Drug Interactions between efavirenz and fosphenytoin

MONITOR: Coadministration of phenytoin and efavirenz may affect the plasma concentrations of both drugs. Specifically, efavirenz levels may decrease due to induction of the CYP450 3A4 and 2B6 enzymatic pathways by phenytoin, whereas phenytoin levels may increase or decrease according to the product labeling for efavirenz. Pharmacokinetic data are not currently available. Phenytoin is a substrate of CYP450 2C9 and 2C19, both of which are inhibited by efavirenz. On the other hand, convulsions have been observed during efavirenz therapy, generally in patients with a known medical history of seizures. This would suggest a possible induction by efavirenz, a known inducer of CYP450 3A4 and possibly other hepatic microsomal enzymes, of the clearance of certain anticonvulsants that are primarily metabolized by the liver such as phenytoin. In two published case reports, patients treated concomitantly with efavirenz and phenytoin had low or undetectable levels of efavirenz despite increasing dosage. Although an early virologic response was observed in both cases, anticonvulsant therapy was changed due to the risk of antiretroviral treatment failure with chronically low efavirenz exposure. In one of the reports, an elevated level of phenytoin was also observed despite no change in dosage.

MANAGEMENT: Given the risk of reduced viral susceptibility and resistance development associated with subtherapeutic antiretroviral drug levels, caution is advised if efavirenz is prescribed in combination with phenytoin. Close clinical and laboratory monitoring of antiretroviral response is recommended, and the efavirenz dosage adjusted as necessary. Alternative treatment that do not affect efavirenz metabolism should be considered whenever possible. Pharmacologic effects and serum phenytoin levels should also be monitored more closely following the addition, discontinuation or change of dosage of efavirenz. Patients should be advised to contact their physician if they experience loss of seizure control or signs and symptoms of phenytoin toxicity such as nausea, vomiting, tremors, ataxia, lethargy, slurred speech, visual disturbances, or changes in mental status.