Profile of suvorexant in the management of insomnia

Drug Design, Development and Therapy Dovepress open access to scientific and medical research Review Drug Design, Development and Therapy downloaded from https://www.dovepress.com/ by 220.179.231.218 on 13-Jul-2020 For personal use only. Open Access Full Text Article Profile of suvorexant in the management of insomnia This article was published in the following Dove Press journal: Drug Design, Development and Therapy 11 November 2015 Number of times this article has been viewed Eliza L Sutton Department of Medicine, University of Washington, Seattle, WA, USA Abstract: Suvorexant, approved in late 2014 in the United States and Japan for the treatment of insomnia characterized by difficulty achieving and/or maintaining sleep, is a dual orexin receptor antagonist and the first drug in its class to reach the market. Its development followed from the 1998 discovery of orexins (also called hypocretins), excitatory neuropeptides originating from neurons in the hypothalamus involved in regulation of sleep and wake, feeding behavior and energy regulation, motor activity, and reward-seeking behavior. Suvorexant objectively improves sleep, shortening the time to achieve persistent sleep and reducing wake after sleep onset, although at approved doses (20 mg) the benefit was subjectively assessed as modest. Its half-life of 12 hours is relatively long for a modern hypnotic; however, at approved doses (20 mg) next-day sedation and driving impairment were much less apparent than at higher doses. Suvorexant is metabolized by the hepatic CYP3A system and should be avoided in combination with strong CYP3A inhibitors. Drug levels are higher in women and obese people; hence, dosing should be conservative in obese women. Administration with food delays drug absorption and is not advised. No dose adjustment is needed for advanced age, renal impairment, or mild-to-moderate hepatic impairment. Suvorexant in contraindicated in narcolepsy and has not been studied in children. In alignment with the changes begun in 2013 in the labeling of other hypnotics, the United States Food and Drug Administration advises that the lowest dose effective to treat symptoms be used and that patients be advised of the possibility of next-day impairment in function, including driving. Infrequent but notable side effects included abnormal dreams, sleep paralysis, and suicidal ideation that were dose-related and reported to be mild. Given its mechanism of action, cataplexy and rapid eye movement (REM) sleep behavior disorder could potentially occur in some patients taking this medication. Keywords: insomnia, hypnotic, dual orexin receptor antagonist, orexin, hypocretin Introduction Correspondence: Eliza L Sutton Department of Medicine, University of Washington Box 354765, 1959 NE Pacific Street, Seattle, WA 98195, USA Email 6035 submit your manuscript | www.dovepress.com Drug Design, Development and Therapy 2015:9 6035–6042 Dovepress © 2015 Sutton. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License. The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. Permissions beyond the scope of the License are administered by Dove Medical Press Limited. Information on how to request permission may be found at: http://www.dovepress.com/permissions.php http://dx.doi.org/10.2147/DDDT.S73224 Powered by TCPDF (www.tcpdf.org) Suvorexant, approved for marketing in the United States by the Food and Drug Administration (FDA) in August 20141 and in Japan by the Pharmaceuticals and Medical Devices Agency in November 2014,2 is first in many categories: • first-ever approved pharmaceutical that acts at orexin receptors; • first sleep medication in a new class since the melatonin receptor agonist ramelteon in 2005; • first sleep medication approved since the FDA began changing labeling, starting with zolpidem in 2013, to reflect heightened caution about the next-day effects of hypnotics.3 Suvorexant enters a market hungry for sleep medications. Insomnia, defined in the International Classification of Sleep Disorders4 as: Dovepress Sutton Persistent difficulty with sleep initiation, duration, consolidation, or quality that occurs despite adequate opportunity and circumstances for sleep, and results in some form of Drug Design, Development and Therapy downloaded from https://www.dovepress.com/ by 220.179.231.218 on 13-Jul-2020 For personal use only. daytime impairment is a very common and bothersome problem. In a 2014 survey in the United States asking about adults’ experience over the prior week, 45% of respondents reported having had difficulty falling asleep at least one night and 16% reported difficulty 5 nights; 52% reported having had difficulty staying asleep at least one night and 23% reported difficulty 5 nights; and 17% of adults reported having taken a prescription or over-the-counter medication for sleep at least once, with 10% reporting use for 5 nights.5 Insomnia of moderate-to-high severity is associated with high health care costs and lost productivity, with productivity particularly affected in those with insomnia who have chronic psychiatric conditions and/or whose insomnia is not treated with prescription or over-the-counter medications.6 Chronic insomnia is also associated with higher rates of workplace and non-work accidents.7 This review will introduce suvorexant, beginning with a summary of orexin system neurobiology and the development of orexin receptor antagonists. It will then touch on considerations that arose during the FDA’s initial review of suvorexant and that affected the dosages approved, and then will focus on clinical considerations including prescribing guidelines and side effects, both observed and potential based on the drug’s unique mechanism, that may occur with its use. Orexin system neurobiology and drug development The neurobiology of sleep and wakefulness is complex. Most existing medications for insomnia act, where the mechanism Table 1 Mechanisms of medications used for sleep Medication(s) Medication class Neurotransmitter system affected for sleep effect Suvorexant Dual orexin receptor antagonist Orexin (hypocretin) Prolonged-release melatonin58 Ramelteon Tasimelteon58 MT agonist (melatonin is nonselective; ramelteon and tasimelteon are selective for MT1 and MT2 receptors) Melatonin (may enhance GABA effect) Zolpidem Zaleplon Zopiclone Eszopiclone Benzodiazepine receptor agonist; GABAA receptor positive allosteric modulator GABAA Doxepin Amitriptyline* Tricyclic antidepressant Histamine (H1) (doxepin at low dose, 3–6 mg) Histamine, serotonin, acetylcholine, norepinephrine (class effect, including doxepin at higher doses) Diphenhydramine Doxylamine Antihistamines His (...truncated)