Suvorexant

Suvorexant

Clinical data
Trade names	Belsomra
Other names	MK-4305; MK4305
AHFS/Drugs.com	Monograph
MedlinePlus	a614046
License data	US DailyMed: Suvorexant
Pregnancy category	AU: B3 US: Safety unclear
Dependence liability	Low
Addiction liability	Low
Routes of administration	By mouth
Drug class	Orexin antagonist
ATC code	N05CM19 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) US: Schedule IV
Pharmacokinetic data
Bioavailability	82% (10 mg)
Protein binding	99.5%
Metabolism	Liver (CYP3A major, CYP2C19 minor)
Metabolites	Hydroxysuvorexant (inactive)
Elimination half-life	12 hours
Excretion	Feces: 66% Urine: 23%
Identifiers
IUPAC name [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone
CAS Number	1030377-33-3 Y
PubChem CID	24965990
IUPHAR/BPS	2890
DrugBank	DB09034 Y
ChemSpider	24662178 Y
UNII	081L192FO9
KEGG	D10082 Y
ChEBI	CHEBI:82698
ChEMBL	ChEMBL1083659 Y
CompTox Dashboard (EPA)	DTXSID90145616
ECHA InfoCard	100.210.546
Chemical and physical data
Formula	C23H23ClN6O2
Molar mass	450.93 g·mol−1
3D model (JSmol)	Interactive image
SMILES C[C@@H]1CCN(CCN1C(=O)C2=C(C=CC(=C2)C)N3N=CC=N3)C4=NC5=C(O4)C=CC(=C5)Cl
InChI InChI=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 N Key:JYTNQNCOQXFQPK-MRXNPFEDSA-N N
(verify)

Suvorexant, sold under the brand name Belsomra, is an orexin antagonist medication which is used in the treatment of insomnia. It is indicated specifically for the treatment of insomnia characterized by difficulties with sleep onset and/or maintenance in adults. Suvorexant causes people to fall asleep faster, stay asleep longer, be awake less in the middle of the night, and have better quality of sleep. The medication is taken by mouth.

Side effects of suvorexant include somnolence, daytime sleepiness, headache, dizziness, abnormal dreams, dry mouth, and impaired driving ability. Rarely, suicidal ideation may occur. The medication is a dual orexin receptor antagonist (DORA). It acts as a selective dual antagonist of the orexin receptors OX₁ and OX₂. Suvorexant has an intermediate elimination half-life of 12 hours and a time to peak of about 2 to 3 hours. It is not a benzodiazepine or Z-drug and does not interact with GABA receptors, instead having a distinct mechanism of action. Tolerance, dependence, withdrawal, and rebound effects do not appear to occur with suvorexant.

Clinical development of suvorexant began in 2006. It was first described in the literature in 2010 and was introduced for medical use in 2014. The medication is a schedule IV controlled substance in the United States and may have a modest potential for misuse at doses higher than those used for therapeutic purposes. Conversely, suvorexant is not a controlled substance in Australia. Suvorexant is not available in generic formulations.

Medical uses

Suvorexant is used for the treatment of insomnia, characterized by difficulties with sleep onset and/or sleep maintenance, in adults. At a dose of 15 to 20 mg and in terms of treatment–placebo difference, it reduces time to sleep onset by up to 10 minutes, reduces time awake after sleep onset by about 15 to 30 minutes, and increases total sleep time by about 10 to 20 minutes. A 2017 systematic review and meta-analysis of randomized controlled trials of suvorexant for insomnia likewise found that the medication improved subjective sleep onset, subjective total sleep time, and subjective sleep quality when assessed at one to three months of treatment.

Network meta-analyses have found orexin receptor antagonists like suvorexant to be superior in sleep-promoting efficacy to many other sleep aids, such as benzodiazepines, Z-drugs, antihistamines, sedative antidepressants (e.g., trazodone, doxepin, amitriptyline, mirtazapine), and melatonin receptor agonists. Network meta-analyses have also found similar efficacy between different orexin receptor antagonists including suvorexant, lemborexant, and daridorexant, although lemborexant may be more effective at the doses used.

Orexin receptor antagonists like suvorexant increase total sleep time predominantly by increasing rapid eye movement sleep (REM) sleep, whereas they have no effect on or even decrease non-rapid eye movement (NREM) sleep. This is in contrast to most other hypnotics, which either do not affect REM sleep or decrease it. The implications of these differences are not fully clear. Unlike certain other hypnotics like benzodiazepines and Z-drugs, orexin receptor antagonists do not disrupt sleep architecture, and this may provide more restful sleep.

It is unclear if suvorexant is safe among people with a history of substance addiction or alcoholism, as these individuals were excluded from clinical trials of suvorexant. A Cochrane review found suvorexant to be effective in the short-term treatment of sleep disturbances in people with dementia with few adverse effects. 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.

Suvorexant is FDA-approved at doses of 5 to 20 mg. Higher doses of up to 40 mg were also submitted for approval but were not authorized by the FDA due to concerns about residual sedation and associated impairment (e.g., driving). In addition to the preceding doses, suvorexant has been assessed at doses of 40 to 100 mg in clinical trials. These doses appeared to be more effective at promoting sleep than lower doses but produced greater residual effects.

Orexin receptor antagonists are not used as first-line treatments for insomnia due to their costs and concerns about possible misuse liability. Generic formulations of orexin receptor antagonists including suvorexant are not yet available.

Available forms

Suvorexant is available in the form of 5, 10, 15, and 20 mg oral film-coated tablets. It is provided as 10- and 30-tablet blister packs as well as 3-tablet starter packs. The availability of these different packs varies by country (all three available in Australia but only 30-tablet packs available in the United States).

Contraindications

Suvorexant is contraindicated in people with narcolepsy. This is its only absolute contraindication. Suvorexant has not been studied in people with severe hepatic impairment and is not recommended in these individuals due to the likelihood of increased suvorexant exposure. On the other hand, suvorexant may be used in people with mild-to-moderate hepatic impairment as well as renal impairment of any severity and no dose adjustment is necessary in these situations. Concomitant use of suvorexant with strong CYP3A4 inhibitors is not recommended due to potential for increased suvorexant exposure while concomitant use of suvorexant with strong CYP3A4 inducers may result in loss of suvorexant exposure and effectiveness. Suvorexant should be used carefully in people with a history of drug misuse or alcoholism due to its drug-liking effects and possible misuse potential at higher-than-approved doses. 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.

Suvorexant has shown teratogenic effects in animals such as decreased body weight at doses much higher than the equivalents of those approved for therapeutic use in humans. Teratogenic effects with therapeutic doses of suvorexant in humans have not been established due to lack of research and available data. Suvorexant is pregnancy category C in the United States. It is unknown whether suvorexant is present in the breast milk, whether it affects lactation in breastfeeding women, and whether it affects breastfed infants. 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. Suvorexant should be used in pregnant and breastfeeding women only if the potential benefit justifies the potential for harm to the baby.

Side effects

Side effects of suvorexant (at doses of 15–20 mg) include somnolence (7% vs. 3% for placebo) and headaches (7% vs. 6% for placebo). Somnolence with suvorexant appears to be dose-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% for placebo. Less common side effects (at 15–20 mg) may include dizziness (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), and cough (2% vs. 1% for placebo). High doses of suvorexant (80 mg) have also been found to produce greater incidences of dizziness (5% vs. 0% for placebo) and abnormal dreams (5% vs. 1% for placebo).

A 2017 systematic review and meta-analysis of suvorexant for the treatment of insomnia found that the medication increased the likelihood of somnolence by 3.5-fold, daytime sleepiness by 3.1-fold, fatigue by 2.1-fold, abnormal dreams by 2.1-fold, and dry mouth by 2.0-fold. Conversely, suvorexant did not significantly differ from placebo in the occurrences of any other assessed adverse effects. This included back pain, diarrhea, dizziness, falls, headache, car accidents/traffic violations, nasopharyngitis, nausea, potential drug misuse, suicidal ideation, complex sleep behaviors, hypnagogic or hypnopompic hallucinations, and sleep paralysis. 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).

The next-day effects of suvorexant have been studied. Suvorexant increases daytime somnolence, may reduce alertness and motor coordination, and impairs driving, with the risks increasing dose-dependently. It may also increase the risk of falling asleep while driving. Driving ability was found to be impaired at doses of 20 and 40 mg in clinical studies. Driving impairment may also occur with lower doses of suvorexant due to variations in individual sensitivity to the medication. In three of four studies, 30 mg suvorexant had no influence on next-day memory or balance, whereas in the remaining study, there was a decrease in morning word recall with 40 mg and an increase in body sway with 20 and 40 mg doses. In another study in elderly people awakened in the night, suvorexant 30 mg impaired balance at 1.5 hours post-dose whereas memory was unaffected. Complex sleep behaviors such as sleepwalking, sleep-driving, and performing other activities while not completely awake (such as making or eating food, making phone calls, and having sex) have also been reported with sleep medications like suvorexant.

Suvorexant may rarely cause worsening of depression or emergent suicidal ideation. A dose-dependent increase in suicidal ideation as assessed with the Columbia 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). 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. Suicidal ideation with suvorexant is considered to be mild. In any case, caution is warranted in use of suvorexant in people with depression, and people who report worsening depression or suicidal thoughts should be promptly evaluated.

Tolerance, withdrawal, and rebound effects do not appear to occur with suvorexant in the treatment of insomnia at studied doses. In three-month clinical studies, no rebound insomnia as assessed by measures of sleep onset or maintenance was observed with discontinuation of suvorexant at doses of 15 to 40 mg. Similarly, no withdrawal effects were observed with discontinuation of suvorexant at these doses.

Orexin receptor antagonists can affect the reward system and produce drug-liking responses in humans. Suvorexant at higher-than-approved doses (40, 80, and 150 mg vs. 20 mg maximum recommended dose) showed similar drug-liking responses to zolpidem (15 and 30 mg) in recreational drug users. 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 drug users. In other studies however, suvorexant showed similar drug liking compared to zolpidem but lower misuse potential on other measures (e.g., overall rate of misuse potential adverse events of 58% for zolpidem and 31% for suvorexant in recreational drug users). The misuse liability of suvorexant is considered to be modest. In any case, it is a controlled substance in the United States due to concerns about potential misuse.

Besides its subjective effects and side effects, suvorexant has been found to cause dose-dependent increases in serum cholesterol levels in clinical trials. These changes in cholesterol levels were +1 mg/dL at 10 mg, +2 mg/dL at 20 mg, +3 mg/dL at 40 mg, and +6 mg/dL at 80 mg relative to –4 mg/dL for placebo. Increases in cholesterol levels with approved doses of suvorexant are small (+1–2 mg/dL at 10–20 mg).

Early studies in rodents found that orexins (derived from Greek "orexis" meaning "appetite") stimulate appetite, feeding behavior, and weight gain while orexin receptor antagonists block these effects. However, subsequent animal studies were more mixed, with the effects being limited and depending on the animal strain. In humans, orexin receptor antagonists including suvorexant have not been found to affect body weight in rigorous clinical trials that lasted up to 12 to 14 months.

Overdose

There is limited experience with overdose of suvorexant. Suvorexant has been assessed in single doses of as high as 240 mg in clinical studies. The medication dose-dependently produces somnolence. High doses of suvorexant may also cause sleep-onset paralysis in some individuals (2% incidence at doses of 40–240 mg). Treatment of suvorexant overdose is based on symptoms and is supportive. Gastric lavage may be used where appropriate whereas the value of dialysis has not been determined. Because suvorexant has high plasma protein binding, hemodialysis is not expected to enhance elimination of suvorexant.

Interactions

CYP3A4 inhibitors can increase exposure to suvorexant while CYP3A4 inducers can decrease exposure to suvorexant. Combination of suvorexant with the strong CYP3A4 inhibitor ketoconazole increased suvorexant overall exposure by about 2.75-fold and peak levels by about 1.25-fold, combination with the moderate CYP3A4 inhibitor diltiazem increased suvorexant overall exposure by about 2-fold and peak levels by about 1.25-fold, and combination with the strong CYP3A4 inducer rifampin decreased suvorexant overall exposure by about 90% and peak levels by about 65%. 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). The substantial decrease in suvorexant exposure with strong CYP3A4 inducers may result in loss of effectiveness.

Examples of important CYP3A4 modulators which are expected to interact with suvorexant include the strong CYP3A4 inhibitors boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, and telithromycin (concomitant use not recommended); the moderate CYP3A4 inhibitors amprenavir, aprepitant, atazanavir, ciprofloxacin, diltiazem, dronedarone, erythromycin, fluconazole, fluvoxamine, fosamprenavir, grapefruit juice, imatinib, and verapamil (lower doses of suvorexant recommended); and the strong CYP3A4 inducers apalutamide, carbamazepine, efavirenz, enzalutamide, phenytoin, rifampin, and St. John's wort (expected to decrease suvorexant effectiveness).

Coadministration of suvorexant with other CNS depressants such as alcohol, benzodiazepines, opioids, and tricyclic antidepressants may increase the risk of CNS depression and daytime impairment. Alcohol and suvorexant do not appear to interact in terms of pharmacokinetics but consumption of alcohol in combination with suvorexant is not advised due to additive CNS depression. Dosage adjustment may be necessary when suvorexant is combined with other CNS depressants. Use of suvorexant in combination with other medications used in the treatment of insomnia is not recommended.

Suvorexant is not expected to cause clinically meaningful inhibition or induction of various cytochrome P450 enzymes and drug transporters. It has been found to not substantially influence the pharmacokinetics of midazolam (CYP3A4 substrate), warfarin (CYP2C9 substrate), digoxin (P-glycoprotein substrate), and combined birth control pills. However, coadministration of suvorexant with digoxin may result in slightly increased digoxin exposure due to inhibition of intestinal P-glycoprotein by suvorexant. Concentrations of digoxin should be monitored during coadministration of suvorexant and digoxin.

Pharmacology

Pharmacodynamics

Suvorexant acts as a selective dual antagonist of the orexin (hypocretin) receptors OX₁ and OX₂. It shows similar binding affinity for the OX₁ and OX₂ receptors in vitro. Its affinities (K_i) for the human orexin receptors are specifically 0.55 nM for the OX₁ receptor and 0.35 nM for the OX₂ receptor. Antagonistic potency or functional inhibition (K_b) of suvorexant at the human orexin receptors are 65 nM for the OX₁ receptor and 41 nM for the OX₂ receptor. Suvorexant is highly selective for the orexin receptors over a large number of other targets (165 receptors and enzymes). In contrast to certain other sedatives and hypnotics, suvorexant is not a benzodiazepine or Z-drug and does not interact with GABA receptors.

Mechanism of action

Suvorexant is thought to exert its therapeutic effects in insomnia by blocking the orexin receptors. The orexin system is a central promoter of wakefulness. Blocking the binding of wake-promoting neuropeptides orexin A and orexin B to the receptors OX₁ and OX₂ is thought to suppress wake drive. Loss of orexin signaling is involved in the etiology of narcolepsy, and disturbances in orexin signaling may also be involved in insomnia. In animals including rats, dogs, and monkeys, suvorexant induces a transient decrease in locomotor activity, dose-dependently promotes sleep, and positively influences sleep architecture.

Pharmacokinetics

Suvorexant levels over a period of 48 hours with single oral doses of 10, 50, and 100 mg suvorexant in healthy young men.

Absorption

The absolute bioavailability of suvorexant is 82% at a dose of 10 mg. Suvorexant exposure is not dose-proportional over a dose range of 10 to 100 mg owing to decreased absorption at higher doses. In one study, suvorexant peak levels were 0.44 μM at 10 mg, 0.87 μM at 50 mg, and 2.12 μM at 100 mg, while overall exposure was 6.7 μM•h at 10 mg, 10.9 μM•h at 50 mg, and 29.8 μM•h at 100 mg. The time to peak levels of suvorexant is 2 to 3 hours regardless of dose but with wide variation (range 30 minutes to 8 hours). Taking suvorexant with food does not modify suvorexant peak levels or area-under-the-curve levels (overall exposure) but does delay the time to peak concentrations by about 1.5 hours. Steady-state levels of suvorexant with once-daily continuous administration are reached within 3 days. Levels of suvorexant accumulate 1- to 2-fold with repeated once-daily administration.

Distribution

The volume of distribution of suvorexant is approximately 49 L. Suvorexant has high plasma protein binding (99.5%). It is bound to albumin and α₁-acid glycoprotein (orosomucoid).

Metabolism

Suvorexant is metabolized primarily by CYP3A enzymes. CYP2C19 also contributes to suvorexant metabolism to a minor extent. The major circulating forms are suvorexant and its metabolite hydroxysuvorexant. The hydroxysuvorexant metabolite is not expected to be pharmacologically active.

Elimination

Suvorexant is eliminated mainly via metabolism. It is excreted primarily in feces (66%) and to a lesser extent in urine (23%).

The elimination half-life of suvorexant is 12 hours, with a range of 9 to 13 hours. In another study, the half-life of suvorexant was 15 hours with a range of 10 to 22 hours. 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.

Specific populations

Age and race do not influence the pharmacokinetics of suvorexant in a clinically meaningfully way. Exposure to suvorexant is slightly higher in women compared to men (C_max 9% higher, AUC 17% higher), however dose adjustments based on gender are generally unnecessary. Suvorexant exposure is greater in people with higher body mass index, such as obese people (C_max 17% higher, AUC 31% higher). This is particularly the case in obese women relative to non-obese women (C_max 25% higher, AUC 46% higher). Suvorexant exposure with a single dose is not greater in people with moderate hepatic insufficiency compared to healthy individuals. However, the half-life of suvorexant was prolonged from 15 hours (range 10–22 hours) to 19 hours (range 11–49 hours) in these individuals. Suvorexant exposure is unchanged in people with severe renal impairment and no dosage adjustment is necessary in these individuals.

Miscellaneous

Peak-normalized semi-log concentrations (% of C_max) of the orexin receptor antagonists suvorexant, lemborexant, daridorexant, and seltorexant with administration in humans. The terminal elimination half-lives in these studies were 12 hours, 55 hours, 6 hours, and 2.5 hours, respectively.

The delayed time to peak levels (2–3 hours) and long elimination half-life (12 hours) of suvorexant have been said to be "less than ideal for a sleep drug". Other orexin receptor antagonists with shorter half-lives and faster onsets of action are theoretically more optimal for therapeutic use as sleep aids. Relative to suvorexant, daridorexant has a shorter half-life (8 hours) while lemborexant has a longer half-life (17–55 hours). The investigational orexin receptor antagonists seltorexant and vornorexant, which are still in clinical trials, have comparatively very short half-lives in the range of 1.5 to 3 hours.

Suvorexant dissociates from the orexin receptors slowly. As a result, its duration may be longer than that suggested by its circulating concentrations and half-life.

Chemistry

Suvorexant is a small-molecule compound. The chemical 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. Its molecular formula is C₂₃H₂₃N₆O₂Cl and its molecular weight is 450.92 g/mol. Suvorexant is a white to off-white powder and is insoluble in water. It is structurally related to other orexin receptor antagonists like lemborexant, daridorexant, and seltorexant.

History

Orexins (also known as hypocretins) were discovered in 1998. Subsequently, they were found to be produced exclusively by a small population of neurons located in the lateral hypothalamus of the brain. Loss of orexin signaling was found to be responsible for narcolepsy in animals and humans and the orexin system was found to show circadian rhythm in its activity, to be essential in regulating sleep–wake cycles, and to be highly conserved across mammalian species. Due to their high potential for use in sleep disorders, these findings led to translational efforts to bring orexin receptor modulators to clinical medicine as therapeutic agents.

Suvorexant was developed by Merck. It entered clinical development in 2006 and was first described in the medical literature in 2010. The medication was approved for the treatment of insomnia by the United States Food and Drug Administration on August 13, 2014. Suvorexant was initially released November 2014 in Japan, then later reached the United States in February 2015, Australia in November 2016, and Canada in November 2018.

Suvorexant marketing exclusivity in the United States is set to expire in January 2023 and patent protection is set to expire in 2029 to 2033.

Society and culture

Names

Suvorexant was developed under the code name MK-4305 and is marketed under the brand name Belsomra.

Availability

Suvorexant has been marketed in the United States, Canada, Australia, Russia, and Japan. Although previously available, suvorexant appears to have been discontinued in Canada. It does not appear to be available in the United Kingdom or other European countries besides Russia.

Legal status

Suvorexant is a schedule IV controlled substance under the Controlled Substances Act in the United States. It is not a controlled substance in Australia, instead being classed as a prescription-only medication (Schedule 4 (S4)) in this country.

Research

Delirium

Suvorexant is under development for the treatment of delirium. As of October 2021, it is in phase III clinical trials for this indication.

Psychiatry

Suvorexant has been studied in the treatment of insomnia in people with psychiatric disorders such as depression and anxiety. It was reported to improve psychiatric symptoms and to decrease cortisol levels in these individuals. A phase 4 clinical trial of suvorexant as an adjunct to antidepressant therapy in people with major depressive disorder and residual insomnia was underway as of 2019.

There is interest in suvorexant and other orexin receptor antagonists in the potential treatment of substance use disorders.

Diabetes

Suvorexant has been studied in people with type 2 diabetes and insomnia and has been reported to improve sleep and metabolic parameters in these individuals. The improvement in metabolic parameters was associated with improved sleep.

External links

• "Suvorexant". Drug Information Portal. U.S. National Library of Medicine.
• Parker I (9 December 2013). "The Big Sleep". The New Yorker.