Ramelteon (Page 5 of 7)

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis
Ramelteon was administered to mice and rats at oral doses of 0, 30, 100, 300, or 1000 mg/kg/day (mice) and 0, 15, 60, 250, or 1000 mg/kg/day (rats). Mice and rats were dosed for two years, except at the high dose (94 weeks for male and female mice and female rats). In mice, dose-related increases in the incidence of hepatic tumors (adenomas, carcinomas, hepatoblastomas) were observed in males and females. The no-effect dose for hepatic tumors in mice (30 mg/kg/day) is approximately 20 times the recommended human dose (RHD) of 8 mg/day based on body surface area (mg/m 2).

In rats, the incidence of hepatic adenoma and benign Leydig cell tumors of the testis was increased in males at doses ≥250 mg/kg/day. In females, the incidence of hepatic adenoma was increased at doses ≥60 mg/kg/day. The incidence of hepatic carcinoma was increased in males and female rats at 1000 mg/kg/day.The no-effect dose for tumors in rats (15 mg/kg/day) is approximately 20 times the RHD based on mg/m 2.

Mutagenesis


Ramelteon was not genotoxic in the in vitro bacterial reverse mutation (Ames) assay, the in vitro mouse lymphoma TK +/- assay, and in in vivo oral micronucleus assays in mouse and rat. Ramelteon was clastogenic in the in vitro chromosomal aberration assay in Chinese hamster lung cells.

Separate studies indicated that the concentration of the M-II metabolite formed in the presence of metabolic activation exceeded the concentration of ramelteon; therefore, the genotoxic potential of the M-II metabolite was also assessed in the in vitro studies.

Impairment of Fertility
When ramelteon (doses of 6 to 600 mg/kg/day) was administered orally to male and female rats prior to and during mating and early gestation, alterations in estrus cyclicity and decreased numbers of corpora lutea, implantations, and live embryos were observed at doses greater than 20 mg/kg/day. The no-effect dose is approximately 24 times the RHD of 8 mg/day based on (mg/m 2). Oral administration of ramelteon (up to 600 mg/kg/day) to male rats had no effects on sperm quality or reproductive performance.

14 CLINICAL STUDIES

14.1 Controlled Clinical Trials

Chronic Insomnia

Three randomized, double-blind trials in subjects with chronic insomnia employing polysomnography (PSG) were provided as objective support of ramelteon’s effectiveness in sleep initiation.

One study enrolled younger adults (aged 18 to 64 years, inclusive) with chronic insomnia and employed a parallel design in which the subjects received a single, nightly dose of ramelteon tablets (8 or 16 mg) or matching placebo for 35 days. PSG was performed on the first two nights in each of Weeks 1, 3, and 5 of treatment. Ramelteon tablets reduced the average latency to persistent sleep at each of the time points when compared to placebo. The 16 mg dose conferred no additional benefit for sleep initiation.

The second study employing PSG was a three-period crossover trial performed in subjects aged 65 years and older with a history of chronic insomnia. Subjects received ramelteon tablets (4 or 8 mg) or placebo and underwent PSG assessment in a sleep laboratory for two consecutive nights in each of the three study periods. Both doses of ramelteon tablets reduced latency to persistent sleep when compared to placebo.

The third study evaluated long term efficacy and safety in adults with chronic insomnia. Subjects received a single, nightly dose of ramelteon tablets 8 mg or matching placebo for six months. PSG was performed on the first two nights of Week 1 and Months 1, 3, 5, and 6. Ramelteon tablets reduced sleep latency at each time point when compared to placebo. In this study, when the PSG results from nights 1 and 2 of Month 7 were compared to the results from nights 22 and 23 of Month 6, there was a statistically significant increase in LPS of 33% (9.5 minutes) in the ramelteon group. There was no increase in LPS in the placebo group when the same time periods were compared.

A randomized, double-blind, parallel group study was conducted in outpatients aged 65 years and older with chronic insomnia and employed subjective measures of efficacy (sleep diaries). Subjects received ramelteon tablets (4 or 8 mg) or placebo for 35 nights. Ramelteon tablets reduced patient-reported sleep latency compared to placebo. A similarly designed study performed in younger adults (aged 18 to 64 years) using 8 and 16 mg of ramelteon did not replicate this finding of reduced patient-reported sleep latency compared to placebo.

While the 16 mg dose was evaluated as a potential treatment for adults, it was shown to confer no additional benefit for sleep initiation and was associated with higher incidences of fatigue, headache and next-day somnolence.

Transient Insomnia

In a randomized, double-blind, parallel-group trial using a first-night-effect model, healthy adults received placebo or ramelteon tablets before spending one night in a sleep laboratory and being evaluated with PSG. Ramelteon tablets demonstrated a decrease in mean latency to persistent sleep as compared to placebo.

14.2 Studies Pertinent to Safety Concerns for Sleep-Promoting Drugs

Results from Human Laboratory Abuse Liability Studies

A human laboratory abuse potential study was performed in 14 subjects with a history of sedative/hypnotic or anxiolytic drug abuse. Subjects received single oral doses of ramelteon tablets (16, 80, or 160 mg), triazolam (0.25, 0.50, or 0.75 mg) or placebo. All subjects received each of the seven treatments separated by a wash-out period and underwent multiple standard tests of abuse potential. No differences in subjective responses indicative of abuse potential were found between ramelteon tablets and placebo at doses up to 20 times the recommended therapeutic dose. The positive control drug, triazolam, consistently showed a dose-response effect on these subjective measures, as demonstrated by the differences from placebo in peak effect and overall 24 hour effect.

Residual Pharmacological Effect in Insomnia Trials

In order to evaluate potential next-day residual effects, the following scales were used: 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 to assess alertness and ability to concentrate. There was no evidence of next-day residual effect seen after two nights of ramelteon use during the crossover studies.

In a 35 night, double-blind, placebo-controlled, parallel-group study in adults with chronic insomnia, measures of residual effects were performed at three time points. Overall, the magnitudes of any observed differences were small. At Week 1, patients who received 8 mg of ramelteon tablets had a mean VAS score (46 mm on a 100 mm scale) indicating more fatigue in comparison to patients who received placebo (42 mm). At Week 3, patients who received 8 mg of ramelteon tablets had a lower mean score for immediate recall (7.5 out of 16 words) compared to patients who received placebo (8.2 words); and the patients treated with ramelteon tablets had a mean VAS score indicating more sluggishness (27 mm on a 100 mm VAS) in comparison to the placebo-treated patients (22 mm). Patients who received ramelteon tablets did not have next-morning residual effects that were different from placebo at Week 5.

Rebound Insomnia/Withdrawal

Potential rebound insomnia and withdrawal effects were assessed in four studies in which subjects received ramelteon tablets or placebo for up to six months; three were 35 day studies, one was a six month study. These studies included a total of 2,533 subjects, of whom 854 were elderly.

Tyrer Benzodiazepine Withdrawal Symptom Questionnaire (BWSQ)
The BWSQ is a self-report questionnaire that solicits specific information on 20 symptoms commonly experienced during withdrawal from benzodiazepine receptor agonists; Ramelteon tablets is not a benzodiazepine receptor agonist.

In two of the three 35 day insomnia studies, the questionnaire was administered one week after completion of treatment; in the third study, the questionnaire was administered on Days 1 and 2 after completion. In all three of the 35 day studies, subjects receiving ramelteon tablets 4, 8 or 16 mg daily reported BWSQ scores similar to those of subjects receiving placebo.

In the six month study, there was no evidence of withdrawal from the 8 mg dose as measured by the BWSQ.

Rebound Insomnia
Rebound insomnia was assessed in the 35 day studies by measuring sleep latency after abrupt treatment discontinuation. One of these studies employed PSG in younger adult subjects receiving ramelteon tablets 8 or 16 mg; the other two studies employed subjective measures of sleep-onset insomnia in elderly subjects receiving ramelteon tablets 4 or 8 mg, and in younger adult subjects receiving ramelteon tablets 8 or 16 mg. There was no evidence that ramelteon tablets caused rebound insomnia during the post-treatment period.

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