Ramelteon, sold under the brand name Rozerem among others, is a melatonin agonist medication which is used in the treatment of insomnia. 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.Side effects of ramelteon include somnolence, dizziness, fatigue, nausea, exacerbated insomnia, and changes in hormone levels. Ramelteon is an analogue of melatonin and is a selective agonist of the melatonin MT1 and MT2 receptors. The half-life and duration of ramelteon are much longer than those of melatonin. Ramelteon is not a benzodiazepine or Z-drug and does not interact with GABA receptors, instead having a distinct mechanism of action.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 and has no known potential for misuse. Medical uses
Insomnia
Ramelteon is approved for the treatment of insomnia characterized by difficulty with sleep onset in adults. In regulatory clinical trials, it was found to significantly reduce latency to persistent sleep (LPS). A 2009 pooled analysis of four clinical trials found that ramelteon at a dose of 8 mg reduced sleep onset by 13 minutes (30% decrease) relative to placebo on the first and second nights of use. Subsequent meta-analyses of longer-duration use have found that ramelteon decreases subjective sleep latency by about 4 to 7 minutes.
The medication is not selectively distributed to red blood cells. Metabolism
Ramelteon is metabolized in the liver primarily by oxidation via hydroxylation and carbonylation. It is also secondarily metabolized to produce glucuronide conjugates. Ramelteon is metabolized mainly by CYP1A2 while CYP2C enzymes and CYP3A4 are involved to a minor extent. The metabolites 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 and 4% in feces. Less than 0.1% of drug is excreted as unchanged ramelteon. Elimination 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 melatonin, 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.