Drug Interaction Report

MONITOR: Coadministration of fostamatinib with inhibitors of CYP450 3A4 may increase exposure to the active metabolite known as R406, the predominant moiety in the systemic circulation following fostamatinib administration. Fostamatinib is metabolized in the gut by alkaline phosphatase to R406, which then undergoes oxidation via CYP450 3A4 and glucuronidation via UGT1A9. In vitro, R406 is also a substrate of the P-glycoprotein (P-gp) efflux transporter. When a single 80 mg dose of fostamatinib (0.53 times the 150 mg dosage) was administered with the potent CYP450 3A4 inhibitor ketoconazole (200 mg twice daily for 3.5 days), R406 peak plasma concentration (Cmax) and systemic exposure (AUC) increased on average by 37% and 102%, respectively, compared to fostamatinib administered alone. When a single 150 mg dose of fostamatinib was administered with the moderate CYP450 3A4 inhibitor verapamil (80 mg three times daily for 4 days), R406 Cmax and AUC increased on average by 6% and 39%, respectively. Increased exposure to R406 may result in increased risk of adverse effects such as diarrhea, hepatotoxicity, hypertension, and neutropenia. Both ketoconazole and verapamil are also significant inhibitors of P-gp, although the extent to which P-gp inhibition may contribute to the interaction is unknown.

MANAGEMENT: Patients should be monitored for toxicities of fostamatinib during concomitant use of potent or moderate CYP450 3A4 inhibitors or dual CYP450 3A4/P-gp inhibitors, and the fostamatinib dosage adjusted as necessary in accordance with the product labeling.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of nilotinib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. Because nilotinib 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.

ADJUST DOSING INTERVAL: Food increases the oral bioavailability of nilotinib. The mechanism of interaction is unknown. Compared to the fast state, nilotinib systemic exposure (AUC) increased by 82% when the dose was given 30 minutes after a high-fat meal. Because nilotinib 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.

MANAGEMENT: Patients treated with nilotinib should avoid consumption of grapefruit, grapefruit juice, and any supplement containing grapefruit extract. In addition, no food should be consumed for at least 2 hours before and 1 hour after a nilotinib dose.