Drug Interactions between letrozole / ribociclib and Rydapt

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as well as clinical and laboratory monitoring may be appropriate for some drugs whenever ribociclib is added to or withdrawn from therapy.

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MONITOR: Coadministration with inhibitors of CYP450 3A4 may increase the plasma concentrations of midostaurin and its active metabolites, which are all substrates of the isoenzyme. The increase in midostaurin concentrations may be particularly pronounced when CYP450 3A4 inhibitors are administered during the first week of midostaurin administration. When a single 50 mg dose of midostaurin was administered to healthy volunteers on day 6 of treatment with the potent CYP450 3A4 inhibitor ketoconazole (400 mg daily for 10 days), midostaurin systemic exposure (AUC) increased by 10.4-fold compared to administration with placebo. The AUC of the two active metabolites, CGP62221 and CGP52421, increased by 3.5- and 1.2-fold, respectively. When multiple doses of midostaurin (100 mg twice daily on days 1 and 2; 50 mg twice daily on days 3 to 28) were coadministered with itraconazole (100 mg twice daily on days 22 to 28 for 13 doses), the plasma concentrations on day 28 (Cmin) of midostaurin, CGP62221 and CGP52421 increased by 2.1-, 1.2- and 1.3-fold, respectively, compared to the corresponding day 21 Cmin concentrations with midostaurin alone. It is not known to what extent midostaurin may interact with weak and moderate CYP450 3A4 inhibitors.

MANAGEMENT: Caution is advised when midostaurin is used with CYP450 3A4 inhibitors. Patients should be closely monitored for increased adverse reactions (e.g., nausea, vomiting, diarrhea, edema, hyperglycemia, hyperuricemia, QT prolongation, neutropenia, lymphopenia, thrombocytopenia, anemia), especially during the first week of consecutive midostaurin administration in patients with advanced systemic mastocytosis and during the first week of midostaurin administration in each cycle of chemotherapy in patients with acute myeloid leukemia.

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