Drug Interaction Report

CONTRAINDICATED: Coadministration of efavirenz and voriconazole may significantly reduce the plasma concentrations of voriconazole and increase the plasma concentrations of efavirenz. The mechanism involves efavirenz induction of voriconazole metabolism via CYP450 2C19, 2C9 and 3A4, and voriconazole inhibition of efavirenz metabolism via CYP450 3A4. In healthy male subjects, administration of voriconazole (400 mg orally every 12 hours for 1 day, then 200 mg every 12 hours) with efavirenz (400 mg orally once a day) for 9 days decreased the steady-state voriconazole peak plasma concentration (Cmax) and systemic exposure (AUC) by an average of 61% and 77%, respectively. Conversely, voriconazole increased the steady-state Cmax and AUC of efavirenz by an average of 38% and 44%, respectively. When adjusted dosages of voriconazole (300 mg orally every 12 hours) and efavirenz (300 mg orally once a day) were coadministered for 7 days, mean voriconazole Cmax was reduced by 36% and AUC by 55%, while mean efavirenz Cmax was reduced by 14% and AUC not significantly affected. In contrast, when voriconazole dosage was increased to 400 mg orally every 12 hours and coadministered with efavirenz (300 mg orally once a day) for 7 days, the changes in Cmax and AUC of each drug were not considered clinically significant relative to steady-state administration of voriconazole or efavirenz alone at their normally recommended dosages. Clinically, the interaction may result in voriconazole treatment failure. In one case report, a 50-year-old HIV-infected male developed breakthrough Candida esophagitis during treatment with an antiretroviral regimen that contained efavirenz 600 mg/day and voriconazole 200 mg orally twice a day for invasive pulmonary aspergillosis. A dosage increase of voriconazole to 350 mg twice daily was required. The concomitant use of intravenous voriconazole and oral efavirenz has not been studied.

MANAGEMENT: Concomitant use of standard dosages of voriconazole with efavirenz dosages of 400 mg every 24 hours or higher is considered contraindicated. If concurrent administration is necessary, the manufacturer recommends that maintenance dosage of voriconazole be increased from 200 mg to 400 mg orally every 12 hours and that of efavirenz be reduced from 600 mg to 300 mg orally once daily. When treatment with voriconazole is stopped, the initial dosage of efavirenz should be restored (and vice versa). No dosage recommendations are available for the concomitant use of intravenous voriconazole and oral efavirenz.

ADJUST DOSING INTERVAL: Administration with food increases the plasma concentrations of efavirenz and may increase the frequency of adverse reactions. According to the product labeling, administration of efavirenz capsules (600 mg single dose) with a high-fat/high-caloric meal (894 kcal, 54 g fat, 54% calories from fat) or a reduced-fat/normal-caloric meal (440 kcal, 2 g fat, 4% calories from fat) was associated with mean increases of 39% and 51% in efavirenz peak plasma concentration (Cmax) and 22% and 17% in systemic exposure (AUC), respectively, compared to administration under fasted conditions. For efavirenz tablets, administration of a single 600 mg dose with a high-fat/high-caloric meal (approximately 1000 kcal, 500-600 kcal from fat) resulted in a 79% increase in mean Cmax and a 28% increase in mean AUC of efavirenz relative to administration under fasted conditions.

GENERALLY AVOID: Alcohol may potentiate the central nervous system (CNS) depressant effects of efavirenz. Concomitant use may result in additive CNS depression and impairment of judgment, thinking, and psychomotor skills. In more severe cases, hypotension, respiratory depression, profound sedation, coma, or even death may occur.

MANAGEMENT: Efavirenz should be taken on an empty stomach, preferably at bedtime. Dosing at bedtime may improve the tolerability of nervous system symptoms such as dizziness, insomnia, impaired concentration, somnolence, abnormal dreams and hallucinations, although they often resolve on their own after the first 2 to 4 weeks of therapy . Patients should be advised of the potential for additive central nervous system effects when efavirenz is used concomitantly with alcohol or psychoactive drugs, and to avoid driving or operating hazardous machinery until they know how the medication affects them.

ADJUST DOSING INTERVAL: Food reduces the oral absorption and bioavailability of voriconazole. According to the product labeling, administration of multiple doses of voriconazole with high-fat meals decreased the mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) by 34% and 24%, respectively, when the drug is administered as a tablet, and by 58% and 37%, respectively, when administered as the oral suspension.

MANAGEMENT: To ensure maximal oral absorption, voriconazole tablets and oral suspension should be taken at least one hour before or after a meal.