Drug Interactions between ivosidenib and Kisqali Femara Co-Pack

GENERALLY AVOID: Ivosidenib can cause prolongation of the QT interval. Theoretically, coadministration with other agents that can prolong the QT interval may result in additive effects and increased risk of ventricular arrhythmias including torsade de pointes and sudden death. Based on an analysis of 171 patients with an isocitrate dehydrogenase-1 mutation who received ivosidenib 500 mg daily, a concentration-dependent QTc interval prolongation of approximately 16.1 msec was observed at steady-state peak plasma concentration (Cmax). In a clinical trial of 258 patients treated with ivosidenib, 9% were found to have a QTc interval greater than 500 msec and 14% had an increase from baseline QTc greater than 60 msec. One patient developed ventricular fibrillation attributed to ivosidenib. The clinical trial excluded patients with baseline QTc >=450 msec and those with a history of long QT syndrome or uncontrolled or significant cardiovascular disease. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia, hypocalcemia). Moreover, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MANAGEMENT: Coadministration of ivosidenib with other drugs that can prolong the QT interval should generally be avoided. Otherwise, close monitoring of electrocardiograms and electrolytes is recommended. If QT prolongation occurs during treatment, withhold and/or reduce dose in accordance with the product labeling. Ivosidenib should be permanently discontinued in patients who develop QT prolongation with signs or symptoms of life-threatening arrhythmia.

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.