The medical letter on drugs and therapeutics july 6 2015

Drugs for Insomnia Pharmacological treatment of insomnia includes prescription drugs, non-prescription medications, and "natural" remedies. Behavioral approaches such as cognitive behavioral therapy, which are not... Liletta - A Third Levonorgestrel-Releasing IUD The FDA has approved Liletta, an intrauterine device (IUD) that releases the synthetic progestin levonorgestrel, for prevention of pregnancy for up to 3 years. The fourth IUD to be... Ryanodex - A New Dantrolene Formulation for Malignant Hyperthermia The FDA has approved a new IV formulation of dantrolene (Ryanodex – Eagle) for prevention and treatment of malignant hyperthermia in adults and children. The new formulation requires... Eliglustat (Cerdelga) - An Oral Drug for Gaucher Disease (online only) The FDA has approved eliglustat (Cerdelga – Genzyme), an oral glucosylceramide synthase inhibitor, for treatment of adults with type 1 Gaucher disease. Eliglustat is metabolized...

The Medical Letter ® on Drugs and Therapeutics Objective Drug Reviews Since 1959 Volume 57 ISSUE ISSUE No 1433 1472 Volume 56 July 6, 2015 IN THIS ISSUE Drugs for Insomnia p 95 Liletta – A Third Levonorgestrel-Releasing IUD p 99 Ryanodex – A New Dantrolene Formulation for Malignant Hyperthermia p 100 Eliglustat (Cerdelga) – An Oral Drug for Gaucher Disease 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 Objective Drug Reviews Since 1959 Volume 57 ISSUE ISSUE No 1433 1472 Volume 56 ▶ July 6, 2015 Take CME Exams ALSO IN THIS ISSUE Liletta – A Third Levonorgestrel-Releasing IUD p 99 Ryanodex – A New Dantrolene Formulation for Malignant Hyperthermia .p 100 Eliglustat (Cerdelga) – An Oral Drug for Gaucher Disease online only Drugs for Insomnia Pharmacological treatment of insomnia includes prescription drugs, non-prescription medications, and "natural" remedies Behavioral approaches such as cognitive behavioral therapy, which are not discussed here, are also used Pharmacologic treatment and behavioral therapy are often combined BENZODIAZEPINE RECEPTOR AGONISTS — Zolpidem (Ambien, and others), zaleplon (Sonata, and generics), and eszopiclone (Lunesta, and generics) are not structural benzodiazepines, but they bind to benzodiazepine receptors All of them decrease sleep latency and are approved for use in patients with sleep-onset insomnia Benzodiazepine receptor agonists differ mainly in their duration of action (see Table 1) Zolpidem is the most widely prescribed hypnotic in the US The FDA has required manufacturers of zolpidem to lower the recommended dose for women and to recommend consideration of a lower dose for men because of concerns about high serum concentrations hours after taking the drug that could impair driving performance or cause falls in the elderly.1 The FDA also recommends that patients not drive or engage in other activities that require mental alertness the day after taking extendedrelease zolpidem even in low doses because levels can still remain high the next day.2 A low-dose sublingual formulation of zolpidem (Intermezzo) is the only hypnotic approved for treatment of insomnia following middle-of-the-night awakening.3 The FDA has also recommended that the starting dose of eszopiclone be reduced to mg for both men and women because one study found that taking an evening dose of mg impaired driving skills, memory, and coordination for more than 11 hours.4 Adverse Effects – Benzodiazepine receptor agonists can impair next-day performance, including driving.5 Complex sleep-related behaviors such as sleepwalking, sleep-eating, and sleep-driving may occur without conscious awareness6,7; risk factors for these behaviors include taking high doses of the drug, taking it at times other than bedtime, and concurrent use with other sedating drugs.8 Hallucinations have been reported Eszopiclone can leave an unpleasant aftertaste Some reports have associated use of hypnotics, particularly zolpidem, with excess mortality and an increased risk of cancer9,10; a cause-and-effect relationship has not been established Benzodiazepine receptor agonists are classified as schedule IV controlled substances; withdrawal, dependence, and abuse can occur Drug Interactions – Zolpidem, eszopiclone, and (minimally) zaleplon are metabolized by CYP3A4 Concurrent administration with a CYP3A4 inhibitor, such as clarithromycin (Biaxin, and generics), could increase the risk of toxicity, but with zolpidem and zaleplon the effect appears to be clinically insignificant Strong CYP3A4 inducers, such as rifampin (Rifadin, and others), could decrease the effectiveness of these drugs.11 Concurrent use of alcohol or other CNS depressants increases the risk of CNS depression BENZODIAZEPINES — Benzodiazepines decrease sleep latency and prolong the first two stages of sleep Like benzodiazepine receptor agonists, the differences between the benzodiazepines are primarily in their duration of action (see Table 1) Adverse Effects – Benzodiazepines can impair next-day performance, including driving.5,12 Complex 95 Published by The Medical Letter, Inc • A Nonprofit Organization The Medical Letter July 6, 2015 Vol 57 (1472) ® Table Some Hypnotics for Insomnia Drug Onset of Action Duration Some Oral Formulations Usual Hypnotic Dose Dose in Elderly Pregnancy Category* Cost1 Benzodiazepine Receptor Agonists Eszopiclone – generic Lunesta (Sunovion) 13 weeks have passed since the last injection Liletta may be inserted immediately after a first-trimester abortion or miscarriage, but the prescribing information recommends that it not be inserted after longer pregnancies until at least weeks have passed and the uterus is fully involuted ▶ July 6, 2015 Vol 57 (1472) ® Ryanodex – A New Dantrolene Formulation for Malignant Hyperthermia The FDA has approved a new IV formulation of dantrolene (Ryanodex – Eagle) for prevention and treatment of malignant hyperthermia in adults and children The new formulation requires fewer vials, less fluid volume, and less time for preparation and administration than other available IV dantrolene products (Dantrium, Revonto) THE DISORDER — Malignant hyperthermia is a rare hypercatabolic reaction characterized by uncontrolled release of calcium ions in skeletal muscle cells that most often occurs in genetically predisposed patients who are exposed to certain inhaled anesthetics or the muscle relaxant succinylcholine Dantrolene, which decreases calcium release from the sarcoplasmic reticulum, has been a drug of choice for treatment of malignant hyperthermia for many years.1 THE NEW FORMULATION — Ryanodex is available in single-use vials containing 250 mg of dantrolene as a lyophilized powder Vials must be reconstituted with mL of sterile water for injection (SWI; not bacteriostatic) Previously approved formulations contain only CONCLUSION — Liletta, a new levonorgestrel-releasing intrauterine device (IUD), offers effective contraception for at least years It does not have any clinical advantage over previously available hormonal IUDs, but the manufacturer sponsors programs that may make it more affordable than other IUDs for many women ■ Liletta Patient Savings Program Patient eligibility requirements Terms and conditions available at: www.lilettacard.com Accessed June 25, 2015 Choice of contraceptives Treat Guidel Med Lett 2010; 8:89 A new low-dose levonorgestrel-releasing IUD (Skyla) Med Lett Drugs Ther 2013; 55:21 DL Eisenberg et al Three-year efficacy and safety of a new 52mg levonorgestrel-releasing intrauterine system Contraception 2015; 92:10 American College of Obstetricians and Gynecologists ACOG Practice Bulletin No 121: Long-acting reversible contraception: implants and intrauterine devices Obstet Gynecol 2011; 118:184 20 mg of dantrolene per vial, and each vial requires reconstitution with 60 mL of SWI Ryanodex contains less mannitol, which is used to increase urine output in malignant hyperthermia, than Dantrium or Revonto Patients receiving the new formulation will require supplementary doses of mannitol.1 ADVERSE EFFECTS — Dantrolene can cause flushing, muscle weakness (including respiratory muscles), dyspnea, dysphagia, somnolence, and dizziness An unpublished study in 61 healthy volunteers (summarized in the package insert) found the adverse effects of Ryanodex to be generally similar to those of an older IV dantrolene formulation, but immediate flushing, dystonia, and dysphagia were more common and declines in hand grip strength occurred more rapidly and were more severe with Ryanodex CONCLUSION — Compared to other dantrolene formulations used for treatment of malignant hyperthermia, Ryanodex is easier and faster to reconstitute and requires less fluid volume for administration, but it is more expensive, has a shorter shelf life, and requires supplementary doses of mannitol ■ Association of Surgical Technologists Guideline statement for malignant hyperthermia in the perioperative environment Revised January 2013 Available at: www.ast.org/AboutUs/ Guideline_Statements Accessed June 25, 2015 Table Administration and Cost of IV Dantrolene Formulation Vials Required1 Fluid Volume Required1 Mannitol Content/Vial Shelf Life Cost2 $798.00 Dantrium (Par) 540 mL 3000 mg 36 months Revonto (US Worldmeds) 540 mL 3000 mg 36 months 630.00 Ryanodex (Eagle) mL 125 mg 24 months 2300.00 Based on an initial 2.5 mg/kg dose for a 70-kg patient (www.ast.org/AboutUs/Guideline_Statements) Approximate WAC for a 175-mg dose Cost of administration not included 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 June 5, 2015 Reprinted with permission by First Databank, Inc All rights reserved ©2015 www.fdbhealth.com/policies/drug-pricing-policy 100 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 Objective Drug Reviews Since 1959 Volume 57 (Issue 1472) ▶ July 6, 2015 Eliglustat (Cerdelga) – An Oral Drug for Gaucher Disease The FDA has approved eliglustat (Cerdelga – Genzyme), an oral glucosylceramide synthase inhibitor, for treatment of adults with type Gaucher disease Eliglustat is metabolized primarily by CYP2D6 Because patients who are CYP2D6 ultra-rapid metabolizers may not achieve therapeutic concentrations and a specific dosage cannot be recommended for indeterminate metabolizers, the FDA has approved the drug only for patients who are extensive, intermediate, or poor metabolizers of CYP2D6 Pronunciation Key Eliglustat: el” i gloo’ stat Cerdelga: sir del’ guh STANDARD TREATMENT — Patients with Gaucher disease have a genetic deficiency of the lysosomal enzyme glucocerebrosidase that leads to accumulation of glucosylceramide in the lysosomes of reticuloendothelial cells, primarily in the liver, spleen, and bone marrow The most common form of the disease (type 1) is characterized by hepatosplenomegaly, hematologic disorders, and bone involvement The standard treatment for Gaucher disease is enzyme replacement therapy with taliglucerase (Elelyso),1 imiglucerase (Cerezyme), or velaglucerase (Vpriv),2 which are all forms of the enzyme glucocerebrosidase These drugs are usually administered as an IV infusion over 1-2 hours every weeks Substrate reduction therapy with miglustat (Zavesca), an earlier glucosylceramide synthase Table Pharmacology Class Glucosylceramide synthase inhibitor Formulation 84 mg capsules Route Oral Mechanism of action Inhibits glucosylceramide synthase Tmax 1.5-2 hrs (EM); hrs (PM) Metabolism Extensive; primarily by CYP2D6 and to a lesser extent by CYP3A4 Elimination Feces (51.4%); urine (41.8%) Half-life (elimination) ~6.5 hrs (EM); ~8.9 hrs (PM) EM = CYP2D6 extensive metabolizers; PM = CYP2D6 poor metabolizers inhibitor, is an alternative for adults with mild to moderate type Gaucher disease who cannot receive enzyme replacement therapy; its use has been limited by severe side effects (diarrhea, weight loss, peripheral neuropathy, tremor) CLINICAL STUDIES — A double-blind trial (ENGAGE) randomized 40 previously untreated patients ≥16 years old with type Gaucher disease with baseline splenomegaly and thrombocytopenia to eliglustat or placebo for months The eliglustat group included 90% extensive, 5% intermediate, and 5% ultra-rapid CYP2D6 metabolizers At the end of the trial, mean spleen volume, the primary endpoint, decreased by 27.8% in patients taking eliglustat and increased by 2.3% in those taking placebo The mean hemoglobin level, mean liver volume, and mean platelet count, all secondary endpoints, were significantly improved in patients taking eliglustat compared to those taking placebo.3 In a 1-year, open-label, noninferiority trial, 160 patients ≥18 years old who had been receiving enzyme replacement therapy for at least years were randomized to oral eliglustat or IV enzyme replacement therapy with imiglucerase The eliglustat group included 4% poor, 11% intermediate, 79% extensive, and 4% ultra-rapid CYP2D6 metabolizers The composite primary endpoint was the percentage of patients whose hemoglobin level, platelet count, liver volume, and spleen volume remained stable (≤1.5 g/dL decrease in hemoglobin, ≤25% decrease in platelets, ≤20% increase in liver volume, and ≤25% increase in spleen volume) After 12 months, eliglustat was noninferior to imiglucerase in the percentage of patients meeting the primary endpoint (85% vs 94%, respectively).4 ADVERSE EFFECTS — Adverse effects occurring in ≥10% of patients in the two clinical trials included fatigue, headache, nausea, diarrhea, back pain, pain in the extremities, and upper abdominal pain DRUG INTERACTIONS — Eliglustat is a substrate of CYP2D6 and CYP3A4 Because high serum concentrations of the drug can prolong the PR, QTc, and e100 Published by The Medical Letter, Inc • A Nonprofit Organization The Medical Letter July 6, 2015 Vol 57 (1472) ® Table Recommendations for Use of Eliglustat with CYP Inhibitors Concomitant Drug(s) Recommended Eliglustat Dosage1 IM EM PM Strong or moderate CYP2D6 inhibitor plus strong or moderate CYP3A inhibitor Contraindicated Contraindicated No dosage adjustment needed Strong or moderate CYP2D6 inhibitor 84 mg once/d 84 mg once/d No dosage adjustment needed Strong CYP3A inhibitor 84 mg once/d Contraindicated Contraindicated Moderate CYP3A inhibitor 84 mg once/d Not recommended Not recommended Weak CYP3A inhibitor No dosage adjustment needed No dosage adjustment needed Not recommended EM = CYP2D6 extensive metabolizers; IM = CYP2D6 intermediate metabolizers; PM = CYP2D6 poor metabolizers The usual dosage of eliglustat for CYP2D6 extensive and intermediate metabolizers is 84 mg twice/d For CYP2D6 poor metabolizers, the usual dosage is 84 mg once/d QRS intervals, concurrent administration of inhibitors of either enzyme5 must be avoided or approached with caution; the FDA has made specific recommendations for dosage adjustments depending on the patient’s CYP2D6 metabolizer status (see Table 2) Coadministration of eliglustat with strong CYP3A inducers, such as rifampin, phenytoin, phenobarbital, carbamazepine, and St John’s wort, which markedly decrease serum concentrations of the drug, is not recommended for CYP2D6 extensive, intermediate, or poor metabolizers Eliglustat is also an inhibitor of P-glycoprotein (P-gp) and CYP2D6 and can increase serum concentrations of drugs that are substrates of these pathways Patients taking digoxin, a P-gp substrate, should have their digoxin serum concentrations measured before starting treatment with eliglustat The dose of digoxin should be reduced by 30% if it is taken concurrently with eliglustat and monitoring should be continued Eliglustat is not recommended for use in patients who are also taking a class IA (e.g., procainamide) or a class III (e.g., amiodarone) antiarrhythmic drug PREGNANCY — Eliglustat is classified as category C (fetal anomalies in rats; no adequate studies in women) for use during pregnancy DOSAGE, ADMINISTRATION, AND COST — CYP2D6 genotyping is required before dosage selection The recommended dosage of eliglustat is 84 mg twice daily for extensive and intermediate CYP2D6 metabolizers and once daily for poor metabolizers The capsules should be swallowed whole, preferably e101 with water, and should not be crushed, dissolved, or opened The drug is not recommended for use in patients with pre-existing cardiac disease or long QT syndrome The cost for weeks' treatment with Cerdelga 84 mg twice daily is $23,800 The cost of weeks’ treatment for a 70-kg patient at a dose of 60 units/kg is $34,892 with Cerezyme, $31,178 with Elelyso, and $30,294 with Vpriv.6 CONCLUSION — Eliglustat (Cerdelga) offers an oral alternative to IV enzyme replacement therapy for treatment of type Gaucher disease It significantly reduced spleen volume compared to placebo and maintained blood counts and liver and spleen volume in patients who switched from imiglucerase (Cerezyme) ■ In brief: taliglucerase (Elelyso) for Gaucher disease Med Lett Drugs Ther 2012; 54:56 In brief: velaglucerase (Vpriv) for Gaucher’s disease Med Lett Drugs Ther 2010; 52:36 PK Mistry et al Effect of oral eliglustat on splenomegaly in patients with Gaucher disease type 1: the ENGAGE randomized clinical trial JAMA 2015; 313:695 TM Cox et al Eliglustat compared with imiglucerase in patients with Gaucher’s disease type stabilised on enzyme replacement therapy: a phase 3, randomised, open-label, non-inferiority trial Lancet 2015; 385:2355 Inhibitors and inducers of CYP enzymes and P-glycoprotein Med Lett Drugs Ther 2013; 55:e44 Approximate WAC 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 June 5, 2015 Reprinted with permission by First Databank, Inc All rights reserved ©2015 www.fdbhealth.com/policies/drugpricing-policy The Medical Letter ® Continuing Medical Education Program medicalletter.org/cme-program Earn Up To 52 Credits Per Year Choose CME from The Medical Letter in the format that’s right for you! ▶ Comprehensive Exam – Available online or in print to Medical Letter subscribers, this 130 question exam enables you to earn 26 credits immediately upon successful completion of the test A score of 70% or greater is required to pass the exam Our comprehensive exams allow you to test at your own pace in the comfort of your home or office Comprehensive exams are offered every January and July enabling you to earn up to 52 credits per year (The July 2014 exam contains 78 questions and provides 13 credits) $49/exam ▶ Free Individual Exams – Free to active subscribers of The Medical Letter Answer 10 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OBJECTIVES: Activity participants will read and assimilate unbiased reviews of FDA-approved and off-label uses of drugs and other treatment modalities Activity participants will be able to select and prescribe, or confirm the appropriateness of the prescribed usage of, the drugs and other therapeutic modalities discussed in The Medical Letter with specific attention to clinical trials, pathophysiology, dosage and administration, drug metabolism and interactions, and patient management Activity participants will make independent and informed therapeutic choices in their practice Upon completion of this program, the participant will be able to: Discuss the pharmacologic options available for treatment of insomnia and compare them based on their efficacy, dosage and administration, adverse effects, and potential drug interactions Review the efficacy and safety of the new levonorgestrel-releasing intrauterine device (Liletta) for prevention of pregnancy Review the efficacy and safety of the new dantrolene formulation (Ryanodex) for treatment of malignant hyperthermia Privacy and Confidentiality: The Medical Letter guarantees our firm commitment to your privacy We not sell any of your information Secure server software (SSL) is used for commerce transactions through VeriSign, Inc No credit card information is stored IT Requirements: Windows XP/Vista/7/8, Mac OS X+; current versions of Microsoft IE, Mozilla Firefox, Google Chrome, Safari, or any other compatible web browser Highspeed connection Have any questions? Call us at 800-211-2769 or 914-235-0500 or e-mail us at: custserv@medicalletter.org Questions start on next page The Medical Letter ® Online Continuing Medical Education DO NOT FAX OR MAIL THIS EXAM To take CME exams and earn credit, go to: medicalletter.org/CMEstatus Issue 1472 Questions (Correspond to questions #1-10 in Comprehensive Exam #73, available January 2016) Drugs for Insomnia Liletta – A Third Levonorgestrel-Releasing IUD Benzodiazepine receptor agonists: a are structural benzodiazepines b all decrease sleep latency c are all similar in their duration of action d all of the above Which of the following IUDs does NOT release levonorgestrel? a Skyla b Paragard T 380A c Mirena d Liletta Both benzodiazepines and benzodiazepine receptor agonists: a can impair next-day performance, including driving b can cause complex sleep-related behaviors c are classified as schedule IV controlled substances d all of the above Compared to Skyla, Liletta: a is FDA-approved for a longer duration of use b has a smaller T-frame c releases a greater amount of active drug d all of the above A 44-year-old man who has been taking Ambien for years read on the internet that ramelteon (Rozerem) is a more natural way to treat insomnia He asks you if he should switch You could tell him that: a ramelteon has been shown to be more effective than Ambien in helping patients fall asleep sooner b ramelteon has been shown to be more effective than Ambien in helping patients stay asleep longer c ramelteon has no potential for abuse and is not a controlled substance d all of the above A 26-year-old woman who had been taking an oral hormonal contraceptive has Liletta inserted on day 10 of her menstrual cycle She asks whether she can stop taking the oral contraceptive after insertion You could tell her that she should: a continue taking the oral hormonal contraceptive for days after successful IUD placement b continue taking the oral hormonal contraceptive until the estimated date of her next period c continue taking the oral hormonal contraceptive every other day for 14 days until the IUD begins releasing levonorgestrel at maximum levels d stop taking the oral hormonal contraceptive now because the IUD begins releasing levonorgestrel immediately after insertion The most serious side effect of suvorexant (Belsomra) is: a next-day somnolence b angioedema c osteoporosis d hepatic injury Used as sleep aids, first-generation antihistamines can cause: a impairment of performance, including driving b urinary retention c next-day sedation d all of the above A possible advantage of Liletta over other hormonal IUDs is a lower: a risk of venous thromboembolism b risk of ectopic pregnancy c risk of perforation d cost Ryanodex – A New Dantrolene Formulation for Malignant Hyperthermia 10 Compared to other IV dantrolene formulations, Ryanodex: a requires less fluid volume for preparation b is more expensive c has a shorter shelf life d all of the above ACPE UPN: Per Issue Exam: 0379-0000-15-472-H01-P; Release: July 6, 2015, Expire: July 6, 2016 Comprehensive Exam 73: 0379-0000-16-073-H01-P; Release: January 2016, Expire: January 2017 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 Z Morrison, Pharm.D., Michael P Viscusi, Pharm.D.; CONSULTING EDITORS: Brinda M Shah, Pharm.D., F Peter Swanson, M.D; SENIOR ASSOCIATE EDITOR: Amy Faucard 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; 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 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, 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 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 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 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 2015 ISSN 1523-2859 Subscriptions (US): year - $129; 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Published by The Medical Letter, Inc • A Nonprofit Organization The Medical Letter July 6, 2015 Vol 57 (1472) ® Table Some Hypnotics for Insomnia Drug Onset of Action Duration Some Oral Formulations Usual... further information call: 800-211-2 769 The Medical Letter ® on Drugs and Therapeutics Objective Drug Reviews Since 1959 Volume 57 ISSUE ISSUE No 1433 1472 Volume 56 ▶ July 6, 2015 Take CME Exams