Drug Interactions between glasdegib and Zofran ODT

GENERALLY AVOID: Glasdegib may 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. The effect of glasdegib administration on corrected QT interval (QTc) was evaluated in 36 healthy study subjects. At therapeutic plasma concentrations for the recommended dose, achieved with a single 150 mg dose, the largest placebo and baseline-adjusted QTc interval change was 8 msec. At twice the therapeutic plasma concentration, achieved with a single 300 mg dose, the QTc change was 13 msec. In a clinical trial that had 98 evaluable patients treated with glasdegib 100 mg in combination with low-dose cytarabine, 5% of patients were found to have a QTc interval greater than 500 msec and 4% had a QTc increase from baseline greater than 60 msec. The clinical trial excluded patients with baseline QTc greater than 470 msec or a history of long QT syndrome or uncontrolled 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). In addition, 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 glasdegib with other drugs that can prolong the QT interval should generally be avoided. Caution and clinical monitoring are recommended if concomitant use is required. Patients should have electrocardiograms (ECGs) performed prior to initiation of treatment with glasdegib, approximately one week after initiation, and then once monthly for the next two months, although patients with risk factors may require more frequent and ongoing ECG monitoring. If QTc interval is greater than 500 msec at any time during treatment, interrupt and reduce glasdegib dosing in accordance with product labeling recommendations. Glasdegib should be permanently discontinued in patients who develop QTc interval prolongation with signs or symptoms of life-threatening arrhythmia. ECGs should be monitored at least weekly for 2 weeks upon the resolution of QTC prolongation to less than or equal to 480 msec. Because hypokalemia and hypomagnesemia are risk factors for ventricular arrhythmias, electrolyte levels should also be obtained prior to and during treatment, and any abnormalities corrected as necessary. 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.

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