Drug Interaction Report

MONITOR: Coadministration of daclizumab with other agents known to induce hepatotoxicity may increase the risk of liver injury. Serious drug-related hepatic injury, including liver failure and autoimmune hepatitis, has been reported across controlled and open-label studies in 1.7% of daclizumab-treated patients and may occur at any time during treatment and up to 5 months after treatment cessation. Fatal cases have occurred. In addition, cases of hepatic injury have occurred in patients taking daclizumab concomitantly with other hepatotoxic drugs; however, the contributory role of these other medicines has not been established.

MANAGEMENT: Caution is advised if daclizumab is used with other potentially hepatotoxic agents, including non-prescription products and herbal supplements. Patients treated with daclizumab should have serum transaminase levels and total bilirubin measured prior to initiation of treatment and monthly during treatment in accordance with the manufacturer's recommendations, and the dosing adjusted or interrupted as necessary. Patients should be advised to seek medical attention if they experience potential signs and symptoms of hepatotoxicity such as fever, rash, itching, anorexia, nausea, vomiting, fatigue, malaise, right upper quadrant pain, dark urine, pale stools, and jaundice.

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.