Drug Interactions between encorafenib and givinostat

GENERALLY AVOID: Givinostat can cause prolongation of the QTc interval. Theoretically, coadministration with other agents that can also prolong the QTc interval may result in additive effects and adverse reactions associated with QT prolongation (e.g., other serious arrhythmias, torsade de pointes, sudden death). The largest mean increase observed in the QTc interval of healthy subjects receiving givinostat at approximately 5 times the dose recommended for Duchenne muscular dystrophy (DMD) in patients weighing 60 kg or more was 13.6 ms (upper confidence interval of 17.1 ms) and occurred 5 hours after dose administration. Clinical trials evaluating the use of givinostat in patients with myeloproliferative neoplasms like polycythemia vera have also documented cases of QTc prolongation. 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 including, but not limited to, cardiac disease, uncontrolled hypothyroidism, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-induced QT prolongation may vary depending on the dosage(s) and specific drug(s) involved.

MONITOR: Givinostat may increase the concentration of CYP450 3A4 substrates via inhibition of the isoenzyme. Givinostat appears to be a weak inhibitor of intestinal CYP450 3A4, but not a significant inhibitor or inducer of hepatic CYP450 3A4; hence, the interaction may be more significant for orally administered CYP450 3A4 substrates. A pharmacokinetic study conducted in healthy volunteers (n=26) found that the peak plasma concentration (Cmax) and systemic exposure (AUC) of a single dose of oral midazolam (2.5 mg) increased from baseline after 3 days of givinostat oral suspension (50 mg twice daily) by 24% and 39%, respectively. After 14 days of coadministration, the Cmax and AUC of oral midazolam had increased by 39% and 67%, respectively. When oral givinostat was studied in combination with intravenous midazolam, only a very slight increase in midazolam's AUC was observed.

MANAGEMENT: Coadministration of givinostat with CYP450 3A4 substrates, particularly orally administered substrates, that can prolong the QT interval should generally be avoided. The manufacturer of givinostat recommends avoiding its use in patients at an increased risk for ventricular arrhythmias, including those with congenital long QT syndrome, coronary artery disease, and/or electrolyte disturbances. If concurrent administration cannot be avoided, electrocardiograms (ECGs) should be obtained at baseline and during concomitant use as clinically indicated. Givinostat should be withheld if the QTc interval is greater than 500 ms or if there is a change from baseline of greater than 60 ms. The labeling of the other medication(s) should also be consulted for additional guidance on therapeutic management in the event of significant toxicity.