Rozerem (ramelteon) is a melatonin receptor agonist, with high binding affinity at the melatonin MT1 and MT2 receptors. The drug exerts high selectivity for these receptors over the MT3 receptor, which has been implicated in a number of additional systems.

Ramelteon is specifically indicated for the treatment of insomnia characterized by difficulty in falling asleep. Unlike many other hypnotic agents, clinical and animal trials of Rozerem did not yield evidence of formation of physical dependence or abuse potential, and the drug is not a controlled substance; overall adverse events occured at rates generally comparable to placebo. These properties suggest that Rozerem may be well tolerated when administered for long treatment courses.

Rozerem is supplied as a round pale orange-yellow film coated tablet. The recommended dose of the drug is one 8 mg tablet once daily, 30 minutes prior to going to bed.

FDA Approval
Approval of Rozerem was supported by a number of clinical trials, investigating the both the efficacy of the drug and the drug’s tolerability and abuse-potential profiles.

Chronic Insomnia
Rozerem was investigated in a pair of randomized, double-blind trials designed to determine the efficacy of the drug for the treatment of chronic insomnia via polysomnography (PSG). This first study enrolled adults ages 18-64, who received one of two doses of the drug (8 mg or 16 mg) or placebo nightly before bed for 35 days. Sleep analysis via PSG was performed on days 1, 2 of weeks 1, 3 and 5. The second study enrolled elderly patients age 65 and older in a three-period crossover trial. Subjects received one of two doses of the drug (4 mg or 8 mg) or placebo in each study period, with PSG analysis performed for 2 consecutive nights in each period. In both studies, each dose of Rozerem produced significant reductions in average latency to persistent sleep onset, compared to placebo.

An additional randomized, double-blind, parallel group study of Rozerem investigated subjective measures of sleep quality using patient-reported sleep diaries. The trial enrolled elderly patients on an outpatient basis, who received one of two doses of the drug (4 mg or 8 mg) or placebo for 35 nights. Both doses reduced patient-reported sleep latency vs. placebo. A fourth trial, using 8 mg and 16 mg doses of the drug in a general adult insomniac population (18-64) did not demonstrate efficacy in this subjective measure.

Transient Insomnia
A randomized, double-blind, parallel-group trial was conducted to investigate the single-dose efficacy of the drug in treating transient insomnia. The trial enrolled healthy adults, who received a single dose of the drug at one of two levels (8 mg or 16 mg) or placebo before a single night of PSG analysis. The 8 mg dose was seen to significantly reduce mean latency to persistent sleep, vs. placebo.

Tolerability: Next-Day Fatigue
Patients in the crossover studies were evaluated for alertness, short term learning and memory performance, and ability to concentrate on the day following treatment, using several diagnostic scales (a Memory Recall Test, a Word List Memory Test, a Visual Analog Mood and Feeling Scale, the Digit-Symbol Substitution Test, and a post-sleep questionnaire). No significant deficits in next-day performance were observed following 2 nights of drug treatment.

In a 35 day, double-blind, placebo-controlled, parallel-group study for the treatment of chronic insomnia, measures of next-day residual effect were observed at 3 time-points. At week 1, patients receiving 8 mg Rozerem indicated more fatigue as measured on the Visual Analog Scale (VAS; 46 mm on a 100 mm scale) than subjects receiving placebo (42 mm). Higher fatigue levels on the VAS was also seen at week 3 (27 mm vs. 22 mm), as was a lower mean number of words recalled in a memory test (7.5 of 16, vs. 8.2 for placebo). By week 5, no deficits in next-day performance were seen.

Tolerability: Withdrawal and Rebound Insomnia
Three long term studies of the drug were conducted to investigate potential withdrawal effects following termination of 35 days of Rozerem treatment. The trials enrolled 2082 subjects (849 age 65 and older) who received doses of 4 mg, 8 mg, or 16 mg Rozerem; potential withdrawal effects were investigated with the Tyrer Benzodiazepine Withdrawal Symptom Questionnaire (BWSQ), administered one week after treatment in 2 of the studies, and on days 1 & 2 after completion in the third. In all 3 studies, there were no significant differences in BWSQ score between Rozerem and placebo.

Rebound insomnia was measured in 3 of the long term insomnia studies via PSG (1 trial) and subjective sleep measures (2 trials) following abrupt treatment termination. In all 3 studies, no regimens of Rozerem produced evidence of rebound insomnia at any time point following treatment.

Tolerability: Endocrine Function
A pair of placebo-contolled studies of Rozerem was conducted to investigate the effect of drug administration on endocrine function. In the first, 99 healthy volunteers received either 16 mg Rozerem or placebo nightly for 4 weeks; subjects were evaluated for changes in the thyroid, adrenal and reproductive axes. No significant endocrinopathies were noted

In the second study, 122 patients with chronic insomnia received 16 mg Rozerem or placebo for 6 months, and were evaluated for changes in the same systems. Results indicated no changes in thyroid or adrenal axis function, but did note abnormalities in the reproductive axis of female patients. Specifically, female patients experienced a significant mean increase in serum prolactin levels from baseline of 34%, compared to a 4% decrease for placebo (p=0.003). Disruptions were not noted in men. 32% of the total study population receiving Rozerem experienced increases in prolactin levels from baseline, vs. 19% for placebo. Menstrual patterns did not vary significantly between groups.

In 12 month open-label study in adult and elderly patients, 2 instances of abnormal morning cortisol levels (with abnormal follow-up ACTH stimulation test results) were observed, and 1 additional female patient developed prolactinoma. The relationship between these events and Rozerem administration was not clear.

Abuse Potential
A placebo- and active-controlled 7-arm-crossover study of the drug was conducted to investigate the abuse potential of the drug. 14 subjects with a history of sedative/hypnotic or anxiolytic drug abuse were enrolled, each of whom received 3 doses of Rozerem (16 mg, 80 mg, or 160 mg), 3 doses of the abusable benzodiazepine triazolam (0.25 mg, 0.50 mg, or 0.75 mg) or placebo; each subject received single doses each of the 7 regimens with a 1 week washout between administrations. Abuse potential was quantified with subjective measures from each patient. Rozerem showed no differences in subjective responses indicative of abuse potential compared to placebo. The positive control drug triazolam showed consistent dose-related subjective ratings indicative of abuse potential in both peak and 24 hour effect.

Ongoing Study Commitments

• Deferred pediatric study under PREA for the treatment of insomnia characterized by difficulty with sleep onset in pediatric patients ages 0 through 16.
  Final Report Submission: July 22, 2012

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Adverse events associated with the use of Rozerem may include, but are not limited to, the following:

• Headache
• Somnolence
• Fatigue
• Dizziness
• Nausea
• Exacerbated Insomnia
• Respiratory Infection

Due to the hypnotic properties of Rozerem, patients are advised to avoid hazardous activities (including the operation of heavy machinery or vehicles) and tasks requiring concentration following dosing. In addition, though potential interactions are as yet unknown, patients should exercise caution if they consume alcohol with the drug.

Absorption and pharmacokinetics of Rozerem can be affected by food intake; patients are advised to avoid taking the drug with or directly after a high-fat meal. In addition, considerable pharmacokinetic interaction has been noted between Rozerem and a number of other classes of drugs, with significant effect on peak and trough plasma drug concentrations, and on total drug exposure. Some of these interactions can be serious or life-threatening. Patients should discuss potential interactions with their physicians.

Rozerem is a melatonin MT1 and MT2 receptor agonist. By binding selectively at these receptors, the drug mimcs and enhances the action of endogenous melatonin, which has been associated with maintenance of circadian sleep rhythm through the inhibitory activity of MT1 and MT2 systems on excitatory wakefulness-promoting circuits in the suprachiasmic nucleus. The drug has a comparatively low affinity for the melatonin MT3 receptor, which has been associated with additional systemic activity including modulation of intra-ocular pressure and leukotriene B4-induced leukocyte adhesion. The drug showed no measurable affinity for a number of other systems, including benzodiazepine receptors, dopamine receptors, opiate receptors, ion channels, and transporters, and no effect on the activity of various enzymes.

Kato K, Hirai K, Nishiyama K, Uchikawa O, Fukatsu K, Ohkawa S, Kawamata Y, Hinuma S, Miyamoto M. Neurochemical properties of ramelteon (TAK-375), a selective MT1/MT2 receptor agonist. Neuropharmacology 2005 Feb;48(2):301-10

Hirai K, Kita M, Ohta H, Nishikawa H, Fujiwara Y, Ohkawa S, Miyamoto M. Ramelteon (TAK-375) accelerates reentrainment of circadian rhythm after a phase advance of the light-dark cycle in rats. Journal of Biological Rhythms 2005 Feb;20(1):27-37

Turek FW, Gillette MU. Melatonin, sleep, and circadian rhythms: rationale for development of specific melatonin agonists. Sleep Medicine 2004 Nov;5(6):523-32

For additional information regarding Rozerem or insomnia, please visit the Rozerem web page.