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Suvorexant, produced by Merck & Co. and sold under the brand name Belsomra, is an orexin antagonist medication used in the treatment of insomnia. It is indicated specifically for the treatment in adults of insomnia characterized by difficulties with sleep onset and/or middle-of-the-night insomnia, total sleep time, and issues with sleep quality. Its effectiveness is modest, and is similar to that of other orexin antagonists, but is lower than that of and . Suvorexant is taken by oral administration.
of suvorexant include somnolence, excessive daytime sleepiness, headache, dizziness, , dry mouth, and impaired next-day driving ability. Rarely, sleep paralysis, sleep-related , complex sleep behaviors like sleepwalking, and suicidal ideation may occur. Drug tolerance, drug dependence, drug withdrawal, and drug rebound 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 , 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 misuse potential. In other places, such as Australia, suvorexant is a prescription-only medicine and is not a . Suvorexant is not available in generic drug. Besides suvorexant, other orexin receptor antagonists like lemborexant and daridorexant have also been introduced.
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 , , , sedative (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 , which either do not affect REM sleep or decrease it. The implications of these differences are not fully clear. Unlike certain other hypnotics like and , 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 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 drug formulations of orexin receptor antagonists including suvorexant are not yet available.
Suvorexant has shown 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.
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 sleep sex). Other narcolepsy-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.
A 2017 systematic review and meta-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. Conversely, suvorexant did not significantly differ from placebo in the rates of any other assessed adverse effects. This included back pain, diarrhea, dizziness, falls, headache, /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 (=0.93, 95% 0.60 to 1.44).
Drug tolerance, drug dependence, drug withdrawal, and 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 40mg. Similarly, no withdrawal effects were observed with discontinuation of suvorexant at these doses. However, in other reports, some tolerance as assessed by diminishing somnolence and rebound insomnia upon discontinuation has been noted.
The orexin augment the signaling of the mesolimbic dopamine reward pathway and are thought to potentiate hedonism tone. Conversely, low orexin signaling may result in anhedonia and orexin receptor antagonists are of interest for the potential treatment of addiction. In line with these findings, suvorexant and other orexin receptor antagonists have not shown misuse liability in animal studies in rats and non-human primates. Paradoxically however, orexin receptor antagonists, including suvorexant, lemborexant, and daridorexant, have consistently shown drug-liking responses in human studies of recreational sedative users. Suvorexant at higher-than-approved doses (40, 80, and 150mg vs. 20mg maximum recommended dose) showed similar drug liking to the Z-drug zolpidem (15 and 30mg) in such individuals. 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). In another study, suvorexant at a dose of 150mg showed greater drug liking than daridorexant (50mg) but similar drug liking to zolpidem (30mg) and higher doses of daridorexant (100–150mg) in recreational sedative users. There was no apparent dose–response relationship for positive measures of misuse potential with suvorexant, in contrast to zolpidem. In the phase III clinical trials, misuse potential adverse events were reported in 3.0% with placebo, 4.1% with 15 or 20mg suvorexant, and 2.6% with 30 or 40mg suvorexant. 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. In any case, suvorexant is a controlled substance in the United States due to concerns about the possibility of misuse.
Besides its subjective side effects, suvorexant has been found to cause dose-dependent increases in serum cholesterol levels in clinical trials. These changes in cholesterol levels were +1.2mg/dL at 10mg, +2.3mg/dL at 20mg, +3.1mg/dL at 40mg, and +6.0mg/dL at 80mg relative to –3.7mg/dL for placebo. Although the increases in cholesterol levels with approved doses of suvorexant (10–20mg) are small, they could be important over a long duration of treatment.
Early studies in rodents found that (derived from Greek language "orexis" meaning "appetite") stimulate appetite, eating, 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 14months.
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 such as alcohol, , , 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 and . It has been found to not substantially influence the pharmacokinetics of midazolam (CYP3A4 substrate), warfarin (CYP2C9 substrate), digoxin (P-glycoprotein substrate), or combined birth control pills. However, coadministration of suvorexant with digoxin may result in slightly increased digoxin exposure due to inhibition of intestine P-glycoprotein by suvorexant. Concentrations of digoxin should be monitored during coadministration of suvorexant and digoxin.
Narcolepsy is a chronic sleep disorder characterized by excessive daytime sleepiness, cataplexy, sleep paralysis, and hypnagogic hallucinations, as well as and fragmented sleep. Narcolepsy with cataplexy, also known as type 1 narcolepsy, is thought to be caused by loss of orexin-producing neurons in the lateral hypothalamus, possibly mediated by autoimmune mechanisms related to environmental triggers in genetically susceptible individuals. 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 cerebrospinal fluid in people with narcolepsy. Similarly, narcolepsy with cataplexy in dogs is caused by a mutation in the gene encoding the OX2 receptor, and knockout mice for genes encoding orexin system proteins such as prepro-orexin or the OX2 receptor show a narcolepsy-like phenotype. Although there is hypersomnolence 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. They do not usually feel well-rested during the day. Besides narcolepsy, the orexin system may also be involved in the etiology of insomnia. In addition, orexin signaling appears to change with age, and this may be involved in aging-related sleep disturbances.
Orexin receptor antagonists may be expected to produce effects similar to those in narcolepsy. 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. (2025). 9783319575346, Springer International Publishing. ISBN 9783319575346 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. In addition, long-term neural changes may develop in narcolepsy to compensate for the orexin deficiency in the condition. In animals and humans, orexin receptor agonists such as orexin-A and danavorexton dose-dependently produce wakefulness and locomotor activity while orexin receptor antagonists like suvorexant transiently reduce locomotor activity and dose-dependently promote sleep. Acute orexin receptor antagonists can promote sleep in animals to a greater extent than what occurs in narcolepsy-like orexin system loss. In addition, little to no cataplexy has been observed even with high doses of orexin receptor antagonists in animals and humans. It is unknown if long-term use of orexin receptor antagonists may produce compensatory neural changes or narcolepsy-like symptoms. An animal study of chronic high-dose suvorexant administration that showed development of narcolepsy-like changes suggests that this may be possible however.
Endogenous orexinergic tone is expected to play an important moderating influence in terms of the effects of orexin receptor modulators. 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.
Suvorexant has high plasma protein binding (99.5%). It is bound to albumin and α1-acid glycoprotein (orosomucoid).
The elimination half-life of suvorexant at a dose of 40mg is 12.2hours, with a range of 8 to 19hours. In another study, the half-life of suvorexant was 15hours with a range of 10 to 22hours. In one study, the half-lives of suvorexant (mean ± SD) were 9.0 ± 7.2hours at 10mg, 10.8 ± 3.6hours at 50mg, and 13.1 ± 5.8hours at 100mg. With doses of 120 to 240mg, the half-lives of suvorexant were 12.1 to 14.5hours in healthy young males and 14.4 to 15.8hours in healthy young females. The half-life of suvorexant's inactive metabolite hydroxysuvorexant is similar to that of suvorexant.
Suvorexant dissociates from the slowly. As a result, its duration may be longer than that suggested by its circulating concentrations and half-life.
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 by the FDA for the treatment of insomnia in the United States on 13 August 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. It was the first orexin receptor antagonist to be introduced for medical use, and was followed by lemborexant in 2019 and daridorexant in 2022. Development of almorexant (ACT-078573) and filorexant (MK-6096) was discontinued, while seltorexant (MIN-202, JNJ-42847922) and vornorexant (ORN-0829, TS-142) are still in clinical trials.
Suvorexant marketing exclusivity in the United States was set to expire in January 2023 and patent protection is set to expire in 2029 to 2033.
There is interest in suvorexant and other orexin receptor antagonists in the potential treatment of substance use disorders, (2025). 9783319575346 ISBN 9783319575346 including alcohol use disorder, (2025). 9783319575346 ISBN 9783319575346 cocaine use disorder, and opioid use disorder.
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