The Medical Letter. On Drugs and Therapeutics

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1 The Medical Letter Published by The Medical Letter, Inc. 145 Huguenot Street, New Rochelle, NY A Nonprofit Publication IN THIS ISSUE (starts on next page) Two Drugs for Weight Loss... p 69 Important Copyright Message The Medical Letter publications are protected by US and international copyright laws. Forwarding, copying or any distribution of this material is prohibited. Sharing a password with a non-subscriber or otherwise making the contents of this site available to third parties is strictly prohibited. By accessing and reading the attached content I agree to comply with US and international copyright laws and these terms and conditions of The Medical Letter, Inc. For further information click: Subscriptions, Site Licenses, Reprints or call customer service at: FORWARDING OR COPYING IS A VIOLATION OF US AND INTERNATIONAL COPYRIGHT LAWS

2 The Medical Letter publications are protected by US and international copyright laws. Forwarding, copying or any other distribution of this material is strictly prohibited. For further information call: The Medical Letter Published by The Medical Letter, Inc. 145 Huguenot Street, New Rochelle, NY A Nonprofit Publication Volume 54 (Issue 1398) September 3, 2012 Updated August 12, Two Drugs for Weight Loss In 2012, the FDA approved one new drug and a new combination of 2 old drugs as adjuncts to lifestyle changes for chronic weight management. Lorcaserin (lor-ca-ser-in; Belviq Arena/Esai) is a selective serotonin 2C receptor agonist. Qsymia (Vivus) is a fixed-dose combination of the weight-loss drug phentermine and an extended-release (ER) formulation of topiramate. The new products are approved for use in obese patients (body mass index [BMI] of >30 kg/m 2 ) and for patients who are overweight (BMI >27 kg/m 2 ) and have one weight-related risk factor such as hypertension, dyslipidemia or type 2 diabetes. OLDER DRUGS FOR WEIGHT LOSS 1 The lipase inhibitor orlistat is modestly effective (patients have lost kg more than with placebo over 1-4 years), but it causes unpleasant adverse effects such as flatulence with discharge, oily spotting and fecal urgency. The sympathomimetic amines, which are approved by the FDA only for short-term use to initiate dietinduced weight loss, are all controlled substances; methamphetamine has a high abuse potential and probably should not be used. All sympathomimetics can increase heart rate, raise blood pressure, and cause nervousness and insomnia. LORCASERIN (Belviq) Activation of the serotonin 2C receptor, which is found mainly in the central nervous system, is thought to suppress appetite and is considered unlikely to cause the hallucinations, cardiac valvulopathy, and pulmonary hypertension that have been associated with activation of other serotonin receptor subtypes. 2 Table 1. Some FDA-Approved Drugs for Treatment of Obesity 1 Drug Some Available Formulations Usual Daily Dosage Cost 2 Lorcaserin Belviq (Esai) 10 mg tabs 10 mg bid $ Phentermine/topiramate ER Qsymia (Vivus) 7.5/46, 15/92 mg 3 7.5/46-15/92 mg once Lipase Inhibitor Orlistat Xenical (Genentech) 120 mg caps 120 mg tid Alli 4 (GSK) 60 mg caps 60 mg tid Sympathomimetic Amines Benzphetamine generic 50 mg tabs mg once Didrex (Pfizer) to 50 mg tid Diethylpropion generic 25 mg, 75 mg ER tabs 25 mg tid or mg once Phendimetrazine generic 35 mg tabs 35 mg bid 8.40 Bontril PDM (Valeant) to 70 mg tid Phentermine generic 15, 30, 37.5 mg caps, 37.5 mg tabs mg once Adipex-P (Teva) 37.5 mg tabs 37.5 mg once Suprenza (Akrimax) 15, 30 mg ODT mg once ODT = orally disintegrating tablets. 1. Weight loss drugs, including over-the-counter medications, are not recommended for use during pregnancy. 2. Cost of 30 days treatment with the lowest strength available based on wholesale acquisition cost (WAC). Source: Analy$ource Monthly (Selected from FDB MedKnowledge ) August 5, Reprinted with permission by FDB, Inc. All rights reserved Actual retail prices may be higher. Medicare does not cover obesity drugs. 3. Also available in 3.75/23 and 11.25/69 mg capsules which are intended for use only during titration. 4. Available over the counter. FORWARDING OR COPYING IS A VIOLATION OF U.S. AND INTERNATIONAL COPYRIGHT LAWS 69

3 Clinical Studies Approval of lorcaserin was based on 3 randomized double-blind trials in obese or overweight adults; the first-year results are listed in Table In the first trial (BLOOM), patients who lost >5% of their body weight after one year on lorcaserin were randomized to continue the drug or switch to placebo for a second year. By the end of the second year, patients who continued on lorcaserin had regained about 25% of the initial weight loss, and those who took lorcaserin during the first year and placebo during year 2 had lost an average of only 1.2 kg more than those who had taken placebo for both years. 3 Table 2. Pharmacology Drug class Formulation Route Tmax Selective serotonin 2C receptor agonist 10-mg tablets Oral hours Half-life 11 hours Metabolism Extensively metabolised in the liver by multiple enzymes to inactive metabolites Execretion Urine (92%), feces (2%) The BLOOM-DM trial was conducted in patients with type 2 diabetes who were also being treated with metformin, a sulfonylurea or both. HbA1c decreased by 0.9% with lorcaserin twice daily, by 1.0% with lorcaserin once daily, and by 0.4% with placebo. 5 Adverse Effects Headache, nausea, and dizziness were the most frequent adverse effects reported with lorcaserin in clinical trials. The discontinuation rates were 50%, 45% and 36% in the 3 studies. Cardiac valvulopathy did not occur more frequently with lorcaserin than with placebo. Euphoria has been reported Table 3. Lorcaserin Clinical Trials Mean % Patients Weight Loss with >5% (52 weeks) Weight Loss BLOOM 3 (average baseline wt: 100 kg) Lorcaserin 10 mg bid 5.8 kg 47.5% (n=1538) Placebo (n=1499) 2.2 kg 20.3% BLOSSOM 4 (average baseline wt: 100 kg) Lorcaserin 10 mg once daily (n=801) 4.7 kg 40.2% 10 mg bid (n=1602) 5.8 kg 47.2% Placebo (n=1601) 2.9 kg 25.0% BLOOM DM 5 (average baseline wt: kg) Lorcaserin 10 mg once daily (n=95) 5.0 kg 44.7% 10 mg bid (n=251) 4.7 kg 37.5% Placebo (n=248) 1.6 kg 16.1% with doses >40 mg. Belviq is a schedule IV controlled substance. Drug Interactions Lorcaserin inhibits CYP2D6; it has increased peak serum concentrations of dextromethorphan, a 2D6 substrate, by 76%. Serotonin syndrome occurred in 2 patients during the clinical trials; one of these patients was also taking dextromethorphan. Dosage and Administration The dosage of lorcaserin recommended by the manufacturer is 10 mg twice daily. If the patient has not lost at least 5% of baseline weight by 12 weeks, the drug should be discontinued. Lorcaserin is contraindicated for use during pregnancy. PHENTERMINE/TOPIRAMATE (Qsymia) Phentermine is a sympathomimetic amine that has been available in the US for many years for short-term (weeks) treatment of obesity. When it was used with fenfluramine ( phen-fen ), the combination was associated with heart valve abnormalities; fenfluramine has since been withdrawn from the market. There have been only rare reports of valvular disease occurring in patients taking phentermine alone. Topiramate (Topamax, and others) is approved for use in epilepsy and migraine, but not for weight control. It has produced significant weight loss in some clinical trials; the mechanism is unclear. Clinical Studies Approval of Qsymia was based on two 56-week trials in which patients were randomized to placebo or to one of 2 doses of phentermine/topiramate; the 1-year results are listed in Table 4. 6,7 In an extension of the CONQUER trial, patients who volunteered to continue their study regimens for an additional 52 weeks lost (in total after 2 years) an average of 9.3% (9.6 kg) and 10.5% (10.9 kg) of their body weight, compared to a loss of 1.8% (2.1 kg) in the placebo group. 8 Adverse Effects Adverse effects that occurred in >5% of patients taking phentermine/topiramate ER and were significantly more frequent than with placebo included dry mouth, paresthesia, constipation, dysgeusia and, with the higher dose, insomnia. Cognitive difficulties affecting attention, concentration and memory were reported. The discontinuation rate of the combination was about 40% in the one-year trials. Topiramate is a carbonic anhydrase inhibitor; metabolic acidosis and kidney stones can occur. Antiepileptic drugs, including topiramate, have been reported to increase the risk of suicidal ideation and behavior. Qsymia is a schedule IV controlled substance. 70 The Medical Letter Volume 54 Issue 1398 September 3, 2012

4 Drug Interactions Topiramate is a mild inducer of CYP3A4 and a mild inhibitor of CYP2C19. Serum potassium concentrations were lower in patients who took both topiramate and hydrochlorothiazide than in those who took either drug alone. Topiramate taken with valproic acid has been associated with hyperammonemia, with and without encephalopathy. Serum concentrations of topiramate decreased about 40% when the drug was taken with phenytoin or carbamazapine. Phentermine is Table 4. Qsymia Trials Mean % Patients Weight Loss with >5% (56 weeks) Weight Loss EQUIP 6 (average baseline wt: kg) Phentermine/topiramate ER 3.75/23 mg (n=241) 6.0 kg 44.9% 15/92 mg (n=512) 12.6 kg 66.7% Placebo (n=514) 1.9 kg 17.3% CONQUER 7 (average baseline wt: 103 kg) Phentermine/topiramate ER 7.5/46 mg (n=498) 8.1 kg 62% 15/92 mg (n=995) 10.2 kg 70% Placebo (n=994) 1.4 kg 21% 1. Diet, drugs and surgery for weight loss. Treat Guidel Med Lett 2011; 9: KM Hurren and HD Berlie. Lorcaserin: an investigational serotonin 2C agonist for weight loss. Am J Health Syst Pharm 2011; 68: SR Smith et al. Multicenter, placebo-controlled trial of lorcaserin for weight management. N Engl J Med 2010; 363: MC Fidler 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: PM O Neill et al. Randomized placebo-controlled clinical trial of lorcaserin for weight loss in type 2 diabetes mellitus: The BLOOM-DM Study. Obesity 2012; 20: DB Allison et al Controlled-release phentermine/topiramate in severely obese adults: a randomized controlled trial (EQUIP). Obesity 2012; 20: KM Gadde et al. Effects of low-dose, controlled-release, phentermine plus topiramate combination on weight and associated comorbidities in overweight and obese adults (CONQUER): a randomised, placebo-controlled, phase 3 trial. Lancet 2011; 377: WT Garvey 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. contraindicated while taking, and for 14 days after stopping, a monoamine oxidase (MAO) inhibitor because of the risk of hypertensive crisis. Pregnancy Topiramate has been associated with a 2- to 5-fold increased risk of oral clefts when taken in the first trimester of pregnancy. Qsymia is contraindicated for use during pregnancy and is available only through a restricted access program (Qsymia REMS) designed to prevent fetal exposure to the drug. Dosage and Administration Phentermine/topiramate ER is taken once daily, preferably in the morning to prevent insomnia. The recommended dosage is 3.75/23 mg for 14 days followed by 7.5/46 mg. If a 3% weight loss is not achieved after 12 weeks on the 7.5/46 mg dose, the dosage may be increased to 11.25/69 mg for 14 days, and then to 15/92 mg. If the patient does not achieve at least a 5% decrease in weight after 12 weeks on the highest dose, the drug should be discontinued gradually; abrupt withdrawal of topiramate can cause seizures even in patients with no history of epilepsy. CONCLUSION Both lorcaserin (Belviq) and the phentermine/topiramate ER combination (Qsymia) taken as adjuncts to diet and exercise may be effective in increasing weight loss in the first year of use, but much less so in the second year. Qsymia appears to be more effective than lorcaserin, but may cause more troublesome adverse effects. The Medical Letter Volume 54 Issue 1398 September 3,

5 The Medical Letter EDITOR IN CHIEF: Mark Abramowicz, M.D. EXECUTIVE EDITOR: Gianna Zuccotti, M.D., M.P.H., F.A.C.P., Harvard Medical School EDITOR: Jean-Marie Pflomm, Pharm.D. ASSISTANT EDITORS, DRUG INFORMATION: Susan M. Daron, Pharm.D., Corinne E. Zanone, Pharm.D. CONSULTING EDITORS: Brinda M. Shah, Pharm.D., F. Peter Swanson, M.D. CONTRIBUTING EDITORS: Carl W. Bazil, M.D., Ph.D., Columbia University College of Physicians and Surgeons Vanessa K. Dalton, M.D., M.P.H., University of Michigan Medical School Eric J. Epstein, M.D., Albert Einstein College of Medicine Jane P. Gagliardi, M.D., M.H.S., F.A.C.P Duke University School of Medicine Jules Hirsch, M.D., Rockefeller University David N. Juurlink, BPhm, M.D., Ph.D., Sunnybrook Health Sciences Centre Richard B. Kim, M.D., University of Western Ontario Hans Meinertz, M.D., University Hospital, Copenhagen Sandip K. Mukherjee, M.D., F.A.C.C., Yale School of Medicine Dan M. Roden, M.D., Vanderbilt University School of Medicine Esperance A.K. Schaefer, M.D., M.P.H., Harvard Medical School F. Estelle R. Simons, M.D., University of Manitoba Neal H. Steigbigel, M.D., New York University School of Medicine Arthur M. F.Yee, M.D., Ph.D., F.A.C.R., Weil Medical College of Cornell University SENIOR ASSOCIATE EDITORS: Donna Goodstein, Amy Faucard ASSOCIATE EDITOR: Cynthia Macapagal Covey MANAGING EDITOR: Susie Wong ASSISTANT MANAGING EDITOR: Liz Donohue PRODUCTION COORDINATOR: Cheryl Brown EXECUTIVE DIRECTOR OF SALES: Gene Carbona FULFILLMENT & SYSTEMS MANAGER: Cristine Romatowski DIRECTOR OF MARKETING COMMUNICATIONS: Joanne F. Valentino VICE PRESIDENT AND PUBLISHER: Yosef Wissner-Levy Founded in 1959 by Arthur Kallet and Harold Aaron, M.D. Copyright and Disclaimer: The Medical Letter is an independent nonprofit organization that provides health care professionals with unbiased drug prescribing recommendations. The editorial process used for its publications relies on a review of published and unpublished literature, with an emphasis on controlled clinical trials, and on the opinions of its consultants. The Medical Letter is supported solely by subscription fees and accepts no advertising, grants or donations. No part of the material may be reproduced or transmitted by any process in whole or in part without prior permission in writing. The editors do not warrant that all the material in this publication is accurate and complete in every respect. The editors shall not be held responsible for any damage resulting from any error, inaccuracy or omission. Subscription Services Mailing Address: The Medical Letter, Inc. 145 Huguenot St. Ste. 312 New Rochelle, NY Customer Service: Call: or Fax: Web Site: custserv@medicalletter.org Permissions: To reproduce any portion of this issue, please your request to: permissions@medicalletter.org Copyright ISSN Subscriptions (US): 1 year - $98; 2 years - $189; 3 years - $279. $49.00 per year for students, interns, residents and fellows in the US and Canada. site license inquiries to: info@medicalletter.org or call x315. Special fees for bulk subscriptions. Special classroom rates are available. Back issues are $12 each. Major credit cards accepted. 72 The Medical Letter Volume 54 Issue 1398 September 3, 2012