Drug Interaction Report

GENERALLY AVOID: Coadministration of tivozanib with strong CYP450 3A4 inducers may decrease the plasma concentrations and therapeutic effects of tivozanib, which has been shown to be a substrate of the isoenzyme, When a single dose of tivozanib (1340 mcg) was administered to healthy volunteers with rifampin (600 mg daily; at steady-state), a strong CYP450 3A4 inducer, tivozanib systemic exposure (AUC) decreased by approximately one-half and its average half-life decreased from 121 to 54 hours, while peak plasma concentration (Cmax) did not change. The clinical effects of strong CYP450 3A4 inducers on repeated daily dosing of tivozanib has not been studied.

MANAGEMENT: Due to the potential for reduced anti-tumor activity, concomitant use of tivozanib with a strong CYP450 3A4 inducer should generally be avoided. If coadministration is necessary, some authorities advise caution, with clinical and laboratory monitoring to be considered whenever a strong CYP450 3A4 inducer is added to or withdrawn from therapy.

GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of carbamazepine. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills.

In a small, randomized, crossover study, the administration of carbamazepine with grapefruit juice (compared to water) increased plasma drug concentrations by approximately 40%. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits.

MANAGEMENT: Patients receiving carbamazepine should be advised to avoid or limit consumption of alcohol. Given the drug's narrow therapeutic index, patients receiving carbamazepine therapy should preferably avoid the regular consumption of grapefruits and grapefruit juice to prevent any undue fluctuations in plasma drug levels. Patients should be advised to report signs of carbamazepine toxicity (nausea, visual disturbances, dizziness, or ataxia) to their physicians.