Drug Interaction Report

MONITOR: Coadministration with phenytoin and/or other enzyme-inducing anticonvulsants may decrease the plasma concentrations of valdecoxib. The mechanism is induction of CYP450 2C9 and 3A4, the isoenzymes responsible for the metabolic clearance of valdecoxib. According to product labeling, coadministration of phenytoin (300 mg once daily) and valdecoxib (40 mg twice a day) for 12 days resulted in decreased steady-state systemic exposure (AUC) of valdecoxib by 27% compared to administration of valdecoxib alone. The pharmacokinetics of phenytoin was not significantly affected in the presence of valdecoxib. No data are available for other anticonvulsants.

MANAGEMENT: Patients already stabilized on valdecoxib may experience loss of pain and inflammation control with the coadministration of phenytoin and/or other enzyme-inducing anticonvulsants such as carbamazepine, oxcarbazepine, phenobarbital, and primidone. Pharmacologic response to valdecoxib should be monitored more closely whenever these agents are added to or withdrawn from therapy, and the valdecoxib dosage adjusted as necessary. In addition, because valdecoxib is a moderate inhibitor of CYP450 2C9 and 2C19 and a weak inhibitor of 2D6 and 3A4, valdecoxib labeling recommends that routine monitoring for alteration of antiepileptic efficacy be performed when therapy with valdecoxib is either initiated or discontinued in patients receiving anticonvulsants.

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.