Drug Interactions between givinostat and Phenergan with Dextromethorphan

MONITOR: Central nervous system- and/or respiratory-depressant effects may be additively or synergistically increased in patients taking multiple drugs that cause these effects, especially in elderly or debilitated patients. Sedation and impairment of attention, judgment, thinking, and psychomotor skills may increase.

MANAGEMENT: During concomitant use of these drugs, patients should be monitored for potentially excessive or prolonged CNS and respiratory depression. Cautious dosage titration may be required, particularly at treatment initiation. Ambulatory patients should be counseled to avoid hazardous activities requiring mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

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.

MANAGEMENT: Coadministration of givinostat with other agents 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 any other QTc prolonging medication(s) should also be consulted for additional guidance on therapeutic management in the event of QTc prolongation.