Ramelteon, sold under the brand name Rozerem among others, is a melatonin agonist

medication A medication (also called medicament, medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy ( pharmacotherapy) is an important part of the medical field an ...

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. It reduces the time taken to fall asleep, but the degree of clinical benefit is small. The medication is approved for long-term use. Ramelteon 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 ramelteon 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 ...

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 ...

fatigue Fatigue describes a state of tiredness that does not resolve with rest or sleep. In general usage, fatigue is synonymous with extreme tiredness or exhaustion that normally follows prolonged physical or mental activity. When it does not resolve ...

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 ...

, exacerbated insomnia, and changes in

hormone A hormone (from the Greek participle , "setting in motion") is a class of signaling molecules in multicellular organisms that are sent to distant organs by complex biological processes to regulate physiology and behavior. Hormones are required ...

levels. Ramelteon is an analogue of

melatonin Melatonin is a natural product found in plants and animals. It is primarily known in animals as a hormone released by the pineal gland in the brain at night, and has long been associated with control of the sleep–wake cycle. In vertebrat ...

and is a selective

agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...

of the

MT₁ and MT₂ receptors. The

half-life Half-life (symbol ) is the time required for a quantity (of substance) to reduce to half of its initial value. The term is commonly used in nuclear physics to describe how quickly unstable atoms undergo radioactive decay or how long stable at ...

and duration of ramelteon are much longer than those of melatonin. Ramelteon 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 and does not interact with GABA receptors, instead having a distinct

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

. Ramelteon was first described in 2002 and was approved for medical use in 2005. Unlike certain other sleep medications, ramelteon is not 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 Sing ...

and has no known potential for misuse.

Medical uses

Insomnia

Ramelteon is approved for the treatment of

characterized by difficulty with sleep onset in adults. In regulatory

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

s, it was found to significantly reduce latency to persistent sleep (LPS). A 2009

pooled analysis A pooled analysis is a statistical Statistics (from German: ''Statistik'', "description of a state, a country") is the discipline that concerns the collection, organization, analysis, interpretation, and presentation of data. In applying ...

of four

s found that ramelteon at a dose of 8 mg reduced sleep onset by 13 minutes (30% decrease) relative to

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 ...

on the first and second nights of use. Subsequent

meta-analyses 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 longer-duration use have found that ramelteon decreases subjective sleep latency by about 4 to 7 minutes. Meta-analyses are mixed on whether ramelteon increases total sleep time. Ramelteon also improves sleep quality ( –0.074, 95% –0.13 to –0.02) and sleep efficiency. The clinical improvement in insomnia with ramelteon is small and of questionable benefit. Ramelteon is approved in the United States but was not approved in the European Union owing to concerns that it lacked effectiveness. The

Committee for Medicinal Products for Human Use The Committee for Medicinal Products for Human Use (CHMP), formerly known as Committee for Proprietary Medicinal Products (CPMP), is the European Medicines Agency's committee A committee or commission is a body of one or more persons subordin ...

(CHMP) of the European Medicines Agency (EMA) noted that ramelteon had only been found to improve sleep onset and not other sleep outcomes, only one of three clinical trials actually found that it improved sleep onset, and that the improvement in sleep onset was too small to be clinically meaningful. The CHMP also noted that the long-term effectiveness of ramelteon had not been demonstrated. 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 ...

's 2017 clinical practice guidelines recommended the use of ramelteon in the treatment of sleep-onset insomnia. It rated the recommendation as weak and the quality of evidence as very low but concluded that the potential benefits outweighed the potential harms. The guidelines found that ramelteon reduces sleep latency by 9minutes (95% 6–12minutes) but does not improve sleep quality. In contrast to ramelteon, the guidelines did not recommend the use of

Circadian rhythm sleep disorders

Melatonin receptor agonists like

and tasimelteon are considered to be effective in regulating sleep–wake cycles and in the treatment of circadian rhythm sleep disorders like delayed sleep phase disorder. Ramelteon has been assessed in only a few studies in the treatment of circadian rhythm sleep disorders, including

jet lag disorder Jet lag is a physiological condition that results from alterations to the body's circadian rhythms caused by rapid long-distance trans-meridian (east–west or west–east) travel. For example, someone flying from New York to London, i.e. from ...

shift work disorder Shift work sleep disorder (SWSD) is a circadian rhythm sleep disorder characterized by insomnia, excessive sleepiness, or both affecting people whose work hours overlap with the typical sleep period. Insomnia can be the difficulty to fall asleep o ...

, and non-24-hour sleep–wake disorder. These studies have been of varying quality and their findings in terms of effectiveness have been mixed. Ramelteon is approved only for treatment of insomnia and is not approved for treatment of circadian rhythm sleep disorders. It was previously under development for treatment of circadian rhythm sleep disorders, but development for these indications was discontinued.

Other uses

Delirium

A systematic review, published in 2014, concluded "ramelteon was found to be beneficial in preventing delirium in medically ill individuals when compared to placebo." A 2022 systematic review and meta-analysis found that the combination of ramelteon and the orexin receptor antagonist suvorexant may reduce the incidence 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 adults

hospitalized A hospital is a health care institution providing patient treatment with specialized health science and auxiliary healthcare staff and medical equipment. The best-known type of hospital is the general hospital, which typically has an emergency ...

patients whereas suvorexant alone was ineffective.

Bipolar disorder

Ramelteon has received attention in

psychiatry Psychiatry is the medical specialty devoted to the diagnosis, prevention, and treatment of mental disorders. These include various maladaptations related to mood, behaviour, cognition, and perceptions. See glossary of psychiatry. Initial p ...

as a possible add-on treatment for

mania Mania, also known as manic syndrome, is a mental and behavioral disorder defined as a state of abnormally elevated arousal, affect, and energy level, or "a state of heightened overall activation with enhanced affective expression together wit ...

bipolar disorder Bipolar disorder, previously known as manic depression, is a mental disorder characterized by periods of depression and periods of abnormally elevated mood that last from days to weeks each. If the elevated mood is severe or associated with ...

. However, to date, the scarce available evidence fails to support the clinical utility of ramelteon and other melatonin receptor agonists such as

for mania.

Available forms

Ramelteon is available in the form of 8 mg oral

film-coated A film coating is a thin polymer-based coat that is typically sprayed on to a solid pharmaceutical dosage form, such as a tablet, capsule, pellet or granule. Film coating can impact both its appearance and its pharmacokinetics making it an ess ...

tablets.

Contraindications

Ramelteon is not recommended for use in people with severe

sleep apnea Sleep apnea, also spelled sleep apnoea, is a sleep disorder in which pauses in breathing or periods of shallow breathing during sleep occur more often than normal. Each pause can last for a few seconds to a few minutes and they happen many tim ...

Adverse effects

s of ramelteon include

(3% vs. 2% for

(3% vs. 2% for placebo),

(4% vs. 3% for placebo),

(3% vs. 2% for placebo), and exacerbated insomnia (3% vs. 2% for placebo). Overall, side effects occurred in 6% with ramelteon and 2% with placebo in

s. Side effects leading to discontinuation occurred in 1% or fewer people. Rarely, anaphylactic reactions,

abnormal thinking A thought disorder (TD) is any disturbance in cognition that adversely affects language and thought content, and thereby communication. A variety of thought disorders were said to be characteristic of people with schizophrenia. A content-thought ...

, and worsening of depression or

suicidal thinking 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 ...

in patients with pre-existing depression may occur with ramelteon. Ramelteon has been found to slightly increase

prolactin Prolactin (PRL), also known as lactotropin, is a protein best known for its role in enabling mammals to produce milk. It is influential in over 300 separate processes in various vertebrates, including humans. Prolactin is secreted from the pit ...

levels in women (+34% vs. –4% with placebo) but not in men and to decrease free

testosterone Testosterone is the primary sex hormone and anabolic steroid in males. In humans, testosterone plays a key role in the development of male reproductive tissues such as testes and prostate, as well as promoting secondary sexual characteris ...

levels (by 3–6% in younger men and by 13–18% in older men). Ramelteon has not been shown to produce dependence and has shown no potential for abuse. The

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 ...

and rebound insomnia that is typical with GABA_A receptor positive modulators like

s and Z-drugs is not present in ramelteon. Increased incidence of

liver The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it ...

and testicular tumors have been observed with ramelteon in rodents but only at doses equivalent to at least 20 times greater than the recommended dose in humans.

Overdose

Ramelteon has been assessed at doses of up to 64 mg in clinical studies.

Interactions

Ramelteon has been evaluated for potential drug interactions with the following medications and showed no significant effects: omeprazole,

theophylline Theophylline, also known as 1,3-dimethylxanthine, is a phosphodiesterase inhibiting drug used in therapy for respiratory diseases such as chronic obstructive pulmonary disease (COPD) and asthma under a variety of brand names. As a member of the ...

dextromethorphan Dextromethorphan (DXM) is a medication most often used as a cough suppressant in over-the-counter cold and cough medicines. It is sold in syrup, tablet, spray, and lozenge forms. In 2022, the FDA approved a formulation of it combined with bu ...

, and

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 ...

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 ...

and

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 ...

. There were no clinically meaningful effects when ramelteon was coadministered with any of these drugs. A drug interaction study showed that there were no clinically meaningful effects or an increase in adverse events when ramelteon and the SSRI

Prozac Fluoxetine, sold under the brand names Prozac and Sarafem, among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. It is used for the treatment of major depressive disorder, obsessive–compulsive disord ...

(fluoxetine) were coadministered. When coadministered with ramelteon, fluvoxamine (strong

CYP1A2 Cytochrome P450 1A2 (abbreviated CYP1A2), a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the human body. In humans, the CYP1A2 enzyme is encoded by the ''CYP1A2'' gene. Function ...

inhibitor) increased AUC approximately 190-fold, and the C_max increased approximately 70-fold, compared to ramelteon administered alone. Ramelteon and fluvoxamine should not be coadministered. has significant drug–drug interaction with the following drugs: . Ramelteon should be administered with caution in patients taking other

inhibitors, 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 ...

inhibitors such as ketoconazole, and strong

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 ...

inhibitors such as fluconazole. Efficacy may be reduced when ramelteon is used in combination with potent CYP enzyme inducers such as rifampin, since ramelteon concentrations may be decreased.

Pharmacology

Pharmacodynamics

Ramelteon is a melatonin receptor agonist with both high affinity for melatonin MT₁ and MT₂ receptors and selectivity over the non-human MT₃ receptor. Ramelteon demonstrates full agonist activity ''in vitro'' in cells expressing human MT₁ or MT₂ receptors, and high selectivity for human MT₁ and MT₂ receptors compared to the non-human MT₃ receptor. The affinity of ramelteon for the MT₁ and MT₂ receptors is 3 to 16 times higher than that of melatonin. Ramelteon has 8-fold higher affinity for the MT₁ receptor over the MT₂ receptor. The binding profile of ramelteon distinguishes it from

, tasimelteon, and

agomelatine Agomelatine, sold under the brand names Valdoxan and Thymanax, among others, is an atypical antidepressant most commonly used to treat major depressive disorder and generalized anxiety disorder. One review found that it is as effective as other ...

. The major

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, ...

of ramelteon, M-II, is active and has approximately one-tenth and one-fifth the binding affinity of the parent molecule for the human MT₁ and MT₂ receptors, respectively, and is 17- to 25-fold less potent than ramelteon in ''in vitro'' functional assays. Although the potency of M-II at MT₁ and MT₂ receptors is lower than the parent drug, M-II circulates at higher concentrations than the parent producing 20- to 100-fold greater mean systemic exposure when compared to ramelteon. M-II has weak affinity for the serotonin 5-HT_2B receptor, but no appreciable affinity for other receptors or enzymes. Similar to ramelteon, M-II does not interfere with the activity of a number of endogenous enzymes. Ramelteon has no appreciable affinity for the GABA receptors or for receptors that bind

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 th ...

cytokine Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in a ...

s, serotonin,

dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. Dopamine constitutes about 8 ...

, noradrenaline,

acetylcholine Acetylcholine (ACh) is an organic chemical that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Par ...

, and

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 opioi ...

s. Ramelteon also does not interfere with the activity of a number of selected enzymes in a standard panel.

Mechanism of action

The activity of ramelteon at the MT₁ and MT₂ receptors is believed to contribute to its sleep-promoting properties, as these receptors, acted upon by endogenous melatonin, are thought to be involved in the maintenance of the

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., endogenous) and responds to ...

underlying the normal sleep–wake cycle.

Pharmacokinetics

Absorption

The total absorption of ramelteon is 84% while its oral

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%. ...

is 1.8%. The low bioavailability of ramelteon is due to extensive first-pass metabolism. The absorption of ramelteon is rapid, with

peak levels Cmax is the maximum (or peak) serum concentration that a drug achieves in a specified compartment or test area of the body after the drug has been administered and before the administration of a second dose. It is a standard measurement in pharm ...

being reached after approximately 0.75 hours (range 0.5–1.5 hours). Food increases peak concentrations of ramelteon by 22% and overall exposure by 31% and delays the time to peak levels by approximately 0.75 hours. The

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 ...

of ramelteon are linear across a dose range of 4 to 64 mg. There is substantial interindividual variability in the peak concentrations and area-under-the-curve levels of ramelteon which is consistent with high first-pass metabolism.

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 A drug ...

of ramelteon is 73.6 L, which suggests substantial

tissue distribution Distribution in pharmacology is a branch of pharmacokinetics which describes the reversible transfer of a drug from one location to another within the body. Once a drug enters into systemic circulation by absorption or direct administration, it mu ...

. The

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 ...

of ramelteon is 82% independently of concentration. Ramelteon is primarily 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 ...

(70%). The medication is not selectively distributed to

red blood cell Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek ''erythros'' for "red" and ''kytos'' for "holl ...

Metabolism

Ramelteon is metabolized in the

primarily by

oxidation Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is the gain of electrons or a ...

via

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 ...

and

carbonylation Carbonylation refers to reactions that introduce carbon monoxide into organic and inorganic substrates. Carbon monoxide is abundantly available and conveniently reactive, so it is widely used as a reactant in industrial chemistry. The term carbo ...

. It is also secondarily metabolized to produce glucuronide conjugates. Ramelteon is metabolized mainly by

while

CYP2C Cytochromes P450 (CYPs) are a superfamily of enzymes containing heme as a cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are important for the clearance of various ...

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different molecule ...

s and

are involved to a minor extent. The

s of ramelteon include M-I, M-II, M-III, and M-IV. Exposure to M-II is approximately 20- to 100-fold higher than to ramelteon.

Elimination

Ramelteon is excreted 84% 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 excreted from the body through the urethra. Cellular ...

and 4% 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 rela ...

. Less than 0.1% of drug is excreted as unchanged ramelteon.

Elimination Elimination may refer to: Science and medicine * Elimination reaction, an organic reaction in which two functional groups split to form an organic product *Bodily waste elimination, discharging feces, urine, or foreign substances from the bo ...

of ramelteon is essentially complete by 96 hours following a single dose. The elimination half-life of ramelteon is 1 to 2.6 hours while the half-life of M-II, the major active metabolite of ramelteon, is 2 to 5 hours. The half-lives of ramelteon and M-II are substantially longer than that of

, which has a half-life in the range of 20 to 45 minutes. Levels of ramelteon and its metabolites at or below the limit of detectability within 24 hours following a dose.

Special populations

Peak levels of ramelteon and overall exposure are about 86% and 97% higher, respectively, in elderly adults compared to younger adults. Conversely, peak levels of M-II are 13% and overall exposure 30% higher in elderly adults than in younger adults. The elimination half-life of ramelteon is 2.6 hours in elderly adults.

History

Ramelteon was first described in the medical literature in 2002. It was approved for use in the United States in July 2005.

Society and culture

Ramelteon has no potential for abuse or drug dependence and is not a

Research

Ramelteon, along with other melatonin receptor agonists like

, has been repurposed in clinical trials as an adjunctive treatment for acute manic episodes in subjects with

. Nonetheless, meta-analytic evidence is based on very few trials and does not allow supporting the use of melatonin receptor agonists as adjunctive options for mania in clinical practice, although the small

sample size Sample size determination is the act of choosing the number of observations or replicates to include in a statistical sample. The sample size is an important feature of any empirical study in which the goal is to make inferences about a populatio ...

do not allow ruling out their beneficial effect.

References

External links

* {{Portal bar , Medicine Benzofurans Indanes Melatonin receptor agonists Propionamides Sedatives Takeda Pharmaceutical Company brands