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| Trade names | Belsomra |
| Other names | MK-4305; MK4305 |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a614046 |
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| Pregnancy category | |
| Dependence liability | Low |
| Addiction liability | Low |
| Routes of administration | By mouth[2] |
| Drug class | Orexin receptor antagonist;Hypnotic;Sedative |
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| Pharmacokinetic data | |
| Bioavailability | 82% (10 mg; lower at higher doses)[2][5] |
| Protein binding | 99.5%[6][2] |
| Metabolism | Liver (CYP3A major,CYP2C19 minor)[2] |
| Metabolites | Hydroxysuvorexant (inactive)[2] |
| Eliminationhalf-life | 12.2 hours (8–19 hours) (40 mg)[2][5][7] |
| Excretion | Feces: 66%[2] Urine: 23%[2] |
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| CompTox Dashboard(EPA) | |
| ECHA InfoCard | 100.210.546 |
| Chemical and physical data | |
| Formula | C23H23ClN6O2 |
| Molar mass | 450.93 g·mol−1 |
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Suvorexant, sold under the brand nameBelsomra, is anorexin antagonist medication which is used in the treatment ofinsomnia.[2][6] It is indicated specifically for the treatment of insomnia characterized by difficulties withsleep onset and/ormaintenance in adults.[2][6] Suvorexant helps withfalling asleep faster,sleeping longer, beingawake less in the middle of the night, and having betterquality of sleep.[2][8] Its effectiveness is modest,[9] and is similar to that of other orexin antagonists, but is lower than that ofbenzodiazepines andZ-drugs.[10] Suvorexant is takenby mouth.[2][11][6]
Side effects of suvorexant includesomnolence,daytime sleepiness and sedation,headache,dizziness,abnormal dreams,dry mouth, and impaired next-daydriving ability.[2][8][12] Rarely,sleep paralysis, sleep-relatedhallucinations,complex sleep behaviors likesleepwalking, andsuicidal ideation may occur.[2][6][9]Tolerance,dependence,withdrawal, andrebound effects do not appear to occur significantly with the medication.[2][13][14] Suvorexant is adual orexin receptor antagonist (DORA).[6] It acts as aselective dualantagonist of theorexinOX1 andOX2 receptors.[6] The medication has an intermediateelimination half-life of 12 hours and atime to peak of about 2 to 3 hours.[2][6] Unlike benzodiazepines and Z-drugs, suvorexant does not interact withGABA receptors, instead having a distinctmechanism of action.[6][15]
Clinical development of suvorexant began in 2006[16] and it was introduced for medical use in 2014.[2][17] The medication is aschedule IVcontrolled substance in the United States and may have a modestpotential for misuse.[18][2][19] In other places, such as Australia, suvorexant is aprescription-only medicine and is not acontrolled drug.[1] Suvorexant is not available ingeneric formulations.[11][20][21] Besides suvorexant, other orexin receptor antagonists likelemborexant anddaridorexant have also been introduced.[22][23]
Suvorexant is used for the treatment ofinsomnia, characterized by difficulties withsleep onset and/or sleep maintenance, in adults.[2][6] At a dose of 15 to 20 mg and in terms of treatment–placebo difference, it reducestime to sleep onset by up to 10 minutes, reducestime awake after sleep onset by about 15 to 30 minutes, and increasestotal sleep time by about 10 to 20 minutes.[2] A 2017systematic review andmeta-analysis ofrandomized controlled trials of suvorexant for insomnia likewise found that the medication improved subjective sleep onset, subjective total sleep time, and subjectivesleep quality when assessed at one to three months of treatment.[8] The effectiveness of approved doses of suvorexant (≤20 mg) in the treatment of insomnia is said to be modest.[9][24][13][25]
Network meta-analyses have assessed the sleep-promoting effects of suvorexant and have compared them to those of other orexin receptor antagonists likelemborexant anddaridorexant as well as to other sleep aids includingbenzodiazepines,Z-drugs,antihistamines, sedativeantidepressants (e.g.,trazodone,doxepin,amitriptyline,mirtazapine), andmelatonin receptor agonists.[10][26][27][28] A majorsystematic review and network meta-analysis of insomnia medications published in 2022 found that suvorexant had aneffect size (standardized mean difference (SMD)) againstplacebo for treatment of insomnia at 4 weeks of 0.31 (95%CITooltip confidence interval 0.01 to 0.62).[10] Suvorexant appeared to be similarly effective at 4 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.,doxepin,doxylamine,trimipramine) showed more similar efficacy (SMDs of 0.30 to 0.55).[10]
Orexin receptor antagonists like suvorexant increase total sleep time predominantly by increasingrapid eye movement sleep (REM) sleep, whereas they have no effect on or even decreasenon-rapid eye movement (NREM) sleep.[29] This is in contrast to most otherhypnotics, which either do not affect REM sleep or decrease it.[22] The implications of these differences are not fully clear.[22] Unlike certain other hypnotics likebenzodiazepines andZ-drugs, orexin receptor antagonists do not disruptsleep architecture, and this might provide more restful sleep.[30][31][32][33]
It is unclear if suvorexant is safe among people with a history ofsubstance addiction oralcoholism, as these individuals were excluded fromclinical trials of suvorexant.[34] ACochrane review found suvorexant to be effective in the short-term treatment of sleep disturbances in people withdementia with few adverse effects.[35] 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.[2]
Suvorexant is approved for the treatment of insomnia by the United StatesFood and Drug Administration (FDA) at doses of 5 to 20 mg and by the AustralianTherapeutic Goods Administration (TGA) and JapanesePharmaceuticals and Medical Devices Agency (PMDA) at doses of 15 mg (in the elderly) and 20 mg (in younger adults).[2][6][1][8] In the United States, the recommended starting dose is 10 mg and the maximum recommended dose is 20 mg.[2][6] Higher doses of 30 and 40 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 mg and concerns about next-day effects and associated impairment (e.g.,driving).[6][34] In addition to the preceding doses, suvorexant has been assessed at higher doses of up to 100 mg in clinical trials.[6][34][36] These higher doses appeared to be more effective at promoting sleep than lower doses but produced greater next-day effects.[6][34][9][36] Lower approved doses of suvorexant in the United States in the range of 5 to 10 mg were not extensively evaluated in clinical trials.[24][25]
TheAmerican Academy of Sleep Medicine's 2017clinical practice guidelines recommend the use of suvorexant in the treatment of sleep-onset and sleep-maintenance insomnia along with various other sleep medications.[37] Orexin receptor antagonists are not used asfirst-line treatments for insomnia due to their costs and concerns about possiblemisuse liability.[26]Generic formulations of orexin receptor antagonists including suvorexant are not yet available.[11][20][21]
Suvorexant is available in the form of 5, 10, 15, and 20 mgoralfilm-coatedtablets.[2][11][19] It is provided as 10- and 30-tabletblister packs as well as 3-tablet starter packs. The availability of these different packs varies by country.[2][1]
Suvorexant iscontraindicated in people withnarcolepsy as it may worsen their symptoms.[2][9] This is its onlyabsolute contraindication.[2] Suvorexant has not been studied in people with severehepatic impairment and is not recommended in these individuals due to the likelihood of increased suvorexant exposure.[2] On the other hand, suvorexant may be used in people with mild-to-moderate hepatic impairment as well asrenal impairment of any severity and no dose adjustment is necessary in these situations.[2] Concomitant use of suvorexant with strongCYP3A4inhibitors is not recommended due to potential for increased suvorexant exposure while concomitant use of suvorexant with strong CYP3A4inducers may result in loss of suvorexant exposure and effectiveness.[2] Suvorexant should be used carefully in people with a history ofdrug misuse oralcoholism due to itsdrug-liking effects and possible misuse potential at doses higher than those approved for therapeutic use.[2][38] Similarly, suvorexant should be used carefully in people with a history ofdepression orsuicidality as it may rarely increasesuicidal ideation.[2][6][9] 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.[2]
Suvorexant has shownteratogenic effects in animals such as decreasedbody weight at doses much higher than the equivalents of those approved for therapeutic use in humans.[2][39] Teratogenic effects with therapeutic doses of suvorexant in humans have not been established due to lack of research and available data.[2][39] Suvorexant ispregnancy category C in the United States.[39] It is unknown whether suvorexant is present in thebreast milk, whether it affectslactation inbreastfeeding women, or whether it affects breastfed infants.[2] 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.[2][39] Suvorexant should be used in pregnant and breastfeeding women only if the potential benefit justifies the potential for harm to the baby.[2][39]
Side effects of suvorexant (at doses of 15–20 mg) includesomnolence (7% vs. 3% forplacebo) andheadaches (7% vs. 6% for placebo).[2] Somnolence with suvorexant appears to bedose-dependent, with rates of 2% at 10 mg, 5% at 20 mg, 10–12% at 40 mg, and 11–12% at 80 mg, relative to 0.4% forplacebo.[2][6] Less common side effects (at 15–20 mg) may includedizziness (3% vs. 2% for placebo),abnormal dreams (2% vs. 1% for placebo),diarrhea (2% vs. 1% for placebo),dry mouth (2% vs. 1% for placebo),upper respiratory tract infection (2% vs. 1% for placebo), andcough (2% vs. 1% for placebo).[2] High doses of suvorexant (80 mg) have also been found to produce greater incidence of dizziness (5% vs. 0% for placebo) and abnormal dreams (5% vs. 1% for placebo).[6]
Less commonly, suvorexant may causesleep paralysis,hypnagogic andhypnopompic hallucinations, andcomplex sleep behaviors (0.2–0.6% vs. 0% for placebo).[2][9] Complex sleep behaviors includesleepwalking,sleep-driving, and engaging in other activities while not completely awake (e.g., making or eating food, making phone calls, andhaving sex).[2] Othernarcoleptic-like symptoms such ascataplexy (sudden weakness or paralysis) may also rarely occur.[24][9] Suvorexant may sometimes cause worsening ofdepression orsuicidal ideation.[2][6] A dose-dependent increase in suicidal ideation as assessed with theColumbia Suicide Severity Rating Scale was seen with suvorexant in clinical trials although rates were very low (0.2% (1/493) at low doses (15–20 mg) and 0.4% (5/1291) at high doses (30–40 mg) relative to 0.1% (1/1025) for placebo).[2][6] It has also been stated however that suicidal ideation was reported in 0% to 1.6% of people taking 10 to 20 mg and 3.4% to 8.2% taking 40 to 80 mg relative to 0% to 0.3% with placebo.[9] Suicidal ideation with suvorexant is considered to be mild.[6][9] 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.[9][2] Besides the clinical trial data, acase report of rapidly worsened depression and onset of suicidal ideation with suvorexant has been published.[40][41]
The next-day effects of suvorexant have been studied.[2] Besides the side effect of daytime somnolence, suvorexant may dose-dependently reducealertness andmotor coordination and impairdriving ability.[2][8] It may also increase the risk of falling asleep while driving.[2] Driving ability was found to be impaired at doses of 20 and 40 mg in clinical studies.[2] Driving impairment may also occur with lower doses of suvorexant due to variations in individual sensitivity to the medication.[2] In three of four studies, 30 mg suvorexant had no influence on next-daymemory orbalance, whereas in the remaining study, there was a decrease in morningword recall with 40 mg and an increase in body sway with 20 and 40 mg doses.[2] In another study in elderly people who were awakened in the night, impaired balance was present at 1.5 hours after taking 30 mg suvorexant whereas memory was unaffected.[2]
A 2017systematic review andmeta-analysis 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.[8][30] Conversely, suvorexant did not significantly differ from placebo in the rates of any other assessed adverse effects.[8][30] This includedback pain,diarrhea, dizziness, falls, headache,car accidents/traffic violations,nasopharyngitis,nausea, potentialdrug misuse, suicidal ideation, complex sleep behaviors, hypnagogic or hypnopompic hallucinations, and sleep paralysis.[8] The overall risk of any adverse event was increased 1.07-fold while discontinuation due to adverse events was unchanged (RRTooltip relative risk = 0.93, 95%CITooltip confidence interval 0.60 to 1.44).[8]
Tolerance,dependence,withdrawal, andrebound effects do not appear to occur with suvorexant in the treatment of insomnia at studied doses.[2][13][14] In three-month clinical studies, no rebound insomnia as assessed by measures of sleep onset or maintenance was observed withdiscontinuation of suvorexant at doses of 15 to 40 mg.[2] Similarly, no withdrawal effects were observed with discontinuation of suvorexant at these doses.[2] However, in other reports, some tolerance as assessed by diminishing somnolence and rebound insomnia upon discontinuation has been noted.[42][12][13]
Theorexinneuropeptides augment the signaling of themesolimbicdopaminereward pathway and are thought to potentiatehedonic tone.[43][44][22][45] Conversely, low orexin signaling may result inlow hedonic tone and orexin receptor antagonists are of interest for the potential treatment ofaddiction.[43][44][22][45] In line with these findings, suvorexant and other orexin receptor antagonists have not shownmisuse liability inanimal studies in rats and non-human primates.[19][46][47][48] Paradoxically however, orexin receptor antagonists, including suvorexant,lemborexant, anddaridorexant, have consistently showndrug-liking responses in human studies ofrecreationalsedative users.[2][49][50][38] Suvorexant at higher-than-approved doses (40, 80, and 150 mg vs. 20 mg maximum recommended dose) showed similar drug liking to theZ-drugzolpidem (15 and 30 mg) in such individuals.[2][34][19][38][51] 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).[34][19] In another study, suvorexant at a dose of 150 mg showed greater drug liking than daridorexant (50 mg) but similar drug liking to zolpidem (30 mg) and higher doses of daridorexant (100–150 mg) in recreational sedative users.[49][38] There was no apparentdose–response relationship for positive measures of misuse potential with suvorexant, in contrast to zolpidem.[19][51] In thephase III clinical trials, misuse potential adverse events were reported in 3.0% with placebo, 4.1% with 15 or 20 mg suvorexant, and 2.6% with 30 or 40 mg suvorexant.[19] 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.[2][19][46] In any case, suvorexant is acontrolled substance in the United States due to concerns about the possibility of misuse.[2][6][19]
Besides its subjective side effects, suvorexant has been found to cause dose-dependent increases in serumcholesterol levels in clinical trials.[2][25] These changes in cholesterol levels were +1.2 mg/dL at 10 mg, +2.3 mg/dL at 20 mg, +3.1 mg/dL at 40 mg, and +6.0 mg/dL at 80 mg relative to –3.7 mg/dL for placebo.[2][25] Although the increases in cholesterol levels with approved doses of suvorexant (10–20 mg) are small, they could be important over a long duration of treatment.[25]
Early studies in rodents found thatorexins (derived fromGreek "orexis" meaning "appetite") stimulateappetite,feeding behavior, andweight gain while orexin receptor antagonists block these effects.[52][53][6] However, subsequent animal studies were more mixed, with the effects being limited and depending on the animalstrain.[52][53][6] In humans, orexin receptor antagonists including suvorexant have not been found to affectbody weight in rigorous clinical trials that lasted up to 12 to 14 months.[53][6]
There is limited experience withoverdose of suvorexant.[2] Suvorexant has been assessed in single doses of as high as 240 mg in clinical studies.[2][7][6][19] The medication dose-dependently producessomnolence.[2] High doses of suvorexant may also causesleep-onset paralysis in some individuals (2% incidence at doses of 40–240 mg).[6] Treatment of suvorexant overdose is based on symptoms and is supportive.[2]Gastric lavage may be used where appropriate whereas the value ofdialysis has not been determined.[2] Because suvorexant has highplasma protein binding,hemodialysis is not expected to enhanceelimination of suvorexant.[2]
CYP3A4inhibitors can increase exposure to suvorexant while CYP3A4inducers can decrease exposure to suvorexant.[2][14][54] Combination of suvorexant with the strong CYP3A4 inhibitorketoconazole increased suvorexantoverall exposure by 2.79-fold andpeak levels by about 1.25-fold, combination with the moderate CYP3A4 inhibitordiltiazem increased suvorexant overall exposure by 2.05-fold and peak levels by about 1.25-fold, and combination with the strong CYP3A4 inducerrifampin decreased suvorexant overall exposure by 88% and peak levels by about 65%.[2][5][54] Theelimination half-life of suvorexant (about 12 hours for suvorexant alone) was increased to 19.4 hours with ketoconazole and to 16.1 hours with diltiazem while it was decreased to 7.7 hours with rifampin.[55][54] Concomitant use of suvorexant with strong CYP3A4 inhibitors is not recommended, while lower doses of suvorexant are recommended with moderate CYP3A4 inhibitors (5 mg starting dose and 10 mg maximum dose generally).[2] The substantial decrease in suvorexant exposure with strong CYP3A4 inducers may result in loss of effectiveness.[2] Suvorexant does not appear to have been assessed in combination with moderate CYP3A4 inducers (e.g.,modafinil).[2][5][54]
Examples of important CYP3A4 modulators which are expected to interact with suvorexant include the strong CYP3A4 inhibitorsboceprevir,clarithromycin,conivaptan,indinavir,itraconazole,ketoconazole,lopinavir,nefazodone,nelfinavir,posaconazole,ritonavir,saquinavir,telaprevir, andtelithromycin (concomitant use not recommended); the moderate CYP3A4 inhibitorsamprenavir,aprepitant,atazanavir,ciprofloxacin,diltiazem,dronedarone,erythromycin,fluconazole,fluvoxamine,fosamprenavir,grapefruit juice,imatinib, andverapamil (lower doses of suvorexant recommended); and the strong CYP3A4 inducersapalutamide,carbamazepine,efavirenz,enzalutamide,phenytoin,rifampin, andSt. John's wort (expected to decrease suvorexant effectiveness).[2][56][14]
Coadministration of suvorexant with otherCNS depressants such asalcohol,benzodiazepines,opioids, andtricyclic antidepressants may increase the risk ofCNS depression anddaytime impairment.[2] Alcohol and suvorexant do not appear to interact in terms ofpharmacokinetics but consumption of alcohol in combination with suvorexant is not advised due to additive CNS depression.[2] Dosage adjustment may be necessary when suvorexant is combined with other CNS depressants.[2] Use of suvorexant in combination with other medications used in the treatment of insomnia is not recommended.[2]
Suvorexant is not expected to cause clinically meaningful inhibition or induction of variouscytochrome P450enzymes anddrug transporters.[2] It has been found to not substantially influence the pharmacokinetics ofmidazolam (CYP3A4substrate),warfarin (CYP2C9 substrate),digoxin (P-glycoprotein substrate), orcombined birth control pills.[2] However, coadministration of suvorexant withdigoxin may result in slightly increased digoxin exposure due to inhibition ofintestinalP-glycoprotein by suvorexant.[2] Concentrations of digoxin should be monitored during coadministration of suvorexant and digoxin.[2]
Suvorexant acts as aselective dualantagonist of theorexin (hypocretin) receptorsOX1 andOX2.[14][57] Thesereceptors are thebiological targets of theendogenouswakefulness-promotingorexinneuropeptidesorexin-A andorexin-B.[22] Thebinding affinities (Ki) of suvorexant at the human orexin receptors are 0.55 nM for the OX1 receptor and 0.35 nM for the OX2 receptor.[57][2][5] The antagonisticpotencies orfunctional inhibition (Kb) of suvorexant at the human orexin receptors are 65 nM for the OX1 receptor and 41 nM for the OX2 receptor.[57] Hence, suvorexant shows similar affinities and antagonistic activities at the OX1 and OX2 receptorsin vitro.[14][57] Suvorexant is highly selective for the orexin receptors over a large number of othertargets (170 screenedoff-targetreceptors,enzymes, andtransporters).[6][58] In contrast to certain other sedatives and hypnotics, suvorexant is not abenzodiazepine orZ-drug and does not interact withGABA receptors.[6][15][5]
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.[2][57] The orexin neuropeptides are produced exclusively by a relatively small population of 20,000 to 80,000neurons located in thelateral hypothalamus in thebrain.[59][60] These neurons project widely throughout the brain and mediateexcitatory signaling to key centers involved insleep–wake regulation, including thenoradrenergiclocus coeruleus,histaminergictuberomammillary nucleus,serotonergicraphe nucleus, anddopaminergicventral tegmental area.[59][61][62][60][63] The orexin system showscircadian rhythmicity in its activity, with high activity during waking and low to no activity during sleep or at night.[59][5][64] Orexin system activity during wakefulness is also higher with behavioral activation and with high-intensity emotions.[65][59]
Narcolepsy is a chronicsleep disorder characterized byexcessive daytime sleepiness,cataplexy,sleep paralysis, andhypnagogic hallucinations, as well assleep attacks andfragmented sleep.[66][62] Narcolepsy with cataplexy, also known astype 1 narcolepsy, is thought to be caused by loss of orexin-producing neurons in the lateral hypothalamus, possibly mediated byautoimmune mechanisms related toenvironmental triggers ingenetically susceptible individuals.[66][65] There is an 80 to 100% loss of orexin-producing neurons in the lateral hypothalamus and very low or undetectable levels of orexin-A incerebrospinal fluid in people with narcolepsy.[61][66][65] Similarly, narcolepsy with cataplexy in dogs is caused by amutation in thegene encoding the OX2 receptor, andknockout mice for genes encoding orexin system proteins such asprepro-orexin or the OX2 receptor show a narcolepsy-likephenotype.[61][66] Although there ishypersomnolence 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.[62][24] They do not usually feel well-rested during the day.[24] Besides narcolepsy, the orexin system may also be involved in theetiology of insomnia.[67][59] In addition, orexin signaling appears to change with age, and this may be involved inage-relatedsleep disturbances.[67][68]
Orexin receptor antagonists may be expected to produce effects similar to those in narcolepsy.[24][52][59] 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.[57][52][59][69] 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.[24][59] In addition, long-term neural changes may develop in narcolepsy to compensate for the orexin deficiency in the condition.[57][52][59][69] In animals and humans, orexin receptor agonists such as orexin-A anddanavorexton dose-dependently producewakefulness andlocomotor activity[62][22][64] while orexin receptor antagonists like suvorexant transiently reduce locomotor activity and dose-dependently promote sleep.[30][31] Acute orexin receptor antagonists can promote sleep in animals to a greater extent than what occurs in narcolepsy-like orexin system loss.[52] In addition, little to no cataplexy has been observed even with high doses of orexin receptor antagonists in animals and humans.[57][52][59][70] It is unknown if long-term use of orexin receptor antagonists may produce compensatory neural changes or narcolepsy-like symptoms.[57] Ananimal study of chronic high-dose suvorexant administration that showed development of narcolepsy-like changes suggests that this may be possible however.[71]
Endogenousorexinergic tone is expected to play an important moderating influence in terms of the effects of orexin receptor modulators.[5] 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.[5]
Theabsolute bioavailability of suvorexant is 82% at a dose of 10 mg.[2] Suvorexant exposure does not increasedose-proportionally over a dose range of 10 to 100 mg, which is likely due to decreasedabsorption at higher doses.[2][5][72] Exposure to suvorexant increases by about 75% with a doubling of dose from 20 mg to 40 mg.[5] Thetime to peak levels of suvorexant is 2 to 3 hours regardless of dose but with wide variation (range 30 minutes to 8 hours).[2][6] Taking suvorexant with food does not modify suvorexantpeak levels orarea-under-the-curve levels (overall exposure) but does delay the time to peak concentrations by about 1.5 hours.[2]Steady-state levels of suvorexant with once-daily continuous administration are reached within 3 days.[2][5] Levels of suvorexantaccumulate minimally, by about 1.2- to 1.6-fold, with repeated once-daily administration.[5][2]
Thevolume of distribution of suvorexant is approximately 49 L.[2] It crosses theblood–brain barrier anddistributes into thecentral nervous system.[57]
Suvorexant has highplasma protein binding (99.5%).[6][2] It is bound toalbumin andα1-acid glycoprotein (orosomucoid).[2]
Suvorexant ismetabolized primarily byhydroxylation viaCYP3Aenzymes.[2][7]CYP2C19 also contributes to suvorexant metabolism to a minor extent.[2] The major circulating forms are suvorexant and itsmetabolite hydroxysuvorexant.[2] The hydroxysuvorexant (M9) metabolite is not expected to bepharmacologically active.[2][7] It showed 10-fold loweraffinity for the orexin receptors than suvorexantin vitro, was asubstrate forP-glycoprotein making it unlikely to cross theblood–brain barrier, and did not show sedative effects in animal studies.[7] Suvorexant also has several other minor metabolites.[7]
Suvorexant iseliminated mainly via metabolism.[2] It isexcreted primarily infeces (66%) predominantly as metabolites and to a lesser extent inurine (23%).[2][5]
Theelimination half-life of suvorexant at a dose of 40 mg is 12.2 hours, with a range of 8 to 19 hours.[2][5][7][6] In another study, the half-life of suvorexant was 15 hours with a range of 10 to 22 hours.[2] In one study, the half-lives of suvorexant (mean ± SD) were 9.0 ± 7.2 hours at 10 mg, 10.8 ± 3.6 hours at 50 mg, and 13.1 ± 5.8 hours at 100 mg.[6] With doses of 120 to 240 mg, the half-lives of suvorexant were 12.1 to 14.5 hours in healthy young males and 14.4 to 15.8 hours in healthy young females.[7] The half-life of suvorexant's inactive metabolite hydroxysuvorexant is similar to that of suvorexant.[7]
Age and race do not influence the pharmacokinetics of suvorexant in a clinically meaningfully way.[2] Exposure to suvorexant is slightly higher in women compared to men (Cmax 9% higher, AUC 17% higher), however dose adjustments based on gender are generally unnecessary.[2] Suvorexant exposure is greater in people with higherbody mass index, such asobese people (Cmax 17% higher, AUC 31% higher).[2] This is particularly the case in obese women relative to non-obese women (Cmax 25% higher, AUC 46% higher).[2] Suvorexant exposure with a single dose is not greater in people with moderatehepatic insufficiency compared to healthy individuals.[2] However, the half-life of suvorexant at a dose of 20 mg was prolonged from 14.7 hours (range 10–22 hours) to 19.1 hours (range 11–49 hours) in these individuals.[2][7] Suvorexant exposure is unchanged in people with severerenal impairment and no dosage adjustment is necessary in these individuals.[2] Similarly to hepatic impairment, the half-life of suvorexant was increased to 19.4 hours when used in combination with the strong CYP3A4 inhibitorketoconazole and to 16.1 hours with the moderate CYP3A4 inhibitordiltiazem while it was decreased to 7.7 hours with the strong CYP3A4 inducerrifampin.[55][54]
The delayed time to peak levels (2–3 hours) and long elimination half-life (12 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.[6][9] Orexin receptor antagonists with shorter half-lives and faster onsets of action are theoretically more optimal for therapeutic use as sleep aids.[6][14] The ideal insomnia medication would not have aduration of action extending beyond about 8 hours.[53] Relative to suvorexant,daridorexant has a shorter half-life (8 hours) whilelemborexant has a longer half-life (17–55 hours).[14] However, although lemborexant has a longerterminal elimination half-life than suvorexant, it appears to be more rapidly cleared in the earlier phases of elimination.[73][14] The investigational agentsseltorexant andvornorexant, which are still in clinical trials, have comparatively very short half-lives in the range of 1.5 to 3 hours.[14][74]
Suvorexant dissociates from theorexin receptors slowly.[6][57] As a result, itsduration may be longer than that suggested by its circulating concentrations and half-life.[6][57]
Suvorexant is asmall-molecule compound.[75] Thechemical name of suvorexant is [(7R)-4-(5-chloro-2-benzoxazolyl)hexahydro-7-methyl-1H-1,4-diazepin-1-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone.[2] Itsmolecular formula is C23H23N6O2Cl and itsmolecular weight is 450.92 g/mol.[2] Suvorexant is a white to off-white powder and islipophilic andinsoluble in water.[2][14] It isstructurally related to other orexin receptor antagonists likelemborexant,daridorexant, andseltorexant.[14][75]
Theorexinneuropeptides were discovered in 1998[22][16] and the role of the orexin system in theetiology ofnarcolepsy was identified between 1999 and 2000.[70] Subsequent research further established the role of the orexin system insleep–wake regulation.[22][16][64] Due to the promising potential of orexin system modulation in the treatment ofsleep disorders, these findings led totranslational efforts to bring orexin receptor modulators to medicine as therapeutic agents.[22][16][64][70][69]
Suvorexant was developed byMerck.[22][16] It enteredclinical development in 2006[16] and was first described in the medical literature in 2010.[76] The medication was approved by the FDA for the treatment of insomnia in the United States on 13 August 2014.[2][11][77] Suvorexant was initially released November 2014 inJapan,[17] then later reached the United States in February 2015,[78]Australia in November 2016, andCanada in November 2018.[79] It was the first orexin receptor antagonist to be introduced for medical use, and was followed bylemborexant in 2019 anddaridorexant in 2022.[57][14][23] Development ofalmorexant (ACT-078573) andfilorexant (MK-6096) was discontinued, whileseltorexant (MIN-202, JNJ-42847922) andvornorexant (ORN-0829, TS-142) are still in clinical trials.[14][22]
Suvorexantmarketing exclusivity in the United States was set to expire in January 2023 andpatent protection is set to expire in 2029 to 2033.[11]
Suvorexant is thegeneric name of the drug and itsINNTooltip International Nonproprietary Name,USANTooltip United States Adopted Name, andJANTooltip Japanese Accepted Name.[80][81] The medication was developed by Merck under the code name MK-4305 and is marketed under the brand name Belsomra.[34]
Suvorexant has been marketed in the United States, Canada, Australia, Russia, and Japan.[82][78][79][17] Although previously available, suvorexant appears to have been discontinued in Canada.[83][82] It does not appear to be available in the United Kingdom or other European countries besides Russia.[84][85][82]
Suvorexant is aschedule IVcontrolled substance under theControlled Substances Act in the United States.[18][86][87] It is not acontrolled drug in Australia, instead being classed as aprescription-only medicine (Schedule 4 (S4)) in this country.[1]
Public Citizen, a progressiveconsumer rightsadvocacy group, issued a letter in June 2013 urging the FDA not to approve suvorexant.[25] In its reasoning, it cited marginal benefits and excessive potential for harm, including next-day effects like driving impairment and possible accidents.[25]Consumer Reports also published articles encouraging consumers to avoid suvorexant due to it being expensive, having limited effectiveness, and posing safety concerns.[88][89]
Suvorexant is under development for the treatment ofdelirium.[90] As of October 2021, it is inphase IIIclinical trials for this indication.[90]
Suvorexant has been studied in the treatment of insomnia in people withpsychiatric disorders such asdepression andanxiety.[30][91][92] It was reported to improve psychiatric symptoms and to decreasecortisol levels in these individuals.[91][30] Aphase IVclinical trial of suvorexant as anadjunct toantidepressant therapy in people withmajor depressive disorder and residual insomnia was underway as of 2019.[30][93] 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.,animal studies and suicidal ideation in clinical trials).[40][46][59] More clinical research is needed to determine the place of orexin receptor antagonists in the treatment of people with depression and anxiety.[40]
There is interest in suvorexant and other orexin receptor antagonists in the potential treatment ofsubstance use disorders,[94][95][44][46][53][22][92] includingalcohol use disorder,[96][97][98]cocaine use disorder,[58] andopioid use disorder.[99]
Suvorexant and other orexin receptor modulators are of interest for possible use in the prevention ofAlzheimer's disease.[92][100]
Suvorexant has been studied in people withtype 2 diabetes and insomnia and has been reported to improve sleep andmetabolic parameters in these individuals.[101][102] The improvement in metabolic parameters appeared to be related to improved sleep.[101][102]
A Proposed Rule by the Drug Enforcement Administration on 02/13/2014
