Suvorexant, sold under the brand name Belsomra, is an
orexin antagonist An orexin receptor antagonist, or orexin antagonist, is a drug that inhibits the effect of orexin by acting as a receptor antagonist of one or both of the orexin receptors, Hypocretin (orexin) receptor 1, OX1 and Hypocretin (orexin) receptor 2, OX2. ...
medication which is used in the treatment of
insomnia
Insomnia, also known as sleeplessness, is a sleep disorder in which people have trouble sleeping. They may have difficulty falling asleep, or staying asleep as long as desired. Insomnia is typically followed by daytime sleepiness, low energy, ...
.
It is indicated specifically for the treatment of insomnia characterized by difficulties with
sleep onset
Sleep onset is the transition from wakefulness into sleep. Sleep onset usually transmits into non-rapid eye movement sleep (NREM sleep) but under certain circumstances (e.g. narcolepsy) it is possible to transit from wakefulness directly into rapid ...
and/or
maintenance
Maintenance may refer to:
Biological science
* Maintenance of an organism
* Maintenance respiration
Non-technical maintenance
* Alimony, also called ''maintenance'' in British English
* Champerty and maintenance, two related legal doctrine ...
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), sometimes called "benzos", are a class of depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed to treat conditions such as anxiety disorders, ...
s and
Z-drug
Nonbenzodiazepines (), sometimes referred to colloquially as Z-drugs (as many of their names begin with the letter "z"), are a class of psychoactive drugs that are very benzodiazepine-like in nature. They are used in the treatment of sleep problem ...
s.
Suvorexant is taken
by mouth
Oral administration is a route of administration where a substance is taken through the mouth. Per os abbreviated to P.O. is sometimes used as a direction for medication to be taken orally. Many medications are taken orally because they are i ...
.
Side effect
In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequence ...
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 asleep ...
,
daytime sleepiness and sedation,
headache
Headache 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 in those with severe headaches.
Headaches can occur as a result ...
,
dizziness
Dizziness is an imprecise term that can refer to a sense of disorientation in space, vertigo, or lightheadedness. It can also refer to disequilibrium or a non-specific feeling, such as giddiness or foolishness.
Dizziness is a common medical c ...
,
abnormal dream
A dream is a succession of images, ideas, emotions, and sensation (psychology), sensations that usually occur involuntarily in the mind during certain stages of sleep. Humans spend about two hours dreaming per night, and each dream lasts around ...
s,
dry mouth
Xerostomia, also known as dry mouth, is dryness in the mouth, which may be associated with a change in the composition of saliva, or reduced salivary flow, or have no identifiable cause.
This symptom is very common and is often seen as a side eff ...
, and impaired next-day
driving
Driving is the controlled operation and movement of a vehicle, including cars, motorcycles, trucks, buses, and bicycles. Permission to drive on public highways is granted based on a set of conditions being met and drivers are required to fol ...
ability.
Rarely,
sleep paralysis
Sleep paralysis is a state, during waking up or falling asleep, in which one is conscious but is completely paralyzed. During an episode, one may hallucinate (hear, feel, or see things that are not there), which often results in fear. Episodes ...
, sleep-related
hallucination
A hallucination is a perception in the absence of an external stimulus that has the qualities of a real perception. Hallucinations are vivid, substantial, and are perceived to be located in external objective space. Hallucination is a combinatio ...
s,
complex sleep behavior
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 slow wave stage of sleep, in a state of low ...
s 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 slow wave stage of sleep, in a state of low ...
, and
suicidal ideation
Suicidal ideation, or suicidal thoughts, means having thoughts, ideas, or ruminations about the possibility of ending one's own life.World Health Organization, ''ICD-11 for Mortality and Morbidity Statistics'', ver. 09/2020MB26.A Suicidal ideatio ...
may occur.
Tolerance
Tolerance or toleration is the state of tolerating, or putting up with, conditionally.
Economics, business, and politics
* Toleration Party, a historic political party active in Connecticut
* Tolerant Systems, the former name of Veritas Software ...
,
dependence,
withdrawal
Withdrawal means "an act of taking out" and may refer to:
* Anchoresis (withdrawal from the world for religious or ethical reasons)
* ''Coitus interruptus'' (the withdrawal method)
* Drug withdrawal
* Social withdrawal
* Taking of money from a ban ...
, and
rebound effect
The rebound effect, or rebound phenomenon, is the emergence or re-emergence of symptoms that were either absent or controlled while taking a medication, but appear when that same medication is discontinued, or reduced in dosage. In the case of re ...
s do not appear to occur significantly with the medication.
Suvorexant is a
dual orexin receptor antagonist An orexin receptor antagonist, or orexin antagonist, is a drug that inhibits the effect of orexin by acting as a receptor antagonist of one or both of the orexin receptors, OX1 and OX2. Medical applications include treatment of sleep disorders su ...
(DORA).
It acts as a
selective dual
antagonist
An antagonist is a character in a story who is presented as the chief foe of the protagonist.
Etymology
The English word antagonist comes from the Greek ἀνταγωνιστής – ''antagonistēs'', "opponent, competitor, villain, enemy, riv ...
of the
orexin
Orexin (), also known as hypocretin, is a neuropeptide that regulates arousal, wakefulness, and appetite. The most common form of narcolepsy, type 1, in which the individual experiences brief losses of muscle tone ("drop attacks" or cataplexy), ...
OX1 and
OX2 receptors.
The medication has an intermediate
elimination half-life
Biological half-life (also known as elimination half-life, pharmacologic 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 bl ...
of 12hours and a
time to peak of about 2 to 3hours.
Unlike benzodiazepines and Z-drugs, suvorexant does not interact with
GABA receptor
The GABA receptors are a class of receptors that respond to the neurotransmitter gamma-aminobutyric acid (GABA), the chief inhibitory compound in the mature vertebrate central nervous system. There are two classes of GABA receptors: GABAA and ...
s, instead having a distinct
mechanism of action
In pharmacology, the term mechanism of action (MOA) refers to the specific biochemical interaction through which a drug substance produces its pharmacological effect. A mechanism of action usually includes mention of the specific molecular targe ...
.
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 regu ...
of suvorexant began in 2006
and it was introduced for medical use in 2014.
The medication is a
schedule IV controlled substance
A controlled substance is generally a drug or chemical whose manufacture, possession and use is regulated by a government, such as illicitly used drugs or prescription medications that are designated by law. Some treaties, notably the Single C ...
in the United States and may have a modest
potential for misuse
Substance abuse, also known as drug abuse, is the use of a drug in amounts or by methods which are harmful to the individual or others. It is a form of substance-related disorder. Differing definitions of drug abuse are used in public health, ...
.
Similarly, suvorexant is a controlled substance in
Australia
Australia, officially the Commonwealth of Australia, is a Sovereign state, sovereign country comprising the mainland of the Australia (continent), Australian continent, the island of Tasmania, and numerous List of islands of Australia, sma ...
being a prescription only
Schedule 4 drug.
Suvorexant is not available in
generic formulations.
Besides suvorexant, other orexin receptor antagonists like
lemborexant
Lemborexant, sold under the brand name Dayvigo, is an orexin antagonist medication which is used in the treatment of insomnia. It is indicated specifically for the treatment of insomnia characterized by difficulties with sleep onset and/or maint ...
and
daridorexant
Daridorexant, sold under the brand name Quviviq, is an orexin antagonist medication which is used for the treatment of insomnia. Daridorexant is taken by mouth.
Side effects of daridorexant include headache, somnolence, and fatigue. The med ...
have also been introduced.
Medical uses
Suvorexant is used for the treatment of
insomnia
Insomnia, also known as sleeplessness, is a sleep disorder in which people have trouble sleeping. They may have difficulty falling asleep, or staying asleep as long as desired. Insomnia is typically followed by daytime sleepiness, low energy, ...
, characterized by difficulties with
sleep onset
Sleep onset is the transition from wakefulness into sleep. Sleep onset usually transmits into non-rapid eye movement sleep (NREM sleep) but under certain circumstances (e.g. narcolepsy) it is possible to transit from wakefulness directly into rapid ...
and/or sleep maintenance, in adults.
At a dose of 15 to 20mg and in terms of treatment–
placebo
A placebo ( ) is a substance or treatment which is designed to have no therapeutic value. Common placebos include inert tablets (like sugar pills), inert injections (like Saline (medicine), saline), sham surgery, and other procedures.
In general ...
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
Sleep is a sedentary state of mind and body. It is characterized by altered consciousness, relatively inhibited Perception, sensory activity, reduced muscle activity and reduced interactions with surroundings. It is distinguished from wakefuln ...
by about 10 to 20minutes.
A 2017
systematic review
A systematic review is a Literature review, 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 publ ...
and
meta-analysis
A meta-analysis is a statistical analysis that combines the results of multiple scientific studies. Meta-analyses can be performed when there are multiple scientific studies addressing the same question, with each individual study reporting me ...
of
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 te ...
s of suvorexant for insomnia likewise found that the medication improved subjective sleep onset, subjective total sleep time, and subjective
sleep quality
Sleep is a sedentary state of mind and body. It is characterized by altered consciousness, relatively inhibited Perception, sensory activity, reduced muscle activity and reduced interactions with surroundings. It is distinguished from wakefuln ...
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
Lemborexant, sold under the brand name Dayvigo, is an orexin antagonist medication which is used in the treatment of insomnia. It is indicated specifically for the treatment of insomnia characterized by difficulties with sleep onset and/or maint ...
and
daridorexant
Daridorexant, sold under the brand name Quviviq, is an orexin antagonist medication which is used for the treatment of insomnia. Daridorexant is taken by mouth.
Side effects of daridorexant include headache, somnolence, and fatigue. The med ...
as well as to other sleep aids including
benzodiazepine
Benzodiazepines (BZD, BDZ, BZs), sometimes called "benzos", are a class of depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed to treat conditions such as anxiety disorders, ...
s,
Z-drug
Nonbenzodiazepines (), sometimes referred to colloquially as Z-drugs (as many of their names begin with the letter "z"), are a class of psychoactive drugs that are very benzodiazepine-like in nature. They are used in the treatment of sleep problem ...
s,
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 re ...
s, sedative
antidepressant
Antidepressants are a class of medication used to treat major depressive disorder, anxiety disorders, chronic pain conditions, and to help manage addictions. Common side-effects of antidepressants include dry mouth, weight gain, dizziness, hea ...
s (e.g.,
trazodone
Trazodone, sold under many brand names, is an antidepressant medication. It is used to treat major depressive disorder, anxiety disorders, and difficulties with sleep. The medication is taken orally.
Common side-effects include dry mouth, fe ...
,
doxepin
Doxepin is a medication falling in the tricyclic antidepressant (TCA) class used to treat major depressive disorder, anxiety disorders, chronic hives, and insomnia. For label updates seFDA index page for NDA 022036/ref> For hives it is a less pre ...
,
amitriptyline
Amitriptyline, sold under the brand name Elavil among others, is a tricyclic antidepressant primarily used to treat cyclic vomiting syndrome (CVS), major depressive disorder and a variety of pain syndromes from neuropathic pain to fibromyalgi ...
,
mirtazapine
Mirtazapine, sold under the brand name Remeron amongst others, is an atypical antidepressant, and as such is used primarily to treat depression. Its effects may take up to four weeks, but can also manifest as early as one to two weeks. It is o ...
), and
melatonin receptor agonist
Melatonin receptor agonists are analogues of melatonin that bind to and activate the melatonin receptor. Agonists of the melatonin receptor have a number of therapeutic applications including treatment of sleep disorders and depression. The disco ...
s.
A major
systematic review
A systematic review is a Literature review, 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 publ ...
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
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 ...
(SMD)) against
placebo
A placebo ( ) is a substance or treatment which is designed to have no therapeutic value. Common placebos include inert tablets (like sugar pills), inert injections (like Saline (medicine), saline), sham surgery, and other procedures.
In general ...
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
Doxepin is a medication falling in the tricyclic antidepressant (TCA) class used to treat major depressive disorder, anxiety disorders, chronic hives, and insomnia. For label updates seFDA index page for NDA 022036/ref> For hives it is a less pre ...
,
doxylamine
Doxylamine, sold under the brand name Unisom among others, is an antihistamine medication which is used in the treatment of insomnia and allergies. In combination with pyridoxine ( vitamin B6), it is also used to treat morning sickness in pregna ...
,
trimipramine
Trimipramine, sold under the brand name Surmontil among others, is a tricyclic antidepressant (TCA) which is used to treat depression. It has also been used for its sedative, anxiolytic, and weak antipsychotic effects in the treatment of insomn ...
) 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 and birds, characterized by random rapid movement of the eyes, accompanied by low muscle tone throughout the body, and the propensity of the sleeper to dream viv ...
(REM) sleep, whereas they have no effect on or even decrease
non-rapid eye movement
Non-rapid eye movement sleep (NREM), also known as quiescent sleep, is, collectively, sleep stages 1–3, previously known as stages 1–4. Rapid eye movement sleep (REM) is not included. There are distinct electroencephalographic and other char ...
(NREM) sleep.
This is in contrast to most other
hypnotic
Hypnotic (from Greek ''Hypnos'', sleep), or soporific drugs, commonly known as sleeping pills, are a class of (and umbrella term for) psychoactive drugs whose primary function is to induce sleep (or surgical anesthesiaWhen used in anesthesia ...
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
benzodiazepine
Benzodiazepines (BZD, BDZ, BZs), sometimes called "benzos", are a class of depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed to treat conditions such as anxiety disorders, ...
s and
Z-drug
Nonbenzodiazepines (), sometimes referred to colloquially as Z-drugs (as many of their names begin with the letter "z"), are a class of psychoactive drugs that are very benzodiazepine-like in nature. They are used in the treatment of sleep problem ...
s, orexin receptor antagonists do not disrupt
sleep architecture
Sleep is a sedentary state of mind and body. It is characterized by altered consciousness, relatively inhibited sensory activity, reduced muscle activity and reduced interactions with surroundings. It is distinguished from wakefulness by a d ...
, and this might provide more restful sleep.
It is unclear if suvorexant is safe among people with a history of
substance addiction
Addiction is a neuropsychological disorder characterized by a persistent and intense urge to engage in certain behaviors, one of which is the usage of a drug, despite substantial harm and other negative consequences. Repetitive drug use o ...
or
alcoholism
Alcoholism is, broadly, any drinking of alcohol (drug), alcohol that results in significant Mental health, mental or physical health problems. Because there is disagreement on the definition of the word ''alcoholism'', it is not a recognize ...
, as these individuals were excluded from
clinical trial
Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, dietar ...
s of suvorexant.
A
Cochrane review
Cochrane (previously known as the Cochrane Collaboration) is a British international charitable organisation formed to organise medical research findings to facilitate evidence-based choices about health interventions involving health professi ...
found suvorexant to be effective in the short-term treatment of sleep disturbances in people with
dementia
Dementia is a disorder which manifests as a set of related symptoms, which usually surfaces when the brain is damaged by injury or disease. The symptoms involve progressive impairments in memory, thinking, and behavior, which negatively affe ...
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 respon ...
(FDA) at doses of 5 to 20mg and by the Australian
Therapeutic Goods Administration
The Therapeutic Goods Administration (TGA) is the medicine and therapeutic regulatory agency of the Australian Government. As part of the Department of Health and Aged Care, the TGA regulates the quality, supply and advertising of medicines, pa ...
(TGA) and Japanese
Pharmaceuticals and Medical Devices Agency
The (PhMDA) is an Independent Administrative Institution responsible for ensuring the safety, efficacy and quality of pharmaceuticals and medical devices in Japan. It is similar in function to the Food and Drug Administration in the United State ...
(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
Driving is the controlled operation and movement of a vehicle, including cars, motorcycles, trucks, buses, and bicycles. Permission to drive on public highways is granted based on a set of conditions being met and drivers are required to fol ...
).
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 include t ...
's 2017
clinical practice guideline
Clinical may refer to: Healthcare
* Of or about a clinic, a healthcare facility
* Of or about the practice of medicine Other uses
* ''Clinical'' (film), a 2017 American horror thriller
See also
*
*
* Clinical chemistry, the analysis of bodily flu ...
s 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 treatment
A therapy or medical treatment (often abbreviated tx, Tx, or Tx) is the attempted remediation of a health problem, usually following a medical diagnosis.
As a rule, each therapy has indications and contraindications. There are many different ...
s for insomnia due to their costs and concerns about possible
misuse liability
Substance abuse, also known as drug abuse, is the use of a drug in amounts or by methods which are harmful to the individual or others. It is a form of substance-related disorder. Differing definitions of drug abuse are used in public health, ...
.
Generic
Generic or generics may refer to:
In business
* Generic term, a common name used for a range or class of similar things not protected by trademark
* Generic brand, a brand for a product that does not have an associated brand or trademark, other ...
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 oral ...
film-coated tablet
Tablet may refer to:
Medicine
* Tablet (pharmacy), a mixture of pharmacological substances pressed into a small cake or bar, colloquially called a "pill"
Computing
* Tablet computer, a mobile computer that is primarily operated by touching the s ...
s.
It is provided as 10- and 30-tablet
blister pack
A blister pack is any of several types of pre-formed plastic packaging used for small consumer goods, foods, and for pharmaceuticals.
The primary component of a blister pack is a cavity or pocket made from a formable web, usually a thermoforme ...
s as well as 3-tablet starter packs.
The availability of these different packs varies by country (all three available in Australia but only 30-tablet packs available in the United States).
Contraindications
Suvorexant is
contraindicated
In medicine, a contraindication is a condition 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 reason to use a certain tre ...
in people with
narcolepsy
Narcolepsy is a long-term neurological disorder that involves a decreased ability to regulate sleep–wake cycles. Symptoms often include periods of excessive daytime sleepiness and brief involuntary sleep episodes. About 70% of those affec ...
as it may worsen their symptoms.
This is its only
absolute contraindication.
Suvorexant has not been studied in people with severe
hepatic impairment
Liver disease, or hepatic disease, is any of many diseases of the liver. If long-lasting it is termed chronic liver disease. Although the diseases differ in detail, liver diseases often have features in common.
Signs and symptoms
Some of the sig ...
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
Kidney failure, also known as end-stage kidney disease, is a medical condition in which the kidneys can no longer adequately filter waste products from the blood, functioning at less than 15% of normal levels. Kidney failure is classified as eit ...
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. It oxidizes small foreign organic molecules (xenobiotics), such as toxins or drugs, so that they can be removed from t ...
inhibitor
Inhibitor or inhibition may refer to:
In 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 neurotra ...
s is not recommended due to potential for increased suvorexant exposure while concomitant use of suvorexant with strong CYP3A4
inducer
In molecular biology, an inducer is a molecule that regulates gene expression. An inducer functions in two ways; namely:
*By disabling repressors. The gene is expressed because an inducer binds to the repressor. The binding of the inducer to the r ...
s may result in loss of suvorexant exposure and effectiveness.
Suvorexant should be used carefully in people with a history of
drug misuse
Substance abuse, also known as drug abuse, is the use of a drug in amounts or by methods which are harmful to the individual or others. It is a form of substance-related disorder. Differing definitions of drug abuse are used in public health, ...
or
alcoholism
Alcoholism is, broadly, any drinking of alcohol (drug), alcohol that results in significant Mental health, mental or physical health problems. Because there is disagreement on the definition of the word ''alcoholism'', it is not a recognize ...
due to its
drug-liking Drug liking is a measure of the pleasurable (hedonic) experience when a person consumes drugs. It is commonly used to study the misuse liability of drugs. Drug liking is often measured using unipolar and bipolar visual analogue scales (VAS), such ...
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
Suicide is the act of intentionally causing one's own death. Mental disorders (including depression, bipolar disorder, schizophrenia, personality disorders, anxiety disorders), physical disorders (such as chronic fatigue syndrome), and subs ...
as it may rarely increase
suicidal ideation
Suicidal ideation, or suicidal thoughts, means having thoughts, ideas, or ruminations about the possibility of ending one's own life.World Health Organization, ''ICD-11 for Mortality and Morbidity Statistics'', ver. 09/2020MB26.A Suicidal ideatio ...
.
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
Human body weight is a person's mass or weight.
Strictly speaking, body weight is the measurement of weight without items located on the person. Practically though, body weight may be measured with clothes on, but without shoes or heavy accessor ...
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 mammary glands located in the breast of a human female. Breast milk is the primary source of nutrition for newborns, containing fat, protein, carbohydrates ( lacto ...
, 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 proces ...
in
breastfeeding
Breastfeeding, or nursing, is the process by which human breast milk is fed to a child. Breast milk may be from the breast, or may be expressed by hand or pumped and fed to the infant. The World Health Organization (WHO) recommends that br ...
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 effect
In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequence ...
s of suvorexant (at doses of 15–20mg) 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 asleep ...
(7% vs. 3% for
placebo
A placebo ( ) is a substance or treatment which is designed to have no therapeutic value. Common placebos include inert tablets (like sugar pills), inert injections (like Saline (medicine), saline), sham surgery, and other procedures.
In general ...
) and
headache
Headache 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 in those with severe headaches.
Headaches can occur as a result ...
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
placebo
A placebo ( ) is a substance or treatment which is designed to have no therapeutic value. Common placebos include inert tablets (like sugar pills), inert injections (like Saline (medicine), saline), sham surgery, and other procedures.
In general ...
.
Less common side effects (at 15–20mg) may include
dizziness
Dizziness is an imprecise term that can refer to a sense of disorientation in space, vertigo, or lightheadedness. It can also refer to disequilibrium or a non-specific feeling, such as giddiness or foolishness.
Dizziness is a common medical c ...
(3% vs. 2% for placebo),
abnormal dream
A dream is a succession of images, ideas, emotions, and sensation (psychology), sensations that usually occur involuntarily in the mind during certain stages of sleep. Humans spend about two hours dreaming per night, and each dream lasts around ...
s (2% vs. 1% for placebo),
diarrhea
Diarrhea, also spelled diarrhoea, is the condition of having at least three loose, liquid, or watery bowel movements each day. It often lasts for a few days and can result in dehydration due to fluid loss. Signs of dehydration often begin wi ...
(2% vs. 1% for placebo),
dry mouth
Xerostomia, also known as dry mouth, is dryness in the mouth, which may be associated with a change in the composition of saliva, or reduced salivary flow, or have no identifiable cause.
This symptom is very common and is often seen as a side eff ...
(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, t ...
(2% vs. 1% for placebo), and
cough
A cough is a sudden expulsion of air through the large breathing passages that can help clear them of fluids, irritants, foreign particles and microbes. As a protective reflex, coughing can be repetitive with the cough reflex following three pha ...
(2% vs. 1% for placebo).
High doses of suvorexant (80mg) have also been found to produce greater incidence of dizziness (5% vs. 0% for placebo) and abnormal dreams (5% vs. 1% for placebo).
Less commonly, suvorexant may cause
sleep paralysis
Sleep paralysis is a state, during waking up or falling asleep, in which one is conscious but is completely paralyzed. During an episode, one may hallucinate (hear, feel, or see things that are not there), which often results in fear. Episodes ...
,
hypnagogic
Hypnagogia is the experience of the transitional state from wakefulness to sleep: the ''hypnagogic'' state of consciousness, during the Sleep onset, onset of sleep. Its opposite state is described as the transitional state from sleep into wakeful ...
and
hypnopompic hallucinations, and
complex sleep behavior
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 slow wave stage of sleep, in a state of low ...
s (0.2–0.6% vs. 0% for placebo).
Complex sleep behaviors include
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 slow wave stage of sleep, in a state of low ...
,
sleep-driving, and engaging in other activities while not completely awake (e.g., making or eating food, making phone calls, and
having sex
Sexual intercourse (or coitus or copulation) is a sexual activity typically involving the insertion and thrusting of the penis into the vagina for sexual pleasure or reproduction.Sexual intercourse most commonly means penile–vaginal penetra ...
).
Other
narcoleptic
Narcolepsy is a long-term neurological disorder that involves a decreased ability to regulate sleep–wake cycles. Symptoms often include periods of excessive daytime sleepiness and brief involuntary sleep episodes. About 70% of those affec ...
-like symptoms such as
cataplexy
Cataplexy is a sudden and transient episode of muscle weakness accompanied by full conscious awareness, typically triggered by emotions such as laughing, crying, or terror. Cataplexy affects approximately 70% of people who have narcolepsy, and is ...
(sudden weakness or paralysis) may also rarely occur.
Suvorexant may sometimes cause worsening of
depression or
suicidal ideation
Suicidal ideation, or suicidal thoughts, means having thoughts, ideas, or ruminations about the possibility of ending one's own life.World Health Organization, ''ICD-11 for Mortality and Morbidity Statistics'', ver. 09/2020MB26.A Suicidal ideatio ...
.
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 occurrence ...
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
Alertness is the state of active attention by high sensory awareness such as being watchful and prompt to meet danger or emergency, or being quick to perceive and act. It is related for psychology . A lack of alertness is a symptom of a ...
and
motor coordination 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 body part involved in t ...
and impair
driving
Driving is the controlled operation and movement of a vehicle, including cars, motorcycles, trucks, buses, and bicycles. Permission to drive on public highways is granted based on a set of conditions being met and drivers are required to fol ...
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 remembered, ...
or
balance
Balance or balancing may refer to:
Common meanings
* Balance (ability) in biomechanics
* Balance (accounting)
* Balance or weighing scale
* Balance as in equality or equilibrium
Arts and entertainment Film
* ''Balance'' (1983 film), a Bulgarian ...
, 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
A systematic review is a Literature review, 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 publ ...
and
meta-analysis
A meta-analysis is a statistical analysis that combines the results of multiple scientific studies. Meta-analyses can be performed when there are multiple scientific studies addressing the same question, with each individual study reporting me ...
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 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 is the most common area ...
,
diarrhea
Diarrhea, also spelled diarrhoea, is the condition of having at least three loose, liquid, or watery bowel movements each day. It often lasts for a few days and can result in dehydration due to fluid loss. Signs of dehydration often begin wi ...
, dizziness, falls, headache,
car accidents/
traffic violation
A moving violation is any violation of the law committed by the driver of a vehicle while it is in motion. The term "motion" distinguishes it from other motor vehicle violations, such as paperwork violations (which include violations involving a ...
s,
nasopharyngitis
The common cold or the cold is a viral infectious disease of the upper respiratory tract that primarily affects the respiratory mucosa of the nose, throat, sinuses, and larynx. Signs and symptoms may appear fewer than two days after exposu ...
,
nausea
Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the ...
, potential
drug misuse
Substance abuse, also known as drug abuse, is the use of a drug in amounts or by methods which are harmful to the individual or others. It is a form of substance-related disorder. Differing definitions of drug abuse are used in public health, ...
, 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
Tolerance or toleration is the state of tolerating, or putting up with, conditionally.
Economics, business, and politics
* Toleration Party, a historic political party active in Connecticut
* Tolerant Systems, the former name of Veritas Software ...
,
dependence,
withdrawal
Withdrawal means "an act of taking out" and may refer to:
* Anchoresis (withdrawal from the world for religious or ethical reasons)
* ''Coitus interruptus'' (the withdrawal method)
* Drug withdrawal
* Social withdrawal
* Taking of money from a ban ...
, and
rebound effect
The rebound effect, or rebound phenomenon, is the emergence or re-emergence of symptoms that were either absent or controlled while taking a medication, but appear when that same medication is discontinued, or reduced in dosage. In the case of re ...
s 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
Orexin (), also known as hypocretin, is a neuropeptide that regulates arousal, wakefulness, and appetite. The most common form of narcolepsy, type 1, in which the individual experiences brief losses of muscle tone ("drop attacks" or cataplexy), ...
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
The mesolimbic pathway, sometimes referred to as the reward pathway, is a dopaminergic pathway in the brain. The pathway connects the ventral tegmentum, ventral tegmental area in the midbrain to the ventral striatum of the basal ganglia in the for ...
dopamine
Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic compound, organic chemical of the catecholamine and phenethylamine families. Dopamine const ...
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 refers to a family of theories, all of which have in common that pleasure plays a central role in them. ''Psychological'' or ''motivational hedonism'' claims that human behavior is determined by desires to increase pleasure and to decre ...
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 engage in certain behaviors, one of which is the usage of a drug, despite substantial harm and other negative consequences. Repetitive drug use o ...
.
In line with these findings, suvorexant and other orexin receptor antagonists have not shown
misuse liability
Substance abuse, also known as drug abuse, is the use of a drug in amounts or by methods which are harmful to the individual or others. It is a form of substance-related disorder. Differing definitions of drug abuse are used in public health, ...
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 geography, art history, ant ...
in rats and non-human primates.
Paradoxically however, orexin receptor antagonists, including suvorexant,
lemborexant
Lemborexant, sold under the brand name Dayvigo, is an orexin antagonist medication which is used in the treatment of insomnia. It is indicated specifically for the treatment of insomnia characterized by difficulties with sleep onset and/or maint ...
, and
daridorexant
Daridorexant, sold under the brand name Quviviq, is an orexin antagonist medication which is used for the treatment of insomnia. Daridorexant is taken by mouth.
Side effects of daridorexant include headache, somnolence, and fatigue. The med ...
, have consistently shown
drug-liking Drug liking is a measure of the pleasurable (hedonic) experience when a person consumes drugs. It is commonly used to study the misuse liability of drugs. Drug liking is often measured using unipolar and bipolar visual analogue scales (VAS), such ...
responses in human studies of
recreational
Recreation is an activity of leisure, leisure being discretionary time. The "need to do something for recreation" is an essential element of human biology and psychology. Recreational activities are often done for enjoyment, amusement, or pleasure ...
sedative
A sedative or tranquilliser is a substance that induces sedation by reducing irritability or excitement. They are CNS depressants and interact with brain activity causing its deceleration. Various kinds of sedatives can be distinguished, but t ...
users.
Suvorexant at higher-than-approved doses (40, 80, and 150mg vs. 20mg maximum recommended dose) showed similar drug liking to the
Z-drug
Nonbenzodiazepines (), sometimes referred to colloquially as Z-drugs (as many of their names begin with the letter "z"), are a class of psychoactive drugs that are very benzodiazepine-like in nature. They are used in the treatment of sleep problem ...
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 behaviora ...
(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 response of an organism, as a function of exposure (or doses) to a stimulus or stressor (usually a chemical) after a certain exposure time. ...
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
A controlled substance is generally a drug or chemical whose manufacture, possession and use is regulated by a government, such as illicitly used drugs or prescription medications that are designated by law. Some treaties, notably the Single C ...
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 any of a class of certain organic molecules called lipids. It is a sterol (or modified steroid), a type of lipid. Cholesterol is biosynthesized by all animal cells and is an essential structural component of animal cell mem ...
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
orexin
Orexin (), also known as hypocretin, is a neuropeptide that regulates arousal, wakefulness, and appetite. The most common form of narcolepsy, type 1, in which the individual experiences brief losses of muscle tone ("drop attacks" or cataplexy), ...
s (derived from
Greek
Greek may refer to:
Greece
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 ...
"orexis" 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 regu ...
,
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 φαγ ...
, 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 wh ...
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
Strain may refer to:
Science and technology
* Strain (biology), variants of plants, viruses or bacteria; or an inbred animal used for experimental purposes
* Strain (chemistry), a chemical stress of a molecule
* Strain (injury), an injury to a mu ...
.
In humans, orexin receptor antagonists including suvorexant have not been found to affect
body weight
Human body weight is a person's mass or weight.
Strictly speaking, body weight is the measurement of weight without items located on the person. Practically though, body weight may be measured with clothes on, but without shoes or heavy accessor ...
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. of suvorexant.
Suvorexant has been assessed in single doses of as high as 240mg in clinical studies.
The medication dose-dependently produces
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 asleep ...
.
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, is the process of cleaning out the contents of the stomach. Since its first recorded use in early 19th century, it has become one of the most routine means of eliminating ...
may be used where appropriate whereas the value of
dialysis Dialysis may refer to:
*Dialysis (chemistry), a process of separating molecules in solution
**Electrodialysis, used to transport salt ions from one solution to another through an ion-exchange membrane under the influence of an applied electric pote ...
has not been determined.
Because suvorexant has high
plasma protein binding
Plasma protein binding refers to the degree to which medications attach to proteins within the blood. A drug's efficiency may be affected by the degree to which it binds. The less bound a drug is, the more efficiently it can traverse or diffuse th ...
,
hemodialysis
Hemodialysis, also spelled haemodialysis, or simply dialysis, is a process of purifying the blood of a person whose kidneys are not working normally. This type of dialysis achieves the extracorporeal removal of waste products such as creatinin ...
is not expected to enhance
elimination of suvorexant.
Interactions
CYP3A4
Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine. It oxidizes small foreign organic molecules (xenobiotics), such as toxins or drugs, so that they can be removed from t ...
inhibitor
Inhibitor or inhibition may refer to:
In 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 neurotra ...
s can increase exposure to suvorexant while CYP3A4
inducer
In molecular biology, an inducer is a molecule that regulates gene expression. An inducer functions in two ways; namely:
*By disabling repressors. The gene is expressed because an inducer binds to the repressor. The binding of the inducer to the r ...
s 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 and antifungal medication used to treat a number of fungal infections. Applied to the skin it is used for fungal skin infections such as tinea, cutaneous candid ...
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 calcium channel blocker medication used to treat high blood pressure, angina, and certain heart arrhythmias. It may also be used in hyperthyroidism if beta blockers cannot be used ...
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
elimination half-life
Biological half-life (also known as elimination half-life, pharmacologic 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 bl ...
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 medication used to treat sleepiness due to narcolepsy, shift work sleep disorder, and obstructive sleep apnea. While it has seen off-label ...
).
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 b ...
,
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. Clarith ...
,
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). The compound was discovered by As ...
,
indinavir
Indinavir (IDV; trade name Crixivan, made by Merck) is a protease inhibitor used as a component of highly active antiretroviral therapy to treat HIV/AIDS. It is soluble white powder administered orally in combination with other antiviral drugs. Th ...
,
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 by mouth ...
,
ketoconazole
Ketoconazole, sold under the brand name Nizoral among others, is an antiandrogen and antifungal medication used to treat a number of fungal infections. Applied to the skin it is used for fungal skin infections such as tinea, cutaneous candid ...
,
lopinavir
Lopinavir is an antiretroviral of the protease inhibitor class. It is used against HIV infections as a fixed-dose combination with another protease inhibitor, ritonavir (lopinavir/ritonavir).
It was patented in 1995 and approved for medical ...
,
nefazodone
Nefazodone, sold formerly under the brand names Serzone, Dutonin, and Nefadar among others, is an atypical antidepressant which was first marketed by Bristol-Myers Squibb (BMS) in 1994 but has since largely been discontinued. BMS withdrew it from ...
,
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 inhibitors (PIs) and like other PIs is almost always used in combination ...
,
posaconazole
Posaconazole, sold under the brand name Noxafil among others, is a triazole antifungal medication.
It was approved for medical use in the United States in September 2006, and is available as a generic medication.
Medical uses
Posaconazole is u ...
,
ritonavir
Ritonavir, sold under the brand name Norvir, is an antiretroviral drug used along with other medications to treat HIV/AIDS. This combination treatment is known as highly active antiretroviral therapy (HAART). Ritonavir is a protease inhibitor a ...
,
saquinavir
Saquinavir (SQV), sold under the brand names Invirase and Fortovase, is an antiretroviral drug used together with other medications to treat or prevent HIV/AIDS. Typically it is used with ritonavir or lopinavir/ritonavir to increase its effect. ...
,
telaprevir
Telaprevir (VX-950), marketed under the brand names Incivek and Incivo, is a pharmaceutical drug for the treatment of hepatitis C co-developed by Vertex Pharmaceuticals and Johnson & Johnson. It is a member of a class of antiviral drugs known as ...
, and
telithromycin
Telithromycin is the first ketolide antibiotic to enter clinical use and is sold under the brand name of Ketek. It is used to treat community acquired pneumonia of mild to moderate severity. After significant safety concerns, the US Food and Drug ...
(concomitant use not recommended); the moderate CYP3A4 inhibitors
amprenavir
Amprenavir (original brand name Agenerase, GlaxoSmithKline) is a protease inhibitor (pharmacology), protease inhibitor used to treat HIV infection. It was approved by the Food and Drug Administration on April 15, 1999, for twice-a-day dosing in ...
,
aprepitant
Aprepitant, sold under the brand name Emend among others, is a medication used to prevent chemotherapy-induced nausea and vomiting (CINV) and to prevent postoperative nausea and vomiting (PONV). It may be used together with ondansetron and de ...
,
atazanavir
Atazanavir, sold under the brand name Reyataz among others, is an antiretroviral medication used to treat HIV/AIDS. It is generally recommended for use with other antiretrovirals. It may be used for prevention after a needlestick injury or other ...
,
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 infec ...
,
diltiazem
Diltiazem, sold under the brand name Cardizem among others, is a calcium channel blocker medication used to treat high blood pressure, angina, and certain heart arrhythmias. It may also be used in hyperthyroidism if beta blockers cannot be used ...
,
dronedarone
Dronedarone, sold under the brand name Multaq, is a medication by Sanofi-Aventis, mainly for the indication of cardiac arrhythmias. It was approved by the FDA on July 2, 2009. It was recommended as an alternative to amiodarone for the treatment ...
,
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 duri ...
,
fluconazole
Fluconazole is an antifungal medication used for a number of fungal infections. This includes candidiasis, blastomycosis, coccidiodomycosis, cryptococcosis, histoplasmosis, dermatophytosis, and pityriasis versicolor. It is also used to prevent ...
,
fluvoxamine
Fluvoxamine, sold under the brand name Luvox and Faverin among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. It is primarily used to treat major depressive disorder and obsessive–compulsive disorder ...
,
fosamprenavir
Fosamprenavir, sold under the brand names Lexiva and Telzir, is a medication used to treat HIV/AIDS. It is a prodrug of the protease inhibitor (pharmacology), protease inhibitor and antiretroviral drug amprenavir. It is marketed by ViiV Healthcare ...
,
grapefruit juice
Grapefruit juice is the juice from grapefruits. It is rich in vitamin C and ranges from sweet-tart to very sour. Variations include white grapefruit, pink grapefruit and ruby red grapefruit juice.The World's Healthiest Foods; Grapefruit. ''The ...
,
imatinib
Imatinib, sold under the brand names Gleevec and Glivec (both marketed worldwide by Novartis) among others, is an oral chemotherapy medication used to treat cancer. Imatinib is a small molecule inhibitor targeting multiple receptor tyrosine kin ...
, and
verapamil
Verapamil, sold under various trade names, is a calcium channel blocker medication used for the treatment of high blood pressure, angina (chest pain from not enough blood flow to the heart), and supraventricular tachycardia. It may also be used ...
(lower doses of suvorexant recommended); and the strong CYP3A4 inducers
apalutamide
Apalutamide, sold under the brand name Erleada among others, is a nonsteroidal antiandrogen (NSAA) medication which is used in the treatment of prostate cancer. It is specifically indicated for use in conjunction with castration in the treatme ...
,
carbamazepine
Carbamazepine (CBZ), sold under the trade name Tegretol among others, is an anticonvulsant medication used primarily in the treatment of epilepsy and neuropathic pain. It is used as an adjunctive treatment in schizophrenia along with other medi ...
,
efavirenz
Efavirenz (EFV), sold under the brand names Sustiva among others, is an antiretroviral medication used to treat and prevent HIV/AIDS. It is generally recommended for use with other antiretrovirals. It may be used for prevention after a needlest ...
,
enzalutamide
Enzalutamide, sold under the brand name Xtandi, is a nonsteroidal antiandrogen (NSAA) medication which is used in the treatment of prostate cancer. It is indicated for use in conjunction with castration in the treatment of metastatic castrat ...
,
phenytoin
Phenytoin (PHT), sold under the brand name Dilantin among others, is an 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 seizures. The intr ...
,
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 ...
, and
St. John's wort
''Hypericum perforatum'', known as St. John's wort, is a flowering plant in the family Hypericaceae and the type species of the genus ''Hypericum''.
Possibly a hybrid between '' H. maculatum'' and '' H. attenuatum'', the species can be found a ...
(expected to decrease suvorexant effectiveness).
Coadministration of suvorexant with other
CNS depressant
A depressant, or central depressant, is a drug that lowers neurotransmission levels, which is to depress or reduce arousal or stimulation, in various areas of the brain. Depressants are also colloquially referred to as downers as they lower the l ...
s such as
alcohol
Alcohol most commonly refers to:
* Alcohol (chemistry), an organic compound in which a hydroxyl group is bound to a carbon atom
* Alcohol (drug), an intoxicant found in alcoholic drinks
Alcohol may also refer to:
Chemicals
* Ethanol, one of sev ...
,
benzodiazepine
Benzodiazepines (BZD, BDZ, BZs), sometimes called "benzos", are a class of depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed to treat conditions such as anxiety disorders, ...
s,
opioid
Opioids are substances that act on opioid receptors to produce morphine-like effects. Medically they are primarily used for pain relief, including anesthesia. Other medical uses include suppression of diarrhea, replacement therapy for opioid us ...
s, and
tricyclic antidepressant
Tricyclic antidepressants (TCAs) are a class of medications that are used primarily as antidepressants, which is important for the management of depression. They are second-line drugs next to SSRIs. TCAs were discovered in the early 1950s and wer ...
s may increase the risk of
CNS depression
Central nervous system (CNS) depression is a physiological state that can result in a decreased rate of breathing, decreased heart rate, and loss of consciousness possibly leading to coma or death.
It is the result of inhibited or suppressed brai ...
and
daytime impairment
Sedation is the reduction of irritability or agitation by administration of sedative drugs, generally to facilitate a medical procedure or diagnostic procedure. Examples of drugs which can be used for sedation include isoflurane, diethyl ether, ...
.
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 determining the fate of substances administered ...
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 (CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are ...
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
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 and procedural sedation, and to treat severe agitation. It works by inducing sleepiness, decreasing anxiety, and causing a loss of a ...
(CYP3A4
substrate),
warfarin
Warfarin, sold under the brand name Coumadin among others, is a medication that is used as an anticoagulant (blood thinner). It is commonly used to prevent blood clots such as deep vein thrombosis and pulmonary embolism, and to prevent strok ...
(
CYP2C9
Cytochrome P450 family 2 subfamily C member 9 (abbreviated CYP2C9) is an enzyme protein. The enzyme is involved in metabolism, by oxidation, of both xenobiotics, including drugs, and endogenous compounds, including fatty acids. In humans, the prote ...
substrate),
digoxin
Digoxin (better known as Digitalis), sold under the brand name Lanoxin among others, is a medication used to treat various heart conditions. Most frequently it is used for atrial fibrillation, atrial flutter, and heart failure. Digoxin is on ...
(
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 pill
The combined oral contraceptive pill (COCP), often referred to as the birth control pill or colloquially as "the pill", is a type of birth control that is designed to be taken orally by women. The pill contains two important hormones: progesti ...
s.
However, coadministration of suvorexant with
digoxin
Digoxin (better known as Digitalis), sold under the brand name Lanoxin among others, is a medication used to treat various heart conditions. Most frequently it is used for atrial fibrillation, atrial flutter, and heart failure. Digoxin is on ...
may result in slightly increased digoxin exposure due to inhibition of
intestinal
The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organs of the digestive system, in humans ...
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 ...
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 chief foe of the protagonist.
Etymology
The English word antagonist comes from the Greek ἀνταγωνιστής – ''antagonistēs'', "opponent, competitor, villain, enemy, riv ...
of the
orexin (hypocretin) receptors
OX1 and
OX2.
These
receptor
Receptor may refer to:
* Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse
*Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a ...
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
Endogenous substances and processes are those that originate from within a living system such as an organism, tissue, or cell.
In contrast, exogenous substances and processes are those that originate from outside of an organism.
For example, es ...
wakefulness
Wakefulness is a daily recurring Human brain, 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 ...
-promoting
orexin
Orexin (), also known as hypocretin, is a neuropeptide that regulates arousal, wakefulness, and appetite. The most common form of narcolepsy, type 1, in which the individual experiences brief losses of muscle tone ("drop attacks" or cataplexy), ...
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
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 33 ...
and
orexin-B
Orexin (), also known as hypocretin, is a neuropeptide that regulates arousal, wakefulness, and appetite. The most common form of narcolepsy, type 1, in which the individual experiences brief losses of muscle tone ("drop attacks" or cataplexy), ...
.
The
binding affinities
In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. The etymology stems from ''ligare'', which means 'to bind'. In protein-ligand binding, the ligand is usually a m ...
(K
i) of suvorexant at the human orexin receptors are 0.55nM for the OX
1 receptor and 0.35nM for the OX
2 receptor.
The antagonistic
potencies or
functional inhibition (K
b) of suvorexant at the human orexin receptors are 65nM for the OX
1 receptor and 41nM for the OX
2 receptor.
Hence, suvorexant shows similar affinities and antagonistic activities at the OX
1 and OX
2 receptors ''
in vitro
''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in biology an ...
''.
Suvorexant is highly selective for the orexin receptors over a large number of other
target
Target may refer to:
Physical items
* Shooting target, used in marksmanship training and various shooting sports
** Bullseye (target), the goal one for which one aims in many of these sports
** Aiming point, in field artillery, fi ...
s (170 screened
off-target
In pharmacology, an antitarget (or off-target) is a receptor, enzyme, or other biological target that, when affected by a drug, causes undesirable side-effects. During drug design and development, it is important for pharmaceutical companies to ens ...
receptor
Receptor may refer to:
* Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse
*Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a ...
s,
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
s, and
transporters).
In contrast to certain other sedatives and hypnotics, suvorexant is not a
benzodiazepine
Benzodiazepines (BZD, BDZ, BZs), sometimes called "benzos", are a class of depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed to treat conditions such as anxiety disorders, ...
or
Z-drug
Nonbenzodiazepines (), sometimes referred to colloquially as Z-drugs (as many of their names begin with the letter "z"), are a class of psychoactive drugs that are very benzodiazepine-like in nature. They are used in the treatment of sleep problem ...
and does not interact with
GABA receptor
The GABA receptors are a class of receptors that respond to the neurotransmitter gamma-aminobutyric acid (GABA), the chief inhibitory compound in the mature vertebrate central nervous system. There are two classes of GABA receptors: GABAA and ...
s.
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, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. N ...
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 cognit ...
in the
brain
A brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as vision. It is the most complex organ in a v ...
.
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
Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as both a hormone and neurotransmitter. The name "noradrenaline" (from Latin '' ad'', ...
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.
The locus coerule ...
,
histaminergic
Histaminergic means "working on the histamine system", and histaminic means "related to histamine".
A histaminergic agent (or drug) is a chemical which functions to directly modulate the histamine system in the body or brain. Examples include his ...
tuberomammillary nucleus
The tuberomammillary nucleus (TMN) is a histaminergic nucleus located within the posterior third of the hypothalamus. It consists of, largely, histaminergic neurons (i.e., histamine-releasing neurons) and is involved with the control of arousal, l ...
,
serotonergic
Serotonergic () or serotoninergic () means "pertaining to or affecting serotonin". Serotonin is a neurotransmitter. A synapse is serotonergic if it uses serotonin as its neurotransmitter. A serotonergic neuron ''produces'' serotonin. A substance is ...
raphe nucleus, and
dopaminergic
Dopaminergic means "related to dopamine" (literally, "working on dopamine"), dopamine being a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain. Dopaminergic brain pathways facilitate d ...
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 the ...
.
The orexin system shows
circadian rhythm
A circadian rhythm (), or circadian cycle, is a natural, internal process that regulates the sleep–wake cycle and repeats roughly every 24 hours. It can refer to any process that originates within an organism (i.e., Endogeny (biology), endogeno ...
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 long-term neurological disorder that involves a decreased ability to regulate sleep–wake cycles. Symptoms often include periods of excessive daytime sleepiness and brief involuntary sleep episodes. About 70% of those affec ...
is a chronic
sleep disorder
A sleep disorder, or somnipathy, is a medical disorder of an individual's sleep patterns. Some sleep disorders are severe enough to interfere with normal physical, mental, social and emotional functioning. Polysomnography and actigraphy are test ...
characterized by
excessive daytime sleepiness
Excessive daytime sleepiness (EDS) is characterized by persistent sleepiness and often a general lack of energy, even during the day after apparently adequate or even prolonged nighttime sleep. EDS can be considered as a broad condition encompass ...
,
cataplexy
Cataplexy is a sudden and transient episode of muscle weakness accompanied by full conscious awareness, typically triggered by emotions such as laughing, crying, or terror. Cataplexy affects approximately 70% of people who have narcolepsy, and is ...
,
sleep paralysis
Sleep paralysis is a state, during waking up or falling asleep, in which one is conscious but is completely paralyzed. During an episode, one may hallucinate (hear, feel, or see things that are not there), which often results in fear. Episodes ...
, and
hypnagogic hallucination
Hypnagogia is the experience of the transitional state from wakefulness to sleep: the ''hypnagogic'' state of consciousness, during the onset of sleep. Its opposite state is described as the transitional state from sleep into wakefulness. Mental ...
s, 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". P ...
mechanisms related to
environmental trigger
An environmental factor, ecological factor or eco factor is any factor, abiotic or biotic, that influences living organisms. Abiotic factors include ambient temperature, amount of sunlight, and pH of the water soil in which an organism lives. Bi ...
s 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 body fluid found within the tissue that surrounds the brain and spinal cord of all vertebrates.
CSF is produced by specialised ependymal cells in the choroid plexus of the ventricles of the bra ...
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, mi ...
in the
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
encoding the OX
2 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
Orexin (), also known as hypocretin, is a neuropeptide that regulates arousal, wakefulness, and appetite. The most common form of narcolepsy, type 1, in which the individual experiences brief losses of muscle tone ("drop attacks" or cataplexy) ...
or the OX
2 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 or physical form and structure, its developmental processes, its biochemical and physiological proper ...
.
Although there is
hypersomnolence
Hypersomnia is a neurological disorder of excessive time spent sleeping or excessive sleepiness. It can have many possible causes (such as seasonal affective disorder) and can cause distress and problems with functioning. In the fifth edition o ...
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 (pronounced ; alternatively: aetiology or ætiology) is the study of causation or origination. The word is derived from the Greek (''aitiologÃa'') "giving a reason for" (, ''aitÃa'', "cause"); and ('' -logÃa''). More completely, e ...
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 or something has been alive or 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 disturbance
A sleep disorder, or somnipathy, is a medical disorder of an individual's sleep patterns. Some sleep disorders are severe enough to interfere with normal physical, mental, social and emotional functioning. Polysomnography and actigraphy are test ...
s.
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
Danavorexton (developmental code name TAK-925) is a selective orexin 2 receptor agonist. It is a small-molecule compound and is administered intravenously. The compound was found to dose-dependently produce wakefulness to a similar degree as ...
dose-dependently produce
wakefulness
Wakefulness is a daily recurring Human brain, 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 ...
and
locomotor activity
Animal locomotion, in ethology, is any of a variety of methods that animals use to move from one place to another. Some modes of locomotion are (initially) self-propelled, e.g., running, swimming, jumping, flying, hopping, soaring and gliding. Th ...
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
Animal testing, also known as animal experimentation, animal research, and ''in vivo'' testing, is the use of non-human animals in experiments that seek to control the variables that affect the behavior or biological system under study. This ...
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. The most common form of narcolepsy, type 1, in which the individual experiences brief losses of muscle tone ("drop attacks" or cataplexy), ...
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
Absorption may refer to:
Chemistry and biology
* Absorption (biology), digestion
**Absorption (small intestine)
*Absorption (chemistry), diffusion of particles of gas or liquid into liquid or solid materials
*Absorption (skin), a route by which ...
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 In the field of pharmacokinetics, the area under the curve (AUC) is the definite integral of the concentration of a drug in blood plasma as a function of time (this can be done using liquid chromatography–mass spectrometry). In practice, the dru ...
(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 prevents solutes in the circulating blood from ''non-selectively'' crossing into the extracellular fluid of ...
and
distributes into the
central nervous system
The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all par ...
.
Suvorexant has high
plasma protein binding
Plasma protein binding refers to the degree to which medications attach to proteins within the blood. A drug's efficiency may be affected by the degree to which it binds. The less bound a drug is, the more efficiently it can traverse or diffuse th ...
(99.5%).
It is bound to
albumin
Albumin is a family of globular proteins, the most common of which are the serum albumins. All the proteins of the albumin family are water-soluble, moderately soluble in concentrated salt solutions, and experience heat denaturation. Albumins ...
and
α1-acid glycoprotein (orosomucoid).
Metabolism
Suvorexant is
metabolized
Metabolism (, from el, μεταβολή ''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 cell ...
primarily by
hydroxylation
In chemistry, hydroxylation can refer to:
*(i) most commonly, hydroxylation describes a chemical process that introduces a hydroxyl group () into an organic compound.
*(ii) the ''degree of hydroxylation'' refers to the number of OH groups in a ...
via
CYP3A
Cytochrome P450, family 3, subfamily A, also known as CYP3A, is a human gene locus. A homologous locus is found in mice.
The CYP3A locus includes all the known members of the 3A subfamily of the cytochrome P450 superfamily of genes. These genes e ...
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
s.
CYP2C19
Cytochrome P450 2C19 (abbreviated CYP2C19) is an enzyme protein. It is a member of the CYP2C subfamily of the cytochrome P450 mixed-function oxidase system. This subfamily includes enzymes that catalyze metabolism of xenobiotics, including some pr ...
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
In pharmacology, biological activity or pharmacological activity describes the beneficial or adverse effects of a drug on organism, living matter. When a drug is a complex chemical mixture, this activity is exerted by the substance's active ingred ...
.
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 Partn ...
for the orexin receptors than suvorexant ''
in vitro
''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in biology an ...
'', was a
substrate for
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 ...
making it unlikely to cross the
blood–brain barrier
The blood–brain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that prevents solutes in the circulating blood from ''non-selectively'' crossing into the extracellular fluid of ...
, 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
Excretion is a process in which metabolic waste
is eliminated from an organism. In vertebrates this is primarily carried out by the lungs, kidneys, and skin. This is in contrast with secretion, where the substance may have specific tasks after lea ...
primarily in
feces
Feces ( or faeces), known colloquially and in slang as poo and poop, 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 large intestine. Feces contain a relati ...
(66%) predominantly as metabolites and to a lesser extent in
urine
Urine is a liquid by-product of metabolism in humans and in many other animals. Urine flows from the kidneys through the ureters to the urinary bladder. Urination results in urine being excretion, excreted from the body through the urethra.
Cel ...
(23%).
The
elimination half-life
Biological half-life (also known as elimination half-life, pharmacologic 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 bl ...
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 (weight) and height of a person. The BMI is defined as the body mass divided by the square of the body height, and is expressed in units of kg/m2, resulting from mass in kilograms and he ...
, such as
obese
Obesity is a medical condition, sometimes considered a disease, in which excess body fat has accumulated to such an extent that it may negatively affect health. People are classified as obese when their body mass index (BMI)—a person's we ...
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
Liver disease, or hepatic disease, is any of many diseases of the liver. If long-lasting it is termed chronic liver disease. Although the diseases differ in detail, liver diseases often have features in common.
Signs and symptoms
Some of the sig ...
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
Kidney failure, also known as end-stage kidney disease, is a medical condition in which the kidneys can no longer adequately filter waste products from the blood, functioning at less than 15% of normal levels. Kidney failure is classified as eit ...
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
ketoconazole
Ketoconazole, sold under the brand name Nizoral among others, is an antiandrogen and antifungal medication used to treat a number of fungal infections. Applied to the skin it is used for fungal skin infections such as tinea, cutaneous candid ...
and to 16.1hours with the moderate CYP3A4 inhibitor
diltiazem
Diltiazem, sold under the brand name Cardizem among others, is a calcium channel blocker medication used to treat high blood pressure, angina, and certain heart arrhythmias. It may also be used in hyperthyroidism if beta blockers cannot be used ...
while it was decreased to 7.7hours 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 ...
.
Miscellaneous
![Peak-normalized concentrations of orexin receptor antagonists with administration in humans](https://upload.wikimedia.org/wikipedia/commons/8/83/Peak-normalized_concentrations_of_orexin_receptor_antagonists_with_administration_in_humans.png)
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 (for ...
extending beyond about 8hours.
Relative to suvorexant,
daridorexant
Daridorexant, sold under the brand name Quviviq, is an orexin antagonist medication which is used for the treatment of insomnia. Daridorexant is taken by mouth.
Side effects of daridorexant include headache, somnolence, and fatigue. The med ...
has a shorter half-life (8hours) while
lemborexant
Lemborexant, sold under the brand name Dayvigo, is an orexin antagonist medication which is used in the treatment of insomnia. It is indicated specifically for the treatment of insomnia characterized by difficulties with sleep onset and/or maint ...
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
Seltorexant, also known by its developmental code names MIN-202 and JNJ-42847922, is an orexin receptor antagonist, orexin antagonist medication which is under development for the treatment of depression (mood), depression and insomnia. It is a b ...
and
vornorexant
Vornorexant, also known by its developmental code names ORN-0829 and TS-142, is an orexin antagonist medication which is under development for the treatment of insomnia
Insomnia, also known as sleeplessness, is a sleep disorder in which peo ...
, 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 receptor
The orexin receptor (also referred to as the hypocretin receptor) is a G-protein-coupled receptor that binds the neuropeptide orexin. There are two variants, OX1 and OX2, each encoded by a different gene (, ).
Both orexin receptors exhibit ...
s slowly.
As a result, its
duration
Duration may refer to:
* The amount of time elapsed between two events
* Duration (music) – an amount of time or a particular time interval, often cited as one of the fundamental aspects of music
* Duration (philosophy) – a theory of time and ...
may be longer than that suggested by its circulating concentrations and half-life.
Chemistry
Suvorexant is a
small-molecule
Within the fields of molecular biology and pharmacology, a small molecule or micromolecule is a low molecular weight (≤ 1000 daltons) organic compound that may regulate a biological process, with a size on the order of 1 nm. Many drugs ar ...
compound.
The
chemical name
A chemical nomenclature is a set of rules to generate systematic names for chemical compounds. The nomenclature used most frequently worldwide is the one created and developed by the International Union of Pure and Applied Chemistry (IUPAC).
The ...
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
In chemistry, 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, ...
is C
23H
23N
6O
2Cl and its
molecular weight
A molecule is a group of two or more atoms held together by attractive forces known as chemical bonds; depending on context, the term may or may not include ions which satisfy this criterion. In quantum physics, organic chemistry, and bioch ...
is 450.92g/mol.
Suvorexant is a white to off-white powder and is
lipophilic
Lipophilicity (from Greek λίπος "fat" and φίλος "friendly"), refers to the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents such as hexane or toluene. Such non-polar solvents are themselves lipop ...
and
insoluble
In chemistry, solubility is the ability of a substance, the solute, to form a solution with another substance, the solvent. Insolubility is the opposite property, the inability of the solute to form such a solution.
The extent of the solubil ...
in water.
It is
structurally
A structure is an arrangement and organization of interrelated elements in a material object or system, or the object or system so organized. Material structures include man-made objects such as buildings and machines and natural objects such as ...
related to other orexin receptor antagonists like
lemborexant
Lemborexant, sold under the brand name Dayvigo, is an orexin antagonist medication which is used in the treatment of insomnia. It is indicated specifically for the treatment of insomnia characterized by difficulties with sleep onset and/or maint ...
,
daridorexant
Daridorexant, sold under the brand name Quviviq, is an orexin antagonist medication which is used for the treatment of insomnia. Daridorexant is taken by mouth.
Side effects of daridorexant include headache, somnolence, and fatigue. The med ...
, and
seltorexant
Seltorexant, also known by its developmental code names MIN-202 and JNJ-42847922, is an orexin receptor antagonist, orexin antagonist medication which is under development for the treatment of depression (mood), depression and insomnia. It is a b ...
.
History
The
orexin
Orexin (), also known as hypocretin, is a neuropeptide that regulates arousal, wakefulness, and appetite. The most common form of narcolepsy, type 1, in which the individual experiences brief losses of muscle tone ("drop attacks" or cataplexy), ...
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 were discovered in 1998
and the role of the orexin system in the
etiology
Etiology (pronounced ; alternatively: aetiology or ætiology) is the study of causation or origination. The word is derived from the Greek (''aitiologÃa'') "giving a reason for" (, ''aitÃa'', "cause"); and ('' -logÃa''). More completely, e ...
of
narcolepsy
Narcolepsy is a long-term neurological disorder that involves a decreased ability to regulate sleep–wake cycles. Symptoms often include periods of excessive daytime sleepiness and brief involuntary sleep episodes. About 70% of those affec ...
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
sleep disorder
A sleep disorder, or somnipathy, is a medical disorder of an individual's sleep patterns. Some sleep disorders are severe enough to interfere with normal physical, mental, social and emotional functioning. Polysomnography and actigraphy are test ...
s, these findings led to
translational
Translation is the communication of the meaning of a source-language text by means of an equivalent target-language text. The English language draws a terminological distinction (which does not exist in every language) between ''transla ...
efforts to bring orexin receptor modulators to medicine as therapeutic agents.
Suvorexant was developed by
Merck
Merck refers primarily to the German Merck family and three companies founded by the family, including:
* the Merck Group, a German chemical, pharmaceutical and life sciences company founded in 1668
** Merck Serono (known as EMD Serono in the Unite ...
.
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 regu ...
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 August 13, 2014.
Suvorexant was initially released November 2014 in
Japan
Japan ( ja, 日本, or , and formally , ''Nihonkoku'') is an island country in East Asia. It is situated in the northwest Pacific Ocean, and is bordered on the west by the Sea of Japan, while extending from the Sea of Okhotsk in the north ...
,
then later reached the United States in February 2015,
Australia
Australia, officially the Commonwealth of Australia, is a Sovereign state, sovereign country comprising the mainland of the Australia (continent), Australian continent, the island of Tasmania, and numerous List of islands of Australia, sma ...
in November 2016, and
Canada
Canada is a country in North America. Its ten provinces and three territories extend from the Atlantic Ocean to the Pacific Ocean and northward into the Arctic Ocean, covering over , making it the world's second-largest country by tot ...
in November 2018.
It was the first orexin receptor antagonist to be introduced for medical use, and was followed by
lemborexant
Lemborexant, sold under the brand name Dayvigo, is an orexin antagonist medication which is used in the treatment of insomnia. It is indicated specifically for the treatment of insomnia characterized by difficulties with sleep onset and/or maint ...
in 2019 and
daridorexant
Daridorexant, sold under the brand name Quviviq, is an orexin antagonist medication which is used for the treatment of insomnia. Daridorexant is taken by mouth.
Side effects of daridorexant include headache, somnolence, and fatigue. The med ...
in 2022.
Development of
almorexant
Almorexant, also known by its development code ACT-078573, is an orexin antagonist, acting as a competitive antagonist of the OX1 and OX2 orexin receptors, which was being developed by the pharmaceutical companies Actelion and GSK for the trea ...
(ACT-078573) and
filorexant
Filorexant (, ; developmental code name MK-6096) is an orexin antagonist which was under development by Merck for the treatment of insomnia, depression, diabetic neuropathy, and migraine. It is a dual antagonist of the orexin OX1 and OX2 re ...
(MK-6096) was discontinued, while
seltorexant
Seltorexant, also known by its developmental code names MIN-202 and JNJ-42847922, is an orexin receptor antagonist, orexin antagonist medication which is under development for the treatment of depression (mood), depression and insomnia. It is a b ...
(MIN-202, JNJ-42847922) and
vornorexant
Vornorexant, also known by its developmental code names ORN-0829 and TS-142, is an orexin antagonist medication which is under development for the treatment of insomnia
Insomnia, also known as sleeplessness, is a sleep disorder in which peo ...
(ORN-0829, TS-142) are still in clinical trials.
Suvorexant
marketing exclusivity in the United States is set to expire in January 2023 and
patent protection
A patent is a type of intellectual property that gives its owner the legal right to exclude others from making, using, or selling an invention for a limited period of time in exchange for publishing an enabling disclosure of the invention."A p ...
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
A controlled substance is generally a drug or chemical whose manufacture, possession and use is regulated by a government, such as illicitly used drugs or prescription medications that are designated by law. Some treaties, notably the Single C ...
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 substance in Australia, instead being classed as a
prescription-only medication (
Schedule 4 (S4)) in this country.
Controversy
Public Citizen
Public Citizen is a non-profit, progressive consumer rights advocacy group and think tank based in Washington, D.C., United States, with a branch in Austin, Texas.
Lobbying efforts
Public Citizen advocates before all three branches of the Unit ...
, 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 business ...
advocacy group
Advocacy groups, also known as interest groups, special interest groups, lobbying groups or pressure groups use various forms of advocacy in order to influence public opinion and ultimately policy. They play an important role in the developm ...
, 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 (also known as acute confusional state) is an organically caused decline from a previous baseline of mental function that develops over a short period of time, typically hours to days. Delirium is a syndrome encompassing disturbances in ...
.
As of October 2021, it is in
phase III clinical trial
Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, dietar ...
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 or psychiatric disorder, is a behavioral or mental pattern that causes significant distress or impairment of personal functioning. Such features may be persistent, relapsing and remitt ...
s such as
depression and
anxiety
Anxiety is an emotion which is characterized by an unpleasant state of inner turmoil and includes feelings of dread over anticipated events. Anxiety is different than fear in that the former is defined as the anticipation of a future threat wh ...
.
It was reported to improve psychiatric symptoms and to decrease
cortisol
Cortisol is a steroid hormone, in the glucocorticoid class of hormones. When used as a medication, it is known as hydrocortisone.
It is produced in many animals, mainly by the ''zona fasciculata'' of the adrenal cortex in the adrenal gland ...
levels in these individuals.
A
phase IV clinical trial
Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, dietar ...
of suvorexant as an
adjunct to
antidepressant
Antidepressants are a class of medication used to treat major depressive disorder, anxiety disorders, chronic pain conditions, and to help manage addictions. Common side-effects of antidepressants include dry mouth, weight gain, dizziness, hea ...
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 low mood, low self-esteem, and loss of interest or pleasure in normally enjoyable activities. Introdu ...
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.,
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 geography, art history, ant ...
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 (including alcohol) despite substantial harm and adverse consequences as a result of their use. Substance use disorders are characterized by an array of mental/emotional, physical, and ...
s,
including
alcohol use disorder
Alcoholism is, broadly, any drinking of alcohol that results in significant mental or physical health problems. Because there is disagreement on the definition of the word ''alcoholism'', it is not a recognized diagnostic entity. Predomin ...
,
cocaine use disorder
Cocaine dependence is a neurological disorder that is characterized by Drug withdrawal, withdrawal symptoms upon cessation from cocaine use. It also often coincides with cocaine addiction which is a biopsychosocial disorder characterized by pers ...
,
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. Op ...
.
Diabetes
Suvorexant has been studied in people with
type 2 diabetes
Type 2 diabetes, 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 urination, ...
and insomnia and has been reported to improve sleep and
metabolic
Metabolism (, from el, μεταβολή ''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 cell ...
parameters in these individuals.
The improvement in metabolic parameters appeared to be related to improved sleep.
References
Further reading
*
*
External links
*
*
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