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Remelteon: Management of insomnia with melatonin receptor agonist


Syed Haris Omar*1, Saba Nabi2, Nehal M3
1Pharmacy Department, Sebai Institute of Health Science, Jeddah-, Saudi Arabia.
2Department of Pharmaceutical Management, Faculty of Management Studies, Jamia Hamdard, New Delhi-110062.
3Ageing Research Laboratories, Department of Zoology, Mithila University, Darbhanga.



Insomnia is characterized by difficulty falling asleep, increased night time wakefulness and inadequate sleep duration etc. This is the general increasing problem among the people due to their living habbits. Melatonin is a ubiquitous natural neurotransmitter-like compound produced primarily by the pineal gland. This agent is involved in numerous aspects of the biological and physiologic regulation of body functions. The role of endogenous melatonin in circadian rhythm disturbances and sleep disorders is well established. Nocturnal melatonin levels and the quality of sleep both decline at puberty; in elderly populations, periods of sleep tend to become shorter and the quality of sleep poorer. This brief review summarizes the pharmacology, pharmacokinetic and the potential therapeutic uses of remelteon, a melatonin receptor agonist.


Insomnia, characterized by difficulty falling asleep, increased night-time wakefulness or inadequate sleep duration. Insomnia can result in daytime consequences, including tiredness, difficulty concentrating, and irritability, as well as increased healthcare utilization and reduced work productivity, lower quality of life or quality of social relationships, and decrements in memory, mood, or cognitive function (Buscemi et al 2005, NCSDR 1998). Acute insomnia refers to periods of difficulty sleeping lasting one day to a few weeks, while chronic insomnia refers to sleep difficulty lasting at least three nights per week for one month or more (NCSDR 1998).

Management of insomnia includes sleep hygiene education, cognitive behavioral therapy, and pharmacological therapy (NCSDR 1998). Pharmacological agents include benzodiazepines, non-benzodiazepine benzodiazepine receptor agonists, antihistamines, antidepressants, melatonin, herbal products, and nutritional supplements (NCSDR 1998, Erman 2005). Melatonin is a neurohormone released from the pineal gland in association with the light-dark cycle that regulates sleep. The sleep-promoting and circadian effects of melatonin are attributed to interactions with two subtypes of human melatonin receptors: MT1 and MT2 (Pandi et al 2005). A third subtype, MT3, is a peripheral receptor (Richardson 2005). Suppression of melatonin production correlates with insomnia. Increasing plasma melatonin concentrations are associated with increased sleepiness (Pandi et al 2005).


Remelteon is a melatonin receptor agonist that was approved by the US Food and Drug Administration (FDA) in July 2005 for the treatment of insomnia characterized by difficulty with sleep onset. It is also under evaluation for use in the treatment of circadian rhythm disorders (Uchikawa et al 2002).


Remelteon is a tricyclic indan derivative that is a potent and selective human melatonin MT1 and MT2 receptor agonist (Uchikawa et al 2002, Kato et al 2005) with a low affinity for the MT3 receptor. Unlike melatonin, it did not exhibit activity at the serotonin 5-HT1A receptor or the dopamine D1 receptor( Miyamoto et al 2003). Remelteon has exhibited sleep-promoting activity in several animal models.


Remelteon is well absorbed orally, but undergoes extensive first-pass metabolism, resulting in an overall oral bioavailability of less than 2% (range 0.5-12%) (Stevenson et al 2004, Amakye et al 2004). Following oral administration, the mean time-to-peak concentration is less than one hour. The mean elimination half-life of Remelteon is approximately 0.8 hours to 2.6 hours (Stubbs and Karim 2003). Remelteon undergoes extensive first-pass metabolism to at least four metabolites, primarily via oxidation to hydroxyl and carbonyl groups, with secondary metabolism to form glucuronide conjugates.


Remelteon is contraindicated in patients with a known hypersensitivity to Remelteon or any of the product ingredients. In addition, Remelteon should not be used by patients with severe hepatic impairment or in combination with fluvoxamine.

Adverse Effects

The most frequently reported adverse reactions in Remelteon clinical trials have included headache, somnolence, fatigue, nausea, dizziness, and insomnia (Erman et al 2006).

Drug Interactions

Remelteon is primarily metabolized via CYP1A2 and, to a lesser extent, via the CYP2C subfamily and CYP3A4. Remelteon does not appear to be an inhibitor or inducer of CYP1A2, CYP3A4, CYP2C9 or CYP2D6.


The recommended dose of Remelteon is 8mg taken within 30 minutes before going to bed. Remelteon should not be taken with or immediately after a high-fat meal. No dosage adjustments are necessary in the elderly or patients with renal impairment.


Remelteon is the first FDA-approved melatonin receptor agonist which reduces the time-to-sleep onset and increases total sleep duration; however, comparative studies with other sleep agents, including melatonin, are necessary to determine comparative efficacy and the place of Remelteon in therapy. Efficacy in placebo-controlled studies has been observed in both acute and chronic insomnia. Similar to eszopiclone, long-term studies have been conducted and recommended us is not limited to 30 days. Remelteon was well tolerated in clinical studies, with little residual sedation, and has not been associated with physical dependence or abuse liability.


Amakye D D, Hibberd M, Stevenson S J. (2004) A phase I study to investigate the absolute bioavailability of a single oral dose of Remelteon (TAK-375) in healthy male subjects. Sleep. 27, A54.

Buscemi N,Vandermeer B, Friesen C et al. (2005) Manifestations and management of chronic insomnia in adults” Summary, Evidence Report/Technology Assessment No. 125 (Prepared by the University of Alberta Evidence-based Practice Center, under Contract No. C400000021), AHRQ Publication No. 05-E021-1, Agency for Healthcare Research and Quality, Rockville, Maryland.

Erman M K. (2005) Therapeutic options in the treatment of insomnia. J Clin Psychiatry. 66,18-23.

Erman M, Seiden D, Zammit G, Sainati S, Zhang J.(2006) An efficacy, safety, and dose-response study of Remelteon in patients with chronic primary insomnia. Sleep Med. 7,17-24.

Kato K, Hirai K, Nishiyama K et al. (2005) Neurochemical properties of Remelteon (TAK-375), a selective MT1/MT2 receptor agonist. Neuropharmacology. 48, 301-310.

Miyamoto M, Kata K, Hirai K, Uchikawa O, Ohkawa S. (2003) TAK-375 and its active metabolite: lack of binding to non-ML receptor binding sites. Sleep. 26,A79.

National Center on Sleep Disorders Research, Insomnia: Assessment and Management in Primary Care, NIH Publication No. 98-4088, National Institutes of Health (1998 September).

Pandi-Perumal S R, Zisapel N, Srinivasan V, Cardinali D P. (2005) Melatonin and sleep in aging population. Exp Gerontology. 40, 911-925.

Richardson G S. (2005) The human circadian system in normal and disordered sleep. J Clin Psychiatry. 66, 3-9.

Stevenson S, Bryson S,Amakye D, Hibberd M. (2004) Study to investigate the absolute
bioavailability of a single oral dose of Remelteon (TAK-375) in healthy male subjects. Clin Pharmacol Ther. 75, P22.

Stubbs C, Karim A. (2003) A safety, tolerance, and pharmacokinetic study of five single doses of TAK-375 in healthy adults. Sleep. 26, A76–A77.

Uchikawa O, Fukatsu K, Tokunoh R et al. (2002) Synthesis of a novel series of tricyclic indan derivatives as melatonin receptor agonists. J Med Chem. 45, 222-224.


First Published August 2007

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