Fluconazole increases nevirapine levels and risk of serious hepatotoxicity

A South African study from Geel and colleagues reported the new data on the potential effect of fluconazole to increase nevirapine plasma levels.

In a single-centre, open-label, single-arm trial the pharmacokinetic parameters of fluconazole were measured alone and in combination with nevirapine in 24 patients on a stable regimen of three nucleoside analogue antiretrovirals.

The nevirapine effect on fluconazole pharmacokinetic parameters was minimal. However, the clearance of nevirapine was halved during concomitant administration of fluconazole resulting in an approximate doubling of nevirapine Cmin, Cmax and AUC.

95% of drug-related adverse events occurred during the period of co-administration of nevirapine and fluconazole.

During this phase 25% (CI 7-43%) of patients developed serious hepatotoxicity including two cases of clinical hepatitis (8.3%) and four cases of transient grade-4 transaminase elevation (16.7%).

The incidence of serious hepatotoxicity with the combination (25.0%) was much higher than reported in other studies using nevirapine alone (8.8%).

The authors concluded that because of pharmacokinetic interaction and the apparent increased incidence of toxicity, the combination of nevirapine and fluconazole should be used with caution.

comment

These results need to be confirmed. This study lacked an interpatient comparison, and only compared treated patients with historical controls of nevirapine used without fluconazole, who are likely to have different patient characteristics.

If both drugs are used together, additional monitoring for nevirapine toxicity should be included.

Itraconazole may be a safer option for treating non-CNS fungal infections and perhaps should be the agent of choice for non-invasive candidiasis in patients on nevaripine.