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.


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.


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. A single report of worsening liver disease with jaundice, ascites, bacterial peritonitis and death in a patient with alcoholic liver disease who had started ramelteon therapy a month before has been reported. Ramelteon is not recommended in patients with impaired hepatic function.

Likelihood score: E* (unproven but suspected rare cause of clinically apparent liver injury).

Mechanism of Injury

Rameltoeon is a synthetic melatonin receptor agonist and is unrelated to melatonin structurally. It is unclear how ramelteon might cause liver injury, but it undergoes extensive first pass uptake by the liver and is metabolized by the cytochrome P450 system (largely CYP 1A2). For these reasons, its metabolism might be altered in persons with liver disease or alcoholism as well as by strong inducers or inhibitors of CYP enzymes.

Outcome and Management

Ramelteon has not been convincingly associated with serum enzyme elevations during therapy or with clinically apparent liver injury. However, persons with preexisting liver disease should either avoid use of ramelteon or be monitored for worsening of liver test results during therapy.

Drug Class: Sedatives and Hypnotics

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



Ramelteon – Rozerem®


Sedatives and Hypnotics


Product labeling at DailyMed, National Library of Medicine, NIH



References updated: 21 May 2018

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