Drug Interactions between Kisqali Femara Co-Pack and stiripentol

MONITOR: The concomitant administration of stiripentol may significantly increase plasma concentrations, pharmacologic effects, and toxicities of drugs that are substrates of CYP450 2C19, 3A4, and/or 2D6. The mechanism is inhibition of cytochrome P-450 metabolism by stiripentol.

MANAGEMENT: Clinical and laboratory monitoring for altered efficacy and safety is recommended during concomitant use. Dosage adjustments may be required if increased plasma levels or effects are observed.

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as well as clinical and laboratory monitoring may be appropriate for some drugs whenever ribociclib is added to or withdrawn from therapy.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 1A2 and/or 3A4 may increase the plasma concentrations of stiripentol, which has been shown in vitro to undergo phase I metabolism via these pathways. Conversely, many of these inhibitors are also substrates of CYP450 1A2 and/or 3A4, and coadministration with stiripentol may alter their plasma concentrations as well. Stiripentol is both an inhibitor and inducer of CYP450 1A2 and 3A4 in vitro. Pharmacokinetic studies in humans are limited; therefore, it is uncertain whether plasma concentrations of concomitantly administered drugs may increase or decrease.

MANAGEMENT: Caution is advised when stiripentol is used with inhibitors of CYP450 1A2 and/or 3A4 that are also substrates of these enzymatic pathways. Patients should be monitored for potentially increased adverse effects of stiripentol such as anorexia, nausea, vomiting, weight loss, somnolence, dizziness, confusion, difficulty concentrating, ataxia, hypotonia, tremor, hyperkinesia, dysarthria, suicidal ideation/behavior, neutropenia, and thrombocytopenia. In addition, clinical and laboratory monitoring may be appropriate for concomitant drugs whenever stiripentol is added to or withdrawn from therapy. Dosage adjustments or alternative treatments may be required if an interaction is suspected.