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- Simpson, D. & Curran, M.P. Drugs (2008) 68: 1901. doi:10.2165/00003495-200868130-00011
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Ramelteon (Rozerem™) is the first melatonin receptor agonist to be approved for the treatment of insomnia; it is not classified as a controlled substance. In patients with chronic insomnia, objectively assessed latency to persistent sleep (LPS) at week 1 was improved with oral ramelteon 8 mg administered 30 minutes before bedtime, compared with placebo, and this effect was maintained throughout the duration of 5-week and 6-month clinical studies. Subjectively assessed sleep latency (sSL) improved in some, but not all, studies. When a statistically significant improvement in sSL occurred at week 1, the effect was maintained throughout the duration of the 5-week studies, but not at all timepoints throughout a 6-month study. Improvements in objectively assessed total sleep time (TST) and sleep efficiency (SE) were only reported during the first week of treatment. Improvements in other objective or subjective measures of sleep were not consistent. Ramelteon was generally well tolerated, did not impair next-day cognitive or motor performance and was not associated with withdrawal symptoms, rebound insomnia or abuse potential. Thus, ramelteon provides a well tolerated option for the treatment of patients with insomnia characterized by difficulty in sleep onset.
Ramelteon is a highly selective melatonin MT1 and MT2 receptor agonist, with no appreciable affinity for the GABA receptor complex or receptors that bind neuropeptides, cytokines, opioids, dopamine or serotonin. Ramelteon enhanced re-entrainment of circadian rhythms to a new light-dark cycle in volunteers, according to measurements of endogenous melatonin secretion offset time. In patients with chronic insomnia, ramelteon was not associated with acute or next-day effects on cognitive or psychomotor function compared with placebo when assessed using standard tests, and had no effect on middle-of-the-night balance/body sway. Doses of ramelteon up to 20-fold greater than that recommended for the treatment of insomnia showed no potential for abuse in adults with a history of sedative abuse.
Ramelteon is rapidly absorbed, with a time to peak serum concentration of 0.75 hours. The total absorption of ramelteon is ≥84%; however, the absolute bioavailability is <2% due to extensive first-pass metabolism. Metabolism is via cytochrome P450 (CYP) isozymes, primarily CYP1A2. Fluvoxamine (a CYP1A2 inhibitor) should not be coadministered with ramelteon, and caution should be exercised with some other drug combinations. Eighty-four percent of the drug is excreted in the urine and ≈4% in the faeces; <0.1% is excreted as unchanged drug. The elimination half-life of ramelteon is ≈1.4 hours.
In patients with chronic insomnia, oral ramelteon 8 mg administered 30 minutes before bedtime improved LPS in the first week and throughout the duration of 5-week and 6-month randomized, double-blind studies. The difference between ramelteon 8 mg/night and placebo for LPS throughout the course of the 5-week study was 11–16 minutes. Ramelteon 8 mg/night improved sSL in some, but not all, studies. When a statistically significant improvement in sSL occurred at week 1, the effect persisted throughout the duration of the 5-week studies, but not at every timepoint throughout the 6-month study. TST, when monitored by polysomnography, was significantly greater with ramelteon 8 mg/night than with placebo only during the first week of the studies in patients with chronic insomnia. The changes in subjectively assessed TST were not consistent. Objectively measured SE was significantly higher in recipients of ramelteon 8 mg/night than with placebo only during the first week. There were no significant differences between ramelteon and placebo for other objective or subjective sleep parameters, including sleep quality, awake time and number of awakenings after sleep onset, and difficulty/ease of falling back to sleep.
In a first-night model of transient insomnia in volunteers, LPS was significantly shorter and TST was significantly longer with ramelteon 8 mg than placebo.
Ramelteon was generally well tolerated, with the majority of adverse events being of mild or moderate severity. According to data from a pooled analysis of phase I–III trials, the most common treatment-emergent adverse events in recipients of ramelteon 8 mg/night or placebo were headache (both 7%), somnolence (5% vs 3%), dizziness (5% vs 3%) and fatigue (4% vs 2%). Discontinuation due to an adverse event occurred in 6% of ramelteon recipients and 2% of placebo recipients. Increases in prolactin levels were reported in a 6-month trial and abnormalities in cortisol levels were reported in ramelteon recipients in an open-label 1-year trial in patients with chronic insomnia.
Ramelteon was not associated with withdrawal effects or rebound insomnia.