Drug Interactions between crizotinib and letrozole / ribociclib

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: Coadministration with ribociclib may increase the plasma concentrations and pharmacologic effects of drugs that are substrates of CYP450 3A4. The proposed mechanism is decreased clearance due to ribociclib-mediated inhibition of CYP450 3A4 metabolism. In healthy study subjects, administration of midazolam, a sensitive CYP450 3A4 substrate, with multiple 400 mg daily doses of ribociclib increased the midazolam peak plasma concentration (Cmax) and systemic exposure (AUC) by 2.1-fold and 3.8-fold, respectively, compared to midazolam administered alone. When given at a clinically relevant dose of 600 mg daily, ribociclib is predicted to increase midazolam Cmax and AUC by 2.4-fold and 5.2-fold, respectively.

MANAGEMENT: Caution is advised when ribociclib is used concomitantly with drugs that undergo metabolism by CYP450 3A4, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever ribociclib is added to or withdrawn from therapy.

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