Drug Interaction Report

MONITOR: Coadministration with inhibitors of CYP450 3A4 and/or P-glycoprotein (P-gp) may increase the plasma concentrations of gilteritinib, which is a substrate of both the isoenzyme and the efflux transporter. When gilteritinib was coadministered with itraconazole, a potent CYP450 3A4 and P-gp inhibitor, gilteritinib peak plasma concentration (Cmax) and systemic exposure (AUC) increased by approximately 20% and 120%, respectively, compared to administration of gilteritinib alone. Gilteritinib Cmax and AUC increased by approximately 16% and 40%, respectively, when coadministered with fluconazole, a moderate CYP450 3A4 inhibitor.

MANAGEMENT: Caution is advised when gilteritinib is used with CYP450 3A4 and/or P-gp inhibitors. Patients should be monitored for adverse effects such as QT interval prolongation, pancreatitis, liver transaminase and bilirubin elevations, edema, infections and stomatitis, and the gilteritinib dosage adjusted as necessary in accordance with the product labeling.

GENERALLY AVOID: Grapefruit juice may significantly increase the plasma concentrations of tolvaptan. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. According to the product labeling, administration of tolvaptan with grapefruit juice resulted in a 1.8-fold increase in tolvaptan systemic exposure. The clinical significance is unknown, although increased pharmacologic effects may be expected. Too rapid correction of hyponatremia increases the risk of osmotic demyelination syndrome, which is associated with dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma, and death.

MANAGEMENT: Patients treated with tolvaptan should avoid consumption of grapefruits and grapefruit juice.