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: Grapefruit juice may increase the plasma concentrations of nilotinib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. Because nilotinib is associated with concentration-dependent prolongation of the QT interval, increased levels may potentiate the risk of ventricular arrhythmias such as torsade de pointes and sudden death.

ADJUST DOSING INTERVAL: Food increases the oral bioavailability of nilotinib. The mechanism of interaction is unknown. Compared to the fast state, nilotinib systemic exposure (AUC) increased by 82% when the dose was given 30 minutes after a high-fat meal. Because nilotinib is associated with concentration-dependent prolongation of the QT interval, increased levels may potentiate the risk of ventricular arrhythmias such as torsade de pointes and sudden death.

MANAGEMENT: Patients treated with nilotinib should avoid consumption of grapefruit, grapefruit juice, and any supplement containing grapefruit extract. In addition, no food should be consumed for at least 2 hours before and 1 hour after a nilotinib dose.

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.