Safety and Subjective Sleep Effects of Ramelteon Administration in Adults and Older Adults With Chronic Primary Insomnia: A 1-Year, Open-Label Study

Objective: To evaluate the long-term safety and subjective sleep effects of ramelteon in adults with chronic insomnia.

Method: Subjects with primary insomnia (DSM-IV-TR criteria) for ≥ 3 months received ramelteon nightly for 1 year; a 3-day placebo run out followed. Subjects aged ≥ 65 years received open-label ramelteon 8 mg (N = 248); those aged 18 to 64 years received ramelteon 16 mg (N = 965). Subjects completed sleep diaries and returned to the clinic at week 1 and at months 1, 2, 3, 4, 6, 8, 10, and 12 for safety assessments and investigator-performed Clinical Global Impressions. The study was conducted from February 2003 through September 2004.

Results: There were no noteworthy changes in vital signs, physical examinations, clinical chemistry, hematology, or urinalysis values and no electrocardiogram changes to suggest adverse cardiac effects. Endocrine values remained within normal range throughout treatment. Consistent statistically significant (p ≥.05) decreases in free thyroxine (in adults) and free testosterone (in older men) were detected. Duration of menses increased by approximately 1 day. A total of 40.8% of subjects reported at least 1 adverse event possibly associated with ramelteon use. The adverse events reported varied considerably, the incidence of individual adverse events was low, and the frequencies of adverse events were similar at months 6 and 12. In both groups, subjective sleep latency and total sleep time improved by month 1 and was sustained during the 1-year period. At 6 months and 1 year, Clinical Global Impressions indices were improved. During placebo run out, subjective sleep latency did increase but did not return to baseline.

Conclusion: Year-long administration of ramelteon was well tolerated. Ramelteon was associated with sustained improvements in subjective sleep latency, subjective total sleep time, and Clinical Global Impressions.

Trial Registration: clinicaltrials.gov Identifier: NCT00671086