Drug Interaction Report

GENERALLY AVOID: Coadministration with potent inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of gilteritinib, which is primarily metabolized by the isoenzyme. When gilteritinib was coadministered with itraconazole, a potent CYP450 3A4 inhibitor, gilteritinib peak plasma concentration (Cmax) and systemic exposure (AUC) increased by approximately 20% and 120%, respectively, compared to administration of gilteritinib alone. Increased exposure to gilteritinib may increase the risk of serious adverse effects such as QT interval prolongation, pancreatitis, liver transaminase and bilirubin elevations, edema, infections, and stomatitis.

MANAGEMENT: Concomitant use of gilteritinib with potent CYP450 3A4 inhibitors should generally be avoided. Alternative agents with no or minimal CYP450 3A4 inhibitory potential are recommended whenever possible. Otherwise, close monitoring for increased adverse effects is advisable, including more frequent ECG monitoring. Gilteritinib treatment should be interrupted or dosage reduced in patients with serious or life-threatening toxicity in accordance with the product labeling.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of ceritinib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Because ceritinib is associated with concentration-dependent prolongation of the QT interval, increased levels may potentiate the risk of ventricular arrhythmias such as torsade de pointes and sudden death. Other, more common side effects such as diarrhea, nausea, vomiting, abdominal pain, hyperglycemia, and bradycardia may also increase.

ADJUST DOSING INTERVAL: Food increases the oral bioavailability of ceritinib. The mechanism of interaction is unknown. Compared to the fast state, administration of a single 500 mg dose of ceritinib with a high-fat meal (approximately 1000 calories; 58 grams of fat) increased ceritinib peak plasma concentration (Cmax) and systemic exposure (AUC) by 41% and 73%, respectively, and administration with a low-fat meal (approximately 330 calories; 9 grams of fat) increased ceritinib Cmax and AUC by 43% and 58%, respectively. A dose of 600 mg or higher taken with a meal is expected to produce systemic exposure exceeding that from a 750 mg dose taken in the fasted state, which may lead to increased adverse effects.

MANAGEMENT: Patients treated with ceritinib should avoid consumption of grapefruit, grapefruit juice, and any supplement containing grapefruit extract. Ceritinib should be administered on an empty stomach (i.e., avoid administration within 2 hours of a meal).

The recommended maximum number of medicines in the 'multikinase inhibitors' category to be taken concurrently is usually one. Your list includes two medicines belonging to the 'multikinase inhibitors' category:

• ceritinib
• gilteritinib

Note: In certain circumstances, the benefits of taking this combination of drugs may outweigh any risks. Always consult your healthcare provider before making changes to your medications or dosage.