Vfend I.V. and Hepatotoxicity

Hepatotoxicity, including clinical hepatitis, cholestasis and fulminant hepatic failure, has been reported infrequently in patients receiving voriconazole. Most cases have been reversible upon discontinuation of therapy, although fatalities have been reported. Hepatic reactions have primarily occurred in patients with serious underlying medical conditions, predominantly hematological malignancy. However, some occurred in patients with no other identifiable risk factor. Therapy with voriconazole should be administered cautiously in all patients but particularly those with preexisting liver disease, liver enzyme abnormalities, or hepatitis. Liver function tests should be evaluated prior to and during the course of therapy. Discontinuation of therapy should be considered if clinical signs and symptoms consistent with liver injury develop that may be attributable to voriconazole.

Voriconazole is primarily metabolized by the liver and has been shown to accumulate significantly in patients with impaired hepatic function. In eight patients with mild (Child-Pugh Class A) and four patients with moderate (Child-Pugh Class B) hepatic impairment given a single 200 mg oral dose, the mean systemic exposure (AUC) was 3.2-fold higher than in matched controls with normal hepatic function. When only the mild group was compared with controls, there was still a 2.3-fold increase in mean AUC. Pharmacokinetic-pharmacodynamic analyses of data from premarketing clinical trials have identified positive associations between plasma voriconazole concentrations and frequency rate of both liver function test abnormalities and visual disturbances, thus dosage adjustments are necessary to avoid undue toxicity. The manufacturer recommends that the standard loading dose regimens be used but that maintenance dose be halved in patients with mild to moderate hepatic cirrhosis. No pharmacokinetic data or dosing recommendations are available for patients with severe hepatic cirrhosis. Voriconazole should only be used in such patients if benefit outweighs the potential risk. No dosage adjustment is necessary for patients with baseline liver function tests up to 5 times the upper limit of normal. However, continued monitoring of liver function tests for further elevations is recommended.