Drug Interaction Report

MONITOR: Coadministration with inducers of CYP450 isoenzymes may decrease the plasma concentrations and pharmacologic effects of ramelteon, which is metabolized by CYP450 1A2 and, to a lesser extent, by CYP450 3A4 and the 2C subfamily of isoenzymes. When a single 32 mg oral dose of ramelteon was administered to healthy volunteers following pretreatment with the potent CYP450 inducer rifampin (600 mg orally once daily for 11 days), total systemic exposure (AUC) to ramelteon and its pharmacologically active metabolite was decreased by an average of approximately 80% (range 40% to 90%). Use with other inducers has not been adequately studied.

MANAGEMENT: The efficacy of ramelteon may be reduced when prescribed with potent inducers of CYP450 isoenzymes such as carbamazepine, enzalutamide, phenobarbital, phenytoin, rifampin, and St. John's wort. Other known inducers include aminoglutethimide, bexarotene, bosentan, dabrafenib, dexamethasone, efavirenz, etravirine, mitotane, modafinil, nafcillin, nevirapine, rifabutin, rifapentine, barbiturates and various other anticonvulsants, although the extent to which they interact with ramelteon is unknown.

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

In a small, randomized, crossover study, the administration of carbamazepine with grapefruit juice (compared to water) increased plasma drug concentrations by approximately 40%. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits.

MANAGEMENT: Patients receiving carbamazepine should be advised to avoid or limit consumption of alcohol. Given the drug's narrow therapeutic index, patients receiving carbamazepine therapy should preferably avoid the regular consumption of grapefruits and grapefruit juice to prevent any undue fluctuations in plasma drug levels. Patients should be advised to report signs of carbamazepine toxicity (nausea, visual disturbances, dizziness, or ataxia) to their physicians.

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.