Drug Interaction Report

GENERALLY AVOID: Coadministration with potent inducers of CYP450 3A4 may decrease the plasma concentrations of vandetanib, which is a substrate of the isoenzyme. In 16 healthy male subjects, coadministration of rifampin (600 mg/day on days 1 to 31) and vandetanib (single 300 mg oral dose on day 10) resulted in an approximately 40% decrease in vandetanib exposure (AUC) and almost 50% decrease in half-life (from 217.6 hours to 116.3 hours) compared to vandetanib administered alone. There was no significant change in the peak plasma concentration (Cmax) of vandetanib. In the presence of rifampin, the Cmax and AUC of a metabolite, N-desmethylvandetanib, increased by 414% and 266%, respectively. Rifampin also increased the Cmax and AUC of another metabolite, vandetanib N-oxide, by approximately 179% and 126%, respectively. However, the plasma concentrations of vandetanib N-oxide were very low throughout, thus the change in absolute plasma levels induced by rifampin was actually quite small. The clinical implications of these changes are unknown. The two metabolites have shown in vitro pharmacologic activity in cellular assays against vascular endothelial growth factor and epidermal growth factor, with N-desmethylvandetanib exhibiting similar potency to parent drug and vandetanib N-oxide exhibiting less than 1/50 the activity of the parent drug.

MANAGEMENT: Concomitant use of vandetanib with potent CYP450 3A4 inducers should generally be avoided.

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.