Drug Interaction Report

MONITOR: Coadministration with inhibitors of CYP450 1A2 may increase the plasma concentrations and pharmacologic effects of ramelteon, which is primarily metabolized by the isoenzyme. In healthy volunteers, administration of a single 16 mg dose of ramelteon following pretreatment with the potent CYP450 1A2 inhibitor fluvoxamine (100 mg orally twice daily for 3 days) resulted in a 70-fold increase in ramelteon peak plasma concentration (Cmax) and a 190-fold increase in systemic exposure (AUC) compared to administration of ramelteon alone. However, fluvoxamine is known to also inhibit CYP450 2C9 and 3A4, both of which contribute significantly to the metabolism of ramelteon. Concomitant administration of ramelteon with less potent CYP450 1A2 inhibitors has not been evaluated.

MANAGEMENT: Caution is advised when ramelteon is used with CYP450 1A2 inhibitors. A reduction in the ramelteon dosage may be necessary in patients who experience excessive sedation or other adverse effects.

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.