Drug Interaction Report

MONITOR: Coadministration with drugs that are inhibitors of CYP450 3A4 may increase the plasma concentrations of tolterodine, which is partially metabolized by the isoenzyme. Tolterodine is primarily metabolized by CYP450 2D6 in most patients (referred to as "extensive metabolizers" or "EMs") to an equipotent, active metabolite, 5-hydroxymethyl tolterodine (5-HMT). However, in patients who are CYP450 2D6-deficient, or so-called "poor metabolizers" or "PMs" of CYP450 2D6 (approximately 7% of Caucasians and less than 2% of Asians and individuals of African descent), tolterodine is primarily metabolized by CYP450 3A4 to N-dealkylated tolterodine. Coadministration of tolterodine with ketoconazole 200 mg daily, a potent CYP450 3A4 inhibitor, increased the tolterodine mean peak plasma concentration (Cmax) by 2-fold and the mean systemic concentrations (AUC) by 2.5-fold in PMs. Data are not available for coadministration of tolterodine with CYP450 3A4 inhibitors in EMs or less potent CYP450 3A4 inhibitors. As tolterodine causes concentration-dependent QT interval prolongation, an increase in its AUC could increase the possibility of experiencing this adverse effect. Likewise, this risk may be further increased if the CYP450 3A4 inhibitor being used also carries a risk of QT prolongation (e.g., asciminib, bepridil, ciprofloxacin, clofazimine, crizotinib, erythromycin, fluconazole, lapatinib, pazopanib, rucaparib).

MANAGEMENT: Caution is advised when tolterodine is used with CYP450 3A4 inhibitors. Clinical and laboratory monitoring, including QTc interval and serum electrolytes, is advised. Patients should have regular ECGs and be monitored for arrhythmias when the QTc interval is prolonged. If the QTc interval becomes markedly prolonged or symptoms of arrhythmia occur, drug discontinuation should be considered. Patients should be advised to seek prompt medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, fainting, palpitation, irregular heart rhythm, shortness of breath, or syncope. Patients should be advised to notify their physician if they experience new or worsening side effects of tolterodine including severe blurry vision, difficulty urinating, dry mouth, headache, drowsiness, dizziness, or GI upset.

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.