Drug Interactions between Kisqali Femara Co-Pack and saxagliptin

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as well as clinical and laboratory monitoring may be appropriate for some drugs whenever ribociclib is added to or withdrawn from therapy.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 inhibitors of CYP450 3A4 may alter the plasma concentrations of saxagliptin and its pharmacologically active metabolite, both of which are substrates of the isoenzyme. In one study, administration of a single 100 mg dose of saxagliptin in combination with the potent CYP450 3A4 inhibitor ketoconazole (200 mg every 12 hours at steady state) resulted in increases to saxagliptin peak plasma concentration (Cmax) by 62% and systemic exposure (AUC) by 2.5-fold. These changes were accompanied by corresponding decreases in the Cmax and AUC of the active metabolite by 95% and 88%, respectively. The pharmacokinetics of ketoconazole were not significantly affected, with Cmax and AUC decreasing by just 16% and 13%, respectively. In another study, saxagliptin Cmax increased by 2.4-fold and AUC increased by 3.7-fold during coadministration of a single 20 mg dose of saxagliptin with ketoconazole (200 mg every 12 hours at steady state), while Cmax and AUC of the active metabolite decreased by 96% and 90%, respectively. When a single 10 mg dose of saxagliptin was coadministered with the moderate CYP450 3A4 inhibitor diltiazem (360 mg long-acting formulation at steady state), saxagliptin Cmax increased by 63% and AUC increased by 2.1-fold, while Cmax of the active metabolite decreased by 44% and AUC decreased by 36%. Coadministration of multiple once-daily doses of saxagliptin (10 mg) and diltiazem did not significantly affect the pharmacokinetics of diltiazem. However, some authorities suggest that these pharmacokinetic effects of ketoconazole and diltiazem on saxagliptin and/or its metabolite are not clinically meaningful.

MANAGEMENT: Pharmacologic response to saxagliptin should be monitored more closely whenever a CYP450 3A4 inhibitor is added to or withdrawn from therapy. Patients should be advised to regularly monitor their blood sugar and counseled on how to recognize and treat hypoglycemia, which may include symptoms such as headache, dizziness, drowsiness, nervousness, confusion, tremor, hunger, weakness, perspiration, and palpitations. The physician should be notified if an interaction is suspected.