Drug Interactions between Fentanyl Transdermal System and nirogacestat

GENERALLY AVOID: Alcohol may potentiate the central nervous system (CNS) depressant effects of opioid analgesics including fentanyl. Concomitant use may result in additive CNS depression and impairment of judgment, thinking, and psychomotor skills. In more severe cases, hypotension, respiratory depression, profound sedation, coma, or even death may occur.

GENERALLY AVOID: Consumption of grapefruit juice during treatment with oral transmucosal formulations of fentanyl may result in increased plasma concentrations of fentanyl, which is primarily metabolized by CYP450 3A4 isoenzyme in the liver and intestine. Certain compounds present in grapefruit are known to inhibit CYP450 3A4 and may increase the bioavailability of swallowed fentanyl (reportedly up to 75% of a dose) and/or decrease its systemic clearance. The clinical significance is unknown. In 12 healthy volunteers, consumption of 250 mL regular-strength grapefruit juice the night before and 100 mL double-strength grapefruit juice one hour before administration of oral transmucosal fentanyl citrate (600 or 800 mcg lozenge) did not significantly affect fentanyl pharmacokinetics, overall extent of fentanyl-induced miosis (miosis AUC), or subjective self-assessment of various clinical effects compared to control. However, pharmacokinetic alterations associated with interactions involving grapefruit juice are often subject to a high degree of interpatient variability. The possibility of significant interaction in some patients should be considered.

MANAGEMENT: Patients should not consume alcoholic beverages or use drug products that contain alcohol during treatment with fentanyl. Any history of alcohol or illicit drug use should be considered when prescribing fentanyl, and therapy initiated at a lower dosage if necessary. Patients should be closely monitored for signs and symptoms of sedation, respiratory depression, and hypotension. Due to a high degree of interpatient variability with respect to grapefruit juice interactions, patients treated with fentanyl should preferably avoid the consumption of grapefruit and grapefruit juice. In addition, patients receiving transdermal formulations of fentanyl should be cautioned that drug interactions and drug effects may be observed for a prolonged period beyond removal of the patch, as significant amounts of fentanyl are absorbed from the skin for 17 hours or more after the patch is removed.

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.