Suvorexant, sold under the brand name Belsomra, is an orexin antagonist medication 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 helps with falling asleep faster, sleeping longer, being awake less in the middle of the night, and having better quality of sleep. Its effectiveness is modest, similar to that other orexin antagonists, but it is lower than that of benzodiazepines and Z-drugs. Suvorexant is taken orally.
Side effects of suvorexant include somnolence, daytime sleepiness and sedation, headache, dizziness, abnormal dreams, dry mouth, and impaired next-day driving ability. Rarely, sleep paralysis, sleep-related hallucinations, complex sleep behaviors like sleepwalking, and suicidal ideation may occur. Tolerance, dependence, withdrawal, and rebound effects do not appear to occur significantly with the medication. Suvorexant is a dual orexin receptor antagonist (DORA). It acts as a selective dual antagonist of the orexin OX1 and OX2 receptors. The medication has an intermediate elimination half-life of 12hours and a time to peak of about 2 to 3hours. Unlike benzodiazepines and Z-drugs, suvorexant does not interact with GABA receptors, instead having a distinct mechanism of action.
Clinical development of suvorexant began in 2006 and it 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. In other places, such as Australia, suvorexant is a prescription-only medicine and is not a controlled drug. Suvorexant is not available in generic formulations. Besides suvorexant, other orexin receptor antagonists like lemborexant and daridorexant have also been introduced.
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 20mg and in terms of treatment–placebo difference, it reduces time to sleep onset by up to 10minutes, reduces time awake after sleep onset by about 15 to 30minutes, and increases total sleep time by about 10 to 20minutes. 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. The effectiveness of approved doses of suvorexant (≤20mg) in the treatment of insomnia is said to be modest.
Network meta-analyses have assessed the sleep-promoting effects of suvorexant and have compared them to those of other orexin receptor antagonists like lemborexant and daridorexant as well as to other sleep aids including benzodiazepines, Z-drugs, antihistamines, sedative antidepressants (e.g., trazodone, doxepin, amitriptyline, mirtazapine), and melatonin receptor agonists. A major systematic review and network meta-analysis of insomnia medications published in 2022 found that suvorexant had an effect size (standardized mean difference (SMD)) against placebo for treatment of insomnia at 4weeks of 0.31 (95% 0.01 to 0.62). Suvorexant appeared to be similarly effective at 4weeks 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).
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 might 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 approved for the treatment of insomnia by the United States Food and Drug Administration (FDA) at doses of 5 to 20mg and by the Australian Therapeutic Goods Administration (TGA) and Japanese Pharmaceuticals and Medical Devices Agency (PMDA) at doses of 15mg (in the elderly) and 20mg (in younger adults). In the United States, the recommended starting dose is 10mg and the maximum recommended dose is 20mg. Higher doses of 30 and 40mg were also submitted to regulatory agencies for approval but were not authorized due to lack of clearly superior efficacy to doses of 15 to 20mg and concerns about next-day effects and associated impairment (e.g., driving). In addition to the preceding doses, suvorexant has been assessed at higher doses of up to 100mg in clinical trials. These higher doses appeared to be more effective at promoting sleep than lower doses but produced greater next-day effects. Lower approved doses of suvorexant in the United States in the range of 5 to 10mg were not extensively evaluated in clinical trials.
The American Academy of Sleep Medicine's 2017 clinical practice guidelines recommend the use of suvorexant in the treatment of sleep-onset and sleep-maintenance insomnia along with various other sleep medications. 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 20mg 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.
Contraindications Suvorexant is contraindicated in people with narcolepsy as it may worsen their symptoms. 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 doses higher than those approved for therapeutic use. Similarly, suvorexant should be used carefully in people with a history of depression or suicidality as it may rarely increase suicidal ideation. 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, or 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 15–20mg) 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 10mg, 5% at 20mg, 10–12% at 40mg, and 11–12% at 80mg, relative to 0.4% for placebo. Less common side effects (at 15–20mg) 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 (80mg) have also been found to produce greater incidence of dizziness (5% vs. 0% for placebo) and abnormal dreams (5% vs. 1% for placebo).
Less commonly, suvorexant may cause sleep paralysis, hypnagogic and hypnopompic hallucinations, and complex sleep behaviors (0.2–0.6% vs. 0% for placebo). Complex sleep behaviors include sleepwalking, sleep-driving, and engaging in other activities while not completely awake (e.g., making or eating food, making phone calls, and having sex). Other narcoleptic-like symptoms, such as cataplexy (sudden weakness or paralysis), may also rarely occur. Suvorexant may sometimes cause worsening of depression or 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 (15–20mg) and 0.4% (5/1291) at high doses (30–40mg) 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 20mg and 3.4% to 8.2% taking 40 to 80mg 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 with worsening depression or suicidal thoughts should be promptly evaluated. Besides the clinical trial data, a case report of rapidly worsened depression and onset of suicidal ideation with suvorexant has been published.
The next-day effects of suvorexant have been studied. Besides the side effect of daytime somnolence, suvorexant may dose-dependently reduce alertness and motor coordination and impair driving ability. It may also increase the risk of falling asleep while driving. Driving ability was found to be impaired at doses of 20 and 40mg 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, 30mg suvorexant had no influence on next-day memory or balance, whereas in the remaining study, there was a decrease in morning word recall with 40mg and an increase in body sway with 20 and 40mg doses. In another study in elderly people who were awakened in the night, impaired balance was present at 1.5hours after taking 30mg suvorexant whereas memory was unaffected.