Drug Interaction Report

MONITOR: Concomitant administration with levamisole and 5-fluorouracil (5-FU) has been reported to increase serum levels of phenytoin. No mechanism has been established for this interaction, and it is unknown whether levamisole or 5-FU, or both, is responsible. However, 5-FU alone was implicated in one case report. A 66-year-old man who had been stabilized on phenytoin for more than 4 years developed symptoms of toxicity in association with elevated phenytoin serum concentrations 11 weeks after starting 5-FU and leucovorin treatment. Symptoms resolved following a reduction in phenytoin dosage, and phenytoin levels were monitored and dosage adjusted accordingly throughout the remainder of chemotherapy treatment. After completion of chemotherapy, the phenytoin dosage was gradually increased to original levels without further incident. The authors suggested that 5-FU may inhibit the metabolism of phenytoin via CYP450 2C9.

MANAGEMENT: Pharmacologic response to phenytoin should be monitored more closely whenever levamisole, 5-FU, or capecitabine (which is metabolized to 5-FU in vivo) is added to or withdrawn from therapy, and the phenytoin dosage adjusted as necessary. Patients should be advised to notify their physician if they experience symptoms of phenytoin toxicity, including drowsiness, visual disturbances, mental status changes, seizures, nausea, or ataxia. It is uncertain whether this interaction may also occur with other hydantoins.