Drug Interactions between Kisqali Femara Co-Pack and revumenib

GENERALLY AVOID: Revumenib causes dose-related prolongation of the QT interval. Coadministration with other agents that can prolong the QT interval may result in additive effects and an increased risk of ventricular arrhythmias including torsade de pointes and sudden death. In clinical trials, QT interval prolongation was reported as an adverse reaction in 29% of patients treated with revumenib at the recommended dosage for relapsed or refractory acute leukemia with a KMT2A translocation. Additionally, Grade 3 QT interval prolongation occurred in 12% of those patients and a greater than 60 msec increase in Fridericia-corrected QT interval (QTcF) from baseline was reported in 18% of patients. 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: It is recommended to avoid revumenib in combination with other drugs that can prolong the QT interval. If concomitant use cannot be avoided, obtain electrocardiograms (ECGs) when initiating, during concomitant use, and as clinically indicated. Serum electrolytes, including potassium, magnesium, and calcium, should be monitored before starting revumenib therapy and monthly during treatment. Revumenib should not be started if baseline QTc is greater than 450 msec. Likewise, treatment should be interrupted and adjusted in accordance with the product labeling in patients who develop QTc prolongation greater than 480 msec. Patients should be advised to seek prompt medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, fainting, palpitation, irregular heart rhythm, shortness of breath, or syncope. Permanently discontinue revumenib in patients who develop QTc interval prolongation with 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.