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DRUG RECORD

 

RAMELTEON

OVERVIEW
Ramelteon

 

Introduction

Ramelteon is a melatonin receptor agonist that is used for the treatment of insomnia. Ramelteon has not been implicated in causing serum enzyme elevations or clinically apparent liver injury.

 

Background

Ramelteon (ra mel' tee on) is a synthetic melatonin receptor agonist with affinity for both the melatonin type 1 and type 2 receptors (MT1 and MT2). These receptors are believed to be involved in the maintenance of the circadian rhythm that regulates the normal sleep-wake cycle. Melatonin itself has been proposed as therapy of sleep disturbances including insomnia and jet lag, but systematic reviews and meta analyses of controlled trials of various melatonin formulations have failed to demonstrate consistent efficacy. In contrast, ramelteon was found to reduce the average latency to persistent sleep with little residual sleepiness the following day or rebound insomnia upon withdrawal. Ramelteon was approved for use in chronic insomnia in the United States in 2005. It is available in 8 mg tablets under the brand name Rozerem. The recommended dose is 8 mg taken orally 30 minutes before going to bed. Side effects are few but may include daytime somnolence, fatigue, dizziness and headache and rarely hypersensitivity reactions with angioedema of the tongue and larynx.

 

Hepatotoxicity

In several clinical trials, ramelteon was found to be well tolerated and not associated with serum enzyme elevations or evidence of liver injury. Despite, wide scale use, it has not been convincingly linked to instances of clinically apparent liver injury. Nevertheless, ramelteon is metabolized by the cytochrome P450 system (predominantly CYP 1A2) which can result in significant drug-drug interactions.

 

Drug Class:  Sedatives and Hypnotics

 

Other Drugs in the Subclass, Melatonin and its Analogues:  Melatonin, Tasimelteon

 

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REPRESENTATIVE TRADE NAMES
Ramelteon – Rozerem®

 

DRUG CLASS
Sedatives and Hypnotics

 

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

 

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DRUG CAS REGISTRY NUMBER MOLECULAR FORMULA STRUCTURE
Ramelteon 196597-26-9 C16-H21-N-O2 Ramelteon Chemical Structure

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REFERENCES
Ramelteon

 

References updated: 08 January 2014

 

  1. Zimmerman HJ. Unconventional drugs. Miscellaneous drugs and diagnostic chemicals. In, Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999, pp. 731-4.  (Expert review of hepatotoxicity published in 1999; melatonin and ramelteon are not discussed).

  2. Larrey D, Ripault MP. Anxiolytic agents. Hepatotoxicity of psychotropic drugs and drugs of abuse. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, p. 455-6.  (Review of hepatotoxicity of hypnotics and sedatives discusses benzodiazepines, buspirone and valerian all of which have been linked to rare cases of liver injury; melatonin and ramelteon are not discussed).

  3. Mihic SJ, Harris RA. Hypnotics and sedatives. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 457-80.  (Textbook of pharmacology and therapeutics).

  4. Penev PD, Zee PC. Melatonin: a clinical perspective. Ann Neurol 1997; 42: 545-53. PubMed Citation  (Discussion of physiological functions of melatonin and potential clinical uses).

  5. Seabra ML, Bignotto M, Pinto LR Jr, Tufik S. Randomized, double-blind clinical trial, controlled with placebo, of the toxicology of chronic melatonin treatment. J Pineal Res 2000; 29: 193-200. PubMed Citation  (Controlled trial of melatonin [10 mg daily] vs placebo for 28 days in 40 volunteers found no changes or abnormalities of serum bilirubin, ALT, AST or Alk P during the 4 weeks of treatment).

  6. Ramelteon(Rozerem) for insomnia. Med Lett Drugs Ther 2005; 47(1221): 89-91. PubMed Citation  (Concise review of the mechanism of action, efficacy and safety of ramelteon published shortly after its approval for use in insomnia in the US; adverse effects include somnolence, dizziness, nausea, fatigue, headache and insomnia, but no mention is made of ALT elevations or hepatotoxicity; mentions that melatonin itself is available in the US only as a "dietary supplement").

  7. Buscemi N, Vandermeer B, Hooton N, Pandya R, Tjosvold L, Hartling L, Vohra S, et al. Efficacy and safety of exogenous melatonin for secondary sleep disorders and sleep disorders accompanying sleep restriction: meta-analysis. BMJ 2006; 332: 385-93. PubMed Citation  (Systematic review of literature on efficacy and safety of melatonin for sleep disorders; in 9 randomized controlled trials there was no overall evidence of benefit; in 10 studies evaluating safety there was no evidence of adverse effects occurring more often than with placebo, with use limited to 3 months).

  8. Erman M, Seiden D, Zammit G, Sainati S, Zhang J. An efficacy, safety, and dose-response study of Ramelteon in patients with chronic primary insomnia. Sleep Med 2006; 7: 17-24. PubMed Citation  (Controlled crossover trial of 4 doses of ramelteon vs placebo in 107 patients with chronic primary insomnia found no difference in rate of side effects compared to placebo, the most common being headache and somnolence; serum enzymes not tested).

  9. Devi V, Shankar PK. Ramelteon: a melatonin receptor agonist for the treatment of insomnia. J Postgrad Med 2008; 54: 45-8. PubMed Citation  (Review of the mechanism of action, efficacy and safety of ramelteon in treatment of insomnia; adverse events include headache, somnolence, dizziness, fatigue, insomnia and nausea; no mention made of ALT elevations or hepatotoxicity; superpharmacological, high doses of ramelteon cause liver cancer in mice).

  10. Mayer G, Wang-Weigand S, Roth-Schechter B, Lehmann R, Staner C, Partinen M. Efficacy and safety of 6-month nightly ramelteon administration in adults with chronic primary insomnia. Sleep 2009; 32: 351-60. PubMed Citation  (Controlled trial of 6 month course of ramelteon vs placebo in 451 adults with primary chronic insomnia; adverse effects were similar between the two groups; no mention of ALT levels).

  11. Morris CJ, Aeschbach D, Scheer FA. Circadian system, sleep and endocrinology. Mol Cell Endocrinol 2012; 349: 91-104. PubMed Citation  (Review of the biologic basis of circadian rhythm including the role of melatonin).

  12. Drugs for insomnia. Treat Guidel Med Lett 2012; 10 (119): 57-60. PubMed Citation  (Guidelines for therapy of insomnia; mentions that benzodiazepine receptor agonists such as zaleplon, benzodiazepines, ramelteon and low doses of doxepin are effective and generally safe; the discussion of adverse events makes no mention of ALT elevations or hepatotoxicity of any of the recommended agents).

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OTHER REFERENCE LINKS
Ramelteon

 

  1. PubMed logoRecent References on Ramelteon

  2. Clinical Trials logoTrials on Ramelteon

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