It is recommended that the standard loading dose regimens be used but that the maintenance dose be halved in patients with mild to moderate hepatic cirrhosis (Child-Pugh Class A and B) receiving voriconazole. No pharmacokinetic data are available for patients with severe hepatic cirrhosis (Child-Pugh Class C) (see DOSAGE AND ADMINISTRATION).

Renal Insufficiency

In a single oral dose (200 mg) study in 24 subjects with normal renal function and mild to severe renal impairment, systemic exposure (AUC) and peak plasma concentration (Cmax) of voriconazole were not significantly affected by renal impairment. Therefore, no adjustment is necessary for oral dosing in patients with mild to severe renal impairment.

In a multiple dose study of IV voriconazole (6 mg/kg IV loading dose x 2, then 3 mg/kg IV x 5.5 days) in 7 patients with moderate renal dysfunction (creatinine clearance 30-50 mL/min), the systemic exposure (AUC) and peak plasma concentrations (Cmax) were not significantly different from those in 6 subjects with normal renal function.

However, in patients with moderate renal dysfunction (creatinine clearance 30-50 mL/min), accumulation of the intravenous vehicle, SBECD, occurs. The mean systemic exposure (AUC) and peak plasma concentrations (Cmax) of SBECD were increased 4-fold and almost 50%, respectively, in the moderately impaired group compared to the normal control group.

Intravenous voriconazole should be avoided in patients with moderate or severe renal impairment (creatinine clearance < 50 mL/min), unless an assessment of the benefit/risk to the patient justifies the use of intravenous voriconazole (see DOSAGE AND ADMINISTRATION - Dosage Adjustment).

A pharmacokinetic study in subjects with renal failure undergoing hemodialysis showed that voriconazole is dialyzed with clearance of 121 mL/min. The intravenous vehicle, SBECD, is hemodialyzed with clearance of 55 mL/min. A 4-hour hemodialysis session does not remove a sufficient amount of voriconazole to warrant dose adjustment.

Drug Interactions

Effects of Other Drugs on Voriconazole

Voriconazole is metabolized by the human hepatic cytochrome P450 enzymes CYP2C19, CYP2C9, and CYP3A4. Results of in vitro metabolism studies indicate that the affinity of voriconazole is highest for CYP2C19, followed by CYP2C9, and is appreciably lower for CYP3A4. Inhibitors or inducers of these three enzymes may increase or decrease voriconazole systemic exposure (plasma concentrations), respectively.

The systemic exposure to voriconazole is significantly reduced or is expected to be reduced by the concomitant administration of the following agents and their use is contraindicated:

Rifampin (potent CYP450 inducer): Rifampin (600 mg once daily) decreased the steady state Cmax and AUC_τ of voriconazole (200 mg Q12h x 7 days) by an average of 93% and 96%, respectively, in healthy subjects. Doubling the dose of voriconazole to 400 mg Q12h does not restore adequate exposure to voriconazole during coadministration with rifampin. Coadministration of voriconazole and rifampin is contraindicated (see CONTRAINDICATIONS, PRECAUTIONS - DRUG INTERACTIONS).

Ritonavir (potent CYP450 inducer; CYP3A4 inhibitor and substrate): The effect of the coadministration of voriconazole and ritonavir (400 mg and 100 mg) was investigated in two separate studies. High-dose ritonavir (400 mg Q12h for 9 days) decreased the steady state Cmax and AUC_τ of oral voriconazole (400 mg Q12h for 1 day, then 200 mg Q12h for 8 days) by an average of 66% and 82%, respectively, in healthy subjects. Low-dose ritonavir (100 mg Q12h for 9 days) decreased the steady state Cmax and AUC_τ of oral voriconazole (400 mg Q12h for 1 day, then 200 mg Q12h for 8 days) by an average of 24% and 39%, respectively, in healthy subjects. Although repeat oral administration of voriconazole did not have a significant effect on steady state Cmax and AUC_τ of high-dose ritonavir in healthy subjects, steady state Cmax and AUC_τ of low-dose ritonavir decreased slightly by 24% and 14% respectively, when administered concomitantly with oral voriconazole in healthy subjects. Coadministration of voriconazole and high-dose ritonavir (400 mg Q12h) is contraindicated. Coadministration of voriconazole and low-dose ritonavir (100 mg Q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. (see CONTRAINDICATIONS, PRECAUTIONS - DRUG INTERACTIONS).

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