Drug Interactions between fosphenytoin and nelfinavir

MONITOR: Coadministration with nelfinavir may decrease the plasma concentrations of phenytoin. The proposed mechanism is nelfinavir induction of phenytoin metabolism via CYP450 2C9. In 12 study subjects, administration of phenytoin (300 mg once daily for 14 days) in combination with nelfinavir (1250 mg twice daily for 7 days) decreased mean phenytoin peak plasma concentration (Cmax), systemic exposure (AUC) and trough plasma concentration (Cmin) by 21%, 29% and 39%, respectively, compared to administration of phenytoin alone. The pharmacokinetics of nelfinavir were not significantly altered. The interaction was suspected in a case report of a 30-year-old HIV-infected patient receiving phenobarbital 100 mg and phenytoin 300 mg per day for generalized tonic-clonic seizures who experienced a seizure recurrence in association with approximately 50% reduced phenytoin levels following initiation of nelfinavir treatment. He had been stabilized on his anticonvulsant regimen for three years, and his last known seizure was 4 years prior to this episode. The seizure was controlled with diazepam 10 mg and phenytoin 100 mg.

MANAGEMENT: The potential for reduced therapeutic effects of phenytoin should be considered during coadministration with nelfinavir. Phenytoin serum levels and pharmacologic effects should be closely monitored and the dosage adjusted accordingly, particularly following initiation or discontinuation of nelfinavir in patients who are stabilized on their anticonvulsant regimen. No dosage adjustment for nelfinavir is recommended.