Co-administration of efavirenz (400 mg orally once daily) with voriconazole (200 mg orally twice daily) decreased voriconazole AUC and Cmax by 77% and 61%, respectively, while efavirenz AUC and Cmax increased by 44% and 38%, respectively. Following co-administration of efavirenz (300 mg once daily) with voriconazole (400 mg twice daily) voriconazole AUC decreased by 7% and Cmax was increased by 23% compared to voriconazole 200 mg twice daily alone. Efavirenz AUC increased by 17% and Cmax was equivalent compared to efavirenz 600 mg once daily alone. When efavirenz is co-administered with voriconazole, the voriconazole maintenance dose must be increased to 400 mg twice daily and the efavirenz dose should be reduced by 50%, i.e., to 300 mg once daily. When treatment with voriconazole is stopped, the initial dosage of efavirenz should be restored.

Efavirenz and voriconazole should not be coadministered at standard doses. When voriconazole is coadministered with efavirenz, voriconazole maintenance dose should be increased to 400 mg every 12 hours and efavirenz dose should be decreased to 300 mg once daily using the capsule formulation (one 200-mg and two 50-mg capsules or six 50-mg capsules). SUSTIVA tablets should not be broken. Coadministration of voriconazole (400 mg twice daily for 1 day, then 200 mg twice daily for 8 days) and efavirenz (400 mg for 9 days) resulted in decreases in voriconazole Cmax and AUC of 61% and 77%. Efavirenz Cmax and AUC increased by 38% and 44% respectively. Reducing the voriconazole dose (to 300 mg twice daily) and efavirenz dose (to 300 mg daily) resulted in decreases in voriconazole Cmax and AUC of 36% and 55% when compared to values obtained with voriconazole alone (400 mg twice daily for 1 day, then 200 mg twice daily for 2 days). Efavirenz Cmax decreased by 14% and there was no change in AUC when compared to values obtained with efavirenz alone (600 mg once daily for 9 days). Coadministration of voriconazole (400 mg twice daily for 5 days) and efavirenz (300 mg once daily for 7 days) resulted in a 23% increase in voriconazole Cmax and a 7% decrease in AUC when compared to values obtained with voriconazole alone (400 mg twice daily for 1 day, then 200 mg twice daily for 2 days). There was no change efavirenz Cmax and a 17% increase in AUC when compared to values obtained with efavirenz alone (600 mg once daily for 9 days).

Different dose combinations of efavirenz (300 mg once daily) and voriconazole (300 or 400 mg twice daily) were assessed in HIV- subjects (n=16) and compared to standard-dose monotherapy with each drug (efavirenz 600 mg once daily or voriconazole 200 mg twice daily). Coadministration of the lower voriconazole dose decreased voriconazaole AUC (55%) and Cmax (36%) and had no effect on efavirenz AUC, but decreased efavirenz Cmax by 14%. In contrast, coadministration of the higher voriconazole dose decreased voriconazole AUC by 7%, but increased Cmax by 23%; efavirenz AUC increased by 17% and Cmax decreased by 4%. Based on the pharmacokinetic data obtained, the authors concluded that when co-administered, voriconazole dose should be increased to 400 mg twice daily and efavirenz dose decreased to 300 mg once daily in order to provide systemic exposures similar to standard-dose monotherapy.

A case report described the use of TDM to manage the voriconazole-efavirenz interaction in an HIV+ subject with cirrhosis, stable on an efavirenz-containing regimen (600 mg once daily) who required voriconazole for treatment of disseminated cryptococcosis following failure of fluconazole and amphotericin/flucytosine. Due to the presence of efavirenz, intravenous voriconazole was added to amphotericin/flucytosine at three times the recommended dose and resulted not only in remission of the cryptococcal clinical symptoms, but also decreased viral load to <50 copies/ml. Trough concentrations were determined on days 11, 23 28 and 35; voriconazole troughs were 2.3, 2.2, 3.9 and 2.8 µg/ml and efavirenz troughs were 4.7, 6.5, 4.7, and 6.5 µg/m, respectively. Voriconazole AUC and Cmax were determined on day 28 and were 35.30 µg.h/ml and 4.81 µg/ml, respectively. Efavirenz AUC and Cmax on the same day were 134.7 µg.h/ml and 8.6 µg/ml, respectively. On day 35, trough concentrations in plasma and CSF were determined and CSF:plasma ratios for voriconazole were 0.35 and for efavirenz were 0.13. The patient was switched to maintenance therapy with oral voriconazole (300 mg twice daily) with efavirenz (600 mg once daily). TDM was performed every three weeks which guided dose modifications, first to decrease efavirenz to 400 mg once daily, and then to decrease both voriconazole (to 200 mg twice daily) and efavirenz (to 300mg once daily). After 15 months of follow up on this regimen, the patient remained symptom free and with an undetectable viral load.