Suvorexant

Suvorexant is used for the treatment of insomnia, characterized by difficulties with sleep onset and/or sleep maintenance, in adults. 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). This is in contrast to most other hypnotics, which either do not affect REM sleep or decrease it. 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. Lower approved doses of suvorexant in the United States in the range of 5 to 10mg were not extensively evaluated in clinical trials. Orexin receptor antagonists are not used as first-line treatments for insomnia due to their costs and concerns about possible misuse liability. 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. 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). Suicidal ideation with suvorexant is considered to be mild. The next-day effects of suvorexant have been studied. Conversely, low orexin signaling may result in low hedonic tone and orexin receptor antagonists are of interest for the potential treatment of addiction. 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. 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. 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. ==Overdose==

There is limited experience with overdose of suvorexant. The medication dose-dependently produces somnolence. High doses of suvorexant may also cause sleep-onset paralysis in some individuals (2% incidence at doses of 40–240mg). 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 2.79-fold and peak levels by about 1.25-fold, combination with the moderate CYP3A4 inhibitor diltiazem increased suvorexant overall exposure by 2.05-fold and peak levels by about 1.25-fold, and combination with the strong CYP3A4 inducer rifampin decreased suvorexant overall exposure by 88% and peak levels by about 65%. 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), or 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. These receptors are the biological targets of the endogenous wakefulness-promoting orexin neuropeptides orexin-A and orexin-B. The antagonistic potencies or functional inhibition (Kb) of suvorexant at the human orexin receptors are 65nM for the OX1 receptor and 41nM for the OX2 receptor. These neurons project widely throughout the brain and mediate excitatory signaling to key centers involved in sleep–wake regulation, including the noradrenergic locus coeruleus, histaminergic tuberomammillary nucleus, serotonergic raphe nucleus, and dopaminergic ventral tegmental area. The orexin system shows circadian rhythmicity in its activity, with high activity during waking and low to no activity during sleep or at night. 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. Orexin receptor antagonists may be expected to produce effects similar to those in narcolepsy. 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. Endogenous orexinergic tone is expected to play an important moderating influence in terms of the effects of orexin receptor modulators. Exposure to suvorexant increases by about 75% with a doubling of dose from 20mg to 40mg. Suvorexant exposure is unchanged in people with severe renal impairment and no dosage adjustment is necessary in these individuals. However, although lemborexant has a longer terminal elimination half-life than suvorexant, it appears to be more rapidly cleared in the earlier phases of elimination. 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 450.92g/mol. Suvorexant is a white to off-white powder and is lipophilic and insoluble in water. It is structurally related to other orexin receptor antagonists like lemborexant, daridorexant, and seltorexant. ==History==

The orexin neuropeptides were discovered in 1998 and the role of the orexin system in the etiology of narcolepsy was identified between 1999 and 2000. Subsequent research further established the role of the orexin system in sleep–wake regulation. 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. ==Society and culture==

Names Suvorexant is the generic name of the drug and its , , and . The medication was developed by Merck under the code name MK-4305 and is marketed under the brand name Belsomra. It is not a controlled drug in Australia, instead being classed as a prescription-only medicine (Schedule 4 (S4)) in this country. Controversy Public Citizen, a progressive consumer rights advocacy group, issued a letter in June 2013 urging the FDA not to approve suvorexant. In its reasoning, it cited marginal benefits and excessive potential for harm, including next-day effects like driving impairment and possible accidents. ==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. 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). cocaine use disorder, and opioid use disorder. Alzheimer's disease Suvorexant and other orexin receptor modulators are of interest for possible use in the prevention of Alzheimer's disease. 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 appeared to be related to improved sleep. == References ==