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 Pharmacologic response to silodosin should be monitored more closely whenever a CYP450 3A4 inhibitor is added to or withdrawn from therapy, and the silodosin dosage adjusted as necessary.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.

MONITOR: Coadministration with inducers of CYP450 3A4 and/or P-glycoprotein (P-gp) may decrease the plasma concentrations of silodosin, which is a substrate of both the isoenzyme and efflux transporter.

MANAGEMENT: The potential for diminished pharmacologic effects of silodosin should be considered during coadministration with CYP450 3A4 and/or P-gp inducers. Alternative treatments may be required if an interaction is suspected.

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.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of ivacaftor. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Elexacaftor and tezacaftor are also CYP450 3A4 substrates in vitro and may interact similarly with grapefruit juice, whereas lumacaftor is not expected to interact.

ADJUST DOSING INTERVAL: According to prescribing information, systemic exposure to ivacaftor increased approximately 2.5- to 4-fold, systemic exposure to elexacaftor increased approximately 1.9- to 2.5-fold, and systemic exposure to lumacaftor increased approximately 2-fold following administration with fat-containing foods relative to administration in a fasting state. Tezacaftor exposure is not significantly affected by administration of fat-containing foods.

MANAGEMENT: Patients treated with ivacaftor-containing medications should avoid consumption of grapefruit juice and any food that contains grapefruit or Seville oranges. All ivacaftor-containing medications should be administered with fat-containing foods such as eggs, avocados, nuts, meat, butter, peanut butter, cheese pizza, and whole-milk dairy products. A typical cystic fibrosis diet will satisfy this requirement.