Drug Interaction Report

MONITOR: Theoretically, coadministration with CYP450 3A4 inhibitors may increase the plasma concentrations of topical tacrolimus. The proposed mechanism involves inhibition of CYP450 3A4-mediated metabolism of tacrolimus, which is primary metabolized by this isoenzyme. However, systemic exposure from topical tacrolimus is reported to be minimal (less than 1 ng/mL) and so clinically significant drug interactions are not expected. Nevertheless, the possibility of an interaction cannot be ruled out.

MANAGEMENT: According to the manufacturer, caution is advised if topical tacrolimus is prescribed with CYP450 3A4 inhibitors. Patients should be monitored for systemic tacrolimus adverse effects including immunosuppression, infection, hyperkalemia, malignancy, nephrotoxicity, neurotoxicity, and hypertension.

GENERALLY AVOID: Grapefruit, grapefruit juice, Seville oranges, and starfruit may significantly increase the plasma concentrations and pharmacologic effects of nirogacestat. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in these fruits. Coadministration of multiple doses of nirogacestat (150 mg twice daily) with the moderate CYP450 3A4 inhibitors erythromycin and fluconazole are predicted to increase the AUC of nirogacestat by 2.73-fold and 3.18-fold, respectively. The interaction has not been studied with grapefruit, Seville oranges, or starfruit. In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition. Increased systemic exposure to nirogacestat may increase the risk of adverse effects including diarrhea, ovarian toxicity, hepatotoxicity, electrolyte abnormalities, and non-melanoma skin cancers.

MANAGEMENT: Patients treated with nirogacestat should avoid consumption of grapefruit, grapefruit juice, Seville oranges, starfruit, or any supplement containing grapefruit.