Drug Interaction Report

MONITOR: Coadministration with potent inhibitors of CYP450 3A4 and/or 2C9 may increase the plasma concentrations and pharmacologic effects of ramelteon, which is partially metabolized by these isoenzymes. In healthy volunteers, administration of a single 16 mg oral dose of ramelteon following pretreatment with the potent CYP450 3A4 inhibitor ketoconazole (200 mg orally twice daily for 4 days) increased ramelteon peak plasma concentration (Cmax) by 36% and systemic exposure (AUC) by 84% compared to administration of ramelteon alone. Likewise, coadministration with fluconazole, a potent CYP450 2C9 inhibitor, resulted in an increase of approximately 150% in the Cmax and AUC of ramelteon following a single 16 mg oral dose. Similar pharmacokinetic changes were also observed with its biologically active metabolite, known as M-II.

MANAGEMENT: Caution is advised if ramelteon is prescribed in combination with potent inhibitors of CYP450 3A4 (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, conivaptan, delavirdine, nefazodone, protease inhibitors, ketolide and certain macrolide antibiotics) and/or CYP450 2C9 (e.g., fluconazole, gemfibrozil, imatinib, miconazole). A reduction in the ramelteon dosage may be necessary in patients who experience excessive sedation.

GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of ramelteon. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills.

ADJUST DOSING INTERVAL: Administration of ramelteon with or immediately after a high-fat/heavy meal may delay the onset of hypnotic effects. In study subjects, administration of a 16 mg dose of ramelteon with a high-fat meal decreased the peak plasma drug concentration (Cmax) by 22% and delayed the median time to reach peak plasma drug concentration (Tmax) by approximately 45 minutes compared to administration in a fasted state.

MANAGEMENT: Patients receiving ramelteon should be advised to avoid the consumption of alcohol. For faster sleep onset, ramelteon should not be administered with or immediately after a high-fat/heavy meal.

Food enhances the oral absorption and bioavailability of tenofovir, the active entity of tenofovir disoproxil fumarate. According to the product labeling, administration of the drug following a high-fat meal increased the mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of tenofovir by approximately 14% and 40%, respectively, compared to administration in the fasting state. However, administration with a light meal did not significantly affect the pharmacokinetics of tenofovir compared to administration in the fasting state. Food delays the time to reach tenofovir Cmax by approximately 1 hour. Tenofovir disoproxil fumarate may be administered without regard to meals.