Drug Interaction Report

MONITOR: Coadministration with fluconazole may increase the plasma concentrations of drugs that are substrates of CYP450 3A4. The mechanism is decreased clearance due to inhibition of CYP450 3A4-mediated metabolism by fluconazole, a moderate inhibitor of the isoenzyme. A 30% increase in serum carbamazepine has been observed during coadministration with fluconazole according to the product labeling. There have also been a few isolated case reports in the medical literature describing an approximate doubling of carbamazepine levels following the addition of fluconazole, resulting in toxicity. Other drugs metabolized by CYP450 3A4 whose plasma levels reportedly are increased by fluconazole include oral contraceptives (ethinyl estradiol and levonorgestrel), cyclosporine, tacrolimus, and cisapride. These interactions have usually been observed with higher dosages of fluconazole (200 mg/day or more).

MANAGEMENT: Caution is advised when fluconazole is used with medications that undergo metabolism by CYP450 3A4, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever fluconazole is added to or withdrawn from therapy.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.