Drug Interaction Report

MONITOR: Coadministration with inhibitors of CYP450 2C8 and/or 2C9 may increase the plasma concentrations of montelukast, which is metabolized by these isoenzymes in addition to CYP450 3A4. When montelukast was administered with the potent CYP450 2C8/2C9 inhibitor gemfibrozil, montelukast systemic exposure (AUC) increased by 4.4-fold. The addition of itraconazole, a potent CYP450 3A4 inhibitor, to gemfibrozil and montelukast did not further increase the AUC of montelukast. Administration of itraconazole alone with montelukast also resulted in no significant increase in the AUC of montelukast, which would suggest that montelukast is primarily metabolized by CYP450 2C8 and 2C9 in vivo.

MANAGEMENT: According to the product labeling, no dosage adjustment of montelukast is required when used in combination with gemfibrozil. However, it may be advisable to monitor patients for potentially increased adverse effects during coadministration with gemfibrozil or other CYP450 2C8/2C9 inhibitors.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of selpercatinib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Inhibition of hepatic CYP450 3A4 may also contribute. The interaction has not been studied with grapefruit juice, but has been reported for other CYP450 3A4 inhibitors. When a single dose of selpercatinib (160 mg) was coadministered with multiple doses of itraconazole (200 mg once daily), a potent CYP450 3A4 inhibitor, selpercatinib peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 30% and 133%, respectively. Based on pharmacokinetic modeling, administration of multiple doses of selpercatinib (160 mg twice daily) with multiple doses of the moderate CYP450 3A4 inhibitors diltiazem (60 mg three times daily), fluconazole (200 mg once daily), or verapamil (80 mg three times daily) is predicted to increase selpercatinib Cmax by 46% to 76% and AUC by 60% to 99%. 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 exposure to selpercatinib may increase the risk of serious adverse effects such as QT interval prolongation, liver transaminase and bilirubin elevations, hypertension, hemorrhage, edema, and hypersensitivity reactions (e.g., fever, rash, arthralgias/myalgias with concurrent decreased platelets or transaminitis).

MANAGEMENT: Until further information is available, it may be advisable for patients to limit or avoid consumption of grapefruit and grapefruit juice during treatment with selpercatinib.