Drug Interaction Report

GENERALLY AVOID: Coadministration with phenytoin or fosphenytoin 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 3A4 and 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.

MONITOR: Cases have been reported in which patients receiving chemotherapy similar to thiotepa and cyclophosphamide have experienced markedly reduced plasma phenytoin concentrations and seizures. Other hydantoins may interact with chemotherapy in a similar manner. The mechanism of this interaction has not been clearly established, but it is proposed that cytotoxic medicinal products may decrease the digestive absorption of phenytoin secondary to mucosal toxicity. Intravenous phenytoin may be less likely to interact with chemotherapy. One study showed that the absorption of phenytoin decreased significantly during chemotherapy.

MANAGEMENT: Given the magnitude of the interaction, use of cyclophosphamide or thiotepa in combination with phenytoin or fosphenytoin 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 or fosphenytoin are required, consideration should be given to dosage reduction of the chemotherapeutic agents and plasma levels of the active metabolites should be monitored to guide further dosing. Additionally, phenytoin levels and seizure activity should be closely monitored during concomitant use and increases in phenytoin dosage during chemotherapy may be necessary.