FDA Issues Safety Labeling Changes for Kaletra

Laurie Barclay, MD

April 10, 2009

April 10, 2009 — The US Food and Drug Administration (FDA) approved changes on April 6 to the product label for lopinavir/ritonavir tablets and oral solution (Kaletra, Abbott Pharmaceuticals) and also issued a new medication guide. The new labeling changes include warnings and precautions regarding QT/QTC interval and PR interval prolongation.

According to the revised label, in some patients, lopinavir/ritonavir prolongs the PR interval, and cases of second- or third-degree atrioventricular block have been reported. In patients who may be at increased risk of developing cardiac conduction abnormalities, such as those with underlying structural heart disease, preexisting conduction system abnormalities, ischemic heart disease, or cardiomyopathies, lopinavir/ritonavir should be used with caution.

The effect on the PR interval of coadministration of lopinavir/ritonavir with other drugs that prolong the PR interval has not yet been determined. Coadministration of lopinavir/ritonavir with calcium channel blockers, beta-adrenergic blockers, digoxin, or atazanavir should be undertaken with caution, and clinical monitoring is recommended, especially for those drugs metabolized by CYP3A.

The label also notes that postmarketing cases of QT interval prolongation and torsade de pointes have been reported. However, the causal relationship of these conditions to lopinavir/ritonavir could not be proven. Lopinavir/ritonavir should be avoided in patients with congenital long QT syndrome or hypokalemia and in patients using other drugs that prolong the QT interval.

In a randomized, placebo and active (moxifloxacin 400 mg once daily) controlled crossover study in 39 healthy adults, the maximum mean time-matched difference in QTcF interval from placebo, after baseline correction, was 5.3 msec (95% upper confidence bound, 8.1 msec) for 400/100 mg twice daily and 15.2 msec (95% upper confidence bound, 18.0 msec) for supratherapeutic 800/200 mg twice daily lopinavir/ritonavir.

In the same trial, PR interval prolongation also occurred on day 3 in subjects receiving lopinavir/ritonavir. After baseline correction, the maximum mean difference from placebo in the PR interval was 24.9 msec (95% confidence interval, 21.5 – 28.3 msec) for 400/100 mg twice daily and 31.9 msec (95% confidence interval, 28.5 – 35.3 msec) for supratherapeutic 800/200 mg twice daily lopinavir/ritonavir.

Lopinavir and ritonavir are protease inhibitors indicated as part of combination therapy for the treatment of HIV infection.