Drug Interactions between crizotinib and M-Phen

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.

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.