Drug Interactions between Kisqali Femara Co-Pack and voclosporin

GENERALLY AVOID: Both voclosporin and ribociclib can cause dose-related 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. A randomized, placebo- and active-controlled (moxifloxacin 400 mg), single dose, parallel study reported that a single dose of voclosporin (given in a dose range from 0.5 mg/kg to 4.5 mg/kg) led to a dose-dependent QTcF prolongation, with maximum mean placebo-adjusted changes from baseline ranging from 6.4 msec (0.5 mg/kg) to 34.6 msec (4.5 mg/kg). A randomized, placebo-controlled, crossover study in healthy subjects (n=31) taking voclosporin 0.3 mg/kg, 0.5 mg/kg, and 1.5 mg/kg twice daily for 7 days did not detect QT prolongation greater than 20 msec. 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, hypomagnesemias). In addition, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

ADJUST DOSE: Coadministration with moderate inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of voclosporin, which is primarily metabolized by the isoenzyme. Elevated plasma concentrations of voclosporin may increase the risk for adverse effects such as acute and/or chronic nephrotoxicity, infection, hypertension, neurotoxicity, and QT prolongation. The risk of QT prolongation in particular may be increased with concomitant use of moderate CYP450 3A4 inhibitors that are also known to prolong the QT interval (e.g., crizotinib, dronedarone, erythromycin, fluconazole). Drug interaction studies have shown that coadministration with the moderate CYP450 3A4 inhibitor verapamil (80 mg three times daily for 10 days) increased the peak plasma concentration (Cmax) systemic exposure (AUC) by approximately 2- and 2.71-fold, respectively. Coadministration with a weak CYP450 3A4 inhibitor is not expected to have a clinically significant effect on voclosporin exposure.

MANAGEMENT: The manufacturer of ribociclib advises that coadministration of ribociclib with other drugs that can prolong the QT interval should generally be avoided. However, if concomitant use is required, caution and clinical and laboratory monitoring are recommended. ECGs should be assessed prior to initiation of treatment, during treatment when clinically necessary, and more frequently if QTcF prolongation occurs at any time during treatment. In addition, the manufacturer of voclosporin recommends a dose reduction of voclosporin to 15.8 mg in the morning and 7.9 mg in the evening when it is used concomitantly with the moderate CYP450 3A4 inhibitor ribociclib. Patients should be monitored for adverse effects associated with voclosporin and advised to notify their doctor if they experience possible signs and symptoms of infection, nephrotoxicity, hypertension, neurotoxicity, and QT prolongation. It is recommended that ribociclib be permanently discontinued if the QTcF interval prolongation is either greater than 500 msec or there is a greater than 60 msec change from baseline and associated with any of the following: Torsades de Pointes, polymorphic ventricular tachycardia, unexplained syncope, or signs/symptoms of serious arrhythmia. 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.

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.