Drug Interactions between gilteritinib and Rythmol SR

MONITOR: Gilteritinib 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. A concentration-related increase in QTcF from baseline was observed across gilteritinib doses ranging from 20 to 450 mg. The predicted mean change in QTcF from baseline at the mean steady-state Cmax (282.0 ng/mL) during daily dosing of 120 mg was 4.96 msec. The effect of gilteritinib 120 mg once a day on the QTc interval has also been evaluated in clinical study patients, which showed an absence of large mean increases (i.e., 20 msec). Of 317 patients with a post-baseline QTc measurement during treatment with gilteritinib 120 mg/day in clinical trials, 4 patients (1.3%) experienced a QTcF >500 msec. Across all doses, 2.3% of patients with relapse/refractory acute myeloid leukemia had a maximum post-baseline QTcF interval >500 msec. Additionally, 7% of patients had an increase in QTc from baseline greater than 60 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, 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: Caution and clinical monitoring are recommended if gilteritinib is used in combination with other drugs that can prolong the QT interval. Patients should have electrocardiograms (ECGs) performed prior to initiation of treatment with gilteritinib, on days 8 and 15 of cycle 1, and prior to the start of the next two subsequent cycles. If QTc interval is greater than 500 msec at any time during treatment or greater than 30 msec of baseline on day 8 of cycle 1, interrupt and reduce gilteritinib dosing in accordance with product labeling recommendations. 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.