Drug Interaction Report

MONITOR: Coadministration with drugs that are known to inhibit both CYP450 3A4 and 2C9 may increase the plasma concentrations of ospemifene, which is primarily metabolized by these isoenzymes, with additional contribution from CYP450 2C19 and other pathways. The interaction has been studied with fluconazole, a moderate CYP450 3A4/potent CYP450 2C9/moderate CYP450 2C19 inhibitor. In 14 postmenopausal women given fluconazole 400 mg once followed by 200 mg daily for a total duration of 8 days, administration of ospemifene 60 mg after breakfast on day 5 of fluconazole treatment resulted in 1.7- and 2.7-fold increases in ospemifene peak plasma concentration (Cmax) and systemic exposure (AUC), respectively, compared to administration of ospemifene alone. The potential for increased risk of adverse events such as hot flush, thromboembolism, and endometrial or breast cancer should be considered.

MANAGEMENT: Caution is advised if ospemifene is used in combination with drugs that are inhibitors of both CYP450 3A4 and 2C9. Patients should be advised to seek medical attention if they develop potential signs and symptoms of thromboembolism such as chest pain, shortness of breath, and pain or swelling in the arms or legs.

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

MANAGEMENT: Patients receiving CNS-active agents should be warned of this interaction and advised to avoid or limit consumption of alcohol. Ambulatory patients should be counseled to avoid hazardous activities requiring complete mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

ADJUST DOSING INTERVAL: Food significantly enhances the oral bioavailability of ospemifene. In a cross-study comparison, administration of a single 60 mg dose of ospemifene with a high-fat/high-calorie meal (860 kcal) in postmenopausal women increased ospemifene peak plasma concentration (Cmax) and systemic exposure (AUC) by 2.3- and 1.7-fold, respectively, compared to administration under fasted condition. Elimination half-life and time to maximum concentration (Tmax) were not altered. In two separate food effect studies where different ospemifene tablet formulations were given to healthy male volunteers, ospemifene Cmax and AUC increased by 2.3- and 1.8-fold, respectively, with a low-fat/low-calorie meal (300 kcal) and 3.6- and 2.7-fold, respectively, with a high-fat/high-calorie meal (860 kcal) relative to fasting.

MANAGEMENT: Ospemifene should be taken once daily with food.