Drug Interactions between crizotinib and cytarabine liposomal / daunorubicin liposomal

GENERALLY AVOID: Crizotinib can cause prolongation of the QT interval, which pharmacokinetic/pharmacodynamic modeling indicate may be concentration-dependent. 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. In clinical trials done in adults on crizotinib (250 mg twice daily) QTcF (Fridericia corrected QT interval) prolongation greater than or equal to 500 msec was observed in 34 of 1619 (2.1%) and an increase from baseline QTcF greater than or equal to 60 msec was observed in 79 of 1585 patients (5%). In clinical studies of pediatric patients (dosed according to body surface area), a prolonged QT interval was observed in approximately 4% of patients. 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, hypocalcemia). Moreover, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MANAGEMENT: Concomitant use of crizotinib with drugs that prolong the QT interval should generally be avoided. ECG and serum electrolytes, including potassium, magnesium, and calcium, should be monitored before starting crizotinib therapy and periodically during treatment according to the manufacturer's labeling. Electrolytes should be replaced as clinically indicated. Crizotinib should not be started if baseline QTc (QT corrected for heart rate) is greater than 500 msec. Likewise, treatment should be interrupted in patients who develop a QTc greater than 500 msec on at least 2 separate ECGs. Once the QTc has recovered to baseline or less than 481 msec, crizotinib can be resumed at the next lower dosage recommended in the manufacturer's labeling. Crizotinib should be permanently discontinued if the patient has a QTc greater than 500 msec or a change greater than or equal to 60 msec from baseline with torsade de pointes, polymorphic ventricular tachycardia, or signs/symptoms of a 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.

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MONITOR: The concomitant or sequential administration of multiple antineoplastic agents may result in additive toxicities, particularly in the bone marrow, gastrointestinal tract and heart.

MANAGEMENT: Close clinical and laboratory monitoring for hematologic and nonhematologic toxicities are recommended when antineoplastic agents are administered concurrently or during close intervals. Dosing adjustments may be necessary. The manufacturers' recommendations and institutional protocols for dosage, treatment regimens, monitoring, and management of toxicities should be consulted.

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