Drug Interaction Report

MONITOR: Coadministration with potent inducers of CYP450 3A4, 2C9, and/or 2C19 may decrease the plasma concentrations of ospemifene, which is metabolized by these isoenzymes. The interaction has been studied with rifampin, a potent CYP450 3A4/moderate CYP450 2C9/moderate CYP450 2C19 inducer. In 12 postmenopausal women pretreated with rifampin 600 mg once daily for 5 days, administration of ospemifene 60 mg after breakfast on day 6 resulted in 51% and 58% decreases in ospemifene peak plasma concentration (Cmax) and systemic exposure (AUC), respectively, compared to administration of ospemifene alone.

MANAGEMENT: The potential for reduced therapeutic effects of ospemifene should be considered when used in combination with potent inducers of CYP450 3A4, 2C9, and/or 2C19.

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.

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.