug Benefits, and Dr Kaddis is Senior Vice President, Sales and Business Development, Diplomat Specialty Pharmacy, Flint, MI

J

udging by the number of drugs that are currently in the pipeline, drug development may be changing in nature but is not showing real signs of slowing down, despite the many uncertainties in the marketplace and the recent economic instabilities in the United States and worldwide. Overall, the number of new drugs approved by the US Food and Drug Administration (FDA) in 2012 exceeded the total annual approvals in the past decade (with the exception of 2009). And this trend is likely to continue in 2013, based on the number of drugs already approved in the first quarter of the year.

One of the most obvious trends in drug development is the accelerating rate of growth of specialty drugs in the pipeline, with an increasing role for the use of genetics and biologic processes, often high-cost processes that are then translated into high cost for the consumer and/or the health plan or employer. This trend is further reflected in the growth in the annual expenditures on specialty drugs seen in the past few years, with an overall annual growth in specialty drug cost by 17%, which is expected to grow by 22% in 2014, according to the most recent drug report from Express Scripts.1 Nevertheless, and despite the relatively small number of patients using specialty drugs compared with the socalled traditional, small-molecule drugs, the overall share of specialty drugs is continuing to grow in the United States, in tandem with the overall cost trend; these 2 phenomena may explain in part the accelerated growth of specialty drugs in the pipeline. By 2018, consumer and payer spending on specialty drugs is expected to exceed the spending on small-molecule drugs.2 This trend has been evident in the growing number of FDA approvals for biologic drugs and new molecular entities (NMEs) that have fallen under the specialty drug category in the past 5 years. In 2008 and 2009, more traditional medicines than biologic drugs were approved by the FDA; by 2010, this trend began to reverse, and for the past 3 years (since 2011), more specialty drugs have been approved by the FDA than traditional drugs, with the total number of approvals growing annually (except for a slight drop in 2010).3 The outlook for 2013 remains promising for drug approvals. As of April 1, 11 new brand-name drugs were approved by the FDA (plus 2 combination drugs that include the antihyperglycemic NME alogliptin [Nesina]

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that was approved on the same day [Table 1]). This example, and the 1 additional oral drug for type 2 diabetes already approved in 2013, further reinforce the strong position of antihyperglycemic drugs in the pipeline; another significant approval so far in 2013 was an oral NME for multiple sclerosis (MS), highlighting the growing focus on oral therapies.

Growing Focus on Specialty and Oral Drugs A recent report from the Pharmaceutical Research and Manufacturers of America (PhRMA) indicates that the current drug pipeline is booming with specialty drugsâ&#x20AC;&#x201D; 907 medicines and vaccines are in various stages of development, including drugs in phases 1 to 3 clinical trials and others that are under review by the FDA.4 These 907 new specialty agents are targeting more than 100 different disease states, among them many rare diseases, according to PhRMA.4 Analysis of these specialty drugs in the pipeline reveals that many of them are either monoclonal antibodies (N = 338) or vaccines (N = 250),4 which reflects the increasing role of biotechnology innovation in the research and development of novel drugs.

The gradual but consistent move toward oral medications is evident in many clinical categories. Even among the biologic and specialty drugs, many are now being developed as oral formulations, which raises the old dilemma of benefits versus potential complications for providers and for patients when very specialized medicines, such as cancer drugs, can now be taken by the patient without supervision, thereby introducing the familiar issue of adherence to the clinical mix of cancer management.

Orphan Drugs Another strong trend evident in the pipeline is the growing number of so-called orphan drugs that target rare diseases. In 2013, the FDA has continued to use its priority review process (which was accelerated last year) to expedite the approval of significant new drugs; this trend is especially apparent in the case of orphan drugs, to facilitate expedited access to unique drugs for patients who have few therapeutic options.

The increasing prevalence of orphan drugs in the pharmaceutical pipeline is further reflected in their share in the overall healthcare expenditures in the past few

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Table 1 FDA New Drug Approvals in First Quarter 2013 (as of April 1, 2013) Drug name

Manufacturer

Indication/route

Approval date

Kazano (alogliptin and metformin hydrochloride tablets)

Takeda

Combination therapy for type 2 diabetes; oral

1/25/13

Nesina (alogliptin tablets)

Takeda

Type 2 diabetes; oral

1/25/13

Oseni (alogliptin and pioglitazone tablets)

Takeda

Combination therapy for type 2 diabetes; oral

1/25/13

Kynamro (mipomersen sodium)

Genzyme

Homozygous familial hypercholesterolemia; SC injection

1/29/13

Ravicti (glycerol phenylbutyrate liquid)

Hyperion Therapeutics

Urea cycle disorders; oral

2/1/13

Pomalyst capsules (pomalidomide)

Celgene

Multiple myeloma; oral

2/8/13

Kadcyla (ado-trastuzumab emtansine [T-DM1])

Genentech

Late-stage HER2-positive breast cancer; IV

2/22/13

Osphena (ospemifene)

Shionogi

Estrogen agonist/antagonist for moderate-tosevere dyspareunia; oral

2/26/13

Lymphoseek (technetium Tc99m tilmanocept)

Navidea Biopharmaceuticals

External lymph node imaging and intraoperative lymphatic mapping; injection

3/13/13

Dotarem (gadoterate meglumine)

Guerbet

Gadolinium-based contrast agent for MRI of the brain, spine, and associated tissues; IV

3/20/13

TOBI Podhaler (tobramycin inhalation powder)

Novartis

Cystic fibrosis with Pseudomonas aeruginosa; inhaled antibiotic

3/22/13

Tecfidera (dimethyl fumarate capsules)

Biogen Idec

Relapsing and/or remitting multiple sclerosis; oral

3/27/13

Invokana (canagliflozin)

Janssen (Johnson & Johnson)

First SGLT-2 inhibitor for type 2 diabetes; oral

3/29/13

FDA indicates US Food and Drug Administration; IV, intravenous; MRI, magnetic resonance imaging; SC, subcutaneous; SGLT-2, sodium glucose cotransporter-2.

years. According to one report, the spending on orphan drugs is now at 6% of the total drug spending in the United States, and this trend is expected to continue.5 And although the total pool of patients for genetically based rare diseases is small, affecting an approximate 25 million Americans, many of those orphan drugs have become “blockbusters,” especially among cancer drugs (eg, rituximab, lenalidomide, imatinib, bortezomib).5

Promising Drugs in Late-Stage Development The key clinical categories in drug development in 2013 resemble the trends seen in the past few years. The disease states with the highest number of drugs in development have not changed much from last year, with only few changes in their “place” in that hierarchy, with cancer drugs leading the way, followed by drugs for central nervous system (CNS) disorders. The approximate numbers of drugs currently in development in the top clinical categories are3: • Cancer, ~320 drugs • CNS disorders, ~140 drugs

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• Infectious diseases, ~80 drugs • Diabetes, ~80 drugs • Respiratory disorders, ~75 drugs • Rheumatoid arthritis, ~70 drugs • Cardiovascular (CV) disease, ~65 drugs.

Table 2 lists some of the major products in key clinical categories (excluding cancer drugs) in the pipeline (as of April 1) that are expected to come up for FDA approval in 2013 and in 2014.

CNS Disorders. Only 5 years ago, the number of CNS drugs in the pipeline was almost identical to that of cancer drugs (between 270 and 280). In 2013, that number is 50% lower, although CNS drugs are still second to cancer drugs in terms of sheer numbers in the pipeline.

The 5 CNS drugs that are scheduled for approval by the FDA in 2013 (Table 2) include Levadex (dihydroergotamine), an oral inhaler for acute migraine (delayed from last year); levomilnacipran, a serotonin norepinephrine reuptake inhibitor (SNRI) for the treatment of depression, that has shown greater potency and selectivity for norepinephrine than other SNRIs; suvorexant, with a

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Table 2 The 2013 Pipeline: Key Drugs in Major Clinical Categories, Excluding Cancer Drug name

Manufacturer

Therapeutic category/route/class

Development stage/comments

Alirocumab (SAR236553)

Regeneron/Sanofi

PCSK9 inhibitor for hypercholesterolemia; monoclonal antibody; SC injection

Phase 3 trials NDA in 2014

AMG 145

Amgen

Monoclonal antibody for hyperlipidemia

Phase 3 trials

Anacetrapib

Merck & Co

Cholesteryl ester transfer protein inhibitor for atherosclerosis; oral

Phase 3 trials

Darapladib

GlaxoSmithKline

Selective lipoprotein-associated phospholipase A2 inhibitor for atherosclerosis

Phase 3 trials

Evacetrapib

Lilly

Cholesteryl ester transfer protein inhibitor; oral

Phase 3 trials

Lixiana (edoxaban)

Daiichi-Sankyo

Factor Xa inhibitor for atrial fibrillation and venous thromboembolism

Phase 3 trials to be released in 2013; approval in 2014

Metreleptin

AstraZeneca

Leptin analog for lipodystrophy

NDA filing 2Q 2013

Otamixaban

Sanofi

Direct Xa inhibitor for acute coronary syndrome; oral

Phase 3 trials

Tredaptive (MK-0524A)

Merck & Co

Niacin plus laropiprant (antiflushing agent) for primary hypercholesterolemia

Phase 3 trial: increase in nonfatal but serious adverse events

Vorapaxar

Merck & Co

Thrombin receptor antagonist for prevention of cardiovascular events in patients with a history of heart attack

NDA filing in 2013

Cardiovascular disease

Pulmonary arterial hypertension Opsumit (macitentan)

Actelion

Dual endothelin receptor antagonist for pulmonary arterial hypertension; oral

PDUFA: 10/22/13

Riociguat

Bayer

Guanylate cyclase stimulant for pulmonary arterial hypertension; oral

PDUFA: 10/11/13

Ryverna

Novartis

Pulmonary arterial hypertension; oral

Approval in 2014

LY2605541 (basal insulin)

Lilly

Advanced weight-reduction mechanism; novel version of basal insulin

Phase 3 trials NDA in 2013

Tresiba (insulin degludec)

Novo Nordisk

Long-acting basal insulin

2/12/13: FDA “complete response” requested new data on cardiovascular effects

Empagliflozin

Boehringer Ingelheim/Lilly

SGLT-2 inhibitor for type 2 diabetes; oral

NDA filed: 3/13

Forxiga (dapagliflozin)

AstraZeneca/ Bristol-Myers Squibb

SGLT-2 inhibitor for type 2 diabetes; oral

FDA “complete response” requested more data; refiling NDA mid-2013; European Commission approval: 11/14/12

Lilly

GLP-1 analog linked to IgG fragment for type 2 diabetes; once weekly

NDA filing in 2013

Eperzan (albiglutide) GlaxoSmithKline

Albumin-based GLP-1 analog; once weekly

NDA filed: 1/14/13

Lyxumia (lixisenatide)

Sanofi

GLP-1 analog; daily

NDA filed: 12/12 European Commission approval: 1/2/13

Merck & Co

Once-weekly oral DPP-4 inhibitor for type 2 diabetes

Phase 3 trials

Diabetes Insulins

SGLT-2

GLP-1 Dulaglutide

DPP-4 MK-3102

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Table 2 The 2013 Pipeline: Key Drugs in Major Clinical Categories, Excluding Cancer (Continued) Drug name

Manufacturer

Therapeutic category/route/class

Development stage/comments NDA filing in 2014

Central nervous system disorders Bitopertin

Roche

Glycine reuptake inhibitor for schizophrenia

Brintellix (vortioxetine)

Takeda/Lundbeck

Multimodal mechanisms for major depressive disorder PDUFA: 10/2/13

Cariprazine

Forest

Atypical antipsychotic for schizophrenia and bipolar mania

Edivoxetine

Lilly

Selective norepinephrine reuptake inhibitor for NDA filing in 2013 depression (adjunctive therapy) and pediatric ADHD

Levadex (dihydroergotamine)

Allergen/MAP

Dihydroergotamine via oral inhaler for acute migraine

PDUFA: 4/15/13

Levomilnacipran

Forest

Serotonin norepinephrine reuptake inhibitor for depression

PDUFA: 7/27/13

Remoxy (oxycodone)

Pfizer

For chronic pain; twice daily; oral

FDA complete response letter in 2012; with gel-cap technology

Suvorexant

Merck & Co

Orexin receptor antagonist for primary insomnia; oral PDUFA: 10/13

Zohydro ER (hydrocodone bitartrate extendedrelease capsules)

Zogenix

Novel extended-release hydrocodone without acetaminophen for chronic pain; oral

PDUFA: 3/1/13, delayed by FDA

Cobicistat

Gilead

Protease inhibitor for HIV; oral

PDUFA: 4/28/13

Daclatasvir

Bristol-Myers Squibb

Antiviral nonstructural 5a inhibitor for HCV; oral

Approval in 2014

Dolutegravir

GlaxoSmithKline/ Shionogi

Integrase inhibitor for HIV; oral

PDUFA: 8/17/13 Priority review

Elvitegravir

Gilead

Protease inhibitor for HIV; oral

PDUFA: 4/27/13

Faldaprevir (BI 201335)

Boehringer Ingelheim

Protease inhibitor for HCV; oral

Approval in 2014

Interferon alpha-2b XL

Flamel Technologies

Interferon for HCV; SC weekly

Approval in 2014

Interferon omega

Boehringer Ingelheim

Interferon for HCV; SC implant every 3 months

Approval in 2014

Locteron

Biolex

Interferon for HCV; SC every other week

Approval in 2014

Peg-interferon lambda

Bristol-Myers Squibb

Interferon for HCV; SC weekly

Approval in 2014

Setrobuvir

Roche

Antiviral nonnucleoside polymerase inhibitor for HCV; oral

Approval in 2014

Simeprevir (TMC435)

Janssen/Medivir

Protease inhibitor for genotype 1 HCV; oral

NDA filed: 3/28/13, ahead of schedule

Sofosbuvir (GS-7977)

Gilead

Nucleotide polymerase inhibitor for chronic HCV; oral

NDA in 2013

Vaniprevir

Merck & Co

Protease inhibitor for HCV; oral

Approval in 2014

PDUFA: 11/28/13

Infectious diseases

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Table 2 The 2013 Pipeline: Key Drugs in Major Clinical Categories, Excluding Cancer (Continued) Drug name

Manufacturer

Therapeutic category/route/class

Development stage/comments

Rheumatic/inflammatory diseases Apremilast

Celgene

PDE-4 inhibitor for psoriatic arthritis, psoriasis; oral

Approval late 2013/early 2014 for psoriatic arthritis, late 2014 for psoriasis

Baricitinib

Incyte/Lilly

JAK inhibitor for RA; oral

Approval in 2014

FosD (fostamatinib disodium)

AstraZeneca/ Rigel

Oral spleen tyrosine kinase (Syk) inhibitor for RA; oral

NDA filing 4Q 2013

Lesinurad

AstraZeneca

Urate transporter 1 inhibitor for hyperuricemia and gout; oral

NDA filing in 2014

Lupuzor (rigerimod)

ImmuPharma

Lupus; SC

Approval in 2013

LymphoCide (epratuzumab)

UCB/ Immunomedics

Monoclonal antibody for lupus; IV

Approval in 2014

Odanacatib

Merck & Co

Cathepsin-K inhibitor for osteoporosis

NDA filing 2013

Sarilumab

Regeneron/Sanofi

Anti窶的L-6 antibody for RA; SC injection

Phase 3 trials

Secukinumab

Novartis

Anti窶的L-17A antibody for RA, psoriasis, psoriatic arthritis; IV/SC

Approval in 2014

Sirukumab

Janssen/ GlaxoSmithKline

Monoclonal antibody for RA; SC

Approval in 2014

Tabalumab

Lilly

Antibody to B-cell activating factor for RA/lupus; IV infusion

Phase 3 trials

Lemtrada (alemtuzumab)

Genzyme/Bayer

Monoclonal antibody for relapsing/remitting MS; IV infusion

PDUFA: 9/28/13

Peginterferon beta-1a

Biogen Idec

Relapsing/remitting MS; SC

Approval in 2014

Tcelna (tovaxin)

Opexa/Merck Serono

Relapsing/remitting MS; SC

Approval in 2014

Anoro Ellipta (vilanterol/umeclidinium bromide)

GlaxoSmithKline

Inhaled fixed-dose LABA/LAMA combination for COPD

PDUFA: 12/18/13

Breo (fluticasone furoate/vilanterol)

GlaxoSmithKline/ Theravance

Combination therapy for COPD, next-generation PDUFA: 5/12/13 inhaled corticosteroid and LABA; dry powder inhaler

QVA149 (indacaterol/glycoﾂｭ pyrronium bromide)

Novartis

Inhaled fixed-dose LABA/LAMA combination for COPD

Phase 3 trials

Striverdi Respimat (olodaterol)

Boehringer Ingelheim

Inhaled LABA for COPD

FDA committee recommends approval; fixed-dose LABA/ LAMA combination (with tiotropium) in phase 3 trials

Zephyr (vilanterol/ umeclidinium)

GlaxoSmithKline/ Theravance

Inhaled fixed-dose LABA/LAMA combination for COPD

NDA filed in 2012

Multiple sclerosis

Respiratory disorders

ADHD indicates attention deficit hyperactivity disorder; COPD, chronic obstructive pulmonary disease; DPP-4, dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1; HCV, hepatitis C virus; IgG, immunoglobulin G; IL, interleukin; IV, intravenous; JAK, Janus kinase; LABA, long-acting beta2-adrenergic agonist; LAMA, long-acting muscarinic antagonist; MTP, microsomal triglyceride transfer protein; MS, multiple sclerosis; NDA, New Drug Application; PCSK9, proprotein convertase subtilisin/kexin type 9; PDE-4, phosphodiesterase-4; PDUFA, Prescription Drug User Fee Act; RA, rheumatoid arthritis; SC, subcutaneous; SGLT-2, sodium glucose cotransporter-2.

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Table 3 Key Cancer Drugs in Late-Stage Development (as of April 1, 2013) Manufacturer

Drug name

Therapeutic category/formulation/class

Comments

AB Science

Masitinib

Pancreatic cancer, GIST

Phase 3 trials

AbbVie

Elotuzumab

Humanized monoclonal antibody for relapsed/refractory multiple myeloma; immunotherapy

Phase 3 trials

Amgen

Trebananib

Recombinant peptide-Fc fusion protein for ovarian cancer

Phase 3 trials

Talimogene laherparepvec

Melanoma; injected intralesionally and disrupts cancer-cell membrane

Phase 3 trials

Rilotumumab

Hepatocyte growth factor/scatter factor inhibitor for gastric cancer

Phase 3 trials

Aveo Pharmaceuticals/ Astellas Pharma

Tivozanib

Advanced renal-cell carcinoma; oral

PDUFA: 7/28/13

Bayer/Algeta

Xofigo (radium-223)

Alpha-emitting particle for castration-resistant prostate cancer with bone metastasis

PDUFA: 8/14/13; priority review

Boehringer Ingelheim

Tomtovok (afatinib)

EGFR and HER2 inhibitor for NSCLC; oral

PDUFA: 7/15/13

Nintedanib

NSCLC, ovarian cancer, idiopathic pulmonary fibrosis; oral, IV

Phase 3 trials

Nivolumab (BMS-936558)

Anti-PD1 monoclonal antibody for NSCLC, melanoma, renal-cell carcinoma; IV solution

Phase 3 trials; forecast $2 billion in 2020

Brivanib

Liver cancer/metastatic CRC; oral

Phase 3 trials

Celgene

Amrubicin

Small-cell lung cancer; IV

Phase 3 trials

Celldex

Rindopepimut

Glioblastoma

Phase 3 trials

Eisai

Farletuzumab

Humanized IgG1 antibody for epithelial ovarian cancer

Phase 3 trials

Lenvatinib

Medullary thyroid cancer

Phase 3 trials

Genentech

Obinutuzumab

Diffuse large B-cell lymphoma, anti-CD20 monoclonal antibody; IV

Phase 3 trials

GlaxoSmithKline

Dabrafenib

Lp-PLA2 inhibitor for metastatic melanoma with BRAF V600; oral

PDUFA: 5/30/13

Trametinib

MEK inhibitor for metastatic melanoma with BRAF V600; oral

PDUFA: 6/3/13

MAGE-A3 ASCI vaccine

Recombinant immunotherapy for melanoma, NSCLC; intramuscular

Phase 3 trials

Janssen Biotech

Daratumumab

Human CD38 monoclonal antibody for relapsed/refractory multiple myeloma

Phase 3 trials

Johnson & Johnson

Ibrutinib

CLL; Burtonâ&#x20AC;&#x2122;s tyrosine kinase inhibitor

NDA in 2013

Trabectedin

Breast/ovarian cancer; IV

Phase 3 trials

Lilly

Enzastaurin

Diffuse large B-cell lymphoma; oral

Phase 3 trials

Necitumumab

Squamous NSCLC; IV

Phase 3 trials

Ramucirumab

Gastric cancer/breast cancer/CRC; IV

Phase 3 trials

BKM120

Breast cancer; oral

Phase 3 trials

Dovitinib lactate

Renal-cell carcinoma; oral

Phase 3 trials

Midostaurin

AML; oral

Phase 3 trials

Panobinostat

Multiple myeloma, other cancers; oral

Phase 3 trials

Lucanix vaccine

For NSCLC; intradermal vaccine

Phase 3 trials

Bristol-Myers Squibb

Novartis

NovaRx Pfizer

Dacomitinib

Second-line treatment of NSCLC; oral

Phase 3 trials

Sanofi

Iniparib

Squamous NSCLC; IV

Phase 3 trials

Sunesis

Vosaroxin

AML, in combination with cytarabine; IV

Phase 3 trials

NOTE: This list does not include potential new indications or formulations for cancer drugs already on the market.

AML indicates acute myelogenous leukemia; CLL, chronic lymphocytic leukemia; CRC, colorectal cancer; EGFR, epidermal growth factor receptor; GIST, gastrointestinal stromal tumor; IgG1, immunoglobulin G1; IV, intravenous; Lp-PLA2, lipoprotein-associated phospholipase A2; NSCLC, nonâ&#x20AC;&#x201C;small-cell lung cancer; PDUFA, Prescription Drug User Fee Act.

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new mechanism of action for primary insomnia; Brintellix (vortioxetine), which has shown mixed efficacy data for major depressive disorders; and cariprazine, an atypical antipsychotic for schizophrenia, with a mechanism similar to Abilify but potentially with an improved safety profile.3 Infectious Diseases. The main activity in 2013 involves new drugs for hepatitis C virus (HCV) infection and HIV infection. The pipeline for HCV infection drugs shows a significant move toward oral therapies, with 5 oral drugs scheduled for FDA approval by 2014; of these, simeprevir is further along in development: a New Drug Application was filed on March 28. In addition, 3 drugs for HIV infection are scheduled for FDA review by August 2013 (Table 2).

Diabetes and Heart Disease. Drugs for diabetes continue to flourish in the 2013 pipeline, reflecting the growing need for improved mechanisms of glucose control for the growing number of patients with type 2 diabetes. On March 29, Invokana (canagliflozin) became the first-in-class sodium glucose cotransporter (SGLT)-2 to receive FDA approval for this patient population. Invokana is expected to generate approximately $416 million in sales by 2016, according to a recent report.6 Earlier in the year, Nesina (alogliptin), an oral dipeptidyl peptidase (DPP)-4 inhibitor was approved, with 2 oral combinations containing alogliptin also approved on the same day. The 2013 pipeline features several SGLT-2 inhibitors, glucagon-like peptide-1 analogs, a novel glargine insulin and insulin degludec, and another DPP-4 (Table 2). Many of these agents may still be approved in 2013, although safety issues have been raised.

The number of drugs for CV disease in the pipeline has been cut by 50% in the past 5 years: in 2008, approximately 130 CV drugs were in the pipeline compared with approximately 60 drugs in 2013.3 Of note, 3 oral drugs for pulmonary arterial hypertension are in late stages of developmentâ&#x20AC;&#x201D;the PDUFA date for Opsumit (macitentan) and riociguat is October 2013, and Ryverna may be approved in 2014.

Respiratory Disorders. Several combination therapies are in development for chronic obstructive pulmonary disease (COPD). The 3 COPD drugs likely to be approved in 2013 are Striverdi Respimat (olodaterol) and the 2 combinations Breo (fluticasone furoate plus vilanterol) and Anoro Ellipta (vilanterol plus umeclidinium bromide). The FDAâ&#x20AC;&#x2122;s advisory committee has already recommended the approval of Striverdi (Table 2).

Rheumatic Diseases. Biologic drugs for rheumatoid arthritis and for other autoimmune diseases continue to have a strong presence in the pipeline; at least 6 drugs for arthritis may be approved in 2013 and 2014 combined, including the oral drugs baricitinib and FosD (fostamatinib disodium), as well as subcutaneous or intravenous sarilumab, secukinumab, sirukumab, and tabalumab, Vol 6, No 3

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some of which are being studied for several indications; other drugs are in late-stage development for lupus, psoriatic arthritis, gout, and osteoporosis (Table 2).

Multiple Sclerosis. Biologics continue to rule the MS drug arena. In March 2013, Tecfidera (dimethyl fumarate capsules) received FDA approval for relapsing and/or remitting MS and is expected to be priced in the $50,000 annual range, based on the current pricing of MS drugs.3 Another promising drug for MS is Lemtrada (alemtuzumab), which is scheduled for FDA review in September. In addition, 2 MS drugs are expected to be approved in 2014 (Table 2).

Cancer. In 2013, perhaps not surprising, cancer remains the top clinical category in the drug pipeline, with the most specialty drugs in development (N = 338).

Table 3 lists the key cancer and hematologic drugs that are in late stages of development. Several cancer drugs have already been approved in 2013, and more are expected to gain approval later this year.

The growth trend in cancer therapies is likely to continue in the foreseeable future, even as many types of cancers are becoming chronic diseases. It is safe to assume that cancer will remain a priority target for drug manufacturers in the near future, with personalized medicine and companion diagnostics becoming increasingly more prominent: the growing innovation in biotechnology is likely to further enhance that trend.

Conclusion The year 2013 may not match 2012 in the total number of drugs that are approved by the FDA, but the strong showing in the first quarter of the year suggests that it may come very close to that level (or could it even surpass it?). Despite the growth in generic drug sales, the overall spending on brand-name drugs and new drug development remain strong. Investment in new technologies and the human genome may lead to further innovations in the pipeline in the coming years. n Author Disclosure Statement Ms Buffery reported no conflicts of interest. Dr Kaddis is an employee of Diplomat Specialty Pharmacy.

References

1. Express Scripts. 2012 Drug Trend Report. March 2013. www.drugtrendreport.com/ docs/ExpressScripts_DTR_0320.pdf. Accessed March 7, 2013.

2. Artemetrx. Specialty drug trend across the pharmacy and medical benefit.

2013. www.artemetrx.com/docs/ARTEMETRX_Specialty_Trend_Rpt.pdf. Accessed March 12, 2013.

3. Kolling BW. Scanning the pharmaceutical pipeline. Presented at: Academy of Managed Care Pharmacy 25th Annual Meeting and Expo; April 5, 2013; San Diego, CA. 4. Pharmaceutical Research and Manufacturers of America. Biologics research promises to bolster future of medicine: more than 900 biologic medicines and vaccines in development. March 11, 2013. www.phrma.org/media/releases/biologics-researchpromises-bolster-future-medicine. Accessed March 17, 2013.

5. Thomson Reuters. The economic power of orphan drugs. 2012. http://thomsonreuters.com/content/science/pdf/orphan_drugs.pdf. Accessed March 28, 2013.

6. Clarke T. FDA approves Johnson & Johnson diabetes drug, canagliflozin. March 29, 2013. www.reuters.com/article/2013/03/29/us-usa-johnsonandjohnson-diabetesidUSBRE92S0EY20130329. Accessed April 5, 2013.

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For the treatment of patients with multiple myeloma who have received at least 2 prior therapies including bortezomib and an immunomodulatory agent and have demonstrated disease progression on or within 60 days of completion of last therapy. Approval is based on response rate.

Clinical benefit, such as improvement in survival or symptoms, has not been verified.

THE POWER OF SECOND-GENERATION PROTEASOME INHIBITION TAKES FLIGHT

Important Safety Information CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS The safety of KYPROLIS was evaluated in clinical studies of 526 patients with relapsed and/or refractory multiple myeloma.

Cardiac Arrest, Congestive Heart Failure, Myocardial Ischemia: Death due to cardiac arrest has occurred within a day of KYPROLIS administration. New onset or worsening of pre-existing congestive heart failure with decreased left ventricular function or myocardial ischemia have occurred following administration of KYPROLIS. Cardiac failure events (e.g., cardiac failure congestive, pulmonary edema, ejection fraction decreased) were reported in 7% of patients.

Monitor for cardiac complications and manage promptly.

Withhold KYPROLIS for Grade 3 or 4 cardiac events until recovery and consider whether to restart KYPROLIS based on a benefit/risk assessment. Patients with New York Heart Association Class III and IV heart failure, myocardial infarction in the preceding 6 months, and conduction abnormalities uncontrolled by medications may be at greater risk for cardiac complications.

Pulmonary Hypertension: Pulmonary arterial hypertension (PAH) was reported in 2% of patients treated with KYPROLIS and was Grade 3 or greater in less than 1% of patients.

Evaluate with cardiac imaging and/or other tests as indicated.

Withhold KYPROLIS for pulmonary hypertension until resolved or returned to baseline and consider whether to restart KYPROLIS based on a benefit/risk assessment.

Pulmonary Complications: Dyspnea was reported in 35% of patients enrolled in clinical trials. Grade 3 dyspnea occurred in 5%; no Grade 4 events, and 1 death (Grade 5) was reported.

Monitor and manage dyspnea immediately; interrupt KYPROLIS until symptoms have resolved or returned to baseline.

Infusion Reactions: Infusion reactions were characterized by a spectrum of systemic symptoms including fever, chills, arthralgia, myalgia, facial flushing, facial edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina. These reactions can occur immediately following infusion or up to 24 hours after administration of KYPROLIS. Administer dexamethasone prior to KYPROLIS to reduce the incidence and severity of reactions. Inform patients of the risk and symptoms, and to contact physician if symptoms of an infusion reaction occur.

Tumor Lysis Syndrome: Tumor lysis syndrome (TLS) occurred following KYPROLIS administration in < 1% of patients. Patients with multiple myeloma and a high tumor burden should be considered to be at greater risk for TLS. Prior to receiving KYPROLIS, ensure that patients are well hydrated. Monitor for evidence of TLS during treatment, and manage promptly. Interrupt KYPROLIS until TLS is resolved.

Kyprolis™ (carfilzomib) for Injection is engineered for selective inhibition1 • Single-agent KYPROLIS phase 2 study results2,* - Overall response rate (ORR) of 22.9% in PX-171-003 study (95% CI: 18.0, 28.5) - Median duration of response of 7.8 months (95% CI: 5.6, 9.2) • Most patients across all phase 2 studies (85%) did not need to discontinue therapy due to an adverse event - Adverse reactions leading to discontinuation included congestive heart failure (2%), cardiac arrest, dyspnea, increased blood creatinine, and acute renal failure (1% each) ADVERSE REACTIONS The safety of KYPROLIS was evaluated in clinical trials of 526 patients with relapsed and/or refractory multiple myeloma.

• Serious adverse reactions were reported in 45% of patients. The most common were pneumonia (10%), acute renal failure (4%), pyrexia (3%), and congestive heart failure (3%) • The most common adverse reactions (incidence ≥ 30%) were fatigue (56%), anemia (47%), nausea (45%), thrombocytopenia (36%), dyspnea (35%), diarrhea (33%), and pyrexia (30%) *Study PX-171-003 was a single-arm, multicenter clinical trial of KYPROLIS in 266 patients with relapsed multiple myeloma and whose disease had a ≤ 25% response to the most recent therapy or had disease progression during or within 60 days of the most recent therapy. At the time of study entry, patients had received a median of 5 prior lines of therapy. The primary endpoint was ORR. Response was determined by Independent Review Committee assessment using International Myeloma Working Group criteria.

References: 1. Demo SD, Kirk CJ, Aujay MA, et al. Antitumor activity of PR-171, a novel irreversible inhibitor of the proteasome. Cancer Res. 2007;67(13):6383-6391.

2. KYPROLIS [prescribing information]. South San Francisco, CA: Onyx Pharmaceuticals, Inc.; 2012.

Thrombocytopenia: KYPROLIS causes thrombocytopenia with platelet nadirs occurring around Day 8 of each 28-day cycle and recovery to baseline by the start of the next 28-day cycle.

In patients with multiple myeloma, 36% of patients experienced thrombocytopenia, including Grade 4 in 10%. Thrombocytopenia following KYPROLIS administration resulted in a dose reduction in 1% of patients and discontinuation of treatment with KYPROLIS in < 1% of patients. Monitor platelet counts frequently during treatment with KYPROLIS. Reduce or interrupt dose as clinically indicated.

Hepatic Toxicity and Hepatic Failure: Cases of hepatic failure, including fatal cases, have been reported (< 1%).

KYPROLIS can cause elevations of serum transaminases and bilirubin. Withhold KYPROLIS in patients experiencing Grade 3 or greater elevations of transaminases, bilirubin, or other liver enzyme abnormalities until resolved or returned to baseline. After resolution, consider if restarting KYPROLIS is appropriate. Monitor liver enzymes frequently.

Embryo-fetal Toxicity: KYPROLIS can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. There are no adequate and well-controlled studies in pregnant women using KYPROLIS. Carfilzomib caused embryo-fetal toxicity in pregnant rabbits at doses that were lower than in patients receiving the recommended dose. Females of reproductive potential should be advised to avoid becoming pregnant while being treated with KYPROLIS.

ADVERSE REACTIONS Serious adverse reactions were reported in 45% of patients. The most common serious adverse reactions were pneumonia (10%), acute renal failure (4%), pyrexia (3%), and congestive heart failure (3%). Adverse reactions leading to discontinuation of KYPROLIS occurred in 15% of patients and included congestive heart failure (2%), cardiac arrest, dyspnea, increased blood creatinine, and acute renal failure (1% each).

The most common adverse reactions (incidence ≥ 30%) were fatigue (56%), anemia (47%), nausea (45%), thrombocytopenia (36%), dyspnea (35%), diarrhea (33%), and pyrexia (30%).

USE IN SPECIFIC POPULATIONS Since dialysis clearance of KYPROLIS concentrations has not been studied, the drug should be administered after the dialysis procedure.

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

©2012 Onyx Pharmaceuticals, Inc., South San Francisco, CA 0512-CARF-243 September 2012

KYPROLIS™ (carfilzomib) for Injection Brief Summary of Prescribing Information. Please see the KYPROLIS package insert for full prescribing information.

INDICATIONS AND USAGE: KYPROLIS is indicated for the treatment of patients with multiple myeloma who have received at least two prior therapies including bortezomib and an immunomodulatory agent and have demonstrated disease progression on or within 60 days of completion of the last therapy. Approval is based on response rate [see Clinical Studies section of full PI]. Clinical benefit, such as improvement in survival or symptoms, has not been verified.

DOSAGE AND ADMINISTRATION: Dosing Guidelines. KYPROLIS is administered intravenously over 2 to 10 minutes, on two consecutive days, each week for three weeks (Days 1, 2, 8, 9, 15, and 16), followed by a 12‑day rest period (Days 17 to 28). Each 28‑day period is considered one treatment cycle (Table 1). In Cycle 1, KYPROLIS is administered at a dose of 20 mg/m2. If tolerated in Cycle 1, the dose should be escalated to 27 mg/m2 beginning in Cycle 2 and continued at 27 mg/m2 in subsequent cycles. Treatment may be continued until disease progression or until unacceptable toxicity occurs [see Dosage and Administration]. The dose is calculated using the patient’s actual body surface area at baseline. Patients with a body surface area greater than 2.2 m2 should receive a dose based upon a body surface area of 2.2 m2. Dose adjustments do not need to be made for weight changes of less than or equal to 20%.

Table 1: KYPROLIS Dosage Regimen for Patients with Multiple Myeloma Cycle 1 Week 1 Week 2 Week 3 Week 4 Day Day Days Day Day Days Day Day Days Days 2 3–7 8 9 10–14 15 16 17–21 22–28 1 KYPROLIS No 20 20 20 No 20 20 No No 20 (20 mg/m2): Dosing Dosing Dosing Dosing Cycles 2 and Beyonda Week 1 Week 2 Week 3 Week 4 Day Day Days Day Day Days Day Day Days Days 2 3–7 8 9 10–14 15 16 17–21 22–28 1 KYPROLIS 27 No 27 27 No 27 27 No No 27 Dosing Dosing Dosing Dosing (27 mg/m2): a If

previous cycle dosage is tolerated.

Hydration and Fluid Monitoring. Hydrate patients to reduce the risk of renal toxicity and of tumor lysis syndrome (TLS) with KYPROLIS treatment [see Warnings and Precautions]. Maintain adequate fluid volume status throughout treatment and monitor blood chemistries closely. Prior to each dose in Cycle 1, give 250 mL to 500 mL of intravenous normal saline or other appropriate intravenous fluid.

Give an additional 250 mL to 500 mL of intravenous fluids as needed following KYPROLIS administration. Continue intravenous hydration, as needed, in subsequent cycles. Also monitor patients during this period for fluid overload [see Warnings and Precautions]. Dexamethasone Premedication. Pre‑medicate with dexamethasone 4 mg orally or intravenously prior to all doses of KYPROLIS during Cycle 1 and prior to all KYPROLIS doses during the first cycle of dose escalation to 27 mg/m2 to reduce the incidence and severity of infusion reactions [see Warnings and Precautions].

Reinstate dexamethasone premedication (4 mg orally or intravenously) if these symptoms develop or reappear during subsequent cycles. Dose Modifications based on Toxicities. Recommended actions and dose modifications are presented in Table 2.

Table 2: Dose Modifications for Toxicitya during KYPROLIS Treatment Hematologic Toxicity • Grade 3a or 4 Neutropenia • Grade 4 Thrombocytopenia [see Warnings and Precautions]

Recommended Action • Withhold dose.

• If fully recovered before next scheduled dose, continue at same dose level.

• If recovered to Grade 2 neutropenia or Grade 3 thrombocytopenia, reduce dose by one dose level (from 27 mg/m2 to 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2).

• If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician.

Non-Hematologic Toxicity Recommended Action • Withhold until resolved or returned to baseline.

Cardiac Toxicity Grade 3 or 4, new onset or worsening of: • After resolution, consider if restarting KYPROLIS at a reduced dose is appropriate (from 27 mg/m2 to • congestive heart failure; 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2).

• decreased left ventricular • If tolerated, the reduced dose may be escalated to the function; previous dose at the discretion of the physician.

• or myocardial ischemia [see Warnings and Precautions] Pulmonary Hypertension • Withhold until resolved or returned to baseline.

• Restart at the dose used prior to the event or reduced [see Warnings and Precautions] dose (from 27 mg/m2 to 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2), at the discretion of the physician.

• If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician.

• Withhold until resolved or returned to baseline.

Pulmonary Complications • Consider restarting at the next scheduled treatment • Grade 3 or 4 with one dose level reduction (from 27 mg/m2 to [see Warnings and Precautions] 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2).

• If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician.

• Withhold until resolved or returned to baseline.

Hepatic Toxicity • After resolution, consider if restarting KYPROLIS is • Grade 3 or 4 elevation of appropriate; may be reinitiated at a reduced dose (from transaminases, bilirubin or other 27 mg/m2 to 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2) liver abnormalities with frequent monitoring of liver function. [see Warnings and Precautions)] • If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician. (continued)

Table 2: Dose Modifications for Toxicitya during KYPROLIS Treatment (continued) • Withhold until renal function has recovered to Grade 1 Renal Toxicity or to baseline and monitor renal function.

• Serum creatinine equal to or • If attributable to KYPROLIS, restart at the next scheduled greater than 2 × baseline treatment at a reduced dose (from 27 mg/m2 to [see Adverse Reactions] 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2).

• If not attributable to KYPROLIS, restart at the dose used prior to the event.

• If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician.

• Withhold until resolved or returned to baseline.

Peripheral Neuropathy • Restart at the dose used prior to the event or reduced • Grade 3 or 4 dose (from 27 mg/m2 to 20 mg/m2, OR from 20 mg/m2 [see Adverse Reactions] to 15 mg/m2), at the discretion of the physician.

• If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician.

• Withhold until resolved or returned to baseline.

Other • Grade 3 or 4 non-hematological • Consider restarting at the next scheduled treatment with one dose level reduction (from 27 mg/m2 to toxicities 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2).

• If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician.

National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 3.0.

a

Administration Precautions. The quantity of KYPROLIS contained in one single‑use vial (60 mg carfilzomib) may exceed the required dose. Caution should be used in calculating the quantity delivered to prevent overdosing. Do not mix KYPROLIS with or administer as an infusion with other medicinal products. The intravenous administration line should be flushed with normal saline or 5% Dextrose Injection, USP immediately before and after KYPROLIS administration. KYPROLIS should not be administered as a bolus. KYPROLIS should be administered over 2 to 10 minutes. Reconstitution and Preparation for Intravenous Administration. KYPROLIS vials contain no antimicrobial preservatives and are intended only for single use. Unopened vials of KYPROLIS are stable until the date indicated on the package when stored in the original package at 2°C to 8°C (36°F to 46°F). The reconstituted solution contains carfilzomib at a concentration of 2 mg/mL. Read the complete preparation instructions prior to reconstitution. Reconstitution/Preparation Steps: 1. Remove vial from refrigerator just prior to use. 2. Aseptically reconstitute each vial by slowly injecting 29 mL Sterile Water for Injection, USP, directing the solution onto the INSIDE WALL OF THE VIAL to minimize foaming. 3. Gently swirl and/or invert the vial slowly for about 1 minute, or until complete dissolution of any cake or powder occurs. DO NOT SHAKE to avoid foam generation. If foaming occurs, allow solution to rest in vial for about 2 to 5 minutes, until foaming subsides. 4. After reconstitution, KYPROLIS is ready for intravenous administration. The reconstituted product should be a clear, colorless solution. If any discoloration or particulate matter is observed, do not use the reconstituted product. 5. When administering in an intravenous bag, withdraw the calculated dose [see Dosage and Administration] from the vial and dilute into 50 mL 5% Dextrose Injection, USP intravenous bag.

6. Immediately discard the vial containing the unused portion. The stabilities of reconstituted KYPROLIS under various temperature and container conditions are shown in Table 3.

Table 3: Stability of Reconstituted KYPROLIS Storage Conditions of Reconstituted KYPROLIS

a

Stabilitya per Container Vial

Syringe

IV Bag (D5Wb)

Refrigerated (2°C to 8°C; 36°F to 46°F)

24 hours

24 hours

24 hours

Room Temperature (15°C to 30°C; 59°F to 86°F)

4 hours

4 hours

4 hours

Total time from reconstitution to administration should not exceed 24 hours. b 5% Dextrose Injection, USP.

WARNINGS AND PRECAUTIONS: Cardiac Arrest, Congestive Heart Failure, Myocardial Ischemia. Death due to cardiac arrest has occurred within a day of KYPROLIS administration. New onset or worsening of pre‑existing congestive heart failure with decreased left ventricular function or myocardial ischemia have occurred following administration of KYPROLIS. Cardiac failure events (e.g., cardiac failure congestive, pulmonary edema, ejection fraction decreased) were reported in 7% of patients. Monitor for cardiac complications and manage promptly. Withhold KYPROLIS for Grade 3 or 4 cardiac events until recovery and consider whether to restart KYPROLIS based on a benefit/risk assessment [see Dosage and Administration]. Patients with New York Heart Association Class III and IV heart failure, myocardial infarction in the preceding 6 months, and conduction abnormalities uncontrolled by medications were not eligible for the clinical trials. These patients may be at greater risk for cardiac complications. Pulmonary Hypertension. Pulmonary arterial hypertension (PAH) was reported in 2% of patients treated with KYPROLIS and was Grade 3 or greater in less than 1% of patients. Evaluate with cardiac imaging and/or other tests as indicated. Withhold KYPROLIS for pulmonary hypertension until resolved or returned to baseline and consider whether to restart KYPROLIS based on a benefit/risk assessment [see Dosage and Administration]. Pulmonary Complications. Dyspnea was reported in 35% of patients enrolled in clinical trials. Grade 3 dyspnea occurred in 5%; no Grade 4 events, and 1 death (Grade 5) was reported. Monitor and manage dyspnea immediately; interrupt KYPROLIS until symptoms have resolved or returned to baseline [see Dosage and Administration and Adverse Reactions]. Infusion Reactions. Infusion reactions were characterized by a spectrum of systemic symptoms including fever, chills, arthralgia, myalgia, facial flushing, facial edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina. These reactions can occur immediately following or up to 24 hours after administration of KYPROLIS. Administer dexamethasone prior to KYPROLIS to reduce the incidence and severity of reactions [see Dosage and Administration]. Inform patients of the risk and symptoms and to contact physician if symptoms of an infusion reaction occur [see Patient Counseling Information]. Tumor Lysis Syndrome. Tumor lysis syndrome (TLS) occurred following KYPROLIS administration in < 1% of patients. Patients with multiple myeloma and a high tumor burden should be considered to be at greater risk for TLS. Prior to receiving KYPROLIS, ensure that patients are well hydrated [see Dosage and Administration]. Monitor for evidence of TLS during treatment, and manage promptly. Interrupt KYPROLIS until TLS is resolved [see Dosage and Administration].Thrombocytopenia. KYPROLIS causes thrombocytopenia with platelet nadirs occurring around Day 8 of each 28‑day cycle and recovery to baseline by the start of the next 28-day cycle. In patients with multiple myeloma, 36% of patients experienced thrombocytopenia, including Grade 4 in 10%. Thrombocytopenia following KYPROLIS administration resulted in a dose reduction in 1% of patients and discontinuation of treatment with KYPROLIS in < 1% of patients. Monitor platelet counts frequently during treatment with KYPROLIS. Reduce or interrupt dose as clinically indicated [see Dosage and Administration].

Hepatic Toxicity and Hepatic Failure. Cases of hepatic failure, including fatal cases, have been

reported (< 1%). KYPROLIS can cause elevations of serum transaminases and bilirubin. Withhold KYPROLIS in patients experiencing Grade 3 or greater elevations of transaminases, bilirubin, or other liver abnormalities until resolved or returned to baseline. After resolution, consider if restarting KYPROLIS is appropriate. Monitor liver enzymes frequently [see Dosage and Administration and Adverse Reactions]. Embryo-fetal Toxicity. KYPROLIS can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. There are no adequate and well‑controlled studies in pregnant women using KYPROLIS. Carfilzomib caused embryo‑fetal toxicity in pregnant rabbits at doses that were lower than in patients receiving the recommended dose. Females of reproductive potential should be advised to avoid becoming pregnant while being treated with KYPROLIS. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations].

ADVERSE REACTIONS: The following adverse reactions are discussed in greater detail in other sections of the labeling: • Cardiac Arrest, Congestive Heart Failure, Myocardial Ischemia [see Warnings and Precautions] • Pulmonary Hypertension [see Warnings and Precautions] • Pulmonary Complications [see Warnings and Precautions] • Infusion Reactions [see Warnings and Precautions] • Tumor Lysis Syndrome [see Warnings and Precautions] • Thrombocytopenia [see Warnings and Precautions] • Hepatic Toxicity and Hepatic Failure [see Warnings and Precautions] The most common adverse reactions (incidence of 30% or greater) to KYPROLIS observed in clinical trials of patients with multiple myeloma were fatigue, anemia, nausea, thrombocytopenia, dyspnea, diarrhea, and pyrexia. Clinical Trials Safety 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 with rates in the clinical trials of another drug, and may not reflect the rates observed in medical practice. A total of 526 patients with relapsed and/or refractory multiple myeloma received KYPROLIS as monotherapy or with pre‑dose dexamethasone. Patients received a median of four treatment cycles with a median cumulative KYPROLIS dose of 993.4 mg. Deaths due to all causes within 30 days of the last dose of KYPROLIS occurred in 37/526 (7%) of patients. Deaths not attributed to disease progression were cardiac in 5 patients (acute coronary syndrome, cardiac arrest, cardiac disorder), end‑organ failure in 4 patients (multi‑organ failure, hepatic failure, renal failure), infection in 4 patients (sepsis, pneumonia, respiratory tract bacterial infection), dyspnea and intracranial hemorrhage in 1 patient each, and 1 patient found dead of unknown causes. Serious adverse reactions were reported in 45% patients. The most common serious adverse reactions were pneumonia (10%), acute renal failure (4%), pyrexia (3%), and congestive heart failure (3%). Adverse reactions leading to discontinuation of KYPROLIS occurred in 15% of patients and included congestive heart failure (2%), cardiac arrest, dyspnea, increased blood creatinine, and acute renal failure (1% each). Adverse reactions occurring at a rate of 10% or greater are presented in Table 4.

Table 4: Incidence of Adverse Reactions Occurring in ≥ 10% of Multiple Myeloma Patients Treated with KYPROLIS

Event Fatigue Anemia Nausea Thrombocytopenia Dyspnea Diarrhea Pyrexia Upper respiratory tract infection Headache Cough Blood creatinine increased Lymphopenia Edema peripheral Vomiting Constipation Neutropenia Back pain Insomnia Chills Arthralgia Muscle spasms Hypertension Asthenia Hypokalemia Hypomagnesemia Leukopenia Pain in extremity Pneumonia Aspartate aminotransferase increased Dizziness Hypoesthesia Anorexia Pain Hyperglycemia Chest wall pain Hypercalcemia Hypophosphatemia Hyponatremia

All Gradesa 292 (55.5) 246 (46.8) 236 (44.9) 191 (36.3) 182 (34.6) 172 (32.7) 160 (30.4) 149 (28.3) 145 (27.6) 137 (26.0) 127 (24.1) 126 (24.0) 126 (24.0) 117 (22.2) 110 (20.9) 109 (20.7) 106 (20.2) 94 (17.9) 84 (16.0) 83 (15.8) 76 (14.4) 75 (14.3) 73 (13.9) 72 (13.7) 71 (13.5) 71 (13.5) 70 (13.3) 67 (12.7) 66 (12.5) 66 (12.5) 64 (12.2) 63 (12.0) 63 (12.0) 62 (11.8) 60 (11.4) 58 (11.0) 55 (10.5) 54 (10.3)

Patients (N = 526) [n (%)] Grade 3 Events 38 (7.2) 111 (21.1) 7 (1.3) 69 (13.1) 25 (4.8) 4 (0.8) 7 (1.3) 17 (3.2) 7 (1.3) 1 (0.2) 13 (2.5) 84 (16.0) 3 (0.6) 5 (1.0) 1 (0.2) 50 (9.5) 15 (2.9) 0 1 (0.2) 7 (1.3) 2 (0.4) 15 (2.9) 12 (2.3) 14 (2.7) 2 (0.4) 27 (5.1) 7 (1.3) 52 (9.9) 15 (2.9) 5 (1.0) 3 (0.6) 1 (0.2) 12 (2.3) 16 (3.0) 3 (0.6) 13 (2.5) 24 (4.6) 31 (5.9)

Grade 4 Events 2 (0.4) 7 (1.3) 0 54 (10.3) 1 (0.2)b 1 (0.2) 2 (0.4) 0 0 0 1 (0.2) 11 (2.1) 0 0 0 4 (0.8) 0 0 0 0 0 2 (0.4) 1 (0.2) 3 (0.6) 0 1 (0.2) 0 3 (0.6)b 1 (0.2) 1 (0.2) 0 0 0 3 (0.6) 0 8 (1.5) 3 (0.6) 3 (0.6)

National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 3.0.

One event was Grade 5 severity.

a

b

Description of Selected Adverse Drug Reactions. Renal Events: The most common renal adverse reactions were increase in blood creatinine (24%) and renal failure (9%), which were mostly Grade 1 or Grade 2 in severity. Grade 3 renal adverse reactions occurred in 6% of patients and Grade 4 events occurred in 1%. Discontinuations due to increased blood creatinine and acute renal failure were 1% each. In one patient, death occurred with concurrent sepsis and worsening renal function [see Dosage and Administration]. Peripheral Neuropathy: Peripheral neuropathy (including all events of peripheral sensory neuropathy and peripheral motor neuropathy) occurred in 14% of patients enrolled in clinical trials. Grade 3 peripheral neuropathy occurred in 1% of patients. Serious peripheral neuropathy events occurred in < 1% of patients, which resulted in dose reduction in < 1% and treatment discontinuation in < 1%. Withhold or discontinue treatment as recommended [see Dosage and Administration]. Herpes Virus Infection: Herpes zoster reactivation was reported in 2% of patients. Consider antiviral prophylaxis for patients who have a history of herpes zoster infection.

DRUG INTERACTIONS: Carfilzomib is primarily metabolized via peptidase and epoxide hydrolase activities, and as a result, the pharmacokinetic profile of carfilzomib is unlikely to be affected by concomitant administration of cytochrome P450 inhibitors and inducers. Carfilzomib is not expected to influence exposure of other drugs [see Clinical Pharmacology section of full PI].

USE IN SPECIFIC POPULATIONS: Pregnancy. Pregnancy Category D [see Warnings and Precautions]. Females of reproductive potential should be advised to avoid becoming pregnant while being treated with KYPROLIS. Based on its mechanism of action and findings in animals, KYPROLIS can cause fetal harm when administered to a pregnant woman. Carfilzomib caused embryo‑fetal toxicity in pregnant rabbits at doses that were lower than in patients receiving the recommended dose. If KYPROLIS is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Carfilzomib was administered intravenously to pregnant rats and rabbits during the period of organogenesis at doses of 0.5, 1, and 2 mg/kg/day in rats and 0.2, 0.4, and 0.8 mg/kg/day in rabbits. Carfilzomib was not teratogenic at any dose tested. In rabbits, there was an increase in pre‑implantation loss at ≥ 0.4 mg/kg/day and an increase in early resorptions and post‑implantation loss and a decrease in fetal weight at the maternally toxic dose of 0.8 mg/kg/day. The doses of 0.4 and 0.8 mg/kg/day in rabbits are approximately 20% and 40%, respectively, of the recommended dose in humans of 27 mg/m2 based on body surface area. Nursing Mothers. It is not known whether KYPROLIS is excreted in human milk. Since many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from KYPROLIS, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use. The safety and effectiveness of KYPROLIS in pediatric patients have not been established.

Geriatric Use. In studies of KYPROLIS there were no clinically significant differences observed in safety and efficacy between patients less than 65 years of age and patients 65 years of age and older. Renal Impairment. The pharmacokinetics and safety of KYPROLIS were evaluated in a Phase 2 trial in patients with normal renal function and those with mild, moderate, and severe renal impairment and patients on chronic dialysis. On average, patients were treated for 5.5 cycles using KYPROLIS doses of 15 mg/m2 on Cycle 1, 20 mg/m2 on Cycle 2, and 27 mg/m2 on Cycles 3 and beyond.

The pharmacokinetics and safety of KYPROLIS were not influenced by the degree of baseline renal impairment, including the patients on dialysis. Since dialysis clearance of KYPROLIS concentrations has not been studied, the drug should be administered after the dialysis procedure [see Clinical Pharmacology section of full PI]. Hepatic Impairment. The safety, efficacy and pharmacokinetics of KYPROLIS have not been evaluated in patients with baseline hepatic impairment. Patients with the following laboratory values were excluded from the KYPROLIS clinical trials: ALT/AST ≥ 3 × upper limit of normal (ULN) and bilirubin ≥ 2 × ULN [see Clinical Pharmacology section of full PI]. Cardiac Impairment. Patients with New York Heart Association Class III and IV heart failure were not eligible for the clinical trials. Safety in this population has not been evaluated.

OVERDOSAGE: There is no known specific antidote for KYPROLIS overdosage. In the event of an overdosage, monitor the patient and provide appropriate supportive care.

NONCLINICAL TOXICOLOGY: Carcinogenesis, Mutagenesis, and Impairment of Fertility.

Carcinogenicity studies have not been conducted with carfilzomib. Carfilzomib was clastogenic in the in vitro chromosomal aberration test in peripheral blood lymphocytes. Carfilzomib was not mutagenic in the in vitro bacterial reverse mutation (Ames) test and was not clastogenic in the in vivo mouse bone marrow micronucleus assay. Fertility studies with carfilzomib have not been conducted. No effects on reproductive tissues were noted during 28‑day repeat‑dose rat and monkey toxicity studies or in 6‑month rat and 9‑month monkey chronic toxicity studies. Animal Toxicology and/ or Pharmacology. Monkeys administered a single bolus intravenous dose of carfilzomib at 3 mg/kg (approximately 1.3 times recommended dose in humans of 27 mg/m2 based on body surface area) experienced hypotension, increased heart rate, and increased serum levels of troponin‑T. The repeated bolus intravenous administration of carfilzomib at ≥ 2 mg/kg/dose in rats and 2 mg/kg/dose in monkeys using dosing schedules similar to those used clinically resulted in mortalities that were due to toxicities occurring in the cardiovascular (cardiac failure, cardiac fibrosis, pericardial fluid accumulation, cardiac hemorrhage/degeneration), gastrointestinal (necrosis/hemorrhage), renal (glomerulonephropathy, tubular necrosis, dysfunction), and pulmonary (hemorrhage/inflammation) systems. The dose of 2 mg/kg/dose in rats is approximately half the recommended dose in humans of 27 mg/m2 based on body surface area. The dose of 2 mg/kg/dose in monkeys is approximately equivalent to the recommended dose in humans based on body surface area.

PATIENT COUNSELING INFORMATION: Discuss the following with patients prior to treatment with KYPROLIS: Instruct patients to contact their physician if they develop any of the following symptoms: fever, chills, rigors, chest pain, cough, or swelling of the feet or legs. Advise patients that KYPROLIS may cause fatigue, dizziness, fainting, and/or drop in blood pressure. Advise patients not to drive or operate machinery if they experience any of these symptoms. Advise patients that they may experience shortness of breath (dyspnea) during treatment with KYPROLIS. This most commonly occurs within a day of dosing. Advise patients to contact their physicians if they experience shortness of breath.

Counsel patients to avoid dehydration, since patients receiving KYPROLIS therapy may experience vomiting and/or diarrhea. Instruct patients to seek medical advice if they experience symptoms of dizziness, lightheadedness, or fainting spells. Counsel females of reproductive potential to use effective contraceptive measures to prevent pregnancy during treatment with KYPROLIS. Advise the patient that if she becomes pregnant during treatment, to contact her physician immediately. Advise patients not to take KYPROLIS treatment while pregnant or breastfeeding. If a patient wishes to restart breastfeeding after treatment, advise her to discuss the appropriate timing with her physician. Advise patients to discuss with their physician any medication they are currently taking prior to starting treatment with KYPROLIS, or prior to starting any new medication(s) during treatment with KYPROLIS.

Manufactured for: Onyx Pharmaceuticals, Inc., 249 East Grand Avenue, South San Francisco, CA 94080 U.S. Patent Numbers: 7,232,818; 7,417,042; 7,491,704; 7,737,112 05-1088-00 ©2012 Onyx Pharmaceuticals, Inc. 1012-CARF-409 September 2012

Perjeta: A New Option for Patients with

HER2-Positive Metastatic Breast Cancer

By Alice Goodman, Medical Writer

B

reast cancer is the most common cancer and the second leading cause of cancer death among women worldwide.1 In the United States, an estimated 39,500 women died of breast cancer in 2011.2

Clinical and Economic Burden of Breast Cancer In 2011, an estimated 230,480 new cases of invasive breast cancer and an additional 57,650 cases of carcinoma in situ were diagnosed in the United States.2 Between 2004 and 2008, the median age of women diagnosed with invasive breast cancer was 61 years.2 Of breast cancer diagnosed between 2001 and 2007, more than 60% of cases were localized, approximately 38% were regional, and approximately 7% were metastatic (stage IV),2 which increases the risk of death.

In patients diagnosed with invasive breast cancer between 2001 and 2007, the estimated 5-year survival was 99% for localized disease, 84% for regional disease, and 23% for metastatic breast cancer.3 In addition to the clinical stage of the disease, molecular markers can provide important prognostic information that can help in selecting treatment. These markers include hormone receptor status (ie, estrogen and progesterone) and HER2 expression. Expression of the estrogen receptor (ER) and progesterone receptor (PR) expression confer a more favorable prognosis; the risk of death is 1.5 to 2 times greater in the absence of ER and PR expression.2 The estimated cost of cancer care for survivors is in the billions of dollars. In 2010, 13.8 million cancer survivors had associated costs of $124.57 billion. In 2020, there will be an estimated 18.1 million cancer survivors, with an estimated price tag of $157.77 billion.4 These figures represent a projected 27% increase in the medical costs of cancer care in the United States from 2010 to 2020. The largest increases are expected in the continuing phase of care for prostate cancer (42%) and female breast cancer (32%).4 In addition to economics, the diagnosis and treatment of breast cancer, especially in the more advanced stages, are associated with quality-of-life and emotional burdens. Patients have to learn how to manage and organize their medical records, be concerned about paying for treatment, adhere to treatment, and they must be prepared to discuss their cancer with family and close

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friends, as well as pay attention to good nutritional principles and incorporate exercise into their daily lives.

HER2-Positive Breast Cancer Overexpression of HER2 (ie, HER2-positive) and triple-negative breast cancer (ie, ER-negative, PR-negative, and HER2-negative status) are associated with a less favorable prognosis. However, the recent availability of HER2-targeted therapies has reversed much of the adverse prognostic impact of HER2 overexpression.2 Approximately 18% to 30% of all breast cancers are HER2-positive, and these tumors have a faster rate of proliferation than tumors that lack overexpression of HER2-neu.5,6 All invasive breast cancers should be tested by gene amplification or protein overexpression assays to identify HER2-positive breast cancers in women who can benefit from HER2-directed therapy.

HER2-Positive Targeted Therapies In 2006, the US Food and Drug Administration (FDA) approved trastuzumab (Herceptin), the first therapy targeted to the HER2-neu receptor. At first, trastuzumabâ&#x20AC;&#x2122;s approval was restricted to the treatment of metastatic breast cancer, but the drug was subsequently found to be effective in early-stage HER2-positive breast cancer. In one of the pivotal studies that led to trastuzumabâ&#x20AC;&#x2122;s approval in the adjuvant setting, trastuzumab reduced the risk of recurrence by 52% and the risk of death by 33% in early-stage HER2-positive breast cancer versus chemotherapy alone.7 In 2010, the FDA approved lapatinib (Tykerb), the second HER2-targeted therapy, which has been shown to be effective in combination with capecitabine for the treatment of HER2-positive advanced breast cancer that has become resistant to trastuzumab.8 The use of lapatinib is limited by its propensity to cause diarrhea, which occurs in approximately 40% of patients who take the drug.9 FDA Approves Perjeta, Third HER2-Targeted Therapy In July 2012, the FDA approved pertuzumab (Perjeta; Genentech), the third HER2-targeted agent for patients with late-stage or metastatic breast cancer who have not received previous therapy for metastatic breast cancer, to be used in combination with the chemotherapy docetaxel.10

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Pertuzumab’s approval was hailed as “an advancement in the treatment of breast cancer that has not been seen since Herceptin was launched over a decade ago.”11 As with trastuzumab, pertuzumab will be studied earlier in the course of breast cancer as adjuvant therapy in the Adjuvant Pertuzumab and Herceptin in Initial Therapy (APHINITY) trial.

Pertuzumab’s Mechanism of Action The mechanism of action of pertuzumab is unique and is different from that of trastuzumab. Trastuzumab binds to subdomain IV of the HER2 extracellular domain and exerts its antitumor effects by blocking HER2 cleavage, stimulating antibody-dependent, cell-medi­ ated cytotoxicity, and inhibiting ligand-independent HER2-mediated mitogenic signaling.12,13 Despite treatment with trastuzumab, most HER2-positive metastatic cancers will progress, which has motivated the development of new targeted therapies, such as pertuzumab.

Pertuzumab is a humanized monoclonal antibody that binds to the HER2 receptor at a different site than trastuzumab. Pertuzumab prevents HER2 from dimerizing (or pairing) with other potential HER receptor partners, including EGFR/HER1, HER3, and HER4, resulting in decreased downstream signaling.14 Pertuzumab and trastuzumab have complementary mechanisms of action, so when these agents are used together, they achieve a more comprehensive blockade of HER2 signaling and greater antitumor activity than either agent alone in experimental models of breast cancer.15 Phase 2 clinical trials of this combination have borne out activity in HER2-positive metastatic breast cancer.16 Dosing and Dose Modification The recommended initial dose of pertuzumab is 840 mg, given as a 60-minute intravenous (IV) infusion, followed every 3 weeks by an IV infusion of 420 mg given over 30 to 90 minutes.13 When trastuzumab is given along with pertuzumab, the recommended initial dose of trastuzumab is 8 mg/kg given as a 90-minute IV infusion, followed every 3 weeks by an IV infusion of 6 mg/kg over 30 to 90 minutes.13 When docetaxel is given along with pertuzumab, the recommended initial dose is an IV infusion of 75 mg/m2.

If the initial dose is well tolerated, the dose of docetaxel may be escalated to 100 mg/m2, given every 3 weeks.13 If the dose of pertuzumab is delayed or missed, and the time between 2 sequential infusions is less than 6 weeks, the 420-mg infusion should be used. Waiting until the next planned dose is not recommended. If the time between 2 sequential infusions is 6 weeks or longer, the initial 840-mg infusion should be readministered as a 60-minute infusion, followed every 3 weeks by an infusion

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elected Baseline Characteristics of the ITT Population Table 1 S of CLEOPATRA Placebo Trastuzumab Characteristic arm, % arm, % Visceral disease

77.8

78.1

ER-positive, PR-positive, or both

49.0

47.0

ER-negative and PR-negative

48.3

52.7

HER2 status 3+ by IHC

91.4

87.1

HER2-positive by FISH

94.3

95.5

CLEOPATRA indicates Clinical Evaluation of Pertuzumab and Trastuzumab; ER, estrogen receptor; FISH, fluorescence in situ hybridization; IHC, immunohistochemistry; ITT, intention-totreat; PR, progesterone receptor.

Source: Baselga J, et al. N Engl J Med. 2012;366:109-119.

of 420 mg over a 30- to 60-minute period. The rate of infusion may be slowed or interrupted if a patient experiences an infusion-related reaction. Discontinue the infusion immediately for any serious hypersensitivity reactions.13 If a patient experiences a decrease in left ventricular ejection fraction (LVEF) to <40% or an LVEF of 40% to 45%, with a ≥10% absolute decrease below baseline values, pertuzumab plus trastuzumab should be withheld for at least 3 weeks. If the LVEF recovers to >45%, or to 40% to 45% associated with an absolute decrease of <10% pretreatment values, pertuzumab may be resumed.13 If the LVEF has not improved over 3 weeks, or declines further, strongly consider discontinuation of per­ tuzumab and trastuzumab.

CLEOPATRA: Phase 3 Clinical Trial The Clinical Evaluation of Pertuzumab and Trastuzumab (CLEOPATRA) phase 3 clinical trial has led to the FDA’s recent approval of pertuzumab in combination with trastuzumab plus docetaxel in the treatment of metastatic breast cancer.16 Trial Design The study was a prospective, randomized, double-­ blind, placebo-controlled trial conducted from February 2008 through July 2010, at 204 centers in 25 countries.

Patients with HER2-positive metastatic breast cancer were randomized in a 1:1 ratio to receive either placebo plus trastuzumab plus docetaxel (control arm) or pertuzumab plus trastuzumab plus docetaxel (experimental arm). Patients were stratified according to geographic region (Asia, Europe, North America, or South America) and previous treatment status (previous adjuvant or neoadjuvant therapy, or no prior therapy).

Progression-free survival (PFS) was the primary end point; this was defined as the time from randomization to

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Table 2 Efficacy in the Randomized Pertuzumab Trial Pertuzumab + Placebo + trastuzumab + trastuzumab + Hazard ratio docetaxel (N = 402) docetaxel (N = 406) (95% CI) P value

Parameter Progression-free survival (independent review) Patients with an event, N Median months, N

191 (47.5%)

242 (59.6%)

18.5

12.4

69 (17.2%)

96 (23.6%)

343

336

275 (80.2%)

233 (69.3%)

19 (5.5%)

14 (4.2%)

256 (74.6%)

219 (65.2%)

20.2

12.5

0.62 (0.51-0.75) <.0001

Overall survival (interim analysis) Patients with an event, N

0.64 (0.47-0.88) .0053a

Objective response rate Patients analyzed, N Objective response (CR + PR), N Complete response, N Partial response, N Median duration of response, months

The HR and P value for the interim analysis of overall survival did not meet the predefined stopping boundary (HR ≤0.603; P ≤.0012).

CI indicates confidence interval; CR, complete response; HR, hazard ratio; PR, partial response.

Source: Pertuzumab (Perjeta) [package insert]. South San Francisco, CA: Genentech, Inc; 2012.

a

the first documented radiographic evidence of progressive disease according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria or death from any cause within 18 weeks after the last assessment of tumors. Secondary end points were overall survival (OS), investigator-­ assessed PFS, the rate of objective response, and safety.16

Patient Population The study enrolled 808 patients with documented locally recurrent, unresectable, or metastatic HER2-positive breast cancer. HER2 status was determined centrally by means of immunohistochemistry or fluorescence in situ hybridization testing. Patients with measurable or and nonmeasurable disease were eligible for the study.

Both treatment groups had comparable demographic and disease characteristics. The median age was 54 years, approximately 32% were Asian, approximately 59% were white, approximately 3% were black, and approximately 5% were other races. Geographic distribution in both arms was similar; approximately 31% were from Asia, 38% from Europe, 17% from North America, and 14% from South America.

Visceral metastases were present in approximately 78% of patients (Table 1). Approximately 48% were ER- or PR-positive, or both; approximately 50% were ER- and PR-negative; and the hormone receptor status of approximately 2% was unknown. Approximately 47% received previous adjuvant or neoadjuvant treatment, with approx-

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imately 40% receiving anthracycline; 25%, hormone therapy; 23%, a taxane; and 11%, trastuzumab.16

Efficacy The PFS was significantly improved in the pertuzumab/­ trastuzumab/docetaxel arm versus the control arm. The results of this trial are shown in Table 2. The median independently assessed PFS was 12.4 months in the control arm versus 18.5 months in the pertuzumab-containing treatment arm, a difference of 6.1 months in favor of the addition of pertuzumab (P <.0001). The improvement in PFS with pertuzumab was observed across all predefined subgroups.16 In 88 patients who were previously treated with adjuvant or neoadjuvant trastuzumab therapy, the median PFS was 10.4 months in the control arm compared with 16.9 months in the pertuzumab arm; among 288 patients previously treated without trastuzumab, median PFS was 12.6 months in the control arm versus 21.6 months in the pertuzumab arm.16 An interim analysis of OS was performed after 165 events occurred; 96 deaths were reported in the control group versus 69 in the pertuzumab arm, a difference that did not meet the prespecified boundary for statistical significance. At a median follow-up of 19.3 months, a strong trend was observed toward a survival benefit with the pertuzumab combination. Both groups were followed up for a median of 19.3 months.16

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Table 3 A dverse Reactions in â&#x2030;Ľ13.5% of Patients (and any Grade 3/4 Reactions): Pertuzumab versus Placebo Body system/ adverse reactions

Pertuzumab + trastuzumab + docetaxel frequency rate (N = 407) All grades, %

Grades 3/4, %

Placebo + trastuzumab + docetaxel frequency rate (N = 397) All grades, %

Grades 3/4, %

General disorders and administration-site conditions Fatigue

37.6

2.2

36.8

3.3

Asthenia

26.0

2.5

30.2

1.5

Peripheral edema

23.1

0.5

30.0

0.8

Mucosal inflammation

27.8

1.5

19.9

1.0

Pyrexia

18.7

1.2

17.9

0.5

Skin and subcutaneous tissue disorders Rash

33.7

0.7

24.2

0.8

Nail disorder

22.9

1.2

22.9

0.3

Diarrhea

66.8

7.9

46.3

5.0

Nausea

42.3

1.2

41.6

0.5

Vomiting

24.1

1.5

23.9

1.5

Stomatitis

18.9

0.5

15.4

0.3

Gastrointestinal disorders

Blood and lymphatic system disorders Neutropenia

52.8

48.9

49.6

45.8

Anemia

23.1

2.5

18.9

3.5

Leukopenia

18.2

12.3

20.4

14.6

Febrile neutropeniaa

13.8

13.0

7.6

7.3

Peripheral neuropathy

32.4

3.2

33.8

2.0

Headache

20.9

1.2

16.9

0.5

Nervous system disorders

Musculoskeletal and connective tissue disorders Myalgia

22.9

1.0

23.9

0.8

Arthralgia

15.5

0.2

16.1

0.8

16.7

0.7

13.4

0.0

14.0

1.0

15.6

2.0

29.2

1.7

26.4

1.5

Infections and infestations Upper respiratory tract infection

Respiratory, thoracic, and mediastinal disorders Dyspnea Metabolism and nutrition disorders Decreased appetite

Reported in association with a fatal outcome.

Source: Pertuzumab (Perjeta) [package insert]. South San Francisco, CA: Genentech, Inc; 2012.

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The objective response rate was 69.3% in the control arm versus 80.2% in the pertuzumab arm.16

Safety Profile Pertuzumab did not appear to add appreciable toxicity to trastuzumab plus docetaxel. The safety profile was generally similar in the 2 treatment arms (Table 3). No increase in left ventricular systolic dysfunction was observed when pertuzumab was included in the treatment. Adverse events that were at least 5% higher in the pertuzumab arm than in the control arm included diarrhea, rash, mucosal inflammation, febrile neutropenia (FN), and dry skin.16 The rates of grade 3 or 4 FN and diarrhea were higher in the pertuzumab arm than in the control arm, with FN occurring in 13.8% versus 7.6% of patients, respectively, and diarrhea in 7.9% versus 5% of patients, respectively.

The incidence of grade 3 or higher FN among Asian patients was 12% for controls and 26% for the pertuzumab arm; in patients from all other geographic regions, the rate of FN was ≤10% in both treatment arms. Most of the deaths were a result of disease progression. The number and causes of other deaths were generally well balanced between the 2 arms. Infections were the most common cause of death resulting from an adverse event.16 Warnings and Precautions Although there are no absolute contraindications to pertuzumab, the FDA approved pertuzumab with a Warning Box regarding the risk of death and severe adverse effect to a fetus associated with this drug. Pertuzumab should not be taken during pregnancy. Before the initiation of pertuzumab, patients should be assessed for pregnancy and should be advised to use contraception during and after treatment with pertuzumab. Women who are inadvertently exposed to pertuzumab during pregnancy should consult the Genentech Adverse Event Line and are encouraged to enroll in the MotHER Pregnancy Registry.13 Although trastuzumab treatment has been reported to lead to decreased LVEF, pertuzumab does not appear to have additive harmful effects on LVEF. When pertuzumab was used in combination with trastuzumab and docetaxel in the CLEOPATRA trial, left ventricular dysfunction was seen in 4.4% versus 8.3% of patients in the placebo arm (ie, placebo plus trastuzumab plus docetaxel); and congestive heart failure was reported in 1% versus 1.8% of patients, respectively. Risk factors for decreased LVEF include previous exposure to anthracyclines or previous radiation to the chest wall.13 Pertuzumab has not been studied in patients with suboptimal pretreatment LVEF values or other conditions associated with impaired LVEF, which include uncontrolled hypertension, recent myocardial infarction, serious

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cardiac arrhythmia, or a cumulative previous exposure to anthracycline >360 mg/m2 doxorubicin or its equivalent.

In patients who are taking pertuzumab, LVEF should be monitored at baseline and then every 3 months to ensure that the LVEF is within normal limits.13 Infusion and hypersensitivity reactions can occur during treatment with pertuzumab. In the CLEOPA­ TRA trial, hypersensitivity or anaphylaxis reactions occurred in 10.8% of patients in the pertuzumab arm versus in 9.1% of those in the placebo arm. Grades 3 and 4 hypersensitivity or anaphylactic reactions were reported in 2% versus 2.5% of patients, respectively.16

Conclusion The availability of increasing numbers of therapeutic options for the treatment of HER2-positive breast cancers provides hope to patients and challenges to clinicians as they determine the optimal use of these agents in combinations and in sequences. The FDA’s approval of pertuzumab for women with HER2 metastatic breast cancer provides an additional therapeutic option for patients, with a new mechanism of action and improved duration of PFS, a welcome addition for this patient population. n References

1. International Agency for Research on Cancer. GLOBOCAN 2008 [cancer fact sheet]. http://globocan.iarc.fr. Accessed September 4, 2012.

2. American Cancer Society. Breast cancer facts and figures 2011-2012. 2011. www. cancer.org/acs/groups/content/@epidemiologysurveilance/documents/document/ acspc-030975.pdf. Accessed September 6, 2012.

3. Howlader N, Noone AM, Krapcho M, et al. SEER cancer statistics review, 19752008. Bethesda, MD: National Cancer Institute; 2011. http://seer.cancer.gov/csr/ 1975_2008/#revision. Accessed September 4, 2012.

4. Mariotto AB, Yabroff KR, Shao Y, et al. Projections of the cost of cancer care in the United States: 2010-2020. J Natl Cancer Inst. 2011;103:117-128.

5. Wolff AC, Hammond ME, Schwartz JN, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. Arch Pathol Lab Med. 2007;131:18-43.

6. Gradishar WJ. HER2 therapy—an abundance of riches. N Engl J Med. 2012;366: 176-178.

7. Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant therapy for operable HER2-positive breast cancer. N Engl J Med. 2005;353:1673-1684.

8. Geyer CE, Forster J, Lindquist D, et al. Lapatinib plus capecitabine for HER-2 positive advanced breast cancer. N Engl J Med. 2006;355:2733-2743.

9. Becze E. Manage diarrhea and skin effects from lapatinib. www.onsconnect. org/2010/06/5min/manage-diarrhea-and-skin-effects-from-lapatinib. June 2010. Accessed September 4, 2012.

10. US Food and Drug Administration. FDA approves Perjeta for type of late-stage breast cancer. June 8, 2012. www.fda.gov/NewsEvents/Newsroom/PressAnnounce ments/ucm307549.htm. Accessed September 25, 2012.

11. BioTrends Research Group. Medical oncologists’ perceptions of newly launched Perjeta are very promising, despite initial concerns of increased cost associated with combining two premium-priced monoclonal antibodies to treat HER2-positive breast cancer [press release]. September 5, 2012. http://finance.yahoo.com/news/medical-­ oncologists-perceptions-newly-launched-133000945.html. Accessed September 6, 2012.

12. Junttila TT, Akita RW, Parsons K, et al. Ligand-independent HER2/HER3/ P13K complex is disrupted by trastuzumab and is effectively inhibited by the P13K inhibitor GDC-0941. Cancer Cell. 2009;15:429-440.

13. Pertuzumab (Perjeta) [package insert]. South San Francisco, CA: Genentech, Inc; 2012.

14. Agus DB, Akita RW, Fox WD, et al. Targeting ligand-activated Erb2 signaling inhibits breast and prostate tumor growth. Cancer Cell. 2002;2:127-137.

15. Lee-Hoeflich ST, Crocker L, Yao E, et al. A central role for HER3 in HER2-amplified breast cancer: implications for targeted therapy. Cancer Res. 2008;68:5878-5887.

16. Baselga J, Cortés J, Kim SB, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012;366:109-119.

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Vol 6, No 3

Iclusig: A New Treatment Option for Adults with CML or Ph+ ALL that Is Resistant/ Intolerant to Previous Therapy with TKIs

By Lynne Lederman, PhD, Medical Writer

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eukemias are cancers involving the bone marrow and blood, and they account for approximately 4% of cancer deaths.1 The majority of leukemias occur in adults aged >20 years, and the incidence is higher in men than in women. Leukemias are classified by the type of cell involved (ie, lymphocytic or myeloid) and the rate of progression (ie, acute or chronic). Chronic myeloid leukemia (CML) and acute lymphocytic leukemia (ALL) account for approximately 2.5% and 6%, respectively, of deaths resulting from leukemia.1 CML arises from the unregulated production of white blood cells in the bone marrow that results from a constitutively active tyrosine kinase that is the fusion product of the Abelson murine leukemia (ABL) gene on chromosome 9 and the breakpoint cluster region (BCR) gene on chromosome 22 after a reciprocal translocation be­ tween these chromosomes forms the Philadelphia chromosome (Ph). A related fusion protein occurs in a subset of cases of ALL (ie, Ph-positive [Ph+] ALL).2-4

The Burden and Impact of CML and ALL The American Cancer Society estimates that almost 6000 new cases each of CML and ALL will be diagnosed in 2013 in the United States, and 610 deaths will result from CML and 1430 deaths from ALL.1 Leukemia is often associated with bleeding, bruising, weight loss, and infections. In acute leukemia, these symptoms may appear suddenly; in chronic leukemia, there may be few symptoms that pro­gress slowly.1 The 5-year survival rate for CML increased from 31% for patients diagnosed during 1990-1992 to 56% for those diagnosed during 2002-2008.1 The increase in survival for patients with CML is mainly the result of the development of targeted therapies,1 known as the BCRABL–specific tyrosine kinase inhibitors (TKIs).5 The 5-year relative survival rate for ALL overall has increased from 41% during the 1975-1977 period to 68% in the 2002-2008 period.1 The prognosis for Ph+ ALL is worse than that for other subtypes of ALL.4 The current treatment options for CML include the TKIs imatinib (Gleevec) and nilotinib (Tasigna), which are specific BCR-ABL TKIs; and dasatinib (Sprycel) and bosutinib (Bosulif), which inhibit both ABL and Src

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kinases.3 These agents may be used as a part of combination therapy for patients with Ph+ ALL.4 Although many patients with CML who receive imatinib have a complete cytogenetic response, 25% of patients have disease that either does not respond initially to imatinib (primary resistance) or that progresses after initial response (secondary resistance).

Secondary resistance may be caused by a mutation in the ABL kinase domain known as the T315I (or gatekeeper) mutation, because it prevents imatinib, dasatinib, and bosutinib from entering the ATP-binding pocket and inhibiting the kinase. Resistance to imatinib and other TKIs is associated with many other mutations and other as-yet unidentified causes. However, the presence of a kinase-domain mutation is associated with a high risk for disease progression.3,6 Patients may also develop intolerance to approved TKIs.3 Therefore, there remains a need for new agents that are effective in patients with resistant disease.

Ponatinib Fills an Unmet Need On December 14, 2012, the US Food and Drug Administration (FDA) granted accelerated approval to ponatinib (Iclusig; ARIAD Pharmaceuticals) based on the results from a phase 2 clinical trial. Ponatinib is indicated for the treatment of adult patients with chronic-phase (CP), accelerated-phase (AP), or blast-phase (BP) CML that is resistant to or is intolerant of previous TKI therapy or for patients with Ph+ ALL that is resistant to or intolerant of previous TKI therapy.7 Ponatinib offers a new treatment option for patients with CML, especially those with the T315I mutation, whose disease is not responding to other agents. According to the FDA, these patients have had few therapeutic options. This approval provides patients with earlier access to ponatinib, while the manufacturer conducts additional studies to confirm the clinical benefit and the safe use of this new agent.8 The prescribing information for ponatinib states that the indication was based on the response rate to the drug, and that no trials have confirmed an improvement in disease-related symptoms or increased survival with this drug.

Mechanism of Action Ponatinib is a TKI that was designed to inhibit the

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aseline Demographics and Disease Characteristics Table 1 B in the Phase 2 Pivotal Trial Efficacy population Characteristic (N = 444) 59 (18-94) Median age, yrs (range)

236 (53) Men, N (%)

108 (47) Women, N (%) 409 (92) ECOG performance status 0 or 1, N (%) 6.1 (0.3-28.5) Median time from diagnosis to first dose, yrs (range) 374 (88) Resistant to previous TKI therapy, N (%) 244 (55) Presence of ≥1 BCR-ABL kinase-domain mutations, N (%) Use of previously approved TKIs, N (%) 29 (7) 1 166 (37) 2 249 (56) ≥3 ECOG indicates Eastern Cooperative Oncology Group; TKI, tyrosine kinase inhibitor.

Source: Iclusig (ponatinib) tablets for oral use [prescribing information]. Cambridge, MA: ARIAD Pharma­ceu­ticals, Inc; December 2012.

BCR-ABL genetic mutations, including drug-resistant mutations that arise during treatment.9 Ponatinib is the only TKI that is active against the T315I mutation of BCR-ABL,7 which is the most frequent mutation, occurring in up to 20% of patients with TKI resistance.2 In vitro, ponatinib inhibited the tyrosine kinase activity of ABL and T315I-mutant ABL, as well as that of additional kinases, including members of the vascular endothelial growth factor receptors, platelet-derived growth factor receptors, fibroblast growth factor receptors, and ephrin receptors; the Src families of kinases; and KIT, RET, TIE2, and FLT3.9,10

Dosing and Administration Ponatinib is administered orally once daily at a recommended dose of 45 mg.9 Dose modification. Dose modifications are suggested if patients experience neutropenia or thrombocytopenia that is unrelated to their leukemia. The dose of ponatinib should be modified or the treatment should be interrupted if serious nonhematologic reactions occur. Treatment may be resumed once the event has resolved, or if the benefit of resuming therapy outweighs the risk; in patients with serious ischemic reactions, in addition to considering the risk-benefit ratio, ponatinib should be resumed only if the patient has no other treatment options.9

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Use with CYP3A inhibitors. The recommended dose should be reduced to 30 mg once daily when administering ponatinib with strong cytochrome (CY) P3A inhibitors.9 Phase 2 Pivotal Clinical Trial Ponatinib was approved on the basis of the pivotal phase 2 Ponatinib Ph+ ALL and CML Evaluation (PACE) trial in patients with CML or Ph+ ALL whose disease was resistant to or intolerant of previous TKI therapy, or whose leukemia had the T315I mutation of BCR-ABL.7,9,11,12 The phase 2 PACE trial was a single-arm, open-label, international, multicenter trial. The starting dose for all patients was 45 mg of ponatinib once daily. A total of 449 patients were enrolled, of whom 444 were evaluable for efficacy. Patients were assigned to 1 of 6 cohorts based on disease phase, resistance or intolerance to previous TKI therapy (ie, dasatinib or nilotinib), and the presence of the T315I mutation. Disease phases included CP-CML, AP-CML, and BP-CML/Ph+ ALL.9,11,12 The primary efficacy end point in CP-CML was major cytogenetic response, which includ­­­ ed complete and partial cytogenetic responses. The primary efficacy end point in patients with AP-CML, BP-CML, and Ph+ ALL was major hematologic response, defined as a complete hematologic response or no evidence of leukemia.9 Patient Population The study included 267 patients with CP-CML (resistant or intolerant cohort, N = 203; T315I mutation cohort, N = 64), 83 patients with AP-CML, 62 patients with BP-CML, and 32 patients with Ph+ ALL.9 Key baseline demographic and disease characteristics of the evaluable patients are listed in Table 1.

Safety Profile At the time of the safety analysis, the median duration of treatment with ponatinib was 337 days in patients with CP-CML, 362 days in patients with AP-CML, 89 days in patients with BP-CML, and 81 days in patients with Ph+ ALL. The median dose intensity was 37 mg, or 83% of the expected 45-mg dose. Overall, the most frequent non­ hematologic adverse reactions (≥20%) were hypertension, rash, abdominal pain, fatigue, headache, dry skin, constipation, arthralgia, nausea, and pyrexia. Hematologic adverse reactions included thrombocytopenia, anemia, neutropenia, lymphopenia, and leukopenia.9 The rates of treatment-emergent adverse events (AEs) resulting in discontinuation were 13% in the patients with CP-CML, 11% in AP-CML, 15% in BP-CML, and 9% in the patients with Ph+ ALL. The most frequent AEs that led to treatment discontinuation were thrombocytopenia (4%) and infections (1%).

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Table 2 E fficacy of Ponatinib in Patients with Resistant or Intolerant Chronic-Phase CML Cohort Patients with resistant/ Patients with T315I intolerant disease mutation (N = 203) (N = 64)

Total patients Cytogenetic response (N = 267) a 54 (48-60) 49 (42-56) 70 (58-81) MCyR, % (95% CI) 44 (38-50) 37 (31-44) 66 (53-77) CCyR, % (95% CI) 84 (49-334) Median time to MCyR, days (range) Median duration of MCyR Not reached a The primary end point for chronic-phase CML cohorts was MCyR, which combines complete and partial cytogenetic responses.

CCyR indicates complete cytogenetic response; CI, confidence interval; CML, chronic myeloid leukemia; MCyR, major cytogenetic response; Ph+, Philadelphia chromosome–positive.

Source: Iclusig (ponatinib) tablets for oral use [prescribing information]. Cambridge, MA: ARIAD Pharma­ceu­ticals, Inc; December 2012.

Dose modifications (delays or reduction) resulting from adverse reactions occurred in 74% of the patients. The most common adverse reactions (≥5%) that led to dose modifications include thrombocytopenia (30%), neutropenia (13%), increases in lipase (12%), rash (11%), abdominal pain (11%), pancreatitis (6%), and alanine aminotransferase, aspartate aminotransferase, or an increase in gamma-glutamyl transferase (6%). Myelo­suppression occurred in all patient populations.

The frequencies of grade 3 or 4 thrombocytopenia, neutropenia, and anemia were higher in patients with APCML, BP-CML, and Ph+ ALL (47%, 57%, and 47%, respectively) than in patients with CP-CML (36%). Patients with Ph+ ALL had the highest rates of grades 3 and 4 neutropenia and leukopenia (63%); patients with BPCML had the highest rates of grades 3 and 4 anemia (55%) and lymphopenia (37%).9

Response At the time of the analysis for response, the median follow-up was 10 months (with a minimum of 6 months of follow-up for all ongoing patients). The median duration of ponatinib treatment was 281 days in patients with CP-CML, 286 days in patients with AP-CML, 89 days in patients with BP-CML, and 81 days in patients with Ph+ ALL.9 The efficacy results for patients with CP-CML are summarized in Table 2.

The efficacy results for patients with AP-CML, BPCML, and Ph+ ALL are summarized in Table 3.

Warnings and Precautions The ponatinib prescribing information contains a Boxed Warning about arterial thrombosis and hepatotoxicity, advising clinicians about the potential for the following serious events9:

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Efficacy of Ponatinib in Patients with Resistant or Table 3 Intolerant Advanced Disease (Including Resistant/ Intolerant and T315I Mutation Cohorts) AP-CML BP-CML Ph+ ALL Hematologic response (N = 83) (N = 62) (N = 32) 52 (41-63) 31 (20-44) 41 (24-59) Major response,a % (95% CI) 47 (33-55) 21 (12-33) 34 (19-53) Complete response,b % (95% CI) 21 (12-176) 29 (12-113) 20 (11-168) Median time to major response, days (range) 9.5 (1.1-17.7) 4.7 3.2 Median time of major (1.8-14.1+) (1.8-8.8+) response, months (range) a Primary end point for patients with AP-CML, BP-CML, and Ph+ ALL was major hematologic response, which combines complete hematologic responses and no evidence of leukemia. b Complete hematologic response.

ALL indicates acute lymphocytic leukemia; AP, accelerated phase; BP, blast phase; CI, confidence interval; CML, chronic myeloid leukemia; Ph+, Philadelphia chromosome–positive.

Source: Iclusig (ponatinib) tablets for oral use [prescribing information]. Cambridge, MA: ARIAD Pharma­ceu­ticals, Inc; December 2012.

• Arterial thrombosis. Cardiovas­cular, cerebrovascular, and peripheral vascular thrombosis, including fatal myocardial infarction and stroke, have occurred in patients receiving ponatinib. In clinical trials, serious arterial thrombosis occurred in 8% of patients receiving ponatinib. In patients receiving ponatinib who develop arterial thrombotic events, ponatinib should be interrupted and discontinuation should be considered.

• Hepatotoxicity. Hepatotoxicity, liver failure, and death have occurred in patients receiving ponatinib. Hepatic

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Table 4 Summary of Ponatinib Warnings and Precautions Potential adverse reactions

Description/events reporteda

Thrombosis/ thromboembolism

CV, cerebrovascular, and peripheral vascular thrombosis; serious arterial thrombosis, 8%; MI, 5%; VTE, 3%; serious cerebral vascular or peripheral arterial events, 2% each Other CV events Congestive heart failure: any grade, 7%; serious, 4% Cardiac arrhythmias: includes bradyarrhythmias (1% required pacemaker implantation; tachyarrhythmias) Hypertension: overall, 67%; serious requiring urgent intervention, 2% Fluid retention: overall, 23%; serious, 3%; 1 fatal brain edema Hepatotoxicity Fatal in 3 patients; AST or ALT elevation, 56% (8% grades 3 or 4) Pancreatitis Clinical, 6%; grade 3, 5%; lipase elevation, 41% Hemorrhage Overall, 24%; serious events including fatal events, 5%; most common with grade 4 thrombocytopenia Myelosuppression Severe, 48% Tumor lysis syndrome Serious in 2 patients (<1%); serious hyperuricemia, 7% Compromised wound healing No formal studies, but could occur Gastrointestinal perforation 1 patient with fistula 38 days postcholecystectomy Embryo-fetal toxicity Can cause fetal harm based on method of operation and animal studies a Percentage refers to proportion of patients in the pivotal trial (N = 444).

ALT indicates alanine aminotransferase; AST, aspartate aminotransferase; CV, cardiovascular; MI, myocardial infarction; VTE, venous thromboembolism.

Source: Iclusig (ponatinib) tablets for oral use [prescribing information]. Cambridge, MA: ARIAD Pharma­ceu­ticals, Inc; December 2012. function should be monitored before and during treatment. For hepatotoxicity, ponatinib should be interrupted and then reduced or discontinued.

Other AEs are summarized in Table 4.

Conclusion Ponatinib is now being further investigated in a phase 3 randomized clinical trial that is comparing ponatinib with imatinib in patients with newly diagnosed CPCML.13 As the second-generation BCR-ABL inhibitors are replacing imatinib in the treatment of newly diagnosed CML, the aim of this trial is to determine if ponatinib is effective in this patient population, and if it has the ability to prevent the emergence of resistant mutations that occur with other TKIs.10,13 A recent commentary by J.M. Goldman regarding the multikinase activity of ponatinib, as well as the preliminary results in patients with CML that is resistant to imatinib and second-generation TKIs, suggest that ponatinib may be “another step forward in the march toward real success with molecularly targeted therapy for cancer.”6 n References

1. American Cancer Society. Cancer Facts & Figures 2013. Atlanta, GA: American Cancer Society; 2013.

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2. Cortez JE, Kantarjian H, Shah NP, et al. Ponatinib in refractory Philadelphia chromosome-positive leukemias. N Engl J Med. 2012;367:2075-2088.

3. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Chronic myelogenous leukemia. Version 3.2013. NCCN.org. Accessed December 19, 2012.

4. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Acute lymphoblastic leukemia. Version 2.2012. NCCN.org. Accessed January 9, 2013.

5. Carella AM, Goldman JM, Martinelli G, et al. Chronic myeloid leukemia: the basis of treatment for tomorrow. Haematologica. 2011;96:1737-1739.

6. Goldman JM. Ponatinib for chronic myeloid leukemia. N Engl J Med. 2012;367: 2148-2149.

7. ARIAD Pharmaceuticals. ARIAD announces accelerated approval by FDA of Iclusig (ponatinib) for patients with CML and Ph+ ALL resistant or intolerant to prior tyrosine kinase inhibitor therapy. December 14, 2012. http://phx.corporate-ir.net/ phoenix.zhtml?c=118422&p=irol-newsArticle_print&ID=1767523&highlight=.

Accessed January 17, 2013.

8. FDA News Release. FDA approves Iclusig to treat two rare types of leukemia. www. fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm332252.htm. Accessed January 17, 2013.

9. Iclusig (ponatinib) tablets for oral use [prescribing information]. Cambridge, MA: ARIAD Pharma­ceu­ticals, Inc; December 2012.

10. O’Hare T, Shakespeare WC, Zhu X, et al. AP24535, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell. 2009;16:401-412.

11. Cortes JE, Kim DW, Pinilla-Ibarz J, et al. PACE: a pivotal phase II trial of ponatinib in patients with CML and Ph+ALL resistant or intolerant to dasatinib or nilotinib, or with the T315I mutation. J Clin Oncol. 2012;30(suppl):Abstract 6503.

12. Cortes J, Kim DW, Pinilla J, et al. PACE: a pivotal phase 2 trial of ponatinib in patients with CML and Ph+ALL resistant or intolerant to dasatinib or nilotinib, or with the T315I mutation. Haematologica. 2012;97(suppl 1):453.

13. ARIAD EPIC PR. ARIAD announced initiation of randomized phase 3 trial of ponatinib in newly diagnosed patients with chronic myeloid leukemia. http://phx. corporate-ir.net/phoenix.zhtml?c=118422&p=irol-newsArticle&ID=1719432 &highlight=. Accessed January 17, 2013.

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Vol 6, No 3

Qsymia: Combination Oral Therapy a

New Weight-Loss Option for Obese or Overweight Patients

By Loretta Fala, Medical Writer

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besity has reached epidemic proportions in the United States.1 Obesity, which is defined as a body mass index (BMI) of ≥30 kg/m2, affects an estimated 78.1 million Americans—more than 35% of all men and women.2,3 Moreover, more than 34% of adults aged ≥20 years are overweight, which is defined as a BMI of ≥25 kg/m2.3

Clinical and Economic Implications of Obesity Obesity is associated with clinically serious and costly consequences, including an increased risk for developing type 2 diabetes, cardiovascular (CV) disease, hypertension, sleep apnea, stroke, dyslipidemia, osteoporosis, and some types of cancer (ie, breast, colon, and endometrial).1,3 Furthermore, obesity is associated with social stigma, discrimination, reduced life expectancy, and a reduced quality of life.1,3 The costs associated with obesity and overweight are staggering. The annual medical burden of obesity has climbed to nearly 10% of all medical spending in the United States, with an annual total of $147 billion.4,5 Moreover, medical costs per person are $1429 higher for obese individuals compared with normal-weight individuals, according to the Centers for Disease Control and Prevention.4 Weight loss achieved by medically recommended approaches is associated with reduced comorbidities in patients with obesity.6 A weight loss of 5% to <10% of an overweight or obese person’s initial body weight can lead to significant improvements in cardio­metabolic health at 1 year, including improved glycemic control, reduced blood pressure (BP), and improved high-density lipoprotein cholesterol and triglyceride levels in those with type 2 diabetes.7 These benefits can be even greater with a weight loss of 10% to 15% of body weight.7 Lifestyle changes may be particularly challenging for patients with physical restrictions that limit their activity, or for those whom the benefit of a multidisciplinary healthcare team is not available.8 Effective, long-term pharmacologic therapies—in conjunction with lifestyle modifications—may provide appropriate patients with a viable option for weight management and improved outcomes.8

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Qsymia Receives FDA Approval On July 17, 2012, the US Food and Drug Administration (FDA) approved the combination of phentermine/ topir­amate extended-release (ER [Qsymia; Vivus]) as an adjunct to a reduced-calorie diet and physical activity for chronic weight management in adults with an initial BMI of ≥30 kg/m2 (ie, obese) or ≥27 kg/m2 (ie, overweight) in the presence of at least 1 weight-related comorbidity, such as hypertension, type 2 diabetes, or dyslipidemia.9 Phentermine and topiramate are each approved by the FDA as a monotherapy, with different indications.

The FDA has required a Risk Evaluation and Mitigation Strategy (REMS) program for phentermine/topiramate ER to manage the known or potential serious risks that are associated with this new combination therapy.

The purpose of this REMS is to inform prescribers and females of reproductive potential about several factors, including the increased risk of congenital malformation, specifically orofacial clefts, in infants exposed to the drug during the first trimester of pregnancy; the importance of pregnancy prevention for women of reproductive potential who are receiving the drug; and the need to discontinue use if pregnancy occurs.10,11 Dosing Phentermine/topiramate ER is dosed orally once daily in the morning, with or without food. Evening dosing should be avoided, because of the possibility of insomnia.

The recommended starting dose is phentermine/topiramate ER 3.75 mg/23 mg daily for 14 days; after 14 days, it is recommended that the dose be increased to phentermine/topiramate ER 7.5 mg/46 mg once daily.10 If a patient has not lost at least 3% of baseline body weight after 12 weeks of treatment with phentermine/ topiramate ER 7.5 mg/46 mg, this dose should be discontinued or escalated. If a patient has not lost at least 5% of baseline body weight after an additional 12 weeks of treatment at the escalated dose of phentermine/topiramate ER 15 mg/92 mg, the patient should discontinue use gradually by taking a dose every other day for at least 1 week before stopping treatment altogether to reduce the possibility of precipitating a seizure.10

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Phentermine/topiramate ER capsules are available in 3.75-mg/23-mg, 7.5-mg/46-mg, 11.25-mg/69-mg, and 15-mg/92-mg dosage strengths. The 3.75-mg/23-mg and the 11.25-mg/69-mg dosages are used for titration purposes only.10

Clinical Pharmacology Mechanism of Action Phentermine is a sympathomimetic amine with pharmacologic activity similar to the prototype drugs of this class that are used to treat obesity, amphetamines (dextroamphetamine and dextroamphetamine/levoamphetamine), which are known as “anorectics” or “anorexigenics.” Although the exact mechanism of action is not known, the effect of phentermine on chronic weight management is likely mediated by the release of catecholamines in the hypothalamus, resulting in reduced appetite and decreased food consumption; other meta­ bolic effects may also be involved.10 The precise mechanism of action of topiramate on chronic weight management is not known. The effect of topir­amate on chronic weight management may be a result of its effects on both appetite suppression and on satiety enhancement, which are induced by a combination of pharmacologic effects, including the augmentation of the activity of the neurotransmitter gamma-aminobutyrate, the modulation of voltage-gated ion channels, the inhibition of AMPA/kainite excitatory glutamate receptors, or the inhibition of carbonic anhydrase.10 Pharmacodynamics Typical actions of amphetamines include central nervous system stimulation and the elevation of BP. Tachyphylaxis and tolerance have been demonstrated with all drugs of this class in which these phenomena have been assessed.10 Cardiac electrophysiology. The effect of phentermine/ topiramate ER on the corrected QT (QTc) interval was evaluated in a randomized, double-blind, placebo- and active (400 mg moxifloxacin)-controlled, parallel-group, crossover study. A total of 54 healthy subjects were ad­ ministered phentermine/topiramate ER 7.5 mg/46 mg at steady state and then titrated to phentermine/topiramate ER 22.5 mg/138 mg at steady state. Phentermine/topira­ mate ER 22.5 mg/138 mg—a supra­thera­peutic dose resulting in phentermine/topiramate ER maximum concentrations (Cmax) of 4 times and 3 times higher than those at the phentermine/topiramate ER 7.5-mg/46-mg dose, respectively—did not affect cardiac repolarization, as measured by the change from baseline in QTc.10 Pharmacokinetics Phentermine. On oral administration of a single phentermine/topiramate ER 15 mg/92 mg, the resulting mean

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plasma phentermine Cmax, time to Cmax (Tmax), area under the concentration curve (AUC) from time zero to the last time with measurable concentration (AUC0-t), and AUC from time zero to infinity (AUC0-∞) are 49.1 ng/mL, 6 hours, 1990 ng•hr/mL, and 2000 ng•hr/mL, respectively.

A high-fat meal does not affect phentermine’s pharmacokinetics for phentermine/topiramate ER 15 mg/92 mg.10 Topiramate. On oral administration of a single phentermine/topiramate ER 15 mg/92 mg, the resulting mean plasma topiramate Cmax, Tmax, AUC0-t, and AUC0-∞ are 1020 ng/mL, 9 hours, 61,600 ng•hr/mL, and 68,000 ng•hr/mL, respectively. A high-fat meal does not affect topiramate’s pharmacokinetics for phentermine/topiramate ER 15 mg/92 mg.10

Clinical Trials The FDA approval of phentermine/topiramate ER was based on 2 randomized, double-blind, placebo-controlled studies—EQUIP and CONQUER—that evaluated its effect on weight loss in conjunction with reduced caloric intake and increased physical activity in obese patients (the EQUIP trial) and in obese and overweight patients with ≥2 significant comorbidities (the CONQUER trial).6,10,12 Both studies had a 4-week titration period, followed by 52 weeks of treatment. In addition, both studies measured 2 coprimary efficacy outcomes after 1 year of treatment (week 56), including the percent weight loss from baseline and treatment response, which was defined as achieving at least 5% weight loss from baseline.10 EQUIP In the EQUIP trial, obese patients (BMI ≥35 kg/m2) were randomized to receive 1 year of treatment with placebo, phentermine/topiramate ER 3.75 mg/23 mg, or phentermine/to­piramate ER 15 mg/92 mg, in a 2:1:2 ratio.6 Patients with type 2 diabetes were excluded from this study. A well-balanced, reduced-calorie diet (approximate 500-kcal daily decrease in caloric intake) was recommended to all patients, and they were offered nutritional and lifestyle modification counseling.6,10 After 1 year of treatment with phentermine/topiramate ER, all dose levels resulted in a significant weight loss compared with placebo (Table 1).6,10 Before week 56, 40% of randomized patients withdrew from the study. The most common adverse events (AEs) were paresthesia, dry mouth, constipation, dysgeusia, and insomnia.6,10 CONQUER In the CONQUER trial, overweight and obese patients were randomized to receive 1 year of treatment with placebo, phentermine/topiramate ER 7.5 mg/46 mg,

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Table 1 EQUIP Trial: Weight Loss at 1 Year in Obese Patients (ITT-LOCF Population)

Analysis method, weight (kg) LS mean change from baseline, % (SE)a

Placebo (N = 498)

Phentermine/topiramate ER, 3.75 mg/23 mg (N = 234)

Phentermine/topiramate ER, 15 mg/92 mg (N = 498)

−1.6 (0.4)

−5.1 (0.5)b

−10.9 (0.4)c

3.5 (2.4-4.7)

9.4 (8.4-10.3)

45

67c

27.6 (20.4-34.8)

49.4 (44.1-54.7)

19

47c

11.4 (5.9-16.9)

39.8 (34.8-44.7)

Difference from placebo (95% CI) Patients losing ≥5% body weight, %

17

b

Risk difference vs placebo (95% CI) Patients losing ≥10% body weight, %

7

b

Risk difference vs placebo (95% CI)

Adjusted for baseline body weight.

P <.001 versus placebo based on LS mean from an analysis of covariance. c P <.01 versus 3.75-mg/23-mg dose.

Type 1 error was controlled across all pairwise treatment comparisons.

CI indicates confidence interval; ER, extended release; ITT-LOCF, intent-to-treat/last-observation-carried-forward; LS, least squares; SE, standard error.

Sources: References 6, 10. a

b

Table 2 CONQUER Trial: Weight Loss at 1 Year in Overweight and Obese Patients with Comorbidities (ITT-LOCF Population)

Analysis method, weight (kg) LS mean change from baseline, % (SE)a

Placebo (N = 979)

Phentermine/topiramate ER, 7.5 mg/46 mg (N = 488)

Phentermine/topiramate ER, 15 mg/92 mg (N = 981)

−1.2 (0.3)

−7.8 (0.4)b

−9.8 (0.3)c

6.6 (5.8-7.4)

8.6 (8.0-9.3)

62

70c

41.3 (36.3-46.3)

49.2 (45.4-53.0)

37

48c

29.9 (25.3-34.5)

40.3 (36.7-43.8)

Difference from placebo (95% CI) Patients losing ≥5% body weight, %

21

b

Risk difference vs placebo (95% CI) Patients losing ≥10% body weight, %

7

b

Risk difference vs placebo (95% CI)

Adjusted for baseline body weight and diabetic status.

P <.001 versus placebo based on LS mean from an analysis of covariance. c P <.01 versus 7.5-mg/46-mg dose.

Type 1 error was controlled across all pairwise treatment comparisons.

CI indicates confidence interval; ER, extended release; ITT-LOCF, intent-to-treat/last-observation-carried-forward; LS, least squares; SE, standard error. a

b

Sources: References 10, 12. or phentermine/topiramate 15 mg/92 mg, in a 2:1:2 ratio.12 Eligible patients had to have a BMI ≥27 kg/m2 and ≤45 kg/m2 (no lower limit on BMI for patients with type 2 diabetes) and ≥2 obesity-related comorbidities, including elevated BP (≥140/90 mm Hg, or ≥130/85 mm Hg for diabetic patients) or a requirement for ≥2 antihypertensive medications; triglycerides ≥200 to 400 mg/dL or receiving treatment with ≥2 lipid-lowering agents; elevated fasting blood glucose (>100 mg/dL) or diabetes; and/or a waist circumference of ≥102 cm for men and ≥88 cm for women.10,12

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At the start of the study, 53% of the patients had hypertension and 16% had type 2 diabetes. Patients were advised to maintain a well-balanced, reduced-calorie diet (500-kcal daily decrease in caloric intake), and all were offered nutritional and lifestyle modification counseling.10,12 Treatment with all doses of phentermine/topiramate ER after 1 year showed significant weight loss compared with placebo (Table 2).10,12 Moreover, 1 year of therapy with phen­ termine/topiramate ER resulted in relative improvements compared with placebo in obesity-related

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ONQUER Trial: Mean Changea from Baseline in Cardiometabolic Comorbidities in Overweight and Obese Table 3 C Patients with Phentermine/Topiramate ER versus Placebo, at 1 Year Phentermine/topiramate Phentermine/topiramate Cardiometabolic Placebo ER, 7.5 mg/46 mg ER, 15 mg/92 mg comorbiditiesb (N = 979) (N = 488) (N = 981) Heart rate, bpm Baseline mean (SD) LS mean change (SE)

72.1 (9.9) –0.3 (0.3)

72.2 (10.1) +0.3 (0.4)

72.6 (10.1) +1.4 (0.3)

Systolic BP, mm Hg Baseline mean (SD) LS mean change (SE)

128.9 (13.5) –2.4 (0.48)

128.5 (13.6) –4.7 (0.63)

127.9 (13.4) –5.6 (0.5)

Diastolic BP, mm Hg Baseline mean (SD) LS mean change (SE)

81.1 (9.2) –2.7 (0.3)

80.6 (8.7) –3.4 (0.4)

80.2 (9.1) –3.8 (0.3)

Total cholesterol, % Baseline mean (SD) LS mean change (SE)

205.8 (41.7) –3.3 (0.5)

201.0 (37.9) –4.9 (0.7)

205.4 (40.4) –6.3 (0.5)

LDL-C, % Baseline mean (SD) LS mean change (SE)

124.2 (36.2) –4.1 (0.9)

120.3 (33.7) –3.7 (1.1)

123.9 (35.6) –6.9 (0.9)

HDL-C, % Baseline mean (SD) LS mean change (SE)

48.9 (13.8) +1.2 (0.7)

48.5 (12.8) +5.2 (0.9)

49.1 (13.8) +6.8 (0.7)

Triglycerides, % Baseline mean (SD) LS mean change (SE)

163.5 (76.3) +4.7 (1.7)

161.1 (72.2) –8.6 (2.2)

161.9 (73.4) –10.6 (1.7)

Fasting insulin, µIU/mL Baseline mean (SD) LS mean change (SE)

17.8 (13.2) +0.7 (0.8)

18.0 (12.9) –3.5 (1.1)

18.4 (17.5) –4.0 (0.8)

Fasting glucose, mg/dL Baseline mean (SD) LS mean change (SE)

106.6 (23.7) +2.3 (0.6)

106.2 (21.0) –0.1 (0.8)

105.7 (21.4) –1.3 (0.6)

Waist circumference, cm Baseline mean (SD) LS mean change (SE)

113.4 (12.2) –2.4 (0.3)

112.7 (12.4) –7.6 (0.4)

113.2 (12.2) –9.2 (0.3)

Adjusted for baseline body weight and diabetic status.

Among the 388 patients with diabetes in this trial, HbA1c reductions from 6.8% baseline were 0.1% with placebo versus 0.4% with phentermine/topiramate ER, in both dosage strengths.

BP indicates blood pressure; bpm, beats per minute; ER, extended release: HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; LS, least squares; SD, standard deviation; SE, standard error.

Source: Reference 10.

a

b

cardiometabolic risk factors, with the exception of heart rate (Table 3).10 The most common AEs were dry mouth, paresthesia, constipation, insomnia, dizziness, and dysgeusia.12

A Recent Trial: SEQUEL Results of a third trial were published in 2012.8 The SEQUEL trial was a double-blind, placebo-controlled extension of the CONQUER trial that assessed the long­

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er-term safety and efficacy of 2 doses of phentermine/ topiramate ER, in conjunction with lifestyle modification, for an additional 52 weeks (total of 108 weeks’ treatment duration).8 At 108 weeks, phentermine/topiramate ER showed significant, sustained weight loss in the intent-to-treat/ last-observation-carried-forward population compared with placebo (P <.001); and significantly more patients achieved ≥5%, ≥10%, ≥15%, and ≥20% weight loss

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compared with placebo (P <.001).8 Phentermine/topiramate ER was also associated with sustained improvements in the clinical manifestations of weight-related cardiometabolic comorbidities, including hyper­glycemia, dyslipidemia, and elevated BP.8 The most common AEs were upper respiratory tract infection, constipation, paresthesia, sinusitis, and dry mouth.8

Safety Profile and Metabolic Properties The effect of phentermine/topiramate ER on CV morbidity and mortality has not been established. The safety and effectiveness of phentermine/to­piramate ER in combination with other products that are intended for weight loss, including prescription and over-the-counter drugs and herbal preparations, have not been established.10 The most common AEs associated with phentermine/ topiramate ER (incidence ≥5% and at a rate of at least 1.5 times placebo) include paresthesia, dizziness, dysgeusia, insomnia, constipation, and dry mouth.10 There are no black box warnings associated with the use of phentermine/topiramate ER. Contraindications Phentermine/topiramate ER is contraindicated in pregnant women; in patients with glaucoma; in patients with hyperthyroidism; in those receiving treatment or within 14 days after treatment with monoamine oxidase inhibitors; and in patients with hypersensitivity to sympathomimetic amines, topiramate, or any of the inactive ingredients in phentermine/topiramate ER.10 Important Safety Information Phentermine/topiramate ER can cause fetal harm.

Women of reproductive potential should have a negative pregnancy test before treatment and monthly thereafter, and they should use effective contraception consistently during therapy with phentermine/topiramate ER. Phentermine/topiramate ER can cause an increase in resting heart rate. Regular measurement of resting heart rate is recommended for all patients taking phentermine/topiramate ER, particularly patients with cardiac or cerebrovascular disease or when initiating or increasing the dose.

Topiramate, a component of phentermine/topiramate ER, increases the risk of suicidal thoughts or behavior in patients taking these drugs for any indication.

Patients should be monitored for the emergence or the worsening of depression, suicidal thoughts or behavior, and/or for any unusual changes in mood or behavior.

Phentermine/topiramate ER should be discontinued in patients who experience suicidal thoughts or behaviors; it is not recommended in patients with a history of suicidal attempts or active suicidal ideation.

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Acute angle closure glaucoma has been reported in patients who are treated with topiramate, a component of phentermine/topiramate ER. Symptoms include acute onset of decreased visual acuity and/or eye pain. Symptoms typically occur within 1 month of the initiation of topiramate, but they may occur at any time during therapy. The primary treatment to reverse symptoms is immediate discontinuation of phentermine/topiramate ER. Mood disorders, including depression and anxiety, as well as insomnia, can occur with phentermine/topiramate ER. In addition, phentermine/topiramate ER has the potential to impair cognitive function, including impairment of concentration/attention, difficulty with memory, and speech or language problems. Patients should be cautioned about operating hazardous machinery, including automobiles.

Hyperchloremic, nonanion gap, metabolic acidosis has been reported in patients being treated with phentermine/topiramate ER. If metabolic acidosis develops and persists, consideration should be given to reducing the dose or discontinuing the use of the drug.

Phentermine/topiramate ER can cause an increase in serum creatinine. If persistent elevations in creatinine occur while taking phentermine/topir­amate ER, the dose should be reduced or the drug should be discontinued.

Weight loss may increase the risk of hypoglycemia in patients with type 2 diabetes mellitus who are being treated with insulin and/or insulin secretagogues (eg, sulfonyl­ ureas). Phen­­ter­mine/topiramate has not been studied in combination with insulin. A reduction in the dose of antidiabetes medications that are non–glucose dependent should be considered to mitigate the risk of hypoglycemia.10

Specific Populations Nursing mothers. Phentermine/topir­amate ER may be present in human milk, because topiramate and amphetamines (phentermine has pharmacologic activity and a chemical structure similar to amphetamines) are excreted in human milk. Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into consideration the importance of the drug to the mother.10 Pediatric use. The safety and effectiveness of phentermine/topiramate ER in pediatric patients aged <18 years have not been established, and the use of phentermine/topiramate ER is not recommended in pediatric patients.10 Geriatric use. Clinical studies of phentermine/topiramate ER did not include sufficient numbers of subjects aged ≥65 years to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at

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the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or of other drug therapies.10 Renal impairment. No dose adjustments are necessary in patients with mild renal impairment. In patients with moderate (creatinine clearance [CrCl] ≥30-<50 mL/min) and severe (CrCl <30 mL/min) renal impairments, the dose should not exceed phentermine/topiramate ER 7.5 mg/46 mg once daily.10 Hepatic impairment. No dose adjustments are necessary in patients with mild hepatic impairment. In patients with moderate hepatic impairment, the dose should not exceed phentermine/topiramate ER 7.5 mg/46 mg once daily. Phentermine/topiramate ER has not been studied in patients with severe hepatic impairment (Child-Pugh score 10-15). Use in this patient population should be avoided.10

Potential for Abuse and Dependence Phentermine/topiramate ER is a Schedule IV controlled substance because it contains phentermine, a Schedule IV drug. Topiramate is not a controlled substance. Phentermine, a component of phentermine/ topiramate ER, is related chemically and pharmacologically to amphetamines, and it has a known potential for abuse. The possibility of abuse of phentermine should be kept in mind when evaluating the desirability of including phentermine/topiramate ER as part of a weight-­ reduction program.10 Phentermine/topiramate ER has not been systematically studied for its potential to produce physical depen­ dence. Limited information on the potential for physical dependence for the individual components of phentermine/topiramate ER is available. Abrupt discontinuation of topiramate has been associated with seizures in patients without a history of seizures or epilepsy. The abrupt cessation of phentermine after prolonged high-dosage administration may result in extreme fatigue, mental depression, and changes on a sleep electroencephalogram. In situations where rapid withdrawal of

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phentermine/topiramate ER is required, appropriate medical monitoring is recommended.10

Conclusion Clinical evidence has established the significant effect of phentermine/to­piramate ER on weight loss, in conjunction with lifestyle modification, in obese patients and overweight patients with significant cardiometabolic comorbidities, such as diabetes type 2, dyslipidemia, and hypertension. Reducing weight in this patient population has been shown to improve overall health, specifically cardiometabolic health. This new combination therapy is another option to help patients reduce and maintain weight loss, in combination with diet and exercise, as a way to improve overall health. n References

1. National Institutes of Health, Department of Health and Human Services. About NIH obesity research. Background. http://obesityresearch.nih.gov/about/. Accessed December 4, 2012.

2. Centers for Disease Control and Prevention. Obesity and overweight for professionals. Causes and consequences. www.cdc.gov/obesity/adult/causes/index.html.

Accessed December 4, 2012.

3. Ogden CL, Carroll MD, Kit BK, Flegal KM. Prevalence of obesity in the United States, 2009-2010. NCHS Data Brief. 2012;82:1-8.

4. Centers for Disease Control and Prevention. Overweight and obesity. Adult obesity facts. www.cdc.gov/obesity/data/adult.html. Accessed December 4, 2012.

5. Finkelstein EA, Trogdon JG, Cohen JW, Dietz W. Annual medical spending attributable to obesity: payer- and service-specific estimates. Health Aff (Millwood).

2009;28:w822-w831.

6. Allison DB, Gadde KM, Garvey WT, et al. Controlled-release phentermine/ topiramate in severely obese adults: a randomized controlled trial (EQUIP). Obesity (Silver Spring). 2012;20:330-342.

7. Wing RR, Lang W, Wadden TA, et al. Benefits of modest weight loss in improving cardiovascular risk factors in overweight and obese individuals with type 2 diabetes. Diabetes Care. 2011;34:1481-1486.

8. Garvey WT, Ryan DH, Look M, et al. Two-year sustained weight loss and metabolic benefits with controlled-release phentermine/topiramate in obese and overweight adults (SEQUEL): a randomized, placebo-controlled, phase 3 extension study. Am J Clin Nutr. 2012;95:297-308.

9. Fitzgerald K. Qsymia for weight management approved by FDA [press release]. July 22, 2012. Med News Today. MediLexicon, Intl. www.medicalnewstoday.com/articles/ 248134.php. Accessed November 29, 2012.

10. Qsymia (phentermine and topiramate extended-release) capsules [prescribing information]. Mountain View, CA: VIVUS; 2012.

11. Qsymia (phentermine and topiramate extended-release) capsules. Risk Evaluation and Mitigation Strategy (REMS). www.qsymiarems.com/. Accessed November 29, 2012.

12. Gadde KM, Allison DB, Ryan DH, et al. Effects of low-dose, controlled-release, phentermine plus topiramate combination on weight and associated comorbidities in overweight and obese adults (CONQUER): a randomized, placebo-controlled, phase 3 trial. Lancet. 2011;377:1341-1352; correction, Lancet. 2011;377:1494.

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POMALYST® (pomalidomide) is indicated for patients with multiple myeloma who have received at least two prior therapies including lenalidomide and bortezomib and have demonstrated disease progression on or within 60 days of completion of the last therapy. Approval is based on response rate. Clinical benefit, such as improvement in survival or symptoms, has not been verified.

NOW APPROVED Introducing an oral medication for patients with refractory multiple myeloma who have received at least two prior therapies, including lenalidomide and bortezomib

WARNING: EMBRYO-FETAL TOXICITY and VENOUS THROMBOEMBOLISM Embryo-Fetal Toxicity • POMALYST is contraindicated in pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting POMALYST treatment • Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after stopping POMALYST treatment POMALYST is only available through a restricted distribution program called POMALYST REMS™.

Venous Thromboembolism • Deep Venous Thrombosis (DVT) and Pulmonary Embolism (PE) occur in patients with multiple myeloma treated with POMALYST. Prophylactic anti-thrombotic measures were employed in the clinical trial. Consider prophylactic measures after assessing an individual patient’s underlying risk factors

CONTRAINDICATIONS: Pregnancy • POMALYST can cause fetal harm and is contraindicated in females who are pregnant. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus • Pomalidomide is a thalidomide analogue and is teratogenic in both rats and rabbits when administered during the period of organogenesis POMALYST is only available under a restricted distribution program, POMALYST REMS™.

Please see brief summary of full Prescribing Information, including Boxed WARNINGS, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS, and Important Safety Information on following pages.

To find out more information about POMALYST, go to www.pomalyst.com or use your smartphone to scan this code.

POMALYST® (pomalidomide) is indicated for patients with multiple myeloma who have received at least two prior therapies including lenalidomide and bortezomib and have demonstrated disease progression on or within 60 days of completion of the last therapy.

Approval is based on response rate. Clinical benefit, such as improvement in survival or symptoms, has not been verified.

Important Safety Information WARNING: EMBRYO-FETAL TOXICITY and VENOUS THROMBOEMBOLISM Embryo-Fetal Toxicity • POMALYST is contraindicated in pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting POMALYST treatment • Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after stopping POMALYST treatment POMALYST is only available through a restricted distribution program called POMALYST REMS™.

Venous Thromboembolism • Deep Venous Thrombosis (DVT) and Pulmonary Embolism (PE) occur in patients with multiple myeloma treated with POMALYST. Prophylactic anti-thrombotic measures were employed in the clinical trial. Consider prophylactic measures after assessing an individual patient’s underlying risk factors

CONTRAINDICATIONS: Pregnancy • POMALYST can cause fetal harm and is contraindicated in females who are pregnant. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus • Pomalidomide is a thalidomide analogue and is teratogenic in both rats and rabbits when administered during the period of organogenesis

WARNINGS AND PRECAUTIONS Embryo-Fetal Toxicity • Females of Reproductive Potential: Must avoid pregnancy while taking POMALYST and for at least 4 weeks after completing therapy. Must commit either to abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control, beginning 4 weeks prior to initiating treatment with POMALYST, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of POMALYST therapy. Must obtain 2 negative pregnancy tests prior to initiating therapy • Males: Pomalidomide is present in the semen of patients receiving the drug. Males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy. Males must not donate sperm • Blood Donation: Patients must not donate blood during treatment with POMALYST and for 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to POMALYST

POMALYST REMS Program Because of the embryo-fetal risk, POMALYST is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called “POMALYST REMS.” Prescribers and pharmacists must be certified with the program; patients must sign an agreement form and comply with the requirements. Further information about the POMALYST REMS program is available at [celgeneriskmanagement.com] or by telephone at 1-888-423-5436.

Venous Thromboembolism: Patients receiving POMALYST have developed venous thromboembolic events reported as serious adverse reactions. In the trial, all patients were required to receive prophylaxis or antithrombotic treatment. The rate of DVT or PE was 3%. Consider anticoagulation prophylaxis after an assessment of each patient’s underlying risk factors.

Hematologic Toxicity: Neutropenia of any grade was reported in 50% of patients and was the most frequently reported Grade 3/4 adverse event, followed by anemia and thrombocytopenia. Monitor patients for hematologic toxicities, especially neutropenia, with complete blood counts weekly for the first 8 weeks and monthly thereafter. Treatment is continued or modified for Grade 3 or 4 hematologic toxicities based upon clinical and laboratory findings. Dosing interruptions and/or modifications are recommended to manage neutropenia and thrombocytopenia.

Hypersensitivity Reactions: Patients with a prior history of serious hypersensitivity associated with thalidomide or lenalidomide were excluded from studies and may be at higher risk of hypersensitivity.

WARNINGS AND PRECAUTIONS (continued) Dizziness and Confusional State: 18% of patients experienced dizziness and 12% of patients experienced a confusional state;

1% of patients experienced grade 3/4 dizziness, and 3% of patients experienced grade 3/4 confusional state. Instruct patients to avoid situations where dizziness or confusion may be a problem and not to take other medications that may cause dizziness or confusion without adequate medical advice.

Neuropathy: 18% of patients experienced neuropathy (approximately 9% peripheral neuropathy). There were no cases of grade 3 or higher neuropathy adverse reactions reported.

Risk of Second Primary Malignancies: Cases of acute myelogenous leukemia have been reported in patients receiving POMALYST as an investigational therapy outside of multiple myeloma.

ADVERSE REACTIONS In the clinical trial of 219 patients who received POMALYST alone (n=107) or POMALYST + low-dose dexamethasone (low-dose dex) (n=112), all patients had at least one treatment-emergent adverse reaction.

• In the POMALYST alone versus POMALYST + low dose dexamethasone arms, respectively, most common adverse reactions (≥30%) included fatigue and asthenia (55%, 63%), neutropenia (52%, 47%), anemia (38%, 39%), constipation (36%, 35%), nausea (36%, 22%), diarrhea (34%, 33%), dyspnea (34%, 45%), upper respiratory tract infection (32%, 25%), back pain (32%, 30%), and pyrexia (19%, 30%) • 90% of patients treated with POMALYST alone and 88% of patients treated with POMALYST + low-dose dex had at least one treatment-emergent NCI CTC Grade 3 or 4 adverse reaction • In the POMALYST alone versus POMALYST + low dose dexamethasone arms, respectively, most common Grade 3/4 adverse reactions (≥15%) included neutropenia (47%, 38%), anemia (22%, 21%), thrombocytopenia (22%, 19%), and pneumonia (16%, 23%). For other Grade 3 or 4 toxicities besides neutropenia and thrombocytopenia, hold treatment and restart treatment at 1 mg less than the previous dose when toxicity has resolved to less than or equal to Grade 2 at the physician’s discretion • 67% of patients treated with POMALYST and 62% of patients treated with POMALYST + low-dose dex had at least one treatment-emergent serious adverse reaction • In the POMALYST alone versus POMALYST + low dose dexamethasone arms, respectively, most common serious adverse reactions (≥5%) were pneumonia (14%, 19%), renal failure (8%, 6%), dyspnea (5%, 6%), sepsis (6%, 3%), pyrexia (3%, 5%) dehydration (5%, 3%), hypercalcemia (5%, 2%), urinary tract infection (0%, 5%), and febrile neutropenia (5%, 1%)

DRUG INTERACTIONS No formal drug interaction studies have been conducted with POMALYST. Pomalidomide is primarily metabolized by CYP1A2 and CYP3A. Pomalidomide is also a substrate for P-glycoprotein (P-gp). Coadministration of POMALYST with drugs that are strong inhibitors or inducers of CYP1A2, CYP3A, or P-gp should be avoided. Cigarette smoking may reduce pomalidomide exposure due to CYP1A2 induction. Patients should be advised that smoking may reduce the efficacy of pomalidomide.

USE IN SPECIFIC POPULATIONS Pregnancy: If pregnancy does occur during treatment, immediately discontinue the drug and refer patient to an obstetrician/

gynecologist experienced in reproductive toxicity for further evaluation and counseling. Report any suspected fetal exposure to POMALYST to the FDA via the MedWatch program at 1-800-332-1088 and also to Celgene Corporation at 1-888-423-5436.

Nursing Mothers: It is not known if pomalidomide is excreted in human milk. Pomalidomide was excreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from POMALYST, 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 POMALYST in patients under the age of 18 have not been established.

Geriatric Use: No dosage adjustment is required for POMALYST based on age. Patients greater than or equal to 65 years of age were more likely than patients less than or equal to 65 years of age to experience pneumonia.

Renal and Hepatic Impairment: Pomalidomide is metabolized in the liver. Pomalidomide and its metabolites are primarily excreted by the kidneys. The influence of renal and hepatic impairment on the safety, efficacy, and pharmacokinetics of pomalidomide has not been evaluated. Avoid POMALYST in patients with a serum creatinine >3.0 mg/dL. Avoid POMALYST in patients with serum bilirubin >2.0 mg/dL and AST/ALT >3.0 x ULN. Please see full Prescribing Information, including Boxed WARNINGS, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS. POMALYST® is a registered trademark of Celgene Corporation.

POMALYST REMS™ is a trademark of Celgene Corporation. ©2013 Celgene Corporation 02/13 US-POM120044

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This brief summary does not include all the information needed to use POMALYST® safely and effectively. See full prescribing information for POMALYST. WARNING: EMBRYO-FETAL TOXICITY and VENOUS THROMBOEMBOLISM Embryo-Fetal Toxicity • POMALYST is contraindicated in pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting POMALYST treatment.

• Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after stopping POMALYST treatment [see Contraindications (4), Warnings and Precautions (5.1), and Use in Specific Populations (8.1, 8.6)].

POMALYST is only available through a restricted distribution program called POMALYST REMS [see Warnings and Precautions (5.2)].

Venous Thromboembolism • Deep Venous Thrombosis (DVT) and Pulmonary Embolism (PE) occur in patients with multiple myeloma treated with POMALYST. Prophylactic anti-thrombotic measures were employed in the clinical trial. Consider prophylactic measures after assessing an individual patient’s underlying risk factors [see Warnings and Precautions (5.3)].

1 INDICATIONS AND USAGE 1.1 Multiple Myeloma: POMALYST is indicated for patients with multiple myeloma who have received at least two prior therapies including lenalidomide and bortezomib and have demonstrated disease progression on or within 60 days of completion of the last therapy.

Approval is based on response rate [see Clinical Studies (14.1)]. Clinical benefit, such as improvement in survival or symptoms, has not been verified.

Neutropenia • ANC* < 500 per mcL or Febrile neutropenia (fever more than or equal to 38.5°C and ANC < 1,000 per mcL)

Interrupt POMALYST treatment, follow CBC weekly.

• ANC return to more than or equal to Resume POMALYST at 3 mg daily.

500 per mcL • For each subsequent drop < 500 per Interrupt POMALYST treatment mcL • Return to more than or equal to 500 Resume POMALYST at 1 mg less per mcL than the previous dose Thrombocytopenia • Platelets < 25,000 per mcL

Interrupt POMALYST treatment, follow CBC weekly

• Platelets return to > 50,000 per mcL Resume POMALYST treatment at 3 mg daily • For each subsequent drop < 25,000 Interrupt POMALYST treatment per mcL • Return to more than or equal to 50,000 per mcL

Resume POMALYST at 1 mg less than previous dose.

*Note: ANC = Absolute Neutrophil Count For other Grade 3 or 4 toxicities hold treatment and restart treatment at 1 mg less than the previous dose when toxicity has resolved to less than or equal to Grade 2 at the physician’s discretion. To initiate a new cycle of POMALYST, the neutrophil count must be at least 500 per mcL, the platelet count must be at least 50,000 per mcL. If toxicities occur after dose reductions to 1 mg, then discontinue POMALYST. 4 CONTRAINDICATIONS Pregnancy POMALYST can cause fetal harm when administered to a pregnant female [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)]. POMALYST is contraindicated in females

5 WARNINGS AND PRECAUTIONS 5.1 Embryo-Fetal Toxicity POMALYST is a thalidomide analogue and is contraindicated for use during pregnancy.

Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death [see Use in Specific Populations (8.1)]. POMALYST is only available through the POMALYST REMS program [see Warnings and Precautions (5.2)]. Females of Reproductive Potential Females of reproductive potential must avoid pregnancy while taking POMALYST and for at least 4 weeks after completing therapy. Females must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control, beginning 4 weeks prior to initiating treatment with POMALYST, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of POMALYST therapy. Two negative pregnancy tests must be obtained prior to initiating therapy. The first test should be performed within 10-14 days and the second test within 24 hours prior to prescribing POMALYST therapy and then weekly during the first month, then monthly thereafter in women with regular menstrual cycles or every 2 weeks in women with irregular menstrual cycles [see Use in Specific Populations (8.6)]. Males Pomalidomide is present in the semen of patients receiving the drug.

Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy. Male patients taking POMALYST must not donate sperm [see Use in Specific Populations (8.6)]. Blood Donation Patients must not donate blood during treatment with POMALYST and for 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to POMALYST. 5.2 POMALYST REMS ™ Program Because of the embryo-fetal risk [see Warnings and Precautions (5.1)], POMALYST is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called “POMALYST REMS.” Required components of the POMALYST REMS program include the following: • Prescribers must be certified with the POMALYST REMS program by enrolling and complying with the REMS requirements.

• Patients must sign a Patient-Prescriber agreement form and comply with the REMS requirements. In particular, female patients of reproductive potential who are not pregnant must comply with the pregnancy testing and contraception requirements [see Use in Specific Populations (8.6)] and males must comply with contraception requirements [see Use in Specific Populations (8.6)].

• Pharmacies must be certified with the POMALYST REMS program, must only dispense to patients who are authorized to receive POMALYST and comply with REMS requirements.

Further information about the POMALYST REMS program is available at [celgeneriskmanagement.com] or by telephone at 1-888-423-5436.

5.3 Venous Thromboembolism Patients receiving POMALYST have developed venous thromboembolic events (Venous Thromboembolism [VTEs]) reported as serious adverse reactions. In the trial, all patients were required to receive prophylaxis or anti-thrombotic treatment; 81% used aspirin, 16% warfarin, 21% heparin, and 3% clopidogrel. The rate of deep vein thrombosis or pulmonary embolism was 3%. Consider anti-coagulation prophylaxis after an assessment of each patient’s underlying risk factors. 5.4 Hematologic Toxicity Neutropenia was the most frequently reported Grade 3/4 adverse event (AE), followed by anemia and thrombocytopenia. Neutropenia of any grade was reported in 50% of patients in the trial. The rate of Grade 3/4 neutropenia was 43%. The rate of febrile neutropenia was 3%. Monitor patients for hematologic toxicities, especially neutropenia. Monitor complete blood counts weekly for the first 8 weeks and monthly thereafter. Patients may require dose interruption and/or modification [see Dosage and Administration (2.2)]. 5.5 Hypersensitivity Reactions Patients with a prior history of serious hypersensitivity associated with thalidomide or lenalidomide were excluded from studies and may be at higher risk of hypersensitivity. 5.6 Dizziness and Confusional State In the trial, 18% of patients experienced dizziness and 12% of patients experienced a confusional state; 1% of patients experienced grade 3/4 dizziness, and 3% of patients experienced grade 3/4 confusional state. Instruct patients to avoid situations where dizziness or confusion may be a problem and not to take other medications that may cause dizziness or confusion without adequate medical advice. 5.7 Neuropathy In the trial, 18% of patients experienced neuropathy, with approximately 9% of the patients experiencing peripheral neuropathy. There were no cases of grade 3 or higher neuropathy adverse reactions reported.

5.8 Risk of Second Primary Malignancies Cases of acute myelogenous leukemia have been reported in patients receiving POMALYST as an investigational therapy outside of multiple myeloma.

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2 DOSAGE AND ADMINISTRATION 2.1 Multiple Myeloma: Females of reproductive potential must have negative pregnancy testing and use contraception methods before initiating POMALYST [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)]. The recommended starting dose of POMALYST is 4 mg once daily orally on Days 1-21 of repeated 28-day cycles until disease progression. POMALYST may be given in combination with dexamethasone [see Clinical Studies (14.1)]. POMALYST may be taken with water. Inform patients not to break, chew or open the capsules. POMALYST should be taken without food (at least 2 hours before or 2 hours after a meal).

2.2 Dose Adjustments for Toxicity: Table 1: Dose Modification Instructions for POMALYST for Hematologic Toxicities Toxicity Dose Modification

who are pregnant. Pomalidomide is a thalidomide analogue, and is teratogenic in both rats and rabbits when administered during the period of organogenesis.

If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

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6 ADVERSE REACTIONS The following adverse reactions are described in detail in other labeling sections: • Fetal Risk [see Boxed Warnings, Warnings and Precautions (5.1, 5.2)] • Venous Thromboembolism [see Boxed Warnings, Warnings and Precautions (5.3)] • Hematologic Toxicity [see Warnings and Precautions (5.4)] • Hypersensitivity Reactions [see Warnings and Precautions (5.5)] • Dizziness and Confusional State [see Warnings and Precautions (5.6)] • Neuropathy [see Warnings and Precautions (5.7)] • Risk of Second Primary Malignancies [see Warnings and Precautions (5.8)] 6.1 Clinical Trials Experience in Multiple Myeloma 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. In clinical trial 1, data were evaluated from 219 patients (safety population) who received treatment with POMALYST + Low Dose Dexamethasone (Low dose Dex) (112 patients) or POMALYST alone (107 patients). Median number of treatment cycles was 5. Sixty three percent of patients in the study had a dose interruption of either drug due to adverse reactions. Thirty seven percent of patients in the study had a dose reduction of either drug due to adverse reactions. The discontinuation rate due to treatment-related adverse reaction was 3%. Tables 2, 3 and 4 summarize all treatment-emergent adverse reactions reported for POMALYST + Low dose Dex and POMALYST alone groups regardless of attribution of relatedness to pomalidomide. In the absence of a randomized comparator arm, it is often not possible to distinguish adverse events that are drug-related and those that reflect the patient’s underlying disease.

Table 2: Adverse Reactions Reported in 10% of Patients in Any Treatment Arm Trial 1 POMALYSTa

System Organ Class/Preferred Term Number(%) of Patients With at Least One Treatment Emergent Adverse Reaction

(N = 107)

POMALYST + Low dose Dex (N=112)

n (%)

n (%)

107 (100)

112 (100)

59 (55)

70 (63)

Pyrexia

20 (19)

34 (30)

Edema peripheral

25 (23)

18 (16)

Chills

10 (9)

12 (11)

Pain

6 (6)

5 (5)

Blood and lymphatic system disorders Neutropenia

56 (52)

53 (47)

Anemia

41 (38)

44 (39)

Thrombocytopenia

27 (25)

26 (23)

Leukopenia

12 (11)

20 (18)

4 (4)

17 (15)

38 (36)

39 (35)

Gastrointestinal disorders Constipation Diarrhea

36 (34)

37 (33)

Nausea

38 (36)

25 (22)

Vomiting

15 (14)

15 (13)

Infections and infestations Pneumonia

25 (23)

32 (29)

Upper respiratory tract infection

34 (32)

28 (25)

8 (8)

18 (16)

Urinary tract infection

(N = 107)

POMALYST + Low dose Dex (N=112)

n (%)

n (%)

Back pain

34 (32)

34 (30)

Musculoskeletal chest pain

23 (22)

22 (20)

Muscle spasms

20 (19)

21 (19)

System Organ Class/Preferred Term Musculoskeletal and connective tissue disorders

Arthralgia

17 (16)

17 (15)

Musculoskeletal pain

12 (11)

17 (15)

Pain in extremity

5 (5)

16 (14)

Muscular weakness

13 (12)

13 (12)

Bone pain

13 (12)

5 (5)

Dyspnea

36 (34)

50 (45)

Cough

15 (14)

23 (21)

Epistaxis

16 (15)

12 (11)

Respiratory, thoracic and mediastinal disorders

Metabolism and nutritional disorders Decreased appetite

23 (22)

20 ( 18)

Hyperglycemia

13 ( 12)

17 ( 15)

Hyponatremia

11 ( 10)

14 ( 13)

Hypercalcemia

22 ( 21)

13 (12)

Hypocalcemia

6 (6)

13 ( 12)

Hypokalemia

11 ( 10)

12 ( 11)

6 ( 6)

18 ( 16)

23 ( 22)

18 ( 16)

Skin and subcutaneous tissue disorders Hyperhidrosis

Fatigue and asthenia

Lymphopenia

Trial 1 POMALYSTa

(continued)

Rash Night sweats

5 ( 5)

14 ( 13)

Dry skin

10 ( 9)

12 ( 11)

Pruritus

16 ( 15)

12 ( 11)

Dizziness

21 ( 20)

19 ( 17)

Tremor

10 ( 9)

14 ( 13)

Headache

14 ( 13)

9 ( 8)

Neuropathy peripheral

11 ( 10)

8 ( 7)

Nervous system disorders

Investigations Blood creatinine increased

16 ( 15)

12 ( 11)

Weight increased

1 ( 1)

12 ( 11)

Weight decreased

15 ( 14)

9 ( 8)

Psychiatric disorders Insomnia

7 ( 7)

16 ( 14)

Confusional state

11 ( 10)

15 ( 13)

Anxiety

12 ( 11)

8 ( 7)

16 ( 15)

11 ( 10)

Renal and urinary disorders Renal failure aPOMALYST

alone arm includes all patients randomized to the pomalidomide alone arm who took study drug; 61 of the 107 patients had dexamethasone added during the treatment period

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General disorders and administration site conditions

Table 2: Adverse Reactions Reported in 10% of Patients in Any Treatment Arm

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Table 3: Grade 3/4 Adverse Reactions Reported in ≥5% of Patients in Any Treatment Arm

Table 4: Serious Adverse Reactions Reported in 2 or more Patients Trial 1

Trial 1 POMALYSTa

System Organ Class/Preferred Term [a] Number(%) of Patients With at Least One Treatment Emergent NCI CTC Grade 3 or 4 Adverse Reaction

(N = 107)

POMALYST + Low dose Dex (N=112)

n (%)

n (%)

96 ( 90)

99 ( 88)

Neutropenia

50 ( 47)

43 ( 38)

Anemia

24 ( 22)

23 ( 21)

Thrombocytopenia

24 ( 22)

21 ( 19)

Leukopenia

6 ( 6)

11 ( 10)

Lymphopenia

2 ( 2)

8 ( 7)

Infections and infestations 26 (23)

2 ( 2)

9 ( 8)

Sepsis

6 ( 6)

3 ( 3)

10 ( 9)

1 ( 1)

12 ( 11)

14 ( 13)

6 ( 6)

3 ( 3)

7 ( 7)

14 ( 13)

13 ( 12)

10 ( 9)

6 ( 6)

4 ( 4)

10 ( 9)

7 ( 6)

Metabolism and nutritional disorders General disorders and administration site conditions Fatigue and asthenia Investigations Blood creatinine increased Respiratory, thoracic and mediastinal disorders Dyspnea Musculoskeletal and connective tissue disorders Back pain Muscular weakness Renal and urinary disorders Renal failure a

POMALYST alone arm includes all patients randomized to the pomalidomide alone arm who took study drug; 61 of the 107 patients had dexamethasone added during the treatment period.

Table 4: Serious Adverse Reactions Reported in 2 or more Patients Trial 1 POMALYSTa (N = 107)

POMALYST + Low dose Dex (N=112)

System Organ Class/Preferred Term

n (%)

n (%)

Number(%) of Patients With at Least One Treatment Emergent Serious Adverse Reaction

72 ( 67)

69 ( 62)

Pneumonia

15 (14)

21 (19)

Urinary tract infection

0 ( 0)

6 ( 5)

Sepsis

6 ( 6)

3 ( 3)

5 (5)

7 (6)

Pyrexia

3 (3)

5 (5)

General physical health deterioration

0 (0)

2 (2)

Atrial fibrillation

2 (2)

3 (3)

Cardiac failure congestive

0 (0)

3 (3)

Infections and infestations

Respiratory, Thoracic and mediastinal disorders Dyspnea

n (%)

n (%)

9 (8)

7 (6)

1 (1)

3 (3)

5 (5)

1 (1)

Dehydration

5 (5)

3 (3)

Hypercalcemia

5 (5)

2 (2)

4 (4)

2 (2)

System Organ Class/Preferred Term Renal and urinary disorders Renal failure Gastrointestinal disorders

General disorders and administration site conditions

Cardiac Disorders

(continued)

Blood and Lymphatic system disorders Febrile neutropenia Metabolism and nutrition disorders

Musculoskeletal and connective tissue disorders Back pain

[a] POMALYST alone arm includes all patients randomized to the POMALYST alone arm who took study drug; 61 of the 107 patients had dexamethasone added during the treatment period.

Other Adverse Reactions Other adverse reactions of POMALYST in patients with multiple myeloma, not described above, and considered important: Ear and Labyrinth Disorders: Vertigo; Hepatobiliary Disorders: Hyperbilirubinemia; Infections and Infestations: Pneumocystis jiroveci pneumonia, Respiratory syncytial virus infection, Neutropenic sepsis; Investigations: Alanine aminotransferase increased; Metabolism and Nutritional Disorders: Hyperkalemia; Renal and Urinary Disorders: Urinary retention; Reproductive System and Breast Disorders: Pelvic Pain; Respiratory, Thoracic and Mediastinal Disorders: Interstitial Lung Disease 7 DRUG INTERACTIONS No formal drug interaction studies have been conducted with POMALYST. Pomalidomide is primarily metabolized by CYP1A2 and CYP3A. Pomalidomide is also a substrate for P-glycoprotein (P-gp).

7.1 Drugs That May Increase Pomalidomide Plasma Concentrations: CYP3A, CYP1A2 or P-gp inhibitors: Co-administration of POMALYST with drugs that are strong inhibitors of CYP1A2, CYP3A (e.g. ketoconazole) or P-gp could increase exposure and should be avoided. 7.2 Drugs That May Decrease Pomalidomide Plasma Concentrations: CYP3A, CYP1A2 or P-gp inducers: Co-administration of POMALYST with drugs that are strong inducers of CYP1A2, CYP3A (e.g. rifampin) or P-gp could decrease exposure and should be avoided.

Smoking: Cigarette smoking may reduce pomalidomide exposure due to CYP1A2 induction. Patients should be advised that smoking may reduce the efficacy of pomalidomide. Dexamethasone: Co-administration of multiple doses of 4 mg POMALYST with 20 mg to 40 mg dexamethasone (a weak inducer of CYP3A) to patients with multiple myeloma had no effect on the pharmacokinetics of pomalidomide compared with pomalidomide administered alone.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category X [see Boxed Warnings and Contraindications (4)] Risk Summary POMALYST can cause embryo-fetal harm when administered to a pregnant female and is contraindicated during pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a human teratogen, inducing a high frequency of severe and life-threatening birth defects such as amelia (absence of limbs), phocomelia (short limbs), hypoplasticity of the bones, absence of bones, external ear abnormalities (including anotia, micropinna, small or absent external auditory canals), facial palsy, eye abnormalities (anophthalmos, microphthalmos), and congenital heart defects. Alimentary tract, urinary tract, and genital malformations have also been documented and mortality at or shortly after birth has been reported in about 40% of infants. Pomalidomide was teratogenic in both rats and rabbits when administered during the period of organogenesis. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. If pregnancy does occur during treatment, immediately discontinue the drug. Under these conditions, refer patient to an obstetrician/ gynecologist experienced in reproductive toxicity for further evaluation and counseling. Report any suspected fetal exposure to POMALYST to the FDA via the MedWatch program at 1-800-332-1088 and also to Celgene Corporation at 1-888-423-5436. Animal Data Pomalidomide was teratogenic in both rats and rabbits in the embryofetal developmental studies, when administered during the period of organogenesis. In rats, pomalidomide was administered orally to pregnant animals at doses of 25 to 1000 mg per kg per day. Malformations of absence of urinary bladder, absence of thyroid gland, and fusion and Cosmos Communications

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17 ( 16)

Urinary tract infection

Hypercalcemia

POMALYST + Low dose Dex (N=112)

constipation

Blood and lymphatic system disorders

Pneumonia

POMALYSTa (N = 107)

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diaphragm or cervical cap. Contraception must begin 4 weeks prior to initiating treatment with POMALYST, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of POMALYST therapy.

Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy. Females of reproductive potential should be referred to a qualified provider of contraceptive methods, if needed. Females of reproductive potential must have 2 negative pregnancy tests before initiating POMALYST. The first test should be performed within 10-14 days, and the second test within 24 hours prior to prescribing POMALYST. Once treatment has started and during dose interruptions, pregnancy testing for females of reproductive potential should occur weekly during the first 4 weeks of use, then pregnancy testing should be repeated every 4 weeks in females with regular menstrual cycles. If menstrual cycles are irregular, the pregnancy testing should occur every 2 weeks. Pregnancy testing and counseling should be performed if a patient misses her period or if there is any abnormality in her menstrual bleeding. POMALYST treatment must be discontinued during this evaluation. Males Pomalidomide is present in the semen of males who take POMALYST. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy. Male patients taking POMALYST must not donate sperm. 8.7 Renal Impairment Pomalidomide and its metabolites are primarily excreted by the kidneys [see Clinical Pharmacology (12.3)]. The influence of renal impairment on the safety, efficacy, and pharmacokinetics of pomalidomide has not been evaluated. Patients with serum creatinine greater than 3.0 mg/dL were excluded in clinical studies. Avoid POMALYST in patients with a serum creatinine greater than 3.0 mg/dL. 8.8 Hepatic Impairment Pomalidomide is metabolized in the liver [see Clinical Pharmacology (12.3)].

The influence of hepatic impairment on the safety, efficacy, and pharmacokinetics of pomalidomide has not been evaluated. Patients with serum bilirubin greater than 2.0 mg/dL and AST/ALT greater than 3.0 x upper limit normal (ULN) were excluded in clinical studies. Avoid POMALYST in patients with serum bilirubin greater than 2.0 mg/dL and AST/ALT greater than 3.0 x ULN. Manufactured for: Celgene Corporation Summit, NJ 07901 POMALYST®, REVLIMID® and THALOMID® are registered trademarks of Celgene Corporation.

POMALYST REMS™ is a trademark of Celgene Corporation.

U.S. Pat. Nos. 5,635,517; 6,045,501; 6,315,720; 6,316,471; 6,476,052; 6,561,976; 6,561,977; 6,755,784; 6,908,432; 8,158,653; 8,198,262; 8,204,763; 8,315,886 ©2005-2013Celgene Corporation, All Rights Reserved.

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misalignment of lumbar and thoracic vertebral elements (vertebral, central and/or neural arches) were observed at all dose levels. There was no maternal toxicity observed in this study. The lowest dose in rats resulted in an exposure (AUC) approximately 85-fold of the human exposure at the recommended dose of 4 mg per day. Other embryofetal toxicities included increased resorptions leading to decreased number of viable fetuses. In rabbits, pomalidomide was administered orally to pregnant animals at doses of 10 to 250 mg per kg per day. Increased cardiac malformations such as interventricular septal defect were seen at all doses with significant increases at 250 mg per kg per day. Additional malformations observed at 250 mg per kg per day included anomalies in limbs (flexed and/or rotated fore- and/or hindlimbs, unattached or absent digit) and associated skeletal malformations (not ossified metacarpal, misaligned phalanx and metacarpal, absent digit, not ossified phalanx, and short not ossified or bent tibia), moderate dilation of the lateral ventricle in the brain, abnormal placement of the right subclavian artery, absent intermediate lobe in the lungs, low-set kidney, altered liver morphology, incompletely or not ossified pelvis, an increased average for supernumerary thoracic ribs and a reduced average for ossified tarsals. No maternal toxicity was observed at the low dose (10 mg per kg per day) that resulted in cardiac anomalies in fetuses; this dose resulted in an exposure (AUC) approximately equal to that reported in humans at the recommended dose of 4 mg per day. Additional embryofetal toxicity included increased resorption. 8.3 Nursing mothers It is not known if pomalidomide is excreted in human milk. Pomalidomide was excreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from POMALYST, 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. 8.4 Pediatric use Safety and effectiveness of POMALYST in patients below the age of 18 have not been established. 8.5 Geriatric use No dosage adjustment is required for POMALYST based on age. Of the total number of patients in clinical studies of POMALYST, 41 percent were 65 and over, while 12 percent were 75 and over.

No overall differences in effectiveness were observed between these patients and younger patients. In this study, patients greater than or equal to 65 years of age were more likely than patients less than or equal to 65 years of age to experience pneumonia. 8.6 Females of Reproductive Potential and Males POMALYST can cause fetal harm when administered during pregnancy [see Use in Specific Populations (8.1)]. Females of reproductive potential must avoid pregnancy while taking POMALYST and for at least 4 weeks after completing therapy. Females Females of reproductive potential must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control simultaneously (one highly effective form of contraception – tubal ligation, IUD, hormonal (birth control pills, injections, hormonal patches, vaginal rings or implants) or partner’s vasectomy and one additional effective contraceptive method – male latex or synthetic condom,

Rayos: A Novel Oral Delayed-Release

Prednisone for the Treatment of Rheumatoid Arthritis and Other Inflammatory Diseases

By Alice Goodman, Medical Writer

R

heumatic conditions comprise a broad spectrum of more than 100 different diseases that affect approximately 50 million Americans. Some of these diseases are seen frequent­­ly, such as rheumatoid arthritis (RA) and gout, and others are relatively rare, including relapsing polychondritis and polymyalgia rheumatica.1,2 The most familiar rheumatic diseases affect the muscles, joints, and bones, and cause chronic joint pain, swelling, stiffness, and fatigue. But rheumatic diseases can also affect other organs and organ systems, including the heart, eyes, lungs, nervous system, blood, vascular system, and skin. Inflammatory rheumatic diseases—RA, lupus, and gout—are the most severe of these conditions and can destroy joints and organs, causing severe pain, disability, and even death.3 Without appropriate treatment, rheumatic diseases can exacerbate other serious coexisting diseases and infections. For example, one third of lupus-related deaths result from serious infections, and the risk for myocardial infarction is 60% higher in patients with RA than in the general population.3

The Burden and Impact of Rheumatic Diseases Rheumatic diseases can occur in the prime of life and can be painful, disabling, life-changing, and costly. More than 7 million people in the United States have inflammatory, autoimmune rheumatic diseases3; of these, 1.3 million adults have RA; 300,000 children have juvenile idiopathic arthritis; between 161,000 and 322,000 adults have systemic lupus erythematosus; between 0.4 million and 3.1 million adults have Sjogren’s syndrome; approximately 300,000 adults have psoriatic arthritis4; and 3 million adults have gout.5 Less common rheumatic diseases include polymyalgia rheumatica, affecting approximately 711,000 adults5; ankylosing spondylitis, affecting 129 of every 100,000 persons6; polymyositis, affecting 13,500 persons6; and relapsing polychondritis, which involves approximately 600 cases in the United States.7 These diseases are difficult and costly to treat. Complex treatment regimens may be required, and the total annual cost is in the billions of dollars in the United States. In 2006, the medical cost of RA and other rheumatic diseases was $127.8 billion,3 which ex­ceeded the

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estimated cost of cancer care by nearly $24 billion.8 RA and rheumatic diseases are currently the leading cause of disability in the United States, accounting for 19% of disability, with back or spine problems representing a close second, at 17%.9 RA can interfere with the ability to work and can lead to mental and emotional problems. In addition, RA can affect different aspects of cognition.3

FDA Approves Rayos for Multiple Indications Delayed-release prednisone (Rayos, Horizon Pharma) was approved by the US Food and Drug Administration (FDA) on July 26, 2012, for the treatment of a broad range of inflammatory-mediated diseases, including rheumatic, respiratory, dermatologic, allergic, endocrine, and hematologic diseases.

The rationale for the development of Rayos rests on chronobiological ob­servations in patients with inflammatory-mediated diseases. The delayed-release system is engineered to address the circadian rhythm of endogenous cortisol and disease symptoms, which reach their peak levels in the early morning hours. Routine morning administration of conventional prednisone does not achieve adequate control of cortisol levels and disease symptoms, but taking delayed-release prednisone at bedtime releases glucocorticoid (ie, prednisone) 4 hours later, in the very early morning hours, which improves symptom control.10 With the recent FDA approval of Rayos, the manufacturer will initially be focusing its marketing efforts on the use of the drug in RA and in polymyalgia rheumatica, and then will be expanding the focus to 6 key inflammatory diseases—RA, polymyalgia rheumatica, psoriatic arthritis, ankylosing spondylitis, asthma, and chronic obstructive pulmonary disease (COPD).11 These 6 diseases are mediated by interleukin (IL)-6.

The Burden and Impact of Asthma and COPD Nearly 25 million Americans suffer from asthma—approximately 8% of all adults and more than 9% of all children.12 The prevalence of asthma has increased across all age-, sex, and ethnic groups.12 Asthma accounts for approximately 497,000 hospitalizations annually in the United States13 and is responsible for more than 10 million missed workdays for adults

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Phase 3 Clinical Trials The 2 pivotal clinical trials that led to the FDA approval of Rayos were conducted in patients with RA. The trials are known as CAPRA (Circadian Administration of Predni­sone in Rheumatoid Arthritis)-1 and CAPRA-2.

CAPRA-1 CAPRA-1 was a 12-week, multicenter, randomized, double-blind trial conducted at 17 centers in Germany and 12 in Poland between August 2004 and April 2006.

After a 2-week screening phase, patients with active RA were randomized to the oral delayed-release prednisone (N = 144) or to oral immediate-release prednisone (N = 144). The delayed-release tablet was taken at bedtime and released active prednisone 4 hours later. Immediate-release prednisone was administered in the morning.

The double-blind treatment phase entailed study visits at baseline (week 0) and after 2, 6, and 12 weeks of treatment. At the end of the double-blind phase, patients were offered delayed-release prednisone in a 9-month open study phase.19 Disease activity was assessed by the 28-joint Disease Activity Score (DAS28) at all visits. Health status was assessed using the Health Assessment Questionnaire (HAQ) at visits 1, 2, and 5, and using the 36-item ShortForm Health Survey (SF-36) at visits 1 and 5. Laborato-

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Figure CAPRA-1 Adverse Events: Delayed-Release Prednisone versus Immediate-Release Prednisone 45 40 35

Delayed-release prednisone Immediate-release prednisone

30

Patients, %

and nearly 13 million missed school days among children.12 Asthma is managed with appropriate treatment and patient education.

The annual cost of asthma is nearly $18 billion in the United States. Direct costs account for approximately $10 billion, and indirect costs account for approximately $8 billion.14 Asthma causes more than 3000 deaths in the United States annually and is a contributing factor for approximately 7000 additional deaths annually.12 COPD is a progressive disease that interferes with the ability to breathe. Smoking is the leading cause of COPD; other causes include exposure to environmental lung irritants, and possibly air pollution.15 Currently, more than 12 million Americans have been diagnosed with COPD, and another 12 million may have the disease but have not been formally diagnosed.16 COPD is a major cause of disability,15 and this disease is the third leading cause of death in the United States.16 In 2002, the direct medical costs of COPD in the United States were estimated at $18 billion, and indirect costs associated with morbidity and mortality were approximately $14.1 billion.15 In 2004, approximately 25% of all cases of dyspnea presenting to the emergency department were related to exacerbations of COPD.17 In 2000, COPD was responsible for 15 million physician office visits18 and 1.5 million visits to the emergency department.15

25 20 15 10 5 0

Any AE Treatment-related AEs leading to

AEs discontinuation

Death

AE indicates adverse event; CAPRA, Circadian Administration of Prednisone in Rheumatoid Arthritis.

Source: Buttgereit F, et al. Lancet. 2008;371:205-214.

ry measures were analyzed. During the double-blind phase, treatment with other disease-modifying antirheumatic drugs (DMARDs) and with nonsteroidal anti-inflammatory drugs (NSAIDs) had to be kept constant.

The use of other therapies was not allowed.19 The primary end point of CAPRA-1 was the relative change from baseline in duration of morning stiffness at the end of the 12-week double-blind phase. Secondary efficacy outcomes included recurrence of joint stiffness, pain intensity each day, quality of sleep, DAS28 score, physicianâ&#x20AC;&#x2122;s global assessment of disease activity, laboratory values, HAQ disability index, and SF-36 scores.19

Patient Population A total of 288 male and female patients (aged 18-80 years) with active disease and a documented history of RA according to American College of Rheumatology (ACR) criteria were enrolled in CAPRA-1. In general, participants were older and predominantly female, which is similar to the population treated in clinical practice.19 Patients randomized to immediate-release prednisone had a longer duration of morning stiffness of the joints than patients taking the delayed-release prednisone.19 Approximately 40% of the patients had disease duration of more than 10 years.19 Efficacy The mean relative change in the duration of morning stiffness of joints from baseline to the end of 12 weeks

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APRA-2: ACR Response Rate at 12 Weeks: DelayedTable 1 C Release Prednisone versus Placeboa Delayed-release Between-group Response prednisone, % Placebo, % difference, % criterion (N = 231) (N = 119) (95% CI) ACR20

47

29

17 (7.2-27.6)

ACR50

22

10

12 (4.4-19.6)

ACR70

7

3

4 (0.1-8.7)

All missing values were imputed as nonresponders.

ACR20 indicates American College of Rheumatology 20% symptom improvement; CAPRA, Circadian Administration of Prednisone in Rheumatoid Arthritis; CI, confidence interval.

Source: Delayed-release prednisone (Rayos) [package insert].

Deerfield, IL: Horizon Pharma USA, Inc; 2012.

a

omponents of ACR Response Criteria at 12 Weeks: Table 2 C Delayed-Release Prednisone versus Placebo Delayed-release prednisone Placebo + 5 mg + DMARD DMARD (N = 231) (N = 119) Parameter

Baseline Week 12 Baseline Week 12

Tender joint count

12.6

7.9

12.5

9.8

Swollen joint count

8.4

4.8

8.6

6.1

Patient assessment of pain

55.3

33.0

50.5

39.6

Patient global assessment

55.2

31.9

54.1

40.4

ACR indicates American College of Rheumatology; DMARD, disease-modifying antirheumatic drug.

Source: Delayed-release prednisone (Rayos) [package insert].

Deerfield, IL: Horizon Pharma USA, Inc; 2012.

was significantly higher with delayed- release prednisone than with immediate-release prednisone, –22.7% versus –0.4%, respectively, reflecting a difference (rounded to the nearest tenth) of 22.4% (P = .045). The patients treated with the delayed-release prednisone achieved a mean reduction of 44 minutes from baseline, with an absolute between-group difference of 29.2 minutes favoring delayed-release prednisone.19 After 2 weeks of treatment, morning stiffness of the joints was im­proved more in the delayed-release prednisone group, with a difference of approximately 10%. The between-group difference continued to increase with longer treatment and reached a plateau of approximately 38% from week 7 until the end of the treatment period.19 No clinically relevant differences were observed for other secondary efficacy end points, with the exception

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of decreased IL-6 levels in the delayed-release group compared with levels that remained constant in the immediate-release prednisone group.19

Safety Profile The results showed no clinically relevant differences in the safety profiles of the 2 treatment groups (Figure).19 In each group, 41% of the patients reported ≥1 adverse event. In approximately one third of all cases, these events were deemed treatment-related. The most frequent adverse event (AE) was a worsening of RA. Other events seen most frequently included upper abdominal pain, nasopharyngitis, headache, flushing, and nausea.19 The AE profile was consistent with the underlying disease, the patient population, and the known safety profiles of prednisone and concomitant treatments for RA.19 Discontinuations because of treatment-related AEs were reported in 8% of the delayed-release group and in 7% of the immediate-release group. The frequency of serious AEs was low—3% in the delayed-release prednisone group and 2% in the immediate-release prednisone group. Only 1 serious event was judged to be related to prednisone (ie, a depressed level of consciousness in the immediate-release group). One death was reported in the immediate-release group and was not considered related to study drug.19 CAPRA-2 Trial Design CAPRA-2 was a 12-week, randomized, double-blind, parallel-group, placebo-controlled study that compared delayed-release prednisone (ie, Rayos) with placebo.

After a 1-week screening period, 350 patients were randomized in a 2:1 ratio to receive delayed-release prednisone 5 mg daily or to placebo in the evening, with or after their evening meal in addition to their standard DMARD treatment.10 The primary end point was the percentage of patients who achieved a 20% improvement in RA signs and symptoms according to ACR criteria (ACR20) at the end of the 12-week treatment phase. Other end points were changes in morning pain, duration of morning stiffness, DAS28, and health-related quality of life (QOL).10 Patient Population The study enrolled 350 patients (aged 18-80 years; mean age, 57 years) with a diagnosis of RA who had been taking DMARDs for at least 6 months. Other eligibility requirements included morning stiffness duration of at least 45 minutes on at least 4 of 7 days of screening, ≥4 swollen joints, and ≥4 tender joints. Baseline demographics were similar in the 2 treatment arms. Approxi­ mately 99% of the patients were taking DMARDs, and

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approximately 72% were taking NSAIDs. At baseline, the 2 groups had comparable scores of pain and other RA-related symptoms, laboratory parameters, and health-related QOL.10

Efficacy Clinical responses with delayed-release prednisone occurred rapidly, with most clinical end points favor­ing this medication over placebo. Differences in response between the 2 groups emerged as early as 2 weeks after the initiation of treatment, and responses were maintained for the remainder of the study.10 As illustrated in Table 1 and Table 2, the ACR20 response rate was 47% for delayed-release prednisone versus 29% for placebo (P <.001), and a 50% improvement in the signs and symptoms of RA, as shown by ACR50, was seen in 22% versus 10% of patients (P <.006), respectively.10,20 A greater reduction in morning stiffness was observed with delayed-release prednisone at week 12 than with the placebo: 55% versus 35% (P <.002), respectively.

Treatment with delayed-release prednisone achieved significantly greater reductions in DAS28 (P <.001), reflecting severity of disease, and fatigue (P = .003) compared with placebo. A significantly greater improvement in physical function was seen with delayed-release prednisone versus placebo (P <.001) at week 12, as reflected by the SF-36 physical component score.10 Safety Profile Delayed-release prednisone was generally well tolerated, with no life-threatening AEs or deaths reported during the trial. The incidence of AEs was similar for delayed-release prednisone (43%) and placebo (49%). The rate of treatment-related AEs was similar in the 2 groups: 7.8% for delayed-release prednisone versus 8.4% for placebo.10 The most frequent AEs in both groups were related to the worsening of RA and included arthralgia and aggravated RA; these events were seen more frequently with placebo than with delayed-release prednisone. The incidence of infection was similar in the 2 groups (13% vs 12%, respectively), as was nasopharyngitis (approximately 4%), the most frequently reported type of infection.10 Serious AEs were reported in 1 patient (0.4%) in the delayed-release prednisone group versus 2 (1.7%) in the placebo group; none of these events were deemed severe or treatment-related. No clinically relevant changes in hematologic or biochemical parameters or vital signs were reported during the 12-week study.10 The study was not sufficiently long to assess any effects on structural damage and disease progression. Longer-term studies are needed to demonstrate safety and tolerability with prolonged treatment.10

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Mechanism of Action of Rayos Glucocorticoids represent a cornerstone of therapy for inflammatory-mediated diseases. Conventional prednisone is typically given in the morning upon awakening, when cortisol levels and symptoms are at their peak.

Patients with RA have severe morning stiffness and pain upon awakening. Designing a drug delivery system for prednisone using the principles of chronotherapy has the goal of optimizing glucocorticoid therapy. By administering delayed-release prednisone at bedtime, the release of the active drug is delayed for approximately 4 hours; thereby, the drug is available to blunt the peak in cortisol, as well as inflammation-related symptoms.1 Dosing For adults, the dosage of delayed-release prednisone should be individualized according to the severity of the RA and the patient’s response. These considerations should also be applied to children, rather than relying strictly on ratios for age or body weight.20 Rayos is a delayed-release formulation of prednisone, and the active substance is released approximately 4 hours after administration. The timing of administration should take into account the drug’s delayed-release pharmacokinetics, as well as the disease under treatment.20 Depending on the disease entity, the initial dose of delayed-release prednisone can range from 5 mg to 60 mg daily. For patients switching to delayed-release prednisone from an­other form of prednisone, an equipotent dose of Rayos should be used.20 Dose Modifications Based on Response Lower doses of delayed-release prednisone should be sufficient for the treatment of less severe disease, whereas higher doses may initially be needed for selected patients with more severe disease. The initial dose should be maintained or adjusted until a satisfactory re­sponse is achieved.

When the response to a trial of delayed-release prednisone is suboptimal, the drug should be stopped and the patient switched to another medication. It is important to individualize dosages of the drug according to the disease being treated and the patient’s response.20 Once a favorable response is achieved with delayed-­ release prednisone, the initial dose should be decreased in small decrements at timed intervals to determine the lowest dosage for maintaining an adequate response. Constant monitoring is required to ensure appropriate dosing.20 Dose Adjustment Adjustments in dosage may be needed for changes in clinical status because of remission or disease exacerbation, the patient’s individual response, and effects of stress that are not disease-related. Treatment should be

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stopped if spontaneous remissions occur. When delayed-release prednisone is discontinued, withdrawal should be gradual, not abrupt.20

slow growth and development.20 The use of corticosteroids during pregnancy is not recommended, because of the potential for birth defects and decreased birth weights.20

Contraindications Delayed-release prednisone is contraindicated in patients with known hypersensitivity to prednisone or any of the formulation’s inactive ingredients. Although anaphylaxis is rare, this event has been reported in patients taking cortico­steroid therapy.20

Conclusion The FDA’s approval of delayed-release prednisone provides a new therapeutic option for patients with RA and with other inflammatory and rheumatic conditions, including polymyalgia rheumatica, psoriatic arthritis, ankylosing spondylitis, asthma, and COPD. This new agent offers an improved mechanism of action that facilitates the optimal release of prednisone very early in the morning, when disease symptoms peak, thereby promoting improved response rate in these patients. Using the oral formulation may also help patients better control their joint pain and inflammation, as well as other symptoms, and enhance their overall function and health-related QOL. n

Warnings and Precautions Patients receiving chronic treatment with delayed-­ release prednisone should be monitored for hypothalamic-­ pituitary-adrenal axis suppression, a condition with the potential to produce corticosteroid insufficiency when treatment with delayed-release prednisone is withdrawn.

Gradual withdrawal will minimize this risk.20 Patients taking this drug are at an increased risk of infection from many types of pathogens. Furthermore, corticosteroids such as delayed-release prednisone can mask signs of infection and increase vulnerability to new infections, as well as exacerbate existing infections and increase the risk of disseminated infections. Prophylaxis should be considered for patients exposed to chickenpox or measles while taking corticosteroids.20 Corticosteroids may increase the risk of reactivation or exacerbation of latent infection, including latent tuberculosis and latent amebiasis. Latent or active amebiasis should be excluded before initiating cortico­steroid therapy if a patient has traveled to tropical countries or if the patient has diarrhea of unknown origin.20 Corticosteroids can alter blood pressure and the retention of salt and water, and they can increase the excretion of potassium and calcium. These agents should be used with caution in patients with congestive heart failure, hypertension, renal insufficiency, or recent myocardial infarction.20 Corticosteroids should also be used with caution in patients with signs of impending gastrointestinal perforation or other gastrointestinal infections or conditions.

These agents can also exacerbate existing behavioral or mood disturbances, reduce bone density, and exert untoward ophthalmic effects with prolonged use.20 Intraocular pressure should be monitored in patients taking cortico­steroids for longer than 6 weeks.20 Administration of live or attenuated vaccines is contraindicated in patients taking immunosuppressive doses of corticosteroids. Killed or inactivated vaccines may be given, but response is not assured. Patients taking cortico­ steroids should not receive vaccination against smallpox.20 Precautions in Special Populations The long-term use of corticosteroids in children can

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References

1. Relapsing polychondritis causes, symptoms and treatment and related disorders.

Everyday Health website. www.everydayhealth.com/health-center/relapsing-polychon dritis.aspx. Updated March 11, 2009. Accessed September 12, 2012.

2. Polymyalgia rheumatica causes, symptoms and treatment and related disorders. Everyday Health website. www.everydayhealth.com/health-center/polymyalgia-rheumatica. aspx. Updated August 7, 2007. Accessed September 12, 2012.

3. American College of Rheumatology. Rheumatic diseases in America: the problem, the impact, and the answers. www.simpletasks.org/resources/ACR. Accessed September 12, 2012.

4. Helmick CG, Felson DT, Lawrence RC, et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part I. Arthritis Rheum. 2008;58:15-25.

5. Lawrence RC, Felson DT, Helmick CG, et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part II. Arthritis Rheum. 2008;58:26-35.

6. Relapsing polychondritis. Virtual Medical Centre website. www.virtualmedical centre.com/diseases/Relapsing%20Polychondritis/649. Modified November 2, 2008.

Accessed September 13, 2012.

7. Jacobson DL, Gange SJ, Rose NR, Graham NM. Epidemiology and estimated population burden of selected autoimmune diseases in the United States. Clin Immunol Immunopathol. 1997;84:223-243.

8. Cancer trends progress report—2009/2010 update: costs of cancer care. National Cancer Institute website. http://progressreport.cancer.gov/2009/doc_detail.asp?pid= 1&did=2009&chid=95&coid=926&mid=. Accessed September 12, 2012.

9. Centers for Disease Control and Prevention. Prevalence and most common causes of disability among adults—United States 2005. MMWR Morb Mortal Wkly Rep. 2009;58:421-426.

10. Buttgereit F, Mehta D, Kirwan J, et al. Low-dose prednisone chronotherapy for rheumatoid arthritis: a randomised clinical trial (CAPRA-2). Ann Rheum Dis. 2013;72:204-210.

11. Horizon Pharma announces FDA approval of RAYOS® (prednisone) delayed-­ release tablets for rheumatoid arthritis and multiple additional indications [press release]. Deerfield, IL: Horizon Pharma; July 26, 2012. www.horizonpharma.com.

Accessed September 12, 2012.

12. Asthma facts and figures. Asthma and Allergy Foundation of America website. www.aafa.org/display.cfm?id=8&sub=42#_ftnref14. Accessed Sep­tem­ber 13, 2012.

13. Moorman JE, Rudd RA, Johnson CA, et al. National surveillance for asthma— United States, 1980-2004. MMWR Surveill Summ. 2007;56:1-14,18-54.

14. Cost of asthma. Asthma and Allergy Foundation of America website. http://aafa. org/display.cfm?id= 6& sub=63&cont=252. Accessed September 12, 2012.

15. National Institutes of Health; National Heart, Lung, and Blood Institute. Chronic obstructive pulmonary disease [data fact sheet]. March 2003. NIH Publication 03-5229. www.uptakemedical.com/pdfs/copd_fact.pdf. Accessed September 13, 2012.

16. COPD: learn more breathe better. National Heart, Lung, and Blood Institute website. www.nhlbi.nih.gov/health/public/lung/copd/health-care-professionals/index.htm.

Accessed September 13, 2012.

17. Skrepnek GH, Skrepnek SV. Epidemiology, clinical and economic burden, and natural history of chronic obstructive pulmonary disease and asthma. Am J Manag Care.

2004;10:S129-S138.

18. National Heart, Lung, and Blood Institute. Morbidity & Mortality: 2012 Chart Book on Cardio­vascular, Lung, and Blood Diseases. Bethesda, US Department of Health and Human Services; 2012. www.nhlbi.nih.gov/resources/docs/2012_Chart Book_508.pdf. Accessed September 13, 2012.

19. Buttgereit F, Doering G, Schaeffler A, et al. Efficacy of modified-release versus standard prednisone to reduce duration of morning stiffness of the joints in rheumatoid arthritis (CAPRA-1): a double-blind, randomised, controlled trial. Lancet. 2008;371:205-214.

20. Delayed-release prednisone (Rayos) [package insert]. Deerfield, IL: Horizon Pharma USA, Inc; 2012.

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Xeljanz: A New Treatment Option for Patients with Rheumatoid Arthritis

By Alice Goodman, Medical Writer

R

heumatoid arthritis (RA) is a chronic autoimmune disease characterized by inflammation of the joints and surrounding tissues. The cause is unknown, but some evidence suggests that infection, genetics, and hormone changes may be associated with RA.1 Approximately 1.3 million Americans are estimated to have RA.2 Although RA can occur at any age, the peak age of onset is between 30 and 55 years.1,2 RA affects women 2 to 3 times more than men.1,3 The symptoms of RA usually occur bilaterally, with wrists, fingers, knees, feet, and ankles being the most common sites of disease. RA typically has a slow onset that is characterized by minor joint pain and swelling, stiffness, and fatigue. Over time, the affected joints may develop a restricted range of motion and the joints may become deformed.1 Other symptoms of RA can include chest pain when taking a breath; dry eyes and mouth; burning, itching, and discharge of the eyes; nodules under the skin; numbness, tingling, or burning of the hands and feet; and difficulty sleeping.1

The Economic Burden of Rheumatoid Arthritis RA is associated with a significant economic burden, including functional impairment and work disability.4 A significantly higher percentage of patients with RA report work disability compared with the general population; 66% of patients with RA lose an average of 39 working days each year.5 The costs to the US economy in terms of work-related disability can amount to billions of dollars annually.6 Functional disability is the most significant predictor of premature mortality and work disability in patients with RA.4 An estimated 25% of patients with RA experience a reduction in their income.7 In 2000, the estimated average annual medical cost associated with RA was $5720 per patient, of which inpatient cost was the largest component.8 This amount is likely to be much higher in 2013. In terms of indirect costs, one study estimated an annual workplace cost of $16,335 per employee with RA; the indirect costs included reduced productivity, absenteeism or disability, and job turnover.9 A Complex Diagnosis One review suggested that genes may account for up

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to 60% of the risk of developing RA.4 Susceptibility genes include HLA-DRB1, with a strong link to the presence of anti­cyclic citrullinated peptide (anti-CCP) antibodies. No single test is available to confirm the diagnosis of RA, but most patients with RA will have some abnormal results on different tests.1 However, test results will be normal for some patients. Two helpful tests are the rheumatoid factor test and the anti-CCP antibody test, but at least 30% of patients with RA have negative results on these 2 tests.1,4 Other tests that can lend supportive evidence for the diagnosis of RA include a complete blood count, C-­ reactive protein (CRP), erythrocyte sedimentation rate (ESR), joint ultrasound or magnetic resonance imaging, joint x-rays, and synovial fluid analysis.1

The Approach to Treatment RA usually requires lifelong treatment, which can include medications, physical therapy, exercise, education, and possibly surgery. Evidence suggests that early, aggressive treatment of RA can delay joint destruction.1 Nonbiologic Drugs The first line of treatment for RA typically entails a nonbiologic disease-modifying antirheumatic drug (DMARD), most often methotrexate. Other nonbiologic DMARDs include leflunomide and chloroquine.

Anti-­inflammatory drugs are also used, including aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen and naproxen.1 Although these drugs are effective at relieving symptoms, they have associated side effects. DMARDs require frequent blood tests for monitoring, and longterm use of NSAIDs can cause irritation of the gastrointestinal tract leading to ulcers and bleeding, and, depending on the NSAID used, possibly heart problems. The selective NSAID celecoxib, although effective for pain relief, carries a Boxed Warning about heart disease and stroke.1 Antimalarial medications are some­ times used in combination with metho­trexate, but these drugs have a slow onset of action. Corticosteroids are effective at reducing joint swelling and inflammation, but it is advisable to take them at low doses and for short periods because of the potential for long-term side effects.1

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Biologic Drugs Over the past decade or so, biologic DMARDs that target the immune system have become available, and these agents can be extremely effective. Biologics are typically reserved for patients with a suboptimal response to nonbiologic DMARDs or other drugs, and they are typically given subcutaneously or intravenously.1 Although biologic agents are effective in treating RA, they carry the risk of serious infections, secondary leukemia and lymphoma, and psoriasis; monitoring is therefore necessary.1 Tofacitinib Approved for Rheumatoid Arthritis The most recently approved biologic agent for the treatment of RA is the Janus kinase (JAK) inhibitor tofa­citinib (Xeljanz; Pfizer). Tofacitinib is the first oral biologic agent for RA to become available in more than 20 years.10 The US Food and Drug Administration (FDA) approved tofacitinib in November 2012 for the treatment of adults with moderate-to-severe active RA who have had an inadequate response to, or are intolerant of, methotrexate. The approval of tofacitinib was granted as monotherapy or in combination with methotrexate or other nonbiologic DMARDs.10 Mechanism of Action Tofacitinib is an oral JAK inhibitor with a novel mechanism of action, targeting JAK1 and JAK3, as well as JAK2. Unlike other biologics that target extracellular molecules, such as proinflammatory cytokines, tofacitinib targets the intracellular signaling pathways that operate as hubs in the inflammatory cytokine network.11 Dosing Schedule The recommended dose of tofacitinib is 5 mg twice daily.12 The drug should be taken orally without food.

The dosage should be reduced to 5 mg once daily for patients with moderate or severe renal insufficiency, patients with moderate hepatic impairment, those receiving potent inhibitors of the cytochrome (CY)P3A4 enzyme, and patients receiving 1 or more concomitant medications that result in moderate inhibition of CYP3A4 and in potent inhibition of CYP2C19.12 Clinical Trials Program The clinical development program for tofacitinib included 2 dose-ranging trials and 5 confirmatory trials.

The 2 dose-ranging trials showed that the 10-mg and 15-mg doses achieved a similar American College of Rheumatology 20% criteria for improvement (ACR20) response in patients with active RA. In all 7 trials, the patients who received tofacitinib demonstrated improvement in clinical response and in physical functioning compared with patients who received placebo.12

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Confirmatory Trials Study I was a 6-month monotherapy trial that included 610 patients with moderate-to-severe active RA whose disease had an inadequate response to a nonbiologic or a biologic DMARD. The patients received tofa­ citinib 5 mg or 10 mg twice daily, or a placebo. At month 3, all of the patients in the placebo group were randomized in a blinded fashion to tofacitinib 5 mg or 10 mg twice daily. The primary end points at month 3 were the percentage of patients who achieved an ACR20 response, changes in the Health Assessment Questionnaire-Disability Index (HAQ-DI), and a 28-joint Disease Activity Score (DAS28)-4(ESR) <2.6.12 Study II was a 12-month trial that enrolled 792 patients with moderate-to-severe active RA and an inadequate response to a nonbiologic DMARD. The patients received tofa­citinib 5 mg or 10 mg twice daily or a placebo added to background DMARD therapy that did not include potent immunosuppressive treatment.

At month 3, the patients who had an inadequate response were advanced to blinded treatment with tofacitinib 5 mg or 10 mg twice daily. At the end of month 6, all placebo-receiving patients were advanced to their second predetermined treatment with tofacitinib 5 mg or 10 mg twice daily in a blinded fashion. The primary end points were the proportion of patients who achieved an ACR20 response at month 6, changes in HAQ-DI at month 3, and a DAS28-4(ESR) <2.6 at month 6.12 Study III was a 12-month trial of 717 patients with moderate-to-severe active RA and an inadequate response to methotrexate. Patients were treated with to­ facitinib 5 mg or 10 mg twice daily, adalimumab 40 mg subcutaneously every other week, or placebo added to background methotrexate. The placebo-receiving patients were advanced to their second predetermined treatment as in Study II. The primary end points were the proportion of patients who achieved an ACR20 response at month 6, changes in the HAQ-DI at month 3, and a DAS28-4(ESR) <2.6 at month 6.12 Study IV is an ongoing 2-year trial with a planned analysis at 1 year that enrolled 797 patients with moderate-to-severe active RA and an inadequate response to methotrexate. The patients were treated with tofacitinib 5 mg or 10 mg twice daily or with placebo added to background metho­ trexate. The placebo-receiving patients were advanced to their second pre­determined treatment as in Study II. The primary end points were the proportion of patients who achieved an ACR20 response at month 6, a mean change from baseline in the van der Heijde–modified total Sharp Score at month 6, changes in the HAQ-DI at month 3, and a DAS284(ESR) <2.6 at month 6.12 Study V was a 6-month trial that enrolled 399 pa-

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Table 1 Tofacitinib versus Placebo: Proportion of Patients with an ACR Response, by Study Study I: Monotherapy in nonbiologic or biologic DMARD inadequate respondersa

Study IV: MTX inadequate Study V: TNF inhibitor respondersb inadequate respondersc Tofacitinib Tofacitinib Tofacitinib Tofacitinib Tofacitinib Tofacitinib 5 mg twice 10 mg twice 5 mg 10 mg Placebo twice daily twice daily 5 mg twice 10 mg twice Placebo daily daily Placebo + MTX + MTX + MTX + MTX + MTX + MTX daily daily Response (N = 122) (N = 243) (N = 245) (N = 160) (N = 321) (N = 316) (N = 132) (N = 133) (N = 134) ACR20 26% 59% 65% 27% 55% 41% 48% 67% 24% Month 3 NAd 69% 51% 70% 25% 50% 62% NAd 54% Month 6 a Inadequate response to at least 1 DMARD (biologic or nonbiologic) because of a lack of efficacy or toxicity. b Inadequate response to MTX defined as the presence of sufficient residual disease activity to meet study entry criteria. c Inadequate response to at least 1 TNF inhibitor because of a lack of efficacy and/or intolerance. d Data for placebo are not available beyond 3 months in Studies I and V because of placebo advancement.

ACR20 indicates American College of Rheumatology 20% criteria for improvement; DMARD, disease-modifying antirheumatic drug; MTX, methotrexate; NA, not available; TNF, tumor necrosis factor.

Source: Xeljanz [package insert]. New York, NY: Pfizer; 2012. tients with moderate-to-severe active RA and an inadequate response to at least 1 approved tumor necrosis factor (TNF)-inhibiting biologic agent. The patients were treated with tofacitinib 5 mg or 10 mg twice daily or placebo in addition to a background methotrexate.

At month 3, all of the patients in the placebo group were randomized in a blinded fashion to tofacitinib 5 mg or 10 mg twice daily. The primary end points at month 3 were the percentage of patients who achieved an ACR30 response, changes in the HAQ-DI, and a DAS28-4(ESR) <2.6.

Patient Response in Clinical Trials All 5 trials had similar ACR20, ACR50, and ACR70 results at months 3 and 6, in that tofacitinib 5 mg or 10 mg twice daily achieved higher response rates versus placebo, with or without background DMARD treatment. Higher ACR20 responses were observed within 2 weeks for tofacitinib compared with placebo. In the 12month trials, the ACR responses to tofacitinib were consistent at months 6 and 12.12 In Studies I and IV, the ACR20 responses to tofacitinib at month 3 ranged from 55% to 65% versus approximately 26% with placebo. The month 6 ACR20 responses ranged from 50% to 70% with tofacitinib, compared with 25% with placebo. In Study V (ie, the inadequate responders to TNF inhibitors), the month 3 ACR20 responses ranged from 41% to 48% on tofacitinib versus 24% with placebo; the month 6 ACR20 responses ranged from 51% to 54% with tofacitinib, and was not available for placebo (Table 1). In Study IV, more patients in the 2 tofacitinib arms plus methotrexate achieved a low level of

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disease activity as measured by a DAS28-4(ESR) <2.6 at 6 months compared with methotrexate alone: 6% for tofacitinib 5 mg twice daily, 13% for tofacitinib 10 mg twice daily, and 1% for placebo.

In addition, looking at the separate components of the ACR responses at month 3 (ie, number of tender and/or swollen joints, pain, patient global assessment, HAQ-DI, physician global assessment, and CRP levels), similar results were seen in all 5 studies for patients receiving tofa­ citinib versus placebo (Table 2).

In all 5 studies, the tofacitinib-treated patients demonstrated greater improvement in physical functioning as measured by changes in HAQ-DI versus placebo at months 3, 6, and 12.12

Tofacitinibâ&#x20AC;&#x2122;s Safety Profile Overall, the use of tofacitinib was associated with an increased risk of serious infections including opportunistic infections, tuberculosis, cancers, and lymphoma. In clinical trials, serious infections were the most common serious adverse event (AE). The percentage of patients who discontinued treatment because of any AE in months 0 to 3 was 4% for tofacitinib and 3% for placebo.12 No cases of tuberculosis were reported in months 0 to 3 in any patients enrolled in the clinical trials. However, during months 0 to 12, tuberculosis was reported in 0 patients in the 5-mg twice-daily group and 6 patients in the 10-mg twice-daily group. Cases of disseminated tuberculosis were also reported.

From months 0 to 3 in the 7 controlled clinical trials, no patient in the placebo group reported malignancy, and 2 patients receiving tofacitinib reported malignancy

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Table 2 Components of ACR Response at 3 Months: Study IV Tofacitinib 5 mg twice daily + MTX (N = 321) Baseline Month 3a

Tofacitinib 10 mg twice daily + MTX (N = 316) Baseline Month 3a

Placebo + MTX (N = 160) Baseline Month 3a

Component (mean)a 24 (14) 13 (14) 23 (15) 10 (12) 23 (13) 18 (14) Number of tender joints (0-68) 14 (8) 6 (8) 14 (8) 6 (7) 14 (9) 10 (9) Number of swollen joints (0-66) b 58 (23) 34 (23) 58 (24) 29 (22) 55 (24) 47 (24) Pain 58 (24) 35 (23) 57 (23) 29 (20) 54 (23) 47 (24) Patient global assessment c 1.41 (0.68) 0.99 (0.65) 1.40 (0.66) 0.84 (0.64) 1.32 (0.67) 1.19 (0.68) Disability index (HAQ-DI) b 59 (16) 30 (19) 58 (17) 24 (17) 56 (18) 43 (22) Physician global assessment 15.3 (19.0) 7.1 (19.1) 17.1 (26.9) 4.4 (8.6) 13.7 (14.9) 14.6 (18.7) CRP, mg/L a Data shown are mean (standard deviation) at month 3. b Visual analog scale: 0 = best, 100 = worst. c Health Assessment Questionnaire-Disability Index (HAQ-DI): 0 = best, 3 = worst; 20 questions; categories, dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities.

ACR indicates American College of Rheumatology; CRP, C-reactive protein; MTX, methotrexate.

Source: Xeljanz [package insert]. New York, NY: Pfizer; 2012. (excluding nonmelanoma skin cancer). During months 0 to 12, malignancies occurred in 5 patients in the 5-mg twice-daily group and 7 patients in the 10-mg twice-­ daily group. The most common types of malignancies observed over 12 months of exposure to tofaci­tinib, and in the long-term extension studies, were lung and breast cancer, followed by gastric, colorectal, renal-cell, and prostate cancer, lymphoma, and malignant melanoma.

Abnormal laboratory tests included lymphocytes, neutrophils, liver enzyme tests, lipids, and serum creatinine. Other AEs occurring in at least 2% of the patients were diarrhea, nasopharyngitis, upper respiratory tract infection, headache, and hypertension. There are no adequate or well-controlled studies in pregnant women.12

Warnings and Contraindications Tofacitinib carries a Boxed Warning for serious infections and ma­­lig­­­nancy.12 Pneumonia, cellulitis, herpes zoster, and urinary tract infections were among the serious infections reported with tofacitinib. Opportunistic infections include tuberculosis and other mycobacterial infections, Cryptococcus, esophageal candidiasis, pneumocytosis, multidermatomal herpes zoster, cytomegalovirus, and BK virus. Some serious infections presented as disseminated infections.

Patients receiving tofacitinib should be monitored for infection, and treatment should be interrupted if a serious infection develops. Patients should also be evaluated and tested for latent or active tuberculosis before initiation of treatment with tofacitinib. Viral reactivation can

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also occur. Other warnings and precautions are listed in the package insert.12

Conclusion Tofacitinib is the most recently FDA-approved oral biologic agent for the treatment of RA. A JAK inhibitor that targets JAK1, JAK2, and JAK3, tofacitinib can be used as a monotherapy or in combination with methotrexate or with other nonbiologic DMARDs in adults with moderate-to-severe RA who have had an inadequate response to methotrexate. n References

1. National Library of Medicine, National Institutes of Health. Rheumatoid arthritis. www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001467/. Accessed February 1, 2013.

2. Helmick CG, Felson DT, Lawrence RC, et al. Nation­al Arthritis Data Workgroup.

Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part 1. Arthritis Rheum. 2008;58:15-25.

3. Lawrence RC, Helmick CG, Arnett FC, et al. Estimates of the prevalence of arthritis and selected musculoskeletal disorders in the United States. Arthritis Rheum.

1998;41:778-779.

4. Epidemiology, genetics and economic burden of rheumatoid arthritis. In: Luqmani R, Pincus T, Boers M, eds. ORL Rheumatoid Arthritis. New York, NY: Oxford University Press; 2010.

5. Burton W, Morrison A, Maclean R, Ruderman E. Systematic review of studies of productivity loss due to rheumatoid arthritis. Occup Med (Lond). 2006;56:18-27.

6. Zhang W, Anis AH. The economic burden of rheumatoid arthritis: beyond health care costs. Clin Rheumatol. 2011;30(suppl 1):S25-S32.

7. Albers JM, Kuper HH, van Riel PL, et al. Socio-economic consequences of rheumatoid arthritis in the first years of the disease. Rheumatology (Oxford). 1999;38:423-430.

8. Cooper NJ. Economic burden of rheumatoid arthritis: a systematic review. Rheumatology (Oxford). 2000;39:28-33.

9. Birnbaum H, Pike C, Kaufman R, Cifaldi M. Employer model of workplace impacts of anti-TNF therapy for rheumatoid arthritis. J Occup Environ Med. 2009;5: 1167-1176.

10. US Food and Drug Administration. FDA approves Xeljanz for rheumatoid arthritis. FDA News Release. November 6, 2012. www.fda.gov/NewsEvents/Newsroom/ PressAnnouncements/ucm327152.htm. Accessed March 15, 2013.

11. Data on file. Tofacitinib: A Novel JAK Inhibitor. New York, NY: Pfizer; 2012.

12. Xeljanz [package insert]. New York, NY: Pfizer; 2012.

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Tudorza Pressair: A Novel Oral Inhalation Therapy for the Maintenance Treatment of Chronic Obstructive Pulmonary Disease– Associated Bronchospasm

By Loretta Fala, Medical Writer

C

hronic obstructive pulmonary disease (COPD) is a life-threatening disease characterized by a persistent blockage of airflow from the lungs.1 COPD is not a single disease but an umbrella term that includes chronic bronchitis and emphysema.1 It is estimated that 14.8 million people in the United States were diagnosed with COPD in 2010.2 In addition, according to the National Health and Nutrition Examination Survey data from 1988 to 1994, another 12 million people may have COPD that has not been diagnosed.2 COPD remains underdiagnosed and subsequently undertreated—factors that may impact beneficial intervention in the early phases of the disease.3,4

COPD Overview COPD is a major cause of disability and the third leading cause of death in the United States, claiming the lives of more than 124,000 people annually.3,5 In 2008, COPD accounted for 56.7% of the 242,350 deaths from lung disease.2 COPD-related deaths are projected to rise by more than 30% globally within the next decade, unless urgent steps are taken to reduce its risk factors—especially tobacco use and tobacco smoke exposure, the primary causes of COPD—as well as other environmental factors.1 Although there is no known cure for COPD, effective management can control its symptoms, reduce the risk of exacerbations and complications, slow the progression of the disease in some cases, and improve patients’ ability to lead active lives.6 Early diagnosis and appropriate management of COPD are crucial, because COPD may worsen over time. Aside from its chronic, progressive nature, COPD exacerbations with acute episodes of worsened symptoms may become more frequent as the disease progresses, leading to emergency department visits and hospitalization.

Although COPD can occur in younger individuals, it has a substantial impact on the elderly population. According to recent data from the Centers for Disease Control and Prevention, the prevalence of COPD has

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increased from 3.2% in people aged 18 to 44 years to more than 11.6% in people aged ≥65 years.7 COPD imposes a substantial burden with respect to respiratory-related and total healthcare costs. The total annual cost of COPD was estimated to be $49.9 billion in 2010, of which $29.5 billion accounted for direct healthcare costs, $8 billion for indirect morbidity costs, and $12.4 billion for indirect mortality costs.3 In a Medicare claims study of hospital readmission rates during a 12-month period, COPD accounted for a 30-day readmission rate of nearly 23%, which ranked it third behind heart failure (27%) and psychoses (25%), and slightly ahead of pneumonia (20%).8,9 In another study, a Medicare cohort with COPD had total healthcare costs that were $20,500 higher than the comparison group (P <.001), with comorbid conditions accounting for 46% of the excess costs.10 Nonadherence to therapy—pharmacologic and nonpharmacologic—is a common barrier to optimal COPD management and may contribute to adverse outcomes and increased healthcare costs.11 Underuse, overuse, and improper use of medications contribute to poor adherence to COPD therapy.12 Treatment adherence is particularly problematic, given the chronic nature of COPD, the presence of comorbid conditions, the use of multiple medications, and the periods of symptom remission.12 Patients with COPD have an increased risk for comorbid conditions, such as hypertension, diabetes, cardiovascular disease, lung cancer, and depression.12,13 Polypharmacy presents particular adherence challenges for elderly patients with COPD.14 In 2011, the practice guidelines for the diagnosis and management of stable COPD were updated and released as a collaborative initiative by the American College of Physicians, the American College of Chest Physicians, the American Thoracic Society, and the European Respiratory Society.15 More recently, in early 2013, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) published updated guidelines for the diagnosis, management, and prevention of COPD.16

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aseline Patient Characteristics in 3 Confirmatory Trials Table 1 B Evaluating the Safety and Efficacy of Aclidinium Bromide Category Baseline characteristics Disease

Clinical diagnosis of COPD

Age

竕･40 years

History of smoking

竕･10 pack-yearsa

FEV1 level

竕･30% and <80% of predicted normal value

FEV1/FVC ratio

<0.7

Patient population

59% male, 93% white

Equivalent of 1 pack of cigarettes daily for 10 years or 0.5 pack daily for 20 years.

COPD indicates chronic obstructive pulmonary disease; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity.

Source: Tudorza Pressair [package insert]. St Louis, MO: Forest Pharmaceuticals, Inc; 2012. a

The treatment goals for patients with COPD include preventing and treating exacerbations, reducing hospitalizations and mortality, relieving dyspnea that restricts activity, and increasing exercise tolerance and health-related quality of life.17 For smokers with COPD, smoking cessation is the most essential step in any treatment plan.6 Pharmacologic treatments include short-acting and long-acting bronchodilators, inhaled steroids, combination inhalers, oral steroids, phosphodiesterase-4 inhibitors, theophylline, and antibiotics.

Additional lung therapies, including oxygen therapy, pulmonary rehabilitation, and lifestyle changes, may be recommended. Surgery may also be an option for some patients with severe disease who do not respond to pharmacologic therapy.6

FDA Approves Tudorza Pressair In July 2012, Tudorza Pressair (aclidinium bromide inhalation powder; Almirall), a long-acting, anticholinergic agent, was approved by the US Food and Drug Administration (FDA) for the long-term maintenance treatment of bronchospasms associated with COPD, including bronchitis and emphysema.18,19 Aclidinium bromide is not indicated for the initial treatment (ie, rescue therapy) of acute episodes of bronchospasms.

Clinical Pharmacology of Tudorza Pressair Aclidinium bromide, a long-acting antimuscarinic agent in the anticholinergic drug class, has a similar affinity to the subtypes of muscarinic receptors M1 to M5.

In the airways, aclidinium bromide exhibits pharmacologic effects through the inhibition of the M3 receptor at the smooth muscle leading to bronchodilation. The

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bronchodilation after inhalation of aclidinium bromide is predominantly a site-specific effect.

In a QT study, aclidinium bromide (200 mcg and 800 mcg) was administered to healthy volunteers once daily for 3 days. No effects on the prolongation of the QT interval were observed.19 In healthy volunteers, the absolute bioavailability of aclidinium bromide is approximately 6%. After twice-daily oral inhalation administration of 400 mcg of aclidinium bromide in healthy individuals, peak steadystate plasma levels were observed within 10 minutes after inhalation.19 Clinical pharmacokinetics studies show that the major route of the metabolism of aclidinium bromide is hydrolysis, which occurs chemically and enzymatically by esterases. Aclidinium bromide is rapidly and extensively hydrolyzed to its alcohol and dithienylglycolic acid derivatives, neither of which bind to muscarinic receptors and both of which are devoid of pharmacologic activity.

Because of the low plasma levels achieved at the clinically relevant doses, aclidinium bromide and its metabolites are not expected to alter the disposition of drugs metabolized by the human cytochrome P450 enzymes.19

Dosing Aclidinium bromide 400 mcg is dosed in 1 oral inhalation that is administered twice daily. A multidose device delivers the dry inhalation powder that meters 400 mcg of aclidinium bromide per actuation to the patient.19 Clinical Studies Data Leading to FDA Approval The FDA approval of aclidinium bromide was based on 4 clinical trials, including a dose-ranging study for nominal dose selection and 3 confirmatory studies.

Dose-Ranging Trial In a phase 2b, double-blind, placebo- and active-comparator窶田ontrolled crossover study that assessed the efficacy and safety of 3 doses of aclidinium bromide in patients with moderate-to-severe COPD, 79 patients were randomized to receive 1 of 5 treatment sequences for 7 days, with a 5- to 9-day washout period.20 The 5 treatment groups included 400 mcg of aclidinium bromide twice daily, 200 mcg of aclidinium bromide twice daily, 100 mcg of aclidinium bromide twice daily, formoterol active control, and placebo.20 In this study, the improvement from baseline in trough forced expiratory volume in 1 second (FEV1) and serial FEV1 on day 7 was significantly greater with aclidinium 400 mcg than with aclidinium 100 mcg. The safety profile of aclidinium bromide was comparable with that of placebo. This study showed that the effect on trough FEV1 and serial FEV1 in patients treated with

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aclidinium bromide 100 mcg twice daily and 200 mcg twice daily was lower compared with patients treated with aclidinium bromide 400 mcg twice daily.19,20 In addition to confirming the use of the twice-daily dosing regimen, this study established aclidinium bromide 200 mcg and 400 mcg as suitable doses for subsequent phase 3 trials.20

Confirmatory Trials The efficacy and safety of aclidinium bromide were evaluated in 3 randomized, double-blind, placebo-controlled trials that included a total of 1276 patients with COPD.19,21-23 Baseline characteristics of these patients are shown in Table 1.

In these 3 trials, 636 patients received aclidinium bromide 400 mcg twice daily and 640 patients received placebo. The patients who received aclidinium bromide 400 mcg had a significant improvement in bronchodilation, as measured by the change from baseline in morning predose FEV1 at 12 weeks (the primary efficacy end point) compared with placebo in all 3 trials (Table 2).19,21-23 Serial spirometry measurements were conducted throughout daytime hours in a subset of patients in the 3 confirmatory trials. Improvement in lung function was maintained for 12 hours after a single dose of aclidinium bromide and remained consistent over the 3- or 6-month treatment periods. Moreover, the mean peak FEV1 improvements with respect to baseline on day 1 were similar at week 12 in all 3 trials. In 2 of the 3 studies, patients receiving aclidinium bromide used less daily rescue albuterol compared with patients who received placebo.19 Safety Profile and Metabolic Properties In 3 placebo-controlled clinical studies, aclidinium bromide was shown to be well tolerated.19,21-23 The most common adverse reactions associated with aclidinium bromide in the 3-month and 6-month trials were headache (6.6%), nasopharyngitis (5.5%), and cough (3.0%) (Table 3). Other adverse reactions that occurred with a frequency of ≥1% in the aclidinium bromide cohort included diarrhea (2.7%), sinusitis (1.7%), rhinitis (1.6%), toothache (1.1%), fall (1.1%), and vomiting (1.1%).

In 3 long-term (40-52 weeks) safety studies of aclidinium bromide 400 mcg administered twice daily, with a total of 891 patients with moderate-to-severe COPD, the adverse events were similar to those reported in the placebo-controlled trials of 3 to 6 months; no new safety findings were reported.19 Precautions and Drug Interactions There are no contraindications associated with the

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Table 2 Aclidinium Bromide versus Placebo: Change from Baseline in Trough FEV1 (L) at Week 12 Confirmatory trial A (N = 375)

Aclidinium 400 mcg

Placebo

1.33

1.38

0.10 (0.01)

–0.02 (0.02)

Baseline Change from baseline LS mean (SE) Treatment difference LS mean (95% CI)

0.12 (0.08-0.16)

Confirmatory trial B (N = 359) Baseline Change from baseline LS mean (SE)

1.25

1.46

0.06 (0.02)

–0.01 (0.02)

Treatment difference LS mean (95% CI)

0.07 (0.03-0.12)

Confirmatory trial Ca (N = 542) Baseline Change from baseline LS mean (SE)

1.51

1.50

0.06 (0.02)

–0.05 (0.02)

Treatment difference LS mean (95% CI)

0.11 (0.07-0.14)

In this 6-month study, placebo-adjusted change from baseline in trough FEV1 at 24 weeks was 0.13 (95% CI, 0.09-0.17).

CI indicates confidence interval; FEV1, forced expiratory volume in 1 second; L, liters; LS, least square; SE, standard error.

Source: Tudorza Pressair [package insert]. St Louis, MO: Forest Pharmaceuticals, Inc; 2012. a

dverse Reactions in ≥1.5% of Patients in PlaceboTable 3 A Controlled Clinical Trials with Tudorza Pressair Treatment Adverse reactions

Tudorza Pressair Placebo (n = 636), N (%) (n = 640), N (%)

Headache

42 (6.6)

32 (5.0)

Nasopharyngitis

35 (5.5)

25 (3.9)

Cough

19 (3.0)

14 (2.2)

Diarrhea

17 (2.7)

9 (1.4)

Sinusitis

11 (1.7)

5 (0.8)

Rhinitis

10 (1.6)

8 (1.2)

Source: Tudorza Pressair [package insert]. St Louis, MO: Forest Pharmaceuticals, Inc; 2012.

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use of aclidinium bromide. This oral inhaler should be used with caution in patients with narrow-angle glaucoma or urinary retention. Patients who develop any signs or symptoms of narrow-angle glaucoma, prostatic hyperplasia, or bladder-neck obstruction should be referred to a physician. Patients with a history of hypersensitivity reactions should be closely monitored for hypersensitivity reactions to aclidinium bromide. In addition, this orally inhaled medication should be used with caution in patients with severe hypersensitivities to milk proteins.

Anticholinergics may interact additively when used concomitantly with anticholinergic medications. Aclidinium bromide should not be administered with other anticholinergic-containing agents.19

Specific Populations There are no adequate and well-controlled studies evaluating the treatment of pregnant women with aclidinium bromide. Aclidinium bromide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

No human studies have investigated the effects of aclidinium bromide on breastfed infants. The excretion of aclidinium bromide in human milk is probable. Caution should be exercised when aclidinium bromide is administered to women who are breastfeeding.

COPD does not normally occur in children. The safety and effectiveness of aclidinium bromide in pediatric patients have not been established.

Based on available data for aclidinium bromide, no adjustment of dosage for renally impaired individuals is warranted. The effects of hepatic impairment on the pharmacokinetics of aclidinium bromide were not studied.19 Conclusion The FDA approval of aclidinium bromide adds a new therapeutic option for the long-term maintenance treatment of patients with COPD, including chronic bronchitis and emphysema. Aclidinium bromide, a long-acting anticholinergic with specificity for muscarinic receptors, is a dry powder formulation for oral inhalation.

In 3 confirmatory trials involving a total of 1276 patients with COPD, those who received aclidinium bromide 400 mcg twice daily demonstrated significantly greater bronchodilation, as measured by the change from baseline in morning predose FEV1 at 12 weeks compared

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with placebo. Aclidinium bromide was well tolerated in patients with COPD. n

References

1. World Health Organization. Chronic obstructive pulmonary disease (COPD).

Fact Sheet 315. November 2012. www.who.int/mediacentre/factsheets/fs315/en/index. html. Accessed February 12, 2012.

2. National Institutes of Health. National Heart, Lung, and Blood Institute. Morbidity & Mortality: 2012 Chart Book on Cardiovascular, Lung, and Blood Diseases.

February 2012. www.nhlbi.nih.gov/resources/docs/2012_ChartBook_508.pdf. Accessed February 15, 2013.

3. American Lung Association. Chronic obstructive pulmonary disease (COPD) fact sheet. February 2011. www.lung.org/lung-disease/copd/resources/facts-figures/COPDFact-Sheet.html. Accessed February 18, 2013.

4. Hill K, Goldstein RS, Guyatt GH, et al. Prevalence and underdiagnosis of chronic obstructive pulmonary disease among patients at risk in primary care. CMAJ. 2010; 182:673-678.

5. National Heart, Lung, and Blood Institute. What is COPD? Updated June 8, 2012. www.nhlbi.nih.gov/health/health-topics/topics/copd/. Accessed February 17, 2013.

6. Mayo Clinic. COPD. www.mayoclinic.com/health/copd/DS00916/METHOD= print&DSECTION=all. Updated February 1, 2013. Accessed February 19, 2013.

7. Centers for Disease Control and Prevention. Chronic obstructive pulmonary disease among adults—United States, 2011. MMWR Morb Mortal Wkly Rep. 2012;61: 938-943. www.cdc.gov/mmwr/preview/mmwrhtml/mm6146a2.htm. Accessed February 22, 2012.

8. Stone J, Hoffman GJ. Medicare hospital readmissions: issues, policy options and PPACA. Congressional Research Service report for Congress. September 21, 2010. www.hospitalmedicine.org/AM/pdf/advocacy/CRS_Readmissions_Report.pdf. Accessed February 19, 2013.

9. Jencks SF, Williams MV, Coleman EA. Rehospitalizations among patients in the Medicare Fee-for-Service Program. N Engl J Med. 2009;360:1418-1428.

10. Menzin J, Boulanger L, Marton J, et al. The economic burden of chronic obstructive pulmonary disease (COPD) in a U.S. Medicare population. Respir Med. 2008;102: 1248-1256.

11. Bourbeau J, Bartlett SJ. Patient adherence in COPD. Thorax. 2008;63:831-838.

12. Restrepo RD, Alvarez MT, Wittnebel LD, et al. Medication adherence issues in patients treated for COPD. Intl J COPD. 2008;3:376-384.

13. Crockett AJ, Price D. Co-morbid disease in COPD—more than a coincidence.

Int J Chron Obstruct Pulmon Dis. 2007;2:399-400.

14. Hanania NA, Sharma G, Sharafkhaneh A. COPD in the elderly patient. Semin Respir Crit Care Med. 2010;31:596-606.

15. Qaseem A, Wilt TJ, Weinberger SE, et al, for the American College of Physicians, the American College of Chest Physicians, the American Thoracic Society, and the European Respiratory Society. Diagnosis and management of stable chronic obstructive pulmonary disease: a clinical practice guideline update from the American College of Physicians, American College of Chest Physicians, American Thoracic Society, and European Respiratory Society. Ann Intern Med. 2011;155:179-191.

16. Global Initiative for Chronic Lung Disease (GOLD). The global strategy for the diagnosis, management, and prevention of COPD. Updated 2013. www.goldcopd. org/uploads/users/files/GOLD_Report_2013_Feb20.pdf. Accessed February 21, 2013.

17. Armstrong C. ACP updates guideline on diagnosis and management of stable COPD. Am Fam Physician. 2012;85:204-205.

18. Paddock C. COPD drug Tudorza Pressair wins FDA approval [press release]. Medical News Today. July 30, 2013. www.medicalnewstoday.com/articles/248417.php. Accessed February 15, 2013.

19. Tudorza Pressair [package insert]. St Louis, MO: Forest Pharmaceuticals, Inc; 2012.

20. Singh D, Magnussen H, Kirsten A, et al. A randomized, placebo- and active-controlled dose-finding study of aclidinium bromide administered twice a day in COPD patients. Pulm Pharmacol Ther. 2012;25:248-253.

21. Jones PW, Singh D, Bateman ED, et al. Efficacy and safety of twice-daily aclidinium bromide in COPD patients: the ATTAIN study. Eur Respir J. 2012;40:830-836.

22. Lasseter K, Dilzer S, Jansat JM, et al. Safety and pharmacokinetics of multiple doses of aclidinium bromide administered twice daily in healthy volunteers. Pulm Pharmacol Ther. 2012;25:193-199.

23. Kerwin EM, D’Urzo AD, Gelb AF, et al; ACCORD I Study Investigators. Efficacy and safety of a 12-week treatment with twice-daily aclidinium bromide in COPD patients (ACCORD COPD I). COPD. 2012;9:90-101.

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Vol 6, No 3

Vascepa: First EPA-Only Omega-3 Therapy Approved by the FDA for Severe Hypertriglyceridemia

By Loretta Fala, Medical Writer

T

riglycerides are important biomarkers of risk for heart disease and stroke, particularly when a patient has low high-density lipoprotein (HDL) cholesterol, elevated levels of low-density lipoprotein (LDL) cholesterol, or type 2 diabetes.1 Non-HDL cholesterol and apolipoprotein B are also predictors of coronary heart disease.2 Furthermore, triglyceride levels that exceed 1000 mg/dL are associated with acute pancreatitis, accounting for approximately 10% of all cases.1

Triglycerides and Heart Disease Over the past 3 decades, the mean triglyceride level of people in the United States has been on the rise, particularly given the increase in the prevalence of obesity, type 2 diabetes, and insulin resistance.1 An estimated 31% of the adult population in the United States has an elevated triglyceride level (≥150 mg/dL), which is also referred to as hypertriglyceridemia. Of US adults, 16.2% have high triglyceride levels, and approximately 1% have very high triglyceride levels (≥500 mg/dL).1 The current designations for hypertriglyceridemia are1: • Borderline high (150 mg/dL-199 mg/dL) • High (200 mg/dL-499 mg/dL) • Very high (≥500 mg/dL).

In a scientific statement, the American Heart Association (AHA) recommended that new triglyceride designations—an optimal fasting triglyceride level of <100 mg/ dL, defined as a parameter of metabolic health, and nonfasting triglyceride levels to be used as a screening measure for individuals with high fasting triglyceride levels.1 A nonfasting level of <200 mg/dL is equivalent to a normal (<150 mg/dL) or to an optimal (<100 mg/dL) fasting triglyceride level, with no further testing required. To identify borderline high (150 mg/dL-199 mg/dL), high (200 mg/dL-499 mg/dL), and very high (≥500 mg/dL) triglyceride levels, fasting samples should be used.1 The AHA statement includes several triglyceride-lowering strategies, including losing 5% to 10% of body weight, eating a Mediterranean-style diet versus a low-fat diet, adding a marine-derived polyunsaturated fatty acid (ie, eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]), reducing carbohydrate intake, eliminating trans fats, and implementing an exercise regimen.1 A 50%

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reduction in triglyceride levels can be attained when all of these strategies are combined. For patients with very high triglyceride levels or with a history of triglyceride-induced pancreatitis, the AHA statement recommends following the previously mentioned strategies, additional dietary changes (including abstinence from alcohol consumption), and the possible use of medium-chain triglycerides and pharmacologic therapies.1 Pharmacologic therapies that are used to lower triglyceride levels include niacin, fibrates, statins, ezetimibe, and omega-3 fatty acid supplements, or appropriate combinations of these agents.1,3 Dietary sources of omega-3 fatty acids include alpha-linolenic acid, EPA, and DHA. Therapeutic doses of both EPA and DHA have been shown to reduce triglyceride levels in patients with varying baseline triglyceride levels.4,5 However, EPA and DHA differ in their effect on lipids.4,6 Unlike EPA, DHA has been shown to increase LDL cholesterol in patients with varying baseline triglyceride levels.5 The continuation of a lipid-lowering diet and exercise regimen is important for patients treated for hypertriglyceridemia. The medical conditions associated with lipid abnormalities, including diabetes, metabolic syndrome, hypothyroidism, and renal disease, as well as alcohol intake, should be managed appropriately.1,4 In addition, medications that may contribute to hypertriglyceridemia, including beta-blockers, thiazides, and estrogens, should be ruled out as potential causes of an elevated triglyceride level; these medications may need to be adjusted, changed, or discontinued.1,4 Despite clinical evidence demonstrating the impor­ tant role of lipid-lowering therapy in cardiovascular health, medication adherence persists as a major challenge in the treatment of hyperlipidemia. A retrospective data analysis of 88,635 patients who received a new lipid-lowering therapy from 2007 to 2008 showed that 65% of patients were nonadherent to their prescribed medication (percentage of days covered, 0.33).7

Hypertriglyceridemia-Related Costs Hypertriglyceridemia is associated with substantial medical costs. An analysis of the medical records of 108,324 health plan members aged ≥18 years from 2008

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Table 1 Characteristics of Patients in the MARINE Study Category

Characteristics

Baseline triglyceride levels, range

500-2000 mg/dL

Median baseline triglyceride level

684 mg/dL

Median baseline LDL cholesterol levels

86 mg/dL

Median baseline HDL cholesterol levels

27 mg/dL

Patients with triglyceride levels of >750 mg/dL

39%

Randomized population Race Sex

White, 88% Male, 76%

Mean age

53 yrs

Mean body mass index

31 kg/m2

Patients receiving concomitant statin therapy

25%

Patients with diabetes

28%

HDL indicates high-density lipoprotein; LDL, low-density lipoprotein; MARINE, Multicenter, Placebo-Controlled, Randomized, Double-Blind, 12-Week Study with an OpenLabel Extension.

Sources: Bays HE, et al. J Clin Lipidol. 2012;6:565-572; Vascepa (icosapent ethyl) capsules [package insert]. Bedminster, NJ: Amarin Pharma, Inc; 2012.

was conducted to assess the impact of hypertriglyceridemia on healthcare costs.8 Costs were adjusted for age, sex, blood pressure, body mass index, smoking history, LDL and HDL cholesterol levels, and conditions such as cardiovascular disease, diabetes, and kidney disease.

After adjusting for these factors, mean total costs were significantly greater for patients with very high or severe hypertriglyceridemia ($8567; 99% confidence interval [CI], $7034-$10,100) compared with those with triglyceride levels of <150 mg/dL ($6186; 99% CI, $6058$6314), those with borderline triglyceride levels of 150 mg/dL to 199 mg/dL ($6449; 99% CI, $6196-$6702), and those with high triglyceride levels of 200 mg/dL to 499 mg/dL ($6376; 99% CI, $6118-$6634).8 Overall, the costs associated with severe hypertriglyceridemia in this analysis were 33% to 38% higher annually, independent of diabetes, cardiovascular disease, heart failure, and hypertension. Outpatient and pharmaceutical costs accounted heavily for the differences in costs.8

A New Treatment Option for Severe Hypertriglyceridemia In July 2012, Vascepa (icosapent ethyl; Amarin

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Pharma), an ethyl ester of EPA, was approved by the US Food and Drug Administration (FDA) as an adjunct to diet to reduce triglyceride levels in adult patients with severe (≥500 mg/dL) hypertriglyceridemia.9 Icosapent ethyl is a pure omega-3 fatty acid and the first EPA-only omega-3 agent to be approved by the FDA for this indication.10 Patients should be placed on an appropriate lipid-­ lowering diet and exercise regimen before receiving icosapent ethyl and should continue the regimen while receiving icosapent ethyl. Attempts should be made to control any medical problems, such as diabetes mellitus and hypothyroidism, and to limit alcohol consumption, which may contribute to lipid abnormalities. Lipid levels should be consistently abnormal before initiating ico­ sapent ethyl. Medications known to exacerbate hypertriglyceridemia (ie, beta-blockers, thiazides, and estrogens) should be discontinued or changed, if possible, before the consideration of triglyceride-lowering drug therapy.4 The effect of icosapent ethyl on the risk for pancreatitis in patients with severe hypertriglyceridemia has not been determined. In addition, the effect of icosapent ethyl on cardiovascular morbidity and mortality in patients with severe hypertriglyceridemia has not been determined.4

Dosing Icosapent ethyl is available as a 1-g soft-gelatin capsule for oral use. The daily dose of icosapent ethyl is 4 g taken as 2 capsules twice daily with food. Icosapent capsules should be swallowed whole and should not be broken open, crushed, dissolved, or chewed.

The patient’s lipid levels should be assessed before initiating therapy, and other causes of high triglyceride levels should be identified and managed as appropriate.

Patients should engage in appropriate nutritional intake and physical activity before receiving icosapent ethyl, which should continue during treatment with icosapent.4 Clinical Pharmacology Evidence suggests that EPA reduces hepatic verylow-density lipoprotein (VLDL) triglycerides synthesis and/or secretion and enhances triglyceride clearance from circulating VLDL particles. Potential mechanisms of action include increased beta oxidation; inhibition of acyl-coenzyme A; 1,2-diacylglycerol acyltransferase; decreased lipogenesis in the liver; and increased plasma lipoprotein lipase activity.4 Peak plasma concentrations of EPA were reached approximately 5 hours after oral administration of ico­sapent ethyl. EPA is mainly metabolized by the liver via beta oxidation similar to dietary fatty acids. The total plasma clearance of EPA at steady state is 684 mL per hour. The plasma elimination half-life of EPA is approximately 89

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Table 2 I cosapent Ethyl versus Placebo: Percent Change from Baseline in Lipid Parameters in Patients with Severe Hypertriglyceridemia (≥500 mg/dL) Icosapent ethyl 4 g daily Placebo (N = 76) (N = 75) Differencea Lipid parameters

Median Median change Median Median change (95% confidence baseline, mg/dL from baseline, % baseline, mg/dL from baseline, % interval)

Triglycerides

680

−27

703

+10

−33b (−45 to −22)

LDL cholesterol

91

−5

86

−3

−2 (−13 to +8)

Non-HDL cholesterol

225

−8

229

+8

−18 (−25 to −11)

Total cholesterol

254

−7

256

+8

−16 (−22 to −11)

HDL cholesterol

27

−4

27

0

VLDL cholesterol

123

−20

124

+14

−29c (−43 to −14)

Apo B

121

−4

118

+4

−9c (−14 to −3)

−4 (−9 to +2)

The difference is the median of the icosapent ethyl percent change less the placebo percent change (HodgesLehmann estimate). b P <.001. c P <.05 (key secondary efficacy end points determined to be significant according to the prespecified multiple comparison procedure).

P values are from the Wilcoxon Rank-Sum Test.

Apo B indicates apolipoprotein B; HDL, high-density lipoprotein; LDL, low-density lipoprotein; VLDL, very-low-density lipoprotein.

Source: Vascepa (icosapent ethyl) capsules [package insert]. Bedminster, NJ: Amarin Pharma, Inc; 2012. a

hours. Icosapent ethyl does not undergo renal excretion.

In clinical trials, plasma total EPA concentrations did not differ significantly between men and women.4 Based on studies of a 4-g daily dose of icosapent ethyl, no drug–drug interactions were observed in patients taking medications that are typical substrates of cytochrome P450 enzymes, including omeprazole, rosiglitazone, warfarin, and atorvastatin.4

Clinical Trials The FDA approval of icosapent ethyl was based on the Multicenter, Placebo-Controlled, Randomized, Double-Blind, 12-Week Study with an Open-Label Extension (MARINE)—a randomized, placebo-controlled, double-blind, phase 3 study of adult patients (N = 151) with severe hypertriglyceridemia (>500 mg/dL).2,4 The primary end point of the 12-week MARINE study was the percentage change in triglycerides from baseline to week 12. The baseline characteristics of patients in this study are outlined in Table 1.2,4 In the MARINE study, icosapent ethyl 4 g daily demonstrated a significant reduction in placebo-adjusted median triglyceride level (33%; P <.001), apolipoprotein B level (9%; P <.05), and in VLDL cholesterol (29%; P <.05). Moreover, the reduction in triglyceride levels observed with icosapent ethyl was not associated with

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elevations in LDL cholesterol levels relative to placebo.4 The changes from baseline in the major lipoprotein lipid parameters for patients receiving icosapent ethyl versus placebo are shown in Table 2.4 In this study, ico­ sapent ethyl 4 g daily also demonstrated significant placebo-adjusted median reductions from baseline in nonHDL cholesterol (18%) and in total cholesterol (16%; P <.001 for both).2,4 In a follow-up exploratory analysis of the MARINE trial, icosapent ethyl 4 g daily demonstrated a significant reduction in particle concentrations of large VLDL, total LDL, small LDL, and total HDL, and a significant reduction in VLDL particle size in patients with triglycerides ≥500 mg/dL.11

Safety Profile In clinical studies, icosapent ethyl was generally well tolerated, with a safety profile similar to that of placebo.

The most common adverse reaction (incidence, >2%, and greater than placebo) was arthralgia (2.3% for icosapent vs 1.0% for placebo).2,4 Omega-3 acids may prolong bleeding time. Patients receiving treatment with icosapent ethyl and other drugs that affect coagulation (eg, antiplatelet agents) should be monitored periodically.

In patients with hepatic impairment, alanine amino-

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transferase and aspartate aminotransferase levels should be monitored periodically during therapy.4 Icosapent ethyl contains ethyl esters of the omega-3 fatty acid EPA, which are obtained from the oil of fish.

Because it is not known whether patients with allergies to fish and/or shellfish are at an increased risk of an allergic reaction, icosapent ethyl should be used with caution in patients who have a known hypersensitivity to fish and/or shellfish.4

Conclusion With the FDA approval of icosapent ethyl in 2012, a new treatment option became available for patients with severe hypertriglyceridemia, a condition that is associated with an increased risk of cardiovascular disease, particularly in the presence of low HDL cholesterol levels and/or elevated LDL cholesterol levels. Icosa­ pent ethyl is the first EPA-only omega-3 agent indicated to reduce triglyceride levels in adults with elevated levels to be used as an adjunct to a lipid-lowering diet and exercise regimen.

In patients with severe hypertriglyceridemia, the daily use of icosapent ethyl for 12 weeks demonstrated a significant reduction in triglycerides, without an increase in LDL cholesterol levels. Moreover, this new medication has shown significant reductions from baseline in nonHDL cholesterol, total cholesterol, VLDL cholesterol, and apolipoprotein B levels. Icosapent ethyl has been

shown to be generally well tolerated for severe hypertriglyceridemia, offering patients a safe and effective treatment option, with a new mechanism of action that may be particularly helpful in some patients. n

References

1. Miller M, Stone NJ, Ballantyne C, et al. Triglycerides and cardiovascular disease: a scientific statement from the American Heart Association. Circulation. 2011;123: 2292-2333.

2. Bays HE, Ballantyne CM, Kastelein JJ, et al. Eicosapentaenoic acid ethyl ester (AMR 101) therapy in patients with very high triglyceride levels (from the Multi-Center, Placebo-Controlled, Randomized, Double-Blind, 12-Week Study with an Open-Label Extension [MARINE] trial). Am J Cardiol. 2011;108:682-690.

3. Mayo Clinic. Triglycerides: why do they matter? Updated September 28, 2012. www.mayo­clinic.com/health/triglycerides/CL00015/METHOD=print. Accessed March 14, 2013.

4. Vascepa (icosapent ethyl) capsules [package insert]. Bedminster, NJ: Amarin Pharma, Inc; 2012.

5. Wei MY, Jacobson TA. Effects of eicosapentaenoic acid versus docosahexaenoic acid on serum lipids: a systematic review and meta-analysis. Curr Atheroscler Rep. 2011;13:474-483. Erratum in Curr Atheroscler Rep. 2012;14:93.

6. Jacobson TA, Glickstein SB, Rowe JD, Soni PN. Effects of eicosapentaenoic acid and docosahexaenoic acid on low-density lipoprotein cholesterol and other lipids: a review. J Clin Lipidol. 2012;6:5-18.

7. Weigand P, McCombs JS, Wang JJ. Factors of hyperlipidemia medication adherence in a nationwide health plan. Am J Manag Care. 2012;18:193-199.

8. Nichols GA, Arondekar B, Garrison LP Jr. Patient characteristics and medical care costs associated with hypertriglyceridemia. Am J Cardiol. 2011;107:225-229.

9. Amarin announces FDA approval of Vascepa (icosapent ethyl) capsules for the reduction of triglyceride levels in adult patients with severe hypertriglyceridemia.

Press release. Bedminster, NJ: Amarin Pharma, Inc; July 26, 2012. http://investor. amarincorp.com/releasedetail.cfm?ReleaseID=696027. Accessed March 18, 2013.

10. A closer look at omega-3 fatty acids. Vascepa (icosapent ethyl). www.vascepa. com/hcp/omega3.shtml. Accessed March 20, 2013.

11. Bays HE, Braeckman RA, Ballantyne CM, et al. Icosapent ethyl, a pure EPA omega-3 fatty acid: effects on lipoprotein particle concentration and size in patients with very high triglyceride levels (the MARINE study). J Clin Lipidol. 2012;6:565-572.

AHDB_PayerPerDerm_40513_AHDB_PayerPerDerm 4/5/13 12:00 PM Page 1

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Vol 6, No 3

Zioptan Receives FDA Approval for Patients with Open-Angle Glaucoma and/or Ocular Hypertension

By Loretta Fala, Medical Writer

G

laucoma is a group of chronic eye diseases that cause irreversible damage to the optic nerve, which leads to serious vision loss and blindness.1 Often associated with increased intraocular pressure, glaucoma affects an estimated 2.2 million people in the United States.1 The population affected by glaucoma is expected to increase to nearly 3 million people by 2020.1 Moreover, glaucoma is projected to become more prevalent as the aging US population increases.2

Glaucoma: Overview Although there are several types of glaucoma, open-angle glaucoma and angle-closure glaucoma are the 2 main types.3 Other types of glaucoma include normal-tension glaucoma, congenital glaucoma, and several variant forms of the open-angle and angle-closure type, such as secondary glaucoma, traumatic glaucoma, neovascular glaucoma, and others.3 Open-angle glaucoma is the most common type, accounting for approximately ≥90% of all glaucoma cases in the United States.3 Glaucoma is a leading cause of blindness in the United States, accounting for approximately 11% of all cases of blindness.4,5 Blindness resulting from glaucoma is 6 to 8 times more prevalent in blacks than in whites.4 In fact, open-angle glaucoma accounts for 19% of all blindness among blacks compared with 6% of blindness in whites.4 Moreover, the risk of visual impairment is 15 times higher in blacks than in whites.4 Glaucoma is particularly devastating, given its potential to destroy retinal ganglion cells (RGCs) in the optic nerve, which subsequently leads to permanent vision loss.1 Based on recent evidence, increased intraocular pressure may prevent RGCs from receiving a brain-­ derived neurotrophic factor, a protein required for RGC survival, from nearby cells in the optic nerve.1 Approximately 70% of patients with glaucoma have a history of elevated intraocular pressure.1 An elevated baseline intraocular pressure has consistently been established as one of the only modifiable risk factors associated with open-angle glaucoma. Other potentially modifiable factors, including intraocular pressure fluctuation and nutrition, are also being researched.6 Vision loss imposes a substantial societal and econom-

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ic burden for many people in the United States, which results in disability, suffering, and loss of productivity.7 Glaucoma has a detrimental effect on a person’s quality of life—including an effect on driving, walking, and reading—and it also may lead to social withdrawal and depression.2 The economic burden of glaucoma increases as the disease progresses.2 In the United States, glaucoma accounts for an estimated $2.9 billion annually in direct costs alone; this total cost is likely an underestimate, given that many patients with glaucoma are unaware that they have the condition.2,8 Glaucoma remains underdiagnosed and misunderstood.2 Individuals with glaucoma may remain undiagnosed, because the disease is relatively asymptomatic, particularly in the early stages, and a person may not seek medical attention until a bilateral field loss of vision occurs.2 In addition, many patients with diagnosed glaucoma are not receiving treatment.2 Over the past decade, substantial strides have been made in understanding and treating glaucoma.1 The Early Manifest Glaucoma Trial, a 6-year collaborative study, reinforced accumulating medical evidence showing that reducing eye pressure in the early stages of glaucoma slowed the disease progression.1,9 The Ocular Hypertension Treatment Study, an important study that included 1636 participants, showed that topical ocular hypotensive therapy delayed or prevented the onset of primary open-angle glaucoma in patients with elevated intraocular pressure, reducing the development of primary open-angle glaucoma by >50% (P <.001).10 A follow-up to that study showed that the use of daily topical ocular hypotensive therapy reduced the development of primary open-angle glaucoma in black patients by nearly 50% (P = .02).11 Improved screening and diagnostic techniques have led to more precise visual assessment tests. The recent development of prostaglandins, a new class of drugs that provides intraocular pressure control with fewer side effects, has further improved the management of glaucoma.1

Zioptan Receives FDA Approval In February 2012, the US Food and Drug Administration (FDA) approved Zioptan (tafluprost ophthalmic solution 0.0015%; Merck & Co), a preservative-free

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Table 1 Reduction in IOP with Tafluprost versus Timolol: Randomized, Double-Masked Study

Patient treatment group (N = 618)

IOP range at baseline (at 3 time points assessed), mm Hg

IOP range at 3 time points during the 12-week visit, mm Hg

23.8-26.1

17.4-18.6

23.5-26.0

17.9-18.5

Tafluprost 0.0015%, preservative free (n = 306) Timolol 0.5%, preservative free (n = 312)

Difference between treatments in IOP reduction were less than the prespecified noninferiority margin Difference was with the upper limits of the 2-sided 95% confidence interval for all 9 time points

IOP indicates intraocular pressure.

Source: Chabi A, at al. Am J Ophthalmol. 2012;153:1187-1196.

prostaglandin analog, to reduce elevated intraocular pressure in patients with open-angle glaucoma, as well as in patients with ocular hypertension (ie, eye pressure), a risk factor for glaucoma.12

Tafluprost can be used concomitantly with other topical ophthalmic drugs to lower intraocular pressure. If more than 1 topical ophthalmic agent is being used, each one should be administered at least 5 minutes apart.13

Clinical Pharmacology Tafluprost ophthalmic solution contains tafluprost 0.0015 mg/mL. Tafluprost is absorbed through the cornea and is hydrolyzed to the biologically active acid metabolite, tafluprost acid. Although its exact mechanism of action is unknown, tafluprost acid, a fluorinated analog of prostaglandin F2α, is a selective prostaglandin F receptor prostanoid receptor agonist that is believed to reduce intraocular pressure by increasing the uveoscleral outflow.

After the administration of 1 drop of the tafluprost 0.0015% solution once daily in each eye of healthy volunteers, the plasma concentrations of tafluprost acid peaked at a median time of 10 minutes on days 1 and 8.

Tafluprost, an ester prodrug, is hydrolyzed to its biologically active acid metabolite in the eye. The acid metabolite is further metabolized through fatty acid β-oxidation and phase 2 conjugation. At 30 minutes after the topical ocular administration of tafluprost 0.0015% ophthalmic solution, the mean plasma tafluprost acid concentrations were below the limit of quantification of the bioanalytic assay (10 pg/mL).13

Clinical Studies Data The FDA’s approval of tafluprost was based on safety and efficacy data from several clinical studies lasting up to 24 months. In these studies, patients with open-angle glaucoma or ocular hypertension and a baseline pressure of 23 mm Hg to 26 mm Hg who received tafluprost, dosed once daily in the evening, showed intraocular pressure reductions between 6 mm Hg and 8 mm Hg at 3 months and between 5 mm Hg and 8 mm Hg at 6 months.13

Dosing and Use The recommended dose of tafluprost ophthalmic solution is 1 drop in the conjunctival sac of the affected eye(s) once daily in the evening. The dose should not exceed once daily, because it has been shown that more frequent administration of prostaglandin analogs may lessen the intraocular pressure–lowering effect.

The reduction of intraocular pressure begins approximately 2 to 4 hours after the first administration of tafluprost ophthalmic solution, with the maximum effect reached after 12 hours.13

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Randomized, Double-Masked, Comparative Study In a randomized, double-masked, multicenter clinical trial, the efficacy and safety of tafluprost 0.0015% (preservative free) was compared with timolol (Timoptic) 0.5% (preservative free), a nonselective beta-adrenergic receptor antagonist, in 618 patients with open-angle glaucoma or ocular hypertension (Table 1).14 This study demonstrated that the intraocular pressure–lowering effect of tafluprost was noninferior to that of timolol.14 After hypotensive treatment was discontinued or washed out, patients with intraocular pressure between ≥23 mm Hg and ≤36 mm Hg in at least 1 eye were randomized in a 1:1 ratio to 12 weeks of therapy with tafluprost 0.0015% or with timolol 0.5%. Intraocular pressure measurements were taken 3 times throughout the day at baseline and at weeks 2, 6, and 12. At each of the 9 assessment time points, the study was powered for a noninferiority margin of 1.5 mm Hg.14 Patient-reported ocular pain, stinging, and irritation were similar in the tafluprost and the timolol groups (4.4% vs 4.6%, respectively). The percentages of patients who reported conjunctival hyperemia were 4.4% for tafluprost and 1.2% for timolol (nominal P = .16).14

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Vol 6, No 3

Table 2 Reduction in IOP in All Patients Treated with Tafluprost: Observational Study

Patients

Mean IOP (± SD) at baselinea

Mean IOP (± SD) after 6-12 weeks of monotherapy with tafluprost 0.0015%

P value

All patients (N = 2123)

19.5 (± 4.4) mm Hg

16.4 (± 2.9) mm Hg

<.001

Last observation carried forward.

IOP indicates intraocular pressure; SD, standard deviation.

Source: Erb C, et al. Adv Ther. 2011;28:575-585.

a

Table 3 IOP Reduction in Subgroups of Patients Switched to Tafluprost Monotherapy: Observational Study Mean IOP at baseline, mm Hg (± SD)

Mean IOP after 6-12 weeks of monotherapy with tafluprost 0.0015%, mm Hg (± SD)

P value

Mean IOP reduction at final visit, mm Hg

Treatment-naïve patients (n = 440)

22.6 (± 3.9)

16.7 (± 2.7)

<.001

–5.9

Previous monotherapy with beta-blockers (n = 307)

20.3 (± 3.5)

16.7 (± 2.6)

<.001

–3.6

Previous monotherapy with carbonic anhydrase inhibitors (n = 158)

19.0 (± 3.6)

16.0 (± 2.6)

<.001

–3.0

Previous monotherapy with prostaglandin analogs (n = 447)

16.8 (± 2.9)

15.8 (± 2.6)

<.001

–1.0

Patient subgroup

IOP indicates intraocular pressure; SD, standard deviation.

Source: Erb C, et al. Adv Ther. 2011;28:575-585.

Observational Study with a Large Patient Population Another study evaluated the efficacy, local tolerability, and safety of preservative-free tafluprost of 2123 patients with ocular hypertension and glaucoma (Table 2).15 Tafluprost significantly reduced intraocular pressure in all patients and also significantly reduced intraocular pressure in all monotherapy subgroups (Table 3).15 Medication changes were made in 41.1% of the patients because of tolerability issues and in 25.6% of the patients because of insufficient efficacy with previous medication.15 After changing these patients’ medication to tafluprost, their tolerability to the treatment improved. At the final visit, 85.7% of the patients rated their tolerability to the treatment as good or very good.15 The reasons for switching therapy to or adding preservative-free tafluprost included local intolerance (41.1%) and efficacy (25.6%), among other reasons. No details for the reason of changing or adding therapy were available for 16.4% of the patients.

During the treatment period, there were only a few

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adverse events. After the final visit, 97.8% of the patients continued treatment with tafluprost. Treatment was discontinued in 18 patients because of local intolerance, in 6 patients because of efficacy issues, in 4 patients who reported systemic side effects, and in 2 patients who preferred using a multidose treatment regimen.15

Safety Profile and Metabolic Properties Tafluprost 0.0015% was evaluated in 905 patients in 5 controlled clinical studies of up to 24 months. In patients treated with tafluprost, the most frequent adverse reaction was conjunctival hyperemia, which was reported in a range of 4% to 20% of the patients. Approximately 1% of the patients discontinued therapy because of ocular adverse reactions.13 Ocular adverse reactions reported in clinical studies (incidence, ≥2%) include13: • Ocular stinging or irritation, 7% • Ocular pruritus, including allergic conjunctivitis, 5% • Cataract, 3% • Dry eye, 3%

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• Ocular pain, 3% • Eyelash darkening, 2% • Growth of eyelashes, 2% • Blurred vision, 2%.

The nonocular adverse reactions reported (incidence, 2%-6%) include: • Headache, 6% • Common cold, 4% • Cough, 3% • Urinary tract infection, 2%.

Macular edema, including cystoid macular edema, has been reported during treatment with prostaglandin F2α analogs. Tafluprost should be used with caution in patients with aphakia, in pseudophakic patients with a torn posterior lens capsule, or in patients with known risk factors for macular edema.

Adverse reactions reported in postmarketing studies include iritis and uveitis. In postmarketing use with prostaglandin analogs, periorbital and lid changes, including deepening of the eyelid sulcus, have been observed.13

Precautions and Warnings There are no contraindications associated with the use of tafluprost. Changes to pigmented tissues, including pigmentation of the iris, eyelid, and eyelashes, have been reported with tafluprost use. Pigmentation is expected to increase as long as tafluprost is administered.

After tafluprost is discontinued, pigmentation of the iris is likely to be permanent, whereas eyelid pigmentation and eyelash changes have been reported to be reversible in some patients.

Tafluprost may gradually change eyelashes and vellus hair in the treated eye. These changes, which include increased length, color, thickness, shape, and number of lashes, are usually reversible when the treatment is discontinued.

Tafluprost should be used with caution in patients with active intraocular inflammation, because inflammation may be exacerbated.13 Specific Populations There are no adequate and well-controlled studies of tafluprost in pregnant women. Tafluprost should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus. It is not known whether tafluprost or its metabolites are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when tafluprost is given to a woman who is breastfeeding.13 No overall clinical differences in safety or effectiveness of tafluprost have been observed between elderly

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and other adult patients using this medication. Tafluprost is not recommended for use in pediatric patients because of the potential safety concerns related to increased pigmentation after long-term, chronic use.13

Conclusion With the FDA approval of tafluprost in 2012, another treatment option became available for the reduction of intraocular pressure in patients with open-angle glaucoma or ocular hypertension—serious conditions that can lead to blindness. Tafluprost ophthalmic solution, a preservative-free prostaglandin analog, was shown to be effective, safe, and generally well tolerated in a broad patient population in several studies lasting up to 24 months.16 Patients with open-angle glaucoma or with ocular hypertension who received tafluprost once daily demonstrated reductions in intraocular pressure and improved eye health outcomes. n References

1. National Institutes of Health. NIH Fact Sheets—Glaucoma. Updated February 14, 2011. http://report.nih.gov/nihfactsheets/ViewFactSheet.aspx?csid=92. Accessed January 28, 2013.

2. Varma R, Lee PP, Goldberg I, Kotak S. An assessment of the health and economic burdens of glaucoma. Am J Ophthalmol. 2011;152:515-522.

3. Glaucoma Research Foundation. Types of glaucoma. Updated May 24, 2012. www.glaucoma.org/glaucoma/types-of-glaucoma.php. Accessed January 28, 2013.

4. Glaucoma Research Foundation. Glaucoma facts and stats. Updated May 24, 2012. www.glaucoma.org/glaucoma/glaucoma-facts-and-stats.php. Accessed January 28, 2013.

5. Kymes SM, Plotzke MR, Li JZ, et al. The increased cost of medical services for people diagnosed with primary open-angle glaucoma: a decision analytic approach.

Am J Ophthalmol. 2010;150:74-81.

6. Coleman AL, Miglior S. Risk factors for glaucoma onset and progression. Surv Ophthalmol. 2008;53(suppl 1):S3-S10.

7. Centers for Disease Control and Prevention. Vision Health Initiative—basic information: fast facts. Updated February 5, 2009. www.cdc.gov/visionhealth/basic_ information/fast_facts.htm. Accessed January 28, 2013.

8. Rein DB, Zhang P, Wirth KE, et al. The economic burden of major adult visual disorders in the United States. Arch Ophthalmol. 2006;124:1754-1760.

9. Heijl A, Leske MC, Bengtsson B, et al. Early Manifest Glaucoma Trial Group.

Reduction of intraocular pressure and glaucoma progression: results from the Early Manifest Glaucoma Trial. Arch Ophthalmol. 2002;120:1268-1279.

10. Kass MA, Heuer DK, Higginbotham EJ, et al. The Ocular Hypertension Treatment Study: a randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma. Arch Ophthalmol.

2002;12:701-713;discussion 829-830.

11. Higginbotham EJ, Gordon MO, Beiser JA, et al; the Ocular Hypertension Treatment Study Group. The Ocular Hypertension Treatment Study: topical medical delays or prevents primary open-angle glaucoma in African American individuals. Arch Ophthalmol. 2004;122:813-820.

12. US Food and Drug Administration. FDA approves Zioptin to treat elevated eye pressure. FDA News Release. February 14, 2012. www.fda.gov/NewsEvents/News room/PressAnnouncements/ucm291966.htm. Accessed January 28, 2013.

13. Zioptan (tafluprost ophthalmic solution) 0.0015% [package insert]. Whitehouse Station, NJ: Merck and Co, Inc; 2012.

14. Chabi A, Varma R, Tsai JC, at al. Randomized clinical trial of the efficacy and safety of preservative-free tafluprost and timolol in patients with open-angle glaucoma or ocular hypertension. Am J Ophthalmol. 2012;153:1187-1196.

15. Erb C, Lanzl I, Seidova SF, Kimmich F. Preservative-free tafluprost 0.0015% in the treatment of patients with glaucoma and ocular hypertension. Adv Ther. 2011;28: 575-585.

16. Pozarowska D. Safety and tolerability of tafluprost in treatment of elevated intraocular pressure in open-angle glaucoma and ocular hypertension. Clin Ophthalmol.

2010;4:1229-1236.

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Zaltrap: A New Option for the Treatment of Patients with Metastatic Colorectal Cancer Resistant to or Progressing After an Oxaliplatin-Containing Regimen

By Lynne Lederman, PhD, Medical Writer

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he American Cancer Society estimated that in 2012 more than 143,000 people in the United States would be diagnosed with colorectal cancer (CRC) and more than 51,000 people would die from it.1

Burden and Impact of Colorectal Cancer CRC is the third most frequently diagnosed cancer and the third leading cause of death of both men and women in the United States.1,2 Nearly all CRCs are adenocarcinomas, which develop from adenomatous polyps (adenomas). Although adenomas are common, only a small percentage develop into CRC, and they do so slowly.2 Patients with early-stage CRC are usually asymp足tomatic; advanced CRC may be associated with blood in the stool, rectal bleeding, and lower abdominal pain. Blood loss can result in anemia, weakness, and fatigue in some patients.1 The relative survival rates for individuals with CRC decline over time, from 83% at 1 year, 64% at 5 years, to 58% at 10 years postdiagnosis.1 Although early-stage CRC is associated with a 90% 5-year survival rate, only 39% of CRCs are detected early.1 The screening for and removal of premalignant polyps have contributed to a decreasing incidence of CRC, as well as to decreasing mortality rates; however, the incidence of CRC has been increasing over the past 2 dec足 ades in individuals aged <50 years, because screening is not recommended for individuals in this age-group (who are at average risk).1,3 The 5-year survival rate for CRC that has spread regionally to adjacent organs or lymph nodes is 69%, but for metastatic CRC (mCRC) that has spread to distant organs, it is a dismal 12%.1 Nonmetastatic CRC is treated surgically, either by endoscopic removal of adenomatous polyps or by colectomy for higher-risk sessile polyps. Colectomy with the removal of lymph nodes is recommended when the polyp specimen is fragmented, has margins that cannot be assessed, or has an unfavorable histopathology. Invasive nonmetastatic CRC is also treated surgically, with colectomy and the removal of regional lymph nodes. Adjuvant therapy is not recommended for noninvasive,

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nonmetastatic CRC (ie, stage I). Patients with low-risk locally invasive (ie, stage II) disease have the option of being followed with observation, enrolling in a clinical trial, or being treated with adjuvant therapy, such as capecitabine or 5-fluorouracil (5-FU) plus leucovorin.

Patients with high-risk stage II disease are candidates for adjuvant chemotherapy with 5-FU plus leucovorin, capecitabine, 5-FU plus leucovorin, and oxaliplatin (FOLFOX); capecitabine plus oxaliplatin (CapeOx); or bolus 5-FU plus leucovorin and oxaliplatin (FLOX).

Stage III disease (ie, invasive disease with positive lymph nodes) is treated with primary surgery followed by adjuvant chemotherapy with FOLFOX, FLOX, single-agent capecitabine, or 5-FU plus leucovorin. The benefits of adjuvant therapy are seen primarily in patients with stage III disease.3,4 Approximately 50% of patients with CRC develop colorectal metastases, and most of them have disease metastatic to the liver that is not resectable.3 Often, mCRC develops after treatment for CRC, but up to 34% of patients present with mCRC to the liver, which has a worse prognosis.3 Surgical resection is an option for some patients, and chemotherapy (eg, with FOLFOX, FOLFIRI [5-FU plus leucovorin and irinotecan], or FOLFOXIRI [infusional 5-FU plus leucovorin, oxaliplatin, and irinotecan]) may render resectable some disease metastatic to the liver or to the lung.3 Other options for metastatic disease include targeted agents, such as bevacizumab (Avastin), a humanized monoclonal antibody that blocks vascular endothelial growth factor (VEGF); cetuximab and panitumu足mab; monoclonal antibodies against the epidermal growth factor receptor; and the polykinase inhibitor regorafenib, all in combination with 5-FU plus leucovorin or other agents.3-5 Despite advances in the treatment of mCRC, its poor prognosis suggests the need for more effective agents or for combination therapies.

FDA Approval of Ziv-Aflibercept On August 3, 2012, the US Food and Drug Administration (FDA) approved ziv-aflibercept (Zaltrap; sanofi-

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aventis) for use in combination with a FOLFIRI chemotherapy regimen to treat adults with mCRC that is resistant to or has progressed after an oxaliplatin-containing regimen.6,7 This approval has generated some controversy concerning the cost versus the benefits of ziv-aflibercept.

Several oncologists wrote in an editorial in the New York Times that Memorial Sloan-Kettering Cancer Center (MSKCC) would not prescribe ziv-aflibercept for patients with advanced CRC, because MSKCC staff believed that ziv-aflibercept was not better than “a similar medicine” (ie, bevacizumab), and because it was priced at more than twice the cost of bevacizumab.8 This is despite data from VELOUR, the phase 3 clinical trial that showed that adding ziv-aflibercept to FOL­ FIRI improved overall survival (OS) compared with FOLFIRI alone,7 as discussed later in this article.

This decision by MSKCC to not use the drug because of cost is not unusual, but such a public disclosure is, although cost issues are increasingly influencing clinical decisions. Of note, 2 of the 3 oncologists authoring the editorial were consultants for a pharmaceutical company that manufactures bevacizumab, the drug that competes with ziv-aflibercept.9 The overall response to the editorial has resulted in a 50% price cut for ziv-aflibercept, although the higher price was based on a higher dose that is not frequently used.10 Nevertheless, the results of the phase 3 clinical trial VELOUR have been called “an important milestone for patients with mCRC.”11

Clinical Pharmacology Description and Mechanism of Action Ziv-aflibercept is a recombinant fusion protein that acts as an angiogenesis inhibitor (ie, a VEGF trap). It was created via recombinant DNA technology and is expressed in Chinese hamster ovary cells. Ziv-aflibercept is a dimeric glycoprotein that includes the VEGF-binding portions of the extracellular domains of the human VEGF receptors 1 and 2 fused to the constant region (ie, Fc portion) of the human immunoglobulin G1. Ziv-aflibercept acts as a soluble receptor binding to the endogenous ligands of human VEGF-A, human VEGF-B, and human placental growth factor. The binding of ziv-aflibercept to these ligands can inhibit their binding to and activation of their receptors. This, in turn, can decrease both neovascularization and vascular permeability. In preclinical models, ziv-aflibercept inhibited formation of new blood vessels in animals and inhibited the growth of colon tumor xenografts in mice.12,13 Dosing and Administration Ziv-aflibercept is indicated for use in combination

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with FOLFIRI for the treatment of mCRC that is resistant to or has progressed after a regimen containing oxaliplatin. Ziv-aflibercept is administered by intravenous (IV) infusion over 1 hour every 2 weeks at a dose of 4 mg/kg. It should be administered before any components of the FOLFIRI regimen.13

VELOUR: A Phase 3 Clinical Trial Ziv-aflibercept was approved by the FDA after a priority review based on the results of the phase 3 clinical trial, VELOUR, a multinational, randomized, double-blind study comparing FOLFIRI in combination with ziv-aflib­ ercept or with placebo in patients with mCRC.7 Study Design The patients enrolled in the trial had mCRC that was resistant to or progressed during or within 6 months of treatment with oxaliplatin-based combination chemotherapy, with or without previous bevacizumab therapy.

A total of 1226 patients were randomly assigned in a 1:1 ratio to receive either 4-mg/kg ziv-aflibercept as a 1-hour IV infusion on day 1 or to receive placebo.13 In addition, all patients received FOLFIRI (180-mg/m2 irinotecan as a 90-minute IV infusion and 400-mg/m2/dL racemic leucovorin as a 2-hour IV infusion on the same day, followed by an IV bolus of 400-mg/m2 5-FU, followed by a continuous IV infusion over 46 hours of 2400-mg/m2 5-FU). This treatment was repeated every 2 weeks until disease progression or until unacceptable toxicity.

The primary efficacy end point was OS. Patients were stratified within treatment groups by Eastern Cooperative Oncology Group performance status and by whether they had received previous treatment with bevacizumab.13 Patient Population Table 1 lists the key baseline demographics and disease characteristics of the patients who were enrolled in VELOUR. Safety Profile In the phase 3 study, the most common any-grade adverse reactions found in ≥20% of patients that oc­curred at a higher rate in the ziv-aflib­ercept arm (≥2% difference between treatment arms) were leukopenia, diarrhea, neutropenia, proteinuria, increased aspartate aminotransferase, stomatitis, fatigue, thrombocytopenia, increased alanine aminotransferase, hypertension, decreased weight, decreased appetite, epistaxis, abdominal pain, dysphonia, increased serum creatinine, and headache.13 The most common grade 3 and grade 4 adverse events (AEs) found in ≥20% of patients that occurred at a higher rate in the ziv-aflibercept arm (≥2% difference between

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Response Efficacy results for ziv-aflibercept plus FOLFIRI versus placebo plus FOLFIRI after a median follow-up of 22.3 months are presented in the Figure and in Table 2. The planned subgroup analysis for OS based on stratification by previous treatment with bevacizumab resulted in a hazard ratio (HR) of 0.86 (95% confidence interval [CI], 0.68-1.1) for patients who received previous treatment with beva­cizumab versus an HR of 0.79 (95% CI, 0.670.93) for those who did not receive previous treatment with bevacizumab.13 Precautions and Discontinuation Ziv-aflibercept should be used with caution in patients with associated conditions; discontinuation of therapy or dose modification is required in several situations, as listed in Table 3.

Specifically, the drug should be discontinued in patients with any of the following conditions13: • Severe hemorrhage • Gastrointestinal (GI) perforation 1.0 1.0 • Compromised wound healing 0.9 0.9 • Fistula formation 0.8 • Hypertensive crisis or hypertensive encephalopathy0.8 • Arterial thromboembolic events 0.7 0.7 • Nephrotic syndrome or thrombotic microangiopathy 0.6 • Reversible posterior leukoencephalopathy syndrome.

0.6 0.5

Temporary Treatment Discontinuation, Delay 0.5 0.4 In addition, ziv-aflibercept should be suspended tempo0.4 rarily at least 4 weeks before elective surgery, and in pa0.3 0.3 tients with recurrent or severe hypertension, until it is 0.2 controlled; in the latter patient population, the dose 0.2 of 13 ziv-aflibercept should be reduced permanently to 2 mg/kg.0.1 0.1 In patients with proteinuria of 2 g per 24 hours, the 0.0 0.0 drug should be discontinued temporarily; when protein0 uria is reduced to <2 g per 24 hours, ziv-aflibercept can0 be resumed. For recurrent proteinuria, ziv-aflibercept should be suspended until proteinuria is <2 g per 24 hours, after which the dose should be permanently reduced to 2 mg/kg.

Ziv-aflibercept should be delayed in patients with neutropenia until the neutrophil count is ≥1.5 × 109/L.13

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aseline Demographics and Disease Characteristics in Table 1 B the Phase 3 Clinical Trial (N = 1226) Characteristica Median age: 61 yrs Sex: male, 59% Race: White, 87% Asian, 7% Black, 3.5% Baseline ECOG performance status: 98% = 0 or 1 Previous oxaliplatin-based combination chemotherapy in metastatic CRC or advanced CRC setting: Ziv-aflibercept/FOLFIRI (n = 612): 90% Placebo/FOLFIRI (n = 614): 89% Received previous bevacizumab in combination with oxaliplatin-based regimen: 28% of patients Treatment arms were similar unless otherwise specified.

ECOG indicates Eastern Cooperative Oncology Group; CRC, colorectal cancer.

Source: Zaltrap (ziv-aflibercept) injection for intravenous infusion [prescribing information]. Bridgewater, NJ: Regeneron Pharmaceuticals, sanofi-aventis; August 2012.

a

Figure Overall Survival of Patients in the Phase 3 Trial, by Treatment Group 1.0 1.0

Symbol=Censor Placebo + FOLFIRI Zaltrap + FOLFIRI

0.9 0.9 0.8 0.8

Probability of surviving

treatment arms) were neutropenia, diarrhea, hypertension, leukopenia, stomatitis, fatigue, proteinuria, and asthenia. The most frequent AEs resulting in the permanent discontinuation of ziv-aflib­ercept therapy in ≥1% of patients included asthenia/fatigue, infections, diarrhea, dehydration, hypertension, stomatitis, venous thromboembolic events, neutropenia, and proteinuria.13 Ziv-aflibercept was approved by the FDA with a Boxed Warning, as described at the end of this article.

0.7 0.7 0.6 0.6 0.5 0.5 0.4 0.4 0.3 0.3 0.2 0.2 0.1 0.1 0.0 0.0

00

66

12 12

6 12 18 Number at risk 6 12 18

Placebo 614 Zaltrap 612

485 498

286 311

18 18 24 24

24 24

30 Time30 (months) 131 51 148 75

30 30 36 36

14 33

36 36

42

42 42

FOLFIRI indicates leucovorin/fluorouracil/irinotecan.

Reprinted from Zaltrap (ziv-aflibercept) injection for intravenous infusion [prescribing information]. Bridgewater, NJ: Regeneron Pharmaceuticals, sanofi-aventis; August 2012.

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Table 2 Main Efficacy Outcomes in VELOUR, a Phase 3 Clinical Trial Placebo + FOLFIRI (N = 614)

Ziv-aflibercept + FOLFIRI (N = 612)

460 (74.9)

403 (65.8)

12.06 (95% CI, 11.07-13.08)

13.50 (95% CI, 12.52-14.95)

Overall survival Deaths, N (%) Median, months Stratified hazard ratio

0.817 (95% CI, 0.714-0.935)

Stratified log-rank test

P = .032

Progression-free survivala Events, N (%) Median, months

454 (73.9)

393 (64.2)

4.67 (95% CI, 4.21-5.36)

6.90 (95% CI, 6.51-7.20)

Stratified hazard ratio

0.758 (95% CI, 0.661-0.869)

Stratified log-rank test

P = .007

b

Overall response rate (CR + PR)

11.1 (95% CI, 8.5-13.8)

c

Stratified Cochran-Mantel-Haenszel test

19.8 (95% CI, 16.4-23.2) P = .001

Progression-free survival based on tumor assessment by the IRC; significance threshold of .001.

Stratified on ECOG performance status (0 vs 1 vs 2) and prior bevacizumab (yes vs no). c Overall objective response rate by IRC. CI indicates confidence interval; CR, complete response; ECOG, Eastern Cooperative Oncology Group; FOLFIRI, leucovorin/fluorouracil/irinotecan; IRC, Independent Review Committee; PR, partial response.

Source: Zaltrap (ziv-aflibercept) injection for intravenous infusion [prescribing information]. Bridgewater, NJ: Regeneron Pharmaceuticals, sanofi-aventis; August 2012. a

b

Table 3 Warnings and Precautions for Ziv-Aflibercept Warnings and precautions

Comments

Recommended monitoring

Fistula formation

May involve GI and non-GI sites

N/A

Grade 3 or 4 hypertension

Occurred in approximately 50% of patients receiving ziv-aflibercept + FOLFIRI during the first 2 cycles

Monitor blood pressure ≥every 2 weeks or as indicated; treat appropriately

Transient ischemic attack, cerebro­vascular accident, and angina pectoris occurred more frequently with ziv-aflibercept + FOLFIRI (2.6%) than with FOLFIRI alone (1.7%)

N/A

Severe proteinuria, nephrotic syndrome, thrombotic microangiopathy

Dipstick analysis and UPCR; a 24-hour urine collection should be obtained for patients with a UPCR of >1

Febrile neutropenia and neutropenic infection

Complete blood count with differential count at baseline and before initiation of each cycle

Increased in patients aged ≥65 years compared with younger patients

Monitor elderly patients closely for diarrhea

Also known as posterior reversible encephalopathy syndrome; usually resolves or improves in days but may lead to neurologic sequelae or death

If diagnosis is confirmed, discontinue ziv-aflibercept

Arterial thromboembolic events Renal events Neutropenia and neutropenic complications Diarrhea and dehydration Reversible posterior leukoencephalopathy syndrome

FOLFIRI indicates leucovorin/fluorouracil/irinotecan; GI, gastrointestinal; N/A, not applicable; UPCR, urinary protein creatinine ratio.

Source: Zaltrap (ziv-aflibercept) injection for intravenous infusion [prescribing information]. Bridgewater, NJ: Regeneron Pharmaceuticals, sanofi-aventis; August 2012.

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Boxed Warning Ziv-aflibercept was approved by the FDA with a Boxed Warning regarding several serious and potentially fatal AEs, including13: • Severe and sometimes fatal hemorrhage, including GI hemorrhage, has been reported in the patients who have received ziv-aflibercept in combination with FOLFIRI. Monitor patients for signs and symptoms of GI bleeding and other severe bleeding. Do not administer ziv-aflibercept to patients with severe hemorrhaging • GI perforation, including fatal GI perforation, can occur in patients re­ceiving ziv-aflibercept; discontinue ziv-aflibercept therapy in patients who experience GI perforation • Severe compromised wound healing can occur in patients receiving ziv-aflibercept/FOLFIRI. Dis­continue ziv-aflibercept in patients with compromised wound healing. Suspend ziv-aflibercept for at least 4 weeks before elective surgery, and do not resume ziv-aflibercept for at least 4 weeks after major surgery and until the surgical wound is fully healed.

Conclusion CRC is a major cause of mortality in the United States. Approximately 50% of these patients develop mCRC. Despite advances in the treatment of mCRC, its poor prognosis suggests the need for more effective agents or for combination therapies. Although alternative therapies are available for this patient population, considering the high mortality rate, the approval of a

new therapeutic option, such as ziv-aflibercept, for patients with this devastating disease may offer improved survival for some of the patients whose disease has failed to respond to previously available, FDA-approved therapies. Clinicians should use proper precautions when prescribing ziv-aflibercept, as specified in the prescribing information. n

References

1. American Cancer Society. Cancer Facts & Figures 2012. Atlanta, GA: American Cancer Society; 2012. www.cancer.org/acs/groups/content/@epidemiologysurveilance/ documents/document/acspc-031941.pdf. Accessed December 21, 2012.

2. American Cancer Society. Colorectal Cancer Facts & Figures 2011-2013. Atlanta, GA: American Cancer Society; 2011. www.cancer.org/acs/groups/content/@epidemiol ogysurveilance/documents/document/acspc-028323.pdf. Accessed December 21, 2012.

3. NCCN Clinical Practice Guidelines in Oncology. Colon cancer. Version 3.2013. www.nccn.org/patients/patient_guidelines/colon/index.html. Accessed November 28, 2012.

4. Venook A. Critical evaluation of current treatments in metastatic colorectal cancer. Oncologist. 2005;10:250-261.

5. He K, Cui B, Li G, et al. The effect of anti-VEGF drugs (bevacizumab and aflibercept) on the survival of patients with metastatic colorectal cancer (mCRC). Onco Targets Ther. 2012;5:59-65.

6. US Food and Drug Administration. FDA approves Zaltrap for metastatic colorectal cancer. News release. August 3, 2012. www.fda.gov/NewsEvents/Newsroom/Press Announcements/ucm314372.htm. Accessed November 28, 2012.

7. Sanofi US/Regeneron Pharmaceuticals. US FDA approves Zaltrap (ziv-aflibercept) after priority review for previously treated metastatic colorectal cancer. Press release. August 3, 2012. www.multivu.com/mnr/57253-sanofi-fda-approves-zaltrap-zivaflibercept. Accessed November 28, 2012.

8. Bach PB, Saltz LB, Wittes RE. In cancer case, cost matters. New York Times.

October 14, 2012. www.nytimes.com/2012/10/15/opinion/a-hospital-says-no-to-an11000-a-month-cancer-drug.html?_r=0. Accessed December 21, 2012.

9. Burstein HJ. A “shot heard ’round the world” on cancer drug costs? J Natl Compr Canc Netw. 2012;10:1315-1316.

10. Goldberg P. Zaltrap price cut in half effective immediately as Sanofi responds to criticism from oncologists. Cancer Letter. 2012;38:1-4.

11. Kim GP. Aflibercept trial is a milestone for patients with metastatic colorectal cancer. Commun Oncol. 2012;9:118-119.

12. Wang TF, Lockhart AC. Aflibercept in the treatment of metastatic colorectal cancer. Clin Med Insights Oncol. 2012;6:19-30.

13. Zaltrap (ziv-aflibercept) injection for intravenous infusion [prescribing information]. Bridgewater, NJ: Regeneron Pharmaceuticals, sanofi-aventis; August 2012.

WCMC_2013Conf_horizontalV280612_Layout 1 8/17/12 1:37 PM Page 1

SECOND ANNUAL CONFERENCE

2013 WORLD CUTANEOUS MALIGNANCIES CONGRESS

TM

• Melanoma • Basal Cell Carcinoma • Cutaneous T-Cell Lymphoma • Squamous Cell Carcinoma • Merkel Cell Carcinoma

July 26-28, 2013 Hyatt Regency La Jolla • at Aventine 3777 La Jolla Village Drive • San Diego, California

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Zytiga Receives an Expanded Indication for Treatment of Patients with Metastatic Castration-Resistant Prostate Cancer Before Chemotherapy

By Loretta Fala, Medical Writer

P

rostate cancer is one of the most common cancers in men. Nearly 2.5 million men in the United States have prostate cancer or have a history of prostate cancer.1 One of 6 men will be diagnosed with prostate cancer during their lifetime. The median age at diagnosis of prostate cancer is 67 years.1 The relative 5-year survival rate for localized or regional disease is nearly 100%.1 Conversely, prostate cancer with distant metastases has a 5-year relative survival rate of only 27.8%. An estimated ≥4% of all cases of prostate cancer metastasize to a distant site within the body.1 Castration-resistant prostate cancer (CRPC) is cancer that is resistant to medical or surgical interventions that lower testosterone levels. Metastatic CRPC is disease that has metastasized to other areas of the body.

Prostate cancer accounts for a total cost of $9.8 billion annually in the United States.2 Earlier diagnosis and management of prostate cancer may improve outcomes and reduce healthcare costs. Despite advances in care and earlier detection and intervention, many patients with prostate cancer progress to advanced disease and will require a patient-tailored treatment plan.3 Drug development has focused on improving therapeutic options for patients with metastatic CRPC, including treatments that extend overall survival, limit disease progression, manage symptoms, and reduce adverse effects.3

Zytiga: Expanded Indication for Use Before Chemotherapy In December 2012, the US Food and Drug Administration (FDA) approved an expanded indication for Zytiga (abiraterone acetate), an oral cytochrome (CY) P17 inhibitor, for the treatment of men with metastatic CRPC before the use of chemotherapy. Zytiga was initially approved by the FDA in April 2011 for the treatment of patients whose prostate cancer progressed after chemotherapy with docetaxel.4 The application of abiraterone acetate for this expanded indication prechemotherapy was expedited under the FDA’s priority review program. According to Richard

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Pazdur, MD, Director of the Office of Oncology Drug Products in the FDA’s Center for Drug Evaluation and Research, this approval “demonstrates the benefit of further evaluating a drug in an earlier disease setting and provides patients and healthcare providers the option of using Zytiga earlier in the course of treatment.”4 Based on the initial FDA approval of abiraterone acetate in 2011, no safety signals were identified for a Risk Evaluation and Mitigation Strategy program.5 The role of abiraterone acetate in the management of men with metastatic CRPC who were not previously treated with chemotherapy was highlighted as a notable advance in the American Society of Clinical Oncology’s annual report titled Clinical Care Advances 2012, which was based on the results of a phase 3 clinical trial.6 The expanded indication of abiraterone acetate in the prechemotherapy setting marks the availability of a non­ chemotherapeutic, hormonal treatment approach for appropriate patients with metastatic CRPC.3

Dosing The recommended dose of abiraterone acetate is 1000 mg (four 250-mg tablets) administered orally once daily in combination with oral prednisone 5 mg twice daily.

Abiraterone acetate must be taken on an empty stomach; no food should be consumed at least 2 hours before abir­ aterone acetate is taken and for at least 1 hour after the dose of abiraterone acetate is taken. The tablets are taken whole with water and should not be crushed or chewed.

For patients with baseline moderate hepatic impairment (Child-Pugh Class B), the starting dose of abir­ aterone acetate should be reduced to 250 mg once daily.

For patients who develop hepatotoxicity during treatment, abiraterone acetate should be held until recovery.

Retreatment may be initiated at a reduced dose. If patients develop severe hepatotoxicity, abiraterone acetate should be discontinued.7 Clinical Pharmacology Abiraterone acetate is a 17 alpha-hydroxylase/C17,20-­ lyase (CYP17) inhibitor indicated in combination with

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prednisone fot the treatment of patients with metastatic CRPC.7 Abiraterone acetate is converted in vivo to abiraterone, an androgen biosynthesis inhibitor that inhibits CYP17, an enzyme that is expressed in testicular, adrenal, and prostatic tumor tissues and is required for androgen biosynthesis.

Abiraterone acetate was shown to decrease serum testosterone and other androgens in patients in a placebo-controlled phase 3 clinical trial.8 It is not necessary to monitor the effect of abiraterone acetate on serum testosterone levels. Changes in serum prostate-specific antigen levels may be observed but have not been shown to correlate with clinical benefit in individual patients.7 In clinical studies of healthy patients and patients with metastatic CRPC, abiraterone acetate plasma concentrations were below detectable levels (<0.2 ng/mL) in >99% of the analyzed samples. After oral administration of abiraterone acetate to patients with metastatic CRPC, maximum plasma abiraterone concentrations are reached in 2 hours (median time).7

Clinical Study Leading to the New Indication The FDA approval of the expanded indication for abir­ aterone acetate was based on a double-blind, placebo-­ controlled, phase 3 clinical trial that included 1088 men (median age, 70 years) with late-stage CRPC who had not received previous cytotoxic chemotherapy. Patients were randomized in a 1:1 ratio to abiraterone acetate 1000 mg once daily or to placebo once daily. Both groups received concomitant prednisone 5 mg twice daily. Patients were receiving a gonadotropin-releasing hormone agonist or were previously treated with orchiectomy.8 Treatment was continued until evidence of radiographic or clinical disease progression—including cytotoxic chemotherapy, radiation, or surgical cancer treatment, pain requiring chronic opioids, or Eastern Cooperative Oncology Group (ECOG) performance status decline to ≥3—or until unacceptable toxicity occurred or withdrawal from the trial. Patients with moderate or severe pain, opiate use for cancer pain, or visceral organ metastases were excluded from this study.8 The primary end points in this study were overall survival and radiographic progression-free survival. The ECOG performance status score was 0 for 76% of the patients and 1 for 24% of the patients. The baseline pain assessment (worst pain over the past 24 hours) was 0 to 1 (ie, asymptomatic) in 66% of the patients and 2 to 3 (ie, mildly symptomatic) in 26% of the patients. Radiographic progression-free survival was assessed using sequential imaging studies and was defined by a bone scan identification of ≥2 new bone lesions with confirmation (Prostate Cancer Working Group 2 criteria) and/or modified Response Evaluation Criteria in Solid Tumors

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April 2013

Overall Survival of Patients Receiving Abiraterone Table 1 Acetate plus Prednisone versus Placebo plus Prednisone (Intent-to-Treat Analysis) Overall survival

Abiraterone acetate, 1000 mg daily (N = 546)

Placebo (N = 542)

200 (37)

234 (43)

35.3 (31.24-35.29)

30.1 (27.30-34.10)

Deaths, N (%) Median survival, months (95% CI) P valuea

.015b

Hazard ratioc (95% CI)

0.792 (0.655-0.956)

P value is derived from a log-rank test stratified by ECOG performance status score (0 vs 1). b Did not meet the prespecified value for statistical significance. c Hazard ratio is derived from a stratified proportional hazards model. A hazard ratio of <1 favors abiraterone acetate.

CI indicates confidence interval; ECOG, Eastern Cooperative Oncology Group.

Source: Zytiga (abiraterone acetate) tablets [package insert].

Horsham, PA: Janssen Biotech, Inc; 2012. a

Radiographic Progression-Free Survival of Patients Table 2 Receiving Abiraterone Acetate plus Prednisone versus Placebo plus Prednisone (Intent-to-Treat Analysis) Radiographic progression-free survival

Abiraterone acetate, 1000 mg daily Placebo (N = 546) (N = 542)

Progression or death, N (%) Median rPFS, months (95% CI) P valuea

150 (28)

251 (46)

NR (11.66-NR)

8.28 (8.12-8.54)

<.001

Hazard ratiob (95% CI)

0.425 (0.347-0.522)

P value is derived from a log-rank test stratified by ECOG performance status score (0 vs 1). b Hazard ratio is derived from a stratified proportional hazards model. A hazard ratio of <1 favors abiraterone acetate.

CI indicates confidence interval; ECOG, Eastern Cooperative Oncology Group; NR, not reached; rPFS, radiographic progression-free survival.

Source: Zytiga (abiraterone acetate) tablets [package insert].

Horsham, PA: Janssen Biotech, Inc; 2012. a

criteria for progression of soft-tissue lesions.8 The overall survival results of the study are shown in Table 1.7 The median overall survival was 5.2 months longer in the abiraterone acetate arm than in the placebo arm (P = .015), which did not meet the prespecified value for statistical significance.8

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At the prespecified radiographic progression-free survival analysis (Table 2), a significant difference was found in the number of patients who showed radiographic evidence of disease progression in the abiraterone acetate group (28%) compared with the placebo group (46%; P <.001).7,8 The primary efficacy of abiraterone acetate has also been supported by several secondary end point results.

Abiraterone plus prednisone significantly increased the median time to initiation of chemotherapy compared with placebo plus prednisone (25.2 months vs 16.8 months, respectively; hazard ratio [HR], 0.580; 95% confidence interval [CI], 0.487-0.691; P <.001).7 Moreover, abiraterone plus prednisone significantly increased the median time to opiate use compared with placebo plus prednisone (median time not reached vs 23.7 months, respectively; HR, 0.686; 95% CI, 0.5660.833; P = .001). The time to opiate use was supported by a delay in patient-reported pain progression favoring the abiraterone acetate arm.7

Adverse Events The most common (â&#x2030;Ľ10%) adverse reactions reported with abiraterone acetate have been fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection, and contusion. The most common (>20%) laboratory abnormalities reported with abiraterone acetate that were more common with this agent than with placebo include anemia, elevated alkaline phosphatase, hypertriglyceridemia, elevated aspartate aminotransferase, hypophosphatemia, elevated alanine aminotransferase, and hypokalemia.7 Contraindications and Precautions Abiraterone acetate is contraindicated in women who are or may become pregnant. It should not be used in patients with severe hepatic impairment (ChildPugh Class C).

Abiraterone acetate should be used with caution in patients with a history of cardiovascular disease. Hypertension should be controlled and hypokalemia should be corrected before and during treatment with this agent. In addition, blood pressure, serum potassium, and fluid retention symptoms should be monitored at least monthly while taking abiraterone.

When abiraterone acetate is used in combination with prednisone, use caution and monitor for symptoms and signs of adrenocortical insufficiency if prednisone is stopped or withdrawn, if the dose of prednisone is re-

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duced, or if the patient experiences unusual stress. An increased dosage of corticosteroids may be indicated before, during, and after stressful situations.

Increases in liver enzymes while using abiraterone have led to drug interruption, dose modification, and/or discontinuation of the medication. Monitor liver function and modify, interrupt, or discontinue abiraterone acetate dosing as recommended in the prescribing information.7 Because abiraterone acetate is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6, coadministration with CYP2D6 substrates that have a narrow therapeutic index should be avoided. If an alternative cannot be used, exercise caution and consider a dose reduction of the CYP2D6 substrate.

Conclusion The expanded indication of abiraterone acetate for use in combination with prednisone for the treatment of men with metastatic CRPC before chemotherapy provides a new treatment option for men with advanced CRPC for use early in the treatment paradigm before the initiation of chemotherapy. Abiraterone acetate has demonstrated improved overall survival, as well as improved radiographic progression-free survival, when used in this patient population before the administration of chemotherapy.

Abiraterone acetate in combination with prednisone is now available as a treatment option either before chemotherapy or after chemotherapy containing docetaxel for appropriate patients with metastatic CRPC whose disease has progressed while receiving androgen-deprivation therapy. n References

1. Surveillance, Epidemiology and End Results Stat Fact Sheets: Prostate. Surveillance, Epidemiology and End Results. http://seer.cancer.gov/statfacts/html/prost.html.

Accessed April 1, 2013.

2. Roehrborn CG, Black LK. The economic burden of prostate cancer. BJU Int. 2011; 108:806-813.

3. Chitre MM, Shears D. Current and future managed care considerations for the treatment of castration-resistant prostate cancer. CDMI Rep. Spring 2013:34-39.

4. US Food and Drug Administration. FDA expands Zytigaâ&#x20AC;&#x2122;s use for late-stage prostate cancer. Press release; December 10, 2012. www.fda.gov/NewsEvents/Newsroom/ PressAnnouncements/ucm331492.htm. Accessed April 2, 2012.

5. US Food and Drug Administration. Center for Drug Evaluation and Research.

Clinical Review of NDA 202379: Zytiga (abiraterone acetate) for metastatic castration-resistant prostate cancer after prior chemotherapy. April 26, 2011. www.access data.fda.gov/drugsatfda_docs/nda/2011/202379Orig1s000MedR.pdf. Accessed April 2, 2013.

6. Roth BJ, Krilov L, Adams S, et al. Clinical cancer advances 2012: annual report on progress against cancer from the American Society of Clinical Oncology. J Clin Oncol. 2013;31:131-161.

7. Zytiga (abiraterone acetate) tablets [prescribing information]. Horsham, PA: Janssen Biotech, Inc; December 2012.

8. Ryan CJ, Smith MR, de Bono JS, et al; for the COU-AA-302 Investigators. Abir­ aterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med. 2013;368:138-148. Erratum in: N Engl J Med. 2013;368:584.

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Vol 6, No 3

VASCEPA® (icosapent ethyl) Capsules, for oral use Brief summary of Prescribing Information Please see Full Prescribing Information for additional information about Vascepa.

1 INDICATIONS AND USAGE VASCEPA® (icosapent ethyl) is indicated as an adjunct to diet to reduce triglyceride (TG) levels in adult patients with severe (≥500 mg/dL) hypertriglyceridemia.

Usage Considerations: Patients should be placed on an appropriate lipid-lowering diet and exercise regimen before receiving VASCEPA and should continue this diet and exercise regimen with VASCEPA. Attempts should be made to control any medical problems such as diabetes mellitus, hypothyroidism, and alcohol intake that may contribute to lipid abnormalities. Medications known to exacerbate hypertriglyceridemia (such as beta blockers, thiazides, estrogens) should be discontinued or changed, if possible, prior to consideration of TG-lowering drug therapy.

Limitations of Use: The effect of VASCEPA on the risk for pancreatitis in patients with severe hypertriglyceridemia has not been determined.

The effect of VASCEPA on cardiovascular mortality and morbidity in patients with severe hypertriglyceridemia has not been determined.

2 DOSAGE AND ADMINISTRATION Assess lipid levels before initiating therapy. Identify other causes (e.g., diabetes mellitus, hypothyroidism, or medications) of high triglyceride levels and manage as appropriate. [see Indications and Usage (1)].

Patients should engage in appropriate nutritional intake and physical activity before receiving VASCEPA, which should continue during treatment with VASCEPA. The daily dose of VASCEPA is 4 grams per day taken as 2 capsules twice daily with food.

Patients should be advised to swallow VASCEPA capsules whole. Do not break open, crush, dissolve, or chew VASCEPA. 4 CONTRAINDICATIONS VASCEPA is contraindicated in patients with known hypersensitivity (e.g., anaphylactic reaction) to VASCEPA or any of its components.

5 WARNINGS AND PRECAUTIONS 5.1 Monitoring: Laboratory Tests In patients with hepatic impairment, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels should be monitored periodically during therapy with VASCEPA. 5.2 Fish Allergy VASCEPA contains ethyl esters of the omega-3 fatty acid, eicosapentaenoic acid (EPA), obtained from the oil of fish. It is not known whether patients with allergies to fish and/or shellfish are at increased risk of an allergic reaction to VASCEPA. VASCEPA should be used with caution in patients with known hypersensitivity to fish and/or shellfish.

6 ADVERSE REACTIONS 6.1 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.

Adverse reactions reported in at least 2% and at a greater rate than placebo for patients treated with VASCEPA based on pooled data across two clinical studies are listed in Table 1.

Table 1. Adverse Reactions Occurring at Incidence >2% and Greater than Placebo in Double-Blind, Placebo-Controlled Trials*

Placebo (N=309) Adverse Reaction Arthralgia

n

%

VASCEPA (N=622) n %

3

1.0

14

2.3

*Studies included patients with triglycerides values of 200 to 2000 mg/dL. An additional adverse reaction from clinical studies was oropharyngeal pain.

7 DRUG INTERACTIONS 7.1 Anticoagulants Some published studies with omega-3 fatty acids have demonstrated prolongation of bleeding time. The prolongation of bleeding time reported in those studies has not exceeded normal limits and did not produce clinically significant bleeding episodes.

Patients receiving treatment with VASCEPA and other drugs affecting coagulation (e.g., anti-platelet agents) should be monitored periodically.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C: There are no adequate and well-controlled studies in pregnant women. It is unknown whether VASCEPA can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. VASCEPA should be used during pregnancy only if the potential benefit to the patient justifies the potential risk to the fetus.

In pregnant rats given oral gavage doses of 0.3, 1 and 2 g/kg/day icosapent ethyl from gestation through organogenesis all drug treated groups had visceral or skeletal abnormalities including: 13th reduced ribs, additional liver lobes, testes medially displaced and/or not descended at human systemic exposures following a maximum oral dose of 4 g/day based on body surface comparisons. Variations including incomplete or abnormal ossification of various skeletal bones were observed in the 2 g/kg/day group at 5 times

human systemic exposure following an oral dose of 4 g/day based on body surface area comparison.

In a multigenerational developmental study in pregnant rats given oral gavage doses of 0.3, 1, 3 g/kg/day ethyl-EPA from gestation day 7-17, an increased incidence of absent optic nerves and unilateral testes atrophy were observed at ≥0.3 g/kg/day at human systemic exposure following an oral dose of 4 g/day based on body surface area comparisons across species. Additional variations consisting of early incisor eruption and increased percent cervical ribs were observed at the same exposures. Pups from high dose treated dams exhibited decreased copulation rates, delayed estrus, decreased implantations and decreased surviving fetuses (F2) suggesting multigenerational effects of ethyl-EPA at 7 times human systemic exposure following 4 g/day dose based on body surface area comparisons across species.

In pregnant rabbits given oral gavage doses of 0.1, 0.3, and 1 g/kg/day from gestation through organogenesis there were increased dead fetuses at 1 g/kg/day secondary to maternal toxicity (significantly decreased food consumption and body weight loss).

In pregnant rats given ethyl-EPA from gestation day 17 through lactation day 20 at 0.3, 1, 3 g/kg/day complete litter loss was observed in 2/23 litters at the low dose and 1/23 middose dams by post-natal day 4 at human exposures based on a maximum dose of 4 g/day comparing body surface areas across species.

8.3 Nursing Mothers Studies with omega-3-acid ethyl esters have demonstrated excretion in human milk. The effect of this excretion is unknown; caution should be exercised when VASCEPA is administered to a nursing mother. In lactating rats, given oral gavage 14C-ethyl EPA, drug levels were 6 to 14 times higher in milk than in plasma.

8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use Of the total number of subjects in clinical studies of VASCEPA, 33% were 65 years of age and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

9 DRUG ABUSE AND DEPENDENCE VASCEPA does not have any known drug abuse or withdrawal effects.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility In a 2-year rat carcinogenicity study with oral gavage doses of 0.09, 0.27, and 0.91 g/kg/day icosapent ethyl, respectively, males did not exhibit drug-related neoplasms. Hemangiomas and hemangiosarcomas of the mesenteric lymph node, the site of drug absorption, were observed in females at clinically relevant exposures based on body surface area comparisons across species relative to the maximum clinical dose of 4 g/day. Overall incidence of hemangiomas and hemangiosarcomas in all vascular tissues did not increase with treatment.

In a 6-month carcinogenicity study in Tg.rasH2 transgenic mice with oral gavage doses of 0.5, 1, 2, and 4.6 g/kg/day icosapent ethyl, drug-related incidences of benign squamous cell papilloma in the skin and subcutis of the tail was observed in high dose male mice. The papillomas were considered to develop secondary to chronic irritation of the proximal tail associated with fecal excretion of oil and therefore not clinically relevant. Drug-related neoplasms were not observed in female mice.

Icosapent ethyl was not mutagenic with or without metabolic activation in the bacterial mutagenesis (Ames) assay or in the in vivo mouse micronucleus assay. A chromosomal aberration assay in Chinese Hamster Ovary (CHO) cells was positive for clastogenicity with and without metabolic activation.

In an oral gavage rat fertility study, ethyl-EPA, administered at doses of 0.3, 1, and 3 g/kg/ day to male rats for 9 weeks before mating and to female rats for 14 days before mating through day 7 of gestation, increased anogenital distance in female pups and increased cervical ribs were observed at 3 g/kg/day (7 times human systemic exposure with 4 g/day clinical dose based on a body surface area comparison).

17 PATIENT COUNSELING INFORMATION 17.1 Information for Patients See VASCEPA Full Package Insert for Patient Counseling Information.

Distributed by: Amarin Pharma Inc. Bedminster, NJ, USA Manufactured by: Banner Pharmacaps, Tilburg, The Netherlands or Catalent Pharma Solutions, LLC, St. Petersburg, FL, USA Manufactured for: Amarin Pharmaceuticals Ireland Limited, Dublin, Ireland

Amarin Pharma Inc. Bedminster, NJ 07921 www.VASCEPA.com © 2012 Amarin Pharmaceuticals Ireland Limited.

All rights reserved.

12/2012 120707

For the treatment of severe hypertriglyceridemia (TG levels ≥ 500 mg/dL)

Clearly the right choice for your formulary VASCEPA® is an optimal TG-lowering agent for your formulary and your members with severe hypertriglyceridemia. VASCEPA® is the first FDA-approved, EPA-only omega-3-fatty acid that significantly lowers median placebo-adjusted TG levels by 33% without increasing LDL-C or HbA1c compared to placebo while also positively affecting a broad spectrum of lipid parameters.1 Consider VASCEPA® an affordable option for your members with severe hypertriglyceridemia (TG levels ≥ 500 mg/dL).

Indications and Usage VASCEPA® (icosapent ethyl) is indicated as an adjunct to diet to reduce triglyceride (TG) levels in adult patients with severe (≥ 500 mg/dL) hypertriglyceridemia.

• The effect of VASCEPA® on the risk for pancreatitis in patients with severe hypertriglyceridemia has not been determined • The effect of VASCEPA® on cardiovascular mortality and morbidity in patients with severe hypertriglyceridemia has not been determined Important Safety Information for VASCEPA® • VASCEPA® is contraindicated in patients with known hypersensitivity (e.g., anaphylactic reaction) to VASCEPA® or any of its components • Use with caution in patients with known hypersensitivity to fish and/or shellfish

• The most common reported adverse reaction (incidence >2% and greater than placebo) was arthralgia • Patients should be advised to swallow VASCEPA® capsules whole; not to break open, crush, dissolve, or chew VASCEPA®

Reference: 1. Bays HE, Ballantyne CM, Kastelein JJ, et al. Eicosapentaenoic acid ethyl ester (AMR101) therapy in patients with very high triglyceride levels (from the multi-center, placebo-controlled, randomized, double blind, 12-week study with an open-label extension [MARINE] trial). Am J Cardiol.

2011;108:682-690.

For more information on VASCEPA® see the brief summary or for the Full Prescribing Information please visit www.VASCEPA.com.

Amarin Pharma Inc. Bedminster, NJ 07921 www.AmarinCorp.com

© 2012 Amarin Pharmaceuticals Ireland Limited.

All rights reserved.

130033 1/2013

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