Drug Interaction Report

MONITOR: Sunitinib can 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. In an open, positive control trial of 24 patients aged 20 to 87 years with advanced malignancies, the maximum QTcF (Fridericia's correction) mean change from baseline was 9.6 msec at plasma concentrations seen with normal recommended doses of sunitinib and 15.4 msec at plasma concentrations approximately twice those seen with recommended doses, compared to 5.6 msec for the positive control of moxifloxacin 400 mg. Elsewhere, increases in the QTc interval to over 500 msec occurred in 0.5% and changes from baseline in excess of 60 msec occurred in 1.1% of 450 solid tumors patients; both of these parameters are recognized as potentially significant changes. Torsade de pointes arrhythmia has been observed in less than 0.1% of sunitinib-exposed 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). 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 is recommended if sunitinib is used in combination with other drugs that can prolong the QT interval. Periodic monitoring with on-treatment electrocardiograms and serum electrolytes (magnesium, potassium) should be considered. 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.

GENERALLY AVOID: Consumption of grapefruit or grapefruit juice during sunitinib therapy may increase the plasma concentrations of sunitinib. The proposed mechanism is inhibition of CYP450 3A4-mediated metabolism by certain compounds present in grapefruit.

MANAGEMENT: Although clinical data are lacking, it may be advisable to avoid the consumption of large amounts of grapefruit or grapefruit juice during sunitinib therapy.