Drug Interaction Report

MONITOR: Coadministration with inhibitors of CYP450 3A4 may increase the plasma concentrations of silodosin, which is primarily metabolized by the isoenzyme. In a pharmacokinetic study, administration of a single 8 mg dose of silodosin with the potent CYP450 3A4 inhibitor ketoconazole (400 mg) resulted in a 3.8-fold increase in silodosin peak plasma concentration (Cmax) and a 3.2-fold increase in systemic exposure (AUC). The interaction has not been studied with moderate CYP450 3A4 inhibitors such as diltiazem, erythromycin, and verapamil.

MANAGEMENT: Caution is advised if silodosin is prescribed in combination with inhibitors of CYP450 3A4. Pharmacologic response to silodosin should be monitored more closely whenever a CYP450 3A4 inhibitor is added to or withdrawn from therapy, and the silodosin dosage adjusted as necessary. Patients should be advised to avoid rising abruptly from a sitting or recumbent position and to notify their physician if they experience dizziness, lightheadedness, syncope, orthostasis, or tachycardia. Taking silodosin at bedtime may minimize the occurrence of orthostatic effects. Patients should also avoid driving or operating hazardous machinery until they know how the medication affects them.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of lapatinib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits.

ADJUST DOSING INTERVAL: Food can significantly increase the oral bioavailability of lapatinib. According to the manufacturer, lapatinib peak plasma concentration (Cmax) was approximately 2.5- and 3-fold higher and systemic exposure (AUC) 3- and 4-fold higher when administered with a low fat meal (5% fat; 500 calories) or with a high-fat meal (50% fat; 1000 calories), respectively, compared to fasting. Dividing the daily dose also resulted in an approximately 2-fold higher systemic exposure at steady state compared to the same total dose administered once daily.

MANAGEMENT: Patients treated with lapatinib should preferably avoid the consumption of grapefruit or grapefruit juice. The manufacturer recommends that lapatinib be administered at least one hour before or one hour after a meal. The lapatinib dose is administered once daily and should not be divided.

ADJUST DOSING INTERVAL: Food may reduce the oral bioavailability of silodosin. The effect of a moderate-fat, moderate-calorie meal on silodosin pharmacokinetics was variable and decreased silodosin maximum plasma concentration (Cmax) by approximately 18% to 43% and systemic exposure (AUC) by 4% to 49% across three different studies. The maximum effect of food (i.e., coadministration with a high-fat, high-calorie meal) on the pharmacokinetics of silodosin was not evaluated. Safety and efficacy clinical trials for silodosin were always conducted in the presence of food intake.

MANAGEMENT: Patients should be instructed to take silodosin with a meal to reduce the risk of adverse events.