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.

Although some in vitro data indicate synergism between macrolide antibiotics and penicillins, other in vitro data indicate antagonism. When these drugs are given together, neither has predictable therapeutic efficacy. Data are available for erythromycin, although theoretically this interaction could occur with any macrolide. Except for monitoring of the effectiveness of antibiotic therapy, no special precautions appear to be necessary.

Clarithromycin may increase and prolong the omeprazole plasma concentration. The mechanism may be related to clarithromycin inhibition of hepatic cytochrome P450 enzymes responsible for omeprazole metabolism. Coadministration of omeprazole may result in an increase in clarithromycin and 14-(R)-hydroxyclarithromycin plasma concentrations. These increases may be due to the effect of omeprazole on gastric pH.

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.

Grapefruit juice may delay the gastrointestinal absorption of clarithromycin but does not appear to affect the overall extent of absorption or inhibit the metabolism of clarithromycin. The mechanism of interaction is unknown but may be related to competition for intestinal CYP450 3A4 and/or absorptive sites. In an open-label, randomized, crossover study consisting of 12 healthy subjects, coadministration with grapefruit juice increased the time to reach peak plasma concentration (Tmax) of both clarithromycin and 14-hydroxyclarithromycin (the active metabolite) by 80% and 104%, respectively, compared to water. Other pharmacokinetic parameters were not significantly altered. This interaction is unlikely to be of clinical significance.