The Medical Letter ® on Drugs and Therapeutics Volume 59 ISSUE ISSUE No 1433 1513 Volume 56 January 30, 2017 IN THIS ISSUE Lixisenatide for Type Diabetes p 19 Pembrolizumab (Keytruda) for First-Line Treatment of Metastatic NSCLC p 22 Inflectra — An Infliximab Biosimilar p 23 Yosprala — A Combination of Aspirin and Omeprazole p 25 Drug Interaction: Dabigatran (Pradaxa) and Statins p 26 Corrections p 26 Comparison Chart of SGLT2 Inhibitors online only Important Copyright Message FORWARDING OR COPYING IS A VIOLATION OF U.S AND INTERNATIONAL COPYRIGHT LAWS The Medical Letter, Inc publications are protected by U.S 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 U.S 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: 800-211-2769 Published by The Medical Letter, Inc • A Nonprofit Organization 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: 800-211-2769 The Medical Letter ® on Drugs and Therapeutics Volume 59 January 30, 2017 Take CME Exams ISSUE ISSUE No 1433 1513 Volume 56 ▶ IN THIS ISSUE Pembrolizumab (Keytruda) for First-Line Treatment of Metastatic NSCLC p 22 Inflectra — An Infliximab Biosimilar p 23 Yosprala — A Combination of Aspirin and Omeprazole p 25 Drug Interaction: Dabigatran (Pradaxa) and Statins p 26 Corrections p 26 Comparison Chart of SGLT2 Inhibitors online only Lixisenatide for Type Diabetes The FDA has approved lixisenatide (Sanofi), a shortacting injectable GLP-1 (glucagon-like peptide-1) receptor agonist, for once-daily treatment of adults with type diabetes, both alone (Adlyxin) and in a fixed-ratio combination with insulin glargine (Soliqua 100/33) Lixisenatide has been available since 2013 in many other countries as Lyxumia It is the fifth GLP-1 receptor agonist to be approved in the US Pronunciation Key Lixisenatide: lix" i sen' a tide Adlyxin: ad lix' in Soliqua: so lee' kwa GLP-1 RECEPTOR AGONISTS — GLP-1 receptor agonists lower glucose levels by potentiating glucosedependent secretion of insulin, suppressing postprandial glucagon secretion, slowing gastric emptying, and promoting satiety They lower glycated hemoglobin (A1C) by about 1-1.5%, have been associated with average weight loss of 1.5-2.8 kg, and rarely cause hypoglycemia.1 The GLP-1 receptor agonist liraglutide (Victoza) has been shown to reduce the overall risk of a major cardiovascular event and the risk of death from cardiovascular causes in patients with type diabetes and high cardiovascular risk.2 Patients who are using a basal insulin such as insulin glargine, which primarily targets fasting plasma glucose, may benefit from addition of a short-acting GLP-1 receptor agonist such as lixisenatide, liraglutide, or exenatide (Byetta) to control postprandial plasma glucose concentrations.3 CLINICAL STUDIES — Lixisenatide – In randomized trials in patients with type diabetes, use of lixisenatide alone and in combination with metformin, a sulfonylurea, pioglitazone, or insulin lowered A1C and reduced weight (see Table 2) In one study in patients inadequately controlled on metformin (GetGoal-X), sponsored by Sanofi, addition of oncedaily lixisenatide was noninferior to addition of twice- Table Pharmacology of Lixisenatide Class Route Tmax (median) Elimination Half-life (terminal) GLP-1 receptor agonist SC injection 1-3.5 hours Renal; glomerular filtration and proteolytic degradation ~3 hours daily exenatide in reducing A1C, but exenatide caused more weight loss than lixisenatide.4 In a randomized, 26-week trial comparing once-daily lixisenatide 20 mcg with once-daily liraglutide 1.8 mg as add-ons to metformin, sponsored by Novo Nordisk, lixisenatide was significantly less effective than liraglutide in reducing A1C (-1.2% vs -1.8%); weight loss was similar with both drugs.5 In a randomized, double-blind trial in 6068 patients with type diabetes who had had either a myocardial infarction or an unstable angina event within the last months, rates of major cardiovascular events over a median follow-up of 25 months were similar with addition of lixisenatide or placebo to conventional therapy (13.4% vs 13.2%).6 Insulin Glargine/Lixisenatide – Approval of insulin glargine/lixisenatide was based on the results of an open-label trial in 736 patients with type diabetes inadequately controlled on basal insulin and one or two oral antihyperglycemic drugs After a 6-week run-in period, patients stabilized on a daily dose of 20-50 units of insulin glargine, with an A1C of 7-10% and fasting blood glucose ≤140 mg/dL, were randomized to receive insulin glargine/lixisenatide or continue on insulin glargine alone for 30 weeks; oral antihyperglycemic drugs other then metformin were discontinued The daily dose ranged from 10 to 60 units of insulin glargine and from to 20 mcg of lixisenatide At week 30, there was a significantly greater reduction in A1C with the combination than with insulin glargine alone (-1.1% vs -0.6%) Mean body weight decreased by 0.7 kg with 19 Published by The Medical Letter, Inc • A Nonprofit Organization The Medical Letter Vol 59 (1513) ® Table Some Lixisenatide Clinical Trials Drug Regimen A1C Weight Change Change (%)1 (kg)1 Lixisenatide 20 mcg/d3 Lixisenatide 20 mcg/d4 Placebo -0.7 -0.9 -0.2 -2.0 -2.0 -2.0 Get Goal-X5 24 wks (n=634) Metformin + Lixisenatide 20 mcg/d3 + Exenatide 10 mcg bid -0.8 -1.0 -3.0 -4.0 Get Goal-F16 24 wks (n=484) Metformin + Lixisenatide 20 mcg/d3 + Lixisenatide 20 mcg/d4 + Placebo -0.8 -0.9 -0.4 -2.7 -2.6 -1.6 Get Goal-M-Asia7 24 wks5 (n=391) Metformin ± sulfonylurea + Lixisenatide 20 mcg/d4 + Placebo -0.8 -0.5 -1.5 -1.2 Get Goal-S8 24 wks (n=859) Sulfonylurea ± metformin + Lixisenatide 20 mcg/d3 + Placebo -0.9 -0.1 -1.8 -0.9 Get Goal-P9 24 wks (n=484) Pioglitazone ± metformin + Lixisenatide 20 mcg/d3 + Placebo -0.9 -0.3 -0.2 +0.2 Get Goal-L10 24 wks (n=495) Basal insulin ± metformin + Lixisenatide 20 mcg/d3 + Placebo -0.7 -0.4 -1.8 -0.5 Get Goal-Duo 111 24 wks (n=446) Insulin glargine ± metformin ± thiazolidinedione + Lixisenatide 20 mcg/d3 -0.7 +0.3 + Placebo -0.4 +1.2 Get Goal Duo-212 26 wks (n=894) Insulin glargine ± metformin + Lixisenatide 20 mcg/d4 -0.6 + Insulin glulisine once/d -0.6 + Insulin glulisine tid -0.8 -0.6 +1.0 +1.4 Get Goal-L Asia13 24 wks (n=311) Basal insulin ± sulfonylurea + Lixisenatide 20 mcg/d3 -0.8 + Placebo +0.11 -0.4 +0.1 Study Monotherapy Get Goal-Mono2 12 wks (n=361) Add-on Therapy Least squares (LS) mean change from baseline VA Fonseca et al Diabetes Care 2012; 35:1225 Lixisenatide 10 mcg once daily for week, 15 mcg once daily for week, and then 20 mcg once daily Lixisenatide 10 mcg once daily for weeks, and then 20 mcg once daily J Rosenstock et al Diabetes Care 2013; 36:2945 GB Bolli et al Diabet Med 2014; 31:176 Study in Asian patients C Yu Pan et al Diabetes Metab Res Rev 2014; 30:726 J Rosenstock et al J Diabetes Complications 2014; 28:386 M Pinget et al Diabetes Obes Metab 2013; 15:1000 10 MC Riddle et al Diabetes Care 2013; 36:2489 11 MC Riddle et al Diabetes Care 2013; 36:2497 12 J Rosenstock et al Diabetes Care 2016; 39:1318 13 Study in Asian patients Y Seino et al Diabetes Obes Metab 2012; 14:90 the combination and increased by 0.7 kg with insulin glargine alone.7 An open-label, 30-week trial in 1170 patients with type diabetes inadequately controlled on metformin compared insulin glargine 10-60 units/lixisenatide 5-20 mcg daily to insulin glargine 10-60 units/day alone and to lixisenatide 10-20 mcg/day alone Reductions in A1C were greater with the combination than with either component alone (-1.6% vs -1.3% with insulin glargine and -0.9% with lixisenatide) Mean body weight decreased by 2.3 kg with lixisenatide alone and by 0.3 kg with the combination, and increased by 1.1 kg with insulin glargine alone.8 20 January 30, 2017 ADVERSE EFFECTS — Nausea, vomiting, and other GI adverse effects occurred in 39.7% of patients treated with lixisenatide in clinical trials, which is similar to the rate with other GLP-1 receptor agonists; 4.3% of patients discontinued the drug because of GI symptoms GLP-1 receptor agonists slow gastric emptying and should not be used in patients with severe gastroparesis Other common adverse effects of lixisenatide were headache (9%) and dizziness (7%) Anaphylaxis occurred in 0.1% of lixisenatide-treated patients Other serious hypersensitivity reactions such as angioedema have also been reported Antibodies to lixisenatide developed in 70% of patients; these patients were more likely to experience allergic or injectionsite reactions and those with the highest antibody concentrations had a reduced glycemic response Use of GLP-1 receptor agonists has been associated with renal insufficiency and worsening of chronic renal failure Their use may also be associated with a risk of acute pancreatitis, but a causal relationship has not been established.1 The most common adverse effect of the insulin glargine/lixisenatide combination is hypoglycemia Allergic and injection-site reactions, lipodystrophy, weight gain, and peripheral edema can occur The incidence of GI adverse effects with the combination was lower than with lixisenatide alone (possibly as a result of more gradual dose titration), but higher than with insulin glargine alone DRUG INTERACTIONS — Since lixisenatide slows gastric emptying, it may decrease the rate and extent of absorption of oral medications taken concomitantly Oral contraceptives should be taken hour before or 11 hours after lixisenatide Lixisenatide does not significantly inhibit or induce any CYP isozymes PREGNANCY AND LACTATION — Lixisenatide has not been studied in pregnant women Administration of lixisenatide to pregnant animals during organogenesis was associated with visceral closure and skeletal defects at systemic exposures 1-6 times higher than those achieved in humans at the recommended dose Low levels of lixisenatide have been detected in rat milk DOSAGE AND ADMINISTRATION — Adlyxin is available in prefilled pens containing 14 preset 10-mcg or 20-mcg doses The recommended starting dosage is 10 mcg SC once daily for 14 days; on day 15, the daily dosage should be increased to 20 mcg The Medical Letter Vol 59 (1513) ® January 30, 2017 Table GLP-1 Receptor Agonists Drug Formulations Albiglutide – Tanzeum (GSK) 30, 50 mg single-dose pen Dulaglutide – Trulicity (Lilly) 0.75 mg/0.5 mL, 1.5 mg/0.5 mL single-dose pen or syringe 0.75 or 1.5 mg SC once/wk3 626.00 250 mcg/mL (1.2, 2.4 mL prefilled pen) or 10 mcg SC bid4,5 668.30 mg single-dose pen or powder for injectable suspension2 mg/mL (3 mL prefilled pen) 50 mcg/mL, 100 mcg/mL (3 mL prefilled pen) mg SC once/wk3,5 622.80 1.2 or 1.8 mg SC once/d3,6 20 mcg SC once/d7,8 498.40 557.20 Exenatide – immediate-release Byetta (AstraZeneca) extended-release Bydureon (AstraZeneca) Liraglutide – Victoza (Novo Nordisk) Lixisenatide – Adlyxin (Sanofi) Usual Adult Dosage Cost1 30 or 50 mg SC once/wk $478.90 Combinations with Long-Acting Insulin Analogs Insulin glargine/lixisenatide – Soliqua 100/33 (Sanofi) 100 units/33 mcg/mL (3 mL prefilled pen) 15 units/5 mcg-60 units/ 20 mcg SC once/d7,9 508.0010 Insulin degludec/liraglutide – Xultophy 100/3.6 (Novo Nordisk) 100 units/3.6 mg/mL (3 mL prefilled pen) 16 units/0.58 mg-50 units/1.8 mg SC once/d11 762.4010 Approximate WAC for weeks’ or 30 days’ treatment at the lowest usual adult dosage WAC = wholesaler acquisition cost or manufacturer’s published price to wholesalers; WAC represents a published catalogue or list price and may not represent an actual transactional price Source: AnalySource® Monthly January 5, 2017 Reprinted with permission by First Databank, Inc All rights reserved ©2017 www.fdbhealth.com/policies/drug-pricing-policy Requires reconstitution before injection Can be given at any time of day, with or without food Starting dosage is mcg twice daily After one month, the dose can be increased to 10 mcg twice daily Should be given within 60 minutes before morning and evening meals (or before the two main meals of the day, approximately hours or more apart) Not recommended for patients with a CrCl 60% You have a 13-year-old male patient with severe Crohn’s disease that has not responded to Remicade His mother asks you if Inflectra might be more effective You could tell her that: a Inflectra has not been approved by the FDA for treatment of Crohn’s disease in children b In a randomized, double-blind trial comparing the two drugs in children with severe Crohn’s disease, Remicade was more effective than Inflectra c In one study, patients with Crohn’s disease who switched from Remicade to Inflectra had a higher rate of disease worsening than those who stayed on Remicade d all of the above Yosprala – A Combination of Aspirin and Omeprazole Yosprala contains: a immediate-release aspirin and delayed-release omeprazole b delayed-release aspirin and delayed-release omeprazole c delayed-release aspirin and immediate-release omeprazole d immediate-release aspirin and immediate-release omeprazole Drug Interaction: Dabigatran (Pradaxa) and Statins 10 A 70-year-old man taking dabigatran etexilate for atrial fibrillation now requires treatment for hyperlipidemia Based on the results of a recent population-based, case-controlled study, which of the following statins might interact with dabigatran and increase his risk of major hemorrhage? a atorvastatin b simvastatin c fluvastatin d rosuvastatin ACPE UPN: Per Issue Exam: 0379-0000-17-513-H01-P; Release: January 30, 2017, Expire: January 30, 2018 Comprehensive Exam 76: 0379-0000-17-076-H01-P; Release: July 2017, Expire: July 2018 PRESIDENT: Mark Abramowicz, M.D.; VICE PRESIDENT AND EXECUTIVE EDITOR: Gianna Zuccotti, M.D., M.P.H., F.A.C.P., Harvard Medical School; EDITOR IN CHIEF: Jean-Marie Pflomm, Pharm.D.; ASSOCIATE EDITORS: Susan M Daron, Pharm.D., Amy Faucard, MLS, Corinne Z Morrison, Pharm.D., Michael P Viscusi, 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; David N Juurlink, BPhm, M.D., Ph.D., Sunnybrook Health Sciences Centre; Richard B Kim, M.D., University of Western Ontario; Franco M Muggia, M.D., New York University Medical Center; 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., Weill Medical College of Cornell University MANAGING EDITOR: Susie Wong; ASSISTANT MANAGING EDITOR: Liz Donohue; EDITORIAL ASSISTANT: Cheryl Brown FULFILLMENT AND SYSTEMS MANAGER: Cristine Romatowski; SITE LICENSE SALES: Gene Carbona, Elaine Reaney-Tomaselli; EXECUTIVE DIRECTOR OF MARKETING AND 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, Inc is an independent nonprofit organization that provides healthcare 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, Inc does not sell advertising or receive any commercial support 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 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 Address: The Medical Letter, Inc 145 Huguenot St Ste 312 New Rochelle, NY 10801-7537 www.medicalletter.org Get Connected: Customer Service: Call: 800-211-2769 or 914-235-0500 Fax: 914-632-1733 E-mail: custserv@medicalletter.org Permissions: To reproduce any portion of this issue, please e-mail your request to: permissions@medicalletter.org Copyright 2017 ISSN 1523-2859 Subscriptions (US): year - $159; years - $298; years - $398 $65 per year for students, interns, residents, and fellows in the US and Canada Reprints - $12 each Site License Inquiries: E-mail: SubQuote@medicalletter.org Call: 800-211-2769 Special rates available for bulk subscriptions The Medical Letter ... etexilate (Pradaxa) and simvastatin (Zocor, and others) or lovastatin (Altoprev, and others), and the risks of taking these drugs concurrently Privacy and Confidentiality: The Medical Letter guarantees... information presented in materials contained in The Medical Letter The Medical Letter will strive to continually improve the CME program through periodic assessment of the program and activities The Medical. .. to pass the exam ACCREDITATION INFORMATION: ACCME: The Medical Letter is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians