The Food and Drug Administration (FDA) has approved updated labeling for Sustiva (efavirenz capsules and tablets; Bristol-Myers Squibb) to include a warning regarding QTc prolongation.
The updated labeling states that QTc prolongation has been observed with the use of efavirenz, and that clinicians should consider alternative treatment for patients being coadministered a drug with a known risk of Torsades de Pointes or in patients at increased risk for Torsades de Pointes.
While there is limited information available on the potential for a pharmacodynamic interaction between efavirenz and drugs that prolong the QTc interval, some changes were made to the Drug Interactions section. Specifically, the labeling now states that alternatives to macrolide antibiotics (ie, clarithromycin) as well as artemether/lumefantrine (an antimalarial) should be considered because of the risk of QT interval prolongation.
The effect of efavirenz on the QTc interval was evaluated in an open-label, positive and placebo controlled, fixed single sequence 3-period, 3-treatment crossover QT study in 58 healthy patients enriched for CYP2B6 polymorphisms. The mean Cmax of efavirenz in subjects with CYP2B6 *6/*6 genotype following the administration of 600mg daily dose for 14 days was 2.25-fold the mean Cmax observed in subjects with CYP2B6 *1/*1 genotype. A positive relationship between efavirenz concentration and QTc prolongation was observed. Based on the concentration-QTc relationship, the mean QTc prolongation and its upper bound 90% confidence interval are 8.7ms and 11.3ms in subjects with CYP2B6*6/*6 genotype following the administration of 600mg daily dose for 14 days.
Efavirenz is an non-nucleoside reverse transcriptase inhibitor of HIV-1; it’s activity is mediated predominately by noncomepetitive inhibition of HIV-1 reverse transcriptase.
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