Suvorexant, sold under the brand name Belsomra, is an orexin antagonist medication which is used in the treatment of

insomnia Insomnia, also known as sleeplessness, is a sleep disorder where people have difficulty sleeping. They may have difficulty falling asleep, or staying asleep for as long as desired. Insomnia is typically followed by daytime sleepiness, low ene ...

. It is indicated specifically for the treatment of insomnia characterized by difficulties with sleep onset and/or

maintenance The technical meaning of maintenance involves functional checks, servicing, repairing or replacing of necessary devices, equipment, machinery, building infrastructure and supporting utilities in industrial, business, and residential installa ...

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, and is similar to that of other orexin antagonists, but is lower than that of

benzodiazepine Benzodiazepines (BZD, BDZ, BZs), colloquially known as "benzos", are a class of central nervous system (CNS) depressant, depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed t ...

s and Z-drugs. Suvorexant is taken

by mouth Oral administration is a route of administration whereby a substance is taken through the Human mouth, mouth, swallowed, and then processed via the digestive system. This is a common route of administration for many medications. Oral administ ...

Side effect In medicine, a side effect is an effect of the use of a medicinal drug or other treatment, usually adverse but sometimes beneficial, that is unintended. Herbal and traditional medicines also have side effects. A drug or procedure usually use ...

s of suvorexant include

somnolence Somnolence (alternatively sleepiness or drowsiness) is a state of strong desire for sleep, or sleeping for unusually long periods (compare hypersomnia). It has distinct meanings and causes. It can refer to the usual state preceding falling aslee ...

, daytime sleepiness and sedation,

headache A headache, also known as cephalalgia, is the symptom of pain in the face, head, or neck. It can occur as a migraine, tension-type headache, or cluster headache. There is an increased risk of Depression (mood), depression in those with severe ...

dizziness Dizziness is an imprecise term that can refer to a sense of disorientation in space, vertigo, or lightheadedness. It can also refer to Balance disorder, disequilibrium or a non-specific feeling, such as giddiness or foolishness. Dizziness is a ...

, abnormal dreams, dry mouth, and impaired next-day

driving Driving is the controlled operation and movement of a land vehicle, including cars, motorcycles, trucks, and buses. A driver's permission to drive on public highways is granted based on a set of conditions being met, and drivers are required to ...

ability. Rarely,

sleep paralysis Sleep paralysis is a state, during waking up or falling asleep, in which a person is conscious but in a complete state of full-body paralysis. During an episode, the person may hallucinate (hear, feel, or see things that are not there), wh ...

, sleep-related

hallucination A hallucination is a perception in the absence of an external stimulus that has the compelling sense of reality. They are distinguishable from several related phenomena, such as dreaming ( REM sleep), which does not involve wakefulness; pse ...

s, complex sleep behaviors like

sleepwalking Sleepwalking, also known as somnambulism or noctambulism, is a phenomenon of combined sleep and wakefulness. It is classified as a sleep disorder belonging to the parasomnia family. It occurs during the slow wave stage of sleep, in a state of ...

, and

suicidal ideation Suicidal ideation, or suicidal thoughts, is the thought process of having ideas or ruminations about the possibility of dying by suicide.World Health Organization, ''ICD-11 for Mortality and Morbidity Statistics'', ver. 09/2020MB26.A Suicidal i ...

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 An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.orexin Orexin (), also known as hypocretin, is a neuropeptide that regulates arousal, wakefulness, and appetite. It exists in the forms of orexin-A and orexin-B. The most common form of narcolepsy, type 1, in which the individual experiences brief loss ...

OX₁ and OX₂ receptors. The medication has an intermediate

elimination half-life Biological half-life (elimination half-life, pharmacological half-life) is the time taken for concentration of a biological substance (such as a medication) to decrease from its maximum concentration ( Cmax) to half of Cmax in the blood plasma. ...

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 In pharmacology, the term mechanism of action (MOA) refers to the specific biochemical Drug interaction, interaction through which a Medication, drug substance produces its pharmacological effect. A mechanism of action usually includes mention o ...

Clinical development Drug development is the process of bringing a new pharmaceutical drug to the market once a lead compound has been identified through the process of drug discovery. It includes preclinical research on microorganisms and animals, filing for regul ...

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

, 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 A placebo ( ) can be roughly defined as a sham medical treatment. Common placebos include inert tablets (like sugar pills), inert injections (like saline), sham surgery, and other procedures. Placebos are used in randomized clinical trials ...

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 A systematic review is a scholarly synthesis of the evidence on a clearly presented topic using critical methods to identify, define and assess research on the topic. A systematic review extracts and interprets data from published studies on ...

and

meta-analysis Meta-analysis is a method of synthesis of quantitative data from multiple independent studies addressing a common research question. An important part of this method involves computing a combined effect size across all of the studies. As such, th ...

randomized controlled trial A randomized controlled trial (or randomized control trial; RCT) is a form of scientific experiment used to control factors not under direct experimental control. Examples of RCTs are clinical trials that compare the effects of drugs, surgical ...

s 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

s, Z-drugs,

antihistamine Antihistamines are drugs which treat allergic rhinitis, common cold, influenza, and other allergies. Typically, people take antihistamines as an inexpensive, generic (not patented) drug that can be bought without a prescription and provides ...

s, sedative

antidepressant Antidepressants are a class of medications used to treat major depressive disorder, anxiety disorders, chronic pain, and addiction. Common side effects of antidepressants include Xerostomia, dry mouth, weight gain, dizziness, headaches, akathi ...

s (e.g.,

trazodone Trazodone is an antidepressant medication used to treat major depressive disorder, anxiety disorders, and insomnia. It is a phenylpiperazine compound of the serotonin antagonist and reuptake inhibitor (SARI) class. The medication is taken or ...

, doxepin,

amitriptyline Amitriptyline, sold under the brand name Elavil among others, is a tricyclic antidepressant primarily used to treat major depressive disorder, and a variety of pain syndromes such as neuropathic pain, fibromyalgia, migraine and tension headac ...

mirtazapine Mirtazapine, sold under the brand name Remeron among others, is an atypical antidepressant, atypical tetracyclic antidepressant, and as such is used primarily to treat Depression (mood), depression. Its effects may take up to four weeks but ca ...

), and melatonin receptor agonists. A major

and network meta-analysis of insomnia medications published in 2022 found that suvorexant had an

effect size In statistics, an effect size is a value measuring the strength of the relationship between two variables in a population, or a sample-based estimate of that quantity. It can refer to the value of a statistic calculated from a sample of data, the ...

( standardized mean difference (SMD)) against

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 Rapid eye movement sleep (REM sleep or REMS) is a unique phase of sleep in mammals (including humans) and birds, characterized by random rapid movement of the eyes, accompanied by low muscle tone throughout the body, and the propensity of the s ...

(REM) sleep, whereas they have no effect on or even decrease non-rapid eye movement (NREM) sleep. This is in contrast to most other

hypnotic A hypnotic (from Ancient Greek, Greek ''Hypnos'', sleep), also known as a somnifacient or soporific, and commonly known as sleeping pills, are a class of psychoactive drugs whose primary function is to sleep induction, induce sleep and to trea ...

s, which either do not affect REM sleep or decrease it. The implications of these differences are not fully clear. Unlike certain other hypnotics like

s 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 Alcoholism is the continued drinking of alcohol despite it causing problems. Some definitions require evidence of dependence and withdrawal. Problematic use of alcohol has been mentioned in the earliest historical records. The World He ...

, as these individuals were excluded from

clinical trial Clinical trials are prospective biomedical or behavioral research studies on human subject research, human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel v ...

s of suvorexant. A

Cochrane review Cochrane is a British international charitable organisation formed to synthesize medical research findings to facilitate evidence-based choices about health interventions involving health professionals, patients and policy makers. It includes ...

found suvorexant to be effective in the short-term treatment of sleep disturbances in people with

dementia Dementia is a syndrome associated with many neurodegenerative diseases, characterized by a general decline in cognitive abilities that affects a person's ability to perform activities of daily living, everyday activities. This typically invo ...

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 The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...

(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.,

). 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 The American Academy of Sleep Medicine (AASM) is a United States professional society for the medical subspecialty of sleep medicine which includes disorders of circadian rhythms. It was established in 1975. The organization's functions includ ...

'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 The word oral may refer to: Relating to the mouth * Relating to the mouth, the first portion of the alimentary canal that primarily receives food and liquid **Oral administration of medicines ** Oral examination (also known as an oral exam or ora ...

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 medicine, a contraindication is a condition (a situation or factor) that serves as a reason not to take a certain medical treatment due to the harm that it would cause the patient. Contraindication is the opposite of indication, which is a rea ...

in people with

narcolepsy Narcolepsy is a chronic neurological disorder that impairs the ability to regulate sleep–wake cycles, and specifically impacts REM (rapid eye movement) sleep. The symptoms of narcolepsy include excessive daytime sleepiness (EDS), sleep-r ...

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 Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine, which in humans is encoded by ''CYP3A4'' gene. It organic redox reaction, oxidizes small foreign organic molecules ( ...

inhibitor Inhibitor or inhibition may refer to: Biology * Enzyme inhibitor, a substance that binds to an enzyme and decreases the enzyme's activity * Reuptake inhibitor, a substance that increases neurotransmission by blocking the reuptake of a neurotransmi ...

s 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

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

. 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 Breast milk (sometimes spelled as breastmilk) or mother's milk is milk produced by the mammary glands in the breasts of women. Breast milk is the primary source of nutrition for newborn infants, comprising fats, proteins, carbohydrates, and a var ...

, whether it affects

lactation Lactation describes the secretion of milk from the mammary glands and the period of time that a mother lactates to feed her young. The process naturally occurs with all sexually mature female mammals, although it may predate mammals. The process ...

breastfeeding Breastfeeding, also known as nursing, is the process where breast milk is fed to a child. Infants may suck the milk directly from the breast, or milk may be extracted with a Breast pump, pump and then fed to the infant. The World Health Orga ...

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

s of suvorexant (at doses of 15–20mg) include

(7% vs. 3% for

) and

s (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

. Less common side effects (at 15–20mg) may include

(3% vs. 2% for placebo), abnormal dreams (2% vs. 1% for placebo),

diarrhea Diarrhea (American English), also spelled diarrhoea or diarrhœa (British English), is the condition of having at least three loose, liquid, or watery bowel movements in a day. It often lasts for a few days and can result in dehydration d ...

(2% vs. 1% for placebo), dry mouth (2% vs. 1% for placebo),

upper respiratory tract infection An upper respiratory tract infection (URTI) is an illness caused by an acute infection, which involves the upper respiratory tract, including the nose, sinuses, pharynx, larynx or trachea. This commonly includes nasal obstruction, sore throat ...

(2% vs. 1% for placebo), and

cough A cough is a sudden expulsion of air through the large breathing passages which can help clear them of fluids, irritants, foreign particles and Microorganism, microbes. As a protective reflex, coughing can be repetitive with the cough reflex fol ...

(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

, hypnagogic and hypnopompic hallucinations, and complex sleep behaviors (0.2–0.6% vs. 0% for placebo). Complex sleep behaviors include

, 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 Narcolepsy is a chronic neurological disorder that impairs the ability to regulate sleep–wake cycles, and specifically impacts REM (rapid eye movement) sleep. The symptoms of narcolepsy include excessive daytime sleepiness (EDS), sleep-r ...

-like symptoms such as cataplexy (sudden weakness or paralysis) may also rarely occur. Suvorexant may sometimes cause worsening of depression or

. 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 In medicine, a case report is a detailed report of the symptoms, signs, diagnosis, treatment, and follow-up of an individual patient. Case reports may contain a demographic profile of the patient, but usually describe an unusual or novel occurrenc ...

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 In physiology, motor coordination is the orchestrated movement of multiple body parts as required to accomplish intended actions, like walking. This coordination is achieved by adjusting kinematic and kinetic parameters associated with each bo ...

and impair

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 Memory is the faculty of the mind by which data or information is encoded, stored, and retrieved when needed. It is the retention of information over time for the purpose of influencing future action. If past events could not be remembe ...

balance Balance may refer to: Common meanings * Balance (ability) in biomechanics * Balance (accounting) * Balance or weighing scale * Balance, as in equality (mathematics) or equilibrium Arts and entertainment Film * Balance (1983 film), ''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

and

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 Back pain (Latin: ''dorsalgia'') is pain felt in the back. It may be classified as neck pain (cervical), middle back pain (thoracic), lower back pain (lumbar) or coccydynia (tailbone or sacral pain) based on the segment affected. The lumbar area ...

, dizziness, falls, headache,

car accident A traffic collision, also known as a motor vehicle collision, or car crash, occurs when a vehicle collides with another vehicle, pedestrian, animal, road debris, or other moving or stationary obstruction, such as a tree, pole or building. T ...

traffic violation A moving violation or traffic violation is any violation of the law committed by the driver of a vehicle while it is in motion. The term "moving" distinguishes it from other motor vehicle violations, such as paperwork violations (which include ...

s, nasopharyngitis,

nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. It can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the throat. Over 30 d ...

, 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). Tolerance, dependence, 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 Medication discontinuation is the ceasing of a medication treatment for a patient by either the clinician or the patient themself. When initiated by the clinician, it is known as deprescribing. Medication discontinuation is an important medical ...

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 Orexin (), also known as hypocretin, is a neuropeptide that regulates arousal, wakefulness, and appetite. It exists in the forms of orexin-A and orexin-B. The most common form of narcolepsy, type 1, in which the individual experiences brief loss ...

neuropeptide Neuropeptides are chemical messengers made up of small chains of amino acids that are synthesized and released by neurons. Neuropeptides typically bind to G protein-coupled receptors (GPCRs) to modulate neural activity and other tissues like the ...

s augment the signaling of the mesolimbic

dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. It is an amine synthesized ...

reward pathway The mesolimbic pathway, sometimes referred to as the reward pathway, is a dopaminergic pathway in the brain. The pathway connects the ventral tegmental area in the midbrain to the ventral striatum of the basal ganglia in the forebrain. The ventral ...

and are thought to potentiate

hedonic Hedonism is a family of philosophical views that prioritize pleasure. Psychological hedonism is the theory that all human behavior is motivated by the desire to maximize pleasure and minimize pain. As a form of egoism, it suggests that people ...

tone. Conversely, low orexin signaling may result in low hedonic tone and orexin receptor antagonists are of interest for the potential treatment of

addiction Addiction is a neuropsychological disorder characterized by a persistent and intense urge to use a drug or engage in a behavior that produces natural reward, despite substantial harm and other negative consequences. Repetitive drug use can ...

. In line with these findings, suvorexant and other orexin receptor antagonists have not shown misuse liability in

animal studies Animal studies is a recently recognised field in which animals are studied in a variety of cross-disciplinary ways. Scholars who engage in animal studies may be formally trained in a number of diverse fields, including art history, anthropology ...

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 A sedative or tranquilliser is a substance that induces sedation by reducing irritability or Psychomotor agitation, excitement. They are central nervous system (CNS) Depressant, depressants and interact with brain activity, causing its decelera ...

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 Zolpidem, sold under the brand name Ambien among others, is a medication primarily used for the short-term treatment of sleeping problems. Guidelines recommend that it be used only after cognitive behavioral therapy for insomnia and after beh ...

(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 The dose–response relationship, or exposure–response relationship, describes the magnitude of the Stimulus–response model, response of an organism, as a Function (mathematics), function of exposure (or Dose (biochemistry), doses) to a Sti ...

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 Cholesterol is the principal sterol of all higher animals, distributed in body Tissue (biology), tissues, especially the brain and spinal cord, and in Animal fat, animal fats and oils. Cholesterol is biosynthesis, biosynthesized by all anima ...

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

s (derived from

Greek Greek may refer to: Anything of, from, or related to Greece, a country in Southern Europe: *Greeks, an ethnic group *Greek language, a branch of the Indo-European language family **Proto-Greek language, the assumed last common ancestor of all kno ...

orexis ''Movement of Animals'' (or ''On the Motion of Animals''; Greek Περὶ ζῴων κινήσεως; Latin ''De Motu Animalium'') is one of Aristotle's major texts on biology. It sets out the general principles of animal locomotion In etho ...

" meaning "appetite") stimulate

appetite Appetite is the desire to eat food items, usually due to hunger. Appealing foods can stimulate appetite even when hunger is absent, although appetite can be greatly reduced by satiety. Appetite exists in all higher life-forms, and serves to reg ...

feeding behavior Feeding is the process by which organisms, typically animals, obtain food. Terminology often uses either the suffixes -vore, -vory, or -vorous from Latin ''vorare'', meaning "to devour", or -phage, -phagy, or -phagous from Greek φαγε ...

, and

weight gain Weight gain is an increase in body weight. This can involve an increase in muscle mass, fat deposits, excess fluids such as water or other factors. Weight gain can be a symptom of a serious medical condition. Description Weight gain occurs ...

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.

Overdose

There is limited experience with

overdose A drug overdose (overdose or OD) is the ingestion or application of a drug or other substance in quantities much greater than are recommended. Retrieved on September 20, 2014.

of suvorexant. Suvorexant has been assessed in single doses of as high as 240mg in clinical studies. The medication dose-dependently produces

. 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 Gastric lavage, also commonly called stomach pumping or gastric irrigation or gastric suction, is the process of cleaning out the contents of the stomach using a tube. Since its first recorded use in the early 19th century, it has become one of the ...

may be used where appropriate whereas the value of dialysis has not been determined. Because suvorexant has high

plasma protein binding Plasma protein binding refers to the degree to which medications attach to blood proteins within the blood plasma. A drug's efficacy may be affected by the degree to which it binds. The less bound a drug is, the more efficiently it can traverse o ...

hemodialysis Hemodialysis, American and British English spelling differences#ae and oe, also spelled haemodialysis, or simply ''"'dialysis'"'', is a process of filtering the blood of a person whose kidneys are not working normally. This type of Kidney dialys ...

is not expected to enhance elimination of suvorexant.

Interactions

s can increase exposure to suvorexant while CYP3A4 inducers can decrease exposure to suvorexant. Combination of suvorexant with the strong CYP3A4 inhibitor

ketoconazole Ketoconazole, sold under the brand name Nizoral, among others, is an antiandrogen, antifungal drug, antifungal, and antiglucocorticoid medication used to treat a number of fungal infections. Applied to the skin it is used for fungal skin inf ...

increased suvorexant overall exposure by 2.79-fold and peak levels by about 1.25-fold, combination with the moderate CYP3A4 inhibitor

diltiazem Diltiazem, sold under the brand name Cardizem among others, is a nondihydropyridine calcium channel blocker medication used to treat high blood pressure, angina, and certain heart arrhythmias. It may also be used in hyperthyroidism if beta b ...

increased suvorexant overall exposure by 2.05-fold and peak levels by about 1.25-fold, and combination with the strong CYP3A4 inducer

rifampin Rifampicin, also known as rifampin, is an ansamycin antibiotic used to treat several types of bacterial infections, including tuberculosis (TB), ''Mycobacterium avium'' complex, leprosy, and Legionnaires' disease. It is almost always used tog ...

decreased suvorexant overall exposure by 88% and peak levels by about 65%. The

of suvorexant (about 12hours for suvorexant alone) was increased to 19.4hours with ketoconazole and to 16.1hours with diltiazem while it was decreased to 7.7hours with rifampin. Concomitant use of suvorexant with strong CYP3A4 inhibitors is not recommended, while lower doses of suvorexant are recommended with moderate CYP3A4 inhibitors (5mg starting dose and 10mg maximum dose generally). The substantial decrease in suvorexant exposure with strong CYP3A4 inducers may result in loss of effectiveness. Suvorexant does not appear to have been assessed in combination with moderate CYP3A4 inducers (e.g.,

modafinil Modafinil, sold under the brand name Provigil among others, is a central nervous system (CNS) stimulant and wakefulness-promoting agent, eugeroic (wakefulness promoter) medication used primarily to treat narcolepsy, a sleep disorder characteri ...

). Examples of important CYP3A4 modulators which are expected to interact with suvorexant include the strong CYP3A4 inhibitors

boceprevir Boceprevir ( INN, trade name Victrelis) is a protease inhibitor used to treat hepatitis caused by hepatitis C virus (HCV) genotype 1. It binds to the HCV nonstructural protein 3 active site. It was initially developed by Schering-Plough, then ...

clarithromycin Clarithromycin, sold under the brand name Biaxin among others, is an antibiotic used to treat various bacterial infections. This includes strep throat, pneumonia, skin infections, '' H. pylori'' infection, and Lyme disease, among others. Clari ...

conivaptan Conivaptan, sold under the brand name Vaprisol, is a non-peptide inhibitor of the receptor for anti-diuretic hormone, also called vasopressin. It was approved in 2004 for hyponatremia (low blood sodium levels). Additionally, Conivaptan is used ...

, indinavir,

itraconazole Itraconazole, sometimes abbreviated ITZ, is an antifungal medication used to treat a number of fungal infections. This includes aspergillosis, blastomycosis, coccidioidomycosis, histoplasmosis, and paracoccidioidomycosis. It may be given ...

, lopinavir, nefazodone,

nelfinavir Nelfinavir, sold under the brand name Viracept, is an antiretroviral medication used in the treatment of HIV/AIDS. Nelfinavir belongs to the class of drugs known as protease inhibitor (pharmacology), protease inhibitors (PIs) and like other PIs ...

, posaconazole,

ritonavir Ritonavir, sold under the brand name Norvir, is an antiretroviral medication used along with other medications to treat HIV/AIDS. This combination treatment is known as highly active antiretroviral therapy (HAART). Ritonavir is a protease inhi ...

, saquinavir, telaprevir, and telithromycin (concomitant use not recommended); the moderate CYP3A4 inhibitors amprenavir, aprepitant, atazanavir,

ciprofloxacin Ciprofloxacin is a fluoroquinolone antibiotic used to treat a number of bacterial infections. This includes bone and joint infections, intra-abdominal infections, certain types of infectious diarrhea, respiratory tract infections, skin ...

, dronedarone,

erythromycin Erythromycin is an antibiotic used for the treatment of a number of bacterial infections. This includes respiratory tract infections, skin infections, chlamydia infections, pelvic inflammatory disease, and syphilis. It may also be used ...

fluconazole Fluconazole is an antifungal medication used for a number of fungal infections. These include candidiasis, blastomycosis, coccidioidomycosis, cryptococcosis, histoplasmosis, dermatophytosis, and tinea versicolor. It is also used to pr ...

fluvoxamine Fluvoxamine, sold under the brand name Luvox among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. It is primarily used to treat major depressive disorder and, perhaps more-especially, obsessive–compu ...

, fosamprenavir, grapefruit juice,

imatinib Imatinib, sold under the brand names Gleevec and Glivec (both marketed worldwide by Novartis) among others, is an oral targeted therapy medication used to treat cancer. Imatinib is a small molecule inhibitor targeting multiple tyrosine kinases ...

, and verapamil (lower doses of suvorexant recommended); and the strong CYP3A4 inducers apalutamide,

carbamazepine Carbamazepine, sold under the brand name Tegretol among others, is an anticonvulsant medication used in the treatment of epilepsy and neuropathic pain. It is used as an adjunctive treatment in schizophrenia along with other medications and as ...

, efavirenz, enzalutamide,

phenytoin Phenytoin (PHT), sold under the brand name Dilantin among others, is an anticonvulsant, anti-seizure medication. It is useful for the prevention of tonic-clonic seizures (also known as grand mal seizures) and focal seizures, but not absence se ...

, and St. John's wort (expected to decrease suvorexant effectiveness). Coadministration of suvorexant with other CNS depressants such as

alcohol Alcohol may refer to: Common uses * Alcohol (chemistry), a class of compounds * Ethanol, one of several alcohols, commonly known as alcohol in everyday life ** Alcohol (drug), intoxicant found in alcoholic beverages ** Alcoholic beverage, an alco ...

opioid Opioids are a class of Drug, drugs that derive from, or mimic, natural substances found in the Papaver somniferum, opium poppy plant. Opioids work on opioid receptors in the brain and other organs to produce a variety of morphine-like effects, ...

s, and

tricyclic antidepressant Tricyclic antidepressants (TCAs) are a class of medications that are used primarily as antidepressants. TCAs were discovered in the early 1950s and were marketed later in the decade. They are named after their chemical structure, which contains ...

s may increase the risk of CNS depression and daytime impairment. Alcohol and suvorexant do not appear to interact in terms of

pharmacokinetics Pharmacokinetics (from Ancient Greek ''pharmakon'' "drug" and ''kinetikos'' "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to describing how the body affects a specific su ...

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 Cytochromes P450 (P450s or CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that mostly, but not exclusively, function as monooxygenases. However, they are not omnipresent; for examp ...

enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...

s and drug transporters. It has been found to not substantially influence the pharmacokinetics of

midazolam Midazolam, sold under the brand name Versed among others, is a benzodiazepine medication used for anesthesia, premedication before surgical anesthesia, and procedural sedation, and to treat psychomotor agitation, severe agitation. It induces ...

(CYP3A4 substrate),

warfarin Warfarin, sold under the brand name Coumadin among others. It is used as an anticoagulant, anticoagulant medication. It is commonly used to prevent deep vein thrombosis and pulmonary embolism, and to protect against stroke in people who ha ...

(

CYP2C9 Cytochrome P450 family 2 subfamily C member 9 (abbreviated CYP2C9) is an enzyme protein. The enzyme is involved in the metabolism, by oxidation, of both xenobiotics, including drugs, and endogenous compounds, including fatty acids. In humans, t ...

substrate),

digoxin Digoxin (better known as digitalis), sold under the brand name Lanoxin among others, is a medication used to treat various heart disease, heart conditions. Most frequently it is used for atrial fibrillation, atrial flutter, and heart failure. ...

(

P-glycoprotein P-glycoprotein 1 (permeability glycoprotein, abbreviated as P-gp or Pgp) also known as multidrug resistance protein 1 (MDR1) or ATP-binding cassette sub-family B member 1 (ABCB1) or cluster of differentiation 243 (CD243) is an important protein ...

substrate), or combined birth control pills. However, coadministration of suvorexant with

may result in slightly increased digoxin exposure due to inhibition of intestinal

by suvorexant. Concentrations of digoxin should be monitored during coadministration of suvorexant and digoxin.

Pharmacology

Pharmacodynamics

Suvorexant acts as a selective dual

antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.orexin (hypocretin) receptors OX₁ and OX₂. These

receptor Receptor may refer to: * Sensory receptor, in physiology, any neurite structure that, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and respond ...

s are the

biological target A biological target is anything within a living organism to which some other entity (like an endogenous ligand or a drug) is directed and/or binds, resulting in a change in its behavior or function. Examples of common classes of biological targets ...

s of the

endogenous Endogeny, in biology, refers to the property of originating or developing from within an organism, tissue, or cell. For example, ''endogenous substances'', and ''endogenous processes'' are those that originate within a living system (e.g. an ...

wakefulness Wakefulness is a daily recurring brain state and state of consciousness in which an individual is conscious and engages in coherent cognition, cognitive and behavioral responses to the external world. Being awake is the opposite of being asleep, ...

-promoting

orexin-A Orexin-A, also known as hypocretin-1, is a naturally occurring neuropeptide and orexin isoform. The orexinergic nucleus in the lateral hypothalamus is the primary orexin projection system in the brain. Structure Orexin-A is a peptide composed of ...

and

orexin-B Orexin (), also known as hypocretin, is a neuropeptide that regulates arousal, wakefulness, and appetite. It exists in the forms of orexin-A and orexin-B. The most common form of narcolepsy, type 1, in which the individual experiences brief losses ...

. The binding affinities (K_i) of suvorexant at the human orexin receptors are 0.55nM for the OX₁ receptor and 0.35nM for the OX₂ receptor. The antagonistic potencies or functional inhibition (K_b) of suvorexant at the human orexin receptors are 65nM for the OX₁ receptor and 41nM for the OX₂ receptor. Hence, suvorexant shows similar affinities and antagonistic activities at the OX₁ and OX₂ receptors ''

in vitro ''In vitro'' (meaning ''in glass'', or ''in the glass'') Research, studies are performed with Cell (biology), cells or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in ...

''. Suvorexant is highly selective for the orexin receptors over a large number of other targets (170 screened off-target

s, and transporters). In contrast to certain other sedatives and hypnotics, suvorexant is not a

or Z-drug and does not interact with GABA receptors.

Mechanism of action

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. The orexin neuropeptides are produced exclusively by a relatively small population of 20,000 to 80,000

neuron A neuron (American English), neurone (British English), or nerve cell, is an membrane potential#Cell excitability, excitable cell (biology), cell that fires electric signals called action potentials across a neural network (biology), neural net ...

s located in the

lateral hypothalamus The lateral hypothalamus (LH), also called the lateral hypothalamic area (LHA), contains the primary orexinergic nucleus within the hypothalamus that widely projects throughout the nervous system; this system of neurons mediates an array of cogni ...

in the

brain The brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It consists of nervous tissue and is typically located in the head (cephalization), usually near organs for ...

. These neurons project widely throughout the brain and mediate

excitatory In neuroscience, an excitatory postsynaptic potential (EPSP) is a postsynaptic potential that makes the postsynaptic neuron more likely to fire an action potential. This temporary depolarization of postsynaptic membrane potential, caused by the ...

signaling to key centers involved in sleep–wake regulation, including the noradrenergic

locus coeruleus The locus coeruleus () (LC), also spelled locus caeruleus or locus ceruleus, is a nucleus in the pons of the brainstem involved with physiological responses to stress and panic. It is a part of the reticular activating system in the reticular ...

, histaminergic tuberomammillary nucleus, serotonergic raphe nucleus, and

dopaminergic Dopaminergic means "related to dopamine" (literally, "working on dopamine"), a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain. Dopaminergic pathways, Dopaminergic brain pathways facil ...

ventral tegmental area The ventral tegmental area (VTA) (tegmentum is Latin for ''covering''), also known as the ventral tegmental area of Tsai, or simply ventral tegmentum, is a group of neurons located close to the midline on the floor of the midbrain. The VTA is th ...

. The orexin system shows

circadian rhythm A circadian rhythm (), or circadian cycle, is a natural oscillation that repeats roughly every 24 hours. Circadian rhythms can refer to any process that originates within an organism (i.e., Endogeny (biology), endogenous) and responds to the env ...

icity in its activity, with high activity during waking and low to no activity during sleep or at night. Orexin system activity during wakefulness is also higher with behavioral activation and with high-intensity emotions.

Narcolepsy Narcolepsy is a chronic neurological disorder that impairs the ability to regulate sleep–wake cycles, and specifically impacts REM (rapid eye movement) sleep. The symptoms of narcolepsy include excessive daytime sleepiness (EDS), sleep-r ...

is a chronic

sleep disorder A sleep disorder, or somnipathy, is a medical disorder affecting an individual's sleep patterns, sometimes impacting physical, mental, social, and emotional functioning. Polysomnography and actigraphy are tests commonly ordered for diagnosing sle ...

characterized by excessive daytime sleepiness, cataplexy,

, and hypnagogic hallucinations, as well as sleep attacks 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 In immunology, autoimmunity is the system of immune responses of an organism against its own healthy cells, tissues and other normal body constituents. Any disease resulting from this type of immune response is termed an " autoimmune disease" ...

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 Cerebrospinal fluid (CSF) is a clear, colorless Extracellular fluid#Transcellular fluid, transcellular body fluid found within the meninges, meningeal tissue that surrounds the vertebrate brain and spinal cord, and in the ventricular system, ven ...

in people with narcolepsy. Similarly, narcolepsy with cataplexy in dogs is caused by a

mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, ...

in the

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

encoding the OX₂ receptor, and

knockout mice A knockout mouse, or knock-out mouse, is a genetically modified mouse (''Mus musculus'') in which researchers have inactivated, or " knocked out", an existing gene by replacing it or disrupting it with an artificial piece of DNA. They are importan ...

for genes encoding orexin system proteins such as prepro-orexin or the OX₂ receptor show a narcolepsy-like

phenotype In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology (physical form and structure), its developmental processes, its biochemical and physiological propert ...

. 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 Etiology (; alternatively spelled aetiology or ætiology) is the study of causation or origination. The word is derived from the Greek word ''()'', meaning "giving a reason for" (). More completely, etiology is the study of the causes, origins ...

of insomnia. In addition, orexin signaling appears to change with age, and this may be involved in

age Age or AGE may refer to: Time and its effects * Age, the amount of time someone has been alive or something has existed ** East Asian age reckoning, an Asian system of marking age starting at 1 * Ageing or aging, the process of becoming older ...

-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. 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

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 Orexin (), also known as hypocretin, is a neuropeptide that regulates arousal, wakefulness, and appetite. It exists in the forms of orexin-A and orexin-B. The most common form of narcolepsy, type 1, in which the individual experiences brief loss ...

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.

Pharmacokinetics

Absorption

The

absolute bioavailability In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation. By definition, when a medication is administered intravenously, its bioavailability is 100%. H ...

of suvorexant is 82% at a dose of 10mg. Suvorexant exposure does not increase dose-proportionally over a dose range of 10 to 100mg, which is likely due to decreased absorption at higher doses. Exposure to suvorexant increases by about 75% with a doubling of dose from 20mg to 40mg. The time to peak levels of suvorexant is 2 to 3hours regardless of dose but with wide variation (range 30minutes to 8hours). 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 1.5hours. Steady-state levels of suvorexant with once-daily continuous administration are reached within 3days. Levels of suvorexant accumulate minimally, by about 1.2- to 1.6-fold, with repeated once-daily administration.

Distribution

The

volume of distribution In pharmacology, the volume of distribution (VD, also known as apparent volume of distribution, literally, ''volume of dilution'') is the theoretical volume that would be necessary to contain the total amount of an administered drug at the same c ...

of suvorexant is approximately 49L. It crosses the

blood–brain barrier The blood–brain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that regulates the transfer of solutes and chemicals between the circulatory system and the central nervous system ...

and distributes into the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...

. Suvorexant has high

(99.5%). It is bound to

albumin Albumin is a family of globular proteins, the most common of which are the serum albumins. All of the proteins of the albumin family are water- soluble, moderately soluble in concentrated salt solutions, and experience heat denaturation. Alb ...

and α₁-acid glycoprotein (orosomucoid).

Metabolism

Suvorexant is metabolized primarily by

hydroxylation In chemistry, hydroxylation refers to the installation of a hydroxyl group () into an organic compound. Hydroxylations generate alcohols and phenols, which are very common functional groups. Hydroxylation confers some degree of water-solubility ...

via

CYP3A Cytochrome P450, family 3, subfamily A, also known as CYP3A, is a human gene locus. A homologous locus is found in mice. These genes encode monooxygenases which catalyze many reactions involved in the synthesis of cholesterol, steroids and other ...

s. CYP2C19 also contributes to suvorexant metabolism to a minor extent. The major circulating forms are suvorexant and its

metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...

hydroxysuvorexant. The hydroxysuvorexant (M9) metabolite is not expected to be pharmacologically active. It showed 10-fold lower

affinity Affinity may refer to: Commerce, finance and law * Affinity (law), kinship by marriage * Affinity analysis, a market research and business management technique * Affinity Credit Union, a Saskatchewan-based credit union * Affinity Equity Pa ...

for the orexin receptors than suvorexant ''

'', was a substrate for

making it unlikely to cross the

, and did not show sedative effects in animal studies. Suvorexant also has several other minor metabolites.

Elimination

Suvorexant is eliminated mainly via metabolism. It is excreted primarily in

feces Feces (also known as faeces American and British English spelling differences#ae and oe, or fæces; : faex) are the solid or semi-solid remains of food that was not digested in the small intestine, and has been broken down by bacteria in the ...

(66%) predominantly as metabolites and to a lesser extent in

urine Urine is a liquid by-product of metabolism in humans and many other animals. In placental mammals, urine flows from the Kidney (vertebrates), kidneys through the ureters to the urinary bladder and exits the urethra through the penile meatus (mal ...

(23%). The

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.

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 Body mass index (BMI) is a value derived from the mass (Mass versus weight, weight) and height of a person. The BMI is defined as the human body weight, body mass divided by the square (algebra), square of the human height, body height, and is ...

, 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 at a dose of 20mg was prolonged from 14.7hours (range 10–22hours) to 19.1hours (range 11–49hours) in these individuals. Suvorexant exposure is unchanged in people with severe renal impairment and no dosage adjustment is necessary in these individuals. Similarly to hepatic impairment, the half-life of suvorexant was increased to 19.4hours when used in combination with the strong CYP3A4 inhibitor

and to 16.1hours with the moderate CYP3A4 inhibitor

while it was decreased to 7.7hours with the strong CYP3A4 inducer

Miscellaneous

Peak-normalized concentrations of orexin receptor antagonists with administration in humans

The delayed time to peak levels (2–3hours) and long elimination half-life (12hours) 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. Orexin receptor antagonists with shorter half-lives and faster onsets of action are theoretically more optimal for therapeutic use as sleep aids. The ideal insomnia medication would not have a

duration of action Pharmacodynamics (PD) is the study of the biochemical and physiologic effects of drugs (especially pharmaceutical drugs). The effects can include those manifested within animals (including humans), microorganisms, or combinations of organisms (fo ...

extending beyond about 8hours. Relative to suvorexant, daridorexant has a shorter half-life (8hours) while lemborexant has a longer half-life (17–55hours). 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. The investigational agents seltorexant and vornorexant, which are still in clinical trials, have comparatively very short half-lives in the range of 1.5 to 3hours. 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 7''R'')-4-(5-chloro-2-benzoxazolyl)hexahydro-7-methyl-1''H''-1,4-diazepin-1-yl5-methyl-2-(2''H''-1,2,3-triazol-2-yl)phenyl]methanone. Its

molecular formula A chemical formula is a way of presenting information about the chemical proportions of atoms that constitute a particular chemical compound or molecule, using chemical element symbols, numbers, and sometimes also other symbols, such as paren ...

is C₂₃H₂₃N₆O₂Cl and its

molecular weight A molecule is a group of two or more atoms that are held together by Force, attractive forces known as chemical bonds; depending on context, the term may or may not include ions that satisfy this criterion. In quantum physics, organic chemi ...

is 450.92g/mol. Suvorexant is a white to off-white powder and is

lipophilic Lipophilicity (from Greek language, Greek λίπος "fat" and :wikt:φίλος, φίλος "friendly") is the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents such as hexane or toluene. Such compounds are c ...

and insoluble in water. It is structurally related to other orexin receptor antagonists like lemborexant, daridorexant, and seltorexant.

History

The

s were discovered in 1998 and the role of the orexin system in the

was identified between 1999 and 2000. Subsequent research further established the role of the orexin system in sleep–wake regulation. Due to the promising potential of orexin system modulation in the treatment of

s, these findings led to translational efforts to bring orexin receptor modulators to medicine as therapeutic agents. Suvorexant was developed by Merck. It entered

clinical development Drug development is the process of bringing a new pharmaceutical drug to the market once a lead compound has been identified through the process of drug discovery. It includes preclinical research on microorganisms and animals, filing for regul ...

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 Japan is an island country in East Asia. Located in the Pacific Ocean off the northeast coast of the Asia, Asian mainland, it is bordered on the west by the Sea of Japan and extends from the Sea of Okhotsk in the north to the East China Sea ...

, then later reached the United States in February 2015,

Australia Australia, officially the Commonwealth of Australia, is a country comprising mainland Australia, the mainland of the Australia (continent), Australian continent, the island of Tasmania and list of islands of Australia, numerous smaller isl ...

in November 2016, and

Canada Canada is a country in North America. Its Provinces and territories of Canada, ten provinces and three territories extend from the Atlantic Ocean to the Pacific Ocean and northward into the Arctic Ocean, making it the world's List of coun ...

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.

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 The Controlled Substances Act (CSA) is the statute establishing federal government of the United States, federal drug policy of the United States, U.S. drug policy under which the manufacture, importation, possession, use, and distribution of ...

in the United States. 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 Public Citizen is an American non-profit, Progressivism in the United States, progressive consumer rights advocacy group, and think tank based in Washington, D.C. It was founded in 1971 by the American activist and lawyer Ralph Nader. Lobbying e ...

, a progressive

consumer rights Consumer protection is the practice of safeguarding buyers of goods and services, and the public, against unfair practices in the marketplace. Consumer protection measures are often established by law. Such laws are intended to prevent businesse ...

advocacy group Advocacy groups, also known as lobby groups, interest groups, special interest groups, pressure groups, or public associations, use various forms of advocacy or lobbying to influence public opinion and ultimately public policy. They play an impor ...

, 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. ''

Consumer Reports Consumer Reports (CR), formerly Consumers Union (CU), is an American nonprofit consumer organization dedicated to independent product testing, investigative journalism, consumer-oriented research, public education, and consumer advocacy. Founded ...

'' also published articles encouraging consumers to avoid suvorexant due to it being expensive, having limited effectiveness, and posing safety concerns.

Research

Delirium

Suvorexant is under development for the treatment of

delirium Delirium (formerly acute confusional state, an ambiguous term that is now discouraged) is a specific state of acute confusion attributable to the direct physiological consequence of a medical condition, effects of a psychoactive substance, or ...

. As of October 2021, it is in phase III

s for this indication.

Psychiatry

Suvorexant has been studied in the treatment of insomnia in people with

psychiatric disorder A mental disorder, also referred to as a mental illness, a mental health condition, or a psychiatric disability, is a behavioral or mental pattern that causes significant distress or impairment of personal functioning. A mental disorder is ...

s such as depression and

anxiety Anxiety is an emotion characterised by an unpleasant state of inner wikt:turmoil, turmoil and includes feelings of dread over Anticipation, anticipated events. Anxiety is different from fear in that fear is defined as the emotional response ...

. It was reported to improve psychiatric symptoms and to decrease

cortisol Cortisol is a steroid hormone in the glucocorticoid class of hormones and a stress hormone. When used as medication, it is known as hydrocortisone. Cortisol is produced in many animals, mainly by the ''zona fasciculata'' of the adrenal corte ...

levels in these individuals. A phase IV

of suvorexant as an adjunct to

therapy in people with

major depressive disorder Major depressive disorder (MDD), also known as clinical depression, is a mental disorder characterized by at least two weeks of pervasive depression (mood), low mood, low self-esteem, and anhedonia, loss of interest or pleasure in normally ...

and residual insomnia was underway as of 2019. 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.,

and suicidal ideation in clinical trials). More clinical research is needed to determine the place of orexin receptor antagonists in the treatment of people with depression and anxiety. There is interest in suvorexant and other orexin receptor antagonists in the potential treatment of

substance use disorder Substance use disorder (SUD) is the persistent use of drugs despite substantial harm and adverse consequences to self and others. Related terms include ''substance use problems'' and ''problematic drug or alcohol use''. Along with substance-ind ...

s, including

alcohol use disorder Alcoholism is the continued drinking of alcohol despite it causing problems. Some definitions require evidence of dependence and withdrawal. Problematic use of alcohol has been mentioned in the earliest historical records. The World Hea ...

, cocaine use disorder, and

opioid use disorder Opioid use disorder (OUD) is a substance use disorder characterized by cravings for opioids, continued use despite physical and/or psychological deterioration, increased tolerance with use, and withdrawal symptoms after discontinuing opioids. ...

Alzheimer's disease

Suvorexant and other orexin receptor modulators are of interest for possible use in the prevention of

Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...

Diabetes

Suvorexant has been studied in people with

type 2 diabetes Type 2 diabetes (T2D), formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent ...

and insomnia and has been reported to improve sleep and

metabolic Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the ...

parameters in these individuals. The improvement in metabolic parameters appeared to be related to improved sleep.

References

External links

* {{Authority control Benzoxazoles Chloroarenes Diazepanes Hypnotics Drugs developed by Merck & Co. Orexin antagonists Sedatives Triazoles