Ramelteon (Page 4 of 6)

12.4 Pharmacokinetics in Special Populations

Age

In a group of 24 elderly subjects aged 63 to 79 years administered a single Ramelteon Tablets 16 mg dose, the mean C max and AUC 0-inf values were 11.6 ng/mL (SD, 13.8) and 18.7 ng∙hr/mL (SD, 19.4), respectively. The elimination half-life was 2.6 hours (SD, 1.1). Compared with younger adults, the total exposure (AUC 0-inf ) and C max of ramelteon were 97 and 86% higher, respectively, in elderly subjects. The AUC 0-inf and C max of M-II were increased by 30 and 13%, respectively, in elderly subjects.

Gender

There are no clinically meaningful gender-related differences in the pharmacokinetics of Ramelteon Tablets or its metabolites.

Hepatic Impairment

Exposure to Ramelteon Tablets was increased almost four-fold in subjects with mild hepatic impairment after seven days of dosing with 16 mg/day; exposure was further increased (more than ten-fold) in subjects with moderate hepatic impairment. Exposure to M-II was only marginally increased in mildly and moderately impaired subjects relative to healthy matched controls. The pharmacokinetics of Ramelteon Tablets have not been evaluated in subjects with severe hepatic impairment (Child-Pugh Class C). Ramelteon Tablets should be used with caution in patients with moderate hepatic impairment [see Warnings and Precautions (5.6)].

Renal Impairment

The pharmacokinetic characteristics of Ramelteon Tablets were studied after administering a 16 mg dose to subjects with mild, moderate, or severe renal impairment based on predose creatinine clearance (53 to 95, 35 to 49, or 15 to 30 mL/min/1.73 m 2 , respectively), and in subjects who required chronic hemodialysis. Wide intersubject variability was seen in Ramelteon Tablet exposure parameters. However, no effects on C max or AUC 0-t of parent drug or M-II were seen in any of the treatment groups; the incidence of adverse events was similar across groups. These results are consistent with the negligible renal clearance of ramelteon, which is principally eliminated via hepatic metabolism. No adjustment of Ramelteon Tablet dosage is required in patients with renal impairment, including patients with severe renal impairment (creatinine clearance of ≤30 mL/min/1.73 m 2) and patients who require chronic hemodialysis.

12.5 Drug-Drug Interactions

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

Effects of Other Drugs on Ramelteon Tablets Metabolism

Fluvoxamine (strong CYP1A2 inhibitor)

When fluvoxamine 100 mg twice daily was administered for three days prior to single-dose co-administration of Ramelteon Tablets 16 mg and fluvoxamine, the AUC 0-inf for ramelteon increased approximately 190-fold, and the C max increased approximately 70-fold, compared to Ramelteon Tablets administered alone. Ramelteon Tablets should not be used in combination with fluvoxamine. Other less strong CYP1A2 inhibitors have not been adequately studied. Ramelteon Tablets 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 AUC 0-inf and C max ) after a single 32 mg dose of Ramelteon Tablets. Efficacy may be reduced when Ramelteon Tablets are used in combination with strong CYP enzyme inducers such as rifampin [see Drug Interactions (7)].

Ketoconazole (strong CYP3A4 inhibitor)

The AUC 0-inf and C max of ramelteon increased by approximately 84% and 36%, respectively, when a single 16 mg dose of Ramelteon Tablets was administered on the fourth day of ketoconazole 200 mg twice daily administration, compared to administration of Ramelteon Tablets alone. Similar increases were seen in M-II pharmacokinetic variables. Ramelteon Tablets 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 (AUC 0-inf and C max ) of ramelteon after a single 16 mg dose of Ramelteon Tablets was increased by approximately 150% when administered with fluconazole. Similar increases were also seen in M-II exposure. Ramelteon Tablets 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, (AUC 0-inf ) and a mean increase of approximately 87% in maximum exposure to ramelteon (C max ) after a single 8 mg dose of Ramelteon Tablets. No change was seen in M-II exposure. Patients should be closely monitored when Ramelteon Tablets are 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, (AUC 0-inf ) and a mean increase of approximately 69% in maximum exposure to ramelteon (C max ) after a single 8 mg dose of Ramelteon Tablets. No change was seen in M-II exposure. Patients should be closely monitored when Ramelteon Tablets are coadministered with doxepin [see Drug Interactions (7)].

Interaction studies of concomitant administration of Ramelteon Tablets 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 Tablets on Metabolism of Other Drugs

Zolpidem

Administration of ramelteon 8 mg once daily for 11 days resulted in an increase in median T max of zolpidem by approximately 20 minutes and exposure to zolpidem (both AUC 0-inf and C max ) was unchanged after a single 10 mg dose of zolpidem. Ordinarily zolpidem should not be given in a patient taking Ramelteon Tablets.

Concomitant administration of Ramelteon Tablets 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 Tablets

With single-dose, daytime coadministration of Ramelteon Tablets 32 mg and alcohol (0.6 g/kg), there were no clinically meaningful or statistically significant effects on peak or total exposure to Ramelteon Tablets. 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 post-dose 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 Tablets is to promote sleep, patients should be cautioned not to consume alcohol when using Ramelteon Tablets.

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 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 a 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.

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/m 2. Oral administration of ramelteon (up to 600 mg/kg/day) to male rats had no effects on sperm quality or reproductive performance.

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