Ramelteon (Page 4 of 6)

12.5 Drug-Drug Interactions

Ramelteon has a highly variable intersubject pharmacokinetic profile (approximately 100% coefficient of variation in Cmax and AUC). As noted above, CYP1A2 is the major isozyme involved in the metabolism of ramelteon; the CYP2C subfamily and CYP3A4 isozymes are also involved to a minor degree.

Effects of Other Drugs on Ramelteon Metabolism

Fluvoxamine (strong CYP1A2 inhibitor)

When fluvoxamine 100 mg twice daily was administered for three days prior to single-dose coadministration of ramelteon 16 mg and fluvoxamine, the AUC0-inf for ramelteon increased approximately 190-fold, and the Cmax increased approximately 70-fold, compared to ramelteon administered alone. Ramelteon should not be used in combination with fluvoxamine. Other less strong CYP1A2 inhibitors have not been adequately studied. Ramelteon should be administered with caution to patients taking less strong CYP1A2 inhibitors [see Contraindications (4), Drug Interactions (7)].

Rifampin (strong CYP enzyme inducer)

Administration of rifampin 600 mg once daily for 11 days resulted in a mean decrease of approximately 80% (40% to 90%) in total exposure to ramelteon and metabolite M-II, (both AUC0-inf and Cmax ) after a single 32 mg dose of ramelteon. Efficacy may be reduced when ramelteon is used in combination with strong CYP enzyme inducers such as rifampin [see Drug Interactions (7)].

Ketoconazole (strong CYP3A4 inhibitor)

The AUC0-inf and Cmax of ramelteon increased by approximately 84% and 36%, respectively, when a single 16 mg dose of ramelteon was administered on the fourth day of ketoconazole 200 mg twice daily administration, compared to administration of ramelteon alone. Similar increases were seen in M-II pharmacokinetic variables. Ramelteon should be administered with caution in subjects taking strong CYP3A4 inhibitors such as ketoconazole [see Drug Interactions (7)].

Fluconazole (strong CYP2C9 inhibitor)

The total and peak systemic exposure (AUC0-inf and Cmax ) of ramelteon after a single 16 mg dose of ramelteon was increased by approximately 150% when administered with fluconazole. Similar increases were also seen in M-II exposure. Ramelteon should be administered with caution in subjects taking strong CYP2C9 inhibitors such as fluconazole [see Drug Interactions (7)].

Donepezil

Administration of donepezil 10 mg once daily for 26 days resulted in a mean increase of approximately 100% in overall exposure to ramelteon, (AUC0-inf ) and a mean increase of approximately 87% in maximum exposure to ramelteon (Cmax ) after a single 8 mg dose of ramelteon tablets. No change was seen in M-II exposure. Patients should be closely monitored when ramelteon is coadministered with donepezil [see Drug Interactions (7)].

Doxepin

Administration of doxepin 10 mg once daily for 23 days resulted in a mean increase of approximately 66% in overall exposure to ramelteon, (AUC0-inf ) and a mean increase of approximately 69% in maximum exposure to ramelteon (Cmax ) after a single 8 mg dose of ramelteon tablets. No change was seen in M-II exposure. Patients should be closely monitored when ramelteon is coadministered with doxepin [see Drug Interactions (7)].

Interaction studies of concomitant administration of ramelteon with fluoxetine (CYP2D6 inhibitor), omeprazole (CYP1A2 inducer/CYP2C19 inhibitor), theophylline (CYP1A2 substrate), dextromethorphan (CYP2D6 substrate), sertraline, venlafaxine, escitalopram, gabapentin, and zolpidem did not produce clinically meaningful changes in either peak or total exposures to ramelteon or the M-II metabolite.

Effects of Ramelteon on Metabolism of Other Drugs

Zolpidem

Administration of ramelteon 8 mg once daily for 11 days resulted in an increase in median Tmax of zolpidem by approximately 20 minutes and exposure to zolpidem (both AUC0-inf and Cmax ) was unchanged after a single 10 mg dose of zolpidem. Ordinarily zolpidem should not be given in a patient taking ramelteon.

Concomitant administration of ramelteon with omeprazole (CYP2C19 substrate), dextromethorphan (CYP2D6 substrate), midazolam (CYP3A4 substrate), theophylline (CYP1A2 substrate), digoxin (p-glycoprotein substrate), warfarin (CYP2C9 [S]/CYP1A2 [R] substrate), venlafaxine, fluvoxamine, donepezil, doxepin, sertraline, escitalopram, and gabapentin did not produce clinically meaningful changes in peak and total exposures to these drugs.

Effect of Alcohol on Ramelteon

With single-dose, daytime coadministration of ramelteon 32 mg and alcohol (0.6 g/kg), there were no clinically meaningful or statistically significant effects on peak or total exposure to ramelteon. However, an additive effect was seen on some measures of psychomotor performance (i.e., the Digit Symbol Substitution Test, the Psychomotor Vigilance Task Test, and a Visual Analog Scale of Sedation) at some postdose time points. No additive effect was seen on the Delayed Word Recognition Test. Because alcohol by itself impairs performance, and the intended effect of ramelteon is to promote sleep, patients should be cautioned not to consume alcohol when using ramelteon.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Ramelteon was administered to mice and rats at oral doses of 0, 30, 100, 300, or 1,000 mg/kg/day (mice) and 0, 15, 60, 250, or 1,000 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/m2).

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 1,000 mg/kg/day. The no-effect dose for tumors in rats (15 mg/kg/day) is approximately 20 times the RHD based on mg/m2.

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.

The M-II metabolite was not tested for genotoxicity. However, it was present in the test medium of the parent drug at concentrations higher than those of the parent.

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/m2. 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 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 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 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 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 before spending one night in a sleep laboratory and being evaluated with PSG. Ramelteon demonstrated a decrease in mean latency to persistent sleep as compared to placebo.

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