Drug Interactions between Cometriq and tucatinib

GENERALLY AVOID: Coadministration with potent inhibitors of CYP450 3A4 may increase the plasma concentrations of cabozantinib, which is a substrate of the isoenzyme. In healthy subjects, administration of the potent CYP450 3A4 inhibitor ketoconazole (400 mg daily for 27 days) increased single-dose plasma cabozantinib systemic exposure (AUC) by 38%. High plasma levels of cabozantinib may increase the risk of QT interval prolongation, which has been associated with ventricular arrhythmias including torsade de pointes and sudden death. 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). 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 cabozantinib with potent CYP450 3A4 inhibitors should generally be avoided. If concomitant use is required, the daily dosage of cabozantinib should be reduced by 40 mg (e.g., 140 mg to 100 mg daily; 100 mg to 60 mg daily). The original dosage may be resumed 2 to 3 days after discontinuation of the potent CYP450 3A4 inhibitor. However, some authorities recommend avoiding concomitant use of cabozantinib during and for 2 weeks after treatment with itraconazole. 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. Patients should also be advised regarding a potential increase in more common side effects of cabozantinib, such as diarrhea, fatigue, nausea, decreased appetite, palmar-plantar erythrodysesthesia syndrome (PPES), hypertension, vomiting, weight loss, and constipation.

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