Drug Interaction Report

ADJUST DOSING INTERVAL: Concurrent administration of agents that increase gastric pH such as proton pump inhibitors (PPIs), histamine type 2 (H2)-receptor antagonists, or antacids may decrease the plasma concentrations of nirogacestat. According to the manufacturer, nirogacestat is poorly soluble at a pH of 6 or more. Reduced therapeutic efficacy may occur.

MANAGEMENT: The manufacturer advises that antacids may be preferable if the use of a gastric acid reducing agent is considered clinically necessary. Dosage of the antacid should be separated from nirogacestat by at least 2 hours.

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.

ADJUST DOSING INTERVAL: Administration with food may increase the absorption of calcium. However, foods high in oxalic acid (spinach or rhubarb), or phytic acid (bran and whole grains) may decrease calcium absorption.

MANAGEMENT: Calcium may be administered with food to increase absorption. Consider withholding calcium administration for at least 2 hours before or after consuming foods high in oxalic acid or phytic acid.

ADJUST DOSING INTERVAL: Bulk-forming laxatives such as guar gum, psyllium, polycarbophil, or methylcellulose may affect the bioavailability of concomitantly administered substances due to their effect on the rate of gastrointestinal transit and gastric emptying.

MANAGEMENT: In general, oral medications should be administered at least 2 hours before or 2 hours after dosing of the bulk-forming laxative.