FDA approved changes to the SUSTIVA label

FDA recently approved changes to the SUSTIVA (efavirenz) product labeling to include a new Warnings and Precautions regarding QTc prolongation. The following main changes to the product labeling were made:

The following sub-section was added in the WARNINGS AND PRECAUTIONS section.

• 5.2 QTc Prolongation: QTc prolongation has been observed with the use of efavirenz [see Drug Interactions (7.3, 7.4) and Clinical Pharmacology (12.2)]. Consider alternatives to SUSTIVA when co-administered with a drug with a known risk of Torsade de Pointes or when administered to patients at higher risk of Torsade de Pointes.

The following new sub-section was added in the DRUG INTERACTIONS section.

• 7.3  QT Prolonging Drugs: There is limited information available on the potential for a pharmacodynamic interaction between SUSTIVA and drugs that prolong the QTc interval. QTc prolongation has been observed with the use of efavirenz [see Clinical Pharmacology (12.2)]. Consider alternatives to SUSTIVA when co-administered with a drug with a known risk of Torsade de Pointes.

Revisions were made in Table 5 and subsection 7.5 for Drugs Without Clinically Significant Interactions with SUSTIVA.

• Specifically the clinical comment for Anti-infective: Clarithromycin now states: Consider alternatives to macrolide antibiotics because of the risk of QT interval prolongation. Likewise for Antimalarials: Artemether/lumefantrine the clinical comment states: Consider alternatives to artemether/ lumefantrine because of the risk of QT interval prolongation.

The following new sub-section was added in the Clinical Pharmacology section.

• 12.2 Pharmacodynamics-Cardiac Electrophysiology: The effect of SUSTIVA 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 subjects enriched for CYP2B6 polymorphisms. The mean Cmax of efavirenz in subjects with CYP2B6 *6/*6 genotype following the administration of 600 mg 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 8.7 ms and 11.3 ms in subjects with CYP2B6*6/*6 genotype following the administration of 600 mg daily dose for 14 days [see Warnings and Precautions (5.2)].

You can view the updated label at Drugs@fda or DailyMed

Steve Morin
Office of Health and Constituent Affairs
Food and Drug Administration

Kimberly Struble
Division of Antiviral Products
Food and Drug Administration

Richard Klein
Office of Health and Constituent Affairs
Food and Drug Administration

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