The interaction of efavirenz with phenytoin has not been studied. There is the potential for reduction or increase in the plasma concentrations of phenytoin. When efavirenz is co-administered with an anticonvulsant that is a substrate of CYP450 isoenzymes, periodic monitoring of anticonvulsant levels should be conducted.

When efavirenz is coadministered with phenytoin, there is the potential for reduction in phenytoin and/or efavirenz plasma levels. Periodic monitoring of anticonvulsant plasma levels should be conducted.

Efavirenz and phenytoin concentrations were determined in a 35 year old HIV+ patient who commenced efavirenz (800 mg once daily) and emtricitabine/tenofovir (200/300 mg once daily). Prior to the initiation of HAART, the patient had achieved therapeutic phenytoin concentrations at a dose of 200 mg twice daily. Following the introduction of HAART, phenytoin was switched to 400 mg once daily (for 5 days) but, following subtherapeutic concentrations, was then increased to 400 mg twice daily. After 14 days of HAART, phenytoin was reduced to 200 mg twice daily. Efavirenz concentrations were measured at days 5 and 15, but were undetectable (<0.05 µg/ml). Efavirenz was increased to 600 mg twice daily on day 20 and phenytoin stopped for levetiracetam and lamotrigine. Efavirenz concentrations were determined at day 34 and were 3.6 µg/ml. Efavirenz was subsequently reduced to 600 mg once daily, but concentrations at this dose are not given in the report. During treatment his HIV viral load decreased from a baseline of >1 million copies/ml to 12400 copies/ml on day 14 and further decreased to 921 copies/ml by day 30.

A bidirectional drug interaction between efavirenz and phenytoin has been reported in a case study of a 39 year old Ethiopian man with toxoplasmic encephalitis who had been stable on phenytoin (300 mg twice daily). Approximately 1 week after initiation of efavirenz (600 mg once daily), a 12 h post dose sample gave an efavirenz concentration of 340 ng/ml which was below the target of 1000 ng/ml. It was decided to rapidly taper the phenytoin dosage, to switch to levetiracetam, and to increase efavirenz to 800 mg once daily. Prior to the efavirenz dose increase, a further 12 h sample was obtained (~18 days after initiation of efavirenz); this was 580 ng/ml and again was below target. A sample obtained ~14 days after the last dose of phenytoin and whilst receiving levetiracetam (1000 mg twice daily) and efavirenz (800 mg once daily) showed an efavirenz concentration of 2500 ng/ml. Efavirenz dosage was reduced to 600 mg once daily; a sample collected 3 weeks after dose reduction showed a concentration of 1960 ng/ml. Phenytoin concentrations were measured whilst receiving efavirenz (600 mg once daily) and showed a gradual increase over ~3 weeks from ~11 µg/ml to 23.5 µg/ml (therapeutic range 10-20 µg/ml). Until more data become available, both phenytoin and efavirenz levels should be monitored closely when the drugs are given concurrently to avoid potential toxicity or treatment failure.