Drug Interactions between fostamatinib and Kisqali Femara Co-Pack

MONITOR: Coadministration with ribociclib may increase the plasma concentrations and pharmacologic effects of drugs that are substrates of CYP450 3A4. The proposed mechanism is decreased clearance due to ribociclib-mediated inhibition of CYP450 3A4 metabolism. In healthy study subjects, administration of midazolam, a sensitive CYP450 3A4 substrate, with multiple 400 mg daily doses of ribociclib increased the midazolam peak plasma concentration (Cmax) and systemic exposure (AUC) by 2.1-fold and 3.8-fold, respectively, compared to midazolam administered alone. When given at a clinically relevant dose of 600 mg daily, ribociclib is predicted to increase midazolam Cmax and AUC by 2.4-fold and 5.2-fold, respectively.

MANAGEMENT: Caution is advised when ribociclib is used concomitantly with drugs that undergo metabolism by CYP450 3A4, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever ribociclib is added to or withdrawn from therapy.

MONITOR: Coadministration with fostamatinib may increase the plasma concentrations of drugs that are substrates of the CYP450 3A4 isoenzyme and/or P-glycoprotein (P-gp) transporter. The proposed mechanism is decreased clearance in the intestine and/or liver due to inhibition of CYP450 3A4-mediated metabolism and P-gp-mediated efflux by fostamatinib. According to the product labeling, administration of a single 40 mg dose of the CYP450 3A4 substrate simvastatin with fostamatinib 100 mg twice daily increased simvastatin peak plasma concentration (Cmax) and systemic exposure (AUC) by 113% and 64%, respectively. In addition, simvastatin acid Cmax increased by 83% and AUC increased by 64%. When the P-gp substrate digoxin (0.25 mg once daily) was administered with fostamatinib (100 mg twice daily), digoxin Cmax and AUC increased by 70% and 37%, respectively.

MANAGEMENT: Caution is advised when fostamatinib is used concurrently with drugs that are known substrates of CYP450 3A4 and/or P-gp, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever fostamatinib is added to or withdrawn from therapy.

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.