Drug Interaction Report

GENERALLY AVOID: Coadministration with phenytoin may result in significantly decreased plasma concentrations of cyclophosphamide and thiotepa, while concentrations of their main active metabolites increase. The proposed mechanism is induction of CYP450 2B6 metabolism by phenytoin. In one study, pharmacokinetics of cyclophosphamide and thiotepa, as well as that of their main active metabolites, were determined in a 42-year-old male patient with relapsing germ-cell cancer receiving two 4-day courses (4 weeks apart) of high-dose chemotherapy with cyclophosphamide (1500 mg/m2/day), thiotepa (60 mg/m2 twice a day), and carboplatin. Blood samples were collected on day 1 of each treatment cycle. Five days prior to the second cycle, the patient began treatment with phenytoin for a generalized epileptic seizure that developed 3 weeks after the first chemotherapy course. Compared to the first cycle, plasma exposure (AUC) to cyclophosphamide and thiotepa was reduced 67% and 29%, respectively, while exposure to 4-hydroxycyclophosphamide and tepa was increased by 51% and 115%, respectively. Because high exposure to these metabolites is associated with increased toxicity, the patient's cyclophosphamide dose was reduced nearly 50% and the thiotepa dose reduced nearly 40% on the third and fourth day of the second cycle. Plasma levels of carboplatin were similar in both courses, so no dose adjustment was made.

MANAGEMENT: Given the magnitude of the interaction, use of cyclophosphamide or thiotepa in combination with phenytoin should be avoided if possible. Anticonvulsants with no significant effects on CYP450 hepatic enzymes such as valproic acid, lamotrigine, or gabapentin may be appropriate alternatives. If phenytoin is required, consideration should be given to dosage reduction of the chemotherapeutic agents. In addition, plasma levels of the active metabolites should be monitored to guide further dosing.

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ADJUST DOSING INTERVAL: Phenytoin bioavailability may decrease to subtherapeutic levels when the suspension is given concomitantly with enteral feedings. The mechanism may be related to phenytoin binding to substances in the enteral formula (e.g., calcium, protein) and/or binding to the tube lumen. Data have been conflicting and some studies have reported no changes in phenytoin levels, while others have reported significant reductions.

MONITOR: Acute consumption of alcohol may increase plasma phenytoin levels. Chronic consumption of alcohol may decrease plasma phenytoin levels. The mechanism of this interaction is related to induction of phenytoin metabolism by ethanol during chronic administration. Other hydantoin derivatives may be similarly affected by ethanol.

MANAGEMENT: Some experts have recommended interrupting the feeding for 2 hours before and after the phenytoin dose, giving the phenytoin suspension diluted in water, and flushing the tube with water after administration; however, this method may not entirely avoid the interaction and is not always clinically feasible. Patients should be closely monitored for clinical and laboratory evidence of altered phenytoin efficacy and levels upon initiation and discontinuation of enteral feedings. Dosage adjustments or intravenous administration may be required until therapeutic serum levels are obtained. In addition, patients receiving phenytoin therapy should be warned about the interaction between phenytoin and ethanol and they should be advised to notify their physician if they experience worsening of seizure control or symptoms of toxicity, including drowsiness, visual disturbances, change in mental status, nausea, or ataxia.

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