Drug Interaction Report

GENERALLY AVOID: Coadministration with potent inducers of CYP450 3A4 may decrease the plasma concentrations of sunitinib and its pharmacologically active metabolite, both of which are substrates of the isoenzyme. In healthy volunteers, administration of a single dose of sunitinib with the potent CYP450 3A4 inducer, rifampin, decreased the combined (i.e., sunitinib plus its primary active metabolite) peak plasma concentration (Cmax) and systemic exposure (AUC) values by 23% and 46%, respectively, compared to administration of sunitinib alone. In addition, when two or more medications with similar adverse effect profiles are given concurrently, the likelihood of experiencing these adverse reactions may be increased. For example, coadministration with other agents that can prolong the QT interval (e.g., apalutamide, encorafenib, enzalutamide) may result in additive effects and an increased risk of ventricular arrhythmias like torsade de pointes.

MANAGEMENT: Concomitant use of sunitinib with potent CYP450 3A4 inducers should generally be avoided. Alternative therapeutic agents with minimal or no enzyme induction potential should be considered whenever possible. If coadministration with a potent CYP450 3A4 inducer is required, a dose increase for sunitinib in 12.5 mg increments up to a maximum of 87.5 mg daily for gastrointestinal stromal tumor (GIST) and renal cell carcinoma (RCC) or 62.5 mg daily for pancreatic neuroendocrine tumors (pNET) may be considered based on careful monitoring of clinical response and tolerability. (Note: This recommendation is based on pharmacokinetic data from healthy volunteers as described above. The safety and efficacy of sunitinib with concomitant CYP450 3A4 inducers have not been established. In two cytokine-refractory metastatic RCC studies, 33 of the 169 patients received sunitinib with a potent CYP450 3A4 inducer with no modification of the starting dose of sunitinib.) If the CYP450 3A4 inducer also carries a risk of prolonging the QT interval, then obtaining more frequent electrocardiograms (ECGs) to monitor the QT interval may be advisable. Patients should be counseled to seek immediate medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, syncope, palpitations, irregular heartbeat, and/or shortness of breath.

GENERALLY AVOID: Concurrent acute use of barbiturates and ethanol may result in additive CNS effects, including impaired coordination, sedation, and death. Tolerance of these agents may occur with chronic use. The mechanism is related to inhibition of microsomal enzymes acutely and induction of hepatic microsomal enzymes chronically.

MANAGEMENT: The combination of ethanol and barbiturates should be avoided.

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.