The Medical Letter ® On Drugs and Therapeutics Published by The Medical Letter, Inc • 145 Huguenot Street, New Rochelle, NY 10801 • A Nonprofit Publication IN THIS ISSUE (starts on next page) In Brief: A Naloxone Auto-Injector (Evzio) p 45 Extended-Release Hydrocodone (Zohydro ER) for Pain p 45 Sublingual Immunotherapy for Allergic Rhinitis p 47 In Brief: Lowering the Dose of Lunesta p 48 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: 800-211-2769 FORWARDING OR COPYING IS A VIOLATION OF U.S AND INTERNATIONAL COPYRIGHT LAWS 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 Published by The Medical Letter, Inc • 145 Huguenot Street, New Rochelle, NY 10801 • A Nonprofit Publication Volume 56 (Issue 1444) June 9, 2014 ALSO IN THIS ISSUE Sublingual Immunotherapy for Allergic Rhinitis p 47 In Brief: Lowering the Dose of Lunesta p 48 IN BRIEF A Naloxone Auto-Injector (Evzio) A recent Medical Letter article reported renewed interest in the intranasal administration (off-label) of the opioid antagonist naloxone because of an increase in deaths from opioid overdose in the US.1 Now the FDA has approved a more practical alternative for emergency treatment of life-threatening opioid overdose in adults and children: a single-dose naloxone auto-injector (Evzio – Kaleo) for intramuscular or subcutaneous use Evzio will be available in kits containing two prefilled 0.4mg auto-injectors with voice guidance and a “trainer” device that also has voice guidance, but does not contain medication or a needle The manufacturer has not published a price for Evzio to date, but news reports indicate that each kit could cost hundreds of dollars, compared to about $20 for a standard 0.4-mg injectable dose of naloxone, which can be given intranasally Intranasal naloxone for treatment of opioid overdose Med Lett Drugs Ther 2014; 56:21 Extended-Release Hydrocodone (Zohydro ER) for Pain The FDA has approved an extended-release oral formulation of the opioid agonist hydrocodone (Zohydro ER – Zogenix) for management of pain severe enough to require continuous, long-term therapy and for which alternative treatment options are inadequate Zohydro ER is the first single-ingredient hydrocodone product to be marketed in the US Hydrocodone has been available for years in combination with acetaminophen (Vicodin, and others) or ibuprofen (Vicoprofen, and others).1 PHARMACOLOGY — Hydrocodone is a semisynthetic opioid It is metabolized primarily by CYP3A4-mediated www.medicalletter.org Take CME Exams N-demethylation to norhydrocodone and to a lesser extent by CYP2D6-mediated O-demethylation to hydromorphone Overall hydrocodone exposure is similar after administration of Zohydro ER or comparable daily doses of immediate-release hydrocodone combination products, but peak concentrations are lower with Zohydro ER and it has a longer half-life Steady state is reached after days of continuous use CLINICAL STUDY — In a clinical trial in opioid-tolerant patients with moderate to severe chronic back pain, those who had been successfully converted from their current opioid to single-agent hydrocodone ER during an initial open-label phase (n = 302) were randomized to continue active treatment with fixed stable doses of twice-daily hydrocodone ER (40-200 mg/day) or switch to placebo in the double-blind phase After 12 weeks, the average daily pain intensity score increased significantly more with placebo than with hydrocodone ER.2 ADVERSE EFFECTS — The most common adverse effects of hydrocodone ER during the clinical trial were constipation, nausea, somnolence, fatigue, headache, dizziness, dry mouth, vomiting, and pruritus Use of hydrocodone, particularly at high doses, has rarely been associated with sensorineural hearing loss.3 Overdosage with any opioid can result in respiratory depression and death Crushing, chewing, snorting, or injecting the contents of Zohydro ER capsules could result in uncontrolled delivery of hydrocodone, possibly leading to overdose and death Hydrocodone ER is classified as category C (teratogenic effects in animals; no adequate human studies) for use during pregnancy Infants born to mothers who received opioid therapy while pregnant may need treatment for neonatal opioid withdrawal syndrome POTENTIAL FOR ABUSE — Hydrocodone is a schedule II controlled substance Combination pain medications containing hydrocodone are currently classified as schedule III, but the DEA, following an FDA recommendation, has proposed reclassification FORWARDING OR COPYING IS A VIOLATION OF U.S AND INTERNATIONAL COPYRIGHT LAWS 45 Table Some Extended-Release Oral Opioids Drug Hydrocodone Zohydro ER (Zogenix) Hydromorphone Exalgo (Mallinckrodt) Morphine Avinza (Pfizer) Kadian (Actavis) generic MS Contin (Purdue) generic Oxycodone OxyContin (Purdue) Oxymorphone Opana ER (Endo) generic Formulations Starting Dosage1 Duration of Action Cost2 10, 15, 20, 30, 40, 50 mg ER caps 10 mg q12h 12 hrs $351.00 8, 12, 16, 32 mg ER tabs Footnote 24 hrs 380.104 30, 45, 60, 75, 90, 120 mg ER caps 10, 20, 30, 40, 50, 60, 70, 80, 100, 130, 150, 200 mg ER caps 20, 30, 50, 60, 80, 100 mg ER caps 15, 30, 60, 100, 200 mg ER tabs 30 mg q24h 30 mg q24h 24 hrs 12-24 hrs 159.00 210.60 15 mg q12h 8-12 hrs 136.80 133.80 40.20 10, 15, 20, 30, 40, 60, 80 mg ER tabs 10 mg q12h 12 hrs 136.20 5, 7.5, 10, 15, 20, 30, 40 mg ER tabs mg q12h 12 hrs 112.80 87.00 For patients who are not opioid tolerant For patients switching from another opioid, starting dosage is based on previous opioid dosage Long-acting formulations are generally not recommended for opioid-naive patients Approximate wholesale acquisition cost (WAC) for 30 days’ treatment at the starting dosage Source: Analy$ource® Monthly (Selected from FDB MedKnowledge™) May 5, 2014 Reprinted with permission by FDB, Inc All rights reserved ©2014 www.fdbhealth.com/policies/drug-pricing-policy Actual retail prices may be higher Only recommended for patients who are opioid tolerant Starting dosage determined by previous opioid dosage Cost for 30 8-mg ER tablets of these products to schedule II The new single-entity, extended-release capsule formulation is not tamperresistant and is expected to be associated with higher levels of abuse than the combination products.4,5 As part of a Risk Evaluation and Mitigation Strategy (REMS) program, the FDA has required that healthcare providers receive training in use of extended-release or long-acting opioids such as hydrocodone ER before prescribing them DRUG INTERACTIONS — Taking hydrocodone ER with a CYP3A4 inhibitor such as clarithromycin (Biaxin, and generics) could result in increased plasma concentrations of the opioid.6 Mixed agonist/antagonist opioid analgesics such as pentazocine (Talwin) or butorphanol (Stadol, and generics) could decrease the analgesic effect of hydrocodone ER and result in withdrawal symptoms Urinary retention and severe constipation, possibly leading to paralytic ileus, could occur with concurrent use of hydrocodone ER and an anticholinergic drug Use of hydrocodone ER within 14 days of a monoamine oxidase inhibitor is not recommended Coadministration of 40% alcohol resulted in a 2.4-fold increase in peak concentrations of hydrocodone ER Taking hydrocodone ER with CNS depressants such as alcohol, sedatives, or other opioids can increase the risk of profound sedation, respiratory depression, coma, and death DOSAGE AND ADMINISTRATION — Opioids have no ceiling on their analgesic effect, except that imposed by adverse effects The recommended starting dosage of Zohydro ER in opioid-naive or opioid non-tolerant 46 patients is 10 mg twice daily The dosage can be increased by 10 mg twice daily as needed every 3-7 days to achieve adequate pain relief For patients switching from another opioid, the dosage depends on the previous drug and its dose; conversion ratios for different opioids are listed in the prescribing information Zohydro ER capsules should be swallowed whole and should not be broken, crushed, dissolved, or chewed To prevent withdrawal symptoms when discontinuing therapy, the dose should be tapered gradually CONCLUSION — The new extended-release formulation of hydrocodone (Zohydro ER) is the first singleentity form of the drug; it permits higher dosing than immediate-release hydrocodone, which is only available in combination with ibuprofen or acetaminophen Like other extended-release opioids, Zohydro ER is likely to be abused, and the FDA has required special training for prescribers □ Drugs for pain Treat Guidel Med Lett 2013; 11:31 RL Rauck et al Single-entity hydrocodone extended-release capsules in opioid-tolerant subjects with moderate-to-severe chronic low back pain: a randomized double-blind, placebo-controlled study Pain Med 2014; Feb 12 (epub) D Krashin et al Extended-release hydrocodone – gift or curse? J Pain Res 2013; 6:53 FDA Background Material – NDA 202880 Zohydro ER (hydrocodone) for the management of moderate to severe chronic pain Meeting of the AADPAC, December 7, 2012 Available at www.fda gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/ Drugs/AnestheticAndAnalgesicDrugProductsAdvisoryCommittee/ ucm330683.pdf Accessed May 29, 2014 Y Olsen and JM Sharfstein Chronic pain, addiction, and Zohydro New Engl J Med 2014; 370:2061 Inhibitors and inducers of CYP enzymes and P-glycoprotein Med Lett Drugs Ther 2013; 55:e44 The Medical Letter • Volume 56 • Issue 1444 • June 9, 2014 Sublingual Immunotherapy for Allergic Rhinitis season in the first year after stopping Grastek, but not in the second year.7 The FDA has approved allergen extracts for sublingual administration as immunotherapy for allergic rhinitis confirmed by a positive skin test or in vitro testing for pollen-specific IgE antibodies: Oralair (Stallergenes S.A./Greer) and Grastek (Merck) for grass polleninduced allergic rhinitis and Ragwitek (Merck) for short ragweed pollen-induced allergic rhinitis ADVERSE EFFECTS — Local adverse effects are common after the first few doses (and sometimes after subsequent doses) with all allergen extracts These include itching of the mouth, ear, and tongue, throat irritation, and oropharyngeal edema Anaphylaxis has occurred rarely; auto-injectable epinephrine should be available These extracts should not be used in patients with unstable or severe asthma or in those with active inflammatory oral lesions or open areas after tooth loss or extraction ALLERGIC RHINITIS — Orally administered secondgeneration H1-antihistamines are the preferred first-line therapy for relief of itching, sneezing, and rhinorrhea associated with mild to moderate allergic rhinitis Intranasal corticosteroids are the most effective drugs available for prevention and relief of allergic rhinitis symptoms, including itching, sneezing, discharge, and congestion, and are the drugs of choice for moderate to severe disease.1 Traditionally, allergen-specific immunotherapy for allergic rhinitis has required subcutaneous injection of gradually increasing doses of the relevant inducing allergen such as tree, grass, or weed pollen It can alter the natural history of the disorder, and the benefits may last for years after injections are discontinued, but its use has been limited by the need for continued (usually monthly) maintenance injections and concerns about local or systemic adverse effects, including, rarely, anaphylaxis Sublingual allergen immunotherapy for treatment of allergic rhinitis and allergic conjunctivitis induced by airborne allergens has been used for years in Europe.2 CLINICAL STUDIES — Randomized, double-blind, placebo-controlled trials with Oralair and Grastek in both adults and children and with Ragwitek in adults have shown that all of these agents, started 3-4 months before and taken daily throughout the pollen season, can reduce symptom scores and use of other medications by 20-40%.3-6 One 5-year study in adults found that taking Grastek for consecutive years reduced symptom scores for years; the effect was sustained during the allergy Oralair and Grastek are classified as category B (no evidence of risk in animals; no human studies) and Ragwitek as category C (risk cannot be ruled out) for use during pregnancy Immunotherapy should not be started during pregnancy DRUG INTERACTIONS — All allergen-extract sublingual tablets should be used with caution in patients also taking a beta-adrenergic blocker, an alpha-adrenergic blocker, an ergot alkaloid, a tricyclic antidepressant, a monoamine oxidase inhibitor, or levothyroxine because these drugs can either potentiate or inhibit the effect of epinephrine if it is needed to treat an allergic reaction DOSAGE AND ADMINISTRATION — Sublingual immunotherapy should begin at least 12 weeks (16 weeks for Oralair) before the start of the allergy season and continue daily for the duration of the season The tablet should be placed under the tongue for at least minute Patients should not eat or drink while taking the tablet and for minutes afterwards Because of the potential for anaphylaxis and laryngopharyngeal edema, the first dose should be administered in a healthcare setting and patients should be observed for at least 30 minutes after the first dose; subsequent doses can be taken at home, but patients should have auto-injectable epinephrine available and be trained in its use The optimal duration of treatment remains to be established Table Sublingual Allergen Immunotherapy Extracts for Allergic Rhinitis Product Pollen Formulations Usual Dosage Cost1 Oralair (Stallergenes S.A/Greer) Sweet vernal, orchard perennial rye, timothy, and Kentucky blue grass 100 IR (~3000 BAUs) sublingual tabs 300 IR (~9000 BAUs) sublingual tabs 10-17 years: 100 IR SL on day 1, then 200 IR on day 2, then 300 IR once/day 18-65 years: 300 IR once/day $10.00 Grastek (Merck) Timothy grass 2800 BAUs sublingual tabs 5-65 years: tab SL once/day 8.30 Ragwitek (Merck) Short ragweed 12 Amb a 1-unit sublingual tabs 18-65 years: tab SL once/day 8.30 IR = index of reactivity; BAUs = bioequivalent allergy units; SL = sublingually Approximate wholesale acquisition cost (WAC) of one tablet Source: Analy$ource® Monthly (Selected from FDB MedKnowledge™) May 5, 2014 Reprinted with permission by FDB, Inc All rights reserved ©2014 www.fdbhealth.com/policies/drug-pricing-policy Actual retail prices may be higher The Medical Letter • Volume 56 • Issue 1444 • June 9, 2014 47 CONCLUSION — Sublingual immunotherapy with Oralair and Grastek for treatment of grass polleninduced allergic rhinitis and with Ragwitek for short ragweed pollen-induced allergic rhinitis can reduce the symptoms of allergic rhinitis How sublingual immunotherapy with pollens compares to subcutaneous immunotherapy in efficacy and safety remains to be established Both are expensive; second-generation H1-antihistamines and intranasal corticosteroids, both available over the counter, are relatively inexpensive options for symptom control □ Drugs for allergic disorders Treat Guidel Med Lett 2013; 11:43 SY Lin et al Sublingual immunotherapy for the treatment of allergic rhinoconjunctivitis and asthma: a systematic review JAMA 2013; 309:1278 LS Cox et al Clinical efficacy of 300IR 5-grass pollen sublingual tablet in a US study: the importance of allergen-specific serum IgE J Allergy Clin Immunol 2012; 130:1327 A Didier et al Sustained 3-year efficacy of pre- and coseasonal 5-grass-pollen sublingual immunotherapy tablets in patients with grass pollen-induced rhinoconjunctivitis J Allergy Clin Immunol 2011; 128:559 J Maloney et al Efficacy and safety of grass sublingual immunotherapy tablet, MK-7243: a large randomized controlled trial Ann Allergy Asthma Immunol 2014; 112:146 PS Creticos et al Randomized controlled trial of a ragweed allergy immunotherapy tablet in North American and European adults J Allergy Clin Immunol 2013; 131:1342 SR Durham et al SQ-standardized sublingual grass immunotherapy: confirmation of disease modification years after years of treatment in a randomized trial J Allergy Clin Immunol 2012; 129:717 IN BRIEF Lowering the Dose of Lunesta The FDA has required the manufacturer of eszopiclone (Lunesta – Sunovion), a benzodiazepine receptor agonist approved for the treatment of insomnia, to lower the current recommended starting dose to mg for both men and women because a new study found that an evening dose of mg can impair driving skills, memory, and coordination for more than 11 hours.1 Eszopiclone’s half-life is longer than that of any other drug in its class, which includes zolpidem (Ambien, and generics) and zaleplon (Sonata, and generics) All benzodiazepine receptor agonists may impair performance the next morning, including driving.2 Anterograde amnesia and complex sleep-related behaviors without conscious awareness may also occur Hallucinations have been reported Like the benzodiazepines, benzodiazepine receptor agonists are schedule IV controlled substances; withdrawal, dependence, and abuse can occur FDA Drug Safety Communication FDA warns of next-day impairment with sleep aid Lunesta (eszopiclone) and lowers recommended dose Available at www.fda.gov/Drugs/DrugSafety/ ucm397260.htm Accessed May 29, 2014 Drugs for insomnia Treat Guidel Med Lett 2012; 10:57 48 Coming Soon in The Medical Letter: Tobramycin Inhalation Solution (Bethkis) for Cystic Fibrosis A Transcutaneous Electrical Nerve Stimulation Device (Cefaly) for Migraine Luliconazole (Luzu) for Tinea Infections Treatment of Atrial Fibrillation The Medical Letter ® On Drugs and Therapeutics 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 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., Weill Medical College of Cornell University SENIOR ASSOCIATE EDITOR: Amy Faucard 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 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 10801-7537 Customer Service: Call: 800-211-2769 or 914-235-0500 Fax: 914-632-1733 Web Site: www.medicalletter.org E-mail: custserv@medicalletter.org Permissions: To reproduce any portion of this issue, please e-mail your request to: permissions@medicalletter.org Subscriptions (US): year - $98; years - $189; years - $279 $49.00 per year for students, interns, residents, and fellows in the US and Canada E-mail site license inquiries to: info@medicalletter.org or call 800-211-2769 x315 Special fees for bulk subscriptions Special classroom rates are available Back issues are $12 each Major credit cards accepted Copyright 2014 ISSN 1523-2859 The Medical Letter • Volume 56 • Issue 1444 • June 9, 2014 The Medical Letter ® Online Continuing Medical Education To take CME exams and earn credit, go to: medicalletter.org/CMEstatus Issue 1444 Questions (Correspond to questions #67-72 in Comprehensive Exam #70, available July 2014) Extended-Release Hydrocodone (Zohydro ER) for Pain Compared to similar doses of immediate-release hydrocodone, Zohydro ER : a is more effective b causes fewer adverse effects c has a longer duration of action d none of the above A 55-year-old man with chronic back pain tells you that he has seen ads on TV for Zohydro ER and asks if he could try it He currently takes Vicodin as needed for back pain but says that he usually only needs one or two tablets a day to control his pain He also takes the anticholinergic drug oxybutynin for urinary incontinence You could tell him that: a you would recommend a starting dose of 50 mg q12h b you have no concerns about Zohydro ER interacting with any of his current medications c he could crush the Zohydro ER capsules if they are too large to swallow d none of the above Zohydro ER : a is not affected by concurrent use of alcohol b is tamper-resistant c is more effective than other long-acting opioids for chronic pain d none of the above Sublingual Immunotherapy for Allergic Rhinitis A mother asks you about the new products that she has heard about for grass pollen allergy and wants to know if they would help her 9-year-old daughter’s allergy symptoms You could tell her that: a they need to be taken daily starting at least 12 weeks before allergy season b after taking them for year, they will prevent symptoms of grass pollen allergy for life c unlike traditional allergen-specific immunotherapy that requires subcutaneous injection, the new sublingual therapies not pose a risk for anaphylaxis d all of the above Adverse effects of the new allergen extracts for sublingual administration as immunotherapy for allergic rhinitis include: a itching of the mouth, ear, and tongue b throat irritation c oropharyngeal edema d all of the above In Brief: Lowering the Dose of Lunesta The recommended starting dose of Lunesta is now: a 0.5 mg b mg c mg d mg ACPE UPN: Per Issue Exam: 0379-0000-14-444-H01-P; 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