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Revision as of 11:55, 31 October 2011 editBeetstra (talk | contribs)Edit filter managers, Administrators172,055 edits Script assisted update of identifiers for the Chem/Drugbox validation project (updated: 'CAS_number').← Previous edit		Latest revision as of 07:05, 14 January 2025 edit undoArthurfragoso (talk | contribs)Extended confirmed users, Template editors4,591 edits dark mode fix
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			{{Short description|Medication used to treat insomnia}}
	{{drugbox
			{{Use dmy dates|date=December 2023}}
	| IUPAC_name = methanone
			{{cs1 config |name-list-style=vanc |display-authors=6}}
	| image = MK4305_structure.png
			{{Drugbox
	| CAS_number = <!-- blanked - oldvalue: 1030377-33-3 -->
			| Verifiedfields = verified
	| ATC_prefix =
			| Watchedfields = verified
	| ATC_suffix =
			| verifiedrevid = 458281672
	| ATC_supplemental =
			| image = Suvorexant.svg
			| image_class = skin-invert-image
			| image2 = Suvorexant-from-xtal-Mercury-3D-bs.png
			| image_class2 = bg-transparent
			| width = 250
			<!--Clinical data -->
			| tradename = Belsomra
			| Drugs.com = {{drugs.com|monograph|suvorexant}}
			| MedlinePlus = a614046
			| DailyMedID = Suvorexant
			| pregnancy_AU = B3
			| pregnancy_AU_comment = <ref name="Belsomra-AU-Label" />
			| pregnancy_category =
			| dependency_liability = Low
			| addiction_liability = Low
			| routes_of_administration = ]<ref name="Belsomra FDA label" />
			| class = ]; ]; ]
			| ATC_prefix = N05
			| ATC_suffix = CJ01
			| ATC_supplemental =
			<!-- Legal status -->
			| legal_AU = S4
			| legal_AU_comment = <ref>{{cite web | title=Prescription medicines: registration of new chemical entities in Australia, 2016 | website=Therapeutic Goods Administration (TGA) | date=21 June 2022 | url=https://www.tga.gov.au/prescription-medicines-registration-new-chemical-entities-australia-2016 | access-date=10 April 2023}}</ref>
			| legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F-->
			| legal_BR_comment =
			| legal_CA = Rx-only
			| legal_CA_comment = <ref>{{cite web | url=https://hpr-rps.hres.ca/reg-content/regulatory-decision-summary-detail.php?lang=en&linkID=RDS00475 | title=Regulatory Decision Summary for Belsomra | date=23 October 2014 }}</ref>
			| legal_DE = <!-- Anlage I, II, III or Unscheduled-->
			| legal_DE_comment =
			| legal_NZ = <!-- Class A, B, C -->
			| legal_NZ_comment =
			| legal_UK = <!-- GSL, P, POM, CD, CD Lic, CD POM, CD No Reg POM, CD (Benz) POM, CD (Anab) POM or CD Inv POM / Class A, B, C -->
			| legal_UK_comment =
			| legal_US = Schedule IV
			| legal_US_comment = <ref name="Belsomra FDA label" />
			| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV-->
			| legal_UN_comment =
			| legal_status = <!--For countries not listed above-->
			<!--Pharmacokinetic data -->
			| bioavailability = 82% (10 mg; lower at higher doses)<ref name="Belsomra FDA label" /><ref name="MerckSharpDohme2013" />
			| protein_bound = 99.5%<ref name="pmid25318834" /><ref name="Belsomra FDA label" />
			| metabolism = ] (] major, ] minor)<ref name="Belsomra FDA label" />
			| metabolites = Hydroxysuvorexant (inactive)<ref name="Belsomra FDA label" />
			| onset =
			| elimination_half-life = 12.2 hours (8–19 hours) (40 mg)<ref name="Belsomra FDA label" /><ref name="MerckSharpDohme2013" /><ref name="DimovaBrarMen2014" />
			| duration_of_action =
			| excretion = ]: 66%<ref name="Belsomra FDA label" /><br />]: 23%<ref name="Belsomra FDA label" />
			<!--Identifiers -->
			| CAS_number_Ref = {{cascite|correct|CAS}}
			| CAS_number = 1030377-33-3
	| PubChem = 24965990		| PubChem = 24965990
	| DrugBank =		| IUPHAR_ligand = 2890
			| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
	| smiles = n5ccnn5-c3ccc(C)cc3C(=O)N2CCN(CCC2C)c(nc1c4)oc1ccc4Cl
			| DrugBank = DB09034
	| C = 23 | H = 23 | Cl = 1 | N = 6 | O = 2
			| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
	| molecular_weight = 450.920 g/mol (free base)
			| ChemSpiderID = 24662178
	| bioavailability =
			| UNII_Ref = {{fdacite|correct|FDA}}
	| protein_bound =
			| UNII = 081L192FO9
	| metabolism =
			| KEGG_Ref = {{keggcite|correct|kegg}}
	| elimination_half-life =
			| KEGG = D10082
	| pregnancy_category =
	| legal_status =		| ChEBI_Ref =
			| ChEBI = 82698
	| routes_of_administration =
			| ChEMBL_Ref = {{ebicite|correct|EBI}}
			| ChEMBL = 1083659
			| NIAID_ChemDB =
			| PDB_ligand =
			| synonyms = MK-4305; MK4305
			<!--Chemical data -->
			| IUPAC_name = methanone
			| C=23 | H=23 | Cl=1 | N=6 | O=2
			| SMILES = C1CCN(CCN1C(=O)C2=C(C=CC(=C2)C)N3N=CC=N3)C4=NC5=C(O4)C=CC(=C5)Cl
			| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
			| StdInChI = 1S/C23H23ClN6O2/c1-15-3-5-20(30-25-8-9-26-30)18(13-15)22(31)29-12-11-28(10-7-16(29)2)23-27-19-14-17(24)4-6-21(19)32-23/h3-6,8-9,13-14,16H,7,10-12H2,1-2H3/t16-/m1/s1
			| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
			| StdInChIKey = JYTNQNCOQXFQPK-MRXNPFEDSA-N
	}}		}}
			<!-- Definition and medical uses -->
			'''Suvorexant''', sold under the brand name '''Belsomra''', is an ] medication which is used in the treatment of ].<ref name="Belsomra FDA label">{{cite web | title=Belsomra- suvorexant tablet, film coated | website=DailyMed | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=e5b72731-1acb-45b7-9c13-290ad12d3951 | access-date=30 January 2020}}</ref><ref name="pmid25318834">{{cite journal | vauthors = Jacobson LH, Callander GE, Hoyer D | title = Suvorexant for the treatment of insomnia | journal = Expert Review of Clinical Pharmacology | volume = 7 | issue = 6 | pages = 711–730 | date = November 2014 | pmid = 25318834 | doi = 10.1586/17512433.2014.966813 | s2cid = 41099462 }}</ref> It is indicated specifically for the treatment of insomnia characterized by difficulties with ] and/or ] in adults.<ref name="Belsomra FDA label" /><ref name="pmid25318834" /> Suvorexant helps with ], ], being ], and having better ].<ref name="Belsomra FDA label" /><ref name="pmid28365447" /> Its effectiveness is modest,<ref name="pmid26648692" /> and is similar to that of other orexin antagonists, but is lower than that of ]s and ]s.<ref name="pmid35843245" /> Suvorexant is taken ].<ref name="Belsomra FDA label" /><ref name="Drugs.com-Belsomra-Generic" /><ref name="pmid25318834" />
			<!-- Side effects and mechanism -->
	'''Suvorexant''' ('''MK-4305''') is an ] receptor antagonist in development by ]<ref>{{Cite doi|10.1021/jm100541c}}</ref><ref>{{Cite doi|10.1021/op1002853}}</ref><ref>{{Cite doi|10.3109/01677063.2011.566953}}</ref> This drug for sleep disorders has passed Phase II trials, and is one of several such compounds currently in development, the others being Actelion's ] and ]'s ].
			]s of suvorexant include ], ], ], ], ]s, ], and impaired next-day ] ability.<ref name="Belsomra FDA label" /><ref name="pmid28365447" /><ref name="pmid26317363">{{cite journal | vauthors = Kishi T, Matsunaga S, Iwata N | title = Suvorexant for Primary Insomnia: A Systematic Review and Meta-Analysis of Randomized Placebo-Controlled Trials | journal = PLOS ONE | volume = 10 | issue = 8 | pages = e0136910 | date = 2015 | pmid = 26317363 | pmc = 4552781 | doi = 10.1371/journal.pone.0136910 | bibcode = 2015PLoSO..1036910K | doi-access = free }}</ref> Rarely, ], sleep-related ]s, ]s like ], and ] may occur.<ref name="Belsomra FDA label" /><ref name="pmid25318834" /><ref name="pmid26648692" /> ], ], ], and ]s do not appear to occur significantly with the medication.<ref name="Belsomra FDA label" /><ref name="pmid28994603" /><ref name="pmid32901578" /> Suvorexant is a ] (DORA).<ref name="pmid25318834" /> It acts as a ] dual ] of the ] ] and ]s.<ref name="pmid25318834" /> The medication has an intermediate ] of 12{{nbsp}}hours and a ] of about 2 to 3{{nbsp}}hours.<ref name="Belsomra FDA label" /><ref name="pmid25318834" /> Unlike benzodiazepines and Z-drugs, suvorexant does not interact with ]s, instead having a distinct ].<ref name="pmid25318834" /><ref name="pmid29487083">{{cite journal|author3-link=Gabriella Gobbi | vauthors = Atkin T, Comai S, Gobbi G | title = Drugs for Insomnia beyond Benzodiazepines: Pharmacology, Clinical Applications, and Discovery | journal = Pharmacological Reviews | volume = 70 | issue = 2 | pages = 197–245 | date = April 2018 | pmid = 29487083 | doi = 10.1124/pr.117.014381 | s2cid = 3578916 | doi-access = free }}</ref>
			<!-- History, society, and culture -->
	==References==
			] of suvorexant began in 2006<ref name="pmid25406050" /> and it was introduced for medical use in 2014.<ref name="Belsomra FDA label" /><ref name="APDNews2014" /> The medication is a ] ] in the United States and may have a modest ].<ref name="FederalRegister2016" /><ref name="Belsomra FDA label" /><ref name="pmid25231363" /> In other places, such as Australia, suvorexant is a ] and is not a ].<ref name="Belsomra-AU-Label" /> Suvorexant is not available in ]s.<ref name="Drugs.com-Belsomra-Generic" /><ref name="pmid30092886" /><ref name="pmid26955275" /> Besides suvorexant, other orexin receptor antagonists like ] and ] have also been introduced.<ref name="pmid35043499" /><ref name="pmid35298826" />
	{{reflist|2}}
			{{TOC limit|3}}
			==Medical uses==
			Suvorexant is used for the treatment of ], characterized by difficulties with ] and/or sleep maintenance, in adults.<ref name="Belsomra FDA label" /><ref name="pmid25318834" /> At a dose of 15 to 20{{nbsp}}mg and in terms of treatment–] difference, it reduces ] by up to 10{{nbsp}}minutes, reduces ] by about 15 to 30{{nbsp}}minutes, and increases ] by about 10 to 20{{nbsp}}minutes.<ref name="Belsomra FDA label" /> A 2017 ] and ] of ]s of suvorexant for insomnia likewise found that the medication improved subjective sleep onset, subjective total sleep time, and subjective ] when assessed at one to three months of treatment.<ref name="pmid28365447" /> The effectiveness of approved doses of suvorexant (≤20{{nbsp}}mg) in the treatment of insomnia is said to be modest.<ref name="pmid26648692" /><ref name="pmid26594338">{{cite journal | vauthors = Kripke DF | title = Is suvorexant a better choice than alternative hypnotics? | journal = F1000Research | volume = 4 | issue = | pages = 456 | date = 2015 | pmid = 26594338 | pmc = 4648222 | doi = 10.12688/f1000research.6845.1 | doi-access = free }}</ref><ref name="pmid28994603" /><ref name="PublicCitizen2013" />
			] have assessed the sleep-promoting effects of suvorexant and have compared them to those of other orexin receptor antagonists like ] and ] as well as to other sleep aids including ]s, ]s, ]s, sedative ]s (e.g., ], ], ], ]), and ]s.<ref name="pmid35843245">{{cite journal | vauthors = De Crescenzo F, D'Alò GL, Ostinelli EG, Ciabattini M, Di Franco V, Watanabe N, Kurtulmus A, Tomlinson A, Mitrova Z, Foti F, Del Giovane C, Quested DJ, Cowen PJ, Barbui C, Amato L, Efthimiou O, Cipriani A | title = Comparative effects of pharmacological interventions for the acute and long-term management of insomnia disorder in adults: a systematic review and network meta-analysis | journal = Lancet | volume = 400 | issue = 10347 | pages = 170–184 | date = July 2022 | pmid = 35843245 | doi = 10.1016/S0140-6736(22)00878-9 | s2cid = 250536370 | url = | doi-access = free | hdl = 11380/1288245 | hdl-access = free }}</ref><ref name="pmid34560134">{{cite journal | vauthors = Wang L, Pan Y, Ye C, Guo L, Luo S, Dai S, Chen N, Wang E | title = A network meta-analysis of the long- and short-term efficacy of sleep medicines in adults and older adults | journal = Neuroscience and Biobehavioral Reviews | volume = 131 | issue = | pages = 489–496 | date = December 2021 | pmid = 34560134 | doi = 10.1016/j.neubiorev.2021.09.035 | s2cid = 237589779 | doi-access = free }}</ref><ref name="pmid34121443">{{cite journal | vauthors = McElroy H, O'Leary B, Adena M, Campbell R, Monfared AA, Meier G | title = Comparative efficacy of lemborexant and other insomnia treatments: a network meta-analysis | journal = Journal of Managed Care & Specialty Pharmacy | volume = 27 | issue = 9 | pages = 1296–1308 | date = September 2021 | pmid = 34121443 | doi = 10.18553/jmcp.2021.21011 | pmc = 10394202 | doi-access = free }}</ref><ref name="pmid34902823">{{cite journal | vauthors = Xue T, Wu X, Chen S, Yang Y, Yan Z, Song Z, Zhang W, Zhang J, Chen Z, Wang Z | title = The efficacy and safety of dual orexin receptor antagonists in primary insomnia: A systematic review and network meta-analysis | journal = Sleep Medicine Reviews | volume = 61 | issue = | pages = 101573 | date = February 2022 | pmid = 34902823 | doi = 10.1016/j.smrv.2021.101573 | s2cid = 244689706 }}</ref> A major ] and network meta-analysis of insomnia medications published in 2022 found that suvorexant had an ] (] (SMD)) against ] for treatment of insomnia at 4{{nbsp}}weeks of 0.31 (95% {{Abbrlink|CI|confidence interval}} 0.01 to 0.62).<ref name="pmid35843245" /> Suvorexant appeared to be similarly effective at 4{{nbsp}}weeks to lemborexant (SMD 0.36, 95% CI 0.08 to 0.63) and daridorexant (SMD 0.23, 95% CI –0.01 to 0.48), whereas benzodiazepines and Z-drugs generally showed larger effect sizes (e.g., SMDs of 0.45 to 0.83) and antihistamines (e.g., ], ], ]) showed more similar efficacy (SMDs of 0.30 to 0.55).<ref name="pmid35843245" />
			Orexin receptor antagonists like suvorexant increase total sleep time predominantly by increasing ] (REM) sleep, whereas they have no effect on or even decrease ] (NREM) sleep.<ref name="pmid32505969">{{cite journal | vauthors = Clark JW, Brian ML, Drummond SP, Hoyer D, Jacobson LH | title = Effects of orexin receptor antagonism on human sleep architecture: A systematic review | journal = Sleep Medicine Reviews | volume = 53 | issue = | pages = 101332 | date = October 2020 | pmid = 32505969 | doi = 10.1016/j.smrv.2020.101332 | s2cid = 219407655 }}</ref> This is in contrast to most other ]s, which either do not affect REM sleep or decrease it.<ref name="pmid35043499" /> The implications of these differences are not fully clear.<ref name="pmid35043499" /> Unlike certain other hypnotics like ]s and ]s, orexin receptor antagonists do not disrupt ], and this might provide more restful sleep.<ref name="pmid30576764" /><ref name="pmid23702225">{{cite journal | vauthors = Pałasz A, Lapray D, Peyron C, Rojczyk-Gołębiewska E, Skowronek R, Markowski G, Czajkowska B, Krzystanek M, Wiaderkiewicz R | title = Dual orexin receptor antagonists - promising agents in the treatment of sleep disorders | journal = The International Journal of Neuropsychopharmacology | volume = 17 | issue = 1 | pages = 157–168 | date = January 2014 | pmid = 23702225 | doi = 10.1017/S1461145713000552 | doi-access = free }}</ref><ref name="pmid35342199">{{cite journal | vauthors = Berger AA, Sottosanti ER, Winnick A, Keefe J, Gilbert E, Hasoon J, Thase ME, Kaye AD, Viswanath O, Urits I | title = Suvorexant in the Treatment of Difficulty Falling and Staying Asleep (Insomnia) | journal = Psychopharmacology Bulletin | volume = 52 | issue = 1 | pages = 68–90 | date = February 2022 | pmid = 35342199 | doi = | pmc = 8896749 }}</ref><ref name="pmid30338596">{{cite journal | vauthors = Herring WJ, Roth T, Krystal AD, Michelson D | title = Orexin receptor antagonists for the treatment of insomnia and potential treatment of other neuropsychiatric indications | journal = Journal of Sleep Research | volume = 28 | issue = 2 | pages = e12782 | date = April 2019 | pmid = 30338596 | doi = 10.1111/jsr.12782 | s2cid = 53019189 }}</ref>
			It is unclear if suvorexant is safe among people with a history of ] or ], as these individuals were excluded from ]s of suvorexant.<ref name="pmid25667197">{{cite journal | vauthors = Patel KV, Aspesi AV, Evoy KE | title = Suvorexant: a dual orexin receptor antagonist for the treatment of sleep onset and sleep maintenance insomnia | journal = The Annals of Pharmacotherapy | volume = 49 | issue = 4 | pages = 477–483 | date = April 2015 | pmid = 25667197 | doi = 10.1177/1060028015570467 | s2cid = 208871440 }}</ref> A ] found suvorexant to be effective in the short-term treatment of sleep disturbances in people with ] with few adverse effects.<ref name="pmid33189083">{{cite journal | vauthors = McCleery J, Sharpley AL | title = Pharmacotherapies for sleep disturbances in dementia | journal = The Cochrane Database of Systematic Reviews | volume = 2020 | issue = 11| pages = CD009178 | date = November 2020 | pmid = 33189083 | pmc = 8094738 | doi = 10.1002/14651858.CD009178.pub4 }}</ref> It is unknown if suvorexant is effective and safe for treatment of sleep problems in children and adolescents as suvorexant has not been studied in this context.<ref name="Belsomra FDA label" />
			Suvorexant is approved for the treatment of insomnia by the United States ] (FDA) at doses of 5 to 20{{nbsp}}mg and by the Australian ] (TGA) and Japanese ] (PMDA) at doses of 15{{nbsp}}mg (in the elderly) and 20{{nbsp}}mg (in younger adults).<ref name="Belsomra FDA label" /><ref name="pmid25318834" /><ref name="Belsomra-AU-Label" /><ref name="pmid28365447" /> In the United States, the recommended starting dose is 10{{nbsp}}mg and the maximum recommended dose is 20{{nbsp}}mg.<ref name="Belsomra FDA label" /><ref name="pmid25318834" /> Higher doses of 30 and 40{{nbsp}}mg were also submitted to regulatory agencies for approval but were not authorized due to lack of clearly superior efficacy to doses of 15 to 20{{nbsp}}mg and concerns about next-day effects and associated impairment (e.g., ]).<ref name="pmid25318834" /><ref name="pmid25667197" /> In addition to the preceding doses, suvorexant has been assessed at higher doses of up to 100{{nbsp}}mg in clinical trials.<ref name="pmid25318834" /><ref name="pmid25667197" /><ref name="pmid23372274" /> These higher doses appeared to be more effective at promoting sleep than lower doses but produced greater next-day effects.<ref name="pmid25318834" /><ref name="pmid25667197" /><ref name="pmid26648692" /><ref name="pmid23372274">{{cite journal | vauthors = Sun H, Kennedy WP, Wilbraham D, Lewis N, Calder N, Li X, Ma J, Yee KL, Ermlich S, Mangin E, Lines C, Rosen L, Chodakewitz J, Murphy GM | title = Effects of suvorexant, an orexin receptor antagonist, on sleep parameters as measured by polysomnography in healthy men | journal = Sleep | volume = 36 | issue = 2 | pages = 259–267 | date = February 2013 | pmid = 23372274 | pmc = 3542986 | doi = 10.5665/sleep.2386 }}</ref> Lower approved doses of suvorexant in the United States in the range of 5 to 10{{nbsp}}mg were not extensively evaluated in clinical trials.<ref name="pmid26594338" /><ref name="PublicCitizen2013" />
			The ]'s 2017 ]s recommend the use of suvorexant in the treatment of sleep-onset and sleep-maintenance insomnia along with various other sleep medications.<ref name="pmid27998379">{{cite journal | vauthors = Sateia MJ, Buysse DJ, Krystal AD, Neubauer DN, Heald JL | title = Clinical Practice Guideline for the Pharmacologic Treatment of Chronic Insomnia in Adults: An American Academy of Sleep Medicine Clinical Practice Guideline | journal = Journal of Clinical Sleep Medicine | volume = 13 | issue = 2 | pages = 307–349 | date = February 2017 | pmid = 27998379 | pmc = 5263087 | doi = 10.5664/jcsm.6470 }}</ref> Orexin receptor antagonists are not used as ]s for insomnia due to their costs and concerns about possible ].<ref name="pmid34560134" /> ] formulations of orexin receptor antagonists including suvorexant are not yet available.<ref name="Drugs.com-Belsomra-Generic" /><ref name="pmid30092886">{{cite journal | vauthors = Janto K, Prichard JR, Pusalavidyasagar S | title = An Update on Dual Orexin Receptor Antagonists and Their Potential Role in Insomnia Therapeutics | journal = Journal of Clinical Sleep Medicine | volume = 14 | issue = 8 | pages = 1399–1408 | date = August 2018 | pmid = 30092886 | pmc = 6086961 | doi = 10.5664/jcsm.7282 }}</ref><ref name="pmid26955275">{{cite journal | vauthors = Lee-Iannotti JK, Parish JM | title = Suvorexant: a promising, novel treatment for insomnia | journal = Neuropsychiatric Disease and Treatment | volume = 12 | issue = | pages = 491–495 | date = 2016 | pmid = 26955275 | pmc = 4772996 | doi = 10.2147/NDT.S31495 | doi-access = free }}</ref>
			===Available forms===
			Suvorexant is available in the form of 5, 10, 15, and 20{{nbsp}}mg ] ] ]s.<ref name="Belsomra FDA label" /><ref name="Drugs.com-Belsomra-Generic" /><ref name="pmid25231363" /> It is provided as 10- and 30-tablet ]s as well as 3-tablet starter packs. The availability of these different packs varies by country.<ref name="Belsomra FDA label" /><ref name="Belsomra-AU-Label" />
			==Contraindications==
			Suvorexant is ] in people with ] as it may worsen their symptoms.<ref name="Belsomra FDA label" /><ref name="pmid26648692" /> This is its only ].<ref name="Belsomra FDA label" /> Suvorexant has not been studied in people with severe ] and is not recommended in these individuals due to the likelihood of increased suvorexant exposure.<ref name="Belsomra FDA label" /> On the other hand, suvorexant may be used in people with mild-to-moderate hepatic impairment as well as ] of any severity and no dose adjustment is necessary in these situations.<ref name="Belsomra FDA label" /> Concomitant use of suvorexant with strong ] ]s is not recommended due to potential for increased suvorexant exposure while concomitant use of suvorexant with strong CYP3A4 ]s may result in loss of suvorexant exposure and effectiveness.<ref name="Belsomra FDA label" /> Suvorexant should be used carefully in people with a history of ] or ] due to its ] effects and possible misuse potential at doses higher than those approved for therapeutic use.<ref name="Belsomra FDA label" /><ref name="pmid34480579" /> Similarly, suvorexant should be used carefully in people with a history of ] or ] as it may rarely increase ].<ref name="Belsomra FDA label" /><ref name="pmid25318834" /><ref name="pmid26648692" /> The medication is indicated for use in adults and the elderly but has not been studied in children and adolescents and hence is not recommended for these individuals.<ref name="Belsomra FDA label" />
			Suvorexant has shown ]ic effects in animals such as decreased ] at doses much higher than the equivalents of those approved for therapeutic use in humans.<ref name="Belsomra FDA label" /><ref name="Drugs.com-Pregnancy" /> Teratogenic effects with therapeutic doses of suvorexant in humans have not been established due to lack of research and available data.<ref name="Belsomra FDA label" /><ref name="Drugs.com-Pregnancy" /> Suvorexant is ] in the United States.<ref name="Drugs.com-Pregnancy">{{cite web | title = Suvorexant Pregnancy and Breastfeeding Warnings | work = Drugs.com | url = https://www.drugs.com/pregnancy/suvorexant.html}}</ref> It is unknown whether suvorexant is present in the ], whether it affects ] in ] women, or whether it affects breastfed infants.<ref name="Belsomra FDA label" /> However, suvorexant has been found to be present in mammary milk in rats and this is likely to be the case in humans as well.<ref name="Belsomra FDA label" /><ref name="Drugs.com-Pregnancy" /> Suvorexant should be used in pregnant and breastfeeding women only if the potential benefit justifies the potential for harm to the baby.<ref name="Belsomra FDA label" /><ref name="Drugs.com-Pregnancy" />
			==Side effects==
			]s of suvorexant (at doses of 15–20{{nbsp}}mg) include ] (7% vs. 3% for ]) and ]s (7% vs. 6% for placebo).<ref name="Belsomra FDA label" /> Somnolence with suvorexant appears to be ], with rates of 2% at 10{{nbsp}}mg, 5% at 20{{nbsp}}mg, 10–12% at 40{{nbsp}}mg, and 11–12% at 80{{nbsp}}mg, relative to 0.4% for ].<ref name="Belsomra FDA label" /><ref name="pmid25318834" /> Less common side effects (at 15–20{{nbsp}}mg) may include ] (3% vs. 2% for placebo), ]s (2% vs. 1% for placebo), ] (2% vs. 1% for placebo), ] (2% vs. 1% for placebo), ] (2% vs. 1% for placebo), and ] (2% vs. 1% for placebo).<ref name="Belsomra FDA label" /> High doses of suvorexant (80{{nbsp}}mg) have also been found to produce greater incidence of dizziness (5% vs. 0% for placebo) and abnormal dreams (5% vs. 1% for placebo).<ref name="pmid25318834" />
			Less commonly, suvorexant may cause ], ] and ]s, and ]s (0.2–0.6% vs. 0% for placebo).<ref name="Belsomra FDA label" /><ref name="pmid26648692" /> Complex sleep behaviors include ], ], and engaging in other activities while not completely awake (e.g., making or eating food, making phone calls, and ]).<ref name="Belsomra FDA label" /> Other ]-like symptoms such as ] (sudden weakness or paralysis) may also rarely occur.<ref name="pmid26594338" /><ref name="pmid26648692" /> Suvorexant may sometimes cause worsening of ] or ].<ref name="Belsomra FDA label" /><ref name="pmid25318834" /> A dose-dependent increase in suicidal ideation as assessed with the ] was seen with suvorexant in clinical trials although rates were very low (0.2% (1/493) at low doses (15–20{{nbsp}}mg) and 0.4% (5/1291) at high doses (30–40{{nbsp}}mg) relative to 0.1% (1/1025) for placebo).<ref name="Belsomra FDA label" /><ref name="pmid25318834" /> It has also been stated however that suicidal ideation was reported in 0% to 1.6% of people taking 10 to 20{{nbsp}}mg and 3.4% to 8.2% taking 40 to 80{{nbsp}}mg relative to 0% to 0.3% with placebo.<ref name="pmid26648692">{{cite journal | vauthors = Sutton EL | title = Profile of suvorexant in the management of insomnia | journal = Drug Design, Development and Therapy | volume = 9 | issue = | pages = 6035–6042 | date = 2015 | pmid = 26648692 | pmc = 4651361 | doi = 10.2147/DDDT.S73224 | doi-access = free }}</ref> Suicidal ideation with suvorexant is considered to be mild.<ref name="pmid25318834" /><ref name="pmid26648692" /> In any case, caution is warranted in use of suvorexant in people with depression, and people with worsening depression or suicidal thoughts should be promptly evaluated.<ref name="pmid26648692" /><ref name="Belsomra FDA label" /> Besides the clinical trial data, a ] of rapidly worsened depression and onset of suicidal ideation with suvorexant has been published.<ref name="pmid30590027">{{cite journal | vauthors = Summers CH, Yaeger JD, Staton CD, Arendt DH, Summers TR | title = Orexin/hypocretin receptor modulation of anxiolytic and antidepressive responses during social stress and decision-making: Potential for therapy | journal = Brain Research | volume = 1731 | issue = | pages = 146085 | date = March 2020 | pmid = 30590027 | pmc = 6591110 | doi = 10.1016/j.brainres.2018.12.036 }}</ref><ref name="pmid29066641">{{cite journal | vauthors = Petrous J, Furmaga K | title = Adverse reaction with suvorexant for insomnia: acute worsening of depression with emergence of suicidal thoughts | journal = BMJ Case Reports | volume = 2017 | issue = | date = October 2017 | pmid = 29066641 | pmc = 5665271 | doi = 10.1136/bcr-2017-222037 }}</ref>
			The next-day effects of suvorexant have been studied.<ref name="Belsomra FDA label" /> Besides the side effect of daytime somnolence, suvorexant may dose-dependently reduce ] and ] and impair ] ability.<ref name="Belsomra FDA label" /><ref name="pmid28365447" /> It may also increase the risk of falling asleep while driving.<ref name="Belsomra FDA label" /> Driving ability was found to be impaired at doses of 20 and 40{{nbsp}}mg in clinical studies.<ref name="Belsomra FDA label" /> Driving impairment may also occur with lower doses of suvorexant due to variations in individual sensitivity to the medication.<ref name="Belsomra FDA label" /> In three of four studies, 30{{nbsp}}mg suvorexant had no influence on next-day ] or ], whereas in the remaining study, there was a decrease in morning ] with 40{{nbsp}}mg and an increase in body sway with 20 and 40{{nbsp}}mg doses.<ref name="Belsomra FDA label" /> In another study in elderly people who were awakened in the night, impaired balance was present at 1.5{{nbsp}}hours after taking 30{{nbsp}}mg suvorexant whereas memory was unaffected.<ref name="Belsomra FDA label" />
			A 2017 ] and ] of suvorexant for the treatment of insomnia found that the medication significantly increased the rate of somnolence by 3.5-fold, daytime sleepiness/sedation by 3.1-fold, fatigue by 2.1-fold, abnormal dreams by 2.1-fold, and dry mouth by 2.0-fold.<ref name="pmid28365447">{{cite journal | vauthors = Kuriyama A, Tabata H | title = Suvorexant for the treatment of primary insomnia: A systematic review and meta-analysis | journal = Sleep Medicine Reviews | volume = 35 | issue = | pages = 1–7 | date = October 2017 | pmid = 28365447 | doi = 10.1016/j.smrv.2016.09.004 }}</ref><ref name="pmid30576764" /> Conversely, suvorexant did not significantly differ from placebo in the rates of any other assessed adverse effects.<ref name="pmid28365447" /><ref name="pmid30576764" /> This included ], ], dizziness, falls, headache, ]s/]s, ], ], potential ], suicidal ideation, complex sleep behaviors, hypnagogic or hypnopompic hallucinations, and sleep paralysis.<ref name="pmid28365447" /> The overall risk of any adverse event was increased 1.07-fold while discontinuation due to adverse events was unchanged ({{Abbrlink|RR|relative risk}} = 0.93, 95% {{Abbrlink|CI|confidence interval}} 0.60 to 1.44).<ref name="pmid28365447" />
			], ], ], and ]s do not appear to occur with suvorexant in the treatment of insomnia at studied doses.<ref name="Belsomra FDA label" /><ref name="pmid28994603">{{cite journal | vauthors = Keks NA, Hope J, Keogh S | title = Suvorexant: scientifically interesting, utility uncertain | journal = Australasian Psychiatry | volume = 25 | issue = 6 | pages = 622–624 | date = December 2017 | pmid = 28994603 | doi = 10.1177/1039856217734677 | s2cid = 206620990 }}</ref><ref name="pmid32901578" /> In three-month clinical studies, no rebound insomnia as assessed by measures of sleep onset or maintenance was observed with ] of suvorexant at doses of 15 to 40{{nbsp}}mg.<ref name="Belsomra FDA label" /> Similarly, no withdrawal effects were observed with discontinuation of suvorexant at these doses.<ref name="Belsomra FDA label" /> However, in other reports, some tolerance as assessed by diminishing somnolence and rebound insomnia upon discontinuation has been noted.<ref name="pmid27471419">{{cite journal | vauthors = Norman JL, Anderson SL | title = Novel class of medications, orexin receptor antagonists, in the treatment of insomnia - critical appraisal of suvorexant | journal = Nature and Science of Sleep | volume = 8 | issue = | pages = 239–247 | date = 2016 | pmid = 27471419 | pmc = 4948724 | doi = 10.2147/NSS.S76910 | doi-access = free }}</ref><ref name="pmid26317363" /><ref name="pmid28994603" />
			The ] ]s augment the signaling of the ] ] ] and are thought to potentiate ] tone.<ref name="pmid35203914">{{cite journal | vauthors = Katzman MA, Katzman MP | title = Neurobiology of the Orexin System and Its Potential Role in the Regulation of Hedonic Tone | journal = Brain Sciences | volume = 12 | issue = 2 | page = 150 | date = January 2022 | pmid = 35203914 | pmc = 8870430 | doi = 10.3390/brainsci12020150 | doi-access = free }}</ref><ref name="pmid22933994">{{cite journal | vauthors = Calipari ES, España RA | title = Hypocretin/orexin regulation of dopamine signaling: implications for reward and reinforcement mechanisms | journal = Frontiers in Behavioral Neuroscience | volume = 6 | issue = | pages = 54 | date = 2012 | pmid = 22933994 | pmc = 3423791 | doi = 10.3389/fnbeh.2012.00054 | doi-access = free }}</ref><ref name="pmid35043499">{{cite journal | vauthors = Jacobson LH, Hoyer D, de Lecea L | title = Hypocretins (orexins): The ultimate translational neuropeptides | journal = Journal of Internal Medicine | volume = 291 | issue = 5 | pages = 533–556 | date = May 2022 | pmid = 35043499 | doi = 10.1111/joim.13406 | s2cid = 248119793 }}</ref><ref name="pmid25254979">{{cite journal | vauthors = Mahler SV, Moorman DE, Smith RJ, James MH, Aston-Jones G | title = Motivational activation: a unifying hypothesis of orexin/hypocretin function | journal = Nature Neuroscience | volume = 17 | issue = 10 | pages = 1298–1303 | date = October 2014 | pmid = 25254979 | pmc = 4335648 | doi = 10.1038/nn.3810 }}</ref> Conversely, low orexin signaling may result in ] and orexin receptor antagonists are of interest for the potential treatment of ].<ref name="pmid35203914" /><ref name="pmid22933994" /><ref name="pmid35043499" /><ref name="pmid25254979" /> In line with these findings, suvorexant and other orexin receptor antagonists have not shown ] in ] in rats and non-human primates.<ref name="pmid25231363" /><ref name="pmid34052815" /><ref name="pmid28279667">{{cite journal | vauthors = Born S, Gauvin DV, Mukherjee S, Briscoe R | title = Preclinical assessment of the abuse potential of the orexin receptor antagonist, suvorexant | journal = Regulatory Toxicology and Pharmacology | volume = 86 | issue = | pages = 181–192 | date = June 2017 | pmid = 28279667 | doi = 10.1016/j.yrtph.2017.03.006 | s2cid = 4789582 }}</ref><ref name="pmid34619288">{{cite journal | vauthors = Asakura S, Shiotani M, Gauvin DV, Fujiwara A, Ueno T, Bower N, Beuckmann CT, Moline M | title = Nonclinical evaluation of abuse liability of the dual orexin receptor antagonist lemborexant | journal = Regulatory Toxicology and Pharmacology | volume = 127 | issue = | pages = 105053 | date = December 2021 | pmid = 34619288 | doi = 10.1016/j.yrtph.2021.105053 | s2cid = 238476630 | doi-access = free }}</ref> Paradoxically however, orexin receptor antagonists, including suvorexant, ], and ], have consistently shown ] responses in human studies of ] ] users.<ref name="Belsomra FDA label" /><ref name="Quviviq FDA label" /><ref name="Dayvigo FDA label">{{cite web | title = Dayvigo - lemborexant tablet, film coated | website = DailyMed | url = https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7074cb65-77b3-45d2-8e8d-da8dc0f70bfd | access-date = 17 June 2021}}</ref><ref name="pmid34480579">{{cite journal | vauthors = Ufer M, Kelsh D, Schoedel KA, Dingemanse J | title = Abuse potential assessment of the new dual orexin receptor antagonist daridorexant in recreational sedative drug users as compared to suvorexant and zolpidem | journal = Sleep | volume = 45 | issue = 3 | date = March 2022 | pmid = 34480579 | doi = 10.1093/sleep/zsab224 | doi-access = free }}</ref> Suvorexant at higher-than-approved doses (40, 80, and 150{{nbsp}}mg vs. 20{{nbsp}}mg maximum recommended dose) showed similar drug liking to the ] ] (15 and 30{{nbsp}}mg) in such individuals.<ref name="Belsomra FDA label" /><ref name="pmid25667197" /><ref name="pmid25231363" /><ref name="pmid34480579" /><ref name="pmid27253658" /> On the other hand, it showed lower misuse potential on all other measures (including an overall rate of misuse potential adverse event of 58% for zolpidem and 31% for suvorexant).<ref name="pmid25667197" /><ref name="pmid25231363" /> In another study, suvorexant at a dose of 150{{nbsp}}mg showed greater drug liking than daridorexant (50{{nbsp}}mg) but similar drug liking to zolpidem (30{{nbsp}}mg) and higher doses of daridorexant (100–150{{nbsp}}mg) in recreational sedative users.<ref name="Quviviq FDA label">{{cite web|url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/214985s000lbl.pdf|title=Quviviq (daridorexant) tablets, for oral use, |website=U.S. ] (FDA)|access-date=3 March 2022}}</ref><ref name="pmid34480579" /> There was no apparent ] for positive measures of misuse potential with suvorexant, in contrast to zolpidem.<ref name="pmid25231363" /><ref name="pmid27253658">{{cite journal | vauthors = Schoedel KA, Sun H, Sellers EM, Faulknor J, Levy-Cooperman N, Li X, Kennedy WP, Cha JH, Lewis NM, Liu W, Bondiskey P, McCrea JB, Panebianco DL, Troyer MD, Wagner JA | title = Assessment of the Abuse Potential of the Orexin Receptor Antagonist, Suvorexant, Compared With Zolpidem in a Randomized Crossover Study | journal = Journal of Clinical Psychopharmacology | volume = 36 | issue = 4 | pages = 314–323 | date = August 2016 | pmid = 27253658 | doi = 10.1097/JCP.0000000000000516 | s2cid = 36758035 }}</ref> In the ] clinical trials, misuse potential adverse events were reported in 3.0% with placebo, 4.1% with 15 or 20{{nbsp}}mg suvorexant, and 2.6% with 30 or 40{{nbsp}}mg suvorexant.<ref name="pmid25231363" /> The misuse liability of suvorexant is considered to be at most modest, and further research is needed to characterize the misuse potential of orexin receptor antagonists.<ref name="Belsomra FDA label" /><ref name="pmid25231363" /><ref name="pmid34052815" /> In any case, suvorexant is a ] in the United States due to concerns about the possibility of misuse.<ref name="Belsomra FDA label" /><ref name="pmid25318834" /><ref name="pmid25231363" />
			Besides its subjective side effects, suvorexant has been found to cause dose-dependent increases in serum ] levels in clinical trials.<ref name="Belsomra FDA label" /><ref name="PublicCitizen2013" /> These changes in cholesterol levels were +1.2{{nbsp}}mg/dL at 10{{nbsp}}mg, +2.3{{nbsp}}mg/dL at 20{{nbsp}}mg, +3.1{{nbsp}}mg/dL at 40{{nbsp}}mg, and +6.0{{nbsp}}mg/dL at 80{{nbsp}}mg relative to –3.7{{nbsp}}mg/dL for placebo.<ref name="Belsomra FDA label" /><ref name="PublicCitizen2013" /> Although the increases in cholesterol levels with approved doses of suvorexant (10–20{{nbsp}}mg) are small, they could be important over a long duration of treatment.<ref name="PublicCitizen2013" />
			Early studies in rodents found that ]s (derived from ] "]" meaning "appetite") stimulate ], ], and ] while orexin receptor antagonists block these effects.<ref name="pmid22759794">{{cite journal | vauthors = Gotter AL, Webber AL, Coleman PJ, Renger JJ, Winrow CJ | title = International Union of Basic and Clinical Pharmacology. LXXXVI. Orexin receptor function, nomenclature and pharmacology | journal = Pharmacological Reviews | volume = 64 | issue = 3 | pages = 389–420 | date = July 2012 | pmid = 22759794 | doi = 10.1124/pr.111.005546 | s2cid = 2038246 }}</ref><ref name="pmid24215799">{{cite journal | vauthors = Hoyer D, Jacobson LH | title = Orexin in sleep, addiction and more: is the perfect insomnia drug at hand? | journal = Neuropeptides | volume = 47 | issue = 6 | pages = 477–488 | date = December 2013 | pmid = 24215799 | doi = 10.1016/j.npep.2013.10.009 | s2cid = 6402764 }}</ref><ref name="pmid25318834" /> However, subsequent animal studies were more mixed, with the effects being limited and depending on the animal ].<ref name="pmid22759794" /><ref name="pmid24215799" /><ref name="pmid25318834" /> In humans, orexin receptor antagonists including suvorexant have not been found to affect ] in rigorous clinical trials that lasted up to 12 to 14{{nbsp}}months.<ref name="pmid24215799" /><ref name="pmid25318834" />
			==Overdose==
			There is limited experience with ] of suvorexant.<ref name="Belsomra FDA label" /> Suvorexant has been assessed in single doses of as high as 240{{nbsp}}mg in clinical studies.<ref name="Belsomra FDA label" /><ref name="DimovaBrarMen2014" /><ref name="pmid25318834" /><ref name="pmid25231363">{{cite journal | vauthors = Citrome L | title = Suvorexant for insomnia: a systematic review of the efficacy and safety profile for this newly approved hypnotic - what is the number needed to treat, number needed to harm and likelihood to be helped or harmed? | journal = International Journal of Clinical Practice | volume = 68 | issue = 12 | pages = 1429–1441 | date = December 2014 | pmid = 25231363 | doi = 10.1111/ijcp.12568 | s2cid = 20955172 | doi-access = free }}</ref> The medication dose-dependently produces ].<ref name="Belsomra FDA label" /> High doses of suvorexant may also cause ] in some individuals (2% incidence at doses of 40–240{{nbsp}}mg).<ref name="pmid25318834" /> Treatment of suvorexant overdose is based on symptoms and is supportive.<ref name="Belsomra FDA label" /> ] may be used where appropriate whereas the value of ] has not been determined.<ref name="Belsomra FDA label" /> Because suvorexant has high ], ] is not expected to enhance ] of suvorexant.<ref name="Belsomra FDA label" />
			==Interactions==
			] ]s can increase exposure to suvorexant while CYP3A4 ]s can decrease exposure to suvorexant.<ref name="Belsomra FDA label" /><ref name="pmid32901578" /><ref name="pmid30810914">{{cite journal | vauthors = Wrishko RE, McCrea JB, Yee KL, Liu W, Panebianco D, Mangin E, Chakravarthy M, Martinez-Cantarin MP, Kraft WK | title = Effect of CYP3A Inhibition and Induction on the Pharmacokinetics of Suvorexant: Two Phase I, Open-Label, Fixed-Sequence Trials in Healthy Subjects | journal = Clinical Drug Investigation | volume = 39 | issue = 5 | pages = 441–451 | date = May 2019 | pmid = 30810914 | pmc = 6929321 | doi = 10.1007/s40261-019-00764-x }}</ref> Combination of suvorexant with the strong CYP3A4 inhibitor ] increased suvorexant ] by 2.79-fold and ] by about 1.25-fold, combination with the moderate CYP3A4 inhibitor ] increased suvorexant overall exposure by 2.05-fold and peak levels by about 1.25-fold, and combination with the strong CYP3A4 inducer ] decreased suvorexant overall exposure by 88% and peak levels by about 65%.<ref name="Belsomra FDA label" /><ref name="MerckSharpDohme2013" /><ref name="pmid30810914" /> The ] of suvorexant (about 12{{nbsp}}hours for suvorexant alone) was increased to 19.4{{nbsp}}hours with ketoconazole and to 16.1{{nbsp}}hours with diltiazem while it was decreased to 7.7{{nbsp}}hours with rifampin.<ref name="HaghparastPondromRay2020">{{cite book | title = Side Effects of Drugs Annual | vauthors = Haghparast P, Pondrom M, Ray SD | chapter = Sedatives and hypnotics | date = 2020 | volume = 42 | pages = 67–79 | publisher = Elsevier | issn = 0378-6080 | doi = 10.1016/bs.seda.2020.08.008 | isbn = 9780128203309 | s2cid = 229269184 }}</ref><ref name="pmid30810914" /> Concomitant use of suvorexant with strong CYP3A4 inhibitors is not recommended, while lower doses of suvorexant are recommended with moderate CYP3A4 inhibitors (5{{nbsp}}mg starting dose and 10{{nbsp}}mg maximum dose generally).<ref name="Belsomra FDA label" /> The substantial decrease in suvorexant exposure with strong CYP3A4 inducers may result in loss of effectiveness.<ref name="Belsomra FDA label" /> Suvorexant does not appear to have been assessed in combination with moderate CYP3A4 inducers (e.g., ]).<ref name="Belsomra FDA label" /><ref name="MerckSharpDohme2013" /><ref name="pmid30810914" />
			Examples of important CYP3A4 modulators which are expected to interact with suvorexant include the strong CYP3A4 inhibitors ], ], ], ], ], ], ], ], ], ], ], ], ], and ] (concomitant use not recommended); the moderate CYP3A4 inhibitors ], ], ], ], ], ], ], ], ], ], ], ], and ] (lower doses of suvorexant recommended); and the strong CYP3A4 inducers ], ], ], ], ], ], and ] (expected to decrease suvorexant effectiveness).<ref name="Belsomra FDA label" /><ref name="FDA2020">{{cite web | title = Drug Development and Drug Interactions <nowiki>|</nowiki> Table of Substrates, Inhibitors and Inducers | publisher = U.S. Food and Drug Administration | website = fda.gov | date = 10 March 2020 | access-date = 5 April 2022 | url = https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers}}</ref><ref name="pmid32901578" />
			Coadministration of suvorexant with other ]s such as ], ]s, ]s, and ]s may increase the risk of ] and ].<ref name="Belsomra FDA label" /> Alcohol and suvorexant do not appear to interact in terms of ] but consumption of alcohol in combination with suvorexant is not advised due to additive CNS depression.<ref name="Belsomra FDA label" /> Dosage adjustment may be necessary when suvorexant is combined with other CNS depressants.<ref name="Belsomra FDA label" /> Use of suvorexant in combination with other medications used in the treatment of insomnia is not recommended.<ref name="Belsomra FDA label" />
			Suvorexant is not expected to cause clinically meaningful inhibition or induction of various ] ]s and ]s.<ref name="Belsomra FDA label" /> It has been found to not substantially influence the pharmacokinetics of ] (CYP3A4 ]), ] (] substrate), ] (] substrate), or ]s.<ref name="Belsomra FDA label" /> However, coadministration of suvorexant with ] may result in slightly increased digoxin exposure due to inhibition of ] ] by suvorexant.<ref name="Belsomra FDA label" /> Concentrations of digoxin should be monitored during coadministration of suvorexant and digoxin.<ref name="Belsomra FDA label" />
			==Pharmacology==
			===Pharmacodynamics===
			Suvorexant acts as a ] dual ] of the ]s ] and ].<ref name="pmid32901578" /><ref name="pmid27860547">{{cite journal | vauthors = Coleman PJ, Gotter AL, Herring WJ, Winrow CJ, Renger JJ | title = The Discovery of Suvorexant, the First Orexin Receptor Drug for Insomnia | journal = Annual Review of Pharmacology and Toxicology | volume = 57 | issue = | pages = 509–533 | date = January 2017 | pmid = 27860547 | doi = 10.1146/annurev-pharmtox-010716-104837 }}</ref> These ]s are the ]s of the ] ]-promoting ] ]s ] and ].<ref name="pmid35043499" /> The ] (K<sub>i</sub>) of suvorexant at the human orexin receptors are 0.55{{nbsp}}nM for the OX<sub>1</sub> receptor and 0.35{{nbsp}}nM for the OX<sub>2</sub> receptor.<ref name="pmid27860547" /><ref name="Belsomra FDA label" /><ref name="MerckSharpDohme2013">{{cite web | author = Merck Sharp and Dohme Corporation | title = Suvorexant Advisory Committee Meeting Briefing Document: Peripheral & Central Nervous System Drugs Advisory Committee Meeting | website = ] | date = 22 May 2013 | access-date = 14 April 2022 | url = https://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/peripheralandcentralnervoussystemdrugsadvisorycommittee/ucm352970.pdf| archive-url = https://web.archive.org/web/20130612065319/https://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/peripheralandcentralnervoussystemdrugsadvisorycommittee/ucm352970.pdf | archive-date = 12 June 2013 }}</ref> The antagonistic ] or ] (K<sub>b</sub>) of suvorexant at the human orexin receptors are 65{{nbsp}}nM for the OX<sub>1</sub> receptor and 41{{nbsp}}nM for the OX<sub>2</sub> receptor.<ref name="pmid27860547" /> Hence, suvorexant shows similar affinities and antagonistic activities at the OX<sub>1</sub> and OX<sub>2</sub> receptors '']''.<ref name="pmid32901578" /><ref name="pmid27860547" /> Suvorexant is highly selective for the orexin receptors over a large number of other ]s (170 screened ] ]s, ]s, and ]s).<ref name="pmid25318834" /><ref name="pmid30796894" /> In contrast to certain other sedatives and hypnotics, suvorexant is not a ] or ] and does not interact with ]s.<ref name="pmid25318834" /><ref name="pmid29487083" /><ref name="MerckSharpDohme2013" />
			====Mechanism of action====
			Suvorexant is thought to exert its therapeutic effects in the treatment of insomnia by blocking the orexin receptors and thereby inhibiting the effects of the endogenous wakefulness-promoting orexin neuropeptides orexin-A and orexin-B.<ref name="Belsomra FDA label" /><ref name="pmid27860547" /> The orexin neuropeptides are produced exclusively by a relatively small population of 20,000 to 80,000 ]s located in the ] in the ].<ref name="pmid21034217">{{cite journal | vauthors = Scammell TE, Winrow CJ | title = Orexin receptors: pharmacology and therapeutic opportunities | journal = Annual Review of Pharmacology and Toxicology | volume = 51 | issue = | pages = 243–266 | date = 2011 | pmid = 21034217 | pmc = 3058259 | doi = 10.1146/annurev-pharmtox-010510-100528 }}</ref><ref name="JenningsdeLecea2019">{{cite book | title = The Orexin/Hypocretin System: Functional Roles and Therapeutic Potential | vauthors = Jennings KJ, de Lecea L | chapter = Hypocretins (Orexins): Twenty Years of Dissecting Arousal Circuits | date = 2019 | pages = 1–29 | publisher = Elsevier | doi = 10.1016/B978-0-12-813751-2.00001-2 | isbn = 9780128137512 | s2cid = 150387562 | url = }}</ref> These neurons project widely throughout the brain and mediate ] signaling to key centers involved in ], including the ] ], ] ], ] ], and ] ].<ref name="pmid21034217" /><ref name="pmid20544785">{{cite journal | vauthors = Gatfield J, Brisbare-Roch C, Jenck F, Boss C | title = Orexin receptor antagonists: a new concept in CNS disorders? | journal = ChemMedChem | volume = 5 | issue = 8 | pages = 1197–1214 | date = August 2010 | pmid = 20544785 | doi = 10.1002/cmdc.201000132 | s2cid = 39427538 }}</ref><ref name="pmid12052911">{{cite journal | vauthors = Taheri S, Zeitzer JM, Mignot E | title = The role of hypocretins (orexins) in sleep regulation and narcolepsy | journal = Annual Review of Neuroscience | volume = 25 | issue = | pages = 283–313 | date = 2002 | pmid = 12052911 | doi = 10.1146/annurev.neuro.25.112701.142826 }}</ref><ref name="JenningsdeLecea2019" /><ref name="pmid19566795">{{cite journal | vauthors = Eriksson KS, Sergeeva OA, Haas HL, Selbach O | title = Orexins/hypocretins and aminergic systems | journal = Acta Physiologica | volume = 198 | issue = 3 | pages = 263–275 | date = March 2010 | pmid = 19566795 | doi = 10.1111/j.1748-1716.2009.02015.x | s2cid = 5133371 }}</ref> The orexin system shows ]icity in its activity, with high activity during waking and low to no activity during sleep or at night.<ref name="pmid21034217" /><ref name="MerckSharpDohme2013" /><ref name="pmid23359095" /> Orexin system activity during wakefulness is also higher with behavioral activation and with high-intensity emotions.<ref name="pmid25728441" /><ref name="pmid21034217" />
			] is a chronic ] characterized by ], ], ], and ]s, as well as ]s and ].<ref name="pmid19555382" /><ref name="pmid12052911" /> Narcolepsy with cataplexy, also known as ], is thought to be caused by loss of orexin-producing neurons in the lateral hypothalamus, possibly mediated by ] mechanisms related to ]s in ] individuals.<ref name="pmid19555382">{{cite journal | vauthors = Nishino S, Okuro M, Kotorii N, Anegawa E, Ishimaru Y, Matsumura M, Kanbayashi T | title = Hypocretin/orexin and narcolepsy: new basic and clinical insights | journal = Acta Physiologica | volume = 198 | issue = 3 | pages = 209–222 | date = March 2010 | pmid = 19555382 | pmc = 2860658 | doi = 10.1111/j.1748-1716.2009.02012.x }}</ref><ref name="pmid25728441">{{cite journal | vauthors = Liblau RS, Vassalli A, Seifinejad A, Tafti M | title = Hypocretin (orexin) biology and the pathophysiology of narcolepsy with cataplexy | journal = The Lancet. Neurology | volume = 14 | issue = 3 | pages = 318–328 | date = March 2015 | pmid = 25728441 | doi = 10.1016/S1474-4422(14)70218-2 | s2cid = 18455770 }}</ref> There is an 80 to 100% loss of orexin-producing neurons in the lateral hypothalamus and very low or undetectable levels of orexin-A in ] in people with narcolepsy.<ref name="pmid20544785" /><ref name="pmid19555382" /><ref name="pmid25728441" /> Similarly, narcolepsy with cataplexy in dogs is caused by a ] in the ] encoding the OX<sub>2</sub> receptor, and ] for genes encoding orexin system proteins such as ] or the OX<sub>2</sub> receptor show a narcolepsy-like ].<ref name="pmid20544785" /><ref name="pmid19555382" /> Although there is ] in narcolepsy, people with the condition do not sleep more overall than normal individuals but instead experience more sleepiness and sleep during daytime in tandem with disturbed sleep at night.<ref name="pmid12052911" /><ref name="pmid26594338" /> They do not usually feel well-rested during the day.<ref name="pmid26594338" /> Besides narcolepsy, the orexin system may also be involved in the ] of insomnia.<ref name="pmid25462194">{{cite journal | vauthors = Nixon JP, Mavanji V, Butterick TA, Billington CJ, Kotz CM, Teske JA | title = Sleep disorders, obesity, and aging: the role of orexin | journal = Ageing Research Reviews | volume = 20 | issue = | pages = 63–73 | date = March 2015 | pmid = 25462194 | pmc = 4467809 | doi = 10.1016/j.arr.2014.11.001 }}</ref><ref name="pmid21034217" /> In addition, orexin signaling appears to change with age, and this may be involved in ]-related ]s.<ref name="pmid25462194" /><ref name="pmid30648559">{{cite journal | vauthors = Zhong HH, Yu B, Luo D, Yang LY, Zhang J, Jiang SS, Hu SJ, Luo YY, Yang MW, Hong FF, Yang SL | title = Roles of aging in sleep | journal = Neuroscience and Biobehavioral Reviews | volume = 98 | issue = | pages = 177–184 | date = March 2019 | pmid = 30648559 | doi = 10.1016/j.neubiorev.2019.01.013 | s2cid = 58640179 }}</ref>
			Orexin receptor antagonists may be expected to produce effects similar to those in narcolepsy.<ref name="pmid26594338" /><ref name="pmid22759794" /><ref name="pmid21034217" /> However, the effects of acute transient pharmacological antagonism of the orexin receptors are not necessarily the same as in the chronic and severe orexin deficiency in narcolepsy.<ref name="pmid27860547" /><ref name="pmid22759794" /><ref name="pmid21034217" /><ref name="JacobsonChenMir2016">{{cite journal | vauthors = Jacobson LH, Chen S, Mir S, Hoyer D | title = Orexin OX<sub>2</sub> Receptor Antagonists as Sleep Aids | journal = Current Topics in Behavioral Neurosciences | volume = 33 | pages = 105–136 | date = 2016 | pmid = 27909987 | doi = 10.1007/7854_2016_47 | publisher = Springer International Publishing | isbn = 978-3-319-57534-6 | eissn = 1866-3389 | doi-access = free }}</ref> Modulation of orexin signaling with orexin receptor antagonists produces effects that occur more at night when drug levels are high and less during the day when levels are low.<ref name="pmid26594338" /><ref name="pmid21034217" /> In addition, long-term neural changes may develop in narcolepsy to compensate for the orexin deficiency in the condition.<ref name="pmid27860547" /><ref name="pmid22759794" /><ref name="pmid21034217" /><ref name="JacobsonChenMir2016" /> In animals and humans, orexin receptor agonists such as orexin-A and ] dose-dependently produce ] and ]<ref name="pmid12052911" /><ref name="pmid35043499" /><ref name="pmid23359095" /> while orexin receptor antagonists like suvorexant transiently reduce locomotor activity and dose-dependently promote sleep.<ref name="pmid30576764" /><ref name="pmid23702225" /> Acute orexin receptor antagonists can promote sleep in animals to a greater extent than what occurs in narcolepsy-like orexin system loss.<ref name="pmid22759794" /> In addition, little to no cataplexy has been observed even with high doses of orexin receptor antagonists in animals and humans.<ref name="pmid27860547" /><ref name="pmid22759794" /><ref name="pmid21034217" /><ref name="pmid26317591" /> It is unknown if long-term use of orexin receptor antagonists may produce compensatory neural changes or narcolepsy-like symptoms.<ref name="pmid27860547" /> An ] of chronic high-dose suvorexant administration that showed development of narcolepsy-like changes suggests that this may be possible however.<ref name="pmid33609365">{{cite journal | vauthors = Kaushik MK, Aritake K, Cherasse Y, Imanishi A, Kanbayashi T, Urade Y, Yanagisawa M | title = Induction of narcolepsy-like symptoms by orexin receptor antagonists in mice | journal = Sleep | volume = 44 | issue = 8 | pages = | date = August 2021 | pmid = 33609365 | doi = 10.1093/sleep/zsab043 | url = | doi-access = free }}</ref>
			Endogenous ] tone is expected to play an important moderating influence in terms of the effects of orexin receptor modulators.<ref name="MerckSharpDohme2013" /> As an example, rising orexin levels during the day may help to competitively offset the next-day residual effects of nightly-dosed orexin receptor antagonists.<ref name="MerckSharpDohme2013" />
			===Pharmacokinetics===
			]
			]
			====Absorption====
			The ] of suvorexant is 82% at a dose of 10{{nbsp}}mg.<ref name="Belsomra FDA label" /> Suvorexant exposure does not increase ] over a dose range of 10 to 100{{nbsp}}mg, which is likely due to decreased ] at higher doses.<ref name="Belsomra FDA label" /><ref name="MerckSharpDohme2013" /><ref name="pmid29705869">{{cite journal | vauthors = Yee KL, McCrea J, Panebianco D, Liu W, Lewis N, Cabalu T, Ramael S, Wrishko RE | title = Safety, Tolerability, and Pharmacokinetics of Suvorexant: A Randomized Rising-Dose Trial in Healthy Men | journal = Clinical Drug Investigation | volume = 38 | issue = 7 | pages = 631–638 | date = July 2018 | pmid = 29705869 | doi = 10.1007/s40261-018-0650-4 | s2cid = 14061889 }}</ref> Exposure to suvorexant increases by about 75% with a doubling of dose from 20{{nbsp}}mg to 40{{nbsp}}mg.<ref name="MerckSharpDohme2013" /> The ] of suvorexant is 2 to 3{{nbsp}}hours regardless of dose but with wide variation (range 30{{nbsp}}minutes to 8{{nbsp}}hours).<ref name="Belsomra FDA label" /><ref name="pmid25318834" /> Taking suvorexant with food does not modify suvorexant ] or ] (overall exposure) but does delay the time to peak concentrations by about 1.5{{nbsp}}hours.<ref name="Belsomra FDA label" /> ] of suvorexant with once-daily continuous administration are reached within 3{{nbsp}}days.<ref name="Belsomra FDA label" /><ref name="MerckSharpDohme2013" /> Levels of suvorexant ] minimally, by about 1.2- to 1.6-fold, with repeated once-daily administration.<ref name="MerckSharpDohme2013" /><ref name="Belsomra FDA label" />
			====Distribution====
			The ] of suvorexant is approximately 49{{nbsp}}L.<ref name="Belsomra FDA label" /> It crosses the ] and ]s into the ].<ref name="pmid27860547" />
			Suvorexant has high ] (99.5%).<ref name="pmid25318834" /><ref name="Belsomra FDA label" /> It is bound to ] and ] (orosomucoid).<ref name="Belsomra FDA label" />
			====Metabolism====
			Suvorexant is ] primarily by ] via ] ]s.<ref name="Belsomra FDA label" /><ref name="DimovaBrarMen2014" /> ] also contributes to suvorexant metabolism to a minor extent.<ref name="Belsomra FDA label" /> The major circulating forms are suvorexant and its ] hydroxysuvorexant.<ref name="Belsomra FDA label" /> The hydroxysuvorexant (M9) metabolite is not expected to be ].<ref name="Belsomra FDA label" /><ref name="DimovaBrarMen2014" /> It showed 10-fold lower ] for the orexin receptors than suvorexant '']'', was a ] for ] making it unlikely to cross the ], and did not show sedative effects in animal studies.<ref name="DimovaBrarMen2014" /> Suvorexant also has several other minor metabolites.<ref name="DimovaBrarMen2014" />
			====Elimination====
			Suvorexant is ] mainly via metabolism.<ref name="Belsomra FDA label" /> It is ] primarily in ] (66%) predominantly as metabolites and to a lesser extent in ] (23%).<ref name="Belsomra FDA label" /><ref name="MerckSharpDohme2013" />
			The ] of suvorexant at a dose of 40{{nbsp}}mg is 12.2{{nbsp}}hours, with a range of 8 to 19{{nbsp}}hours.<ref name="Belsomra FDA label" /><ref name="MerckSharpDohme2013" /><ref name="DimovaBrarMen2014" /><ref name="pmid25318834" /> In another study, the half-life of suvorexant was 15{{nbsp}}hours with a range of 10 to 22{{nbsp}}hours.<ref name="Belsomra FDA label" /> In one study, the half-lives of suvorexant (mean ± SD) were 9.0 ± 7.2{{nbsp}}hours at 10{{nbsp}}mg, 10.8 ± 3.6{{nbsp}}hours at 50{{nbsp}}mg, and 13.1 ± 5.8{{nbsp}}hours at 100{{nbsp}}mg.<ref name="pmid25318834" /> With doses of 120 to 240{{nbsp}}mg, the half-lives of suvorexant were 12.1 to 14.5{{nbsp}}hours in healthy young males and 14.4 to 15.8{{nbsp}}hours in healthy young females.<ref name="DimovaBrarMen2014" /> The half-life of suvorexant's inactive metabolite hydroxysuvorexant is similar to that of suvorexant.<ref name="DimovaBrarMen2014" />
			====Specific populations====
			Age and race do not influence the pharmacokinetics of suvorexant in a clinically meaningfully way.<ref name="Belsomra FDA label" /> Exposure to suvorexant is slightly higher in women compared to men (C<sub>max</sub> 9% higher, AUC 17% higher), however dose adjustments based on gender are generally unnecessary.<ref name="Belsomra FDA label" /> Suvorexant exposure is greater in people with higher ], such as ] people (C<sub>max</sub> 17% higher, AUC 31% higher).<ref name="Belsomra FDA label" /> This is particularly the case in obese women relative to non-obese women (C<sub>max</sub> 25% higher, AUC 46% higher).<ref name="Belsomra FDA label" /> Suvorexant exposure with a single dose is not greater in people with moderate ] compared to healthy individuals.<ref name="Belsomra FDA label" /> However, the half-life of suvorexant at a dose of 20{{nbsp}}mg was prolonged from 14.7{{nbsp}}hours (range 10–22{{nbsp}}hours) to 19.1{{nbsp}}hours (range 11–49{{nbsp}}hours) in these individuals.<ref name="Belsomra FDA label" /><ref name="DimovaBrarMen2014">{{cite web | vauthors = Dimova H, Brar S, Men A | title = Application Number: 204569Orig1s000. Clinical Pharmacology/Biopharmaceutics Review. Suvorexant (MK-4305). | date = 2014 | publisher = ] (]) | url = https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/204569Orig1s000ClinPharmR.pdf| archive-url = https://web.archive.org/web/20220305191601/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/204569Orig1s000ClinPharmR.pdf | archive-date = 5 March 2022 }}</ref> Suvorexant exposure is unchanged in people with severe ] and no dosage adjustment is necessary in these individuals.<ref name="Belsomra FDA label" /> Similarly to hepatic impairment, the half-life of suvorexant was increased to 19.4{{nbsp}}hours when used in combination with the strong CYP3A4 inhibitor ] and to 16.1{{nbsp}}hours with the moderate CYP3A4 inhibitor ] while it was decreased to 7.7{{nbsp}}hours with the strong CYP3A4 inducer ].<ref name="HaghparastPondromRay2020" /><ref name="pmid30810914" />
			====Miscellaneous====
			] concentrations (% of ]) of the orexin receptor antagonists suvorexant, ], ], and ] with administration in humans.<ref name="pmid32901578" /> The ] in these studies were 12{{nbsp}}hours, 55{{nbsp}}hours, 6{{nbsp}}hours, and 2.5{{nbsp}}hours, respectively.<ref name="pmid32901578" />]]
			]) of the orexin receptor antagonists suvorexant (SUV; 20{{nbsp}}mg) and ] (LEM; 10{{nbsp}}mg) with administration at ] in humans.<ref name="pmid34553844" />]]
			The delayed time to peak levels (2–3{{nbsp}}hours) and long elimination half-life (12{{nbsp}}hours) of suvorexant are less than ideal for an insomnia medication as they result in a delayed onset of effect and significant next-day side effects such as daytime sedation.<ref name="pmid25318834" /><ref name="pmid26648692" /> Orexin receptor antagonists with shorter half-lives and faster onsets of action are theoretically more optimal for therapeutic use as sleep aids.<ref name="pmid25318834" /><ref name="pmid32901578" /> The ideal insomnia medication would not have a ] extending beyond about 8{{nbsp}}hours.<ref name="pmid24215799" /> Relative to suvorexant, ] has a shorter half-life (8{{nbsp}}hours) while ] has a longer half-life (17–55{{nbsp}}hours).<ref name="pmid32901578">{{cite journal | vauthors = Muehlan C, Vaillant C, Zenklusen I, Kraehenbuehl S, Dingemanse J | title = Clinical pharmacology, efficacy, and safety of orexin receptor antagonists for the treatment of insomnia disorders | journal = Expert Opinion on Drug Metabolism & Toxicology | volume = 16 | issue = 11 | pages = 1063–1078 | date = November 2020 | pmid = 32901578 | doi = 10.1080/17425255.2020.1817380 | s2cid = 221572078 }}</ref> However, although lemborexant has a longer ] than suvorexant, it appears to be more rapidly cleared in the earlier phases of elimination.<ref name="pmid34553844">{{cite journal | vauthors = Kishi T, Nishida M, Koebis M, Taninaga T, Muramoto K, Kubota N, Moline M, Sakuma K, Okuya M, Nomura I, Iwata N | title = Evidence-based insomnia treatment strategy using novel orexin antagonists: A review | journal = Neuropsychopharmacol Rep | volume = 41 | issue = 4 | pages = 450–458 | date = December 2021 | pmid = 34553844 | pmc = 8698673 | doi = 10.1002/npr2.12205 | url = }}</ref><ref name="pmid32901578" /> The investigational agents ] and ], which are still in clinical trials, have comparatively very short half-lives in the range of 1.5 to 3{{nbsp}}hours.<ref name="pmid32901578" /><ref name="pmid35296912">{{cite journal | vauthors = Uchiyama M, Kambe D, Imadera Y, Kajiyama Y, Ogo H, Uchimura N | title = Effects of TS-142, a novel dual orexin receptor antagonist, on sleep in patients with insomnia: a randomized, double-blind, placebo-controlled phase 2 study | journal = Psychopharmacology | volume = 239| issue = 7| date = March 2022 | pages = 2143–2154 | pmid = 35296912 | doi = 10.1007/s00213-022-06089-6 | pmc = 9205809 | s2cid = 247498033 }}</ref>
			Suvorexant dissociates from the ]s slowly.<ref name="pmid25318834" /><ref name="pmid27860547" /> As a result, its ] may be longer than that suggested by its circulating concentrations and half-life.<ref name="pmid25318834" /><ref name="pmid27860547" />
			==Chemistry==
			Suvorexant is a ] compound.<ref name="pmid25489915">{{cite journal | vauthors = Christopher JA | title = Small-molecule antagonists of the orexin receptors | journal = Pharmaceutical Patent Analyst | volume = 3 | issue = 6 | pages = 625–638 | date = 2014 | pmid = 25489915 | doi = 10.4155/ppa.14.46 }}</ref> The ] of suvorexant is methanone.<ref name="Belsomra FDA label" /> Its ] is C<sub>23</sub>H<sub>23</sub>N<sub>6</sub>O<sub>2</sub>Cl and its ] is 450.92{{nbsp}}g/mol.<ref name="Belsomra FDA label" /> Suvorexant is a white to off-white powder and is ] and ] in water.<ref name="Belsomra FDA label" /><ref name="pmid32901578" /> It is ] related to other orexin receptor antagonists like ], ], and ].<ref name="pmid32901578" /><ref name="pmid25489915" />
			==History==
			The ] ]s were discovered in 1998<ref name="pmid35043499" /><ref name="pmid25406050">{{cite journal | vauthors = Preskorn SH | title = CNS drug development: lessons from the development of ondansetron, aprepitant, ramelteon, varenicline, lorcaserin, and suvorexant. Part I | journal = Journal of Psychiatric Practice | volume = 20 | issue = 6 | pages = 460–465 | date = November 2014 | pmid = 25406050 | doi = 10.1097/01.pra.0000456594.66363.6f | s2cid = 35086648 }}</ref> and the role of the orexin system in the ] of ] was identified between 1999 and 2000.<ref name="pmid26317591">{{cite journal | vauthors = Roecker AJ, Cox CD, Coleman PJ | title = Orexin Receptor Antagonists: New Therapeutic Agents for the Treatment of Insomnia | journal = Journal of Medicinal Chemistry | volume = 59 | issue = 2 | pages = 504–530 | date = January 2016 | pmid = 26317591 | doi = 10.1021/acs.jmedchem.5b00832 }}</ref> Subsequent research further established the role of the orexin system in ].<ref name="pmid35043499" /><ref name="pmid25406050" /><ref name="pmid23359095" /> Due to the promising potential of orexin system modulation in the treatment of ]s, these findings led to ] efforts to bring orexin receptor modulators to medicine as therapeutic agents.<ref name="pmid35043499" /><ref name="pmid25406050" /><ref name="pmid23359095">{{cite journal | vauthors = Mieda M, Sakurai T | title = Orexin (hypocretin) receptor agonists and antagonists for treatment of sleep disorders. Rationale for development and current status | journal = CNS Drugs | volume = 27 | issue = 2 | pages = 83–90 | date = February 2013 | pmid = 23359095 | doi = 10.1007/s40263-012-0036-8 | s2cid = 43352827 }}</ref><ref name="pmid26317591" /><ref name="JacobsonChenMir2016" />
			Suvorexant was developed by ].<ref name="pmid35043499" /><ref name="pmid25406050" /> It entered ] in 2006<ref name="pmid25406050" /> and was first described in the medical literature in 2010.<ref name="pmid20565075">{{cite journal | vauthors = Cox CD, Breslin MJ, Whitman DB, Schreier JD, McGaughey GB, Bogusky MJ, Roecker AJ, Mercer SP, Bednar RA, Lemaire W, Bruno JG, Reiss DR, Harrell CM, Murphy KL, Garson SL, Doran SM, Prueksaritanont T, Anderson WB, Tang C, Roller S, Cabalu TD, Cui D, Hartman GD, Young SD, Koblan KS, Winrow CJ, Renger JJ, Coleman PJ | title = Discovery of the dual orexin receptor antagonist methanone (MK-4305) for the treatment of insomnia | journal = Journal of Medicinal Chemistry | volume = 53 | issue = 14 | pages = 5320–5332 | date = July 2010 | pmid = 20565075 | doi = 10.1021/jm100541c }}</ref> The medication was approved by the FDA for the treatment of insomnia in the United States on 13 August 2014.<ref name="Belsomra FDA label" /><ref name="Drugs.com-Belsomra-Generic">{{cite web | title = Belsomra Generic Belsomra Availability | work = Drugs.com | url = https://www.drugs.com/availability/generic-belsomra.html}}</ref><ref>{{cite press release | title=FDA approves new type of sleep drug, Belsomra | website=U.S. ] (FDA) | date=13 August 2014 | url=https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm409950.htm | archive-url=https://web.archive.org/web/20170214122028/https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm409950.htm | archive-date=14 February 2017 | url-status=dead | access-date=30 January 2020}}</ref> Suvorexant was initially released November 2014 in ],<ref name="APDNews2014">{{cite web|url=http://en.apdnews.com/news/7ff7b8a890574d1cbb50675732d6873a.html|title=New hypnotic drug without addiction to be released in Japan first|access-date=6 November 2014|archive-date=6 November 2014|archive-url=https://archive.today/20141106123821/http://en.apdnews.com/news/7ff7b8a890574d1cbb50675732d6873a.html|url-status=dead}}</ref> then later reached the United States in February 2015,<ref name="SleepReview2015">{{cite web|title=Merck's Insomnia Medicine Belsomra C-IV Now Available in US|url=http://www.sleepreviewmag.com/2015/02/mercks-insomnia-medicine-belsomra-c-iv-now-available-us/|website=www.sleepreviewmag.com|date=3 February 2015|publisher=Sleep Review|access-date=9 September 2015}}</ref> ] in November 2016, and ] in November 2018.<ref name="HealthCanada2020">{{cite web|title=Regulatory Decision Summary - Belsomra - Health Canada|url=https://hpr-rps.hres.ca/reg-content/regulatory-decision-summary-detail.php?lang=en&linkID=RDS00475|website=hpr-rps.hres.ca|date = 23 October 2014|publisher=Government of Canada|access-date=6 February 2020}}</ref> It was the first orexin receptor antagonist to be introduced for medical use, and was followed by ] in 2019 and ] in 2022.<ref name="pmid27860547" /><ref name="pmid32901578" /><ref name="pmid35298826">{{cite journal | vauthors = Markham A | title = Daridorexant: First Approval | journal = Drugs | volume = 82 | issue = 5 | pages = 601–607 | date = April 2022 | pmid = 35298826 | doi = 10.1007/s40265-022-01699-y | pmc = 9042981 | s2cid = 247501311 }}</ref> Development of ] (ACT-078573) and ] (MK-6096) was discontinued, while ] (MIN-202, JNJ-42847922) and ] (ORN-0829, TS-142) are still in clinical trials.<ref name="pmid32901578" /><ref name="pmid35043499" />
			Suvorexant ] in the United States was set to expire in January 2023 and ] is set to expire in 2029 to 2033.<ref name="Drugs.com-Belsomra-Generic" />
			==Society and culture==
			===Names===
			''Suvorexant'' is the ] of the drug and its {{Abbrlink|INN|International Nonproprietary Name}}, {{Abbrlink|USAN|United States Adopted Name}}, and {{Abbrlink|JAN|Japanese Accepted Name}}.<ref name="ChemIdPlus">{{cite web | title = Suvorexant | url = https://chem.nlm.nih.gov/chemidplus/name/suvorexant%20%5Busan%3Ainn%5D | work = ChemIDplus | publisher = U.S. National Library of Medicine }}</ref><ref name="KEGG">{{cite web | title = Suvorexant | url = https://www.kegg.jp/entry/D10082 | work = KEGG DRUG Database }}</ref> The medication was developed by Merck under the code name MK-4305 and is marketed under the brand name Belsomra.<ref name="pmid25667197" />
			===Availability===
			Suvorexant has been marketed in the United States, Canada, Australia, Russia, and Japan.<ref name="Micromedex">{{cite web | title = Availability | url = https://www.micromedexsolutions.com/micromedex2/librarian/ | work = IBM Micromedex }}</ref><ref name="SleepReview2015" /><ref name="HealthCanada2020" /><ref name="APDNews2014" /> Although previously available, suvorexant appears to have been discontinued in Canada.<ref name="HealthCanada-DPD">{{cite web | title = Drug Product Database online query | work = Government of Canada | date = 25 April 2012 | url = https://health-products.canada.ca/dpd-bdpp/}}</ref><ref name="Micromedex" /> It does not appear to be available in the United Kingdom or other European countries besides Russia.<ref name="EMC">{{cite web | title = No search results for suvorexant | url = https://www.medicines.org.uk/emc/search?q=suvorexant | work = Datapharm | publisher = Electronic Medicines Compendium (EMC) }}</ref><ref name="EMA">{{cite web | title = Search for Suvorexant: 0 results | work = European Medicines Agency | url = https://www.ema.europa.eu/en/medicines?search_api_views_fulltext=Suvorexant}}</ref><ref name="Micromedex" />
			===Legal status===
			Suvorexant is a ] ] under the ] in the United States.<ref name="FederalRegister2016">{{cite web |url=https://www.federalregister.gov/articles/2014/02/13/2014-03124/schedules-of-controlled-substances-placement-of-suvorexant-into-schedule-iv |title=Schedules of Controlled Substances: Placement of Suvorexant into Schedule IV |author=<!--Staff writer(s); no by-line.--> |date=13 February 2014 |website=federalregister.gov |publisher=] |access-date=10 August 2016 |quote=A Proposed Rule by the Drug Enforcement Administration on 02/13/2014}}</ref><ref name="pmid25167596">{{cite journal | title = Schedules of controlled substances: placement of suvorexant into Schedule IV. Final rule | journal = Federal Register | volume = 79 | issue = 167 | pages = 51243–51247 | date = August 2014 | pmid = 25167596 | url = http://www.gpo.gov/fdsys/pkg/FR-2014-08-28/pdf/2014-20515.pdf | last1 = Drug Enforcement Administration | first1 = Department of Justice }}</ref><ref>{{Cite web|url=http://www.deadiversion.usdoj.gov/fed_regs/rules/2014/fr0828.htm|title=Rules - 2014 - Final Rule: Placement of Suvorexant into Schedule IV|website=www.deadiversion.usdoj.gov|access-date=3 April 2016|archive-date=17 April 2016|archive-url=https://web.archive.org/web/20160417103439/http://www.deadiversion.usdoj.gov/fed_regs/rules/2014/fr0828.htm|url-status=dead}}</ref> It is not a ] in Australia, instead being classed as a ] (] (S4)) in this country.<ref name="Belsomra-AU-Label">{{cite web | title = Belsomra (suvorexant) | work = Australian Product Information | url = https://www.guildlink.com.au/gc/ws/msd/pi.cfm?product=mkpbelso }}</ref>
			===Controversy===
			], a progressive ] ], issued a letter in June 2013 urging the FDA not to approve suvorexant.<ref name="PublicCitizen2013">{{cite web | title = Letter to the FDA Opposing Approval of the Sleep Medicine Suvorexant | work = Public Citizen Inc. | date = 14 June 2013 | url = https://www.citizen.org/article/letter-to-the-fda-opposing-approval-of-the-sleep-medicine-suvorexant/}}</ref> In its reasoning, it cited marginal benefits and excessive potential for harm, including next-day effects like driving impairment and possible accidents.<ref name="PublicCitizen2013" /> '']'' also published articles encouraging consumers to avoid suvorexant due to it being expensive, having limited effectiveness, and posing safety concerns.<ref name="ConsumerReports2015">{{cite web | title = Here's why you can skip the new insomnia drug, Belsomra: It's expensive, barely helps, and poses safety concerns | url = https://www.consumerreports.org/cro/news/2015/07/skip-new-insomnia-drug-belsomra/index.htm | date = 12 July 2015 | work = Consumer Report }}</ref><ref name="ConsumerReports2016">{{cite web | title = FDA Fields Complaints on Sleeping Pill Suvorexant: A recent analysis looks into reports of problems with the prescription sleep drug Belsomra | vauthors = Carr T | date = 5 February 2016 | work = Consumer Reports | url = https://www.consumerreports.org/drugs/fda-fields-complaints-on-sleeping-pill-suvorexant-belsomra/}}</ref>
			==Research==
			===Delirium===
			Suvorexant is under development for the treatment of ].<ref name="AdisInsight">{{cite web | title = Suvorexant - Merck & Co | url = https://adisinsight.springer.com/drugs/800027707 | work = AdisInsight | publisher = Springer Nature Switzerland AG }}</ref> As of October 2021, it is in ] ]s for this indication.<ref name="AdisInsight" />
			===Psychiatry===
			Suvorexant has been studied in the treatment of insomnia in people with ]s such as ] and ].<ref name="pmid30576764">{{cite journal | vauthors = Shariq AS, Rosenblat JD, Alageel A, Mansur RB, Rong C, Ho RC, Ragguett RM, Pan Z, Brietzke E, McIntyre RS | title = Evaluating the role of orexins in the pathophysiology and treatment of depression: A comprehensive review | journal = Progress in Neuro-Psychopharmacology & Biological Psychiatry | volume = 92 | issue = | pages = 1–7 | date = June 2019 | pmid = 30576764 | doi = 10.1016/j.pnpbp.2018.12.008 | s2cid = 56482209 }}</ref><ref name="pmid28584695">{{cite journal | vauthors = Nakamura M, Nagamine T | title = Neuroendocrine, Autonomic, and Metabolic Responses to an Orexin Antagonist, Suvorexant, in Psychiatric Patients with Insomnia | journal = Innovations in Clinical Neuroscience | volume = 14 | issue = 3–4 | pages = 30–37 | date = 2017 | pmid = 28584695 | pmc = 5451036 | doi = }}</ref><ref name="pmid37015302" /> It was reported to improve psychiatric symptoms and to decrease ] levels in these individuals.<ref name="pmid28584695" /><ref name="pmid30576764" /> A ] ] of suvorexant as an ] to ] therapy in people with ] and residual insomnia was underway as of 2019.<ref name="pmid30576764" /><ref name="NCT02669030">{{ClinicalTrialsGov|NCT02669030|A Six Week, Randomized, Double-Blind Placebo-Controlled, Suvorexant Augmentation Study of Antidepressant Treatment of Major Depressive Disorder With Residual Insomnia}}</ref> Although orexin receptor antagonists including suvorexant could be useful for treatment of depression and anxiety, there is also indication that they could have harmful effects in these conditions (e.g., ] and suicidal ideation in clinical trials).<ref name="pmid30590027" /><ref name="pmid34052815">{{cite journal | vauthors = Fragale JE, James MH, Avila JA, Spaeth AM, Aurora RN, Langleben D, Aston-Jones G | title = The Insomnia-Addiction Positive Feedback Loop: Role of the Orexin System | journal = Frontiers of Neurology and Neuroscience | volume = 45 | issue = | pages = 117–127 | date = 2021 | pmid = 34052815 | pmc = 8324012 | doi = 10.1159/000514965 | isbn = 978-3-318-06843-6 }}</ref><ref name="pmid21034217" /> More clinical research is needed to determine the place of orexin receptor antagonists in the treatment of people with depression and anxiety.<ref name="pmid30590027" />
			There is interest in suvorexant and other orexin receptor antagonists in the potential treatment of ]s,<ref name="pmid31782044">{{cite journal | vauthors = Han Y, Yuan K, Zheng Y, Lu L | title = Orexin Receptor Antagonists as Emerging Treatments for Psychiatric Disorders | journal = Neuroscience Bulletin | volume = 36 | issue = 4 | pages = 432–448 | date = April 2020 | pmid = 31782044 | pmc = 7142186 | doi = 10.1007/s12264-019-00447-9 }}</ref><ref name="pmid28012090">{{cite journal | vauthors = James MH, Mahler SV, Moorman DE, Aston-Jones G | title = A Decade of Orexin/Hypocretin and Addiction: Where Are We Now? | journal = Current Topics in Behavioral Neurosciences | volume = 33 | issue = | pages = 247–281 | date = 2017 | pmid = 28012090 | pmc = 5799809 | doi = 10.1007/7854_2016_57 | isbn = 978-3-319-57534-6 }}</ref><ref name="pmid22933994" /><ref name="pmid34052815" /><ref name="pmid24215799" /><ref name="pmid35043499" /><ref name="pmid37015302" /> including ],<ref name="pmid31837287">{{cite journal | vauthors = Campbell EJ, Norman A, Bonomo Y, Lawrence AJ | title = Suvorexant to treat alcohol use disorder and comorbid insomnia: Plan for a phase II trial | journal = Brain Research | volume = 1728 | issue = | pages = 146597 | date = February 2020 | pmid = 31837287 | doi = 10.1016/j.brainres.2019.146597 | s2cid = 209179981 }}</ref><ref name="pmid27909991">{{cite journal | vauthors = Walker LC, Lawrence AJ | title = The Role of Orexins/Hypocretins in Alcohol Use and Abuse | journal = Current Topics in Behavioral Neurosciences | volume = 33 | issue = | pages = 221–246 | date = 2017 | pmid = 27909991 | doi = 10.1007/7854_2016_55 | isbn = 978-3-319-57534-6 | doi-access = free }}</ref><ref name="pmid30081035">{{cite journal | vauthors = Campbell EJ, Marchant NJ, Lawrence AJ | title = A sleeping giant: Suvorexant for the treatment of alcohol use disorder? | journal = Brain Research | volume = 1731 | issue = | pages = 145902 | date = March 2020 | pmid = 30081035 | doi = 10.1016/j.brainres.2018.08.005 | s2cid = 51926191 }}</ref> ],<ref name="pmid30796894">{{cite journal | vauthors = Simmons SJ, Gentile TA | title = Cocaine abuse and midbrain circuits: Functional anatomy of hypocretin/orexin transmission and therapeutic prospect | journal = Brain Research | volume = 1731 | issue = | pages = 146164 | date = March 2020 | pmid = 30796894 | pmc = 6702109 | doi = 10.1016/j.brainres.2019.02.026 }}</ref> and ].<ref name="pmid31986520">{{cite journal | vauthors = James MH, Fragale JE, Aurora RN, Cooperman NA, Langleben DD, Aston-Jones G | title = Repurposing the dual orexin receptor antagonist suvorexant for the treatment of opioid use disorder: why sleep on this any longer? | journal = Neuropsychopharmacology | volume = 45 | issue = 5 | pages = 717–719 | date = April 2020 | pmid = 31986520 | pmc = 7265392 | doi = 10.1038/s41386-020-0619-x }}</ref>
			===Alzheimer's disease===
			Suvorexant and other orexin receptor modulators are of interest for possible use in the prevention of ].<ref name="pmid37015302">{{cite journal | vauthors = Ten-Blanco M, Flores Á, Cristino L, Pereda-Pérez I, Berrendero F | title = Targeting the orexin/hypocretin system for the treatment of neuropsychiatric and neurodegenerative diseases: From animal to clinical studies | journal = Front Neuroendocrinol | volume = 69 | issue = | pages = 101066 | date = April 2023 | pmid = 37015302 | doi = 10.1016/j.yfrne.2023.101066 | s2cid = 257902333 | url = | doi-access = free | hdl = 2445/201170 | hdl-access = free }}</ref><ref name="pmid36897120">{{cite journal | vauthors = Lucey BP, Liu H, Toedebusch CD, Freund D, Redrick T, Chahin SL, Mawuenyega KG, Bollinger JG, Ovod V, Barthélemy NR, Bateman RJ | title = Suvorexant Acutely Decreases Tau Phosphorylation and Aβ in the Human CNS | journal = Ann Neurol | volume = 94| issue = 1| pages = 27–40| date = March 2023 | pmid = 36897120 | doi = 10.1002/ana.26641 | pmc = 10330114 | s2cid = 257444346 | url = }}</ref>
			===Diabetes===
			Suvorexant has been studied in people with ] and insomnia and has been reported to improve sleep and ] parameters in these individuals.<ref name="pmid34401953">{{cite journal | vauthors = Schipper SB, Van Veen MM, Elders PJ, van Straten A, Van Der Werf YD, Knutson KL, Rutters F | title = Sleep disorders in people with type 2 diabetes and associated health outcomes: a review of the literature | journal = Diabetologia | volume = 64 | issue = 11 | pages = 2367–2377 | date = November 2021 | pmid = 34401953 | pmc = 8494668 | doi = 10.1007/s00125-021-05541-0 }}</ref><ref name="pmid32911037">{{cite journal | vauthors = Yoshikawa F, Shigiyama F, Ando Y, Miyagi M, Uchino H, Hirose T, Kumashiro N | title = Chronotherapeutic efficacy of suvorexant on sleep quality and metabolic parameters in patients with type 2 diabetes and insomnia | journal = Diabetes Research and Clinical Practice | volume = 169 | issue = | pages = 108412 | date = November 2020 | pmid = 32911037 | doi = 10.1016/j.diabres.2020.108412 | s2cid = 221623696 }}</ref> The improvement in metabolic parameters appeared to be related to improved sleep.<ref name="pmid34401953" /><ref name="pmid32911037" />
			== References ==
			{{Reflist}}
			== Further reading ==
			* {{cite web | author = Merck Sharp and Dohme Corporation | title = Suvorexant Advisory Committee Meeting Briefing Document: Peripheral & Central Nervous System Drugs Advisory Committee Meeting | website = ] | date = 22 May 2013 | url = https://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/peripheralandcentralnervoussystemdrugsadvisorycommittee/ucm352970.pdf| archive-url = https://web.archive.org/web/20130612065319/https://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/peripheralandcentralnervoussystemdrugsadvisorycommittee/ucm352970.pdf | archive-date = 12 June 2013 }}
			* {{cite web | vauthors = Dimova H, Brar S, Men A | title = Application Number: 204569Orig1s000. Clinical Pharmacology/Biopharmaceutics Review. Suvorexant (MK-4305). | date = 2014 | publisher = ] (]) | url = https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/204569Orig1s000ClinPharmR.pdf| archive-url = https://web.archive.org/web/20220305191601/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/204569Orig1s000ClinPharmR.pdf | archive-date = 5 March 2022 }}
			== External links ==
			* {{cite magazine | vauthors = Parker I | title=The Big Sleep | magazine=] | date=9 December 2013 | url=https://www.newyorker.com/magazine/2013/12/09/the-big-sleep-2 }}
			{{Insomnia pharmacotherapies}}
	{{Hypnotics and sedatives}}		{{Hypnotics and sedatives}}
			{{Orexin receptor modulators}}
	{{Neuropeptide agonists and antagonists}}
			{{Portal bar | Medicine}}
			{{Authority control}}
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